EA045333B1 - PYRAZOLE DERIVATIVES AS MALT1 INHIBITORS - Google Patents

Description

Scope of the invention

The present invention provides novel compounds that are MALT1 (mucosal associated lymphoma translocation protein 1) inhibitors. These compounds can be used to treat a disease, syndrome, condition or disorder, particularly a MALT1-related disease, syndrome, condition or disorder, including, without limitation, cancer and immunological diseases. The present invention also relates to pharmaceutical compositions containing one or more such compounds, methods for preparing such compounds and compositions, and the use of such compounds or pharmaceutical compositions for the treatment of cancer and autoimmunological diseases, syndromes, disorders or conditions associated with a MALT1 inhibitor.

Prerequisites for creating the invention

MALT1 (mucosal associated lymphoma translocation protein 1) is a key mediator of the classical NF _K B signaling pathway. MALT1 is the only human paracaspase, and it transmits signals from the B cell receptor (BCR) and the T cell receptor ( TCR). MALT1 is the active subunit of the CBM complex, which is formed upon receptor activation. The CBM complex is composed of multiple subunits of three proteins: CARD11 (caspase recruitment domain family member 11), BCL10 (B cell CCL/Lymphoma 10), and MALT1. There are two mechanisms by which MALT1 influences NF _K B signaling: first, MALT1 functions as a scaffolding protein and recruits NF _K B signaling proteins such as TRAF6, TAB-TAK1 or NEMO-IKKa/β; and second, MALT1, as a cysteine protease, cleaves and thus deactivates negative regulators of the NF _K B signaling pathway, such as RelB, A20 or CYLD. The net endpoint of MALT1 activity is the translocation of the _NFKB transcription factor complex into the nucleus and activation of _NFKB signaling (Jaworski et al., Cell Mol Life Science 2016. 73, 459-473).

Constitutive activation of the NF _K B signaling pathway is a hallmark of ABC-DLBCL (diffuse large B cell lymphoma subtype characterized by cells similar to activated B cells), a more aggressive form of DLBCL. DLBCL is the most common form of non-Hodgkin's lymphoma (NHL), accounting for approximately 25% of lymphoma cases, with ABC-DLBCL accounting for approximately 40% of DLBCL cases. Activation of the NF _K B signaling pathway is caused by mutations in signaling components such as CD79A/B, CARD11, MYD88, or A20 in patients with ABC-DLBCL (Staudt, Cold Spring Harb Perspect Biol 2010, 2; Lim et al., Immunol Rev 2012, 246, 359-378).

The use of BTK inhibitors, such as ibrutinib, provides a clinical test of the concept of the effectiveness of inhibition of NF _K B signaling in ABC-DLBCL. MALT1 is downstream of BTK in the NF _K B signaling pathway, and a MALT1 inhibitor may be suitable for targeted use in patients with ABC-DLBCL who do not respond to ibrutinib, mainly patients with CARD11 mutations, as well as for the treatment of patients who have become resistant to ibrutinib .

Small molecule inhibitors of MALT1 protease have demonstrated efficacy in preclinical models of ABC-DLBCL (Fontan et al., Cancer Cell 2012, 22, 812-824; Nagel et al., Cancer Cell 2012, 22, 825-837). Interestingly, covalent inhibitors of the catalytic site and allosteric inhibitors of the protease function of MALT1 have been described, indicating the possibility of using inhibitors of this protease as pharmaceutical agents (Demeyer et al., Trends Mol Med 2016, 22, 135-150).

The chromosomal translocation generating the API2-MALT1 fusion oncoprotein is the most common mutation identified in MALT lymphoma (mucosal associated lymphoid tissue lymphoma). API2-MALT1 is a potent activator of the NF _K B pathway (Rosebeck et al., World J Biol Chem 2016, 7, 128-137). API2-MALT1 mimics the ligand-bound TNF receptor, stimulates TRAF2-dependent ubiquitination of RIP1, which acts as a scaffold for activation of canonical NF _K B signaling. Moreover, API2-MALT1 has been shown to cleave and form a stable, constitutively active fragment of NF _{K B} B-inducing kinase (NIK), thereby activating the non-canonical NF _K B pathway (Rosebeck et al., Science, 2011, 331, 468-472).

Along with lymphomas, MALT1 has been shown to play an important role in innate and adaptive immunity (Jaworski M, et al., Cell Mol Life Sci. 2016). A MALT1 protease inhibitor may attenuate the onset and progression of experimental allergic encephalomyelitis in mice, a mouse model of multiple sclerosis (Mc Guire et al., J. Neuroinflammation 2014, 11, 124). Mice expressing a catalytically inactive mutant form of MALT1 showed loss of marginal zone B cells and B1 B cells, as well as a general immune deficiency characterized by decreased activation and proliferation of T and B cells. However, these mice also developed spontaneous multiorgan autoimmune inflammation at 9 to 10 weeks of age. It is still not clear why mice with knockout of the functionally inactive MALT1 protease show breakthrough tolerance, while normal MALT1 knockout mice do not. According to one hypothesis, the imbalance of immune homeostasis in mice knocked out of the functionally inactive protease MALT1 may be caused by an incomplete deficiency of T and B cells, but by a severe deficiency of immunoregulatory cells (Jaworski et al., EMBO J. 2014; Gewies et al., Cell Reports 2014; Bornancin et al., J. Immunology 2015; Yu et al., PLOS One 2015). Similarly, MALT deficiency in humans is associated with combined immunodeficiency disorder (McKinnon et al., J. Allergy Clin. Immunol. 2014, 133, 1458-1462; Jabara et al., J. Allergy Clin. Immunol. 2013, 132, 151-1462). 158; Punwani et al., J. Clin. Immunol. 2015, 35, 135-146). Given the difference between genetic mutation and pharmacological inhibition, the phenotype of functionally inactive MALT1 protease knockin mice may not resemble the phenotype of patients treated with MALT1 protease inhibitors. Reducing the number of immunosuppressive T cells through inhibition of MALT1 protease may be beneficial for cancer patients through the potential to enhance antitumor immunity.

Thus, the MALT1 inhibitors of the present invention may provide a beneficial therapeutic effect in patients suffering from cancer and/or immunological diseases.

Summary of the invention

The present invention relates to compounds of formula (I):

*5

Formula (I) where R1 is selected from the group consisting of

i) naphthalen-1-yl, optionally substituted with fluorine or amino group; and ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, cyclopropyl, methoxymethyl, difluoromethyl, 1,1-difluoroethyl, hydroxymethyl, 1-hydroxyethyl, 1- ethoxyethyl, hydroxy, methoxy, ethoxy, fluorine, chlorine, bromine, methylthio, cyano, amino, methylamino, dimethylamino, 4oxotetrahydrofuran-2-yl, 5-oxopyrrolidin-2-yl, 1,4-dioxanyl, aminocarbonyl, methylcarbonyl, methylaminocarbonyl, oxo, 1-(tert-butoxycarbonyl)azetidin-2-yl, N-(methyl)formamidomethyl, tetrahydrofuran-2-yl, 3-hydroxy-pyrrolidin-1-yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin- 3-yl or azetidin-2-yl;

R2 is selected from the group consisting of C _1-4 alkyl, 1-methoxyethyl, difluoromethyl, fluorine, chlorine, bromine, cyano and trifluoromethyl;

G1 is N or C(R4);

G2 represents N or C(R ₃ ); so that in any case only one of G1 and G2 is N;

R ₃ is independently selected from the group consisting of trifluoromethyl, cyano, C _1-4 alkyl, fluorine, chlorine, bromine, methylcarbonyl, methylthio, methylsulfinyl and methanesulfonyl; or, if G ₁ represents N, R ₃ is further selected from C _1-4 alkoxycarbonyl;

R ₄ is selected from the group consisting of

i) hydrogen if G2 is N;

ii) C _1-4 alkoxy;

iii) cyano;

iv) cyclopropyloxy;

v) heteroaryl selected from the group consisting of triazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, tetrazolyl, oxadiazolyl, imidazolyl, 2-amino-pyrimidin-4-yl, 2H[1,2,3]triazolo[4, 5-c]pyridin-2-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl, 3H-[1,2,3]triazolo[4,5b]pyridin- 3-yl, 1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl, wherein the heteroaryl is optionally substituted with one or two substituents independently selected from oxo, C _1-4 alkyl, carboxy, methoxycarbonyl , aminocarbonyl, hydroxymethyl, aminomethyl, (dimethylamino)methyl, amino, methoxymethyl, trifluoromethyl, amino(C _2-4 alkyl)amino or cyano;

vi) 1-methyl-piperidin-4-yloxy;

vii) 4-methyl-piperazin-1-ylcarbonyl;

viii) (4-aminobutyl)aminocarbonyl;

ix) (4-amino)butoxy;

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x) 4-(4-aminobutyl)piperazin-1-ylcarbonyl;

xi) methoxycarbonyl;

xii) 5-chloro-6-(methoxycarbonyl)pyridin-3-ylaminocarbonyl;

xiii) 1,1-dioxo-isothiazolidin-2-yl;

xiv) 3-methyl-2-oxo-2,3-dihydro-1 H-imidazol-1 -yl;

xv) 2-oxopyrrolidin-1-yl;

xvi) (E)-(4-aminobut-1-ene)-1-yl-aminocarbonyl;

xvii) difluoromethoxy; and xviii) morpholin-4-ylcarbonyl;

R5 is independently selected from the group consisting of hydrogen, chlorine, fluorine, bromine, methoxy, methylsulfonyl, cyano, C1.4 alkyl, ethynyl, morpholin-4-yl, trifluoromethyl, hydroxyethyl, methylcarbonyl, methylsulfinyl, 3-hydroxy-pyrrolidin-1 -yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin-3-yl, azetidin-2-yl, methylthio and 1,1-difluoroethyl;

or R4 and R5 can be taken together to form 8-chloro-4-methyl-3-oxo-3,4-dihydro-2Hbenzo[b][1,4]oxazin-6-yl, 8-chloro-3-oxo -3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 2-methyl-1-oxo1,2,3,4-tetrahydroisoquinolin-7-yl, 4-methyl-3 - oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 3-oxo3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4b]pyridin-5-yl, 2,3-dihydro-[1,4]dioxino[2,3 -b]pyridin-5-yl, 1,3-dioxolo[4,5]pyridin-5-yl, 1oxo-1,3-dihydroisobenzofuran-5-yl, 2,2-dimethylbenzo[d][1,3] dioxol-5-yl, 2,3dihydrobenzo[b][1,4]dioxin-6-yl, 1-oxoisoindolin-5-yl or 2-methyl-1-oxoisoindolin-5-yl, 1Hindazol-5-yl;

R6 is hydrogen, C _1-4 alkyl, fluorine, 2-methoxyethoxy, chlorine, cyano or trifluoromethyl;

R ₇ represents hydrogen or fluorine;

provided that the compound of formula (I) is other than a compound in which R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), and R4 is 2H-1,2,3-triazole -2-yl, G2 is N and R5 is hydrogen;

compounds wherein R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is 1H-imidazol-1-yl, G2 is N, and R5 is chlorine;

compounds wherein R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C( _R4 ), wherein R4 is 1H-1,2,3-triazol-1-yl, G2 is N, a R5 is hydrogen;

compounds wherein R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is hydrogen, G2 is N, and R5 is fluorine;

N-(2-chloro-3-pyridinyl)-5-methyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide;

N-(3-chloro-4-methoxyphenyl)-5-methyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide; And

5-methyl-M-3-pyridinyl-1-(2-quinolinyl)-III-pyrazole-4-carboxamide;

or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof.

The present invention also provides a pharmaceutical composition containing or consisting of and/or essentially consisting of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and/or a pharmaceutically acceptable diluent and a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

In addition, methods are provided for preparing a pharmaceutical composition containing or consisting of and/or essentially consisting of a mixture of a compound of formula (I) and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and/or a pharmaceutically acceptable diluent.

The present invention further provides methods for treating or ameliorating a disease, syndrome, condition or disorder in a subject, including a mammal and/or a human, whose disease, syndrome or condition is dependent on MALT1 inhibition, including, without limitation, cancer and/or immunological diseases, using a compound of formula (I).

The present invention also relates to the use of any of the compounds described herein in the preparation of a medicament, the medicament being prepared for the treatment of a disease, syndrome, condition or disorder that is dependent on MALT1 inhibition, including cancer and/or immunological diseases.

The present invention also relates to the preparation of substituted pyrazole derivatives that act as MALT1 inhibitors.

Examples of the invention are methods of treating a disease, syndrome, condition or disorder mediated by MALT1 selected from the group consisting of lymphoma, leukemia, carcinoma and sarcoma, for example non-Hodgkin lymphoma, diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma,

- 3 045333 Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia , acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain tumors (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer, including non-small cell, stomach cancer, endometrial cancer, melanoma, pancreatic cancer , liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyelosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, cancer urothelium, vaginal cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer, and GIST (gastrointestinal stromal tumor), the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions, described in the present invention consists of or essentially consists of such administration.

In another embodiment, the present invention provides a compound of formula (I) for use in the treatment of a disease, syndrome, condition or disorder dependent on MALT1 inhibition selected from the group consisting of lymphoma, leukemia, carcinoma and sarcoma, for example non-Hodgkin's lymphoma, diffuse B -large cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain tumors (gliomas ), glioblastoma, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer, including non-small cell cancer, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma , osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyelosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial cancer, vaginal cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer , cheek cancer, oral cancer, and GIST (gastrointestinal stromal tumor).

In another embodiment, the present invention provides a composition containing a compound of formula (I) for the treatment of a disease, syndrome, condition or disorder dependent on MALT1 inhibition selected from the group consisting of lymphoma, leukemia, carcinoma and sarcoma, for example, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryo cytic leukemia, promyelocytic leukemia, erythroleukemia, brain tumors (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer, including non-small cell cancer, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer , sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyelosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial cancer, vaginal cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer, and GIST (gastrointestinal stromal tumor).

In another embodiment, the present invention provides a composition containing a compound of formula (I) for the treatment of a disease, syndrome, condition or disorder dependent on MALT1 inhibition selected from the group consisting of diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma ( MCL), follicular lymphoma (FL) and mucosal associated lymphoid tissue (MALT) lymphoma.

An embodiment of the present invention provides a composition containing a compound of formula (I) for the treatment of immunological diseases that depend on MALT1 inhibition, including, without limitation, autoimmune and inflammatory diseases, for example arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or graft rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis, including atopic, dermatomyositis, psoriasis, Behçet's disease , uveitis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjögren's disease, blistering diseases, antibody-mediated vasculitic syndromes, immune complex vasculitis, allergic diseases, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including edema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis and polymyositis.

In another embodiment, the present invention provides a composition containing a compound of formula (I) for the treatment of a disease, syndrome, condition or disorder dependent on MALT1 inhibition selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis (PA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma and chronic obstructive pulmonary disease (COPD).

Another embodiment of the present invention relates to a pharmaceutical composition containing a compound of formula (I).

Detailed Description of the Invention

With reference to substituents, the term independently refers to the situation where the substituents may be the same or different from each other in the event that more than one substituent may be present.

The term alkyl, used alone or as part of a group of substituents, denotes linear and branched carbon chains having from 1 to 8 carbon atoms. Therefore, the numbers of carbon atoms indicated (eg, C1-8) independently indicate the number of carbon atoms in the alkyl functional group or the alkyl moiety of a larger alkyl-containing substituent. In substituent groups with multiple alkyl groups, such as (C1_ ₆ alkyl)2amino-, C1_ ₆ alkyl groups, dialkylamino may be the same or different.

The term alkoxy refers to an -O-alkyl group, the term alkyl being as defined above.

The terms alkenyl and alkynyl denote linear and branched carbon chains having from 2 to 8 carbon atoms, the alkenyl chain containing at least one double bond and the alkynyl chain containing at least one triple bond.

The term cycloalkyl refers to saturated or partially saturated monocyclic or polycyclic hydrocarbon rings having from 3 to 14 carbon atoms. Examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.

The term heterocyclyl refers to a non-aromatic monocyclic or bicyclic ring system having from 3 to 10 ring members that include at least 1 carbon atom and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. Included in the term heterocyclyl is a 5-7 member non-aromatic cyclic ring of which 1-2 members are N, or a 5-7 member non-aromatic cyclic ring of which 0, 1 or 2 members are N and up to 2 members are O or S, and at least one member must be N, O or S; wherein the ring optionally contains from 0 to 1 unsaturated bond, and if the ring consists of 6 or 7 members, it optionally contains up to 2 unsaturated bonds. The carbon ring members forming a heterocyclic ring may be fully saturated or partially saturated. The term heterocyclyl also includes two 5-membered monocyclic heterocycloalkyl groups bridged to form a bicyclic ring. Such groups are not considered fully aromatic and are not designated heteroaryl groups. If the heterocycle is bicyclic, both rings of the heterocycle are non-aromatic and at least one of the rings contains a heteroatom ring member. Examples of heterocyclic groups include, but are not limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. Unless otherwise specified, a heterocycle is attached to its side group on any heteroatom or carbon atom to form a stable structure.

The term aryl refers to an unsaturated aromatic monocyclic or bicyclic ring of 6-10 carbon members. Examples of aryl rings include phenyl and naphthalenyl.

The term heteroaryl refers to an aromatic monocyclic or aromatic bicyclic ring system having 5-10 ring members, which contains carbon atoms and 1-4 heteroatoms independently selected from the group consisting of N, O and S. The term heteroaryl also includes aromatic 5- or 6 -membered rings, wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen and sulfur atoms. In the case of 5-membered rings, the heteroaryl ring preferably contains one member representing a nitrogen, oxygen or sulfur atom, as well as up to 3 additional nitrogen atoms. In the case of 6-membered rings, the heteroaryl ring preferably contains from 1 to 3 nitrogen atoms. In the case where a 6-membered ring has 3 nitrogen atoms, a maximum of 2 nitrogen atoms are adjacent. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazole silt, benzothiazolyl, ben- 5 045333 zoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Unless otherwise specified, heteroaryl is attached to its side group on any heteroatom or carbon atom, resulting in a stable structure.

The term halogen atom or halogen refers to fluorine, chlorine, bromine and iodine atoms.

The term carboxy denotes the group -C(=O)OH.

The term formyl refers to the group -C(=O)H.

The term oxo or oxido denotes a (=O) group.

If the term alkyl or aryl, or any of the prefixes derived from these roots, appears in the name of a substituent (eg, arylalkyl, alkylamino), that name should be interpreted to include the limitations noted above for the terms alkyl and aryl. The number of carbon atoms indicated (eg, C1-C6) refers independently to the number of carbon atoms in the alkyl functional group, aryl functional group, or in the alkyl portion of a larger substituent that has alkyl as a prefix in its name. For alkyl and alkoxy substituents, the stated number of carbon atoms includes all independent members within the specified range. For example, _C1-6 alkyl will include separately methyl, ethyl, propyl, butyl, pentyl and hexyl, as well as subcombinations thereof (e.g., _C1-2 , _C1-3 , _C1-4 , C1-5, C2-6, C3-6, C4-6, C5-6, C2-5, etc.).

In general, according to the standard rules of nomenclature used throughout this specification, the terminal portion of the specified side chain is described first, followed by the description of adjacent functional groups towards the point of chain attachment. Thus, for example, the substituent name C1-C6 alkylcarbonyl denotes a group of the formula:

C----C^-C^alkyl

The label R in a stereocenter indicates that the stereocenter has a pure R configuration as defined in the art; similarly, the label S denotes that the stereocenter is in pure S configuration. As used herein, the labels *R or *S in a stereocenter are used to indicate that the stereocenter has a pure but unknown absolute configuration. As used herein, the label RS denotes a stereocenter existing in the form of a mixture of R and S configurations.

A compound containing one stereocenter without a stereolinkage designation is a mixture of two enantiomers. A compound containing two stereocenters without a stereolinkage designation for both of them is a mixture of four diastereomers. A compound with two stereocenters, where both are designated RS, and stereolinkage designations, is a mixture of two enantiomers with a relative stereochemical structure as shown in the figure. A compound with two stereocenters, where both are designated *RS, and stereolinkage designations, is a mixture of two enantiomers with a single but unknown relative stereochemical structure.

Undesignated stereocenters, indicated in the structural formula without stereobond designation, are mixtures of R and S configurations. For unlabeled stereocenters shown with stereobond symbols, the relative and absolute stereochemical structures correspond to the formula shown in the figure.

Unless otherwise stated, the definition of any substituent or variable at a particular position in the molecule is intended to be independent of corresponding definitions elsewhere in the molecule. It will be appreciated that one skilled in the art can select the substituents and substitution patterns of the compounds of the present invention to form chemically stable compounds that can be readily synthesized by methods known in the art, as well as the methods set forth herein.

The term subject means an animal, preferably a mammal, most preferably a human, that is the subject of treatment, observation or experiment.

The term "therapeutically effective amount" means that amount of an active compound or pharmaceutical agent, including a compound of the present invention, that produces a biological or medical response in a tissue system of an animal or human required by a researcher, veterinarian, physician, or other clinician, including reducing or inhibiting the activity of an enzyme or protein or relieving symptoms, alleviating conditions, slowing or delaying the progression of a disease, or preventing a disease.

In one embodiment, the term therapeutically effective amount refers to an amount of a compound of the present invention that, when administered to a subject, is effective in (1) at least partially attenuating, inhibiting, preventing and/or alleviating a condition or disorder or disease (i) mediated MALT 1; or (ii) associated with MALT1 activity; or (iii) characterized by activity (normal or abnormal) of MALT1; or (2) reduction or inhibition of MALT1 activity; or (3) reduction or inhibition of MALT 1 expression; or (4) changes in MALT 1 protein levels.

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The term composition means a product comprising specified ingredients in therapeutically effective amounts, as well as any product obtained directly or indirectly from combinations of specified ingredients in specified amounts.

The term MALT1-mediated refers to any disease, syndrome, condition or disorder that would occur in the absence of MALT1, but can occur in the presence of MALT1. Acceptable examples of a MALT1-mediated disease, syndrome, condition, or disorder include, but are not limited to, lymphomas, leukemias, carcinomas, and sarcomas, e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma ( FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML) ), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain tumors (gliomas), glioblastomas, breast cancer, colorectal cancer /colon cancer, cancer prostate cancer, lung cancer, including non-small cell cancer, stomach cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyelosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial cancer, vaginal cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer, and GIST (gastrointestinal stromal tumor ).

As used herein, the term MALT1 inhibitor refers to an agent that suppresses or reduces at least one condition, symptom, disorder and/or disease associated with MALT1.

Unless otherwise specified, as used herein, the term influence or influence (when referring to a disease, syndrome, condition or disorder dependent on MALT1 inhibition) includes a reduction in the frequency and/or severity of one or more symptoms or manifestations of the specified disease, syndrome, conditions or disorders; and/or involves preventing the development of one or more symptoms or manifestations of said disease, syndrome, condition or disorder or the development of a disease, condition, syndrome or disorder.

As used herein, the term treat, cure, therapy for any disease, condition, syndrome or disorder refers in one embodiment to alleviating the disease, condition, syndrome or disorder (i.e. slowing, stopping or suppressing the progression of the disease or at least one from its clinical symptoms). In another embodiment, the term treat, treatment, therapy refers to the attenuation or alleviation of at least one physical parameter, including one that may be unrecognizable to the patient. In yet another embodiment, the term treat, treatment, therapy refers to the modulation of a disease, condition, syndrome or disorder, either physically (eg, stabilization of a recognizable symptom), physiologically (eg, stabilization of a physical parameter), or both. In yet another embodiment, the term treat, treatment, therapy refers to preventing or delaying the onset or progression of a disease, condition, syndrome or disorder.

The compounds of the present invention are used in methods of treating or ameliorating a disease, syndrome, condition or disorder dependent on MALT1 inhibition. Such methods involve administering to a subject, including an animal, mammal and human, requiring such treatment, relief and/or prophylaxis, a therapeutically effective amount of a compound of formula (I) or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt thereof, or consists of and/or essentially consist of this method.

One embodiment of the present invention provides a method of treating a MALT1-dependent or MALT1-mediated disease or condition in a subject requiring such treatment, including an animal, mammal, and human, comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

In another embodiment, the MALT1-dependent or MALT1-mediated disease or condition is selected from cancers of hematopoietic origin or solid tumors, such as chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin's lymphoma and other B cell lymphomas.

In particular, the compounds of formula (I) or their enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form are used for the treatment or amelioration of diseases, syndromes, conditions or disorders such as diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL) and mucosal associated lymphoid tissue (MALT) lymphoma.

More specifically, the compounds of formula (I) or their enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form are used for the treatment or amelioration of diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL) and lymphoma associated with mucosal lymphoid tissue (MALT), which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof, as described herein.

In addition, the compounds of formula (I) or their enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form are used for the treatment or amelioration of an immunological disease, syndrome, disorder or condition selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis (PsA) ), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma and chronic obstructive pulmonary disease (COPD).

Embodiments of the present invention include a compound of formula (I):

Rs

Formula (I) where AA) R1 represents

i) naphthalen-1-yl, optionally substituted with fluorine or amino group; or ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxymethyl, difluoromethyl, 1,1-difluoroethyl, hydroxymethyl, 1-hydroxyethyl, hydroxy, methoxy, fluorine , chlorine, bromine, cyano, amino, methylamino, 4-oxotetrahydrofuran-2-yl, 5-oxopyrrolidin-2-yl, 1,4-dioxanyl, aminocarbonyl, methylaminocarbonyl, oxo, N-(methyl)formamidomethyl, tetrahydrofuran-2- yl, 3hydroxy-pyrrolidin-1-yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin-3-yl or azetidin-2yl;

BB) R1 represents

i) naphthalen-1-yl, optionally substituted with fluorine or amino group; or ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, difluoromethyl, hydroxymethyl, 1-hydroxyethyl, hydroxy, fluorine, cyano, amino, aminocarbonyl, methylaminocarbonyl, oxo, tetrahydrofuran-2-yl, 3 -hydroxypyrrolidin-1-yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin-3-yl or azetidin-2-yl;

CC) R1 represents

i) naphthalen-1-yl, optionally substituted with an amino or fluorine substituent; or ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from hydroxymethyl, 1-hydroxyethyl, hydroxy, fluorine, cyano, amino, 3hydroxyazetidinyl or oxo;

DD) R1 represents

i) naphthalen-1-yl, 4-amino-naphthalen-1-yl, 4-fluoronaphthalen-1-yl or 5-fluoronaphthalen-1-yl; or ii) heteroaryl is selected from the group consisting of isoquinolin-1-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-8-yl, quinolin-7-yl, cinnolin-4-yl, imidazo[1,2- a]pyrazin-8-yl, phthalazin-1-yl, naphthyridin-5-yl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, furo[ 2,3-c]pyridin-7-yl, quinoxalin-5-yl, 1H-indazolylfuro[3,2-b]pyridin-7-yl, pyrazolo[1,5-a]pyrazin-4-yl, quinolin- 4yl, quinolin-5-yl, 1-aminoisoquinolin-4-yl, 1-oxo-1,2-dihydroisoquinolin-5-yl, benzo[b]thiazol-7yl, 1-hydroxyisoquinolin-5-yl, benzo[b] [1,2,3]thiadiazol-7-yl, thieno[2,3-c]pyridin-4-yl, pyrazolo[1,5-a]pyridin-4-yl, thieno[3,2-b]pyridine -7-yl, 2-oxo-1,2-dihydroquinolin-4-yl, 1-amino-8fluoroisoquinolin-4-yl, 8-fluoroisoquinolin-4-yl, 1-cyanoisoquinolin-5-yl, pyrrolo[2,1f ][1,2,4]triazin-4-yl, 7-(1-hydroxyethyl)thieno[2,3-c]pyridin-4-yl, thieno[2,3-b]pyrimidin-4-yl, thieno [2,3-c]pyridin-7-yl, 1,7-naphthyridin-5-yl, pyrrolo[1,2-a]pyrazin-1-yl, imidazo[1,2-a]pyridin-5-yl, 1 -aminocarbonyl-isoquinolin-4-yl, benzo[b]thiazol-4-yl, 8-fluoro-1-hydroxyisoquinolin-4-yl, thieno[3,2-b]pyrimidin-4-yl, 8-fluorimidazo[1 ,2-a]pyridin-5-yl, 3-methylimidazo[1,2-a]pyridin-5-yl, 1-oxo-quinolin-4-yl, 8-aminoquinolin-5-yl, benzo[b]oxazol-4 -yl, 3-methylthieno[3,2-b]pyridin7-yl, 1-(hydroxymethyl)isoquinolin-4-yl, (3R-hydroxypyrrolidin-1-yl)isoquinolin-4-yl, (1hydroxyethyl)isoquinolin-4- yl, 8-fluoroisoquinolin-4-yl, 2-(difluoromethyl)quinolin-4-yl, 8

- 8 045333 fluoroquinolin-5-yl, 1-hydroxyisoquinolin-4-yl, 1-(tetrahydrofuran-2-yl)isoquinolin-4-yl, 7(difluoromethyl)thieno[2,3-c]pyridin-4-yl, 1-(1-hydroxyethyl)isoquinolin-4-yl, 1-cyanoisoquinolin-4-yl, 1-(1(R)-hydroxyethyl)isoquinolin-4-yl, quinazolin-4-yl, 2-methylimidazo[1,2-a ]pyridin-3-yl, thiazolo[5,4-d]pyrimidin-7-yl, 6-N-oxido-N-pyrazol-1-yl)thieno[2,3-c]pyridin-4-yl, imidazo [1,2a]pyridin-3-yl, furo[2,3-d]pyrimidin-4-yl, 2-fluoroquinolin-5-yl, isoquinolin-5-yl, benzo[d]isothiazol-3-yl, 7 -methylpyrazolo[1,5-a]pyridin-4-yl, 1-(hydroxyethyl)quinolin-4-yl, 1(methoxymethyl)isoquinolin-4-yl, 1-fluoroisoquinolin-4-yl, 1-(difluoromethyl)isoquinoline -4-yl, 8-fluoroquinolin-4-yl, 8-fluoroquinolin-5-yl, 1-(tetrahydrofuran-2(R)-yl)isoquinolin-4-yl, 2-amino[1,2,4]triazolo[1 ,5-a]pyridin-5-yl, 1-(4-oxotetrahydrofuran-2-yl)isoquinolin-4-yl, 2(aminocarbonyl)quinolin-4-yl, 1H-indazol-7-yl, 1-(1 ,4-dioxan-2-yl)isoquinolin-4-yl, 2methylimidazo[1,2-a]pyridin-5-yl, 1-chloroisoquinolin-4-yl, 2-cyanoquinolin-4-yl, 8-fluoro-1 (methylamino)isoquinolin-4-yl, benzo[d]isoxazol-3-yl, 2-aminobenzo[d]thiazol-7-yl, 2-fluoroquinolin5-yl, 1,7-naphthyridin-4-yl, imidazo[1 ,2-a]pyrazin-5-yl, (N((methyl)formamido)methyl)isoquinolin-4yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, 2-methylbenzo[ d]oxazol-7-yl, 1,5-naphthyridin-4-yl, 5oxopyrrolidin-2-ylisoquinolin-4-yl, 1-methyl-1H-indazol-3-yl, 8-fluorimidazo[1,2-a] pyridin-5-yl, 1 -(tetrahydrofuran-2-yl)isoquinolin-4-yl, 1 -(4-oxotetrahydrofuran-2-yl)isoquinolin-4-yl, 1-(1,1difluoroethyl)isoquinolin-4-yl , 1 -(1(*S)-hydroxyethyl)isoquinolin-4-yl, 1 -(methylamino)isoquinolin-4-yl, 4-fluoroisoquinolin-1-yl, 1H-pyrazolo[4,3-b]pyridin-7-yl , 5-fluoroquinolin-8-yl, 6fluoroimidazo[1,2-a]pyridin-5-yl, 2-methylfuro[3,2-b]pyridin-7-yl, 8-(difluoromethyl)quinolin-5-yl, 1(4-oxotetrahydrofuran-2H-yl)isoquinolin-4-yl, 1 -(dimethylamino)isoquinolin-4-yl, 1 -methyl-1Hpyrazolo[3,4-c]pyridin-7-yl, 2-methyl[1 ,2,4]triazolo[1,5-a]pyridin-5-yl, 2-methoxyquinolin-4-yl, imidazo[1,2-a]pyrimidin-5-yl, 2-(difluoromethyl)thieno[2, 3-c]pyridin-4-yl, quinolin-5-yl, 1-(1ethoxyethyl)isoquinolin-4-yl, 2-(azetidin-2-yl)quinolin-4-yl, 2-methylbenzo[d]thiazol- 7-yl, 2-acetylquinolin-4-yl, 1-(methylthio)isoquinolin-4-yl, 2-aminoquinolin-5-yl, 1-methoxyisoquinolin-5-yl, imidazo[1,2-b]pyridazin-6-yl, 1 -(pyrrolidin-2-yl)isoquinolin-4-yl, 4-(difluoromethyl)quinolin-5-yl, 1-acetylisoquinolin-5-yl, 2-aminoquinolin-5-yl, 1-(azetidin-2-yl)isoquinolin- 4-yl, 1-ethoxyisoquinolin-4-yl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl, 1-aminoisoquinolin-5-yl, 1-methyl1H-indazol-4-yl, 2- aminoquinolin-4-yl, 2-oxo-1,2-dihydroquinolin-5-yl, 1-(azetidin-3yl)isoquinolin-4-yl, 2-methylthieno[3,2-b]pyridin-7-yl, benzo [d] [ 1,2,3]thiadiazol-4-yl, 1-(1(S)hydroxyethyl)isoquinolin-5-yl, imidazo[1,2-a]pyridin-8-yl, 2-methyl-1 -oxo-1,2-dihydroisoquinolin5-yl, 2-(tetrahydrofuran-2-yl)quinolin-5-yl, 1-(1(R)-hydroxyethyl)isoquinolin-5-yl, 1,6naphthyridin-4-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl, 2-aminocarbonyl-quinolin-5-yl, 2-chloroquinolin-5-yl, 2-chloroquinolin-4-yl, 2-cyanoquinolin-5-yl, 1- aminoisoquinolin-5-yl, 2-methoxyquinolin-5-yl, 2-methylbenzo[d]oxazol-4-yl, 2-(difluoromethyl)quinolin-5-yl, 2-(azetidin-2yl)quinolin-5-yl, 1- (azetidin-2-yl)isoquinolin-5-yl, 1,5-bis(tetrahydrofuran-2-yl)isoquinolin-4-yl, 1-oxo-1,2-dihydroisoquinolin-4-yl, 2-methyl-1 -oxo-1,2-dihydroisoquinolin-4-yl, 1-(3hydroxyazetidin-1 -yl)isoquinolin-4-yl, 8-fluoro-1 -(3-hydroxyazetidin-1 -yl)isoquinolin-4-yl, ( R)-8-fluoro-1 -(3 -hydroxypyrrolidin-1 -yl)isoquinolin-4-yl, (S)-8-fluoro-1 -(3 -hydroxypyrrolidin-1 yl)isoquinolin-4-yl, 3-(hydroxyazetidine -1-yl)thieno[2,3-c]pyridin-4-yl, 8-(3-hydroxyazetidin-1yl)imidazo[1,2-a]pyridin-5-yl, 7-(3-hydroxyazetidin-1 -yl)pyrazolo[1,5-a]pyridin-4-yl, 1-(3hydroxyazetidin-1-yl)isoquinolin-5-yl and 1-(1-tert-butoxycarbonyl azetidin-2-yl)isoquinolin-5-yl ;

EE) R1 represents

i) naphthalen-1-yl, or 4-fluoronaphthalen-1-yl, 4-amino-naphthalen-1-yl, or 5-fluoronaphthalen-1-yl; or ii) heteroaryl selected from the group consisting of thieno[3,2-c]pyridin-4-yl, isoquinolin-4-yl, 8-fluoroquinolin-4-yl, furo[3,2-c]pyridin-4 -yl, quinolin-5-yl, furo[2,3-c]pyridin-7-yl, benzofuran4-yl, 1,7-naphthyridin-5-yl, pyrrolo[1,2-a]pyrazin-1-yl , imidazo[1,2-a]pyridin-5-yl, 1aminocarbonyl-isoquinolin-4-yl, pyrrolo[1,2-a]pyrazin-1-yl, benzo[d]thiazol-4-yl, 8-fluoro -1hydroxyisoquinolin-4-yl, thieno[3,2-d]pyrimidin-4-yl, 8-fluorimidazo[1,2-a]pyridin-5-yl, 3methylimidazo[1,2-a]pyridin-5-yl , 1-aminoisoquinolin-4-yl, 1-oxo-quinolin-4-yl, 8-aminoquinolin5-yl, benzo[d]oxazol-4-yl, 3-methylthieno[3,2-b]pyridin-7-yl , 1-(hydroxymethyl)isoquinolin-4-yl, (3R-hydroxypyrrolidin-1-yl)isoquinolin-4-yl, (1-hydroxyethyl)isoquinolin-4-yl, 8-fluoroisoquinolin-4-yl, 2-(difluoromethyl )quinolin-4-yl, 8-fluoroquinolin-5-yl, 1-hydroxyisoquinolin-4-yl, benzo[d]thiazol-4-yl, 1-aminoisoquinolin-4-yl, 1-(tetrahydrofuran-2-yl)isoquinolin- 4-yl, 7(difluoromethyl)thieno[2,3-c]pyridin-4-yl, 1-(1-hydroxyethyl)isoquinolin-4-yl, 1-cyanoisoquinolin-4yl, 1 -(1(R)-hydroxyethyl )isoquinolin-4-yl, quinazolin-4-yl, 2-methylimidazo[1,2-a]pyridin-3-yl, thiazolo[5,4-d]pyrimidin-7-yl, imidazo[1,2-a ]pyridin-5-yl, benzo[d][1,2,3]thiadiazol-7-yl, 6-Noxido-1H-pyrazol-1-yl)thieno[2,3-c]pyridin-4-yl, imidazo[1,2-a]pyridin-3-yl, furo[2,3d]pyrimidin-4-yl, 2-fluoroquinolin-5-yl, isoquinolin-5-yl, benzo[d]isothiazol-3-yl, 7methylpyrazolo[1,5-a]pyridin-4-yl, 1-oxo-1,2-dihydroisoquinolin-4-yl, 2-methyl-1-oxo-1,2dihydroisoquinolin-4-yl, 1 -(3-hydroxyazetidine -1 -yl)isoquinolin-4-yl, 8-fluoro-1-(3hydroxyazetidin-1-yl)isoquinolin-4-yl, (R)-8-fluoro-1-(3-hydroxypyrrolidin-1-yl)isoquinoline -4-yl, (S)-8-fluoro-1-(3-hydroxypyrrolidin-1-yl)isoquinolin-4-yl, 3-(hydroxyazetidin-1-yl)thieno[2,3- 9 045333

c]pyridin-4-yl, 8-(3-hydroxyazetidin-1-yl)imidazo[1,2-a]pyridin-5-yl, 7-(3-hydroxyazetidin-1-yl)pyrazolo[1,5-a ]pyridin-4-yl, 1-(3-hydroxyazetidin-1-yl)isoquinolin-5-yl and 1(hydroxyethyl)quinolin-4-yl;

FF) R ₂ is independently selected from the group consisting of methyl, isopropyl, cyano, bromine, chlorine and trifluoromethyl;

GG) R2 is independently selected from the group consisting of methyl, isopropyl, cyano and trifluoromethyl;

HH) R2 is trifluoromethyl;

II) R ₃ is independently selected from the group consisting of trifluoromethyl, cyano, methylcarbonyl, methylthio, methylsulfinyl, methanesulfonyl and chlorine; or, if G1 is N, _R3 is further selected from _C1-4 alkoxycarbonyl;

JJ) R ₃ is independently selected from the group consisting of trifluoromethyl, cyano and chlorine;

KK) G2 represents N or C(R ₃ ), and R ₃ represents chlorine;

LL) G2 represents N;

MM) R4 is selected from the group consisting of

i) hydrogen if G2 is N;

ii) C _1-4 alkoxy;

iii) cyano;

iv)cyclopropyloxy;

v) carboxy;

vi) heteroaryl selected from the group consisting of triazolyl, oxazolyl, pyrazolyl, thiazolyl, oxadiazolyl, imidazolyl and pyrimidin-4-yl, wherein the heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of C _1-4 alkyl, carboxy, methoxycarbonyl, hydroxymethyl, aminocarbonyl, (dimethylamino)methyl, amino, methoxymethyl, trifluoromethyl, amino(C _2-4 alkyl)amino and cyano;

vii) 1-methyl-piperidin-4-yloxy;

viii) 4-methyl-piperazin-1-ylcarbonyl;

ix) (4-aminobutyl)aminocarbonyl;

x) (4-amino)butoxy;

xi) methoxycarbonyl;

xii) 5-chloro-6-(methoxycarbonyl)pyridin-3-ylaminocarbonyl;

xiii) 1,1-dioxo-isothiazolidin-2-yl; and xiv) morpholin-4-ylcarbonyl;

NN) R4 is selected from the group consisting of

i) hydrogen;

ii) C _1-4 alkoxy;

iii) cyano;

iv) cyclopropyloxy;

v) heteroaryl selected from the group consisting of triazolyl, oxazolyl, pyrazolyl, thiazolyl, oxadiazolyl and imidazolyl, wherein the heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of methyl, carboxy, methoxycarbonyl, hydroxymethyl, aminocarbonyl, (dimethylamino )methyl and amino, methoxymethyl;

vi) (4-amino)butoxy;

vii) methoxycarbonyl;

viii) 5-chloro-6-(methoxycarbonyl)pyridin-3-ylaminocarbonyl; and ix) 1,1-dioxo-isothiazolidin-2-yl;

OO) R4 is selected from the group consisting of

i) methoxy;

ii) heteroaryl independently selected from the group consisting of 2H-1,2,3-triazol-2-yl, 4carboxy-2H-1,2,3-triazol-2-yl, 4-(hydroxymethyl)-2H-1 ,2,3-triazol-2-yl, 4-methyl-2H-1,2,3-triazol-2-yl, oxazol-2-yl, 4-amino-2H-1,2,3-triazol-2-yl , 4-(hydroxymethyl)-1H-pyrazol-1-yl, 4(hydroxymethyl)-2H-1,2,3-triazol-2-yl, 4-((dimethylamino)methyl)-2H-1,2,3 -triazol-2-yl, 4methoxycarbonyl-2H-1,2,3-triazol-2-yl, 4-aminocarbonyl-2H-1,2,3-triazol-2-yl, 1 -methyl-1H-pyrazol3- yl, 1,3,4-oxadiazol-2-yl, 2-methyl-2H-tetrazol-5-yl, 5-amino-1-methyl-1H-pyrazol-3-yl, 4(hydroxymethyl)-1H- pyrazol-1-yl, 4-cyano-2H-1,2,3-triazol-2-yl, 5-amino-1H-1,2,3-triazol-1-yl, 2H1,2,3-triazol- 4-yl, 2H-tetrazol-5-yl, 4-(aminomethyl)-1H-pyrazol-1-yl, 4-(methoxymethyl)-2H-1,2,3triazol-2-yl, 2-methyl-2H -tetrazol-5-yl and 4-methyl-1H-1,2,3-triazol-1-yl; and iii) methoxycarbonyl;

PP) R4 is independently selected from the group consisting of 2H-1,2,3-triazol-2-yl, 4-carboxy-2H-1,2,3triazol-2-yl, 4-(hydroxymethyl)-2H-1, 2,3-triazol-2-yl, 4-methyl-2H-1,2,3-triazol-2-yl, oxazol-2-yl, 1H-imidazol-2-yl, 4-amino-2H-1, 2,3-triazol-2-yl, 4-(hydroxymethyl)-1H-pyrazol-1-yl, 4(hydroxymethyl)-2H-1,2,3-triazol-2-yl, 4-((dimethylamino)methyl )-2H-1,2,3-triazol-2-yl, 4methoxycarbonyl-2H-1,2,3-triazol-2-yl, 4-aminocarbonyl-2H-1,2,3-triazol-2-yl, 1 -methyl-1 H-pyrazole- 10 045333

3-yl and 1,3,4-oxadiazol-2-yl;

QQ) R5 is hydrogen, chlorine, fluorine, bromine, cyano, methyl, ethyl or trifluoromethyl; or

R4 and R5 can be taken together to form 8-chloro-4-methyl-3-oxo-3,4-dihydro-2Hbenzo[b][1,4]oxazin-6-yl or 8-chloro-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl;

RR) R ₅ is hydrogen, chlorine, bromine, cyano or trifluoromethyl; or R ₄ and R ₅ can be taken together to form 8-chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl or 8chloro-3 -oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl; SS) R5 is hydrogen, chlorine, bromine or cyano;

TT) R5 is hydrogen, chlorine or cyano;

UU) R ₆ represents hydrogen or methyl;

W) R ₇ represents hydrogen;

and any combination of embodiments AA)-W) described above, provided that it is understood that combinations in which different embodiments of the same substituent are combined are excluded; so that in any case only one of G ₁ and G ₂ is N;

and, provided that the compound of formula (I) is other than a compound in which R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), and R4 is 2H-1,2,3 -triazol-2-yl, G2 is N and R5 is hydrogen;

compounds wherein R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is 1H-imidazol-1-yl, G2 is N, and R5 is chlorine;

compounds in which R1 represents isoquinolin-8-yl, R2 represents trifluoromethyl, _G1 represents C( _R4 ), and _R4 represents 1H-1,2,3-triazol-1-yl, _G2 represents is N and R5 is hydrogen;

compounds wherein R ₁ is isoquinolin-8-yl, R ₂ is trifluoromethyl, G1 is C(R4), wherein R4 is hydrogen, G2 is N, and R5 is fluorine;

N-(2-chloro-3-pyridinyl)-5-methyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide;

N-(3-chloro-4-methoxyphenyl)-5-methyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide; And

-methyl-N-3-pyridinyl-1-(2-quinolinyl)-1 H-pyrazole-4-carboxamideα;

or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof.

Embodiments of the present invention include a compound of formula (I):

*5

Formula (I) where R1 is selected from the group consisting of

i) naphthalen-1-yl, 4-amino-naphthalen-1-yl or 4-fluoronaphthalen-1-yl, 5-fluoronaphthalen-1-yl; and ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxymethyl, difluoromethyl, 1,1-difluoroethyl, hydroxymethyl, 1-hydroxyethyl, hydroxy, methoxy, fluorine, chlorine, bromine, cyano, amino, methylamino, 4-oxotetrahydrofuran-2-yl, 5-oxopyrrolidin-2-yl, 1,4dioxanyl, aminocarbonyl, methylaminocarbonyl, oxo, N-(methyl)formamidomethyl, tetrahydrofuran-2-yl , 3-hydroxy-pyrrolidin-1-yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin-3-yl or azetidin-2-yl;

R ₂ is independently selected from the group consisting of methyl, isopropyl, cyano, bromine, chlorine and trifluoromethyl;

G ₁ represents N or C(R ₄ );

G2 represents N or C(R ₃ ); so that in any case only one of G1 and G2 is N;

R3 is independently selected from the group consisting of trifluoromethyl, cyano, methylcarbonyl, methylthio, methylsulfinyl, methanesulfonyl and chlorine; or, if G1 is N, R3 is further selected from C _1-4 alkoxycarbonyl;

R4 is independently selected from the group consisting of

i) hydrogen if G2 is N;

ii) C _1-4 alkoxy;

iii) cyano;

iv) cyclopropyloxy;

- 11 045333

v) carboxy;

vi) heteroaryl selected from the group consisting of triazolyl, oxazolyl, pyrazolyl, thiazolyl, oxadiazolyl, imidazolyl and pyrimidin-4-yl, wherein the heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of C _1-4 alkyl, carboxy, methoxycarbonyl, hydroxymethyl, aminocarbonyl, (dimethylamino)methyl, amino, methoxymethyl, trifluoromethyl, amino( _C2.4 alkyl)amino and cyano;

vii) 1-methyl-piperidin-4-yloxy;

viii) 4-methyl-piperazin-1-ylcarbonyl;

ix) (4-aminobutyl)aminocarbonyl;

x) (4-amino)butoxy;

xi) methoxycarbonyl;

xii) 5-chloro-6-(methoxycarbonyl)pyridin-3-ylaminocarbonyl;

xiii) 1,1-dioxo-isothiazolidin-2-yl; and xiv) morpholin-4-ylcarbonyl;

R5 is hydrogen, chlorine, fluorine, bromine, cyano, methyl, ethyl or trifluoromethyl; or R4 and R5 can be taken together to form 8-chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin6-yl or 8-chloro-3-oxo -3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl;

R ₆ represents hydrogen or methyl;

R ₇ represents hydrogen;

and, provided that the compound of formula (I) is other than a compound in which R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C( _R4 ), and R4 is 2H-1,2, 3-triazol-2-yl, G2 is N and R5 is hydrogen;

compounds wherein R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is 1H-imidazol-1-yl, G2 is N, and R5 is chlorine;

compounds in which R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is 1H-1,2,3-triazol-1-yl, G2 is N, a R5 represents hydrogen;

compounds wherein R ₁ is isoquinolin-8-yl, R ₂ is trifluoromethyl, G1 is C(R4), wherein R4 is hydrogen, G2 is N, and R5 is fluorine;

N-(3-chloro-4-methoxyphenyl)-5-methyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide; And

5-methyl-N-3-pyridinyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide;

or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof.

Embodiments of the present invention include a compound of formula (I):

Rs

Formula (I) where R1 is selected from the group consisting of

i) naphthalen-1-yl, optionally substituted with fluorine or amino group; or ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, difluoromethyl, hydroxymethyl, 1-hydroxyethyl, hydroxy, fluorine, cyano, amino, aminocarbonyl, methylaminocarbonyl, oxo, tetrahydrofuran-2-yl, 3-hydroxypyrrolidin-1-yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin-3-yl or azetidin-2-yl;

R ₂ is selected from the group consisting of methyl, isopropyl, cyano and trifluoromethyl;

G1 represents N or C(R ₄ );

G2 represents N or C(R ₃ ); so that in any case only one of G1 and G2 is N;

R ₃ is independently selected from the group consisting of trifluoromethyl, cyano and chlorine;

R4 is independently selected from the group consisting of

i) hydrogen;

ii) C _1-4 alkoxy;

iii) cyano;

iv) cyclopropyloxy;

v) heteroaryl selected from the group consisting of triazolyl, oxazolyl, pyrazolyl, thiazolyl, oxadiazolyl and imidazolyl, wherein the heteroaryl is optionally substituted with one or two substituents

- 12 045333 independently selected from the group consisting of methyl, carboxy, methoxycarbonyl, hydroxymethyl, aminocarbonyl, (dimethylamino)methyl and amino, methoxymethyl;

vi) (4-amino)butoxy;

vii) methoxycarbonyl;

viii) 5-chloro-6-(methoxycarbonyl)pyridin-3-ylaminocarbonyl; and ix) 1,1-dioxo-isothiazolidin-2-yl;

R5 is hydrogen, bromine or cyano;

R6 is hydrogen or methyl;

R7 is hydrogen;

provided that the compound of formula (I) is other than a compound in which R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), and _R4 is 2H-1,2,3- triazol-2-yl, G2 is N and R5 is hydrogen;

compounds wherein R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is N-imidazol-1-yl, G2 is N, and R5 is chlorine;

compounds in which R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is 1H-1,2,3-triazol-1-yl, G2 is N, a R5 represents hydrogen;

compounds wherein R1 is isoquinolin-8-yl, R2 is trifluoromethyl, _G1 is C(R4), wherein R4 is hydrogen, G2 is N, and R5 is fluorine;

N-(3-chloro-4-methoxyphenyl)-5-methyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide; And

5-methyl-N-3-pyridinyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide;

or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof.

Embodiments of the present invention include a compound of formula (I):

o ^R i

Formula (I), where R ₁ is selected from the group consisting of

i) naphthalen-1-yl, optionally substituted with fluorine or amino group; and ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from hydroxymethyl, 1-hydroxyethyl, hydroxy, fluorine, cyano, amino, oxo, 3hydroxy-pyrrolidin-1-yl, pyrrolidin-2-yl, 3- hydroxyazetidinyl, azetidin-3-yl or azetidin-2yl;

R2 is selected from the group consisting of methyl, isopropyl, cyano and trifluoromethyl;

G1 represents N or C(R ₄ );

G2 represents N or C(R ₃ ); so that in any case only one of G1 and G2 is N;

R3 is independently selected from the group consisting of trifluoromethyl, cyano and chlorine;

R4 is selected from the group consisting of

i) methoxy;

ii) heteroaryl selected from the group consisting of 2H-1,2,3-triazol-2-yl, 4-carboxy-2H-1,2,3triazol-2-yl, 4-(hydroxymethyl)-2H-1, 2,3-triazol-2-yl, 4-methyl-2H-1,2,3-triazol-2-yl, oxazol-2-yl, 4-amino-2H-1,2,3-triazol-2- yl, 4-(hydroxymethyl)-1H-pyrazol-1-yl, 4-(hydroxymethyl)-2H-1,2,3triazol-2-yl, 4-((dimethylamino)methyl)-2H-1,2,3 -triazol-2-yl, 4-methoxycarbonyl-2H-1,2,3-triazol-2yl, 4-aminocarbonyl-2H-1,2,3-triazol-2-yl, 1-methyl-1H-pyrazol-3 -yl, 1,3,4-oxadiazol-2-yl, 2methyl-2H-tetrazol-5-yl, 5-amino-1-methyl-1H-pyrazol-3-yl, 4-(hydroxymethyl)-1H-pyrazole -1-yl, 4cyano-2H-1,2,3-triazol-2-yl, 5-amino-1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-4 -yl, 2H-tetrazol-5yl, 4-(aminomethyl)-1H-pyrazol-1-yl, 4-(methoxymethyl)-2H-1,2,3-triazol-2-yl, 2-methyl-2H-tetrazol5 -yl and 4-methyl-1H-1,2,3-triazol-1-yl; and iii) methoxycarbonyl;

R5 is hydrogen, chlorine or cyano;

R6 is hydrogen or methyl;

R7 is hydrogen;

with the proviso that the compound of formula (I) is other than N-(3-chloro-4-methoxyphenyl)-5-methyl-1-(2-13045333 quinolinyl)-1H-pyrazole-4-carboxamide;

or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof.

Embodiments of the present invention include a compound of formula (I):

*5

Formula (I) wherein R ₁ is independently selected from the group consisting of

i) naphthalen-1-yl, 4-amino-naphthalen-1-yl, 4-fluoronaphthalen-1-yl or 5-fluoronaphthalen-1-yl; and ii) heteroaryl selected from the group consisting of isoquinolin-1-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-8-yl, quinolin-7-yl, cinnolin-4-yl, imidazo[1 ,2-a]pyrazin-8-yl, phthalazin1-yl, naphthyridin-5-yl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, furo [2,3-e]pyridin-7-yl, quinoxalin-5-yl, 1H-indazolylfuro[3,2-b]pyridin-7-yl, pyrazolo[1,5-a]pyrazin-4-yl, quinolin4-yl , quinolin-5-yl, 1-aminoisoquinolin-4-yl, 1-oxo-1,2-dihydroisoquinolin-5-yl, benzo[d]thiazol-7-yl, 1-hydroxyisoquinolin-5-yl, benzo[d][ 1,2,3]thiadiazol-7-yl, thieno[2,3-c]pyridin-4-yl, pyrazolo[1,5-a]pyridin-4-yl, thieno[3,2-b]pyridin- 7-yl, 2-oxo-1,2-dihydroquinolin-4-yl, 1-amino-8fluoroisoquinolin-4-yl, 8-fluoroisoquinolin-4-yl, 1-cyanoisoquinolin-5-yl, pyrrolo[2,1f] [ 1,2,4]triazin-4-yl, 7-( 1 -hydroxyethyl)thieno[2,3-c]pyridin-4-yl, thieno[2,3-d]pyrimidin-4-yl, thieno[ 2,3-e]pyridin-7-yl, 1,7-naphthyridin-5-yl, pyrrolo[1,2-a]pyrazin-1-yl, imidazo[1,2-a]pyridin-5-yl, 1 - aminocarbonyl-isoquinolin-4-yl, benzo[d]thiazol-4-yl, 8-fluoro-1-hydroxyisoquinolin-4-yl, thieno[3,2-d]pyrimidin-4-yl, 8-fluorimidazo[1, 2-a]pyridin-5-yl, 3-methylimidazo[1,2-a]pyridin-5-yl, 1-oxo-quinolin-4-yl, 8-aminoquinolin-5-yl, benzo[0]oxazol-4- yl, 3-methylthieno[3,2-b]pyridin7-yl, 1-(hydroxymethyl)isoquinolin-4-yl, (3R-hydroxypyrrolidin-1-yl)isoquinolin-4-yl, (1hydroxyethyl)isoquinolin-4-yl , 8-fluoroisoquinolin-4-yl, 2-(difluoromethyl)quinolin-4-yl, 8-fluoroquinolin-5-yl, 1-hydroxyisoquinolin-4-yl, 1-(tetrahydrofuran-2-yl)isoquinolin-4-yl, 7 (difluoromethyl)thieno[2,3-e]pyridin-4-yl, 1-(1-hydroxyethyl)isoquinolin-4-yl, 1-cyanoisoquinolin-4-yl, 1-(1 (R)-hydroxyethyl)isoquinoline-4- yl, quinazolin-4-yl, 2-methylimidazo[1,2-a]pyridin-3-yl, thiazolo[5,4-d]pyrimidin-7-yl, 6-N-oxido-1 H-pyrazol-1 -yl)thieno[2,3-e]pyridin-4-yl, imidazo[1,2a]pyridin-3-yl, furo[2,3-d]pyrimidin-4-yl, 2-fluoroquinolin-5-yl , isoquinolin-5-yl, benzo[d]isothiazol-3-yl, 7-methylpyrazolo[1,5-a]pyridin-4-yl, 1-(hydroxyethyl)quinolin-4-yl, 1(methoxymethyl)isoquinolin- 4-yl, 1-fluoroisoquinolin-4-yl, 1-(difluoromethyl)isoquinolin-4-yl, 8-fluoroquinolin-4-yl, 8-fluoroquinolin-5-yl, 1-(tetrahydrofuran-2(R)-yl)isoquinoline -4-yl, 2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl, 1 -(4-oxotetrahydrofuran-2-yl)isoquinolin-4-yl, 2-(aminocarbonyl )quinolin-4-yl, 1H-indazol-7-yl, 1-(1,4-dioxan-2-yl)isoquinolin-4-yl, 2methylimidazo[1,2-a]pyridin-5-yl, 1- chloroisoquinolin-4-yl, 2-cyanoquinolin-4-yl, 8-fluoro-1(methylamino)isoquinolin-4-yl, benzo[d]isoxazol-3-yl, 2-aminobenzo[0]thiazol-7-yl, 2-fluoroquinolin5-yl, 1,7-naphthyridin-4-yl, imidazo[1,2-a]pyrazin-5-yl, (N-((methyl)formamido)methyl)isoquinolin-4yl, [1,2, 4]triazolo[1,5-a]pyridin-5-yl, 2-methylbenzo[d]oxazol-7-yl, 1,5-naphthyridin-4-yl, 5oxopyrrolidin-2-ylisoquinolin-4-yl, 1 - methyl-1 N-indazol-3-yl, 8-fluorimidazo[1,2-a]pyridin-5-yl, 1 -(tetrahydrofuran-2-yl)isoquinolin-4-yl, 1 -(4-oxotetrahydrofuran-2 -yl)isoquinolin-4-yl, 1-(1,1difluoroethyl)isoquinolin-4-yl, 1-(1(* S)-hydroxyethyl)isoquinolin-4-yl, 1 -(methylamino)isoquinolin-4-yl, 4- fluoroisoquinolin-1-yl, 1H-pyrazolo[4,3-b]pyridin-7-yl, 5-fluoroquinolin-8-yl, 6fluorimidazo[1,2-a]pyridin-5-yl, 2-methylfuro[3, 2-b]pyridin-7-yl, 8-(difluoromethyl)quinolin-5-yl, 1(4-oxotetrahydrofuran-2H-yl)isoquinolin-4-yl, 1 -(dimethylamino)isoquinolin-4-yl, 1 - methyl-1Hpyrazolo[3,4-c]pyridin-7-yl, 2-methyl[1,2,4]triazolo[1,5-a]pyridin-5-yl, 2-methoxyquinolin-4-yl, imidazo[ 1,2-a]pyrimidin-5-yl, 2-(difluoromethyl)thieno[2,3-e]pyridin-4-yl, quinolin-5-yl, 1-(1ethoxyethyl)isoquinolin-4-yl, 2- (azetidin-2-yl)quinolin-4-yl, 2-methylbenzo[d]thiazol-7-yl, 2-acetylquinolin-4-yl, 1 -(methylthio)isoquinolin-4-yl, 2-aminoquinolin-5-yl, 1-methoxyisoquinolin-5yl, imidazo[1,2-b]pyridazin-6-yl, 1-(pyrrolidin-2-yl)isoquinolin-4-yl, 4-(difluoromethyl)quinolin-5yl, 1-acetylisoquinolin-5- yl, 2-aminoquinolin-5-yl, 1-(azetidin-2-yl)isoquinolin-4-yl, 1-ethoxyisoquinolin-4-yl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl , 1-aminoisoquinolin-5-yl, 1-methyl1H-indazol-4-yl, 2-aminoquinolin-4-yl, 2-oxo-1,2-dihydroquinolin-5-yl, 1-(azetidin-3yl)isoquinolin- 4-yl, 2-methylthieno[3,2-b]pyridin-7-yl, benzo[e] [1,2,3]thiadiazol-4-yl, 1-(1 (S)hydroxyethyl)isoquinoline-5- yl, imidazo[1,2-a]pyridin-8-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin5-yl, 2-(tetrahydrofuran-2-yl)quinolin-5-yl, 1-( 1(R)-hydroxyethyl)isoquinolin-5-yl, 1,6naphthyridin-4-yl, 1H-pyrazolo[3,4-е]pyrimidin-4-yl, 2-aminocarbonyl-quinolin-5-yl, 2chloroquinolin-5 -yl, 2-chloroquinolin-4-yl, 2-cyanoquinolin-5-yl, 1-aminoisoquinolin-5-yl, 2-methoxyquinolin-5-yl, 2-methylbenzo[d]oxazol-4-yl, 2-(difluoromethyl) quinolin-5-yl, 2-(azetidin-2yl)quinolin-5-yl, 1-(azetidin-2-yl)isoquinolin-5-yl, 1,5-bis(tetrahydrofuran-2-yl)isoquinolin-4- silt,

- 14 045333

-oxo-1,2-dihydroisoquinolin-4-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl, 1 -(3hydroxyazetidin-1 -yl)isoquinolin-4-yl, 8-fluoro- 1 -(3-hydroxyazetidin-1 -yl)isoquinolin-4-yl, (R)-8fluoro-1 -(3-hydroxypyrrolidin-1 -yl)isoquinolin-4-yl, (S)-8-fluoro-1 - (3-hydroxypyrrolidin-1yl)isoquinolin-4-yl, 3-(hydroxyazetidin-1-yl)thieno[2,3-c]pyridin-4-yl, 8-(3-hydroxyazetidin-1yl)imidazo[1, 2-a]pyridin-5-yl, 7-(3-hydroxyazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl, 1 -(3-hydroxyazetidin-1-yl)isoquinolin-5-yl and 1-(1-tert-butoxycarbonyl azetidin-2-yl)isoquinolin-5-yl;

R2 represents trifluoromethyl;

G1 represents N or C(R ₄ );

G2 represents N or C(R ₃ ); so that in any case only one of G1 and G2 is N;

R ₃ is independently selected from the group consisting of trifluoromethyl, cyano and chlorine;

R4 is independently selected from the group consisting of 2H-1,2,3-triazol-2-yl, 4-carboxy-2H-1,2,3triazol-2-yl, 4-(hydroxymethyl)-2H-1,2, 3-triazol-2-yl, 4-methyl-2H-1,2,3-triazol-2-yl, oxazol-2-yl, 1H-imidazol-2-yl, 4-amino-2H-1,2, 3-triazol-2-yl, 4-(hydroxymethyl)-1H-pyrazol-1-yl, 4(hydroxymethyl)-2H-1,2,3-triazol-2-yl, 4-((dimethylamino)methyl)- 2H-1,2,3-triazol-2-yl, 4methoxycarbonyl-2H-1,2,3-triazol-2-yl, 4-aminocarbonyl-2H-1,2,3-triazol-2-yl, 1- methyl-1H-pyrazol3-yl and 1, 3, 4-oxadiazol-2-yl;

R5 is hydrogen, bromine or cyano;

R6 is hydrogen or methyl;

R ₇ represents hydrogen;

or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof. Embodiments of the present invention include a compound of formula (I):

Rs

Formula (I) wherein R1 is independently selected from the group consisting of

i) naphthalen-1-yl, 4-amino-naphthalen-1-yl, 4-fluoronaphthalen-1-yl or 5-fluoronaphthalen-1-yl; and ii) heteroaryl selected from the group consisting of thieno[3,2-c]pyridin-4-yl, isoquinolin-4-yl, 8-fluoroquinolin-4-yl, furo[3,2-e]pyridin-4 -yl, quinolin-5-yl, furo[2,3-c]pyridin-7-yl, benzofuran4-yl, 1,7-naphthyridin-5-yl, pyrrolo[1,2-a]pyrazin-1-yl , imidazo[1,2-a]pyridin-5-yl, 1aminocarbonyl-isoquinolin-4-yl, pyrrolo[1,2-a]pyrazin-1-yl, benzo[d]thiazol-4-yl, 8-fluoro -1hydroxyisoquinolin-4-yl, thieno[3,2-d]pyrimidin-4-yl, 8-fluorimidazo[1,2-a]pyridin-5-yl, 3methylimidazo[1,2-a]pyridin-5-yl , 1-aminoisoquinolin-4-yl, 1-oxo-quinolin-4-yl, 8-aminoquinolin5-yl, benzo[d]oxazol-4-yl, 3-methylthieno[3,2-b]pyridin-7-yl , 1-(hydroxymethyl)isoquinolin-4-yl, (3R-hydroxypyrrolidin-1-yl)isoquinolin-4-yl, (1-hydroxyethyl)isoquinolin-4-yl, 8-fluoroisoquinolin-4-yl, 2-(difluoromethyl )quinolin-4-yl, 8-fluoroquinolin-5-yl, 1-hydroxyisoquinolin-4-yl, benzo[d]thiazol-4-yl, 1-aminoisoquinolin-4-yl, 1-(tetrahydrofuran-2-yl)isoquinolin- 4-yl, 7(difluoromethyl)thieno[2,3-e]pyridin-4-yl, 1-(1-hydroxyethyl)isoquinolin-4-yl, 1-cyanoisoquinolin-4yl, 1 -(1(R)-hydroxyethyl )isoquinolin-4-yl, quinazolin-4-yl, 2-methylimidazo[1,2-a]pyridin-3-yl, thiazolo[5,4-d]pyrimidin-7-yl, imidazo[1,2-a ]pyridin-5-yl, benzo[d][1,2,3]thiadiazol-7-yl, 6-Noxido-1H-pyrazol-1-yl)thieno[2,3-e]pyridin-4-yl, imidazo[1,2-a]pyridin-3-yl, furo[2,3d]pyrimidin-4-yl, 2-fluoroquinolin-5-yl, isoquinolin-5-yl, benzo[d]isothiazol-3-yl, 7methylpyrazolo[1,5-a]pyridin-4-yl, 1-oxo-1,2-dihydroisoquinolin-4-yl, 2-methyl-1-oxo-1,2dihydroisoquinolin-4-yl, 1-(3-hydroxyazetidine -1-yl)isoquinolin-4-yl, 8-fluoro-1-(3hydroxyazetidin-1-yl)isoquinolin-4-yl, (R)-8-fluoro-1-(3-hydroxypyrrolidin-1-yl)isoquinoline -4-yl, (S)-8-fluoro-1-(3-hydroxypyrrolidin-1-yl)isoquinolin-4-yl, 3-(hydroxyazetidin-1-yl)thieno[2,3e]pyridin-4-yl , 8-(3-hydroxyazetidin-1-yl)imidazo[1,2-a]pyridin-5-yl, 7-(3-hydroxyazetidin-1yl)pyrazolo[1,5-a]pyridin-4-yl, 1 -(3-hydroxyazetidin-1-yl)isoquinolin-5-yl and 1(hydroxyethyl)quinolin-4-yl;

R2 represents trifluoromethyl;

G1 represents N or C(U);

G2 represents N or C(R ₃ ); so that in any case only one of G1 and G2 is N;

R3 is independently selected from the group consisting of trifluoromethyl, cyano and chlorine;

R ₄ is independently selected from the group consisting of 2H-1,2,3-triazol-2-yl, 4-carboxy-2H-1,2,3triazol-2-yl, 4-(hydroxymethyl)-2H-1,2 ,3-triazol-2-yl, 4-methyl-2H-1,2,3-triazol-2-yl, oxazol-2-yl, 1H-imidazol-2-yl, 4-amino-2H-1,2 ,3-triazol-2-yl, 4-(hydroxymethyl)-1H-pyrazol-1-yl, 4(hydroxymethyl)-2H-1,2,3-triazol-2-yl, 4-((dimethylamino)methyl) -2H-1,2,3-triazol-2-yl, 4- 15 045333 methoxycarbonyl-2H-1,2,3-triazol-2-yl, 4-aminocarbonyl-2H-1,2,3-triazol-2 -yl, 1-methyl-1H-pyrazol3-yl and 1,3,4-oxadiazol-2-yl;

R5 is hydrogen, chlorine or cyano;

R6 is hydrogen or methyl;

R7 is hydrogen;

or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof.

Additional embodiments of the present invention include the compounds of formula (I) as defined herein, or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof, as exemplified in the listing in Table 1. 1 below.

Table 1

- 16 045333

ⁿ HMC 4 1-(Naphthalene-1-yl)-5- (trifluoromethyl)-N-(5- (trifluoromethyl)pyridine-3- yl)-1H-pyrazole-4- carboxamide ШД А Г ¹ ' *8 5 N-(5-Cyanopyridin-3-yl)1-(naphthalen-1-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide η 5 d? p> WITH" 6 1-(Quinolin-5-yl)-5- (trifluoromethyl)-N-(2- (trifluoromethyl)pyridin-4yl)-1H-pyrazole-4carboxamide 1 °®^Ν Jf 9 CF ₃ J - ⁿ qQ G ⁿ 7 N-(5-Chloro-6- methoxypyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide _S QO Η o=U s. 8 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)—1—(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide Q ^I L\o M cxx 9 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)—1—(3-methylisoquinolin1-yl)-5-(trifluoromethyl)1 L-pyrazol-4-carboxamide ςο I'm about λ*3 10 N- (3-Chloro-4- methoxyphenyl)-1- (isoquinolin-8-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide

- 17 045333

AND . eleven N-(3-Chloro-4-(2H-1,2,3triazol-2-yl)phenyl)-1(isoquinolin-8-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide QQ Ch/ ί th L O ³ 12 N-(3-Chloro-4-(1H-pyrazol1-yl)phenyl)-1(isoquinolin-8-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide and 13 Ν- (6-Cyano-5- (trifluoromethyl)pyridin-3yl)-1-(isoquinolin-8-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide pl ₂ N4 j J j? SRz •'- I Ν— 14 N-(4-(2-Aminopyrimidin-4yl)-3-chlorophenyl)-1- (isoquinolin-8-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide CQ in L > X & ^ϋ 15 N-(5-Chloro-6-(1H-pyrazol1-yl)pyridin-3-yl)-1(isoquinolin-8-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide 4c ^f vQ w 16 R-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-isobutyl-1- (quinolin-5-yl)-1Hpyrazole-4-carboxamide

- 18 045333

/^N O 17 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-ETHYL-1-(quinolin-5yl)-1H-pyrazol-4carboxamide w 18 N-(3-Chloro-4-(1H-1,2,3triazol-1-yl)phenyl)-1(isoquinolin-8-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide 0 19 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(isoquinolin-8-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide _ςο H> °l ° V-/ OJI Z\Ό ⁶ 20 N-(5-Chloro-6-(1,1- dioxidoisothiazolidin-2yl)pyridin-3-yl)-1(isoquinolin-8-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide vP ko /V οό’ 21 N-(5-Chloro-6-(1-methyl-1Hpyrazol-3-yl)pyridin-3yl)-1-(isoquinolin-8-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide Oh, Ρζΐ s I ¹ ° '^8 Ν- ⁷ 22 N-(5-Chloro-6-(oxazol-2yl)pyridin-3-yl)-1(isoquinolin-8-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide

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1 23 Ν- (5-Chloro-6- methoxypyridin-3-yl)-1(isoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide 1 O, lt Duu ^χ ·» 24 Ν- (5-Cyano-6- methoxypyridin-3-yl)-1(isoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide ci CHDR R 25 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(3-fluoroquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide 00 a.s. D Y OD 26 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-isopropyl-1- (quinolin-5-yl)-1Hpyrazole-4-carboxamide uo h> o=/ ^s TG Y~Y Od 27 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(6-methylquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide A y/ ⁰⁼ l yf CX 28 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(8-methylquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide

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29 N-(3-Chloro-4-(3-methyl-1H1,2,4-triazol-1- yl)phenyl)-1-(isoquinolin8-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide o R thirty N- (5-Chloro-b-(3-methyl-1H1,2,4-triazol-1yl)pyridin-3-yl)— 1 — (isoquinolin-8-yl)-5(trifluoromethyl)-1Hpyrazol-4- carboxamide n ABOUT ^o ^9 C0 31 N-(3-Chloro-4-(5-methyl-1H1,2,4-triazol-1- yl)phenyl)— 1 —(isoquinolin8-yl)-5-(trifluoromethyl)- 1 L-pyrazole-4-carboxamide An N-^N TJ 9 CF ₃ ''^8 32 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(isoquinolin-4-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide O Y ъ-ъ 0 , ^o оУ 33 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(4-methylisoquinolin8-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide ^Uy ^H Xi pf 34 1-(Benzofuran-4-yl)-N-(5chloro-6-{2Η-Ύ,2,3-triazol2-yl)pyridin-3-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide

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Λχ ABOUT 35 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(1-methoxyethyl)-1(quinolin-5-yl)-1Hpyrazol-4-carboxamide 36 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(6-methylisoquinolin4-yl)-5-(trifluoromethyl)IH-pyrazol-4-carboxamide I Ό }=Ό /to XYS ''VO 37 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2-methylquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide ^N 38 N-(3-Chloro-4-(2H-1,2,3triazol-2-yl)phenyl)-1(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide с с С) 07 ^s 39 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-methyl-1-(quinolin-5yl)-3H-pyrazol-4carboxamide 6ο S> o=/ ZX C? z-z 7' 40 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(8-fluoroquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide

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IN' 12 \=o 1 V" co 41 N-(b-Cyano-5-fluoropyridin3-yl)-1-(isoquinolin-4yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide O /^8=° =Άλτ>. ^8 42 N-(5-Chloro-b-(1,1- dioxidoisothiazolidin-2yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide An JG /} j? CFj 43 N-(3-Chloro-4-(1H-1,2,3triazol-1-yl)phenyl)-1(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide O.O. e 0 44 Methyl 3-chloro-5-(3-chloro-5(1-(isoquinolin-4-yl)-5- (trifluoromethyl)-1H- pyrazole-4- carboxamido)picolinamido ) picolinate ^JW >, 45 N- (5-Chloro-6-( (1- metilpiperidine-4- yl)oxy)pyridin-3-yl)-1(isoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide A 2=/ Vz-s rQ SA cd 46 N-(5-Chloro-6-(1R-pyrazol1-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide

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/^N Ν' ^Ν χ^ ₄ J? ^CF 3 47 N-(5-Cyano-6-(2L-1,2,3triazol-2-yl)pyridin-3yl)-1-(isoquinolin-4-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide o G 1 y CF ₃ 48 N-(5-Chloro-6-(4- methylpiperazine-1- carbonyl)pyridin-3-yl)-1(isoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide 49 Ν- (6-Cyano-5- (trifluoromethyl)pyridin-3yl)-1-(isoquinolin-4-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide With? SV 50 N-(5-Chloro-6-(oxazol-2yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide <V С1 ^g хх h 51 N-(3-Chloro-4-(5-methyl-1H1,2,4-triazol-1- yl)phenyl)-1-(isoquinolin4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide km Chl™ '^B 52 N-(5-Chloro-6-(1-methyl-1Hpyrazol-3-yl)pyridin-3yl)-1-(isoquinolin-4-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide

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N- (5-Chloro-6-(3-methyl-1H1,2,4-triazol-1yl)pyridin-3-yl)— 1 — (isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4- carboxamide

N- (5-Chloro-6-(5-methyl-1H1,2,4-triazol-1yl)pyridin-3-yl)— 1 — (isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4- carboxamide

N-(3-Chloro-4-(3-methyl-1H1,2,4-triazol-155 yl)phenyl)-1-(isoquinolin4-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide

N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(difluoromethyl)-1(isoquinolin-1-yl)-1Hpyrazol-4-carboxamide

N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-357 yl)-1-(isoquinolin-1-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide

N-(4-(2-aminopyrimidin-4yl)-3-chlorophenyl)-158 (isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide

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XI w F ³ Gun w 59 R-(3-Cyano-4-(2R-1,2,3triazol-2-yl)phenyl)-1(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide ςο 4th L // t ⁰ 60 N-(5-Chloro-6-(2R-1,2,3triazol-2-yl)pyridin-3yl)-1-(quinolin-5-yl)-1Hpyrazol-4-carboxamide <h \=° STj Si 61 N-(5-Fluoro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(isoquinolin-4-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide And V/o sS Sat 62 N-(3-Cyano-4-(1H-1,2,3triazol-1-yl)phenyl)-1(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide jC 9 CF ₃ 63 N-(5-Chloro-6-(thiazol-2yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide ¢0 4 θ o ° 64 N-(5-Chloro-6-(2R-1,2,3triazol-2-yl)pyridin-3yl)-5-methyl-1-(quinoline-4- yl)-1R-pyrazole-4carboxamide

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OCX th L O ⁶ 65 N-(5-Chloro-6-(2R-1,2,3triazol-2-yl)pyridin-3yl)-1-(3-methylquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide s, I 1 У CF3 66 N-(5-Chloro-6-(2R-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-methylisoquinolin4-yl)-5-(trifluoromethyl)IH-pyrazol-4-carboxamide V 67 N-(5-Chloro-6-(2R-1,2,3triazol-2-yl)pyridin-3yl)-1-(6-fluoroquinolin-7yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide AN VNyN L ] 5? cf ₃ V® 68 N-(5-Chloro-6-(2R-1,2,3triazol-2-yl)pyridin-3yl)-1-(7R-indazol-4-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide U 1 Cm 69 N-(5-Chloro-6-(1,3,4oxadiazol-2-yl)pyridin3-yl)-1-(isoquinolin-4yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide 00 r*> ZT o ³ 70 N-(5-Chloro-6-(7R-imidazol1-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide

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'ABOUT /To 'sr Q Si 71 N-(6-(2H-1,2,3-Triazol-2yl)pyridin-3-yl)— 1—(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide o ΗνΑ^Ν > X 1 0 F ^Fj /=^8 72 N-(4-Aminobutyl)-3-chloro5- (1-(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazole-4- carboxamido)picolinamide O ° CF k. and it CFi ^p z ^s ^^уАф l-n η Γ Ν—/ \=ς Vjr 73 1-(Isoquinolin-4-yl)-N-(2methyl-6- (trifluoromethyl)pyridin-4yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide ^°y>o Ν Α _ο „X L β Рз G 74 Methyl 6-chloro-4-(1- (isoquinolin-4-yl)-5- (trifluoromethyl)-1H- pyrazole-4- carboxamido)picolinate •φ 75 Methyl 4-(1-(isoquinolin-4yl)-5-(trifluoromethyl)-1Hpyrazol-4- carboxamido)picolinate /^Ν *Yes G and ο w I 76 M-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(isoquinolin-4-yl)- I L-pyrazole-4-carboxamide 4\ζ^ ^Ν ο 77 N-(2-Cyanopyridin-4-yl)1-(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide

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1 ⁵ ¢0 78 N-(5-Cyano-6-(1-methyl-7Hpyrazol-3-yl)pyridin-3yl)-1-(isoquinolin-4-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide 79 N-(5-Chloro-6- cyclopropoxypyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide 80 N- (5-Cyano-6-( (1 - metilpiperidine-4- yl)oxy)pyridin-3-yl)-1- (isoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide 3^1 and I?* nc^^^A / - Η Ρ ^Ν “\ 7 E=( w 81 N-(5-Cyano-6- ethoxypyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide ^N L=/ ί / 82 N-(5-Cyanopyridin-3-yl)1-(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide ³ⁿ . %-ъ 0 ώ 83 N-(5-Cyano-6-(2L-1,2,3triazol-2-yl)pyridin-3yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide

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N-(b-(4-Aminobutoxy)-5cyanopyridin-3-yl)-1(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide

N-(5-Cyano-bmethoxypyridin-3-yl)-1(quinolin-5-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide

N-(5-Cyano-b-(1H-1,2,4triazol-1-yl)pyridin-3yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide

N-(8-Chloro-3-oxo-3,4dihydro-2Hbenzo[b][1,4]oxazin-6yl)-1-(isoquinolin-4-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

N-(5-Cyano-bcyclopropoxypyridin-388 yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide

N-(5-Cyano-b-(1-methyl-1Hpyrazol-3-yl)pyridin-389 yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide

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90 N-(5-Cyano-6-(2L-1,2,3triazol-2-yl)pyridin-3yl)-1-(thieno[3,2- c]pyridin-4-yl)-5(trifluoromethyl)- 1Hpyrazole-4-carboxamide COl i? η X?*“Су ^N О 91 N- (5-Chloro-6-(oxazol-2yl)pyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide .Ф ^b x> 0=^ 0“ И“И P ^И * 92 N-(5-Cyano-6-(2L-1,2,3triazol-2-yl)pyridin-3yl)-1-(8-fluoroquinolin-4yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide P g LD A 93 1-(Cinnolin-4-yl)-N-(5cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide if tO 94 N-(5-Cyano-6-(2L-1,2,3triazol-2-yl)pyridin-3yl)-1-(furo[3,2- c]pyridin-4-yl)-5(trifluoromethyl)- 1Hpyrazole-4-carboxamide Cl 95 N-(8-Chloro-4-methyl-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazine-6- yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide

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O 96 N-(5-Cyano-6-(4- methylpiperazine-1- carbonyl)pyridin-3-yl)-1(isoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide /k A ⁹ 03 97 N-(8-Chloro-4-methyl-3-oxo3,4-dihydro-2R- benzo[b][1,4]oxazin-6yl)-1-(isoquinolin-4-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide Σ J) ft CF ₃ 98 N-(5-Chloro-6-(1-methyl-1Nimidazol-2-yl)pyridin-3yl)-1-(isoquinolin-4-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide ^N Ά^ζθ 99 N-(5-Cyano-b-(2R-1,2,3triazol-2-yl)pyridin-3yl)-1-(furo[2,3-c]pyridin-7-yl)-5(trifluoromethyl)- 1Hpyrazole-4-carboxamide C 3-3 P X r^Y^3 03 100 N-(5-Cyano-6-(2R-1,2,3triazol-2-yl)pyridin-3yl)-1-(1,6-naphthyridin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide o η ₂ ν^^^Χ4γ^ 4 o ZsADD F* 101 N- (6-(4-(4- Aminobutyl)piperazine-1carbonyl)-5-cyanopyridin3-yl)-1-(isoquinolin-4yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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co tn 1 o v-X 102 N-(5-Cyano-6-(2R-1,2,3triazol-2-yl)pyridin-3yl)-1-(phthalazin-1-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide ο ^Η L ^Ν ^ / ' ^m ' b 103 N-(5-Cyano-6-(2L-1,2,3triazol-2-yl)pyridin-3yl)-1-(imidazo[1,2a]pyrazin-8-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide XI? , ^STz <ο 104 N-(5-Chloro-6-(1R-imidazol2-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide ςο YM 4 G 105 N-(5-Cyano-6-(2R-1,2,3triazol-2-yl)pyridin-3yl)-1-(quinoxalin-5-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide Χ /Ν ρ XX, Χ ^ζ \=ζ Ο 106 N-(5-Chloro-6- (difluoromethoxy)pyridin-3yl)-1-(isoquinolin-4-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide (Χ ^ν α u X ΧχΟ 107 N-(5-Chloro-6-(2oxopyrrolidin-1yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide

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A> o =/ zx Λ .g 1 108 Methyl 2-(3-Chloro-5-(1- (quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4- carboxamido)pyridin-2yl)-2H-1,2,3-triazole-4carboxylate O 109 2-(3-Chloro-5-(1-(quinolin5-yl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamido)pyridin-2yl)-2H-1,2,3-triazole-4carboxylic acid ή At OJ Ν_Ζ 110 1-(1-Amino-8- fluoroisoquinolin-4-yl)-N(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide 111 1-(1-Amino-8- fluoroisoquinolin-4-yl)-N(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide /^Ν V%n A V^ ⁰ 112 N-(5-Chloro-2-methyl-6-(2H1,2,3-triazol-2- yl)pyridin-3-yl)-1-(1- oxo-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-OXO-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide

1-(Benzo[d]thiazol-7-yl)N-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4- carboxamide

N-(5-Chloro-6-(4(hydroxymethyl)-2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-OKCO-1,2dihydroisoquinolin-5-yl)5-( trifluoromethyl)-1Hpyrazole-4-carboxamide

N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl) - 1 - (1 - hydroxyisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide

N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(8-fluoroisoquinolin4-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide

N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(8-fluoroisoquinolin4-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide

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o =/ ΖΞ ζ 119 1- (Benzo[c1][1,2,3]thiadiazole -7-yl)-N-(5-cyano-6-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide ΛΝ _F F JM ί? T ^F ci'^XiAXJl / - n Q^+Λ D'/ /=\ ^S X *Ν Ν 120 1- (Benzo[c1] [1,2,3] thiadiazole -7-yl)-N-(5-chloro-6-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide Chf 121 1- (Benzo[b][1,2,3]thiadiazole -7-yl)-N-(5-chloro-2-methyl6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide α _γ% O ^ 122 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(5-fluoronaphthalen-1yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide /^Ν ABOUT- 123 N-(5-Chloro-2-methyl-6-(2H1,2,3-triazol-2- yl)pyridin-3-yl)-1-(8fluoroisoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide

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^Η,Ν Λλ Ν ρ Qr° 134 N-(6-(4-Amino-2H-1,2,3triazol-2-yl)-5chloropyridin-3-yl)-1-(1oxo-l,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Ηpyrazole -4-carboxamide ^Η °ν /SN FF HH W 135 N-(5-Chloro-6-(4- (hydroxymethyl)-1Hpyrazol-1-yl)pyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide _ 136 N-(5-Chloro-6-(4- (hydroxymethyl)-2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide °==ζ ΖΓ y ζ-ζ ϊ. ° 1 137 N-(5-Chloro-6-(4- ((dimethylamino)methyl)-2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide Ζ^Ν V ^th Ν _F ο 138 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(quinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide

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139 N-(5-Bromo-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide CH„ Λ-ιϊ 140 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(pyrrolo[2,1- f] [1,2,4]triazin-4-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide tL o =/ 2ΞΕ z-z L ^d ° 141 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(pyrazolo[1,5a]pyrazin-4-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide at the oU 142 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(thieno[2,3d]pyrimidin-4-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide 143 N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(thieno[2,3c]pyridin-7-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide °Xa _n H ₂ NN «А π F ' i : w 144 2-(3-Chloro-5-(1-(quinolin5-yl)-5-(trifluoromethyl)1H-pyrazol-4carboxamido)pyridin-2yl)-2H-1,2,3-triazol-4carboxamide

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ίί ‘h-O Ο 145 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1,7-naphthyridin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide 27 JI J-ZV ^b // LJ χ^ ^ζ b 146 N-(6-(2H-1,2,3-Triazol-2yl)-5- (trifluoromethyl)pyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide & 1 l Λ___ J/ °=( 147 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(pyrrolo[1,2a]pyrazin-1-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide F /=N ^F \U ^F 148 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(pyrrolo[1,2a]pyrazin-1-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide ^z ju Я2 & Ou 149 N-(5-Cyano-6-(2-methyl-2Htetrazol-5-yl)pyridin-3yl)—1—(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide

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150 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(furo[3,2- b]pyridin-7-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide Ν about TsML ^Ν Y( 151 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2-methylfuro[3,2— b]pyridin-7-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide SU ,, DC ABOUT 152 N- (5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(4-fluoro-2methoxyphenyl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide □ Y~ in 153 1-(Benzo[d]thiazol-7-yl)N-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4- carboxamide ⁿ ₂ MchGd Vshn [W % Si' y=/ 154 N-(6-(4-Amino-2H-1,2,3- triazol-2-yl)-5- chloropyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide

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155 1-(1-Aminoisoquinoline-4- yl)-N-(5-chloro-b-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide 156 1-(1-Aminoisoquinolin-4yl)-N-(5-cyano-b-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide ο=° ^-ΝΗ 157 N- (5-Chloro-b-(1-methyl-1Hpyrazol-3-yl)pyridin-3yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazol-4- carboxamide CXi't '1 τγ\_ΓΛ \=Ζ ^-ЪН 158 1-(1-0KSO-1,2- dihydroisoquinolin-5-yl)- 5-(trifluoromethyl)-N-(2- (trifluoromethyl)pyridine-4- yl)-1H-pyrazole-4carboxamide \ ^F \ ^F /У Va ^F y ί 1 Γ Ν—f y-NH ν _Ν ^Ν^Ν У/ N=/ У\ ' (J nh ₂ 159 1-(2-Amino- [1,2,4]triazolo[1,5a]pyridin-5-yl)-N-(5- cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide

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2^4 Q \ // Ί 2-2 O <4 1™ Ou 160 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-3-fluoro-1-(quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide Ογ s ^ρ ύ ) \_ _n X—NH 161 N-(2,5-Dimethyl-6-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1-(1- oxo-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide _CI -V N^\_-. _N \__ 0 3 J ] TO N^ZH '— ^and 44 162 N-(6-(2H- [1,2,3]Triazolo[4,5c]pyridin-2-yl)-5chloropyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide γ ci 4¾ G ⁿ 163 N-(6-(1H- [1,2,3]Triazolo[4,5— c]pyridin-1-yl)-5chloropyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide UY Oz pi J 4 & Ό 164 N-(6-(2H[1,2,3]Triazolo[4,5— b]pyridin-2-yl)-5chloropyridin-3-yl)-1(quinolin-5-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide

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Ν 1 p 165 Ν-(6-(ZN- [1,2,3]Triazolo[4,5b]pyridin-3-yl)-5chloropyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide o ^ΝΗ HN J _F F O O- ^r H / ^N \^=/ O' 166 N-(3-Chloro-4-(5-OXO-4,5dihydro-1H-1,2,4-triazol3-yl)phenyl)-1-(quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide L/O Qr° 167 1-(I-Okco-1,2- dihydroisoquinolin-5-yl)- 5-(trifluoromethyl)-N-(5- (trifluoromethyl)pyridine-3- yl)-1H-pyrazole-4carboxamide y θχ Oi ci l ⁰ U, 168 N-(5-Chloro-6-(5- (hydroxymethyl)-1H-1,2,3triazol-1-yl)pyridin-3yl)-1-(I-Okco-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide cd O w O’в 169 N-(5-Chloro-2-methyl-6-(1methyl-1H-pyrazol-3yl)pyridin-3-yl)-1-(1oxo-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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F ^F jf O UF “ Γ/Μ) nJ /=( U 170 N-(5-Chloro-2-methyl-6-(1Hpyrazol-1-yl)pyridin-3yl)-1-(I-OKCO-I,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazol-4- carboxamide JO EZ 2=0 U~U7 U o 171 N-(5-Chloro-2-methyl-4-(2H- 1,2,3-triazole-2- yl)phenyl)— 1 —(1-oxo-1,2- dihydroisoquinolin-5-yl)- 5-(trifluoromethyl)-1H- pyrazole-4-carboxamide οό Ίφ о S---Ч· il and ' ° U ^s 172 N-(5-Chloro-2-fluoro-4-(2H1,2,3-triazole-2- yl)phenyl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide . λ o /=O UL Ζ 00' f'\f 173 N-(5-Chloro-6-(4- (methoxymethyl)-2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide η ₂ ν ^ _ν Mu _x ^F \U .....A 174 N-(4-(4-(Aminomethyl)-1Hpyrazol-1-yl)-3chlorophenyl)-1-(quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide

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N-(3-Chloro-4-(4(hydroxymethyl)-1Hpyrazol-1-yl)phenyl)-1175 (quinolin-5-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide

N-(5-Cyano-2-methyl-6-(2H1,2,3-triazol-2yl)pyridin-3-yl)-1-(1176 oxo-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl) -1Hpyrazol-4-carboxamide N-(5-Cyano-6-(4(hydroxymethyl)-2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(quinolin-5-yl)-5( trifluoromethyl)-1Hpyrazole-4-carboxamide

N-(6-(5-Amino-1H-1,2,3triazol-1-yl)-5chloropyridin-3-yl)— 1 —(1178 oxo-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)- 1Hpyrazole-4-carboxamide

N-(5-Chloro-6-(4-cyano-2H1,2,3-triazol-2yl)pyridin-3-yl)—1—

179 (quinolin-5-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide

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η ο /° ,0./ 0’ 1 180 1-(1-Aminoisoquinolin-4yl)-N-(5-chloro-2-methyl-6(2H-1,2,3-triazol-2- yl)pyridin-3-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide 1 > Short circuit /° HR 1 hour Ου 181 N-(6-(5-Amino-1-methyl-1Hpyrazol-3-yl)-5cyanopyridin-3-yl)-1- (quinolin-5-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide to and Ό Λ’ 182 N-(5-Chloro-6-(4- (hydroxymethyl)-1Hpyrazol-1-yl)pyridin-3yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide Ν ^ΗίΝ 4 ϊ VU ^F if η ο f--./ □ΌΑ _Τ Ό J ^F ,_, η ίςχΟΛ ο=° —ΝΉ 183 N-(6-(5-Amino-1-methyl-1Hpyrazol-3-yl)-5chloropyridin-3-yl)—1—(1oxo-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide Cl F Yu ^N _ν )—tf—V π 'η C Ν—ΝΗ φ. JUU' ¹ '>W /ύΐ ίΎ 184 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)—1—(8-fluoro-1hydroxyisoquinolin-4-yl)5-(trifluoromethyl)-1Hpyrazol-4- carboxamide

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az π O 185 N-(5-Bromo-2-methyl-6-(2H1,2,3-triazol-2- yl)pyridin-3-yl)-1-(1- oxo-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide '-- With/ 186 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-cyano-1-(quinoline-5- yl)-1H-pyrazole-4carboxamide . . ^--4- SG 187 3-Chloro-N-(5-chloro-6-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1- (quinolin-5-yl)—1H—pyrazole-4-carboxamide Сх u _У Х _Х Ά—Χ Z у/ ^о= К l & ⁰ 188 5-BpoM-N-(5-chloro-6-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1- (quinolin-5-yl)-1Hpyrazole-4-carboxamide l ^e /y/ ©y < I h ίίχ-2 ^and 189 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(imidazo[1,2a]pyridin-3-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide F ^F wT° 190 N-(5-Ethynyl-2-methyl-6(2H-1,2,3-triazol-2- yl)pyridin-3-yl)-1-(1- oxo-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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CL · g ^F A / o F^z JI 7^T ^H Г N-/ \\ x ⁷ \=/ XX 191 N-(5-Chloro-2-methyl-b-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)— 1 — (isoquinolin-4-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide M, C 192 N-(5-Chloro-b-(1,3,4 - oxadiazol-2-yl)pyridin3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide O'L· G0 193 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(imidazo[1,2a]pyridin-5-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide An VGA. _F Г £ ? ^F X _F αΆ>Λ Α / ^F ^N ^Z N—/ a 194 N-(5-Chloro-2-methyl-b-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)—1— (imidazo[1,2-a]pyridin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide R__\—* O and/ \-Λ- CFS 195 N-(5-Chloro-2-ethyl-b-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)—1— (imidazo[1,2-a]pyridine-5- yl)-5-(trifluoromethyl)-1H- pyrazole-4-carboxamide

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196

197

N-(2,5-Diethyl-b-(2H1,2,3-triazol-2yl)pyridin-3-yl)— 1—(imidazo[1,2-a]pyridin-5yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide

N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(pyrazolo[1,5-a]pyridin-4-yl)-5(trifluoromethyl)- 1Hpyrazol-4-carboxamide N-(5-Chloro-2-methyl-6-(2H1,2,3-triazol-2yl)pyridin-3-yl)— 1 —

198 (pyrazolo[1,5-a]pyridin4-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridine -3yl)-1- (2199 methylimidazo[1,2a]pyridin-5-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide

200

N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(imidazo[1,2a]pyridin-5-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide

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/ Η o F^y J Af ⁿ O-P Ό 201 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(3-chloroimidazo[1,2-a]pyridin-5-yl)-5- (trifluoromethyl)-1H-pyrazole4-carboxamide % F / 1 o F^/ ci^AAk JZ? ⁿ ]AnPa / N-/ V 202 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(8-fluorimidazo[1,2-a]pyridin-5-yl)-5(trifluoromethyl )-1Hpyrazole-4-carboxamide ^An 4k ^N N—/ O 203 N-(5-Chloro-2-methyl-b-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1-(8- fluorimidazo[1,2— a]pyridin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide An nA Г \ F // PF^/ J^ ^F H / ί _z N—/ y—F / N—/ O 204 N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(8-fluorimidazo[1,2-a]pyridin-5-yl)-5(trifluoromethyl )-1Hpyrazole-4-carboxamide Cbs _F ⁼ Wy 205 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(b-fluorimidazo[1,2a]pyridin-5-yl)-5(trifluoromethyl)- 1Hpyrazole-4-carboxamide

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h O yah g—-/ ⁰ LCH 7 > /H . 1 hour 206 1-(2-Methylimidazo[1,2 - a]pyridin-5-yl)-5- (trifluoromethyl)-N-(2- (trifluoromethyl)pyridin-4yl)-1H-pyrazole-4carboxamide F A f? *JL II 7^f Ά * cAf UO 207 1-(7-Methylpyrazolo[1,5- a]pyridin-4-yl)-5- (trifluoromethyl)-N-(2- (trifluoromethyl)pyridin-4yl)-1H-pyrazole-4carboxamide ΝΆ _l FF AH JT ^F AA ^F iz ^N —\ / Α ^? N—/A 208 1-(Imidazo[1,2-a]pyridin5-yl)-5-(trifluoromethyl)-N(2-(trifluoromethyl)pyridin4-yl)-1H-pyrazol-4carboxamide '^Ag- 209 1-(8-Fluorimidazo[1,2 - a]pyridin-5-yl)-5- (trifluoromethyl)-N-(2- (trifluoromethyl)pyridin-4yl)-1H-pyrazole-4carboxamide 210 1-(7-(3-Hydroxyazetidin1-yl)thieno[2,3-c]pyridin4-yl)-5-(trifluoromethyl)-N(2-(trifluoromethyl)pyridin4-yl)-1H-pyrazol-4carboxamide

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if BI ζΧ ³ 211 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(3methylimidazo[1,2a]pyridin-5-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide ο κΖ У ώ 212 N-(2-Methyl-1-oxo1,2,3,4- tetrahydroisoquinolin-7yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide ώ /~Ο Ts/-y=o κζ /° Luke 7 1 00 213 N-(3-(Methylsulfonyl)-4(1H-1,2,3-triazol-1yl)phenyl)-1-(quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide /уОу 214 N-(4-Methyl-3-oxo-3, 4dihydro-2H- benzo[b][1,4]oxazin-6yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide /M.Х ^Χν ' ^ν >0 ο ^F X O 215 N- (3-(Methylsulfonyl)-4(2H-1,2,3-triazole-2- yl)phenyl)-1-(quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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Butt? f a h [In—CT ABOUT 216 N-(2-Methyl-1-oxo-1,2dihydroisoquinolin-7-yl) 1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide w 217 N- (3-Oxo-3,4-dihydro-2Hbenzo[b][1,4]oxazin-6yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide ΧΣί f ^f Sl X ^N VV w 218 N-(5-Methyl-6-(3-methyl-2oxo-2,3-dihydro-1Nimidazol-1-yl)pyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide AN n^x^-nf J 3 O \3-F _N ^AjAJ _N ' Ϋ 219 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2- methylbenzo[d]oxazol-4yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide 0 220 1-(2-Chloroquinolin-4-yl)-N(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide A\ 1 r X, _α Α^ιΑγ\Α/ Q Cl 221 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2-chloroquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide

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π J-К π V ^th 222 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1H-pyrazolo[3,4d]pyrimidin-4-yl)-5(trifluoromethyl)- 1Hpyrazole-4-carboxamide 'U Jo O/ ⁴ I h So 223 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1,6-naphthyridin-4yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide υ^ ^Ν \/Ν. F K-Jp w 224 N-(5-Cyano-6-(4- methylpiperazine-1- yl)pyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide Jz< 00 Ph T X 2yJ ^Q \ ZK o ,-ζ 0 z 225 N-(1-Methyl-1H- pyrazolo[3,4-b]pyridin-5yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide fc-z KZ Jo 0/ *04 I Ό 226 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2-methyl-1-oxo- 1,2-dihydroisoquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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7 ⁱ lХ HV _N / FV \__( λ Fp N 227 N-(5-Chloro-6-(5-cyano-1H- 1,2,3-triazole-1- yl)pyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide qO obu ft ^o: X 228 2-(2-Chloro-4-(1-(quinolin5-yl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamido)phenyl)-2H1,2,3-triazole-4carboxylic acid a. €й ma ^x 2 p-'-'rA 1 h Ou a 229 N-(1H-Pyrazolo[3,4— b]pyridin-5-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide 0 >o o~z 60’ 230 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(imidazo[1,2-a]pyridin-8-yl)-5(trifluoromethyl)- 1Hpyrazole-4-carboxamide ,u O={ ИИ 0 a—a 4 И ^α 231 1- (Benzo[c1] [1,2,3] thiadiazole -4-yl)-N-(5-chloro-6-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide

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--- ^and l L Op ο=ζ X ^g Od ⁵ 232 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2-methylthieno[3,2- b]pyridin-7-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide p o 1 ² CXfj 233 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(imidazo[1,5a]pyridin-5-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide Mi _{0 F} y 234 1-(3-Chloro-5-(1-(quinolin5-yl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamido)pyridin-2yl)-1H-1,2,3-triazole-4carboxylic acid XN^ _in Длъ 1 Г>\_ГА Г/ УУ W 235 N-(5-Methoxy-6-(1H-1,2,3triazol-1-yl)pyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide 236 N-(4-Aminobutyl)-3-cyano5-(1-(isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazole-4carboxamido)picolinamide O-M 237 2-Cyano-4-(1-(quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4- carboxamido)benzoic acid

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wo gu if 2. And 238 N-(4-(4-(Aminomethyl)-1Hpyrazol-1-yl)-3methylphenyl)-1-(quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide Ν /^N III f F N Wo 239 N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-methyl-1Nindazol-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide lch Γ\\ Hi -Λ j) T 4 cr Y=I 240 N-(5-Methyl-b-(1-methyl-1Htetrazol-5-yl)pyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide /=N F Tsl— 241 N- (5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-methyl-1Hpyrazolo[3,4-b]pyridin-4yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide g/ O No. 1 ft. / U~O °=\ et U and Chu · ⁵ 242 N- (5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(imidazo[1,2- b]pyridazin-b-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide /^N _С1 '' ^l '1 ^N / V/ y / ⁰ o—N 243 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1methoxyisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide

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HjN “Ax. O' 244 2-(2-Chloro-4-(1-(quinolin5-yl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamido)phenyl)-2H1,2,3-triazole-4carboxamide .94 nJ ,ό op □=( rf IX\ \y7 k 245 N- (5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2- methylbenzo[d]thiazol-4yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide °L /^N lCHi H _? N\4F O' 246 1-(3-Chloro-5-(1-(quinolin5-yl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamido)pyridin-2yl)-1H-1,2,3-triazole-4carboxamide .¼ J 1 O^\ YM L i 247 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2- methylbenzo[d]thiazol-7yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide C AOo А/ /=\ G ⁿ 248 N-(6-(5-(Aminomethyl)-1H- 1,2,3-triazol-1-yl)-5- chloropyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide

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About N'th - vy 249 Methyl 1-(3-chloro-5-(1- (quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4- carboxamido)pyridin-2yl)-1H-1,2,3-triazole-4carboxylate \\ o b x = o LS/ W ⁼ 250 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(imidazo[1,2a]pyrimidin-5-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide X% L j ° ^F O 1 n 1/44 O* 251 N-(5-Methoxy-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide 0½,J L4\Oe —Ν Γ \ 252 1-(Benzo[d]thiazol-4-yl)- N-(5-chloro-2-methyl-6-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide / Cl ' ' Ά ί ’ 253 N-(5-Chloro-6-(5- (methoxymethyl)-1H-1,2,3triazol-1-yl)pyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide

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^o= \vd A o*- 254 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2-methyl[1,2,4]triazolo[1,5-a]pyridin- 5-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide \ O. fk N__/ i F ^H С'О ^N kJ 255 3-(3-Cyano-5-(1-(quinolin5-yl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamido)pyridin-2yl)-1-methyl-1H-pyrazole-5carboxylic acid °νΟ^ ^Ν o p F Uo o 256 Methyl 2-(2-chloro-4-(1- (quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4- carboxamido)phenyl)-2H1,2,3-triazole-4carboxylate \ z ^N -N n _x IL V\x F ⁿ ^ uV _n u ^N \=Z w 257 N-(5-Cyano-6-(2-methyl-2H- 1,2,3-triazole-4- yl)pyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide n h /* EX 0' Ύ J-h 1 b CO 258 Methyl 3-chloro-5-(1- (quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4- carboxamido)picolinate

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tai' Zyj °\ ZM 1!2Z 259 N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-methyl-1Hpyrazolo[3,4-c]pyridin-7yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide \ X Qy>W-rO ^F ^ ί J 260 N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-methyl-1Nindazol-7-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide Q У / ° /4 J Х ^x /А _ш co' 4 261 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(5-fluoroquinolin-8yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide CL·. , DHL'T*o-fE HN. χ+ N 262 N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1H-pyrazolo[4,3- b]pyridin-7-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide b /O 2)-21 Rch oL ZK / t? ² 263 N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(4-fluoroisoquinolin1-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide Cl\___ FF _XT ^¼¾¾ 264 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-fluoroisoquinolin4-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide

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To No. 1 to ΰ- 265 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-methyl-1Hpyrazolo[3,4-b]pyridin-3yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide * F / F^Z _n ^NA .Lu Vf ΐΌ/Λ / 266 N- (5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-methyl-1Nindazol-3-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide ο<ζο Y ^r Cy Ύ /4/ γ JO Ou 267 Methyl 3-(3-cyano-5-(1- (quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4- carboxamido)pyridin-2yl)-1-methyl-1H-pyrazole-5carboxylate 4 Y L ₂ NG\ 268 N-(5-Cyano-6-(1-methyl-1Hpyrazol-3-yl)pyridin-3yl)-1-(8-fluoroquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide U? F* 269 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1,5-naphthyridin-4yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide

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QQ T z-z 270 Ν- (5-Chloro-6-(5- ((dimethylamino)methyl)-1H- 1,2,3-triazole-1- yl)pyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide Gu vZI Uh γ^ b Aw 271 N- (5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2- methylbenzo[d]oxazol-7yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide /^N H ₂ NN^X^A „ F X- w 272 N-(6-(4-(Aminomethyl)-2H- 1,2,3-triazol-2-yl)-5- chloropyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide \ Cl O-Λ HOUNH XU SG\_/T N 273 N-(5-Chloro-6-(1-methyl-1Hpyrazol-3-yl)pyridin-3yl)-1-(8-fluoroquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide ^N N=/ jl^J 274 1-([1,2,4]Triazolo[1,5a]pyridin-5-yl)-N-(5Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide

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N. _N Vk-VU-MI ^{ν ν=/} /i 275 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(imidazo[1,2a]pyrazin-5-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide Ό 9 of Ά° Αο ΟΟ 276 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1,7-naphthyridin-4yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide _n .Xj τχ Λ Υ ^{Ν F} F ^F 277 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2-fluoroquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide SCH% o "AA> A ^p/ 278 1-(2-Aminobenzo[d]thiazol- 7-yl)-N-(5-chloro-6-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide hhd 279 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(isothiazolo [5,4- b]pyridin-3-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide r=\ N^ f4/ ^F <Х> /-NH j' Ιί Ί Жгв N 280 N- (5-Cyano-6-(1H-ruggo11-yl)pyridin-3-yl)-1(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide

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/^N 40,. Ar o y M _n 4' V 292 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(furo[2,3- d]pyrimidin-4-yl)-5(trifluoromethyl)- 1Hpyrazole-4-carboxamide An Ba 7 // ? o f^7 Cl^xX\ D/O h V\ XA l=/ 4 Λ N 293 1- (Benzo[b][1,2,3]thiadiazole -7-yl)-N-(5-chloro-6-(1— methyl-1H-pyrazole-3- yl)pyridin-3-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide L ν ^ν \^ν f ^f J η about their N^S 294 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(thiazolo[5,4d]pyrimidin-7-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide rC) AX /у/ ⁰ \ d O 295 N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2methylimidazo[1,2a]pyridin-3-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide a aU h VP /° J ^- C zap* 1 h Co 296 N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)—1—(quinazolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide

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QQ ί* 1 Tu/ if ii^z ⁱ 297 1-(Benzo[d]thiazol-4-yl)N-(5-cyano-2-methyl-6-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide An Ότ° v •Op ^N 0S 298 1-(Benzo[d]thiazol-4-yl)N-(5-cyano-2-methyl-4-(2H- 1,2,3-triazole-2- yl)phenyl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide 0 О-кОоХО ШН^ ¹ )=/ Г ^α Λ V 299 N-(6-(4-Amino-2H-1,2,3triazol-2-yl)-5chloropyridin-3-yl)—1— (benzo[d]thiazol-4-yl)-5(trifluoromethyl)-1Hpyrazole -4-carboxamide COxx G Τι 3 ^F ό U ^s 300 1-(Benzo[d]thiazol-4-yl)- N-(2,5-dimethyl-6-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide rT> —» A/S Tyf o J ь ZK O C ^Z 301 1- (Benzo[b][1,2,3]thiadiazole -7-yl)-N-(5-chloro-2-fluoro4-(2H-1,2,3-triazol-2yl)phenyl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide

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Oh UU U U Πό 41 302 N-(5-Chloro-2-fluoro-4-(2H1,2,3-triazole-2- yl)phenyl)-1-(8- fluoroisoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide Mi _F D'-G DD x F III ^F / ^f _a lA,ld al G / \=/ ^N /—\ ^s v ^N 303 1- (Benzo[c1] [1,2,3] thiadiazole -7-yl)-N-(5-chloro-2-methyl- 6-(1H-pyrazole-1- yl)pyridin-3-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide Cl ' A vX ^H ζ/ ^Ν Μ w 304 N-(5-Chloro-6-(4-methyl-1H- 1,2,3-triazole-1- yl)pyridin-3-yl)-1- (quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide n^n —Ν D χτ F o ^F -7 O 305 N-(5-Methyl-6-(2-methyl-2Ntetrazol-5-yl)pyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide O* y 1 h €u 306 1-(Benzo[d]thiazol-4-yl)N-(5-chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4- carboxamide Cl NN o ^x АХХХ D Cr 307 N-(5-Chloro-6-(2H-tetrazol5-yl)pyridin-3-yl)-1(quinolin-5-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide

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An Ν π F xxw 308 N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(8-fluoroquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide z^N \\ II f J Ί f? ^Ρ ~Ά- Gi-'^ke^X^UX/ - ^H 7 ^N XX w 309 N- (5-Chloro-b-(2H-1,2,3triazol-4-yl)pyridin-3yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide ¢0 b 1 °f~CJ □X ZK X 310 N-(5-Cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(3-methylthieno[3,2- b]pyridin-7-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide Λν _F ^F -CA\X 311 1-(Benzo[d]oxazol-4-yl)N-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4- carboxamide N π Ί * O 312 N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(4-fluoronaphthalen-1yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide 0 ' t YA „ A F XI j? 3 XX w 313 Methyl 2-cyano-4-(1- (quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4- carboxamido)benzoate

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2' V' r^\ 314 1- (Benzo[c1] [1,2,3] thiadiazol -7-yl)-N-(5-cyano-2- methyl 6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide / ι F ν\\ ο ^f 4- _f 315 N-(5-Cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(thieno[3,2d]pyrimidin-4-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide a. · N^S 316 1-(Benzo[d]thiazol-4-yl)N-(5-cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4- carboxamide xHl? X fr of 0 (f,2 317 N-(5-Chloro-2-methyl-4-(2H- 1,2,3-triazole-2- yl)phenyl)—1—(8- fluoroisoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide l 9 u ^? About CW <4' 318 N-(5-Chloro-2-methyl-b-(2H1,2,3-triazol-2- yl)pyridin-3-yl)-1-(7methylpyrazolo[1,5a]pyridin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide

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vXU' 319 1-(Pyrazolo[1,5- a]pyridin-4-yl)-5- (trifluoromethyl)-N-(2- (trifluoromethyl)pyridin-4yl)-1H-pyrazole-4carboxamide O- 320 1-(8-Fluoroisoquinoline-4- yl)-5-(trifluoromethyl)-N- (2-(trifluoromethyl)pyridin4-yl)-1H-pyrazol-4carboxamide about TT Jf WITH& 321 N-(5-Chloro-2-methyl-b-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)— 1 — (thieno[2,3-c]pyridine-4- yl)-5-(trifluoromethyl)-1H- pyrazole-4-carboxamide /=^N Cl A i 1 _F U UCHA _o ^f Uf Al I 1 /g\ / V-h ^H L , ⁿ u^/ O 322 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1- (dimethylamino)isoquinolin4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide Yd'/v' 323 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1- (methylamino)isoquinolin-4yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide Cl F _F UjW 324 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)—1—(8-fluoro-1- (methylamino)isoquinolin-4yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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N-(5-Cyano-b-(2Η-1,2,3-

triazol-2-yl)pyridin-3yl)-1-(8-fluoro-1(methylamino)isoquinolin-4 yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

1-(8-Aminoquinolin-5-yl)N-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide 1 -(1-Aminoisoquinoline-4

yl)-N-(5-chloro-2-fluoro-4(2H-1,2,3-triazol-2yl)phenyl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide 1-(1-Aminoisoquinolin-5yl) -N-(5-cyano-b-(2H1,2,3-triazol-2328 yl)pyridin-3-yl)-5(trifluoromethyl)-1Hpyrazol-4-carboxamide

1-(2-Aminoquinolin-4-yl)N-(5-cyano-b-(2H-1,2,3329 triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide 1-(1-Aminoisoquinolin-5yl)-N-(5-chloro-b-(2H1,2,3-triazol-2330 yl)pyridin-3-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide

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Cl N l О Ap ^F F / \ /~NH ₂ ^N 331 1-(2-Aminoquinolin-5-yl)N-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide 2 ^s /=O rt/ 1 K ^z 332 1-(2-Aminoquinolin-5-yl)N-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide \ P * V\Ny _F / r- ^N O 333 1-(1-Aminoisoquinoline-4- yl)-N-(5-chloro-2-methyl-6- (1-methyl-1H-pyrazole-3- yl)pyridin-3-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide ^ς Αχα» ^N about 334 1-(1-Aminoisoquinolin-4yl)-N-(2,5-dimethyl-6-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide ΐχ ' F N'XY O F-C, J 4 1 7 l-\ _// y—ΝΗϊ ⁿ «a/ \=\ o 335 1-(1-Aminoisoquinoline-4- yl)-N-(5-chloro-2-methyl-4- (2H-1,2,3-triazole-2- yl)phenyl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide Ζ^Ν ^VV _F F Jf O VY-F ^H IL ύ ⁷ \=z O 336 1-(1-Aminoisoquinolin-4yl)-N-(5-chloro-2-methyl-6- (1H-pyrazol-1-yl)pyridin3-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide

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F II Λ 1 / l-N y-^ Η y , ^Ν \_/ Ο 337 1-(1-Aminoisoquinolin-4yl)-N-(5-cyano-2-methyl-4- (2H-1,2,3-triazole-2- yl)phenyl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide CO F Ο 338 1-(1-Aminoisoquinolin-4yl)-N-(5-cyano-2-methyl-6- (2H-1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide ο 339 1-(1-Aminoisoquinolin-4yl)-5-(trifluoromethyl)-N- (2-(trifluoromethyl)pyridin4-yl)-1H-pyrazol-4carboxamide ο 340 1-(1-Aminoisoquinolin-4yl)-N-(2-cyanopyridin-4yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide _F 341 1-(1-Aminoisoquinolin-4yl)-N-(5-chloro-2-methyl-6- (4-methyl-2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide O 342 1-(1-Aminoisoquinolin-4yl)-5-(trifluoromethyl)-N- (5-(trifluoromethyl)pyridin3-yl)-1H-pyrazol-4carboxamide

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- ABOUT 343 1-(1-Aminoisoquinoline-4- yl)-N-(5-bromo-2-methyl-6- (2H-1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide ict be T X W th—ζ \ and \ ^G 344 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2-oxo-1,2dihydroquinolin-5-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide P iiо o 345 N-(5-Chloro-b- methoxypyridin-3-yl)-1- (1-OXO-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide F Ch—NH 346 N-(5-Cyanopyridin-3-yl)1- (1-oxo-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide I \Ov ⁿ In-A ^g/ /=/ 4 / ° NH 347 N-(2-Methylpyridin-4-yl)1-(1-oxo-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide Q° 348 N-(b-Methyl-5- (trifluoromethyl)pyridin-3yl)-1-(1-oxo-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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Qr° 349 1-(I-Okco-1,2dihydroisoquinolin-5-yl)- N-(pyridin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide Ά Qr° 350 N—(2-Cyclopropylpyridin4-yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide 0 Ά Q° 351 3-Chloro-N,N-dimethyl-5-(1(1-oxo-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazol-4- carboxamido)picolinamide 0 Ά Qr° 352 3-Chloro-N-methyl-5-(1-(1oxo-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazol-4- carboxamido)picolinamide Z f ^f Ά Ah 353 N-(5-Chloropyridin-3-yl)-1(1-oxo-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide Na. Wp wT° 354 N-(6-Cyano-5- (trifluoromethyl)pyridin-3yl)-1-(1-oxo-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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0 ^F 355 Methyl 3-chloro-5- (1- (1- oxo-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazol-4- carboxamido)picolinate Cr° ^NH 356 N- (2-Cyanopyridin-4-yl)1- (1-OKCO-1,2- Dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide O ⁴¹ y=o hum rU o 357 N-(2-(2-Methoxyethoxy)-5(trifluoromethyl)pyridin-3yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide O _ У0 0=y \~y Z^z \ <д ^s 358 N-(5-Chloro-2-methyl-6-(2H1,2,3-triazol-2- yl)pyridin-3-yl)-1-(2oxo-1,2-dihydroquinolin4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide O U u=o rU o 359 N-(5-Chloro-2-methyl-6-(4methyl-2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(1oxo-1,2dihydroisoquinolin-5-yl)5- (trifluoromethyl)-1Hpyrazole-4-carboxamide .у/0 o=/ zr α 360 N-(2-Methoxypyridin-4yl)-1-(1-OKCO-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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0¾¾ ch 4 )=° N.H. 361 N-(2-Morpholinopyridin-4yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide 'HLHz Qt° 362 N-(5-Chloro-2-methyl-6-(4methyl-1H-1,2,3-triazol-1yl)pyridin-3-yl)-1-(1oxo-1,2dihydroisoquinolin-5-yl)5- (trifluoromethyl)-1Hpyrazole-4-carboxamide /¾ ϋ° 363 N-(5-(2H-1,2,3-Triazol-2yl)pyridin-3-yl)-1-(1oxo-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazol-4-carboxamide /f O 4 ίζ About 364 1-(Thieno[2,3-c]pyridin-4yl)-5-(trifluoromethyl)-N- (2-(trifluoromethyl)pyridin4-yl)-1H-pyrazol-4carboxamide 4/ 2nd £у-2 2=о 4X7 'й'^/'h 1 ™ Gi ХХф' ² * 365 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1- (tetrahydrofuran-2yl)isoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide

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XX ci ^Ν Y /y. yLI /=Ν O hell 366 1-(1.5- Bis(tetrahydrofuran-2yl)isoquinolin-4-yl)-N-(5chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide DN C1 ^F ,π Τη p IA JI L~T \__/ ^F ΛΛΗθϋ ^N \=N ' O 367 1-(1-(1,4-Dioxane-2- yl)isoquinolin-4-yl)-N-(5chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide L o χΛ 368 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl) -1-(1-(1- ethoxyethyl)isoquinolin-4yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide /D Cl /\Η° 369 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl) -1-(1-(5oxopyrrolidin-2- yl)isoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide ζΑγΆ mi Λ ] /у/ °=/ JK o 370 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl) -1-(1-(4- oxotetrahydrofuran-2yl)isoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide

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CU, W-rn w 371 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-(1- Hydroxyethyl)isoquinolin4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide /JCl O' \—0 372 N- (5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1- (2- (tetrahydrofuran-2yl)quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide cu. XX. ' ABOUT 373 N- (5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1- ((Nmethylformamido)methyl)isoh inolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide /Ό Cl JX ^H L / ^N / ^N O J/ 374 N- (5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2-(1- Hydroxyethyl)quinolin-4yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide Av ci Xxp- w 375 1-(2-Acetylquinolin-4-yl)N-(5-chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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Z^N Cl VyX F 376 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(7-(1- hydroxyethyl)thieno[2,3- c]pyridin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide O 377 1-(1-Aminoisoquinolin-4yl)-N-(6-methyl-5- (trifluoromethyl)pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide /^N Cl I A 1 Ν Ύ 4 N AL ^F Ш 378 1-(1-Acetylisoquinoline-5- yl)-N-(5-chloro-b-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide a r ' A-Ov·^ H Dw w 379 1-(1-(Azetidine-2- yl)isoquinolin-4-yl)-N-(5chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide A? _C1 Ul, oh 380 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-(pyrrolidin-2yl)isoquinolin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide

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/O I ¹ F h g nJ ^N Q 381 1-(2-(Azetidine-2- yl)quinolin-5-yl)-N-(5chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide O 1 4 a.y. 382 1-(2-(Azetidine-2- yl)quinolin-4-yl)-N-(5chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide riJ ° 4 383 Tert-butyl 2—(5-(4-( (5— chloro-b-(2H-1,2,3-triazol2-yl)pyridin-3yl)carbamoyl)-5- (trifluoromethyl)-1Hpyrazol-1-yl)isoquinolin1-yl)azetidine-1carboxylate STs^n'* n. An ν 'Ύ. У 7 ^N Vn ^h 384 1-(1-(Azetidine-2- yl)isoquinolin-5-yl)—N—(5chloro-b-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide An ci AA k'ChЪn vy 385 N- (5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1- (hydroxymethyl)isoquinolin-4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide

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Hu α F O zakh 386 4-(4-( (5-Chloro-b-(2H- 1,2,3-triazole-2- yl)pyridine-3- yl)carbamoyl)-5- (trifluoromethyl)-1Hpyrazol-1-yl)quinoline-2carboxamide f Avy,· U ^N X Ll N Ν* ¹ ? V.J. 387 4- (4-( (5-Chloro-b-(2H- 1,2,3-triazole-2- yl)pyridine-3- yl)carbamoyl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)isoquinoline1-carboxamide _Z= H 43 Λ J ^0< Ym A 0 388 5- (4-( (5-Chloro-b-(2H- 1,2,3-triazole-2- yl)pyridine-3- yl)carbamoyl)-5- (trifluoromethyl)-1Hpyrazol-1-yl)quinoline-2carboxamide /A g X J / ^F 4/ 'Χχ /° Ch-N NH ₂ 389 5- (4-( (5-Chloro-6-(2H- 1,2,3-triazole-2- yl)pyridine-3- yl)carbamoyl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)isoquinoline1-carboxamide XN ci BEHIND A.A. 390 4-(4-((5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)carbamoyl)-5- (trifluoromethyl)-1H-pyrazol1-yl)-M-methylisoquinoline-1carboxamide

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14 X o=/ zr ΰ-^j z-z 391 4-(4-( (5-Chloro-6-(2H- 1,2,3-triazole-2- yl)pyridine-3- yl)carbamoyl)-5- (trifluoromethyl)-1Hpyrazol-1-yl)thieno[2,3c]pyridine-7-carboxamide Z*N Cl V ^N Y< F 392 4- (4-( (5-Chloro-6-(2H- 1,2,3-triazole-2- yl)pyridine-3- yl)carbamoyl)-5- (trifluoromethyl)-1Hpyrazol-1-yl)-Nmethylthieno[2,3-c]pyridine7-carboxamide %]U Si' ^W\h ₂ 393 4-(4-((5-Chloro-2-methyl-6(2H-1,2,3-triazol-2- yl)pyridine-3- yl)carbamoyl)-5- (trifluoromethyl)-1Hpyrazol-1-yl)thieno[2,3c]pyridine-7-carboxamide zz z ^x 7^4 1 h h 394 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1- (difluoromethyl)isoquinolin4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide /^γ ci “Ά _ν α-. ^h X ⁿ S^ w /— ^F 395 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2- (difluoromethyl)quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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/A Cl VU. in oJaZ ^H xoo Ν У—/ R / \ Yj 396 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1- (4- (difluoromethyl)quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide /k ^C1 Άα L a. a Ν /—\ ^F W* 397 N- (5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(8- (difluoromethyl)quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide SaA' ^Η U ^N vjM V—Ϊ F 44 398 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(7- (difluoromethyl)thieno[2,3c]pyridin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide Ay Cl k,jrA ^J « 399 N- (5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2- (difluoromethyl)thieno[2,3- c]pyridin-4-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide N XL ^F ^'53 Fk J / ~ ^F Za ^f Ш 400 N- (5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1- (difluoromethyl)isoquinolin5-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide

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pf Cl V ^N O\ F _F ft 7 9 ^F ^£ Vf JT^F / ^{F H} [ , ^N ~4 ,N w 401 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(2- (difluoromethyl)quinolin-4yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide An ci VU f O gL ⁿ C* y L\ W 402 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-(1,1difluoroethyl)isoquinolin-4yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide Ώ y 1 hour OO 403 1-(1-(Azetidine-3- yl)isoquinolin-4-yl)-N-(5chloro-b-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide O ? O I 'Ά ⁿ N /~\ °— O 404 N- (5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1- (methoxymethyl)isoquinolin4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide ABOUT JL ^ co y ZK Oh~ 405 4- (4-( (5-Chloro-b-(2H- 1,2,3-triazol-2yl)pyridin-3yl)carbamoyl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)quinoline 1- oxide

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w 406 4-(4-( (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3- yl)carbamoyl)-5- (trifluoromethyl)-1H-pyrazole- 1-yl)isoquinoline 2-oxide o Μ U ζ Q-D <15 O' 407 5- (4-( (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)carbamoyl)-5- (trifluoromethyl)-1H-pyrazol1-yl)isoquinoline 2-oxide cu , Wo aa W ^{+ Or} 408 5-(4-((5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)carbamoyl)-5- (trifluoromethyl)-1H-pyrazol1-yl)quinoline 1-oxide /U _C1 Ν' ² // F UU j ⁿ XM 409 4- (4- ( (5-Chloro-6-(2H- 1,2,3-triazole-2- yl)pyridine-3- yl)carbamoyl)-5- (trifluoromethyl)-1Hpyrazol-1-yl)thieno[2,3c]pyridine 6-oxide W^L vy? o y ^σ -^— zz ^d 410 4-(4-( (5-Chloro-2-methyl-6- (2H-1,2,3-triazole-2- yl)pyridine-3- yl)carbamoyl)-5- (trifluoromethyl)-1H-pyrazol1-yl)thieno[2,3-c]pyridine 6-oxide

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/^ν ci 411 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1-cyanoisoquinolin5-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide /4 Cl FN ChSh ^H Xg w 412 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)— 1 -(2-cyanoquinolin-4yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide F ci _ 1__ _r _ ζΝ 413 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)—1—(2-cyanoquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide Λ zz O^ ^g MZ 4° 1 4 CO Ϊ 414 N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)—1—(1-cyanoisoquinolin4-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide Cl 415 N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(7-cyanothieno[2,3c]pyridin-4-yl)-5(trifluoromethyl)- 1Hpyrazole-4-carboxamide 11/ ^Ο Λ zr 0— zz 416 N-(5-Chloro-2-methyl-6-(2H1,2,3-triazol-2- yl)pyridin-3-yl)—1—(7cyanothieno[2,3-c]pyridin4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide

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427 (R)-N-(5-Chloro-6-(2H1,2,3-triazol-2yl)pyridin-3-yl)-1-(1-(3hydroxypyrrolidin-1yl)isoquinolin-4-yl)-5 (trifluoromethyl)-1Hpyrazol-4-carboxamide N-(5-Cyano-6methoxypyridin-3-yl)-1(1-oxo-1,2428 dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

N-(5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(1429 (methylthio)isoquinolin-4yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide

N- (5-Chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(7-(3430 hydroxyazetidin-1yl)thieno[2,3-c]pyridin-4yl) -5-(trifluoromethyl)-1Hpyrazol-4-carboxamide (S)-N-(5-Chloro-6-(2H1,2,3-triazol-2yl)pyridin-3-yl)-1- (7- (3431 Hydroxypyrrolidin-1yl)thieno[2,3-c]pyridin-4yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

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432 (R)-N-(5-Chloro-b-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1-(7-(3hydroxypyrrolidin-1- yl)thieno[2,3-c]pyridin-4yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide 433 N-(5-Chloro-2-methyl-b-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1-(7-(3hydroxyazetidin-1- yl)thieno[2,3-c]pyridin-4yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide hi® 434 N-(5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(7-methylthieno[2,3c]pyridin-4-yl)-5(trifluoromethyl)- 1Hpyrazole-4-carboxamide Z^N Cl Xg' 435 N- (5-Chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3yl)-1-(7cyclopropylthieno[2,3c]pyridin-4-yl)-5(trifluoromethyl)-1Hpyrazol- 4-carboxamide ZX ci N-®-X. f Ul> <g.o 436 (*R)-N-(5-Chloro-b-(2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1-(1(tetrahydrofuran-2- yl)isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide

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M, hml EAT MU 437 (*S) -N- (5-Chloro-6- (2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1-(1(tetrahydrofuran-2- yl)isoquinolin-4-yl)-5(trifluoromethyl)-1Hpyrazole-4-carboxamide ⁿ O ° 438 (*R) -N- (5-Chloro-6- (2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1-(1-(4- oxotetrahydrofuran-2- yl)isoquinolin-4-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide Od, Lda o 439 (*S) -N- (5-Chloro-6- (2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1-(1-(4- oxotetrahydrofuran-2- yl)isoquinolin-4-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide ©Ή ...../ Oi AND JK 440 (*R) -N- (5-Chloro-6- (2H- 1,2,3-triazole-2- yl)pyridin-3-yl)—1—(2(tetrahydrofuran-2- yl)quinolin-5-yl)-5- (trifluoromethyl)-1Hpyrazole-4-carboxamide °o ggt^ /0 ou d ζ-ζ 441 (*S) -N- (5-Chloro-6- (2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1-(2- (tetrahydrofuran-2- yl)quinolin-5-yl)-5- (trifluoromethyl)-1H- pyrazole-4-carboxamide

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Τι Ζ,—Z o 1 hour with 442 (*R) -N- (5-Chloro-6- (2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1-(1-(1hydroxyethyl)isoquinolin4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide _C1 Ό yy /=N / ⁿ C * Λ Γό he VO 443 (*S) -N- (5-Chloro-6- (2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1-(1-(1hydroxyethyl)isoquinolin4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide O G Sm GM Ό X ² 444 CR) -N- (5-Chloro-6- (2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1- (1-(1hydroxyethyl)isoquinoline- 5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide GO A M _h /\\ -Jo ^-4 ί / V 3—« ⁴ s Ms 445 (*S) -N- (5-Chloro-6- (2H- 1,2,3-triazole-2- yl)pyridin-3-yl)-1-(1-(1hydroxyethyl)isoquinolin5-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide O '--ΝΗ 446 N-(5-Cyano-2-methyl-4-(2H1,2,3-triazole-2- yl)phenyl)—1—(1-OXO-1,2dihydroisoquinolin-5-yl)5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

- 97 045333 mules (I):

In a further embodiment, the present invention relates to the compound forRs

Formula (I) selected from the group consisting of

N-(2-cyanopyridin-4-yl)-1-(naphthalen-1-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide;

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N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(naphthalen-1-yl)-5-(trifluoromethyl)-2H-pyrazol- 4-carboxamide;

1-(naphthalen-1-yl)-5-(trifluoromethyl)-N-(2(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-carboxamide;

1-(naphthalen-1-yl)-5-(trifluoromethyl)-N-(5(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-carboxamide;

N-(5-cyanopyridin-3-yl)-1-(naphthalen-1-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide;

1-(quinolin-5-yl)-5-(trifluoromethyl)-R-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-6-methoxypyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide;

R-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

R-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3methylisoquinolin-1-yl)-5-(trifluoromethyl)-1H-pyrazole -4carboxamide;

R-(3-chloro-4-methoxyphenyl)-1-(isoquinolin-8-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide;

N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(isoquinolin-8yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

R-(3-chloro-4-(1H-pyrazol-1-yl)phenyl)-1-(isoquinolin-8-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide;

R-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-1-(isoquinolin-8yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

R-(4-(2-aminopyrimidin-4-yl)-3-chlorophenyl)-1-(isoquinolin-8yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

R-(5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

R-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-isobutyl-1-(quinolin-5-yl)-1H-pyrazol-4-carboxamide ;

R-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-ethyl-1(quinolin-5-yl)-1H-pyrazol-4- carboxamide;

R-(3-chloro-4-(1H-1,2,3-triazol-1-yl)phenyl)-1-(isoquinolin-8yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

R-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-99 045333 (isoquinolin-8-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

N-(5-chloro-b-(1,1-dioxidoizothiazolidin-2-yl)pyridin-3-yl)1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-b-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1(isoquinolin-8-yl)-5-(trifluoromethyl)-2H-pyrazol-4- carboxamide;

N-(5-chloro-b-(oxazol-2-yl)pyridin-3-yl)-1-(isoquinolin-8yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-b-methoxypyridin-3-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)-IH-pyrazole-4-carboxamide;

N-(5-cyano-b-methoxypyridin-3-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-isopropyl-1-(quinolin-5-yl)-1H-pyrazol-4-carboxamide ;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(bmethylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(3-chloro-4-(3-methyl-2H-1,2,4-triazol-1-yl)phenyl)-1(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-chloro-b-(3-methyl-IH-l,2,4-triazol-1-yl)pyridin-3-yl)-1 (isoquinolin-8-yl)-5-(trifluoromethyl)- 2H-pyrazole-4-carboxamide;

N-(3-chloro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4methylisoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole -4carboxamide;

1-(benzofuran-4-yl)-N-(5-chloro-b-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4 -carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(1methoxyethyl)-1-(quinolin-5-yl)-1H-pyrazole -4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(bmethylisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4- 100 045333 carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(isoquinolin-4yl)-5-(trifluoromethyl)-2H-pyrazol-4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-1(quinolin-5-yl)-1H-pyrazol-4- carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(b-cyano-5-fluoropyridin-3-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-b-(1,1-dioxidoizothiazolidin-2-yl)pyridin-3-yl)1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(3-chloro-4-(1H-1,2,3-triazol-1-yl)phenyl)-1-(isoquinolin-4yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

methyl 3-chloro-5-(3-chloro-5-(1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamido)picolinamido)picolinate;

N-(5-chloro-b-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-2H-pyrazole-4-carboxamide ;

N-(5-chloro-b-(1H-pyrazol-1-yl)pyridin-3-yl)-1-(isoquinolin-4yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-chloro-b-(4-methylpiperazin-1-carbonyl)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

N-(b-cyano-5-(trifluoromethyl)pyridin-3-yl)-1-(isoquinolin-4yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-b-(oxazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(3-chloro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-chloro-b-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxamide;

N-(5-chloro-b-(3-methyl-IH-l,2,4-triazol-1-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

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N-(5-chloro-6-(5-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-1 (isoquinolin-4-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

N-(3-chloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(difluoromethyl)-1-(isoquinolin-1-yl)-1H-pyrazol- 4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(isoquinolin-1-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(4-(2-aminopyrimidin-4-yl)-3-chlorophenyl)-1-(isoquinolin-4yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(3-cyano-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(isoquinolin-4 yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinolin-5-yl)-1H-pyrazol-4-carboxamide;

N-(5-fluoro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(3-cyano-4-(1H-1,2,3-triazol-1-yl)phenyl)-1-(isoquinolin-4 yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-6-(thiazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N- (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-1 (quinolin-4-yl)-1H-pyrazol-4- carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1methylisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6fluoroquinolin-7-yl)-5-(trifluoromethyl)-2H-pyrazole -4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1Nindazol-4-yl)-5-(trifluoromethyl)-7H-pyrazole -4-carboxamide;

N-(5-chloro-6-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxamide;

N-(5-chloro-6-(1H-imidazol-1-yl)pyridin-3-yl)-1-(isoquinolin4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-102 045333 yl)-5-(trifluoromethyl)-1H-pyrazol-4 -carboxamide;

N-(4-aminobutyl)-3-chloro-5-(1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamido)picolinamide;

1-(isoquinolin-4-yl)-N-(2-methyl-b-(trifluoromethyl)pyridin-4yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

methyl 6-chloro-4-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamido)picolinate;

methyl 4-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamido)picolinate;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-1H-pyrazol-4-carboxamide;

N-(2-cyanopyridin-4-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-cyano-b-(1-methyl-2H-pyrazol-3-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-3H-pyrazol-4- carboxamide;

N-(5-chloro-b-cyclopropoxypyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide;

N-(5-cyano-b-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-3H-pyrazole-4-carboxamide ;

N-(5-cyano-b-ethoxypyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-cyanopyridin-3-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(b-(4-aminobutoxy)-5-cyanopyridin-3-yl)-1-(isoquinolin-4yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

N-(5-cyano-b-methoxypyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-cyano-b-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(8-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-b-yl)1-(isoquinolin-4-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

N-(5-cyano-b-cyclopropoxypyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide;

N-(5-cyano-b-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-103 045333 (quinolin-5-yl)-5-(trifluoromethyl)-7H-pyrazole -4-carboxamide;

N- (5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(thieno[3,2-c]pyridin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-b-(oxazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8fluoroquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

1-(cinnolin-4-yl)-N-(5-cyano-b-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4 -carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(furo[3,2-c]pyridin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(8-chloro-4-methyl-3-oxo-3,4-dihydro-2Hbenzo[b][1,4]oxazin-b-yl)-1-(quinolin-5-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-cyano-b-(4-methylpiperazin-1-carbonyl)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

N-(8-chloro-4-methyl-3-oxo-3,4-dihydro-2Hbenzo[b][1,4]oxazin-b-yl)-1-(isoquinolin-4-yl)-5-( trifluoromethyl)1H-pyrazole-4-carboxamide;

N-(5-chloro-b-(1-methyl-1H-imidazol-2-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(furo[2,3-c]pyridin-7-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,6-naphthyridin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

N-(b-(4-(4-aminobutyl)piperazine-1-carbonyl)-5-cyanopyridin3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(phthalazin-1-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(imidazo[1,2-a]pyrazin-8-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

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N-(5-chloro-6-(1H-imidazol-2-yl)pyridin-3-yl)-1-(isoquinolin4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinoxalin-5-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

tert-butyl 2-(5-(4-((5-chloro-6-(2H-1,2,3-triazol-2 yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H- pyrazol-1yl)isoquinolin-1-yl)azetidine-1-carboxylate;

N-(3-(methylsulfonyl)-4-(1H-1,2,3-triazol-1-yl)phenyl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxamide;

1-(1,5-bis(tetrahydrofuran-2-yl)isoquinolin-4-yl)-N-(5-chloro6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

1-(1-(azetidin-2-yl)isoquinolin-5-yl)-N-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(3-(methylsulfonyl)-4-(2H-1,2,3-triazol-2-yl)phenyl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxamide;

N-(2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)-1-(quinolin-5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

1-(2-(azetidin-2-yl)quinolin-5-yl)-N- (5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

1-(benzo[d]thiazol-4-yl)-N-(2,5-dimethyl-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

N-(5-methyl-6-(3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(2,5-diethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(imidazo[1,2-a]pyridin-5-yl)- 5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

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N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2(difluoromethyl)quinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methylbenzo[d]oxazol-4-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methoxyquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide 1-(1-aminoisoquinolin-5-yl)-N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2cyanoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

1-(2-methylimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-N(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-carboxamide;

1-(2-chloroquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2chloroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N- (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2(tetrahydrofuran-2-yl)quinolin-5-yl)-5 -(trifluoromethyl)-1H-pyrazole 4-carboxamide;

5-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline -2carboxamide;

N- (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1Hpyrazolo[3,4-d]pyrimidin-4-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,6naphthyridin-4-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

N-(5-cyano-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

Cr)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(1-hydroxyethyl)isoquinolin-5-yl)- 5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(benzo[d]thiazol-4-yl)-N-(5-cyano-2-methyl-4-(2H-1,2,3triazol-2-yl)phenyl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

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CR}-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2(tetrahydrofuran-2-yl)quinolin-5-yl )-5-(trifluoromethyl)-1H-pyrazole 4-carboxamide;

N-(5-chloro-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1-(quinolin-5yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methyl-1-oxo-1,2-dihydroisoquinolin-5-yl) -5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-chloro-6-(5-cyano-1H-1,2,3-triazol-1-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

2-(2-chloro-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamido)phenyl)-2H-1,2,3-triazole-4-carboxylic acid;

N-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(imidazo[1,2-a]pyridin-8-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

(*S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(1-hydroxyethyl)isoquinolin-5-yl )-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(2-methylpyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

1-(benzo[d][1,2,3]thiadiazol-4-yl)-N-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)- 5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methylthieno[3,2-b]pyridin-7-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(1-(azetidin-3-yl)isoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3 triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(imidazo[1,5-a]pyridin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

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1-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-4 -carboxylic acid;

N-(5-methoxy-6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-oxo1,2-dihydroquinolin-5-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(4-aminobutyl)-3-cyano-5-(1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamido)picolinamide;

2-cyano-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamido)benzoic acid

N-(4-(4-(aminomethyl)-1H-pyrazol-1-yl)-3-methylphenyl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

1-(2-aminoquinolin-4-yl)-N-(5-cyano-b-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1methyl-1H-indazol-4-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

1-(1-aminoisoquinolin-5-yl)-N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H- pyrazole-4-carboxamide;

N-(5-methyl-b-(1-methyl-1H-tetrazol-5-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1methyl-1H-pyrazolo[3,4-b]pyridin-4- yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1ethoxyisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4carboxamide;

1-(1-(azetidin-2-yl)isoquinolin-4-yl)-N-(5-chloro-b-(2H-1,2,3 triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(2-aminoquinolin-5-yl)-N-(5-chloro-b-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

1-(1-acetylisoquinolin-5-yl)-N-(5-chloro-b-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

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N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4(difluoromethyl)quinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(pyrrolidin-2-yl)isoquinolin-4-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-1-(isoquinolin-4yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(imidazo[1,2-b]pyridazin-6-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(2,5-dimethyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H -pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4carboxamide;

1-(2-aminoquinolin-5-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

2-(2-chloro-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamido)phenyl)-2H-1,2,3-triazole-4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(methylthio)isoquinolin-4-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-fluoro-1(quinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methylbenzo[d]thiazol-4-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

1-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-4 -carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-cyano-1(quinolin-5-yl)-1H-pyrazol-4- carboxamide;

1-(7-methylpyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-N(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-carboxamide;

N-(6-(2H—[1,2,3]triazolo[4,5-c]pyridin-2-yl)-5-chloropyridin- 109 045333

3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide;

1-(2-acetylquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methylbenzo[d]thiazol-7-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(6-(5-(aminomethyl)-1H-1,2,3-triazol-1-yl)-5-chloropyridin3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4carboxamide;

1-(2-(azetidin-2-yl)quinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1ethoxyethyl)isoquinolin-4-yl)-5-(trifluoromethyl )-1H-pyrazole-4carboxamide;

methyl 1-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol- 4carboxylate;

1-(imidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-N-(2(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-2-ethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(imidazo[1,2-a]pyridin-5-yl )-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2(difluoromethyl)thieno[2,3-c]pyridin-4- yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(imidazo[1,2-a]pyrimidin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-methoxy-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methoxyquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

1-(benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-2-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)- 5-(trifluoromethyl)-1H-pyrazole-4-110 045333 carboxamide;

N-(2,5-dimethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1oxo-1,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(benzo[d]thiazol-4-yl)-N-(5-chloro-2-methyl-b-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-b-(5-(methoxymethyl)-1H-1,2,3-triazol-1yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(b-(2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-5-chloropyridin3-yl)-1-(quinolin-5-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methyl-[1,2,4]triazolo[1,5-a ]pyridin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

3-(3-cyano-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamido)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid acids;

1-(benzo[d]thiazol-4-yl)-N-(5-cyano-2-methyl-b-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-b-(1-methyl-1Hpyrazol-3-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H -pyrazole-4carboxamide;

N-(b-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-5-chloropyridin3-yl)-1-(quinolin-5-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamide;

methyl 2-(2-chloro-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamido)phenyl)-2H-1,2,3-triazole-4-carboxylate;

N-(5-cyano-b-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)1-(quinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

N-(3-chloro-4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-Zyl)phenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

methyl 3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H- 111 045333 pyrazole-4-carboxamido)picolinate;

N-(b-(1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-5-chloropyridin3-yl)-1-(quinolin-5-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyanopyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1methyl-1H-pyrazolo[3,4-c]pyridin-7- yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-b-(1H-pyrazol 1-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(dimethylamino)isoquinolin-4-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8(difluoromethyl)quinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

(*R)-N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(4-oxotetrahydrofuran-2-yl)isoquinoline -4-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methylfuro[3,2-b]pyridin-7-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(difluoromethyl)isoquinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1methyl-1H-indazol-7-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(bfluorimidazo[1,2-a]pyridin-5-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5fluoroquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1Hpyrazolo[4,3-b]pyridin-7-yl)-5 -(trifluoromethyl)-1H-pyrazole-4- 112 045333 carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4fluoroisoquinolin-1-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide 5-(4-((5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1 -yl)isoquinoline-1carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(methylamino)isoquinolin-4-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

(*S)-N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(1-hydroxyethyl)isoquinolin-4-yl )-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1,1difluoroethyl)isoquinolin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

5-chloro-N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinolin-5-yl)-1H-pyrazol-4- carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-4-(2H-1,2,3triazol-2-yl)phenyl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1methoxyisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4carboxamide;

(*S)-N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(4-oxotetrahydrofuran-2-yl)isoquinoline -4-yl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide;

(*S)-N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(tetrahydrofuran-2-yl)isoquinoline-4 -yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1methyl-1H-pyrazolo[3,4-b]pyridin-3- yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-chloro-2-methyl-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(8-fluorimidazo[1,2-a]pyridin-5 -yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamide;

- 113 045333

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1methyl-1H-indazol-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(5oxopyrrolidin-2-yl)isoquinolin-4-yl)- 5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

methyl 3-(3-cyano-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamido)pyridin-2-yl)-1-methyl-1H-pyrazole-5carboxylate;

N-(5-cyano-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(8fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4 -carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,5naphthyridin-4-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

N-(5-chloro-6-(5-((dimethylamino)methyl)-1H-1,2,3-triazol-1yl)pyridin-3-yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methylbenzo[d]oxazol-7-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(6-(4-(aminomethyl)-2H-1,2,3-triazol-2-yl)-5-chloropyridin3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4carboxamide;

N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(8fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4 -carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(5-cyano-2-methyl-4-(2H-1,2,3triazol-2-yl)phenyl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

1-(benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-2-fluoro-4-(2H1,2,3-triazol-2-yl)phenyl)- 5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

1-([1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-(5-cyano-6-(2H1,2,3-triazol-2-yl)pyridin-3 -yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-((Nmethylformamido)methyl)isoquinolin-4-yl)-5 -(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-114 045333 (imidazo[1,2-a]pyrazin-5-yl) -5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,7naphthyridin-4-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

N-(5-chloro-2-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-(1oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

1-(2-aminobenzo[d]thiazol-7-yl)-N-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(isothiazolo[5,4-b]pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-6-(1H-pyrrol-1-yl)pyridin-3-yl)-1-(quinolin-5yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4carboxamide;

1-(2-aminobenzo[d]thiazol-7-yl)-N-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(6-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)pyridin-3-yl) 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H- pyrazole-4-carboxamide;

1-(benzo[d]isoxazol-3-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

1-(1-OXO-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoro1-(methylamino)isoquinolin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

5-bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinolin-5-yl)-1H-pyrazol-4- carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2cyanoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

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N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1chloroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide 1-(pyrazole[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-N-(2(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methylimidazo[1,2-a]pyridin-5-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-carboxamide;

1-(1-(1,4-dioxan-2-yl)isoquinolin-4-yl)-N-(5-chloro-b-(2H1,2,3-triazol-2-yl)pyridin-3-yl )-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1H—indazol-7-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

4-(4-((5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline -2carboxamide;

N-(5-chloro-b-(5-(hydroxymethyl)-1H-1,2,3-triazol-1yl)pyridin-3-yl)-1-(1-OXO-1,2-dihydroisoquinoline-5- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1—(4—oxotetrahydrofuran-2-yl)isoquinolin-4-yl )-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(b-(4-amino-2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1(benzo[d]thiazol-4-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-(5-cyanob-(2H-1,2,3-triazol-2-yl )pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

(*R)-N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(tetrahydrofuran-2-yl)isoquinoline-4 -yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-bromo-b-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-chloro-b-(oxazol-2-yl)pyridin-3-yl)-1-(8-fluoroquinolin-5yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

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N-(5-chloro-b-methoxypyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(difluoromethyl)isoquinolin-4-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(methoxymethyl)isoquinolin-4-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(1hydroxyethyl)quinolin-4-yl)-5-(trifluoromethyl )-1H-pyrazole-4carboxamide;

N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 (7-methylpyrazolo[1,5-a]pyridin-4 -yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-2-fluoro-4-(2H-1,2,3triazol-2-yl)phenyl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

1-(benzo[d]isothiazol-3-yl)-N-(5-chloro-b-(2H-1,2, 3-triazol-2 yl)pyridin-3-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(isoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(furo[2,3-d]pyrimidin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(imidazo[1,2-a]pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-2-methyl-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 (imidazo[1,2-a]pyridin-5-yl )-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

4-(4-((5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)thieno [2,3—

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c]pyridine 6-oxide;

1-(benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-6-(1-methyl-1Hpyrazol-3-yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(thiazolo[5,4-d]pyrimidin-7-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methylimidazo[1,2-a]pyridin-3-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-6-methoxypyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-2-methyl-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl) 1-(1-OXO-1,2-dihydroisoquinolin-5-yl)- 5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinazolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(8fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide

N-(5-chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1oxo-1,2-dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamide;

(*R)-N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(1-hydroxyethyl)isoquinolin-4-yl )-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1cyanoisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4carboxamide;

N-(5-chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo1,2-dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1hydroxyethyl)isoquinolin-4-yl)-5-(trifluoromethyl )-1H-pyrazole-4carboxamide;

N-(5-cyano-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-118 045333 oxo-1,2-dihydroisoquinolin-5-yl) -5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-6-(4-methyl-1H-1,2,3-triazol-1-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

N-(5-methyl-6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7(difluoromethyl)thieno[2,3-c]pyridin-4- yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(tetrahydrofuran-2-yl)isoquinolin-4-yl)-5 -(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-chloro-6-(4-(methoxymethyl)-2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(4-(4-(aminomethyl)-1H-pyrazol-1-yl)-3-chlorophenyl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

1-(benzo[d]thiazol-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1hydroxyisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4carboxamide;

N-(5-chloro-6-(2H-tetrazol-5-yl)pyridin-3-yl)-1-(quinolin-5yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2(difluoromethyl)quinolin-4-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8fluoro-1-(methylamino)isoquinolin-4-yl)-5- (trifluoromethyl)-1H-pyrazole 4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-4-yl)pyridin-3-yl)-1-119 045333 (quinolin-5-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

N-(5-chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(8fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1methyl-2-oxo-1,2-dihydroquinolin-4-yl) -5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

(*R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(3-hydroxypyrrolidin-1-yl)isoquinoline -4-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1(hydroxymethyl)isoquinolin-4-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3methylthieno[3,2-b]pyridin-7-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(benzo[d]oxazol-4-yl)-N-(5-cyano-b-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(3-chloro-4-(4-(hydroxymethyl)-1H-pyrazol-1-yl)phenyl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-cyano-2-methyl-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)1-(1-oxo-1,2-dihydroisoquinolin-5-yl )-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

1-(8-aminoquinolin-5-yl)-N-(5-cyano-b-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

4-(4-((5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline 1-oxide;

N-(5-cyano-b-(4-(hydroxymethyl)-2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

methyl 2-cyano-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamido)benzoate;

N-(b-(5-amino-1H-1,2,3-triazol-1-yl)-5-chloropyridin-3-yl)-1(1-OXO-1,2-dihydroisoquinolin-5-yl) -5-(trifluoromethyl)-1H-pyrazole4-carboxamide;

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N-(5-chloro-6-(4-cyano-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(imidazo[1,2-a]pyridin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-cyano-2-methyl-6-(2H1,2,3-triazol-2-yl)pyridin-3 -yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8fluorimidazo[1,2-a]pyridin-5-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(6-(5-amino-1-methyl-1H-pyrazol-3-yl)-5-cyanopyridin-Zyl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide

N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

N-(5-chloro-6-(4-(hydroxymethyl)-1H-pyrazol-1-yl)pyridin-3yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3methylimidazo[1,2-a]pyridin-5-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(6-(5-amino-1-methyl-1H-pyrazol-3-yl)-5-chloropyridin-3-yl) 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8fluorimidazo[1,2-a]pyridin-5-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(thieno[3,2-d]pyrimidin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoro1-hydroxyisoquinolin-4-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

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1-(benzo[d]thiazol-4-yl)-N-(5-cyano-b-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(pyrrolo[1,2-a]pyrazin-1-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(b-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl) 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H- pyrazole-4-carboxamide;

1-(benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-b-(2H-1,2,3triazol-2-yl)pyridin-3-yl)- 5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

4-(4-((5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinoline -1 carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(imidazo[1,2-a]pyridin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(pyrrolo[1,2-a]pyrazin-1-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-b-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,7-naphthyridin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamido)pyridin-2-yl)-2H-1,2,3-triazol-4 -carboxamide;

N-(5-chloro-2-methyl-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 (pyrazole[1,5-a]pyridin-4-yl )-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(5-cyano-b-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(thieno[2,3-e]pyridin-7-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-122 045333 (thieno[2,3-d]pyrimidin-4-yl) -5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-b-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(pyrazole[1,5-a]pyrazin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-(1hydroxyethyl)thieno[2,3-e]pyridin-4 -yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(pyrrolo[2,Ι-f][1,2,4]triazin- 4-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamide;

N-(5-chloro-b-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(1oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

methyl 2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamido)pyridin-2-yl)-2H-1,2,3-triazol- 4carboxylate;

N-(5-chloro-b-(4-((dimethylamino)methyl)-2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(quinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-bromo-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

1-(benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-2-methyl-b-(2H1,2,3-triazol-2-yl)pyridin-3 -yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1cyanoisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4carboxamide;

N-(5-chloro-b-(4-(hydroxymethyl)-2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-chloro-b-(4-(hydroxymethyl)-1H-pyrazol-1-yl)pyridin-3-123 045333 yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(pyrazole[1,5-a]pyrazin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl )-1H-pyrazole-4carboxamide;

N-(6-(4-amino-2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1(1-OXO-1,2-dihydroisoquinolin-5-yl) -5-(trifluoromethyl)-1H-pyrazole 4-carboxamide;

N-(6-(4-amino-2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

1-(1-amino-8-fluoroisoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(3-cyano-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(quinolin-5yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-oxo1,2-dihydroquinolin-4-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(4-aminonaphthalen-1-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4fluoro-2-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-D-quinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-D-quinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H -pyrazole-4carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-124 045333 (thieno[3,2-b]pyridin-7-yl) -5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-bromo-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(1-OXO-1,2-dihydroisoquinolin-5-yl )-5-(trifluoromethyl)-1H-pyrazole 4-carboxamide;

N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(1-OXO-1,2-dihydroisoquinolin-5-yl )-5-(trifluoromethyl)-1H-pyrazole 4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(pyrazolo[1,5-a]pyridin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-b-(oxazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide ;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(thieno[2,3-b]pyridin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(thieno[2,3-c]pyridin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-b-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(quinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

N-(5-chloro-2-methyl-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl )-1H-pyrazole-4carboxamide;

1-(benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-cyano-b-(2H-1,2,3triazol-2-yl)pyridin-3-yl)- 5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-cyano-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1hydroxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4- 125 045333 carboxamide;

1-(benzo[d]thiazol-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

N-(5-chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide;

1-(benzo[d]thiazol-7-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1oxo-1,2-dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(1-amino-8-fluoroisoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamido)pyridin-2-yl)-2H-1,2,3-triazol-4 -carboxylic acid;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(furo[3,2-b]pyridin-7-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide;

4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)thieno [2,3c]pyridine-7-carboxamide;

1-(7-(3-hydroxyazetidin-1-yl)thieno[2,3-c]pyridin-4-yl)-5(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H -pyrazole-4carboxamide;

N-(5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H -pyrazole-4carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(5-bromo-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4carboxamide;

N-(5-chloro-2-methyl-6-(4-methyl-1H-1,2,3-triazol-1-yl)pyridin3-yl)-1-(1-OKCO-1,2-dihydroisoquinoline- 5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(2-morpholinopyridin-4-yl)-1-(1-oxo-1,2- 126 045333 dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(2-methoxypyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

1-(1-aminoisoquinolin-4-yl)-5-(trifluoromethyl)-N-(5(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-carboxamide;

1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-(4-methyl-2H1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-ethynyl-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) 1-(1-OXO-1,2-dihydroisoquinolin-5-yl )-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-chloro-2-methyl-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin3-yl)-1-(1-oxo-1,2-dihydroisoquinoline- 5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2methyl-1-oxo-1,2-dihydroisoquinolin-4-yl) -5-(trifluoromethyl)-1Hpyrazole-4-carboxamide;

(*R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7(3-hydroxypyrrolidin-1-yl)thieno [2,3-c]pyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide;

N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(7-chlorothieno[2,3-c]pyridin-4 -yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide;

(*S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7(3-hydroxypyrrolidin-1-yl)thieno [2,3-c]pyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide;

N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(7-cyanothieno[2,3-c]pyridin-4 -yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide;

N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(7-(3-hydroxyazetidin-1-yl)thieno[ 2,3-c]pyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide;

4-(4-((5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1 -yl)thieno[2,3c]pyridine-7-carboxamide;

- 127 045333

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7cyclopropylthieno[2,3-c]pyridin-4-yl)-5 -(trifluoromethyl)-1Hpyrazole-4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7methylthieno[2,3-c]pyridin-4-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7cyanothieno[2,3-c]pyridin-4-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

4-(4-((5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)- Nmethylthieno[2,3-c]pyridine-7-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-(3hydroxyazetidin-1-yl)thieno[2,3-c ]pyridin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7chlorothieno[2,3-c]pyridin-4-yl)-5 -(trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(1-aminoisoquinolin-4-yl)-5-(trifluoromethyl)-N-(2(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-carboxamide;

N-(b-methyl-5-(trifluoromethyl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-(pyridin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide;

N-(2-cyclopropylpyridin-4-yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

3-chloro-N,N-dimethyl-5-(1-(1-oxo-1,2-dihydroisoquinolin-5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)picolinamide;

1-(1-aminoisoquinolin-4-yl)-N-(2-cyanopyridin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide;

3-chloro-N-methyl-5-(1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamido)picolinamide;

1-(1-aminoisoquinolin-4-yl)-N-(b-methyl-5(trifluoromethyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-128 045333 carboxamide;

N-(5-chloropyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

1-(thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-N-(2(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-carboxamide;

1-(8-fluoromidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-N-(2(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-carboxamide;

N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

methyl 3-chloro-5-(1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamido)picolinate;

1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-N-(2(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-carboxamide;

N-(2-cyanopyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

N-(2-(2-methoxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1-(1oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide ;

N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(thieno[2,3-c]pyridin-4-yl )-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(2-OXO-1,2-dihydroquinolin-4-yl )-5-(trifluoromethyl)-1H-pyrazole-4carboxamide;

N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1(1-OXO-1,2-dihydroisoquinolin-5-yl )-5-(trifluoromethyl)-1H-pyrazole4-carboxamide;

(*S)-N-(5-chloro-b-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2(tetrahydrofuran-2-yl)quinolin-5 -yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamide;

or a pharmaceutically acceptable salt form thereof.

For medical use, the salts of the compounds of formula (I) are non-toxic pharmaceutically acceptable salts. However, other salts can be used to prepare the compounds of formula (I) or pharmaceutically acceptable salt forms thereof.

Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts, which, for example, can be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid, such as, for example, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid , acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, when the compounds of formula (I) bear an acidic functionality, suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; as well as salts formed with suitable organic ligands, such as quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate , gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine mmonia salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide and valerate.

Representative acids and bases that can be used to prepare pharmaceutically acceptable salts include acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid , 4-acetamidobenzoic acid

- 129 045333 slot, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid , ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α- oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (-)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid , (±)-DLmandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-Ltartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; as well as bases, including ammonia, L-arginine, benetamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamine)ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole , L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)morpholine, piperazine, potassium hydroxide, 1-(2hydroxyethyl)pyrrolidine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

The compounds of formula (I) may be prodrugs. In general, such prodrugs will be functional derivatives of compounds that are easily converted into the desired compound in vivo. Thus, in embodiments of the present invention describing methods of treatment or prevention, the term administration covers the treatment or prevention of various described diseases, conditions, syndromes and disorders either using a specifically described compound or using a compound that has not been specifically described but which converted to the established compound in vivo after administration to the patient. Standard techniques for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

When compounds in accordance with embodiments of this invention have at least one chiral center, they may suitably exist as enantiomers. If compounds have two or more chiral centers, they may additionally exist as diastereomers. It should be understood that all such isomers and mixtures thereof are included within the scope of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also included within the scope of the present invention. Those skilled in the art will understand that the term compound as used herein includes solvated compounds of formula (I).

In cases where methods for preparing compounds in accordance with certain embodiments of the present invention result in the formation of a mixture of stereoisomers, these isomers can be separated by standard methods, such as preparative chromatography. The compounds can be obtained in racemic form or the individual enantiomers can be obtained by enantiospecific synthesis or by resolution. The compounds can, for example, be separated into their respective enantiomers by standard methods, such as the formation of diastereomeric pairs by salt formation with an optically active acid such as, for example, (-)-di-p-toluoyl-Dtartaric acid and/or (+)- di-p-toluoyl-L-tartaric acid, followed by fractional crystallization and reduction of the free base. Compounds can also be separated by formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, compounds can be separated using a chiral HPLC column.

One embodiment of the present invention relates to a composition, including a pharmaceutical composition, comprising, and/or consisting essentially of, a (+)-enantiomer of a compound of formula (I), wherein said composition is substantially free of the (-)-isomer of said compound . As used herein, substantially free means the presence of less than about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2%, and even more preferably less than about 1% of the (-)-isomer contained in calculated as:

_{z h} (mass of (+) enantiomer) ___ % (t) enantiomer =-------------------------------- -----------x 100 (mass(1)-enantiomer) । (mass(-)-enantiomer)

Another embodiment of the present invention is a composition, including a pharmaceutical composition, which contains, consists of, and is substantially composed of a (-)-enantiomer of a compound of formula (I), wherein said composition is substantially free of said (+)-isomer. 045333 connection. As used herein, substantially free means less than about 25%, preferably less than about 10%, more preferably less than about

5%, even more preferably less than about 2% and even more preferably less than about 1% of the (+) isomer, the content of which is calculated as:

(mass of (-) enantiomer) % (-) enantiomer = (mass of (+) enantiomer) + (mass of (-) enantiomer) xO0

It is intended that within the scope of the present invention any one or more element(s), especially those referred to in connection with a compound of formula I, will include all isotopes and mixtures of isotopes of said element(s) occurring naturally either synthesized, in naturally occurring form or in isotopically enriched form. For example, reference to hydrogen also covers 1H, ^2H (D) and ^3H (T). Likewise, references to carbon and oxygen cover, within their scope, ¹² C, ¹³ C, and ¹⁴ C, and ¹⁶ O, and ¹⁸ O, respectively. Isotopes can be radioactive or non-radioactive. The radiolabeled compounds of formula (I) may contain one or more radioactive isotope(s) selected from the group consisting of ³ H, ¹¹ C, ¹⁸ F, ¹²² I, ¹²³ I, ¹²⁵ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. The radioactive isotope is preferably selected from the group consisting of ² H, ³ H, 11 C and ¹⁸ F.

During the use of any of the methods for preparing the compounds of various embodiments of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules in question. For these purposes, standard protecting groups can be used, for example those described in Protective Groups in Organic Chemistry, Second Edition, J.F.W. McOmie, Plenum Press, 1973; T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. Protecting groups can subsequently be removed at a convenient stage using methods known in the art.

Although the compounds of the embodiments of the present invention (including their pharmaceutically acceptable salts and pharmaceutically acceptable hydrates) can be administered separately, they will essentially be administered as a supplement with a pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent selected based on the intended route of administration and standard pharmaceutical or veterinary practice. Thus, specific embodiments of the present invention relate to pharmaceutical and veterinary compositions containing compounds of formula (I) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent.

As an example, in the pharmaceutical compositions of embodiments of the present invention, the compounds of formula (I) may be mixed with any suitable binder(s), lubricant(s), suspending agent(s). (s), coating agent(s), solubilizing agent(s) and combinations thereof.

Solid oral dosage forms, such as tablets or capsules, containing the compounds of the present invention can be administered in at least one dosage form at a time depending on the situation. The compounds can also be administered in sustained release formulations.

Additional oral forms in which compounds of the invention may be administered include elixirs, solutions, syrups and suspensions; each of which optionally contains flavorings and colors.

Alternatively, the compounds of formula (I) may be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or powder. For example, they can be included in a cream containing or consisting and/or essentially consisting of an aqueous emulsion, polyethylene glycols or liquid paraffin. If desired, at a concentration of from about 1 wt.% to about 10 wt.% cream, they can also be included in an ointment composition containing a wax or semi-solid paraffin as a base along with any stabilizers and preservatives, consisting of and/or essentially consisting of them. An alternative route of administration includes transdermal administration using a dermal or transdermal patch.

The pharmaceutical compositions of the present invention (as well as the compounds of the present invention individually) can also be administered parenterally by injection, for example, by intracavernosal, intravenous, intramuscular, subcutaneous, intradermal or intrathecal administration. In this case, the compositions will also include at least one suitable carrier, a suitable excipient and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of the present invention are best used in the form of a sterile aqueous solution, which may contain other substances, such as salts and monosaccharides, in sufficient quantities to obtain a solution isotonic with blood.

For buccal or sublingual administration, the pharmaceutical compositions of the present invention can be administered in the form of tablets or lozenges, which can be prepared traditionally.

- 131 045333 way.

As a further example, pharmaceutical compositions containing as an active ingredient at least one of the compounds of formula (I) can be prepared by admixing the compound(s) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent and/or a pharmaceutically acceptable excipient in accordance with conventional pharmaceutical mixing methods. The carrier, excipient and diluent can take a wide variety of forms depending on the desired route of administration (eg, oral, parenteral, etc.). Thus, for liquid oral preparations such as suspensions, syrups, elixirs and solutions, suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations such as powders, capsules and tablets, acceptable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like. Solid oral preparations may also optionally be coated with substances such as sugar or an enteric coating so as to modulate the primary site of absorption and disintegration. For parenteral administration, the carrier, excipient and diluent typically include sterile water, and other ingredients may be added to improve solubility and preserve the composition. Suspensions or solutions for injections can also be prepared using aqueous vehicles together with appropriate additives such as solubilizers and preservatives.

A therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof includes a dose range from about 0.1 mg to about 3000 mg or any specified amount or range within that range, particularly from about 1 mg to about 1000 mg or any specified amount or a range within a specified range, or more specifically from about 10 mg to about 500 mg or any specified amount or range within a specified range of the active ingredient at a dosage regimen of about 1 to about 4 times per day for an average person (70 kg); although it will be apparent to one skilled in the art that the therapeutically effective amount of a compound of formula (I) varies depending on the diseases, syndromes, conditions and disorders being treated.

For oral administration, the pharmaceutical composition is preferably provided in the form of tablets containing about 1.0, about 10, about 50, about 100, about 150, about 200, about 250 and about 500 milligrams of a compound of formula (I).

An embodiment of the present invention relates to a pharmaceutical composition for oral administration containing a compound of formula (I) in an amount of from about 25 mg to about 500 mg.

The compounds of formula (I) may advantageously be administered in a single daily dosage, or the total daily dosage may be administered in divided dosages twice, three times, or four times (4x) per day.

Optimal dosages for administration of a compound of formula (I) can be readily determined and will vary depending on the particular compound used, the route of administration, the content of the active substance in the preparation and the progression of the disease, syndrome, condition or disorder. In addition, the need to adjust the dose to achieve the appropriate therapeutic level and the desired therapeutic effect will be influenced by factors associated with the particular subject receiving treatment, including sex, age, body weight, diet of the subject and time of administration. Therefore, the doses given above are examples for the average case. Of course, there may be individual cases in which the use of a larger or smaller range of doses is required, and such cases are within the scope of the present invention.

The compounds of formula (I) can be administered in the form of any of the compositions described above and in accordance with any of the dosage regimens described above, or using any compositions and dosage regimens conventional in the art, in any case where the administration of a compound of formula is required to a subject in need thereof (I).

In an embodiment, cancers that may benefit from treatment with the MALT1 inhibitors of the present invention include, but are not limited to, lymphomas, leukemias, carcinomas, and sarcomas, e.g., non-Hodgkin's lymphoma, diffuse strong B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) ), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain tumors (gliomas) ), glioblastoma, breast cancer, colorectal cancer/ colon cancer, prostate cancer, lung cancer, including non-small cell cancer, stomach cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyelosarcoma, medulloblastoma, neuroblastoma, cancer

- 132 045333 cervical, kidney cancer, urothelial cancer, vaginal cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer, and GIST (gastrointestinal stromal tumor).

In another embodiment, the MALT1 inhibitors of the present invention can be used to treat immunological diseases, including, without limitation, autoimmune and inflammatory diseases, such as arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or graft rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis, including atopic, dermatomyositis, psoriasis, Behçet's disease, uveitis, myasthenia gravis, Graves' disease, thyroiditis Hashimoto's, Sjögren's disease, blistering diseases, antibody-mediated vasculitic syndromes, immune complex vasculitis, allergic diseases, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including edema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis and polymyositis.

In another embodiment of the present invention, the compounds of the present invention can be used in combination with one or more other therapeutic agents, more particularly with other anti-cancer agents, for example chemotherapeutic, anti-proliferative or immunomodulatory agents, or with excipients for cancer therapy, for example immunosuppressive or anti-inflammatory agents .

Possible combinations of compounds of the present invention include, but are not limited to, BTK (Bruton's tyrosine kinase) inhibitors such as ibrutinib, SYK inhibitors, PKC inhibitors, PI3K pathway inhibitors, BCL family inhibitors, JAK inhibitors, PIM kinase inhibitors, rituximab, or other antibodies that bind with B-cell antigen, as well as immune cell redirection agents (eg, blinatumomab or chimeric antigen receptor (CAR) T cells) and immunomodulatory agents such as daratumumab, anti-PD1 antibodies, and anti-PD-L1 antibodies .

General synthesis methods

Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and shown in the following schemes and examples. While the diagrams are provided by way of illustration, the present invention should not be construed as being limited to the chemical reactions and conditions described in the schemes and examples. Compounds similar to the target compounds of these examples can be prepared according to similar routes. The described compounds are suitable for use as pharmaceutical agents as described herein. The various starting materials indicated in the diagrams and used in the examples are commercially available or can be prepared by methods well known to those skilled in the art.

In the present description, in particular in the diagrams and examples, the following abbreviations are used:

ACN: acetonitrile;

AcOH: acetic acid;

BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene;

Boc: tert-butyl carbamate;

BuLi: butyllithium;

Cbz: benzylcarbamate;

DCM: dichloromethane;

DMA: dimethylacetamide;

DME: ethylene glycol dimethyl ether;

DMF: dimethylformamide;

DMSO: dimethyl sulfoxide;

EA: ethyl acetate;

Et: ethyl;

Et ₂ O: diethyl ether;

EtOAc: ethyl acetate;

EtOH: ethyl alcohol;

FCC: flash column chromatography;

h: hour(s);

HATU: O-(7-azabenzotriazol-1-yl)-N.N.N'N'-tetramethyluronium hexafluorophosphate;

HCHO: formaldehyde;

HCl: hydrochloric acid;

HPLC: high performance liquid chromatography;

KCN: potassium cyanide;

LCMS: high pressure liquid chromatography with mass spectrometry;

LDA: lithium diisopropylamide;

- 133 045333

LiOH: lithium hydroxide;

Me: methyl;

MeCN: acetonitrile;

MeOH: methyl alcohol;

mg: milligram;

min: minute(s);

NaCN: sodium cyanide;

NaOH: sodium hydroxide;

NaOtBu: sodium tert-butoxide;

NH ₄ Cl: ammonium chloride;

Pd/C: palladium on activated carbon;

Pd2(dba) ₃ : tris(dibinsylideneacetone)dipalladium;

Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium;

Pd(OAc)2: palladium diacetate;

Pd(PPh ₃ ) ₄ : tetrakis(triphenylphosphine)palladium;

PPh ₃ : triphenylphosphine;

p-TsOH: p-toluenesulfonic acid;

CT or CT: room temperature;

TBAF: tetrabutylammonium fluoride;

TMSI: iodotrimethylsilane;

t-Bu: tert-butyl;

TFA: trifluoroacetic acid;

TFAA: trifluoroacetic anhydride;

THF: tetrahydrofuran;

TLC: thin layer chromatography;

Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;

Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

For example, compounds of formula (Ia) wherein R ₇ is hydrogen can be prepared according to the process shown in Scheme 1.

Scheme 1

or NMe _;

Re

Amide bonding, or 1G, base

The carboxylic acid of formula (1A) can be treated with carbonyldiimidazole followed by the addition of a malonic acid monoester of formula (1B) wherein R' is C _1-4 alkyl, and a base such as isopropylmagnesium chloride to produce the keto ester of formula (1C). Condensation with triethylorthoformate in acetic anhydride or with 1,1-dimethoxy-N,Ndimethylmethanamine can give 2-ethoxymethylidene-3-oxoester (or 2((dimethylamino)methylidene-3-oxoester) of formula (1D). Compound of formula (1D ) can be reacted with a hydrazine of formula (1E) to produce a pyrazole of formula (1F).Hydrolysis of the ester group can be accomplished by treatment with aqueous sodium hydroxide in the presence of an alcohol co-solvent to form the corresponding carboxylic acid intermediate, which can then be converted to the compound of formula (I) by amide coupling with a compound of formula (1G). The amide coupling can be carried out, for example, in the presence of phosphorus oxychloride in pyridine to produce the corresponding acid chloride, followed by treatment with a compound of formula (1G) in the presence of a base. In one embodiment, the amide coupling reaction carried out in the presence of a suitable amide coupling reagent, such as HATU, in the presence of a base, for example, but not limited to, diisopropylethylamine.

In an alternative embodiment, the pyrazole ester of formula (1F) can be directly

- 134 045333 converted into a compound of formula (I) by treatment with a compound of formula (1G) and a base such as potassium tert-butoxide.

An alternative method for the synthesis of compounds of formula (Ia), where R ₇ represents hydrogen, is presented in Scheme 2.

Scheme 2

Aniline (1G) can be coupled with lithium acetoacetate of formula (2A) in the presence of a coupling reagent such as BOP, a base such as DIPEA, and a solvent such as NMP to form a compound of formula (2B). The compound of formula (2B) can subsequently be reacted with DMFADMA (2C) in the presence of an acid such as TsOH, or with triethoxymethane (2D) in AcOH to produce a compound of formula (2E) or (2F), respectively. A compound of formula (2E) or (2F) can subsequently be treated with hydrazine of formula (1E) to obtain a compound of formula (I).

Scheme 3 shows the preparation of certain hydrazine intermediates of formula (1E) used to prepare the compounds of formula (I) of the present invention.

Scheme 3

H ₂

1. _NaNO2 , HCI

Pt/C

R _r NH ₂

3B

2. SnCl ₂ or ascorbic acid

R-,-ΝΗΝΗ;,

1E

FOR /-SiliCh

PATH 2

R _r X ZS

X = Br, CI, I n' ^N ^

HCI, H ₂ O phosphine ligand, base ““V'nA-bu o

Rl-B(OH) ₂ ----------------►

WE Si-catalyst

R _r NHNH ₂

1E

PATH

PATH 4 JI D

[O]

Ο' ^Α Ά 3J or ο

3I .z^x

PATH 5 ^z z

ZN

N

R^ N,JDt-Bu deprotection t-BuO'

3F

R _r NHNH ₂

1E

POC1 ₃ /DMF or

DOM g ₃ / DMF

OR

TFAA/TVAG or

TMS1 nh ₂ nh ₂

Pd cat., phosphine ligand, base ζ' ^Α γ ^χ νη ₂ νη ₂ ^Α 'ζ'' ^Ζ 4 *

3G

At least one A is N X = halogen

Z = CH or N

R _r NHNH ₂

1E-2

G ^{; A} H ,NHNH ₂

1E-1

X = Cl, Br, I

Z = C or N

- 135 045333

The heteroarylamine of formula (3B) can be converted to the diazonium salt of the heteroaryl by treatment with sodium nitrite in an acidic environment. This intermediate can be reduced with a reducing reagent such as tin(II) chloride or ascorbic acid to form hydrazine of formula (1E). If heteroarylamines of formula (3B) are not commercially available, they can be prepared by reducing heteronitroarene (3A) using hydrogen and Pt/C or other conventional nitro reduction conditions (path number one).

R ₁ -substituted chlorides, bromides and iodides can undergo palladium-catalyzed Buchwald-Hartwig coupling to benzophenone hydrazine in the presence of a ligand such as xanthos and a base such as sodium t-butoxide to form the hydrazine of formula (3D). Acid hydrolysis allows one to obtain hydrazine of formula (1E) (path number two).

Ri-substituted boronic acids can also act as precursors for compounds of formula (1E) in the synthetic pathway represented as pathway number three. A boronic acid of formula (3E) can undergo Cu ²⁺ (e.g., Cu(OAc) ₂ , TEA in CH ₂ Cl ₂ -catalyzed addition to di-tert-butyl azodicarboxylate to produce an intermediate of formula (3F) that can be deprotected in acidic acid. environment to obtain the compound of formula (1E). Heteroarylhydrazines of formula (1E-1) having a nitrogen atom in the ortho or para position relative to the hydrazine functionality can be prepared by direct substitution of halogen with hydrazine or hydrazine hydrate. Uncommercially available (hetero)halogenarenes of formula (3G) can be prepared from the corresponding (hetero)arenes (3I) using an oxidizing agent such as mCPBA to form the N-oxide (3J) (or (3K)), which can subsequently be converted to (hetero)haloarene 3G by treatment with POCl ₃ and DMF, POG ₃ /DMF, TFUA/TBAF or TMSI (path number four). In an alternative embodiment, the halogenation of the (hetero)arene of formula (3H) can be subjected to palladium-catalyzed cross-coupling with hydrazine to directly produce intermediate (1E-2) (route number five).

Scheme 4 illustrates several available routes for the synthesis of intermediate (1G-1), with G1 being C(R4).

Scheme 4

1G-1

Compound (B-1) can be reacted with a compound of formula R4H in the presence of a base such as C ₂ CO ₃ in a solvent such as DMF to produce a compound of formula (4B). In an alternative embodiment, the compound of formula (4C) can be treated with a cross-linking reagent such as a boron reagent of formula (4D) or a tin reagent of formula R ₄ Sn(Bu) ₃ ; in the presence of a palladium catalyst, including, without limitation, Pd(dppf)Cl ₂ or Pd(PPh ₃ ) ₄ ; in a suitable solvent or solvent system such as DMF, dioxane/water, etc.; to obtain the compound of formula (4B). Another suitable route involves reacting a compound of formula (4C) with a compound of formula R ₄ H in the presence of a coupling reagent of formula CuI with a base such as C ₂ CO ₃ and in a solvent such as DMF to produce a compound of formula (4B). The compound of formula (4B) can be reduced to the compound of formula (1G-1) using a reducing reagent such as Zn or Fe, in the presence of NH ₄ Cl, in a solvent such as MeOH.

Scheme 5 illustrates the preparation of certain compounds of formula (I) wherein R6 is not hydrogen.

- 136 045333

Scheme 5

Scheme 6 illustrates the preparation of certain compounds of formula (I) of the present invention.

Scheme 6

In the situation in which L is H, alkylation of compounds of formulas 6A, 6C and 6E can occur through the formation of a radical from R1A-L obtained by treatment with ammonium persulfate and (IR[DF(CF ₃ )PPY]2(DTBPY))PF ₆ , in a mixture of CH3CN or DMSO and TFA under blue light irradiation.

In an alternative embodiment, when L is H, alkylation of compounds of formulas 6A, 6C and 6E can occur by forming a radical from R1A-L obtained by treatment with BPO and (IR[DF(CF ₃ )PPY]2( DTBPY))PF ₆ in MEON and TFA when irradiated with blue light LED.

When L is H, alkylation of compounds of formulas 6A, 6C and 6E can occur through the formation of a radical from R1A-L obtained by treatment with iron (II) sulfate heptahydrate and hydrogen peroxide in a mixture of water and CH3CN or DMSO and H2SO4.

When L is zinc sulfonate, alkylation of compounds of formulas 6A, 6C and 6E can occur through the formation of a radical from R1A-L obtained by treatment with t-butyl hydroperoxide in a mixture of water and DCM and TFA.

Likewise, when L is -COOH or a BF3 salt, alkylation of compounds of formulas 6A, 6C and 6E can occur by the formation of a radical from R1A-L obtained by treatment with ammonium persulfate and silver nitrate in a mixture of water and DCM, or CH3CN, or DMSO, or dioxane and TFA.

The compounds of formulas 6A, 6C and 6E can be converted to the corresponding N-oxides by treatment with an oxidizing agent such as m-CPBA in DCM or THF. Said N-oxides may optionally be converted to the corresponding ortho-CN derivatives using trimethylsilyl

- 137 045333 cyanide and DBU in a solvent such as THF. These N-oxides can also be converted to the corresponding alkoxy and cycloalkoxy derivatives by the action of an acid anhydride, Na2CO ₃ containing suitable alkyl-OH or cycloalkyl-OH reagent substituents.

In an alternative embodiment, the N-oxides of the compounds of formulas 6A, 6C and 6E can be converted to the corresponding ortho-chloro derivatives by the action of POCl ₃ optionally in a solvent such as CHCl ₃ which can be used as an intermediate to produce C _1-6 alkylthio,

The _1-6 cycloalkylthio sulfur-linked heterocyclic rings of the present invention. Likewise, ortho-chloro derivatives can react with suitably substituted amines to produce the _C1-6 alkylamino, _C1-6 cycloalkylamino or N-linked heterocyclic rings of the present invention. Or the ortho-chloro derivatives may in a subsequent step undergo a Suzuki-type reaction with a suitably substituted alkyl or cycloalkyl boronic acid to form a compound of formula (I).

Installed examples

In the following examples, certain synthetic products are listed as being isolated as a residue. One skilled in the art will appreciate that the term residue is not limiting to the physical state in which the product is isolated and may include, for example, solid, oil, foam, gum, syrup, and the like.

Example 1.

1-(Benzofuran-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 34

Sodium hydride in mineral oil (7.6 g, 60% purity, 0.19 mol) was added in portions to a 0° C. (ice/water) solution consisting of 3-bromophenol (30 g, 0.17 mmol) and DMF (200 ml) and the resulting mixture was stirred for 10 min at 0°C. 2-bromo-1,1diethoxyethane (31 mL, 0.21 mmol) was added to the mixture at 0° C., and the resulting mixture was stirred at 120° C. for 16 hours and then cooled to room temperature. The resulting solution was poured into water and extracted using ethyl acetate. The organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified using FCC (petroleum ether:ethyl acetate=10:1) to give compound 1a (50 g, 99%) as colorless oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.18-7.04 (m, 3H), 6.89-6.82 (m, 1H), 4.82 (t, J=5, 2 Hz, 1H), 3.99 (d, J=5.2 Hz, 2H), 3.83-3.72 (m, 2H), 3.69-3.58 (m, 2H), 1, 26 (t, J=7.2 Hz, 6H).

B. 4-Bromobenzofuran (1b) and 5-bromobenzofuran (1c)

Polyphosphoric acid (PPA) (175 g, 519 mmol) was added to a solution consisting of 1-bromo-3(2,2-diethoxyethoxy)benzene, 1a (50.0 g, 173 mmol) and toluene (200 ml) at room temperature temperature in the atmosphere Ar( _g ). The resulting mixture was stirred at 110°C for 4 hours, after which it was cooled to room temperature. The resulting mixture was quenched with chilled water and extracted using ethyl acetate. The organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified using FCC (petroleum ether:ethyl acetate=20:1) to give a mixture of compounds 1b and 1c (21 g, 62%) in in the form of a colorless oil.

1H NMR (400 MHz, CDCI3) δ ppm 7.70 (s, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.61 (d, J=2.0 Hz , 1H), 7.47 (d, J=8.0 Hz, 2H), 7.43-7.34 (m, 2H), 7.18 (t, J=8.0 Hz, 1H), 6 .83 (d, J=1.2 Hz, 1H), 6.76 (d, J=1.2 Hz, 1H).

- 138 045333

C. 1-(Benzofuran-4-yl)-2-(diphenylmethylene)hydrazine, 1d

A mixture consisting of compounds 1b and 1c (21 g, 53 mmol), (diphenylmethylene)hydrazine (13 g, 64 mmol), palladium(II) acetate (1.2 g, 5.3 mmol), Xphos (5.1 g, 11 mmol), sodium hydroxide (4.3 g, 0.11 mol) and t-AmOH (150 ml) were stirred at 100°C for 16 h and then cooled to room temperature.

The suspension was filtered and the plate was washed with ethyl acetate.

The filtrate was concentrated to dryness under reduced pressure to give the crude product, which was purified using FCC (petroleum ether:ethyl acetate=10:1) to give compound 1d (5.8 g, 17%) as a brown oil. LCMS (ESI): mass calculated for C ₂₁ H ₁₆ N ₂ O - 312.13, obtained m/z - 313.1 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.77 (s, 1H), 7.66-7.60 (m, 4H), 7.59-7.52 (m, 2H), 7 .43-7.29 (m, 5H), 7.22-7.16 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.98-6.95 (m , 1H), 6.90 (d, J=8.0 Hz, 1H). LCMS (ESI) m/z M+1: 313.0.

D. Benzofuran-4-ylhydrazin dihydrochloride, 1e

Conc. HCl (50 ml) was added to a solution consisting of 1-(benzofuran-4-yl)-2(diphenylmethylene)hydrazine, 1d (4.8 g, 15 mmol) and EtOH (5 ml). The resulting mixture was stirred at room temperature for 16 hours, concentrated to dryness under reduced pressure to obtain a precipitate, which was added to water (10 ml). The resulting mixture was basified with 2 M NaOH to pH 13 and extracted using ethyl acetate (30 mlx3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to give crude product 1e (1.1 g, crude), which was used in the next reaction without further purification.

E. Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f

Ethyl 4,4,4-trifluoro-3-oxobutanoate (30 g, 162.9 mmol) was added to a solution of triethoxymethane (72.4 g, 488.8 mmol) in acetic anhydride (50 ml). The mixture was stirred at 135°C for 18 hours. The brown mixture was concentrated to give ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (38 g, 97.1%) as a brown oil. which was used in the next reaction without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.23-1.33 (m, 3H), 1.40 (dt, J=14.18, 7.19 Hz, 3H), 4.19 -4.36 (m, 4 N), 7.66-7.87 (m, 1 N).

F. Ethyl 1-(benzofuran-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 1g

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (1.43 g, 5.97 mmol), benzofuran-4-ylhydrazine dihydrochloride, 1e (1.10 g, 4.98 mmol), triethylamine (1.39 ml, 9.95 mmol) and ethanol (20 ml) were stirred at 80°C for 16 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure, diluted with water (15 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified using FCC (petroleum ether:ethyl acetate=3:1) to give compound 1g (250 mg, 15%) in in the form of yellow oil. LCMS (ESI): mass calculated for C ₁₅ H ₁₁ F ₃ N ₂ O ₃ - _324.07 , obtained m/z - 324.9 [M+H]+.

1H NMR (400 MHz, CDCI3) δ ppm 8.20 (s, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.68-7.63 (m, 1H) , 7.40 (t, J=8.0

- 139 045333

Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 6.61 (dd, J=0.8, 2.4 Hz, 1H), 4.43-4.36 (m , 2H), 1.42-1.38 (m, 3H). LCMS (ESI) m/z M+1: 324.9.

G. 1-(Benzofuran-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 1h

A solution consisting of lithium hydroxide hydrate (97.1 mg, 2.31 mmol) and water (5 ml) was added to a solution consisting of ethyl 1-(benzofuran-4-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxylate, 1g (250 mg, 0.771 mmol) and ethanol (10 ml). The mixture was stirred at room temperature for 16 hours. The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product, which was poured into water (5 ml) and acidified with 3N HCl to about pH 5. The resulting mixture was filtered and the filter cake was washed with water (5 ml) and subsequently dried under reduced pressure to obtain compound 1h (200 mg, 88%) as a yellow solid. LCMS (ESI): mass calculated for C ₁₃ H ₇ F ₃ N ₂ O ₃ . _296.04 , resulting m/z - 337.9 [M+H+CH ₃ CN]+.

^1H NMR (400 MHz, DMSO-d6) δ ppm 13.40 (br.s, 1H), 8.32 (s, 1H), 8.14 (d, J=2.4 Hz, 1H ), 7.87 (d, J=8.4 Hz, 1H), 7.53-7.41 (m, 2H), 6.76 (dd, J=1.2, 2.4 Hz, 1H) .

H. 3-Chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine, 1i

Mixture of 2,3-dichloro-5-nitropyridine (50 g, 259.08 mmol), 1H-1,2,3-triazole (19.683 g, 284.99 mmol), potassium carbonate (46.549 g, 336.81 mmol) and CH3CN (200 ml) was heated to 40°C and stirred overnight. Ethyl acetate (500 ml) was added. The mixture was washed with water (500 mlx2) and brine (500 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was triturated with DCM (100 ml), filtered and the solid was collected to give 1i (40 g, 68%) as an off-white solid. LC-MS: (ES, m/z): [M+1]+ 225.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.40 (d, J=2.0 Hz, 1H), 9.15 (d, J=2.0 Hz, 1H), 8, 33 (s, 2H).

I. 5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j

Cl /=(

3-Chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine, 1i (20 g, 88.656 mmol), MeOH (500 ml) and Pt/C (2 g, 5 %, 0.513 mmol) was added to a 1000 ml hydrogenation bottle. The resulting mixture was stirred under H ₂ (30 psi) at 25° C. for 20 hours. The suspension was filtered through a pad of diatomaceous earth and the filter residue was washed with ethyl acetate (100 ml). The filtrate was concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative reverse phase HPLC (0-50% (v/v) CH3CN and water with 0.05% NH3), followed by lyophilization to dryness to give the compound 1j (10.4 g, 60%) as an off-white solid. LC-MS: (ES, m/z): [M+1]+ 196.1;

1H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (s, 2H), 7.83 (d, J=2.0 Hz, 1H), 7.21 (d, J=2, 4 Hz, 1H), 6.19 (s, 2H).

J. 1-(Benzofuran-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 34

POCl ₃ (112 mg, 0.729 mmol) was added dropwise to a solution consisting of 1-(benzofuran-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 1h (180 mg, 0.608 mmol), 5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-amine, 1j (131 mg, 0.668 mmol) and pyridine (5 ml) at 0°C. The mixture was stirred at 0°C for 1 hour. The resulting mixture was diluted with sat. aqueous NaHCO3 (10 ml) and extracted using ethyl acetate (15 mlx3). The organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated to dryness under reduced pressure to obtain a crude residue, which was purified using FCC (petroleum ether:ethyl acetate = 1:1) to obtain crude compound 34 (180 mg ). Additional purification by preparative reverse phase HPLC (43-73% (v/v) CH3CN and water with 0.05% NH3) provided compound 34, which was subsequently suspended in water (10 ml), frozen using dry ice/ acetone and subsequently lyophilized to dryness to obtain compound 34 (166.10 mg, 57%). LCMS (ESI): mass calculated for C ₂₀ H ₁₁ ClF ₃ N ₇ O2. _473.06 , resulting m/z - 473.9 [M+H]+.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.77 (d, J=2.4 Hz, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.26 ( s, 1H), 8.16 (s, 1H), 7.95 (s, 2H), 7.76-7.68 (m, 2H), 7.47-7.41 (m, 1H), 7 .33 (d, J=7.6 Hz, 1H), 6.63 (d, J=1.6 Hz, 1H).

Example 2.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(naphthalen-1-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 2

Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (200 mg, 0.833 mmol) was added to a solution consisting of naphthalen-1-ylhydrazine (162 mg, 0.833 mmol), triethylamine (168 mg , 1.67 mmol) and ethanol (5 ml). The mixture was refluxed at 80°C for 16 hours. The resulting mixture was concentrated to dryness under reduced pressure to obtain a crude residue, which was purified by preparative high performance liquid chromatography using Phenomenex Gemini 150x25 mmx10 μm (50-80% (vol./ vol.) ACN and water with 0.05% NH3) to obtain compound 2a. Compound 2a was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to give compound 2a (129.80 mg, 47%). LCMS (ESI): mass calculated for C ₁₇ H ₁₃ F ₃ N ₂ O ₂ . ₃₃₄ , 293, resulting m/z - 335.1 [M+H]+.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.26 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.95 (d, J=8, 0 Hz, 1H), 7.597.50 (m, 4H), 7.19 (d, J=8.0 Hz, 1H), 4.42 (k, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H). LCMS (ESI) m/z M+1: 335.0.

B. 1-(Naphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 2b

A solution consisting of ethyl 1-(naphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 2a (1.20 g, 3.59 mmol), LiOH (452 mg, 10.8 mmol) and water:EtOH (12 ml, 1:2) mixtures were stirred at room temperature for 16 hours. The solution was neutralized to about pH 7 with 4 M HCl, extracted with ethyl acetate (30 ml x 3) and dried over anhydrous Na ₂ SO ₄ . The extracts were concentrated to dryness under reduced pressure to give 2b (1.00 g, 78%), which was used in the next reaction without further purification. LCMS (ESI): mass calculated for C ₁₅ H ₉ F ₃ N ₂ O ₂ . ₃₀₆ , 23 9, resulting m/z - 306.9 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.43 (br.s, 1H), 8.38 (s, 1H), 8.21 (d, J=8.0 Hz, 1H ), 8.12 (d, J=8.0 Hz, 1H), 7.80-7.74 (m, 1H), 7.72-7.55 (m, 4H), 7.09 (d, J=8.0 Hz, 1H).

C. Ν-(5-χλορ-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(naphthalen-1-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 2

POCl3 (90.1 mg, 0.588 mmol) was added dropwise to a solution consisting of 1-(naphthalen-1-yl)-5-141 045333 (trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 2b (150 mg, 0.490 mmol), 5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-amine, 1j (105 mg, 0.539 mmol) and pyridine (2 ml). The mixture was stirred at 0°C for 1 hour. The resulting mixture was concentrated to dryness under reduced pressure to obtain the crude product, which was purified using preparative reverse phase HPLC (46-76% (v/v) ACN and water with 0. 05% NH ₃ ) to obtain compound 2, which was subsequently suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to obtain compound 2 (102.30 mg, 43%). LCMS (ESI): mass calculated for C ₂₂ H ₁₃ ClF ₃ N ₇ O - 483.833, obtained m/z - 484.1 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.08 (br.s, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.57 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.20 (s, 2H), 8.15 (d, J=7.2 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.76-7.62 (m, 3H), 7.13 (d, J=8.0 Hz, 1H). LCMS (ESI) m/z M+1: 483.9.

Example 3.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide, compound 8

A. Ethyl 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 3a

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (905 mg, 3.77 mmol), 5-hydrazinylquinoline (500 mg, 3.14 mmol) and ethanol (20 ml) was stirred at 80°C for 16 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure and subsequently purified by FCC (petroleum ether:ethyl acetate=1:1) to obtain compound 3a (530 mg, 84%) as a brown solid. LCMS (ESI): mass calculated for C ₁₆ H ₁₂ F ₃ N ₃ O _2-335 , 09, obtained m/z - 335.8 [M+H]+.

1H NMR (400 MHz, SPS13) δ ppm 9.02 (dd, J=1.6, 4.0 Hz, 1H), 8.33 (d, J=8.4 Hz, 1H), 8 .27 (s, 1H), 7.86-7.79 (m, 1H), 7.64-7.56 (m, 2H), 7.46 (dd, J=4.4, 8.8 Hz , 1H), 4.43 (k, J=6.8 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H). LCMS (ESI) m/z M+1: 335.8.

B. 1-(Quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b

A solution consisting of lithium hydroxide hydrate (375 mg, 8.95 mmol) in water (5 ml) was added to a solution consisting of ethyl 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4 -carboxylate, 3a (1.00 g, 2.98 mmol) in ethanol (10 ml). The resulting solution was stirred at room temperature for 16 hours, concentrated to dryness under reduced pressure, and the resulting mixture was poured into water (2 ml). The aqueous mixture was acidified with 3 N HCl to about pH 5, filtered and the filter cake washed with water (10 ml) and dried under reduced pressure to obtain compound 3b (910 mg, 99%) as a yellow solid. LCMS (ESI): mass calculated for C ₁₄ H ₈ F ₃ N ₃ O _2-307 , 06, obtained m/z - 308.0 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.03 (s, 1H), 8.40 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.00-7.82 (m, 2H), 7.69-7.54 (m, 2H). LCMS (ESI) m/z M+1: 308.0.

C. 1-(Quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, 3 s

Oxalyl dichloride (0.0830 ml, 0.976 mmol) was added to the solution consisting of 1-(quinolin-5-yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b (200 mg, 0.651 mmol), dichloromethane (15 ml) and

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DMF (catalytic amount). The solution was stirred at room temperature for 1 hour.

The resulting solution was concentrated to dryness to give compound 3c (200 mg, crude), which was used in the next reaction without further purification.

D. N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 8

Solution consisting of 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-nirazol-4-carbonyl chloride, 3 s (200 mg, 0.614 mmol), 5-chloro-6-(2H-1, 2,3-triazol-2-yl)pyridin-3-amine, 1j (144 mg, 0.737 mmol) and pyridine (10 ml) were stirred at 90°C for 1 hour and then cooled to room temperature. The mixture was concentrated to dryness under reduced pressure and subsequently purified by preparative HPLC using a Kromasil 150 x 25 mm x 10 µm column (32-62% (v/v) CH3CN and water with 0.05% NH ₃ ) to give compound 8 (149.20 mg , 50%) in the form of a white solid. LCMS (ESI): mass calculated for C ₂₁ H ₁₂ ClF ₃ N ₈ O - 484.08, obtained m/z - 485.1 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.05-9.02 (m, 1H), 8.78 (d, J=2.0 Hz, 1H), 8.54 (d, J=2.4 Hz, 1H), 8.39-8.34 (m, 2H), 8.23 (s, 1H), 7.96 (s, 2H), 7.88-7.82 (m , 1H), 7.66-7.57 (m, 2H), 7.48 (dd, J=4.0, 8.0 Hz, 1H). LCMS (ESI) m/z M+1: 485.0.

Example 4.

N-(3-Chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 38

A. 4-Hydrazinyl isoquinoline, 4a

To a stirred solution of isoquinoline-4-amine (5.0 g, 34.68 mmol) in HCl (50 ml, 5N) at 0°C was added a solution of sodium nitrite (NaNO ₂ , 3.59 g, 52.02 mmol) in water at 0°C. The reaction mixture was stirred at 0°C for 30 min and a solution of tin(II) chloride dehydrate (SnCl ₂ , 2-H2O, 19.56 g, 86.70 mmol) in concentrated hydrochloric acid (5 ml) was added dropwise. The mixture was stirred at room temperature for 2 hours. The pH of the mixture was adjusted to about 12-14 with 20% aqueous sodium hydroxide solution. At this point, the mixture was extracted using ethyl acetate (200 mlx3). The combined organic extracts were washed with saline (300 ml). The organic portion was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (petroleum ether/ethyl acetate=100:0 - ethyl acetate/methanol=90:10) to give 4a (1.15 g, 20.8%) as a brown solid, which was used in following reaction without further purification.

B. Ethyl 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-πyrazole-4-carboxylate, 4b

A mixture of 4-hydrazinyl isoquinoline, 4a (1.15 g, 7.224 mmol) and ethyl (2)-2-(ethoxymethylene)-4,4,4trifluoro-3-oxobutanoate, 1f (2.08 g, 8.669 mmol) in EtOH ( 30 ml) was stirred at 80°C for 16 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-70:30) to give 4b (1.77 g, 72.98%) as a yellow solid. LCMS (ESI) m/z M+1: 335.9;

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.41 (t, J=7.06 Hz, 3H), 4.42 (k, J=7.06 Hz, 2H), 7.31 ( d, J=8.38 Hz,

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1H), 7.70-7.80 (m, 1H), 8.12 (dd, J=7.28, 1.10 Hz, 1H), 8.28 (s, 1H), 8.58 (s , 1H), 9.41 (s, 1H). C. 1-(Isoquinolin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, 4c

A solution of ethyl 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 4b (500 mg, 1.49 mmol) in concentrated hydrochloric acid (5 ml) was stirred at 130°C in for 3 hours. The solvent was concentrated under reduced pressure to give 4c (465.61 mg, 100%) as a yellow solid. LCMS (ESI) m/z M+1: 307.9.

D. 2-(2-Chloro-4-nitrophenyl)-2H-1,2,3-triazole, 4d

K2CO3 (1.89 g, 13.7 mmol). The reaction mixture was stirred overnight at 55°C. The reaction mixture was concentrated to give a crude oil. The crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 100/0 to 20/80) to give 4d (1 g, 65.1%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.88-8.02 (m, 3H), 8.28 (dd, J=8.93, 2.54 Hz, 1H), 8.49 (d, J=2.21 Hz, 1H).

E. 3-Chloro-4-(2H-1,2,3-triazol-2-yl)aniline, 4e

C.I.

To a solution of 2-(2-chloro-4-nitrophenyl)-2H-1,2,3-triazole, 4d (1 g, 4.45 mmol) in MeOH/THF/water (5 ml/10 ml/5 ml ) Fe(0) (1.243 g, 22.26 mmol) and ammonium chloride (1.191 g, 22.26 mmol) were added. The reaction mixture was stirred at 60°C for 2 hours.

The reaction mixture was filtered and the organic solvent was concentrated under reduced pressure. Water (10 ml) was added and the mixture was extracted using ethyl acetate (15 ml x 3). The organic extracts were dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 0/100) to give 3-chloro-4( 2H-1,2,3-triazol-2-yl)aniline, 4e (0.7 g, 80.8%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 3.96 (br.s, 2H), 6.63 (d, J=8.41 Hz, 1H), 6.81 (d, J=1 .96 Hz, 1H), 7.31 (d, J=8.61 Hz, 1H), 7.84 (s, 2H).

F. N-(3-Chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole

4-carboxamide, compound 38

To a solution of 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 4c (60 mg, 0.195 mmol), 3-chloro-4-(2H-1,2,3 -triazol-2-yl)aniline, 4e (45.6 mg, 0.234 mmol) and pyridine (77.2 mg, 0.98 mmol) in dichloromethane (5 ml) was added dropwise with POCl ₃ (89.8 mg, 0 .59 mmol). The reaction mixture was stirred at 20°C for 1 hour. Saturated aqueous NaHCO ₃ (20 ml) was added and the mixture was extracted using dichloromethane (20 ml x 2). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give a yellow oil. The yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - petroleum ether/ethyl acetate=0:1) to give compound 38 (35 mg, 35.8%) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.34 (d, J=8.41 Hz, 1H), 7.58-7.68 (m, 2H), 7.72-7.84 (m, 2H), 7.89 (s, 2H), 7.96-8.06 (m, 2H), 8.15 (d, J=7.43 Hz, 1H), 8.24 (s, 1H), 8.60 (s, 1H), 9.44 (s, 1H); LCMS (ESI) m/z M+1: 483.9.

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Example 5.

N-(3-Cyano-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 59

A. 5-Nitro-2-(2H-1,2,3-triazol-2-yl)benzonitrile, 5a

2-Fluoro-5-nitrobenzonitrile (500 mg, 3.01 mmol), 2H-1,2,3-triazole (228.68 mg, 3.311 mmol) and K2CO3 (832.02 mg, 6.02 mmol) were added to THF (10 ml) and stirred at 25°C for 16 hours. The reaction mixture was filtered and the collected solid was washed with ethyl acetate (30 ml x 3). The combined organic layers were concentrated under reduced pressure to leave a crude residue as a yellow solid, which was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate, 100:0-50:50) to give 5-nitro-2-(2H1,2 ,3-triazol-2-yl)benzonitrile, 5a (140 mg, 21.6%) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.72 (d, J=2.6 Hz, 1H), 8.56 (dd, J=2.5, 9.2 Hz, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.03 (s, 2H).

B. 5-Amino-2-(2H-1,2,3-triazol-2-yl)benzonitrile, 5b

5-Nitro-2-(2H-1,2,3-triazol-2-yl)benzonitrile, 5a (140 mg, 0.651 mmol) was dissolved in THF (8 ml), to which Fe(0) (363, 36 mg, 6.507 mmol), NH ₄ Cl (348.04 mg, 6.507 mmol) and water (8 ml). The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with ethyl acetate (20 mlx3). Water (50 mL) was added and the organic layer was separated, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to dryness to give crude 5b (140 mg) as a yellow solid, which was used in the next reaction without further purification. LCMS (ESI) m/z M+1: 186.1.

C. N-(3-Cyano-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol4-carboxamide , connection 59

5-Amino-2-(2H-1,2,3-triazol-2-yl)benzonitrile, 5b (67.03 mg, 0.21 mmol), 1-(isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxylic acid, 4c (66.95 mg, 0.315 mmol) and pyridine (74.84 mg, 0.946 mmol) were dissolved in dichloromethane (3 ml) and POCl ₃ (48.36 mg, 0.315 mmol). The mixture was stirred at 25°C for 16 hours. Saturated aqueous NH4Cl (20 ml) was added and the mixture was extracted using dichloromethane (20 ml x 2). The combined organic extracts were dried over Na2SO4, filtered and the filtrates concentrated under reduced pressure to give a yellow oil. The oil was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100:0 to 40/60) to give 59 (38 mg, 36.3%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.11 (br.s, 1H), 9.59 (br.s, 1H), 8.77 (br.s, 1H), 8 .58 (br.s, 1H), 8.38 (br.s, 2H), 8.29-8.04 (m, 4H), 8.01-7.69 (m, 2H), 7.27 (b.d., J=5.5 Hz, 1H). LCMS (ESI) m/z M+1: 475.0.

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Example 6.

N-(5-Chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 50

A. 2-(3-Chloro-5-nitropyridin-2-yl)oxazole, 6a

2,3-Dichloro-5-nitropyridine (216 mg, 1.119 mmol) and 2-(tributylstannyl)oxazole (400.1 mg, 1.119 mmol) were dissolved in DMF (3 mL) and purged with N2. Pd(PPh ₃ ) ₄ (129 mg, 0.112 mmol) was added and the reaction mixture was stirred at 110°C for 16 hours. The combined reaction mixture was concentrated under reduced pressure to give a crude black oil. The oil was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 70/30) to give 2-(3-chloro-5-nitropyridin-2-yl)oxazole, 6a (150 mg, 59.4% ) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.49-7.55 (m, 1H), 7.93-7.99 (m, 1H), 8.66-8.72 (m, 1H), 9.40-9.47 (m, 1H); LCMS (ESI) m/z M+1: 225.9.

B. 5-Chloro-6-(oxazol-2-yl)pyridin-3-amine, 6b

2-(3-Chloro-5-nitropyridin-2-yl)oxazole, 6a (88 mg, 0.39 mmol), Fe(0) (217.8 mg, 3.90 mmol) and NH ₄ Cl (208, 6 mg, 3.90 mmol) was added to a mixture of THF (5 ml) and water (1 ml). The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with ethyl acetate (20 mlx3). The combined filtrates were concentrated to dryness to give a crude yellow oil as the product. The crude product was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 50/50 to 0/100) to give 5-chloro-6-(oxazol-2-yl)pyridin-3-amine, 6b (50 mg, 65 .5%) as a yellow oil, which was used in the next reaction without further purification.

C. N-(5 -chloro-6-(oxazol-2-yl)pyridin-3-yl)-1 -(isoquinolin-4-yl)-5 -(trifluoromethyl)-1 H-pyrazol-4carboxamide, compound 50

POCl ₃ (78.4 mg, 0.511 mmol) was added to a mixture of 5-chloro-6-(oxazol-2-yl)pyridin-3-amine, 6b (50 mg, 0.256 mmol), 1-(isoquinolin-4-yl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 4c (62.8 mg, 0.204 mmol) and pyridine (101 mg, 1.278 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at 20°C for 16 hours. Water (20 ml) was added to the mixture. The mixture was extracted using dichloromethane (30 ml). The organic layer was concentrated under reduced pressure to give the crude product, which was purified by preparative reverse phase HPLC (water (0.05% HCl): MeCN 76-46%) and lyophilized to give N-(5-chloro-6-( Oxazol-2yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide, compound 50 (28 mg, 22.6%) as a solid white.

1H NMR (400 MHz, methanol-d4) δ ppm 7.50 (s, 1H), 7.65 (d, J=8.38 Hz, 1H), 8.11-8.21 (m, 2H), 8.27 (t, J=7.20 Hz, 1H), 8.53 (s, 1H), 8.60-8.70 (m, 2H), 8.97 (br.s, 1H ), 9.05 (s, 1H), 9.98 (s, 1H); LCMS (ESI) m/z M+1: 484.9.

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Example 7.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)niridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 47

A. 5-Nitro-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, 7a

Mixture of 2-chloro-5-nitronicotinonitrile (600 mg, 3.27 mmol), 1,2,3-triazole (270 mg, 3.92 mmol) and K ₂ CO ₃ (1.35 g, 9.8 mmol) in CH3CN (10 ml) was stirred at 30°C for 2 hours. The yellow solid was collected by filtration and washed with ethyl acetate (100 ml). The filtrate was concentrated under reduced pressure to give the crude product, which was washed with dichloromethane (10 ml). The solid was dried under reduced pressure to give 5nitro-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, 7a (0.4 g, 56.6%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 9.43 (d, J=2.35 Hz, 1H), 9.59 (d, J=2, 35 Hz, 1H).

B. 5-Amino-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, 7b

Solution of 5-nitro-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, 7a (353 mg, 1.6 mmol), Fe(0), (456 mg, 8.2 mmol) and NH ₄ Cl (437 mg, 8.2 mmol) in THF/MeOH/water (4:2:1, 35 ml) was stirred at 60°C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product in the form of a yellow oil. Water (20 ml) was added to the yellow oil. The mixture was extracted with ethyl acetate (30x3 ml), dried over MgSO ₄ , filtered and the filtrate concentrated under reduced pressure to give 5-amino-2-(2H-1,2,3triazol-2-yl)nicotinonitrile, 7b (200 mg , 65.7%) as a white solid, which was used in the next reaction without further purification.

1H NMR (400 MHz, methanol-d ₄ ) δppm 7.46 (d, J=3.09 Hz, 1 H), 8.00 (s, 2H), 8.10 (d, J=3 .09 Hz, 1H).

C. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 47

POCl ₃ (82.36 mg, 0.537 mmol) was added to a mixture of 5-amino-2-(2H-1,2,3-triazol-2yl)nicotinonitrile, 7b (50 mg, 0.269 mmol), 1-(isoquinoline-4 -yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylic acid, 4c (66 mg, 0.215 mmol) and pyridine (106 mg, 1.343 mmol) in dichloromethane (5 ml) and the mixture was stirred at 20°C for 2 h. Water (20 ml) was added and the mixture was extracted using dichloromethane (30 ml). The organic layer was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (water (0.05% HCl): MeCN 84:16 to 66:44). The pure fractions were collected, the organic solvents were concentrated under reduced pressure, and the mixture was lyophilized to dryness to give 47 (29 mg, 22.7%) as a yellow solid.

1H NMR (400 MHz, methanol^) δ ppm 7.51 (d, J=8.82 Hz, 1H), 7.97-8.03 (m, 1H), 8.07-8.16 (m, 3H), 8.47-8.51 (m, 2H), 8.85 (s, 1H), 8.91 (d, J=2.43 Hz, 1H), 9.08 (br. s, 1H), 9.75 (s, 1H); LCMS (ESI) m/z M+1: 476.0.

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Example 8.

Ν-(5-ΧΛορ-6-(1 -methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1 -(isoquinolin-4-yl)-5 -(trifluoromethyl)-1Hpyrazol-4- carboxamide, compound 52

6-Bromo-5-chloropyridin-3-amine (383.87 mg, 1.85 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2dioxabopolan-2-yl) -1H-pypazole (350 mg, 1.682 mmol) and Na ₂ CO ₃ (356.58 mg, 3.364 mmol) were added to dioxane/water (9:1, 6 ml) and purged with N ₂ . Pd(dppf)Cl ₂ (123.09 mg, 0.168 mmol) was added and the reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with ethyl acetate (20 mlx3). The combined filtrates were concentrated to dryness to give a crude black oil. The black oil was purified using preparative reverse phase HPLC. The pure fractions were collected, the organic solvents were concentrated under reduced pressure and the mixture was lyophilized to dryness to give 5-chloro6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine, 8a (150 mg, 42.7%, yield ) as a yellow oil. LCMS (ESI) m/z M+1: 209.1.

B. N-(5 -Chloro-6-(1 -methyl-1 H-pyrazol-3 -yl)pyridin-3 -yl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide, compound 52

To a solution of ethyl 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 4b (106.95 mg, 0.335 mmol), 5-chloro-6-(1-methyl-1H -piρazol-3-yl)pypidin-3-αminα, 8a (70 mg, 0.335 mmol) and pyridine (132.69 mg, 1.677 mmol) in dichloromethane (5 ml) were added dropwise with POCl ₃ (102.88 mg, 0.671 mmol). The reaction mixture was stirred at 20°C for 1 hour. A saturated aqueous solution of NaHCO ₃ (20 ml) was added and the mixture was extracted using dichloromethane (20 mlx2). The combined organic phases were washed with brine and dried over Na ₂ SO ₄ . The mixture was filtered and the filtrates were concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was purified by silica gel flash column chromatography (dichloromethane:MeOH=100:0 to 80:20) to give a precipitate, which was further purified by preparative reverse phase HPLC. The pure fractions were collected, the organic solvents were concentrated under reduced pressure and the mixture was lyophilized to dryness to give N-(5-chloro-6-(1-methyl-1Hpiρazol-3-yl)pypidin-3-yl)-1-(isoquinoline-4- yl)-5-(tifthomethyl)-1H-piphazol-4-caboxamide, compound 52 (45 mg, 26.7%) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.03 (br.s, 1H), 9.60 (s, 1H), 8.83 (d, J=2.0 Hz, 1H ), 8.77 (s, 1H), 8.58 (s, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.36 (d, J=8.2 Hz, 1H ), 7.96-7.89 (m, 1H), 7.88-7.82 (m, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 3.91 (s, 3H). LCMS (ESI) m/z M+1: 497.9.

Example 9.

N-(5-Χloρ-6-(2H-1,2,3-thiazol-2-yl)pipidin-3-yl)-1-(isoquinolin-4-yl)-5-(tρifthoρmethyl)-1Hpyrazol-4 -carboxamide, compound 32

Ethyl 1-(isoquinolin-4-yl)-5(tρiftomethyl)-1H-pyρazol-4-caboxylate, 4b (67 mg, 0.2 mmol), 5-chloro-6 was placed into a 20 mL vial equipped with a stirrer. -(2H-1,2,3-thiazole-2

- 148 045333 yl)pyridin-3-amine, 1j (39.9 mg, 0.204 mmol) and THF (0.67 ml, 0.3 M, 0.201 mmol). The resulting solution was treated with 1.01 M KOtBu/THF (0.32 mL, 1.01 M, 0.323 mmol) at once at room temperature and subsequently stirred for 25 min. The reaction mixture was then partitioned between 5M NH ₄ Cl (1 ml) and ethyl acetate (2 ml) and the organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness to form a beige foam (78 mg). The foam was purified by flash column chromatography on a 12 g Silicycle HP column (10-100% EtOAc in heptane, 25 column volumes, subsequently isocratic EtOAc) to give compound 32 as a foam (27.4 mg, 28%).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.45 (s, 1H), 8.80 (d, J=2.53 Hz, 1H), 8.66 (br.s, 1H), 8.49-8.59 (m, 2H), 8.25 (s, 1H), 8.16 (dd, J=1.52, 7.07 Hz, 1H), 7.92-8.00 ( m, 2H), 7.71-7.83 (m, 2H); MS m/e 485.0 (M+H).

Example 10.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-1-yl)-5-(trifluoromethyl)-1H pyrazol- 4-carboxamide, compound 57

A. 1-Hydrazinyl isoquinoline, 10a

1Chloroisoquinoline (341.8 mg, 2.089 mmol) and hydrazine (0.66 mL, 1.021 g/mL, 21.028 mmol) were placed in a 2-5 mL Biotage microwave vial equipped with a stirrer at room temperature and the vial was deaerated. purging with argon (4x) and stirring the reaction mixture at 150°C for 20 minutes. The resulting dark yellow homogeneous solution was allowed to cool to room temperature, during which time a precipitate formed. The precipitate was taken into 3:1 water/CH ₃ CN (2 mL) and the solids were collected by filtration.

The yellow filter cake was washed with water (2 ml x 3) and subsequently dissolved in DCM (6 ml). The DCM mixture was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to give 10a as a yellow solid (189 mg, 57%).

B. Ν-(5-Χλορ-6-(2Η-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(isoquinolin-1 -yl)-5 -(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 57

1-hydrazinyl isoquinoline, 10a (45.5 mg, 0.286 mmol), THF (0.41 ml, 0.7 M, 0.287 mmol) and 0.5 M ethyl 2-(ethoxymethylene) were placed in a 4 ml vial equipped with a stirrer. -4,4,4-trifluoro-3-oxobutanoate, I/THF (0.57 ml, 0.5 M, 0.285 mmol) and stirred the reaction mixture at room temperature for 10 minutes, and then stirred for 90 minutes at 70° WITH. Calcium sulfate (183 mg, 1.34 mmol) was subsequently added to the reaction mixture and stirred at 70°C for 10 minutes. The reaction mixture was further cooled to room temperature, treated with 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3amine, 1j (56.6 mg, 0.288 mmol) and 1.01 M KOtBu /THF (0.42 ml, 1.01 M, 0.424 mmol) in separate portions at room temperature and the resulting dark reaction mixture was stirred at room temperature for 30 minutes. The dark reaction mixture was subsequently partitioned between 5 M NH4Cl (1 ml) and ethyl acetate (1 ml) and the organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (50-100% EtOAc in heptane, 10 column volumes) followed by purification with a mixture (1:1 acetone/heptane; isocratic) to give compound 57 (21.3 mg, 15%).

Ή NMR (400 MHz, CDCl3) δ ppm 8.77 (d, J=2.02 Hz, 1H), 8.50-8.53 (m, 2H), 8.26 (s, 1H) , 7.91-8.02 (m, 4H), 7.83 (ddd, J=2.78, 5.56, 8.34 Hz, 1H), 7.67-7.72 (m, 2H) ; MS m/e 485.1 (M+H).

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Example 11.

N-(3-cyano-4-(1H-1,2,3-triazol-1-yl)phenyl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 62

A. 5-Nitro-2-(1H-1,2,3-triazol-1-yl)benzonitrile, 11a

O _Z N ' ^N , 11a

2-Fluoro-5-nitrobenzonitrile (500 mg, 3.01 mmol), triazole (228.7 mg, 3.31 mmol) and K ₂ CO ₃ (832.0 mg, 6.02 mmol) were added to THF (10 ml) and stirred at 25°C for 16 hours. The reaction mixture was filtered and the residue was washed with ethyl acetate (30 mlx3). The combined organic layers were concentrated under reduced pressure to give a crude yellow solid. The crude solid was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100:0 to 50:50) to give 5-nitro-2-(1H-1,2,3-triazol-1-yl)benzonitrile, 11a (500 mg, 77.2%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.74 (d, J=2.6 Hz, 1H), 8.65 (dd, J=2.4, 9.0 Hz, 1H), 8.48 (d, J=0.9 Hz, 1H), 8.27 (d, J=9.0 Hz, 1H), 7.98 (d, J=0.9 Hz, 1H).

B. 5-Amino-2-(1H-1,2,3-triazol-1-yl)benzonitrile, 11b h ₂ nVAc _N , _11b

5-Nitro-2-(1H-1,2,3-triazol-1-yl)benzonitrile, 11a (500 mg, 2.32 mmol) was dissolved in THF (10 ml) to which Fe(0) ( 1297.7 mg, 23.24 mmol), NH ₄ Cl (1243.0 mg, 23.24 mmol) and water (10 ml). The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with ethyl acetate (20 mlx3). Water (30 ml) was added and the organic layer was separated, dried over Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness to give crude 5-amino-2-(1H-1,2,3-triazol-1-yl)benzonitrile, 11b (460 mg, 104.4%, crude) as a yellow solid. LCMS (ESI) m/z M+1: 185.9.

C. N-(3-Cyano-4-(1H-1,2,3-triazol-1-yl)phenyl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol4-carboxamide , connection 62

1-(Isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 4c (75.1 mg, 0.23 mmol), 5-amino-2-(1H-1.2 ,3-triazol-1-yl)benzonitrile, 11b (66.4 mg, 0.35 mmol) and pyridine (83.1 mg, 1.05 mmol) were dissolved in dichloromethane (3 ml) and POCl ₃ (53, 7 mg, 0.35 mmol). The mixture was stirred at 25°C for 16 hours. Saturated. aqueous NH ₄ Cl solution (20 ml) and the mixture was extracted using dichloromethane (20 ml x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give a crude yellow oil. The crude oil was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN, then: A (62%) and B (38%), finally: A: (32%) and B (68 %)). The pure fractions were collected, concentrated under reduced pressure and lyophilized to dryness to give 62 (35 mg, 29%) as a white solid. LCMS (ESI) m/z M+1: 185.9;

1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1H), 9.69 (s, 1H), 8.86 (s, 1H), 8.77 (br.d, J=4.0 Hz, 2H), 8.53 (br.d, J=1.3 Hz, 1H), 8.43 (br.d, J=8.3 Hz, 1H), 8.31 ( br.d, J=8.8 Hz, 1H), 8.07 (s, 1H), 8.03-7.96 (m, 1H), 7.96-7.87 (m, 2H), 7 .35 (br.d, J=8.5 Hz, 1H).

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Example 12.

N-(5-Cyano-6-( 1 -methyl-1 H-pyrazol-3 -yl)pyridin-3 -yl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1 Npyrazol-4 -carboxamide, compound 78

A. 5-Amino-2-chloronicotinonitrile, 12a

2-Chloro-5-nitronicotinonitrile (500 mg, 2.72 mmol) was dissolved in THF (10 ml), to which Fe(0) (1521.2 mg, 27.24 mmol), NH ₄ Cl (1457, 1 mg, 27.24 mmol) and water (10 ml). The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with ethyl acetate (20 mlx3). Water (50 ml) was added and the organic layer was separated, dried over Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness to give a crude yellow solid. The crude solid was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 80/20) to give 5-amino-2-chloronicotinonitrile, 12a (270 mg, 64.5%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.73 (d, J=2.8 Hz, 1H), 7.04 (d, J=2.8 Hz, 1H), 4.96 ( us.s, 2N).

B. 5-Amino-2-(1-methyl-1H-nirazol-3-yl)nicotinonitrile, 12b

5-Amino-2-chloronicotinonitrile, 12a (100 mg, 0.65 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole (135.5 mg, 0.65 mmol) and Na ₂ CO ₃ (138.0 mg, 1.30 mmol) were added to the dioxane/water mixture (9:1, 6 ml) and the reaction mixture was purged with N ₂ . Pd(dppf)Cl ₂ (47.6, 0.065 mmol) was added and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated to dryness to obtain a crude black oil. The crude oil was purified by silica gel flash column chromatography (dichloromethane/MeOH 100/0 to 90/10) to give 5-amino-2-(1-methyl-1H-pyrazol-3-yl)nicotinonitrile, 12b (100 mg, 51.3%) in the form of a black solid. LCMS (ESI) m/z M+1: 200.1.

C. N-(5-Cyano-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)1H-pyrazol- 4-carboxamide, compound 78

1-(Isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 4c (70 mg, 0.22 mmol), 5-amino-2-(1-methyl-1H-pyrazole -3-yl)nicotinonitrile, 12b (97.8 mg, 0.33 mmol) and pyridine (74.5 mg, 0.98 mmol) were dissolved in dichloromethane (3 ml) and POCl ₃ (50.0 mg, 0 .32 mmol). The mixture was stirred at 25°C for 16 hours. Saturated. aqueous NaHCO ₃ solution (20 ml) and the mixture was extracted using dichloromethane (20 ml x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give a crude yellow oil. The oil was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (75%/25% - 48%/52%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to give 78 (50 mg, 46%) as a yellow solid LCMS (ESI) m/z M+1: 489.0.

1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (s, 1H), 9.64 (s, 1H), 9.13 (d, J=1.8 Hz, 1H), 8 .81 (s, 1H), 8.67 (br.s, 2H), 8.39 (br.d, J=8.2 Hz, 1H), 7.99-7.91 (m, 1H), 7.90-7.80 (m, 2H), 7.29 (br.d, J=8.2 Hz, 1H), 6.85 (d, J=1.8 Hz, 1H), 3.94 (s, 3H).

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Example 13.

N-(5-Cyαno-6-(1 -methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5 -(trifluoromethyl)-1Hpyrazol-4- carboxamide, compound 89

A. 5-Hydrazinylquinoline, 13a

To a stirred solution of isoquinoline-4-amine (3.5 g, 24.28 mmol) in HCl (35 ml, 5 N) at 0°C was added a solution of sodium nitrite (NaNO ₂ , 2.51 g, 36.42 mmol) in water at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and a solution of tin(II) chloride dihydrate (SnCl ₂ , 2-H2O, 13.695 g, 60.69 mmol) in concentrated hydrochloric acid (6.5 ml) was added dropwise. The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 12-14 using a 20% aqueous sodium hydroxide solution. The mixture was extracted using ethyl acetate (200 mlx3). The combined organic layers were washed with brine (300 ml). The organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (petroleum ether/ethyl acetate=100:0 - ethyl acetate/methanol=90:10) to give compound 13a (1.5 g, 39%) as a brown solid.

B. Ethyl 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 13b

A solution of 5-hydrazinylquinoline, 13a (1.5 g, 9.42 mmol) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3oxobutanoate, 1f (2.716 g, 11.31 mmol) in EtOH (40 ml ) was stirred at 80°C for 16 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100:0-70:30) with yielding crude compound 13b (2.56 g, 80.9%) as a yellow solid. LCMS (ESI) m/z M+1: 336.4.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.34-1.47 (m, 3H), 4.36-4.48 (m, 2H), 7.41-7.50 (m , 1H), 7.55-7.67 (m, 2H), 7.77-7.86 (m, 1H), 8.25 (s, 1H), 8.29-8.38 (m, 1H ), 8.96-9.06 (m, 1H).

C. N-(5-Cyano-6-(1 -methyl-1 H-pyrazol-3-yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide, compound 89

1-(Quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b (102.2 mg, 0.33 mmol), 5-amino-2-(1-methyl-1H -pyrazol-3-yl)nicotinonitrile, 12b (150 mg, 0.50 mmol) and pyridine (118.47 mg, 1.50 mmol) were dissolved in dichloromethane (3 ml) and POCl ₃ (76.496 mg, 0.499 mmol) was added. . The mixture was stirred at 25°C for 16 hours. Saturated. aqueous NaHCO ₃ solution (20 ml) and the mixture was extracted using dichloromethane (20 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give a crude yellow oil. The oil was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (75%/25% - 45%/55%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to give 89 (85 mg, 52%) as a yellow solid LCMS (ESI) m/z M+1: 489.1;

1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 9.14 (dd, J=2.4, 11.9 Hz, 2H), 8.74-8.61 (m, 2H), 8.39 (d, J=8.6 Hz, 1H), 8.07-7.95 (m, 2H), 7.86-7.73 (m, 3H), 6.84 (d , J=1.8 Hz, 1H), 3.94 (s, 3H).

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Example 14.

Ν-(5-ΧΛορ-6-( 1 H-pyrazol-1 -yl)pyridin-3-yl)-1 -(isoquinolin-4-yl)-5 -(trifluoromethyl)-1 H-pyrazol4-carboxamide, compound 46

A. 3-Χloρ-5-nito-2-(1H-piρazol-1-yl)pipidine, 14a

2,3-Dichloro-5-nitropyridine (1 g, 5.18 mmol), pyrazole (529 mg, 7.77 mmol) and C ₂ CO ₃ (5.06 g, 15.50 mmol) were added to DMF (15 ml) and stirred at 20°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude yellow oil. The yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 - petroleum ether/ethyl acetate=10:1) to give compound 14a (511 mg, 43.907%) as a yellow solid. LCMS (ESI) m/z M+1: 224.8;

^1H NMR (400 MHz, CDCl ₃ ) δ ppm 6.57 (d, J=1.76 Hz, 1H), 7.90 (s, 1H), 8.37-8.46 (m, 1H), 8.42 (d, J=2.65 Hz, 1H), 8.71 (d, J=2.21 Hz, 1H), 9.21 (d, J=2.21 Hz, 1H) .

B. 5-Χloρ-6-(1H-niρazol-1-yl)pypidin-3-amine, 14b

3-Χloρ-5-nito-2-(1H-piρazol-1-yl)pipidine, 14a (500 mg, 2.26 mmol) was added to the Fe(0) mixture (621.6 mg, 11.13 mmol), NH ₄ Cl (595.4 mg, 11.13 mmol) in MeOH (10 ml), water (5 ml) and THF (20 ml). The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude yellow oil. The crude oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 - petroleum ether/ethyl acetate=0:1) to give compound 14b (300 mg, 69.2%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 6.44 (s, 1H), 7.15 (d, J=2.35 Hz, 1H), 7.75 (s, 1H), 7 .85-7.91 (m, 2H).

C. N-(5-Chloro-6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide, connection 46

POCl ₃ (78.8 mg, 0.514 mmol) was added to a mixture of 5-chloro-6-(1H-piρazol-1-yl)pipidin-3-amine, 14b (50 mg, 0.26 mmol), 1-(isoquinoline -4-yl)-5-(tρifthoρmethyl)-1H-piρazol-4-caboxylic acid, 4c (63.1 mg, 0.21 mmol) and pyridine (101.6 mg, 1.3 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at 20°C for 16 hours. Water (20 ml) was added to the mixture. The mixture was extracted using dichloromethane (30 ml). The organic layer was concentrated under reduced pressure to give the crude product, which was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (57%/43% - 27%/ 73%).

1H NMR (400 MHz, methanol-04) δ ppm 6.57 (t, J=2.09 Hz, 1H), 7.38 (d, J=8.60 Hz, 1H), 7.78 -7.95 (m, 3H), 8.16 (d, J=2.43 Hz, 1H), 8.33 (d, J=8.16 Hz, 1H), 8.41 (s, 1H) , 8.61-8.66 (m, 2H), 8.77 (d, J=2.21 Hz, 1H), 9.51 (s, 1H).

Example 15.

N-(3 -Chloro-4-(5-methyl-1H-1,2,4-triazol-1 -yl)phenyl)-1 -(isoquinolin-4-yl)-5 -(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 51

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MV

A. 1-(2-Chloro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole, 15a

2-Chloro-1-fluoro-4-nitrobenzene (1.6 g, 9.11 mmol), 5-methyl-1H-1,2,4-triazole (1.14 g, 13.7 mmol) and C ₂ CO ₃ (8.9 g, 27.3 mmol) was added to DMF (15 ml). The mixture was stirred at 20°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude yellow oil. The crude oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate=7:3 - petroleum ether/ethyl acetate=3:7) to give compound 15a (1.5 g, 69%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 2.38-2.56 (m, 1H), 2.39-2.44 (m, 1H), 2.51 (s, 2H), 7 ,60-7.67 (m, 1H), 7.90 (d, J=8.82 Hz, 1H), 8.02 (s, 1H), 8.23-8.33 (m, 1H) , 8.43-8.50 (m, 1H), 8.69 (s, 1H).

B. 3-Chloro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline, 15b

1-(2-Chloro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole, 15a (1500 mg, 2.26 mmol) was added to the Fe(0) mixture (877 mg, 15.71 mmol), NH ₄ Cl (840 mg, 15.71 mmol) in MeOH (10 ml), water (5 ml) and THF (20 ml). The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude yellow oil. The crude oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1 - petroleum ether/ethyl acetate=0:1) to give compound 15b (1200 mg, 91.5%) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm 2.90 (s, 3H), 6.52-6.61 (m, 1H), 6.69-6.77 (m, 1H), 7, 06 (d, J=8.61 Hz, 1H), 7.16 (d, J=8.61 Hz, 1H), 7.87 (s, 1H), 7.96 (s, 1H), 8 , 15 (s, 1H).

C. N-(3-Chloro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 51

MV

POCl ₃ (110.23 mg, 0.719 mmol) was added to a mixture of 3-chloro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline, 15b (150 mg, 0.36 mmol ), 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 4c (88.3 mg, 0.29 mmol) and pyridine (142.2 mg, 1.8 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at 20°C for 16 hours. Water (20 ml) was added to the mixture. The mixture was extracted using dichloromethane (30 ml). The organic layer was concentrated under reduced pressure to give the crude product, which was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (62%/38% - 32%/ 68%).

1H NMR (400 MHz, methanol-d ₄ ) δ ppm 2.50 (s, 3H), 7.48 (d, J=8.38 Hz, 1H), 7.64 (d, J=8 ,82 Hz, 1H), 7.84 (dd, J=8.60, 2.20 Hz, 1H), 7.92-7.98 (m, 1H), 8.00-8.06 (m, 1H), 8.22 (d, J=2.20 Hz, 1H), 8.39-8.48 (m, 2H), 8.67 (br.s, 1H), 8.82 (br.s , 1H), 9.01 (s, 1H), 9.53-9.91 (m, 1H), 9.72 (br.s, 1H).

Example 16.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 83

POC13 (49.4 mg, 0.32 mmol) was added to a mixture of 5-amino-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, 7b (30 mg, 0.161 mmol), 1-( quinolin-5-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, 3b (49.5 mg, 0.16 mmol) and pyridine (63.7 mg, 0.81 mmol) in dichloromethane ( 3 ml). Stir the reaction mixture

- 154 045333 was kept at a temperature of 20°C for 2 hours. Water (20 ml) was added to the mixture. The mixture was extracted using dichloromethane (30 ml). The organic layers were concentrated under reduced pressure to give the crude product, which was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (67%/33% - 37%/ 63%).

¹ H NMR (400 MHz, methanol^) δppm 8.07-8.21 (m, 4H), 8.32 (t, J=8.03 Hz, 1H), 8.48-8.57 (m, 3H), 8.94 (d, J=2.26 Hz, 1H), 9.10-9.18 (m, 1H), 9.35 (d, J=4.02 Hz, 1H) .

Example 17.

N-(5-Cyano-6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5-(trifluoromethyl)-1 Npyrazol- 4-carboxamide, compound 86

A. 5-Nitro-2-(1H-1,2,4-triazol-1-yl)nicotinonitrile, 17a

K ₂ CO ₃ (564.7 mg, 4.09 mmol) was added to a solution of 2-chloro-5-nitronicotinonitrile (250 mg, 1.36 mmol) 1,2,4-triazole (141.1 mg, 2.04 mmol) in MeCN (5 ml). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude yellow oil. The crude oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - petroleum ether/ethyl acetate=1:2) to give compound 17a (200 mg, 67.9%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.31 (s, 1H), 9.02 (d, J=2.51 Hz, 1H), 9.28 (s, 1H), 9 .48 (d, J=2.51 Hz, 1H).

B. 5-Amino-2-(1H-1,2,4-triazol-1-yl)nicotinonitrile, 17b

5-Nitro-2-(1H-1,2,4-triazol-1-yl)nicotinonitrile, 17a (100 mg, 0.46 mmol) was added to the Fe(0) mixture (206.7 mg, 3.7 mmol ), NH ₄ Cl (198.0 mg, 3.70 mmol) in THF (4 ml) and water (1 ml). The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with ethyl acetate (20 mlx3). The combined filtrates were concentrated to dryness to give a crude yellow solid. The crude solid was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 50/50 to 0/100) to give 17b (55 mg, 64%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.08-4.17 (m, 2H), 7.35-7.42 (m, 1H), 7.39 (d, J=2 .65 Hz, 1H), 8.17 (s, 1H), 8.93 (s, 1H).

C. N-(5-Cyano-6-(1H-1,2,4-triazol-1 -yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 86

POCl ₃ (82.4 mg, 0.54 mmol) was added to a mixture of 5-amino-2-(1H-1,2,4-triazol-1-yl)nicotinonitrile, 17b (50 mg, 0.269 mmol), 1- (quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b (82.5 mg, 0.27 mmol) and pyridine (106.2 mg, 1.34 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at 20°C for 2 hours. Water (20 ml) was added to the mixture. The mixture was extracted using dichloromethane (30 ml). The organic layer was concentrated under reduced pressure to give the crude product, which was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (65%/35% - 35%/ 65%).The crude fractions were concentrated under reduced pressure and lyophilized to dryness to give compound 86 (84 mg, 66%) in

- 155 045333 in the form of a white solid. LCMS (ESI) m/z M+1: 475.9;

'H NMR (400 MHz, methanol-d ₄ ) δ ppm 8.16-8.24 (m, 2H), 8.31-8.39 (m, 2H), 8.50 (s, 1H ), 8.55 (d, J=8.82 Hz, 1H), 8.64 (d, J=8.60 Hz, 1H), 8.88 (d, J=2.43 Hz, 1H), 9.09 (d, J=2.65 Hz, 1H), 9.35-9.43 (m, 2H).

Example 18.

N-(5-Chloro-6-cyclopropoxypyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide, compound 79

A. 3-Chloro-2-cyclopropoxy-5-nitropyridine, 18a

Cyclopropanol (4.304 g, 74.10 mmol) was slowly added to a mixture of NaH (4.042 g, 101.0 mmol) in THF (30 mL) at room temperature. The mixture was stirred at 40°C for 1 hour. 2,3-dichloro-5-nitropyridine in THF (20 ml) was added to the mixture at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (50 ml). The mixture was extracted using ethyl acetate (200 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 100/0 to 90/10) to give 3-chloro-2-cyclopropoxy-5nitropyridine, 18a (9 g, 53%) as a yellow solid.

B. 5-Chloro-6-cyclopropoxypyridin-3-amine, 18b, _18b

3-Chloro-2-cyclopropoxy-5-nitropyridine, 18a (18 g, 76.79 mmol) was dissolved in MeOH/THF/water (2:4:1, 100 ml). Fe(0) (21.47 g, 384 mmol) and NH4CI (20.54 g, 384 mmol) were added. The reaction mixture was stirred at 60°C for 2 hours. Ethyl acetate (200 ml) was added to the mixture. The precipitate was removed by filtration. The precipitate was washed with ethyl acetate (100 ml) and the filtrate was concentrated under reduced pressure. A 10% NaHCO ₃ solution (100 ml) was added to the mixture and the mixture was extracted using ethyl acetate (100 mlx2). The organic portion was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude yellow oil. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - petroleum ether/ethyl acetate=1:2) to give compound 18b (12 g, 78.3%) as a yellow oil.

'H NMR (400 MHz, CDCI3) δ ppm 0.78 (d, J=4.52 Hz, 4H), 3.43 (br.s, 2H), 4.22 (p, J=4 .58 Hz, 1H), 7.10 (d, J=2.76 Hz, 1H), 7.62 (d, J=2.51 Hz, 1H).

C. N-(5-Chloro-6-cyclopropoxypyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide, compound 79

HATU (111.6 mg, 0.294 mmol) was added to a mixture of 5-chloro-6-cyclopropoxypyridin-3-amine, 18b (58.7 mg, 0.29 mmol), 1-(quinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b (75.1 mg, 0.245 mmol) and DIEA (94.85 mg, 0.73 mmol) in DMF (3 ml). The mixture was stirred at room temperature for 2 hours. Water (10 ml) was added to the mixture and the mixture was extracted using ethyl acetate (30 ml x 2). The organic layer was separated, dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness to give a crude yellow solid. The crude solid was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - petroleum ether/ethyl acetate=0:1) to give compound 79 (90 mg, 76%) as a white solid. LCMS (ESI) m/z M+1: 473.9.

'H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (br.s, 2H), 0.77-0.83 (m, 2H), 4.33 (dt, J=6, 21, 3.04 Hz, 1H), 7.56-7.63 (m, 1H), 7.65-7.71 (m, 1H), 7.87-7.93 (m, 1H), 7 .95-8.00 (m, 1H), 8.29 (d, J=2.26 Hz, 1H), 8.33 (d, J=8.28 Hz, 1H), 8.45 (d, J=2.5' Hz, 1H), 8.51 (s, 1H), 9.06 (dd, J=4.39, 1.38 Hz, 1H), 10.80 (s, 1H).

- 156 045333

Example 19.

N-(5-Chloro-6-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide , connection 69

A. Methyl 5-amino-3-chloropicolinate, 19a o

H ₂ N-%% _19a

Stirred solution of 5-amino-2-bromo-3-chloropyridine (800 mg, 3.856 mmol), dppf (213.8 mg, 0.386 mmol) and NEt ₃ (1.17 g, 11.6 mmol) in MeOH (4 ml ) and toluene (20 ml) were carbonylated at 70°C (35 psi) using Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (314.9 mg, 0.386 mmol) as a catalyst for 16 hours. After CO uptake (1 equiv.), the catalyst was removed by filtration and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 70/30) to give methyl 5-amino-3-chloropicolinate, 19a (400 mg, 56%) as a red solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 3.95 (s, 3H), 4.20 (br.s, 2H), 7.02 (d, J=2.43 Hz, 1H), 8.01 (d, J=2.43 Hz, 1H).

B. Methyl 3-chloro-5-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)picolinate, 19b

To a solution of methyl 5-amino-3-chloropicolinate, 19a (270 mg, 1.45 mmol), 1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 4c (387, 9 mg, 1.206 mmol) and pyridine (388 μl, 4.82 mmol) in dichloromethane (3 ml) was added dropwise with POCl ₃ (221 μl, 2.41 mmol). The reaction mixture was stirred at 20°C for 1 hour. Saturated. aqueous NaHCO ₃ solution (20 ml) and the mixture was extracted using dichloromethane (20 mlx2). The combined organic extracts were washed with brine and dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give a crude yellow oil. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - petroleum ether/ethyl acetate=0:1) to give methyl 3-chloro-5-(1-(isoquinolin-4-yl)-5-(trifluoromethyl )-1H-pyrazole4-carboxamido) picolinate, 19b (190 mg, 33%) as a yellow solid. LCMS (ESI) m/z M+1: 475.9.

C. N-(5-Chloro-6-(hydrazinecarbonyl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide, 19c

To a solution of methyl 3-chloro-5-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamido)picolinate, 19b (170 mg, 0.36 mmol) in EtOH (5 ml) added 85% NH ₂ NH ₂ -H ₂ O (2 ml) at room temperature. The mixture was heated to 80°C and stirred for 4 hours. The solvent was concentrated under reduced pressure to give a red solid. The red solid was washed with a mixture of petroleum ether (5 ml) and ethyl acetate (1 ml) to give the compound

19c (160 mg, 83%) as a red solid. LCMS (ESI) m/z M+1: 476.0.

D. N-(5-Chloro-6-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 69

To a solution of N-(5-chloro-6-(hydrazinecarbonyl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide, 19c (160 mg, 0.296 mmol) and triethyl orthoformate (131.6 mg, 0.888 mmol) in toluene (3 ml) was added HOAc (5.3 mg, 0.09 mmol) at room temperature. The mixture was heated to 100°C for 2 hours. The solvent was concentrated to give a crude yellow oil. The crude oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - ethyl acetate/methanol=5:1) to give compound 69 (26.8 mg, 17%) as a white solid. LCMS (ESI) m/z M+1: 485.9;

Ή NMR (400 MHz, CDCl ₃ ) δ ppm 7.34 (d, J=7.72 Hz, 1H), 7.75-7.83 (m, 2H), 8.16 (d, J =8.16 Hz, 1H), 8.29 (s, 2H) 8.60 (s, 2H), 8.75 (d, J=3.97 Hz, 2H), 9.45 (s, 1H) .

Example 20.

N-(5 -Chloro-6-(3 -methyl-1H-1,2,4-triazol-1 -yl)pyridin-3 -yl)-1 -(isoquinolin-4-yl)-5 -(trifluoromethyl) 1H-pyrazol-4-carboxamide, compound 53 and N-(5-Chloro-6-(5-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)1-(isoquinoline- 4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 54

A. 3-Chloro-2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitropyridine (20a) and 3-chloro-2-(5-methyl-1H-1, 2,4triazol-1-yl)-5-nitropyridine (20a-1)

2,3-Dichloro-5-nitropyridine (2 g, 10.36 mmol), 3-methyl-1H-1,2,4-triazole (1.722 g, 20.73 mmol) and C ₂ CO ₃ (6.798 g, 20.73 mmol) was added to DMF (30 ml) and the reaction mixture was stirred at rt for 12 hours. The reaction mixture was quenched with water (200 ml). The mixture was extracted using ethyl acetate (100 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100:0 to 50:50) to give a mixture of compounds 20a and 20a-1 (780 mg, 31%) as a white solid.

B. 5-Chloro-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-amine (20b) and 5-chloro-6-(5-methyl-1H-1 ,2,4triazol-1-yl)pyridin-3-amine (20b-1)

A mixture of 3-chloro-2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitropyridine, 20a and 3-chloro-2-(5-methyl-1H1,2,4- triazol-1-yl)-5-nitropyridine, 20a-1 (780 mg, 1.63 mmol) was dissolved in MeOH (20 ml) and Zn(0) (1.058 g, 16.28 mmol) and aqueous NH ₄ Cl were added (20 ml). The reaction mixture was stirred at rt for

- 158 045333

h. The reaction mixture was filtered through a layer of diatomaceous earth and the layer was washed with ethyl acetate (20 mlx3). Water (50 ml) was added and the organic layer was separated, dried over Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness to give a crude mixture of compounds 20b and 20b-1 (400 mg,

59%) in the form of a yellow solid.

¹ H NMR (400 MHz, methanol-d ₄ ) δppm 2.43 (s, 3H), 2.85 (d, J=0.66 Hz, 1H), 2.99 (s, 1H), 7.21-7.23 (m, 1H), 7.82 (d, J=2.65 Hz, 1H), 7.86 (dd, J=4.85, 2.43 Hz, 1H), 8 .02 (s, 1H), 8.61-8.65 (m, 1H), 8.63 (s, 1H).

C. N-(5-Chloro-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl )-1H-pyrazol-4-carboxamide, compound 53, and N-(5-chloro-6-(5-methyl-1H-1,2,4-triazol-1yl)pyridin-3-yl)-1-( isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide, compound 54

Connection 53 Connection 5 ₄

A mixture of compounds 5-chloro-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-amine, 20b and 5-chloro-6-(5methyl-1H-1,2, 4-triazol-1-yl)pyridin-3-amine, 20b-1 (100 mg, 0.31 mmol), 1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid , 4c (263.0 mg, 0.63 mmol) and pyridine (62.0 mg, 0.78 mmol) were dissolved in dichloromethane (10 ml) and POCl ₃ (96.2 mg, 0.63 mmol) was added. The mixture was stirred at rt for 2.5 hours. Saturated. aqueous NH ₄ Cl solution (20 ml) and the mixture was extracted using dichloromethane (20 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give a crude yellow oil. The crude oil was purified by reverse phase HPLC (A: water (0.05% HCl)-CAN, B: MeCN, A/B: (48%/52%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to obtain a mixture of compounds 53 and 54 (90 mg) The mixture was separated by supercritical fluid chromatography (0.1% NH3H2O:MEOH. Mobile phase: A: CO2 B: 0.1% NH3H2O:MEOH; A/B 75/25).

Compound 53: N-(5-chloro-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide, (37.8 mg, 24.1%) as a white solid. LCMS (ESI) m/z M+1: 498.9.

^1H NMR (400 MHz, DMSO-d6) δ ppm 2.34-2.40 (m, 3H), 7.27-7.30 (m, 1H), 7.81-7.90 ( m, 1H), 7.907.97 (m, 1H), 8.33-8.41 (m, 1H), 8.66-8.72 (m, 1H), 8.74-8.82 (m, 2H), 8.86-8.98 (m, 2H), 9.60 (s, 1H).

Compound 54: N-(5-chloro-6-(5-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide (18.4 mg, 11.7%) as a white solid. LCMS (ESI) m/z M+1: 499.0.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.34-2.37 (m, 3H), 7.23-7.32 (m, 1H), 7.82-7.90 (m, 1H), 7.917.98 (m, 1H), 8.06-8.12 (m, 1H), 8.33-8.41 (m, 1H), 8.59-8.64 (m , 1H), 8.65-8.70 (m, 1H), 8.75-8.81 (m, 1H), 8.85-8.90 (m, 1H), 9.58-9.64 (m, 1H).

Example 21.

N-(3-Chloro-4-(1H-1,2,3-triazol-1-yl)phenyl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamide, connection 18

A. 1-(2-Chloro-4-nitrophenyl)-1H-1,2,3-triazole, 21a

K2CO3 (1.89 g, 13.672 mmol). The reaction mixture was stirred overnight at 55°C. The reaction mixture was concentrated to give the crude product as an oil. The crude product was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 20/80 to give 1-(2-chloro-4-nitrophenyl)-1H1,2,3-triazole, 21a (400 mg, 26 .1%) in the form of a yellow solid.

¹ H NMR (400 MHz, CDCl3) δ ppm 7.92-8.00 (m, 2H), 8.20 (s, 1H), 8.35 (dd, J=8.71, 2, 32 Hz, 1H), 8.51

- 159 045333 (d, J=2.43 Hz, 1H)

B. 3-Chloro-4-(1H-1,2,3-triazol-1-yl)aniline, 21b

To a solution of 1-(2-chloro-4-nitrophenyl)-1H-1,2,3-triazole, 21a (400 mg, 1.781 mmol) in MeOH/THF/water (5 ml/10 ml/5 ml) was added Fe(0) (497 mg, 8.905 mmol) and ammonium chloride (476 mg, 8.905 mmol). The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was filtered and the organic solvent was concentrated. Water (10 ml) was added and the mixture was extracted using ethyl acetate (15 ml x 3). The separated organic layer was dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain a crude solid. The crude solid was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 0/100 to give 3-chloro-4-(1H-1,2,3-triazol-1-yl)aniline, 21b ( 300 mg, 86.6%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 4.03 (br.s, 2H), 6.66 (dd, J=8.41, 2.15 Hz, 1H), 6.82 (d , J=1.96 Hz, 1H), 7.32 (d, J=8.61 Hz, 1H), 7.85 (d, J=14.09 Hz, 2H)

C. N-(3-Chloro-4-(1H-1,2,3-triazol-1-yl)phenyl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazol4- carboxamide, compound 18

To a solution of 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (50 mg, 0.16 mmol), 3-chloro-4-(1H-1,2,3 -triazol-1-yl) aniline, 21b (37 mg, 0.19 mmol) and pyridine (63 mg, 0.8 mmol) in dichloromethane (2 ml), POCl ₃ (49.4 mg, 0. 32 mmol). The reaction mixture was stirred at 20°C for 1 hour. Water (5 ml) was added and the reaction mixture was extracted using dichloromethane (5 ml x 3). The combined organic extracts were washed with brine and dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give a crude yellow oil. The crude oil was purified by reverse phase HPLC (A: water (0.05% ammonium hydroxide v/v), B: MeCN; subsequently: A/B (60%/40% - 70%/30%). Crude fractions concentrated under reduced pressure and lyophilized to dryness to give compound 18 (30 mg, 39%) as a white solid LCMS (ESI) m/z M+1: 483.9;

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.37 (d, J=8.38 Hz, 1H), 7.61-7.69 (m, 2H), 7.75-7.85 (m, 2H), 7.90 (s, 1H), 7.96 (s, 1H), 8.03 (s, 1H), 8.12-8.20 (m, 2H), 8.27 ( s, 1H), 8.64 (s, 1H), 9.46 (s, 1H).

Example 22.

N-(5-Cyαno-6-(2H-1,2,3-triazol-2-yl)niridin-3-yl)-1-(thieno[3,2-c]pyridin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxalamide, compound 90

A. 4-Hydrazinylthieno[3,2-c]pyridine, 22a

A mixture of 4-chlorothieno[3,2-c]pyridine (150 mg, 0.88 mmol) in hydrazine hydrate (4 ml) was stirred at 80°C for 12 hours. The mixture was extracted using dichloromethane (30 mlx2). The organic portion was concentrated under reduced pressure to give the crude product (120 mg, 82%) as a yellow solid.

B. Ethyl 1-(thieno[3,2-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 22b

Solution of 4-hydrazinylthieno[3,2-c]pyridine, 22a (120 mg, 7.26 mmol) and ethyl 2-(ethoxymethylene) - 160 045333

4,4,4-Trifluoro-3-oxobutanoate, 1f (227 mg, 0.944 mmol) in EtOH (50 ml) was stirred at 80°C for 16 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to give the crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-70:30) to give compound 22b (120 mg, 48%) as a yellow solid. LCMS (ESI) m/z M+1: 341.9.

C. 1-(Thieno[3,2-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 22c

A solution of ethyl 1-(thieno[3,2-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 22b (120 mg, 0.352 mmol) in concentrated hydrochloric acid (3 ml) stirred at 130°C for 3 hours. The solvent was concentrated under reduced pressure to give the crude product (110 mg, 100%) as a yellow solid, which was used in the next reaction without further purification. LCMS (ESI) m/z M+1: 313.8.

D. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[3,2-c]pyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 90

To a solution of 1-(thieno[3,2-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 22c (90 mg, 0.29 mmol), 5-amino- 2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, 7b (45.6 mg, 0.23 mmol) and pyridine (115.9 µl, 1.44 mmol) in dichloromethane (5 ml) POCl ₃ (52.6 µl, 0.575 mmol) was added dropwise. The reaction mixture was stirred at 20°C for 1 hour. Saturated. aqueous NaHCO ₃ solution (20 ml) and the mixture was extracted using dichloromethane (20 mlx2). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give a crude yellow oil. The crude oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - petroleum ether/ethyl acetate=0:1) to give compound 90 (71.2 mg, 51%) as a white solid. LCMS (ESI) m/z M+1: 481.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.45 (d, J=5.51 Hz, 1H), 8.11 (d, J=5.51 Hz, 1H), 8, 30 (s, 2H), 8.39 (d, J=5.51 Hz, 1H), 8.46 (d, J=5.51 Hz, 1H), 8.60 (s, 1H), 8, 88 (d, J=2.43 Hz, 1H), 9.11 (d, J=2.43 Hz, 1H), 11.46 (s, 1H).

Example 23.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-methylquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 27

A. 5-Hydrazinyl-6-methylquinoline, 23a

A solution of 6-methylquinoline-5-amine (800 mg, 5.06 mmol) in concentrated hydrochloric acid (5 ml) was stirred at 0°C for 10 min. A solution of sodium nitrite (419 mg, 6.07 mmol) and water (0.5 ml) was slowly added, subsequently stirred at 0°C for 1 hour. L-ascorbic acid (935 mg, 5.31 mmol) for 10 min. The mixture was warmed to room temperature and stirred for 1 hour and then heated at 80°C for 30 minutes. Water (4 ml) was added. The suspension was cooled to 0°C and stirred for 2 hours. The resulting mixture was basified to pH 10 with 4M aq. NaOH, extracted with ethyl acetate (30 mlx3) and dried over anhydrous Na ₂ SO ₄ . The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product, which was purified using FCC

- 161 045333 (petroleum ether:ethyl acetate=100:0-30:70) to obtain compound 23a (150 mg, 17%).

^1H NMR (400 MHz, DMSO-06) δ ppm 8.93-8.89 (m, 1H), 8.75-8.72 (m, 1H), 7.49 (d, J= 7.6 Hz, 1H), 7.46 (d, J=6.8 Hz, 1H), 7.40-7.35 (m, 1H), 4.87-4.60 (m, 1H), 2.52-2.50 (m, 2H), 2.42 (s, 3H).

B. Ethyl 1-(6-methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 23b

FT O

O, 23b

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (130 mg, 0.541 mmol), 5-hydrazinyl-6-methylquinoline, 23a (113 mg, 0.541 mmol) and ethanol (5 ml) was refluxed at 80°C for 16 hours and then cooled to room temperature. The mixture was concentrated to dryness under reduced pressure to obtain the crude product, which was purified using FCC (petroleum ether: ethyl acetate=100:0-50:50) to obtain compound 23b (130 mg, 60%).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.91 (d, J=3.2 Hz, 1H), 8.31 (s, 1H), 8.20 (d, J=9.2 Hz, 1H), 7.66 (d, J=8.8 Hz 1H), 7.42-7.29 (m, 2H), 4.41 (k, J=6.8 Hz, 2H), 2 .21 (s, 3H), 1.40 (t, J=7.2 Hz, 3H).

C. 1-(6-Methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 23c

A solution consisting of ethyl 1-(6-methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, 23b (100 mg, 0.286 mmol), NaOH (34.4 mg, 0.859 mmol) and mixture water:EtOH (3 ml, 1:2) was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure, neutralized to pH 7 with 4N aq. HCl and solid, compound 23, were collected by filtration (90 mg, crude) and used in the next reaction without further purification. LCMS (ESI): R _T =0.65 min, mass calculated for C ₁ 5H ₁₀ F ₃ N ₃ O _2-3 2 ₁ , 254, obtained m/z -322.0 [M+H]+.

D. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-methylquinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 27

POCl ₃ (45.8 mg, 0.299 mmol) was added dropwise to a solution consisting of 1-(6-methylquinolin-5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 23c (80.0 mg , 0.249 mmol), 5-chloro-6-(2I-1,2,3triazol-2-yl)pyridin-3-amine, 1j (97.4 mg, 0.498 mmol) and pyridine (5 ml). The mixture was stirred at 0°C for 1 hour. The resulting mixture was poured into sat. aqueous NaHCO ₃ (10 ml), extracted with ethyl acetate (10 ml x 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain the crude product, which was purified by preparative high performance liquid chromatography using a Boston Green ODS 150 x 30 mm x 5 column µm (27-57% (v/v) ACN and water with 0.05% HCl) to give compound 27. The product was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness with yielding compound 27 (23.5 mg, 18%). LCMS (ESI): mass calculated for C22H14ClF ₃ N8O - 498.848, obtained m/z - 499.0 [M+H]+.

1H NMR (400 MHz, DMSO-06) δ ppm 11.50 (s, 1H), 9.08 (dd, J=1.2, 4.0 Hz, 1H), 8.95 (d, J=2.0 Hz, 1H), 8.79-8.73 (m, 2H), 8.32 (d, J=8.8 Hz, 1H), 8.21 (s, 2H), 7. 98 (d, J=8.8 Hz, 1H), 7.74 (dd, J=4.4, 8.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 2.24 (s, 3H).

Example 24.

N-(5-Chloro-6-methoxypyridin-3-yl)-1 -(quinolin-5-yl)-5 -(trifluoromethyl)-1 H-pyrazole-4carboxamide, compound 7

- 162 045333

A. 1-(Quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, 24a

Oxalyl dichloride (0.0830 ml, 0.976 mmol) was added to the solution consisting of 1-(quinolin-5-yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b (200 mg, 0.651 mmol), dichloromethane (15 ml) and DMF (catalytic amount). The resulting solution was stirred at room temperature for 1 hour. The resulting solution was concentrated to dryness to give compound 24a (200 mg, crude), which was used in the next reaction without further purification.

B. N-(5-Chloro-6-methoxypyridin-3 -yl)-1 -(quinolin-5 -yl)-5 -(trifluoromethyl)-1 H-pyrazole-4carboxamide, compound 7

A solution consisting of 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, 24a (200 mg, 0.614 mmol), 5-chloro-6-methoxypyridin-3-amine ( 117 mg, 0.737 mmol) and pyridine (10 ml) were stirred at 90°C for 1 hour and then cooled to room temperature. The resulting mixture was concentrated to dryness under reduced pressure to give the crude product, which was purified by reverse phase HPLC (38-68% (v/v) CH3CN and water with 0.05% _NH3 ) to give compound 7 (74, 80 mg, 27%) as a brown solid. LCMS (ESI): mass calculated for C ₂₀ H ₁₃ ClF ₃ N ₅ O _2-447 , 07, obtained m/z - 448.1 [M+H] ⁺ .

1H NMR (400 MHz, CDCl3) δ ppm 9.03 (dd, J=1.6, 4.4 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 8 .28-8.10 (m, 3H), 7.88-7.80 (m, 1H), 7.70 (s, 1H), 7.66-7.59 (m, 2H), 7.47 (dd, J=4.4, 8.4 Hz, 1H), 4.04 (s, 3H).

Example 25.

1-(Quinolin-5-yl)-5-(trifluoromethyl)-N2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4carboxamide, compound 6

A solution consisting of 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, 24a (200 mg, 0.614 mmol), 2-(trifluoromethyl)pyridin-4-amine (119 mg, 0.737 mmol) and pyridine (10 ml) were stirred at 90°C for 1 hour and then cooled to room temperature. The resulting mixture was concentrated to dryness under reduced pressure to give the crude product, which was purified by reverse phase HPLC (43-63% (v/v) CH3CN and water with 0.05% _NH3 ) to give compound 6 (107, 30 mg, 39%) as a white solid. LCMS (ESI): mass calculated for C20H11F6N5O - 451.09, obtained m/z - 452.1 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.04 (dd, J=1.6, 4.4 Hz, 1H), 8.71 (d, J=5.6 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.88-7.81 (m, 2H), 7.67-7.57 (m, 2H), 7.49 (dd, J=4.4, 8.4 Hz, 1H).

Example 26.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-methylquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 28

- 163 045333

A. 5-Hydrazinyl-8-methylquinoline, 26a

J^^nhnh ₂ cx T J ' 26a

A solution of sodium nitrite (65.4 mg, 0.948 mmol) and water (0.5 ml) was added dropwise to a solution consisting of 8-methylquinoline-5-amine (100 mg, 0.632 mmol) and concentrated hydrochloric acid (4 ml) , at temperatures from -10°C to 0°C. The mixture was stirred at -10°C to 0°C for 1.5 hours. A solution consisting of SnCl ₂ (285 mg, 1.26 mmol) and concentrated hydrochloric acid (0.5 ml) was added dropwise at temperature from -10°C to 0°C, the mixture was subsequently stirred at room temperature for 16 hours and then filtered. The collected solid was washed with MeOH (2 mlx2) to give compound 26a (90 mg, crude), which was used in the next reaction without further purification. LCMS (ESI): mass calculated for C ₁₀ H ₁₁ N ₃ . ₁₇₃ , 214, resulting m/z - 174.2 [M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (br.s, 2H), 9.82-9.31 (m, 1H), 9.14 (d, J=4, 4 Hz, 1H), 9.05 (d, J=8.4 Hz, 1H), 7.98-7.85 (m, 1H), 7.80 (d, J=7.6 Hz, 1H) , 7.17 (d, J=8.0 Hz, 1H), 2.71 (s, 3H).

B. Ethyl 1-(8-methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 26b

Fii, 26b

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (87.8 mg, 0.366 mmol), 5-hydrazinyl-8-methylquinoline, 26a (90.0 mg, 0.366 mmol) and ethanol (3 ml) were refluxed at 80°C for 16 h and then cooled to room temperature. The mixture was concentrated to dryness under reduced pressure to give the crude product, which was purified using FCC (petroleum ether:ethyl acetate=100:0-70:30) to give compound 26b (90 mg, 70%).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.06-8.98 (m, 1H), 8.24 (s, 1H), 7.66 (d, J=8.0 Hz, 1H ), 7.58-7.43 (m, 3H), 4.41 (d, J=6.8 Hz, 2H), 2.90 (s, 3H), 1.41 (t, J=7, 2 Hz, 3H).

C. 1-(8-Methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 26c

A solution of ethyl 1-(8-methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 26b (70 mg, 0.20 mmol), NaOH (24.0 mg, 0.601 mmol) and a mixture of water:EtOH (3 ml, 1:2) was stirred at room temperature for 16 hours. The reaction mixture was neutralized to pH 7 with 4M aq. HCl and then concentrated to dryness under reduced pressure to give crude compound 26c (110 mg, crude), which was used in the next reaction without further purification. LCMS (ESI): mass calculated for C ₁₅ H ₁₀ F ₃ N ₃ O _2-321 , 254, obtained m/z - 322.0 [M+H] ⁺ .

D. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-methylquinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 28

POCl ₃ (52.7 mg, 0.344 mmol) was added dropwise to a solution of ethyl 1-(8-methylquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate, 26c (100 mg, 0.286 mmol) , 5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-amine, 1j (112 mg, 0.573 mmol) and pyridine (3 ml). The mixture was stirred at 0°C for 1 hour. The resulting mixture was poured into sat. aqueous NaHCO ₃ (10 ml), extracted using

- 164 045333 ethyl acetate (10 mlx3), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified using reverse phase HPLC (48-78% (v/v) ACN and water with 0.05% NH ₃ ) to obtain pure compound 28. The compound was suspended as (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to obtain compound 28 (39.20 mg, 27%). LCMS (ESI): mass calculated for C ₂₂ H ₁₄ ClF ₃ N ₈ O - 498.848, obtained m/z - 498.9 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.08 (dd, J=1.6, 4.0 Hz, 1H), 8.86 (d, J=2.4 Hz, 1H ), 8.68 (d, J=2.4 Hz, 1H), 8.57 (s, 1H), 8.19 (s, 2H), 7.85-7.79 (m, 2H), 7 .68 (dd, J=4.4, 8.4 Hz, 1H), 7.57 (dd, J=1.6, 8.4 Hz, 1H), 2.85 (s, 3H).

Example 27.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 65

Cl

A. 3-Methyl-5-nitroquinoline (27a) and 3-methyl-8-nitroquinoline (27a-1)

HNO ₃ (4.72 ml, 105 mmol) was added dropwise to a mixture consisting of 3-methylquinoline (5.0 g, 35 mmol) and H2SO4 (5 ml) at 0°C and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was neutralized to pH 7 with 1M aq. NaOH, extracted with ethyl acetate (30 mlx3), and the extracts were concentrated under reduced pressure, and purified using FCC (petroleum ether:ethyl acetate = 100:0-50:50) to obtain a mixture of compounds 27a and 27a-1 (4 g, thirty%). LCMS (ESI): mass calculated for C ₁₀ H ₈ N ₂ O _2-188 , 18, obtained m/z - 189.0 [M+H]+.

B. 3-Methylquinoline-5-amine, 27b

A' , 27b

A mixture of 3-methyl-5-nitroquinoline (27a) and 3-methyl-8-nitroquinoline (27a-1) (3.50 g, 9.30 mmol), MeOH (30 ml) and anhydrous Pd/C (350 mg, 5%) was added to a 500 ml hydrogenation bottle. The mixture was stirred under H ₂ (30 psi) at room temperature for 16 hours. The suspension was filtered through a pad of diatomaceous earth and the layer was washed with MeOH (100 ml). The filtrate was concentrated to dryness under reduced pressure to obtain crude compound 27b, which was purified using FCC (ethyl acetate:methanol=100:0-95:5) to obtain compound 27b (300 mg, 20%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.64 (d, J=1.6 Hz, 1H), 8.30 (s, 1H), 7.37-7.30 (m , 1H), 7.15 (d, J=8.0 Hz, 1H), 6.68 (d, J=7.2 Hz, 1H), 5.83 (s, 2H), 2.46 (s , 3H).

C. 5-Hydrazinyl-3-methylquinoline, 27c

A solution of sodium nitrite (131 mg, 1.90 mmol) and water (1 ml) was added dropwise to a solution of 3methylquinoline-5-amine, 27b (200 mg, 1.26 mmol) and concentrated hydrochloric acid (1 ml) at a temperature of -10°C to 0°C. The mixture was stirred at a temperature of -10°C to 0°C for 1.5 hours. A solution consisting of SnCl ₂ (571 mg, 2.53 mmol) and concentrated hydrochloric acid (1 ml) was added dropwise at a temperature of - 10°C to 0°C, the mixture was subsequently stirred at room temperature for 16 hours. The suspension was filtered to obtain compound 27c (200 mg, crude), which was used in the next step without purification. LCMS (ESI): mass calculated for C ₁₀ H ₁₁ N ₃ . ₁₇₃ , 214, resulting m/z - 174.0 [M+H]+.

- 165 045333

D. Ethyl 1-(3-methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 27d

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (195 mg, 0.813 mmol), 5-hydrazinyl-3-methylquinoline, 27c (200 mg, 0.813 mmol), triethylamine (164 mg, 1.63 mmol) and ethanol (2 ml) were stirred at 80°C for 16 h and then cooled to room temperature. The reaction mixture was concentrated to dryness under reduced pressure to give the crude product, which was purified using FCC (petroleum ether:ethyl acetate=100:0-60:40) to give compound 27d (100 mg, 35%).

1H NMR (400 MHz, CDC13) δ ppm 8.85 (d, J=2.0 Hz, 1H), 8.27 (d, J=8.0 Hz, 2H), 7.76-7 .70 (m, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.33-7.29 (m, 1H), 4.43 (k, J=7.2 Hz, 2H), 2.48 (s, 3H), 1.42 (t, J=7.2 Hz, 3H).

E. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylquinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 65

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (44.8 mg, 0.229 mmol) and THF (0.5 ml) was added to potassium tert-butoxide in THF (0.687 ml, 0.687 mmol, 1 M) at 0°C, a solution consisting of ethyl 1-(3-methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole was subsequently added -4carboxylate, 27d (60.0 mg, 0.229 mmol) and THF (0.5 ml). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by reverse phase HPLC (41-71% (v/v) ACN and water with 0.05% NH3) to obtain pure compound 65. The product was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to obtain compound 65 (45.40 mg, 40%). LCMS (ESI): mass calculated for C22H14CIF3N8O - 498.848, obtained m/z - 499.0 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 11.28 (br.s, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.88 (d, J= 2.4 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.60 (s, 1H), 8.31-8.27 (m, 1H), 8.20 ( s, 2H), 7.92-7.85 (m, 2H), 7.40-7.38 (m, 1H), 2.47 (s, 3H).

Example 28.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 40

A. 8-Fluoro-5-hydrazinylquinoline, 28a

A solution of sodium nitrite (95.7 mg, 1.39 mmol) and water (0.5 ml) was added dropwise to a solution consisting of 8-fluoroquinoline-5-amine (150 mg, 0.925 mmol) and conc. hydrochloric acid (4 ml, 36%) at a temperature from -10°C to 0°C. The mixture was stirred at temperatures between -10°C and 0°C for 1.5 hours. A solution of SnCl ₂ (417 mg, 1.85 mmol) and conc. hydrochloric acid (1 ml) was added dropwise at a temperature of -10°C to 0°C and the reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered. The resulting solid was washed with MeOH (1 mL x 2 ) and dried under reduced pressure to give 28a (220 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI): mass calculated for C ₉ H ₈ FN ₃ . ₁₇₇ , 178, obtained m/z -178.1 [M+H]+.

- 166 045333

B. Ethyl 1-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 28b

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (207 mg, 0.864 mmol), 8-fluoro-5-hydrazinylquinoline HCl salt, 28a (360 mg, 0.864 mmol ), triethylamine (175 mg, 1.73 mmol) and ethanol (5 ml) were refluxed at 80°C for 16 hours and then cooled to room temperature. The reaction mixture was concentrated to dryness under reduced pressure to give the crude product, which was purified using FCC (petroleum ether:ethyl acetate=100:0-70:30) to give compound 28b (100 mg, 33%).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.06 (dd, J=1.6, 4.0 Hz, 1H), 8.25 (s, 1H), 7.61-7.48 (m, 4H), 4.41 (k, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).

C. 1-(8-Fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 28c

A solution of ethyl 1-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 28b (100 mg, 0.283 mmol), NaOH (34.0 mg, 0.849 mmol) and mixture water:EtOH (3 ml, 1:2) was stirred at room temperature for 16 hours. The solution was neutralized to pH 7 with 4M aq. HCl and then concentrated to dryness under reduced pressure to give compound 28c (120 mg, crude), which was used in the next reaction without further purification. LCMS (ESI): mass calculated for C ₁₄ H ₇ F ₄ N ₃ O ₂ . _325.2 1 8, the resulting m/z is 325.9 [M+H]+.

D. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 40

POCl ₃ (56.6 mg, 0.369 mmol) was added dropwise to a solution of 1-(8-fluoroquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 28c (100 mg, 0.307 mmol) , 5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine, 1j (120 mg, 0.615 mmol) and pyridine (5 ml) at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified using reverse phase HPLC (38-68% (v/v) ACN and water with 0.05% NH3) to obtain pure compound 40. The compound was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to obtain compound 40 (20.10 mg, 13%). LCMS (ESI): mass calculated for C21H11QF4N8O 502.812, obtained m/z - 502.9 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.28 (br.s, 1H), 9.13 (dd, J=1.6, 4.0 Hz, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.60 (s, 1H), 8.20 (s, 2H), 8.00 (dd, J=4.4, 8.4 Hz, 1H), 7.87-7.78 (m, 2H), 7.67 (d, J=8.4 Hz, 1H).

Example 29.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 25

A. 3-Fluoro-5-hydrazinylquinoline, 29a

- 167 045333

A solution of sodium nitrite (95.7 mg, 1.39 mmol) and water (0.5 ml) was added dropwise to a solution consisting of 3-fluoroquinoline-5-amine (150 mg, 0.925 mmol) and concentrated hydrochloric acid (4 ml, 36%), at temperatures from -10°C to 0°C. The mixture was stirred at a temperature of -10°C to 0°C for 1.5 hours. A solution of SnCl ₂ (417 mg, 1.85 mmol) and concentrated hydrochloric acid (1 ml) was added dropwise at a temperature of -10° From to 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was filtered. The resulting solid was washed with MeOH (1 mlx2) and dried under reduced pressure to give compound 29a (220 mg, crude), which was used in the next reaction without further purification. LCMS (ESI): mass calculated for C ₉ H ₈ FN ₃ . ₁₇₇ , 178, obtained m/z -178.1 [M+H]+.

B. Ethyl 1-(3-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 29b

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (211 mg, 0.880 mmol), 3-fluoro-5-hydrazinylquinoline, 29a (220 mg, 0.880 mmol), triethylamine (178 mg, 1.76 mmol) and ethanol (5 ml) were refluxed at 80°C for 16 hours and then cooled to room temperature. The reaction mixture was concentrated to dryness under reduced pressure to obtain crude compound 29b, which was purified using FCC (petroleum ether:ethyl acetate=100:0-70:30) to obtain compound 29b (160 mg, 51%).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.94-8.89 (m, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.28 (s, 1H ), 7.83-7.76 (m, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.25-7.19 (m, 1H), 4.43 (k, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).

C. 1-(3-Fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 29c

Solution consisting of ethyl 1-(3-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 29b (160 mg, 0.453 mmol), NaOH (54.3 mg, 1.54 mmol) and a mixture of water:EtOH (3 ml, 1:2) were stirred at room temperature for 16 hours. The solution was neutralized to pH 7 with 4M aq. The HCl and the resulting solid were collected by filtration to give compound 29c (150 mg, crude), which was used in the next reaction without further purification. LCMS (ESI): mass calculated for C ₁₄ H ₇ F ₄ N ₃ O ₂ . ₃₂₅ , 2 1 8, resulting m/z - 325.9 [M+H]+.

D. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-fluoroquinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 25

POCl ₃ (5.7 mg, 0.037 mmol) was added dropwise to a solution of 1-(3-fluoroquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 29c (160 mg, 0.492 mmol) , 5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine, 1j (192 mg, 0.984 mmol) and pyridine (5 ml). The mixture was stirred at 0°C for 1 hour. The resulting mixture was poured into sat. aqueous NaHCO ₃ (10 ml), extracted with ethyl acetate (10 ml x 3), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give crude compound 25, which was purified using reverse phase HPLC (42- 72% (v/v) ACN and H2O with 0.05% NH3) to give pure compound 25. The product was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to give compound 25 (53.60 mg, 21%). LCMS (ESI): mass calculated for C ₂₁ H ₁₁ ClF ₄ N ₈ O - 502.812, obtained m/z - 502.9 [M+H]+.

^1H NMR (400 MHz, DMSO-d6) δ ppm 11.24 (br.s, 1H), 9.14 (d, J=2.8 Hz, 1H), 8.88 (d, J =2.4 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H), 8.61 (s, 1H), 8.40 (d, J=7.6 Hz, 1H), 8.21 (s, 2H), 8.03-7.96 (m, 2H), 7.52-7.49 (m, 1H).

Example 30.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-methylisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 36

- 168 045333, ^C|

A. 4-(2-(Diphenylmethylene)hydrazinyl)-6-methylisoquinoline, 30a

Blend of 4-bromo-6-methylisoquinoline (500 mg, 2.25 mmol), benzophenone hydrazone (442 mg, 2.25 mmol), BINAP (140 mg, 0.225 mmol), palladium (II) acetate (50.5 mg, 0.225 mmol), sodium tert-butoxide (325 mg, 3.38 mmol) and toluene (3 ml) were heated to 100°C and stirred for 20 hours under N2 and then cooled to room temperature. The mixture was filtered and concentrated to give a black oil, which was purified using FCC (petroleum ether:ethyl acetate=30:70) to give compound 30a (280 mg, 37%) as a yellow solid. LCMS (ESI): mass calculated for C ₂₃ H ₁₉ N3.337.4, obtained m/z - 338.0 [M+H]+.

B. 4-Hydrazinyl-6-methylisoquinoline hydrochloride, 30b

Mixture of 4-(2-(diphenylmethylene)hydrazinyl)-6-methylisoquinoline, 30a (260 mg, 0.771 mmol), conc. hydrogen chloride (10 ml, 12 M in water, 43 mmol) and EtOH (1 ml) were stirred for 20 hours at room temperature. The solid was collected by filtration, washed with DCM (3 mLx2) and dried under reduced pressure to give 30b (145 mg, 76%) as a yellow solid, which was used in the next reaction without further purification. LCMS (ESI): Mass calculated for C ₁₀ HhN _3-173 , 2, obtained m/z - 174.1 [M+H]+.

C. Ethyl 1-(6-methylisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 30c

Mixture of 4-hydrazinyl-6-methylisoquinoline hydrochloride, 30b (145 mg, 0.589 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (200 mg, 0.707 mmol), triethylamine (0.246 ml , 1.77 mmol) and EtOH (5 ml) were heated to 90°C and stirred for 20 hours and then cooled to room temperature. The mixture was concentrated under reduced pressure to give a yellow oil, which was purified using FCC (ethyl acetate:petroleum ether=40:60) to give compound 30c (96 mg, 47%) as a yellow solid. LCMS (ESI): mass calculated for C17H14F3N3O2.349.3, obtained m/z - 350.1 [M+H]+.

D.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-methylisoquinolin-4-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 36

Ethyl 1-(6-methylisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 30c (90.0 mg, 0.258 mmol) in THF (0.5 ml) and 5-chloro- 6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (50.4 mg, 0.258 mmol) in THF (0.5 ml) was added to a suspension of potassium tert-butoxide (43 .4 mg, 0.386 mmol) in THF (2 ml) at 0°C. The mixture was stirred at room temperature for 20 hours and then evaporated under reduced pressure to obtain a yellow solid, which was purified by reverse phase HPLC (CH3CN in alkaline water (0.05% NH3-H2O) 45-75%, v/v). The resulting residue was resuspended in water (50 ml) and the resulting mixture was lyophilized to dryness to completely remove residual solvent. Compound 36 (40.40 mg, 31%) was obtained as an off-white solid

- 169 045333 colors. LCMS (ESI): mass calculated for C ₂₂ H ₁₄ ClF ₃ N ₈ O - 498.8, obtained m/z - 498.9 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.28 (br.s, 1H), 9.53 (s, 1H), 8.88 (d, J=2.0 Hz, 1H ), 8.72 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.63 (s, 1H), 8.28 (d, J=8.4 Hz, 1H ), 8.20 (s, 2H), 7.72 (dd, J=1.6, 8.8 Hz, 1H), 7.08 (s, 1H), 2.53-2.52 (m, 3H).

Example 31.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylisoquinolin-1-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 9

Cl

A. 3-Methylisoquinoline 2-oxide, 31a

3-Chloroperoxybenzoic acid (2.53 g, 14.7 mmol) was added portionwise to a mixture consisting of 3-methylisoquinoline (1.91 g, 13.3 mmol) and DCM (10 ml). The resulting mixture was stirred for 2 days at room temperature, then diluted with DCM (100 ml), washed with aqueous NaHCO ₃ (70 mlx2) and saline (70 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give 31a (1.4 g, 66%) as a yellow solid, which was used in the next reaction without further purification. LCMS (ESI): mass calculated for C ₁₀ H ₉ NO - 159.2, obtained m/z - 160.0 [M+H]+.

B. 1-Chloro-3-methylisoquinoline, 31b

To a stirred solution of 3-methylisoquinoline 2-oxide, 31a (1.40 g, 8.80 mmol) in anhydrous CH ₂ Cl ₂ (5 ml) at 0°C was added phosphorus oxychloride (0.902 ml, 9.67 mmol), and DMF (0.338 mL, 4.40 mmol) was then added dropwise under argon. The resulting reaction mixture was warmed to room temperature and stirred for 20 hours. A saturated aqueous sodium carbonate solution was slowly added to the reaction mixture to adjust the pH to 7-8. The resulting mixture was separated and the aqueous phase was extracted with dichloromethane. The organic extracts were combined and washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give crude compound 31b, which was purified using flash column chromatography (ethyl acetate:petroleum ether=20:80) to give compound 31b (670 mg, 43%) as a yellow oil. LCMS (ESI): mass calculated for C ₁₀ H ₈ ClN - 177.6, obtained m/z - 177.9 [M+H]+.

C. 1-Hydrazinyl-3-methylisoquinoline, 31c

NH >4 VjH ₂ , 31s

A mixture of 1-chloro-3-methylisoquinoline, 31b (670 mg, 3.77 mmol), hydrazine hydrate (4.44 g, 75.4 mmol) and EtOH (5 ml) was heated to 90 °C and stirred for 20 h , and then cooled to room temperature. The mixture was concentrated to give a yellow solid, which was dissolved in ethyl acetate (100 ml), washed with water (100 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give compound 31c (715 mg, 98 %) in the form of a yellow solid. The crude product was used directly without further purification. LCMS (ESI): mass calculated for C10H11N3.173.2, obtained m/z - 174.0 [M+H]+.

D. Ethyl 1-(3-methylisoquinolin-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 31d

- 170 045333

A mixture of 1-hydrazinyl-3-methylisoquinoline, 31c (710 mg, 4.10 mmol), ethyl 2-(ethoxymethylene)-4,4,4trifluoro-3-oxobutanoate, 1f (1.27 g, 4.51 mmol) and EtOH (15 ml) was heated to 90°C and stirred for 20 hours and then cooled to room temperature. The mixture was concentrated under reduced pressure to give a yellow solid, which was treated with MeOH (5 ml) and stirred for 15 minutes. The solid was collected by filtration, washed with MeOH (3 mlx2) and dried under reduced pressure at room temperature to give compound 31d (823.2 mg, 56%). LCMS (ESI): mass calculated for C ₁₇ H ₁₄ F ₃ N ₃ O ₂ . ₃₄₉ , 3, obtained m/z - 350.0 [M+H] ⁺ .

1H NMR (400 MHz, CDCI3) δ 8.27 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.77-7.66 (m, 2H), 7.59 -7.48 (m, 2H), 4.42 (k, J=7.2 Hz, 2H), 2.73 (s, 3H), 1.42 (t, J=7.2 Hz, 3H) .

E. 1-(3-Methylisoquinolin-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 31e

Mixture of ethyl 1-(3-methylisoquinolin-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 31d (220 mg, 0.630 mmol), lithium hydroxide (45.2 mg, 1.89 mmol) , MeOH (1 ml), THF (1 ml) and water (1 ml) were stirred for 20 h at room temperature. The pH of the mixture was adjusted to 2 using 6N aq. HCl. Organic solvents were removed under reduced pressure. The residue was diluted with water (30 ml) and extracted using ethyl acetate (30 mlx2). The organic layers were combined and dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give compound 31e (140 mg, 69%) as a yellow solid. LCMS (ESI): mass calculated for Ci ₅ Hi ₀ F ₃ N ₃ O _2-321 , 2, obtained m/z -322.0 [M+H]+.

F.

N(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylisoquinolin-1-yl)-5(trifluoromethyl)-1H-pyrazole -4-carboxamide, compound 9

Phosphorus oxychloride (0.049 ml, 0.52 mmol) was added dropwise to a solution consisting of 1-(3methylisoquinolin-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 31e (140 mg, 0.436 mmol), 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (93.8 mg, 0.479 mmol) and pyridine (2 ml). The mixture was stirred at 0°C for 1 hour and then concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC using a Phenomenex Gemini C18 150 x 25 mm x 5 µm column (50-80% (v/v) CH ₃ CN and water with 0.05% NH ₃ ) to obtain pure compound 9. The compound was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to obtain compound 9 (96.10 mg, 44%) in the form of a white solid. LCMS (ESI): mass calculated for C22Hi4C1F ₃ N8O - 498.8, obtained m/z - 498.9 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ ppm 11.28 (br.s, 1H), 8.89 (s, 1H), 8.70 (s, 1H), 8.63 (s, 1H), 8.21 (s, 2H), 8.11 (d, J=8.4 Hz, 1H), 8.04 (s, 1H), 7.90 (m, 1H), 7.73 ( m, 1H), 7.60 (d, J=8.4 Hz, 1H), 2.68 (s, 3H).

Example 32.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methylisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 66 ci

A. 4-(2-(Diphenylmethylene)hydrazinyl)-1-methylisoquinoline, 32a

A mixture consisting of 4-bromo-1-methylisoquinoline (800 mg, 3.60 mmol), (diphenylmethylene)hydrazine (707 mg, 3.60 mmol), BINAP (224 mg, 0.360 mmol), palladium(P) acetate ( 80.9 mg, 0.360 mmol), t-BuONa (1.04 g, 10.8 mmol) and 1,4-dioxane (20 ml) were stirred at 100°C for 16 h and then cooled to room temperature. The suspension was filtered through a pad of diatomaceous earth and the layer was washed with ethyl acetate (30 ml). The filtrate was concentrated to dryness under reduced

- 171 045333 pressure to obtain a crude product, which was added to water (15 ml). The resulting mixture was extracted using ethyl acetate (20 mlx3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to give crude compound 32a, which was purified using FCC (petroleum ether:ethyl acetate=4:1) to give compound 32a (500 mg, 41 %) as brown oil. LCMS (ESI): mass calculated for C ₂₃ H ₁₉ N ₃ - _337.16 , obtained m/z - 337.9 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.74 (s, 1H), 8.11-8.05 (m, 1H), 7.87 (s, 1H), 7.70- 7.64 (m, 4H), 7.63-7.59 (m, 1H), 7.58-7.53 (m, 2H), 7.49-7.43 (m, 2H), 7. 41-7.31 (m, 4H), 2.91 (s, 3H).

B. 4-Hydrazinyl-1-methylisoquinoline, 32b

Conc. HCl (5 ml) was added to a solution consisting of 4-(2-(diphenylmethylene)hydrazinyl)-1methylisoquinoline, 32a (500 mg, 1.48 mmol) and EtOH (2 ml). The resulting solution was stirred at room temperature for 16 hours. The resulting mixture was added to dichloromethane (20 ml), filtered and the layer was washed with dichloromethane (10 ml). The organic solution was concentrated to dryness under reduced pressure to give compound 32b (940 mg, crude), which was used in the next reaction without further purification. LCMS (ESI): mass calculated for C ₁₀ H ₁₁ N _3-173 , 10, obtained m/z - 174.1 [M+H]+.

C. Ethyl 1-(1-methylisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 32c

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (984 mg, 4.10 mmol), 4-hydrazinyl-1-methylisoquinoline, 32b (840 mg, 3.41 mmol), triethylamine (0.950 ml, 6.83 mmol) and ethanol (20 ml) were stirred at 80°C for 16 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product, which was added to water (10 ml). The resulting mixture was extracted using ethyl acetate (20 mlx3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to give compound 32c, which was purified using FCC (petroleum ether:ethyl acetate=4:1) to give compound 32c (250 mg, 21% ) in the form of a brown solid. LCMS (ESI): mass calculated for C ₁₇ H ₁₄ F ₃ N ₃ O ₂ - _349.10 , obtained m/z - 349.9 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.45 (s, 1H), 8.29-8.21 (m, 2H), 7.77-7.68 (m, 2H), 7 ,28-7.23 (m, 1H), 4.42 (k, J=7.2 Hz, 2H), 3.07 (s, 3H), 1.41 (t, J=7.2 Hz, 3H).

D.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methylisoquinolin-4-yl)-5 (trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 66

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (193 mg, 0.988 mmol) and THF (1 ml) and a solution consisting of Ethyl 1-(1-methylisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, 32c (230 mg, 0.658 mmol) and THF (1 ml) were added to the solution consisting of potassium tert-butoxide (1, 98 ml, 1.98 mmol, 1M in THF) at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was added to water (5 ml) and extracted with ethyl acetate (15 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC using a Kromasil 150 x 25 mm x 10 µm column (35-65% (v/v) CH3CN and water with 0.05% NH ₃ ) to give pure compound 66. The product was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to give compound 66 (126.40 mg, 38% ). LCMS (ESI): mass calculated for C ₂₂ H ₁₇ ClN ₈ O - 444.12, obtained m/z - 449.0 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.29 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.68 (d, J=2 ,4 Hz, 1H), 8.62 (d, J=9.2 Hz, 2H), 8.42 (d, J=8.0 Hz, 1H), 8.20 (s, 2H), 7, 94-7.83 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 3.04 (s, 3H).

- 172 045333

Example 33.

N-(5-Chloro-6-methoxypyridin-3-yl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxamide, compound 23

A. Ethyl 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, 33a

4-chloroisoquinoline (103.6 mg, 0.633 mmol), dimer of palladium(P) chloride (pi-cinnamyl) (9.1 mg, 0.0176 mmol), n-[2-( di-1adamantylphosphino)phenyl]morpholine (22 mg, 0.0475 mmol), sodium tert-butoxide (110 mg, 1.145 mmol), hydrazine hydrate (0.0614 ml, 1.032 g/ml, 1.266 mmol) and toluene (6, 3 ml) in air at room temperature. The dark yellow mixture was rapidly bubbled with argon gas for 1 min, and the vial was subsequently sealed and stirred at 100°C under argon overnight (14 h). The reaction mixture was further cooled to room temperature and treated with ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (0.123 ml, 1.235 g/ml, 0.633 mmol) and stirred at 100°C under air ( in a closed state). After 20 min at 100°C, the reaction mixture was concentrated at 46°C under reduced pressure to obtain a light green residue. The residue was taken into THF (3 ml) and stirred at 60°C for 5 min to dissolve compound 33a from the reaction mixture as much as possible, and the reaction mixture was subsequently cooled to room temperature. The amber solution in THF (assumed 0.2 M) was divided into two vials (4 mL) and used immediately in the next step without further purification or characterization.

B. N-(5-Chloro-6-methoxypyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide, compound 23

C.I.

A crude solution of ethyl 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 33a in THF (step A, expected 106 mg, 0.316 mmol) was treated with 5-chloro-6-methoxypyridine- 3amine (52.7 mg, 0.332 mmol) and stirred the mixture until homogeneous. The mixture was subsequently treated with KOtBu (56 mg, 0.499 mmol) in one dose and the resulting dark reddish reaction mixture was stirred at room temperature in air (closed) for 45 minutes. Next, about 100 mg of thiol-functionalized silica gel (1.2 mmol/g, ~3 eq.) was added and the reaction mixture was stirred at room temperature for another 45 min. The mixture was subsequently filtered and concentrated to give a dark residue (136 mg), which was dissolved in a co-solvent (0.14 ml DMSO/0.2 ml DCM) and purified by flash column chromatography (10-100% EtOAc in heptane at 24 column volumes) . Concentration from MeOH provided 23 as a white foam (11.6 mg, 8% from a total of 3 steps).

1H NMR (400 MHz, CDCl3) δ ppm 9.43 (s, 1H), 8.54 (s, 1H), 8.08-8.26 (m, 5H), 7.77 (quind, 2H), 7.34 (br.d, J=7.58 Hz, 1H), 4.03 (s, 3H); MS m/e 448.0 (M+H).

Example 34.

X-(5-Cyano-6-methoxypyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 24

CN

A solution of crude ethyl 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 33a in THF (106 mg, 0.316 mmol expected) was worked up as described in Example 33, Step B, replacing

- 173 045333

5-chloro-6-methoxypyridin-3-amine with 5-amino-2-methoxynicotinonitrile (47.4 mg, 0.318 mmol), and quenched the reaction mixture with solid NH ₄ Cl rather than thiol-functionalized silica gel. Purification was achieved at the next concentration from MeOH, compound 24 (18 mg, 13% total from 3 steps).

^1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.45 (s, 1H), 8.61 (s, 1H), 8.45 (s, 2H), 8.24 (s, 1H) , 8.17 (d, J=7.58 Hz, 1H), 7.74-7.83 (m, 2H), 7.69 (s, 1H), 7.28-7.37 (m, 1H ), 4.08 (s, 3H). MS m/e 439.2 (M+H).

Example 35.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,6-naphthyridin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 100

A. 5-Hydrazinyl-1,6-naphthyridine, 35a

A solution of 5-chloro-1,6-naphthyridine (150 mg, 0.91 mmol) was added to hydrazine hydrate (3 ml), the mixture was heated to 80°C and stirred for 16 hours. The mixture provided compound 35a as a solid, collected by filtration. (100 mg, 42%). LCMS (ESI) m/z M+1: 161.1.

B. Ethyl 1-(1,6-naphthyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 35b

A solution consisting of 5-hydrazinyl-1,6-naphthyridine, 35a (100 mg, 0.38 mmol) and ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (119.5 mg, 0.50 mmol) in ethanol (5 ml) was stirred at 80°C for 4 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain crude compound 35b.

The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-70:30) to give compound 35b as a yellow solid (100 mg, 85.5%). LCMS (ESI) m/z M+1: 337.1.

C. 1-(1,6-Naphthyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 35c

To a solution of ethyl 1-(1,6-naphthyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 35b (90 mg, 0.27 mmol) in water (1 ml) and ethanol ( 1 ml) NaOH (12.85 mg, 0.32 mmol) was added at room temperature. The mixture was stirred for 3 hours. 2N HCl (aq) was added to the mixture to adjust to pH 2. The solvent was removed under reduced pressure to give crude compound 35c as a white solid (82.5 mg, 100%). LCMS (ESI) m/z M+1: 308.8.

D. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,6-naphthyridin-5-yl)-5-( trifluoromethyl)1H-pyrazole-4-carboxamide, compound 100

Phosphoryl trichloride (49.4 mg, 0.32 mmol) was added to a mixture of 1-(1,6-naphthyridin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 35c (82 mg, 0 .27 mmol), 5-amino-2-(2H-1,2,3triazol-2-yl)nicotinonitrile, 7b (59.4 mg, 0.32 mmol) and pyridine (107 μl, 1.33 mmol) in dichloromethane at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Saturated solution was added to the mixture. NH ₄ Cl (aq) solution (10 ml). The mixture was extracted using

- 174 045333 dichloromethane (30 ml). The organic extracts were washed with water (5 ml) and brine (10 ml), dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0 - ethyl acetate/methanol=90:10). The solvent was removed under reduced pressure to obtain compound 100 as a white solid (56.4 mg, 43%). LCMS (ESI) m/z M+1: 447.0.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.63 (dd, J=8.60, 4.19 Hz, 1H), 8.03 (s, 2H), 8.15 (s, 1H), 8.16-8.22 (m, 2H), 8.27 (s, 1H), 8.73 (d, J=5.73 Hz, 1H), 8.83 (d, J=2 .65 Hz, 1H), 8.96 (d, J=2.65 Hz, 1H), 9.21 (dd, J=4.30, 1.65 Hz, 1H).

Example 36 N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[2,3-c]pyridin-7-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 99

A. 7-Hydrazinylfuro[2,3-c]pyridine, 36a

7-ChloroFuro[2,3-c]pyridine (300 mg, 1.95 mmol) was dissolved in ethanol (5 ml), hydrazine hydrate (345 mg, 5.86 mmol) was added and the reaction mixture was stirred at 110°C for 16 h. The reaction mixture was concentrated under reduced pressure to give crude compound 36a as a yellow solid. Compound 36a was purified by silica gel flash column chromatography (dichloromethane/MeOH 100/0 to 80/20) to give 36a as a yellow solid (250 mg, 83.9%). LCMS (ESI) m/z M+1: 150.1.

B. Ethyl 1-(furo[2,3-c]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 36b

7-Hydrazinylfuro[2,3-e]pyridine, 36a (250 mg, 1.64 mmol) was dissolved in ethanol (10 ml), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate was added, 1f (788 mg, 3.28 mmol) and stirred the reaction mixture at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude yellow oil. The oil was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 80/20) to give 36b as a yellow oil (360 mg, 68%). LCMS (ESI) m/z M+1: 325.9.

C. 1-(Furo[2,3-c]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 36c

Concentrated HCl (4.7 mL) was added to ethyl 1-(furo[2,3-c]pyridin-7-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxylate, 36b (170 mg, 0.52 mmol) and stirred the reaction mixture at 130°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound 36c as a yellow solid (160 mg, 98%), which was used in the next reaction without further purification. LCMS (ESI) m/z M+1: 297.9.

D.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[2,3-c]pyridin-7-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 99

- 175 045333

1-(Furo[2,3-c]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 36c (160 mg, 0.51 mmol), 5-amino-2- (2H-1,2,3-triazol-2-yl)nicotinonitrile, 7b (63.8 mg, 0.34 mmol) and pyridine (122 mg, 1.54 mmol) were dissolved in dichloromethane (3 ml) and trichloride was added phosphoryl (78.8 mg, 0.51 mmol). The mixture was stirred at 25°C for 16 hours. Saturated. aqueous NaHCO ₃ solution (20 ml) and the mixture was extracted using dichloromethane (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give crude compound 99 as a yellow oil. The oil was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (65%/35% - 40%/60%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness yielding compound 99 as a yellow solid (65 mg, 41%) LCMS (ESI) m/z M+1: 465.9;

1H NMR (400 MHz, DMSO-d6) δ ppm 11.41 (s, 1H), 9.06 (d, J=2.4 Hz, 1H), 8.83 (d, J=2, 4 Hz, 1H), 8.53 (s, 1H), 8.48 (d, J=5.7 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.29 (s, 2H), 7.95 (dd, J=0.9, 5.7 Hz, 1H), 7.13 (dd, J=0.9, 2.2 Hz, 1H).

Example 37.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[3,2-c]pyridin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 94

A. 4-Hydrazinylfuro[3,2-c]pyridine, 37a

A mixture of 4-chlorofuro[3,2-c]pyridine (200 mg, 1.30 mmol) in hydrazine (6.52 g, 130 mmol) was stirred at 80°C for 12 hours. The reaction mixture was extracted using dichloromethane (30 mlx2). The organic layer was separated and concentrated to give 37a as a yellow solid (0.15 g, 77%).

B. Ethyl 1-(furo[3,2-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 37b

A solution consisting of 4-hydrazinylfuro[3,2-c]pyridine, 37a (150 mg, 1.01 mmol) and ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (314 mg, 1.31 mmol) in ethanol (5 ml) was stirred at 80°C for 3 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:070:30) to give crude compound 37b as a yellow solid (170 mg, 51%). LCMS (ESI) m/z M+1: 325.9.

C. 1-(Furo[3,2-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 37c

A mixture of ethyl 1-(furo[3,2-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 37b (170 mg, 0.52 mmol) in concentrated HCl (4, 4 ml) was stirred at 110°C for 5 hours. The solvent was removed under reduced pressure to obtain compound 37c as a yellow solid

- 176 045333 colors (155 mg, 100%). LCMS (ESI) m/z M+1: 297.9.

D. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[3,2-c]pyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 94

Phosphoryl trichloride (61.6 μL, 0.67 mmol) was added to a mixture of 1-(Furo[3,2-c]pyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 37c ( 100 mg, 0.34 mmol), 5-amino-2-(2I-1,2,3triazol-2-yl)nicotinonitrile, 7b (75.2 mg, 0.40 mmol) and pyridine (135 µl, 1, 68 mmol) in dichloromethane at 0°C. The reaction mixture was stirred at room temperature for 2 hours. Saturated solution was added to the mixture. aqueous solution of NH4Cl (aq) (10 ml). The mixture was extracted using dichloromethane (30 ml). The organic extracts were washed with water (5 ml) and brine (10 ml), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (65%/35% - 35%/65%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to obtain compound 94 as a white solid (73.6 mg, 46%) LCMS (ESI) m/z M+1: 447.0;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.13 (d, J=1.32 Hz, 1H), 7.94-7.99 (m, 1H), 8.30 ( s, 2H), 8.33 (d, J=2.21 Hz, 1H), 8.49 (d, J=5.73 Hz, 1H), 8.55 (s, 1H), 8.85 ( d, J=2.43 Hz, 1H), 9.07 (d, J=2.43 Hz, 1H), 11.45 (s, 1H).

Example 38.

1-(Cinnolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 93

A. 4-Hydrazinylcinnoline, 38a

4-Chlorocinnoline (212 mg, 1.288 mmol) and hydrazine (0.4 mL, 1.021 g/mL, 12.745 mmol) were placed in a stirrer vial and the mixture was deaerated and purged with argon (4x). Within 1-2 minutes at room temperature, the reaction mixture turned into a homogeneous amber solution and spontaneously heated to an orange paste. The reaction mixture was subsequently heated at 110°C for 5 min. The reaction mixture was allowed to cool to room temperature, water (8 ml) was added to the resulting paste, and the mixture was filtered. The filter cake was washed with water (4 mlx2) and dried under reduced pressure to obtain compound 38a as a yellow powder (142.1 mg, 69%).

B. Ethyl 1-(cinnolin-4-yl)-5-(trifluoromethyl)-1I-pyrazole-4-carboxylate, 38b

A solution consisting of 4-hydrazinylcinnoline, 38a (100 mg, 0.51 mmol) and ethyl 2-(ethoxymethylene)4,4,4-trifluoro-3-oxobutanoate, 1f (244 mg, 1.02 mmol) in ethanol ( 5 ml) was stirred at 80°C for 3 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain crude compound 38b.

The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-70:30) to obtain crude compound 38b as a solid.

- 177 045333 va yellow (90 mg, 53%). LCMS (ESI) m/z М+1:336.9.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.42 (t, J=7.17 Hz, 3H), 4.43 (k, J=7.28 Hz, 2H), 7.54 ( d, J=8.60 Hz, 1H), 7.87 (t, J=7.61 Hz, 1H), 7.99 (td, J=7.72, 1.10 Hz, 1H), 8, 33 (s, 1H), 8.74 (d, J=8.60 Hz, 1H), 9.33 (s, 1H).

C. 1-(Cinnolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 38c

A mixture of ethyl 1-(cinnolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 38b (90 mg, 0.27 mmol) in concentrated HCl (2.23 ml) was stirred at 110°C for 5 hours. The solvent was removed under reduced pressure to obtain compound 38c as a yellow solid (82 mg, 100%). LCMS (ESI) m/z M+1: 308.9.

D. 1-(Cinnolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 93

Phosphoryl trichloride (163.2 mg, 1.01 mmol) was added to a mixture of 1-(cinnolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 38c (82 mg, 0.27 mmol) , 5-amino-2-(2H-1,2,3triazol-2-yl)nicotinonitrile, 7b (59.4 mg, 0.32 mmol) and pyridine (126 mg, 1.60 mmol) in dichloromethane at 0° WITH. The reaction mixture was stirred at room temperature for 2 hours. Saturated solution was added to the mixture. NH ₄ Cl (aq) (10 ml). The mixture was extracted using dichloromethane (30 mlx2). The organic extracts were washed with water (5 ml) and brine (10 ml), dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (62%/38% - 32%/68%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to obtain compound 93 as a pale yellow solid (20 mg, 16%) LCMS (ESI) m/z M+1: 477.0;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.58 (d, J=8.38 Hz, 1H), 8.01-8.10 (m, 1H), 8.15 (t , J=7.50 Hz, 1H), 8.29 (s, 2H), 8.71 (s, 1H), 8.74 (d, J=8.60 Hz, 1H), 8.87 (d , J=2.65 Hz, 1H), 9.09 (d, J=2.65 Hz, 1H), 9.77 (s, 1H), 11.37 (s, 1H).

Example 39.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 92

A. 8-Fluoro-4-hydrazinylquinoline, 39a

4-Chloro-8-fluoroquinoline (300 mg, 1.65 mmol) was dissolved in ethanol (5 ml), hydrazine hydrate (292 mg, 5.0 mmol) was added and the reaction mixture was stirred at 80°C for 16 hours. Reaction the mixture was concentrated under reduced pressure to obtain crude compound 39a as a yellow solid. The solid was purified by silica gel flash column chromatography (dichloromethane/MeOH 100/0 to 80/20) to give 39a as a yellow solid (350 mg, 82%). LCMS (ESI) m/z M+1: 178.1.

B. Ethyl 1-(8-fluoroquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 39b

- 178 045333

A solution consisting of 8-fluoro-4-hydrazinylquinoline, 39a (350 mg, 1.35 mmol) and ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (648 mg, 2.70 mmol ) in ethanol (10 ml) was stirred at 80°C for 16 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:080:20). The solvent was removed under reduced pressure to give 39b as a yellow solid (780 mg, 61%).

C. 1-(8-Fluoroquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 39c

A mixture of ethyl 1-(8-fluoroquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 39b (150 mg, 0.43 mmol) in concentrated HCl (10 ml) was stirred at 130°C for 4 hours. The solvent was concentrated under reduced pressure to give compound 39c as a yellow solid (140 mg, 100%). LCMS (ESI) m/z M+1: 325.9.

D. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroquinolin-4-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 92

Phosphoryl trichloride (81.2 mg, 0.53 mmol) was added to a mixture of 1-(8-fluoroquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 39c (150 mg, 0.46 mmol), 5-amino-2-(2H-1,2,3triazol-2-yl)nicotinonitrile, 7b (65.7 mg, 0.35 mmol) and pyridine (126 mg, 1.60 mmol) in dichloromethane ( 3 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. Saturated solution was added to the mixture. NH ₄ Cl (aq) (10 ml). The mixture was extracted using dichloromethane (30 mlx2). The organic layer was washed with water (5 ml) and brine (10 ml), dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (57%/43% 27%/73%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to give 92 as a yellow solid (54 mg, 31%) LCMS (ESI) m/z M+1: 493.9;

^1H NMR (400 MHz, DMSO-d6) δ ppm 11.41 (s, 1H), 9.21 (d, J=4.4 Hz, 1H), 9.10 (d, J=2 .2 Hz, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.68 (s, 1H), 8.29 (s, 2H), 8.01 (d, J=4 .4 Hz, 1H), 7.82-7.67 (m, 2H), 7.14 (d, J=8.4 Hz, 1H).

Example 40.

N-(5-Chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 91

Phosphoryl trichloride (38.5 mg, 0.25 mmol) was added to a mixture of 1-(quinolin-5-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxylic acid, 3b (51.4 mg, 0.17 mmol), 5-chloro-6-(oxazol-2-yl)pyridin-3-amine, 6b (60 mg, 0.25 mmol) and pyridine (60 mg, 0.75 mmol) in dichloromethane (3 ml) at 0°C. Reaction mixture

- 179 045333 was stirred at room temperature for 16 hours. Saturated solution was added to the mixture. NaHCO ₃ (aq) (20 ml). The mixture was extracted using dichloromethane (20 mlx2). The organic layer was washed with water (5 ml), dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (64%/36% - 34%/66%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to obtain compound 91 as a yellow solid (40 mg, 49%) LCMS (ESI) m/z M+1: 484.9;

^1H NMR (400 MHz, DMSO-d6) δ ppm 11.40 (s, 1H), 9.11 (dd, J=2.1, 3.6 Hz, 1H), 9.01 (d , J=1.5 Hz, 1H), 8.66 (s, 1H), 8.59 (d, J=2.2 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H ), 8.32 (s, 1H), 8.05-7.94 (m, 2H), 7.79-7.71 (m, 2H), 7.49 (s, 1H).

Example 41.

N-(5-Cyano-6-cyclopropoxypyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide, compound 88

A. 2-Cyclopropoxy-5-nitronicotinonitrile, 41a

2-Chloro-5-nitronicotinonitrile (300 mg, 1.64 mmol) and cyclopropanol (380 mg, 6.54 mmol) were added to potassium carbonate (339 mg, 2.45 mmol), and the mixture was stirred at room temperature overnight . The mixture was concentrated to dryness and diluted in ethyl acetate (5 ml). Water (10 ml) was added to the reaction mixture. The mixture was extracted using ethyl acetate (10 mlx3). The combined organic extracts were dried over Na2SO4, filtered and the filtrate concentrated to dryness to give crude compound 41a. The crude product was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 60/40) to give 41a as a yellow solid (310 mg, 92%).

1H NMR (400 MHz, DMSO-d6) δ ppm 0.85-0.90 (m, 4H), 4.52-4.58 (m, 1H), 9.18 (d, J=2 .76 Hz, 1H), 9.35 (d, J=2.76 Hz, 1H).

B. 5-Amino-2-cyclopropoxynicotinonitrile, 41b

Fe(0) (422 mg, 7.56 mmol) and NH ₄ Cl (404 mg, 7.56 mmol) were added to a solution of 2-cyclopropoxy-5nitronicotinonitrile, 41a (310 mg, 1.51 mmol) in THF (10 ml ), methanol (10 ml) and water (10 ml). The reaction mixture was stirred at 65°C for 2 hours. The mixture was filtered. Added sat. an aqueous solution of NaHCO ₃ to bring the pH of the reaction mixture to 7-8. The mixture was extracted using ethyl acetate (10 mlx3). The organic extracts were dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give 41b as a yellow solid (280 mg, 87%). LCMS (ESI) m/z M+1: 175.8.

C. N-(5-Cyano-6-cyclopropoxypyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide, compound 88

2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (186 mg, 0.49 mmol) was added to the solution of 1-(quinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b (100 mg, 0.325 mmol), 5-amino-2-cyclopropoxynicotinonitrile, 41b (97.1 mg, 0.46 mmol) and triethylamine (142 µl, 0. 81 mmol) in DMF (2 ml). The reaction mixture was stirred at room temperature for 1 hour. Water (5 ml) was added to the mixture. The aqueous portion was extracted using dichloromethane (5 mlx3). The separated organic layer was dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (74%/26% - 44%/56%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to obtain compound 88 in the form of a white solid (90 mg, 43%). LCMS (ESI) m/z M+1:

465.0;

^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.75-0.80 (m, 2H), 0.81-0.87 (m, 2H), 4.39 (tt, J =6.12, 3.14 Hz, 1H), 7.63-7.73 (m, 2H), 7.91-7.95 (m, 1H), 7.96-8.02 (m, 1H ), 8.34 (d, J=8.38 Hz, 1H), 8.52-8.58 (m, 2H), 8.75 (d, J=2.43 Hz, 1H), 9.08 (dd, J=4.08, 1.65 Hz, 1H), 11.01 (br.s, 1H).

Example 42.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(phthalazin-1-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 102

A. 1 -G idrasinylphthalazine, 42a

A mixture of 1-chlorophthalazine (350 mg, 2.13 mmol) in hydrazine (5.32 g, 106.3 mmol) was stirred at 80°C for 4 hours. The mixture was extracted using dichloromethane (50 mlx2). The organic layer was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-0:100) to give crude compound 42a as a yellow solid (0.25 g, 73.3%).

B. Ethyl 1-(phthalazin-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 42b

A solution consisting of 1-hydrazinylphthalazine, 42a (250 mg, 1.56 mmol) and ethyl 2-(ethoxymethylene)4,4,4-trifluoro-3-oxobutanoate, 1f (750 mg, 3.12 mmol) in ethanol ( 5 ml) was stirred at 80°C for 3 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-70:30) to give crude compound 42b as a yellow solid (160 mg, 27.4%). LCMS (ESI) m/z M+1: 336.9.

C. 1-(Phthalazin-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 42c

A mixture of ethyl 1-(phthalazin-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 42b (160 mg, 0.43 mmol) in concentrated HCl (3.5 ml) was stirred at 110°C for 5 hours. The solvent was removed under reduced pressure to obtain compound 42c as a yellow solid (140 mg, 100%). LCMS (ESI) m/z M+1: 308.9.

D. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(phthalazin-1-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 102

- 181 045333

Phosphoryl trichloride (218.2 mg, 1.42 mmol) was added to a mixture of 1-(phthalazin-1-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 42c (130 mg, 0.36 mmol) , 5-amino-2-(2H-1,2,3triazol-2-yl)nicotinonitrile, 7b (79.5 mg, 0.43 mmol), pyridine (170 mg, 2.14 mmol) in dichloromethane (10 ml ) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. Water (20 ml) was added to the mixture. The mixture was extracted using dichloromethane (20 mlx2). The organic portion was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (65%/35% - 35%/65%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to obtain compound 102 as a white solid (15 mg, 9%) LCMS (ESI) m/z M+1: 477.0;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.81 (d, J=8.38 Hz, 1H), 8.14-8.25 (m, 2H), 8.44 ( d, J=7.72 Hz, 1H), 8.73 (s, 1H), 8.89 (d, J=2.43 Hz, 1H), 9.12 (d, J=2.43 Hz, 1H), 9.98 (s, 1H), 11.45 (s, 1H).

Example 43.

Methyl 3 -chloro-5 -(3 -chloro-5-( 1 -(isoquinolin-4-yl)-5 -(trifluoromethyl)-1 H-pyrazole-4carboxamido)picolinamido)picolinate, compound 44

Mixture of 6-bromo-5-chloropyridin-3-amine (500 mg, 2.41 mmol), 1,1-bis(diphenylphosphino)ferrocene (134 mg, 0.24 mmol) and triethylamine (732 mg, 7.23 mmol ) in MeOH (3 ml) and toluene (15 ml) was heated at 70°C in a CO atmosphere (35 psi) with palladium(II) dichloro[1,1'bis(diphenylphosphino)ferrocene]dichloromethane adduct (catalyst , 197 mg, 0.24 mmol) and the mixture was stirred overnight. After CO uptake (1 eq), the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 50/50) to give 43a as a red solid (300 mg, 67%).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 3.96 (s, 3H), 4.14-4.24 (m, 2H), 7.03 (d, J=2.26 Hz, 1H ), 8.03 (d, J=2.51 Hz, 1H).

B. Methyl 3-chloro-5-(3-chloro-5-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamido)picolinamido)picolinate, compound 44 o

Phosphoryl trichloride (29.8 mg, 0.32 mmol) was added dropwise to a solution of 1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 4c (50 mg, 0.16 mmol), methyl 5-amino-3chloropicolinate, 43a (38.8 mg, 0.21 mmol) and pyridine (64.7 mg, 0.80 mmol) in dichloromethane (2 ml). The reaction mixture was stirred at room temperature for 1 hour. Water (5 ml) was added to the mixture. The aqueous portion was extracted using dichloromethane (5 mlx3). The separated organic extracts were dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (55%/45% - 25%/75%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to obtain compound 44 as a white solid (22 mg, 21%) LCMS (ESI) m/z M+1: 629.8;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.90 (s, 3H), 7.30 (d, J=8.38 Hz, 1H), 7.84-8.00 (m , 2H), 8.39 (d, J=8.16 Hz, 1H), 8.58 (dd, J=10.69, 1.87 Hz, 2H), 8.68 (s, 1H), 8 .81 (s, 1H), 9.01 (dd, J=10.03, 1.87 Hz, 2H),

- 182 045333

9.64 (s, 1H), 11.36 (d, J=19.40 Hz, 2H).

Example 44.

Ν-(5-ΧΛορ-6-(2Η-1,2,3-triazol-2-yl)pyridin-3-yl)-5-ethyl-1-(quinolin-5-yl)-1 H-pyrazol- 4carboxamide, compound 17

A. 3-(Ethoxymethylene)-1-methoxyhexane-2,4-dione, 44a

A solution consisting of ethyl 3-oxopentanoate (1.0 g, 6.9 mmol), triethoxymethane (3.1 g, 21 mmol) and acetic anhydride (20 ml) was stirred at 135 °C for 16 h and then cooled to room temperature. The resulting mixture was concentrated to dryness under reduced pressure to give crude compound 44a (1.8 g, crude), which was used in the next reaction without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.69-7.54 (m, 1H), 4.33-4.15 (m, 4H), 2.70 (dd, J=7, 6, 13.2 Hz, 2H), 1.41-1.26 (m, 6H), 1.13-1.05 (m, 3H).

B. 5-Hydrazinylquinoline, 44b

ΗΝ—ΛΛ , 44b

A solution consisting of 5-aminoquinoline (1.0 g, 6.9 mmol) and concentrated hydrochloric acid (5 ml) was stirred at 0°C (ice/water) for 10 minutes. A solution of sodium nitrite (0.57 g, 8.3 mmol) and water (0.5 ml) was added to the cold reaction mixture over 10 min and stirred at 0°C (ice/water) for 1 h L-ascorbic acid (1.3 g, 7.3 mmol) was added to the reaction mixture over 10 minutes. The resulting mixture was warmed to room temperature and stirred for 50 minutes. The reaction mixture was subsequently heated at 80°C for 20 min and water (4 ml) was added.

The suspension was again cooled to 0° C. (ice/water) and stirred for 2 hours. The solid was collected by filtration and washed with methanol to give compound 44b (870 mg, 79%).

1H NMR (400 MHz, DMSO-d6) δ ppm 10.01 (br.s, 1H), 9.28-9.13 (m, 2H), 8.06-7.86 (m, 3H ), 7.33-7.20 (m, 1H).

C. Ethyl 5-ethyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate, 44c

A solution consisting of 3-(ethoxymethylene)-1-methoxyhexane-2,4-dione, 44a (755 mg, 3.77 mmol), 5-hydrazinylquinoline, 44b (500 mg, 3.14 mmol) and ethanol (15 ml), stirred at 80°C for 16 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to give the crude product, which was purified using FCC (dichloromethane:methanol=10:1) to give compound 44c (700 mg, 75%) as a brown solid. The solid was purified by reverse phase HPLC (95% water containing 0.038% TFA (solvent A) and 5% acetonitrile containing 0.02% TFA (solvent B), then gradient to 5% solvent A and 95% solvent B) .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.17-9.11 (m, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.17 (s , 1H), 8.06 (t, J=8.0 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.83-7.78 (m, 1H), 7 .77-7.71 (m, 1H), 4.30 (k, J=7.2 Hz, 2H), 2.78-2.68 (m, 2H), 1.33 (t, J=7 .2 Hz, 3H), 0.92 (t, J=7.6 Hz, 3H).

D. 5-Ethyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid, 44d

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A solution consisting of lithium hydroxide hydrate (298 mg, 7.11 mmol) and water (5 ml) was added to a solution consisting of ethyl 5-ethyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate , 44c (700 mg, 2.37 mmol) and ethanol (10 ml). The resulting solution was stirred at room temperature for 16 hours. The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product, which was poured into water (3 ml) and acidified with 3N HCl to pH 5. The precipitate was removed by filtration, the filter residue was washed with water (3 ml) and subsequently dried under reduced pressure to obtain compound 44d (400 mg, 63%) as a brown solid. LCMS (ESI): R _T =0.54 min, mass calculated for C ₁₅ H ₁₃ N ₃ O ₂ . ₂₆₇ , 10, resulting m/z - 268.0 [M+H]+. Purification by reverse phase HPLC (95% water containing 0.038% TFA (solvent A) and 5% acetonitrile containing 0.02% TFA (solvent B), followed by a gradient to 5% solvent A and 95% solvent B) allowed receive connection 44d.

^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.55 (br.s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.10 (s, 1H), 7.97-7.91 (m, 1H), 7.82 (d, J=7.2 Hz, 1H), 7, 63-7.53 (m, 2H), 2.77-2.65 (m, 2H), 0.88 (t, J=7.6 Hz, 3H).

E. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-ethyl-1-(quinolin-5-yl)-1H-pyrazole -4carboxamide, compound 17

POCl ₃ (172 mg, 1.12 mmol) was added dropwise to a solution consisting of 5-ethyl-1-(quinolin-5yl)-1H-pyrazole-4-carboxylic acid, 44d (250 mg, 0.935 mmol), 5 -chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-amine, 1j (201 mg, 1.03 mmol) and pyridine (5 ml) at 0°C. The resulting mixture was stirred at 0°C for 1 hour. Saturated. aqueous NaHCO ₃ (10 ml) and the mixture was extracted using ethyl acetate (15 ml x 3). The organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude material was purified by reverse phase HPLC (40-50% (v/v) CH ₃ CN and water with 0.05% NH ₃ ) to give compound 17 (100 mg). Compound 17 was further purified by reverse phase HPLC (30-60% (v/v) CH ₃ CN and water with 10 mM NH4HCO3) to give pure compound 17, which was suspended in water (10 ml), frozen using dry ice /acetone and subsequently lyophilized to dryness to obtain compound 17 (56.50 mg, 13%). LCMS (ESI): R _T =4.51 min, mass calculated for C ₂₂ H ₁₇ ClN ₈ O - 444.12, obtained m/z - 445.0 [M+H]+.

1H NMR (400 MHz, CDCl3) δ ppm 9.02 (dd, J=1.6, 4.4 Hz, 1H), 8.78 (d, J=2.4 Hz, 1H), 8 .54 (d, J=2.4 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7 .96 (s, 2H), 7.89-7.83 (m, 1H), 7.65-7.57 (m, 2H), 7.46 (dd, J=4.4, 8.4 Hz , 1H), 2.88 (br.s, 2H), 1.07 (t, J=7.6 Hz, 3H).

Example 45.

Ν-(5-Χλορ-6-(2Η- 1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1 H-indazol-4-yl)-5 -(trifluoromethyl)- 1Hpyrazole-4-carboxamide, compound 68

A. 4-(2-(Diphenylmethylene)hydrazinyl)-1H-indazole, 45 a

Mixture consisting of 4-bromo-1H-indazole (1.50 g, 0.760 mmol), (diphenylmethylene)hydrazine (1.49 g, 7.61 mmol), t-BuONa (2.19 g, 22.8 mmol ), Pd ₂ (dba) ₃ (697 mg, 0.760 mmol), Xantphos (440 mg, 0.760 mmol) and 1,4-dioxane (20 ml) were stirred at 110°C for 24 hours under N ₂ atmosphere. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a residue, which was purified by FCC (petroleum ether:ethyl acetate=1:2) to give compound 45a (1 g, 42%).

1H NMR (400 MHz, CDC13) δ ppm 10.37 (br.s, 1H), 8.52 (s, 1H), 7.95 (s, 1H), 7.67-7.56 ( m, 5H), 7.427.33 (m, 5H), 7.25-7.21 (m, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.54 (d, J =7.6 Hz, 1H).

B. 4-Hydrazinyl-1H-indazole, 45b

Mixture consisting of 4-(2-(diphenylmethylene)hydrazinyl)-1H-indazole, 45a (800 mg, 2.56 mmol), conc. HCl (10 ml) and ethanol (5 ml) were stirred at room temperature for 16 hours. Ethanol was removed under reduced pressure and the aqueous phase was extracted using ethyl acetate (20 ml x 2). The extracts were concentrated to dryness under reduced pressure to give compound 45b (450 mg, 95%).

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.50 (br.s, 3H), 8.17 (s, 1H), 7.28-7.20 (m, 1H), 7 .09 (d, J=8.5 Hz, 1H), 6.55 (d, J=7.3 Hz, 1H).

C. Ethyl 1-(1H-indazol-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 45c/, 45c

Mixture consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, compound 1f (39.0 mg, 0.160 mmol), 4-hydrazinyl-1H-indazole, 45b (30.0 mg, 0.160 mmol), triethylamine (18.0 mg, 0.180 mmol) and ethanol (3 ml) were stirred at 80°C for 16 hours. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure to obtain a residue, which was purified using FCC (petroleum ether:ethyl acetate=2:1) to give crude compound 45c (550 mg). The product from chromatography (550 mg) was further purified by preparative HPLC (32-62% (v/v) CH3CN and water with 0.05% NH3) to obtain compound 45c, which was suspended in water (10 ml), the mixture was frozen with using dry ice/acetone and subsequently lyophilized to dryness to give compound 45c (260 mg, 33%).

1H NMR (400 MHz, CDCI3) δ ppm 11.01 (br.s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.65 (d, J= 8.4 Hz, 1H), 7.50-7.46 (m, 1H), 7.23 (d, J=7.2 Hz, 1H), 4.42 (k, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).

D. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1H-indazol-4-yl)-5 -(trifluoromethyl )-1Hpyrazole-4-carboxamide, compound 68

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (79.6 mg, 0.410 mmol) and THF (1 ml) was added dropwise to a solution of t-BuOK (1.02 ml, 1.02 mmol, 1 M in THF) at 0°C. Subsequently, a solution consisting of ethyl 1-(1H-indazol-4-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxylate, 45c (20.0 mg, 0.0600 mmol) and THF (1 ml) was added dropwise ). The mixture was warmed to room temperature and stirred for 16 hours and then quenched with water and extracted with ethyl acetate (50 ml x 3). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to give a residue, which was purified by reverse phase HPLC (26-56% (v/v) CH ₃ CN and water with 0 .05% KH ₃ ) to give pure compound 68. The product was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to give compound 68 (70 mg, 44%).

1H NMR (400 MHz, DMSO-d6) δ ppm 13.63 (br.s, 1H), 11.29 (br.s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.54 (s, 1H), 8.20 (s, 2H), 7.88 (s, 1H), 7.82 ( d, J=8.4 Hz, 1H), 7.60-7.51 (m, 1H), 7.32 (d, J=7.6 Hz, 1H).

Example 46.

1-(Naphthalen-1-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4carboxamide, compound 3

POC13 (90.1 mg, 0.588 mmol) was added dropwise to a solution consisting of 1-(naphthalen-1-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 2b (150 mg, 0.490 mmol) , 2-(trifluoromethyl)pyridine- 185 045333

4-amine (87.3 mg, 0.539 mmol) and pyridine (3 ml). The mixture was stirred at 0°C for 1 hour. The resulting mixture was concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative high performance liquid chromatography using a Kromasil 150x25 mmx10 μm column (55-55% (v/v) ACN and water with 0.05% NH ₃ ) to obtain pure compound 3. The product was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to obtain compound 3 (76.90 mg, 35%) .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.28 (br.s, 1H), 8.72 (d, J=6.0 Hz, 1H), 8.56 (s, 1H), 8.25 (d, J=6.4 Hz, 2H), 8.15 (d, J=7.6 Hz, 1H), 7.99 (d, J=4.8 Hz, 1H) , 7.83-7.76 (m, 1H), 7.75-7.60 (m, 3H), 7.12 (d, J=8.0 Hz, 1H).

Example 47.

1-(Naphthalen-1-yl)-5-(trifluoromethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4carboxamide, compound 4

POCl ₃ (120 mg, 0.784 mmol) was added dropwise to a solution consisting of 1-(naphthalen-1-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 2b (200 mg, 0.653 mmol), 5-(trifluoromethyl)pyridin3-amine (116 mg, 0.718 mmol) and pyridine (3 ml). The mixture was stirred at 0°C for 1 hour. The resulting mixture was concentrated to dryness under reduced pressure to obtain the crude product, which was purified using reverse phase HPLC (54-84% (v/v) ACN and water with 0.05 % NH3) to obtain pure compound 4. The product was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to obtain compound 4 (81.70 mg, 28%). LCMS (ESI): R _T =4.32 min, mass calculated for C ₂₁ H ₁₂ F ₆ N ₄ O - 450.337, obtained m/z - 451.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 11.15 (br.s, 1H), 9.14 (s, 1H), 8.77 (s, 1H), 8.62 (s, 1H), 8.55 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.15 (d, J=7.6 Hz, 1H), 7.83-7, 77 (m, 1H), 7.75-7.61 (m, 3H), 7.12 (d, J=8.0 Hz, 1H).

Example 48.

N-(5-Cyanopyridin-3-yl)-1-(naphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 5

POCl ₃ (22.9 mg, 0.149 mmol) was added dropwise to a solution consisting of 1-(naphthalen-1-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 48b (200 mg, 0.653 mmol ), 5-aminonicotinonitrile (85.6 mg, 0.718 mmol) and pyridine (5 ml). The mixture was stirred at 0°C for 1 hour. The resulting mixture was washed with water (20 ml), extracted with ethyl acetate (10 mlx3), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC (46-76% (v/v) ACN and water with 0.05% NH ₃ ) to give pure compound 5 (74.90 mg, 28%). LCMS (ESI): R _T =5, 12 min, mass calculated for C ₂₁ H ₁₂ F ₃ N ₅ O - 407.348, obtained m/z - 408.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 11.15 (s, 1H), 9.12 (d, J=2.4 Hz, 1H), 8.81 (d, J=2, 0 Hz, 1H), 8.65 (t, J=2.0 Hz, 1H), 8.55 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.17 -8.12 (m, 1H), 7.81-7.76 (m, 1H), 7.75-7.61 (m, 3H), 7.13 (d, J=8.4 Hz, 1H ).

Example 49.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(difluoromethyl)-1-(isoquinolin-1-yl)-1Hpyrazol-4 -carboxamide, compound 56

1-hydrazinyl isoquinoline, 10a (44.9 mg, 0.282 mmol), THF (0.56 ml, 0.5 M, 0.28 mmol), ethyl 2-(ethoxymethylene)-4,4 were placed in a 4 ml vial with a stirrer -difluoro-3-oxobutanoate/THF (0.56 ml, 0.5 M, 0.28 mmol) and the resulting amber homogeneous solution were stirred at room temperature

- 186 045333 (closed) for 10 minutes, followed by stirring at 70°C for 1 hour. The reaction mixture was subsequently cooled to room temperature and treated with calcium sulfate (184 mg, 1.352 mmol) and stirred (closed) within 10 min. The reaction mixture was further cooled to room temperature, treated with 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3amine, 1j (55.7 mg, 0.284 mmol) and 1.01 M KOtBu /THF (0.42 ml, 0.424 mmol) and the resulting dark reaction mixture was stirred at room temperature for 3 hours. The mixture was partitioned between 5 M NH ₄ Cl (1 ml) and ethyl acetate (1 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to give a clear red/amber oil (119 mg). This oil was purified by flash column chromatography on a 12 g Silicycle HP column (50-100% EtOAc in heptane using 10 column volumes, subsequently isocratic) to yield crude compound 56 (43 mg) as a beige solid. The solid was crystallized from MeOH (1 ml) to give the compound as an off-white powder (31.3 mg, 24%) after washing the MeOH crystals (2x0.5 ml).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.72-8.75 (m, 1H), 8.55-8.57 (m, 1H), 8.51 (d, J=5, 56 Hz, 1H), 8.398.44 (m, 1H), 8.34 (s, 1H), 7.97-8.02 (m, 2H), 7.96 (s, 2H), 7.88- 7.91 (m, 1H), 7.80-7.87 (m, 1H), 7.67-7.73 (m, 1H), 7.40 (t, J=53.1 Hz, 1H) ; MS m/e 467.1 (M+H).

Example 50.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-isopropyl-1-(quinolin-5-yl)-1H-pyrazol-4carboxamide , connection 26

A. Ethyl 2-(ethoxymethylene)-4-methyl-3-oxopentanoate, 50a

A solution consisting of ethyl 4-methyl-3-oxopentanoate (500 mg, 3.16 mmol), triethoxymethane (1.41 mg, 9.48 mmol) and Ac ₂ O (5 ml) was stirred at 130°C for 16 h and then cooled to room temperature and concentrated to dryness under reduced pressure to give compound 50a (550 mg, crude), which was used in the next reaction without further purification.

B. Ethyl 5-isopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate, 50b

Solution consisting of ethyl 2-(ethoxymethylene)-4-methyl-3-oxopentanoate, 50a (550 mg, 2.57 mmol), 5-hydrazinylquinoline, 13a (408 mg, 2.57 mmol) and ethanol (5 ml) stirred at 80°C for 16 hours and then cooled to room temperature and concentrated to dryness under reduced pressure to give the crude product, which was purified using FCC (dichloromethane:methanol=100:090:10) to give compound 50b (450 mg , 57%). LCMS (ESI): R _T =0.75 min, mass calculated for C ₁₈ H ₁₉ N ₃ O _2-309 , 3 62, obtained m/z - 310.0 [M+H]+. The compound was further purified by reverse phase HPLC (95% water containing 0.038% TFA (solvent A) and 5% acetonitrile containing 0.02% TFA (solvent B) and then gradient to 5% solvent A and 95% solvent B).

C. 5-Isopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid, 50c

A solution consisting of ethyl 5-isopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate, 50b (450 mg, 1.46 mmol), LiOH (183 mg, 4.36 mmol) and mixture water:EtOH (6 ml, 1:2) was stirred at room temperature for 16 hours. The solution was neutralized to pH 7 with 4M aq. The HCl and solid were collected by filtration to give compound 50c (280 mg, crude), which was used in the next step without purification. LCMS (ESI): R _T =0.62 min, mass calculated for C ₁₆ H ₁₅ N ₃ O _2-281 , 3 09, obtained m/z - 282.0 [M+H] ⁺ .

D. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-isopropyl-1-(quinolin-5-yl)-1H-pyrazole -4carboxamide, compound 26

- 187 045333

POCl ₃ (183 mg, 1.19 mmol) was added dropwise to a solution consisting of 5-isopropyl-1(quinolin-5-yl)-1H-pyrazol-4-carboxylic acid, 50c (280 mg, 0.995 mmol), 5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine, 1j (389 mg, 1.99 mmol) and pyridine (5 ml). The mixture was stirred at 0°C for 1 hour.

The resulting mixture was poured into sat. aqueous NaHCO ₃ (10 ml), extracted with ethyl acetate (10 ml x 3), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified using reverse phase HPLC (40-70 % (v/v) ACN and H ₂ O with 0.05% NH ₃ ) to obtain pure compound 26. Compound 26 was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness with yielding compound 26 (48.60 mg, 10%). LCMS (ESI): RT=4.79 min, mass calculated for C ₂₃ H1 ₉ ClN ₈ O - 458.903, obtained m/z - 459.0 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.70 (s, 1H), 9.04 (dd, J=1.6, 4.4 Hz, 1H), 8.91 (d, J=2.8 Hz, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.48 (s, 1H), 8.30 (d, J=8.8 Hz, 1H) , 8.18 (s, 2H), 7.99-7.95 (m, 1H), 7.83-7.82 (m, 1H), 7.64 (dd, J=4.4, 8, 4 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 3.10-3.00 (m, 1H), 1.28-1.13 (m, 6H).

Example 51.

N-(5 -Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-5 -isobutyl-1 -(quinolin-5 -yl)-1 H-pyrazol- 4carboxamide, compound 16

A. Ethyl 2-(ethoxymethylene)-5-methyl-3-oxohexanoate, 51a

A solution consisting of ethyl 5-methyl-3-oxohexanoate (500 mg, 2.90 mmol), triethoxymethane (1.29 mg, 8.71 mmol) and Ac2O (5 ml) was stirred at 130 °C for 16 h The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure to give crude compound 51a (580 mg, 88%), which was used in the next step without purification.

B. Ethyl 5-isobutyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate, 51b

A solution consisting of ethyl 2-(ethoxymethylene)-5-methyl-3-oxohexanoate, 51a (430 mg, 1.89 mmol), 5-hydrazinylquinoline, 13a (300 mg, 1.89 mmol) and ethanol (10 ml) , refluxed at 80°C for 16 hours and then cooled to room temperature and concentrated to dryness under reduced pressure to obtain crude compound 51b, which was purified using FCC (dichloromethane:methanol=100:0-95:5) to give compound 51b (330 mg, 54%).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.22-9.15 (m, 1H), 8.49-8.41 (m, 1H), 8.20 (s, 1H), 8.14-8.06 (m, 1H), 7.97 (d, J=6.8 Hz, 2H), 7.85-7.77 (m, 1H), 4.29 (d, J= 6.8 Hz, 2H), 2.74 (d, J=7.2 Hz, 2H), 1.61-1.48 (m, 1H), 1.31 (t, J=6.8 Hz, 3H), 0.70-0.50 (m, 6H).

C. 5-Isobutyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid, 51c

Solution consisting of ethyl 5-isobutyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate, 51b (200 mg,

- 188 045333

0.618 mmol), LiOH (77.9 mg, 1.86 mmol) and eoga:EtOH (6 mL, 1:2) were stirred at room temperature for 16 hours. The reaction mixture was neutralized to pH 7 with 4N aq. HCl, extracted with ethyl acetate (10 mlx3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness under reduced pressure to give crude compound 51c (160 mg), which was used in the next reaction without further purification.

D. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-isobutyl-1-(quinolin-5-yl)-1H-pyrazole -4carboxamide, compound 16

POCl ₃ (74.8 mg, 0.488 mmol) was added dropwise to a solution consisting of 5-isobutyl-1(quinolin-5-yl)-1H-pyrazol-4-carboxylic acid, 51c (140 mg, 0.474 mmol), 5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine, 1j (87.4 mg, 0.447 mmol) and pyridine (5 ml). The mixture was stirred at 0°C for 1 hour. The resulting mixture was washed with water (20 ml), extracted with ethyl acetate (10 mlx3), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by reverse phase HPLC (40-70% (v/v) ACN and water with 0.05% NH ₃ ) to give pure compound 16. Compound 16 was suspended in water (10 ml), the mixture was frozen with using dry ice/acetone and subsequently lyophilized to dryness to obtain compound 16 (24.30 mg, 11%). LCMS (ESI): R _T =3.66 min, mass calculated for C ₂₄ H ₂₁ ClN ₈ O - 472.93, obtained m/z - 473.0 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.63 (br.s, 1H), 9.05-9.02 (m, 1H), 8.91-8.89 (m , 1H), 8.72-8.71 (m, 1H), 8.55 (s, 1H), 8.30-8.26 (m, 1H), 8.19 (s, 2H), 7, 99-7.93 (m, 1H), 7.85-7.81 (m, 1H), 7.69-7.61 (m, 2H), 2.85-2.78 (m, 2H), 1.66-1.57 (m, 1H), 0.62 (d, J=6.0 Hz, 6H).

Example 52.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-1-(quinolin-5-yl)-1H-pyrazol-4carboxamide , connection 39

A. Ethyl 2-(ethoxymethylene)-3-oxobutanoate, 52a

A solution consisting of ethyl 3-oxobutanoate (10.0 g, 76.8 mmol), triethyl orthoformate (38.3 g, 230 mmol) and acetic anhydride (100 ml) was stirred at 135°C for 18 hours. The mixture was concentrated to dryness under reduced pressure to give compound 52a (21 g, crude), which was used in the next reaction without further purification.

1H NMR (400 MHz, CDCl3) δ ppm 7.64, 7.61 (s, 1H), 4.30-4.18 (m, 4H), 2.32, 3.38 (s, 3H ), 1.40-1.27 (m, 6H).

B. Ethyl 5-methyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate, 52b

A mixture consisting of ethyl 2-(ethoxymethylene)-3-oxobutanoate, 52a (1.50 g, 8.06 mmol), 5-hydrazinylquinoline, 13a (1.28 g, 8.06 mmol), triethylamine (0.89 g, 8.86 mmol) and ethanol (15 ml), stirred at 80°C for 16 hours. The mixture was concentrated to dryness under reduced pressure to obtain a crude residue, which was purified using FCC (petroleum ether: ethyl acetate = 2:11:2) to give compound 52b (520 mg, 23%).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.02-8.97 (m, 1H), 8.32-8.27 (m, 1H), 8.16 (s, 1H), 7 .83 (dd, J=7.2,

- 189 045333

8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.56 (dd, J=1.2, 7.2 Hz, 1H), 7.44 (dd, J=4.0, 8.4 Hz, 1H), 7.27 (s, 1H),

4.40-4.34 (m, 2H), 2.38 (s, 3H), 1.43-1.39 (m, 3H).

C. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)trimethyl-3-yl)-5-methyl-1-(quinolin-5-yl)-1H-pyrazole -4carboxamide, compound 39

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (194 mg, 0.990 mmol) and THF (2 ml) was added dropwise to the solution t-BuOK (3.3 ml, 3.3 mmol, 1M in THF) at 0°C. A solution consisting of ethyl 5-methyl-1-(quinolin-5-yl)-1H-pyrazol-4-carboxylate, 52b (186 mg, 0.660 mmol) and THF (2 ml) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours and then quenched with water and extracted with ethyl acetate (50 ml x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and the filtrate concentrated to dryness under reduced pressure to give crude compound 39, which was purified by reverse phase chromatography (33-43% (v/v) CH3CN and water with 0.05% NH ₃ ) to obtain pure compound 39. The product was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to obtain compound 39 (61.3 mg, 22%). LCMS (ESI): R _T =4.16 min, mass calculated for C ₂₁ H ₁₅ ClN ₈ O - 430.850, obtained m/z - 431.0 (M+H)+.

¹ H NMR (400 MHz, CDCl3) δ ppm 9.02 (dd, J=1.6, 4.0 Hz, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H), 8.33 (d, J=8.4 Hz, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 7.95 (s, 2H), 7.89-7.83 (m, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.60 (d, J=7.2 Hz , 1H), 7.47 (dd, J=4.4, 8.4 Hz, 1H), 2.47 (s, 3H).

Example 53.

Ν-(5-Χλορ-6-(2Η-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(1-methoxyethyl)-1-(quinolin-5-yl)-1Hpyrazole -4-carboxamide, compound 35

A. Ethyl 4-methoxy-3-oxopentanoate, 53 a

Bis(1H-imidazol-1-yl)methanone (8.57 g, 52.8 mmol) was added to a solution consisting of 2 methoxypropanoic acid (5.00 g, 48.0 mmol) and THF (100 ml) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. In a separate flask, isopropylmagnesium chloride (110 ml, 144 mmol, 1.3 M in THF) was added dropwise to a solution consisting of 3-ethoxy-3-oxopropanoic acid (9.52 g, 72.0 mmol) and THF (90 ml) at 0°C. The mixture was stirred at room temperature for 3 hours. This solution was added dropwise to the acylimidazole solution at 0°C and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with an aqueous solution of citric acid (25 ml, 10 wt.%) and extracted using ethyl acetate (100 mlx3). The combined organic extracts were washed with sat. aqueous NaHCO3, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give a residue, which was purified using FCC (petroleum ether:ethyl acetate=10:1) to give compound 53a (3.6 g, 43%) .

'H NMR (400 MHz, CDCl3) δ ppm 4.21-4.19 (m, 2H), 3.86-3.79 (m, 1H), 3.39-3.38 (m, 3H), 3.36 (s, 2H), 1.29-1.26 (m, 6H).

B. Ethyl 2-(ethoxymethylene)-4-methoxy-3-oxopentanoate, 53b

A solution consisting of ethyl 4-methoxy-3-oxopentanoate, 53a (3.60 g, 20.6 mmol), triethyl orthoformate (9.19 g, 1.72 mmol) and acetic anhydride (30 ml) was stirred at 135° C for 18 hours. Mixture

- 190 045333 was cooled to room temperature and concentrated to dryness under reduced pressure to give compound 53b (5.4 g), which was used in the next reaction without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.70 (s, 0.5H), 7.58 (s, 0.5H), 4.30-4.21 (m, 4H), 3.60 (k, J=7.2 Hz,

1H), 3.35, 3.32 (s, 3H), 1.38-1.29 (m, 9H).

C. Ethyl 5-(1-methoxyethyl)-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate, 53c

Mixture consisting of ethyl 2-(ethoxymethylene)-4-methoxy-3-oxopentanoate, 53b (600 mg, 2.61 mmol), 5-hydrazinylquinoline, 13a (414 mg, 2.61 mmol), triethylamine (290 mg, 2.87 mmol) and ethanol (12 ml), stirred at 80°C for 16 hours. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure to obtain a residue, which was purified using FCC (dichloromethane:methanol=10:1 ) to give compound 53c (300 mg, 35%).

^1H NMR (400 MHz, CDC4) δ ppm 9.00-8.93 (m, 1H), 8.28 (d, J=8.4 Hz, 1H), 8.17 (s, 1H ), 7.80 (dd, J=7.2, 8.4 Hz, 1H), 7.65 (br.d, J=7.2 Hz, 1H), 7.62-7.56 (m, 1H), 7.41 (dd, J=4.0, 8.4 Hz, 1H), 5.29-5.14 (m, 1H), 4.44-4.32 (m, 2H), 3 .33-2.91 (m, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.36-1.27 (m, 3H).

D. 5-(1-Methoxyethyl)-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid, 53d

Y„

Mixture consisting of ethyl 5-(1-methoxyethyl)-1-(quinolin-5-yl)-1H-pyrazol-4-carboxylate, 53c (265 mg, 0.840 mmol), aq. NaOH (2.44 ml, 2.44 mmol, 1 M) and ethanol (3 ml) were stirred at room temperature for 16 hours. The mixture was neutralized with 1 M HCl and extracted with ethyl acetate (50 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to give compound 53d (120 mg, 50%).

1H NMR (400 MHz, CD3OD) δ ppm 8.97 (dd, J=1.6, 4.4 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H), 8 .19 (s, 1H), 7.93 (dd, J=7.2, 8.4 Hz, 1H), 7.80 (d, J=6.4 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.60 (dd, J=4.4, 8.4 Hz, 1H), 5.365.24 (m, 1H), 3.32 (s, 3H), 1, 37-1.29 (m, 3H).

E. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(1-methoxyethyl)-1-(quinolin-5-yl) -1Hpyrazole-4-carboxamide, compound 35

POCl ₃ (0.1 ml) was added to a mixture consisting of 5-(1-methoxyethyl)-1-(quinolin-5-yl)-1H-pyrazol-4carboxylic acid, 53d (120 mg, 0.40 mmol), 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (78.95 mg, 0.40 mmol) and pyridine (3 ml) at 0°C. The mixture was stirred at 0°C for 1 hour and then quenched with aq. _NaHCO3 . The mixture was extracted using ethyl acetate (50 mlx3) and the combined organic extracts were dried over Na2SO4, filtered and the filtrate was concentrated to dryness under reduced pressure to give a residue, which was purified by reverse phase HPLC (16-46% (v/v) CH3CN and water with 0.05% NH4HCO3) to give pure compound 35.

Compound 35 was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to give compound 35 (29.1 mg, 15%). LCMS (ESI): R _T =4.61 min, mass calculated for C ₂₃ H ₁₉ ClN ₈ O ₂ . ₄₇₄ , 902, resulting m/z - 475.0 [M+H]+.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 10.72 (s, 0.5H), 10.68 (s, 0.5H), 9.08-9.01 (m, 1H), 8 .79-8.78 (m, 1H), 8.50 (dd, J=2.0, 7.6 Hz, 1H), 8.44 (s, 1H), 8.39 (s, 0.5H ), 8.37 (s, 0.5H), 7.94 (s, 2H), 7.92-7.84 (m, 1H), 7.73 (d, J=8.4 Hz, 0. 5H), 7.67 (d, J=7.2 Hz, 0.5H), 7.55-7.46 (m, 2H), 4.41 (k, J=6.4 Hz, 0.5H ), 4.30 (k, J=6.4 Hz, 0.6H), 3.54 (s, 1.4H), 3.25 (s, 1.7H), 1.68 (d, J= 6.8 Hz, 1.6H), 1.42 (d, J=6.8 Hz, 1.4H).

- 191 045333

Example 54.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-methylisoquinolin-8-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 33

A. 8-(2-(Diphenylmethylene)hydrazinyl)-4-methylisoquinoline, 54a

Palladium diacetate (30.3 mg, 0.135 mmol) and Binap (84.1 mg, 0.135 mmol) were added to a solution consisting of 8-bromo-4-methylisoquinoline (300 mg, 1.35 mmol), (diphenylmethylene)hydrazine ( 265 mg, 1.35 mmol), sodium tert-butoxide (389 mg, 4.05 mmol) and 1,4-dioxane (5 ml). The mixture was heated at 100°C for 16 hours and then cooled to room temperature. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude compound 54a, which was purified using FCC (petroleum ether:ethyl acetate=100:0-70:30) to obtain compound 54a (250 mg, 55%).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (s, 1H), 9.41 (s, 1H), 8.40 (s, 1H), 8.14-8.08 ( m, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.70-7.63 (m, 4H), 7.59-7.55 (m, 2H), 7.54 -7.50 (m, 2H), 7.44-7.42 (m, 3H), 2.67 (s, 3H).

B. 8-Hydrazinyl-4-methylisoquinoline, 54b

Solution consisting of 8-(2-(diphenylmethylene)hydrazinyl)-4-methylisoquinoline, 54a (250 mg, 0.741 mmol), conc. HCl (4 ml) and EtOH (2 ml) were stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (10 ml) and washed with dichloromethane (20 ml). The mixture was concentrated under reduced pressure to give crude compound 54b (180 mg, crude), which was used in the next reaction without further purification.

C. Ethyl 1-(4-methylisoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 54c

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (150 mg, 0.650 mmol), 8-hydrazinyl-4-methylisoquinoline, 54b (160 mg, 0.650 mmol), triethylamine (132 mg, 1.30 mmol) and ethanol (5 ml), stirred at 80°C for 16 hours and then cooled to room temperature and concentrated to dryness under reduced pressure to give crude compound 54c, which was purified using FCC ( petroleum ether:ethyl acetate=100:0-70:30) to give compound 54c (110 mg, 48%).

¹ H NMR (400 MHz, CDCl3) δ ppm 8.54 (s, 1H), 8.27 (s, 1H), 8.16 (d, J=8.4 Hz, 1H), 7, 96 (t, J=7.6 Hz, 1H), 7.82 (dd, J=7.2, 8.4 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 4.42 (k, J=7.2 Hz, 2H), 2.69 (s, 3H), 1.41 (t, J=7.2 Hz, 3H).

D.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-methylisoquinolin-8-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 33

Solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (56.0 mg, 0.286 mmol)

- 192 045333 and THF (1 ml) were added to potassium tert-butoxide (0.8 ml, 0.8 mmol, 1M in THF) at 0°C, subsequently a solution consisting of ethyl 1-(4-methylisoquinoline- 8-yl)-5-(trifluoromethyl)-1H-nirazole-4carboxylate, 54c (100 mg, 0.286 mmol) and THF (1 ml). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified using preparative high performance liquid chromatography on a Phenomenex Gemini 150x25 mmx5 μm column (45-75% (v/v) ACN and water with 0.05% NH ₃ ) to obtain pure compound 33. The product was suspended in water (10 ml), the mixture was frozen using dry ice/acetone and subsequently lyophilized to dryness to obtain compound 33 (31.50 mg, 22%) . LCMS (ESI): R _T =4.46 min, mass calculated for C ₂₂ H ₁₄ ClF ₃ N ₈ O 498.848, obtained m/z - 499.0 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.84 (d, J=2.4 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H), 8 .58 (s, 1H), 8.55 (s, 1H), 8.45 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.19 (s, 2H) , 8.06-7.96 (m, 2H), 2.71 (s, 3H).

Example 55.

N-(8-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 95

A. 2-Chloro-N-(3-chloro-2-hydroxy-5-nitrophenyl)acetamide, 55a

Chloroacetyl chloride (1.98 g, 17.5 mmol) was added to a solution of 2-amino-6-chloro-4-nitrophenol (3.0 g, 15.9 mmol), triethylamine (3.2 g, 31.8 mmol ) in dichloromethane (30 ml). The mixture was stirred at rt for 3 hours. Water (50 ml) and dichloromethane (50 ml) were added to the mixture. The organic layer was separated and washed with brine (50 mL), dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give compound 55a as a yellow oil (4.0 g, 94.9%) which was used in the next reaction without additional cleaning.

B. 8-Chloro-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one, 55b

Sodium methoxide (896.8 mg, 16.6 mmol) was added to a solution of 2-chloro-N-(3-chloro-2-hydroxy-5nitrophenyl) acetamide, 55a (4.0 g, 15.1 mmol) in methanol ( 40 ml). The mixture was stirred at 80°C for 16 hours. Water (150 ml) and dichloromethane (100 ml) were added to the mixture. The organic layer was separated, washed with brine (100 mL), dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give 55b as a yellow oil. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - petroleum ether/ethyl acetate=1:1) to give compound 55b as a yellow solid (2.5 g, 73%).

1H NMR (400 MHz, methanol-64) δ ppm 4.84 (s, 2H), 7.72 (d, J=2.65 Hz, 1H), 7.98 (d, J=2, 65 Hz, 1H).

C. 8-Chloro-4-methyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one, 55c

Iodomethane (931 mg, 6.56 mmol) was added to a mixture of 8-chloro-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)one, 55b (500 mg, 2.19 mmol) and potassium carbonate (1.51 g, 10.94 mmol) in DMF (5 ml). The mixture was stirred at 25°C for 18 hours. The solvent was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 petroleum ether/ethyl acetate=1:1) to give compound 55c as a white solid (0.3 g, 56.5%).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 3.44 (s, 3H), 4.85 (s, 2H), 7.78 (d, J=2.51 Hz, 1H), 8, 04 (d, J=2.51

- 193 045333

Hz, 1H).

D. 6-Amino-8-chloro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 55d

Zinc (804 mg, 12.37 mmol) was added to a solution of 8-chloro-4-methyl-6-nitro-2H-benzo[b][1,4]oxazin3(4H)-one, 55c (300 mg, 1. 24 mmol) in aqueous NH ₄ Cl (2 ml) and methanol (2 ml). The mixture was stirred at rt for 16 hours. Aqueous NaHCO ₃ was added to the suspension to adjust the pH to 9-10 and the mixture was filtered through a layer of diatomaceous earth. The filter residue was washed with dichloromethane (30 mlx3). The combined filtrates were washed with brine (100 mL), dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give 55d as a brown solid. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2:1 - petroleum ether/ethyl acetate=0:1) to give compound 55d as a yellow solid (200 mg, 76.1%).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 3.31 (s, 3H), 4.61 (s, 2H), 6.23 (d, J=2.43 Hz, 1H), 6, 42 (d, J=2.43 Hz, 1H).

E. N-(8-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(quinolin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 95

1-(Quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b (120 mg, 0.39 mmol), 6amino-8-chloro-4-methyl-2H-benzo[ b][1, 4]oxazin-3(4H)-one, 55d (100 mg, 0.47 mmol) and HATU (223 mg, 0.59 mmol) were dissolved in DIPEA (253 mg, 1.96 mmol) and DMF (2 ml). The mixture was stirred at 25°C for 3 hours. Saturated. aqueous NH ₄ Cl solution (20 ml) and the mixture was extracted using dichloromethane (20 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give 95 as a crude brown oil. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (70%/30% - 40%/60%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to obtain compound 95 as a pale white solid (139 mg, 71%) LCMS (ESI): m/z - 501.9 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 3.27 (s, 3H), 4.77 (s, 2H), 7.47 (s, 1H), 7.57-7.63 ( m, 1H), 7.647.70 (m, 2H), 7.87-7.92 (m, 1H), 7.93-7.99 (m, 1H), 8.31 (d, J=8, 60 Hz, 1H), 8.50 (s, 1H), 9.04 (d, J=2.65 Hz, 1H), 10.74 (s, 1H).

Example 56.

N-(4-(2-Aminopyrimidin-4-yl)-3-chlorophenyl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamide, compound 58

A. 4-(2-Chloro-4-nitrophenyl)pyrimidin-2-amine, 56a

th, 56a

Mixture of 2-(2-chloro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250 mg, 0.882 mmol), 2-amino-4-chloropyrimidine (126 mg, 0.97 mmol) and cesium carbonate (862 mg, 2.65 mmol) in dioxane/water (4:1) were stirred at rt. Pd(PPh ₃ ) ₂ Cl ₂ was added under N2 atmosphere at rt. The reaction mixture was stirred overnight at 80°C. The mixture was filtered through a pad of diatomaceous earth and the filter residue was washed with ethyl acetate (50 ml). The filtrate was washed with water (10 ml). The organic layer was separated and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 100/0 to 0/100)

- 194 045333 to obtain compound 56a in the form of a yellow solid (155 mg, 70%). LCMS (ESI): m/z 250.9 [M+H]+.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 5.17 (br.s, 2H), 6.99 (d, J=5.07 Hz, 1H), 7.78 (d, J= 8.38 Hz, 1H),

8.21 (dd, J=8.49, 2.09 Hz, 1H), 8.36 (d, J=2.20 Hz, 1H), 8.43 (d, J=5.07 Hz, 1H ).

B. 4-(4-Amino-2-chlorophenyl)pyrimidin-2-amine, 56b

NHj N^N χύ H _a N^^CI _{r 56b}

4-(2-Chloro-4-nitrophenyl)pyrimidin-2-amine, 56a (132 mg, 0.53 mmol), Fe(0) (294 mg, 5.27 mmol) and NH ₄ Cl (282.5. 27 mmol) was added to a mixture of THF (5 ml) and water (1 ml). The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with ethyl acetate (20 mlx3). The combined filtrates were concentrated to dryness to give crude compound 56b as a yellow solid. The crude compound was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 50/50 to 0/100) to give 56b as a yellow solid (85 mg, 73%).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.76-3.88 (m, 2H), 4.98 (br.s, 2H), 6.57 (dd, J=8.27 , 2.32 Hz, 1H), 6.68 (d, J=2.21 Hz, 1H), 6.96 (d, J=5.07 Hz, 1H), 7.41 (d, J=8 .38 Hz, 1H), 8.22 (d, J=5.29 Hz, 1H).

C. N-(4-(2-Aminopyrimidin-4-yl)-3-chlorophenyl)-1 -(isoquinolin-4-yl)-5 -(trifluoromethyl)-1 Hpyrazol-4-carboxamide, compound 58

4-(4-Amino-2-chlorophenyl)pyrimidin-2-amine, 56b (80 mg, 0.36 mmol), 1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 4c (111 mg, 0.36 mmol) and HATU (207 mg, 0.54 mmol) were dissolved in triethylamine (234 mg, 1.81 mmol) and DMF (2 ml). The mixture was stirred at 25°C for 3 hours. Saturated. aqueous NH4Cl solution (20 ml) and the mixture was extracted using dichloromethane (20 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give crude compound 58 as a yellow oil. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (82%/18% - 52%/48%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to obtain compound 58 as a pale white solid (20.1 mg, 11%) LCMS (ESI): m/z - 510.0 (M+H)+.

¹ H NMR (400 MHz, methanol^) δ ppm 7.46 (d, J=6.61 Hz, 1H), 7.57 (d, J=8.60 Hz, 1H), 7.83 -7.89 (m, 2H), 8.02-8.07 (m, 1H), 8.12-8.19 (m, 2H), 8.39 (d, J=6.62 Hz, 1H ), 8.46 (s, 1H), 8.55 (d, J=8.38 Hz, 1H), 8.91 (s, 1H), 9.83 (s, 1H).

Example 57.

N-(8-Chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide, compound 87

A. 6-Amino-8-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one, 57a

Zinc(0) (426.5 mg, 6.56 mmol) was added to a solution of 8-chloro-6-nitro-2H-benzo[b][1,4]oxazin3(4H)-one, 55b (150 mg, 0 .66 mmol) in aqueous NH4Cl (2 ml) and MeOH (2 ml). The mixture was stirred at rt for 16 hours. Aqueous NaHCO ₃ was added to the suspension to adjust the pH to 9-10 and the mixture was filtered through a layer of diatomaceous earth. The filter residue was washed with dichloromethane (30 mlx3). The combined filtrates were washed with brine (100 mL), dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give 57a as a brown solid. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2:1 - petroleum ether/ethyl acetate=0:1) to give compound 57a as a yellow solid (90 mg, 69.1%).

1H NMR (400 MHz, CDCl3) δ ppm 3.57 (br.s, 2H), 4.61 (s, 2H), 6.05 (d, J=2.43 Hz, 1H), 6 .39 (d, J=2.43 Hz, 1H), 7.90-8.05 (m, 1H).

B. N-(8-Chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 87

1-(Isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 4c (100 mg, 0.29 mmol), 6-amino-8-chloro-2H-benzo[b] [1,4]oxazin-3(4H)-one, 57a (57.1 mg, 0.29 mmol), HATU (164.1 mg, 0.43 mmol) and DIEA (185.9 mg, 1.44 mmol) was dissolved in DMF (2 ml). The mixture was stirred at 25°C for 3 hours. Saturated. aqueous NH ₄ Cl solution (20 ml) and the mixture was extracted using dichloromethane (20 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give crude compound 87 as a yellow oil. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; subsequently: A/B (95%/5% - 65%/35%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to obtain compound 87 as a pale white solid (54 mg, 38%) LCMS (ESI): m/z - 487.9 (M+H)+.

1H NMR (400 MHz, methanol-I4) δ ppm 4.68 (s, 2H), 7.36 (d, J=2.21 Hz, 1H), 7.43 (d, J=2, 43 Hz, 1H), 7.55 (d, J=8.38 Hz, 1H), 8.00-8.08 (m, 1H), 8.11-8.19 (m, 1H), 8, 37 (s, 1H), 8.54 (d, J=8.16 Hz, 1H), 8.90 (s, 1H), 9.82 (s, 1H).

Example 58.

Ν-(5-Χλορ-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide, connection 42

A. 2-(3-Chloro-5-nitropyridin-2-yl)isothiazolidine 1,1-dioxide, 58a

£,58a (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (46.1 mg, 0.30 mmol) and copper iodide (56.3 mg, 0.30 mmol) were added to mixture 2, 3-dichloro-5-nitropyridine (571 mg, 2.96 mmol), isothiazolidine-1,1 dioxide (430 mg, 3.55 mmol) and potassium carbonate (817.5 mg, 5.92 mmol) in dioxane (6 ml ) in an N ₂ atmosphere. The reaction mixture was stirred at 100°C for 16 hours. The mixture was filtered and the filtrate was extracted using ethyl acetate.

The organic extracts were dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate=50:50) to give compound 58a as a white solid (600 mg, 73%).

B. 2-(5-Amino-3-chloropyridin-2-yl)isothiazolidine 1,1-dioxide, 58b

2-(3-Chloro-5-nitropyridin-2-yl)isothiazolidine 1,1-dioxide, 58a (600 mg, 2.12 mmol), Fe(0) (967 mg, 17.29 mmol) and NH ₄ Cl (925 mg, 17.29 mmol) was added to a mixture of THF (6 ml), MeOH (3 ml) and water (1.5 ml). The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with ethyl acetate (20 mlx3). Combined filtrates

- 196 045333 concentrated to dryness to give crude compound 58b as a yellow oil (530 mg,

99%).

C. Ν-(5-Χλορ-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3-yl)-1 -(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4- carboxamide, compound 42

Phosphoryl trichloride (0.052 ml, 0.57 mmol) was added to a solution of 1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 4c (60 mg, 0.19 mmol), 2 -(5-amino-3-chloropyridin-2yl)isothiazolidine 1,1-dioxide, 58b (60.6 mg, 0.245 mmol) and pyridine (0.091 ml, 1.13 mmol) in dichloromethane at room temperature. The mixture was stirred for 2 hours. The mixture was poured into water (10 ml) and the mixture was extracted using dichloromethane (20 mlx2). The separated organic layer was dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC (0.05% ammonium hydroxide v/v); In: MeCN; subsequently: A/B (65%/35% - 35%/65%). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to give compound 42 as a white solid (35.6 mg, 35%). LCMS (ESI): m/z - 536.9 [M+H]+.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 2.53-2.60 (m, 2H), 3.19 (br.t, J=7.50 Hz, 2H), 4.05 (br .t, J=6.84 Hz, 2H), 7.29 (br.d, J=7.94 Hz, 1H), 7.73 (dt, J=13.40, 6.64 Hz, 2H) , 7.94 (br.s, 1H), 8.09 (br.d, J=8.16 Hz, 1H), 8.19 (s, 1H), 8.29 (br.s, 1H), 8.44 (br.s, 1H), 8.55 (s, 1H), 9.38 (s, 1H).

Example 59.

K-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(isoquinolin-4-yl)-1 H-pyrazol-4carboxamide, compound 76

A. Ethyl 1-(isoquinolin-4-yl)-1H-pyrazole-4-carboxylate, 59a

A solution consisting of ethyl 2-formyl-3-oxopropanoate (90.5 mg, 0.628 mmol), 4hydrazinyl isoquinoline, 4a (100 mg, 0.628 mmol) and 2-propanol (2 ml) was stirred at 80°C overnight, and then cooled to room temperature and concentrated to dryness under reduced pressure to obtain the crude product, which was purified using FCC (petroleum ether:ethyl acetate=100:0-80:20) to obtain compound 59a (140 mg, 84%). LCMS (ESI): R _T =0.70 min, mass calculated for C ₁₅ H ₁₃ N ₃ O ₂ - ₂₆₇ , 283, obtained m/z - 268.0 [M+H]+.

B. N-(5 -Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(isoquinolin-4-yl)-1 H-pyrazol-4carboxamide, connection 76

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (87.8 mg, 0.449 mmol) and THF (1 ml) was added to 1M potassium tert-butoxide in THF (1.35 ml, 1.35 mmol) at 0°C, subsequently adding a solution consisting of ethyl 1-(isoquinolin-4-yl)-1H-pyrazol-4-carboxylate, 59a (120 mg, 0.449 mmol) and THF (1 ml). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified using preparative reverse phase HPLC (30-60% (v/v) ACN and H ₂ O with 0 .05% NH ₃ ). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to give compound 76 (69.3 mg, 36%). LCMS (ESI): R _T =4.36 min, mass calculated for C ₂₀ H ₁₃ ClN ₈ O - 416.823, obtained m/z - 416.9 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.74 (br.s, 1H), 9.52 (s, 1H), 9.01 (s, 1H), 8.88 (d, J=2 .4 Hz, 1H), 8.76 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.54 (s, 1H), 8.35 (d, J=8 .0 Hz, 1H), 8.19 (s, 2H), 7.98-7.92 (m, 2H), 7.89-7.84 (m, 1H).

Example 60.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-1-(quinolin-4-yl)-1H-pyrazol-4carboxamide , connection 64

A. 7-Chloro-4-methoxyquinoline, 60a

4,7-Dichloroquinoline (6.00 g, 30.3 mmol) was added portionwise to a solution consisting of sodium methoxide (1.80 g, 33.3 mmol) and methanol (60 ml) at room temperature. The mixture was stirred at 80°C for 12 hours and then quenched with water and extracted with ethyl acetate (200 mlx3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a residue, which was purified using FCC (petroleum ether: ethyl acetate = 2:1-1:2) to obtain compound 60a (4, 1 g, 70%).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.73 (d, J=5.2 Hz, 1H), 8.11 (D, J=8.8 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.43 (dd, J=2.0, 8.8 Hz, 1H), 6.71 (d, J=5.2 Hz, 1H), 4 .03 (s, 3H).

B. 4-Methoxyquinoline, 6Ob

A mixture consisting of 7-chloro-4-methoxyquinoline, 60a (4.10 g, 21.1 mmol), anhydrous Pd/C (400 mg, 10 wt%, 0.377 mmol) and methanol (100 ml) was stirred at room temperature. temperature for 16 hours in H2 atmosphere (15 psi). The mixture was filtered through a pad of diatomaceous earth and the layer was washed with methanol (50 ml). The filtrate was concentrated to dryness under reduced pressure to obtain a residue, which was dissolved in aqueous NaHCO ₃ (80 ml) and extracted with ethyl acetate (100 ml x 3 ). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product, which was purified using FCC (petroleum ether:ethyl acetate = 1:3) and further purified by reverse phase HPLC (10- 40% (v/v) CH3CN and _H2O with 0.05% NH3). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to give compound 60b (1.1 g, 33%).

1H NMR (400 MHz, CDCl3) δ 8.74 (d, J=5.2 Hz, 1H), 8.22-8.15 (m, 1H), 8.03 (d, J=8.4 Hz , 1H), 7.73-7.65 (m, 1H), 7.51-7.47 (m, 1H), 6.72 (d, J=5.2 Hz, 1H), 4.03 ( s, 3H).

S. 4 -Hydrazinylquinoline, 60c

A mixture consisting of 4-methoxyquinoline, 60b (1.00 g, 6.28 mmol), hydrazine hydrate (10 ml, 85 wt%) and ethanol (5 ml) was refluxed for 16 hours. The ethanol was subsequently removed under reduced pressure and the resulting aqueous mixture was filtered to obtain compound 60c (713 mg, 71%), which was dried under reduced pressure.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.37 (d, J=5.2 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7, 74 (d, J=8.4 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 6.83 ( d, J=5.2 Hz, 1H), 4.37 (br.s, 1H).

D. Ethyl 5-methyl-1-(quinolin-4-yl)-1H-pyrazole-4-carboxylate, 60d

- 198 045333

A mixture consisting of ethyl 2-(ethoxymethylene)-3-oxobutanoate, 52a (418 mg, 2.25 mmol), 4-hydrazinylquinoline, 60c (220 mg, 1.12 mmol) and ethanol (8 ml) was stirred at 80°C in for 16 hours. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure to give a residue, which was purified using FCC (petroleum ether:ethyl acetate=2:1) to give compound 60d (320 mg, 51%).

1H NMR (400 MHz, CDCI3) δ ppm 9.08 (d, J=4.8 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.18 (s , 1H), 7.837.79 (m, 1H), 7.61-7.57 (m, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.40 (d, J= 4.4 Hz, 1H), 4.37 (k, J=7.2 Hz, 2H), 2.42 (s, 3H), 1.41 (t, J=7.2 Hz, 3H).

E. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-1-(quinolin-4-yl)-1H-pyrazole -4 carboxamide, compound 64

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (229 mg, 1.17 mmol) and THF (1 ml) was added dropwise to a solution of t-BuOK (3.2 ml, 3.2 mmol, 1M in THF) at 0°C. A solution consisting of ethyl 5-methyl-1-(quinolin-4-yl)-1H-pyrazol-4-carboxylate, 60d (300 mg, 1.07 mmol) and THF (1 ml) was then added dropwise. The resulting mixture was warmed to room temperature and stirred for 16 hours and then quenched with water and extracted with ethyl acetate (50 mlx3). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to give a residue which was purified by preparative reverse phase HPLC (30-60% (v/v) CH3CN and H ₂ O with 0.05% NH ₃ ). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to give compound 64 (153 mg, 33%). LCMS (ESI): R _T =4.52 min, mass calculated for C ₂₁ H ₁₅ ClN8O - 430.850, obtained m/z - 431.0 (M+H)+.

1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.14 (d, J=4.4 Hz, 1H), 8.92 (d, J=2.4 Hz, 1H ), 8.71 (d, J=2.4 Hz, 1H), 8.57 (s, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.19 (s, 2H ), 7.93-7.89 (m, 1H), 7.78 (d, J=4.4 Hz, 1H), 7.73-7.69 (m, 1H), 7.49 (d, J=8.0 Hz, 1H), 2.45 (s, 3H).

Example 61.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-1H-pyrazol-4-carboxamide, compound 60

A. Ethyl 1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate, 61a

Copper(II) acetate (1.43 g, 7.88 mmol) was added to a mixture consisting of ethyl 1H-pyrazole-4carboxylate (368 mg, 2.63 mmol), quinolin-5-ylboric acid (500 mg, 2. 89 mmol), molecular sieve (4A, 30 mg), pyridine (624 mg, 7.88 mmol), pyridine-1-oxide (750 mg, 7.88 mmol) and DMF (10 ml). The reaction mixture was stirred under O ₂ atmosphere (1 atm, balloon) at room temperature for 16 hours. The suspension was filtered through a pad of diatomaceous earth and the layer was washed with ethyl acetate (100 ml). The filtrate was washed with water (100 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product, which was purified using FCC (petroleum ether:ethyl acetate = 100:0-70:30) with obtaining compound 61a (160 mg, 23%).

- 199 045333

1H NMR (400 MHz, CDCl3) δ 9.00 (d, J=4.0 Hz, 1H), 8.32-8.22 (m, 4H), 7.82-7.78 (m, 1H) , 7.62 (d, J=7.2

Hz, 1H), 7.48 (dd, J=4.4, 8.4 Hz, 1H), 4.37 (k, J=7.2 Hz, 2H), 1.40 (t, J=7 ,2 Hz, 3H).

B. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-1H-pyrazol-4-carboxamide , connection 60

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (102 mg, 0.524 mmol) and THF (1 ml) was added to 1 M tert -potassium butoxide in THF (1.57 ml, 1.57 mmol) at 0°C, subsequently adding a solution consisting of ethyl 1-(quinolin-5-yl)-1H-pyrazol-4-carboxylate, 61a (140 mg , 0.524 mmol) and THF (1 ml). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified using preparative reverse phase HPLC (30-60% (v/v) ACN and H ₂ O with 0 .05% NH ₃ ). The crude fractions were concentrated under reduced pressure and lyophilized to dryness to give compound 60 (104.50 mg, 49%). LCMS (ESI): R _T =4.01 min, mass calculated for C ₂₀ H ₁₃ ClN ₈ O - 416.823, obtained m/z - 417.0 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (dd, J=1.6, 4.0 Hz, 1H), 8.96 (s, 1H), 8.88 (d, J=2 ,4 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.50 (s, 1H), 8.33-8.28 (m, 1H), 8.24 (d , J=8.4 Hz, 1H), 8.19 (s, 2H), 7.98-7.92 (m, 1H), 7.897.85 (m, 1H), 7.68 (dd, J= 4.0, 8.4 Hz, 1H).

Example 61.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 37

A. Ethyl 1-(2-methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 61a

Mixture of 5-chloro-2-methylquinoline (200 mg, 1.12 mmol), hydrazine hydrate (0.111 ml, 98%, 2.25 mmol), palladium(P)(pi-cinnamyl) chloride dimer (16 mg, 0.030 mmol ), N-[2-(di-1adamantylphosphino)phenyl]morpholine (42 mg, 0.090 mmol), sodium tert-butoxide (216 mg, 2.25 mmol) and toluene (11 ml, 0.1 M, 1.1 mmol) was bubbled with argon for 1 min, sealed and stirred at 100°C for 2.5 h, and then cooled to room temperature and treated with ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (270 mg, 1.13 mmol) in one dose in air. The reaction mixture was subsequently sealed in air and stirred at 100°C for 40 min, then at 90°C for another 20 h, and then cooled to room temperature. The mixture was filtered and concentrated under reduced pressure to give a yellow oil, which was purified using FCC (petroleum ether:ethyl acetate=40:60) to give compound 61a (210 mg, 16%). LCMS (ESI): R _T =0.75 min, mass calculated for C ₁₇ H ₁₄ F ₃ N ₃ O _2-349 , 3, obtained m/z - 350.0 [M+H] ⁺ .

B. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylquinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 37

Ethyl 1-(2-methylquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 61a (210 mg, 0.180 mmol) in THF (1 ml) and 5-chloro-6-(2H -1,2,3-triazol-2-yl)pyridin-3-amine, 1j (117 mg, 0.601 mmol) in THF

- 200 045333 (1 ml) was added to a suspension of potassium tert-butoxide (101 mg, 0.902 mmol) in THF (3 ml) at 0°C. The mixture was stirred at room temperature for 20 hours and then concentrated under reduced pressure to give a yellow solid, which was purified by preparative reverse phase HPLC (42-72% (v/v) CH3CN and _H2O with 0.05% NH3) 42% to 72%, v/v) and lyophilized to give compound 37 (12.0 mg, 13%). LCMS (ESI): RT=4.34 min, mass calculated for C22H14OT3N8O - 498.093, obtained m/z - 499.0 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ 11.30 (br.s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.68 (d, J=2.0 Hz , 1H), 8.58 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.20 (s, 2H), 7.92 (dd, J=7.2, 8.4 Hz, 1H), 7.83 (d, J=7.2 Hz, 1H), 7.59-7.53 (m, 1H), 7.52-7.47 (m, 1H), 2.72 (s, 3H).

Example 62.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-fluoroquinolin-7-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 67

A. 5-Bromo-6-fluoroquinoline, 62a and 7-bromo-6-fluoroquinoline, 62a-1

Water (11.38 ml) was added to a solution consisting of 3-bromo-4-fluoroaniline (10 g, 53 mmol), sodium 3-nitrobenzenesulfonate (21 g, 95 mmol) and propane-1,2,3-triol (14 g , 0.15 mol). The resulting mixture was carefully treated with concentrated H ₂ SO ₄ (21.1 ml) and subsequently heated to 150°C with stirring for 2 hours and then cooled to room temperature. The resulting mixture was carefully neutralized with 5N sodium hydroxide, filtered through a pad of diatomaceous earth and washed with dichloromethane (50 ml). The resulting mixture was extracted using dichloromethane (100 mlx3) and the combined organic extracts were dried over Na ₂ SO ₄ , filtered and the filtrate concentrated to give the crude product, which was purified using FCC (petroleum ether:ethyl acetate=3:1) to give compounds 62a and 62a-1 (9.5 g, 80%). LCMS (ESI): RT=0.64, 0.68 min, mass calculated for C ₉ H ₅ BrFN -224.96, obtained m/z - 227.6 [M+H]+.

1H NMR (400 MHz, CDCl3) δ 8.96-8.87 (m, 2H), 8.55 (d, J=8.8 Hz, 1H), 8.39 (d, J=6.8 Hz , 1H), 8.15-8.07 (m, 2H), 7.60-7.42 (m, 4H).

B. 5-(2-(Diphenylmethylene)hydrazinyl)-6-fluoroquinoline, 62b and 7-(2-(diphenylmethylene)hydrazinyl)-6fluoroquinoline, 62b-1

Mixture of 5-bromo-6-fluoroquinoline, 62a and 7-bromo-6-fluoroquinoline, 62a-1 (10 g, 22 mmol), (diphenylmethylene)hydrazine (4.3 g, 22 mmol), 2,2'-bis (diphenylphosphino)-1,1'-binaphthyl (1.4 g, 2.2 mmol), palladium(P) acetate (0.50 g, 2.2 mmol), t-BuONa (6.4 g, 66 mmol ) and 1,4-dioxane (150 ml) were stirred at 100°C for 16 hours. The suspension was filtered through a layer of diatomaceous earth and the layer was washed with ethyl acetate (30 ml). The filtrate was concentrated to dryness under reduced pressure to obtain the crude product, which was added to water (30 ml). The resulting mixture was extracted using ethyl acetate (50 mlx3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to give the crude product, which was purified using FCC (petroleum ether:ethyl acetate=3:1) to give compounds 62b and 62b-1 (5 g, 33%). LCMS (ESI): RT=0.68 min, mass calculated for C ₂₂ H ₁₆ FN ₃ . ₃₄₁ , 13, obtained m/z - 341.9 [M+H]+.

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C. 6-Fluoro-5-hydrazinylquinoline, 62c and 6-fluoro-7-hydrazinylquinoline, 62c-1

F η ₂ ν-νή f o Ή

U, 62s ^=/, 62s-1

Concentrated HCl (10 ml) was added to a solution consisting of 5-(2(diphenylmethylene)hydrazinyl)-6-fluoroquinoline, 62b and 7-(2-(diphenylmethylene)hydrazinyl)-6fluoroquinoline, 62b-1 (5.0 g, 7.3 mmol) and EtOH (3 ml). The resulting solution was stirred at room temperature for 16 hours. The resulting mixture was treated with water (30 ml) and extracted using dichloromethane (30 mlx3). The aqueous phase was made alkaline with 5M NaOH to pH 12. The suspension was filtered and the collected solids were washed with water (20 mL) and dried under reduced pressure to give compounds 62c and 62c-1 (1.2 g, 46%). LCMS (ESI): RT=1.24 min, mass calculated for C ₉ H ₈ FN _3-177 , 07, obtained m/z - 178.1 [M+H]+.

D. Ethyl 1-(6-fluoroquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 62d

G, 62d

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (1.79 g, 7.45 mmol), 6-fluoro-5-hydrazinylquinoline and 6-fluoro-7- hydrazinylquinoline, 62c and 62c-1 (1.10 g, 6.21 mmol) and ethanol (20 ml) were stirred at 80°C for 16 h and then cooled to room temperature.

The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product. The product was purified by FCC (eluent: petroleum ether:ethyl acetate=3:1) to give the title compound (1.3 g, 59%). LCMS (ESI): R _T =3.90 min, mass calculated for C ₁₆ H ₁₁ F ₄ N ₃ O _2-353 , 08, obtained m/z - 353.9 [M+H]+.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.01 (d, J=4.0 Hz, 1H), 8.30-8.18 (m, 3H), 7.65 (d, J=9, 7 Hz, 1H), 7.55 (dd,

J=4.2, 8.4 Hz, 1H), 4.41 (k, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).

E. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-fluoroquinolin-7-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 67

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (249 mg, 1.27 mmol) and THF (1 ml), and solution , consisting of ethyl 1-(6-fluoroquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, 62d (300 mg, 0.849 mmol) and THF (1 ml), was added to the solution consisting of tert -potassium butoxide (2.55 ml, 2.55 mmol, 1M in THF) at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was added to water (5 ml) and extracted with ethyl acetate (15 ml x 3).

The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative reverse phase HPLC (35-55% (v/v) CH3CN and H ₂ O with 10 mM NH4HCO3) and lyophilized to give compound 67 (70.7 mg, 17%). LCMS (ESI): RT=5.05 min, mass calculated for C ₂₁ H ₁₁ ClF ₄ N ₈ O - 502.07, obtained m/z -502.9 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ 10.81 (br.s, 1H), 9.06 (d, J=4.0 Hz, 1H), 8.85 (d, J=2.4 Hz , 1H), 8.67 (d, J=2.4 Hz, 1H), 8.59 (s, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.50 (d , J=7.2 Hz, 1H), 8.25-8.17 (m, 3H), 7.76 (dd, J=4.2, 8.4 Hz, 1H).

Example 63.

N-(5-Chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide , connection 21

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A. 8-Hydrazinyl isoquinoline, 63a

To a stirred solution of isoquinoline-8-amine (4.3 g, 29.8 mmol) in concentrated HCl (43 ml, 215 mmol) at 0°C was added a solution of sodium nitrite (3.1 g, 44.7 mmol) in water (5 ml) at temperatures below 0°C. The reaction mixture was stirred at 0°C for 30 min and a solution of tin chloride (16.8 g, 74.6 mmol) in concentrated HCl (8 ml) was added dropwise. The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 12-14 with 20% aqueous sodium hydroxide solution. The mixture was extracted using ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (petroleum ether/ethyl acetate=100:0 ethyl acetate/methanol=90:10) to give 63a (2.83 g, 60%) as a brown solid.

B. Ethyl 1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 63b ^F > ^F Z—

X,63b

A solution consisting of 8-hydrazinyl isoquinoline, 63a (2.83 g, 17.8 mmol) and ethyl 2-(ethoxymethylene)4,4,4-trifluoro-3-oxobutanoate, 1f (5.12 g, 21.3 mmol ) in ethanol (42 ml) was stirred at 80°C for 16 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain the crude product, which was subsequently purified by silica gel column chromatography (petroleum ether/ethyl acetate=100: 0-70:30) to give 63b as a yellow solid (3.14 g, 53%). MS m/e 335.9 (M+H).

C. 1-(Isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 63 s

V th fAAoh

Oh, 63s

NaOH (375 mg, 9.4 mmol) was added to a solution of ethyl 1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxylate, 63b (3.14 g, 9.4 mmol) in methanol (5 ml) and water (15 ml) at room temperature. The mixture was stirred for 4 hours.

The solvent was concentrated under reduced pressure to give 63c as a yellow solid (3.093 g, 100%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (s, 1H), 8.77 (d, J=5.3 Hz, 1H), 8.53-8.37 (m , 3H), 8.23-8.16 (m, 1H), 8.11 (d, J=7.1 Hz, 1H).

D. N-(5-Chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)1H-pyrazol- 4-carboxamide, compound 21

To a solution of 1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 63 s (95 mg, 0.29 mmol), 5-chloro-6-(1-methyl- 1H-pyrazol-3-yl)pyridin-3-amine, 8a (60 mg, 0.29 mmol) and pyridine (132.7 mg, 1.7 mmol) in dichloromethane (5 ml) was added dropwise with POCl ₃ (102 .9 mg, 0.67 mmol). The reaction mixture was stirred at 20°C for 1 hour. A saturated aqueous solution of NaHCO ₃ (20 ml) was added and the mixture was extracted using dichloromethane (20 mlx2). The combined organic phases were washed with brine and dried over Na ₂ SO ₄ . The mixture was filtered and the filtrates were concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was purified by preparative HPLC to give 21 as a white solid (55 mg, 38%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.02 (s, 1H), 8.82 (d, J=2.2 Hz, 1H), 8.67 (d, J=5 .7 Hz, 1H), 8.60

- 203 045333 (s, 1H), 8.54 (s, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.29 (d, J=7.4 Hz, 1H), 8.08-8.03 (m, 1H), 8.00-7.93 (m, 2H), 7.77 (d, J=2.2 Hz, 1H), 6.75 (d, J= 2.2 Hz, 1H), 3.92 (s, 3H). MS m/e 498.1 (M+H).

Example 64.

N-(2-Cyanopyridin-4-yl)-1-(naphthalen-1-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, compound 1

POC13 (0.3 ml) was added dropwise

to a solution consisting of 1-(naphthalen-1-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxylic acid 2b (150 mg, 0.490 mmol), 4-aminopicolinonitrile (64.2 mg, 0.539 mmol) and pyridine (5 ml). The mixture was stirred at 0°C for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain the crude product, which was purified using preparative HPLC (40-70% (v/v) ACN and H ₂ O with 0.05% NH3) to obtain compound 1. Compound 1 was concentrated to dryness under reduced pressure (101.30 mg, 51%). LCMS (ESI): R _T =5.45 min, mass calculated for C ₂₁ H ₁₂ F ₃ N ₅ O - 407.348, obtained m/z - 408.0 [M+H]+.

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 8.71 (d, J=5.2 Hz, 1H), 8.56 (s, 1H), 8 .30 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.00 (d, J=4, 0 Hz, 1H), 7.83-7.77 (m, 1H), 7.76-7.62 (m, 3H), 7.14 (d, J=8.0 Hz, 1H).

Example 65.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)niridin-3-yl)-1-(imidazo[1,2-a]pyrazin-8-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 103

A. tert-Butyl 2-(imidazo[1,2-a]pyrazin-8-yl)hydrazine-1-carboxylate, 65a

8-Chloroimidazo[1,2-a]pyrazine (400 mg, 2.6 mmol) and tert-butyl hydrazine carboxylate (516.4 g, 3.9 mmol) were dissolved in THF (8 ml), sodium hydride (312, 5 mg, 7.8 mmol) and the mixture was stirred at 30°C for 16 hours. Saturated aqueous NH4Cl (10 ml) was added and the mixture was extracted using EtOAc (10 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a black oil. The crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 100/0 to 30/70). The solvent was concentrated under reduced pressure to give compound 65a as a yellow solid (220 mg, 28%). LCMS (ESI): m/z - 250.1 [M+H]+.

B. 8-Hydrazinylimidazo[1,2-a]pyrazine, 65b

tert-Butyl 2-(imidazo[1,2-a]pyrazin-8-yl)hydrazine-1-carboxylate, 65a (220 mg, 0.72 mmol) was suspended in dichloromethane (5 ml) and HCl/dioxane was added ( 10 ml). The reaction mixture was stirred at 30°C for 1 hour, subsequently concentrated under reduced pressure to obtain compound 65b as a yellow solid. The solid was used in the next step without further purification.

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C. Ethyl 1-(imidazo[1,2-a]pyrazin-8-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxylate, 65c

8-Hydrazinylimidazo[1,2-a]pyrazine, 65b (160 mg, 1.1 mmol) and triethylamine (325.6 mg, 3.2 mmol) were dissolved in ethanol (3 ml), ethyl 2-(ethoxymethylene) was added -4,4,4-trifluoro-3-oxobutanoate, 1f (515.3 mg, 2.15 mmol) and stirred the mixture at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude brown solid. . The solid was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 100/0 to 20/80). The solvent was concentrated under reduced pressure to give compound 65c as a yellow oil (160 mg, 41%). LCMS (ESI): m/z - 326.0 [M+H]+.

D. 1-(Imidazo[1,2-a]pyrazin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 65d

Lithium hydroxide monohydrate (183.4 mg, 4.4 mmol) was added to ethyl 1-(imidazo[1,2-a]pyrazin-8yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 65c (160 mg, 0.44 mmol) and stirred the mixture at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude yellow solid, which was used in the next step without further purification (160 mg).

E. N-(5-Cyano-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-α]pyrazin-8-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 103

To a solution of 1-(imidazo[1,2-a]pyrazin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 65d (115 mg, 0.39 mmol), 5-amino- 2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, 7b (47.9 mg, 0.26 mmol) and pyridine (91.5 mg, 1.2 mmol) in dichloromethane (3 ml) POCl ₃ (59.1 mg, 0.39 mmol) was added dropwise. The reaction mixture was stirred at 20°C for 16 hours. A saturated aqueous solution was added

NaHCO ₃ (20 ml) and the mixture was extracted using dichloromethane (20 mlx2). The combined organic phases were washed with brine and dried over Na ₂ SO ₄ . The mixture was filtered and the filtrates were concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was purified by preparative HPLC to give compound 103 as a white solid (5 mg, 4%).

1H NMR (400 MHz, methanol^) δ ppm 9.04 (br.s, 1H), 8.89 (d, J=2.6 Hz, 1H), 8.86 (d, J=4 ,6 Hz, 1H),

8.50-8.43 (m, 2H), 8.19 (d, J=4.6 Hz, 1H), 8.16 (s, 1H), 8.13 (s, 2H). LCMS (ESI): m/z - 465.9 [M+H]+.

Example 66.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinoxalin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 105

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A. Di-tert-butyl 1-(quinoxalin-5-yl)hydrazine-1,2-dicarboxylate, 66a

5-Bromoquinoxaline (300 mg, 1.44 mmol) and di-tert-butyl hydrazine-1,2-dicarboxylate (500 mg, 2.15 mmol) were dissolved in DMF (5 ml). Add CuI (27.5 mg, 0.14 mmol) and K ₃ PO ₄ (609.3 mg, 2.87 mmol) and flush with N2, then add cyclohexane-1,3-diamine (32.8 mg, 0. 29 mmol) and stirred the reaction mixture at 110°C for 16 hours. The reaction mixture was filtered through a pad of diatomaceous earth and washed the layer with EtOAc (20 mlx3). The filtrate was concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate=50:50) and the solvents were removed under reduced pressure to give 66a as a brown oil (0.3 g, 58%) . LCMS (ESI): m/z - 383.0 [M+H]+.

B. 5-Hydrazinylquinoxaline, 66b

Di-tert-butyl 1-(quinoxalin-5-yl)hydrazin-1,2-dicarboxylate, 66a (300 mg, 0.48 mmol) in HCl in dioxane (10 ml) was stirred at 28°C for 2 h. The solvent was concentrated under reduced pressure to give compound 66b.

C. Ethyl 1-(quinoxalin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 66c

5-Hydrazinylquinoxaline, 66b (200 mg, 1.0 mmol) was dissolved in ethanol (5 ml), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (336.4 mg, 1. 53 mmol) and stirred the mixture at 80°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product as a brown solid. The solid was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 50/50) and the solvent was concentrated under reduced pressure to give 66c as a yellow oil (155 mg, 26%). LCMS (ESI): m/z - 336.9 [M+H]+.

D. 1-(Quinoxalin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 66d

Lithium hydroxide monohydrate (92 mg, 2.2 mmol) was added to ethyl 1-(quinoxalin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate, 66c (125 mg, 0.37 mmol) and stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product as a yellow solid. The crude product was used in the next step without further purification (95 mg).

E. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinoxalin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 105

To a solution of 1-(quinoxalin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 66d (56.2 mg,

- 206 045333

0.30 mmol), 5-amino-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, 7b (100 mg, 0.30 mmol) and pyridine (119 mg, 1.5 mmol) in dichloromethane (5 ml) POCl ₃ (92.5 mg, 0.60 mmol) was added dropwise. The reaction mixture was stirred at 20°C for 16 hours. A saturated aqueous solution of NaHCO ₃ (20 ml) was added and the mixture was extracted using dichloromethane (20 mlx2). The combined organic phases were washed with brine and dried over Na ₂ SO ₄ . The mixture was filtered and the filtrates were concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was purified by preparative HPLC to give compound 105 as a white solid (21 mg, 15%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.04-8.11 (m, 1H), 8.19-8.23 (m, 1H), 8.29 (s, 2H), 8.39 (d, J=8.38 Hz, 1H), 8.56 (s, 1H), 8.87 (d, J=2.43 Hz, 1H), 8.97 (d, J=1 .54 Hz, 1H), 9.05-9.12 (m, 2H), 11.29 (s, 1H). LCMS (ESI): m/z - 477.0 [M+H]+.

Example 67.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-1H-pyrazol-4carboxamide, compound 76

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (87.8 mg, 0.449 mmol) and THF (1 ml) was added to 1M potassium tert-butoxide in THF (1.35 ml, 1.35 mmol) at 0°C, subsequently adding a solution consisting of ethyl 1-(isoquinolin-4-yl)-1H-pyrazol-4-carboxylate, 59a (120 mg, 0.449 mmol) and THF (1 ml). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified using preparative reverse phase HPLC (30-60% (v/v) ACN and H ₂ O with 0 .05% NH ₃ ) and lyophilized to give compound 76 (69.3 mg, 36%). LCMS (ESI): R _T =4.36 min, mass calculated for C ₂₀ H ₁₃ ClN ₈ O - 416.823, obtained m/z -416.9 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.74 (br.s, 1H), 9.52 (s, 1H), 9.01 (s, 1H), 8.88 (d, J=2.4 Hz, 1H), 8.76 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.54 (s, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.19 (s, 2H), 7.98-7.92 (m, 2H), 7.89-7.84 (m, 1H)

Example 68.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-1-(quinolin-4-yl)-1H-pyrazol-4carboxamide , connection 64

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (229 mg, 1.17 mmol) and THF (1 ml) was added dropwise to a solution of t-BuOK (3.2 ml, 3.2 mmol, 1M in THF) at 0°C. A solution consisting of ethyl 5-methyl-1-(quinolin-4-yl)-1H-pyrazol-4-carboxylate, 60d (300 mg, 1.07 mmol) and THF (1 ml) was then added dropwise. The resulting mixture was warmed to room temperature and stirred for 16 hours and then quenched with water and extracted with ethyl acetate (50 mlx3). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to give a residue which was purified by preparative reverse phase HPLC (30-60% (v/v) CH3CN and H ₂ O with 0.05% NH3) and lyophilized to give compound 64 (153 mg, 33%). LCMS (ESI): R _T =4.52 min, mass calculated for C ₂₁ H ₁₅ ClN ₈ O - 430.850, obtained m/z - 431.0 (M+H)+.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.66 (s, 1H), 9.14 (d, J=4.4 Hz, 1H), 8.92 (d, J=2, 4 Hz, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.57 (s, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.19 (s, 2H), 7.93-7.89 (m, 1H), 7.78 (d, J=4.4 Hz, 1H), 7.73-7.69 (m, 1H), 7. 49 (d, J=8.0 Hz, 1H), 2.45 (s, 3H).

Example 69.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-ul)-1-(quinolin-5-ul)-1H-pyrazol-4-carboxamide, compound 60

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A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (102 mg, 0.524 mmol) and

THF (1 ml) was added to 1M potassium tert-butoxide in THF (1.57 ml, 1.57 mmol) at 0°C, subsequently a solution consisting of ethyl 1-(quinolin-5-yl)-1H- pyrazole-4-carboxylate, 61a (140 mg, 0.524 mmol) and THF (1 ml). The resulting mixture was stirred at room temperature for 16 hours.

the stock mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative reverse phase HPLC (30-60% (v/v) ACN and _H2O with 0.05% NH3) to give compound 60 (104 .50 mg, 49%). LCMS (ESI): R _T =4.01 min, mass calculated for C ₂₀ H ₁₃ ClN ₈ O - 416.823, obtained m/z - 417.0 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ 9.04 (dd, J=1.6, 4.0 Hz, 1H), 8.96 (s, 1H), 8.88 (d, J=2, 4 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.50 (s, 1H), 8.33-8.28 (m, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.19 (s, 2H), 7.98-7.92 (m, 1H), 7.897.85 (m, 1H), 7.68 (dd, J=4 ,0, 8.4 Hz, 1H).

Example 70.

Methyl 2-(3-chloro-5 -(1 -(quinolin-5 -yl)-5 -(trifluoromethyl)-1 H-pyrazole-4-carboxamido)pyridin-2yl)-2H-1,2,3-triazole -4-carboxylate, compound 108

A. A mixture of methyl 1-(3-chloro-5-nitropyridin-2-yl)-1H-1,2,3-triazol-5-carboxylate with methyl 2-(3chloro-5-nitropyridin-2-yl)-2H -1,2,3-triazole-4-carboxylate, 70a

Potassium carbonate (7249.14 mg, 52.45 mmol) was added to a solution of 2,3-dichloro-5-nitropyridine (7249.14 mg, 17.48 mmol) and methyl 1h-1,2,3-triazole-4- carboxylate (2000 mg, 15.76 mmol) in MeCN (20 ml). The mixture was reacted at 60°C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified using FFS (petroleum ether/ethyl acetate=100:0 - petroleum ether/ ethyl acetate=40:60). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid.

B. Methyl 2-(5-amino-3-chloropyridin-2-yl)-2H-1,2,3-triazole-4-carboxylate, 108b

A mixture of methyl 1-(3-chloro-5-nitropyridin-2-yl)-1H-1,2,3-triazole-5-carboxylate and methyl 2-(3-chloro-5-nitropyridin-2-yl)-2H-1 ,2,3-triazole-4-carboxylate (2500 mg, 4.41 mmol) was added to a solution of Fe (1230 mg, 22.04 mmol) and NH ₄ Cl (1178 mg, 22.04 mmol) in THF (10 ml )/water (5 ml). The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with EtOAc (50 mlx2). The combined filtrates were concentrated to dryness to give the crude product as a yellow solid, which was purified using FFS (petroleum ether/ethyl acetate=50:50 - petroleum ether/ethyl acetate=0:100). The required fractions were collected and the solvent was concentrated under reduced pressure.

1H NMR (400 MHz, chloroform-d) δ ppm 3.98 (s, 3H), 4.17 (br.s, 2H), 7.17 (d, J=2.43 Hz, 1H) , 7.91 (d, J=2.65 Hz, 1H), 8.30 (s, 1H).

C. Methyl 2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2yl)-2H-1,2,3- triazole-4-carboxylate, compound 108

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1-(Quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (240.87 mg, 0.77 mmol), methyl 2-(5-amino-3-chloropyridine-2- yl)-2H-1,2,3-triazole-4-carboxylate (200 mg, 0.79 mmol), POCl ₃ (142.24 mg, 0.93 mmol) were dissolved in DCM (8 ml) and pyridine ( 183.44 mg, 2.32 mmol). The mixture was stirred at 25°C for 1 hour, saturated was added. NaHCO ₃ (30 ml) and extracted using

CH ₂ Cl ₂ (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates

concentrated under reduced pressure to give a brown oil, which was purified using FFS (petroleum ether/ethyl acetate=50:50 - petroleum ether/ethyl acetate=0:100). The desired fractions were collected and the solvent was concentrated under reduced pressure to obtain the product as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 3.90 (s, 3H), 7.58-7.62 (m, 1H), 7.64-7.69 (m, 1H), 7.90-7.99 (m, 2H), 8.32 (d, J=8.38 Hz, 1H), 8.59 (s, 1H), 8.69 (s, 1H), 8.71 (d, J=2.21 Hz, 1H), 8.87 (d, J=2.43 Hz, 1H), 9.05 (dd, J=3.97, 1.54 Hz, 1H), 11 .32 (s, 1H). LCMS (ESI) m/z M+1: 543.2.

Example 109.

2-(3-Chloro-5 -(1 -(quinolin-5-yl)-5 -(trifluoromethyl)-1 H-pyrazol-4-carboxamido)pyridin-2-yl)-2H1,2,3-triazol- 4-carboxylic acid, compound 109

NaOH (63.528 mg, 1.588 mmol) was added to the solution of methyl 2-(3-chloro-5-(1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2-yl )-2H-1,2,3-triazole-4-carboxylate, compound 108 (445 mg, 0.794 mmol) in a mixture of EtOH/H ₂ O=1:1 (5 ml) was reacted at 18°C for 2 h. The solvent was concentrated under reduced pressure, a 1M HCl solution was added to the mixture to adjust the pH to ~5, and a solid formed. The solid was collected to give the product.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.58-7.62 (m, 1H), 7.64-7.69 (m, 1H), 7.90-7.99 (m , 2H), 8.32 (d, J=7.94 Hz, 1H), 8.58 (d, J=11.47 Hz, 2H), 8.70 (d, J=2.21 Hz, 1H ), 8.87 (d, J=2.21 Hz, 1H), 9.05 (dd, J=3.97, 1.54 Hz, 1H), 11.34 (s, 1H). LCMS (ESI) m/z M+1: 542.9.

Example 110.

1-(1-Amino-8-fluoroisoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 110

A. 8-Fluoro-4-hydrazinyl isoquinoline, 110a

A mixture of palladium(II) chloride dimer (pi-cinnamyl) (103.14 mg, 0.20 mmol) and N-[2-(di-1adamantylphosphino)phenyl]morpholine (184.6 mg, 0.40 mmol) in dioxane (20 ml) was deaerated using argon (4x). The resulting clear yellow solution was stirred at room. temp, in argon atmosphere for 10 min. 4-Bromo-8-fluoroisoquinoline (900 mg, 3.98 mmol) and tBuONa (765.27 mg, 7.96 mmol) were added to the mixture and purged with argon (4x). The resulting yellow reaction mixture was stirred at room temperature for 5 min and subsequently treated with hydrazine (398.63 mg, 7.96 mmol) via syringe and purged with argon (4x). Subsequently, the mixture was stirred at 55°C under argon atmosphere for 2 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product as a brown solid.

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B. Ethyl 1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 110b

8-Fluoro-4-hydrazinyl isoquinoline (700 mg, 3.95 mmol) was added to a solution of ethyl ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (1423.34 mg, 5.93 mmol) in EtOH (15 ml) was reacted at 80°C for 1 hour. The mixture was concentrated under reduced pressure, subsequently purified by FFS (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate=80:20). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a brown oil. LCMS (ESI) m/z M+1: 353.9.

C. 4-(4-(Ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-8-fluoroisoquinoline 2-oxide, 110c

m-CPBA (700 mg, 3.95 mmol) was added to a solution of ethyl 1-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (800 mg, 2.25 mmol) in DCM (10 ml) and reacted at 30°C for 2 hours. The mixture was added to 40 ml of sat. Na ₂ CO ₃ solution, extracted with 50 ml CH ₂ Cl ₂ , the organic layer was concentrated under reduced pressure and purified using FFS (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate=50:50). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow oil. LCMS (ESI) m/z M+1: 370.0.

D. Ethyl 1-(1-chloro-8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 110d

POCl ₃ (5 ml) was added to a solution of 4-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-8-fluoroisoquinoline 2-oxide (720 mg, 1.95 mmol) in CHCl ₃ ( 15 ml) and reacted at 70°C for 2 hours. The mixture was added to 30 ml of sat. Na ₂ CO ₃ solution, extracted with 30 ml CH ₂ Cl ₂ , the organic layer was concentrated under reduced pressure, subsequently purified using FFS (petroleum ether/ethyl acetate=100:0 petroleum ether/ethyl acetate=85:15). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a colorless oil. LCMS (ESI) m/z M+1: 388.0.

E. 1-(1-Chloro-8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 110e

LiOH (70.415 mg, 2.940 mmol) was added to a solution of ethyl 1-(thieno[2,3-c]pyridin-7-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (240 mg, 0.59 mmol ) in THF/H ₂ O=1:1 (10 ml) and reacted at 23°C for 2 hours. The solvent was concentrated under reduced pressure, a 1 M HCl solution was added to the mixture to adjust the pH to ~ 5, and EtOAc was added to mixture (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the product as a brown oil. LCMS (ESI) m/z M+1: 359.9.

F.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-chloro-8-fluoroisoquinolin-4-yl)-5 (trifluoromethyl )-1H-pyrazole-4-carboxamide, 110f

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ci, iiof

1-(1-Chloro-8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid (210 mg, 0.22 mmol), 5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-amine (107.93 mg, 0.55 mmol), POCl ₃ (96.69 mg, 0.63 mmol) were dissolved in DCM (5 ml) and added pyridine (124.7 mg, 1.58 mmol). The mixture was stirred at 25°C for 1 hour, saturated was added. NaHCO ₃ (10 ml) and extracted using CH ₂ Cl ₂ (15 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the product as a brown oil. LCMS (ESI) m/z M+1: 536.9.

G. 1-(1-Amino-8-fluoroisoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 110

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-chloro-8-fluoroisoquinolin-4-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide (200 mg, 0.18 mmol) in NH3-H2O (12 ml) was reacted at 80°C for 16 hours. The solvent was concentrated under reduced pressure to give the crude compound, which was purified by preparative HPLC (77-57% (v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to give the title compound (29 mg, 31.5%). LCMS (ESI) m/z M+1: 518.0.

^1H NMR (400 MHz, DMSO-d6) δ ppm 6.77 (d, J=8.53 Hz, 1H), 7.56 (dd, J=12.92, 7.91 Hz, 1H ), 7.817.91 (m, 1H), 8.20 (s, 2H), 8.22 (s, 1H), 8.61 (s, 1H), 8.70 (d, J=2.01 Hz , 1H), 8.89 (d, J=2.01 Hz, 1H), 11.36 (s, 1H).

Example 111.

1-(1-Amino-8-fluoroisoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 111

A. 1-(1-Chloro-8-fluoroisoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, 111a

1-(1-Chloro-8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 110e (230 mg, 0.588 mmol), 5-amino-2-(2H -1,2,3-triazol-2-yl)nicotinonitrile (109.474 mg, 0.588 mmol), POCl ₃ (108.195 mg, 0.706 mmol) were dissolved in DCM (5 ml) and pyridine (139.537 mg, 1.764 mmol) was added. The mixture was stirred at 25°C for 1 hour, saturated was added. NaHCO ₃ (10 ml) and extracted using CH ₂ Cl ₂ (15 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude compound as a brown oil, which was purified using FFS (petroleum ether/ethyl acetate=10:1 - ethyl acetate). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a colorless oil. LCMS (ESI) m/z M+1: 528.1.

B. 1-(1 -Amino-8-fluoroisoquinolin-4-yl)-N-(5 -cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 - (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 111

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1-(1-Chloro-8-fluoroisoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide (140 mg, 0.262 mmol) in NH ₃ -H ₂ O (10 ml) was stirred at 60°C for 2 hours. The solvent was concentrated under reduced pressure to give the crude compound, which was purified at using preparative HPLC (83-53% (v/v) CH ₃ CN and H2O with 0.05% HCl) and lyophilized to dryness to give the title compound (50.0 mg, 37.6%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.79 (d, J=8.28 Hz, 1H), 7.60 (dd, J=12.92, 7.91 Hz, 1H ), 7.90 (td, J=8.16, 5.27 Hz, 1H), 8.27 (s, 1H), 8.32 (s, 2H), 8.64 (s, 1H), 8 .91 (d, J=2.51 Hz, 1H), 9.15 (d, J=2.26 Hz, 1H). LCMS (ESI) m/z M+1: 508.9. 11.51 (s, 1H).

Example 112.

N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 112

A. 5-Hydrazinyl isoquinoline, 112a

To a stirred solution of isoquinoline-5-amine (30 g, 208.1 mmol) in concentrated HCl (300 ml) at 0°C was added a solution of sodium nitrite (21.5 g, 312.1 mmol) in H2O (85 ml) at temperature below 0°C. The reaction mixture was stirred at 0°C for 30 min and a solution of tin(II) chloride dehydrate (117.4 g, 520.2 mmol) dissolved in concentrated HCl (55 ml) was added dropwise. The mixture was stirred at room temperature for 3 hours. The mixture was adjusted to pH 12-14 using a 20% aqueous sodium hydroxide solution. The mixture was extracted using ethyl acetate. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a yellow solid (27 g, 81.5% yield).

B. Ethyl 1-(isoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 112b

A solution consisting of 5-hydrazinyl isoquinoline (27 g, 169.6 mmol) and ethyl 2-(ethoxymethylene)4,4,4-trifluoro-3-oxobutanoate (40.7 g, 169.6 mmol) in EtOH (300 ml ) was stirred at 60°C for 3 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-70:30). The solvent was concentrated to give the title compound as a yellow solid (22 g, 38.7% yield). LCMS (ESI) m/z M+1: 336.0.

C. 5-(4-(Ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinoline 2-oxide, 112c

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To a cooled (0°C) solution of ethyl 1-(isoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate (3 g, 8.95 mmol) in DCM (40 ml) was added mCPBA (4, 63 g, 26.8 mmol) over 10 min. The mixture was warmed to rt and allowed to stir overnight. The solution was washed twice with semi-saturated aqueous sodium bisulfite solution (100 ml) to destroy excess oxidizing agent. The mixture was then washed twice with semi-saturated aqueous potassium carbonate solution (100 ml) and saline (100 ml). The extracts were dried over magnesium sulfate, filtered and concentrated to give a crude oil, which was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 20/80). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the title product as a yellow solid (2 g, 63.6% yield). LCMS (ESI) m/z M+1: 351.9.

D. Ethyl 1-(1-chloroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 112d ^N , 112d

A solution consisting of POCl ₃ (16.6 g, 108.2 mmol) and 5-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1Hpyrazol-1-yl)isoquinoline 2-oxide (19 g, 54.1 mmol) in CHCl ₃ (40 ml) was stirred at 60°C for 3 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-70:30). The solvent was concentrated to give the title compound as a yellow solid (12 g, 60.0% yield). LCMS (ESI) m/z M+1: 369.9.

E. 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 112e

A mixture of ethyl 1-(1-chloroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (12 g, 32.546 mmol) in concentrated HCl (20 ml) was stirred at 120°C for 3 h The solvent was concentrated under reduced pressure to give the product as a yellow solid (11 g, 83% yield). LCMS (ESI) m/z M+H: 324.1.

F. N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline- 5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 112

POCl ₃ (5.26 g, 30.3 mmol) was added to a solution of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (7, 0 g, 17.2 mmol), 5-chloro-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine (3.96 g, 18.9 mmol) in pyridine (20 ml). The mixture was stirred at rt for 3 hours, 50 ml of sat. was added to the mixture. NaHCO ₃ (500 ml), extracted using CH ₂ Cl ₂ (500 mlx2). The organic layer was washed with brine (200 ml), dried over MgSO ₄ and concentrated under reduced pressure to obtain the crude product, which was purified using preparative HPLC (5-60% (v/v) CH3CN and H ₂ O with 0. 05% HCl) and concentrated to dryness to give the title compound (5.7 g, 64.4% yield) as a white solid. LCMS (ESI) m/z M+1: 515.2.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.54 (s, 3H), 5.67 (d, J=7.50 Hz, 1H), 7.28 (dd, J=7, 17, 5.84 Hz, 1H), 7.66 (t, J=7.83 Hz, 1H), 7.93 (dd, J=7.61, 0.99 Hz, 1H), 8.14- 8.20 (m, 2H), 8.43 (t, J=3.97 Hz, 2H), 8.51 (s, 1H), 10.59 (s, 1H), 11.61 (br.d. , J=5.29 Hz, 1H).

Example 113.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 113

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A. 5-Bromo-1-methoxyisoquinoline, 113a

Iodomethane (9.50 g, 66.95 mmol) was added to a solution of 5-bromoisoquinolin-1(2H)-one (5 g, 22.32 mmol), Ag ₂ CO ₃ (18.46 g, 66.95 mmol) in CH3CN (100 ml). The mixture was stirred at 40°C for 16 hours. The mixture was filtered and washed with ethyl acetate (100 mlx3). The filtrate was collected and concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100:1 to 10:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 113a (2 g, 37.6% yield) as a white oil.

B. 5-Hydrazinyl-1-methoxyisoquinoline, 113b

A mixture of {Pd(cinnamyl)Cl} ₂ (217.607 mg, 0.420 mmol) and Mor-DalPhos (389.476 mg, 0.840 mmol) in dioxane (60 ml) was purged with argon (4x). The resulting clear yellow solution was stirred at room. temp, in argon atmosphere for 10 min. Compound 113a (2 g, 8.401 mmol) and t-BuONa (1612.896 mg, 16.801 mmol) were added to the mixture and the mixture was purged with argon (4x). The resulting yellow reaction mixture was stirred at room. temp, for 5 min and subsequently treated with hydrazine hydrate (858.230 mg, 16.801 mmol) via syringe. The reaction mixture was purged with argon (4x). Subsequently, the mixture was stirred at 50°C under argon atmosphere for 4 hours. The mixture was filtered and washed with ethyl acetate (50 mlx3). The filtrate was collected and concentrated to give crude compound 113b (1.6 g) as a yellow solid, which was used directly in the next step.

C. Ethyl 1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 113c

5-Hydrazinyl-1-methoxyisoquinoline solution, compound 113b (1.6 g, 8.46 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (3.05 g, 12.68 mmol ), triethylamine (2.562 g, 25.368 mmol) in EtOH (50 ml) was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100:0 to 10:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give compound 113c (2.2 g, 71.2% yield) as a yellow solid. LCMS (ESI) m/z M+1: 365.9.

D. 1-(1-Hydroxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 113d

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Ethyl 1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 113c (1 g, 2.74 mmol) was added to HCl (10 mL). The mixture was stirred at 130°C for 3 hours and concentrated under reduced pressure to give compound 113d (530 mg, 55.5% yield) as a brown solid, which was used directly in the next step. LCMS (ESI) m/z M+H: 323.9.

E. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 113

1-(1-Oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 113d (170 mg, 0.37 mmol), 5-amino-2 -(2H-1,2,3-triazol-2-yl)nicotinonitrile, (69.15 mg, 0.37 mmol) and pyridine (0.15 ml, 1.86 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (0.14 ml, 1.49 mmol) was added. The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC (35-65% (v/v) CH ₃ CN and H ₂ O with 0 .05% HCl) and lyophilized to dryness to give the title compound (46 mg, 24.6%). LCMS (ESI) m/z M+1: 491.9.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.62 (1H, br.d, J=5.51 Hz), 11.30 (1H, s), 9.06 (1H, d, J=2.65 Hz), 8.85 (1H, d, J=2.43 Hz), 8.53 (1H, s), 8.42 (1H, d, J=7.94 Hz) , 8.29 (2H, s), 7.89-7.98 (1H, m), 7.66 (1H, t, J=7.94 Hz), 7.28 (1H, dd, J=7 ,28, 6.17 Hz), 5.64 (1 N, d, J=7.28 Hz).

Example 114.

1-(Benzo[d]thiazol-7-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 114

A. 7-Hydrazinylbenzo[d]thiazole, 114a

7-Bromobenzo[d]thiazole (300 mg, 1.40 mmol), palladium(i)chloride dimer (picinnamyl) (36.3 mg, 0.07 mmol), N-[2-(di-1- Adamantylphosphino)phenyl]morpholine (64.97 mg, 0.14 mmol) and sodium tert-butoxide (269.35 mg, 2.80 mmol) were dissolved in dioxane (20 ml) under N ₂ atmosphere. Hydrazine hydrate (140.30 mg, 2.80 mmol) was added and stirred at 50°C for 2 hours. The combined mixture was filtered and the solid was washed with 10 ml ethyl acetate. The solvent was concentrated under reduced pressure to obtain the title compound (200 mg, 86.4%) as a brown solid.

B. Ethyl 1-(benzo[b]thiazol-7-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, 114b

7-Hydrazinylbenzo^]thiazole (200 mg, 1.21 mmol) was dissolved in ethanol (5 ml), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (436.11 mg, 1.82 mmol). The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product as a yellow solid, which was purified using FCC (eluent: petroleum ether/ethyl acetate 100/0 to 70/30) to obtain the title compound (195 mg, 43.6%) as a white solid. LCMS (ESI) m/z M+1: 342.0.

C. 1-(Benzo^]thiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 114c

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Ethyl 1-(benzo^]thiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (195 mg, 0.53 mmol) was dissolved in THF (10 ml) and aqueous (10 ml) was added. sodium hydroxide (31.64 mg, 0.79 mmol). The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was adjusted to pH 5 with HCl (2N), extracted with EtOAc (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude title compound (140 mg, 81.8%) as a brown solid. LCMS (ESI) m/z M+1: 313.9.

D. 1-(Benzo[d]thiazol-7-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)1H-pyrazole-4-carboxamide, compound 114

1-(Benzo[d]thiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (140 mg, 0.37 mmol), 5-amino-2-(2H-1,2 ,3-triazol-2-yl)nicotinonitrile (81.71 mg, 0.44 mmol), pyridine (173.59 mg, 2.20 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (224 .33 mg, 1.46 mmol). The mixture was stirred at 25°C for 4 hours and saturated. NaHCO ₃ (40 ml) and extracted using CH ₂ Cl ₂ (40 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil, which was purified by preparative HPLC (25-55% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (49.0 mg, 27.8%). LCMS (ESI) m/z M+1: 481.9.

Ή NMR (400 MHz, DMSO-d6) δ=11.52 (s, 1H), 9.00 (d, J=2.6 Hz, 1H), 8.78 (d, J=2.6 Hz, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 8.37 (dd, J=1.4, 2.5 Hz, 1H), 8.27 (s, 2H), 7.28 (dd, J=1.3, 4.6 Hz, 1H), 7.20 (dd, J=2.6, 4.4 Hz, 1H).

Example 115.

N-(5-Chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(1-oxo-1,2dihydroisoquinoline-5- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 115

A. 5-Hydrazinyl-1-methoxyisoquinoline, 115a

A mixture of {Pd(cinnamyl)Cl} ₂ (457 mg, 0.88 mmol) and Mor-DalPhos (818 mg, 1.76 mmol) in dioxane (50 ml) was deaerated using argon (4x). The resulting clear yellow solution was stirred at room. temp, in argon atmosphere for 10 min. 5-Bromo-1methoxyisoquinoline (4.2 g, 17.6 mmol) and sodium t-butoxide (3.39 g, 35.3 mmol) were added to the mixture and the mixture was deaerated using argon (4x). The resulting yellow reaction mixture was stirred at room. temp for 5 min and subsequently treated with hydrazine (1.77 g, 35.3 mmol) via syringe. The mixture was then stirred at 50° C. under argon for 2 hours. The precipitate was filtered, washed with ethyl acetate (200 ml) and dried under reduced pressure to obtain the product (3.4 g).

B. Ethyl 1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 115b

- 216 045333

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (8.89 g, 37.0 mmol), 5-hydrazinyl-1-methoxyisoquinoline (3.4 g, 18 .5 mmol) and ethanol (200 ml) were stirred at 80°C for 3 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure and subsequently purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-70:30) to obtain the product as a white solid (5.4 g, 80%).

C. 1-(1-Methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 115c

Sodium hydroxide (1.15 g, 28.7 mmol) was added to a solution of ethyl 1-(1-methoxyisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (3.0 g, 8.2 mmol) in THF/H ₂ O (2:1, 15 ml) and the mixture was heated at 23°C for 2 hours. The solvent was concentrated under reduced pressure, a solution of 1 M HCl was added to the mixture to adjust the pH to ~ 5 and the mixture was extracted with using EtOAc (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the product as a yellow solid (2.5 g, 90.3% yield). LC-MS: (ES, m/z): [M+1]+ 338.0.

D. Methyl 2-(3-chloro-5-(1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4-carboxamido)pyridin-2-yl)-2H-1 ,2,3-triazole-4-carboxylate, 115d

1-(1-Methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1000 mg, 2.97 mmol), methyl 2-(5-amino-3-chloropyridine-2- yl)-2H-1,2,3-triazole-4-carboxylate (827.30 mg, 3.26 mmol), POCl ₃ (545.58 mg, 3.56 mmol) were dissolved in DCM (6 ml) and added pyridine (703.63 mg, 8.90 mmol). The mixture was stirred at 25°C for 1 hour, saturated was added. NaHCO ₃ (10 ml) and extracted using CH ₂ Cl ₂ (15 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil, which was purified using FFS (petroleum ether/ethyl acetate=50:50 - petroleum ether/ethyl acetate=0:100 ). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow oil. LCMS (ESI) m/z M+1: 573.1.

E. N-(5-Chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methoxyisoquinolin5-yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide, 115e

Methyl 2-(3 -chloro-5 -(1-(1 -methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamido)pyridin-2-yl)-2H-1,2,3 -triazole-4-carboxylate (250 mg, 0.38 mmol) was dissolved in THF (5 ml) at 0°C, LiAlH ₄ (49.85 mg, 1.31 mmol) was added slowly. The reaction mixture was stirred at room temperature for 2 hours. Water (80 μl) was added to the mixture at 0°C and the mixture was stirred for 10 minutes. NaOH (80 μL, 15% in water) was added to the mixture at 0°C and the mixture was stirred for 10 min. Water (240 μL) was added to the mixture at 0°C and the mixture was stirred for 10 min. MgSO4 was added to the mixture and the mixture was filtered. The filtrate was concentrated to give the crude product as a brown oil (200 mg, 86.8%). LCMS (ESI) m/z M+1: 545.0.

C. N-(5-Chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2

- 217 045333 dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 115

K N-(5-Chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methoxyisoquinolin5-yl)-5- (trifluoromethyl)-1H-pyrazole-4-carboxamide (200 mg, 0.33 mmol) and conc. HCl (4 ml) was added to iPrOH (8 ml), stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure to give the crude product as a brown oil, which was purified by preparative HPLC (75-45% (vol. /vol.) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to obtain the title compound (108 mg, 62.4%). LCMS (ESI) m/z M+1: 530.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.63 (s, 2H), 5.63 (d, J=7.06 Hz, 1H), 7.28 (dd, J=7 ,39, 5.84 Hz, 1H), 7.65 (t, J=7.83 Hz, 1H), 7.94 (d, J=7.50 Hz, 1H), 8.05 (s, 1H ), 8.42 (d, J=7.94 Hz, 1H), 8.52 (s, 1H), 8.63 (d, J=2.20 Hz, 1H), 8.81 (d, J =2.21 Hz, 1H), 11.22 (s, 1H), 11.62 (br.d, J=5.95 Hz, 1H).

Example 116.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-hydroxyisoquinolin-5-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 116

A. N-(5 -Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-1-(1 -methoxyisoquinolin-5 -yl)-5 (trifluoromethyl)- 1H-pyrazole-4-carboxamide, 116a

1-(1-Methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (200 mg, 0.587 mmol), 5-chloro-6-(2H-1,2,3-triazole -2-yl)pyridin-3-amine (117.16 mg, 0.60 mmol), POCl ₃ (108.05 mg, 0.71 mmol) were dissolved in DCM (8 ml) and pyridine (139.35 mg) was added , 1.76 mmol). The mixture was stirred at 25°C for 1 hour, saturated was added. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil, which was purified by preparative HPLC (50-20% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (142 mg, 46.7%). LCMS (ESI) m/z M+1: 514.9.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.10 (s, 3H), 6.56 (d, J=6.17 Hz, 1H), 7.78-7.85 ( m, 1H), 8.06 (d, J=6.39 Hz, 1H), 8.10 (d, J=5.95 Hz, 1H), 8.18 (s, 2H), 8.45 ( d, J=8.16 Hz, 1H), 8.56 (s, 1H), 8.66 (d, J=2.21 Hz, 1H), 8.83 (d, J=2.21 Hz, 1H), 11.25 (s, 1H).

B. N-(5 -Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-1-(1 -hydroxyisoquinolin-5 -yl)-5 - (trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 116

K N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methoxyisoquinolin-5-yl)-5(trifluoromethyl)-1H -pyrazole-4-carboxamide (70 mg, 0.14 mmol) and conc. HCl (4 ml) was added to i-PrOH (8 ml), stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (84-54% ( v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to obtain the indicated

- 218 045333 in the title of the compound (47 mg, 69.4%). LCMS (ESI) m/z M+1: 500.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 5.63 (d, J=7.50 Hz, 1H), 7.27 (dd, J=7.17, 6.06 Hz, 1H ), 7.65 (t, J=7.83 Hz, 1H), 7.93 (d, J=7.06 Hz, 1H), 8.16 (s, 2H), 8.41 (d, J =7.94 Hz, 1H), 8.53 (s, 1H), 8.64 (d, J=2.21 Hz, 1H), 8.82 (d, J=2.20 Hz, 1H), 11.25 (s, 1H), 11.62 (br.d, J=5.73 Hz, 1H).

Example 117.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 117

A. 4-Bromo-8-fluoroisoquinoline, 117a

To a solution of 8-fluoroisoquinoline (0.5 g, 3.40 mmol) in CCl ₄ (15 ml) was added 1-bromopyrrolidine-2,5dione (604.78 mg, 3.40 mmol) and (E)-3,3 '-(diazen-1,2-diyl)bis(2-methylpropanenitrile) (55.8 mg, 0.34 mmol). The mixture was stirred at 80°C for 3 hours. The solvent was concentrated under reduced pressure to obtain a crude product, which was purified using FCC (petroleum ether/ethyl acetate=1:0 - petroleum ether/ethyl acetate=1:1) to obtain the title compound (0.21 g, 27.1%) as a yellow oil. LCMS (ESI) m/z M+1: 225.9.

1H NMR (400 MHz, chloroform-d) δ ppm 9.44 (1H, s), 8.78 (1H, s), 7.93 (1H, br.d, J=8.38 Hz) , 7.74 (1H, td, J=7.94, 5.51 Hz), 7.27-7.36 (1H, m).

B. 8-Fluoro-4-hydrazinyl isoquinoline, 117b

' ^NH *, 117b

Palladium(P)chloride dimer (pi-cinnamyl) (23.81 mg, 0.046 mmol) and 4-(2-(di((3S,5S,7S)-adamantan1-yl)phosphino)phenyl)morpholine (42.62 mg, 0.092 mmol) was added to dioxane (8 ml) and immediately removed the air using N ₂ . The resulting solution was stirred at room. temp, in N ₂ atmosphere for 10 min. Subsequently, sodium 2-methylpropan-2-olate (176.69 mg, 1.84 mmol) and 4-bromo-8fluoroisoquinoline (210 mg, 0.92 mmol) were added, sealed, and air removed using N2. The resulting mixture was stirred at room. temp for 5 min and subsequently treated with hydrazine hydrate (92.04 mg, 1.84 mmol) via syringe. The mixture was stirred at 50°C in an N ₂ atmosphere for 1.5 hours and filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow solid (260 mg). The mixture was directly used in the next step.

C. Ethyl 1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 117c

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (1.762 g, 7.34 mmol), 8-fluoro-4-hydrazinyl isoquinoline (260 mg, 1.47 mmol) and ethanol (10 ml) was stirred at 80°C for 2 hours. The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product, which was purified using FCC (petroleum ether:ethyl acetate=100/0-70/30) to obtain the title compound (0.22 g, 42.4%) as a yellow solid. LCMS (ESI) m/z M+1: 354.0.

D. 1-(8-Fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 117d

- 219 045333

Sodium hydroxide (37.36 mg, 0.93 mmol) was added to a solution of ethyl 1-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (220 mg, 0.62 mmol) in THF/H ₂ O=3:1 (12 ml). The mixture was stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure and 20 ml of H ₂ O was added to the mixture. The mixture was acidified using 1 M hydrogen chloride to pH 5 and extracted with ethyl acetate (20 ml x 3 ). The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the product as a yellow solid (160 mg, 79.0%).

E. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide, compound 117

1-(8-Fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (80 mg, 0.25 mmol), 5-chloro-6-(2H-1,2,3 -triazol-2-yl)pyridin-3-amine (48.12 mg, 0.25 mmol), pyridine (0.10 ml, 1.23 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride was added (0.090 ml, 0.98 mmol). The mixture was stirred at 25°C for 2 hours, saturated was added. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (43-73% (v/v) CH3CN and H ₂ O with 0.05 % HCl) and lyophilized to dryness to obtain the title compound (35 mg, 28.2%). LCMS (ESI) m/z M+1: 502.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (1H, s), 9.73 (1H, s), 8.93 (1H, s), 8.85 (1H, d, J=1.98 Hz), 8.67 (1H, d, J=2.21 Hz), 8.65 (1H, s), 8.17 (2H, s), 7.90-7.98 ( 1H, m), 7.69 (1H, dd, J=10.36, 8.38 Hz), 7.12 (1H, d, J=8.60 Hz).

Example 118.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 118

1-(8-Fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (80 mg, 0.25 mmol), 5-amino-2-(2H-1,2,3 -triazol-2-yl)nicotinonitrile, (45.8 mg, 0.25 mmol), pyridine (0.10 ml, 1.23 mmol) was dissolved in CH2Cl2 (10 ml) and phosphorus oxychloride (0.090 ml, 0. 98 mmol). The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (43-63% (v/v) CH3CN and H ₂ O with 0.05 % HCl) and lyophilized to dryness to obtain the title compound (36 mg, 29.1%). LCMS (ESI) m/z M+1: 493.9.

'H NMR (400 MHz, DMSO-d6) δ ppm 11.40 (1H, s), 9.73 (1H, s), 9.09 (1H, d, J=2.43 Hz), 8.93 (1H, s), 8.87 (1H, d, J=2.43 Hz), 8.65 (1H, s) 8.29 (2H, s), 7.89-7.99 ( 1H, m), 7.64-7.72 (1H, m), 7.12 (1H, d, J=8.38 Hz).

Example 119.

1-(Benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 119

A. 7-Hydrazinylbenzo[d][1,2,3]thiadiazole, 119a

- 220 045333

To a stirred solution of benzo[d][1,2,3]thiadiazol-7-amine (2 g, 13.23 mmol) in HCl (6 N, 50 ml) at -10°C was added a solution of sodium nitrite (1.37 g, 19.85 mmol) in H2O (20 ml) at a temperature below -20°C. The reaction mixture was stirred at rt for 0.5 hour. Subsequently cooled to 20°C, tin(n) chloride dihydrate (5.97 g, 26.45 mmol) was added to the mixture in portions and stirred for 1 hour. The reaction mixture was made alkaline. using 3 M NaOH and the aqueous layer was extracted using EtOAc (200 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude product (2.5 g) as a brown solid, which was used in the next step without further purification. LCMS (ESI) m/z M+1: 167.1.

B. Ethyl 1-(benzo^][1,2,3]thiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 119b

7-Hydrazinylbenzo[d][1,2,3]thiadiazole (2.5 g, 5.71 mmol) was dissolved in ethanol (30 ml), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3 was added -oxobutanoate (3.28 g, 13.64 mmol) and stirred at 70°C for 2 hours and then cooled to room temperature. The combined mixture was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified using FCC (eluent: petroleum ether/ethyl acetate 100/0 to 85/15) to give the title compound (1.2 g, 61. 4%) as a yellow solid. LCMS (ESI) m/z M+1: 342.9.

C. 1-(Benzo^][1,2,3]thiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 119c

Ethyl 1-(benzo^][1,2,3]thiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1.2 g, 3.51 mmol) was dissolved in THF (8 ml) and water (8 ml). Lithium hydroxide (251.87 mg, 10.52 mmol) was added. The reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was adjusted to pH 5 using HCl (2N), extracted using CH ₂ Cl ₂ /MeOH (10/1, 60 mlx5). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude title compound (900 mg, 81.0%) as a yellow solid. LCMS (ESI) m/z M+1: 315.1.

D. 1-(Benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 119

1-(Benzo^][1,2,3]thiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (300 mg, 0.95 mmol), 5-amino-2- (2H-1,2,3-triazol-2-yl)nicotinonitrile, (229.0 mg, 1.23 mmol) and pyridine (449.05 mg, 5.68 mmol) were dissolved in CH ₂ Cl ₂ (30 ml ) and phosphorus oxychloride (435.23, 2.84 mmol) was added. The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (50 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (45-75% (v/v) CH3CN and H2O with 0 .05% HCl) and lyophilized to dryness to give the title compound (200 mg, 43.1%). LCMS (ESI) m/z M+1: 483.0.

L NMR (400 MHz, DMSO-d6) δ=11.47 (s, 1H), 9.08 (d, J=2.4 Hz, 1H), 8.99 (d, J=8.4 Hz, 1H), 8.85 (d, J=2.2 Hz, 1H), 8.63 (s, 1H), 8.31 (s, 2H), 8.15-8.10 (m, 1H), 8.06-7.99 (m, 1H).

Example 120.

1-(Benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 120

- 221 045333

1-(Benzo^][1,2,3]thiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.28 mmol), 5-chloro-6- (2H-1,2,3-triazol-2-yl)pyridin-3-amine, (53.95 mg, 0.28 mmol), pyridine (130.9 mg, 1.66 mmol) was dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (126.87, 0.83 mmol) was added. The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (50 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (45-75% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (18 mg, 13.2%). LCMS (ESI) m/z M+1: 492.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ= 11.43 (s, 1H), 8.99 (d, J=8.2 Hz, 1H), 8.84 (d, J=2.2 Hz , 1H), 8.66 (d, J=2.2 Hz, 1H), 8.64 (s, 1H), 8.20 (s, 2H), 8.15-8.10 (m, 1H) , 8.06-8.00 (m, 1H).

Example 121.

1-(Benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridine -3-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 121

1-(Benzo[d][1,2,3]thiadiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (149.93 mg, 0.47 mmol), 5-chloro -2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, (109.09 mg, 0.52 mmol), pyridine (224.52 mg, 2.84 mmol) was dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (217.62 mg, 1.42 mmol) was added. The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (50 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (45-75% (v/v) CH3CN and H2O with 0 .05% HCl) and lyophilized to dryness to give the title compound (102 mg, 42.4%). LCMS (ESI) m/z M+1: 505.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ=10.73 (s, 1H), 8.98 (d, J=8.2 Hz, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 8.19 (s, 2H), 8.13-8.09 (m, 1H), 8.06-8.01 (m, 1H), 2.56 (s, 3H).

Example 122.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoronaphthalen-1-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 122

A. (5-Fluoronaphthalen-1-yl)hydrazine, 122a

A mixture of {Pd(cinnamyl)Cl} ₂ (11.51 mg, 0.022 mmol) and Mor-DalPhos (20.60 mg, 0.044 mmol) in dioxane (2 ml) was deaerated using argon (4x). The resulting clear yellow solution was stirred at room. pace. in an argon atmosphere for 10 minutes. 1-Bromo5-fluoronaphthalene (100 mg, 0.44 mmol) and t-BuONa (85.31 mg, 0.89 mmol) were added to the mixture and the mixture was deaerated using argon (4x). The resulting yellow mixture was stirred at room. pace. for 5 min and subsequently treated with hydrazine hydrate (45.40 mg, 0.889 mmol) via syringe. The reaction mixture was deaerated using argon (4x). Subsequently the mixture

- 222 045333 was stirred at 50°C in an argon atmosphere for 4 hours. The mixture was filtered and washed with ethyl acetate (5 mlx3). The filtrate was collected and concentrated to give the crude product (100 mg, >100% yield) as a brown solid which was used directly in the next step.

B. Ethyl 1-(5-fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 122b

Solution of (5-fluoronaphthalen-1-yl)hydrazine, 122a (100 mg, 0.57 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (204.48 mg, 0.85 mmol) , triethylamine (171.97 mg, 1.70 mmol) in EtOH (10 ml) was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate from 20 :1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 122b (100 mg, 46.7% yield) as a yellow solid. LCMS (ESI) m/z M+1: 352.9.

C. 1-(5-Fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 122c

Solution of ethyl 1-(5-fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 122b (100 mg, 0.27 mmol), LiOH (22.23 mg, 0.53 mmol ) in MeOH (10 ml), THF (10 ml) and water (10 ml) were stirred at rt for 3 hours. 5% KHSO4 was added to the mixture to adjust the pH to 3 ~ 4. Water (100 ml) was added to the mixture ) and ethyl acetate (100 ml). The organic layer was washed with brine (50 mL), dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give 122c (90 mg, 94.1% yield) as a yellow solid, which was directly used in the next step. LCMS (ESI) m/z M+H: 324.8.

D. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(5-fluoronaphthalen-1 -yl)-5 -(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 122

POCl ₃ (76.46 mg, 0.50 mmol) was added to a solution of 1-(5-fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxylic acid, 122c (90 mg, 0.25 mmol ), 5-amino-2-(2H-1,2,3-triazol-2yl)nicotinonitrile (46.42 mg, 0.25 mmol), pyridine (49.30 mg, 0.62 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at rt for 2 hours, and 50 ml of water and 50 ml of CH ₂ Cl ₂ were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (47-77% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to obtain the title compound (33.5 mg, 26.5% yield) as a white solid. LCMS (ESI) m/z M+1: 492.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (d, J=2.43 Hz, 1H), 8.86 (d, J=2.43 Hz, 1H), 8.58 (s, 1H), 8.32 (d, J=8.38 Hz, 1H), 8.28 (s, 2H), 7.90 (d, J=7.28 Hz, 1H), 7.74 -7.83 (m, 1H), 7.60 (td, J=8.10, 5.62 Hz, 1H), 7.49 (dd, J=10.47, 7.61 Hz, 1H), 6.93 (d, J=8.38 Hz, 1H).

Example 123.

N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 123

- 223 045333

A. 8-Fluoro-4-hydrazinyl isoquinoline, 123a hnh ₂ , 123a

A mixture of {Pd(cinnamyl)Cl} ₂ (68.76 mg, 0.13 mmol) and Mor-DalPhos (123.06 mg, 0.27 mmol) in dioxane (10 ml) was deaerated using argon (4x) . The resulting clear yellow solution was stirred at room. temp, in argon atmosphere for 10 min. 4-Bromo8-fluoroisoquinoline (600 mg, 2.65 mmol) and t-BuONa (509.63 mg, 5.31 mmol) were added to the mixture and deaerated using argon (4x). The resulting yellow reaction mixture was stirred at room. temp for 5 min and subsequently treated with hydrazine hydrate (271.18 mg, 5.31 mmol) via syringe. The reaction mixture was deaerated using argon (4x). The mixture was subsequently stirred at 50°C under argon for 2 hours. The mixture was filtered and washed with ethyl acetate (50 mLx3), the filtrate was collected and concentrated to give crude compound 123a (510 mg, >100% yield) as a brown solid. , which was directly used in the next stage.

B. Ethyl 1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 123b

Solution of 8-fluoro-4-hydrazinyl isoquinoline, 123a (510 mg, 2.88 mmol), ethyl 2-(ethoxymethylene)-4,4,4trifluoro-3-oxobutanoate (1037.0 mg, 4.32 mmol), triethylamine ( 872.17 mg, 8.64 mmol) in EtOH (20 ml) was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 5:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 123b (510 mg, 40.7% yield) as a yellow solid. LCMS (ESI) m/z M+1: 353.9.

C. 1-(8-Fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 123c f ₃ c 2 )=( n ^J

F—t Λ ' 123c

Solution of ethyl 1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 123b (510 mg, 1.17 mmol), LiOH (98.21 mg, 2.34 mmol ) in THF (20 ml) and water (20 ml) was stirred at rt for 2 hours. 5% KHSO4 was added to the mixture to adjust the pH to 3 ~ 4. Water (100 ml) and ethyl acetate (100 ml) were added to the mixture ). The organic layer was washed with brine (50 ml), dried over MgSO ₄ and concentrated under reduced pressure to give 123c (420 mg) as a yellow solid, which was directly used in the next step. LCMS (ESI) m/z M+H: 325.9.

D. X-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 123

POCl ₃ (198.02 mg, 1.29 mmol) was added to a solution of 1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxylic acid, 123c (210 mg, 0.65 mmol), 5-chloro-2-methyl-6-(2H-1,2,3-triazol-2yl)pyridin-3-amine (162.44 mg, 0.78 mmol), pyridine (127.69 mg 1 .61 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at rt for 3 hours, 50 ml of H2O and 50 ml of CH ₂ Cl ₂ were added to the mixture.

The organic layer was washed with brine (50 ml), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (37-67% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to obtain the title compound (86.0 mg, 25.8% yield) as a white solid. LCMS (ESI) m/z M+1: 516.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.66 (s, 1H), 9.72 (s, 1H), 8.91 (s, 1H), 8.62 (s, 1H ), 8.42 (s, 1H), 8.16 (s, 2H), 7.94 (td, J=8.10, 5.62 Hz, 1H), 7.68 (dd, J=10, 36, 7.94 Hz, 1H), 7.13 (d, J=8.38 Hz, 1H), 2.54 (s, 3H).

Example 124.

N-(5-Cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5- 224 045333 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 124

POCl ₃ (94.27 mg, 0.62 mmol) was added to a solution of 1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxylic acid (100 mg, 0.31 mmol) , 5-amino-6-methyl-2-(2H-1,2,3-triazol-2yl)nicotinonitrile (73.87 mg, 0.37 mmol), pyridine (60.81 mg 0.77 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at rt for 3 hours, 50 ml of H ₂ O and 50 ml of CH ₂ Cl ₂ were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO ₄ and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (3060% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to obtain the title compound (37.6 mg, 24.1% yield) as a white solid. LCMS (ESI) m/z M+1: 507.9.

^1H NMR (400 MHz, DMSO-d6) δ ppm 10.71 (s, 1H), 9.72 (s, 1H), 8.91 (s, 1H), 8.64 (d, J =15.88 Hz, 2H), 8.29 (s, 2H), 7.90-7.98 (m, 1H), 7.64-7.72 (m, 1H), 7.13 (d, J=8.60 Hz, 1H), 2.64 (s, 3H).

Example 125.

N-(5-Chloro-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, 125

A. A mixture of 3-chloro-2-(4-methyl-2H-1,2,3-triazol-2-yl)-5-nitropyridine and 3-chloro-2-(4-methyl-1H-1,2, 3triazol-1-yl)-5-nitropyridine, 125a

A solution of 4-methyl-1H-1,2,3-triazole (500 mg, 6.02 mmol), 2,3-dichloro-5-nitropyridine (1277.42 mg, 6.62 mmol), K ₂ CO ₃ ( 2491.22 mg, 18.05 mmol) in CH3CN (5 ml) was stirred at rt for 12 hours. The mixture was concentrated under reduced pressure, the crude product by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 1:1 ). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 125a (1.1 g, 76.3%) as a yellow solid. LCMS (ESI) m/z M+1: 239.7.

B. A mixture of 5-chloro-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-amine and 5-chloro-6-(4-methyl-1H-1,2 ,3triazol-1-yl)pyridin-3-amine, 125b

Zn (1491.96 mg, 22.95 mmol) was added to a solution of a mixture of 3-chloro-2-(4-methyl-2H-1,2,3-triazol-2-yl)5-nitropyridine and 3-chloro-2 -(4-methyl-1H-1,2,3-triazol-1-yl)-5-nitropyridine, 125a (1.1 g, 2.30 mmol) in aq. NH ₄ Cl (30 ml) and H ₂ O (30 ml). The mixture was stirred at rt for 16 hours. Aq. was added to the suspension.

NaHCO ₃ to adjust the pH to 9~10 and the mixture was filtered through a layer of diatomaceous earth. The filter residue was washed with CH ₂ Cl ₂ (100 mlx3). The combined filtrates were washed with brine (200 ml), dried over MgSO ₄ and concentrated under reduced pressure to give a mixture of 5-chloro-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3 -amine and 5-chloro-6-(4-methyl-1H-1,2,3triazol-1-yl)pyridin-3-amine, 125b (1 g) as a brown solid, which was used directly for the next step . LCMS (ESI) m/z M+H: 209.7.

C. N-(5-Chloro-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-( trifluoromethyl)1H-pyrazole-4-carboxamide, compound 125

- 225 045333

POCl ₃ (182.86 mg, 1.19 mmol) was added to a solution of 125b (300 mg, 0.72 mmol), 1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (183.19 mg, 0.60 mmol), pyridine (117.91 mg, 1.49 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at rt for 2 hours, 50 ml of H ₂ O and 50 ml of CH ₂ Cl ₂ were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO ₄ and concentrated under reduced pressure to obtain the crude product, which was purified using preparative HPLC (35-65 (v/v) CH3CN and H ₂ O with 0.05 % HCl) and lyophilized to dryness to obtain the title compound (208 mg, 69.8% yield) as a white solid. LCMS (ESI) m/z M+1: 499.0.

1H NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s, 1H), 9.06 (t, J=2.54 Hz, 1H), 8.89 (s, 1H), 8 ,60-8.75 (m, 2H), 8.33 (d, J=8.38 Hz, 1H), 7.88-8.03 (m, 3H), 7.68 (d, J=2 .65 Hz, 2H), 2.34 (s, 3H).

Example 126.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-b]niridin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 126

A. 4-Hydrazinylthieno[2,3-b]pyridine, 126a

A solution of 4-chlorothieno[2,3-b]pyridine (600 mg, 3.54 mmol) in hydrazine (5 ml, 98%) was stirred at 100°C overnight. The solid was filtered and washed with 2 ml of water. The solid was collected and dried to give 126a (550 mg, 88.2% yield) as a white solid. LCMS (ESI) m/z M+1: 165.9.

B. Ethyl 1-(thieno[2,3-b]niridin-4-yl)-5-(trifluoromethyl)-1H-nirazol-4-carboxylate, 126b

A solution of 4-hydrazinylthieno[2,3-b]niridine (300 mg, 1.70 mmol), ethyl 2-(ethoxymethylene)-4,4,4trifluoro-3-oxobutanoate (613.23 mg, 2.55 mmol) in EtOH (5 ml) was stirred at 80°C for 3 hours. The mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 20/80). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 126b (500 mg, 86.1% yield) as a yellow solid.

C. 1-(Thieno[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 126c

Solution of ethyl 1-(thieno[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, 126b (150 mg, 0.44 mmol), LiOH (18.44 mg, 0.44 mmol) in EtOH/H ₂ O (2/1.2 ml) was stirred at room temperature overnight. 1N HCl solution was added to neutralize the reaction solution. The mixture was extracted using ethyl acetate (5 mlx3). The separated organic layer was dried (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated to give 126c (137 mg, crude) as a yellow solid. LCMS (ESI) m/z M+1: 313.9.

D. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)πpyridin-3-yl)-1-(thieno[2,3-b]πpyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 126

- 226 045333

Phosphorus oxychloride (41.66 μL, 0.45 mmol) was added to a solution of 1-(thieno[2,3-b]pyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 126c ( 70 mg, 0.22 mmol), 5-amino-2-(2H-1,2,3triazol-2-yl)nicotinonitrile (62.40 mg, 0.34 mmol), pyridine (180.73 µl, 2. 24 mmol) in CH ₂ Cl ₂ (2 ml). The mixture was stirred at room temperature for 2 hours and 5 ml of H2O was added to the mixture. Added sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 mlx3). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (42-72% (v/v) CH3CN and H ₂ O with 0.05 % HCl) and lyophilized to dryness to obtain the title compound (50 mg, 46.4%). LCMS (ESI) m/z M+1: 481.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.17 (d, J=6.17 Hz, 1H), 7.73 (d, J=5.07 Hz, 1H), 8.13 (d, J=6.17 Hz, 1H), 8.31 (s, 2H), 8.62 (s, 1H), 8.84 (d, J=4.85 Hz, 1H), 8.87 (d, J=2.43 Hz, 1H), 9.08 (d, J=2.43 Hz, 1H), 11.36 (s, 1H).

Example 127.

N-(5-Chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazol- 4-carboxamide, compound 127

5-Bromo-3-chloropicolinic acid (15 g, 63.44 mmol) was suspended in CH2Cl2 (250 ml) and stirred at 0°C. Oxalyl chloride (15 mL, 176.09 mmol) was added dropwise followed by DMF (dropwise). The reaction mixture was stirred at 0°C for 1 hour and stirred at 20°C for 1 hour. The yellow solution was concentrated under reduced pressure to give the compound (17 g) as a yellow solid.

B. 5-bromo-3-chloro-N-(2,2-dimethokCethyl)picOlinamide, 127b

5-Bromo-3-chloropicolinoyl chloride (17 g, 66.69 mmol) was dissolved in CH ₂ Cl ₂ (250 ml) and added dropwise to a mixture of 2,2-dimethoxyethanamine (14.02 g, 133.39 mmol) and TEA (13.50 g, 133.39 mmol) at 0°C. The mixture was stirred at 0°C for 1.5 hours. H2O (300 ml) was added and extracted with CH ₂ Cl ₂ (300 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil, which was purified by flash column chromatography on silica gel (eluent: CH ₂ Cl ₂ /ethyl acetate 100/0 to 80 /20). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (16 g, 74.1%) as a yellow solid.

C. 5-Bromo-3-chloro-N-(2-oxCOEthyl)picolinamide, 127c

To a solution of 5-bromo-3-chloro-N-(2,2-dimethoxyethyl)picolinamide (16 g, 49.45 mmol) in MeCN (160 ml) was added 2 N HCl (160 ml). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was adjusted to pH 7.5 using sat. NaHCO ₃ , extracted using EtOAc (200 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude product (12 g, 87.5%) as a yellow solid. LCMS (ESI) m/z M+1: 278.8.

D. 2-(5-Bromo-3-chloropyridin-2-yl)oxazole, 127d

5-Bromo-3-chloro-N-(2-oxoethyl)picolinamide (12 g, 43.24 mmol) was dissolved in dioxane (200 ml) and phosphorus oxychloride (19.89 g, 129.73 mmol) was added. The reaction mixture was stirred at 80°C for 6 hours. The reaction mixture was poured into water (800 ml), stirred at rt for 0.5 hours, subsequently extracted using EtOAc (400 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give a black oil. The black oil was purified by silica gel flash column chromatography (eluent: petroleum ether/ethyl acetate 100/0 to 70/30) to give the title compound (1.5 g,

13.3%) in the form of a yellow solid. LCMS (ESI) m/z M+1: 258.9.

E. tert-Butyl (5-chloro-6-(oxazol-2-yl)pyridin-3-yl)carbamate, 127e

2-(5-Bromo-3-chloropyridin-2-yl)oxazole (1.5 g, 5.78 mmol) and tert-butyl carbamate (1.35 g, 11.56 mmol) were dissolved in dioxane (30 ml) , add Pd ₂ (dba) ₃ (264.67 mg, 0.29 mmol), Xantphos (333.48 mg, 0.58 mmol) and cesium carbonate (3.77 g, 11.56 mmol) and flush with N ₂ within 1 min. The reaction mixture was stirred at 90°C for 16 hours. The combined mixture was filtered through a pad of diatomaceous earth and the layer was washed with EtOAc (50 mlx3). The filtrates were concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 40/60). The desired fraction was collected and the solvent was concentrated under reduced pressure to obtain the title compound (970 mg, 61.4%) as a yellow solid. LCMS (ESI) m/z M+1: 296.1.

F. 5-Chloro-6-(oxazol-2-yl)pyridin-3-amine, 127f tert-Butyl (5-chloro-6-(oxazol-2-yl)pyridin-3-yl)carbamate (970 mg, 3.28 mmol) was dissolved in CH ₂ Cl ₂ (5 ml) and a mixture of HCl/dioxane (5.4 ml, 21.6 mmol) was added. The reaction mixture was stirred at 30°C for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a yellow oil, adjusted to pH 8 using sat. Na ₂ CO ₃ , extracted using CH ₂ Cl ₂ (50 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the product (650 mg, 95.4%) as a yellow oil. LCMS (ESI) m/z M+1: 196.1.

G. N-(5-Chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 127

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (876.66 mg, 2.25 mmol), 5-chloro-6- (oxazol-2-yl)pyridin-3-amine (400 mg, 2.05 mmol) and pyridine (970.52 mg, 12.27 mmol) were dissolved in CH ₂ Cl ₂ (40 ml) and phosphorus oxychloride (940 .66 mg, 6.14 mmol). The mixture was stirred at 25°C for 3 hours, saturated was added. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (34-54% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (240 mg, 23.2%). LCMS (ESI) m/z M+1: 500.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ=11.64 (br.d, J=5.3 Hz, 1H), 11.29 (s, 1H), 8.97 (s, 1H), 8 ,63-8.53 (m, 2H), 8.44 (d, J=8.2 Hz, 1H), 8.34 (s, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.51 (s, 1H), 7.30 (t,

- 228 045333

J=6.6 Hz, 1H), 5.66 (d, J=7.3 Hz, 1H).

Example 128.

N-(5-Cyαno-6-(2H-1,2,3-triazol-2-yl)niridin-3-yl)-1-(thieno[3,2-b]niridin-7-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 128

A. 7-Hydrazinylthieno[3,2-b]pyridine, 128a

7-Chlorothieno[3,2-b]pyridine (180 mg, 1.06 mmol) in NH2NH2-H2O (7 ml) was reacted at 26°C for 16 hours. The mixture was extracted using 20x3 ml CH ₂ Cl ₂ , the solvent was concentrated under reduced pressure to obtain the desired compound.

B. Ethyl 1-(thieno[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 128b

7-Hydrazinylthieno[3,2-b]pyridine (90 mg, 0.55 mmol) was added to a solution of ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (196.25 mg, 0.82 mmol ) in EtOH (5 ml) and reacted at 80°C for 3 hours. The mixture was concentrated under reduced pressure, subsequently purified by FFS (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate=60:40). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a brown oil. LCMS (ESI) m/z M+1: 342.2.

C. 1-(Thieno[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 128c

NaOH (25.23 mg, 0.63 mmol) was added to a solution of ethyl 1-(thieno[3,2-b]pyridin-7-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (75 mg, 0.21 mmol) in EtOH/H ₂ O=1:1 (3 ml) and reacted at 28°C for 2 hours. The solvent was concentrated under reduced pressure to obtain the desired compound. LCMS (ESI) m/z M+1: 314.2.

D.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[3,2-b]pyridin-7-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 128

1-(Thieno[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid (65 mg, 0.19 mmol), 5-amino-2-(2H -1,2,3-triazol-2-yl)nicotinonitrile (42.76 mg, 0.23 mmol), POCl ₃ (35.21 mg, 0.23 mmol) were dissolved in DCM (2 ml) and pyridine ( 45.41 mg, 0.57 mmol). The mixture was stirred at 25°C for 2 hours, saturated was added. NH ₄ Cl (20 ml) and extracted using CH ₂ Cl ₂ (20 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (73-43% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (46 mg, 49.7%). LCMS (ESI) m/z M+1: 481.9.

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1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.67 (br.d, J=4.63 Hz, 1H), 7.75 (d, J=5.51 Hz, 1H), 8.21-8.38 (m, 1H), 8.23-8.37 (m, 2H), 8.74 (s, 1H), 8.87-8.96 (m, 2H), 9. 14 (d, J=2.21 Hz, 1H), 11.66 (s, 1H).

Example 129.

N-(3-Chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide, compound 129

A. 2-(2-Chloro-4-nitrophenyl)-2H-1,2,3-triazole, 129a ι<γ ^Ν ' ^Ν

A ^- , 129a

2-Chloro-1-fluoro-4-nitrobenzene (3 g, 17.09 mmol), 1H-1,2,3-triazole (1.30 g, 18.80 mmol) and potassium carbonate (3.54 g, 25.63 mmol) was added to DMF (50 ml) and stirred at 55°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product as a yellow solid. Added sat. NH4Cl (100 ml) and extracted using EtOAc (100 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow solid, which was purified using FCC (eluent: petroleum ether/ethyl acetate 100/0 to 60/40) to obtain the title compound (1.9 g, 49.5%) as a yellow solid.

1H NMR (400 MHz, chloroform-d) δ=8.49 (d, J=2.5 Hz, 1H), 8.28 (dd, J=2.5, 8.8 Hz, 1H), 7, 97 (s, 2H), 7.93 (d, J=8.8 Hz, 1H), 7.95-7.91 (m, 1H).

B. 3-Chloro-4-(2H-1,2,3-triazol-2-yl)aniline, 129b

Η ₂ Ν·%Α| _129b

2-(2-Chloro-4-nitrophenyl)-2H-1,2,3-triazole (1.9 g, 8.46 mmol) was dissolved in THF (20 ml) and Fe (2.83 g, 50, 76 mmol), NH ₄ Cl (2.72 g, 50.76 mmol) and H2O (20 ml). The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with EtOAc (30 mlx3). The filtrates were concentrated to dryness to give the crude product as a yellow solid, which was purified using FCC (eluent: petroleum ether/ethyl acetate 100/0 to 70/30). The desired fractions were collected and the solvent was concentrated under reduced pressure to give (1.5 g, 89.5%) as a yellow solid. LCMS (ESI) m/z M+1: 194.8.

C. N-(3-Chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 (trifluoromethyl )-1 H-pyrazole-4-carboxamide, 129

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (300 mg, 0.77 mmol), 3-chloro-4-(2H -1,2,3-triazol-2-yl)aniline (182.95 mg, 0.92 mmol) and pyridine (608.89 mg, 7.70 mmol) were dissolved in CH ₂ Cl ₂ (15 ml) and added phosphorus oxychloride (354.09 mg, 2.31 mmol). The mixture was stirred at 25°C for 3 hours, saturated was added. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (40-40% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (135 mg, 34.8%). LCMS (ESI) m/z M+1: 499.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ=11.64 (br.d, J=5.5 Hz, 1H), 11.02 (s, 1H), 8.52 (s, 1H), 8 .44 (d, J=8.2 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.15 (s, 2H), 7.94 (d, J=7, 5 Hz, 1H), 7.86 (dd, J=2.1, 8.7 Hz, 1H), 7.71 (d, J=8.8

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Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.30 (t, J=6.6 Hz, 1H), 5.67 (d, J=7.1 Hz, 1H).

Example 130.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)niridin-3-yl)-1-(2-D-quinolin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 130

A. 2-E-quinoline, 130a

A solution of quinoline-2-carboxylic acid (1.5 g, 8.66 mmol), silver(I) carbonate (238.85 mg, 0.87 mmol) and deuteroxide (9 ml) in DMSO (45 ml) was stirred at 140 °C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product as a colorless oil, which was purified using FCC (petroleum ether:ethyl acetate=100:0 - petroleum ether/ethyl acetate=0:100) with obtaining the title compound (0.88 g, 78.049%) as a colorless oil.

B. 5-Bromo-2D-quinoline, 130b

1-Bromopyrrolidine-2,5-dione (1.203 g, 6.76 mmol) was added to a solution of 2-D-quinoline (0.88 g, 6.76 mmol) in conc. H ₂ SO ₄ (15 ml). The reaction mixture was poured onto 75 ml of crushed ice, and the pH was adjusted to 9.0 using conc. aq NH3, the alkaline suspension was subsequently extracted using ethyl acetate (3x30 ml). The combined organic fractions were washed with 1.0 M NaOH, followed by water, dried (MgSO ₄ ), filtered, concentrated to give the crude product, which was purified using FCC (petroleum ether:ethyl acetate=100:0-0:100) to give product of relatively high purity, which was purified by preparative HPLC (10-40% (v/v) CH ₃ CN and H ₂ O with 0.05% ammonium hydroxide) and lyophilized to dryness to give the title compound (390 mg , 27.6%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (1H, d, J=8.78 Hz), 8.18 (1H, d, J=8.53 Hz), 8.09 (1H, d, J=7.53 Hz), 7.77-7.87 (2H, m).

C. 2-D-5-hydrazinylquinoline, 130c

D _130c

Palladium(P)chloride dimer (pi-cinnamyl) (24.78 mg, 0.048 mmol) and 4-(2-(di((3S,5S,7S)-adamantan1-yl)phosphino)phenyl)morpholine (44.35 mg, 0.096 mmol) was added to dioxane (10 ml), immediately purged with N2. The resulting solution was stirred at room. temp, under N2 atmosphere for 10 min and subsequently sodium 2-methylpropan-2-olate (183.88 mg, 1.91 mmol) and 5-bromo-2-D-quinoline (200 mg, 0.96 mmol). The reaction vessel was sealed and purged with N ₂ . The resulting reaction mixture was stirred at room. temp for 5 min and subsequently treated with hydrazine hydrate (95.78 mg, 1.91 mmol) via syringe. The reaction mixture was stirred at 50°C under N ₂ for 1.5 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product as a yellow solid (140 mg, 91.4%), which was directly used in next stage without additional purification.

D. Ethyl 1-(2-D-quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 130d

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, (1.05 g, 4.37 mmol), 2-D-5-hydrazinylquinoline (140 mg, 0.87 mmol ) and ethanol (10 ml) were stirred at 80°C for 2 hours.

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The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product, which was purified using FCC (petroleum ether:ethyl acetate=100/0-50/50) to obtain the title compound (0.26 g, 87.7%) as yellow solid. LCMS (ESI) m/z M+1: 336.9.

E. 1-(2-D-Quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 130e

Sodium hydroxide (45.96 mg, 1.15 mmol) was added to a solution of ethyl 1-(2-D-quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (260 mg, 0.77 mmol) in THF/H2O 3:1 (12 ml). The mixture was reacted at room temperature for 16 hours, the solvent was concentrated under reduced pressure, and 20 ml of H ₂ O was added to the mixture. The mixture was acidified using 1M hydrogen chloride to pH 5 and extracted using ethyl acetate (20 mlx3). The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the product as a white solid (200 mg, 84.695%).

F. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-D-quinolin-5-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide, compound 130

1-(2-D-quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.32 mmol), 5-amino-2-(2H-1,2,3 -triazol-2-yl)nicotinonitrile, (60.40 mg, 0.32 mmol), pyridine (0.13 ml, 1.62 mmol) was dissolved in CH2Cl2 (10 ml) and phosphorus oxychloride (0.12 ml, 1.30 mmol). The mixture was stirred at 25°C for 2 hours, saturated was added. NaHCO ₃ (20 ml) and the mixture was extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (21-51% (v/v) CH3CN and H ₂ O with 0 .05% HCl) and lyophilized to dryness to give the title compound (45 mg, 28.8%). LCMS (ESI) m/z M+1: 477.0.

1H NMR (400 MHz, methanol^) δ ppm 12.20 (1H, s), 9.93 (1H, d, J=2.51 Hz), 9.71 (1H, d, J=2 .51 Hz), 9.43 (1H, s), 9.12-9.18 (3H, m), 8.73-8.84 (2H, m), 8.42-8.53 (2H, m).

Example 131.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-D-quinolin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 131

1-(2^-quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (240.00 mg, 0.78 mmol), 5-chloro-6-(2H-1, 2,3-triazol-2-yl)pyridin-3-amine, (152.31 mg, 0.78 mmol), pyridine (0.31 ml, 3.89 mmol) was dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (0.285 mL, 3.12 mmol) was added. The mixture was stirred at 25°C for 2 hours, saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (25-55% (v/v) CH3CN and H ₂ O with 0.05 % HCl) and lyophilized to dryness to obtain the title compound (183 mg, 48.4%). LCMS (ESI) m/z M+1: 485.9.

^1H NMR (400 MHz, DMSO-d6) δ ppm 11.40 (1H, s), 8.91 (1H, d, J=2.01 Hz), 8.72 (1H, d, J =2.01 Hz),

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8.66 (1H, s), 8.36 (1H, d, J=8.28 Hz), 8.21 (2H, s), 7.93-8.05 (2H, m), 7.64 -7.74 (2H, m).

Example 132.

1-(4-Aminonaphthalen-1-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 132

A. (4-Nitronaphthalen-1-yl)hydrazine, 132a

A solution of 1-fluoro-4-nitronaphthalene (670 mg, 3.51 mmol) in iPrOH (20 ml) was added with N2H4-H2O (460 mg, 9.19 mmol) and heated to 60°C for 2 hours. After cooling to The CT solid was collected, washed with H ₂ O (5 ml) and EtOH (5 ml) and subsequently dried under vacuum to obtain the product as a yellowish solid (500 mg, 70.2%).

B. Ethyl 1-(4-nitronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 132b

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (827.39 mg, 3.445 mmol), (4-nitronaphthalen-1-yl)hydrazine (500 mg, 2.461 mmol) and ethanol (30 ml) was stirred at 25°C for 2 hours. The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product, which was purified using FCC (petroleum ether:ethyl acetate=100/00/100) to obtain the title compound (0.8 g, 85.7%) as a yellow oil. LCMS (ESI) m/z M+1: 380.0.

C. 1-(4-Nitronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 132c

Sodium hydroxide (126.54 mg, 3.16 mmol) was added to a solution of ethyl 1-(4-nitronaphthalen-1-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (800 mg, 2.11 mmol) in THF/H2O 1:1 (20 ml). The mixture was stirred at room temperature for 16 hours, the solvent was concentrated under reduced pressure, and 20 ml of H ₂ O was added to the mixture. The mixture was acidified using 1M hydrogen chloride to pH 5 and extracted using ethyl acetate (20 mlx3). The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the product as a yellow solid (630 mg, 85.0%). LCMS (ESI) m/z M+1: 352.0.

D.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(4-nitronaphthalen-1-yl)-5 (trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 132d

1-(4-Nitronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (400 mg, 1.14 mmol), 5-amino-2-(2H-1,2,3 -triazol-2-yl)nicotinonitrile, (212.02 mg, 1.14 mmol), pyridine (0.46 ml, 5.69 mmol) was dissolved in CH ₂ Cl ₂ (20 ml) and phosphorus oxychloride (0. 42 ml, 4.56 mmol). The mixture was stirred at 25°C for 2 hours, saturated was added. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to obtain the crude product, which was purified using FCC (petroleum ether:ethyl acetate = 100/0-0/100) to obtain the title compound (0.41 g, 61.7%) as a yellow solid.

LCMS (ESI) m/z M+1: 520.1.

E.

1-(4-Aminonaphthalen-1-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 132

Fe (196.27 mg, 3.52 mmol) and NH ₄ Cl (188.0 mg, 3.52 mmol) were added to a mixture of N-(5-cyano-6-(2H1,2,3-triazol-2- yl)pyridin-3-yl)-1-(4-nitronaphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide (410 mg, 0.70 mmol) in THF (20 ml), H ₂ O (10 ml), MeOH (10 ml). The reaction mixture was stirred at 70°C for 2 hours, filtered through a pad of diatomaceous earth and washed with EtOAc (20 mlx2). The combined filtrates were concentrated to dryness to give a crude brown solid, which was purified by preparative HPLC (35-65% (v/v) CH3CN and H2O with 0.05% ammonium hydroxide) and lyophilized to dryness to give the title compound (220 mg, 63.4%). LCMS (ESI) m/z M+1: 490.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.39 (1H, s), 9.10 (1H, d, J=2.20 Hz), 8.88 (1H, d, J =2.43 Hz), 8.49 (1H, s) 8.30 (2H, s), 8.15-8.24 (1H, m), 7.44-7.53 (2H, m), 7.40 (1H, d, J=7.94 Hz), 6.86-6.93 (1H, m), 6.78 (1H, d, J=8.16 Hz).

Example 133.

N-(3-Cyano-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 133

A. 5-Nitro-2-(2H-1,2,3-triazol-2-yl)benzonitrile, 133a

2-Fluoro-5-nitrobenzonitrile (500 mg, 3.01 mmol), 1H-1,2,3-triazole (228.68 mg, 3.31 mmol) and potassium carbonate (832.02 mg, 6.02 mmol ) was added to MeCN (10 ml) and stirred at 25°C for 16 hours. The reaction mixture was filtered and the residue was washed with EtOAc (30 ml x 2). The combined organic layers were concentrated under reduced pressure to give a crude yellow solid, which was purified using FCC (petroleum ether/ethyl acetate 100:0 to 70:30) to give the title compound (600 mg, 92.6%) in as a white solid.

1H NMR (400 MHz, chloroform-d) δ=8.72 (d, J=2.6 Hz, 1H), 8.55 (dd, J=2.4, 9.0 Hz, 1H), 8, 42 (d, J=9.3 Hz, 1H), 8.03 (s, 2H).

B. 5-Amino-2-(2H-1,2,3-triazol-2-yl)benzonitrile, 133b

5-Nitro-2-(2H-1,2,3-triazol-2-yl)benzonitrile (600 mg, 2.79 mmol) was dissolved in THF (10 ml) and Fe (1.25 g, 22.31) was added mmol), NH ₄ Cl (1.19 g, 22.31 mmol) and H ₂ O (10 ml). The reaction mixture was stirred at 80°C for 4 hours, filtered through a pad of diatomaceous earth and washed with EtOAc (20 mlx3). The filtrates were concentrated to dryness to give the crude product as a yellow solid, which was purified by FCC (eluent: petroleum ether/ethyl acetate 100/0 to 50/50). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (440 mg, 82.1%) as a yellow oil. LCMS (ESI) m/z M+1: 186.1.

1H NMR (400 MHz, DMSO-d6) δ=8.08 (s, 2H), 7.57 (d, J=8.8 Hz, 1H), 6.99 (d, J=2.6 Hz, 1H), 6.94 (dd, J=2.6, 8.8 Hz, 1H), 5.98 (s, 2H).

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C. N-(3-Cyano-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide , connection 133

5-Amino-2-(2H-1,2,3-triazol-2-yl)benzonitrile (110.98 mg, 0.58 mmol), 1-(quinolin-5-yl)-5(trifluoromethyl)-1H -pyrazole-4-carboxylic acid (120 mg, 0.39 mmol) and pyridine (45.7 mg, 0.58 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (88.58 mg, 0 .58 mmol). The mixture was stirred at 25°C for 16 hours, saturated was added. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (50 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow solid, which was purified by preparative HPLC (35-65% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to obtain the title compound (87 mg, 47.8%). LCMS (ESI) m/z M+1: 474.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 11.22 (s, 1H), 9.11 (dd, J=1.9, 3.9 Hz, 1H), 8.62 (s, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.28 (s, 2H), 8.26-8, 21 (m, 1H), 8.17-8.11 (m, 1H), 8.05-7.98 (m, 1H), 7.98-7.94 (m, 1H), 7.76- 7.68 (m, 2H).

Example 134.

X-(6-(4-Amino-2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl)- 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 134

A.

2-(3-Chloro-5-(1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4 carboxamido)pyridin-2-yl)-2H-1,2,3 -triazole-4-carboxylic acid, 134a

NaOH (72.62 mg, 1.82 mmol) was added to the solution of methyl 2-(3-chloro-5-(1-(1-methoxyisoquinolin-5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido) pyridin-2-yl)-2H-1,2,3-triazole-4-carboxylate (600 mg, 0.91 mmol) in THF/H2O 1:1 (10 ml) and reacted at 23°C for 2 hours. The solvent was concentrated under reduced pressure, a 1M HCl solution was added to the mixture to adjust to pH 5, and a solid formed. The solid was collected to give the product. LCMS (ESI) m/z M+1: 530.9.

IN.

Tert-butyl(2-(3-chloro-5-(1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamido)pyridin-2-yl)-2H-1, 2,3-triazol-4-yl)carbamate, 134b

To a solution of 2-(3 -chloro-5 -(1-(1 -methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamido)pyridin-2-yl)-2H-1,2, 3-triazole-4-carboxylic acid (500 mg, 0.82 mmol) in t-BuOH (10 ml), DPPA (271.3 mg, 0.99 mmol) and TEA (249.4 μl, 2.47) were added mmol) in an N ₂ atmosphere. The mixture was stirred at 80°C overnight, saturated was added. NaHCO ₃ (20 ml) and extracted using EtOAc (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2:1 - petroleum ether/ethyl acetate=1:2). The desired fractions were collected and the solvent was concentrated under reduced pressure to obtain the product as a yellow solid. LCMS (ESI) m/z M+1: 630.0.

C. N-(6-(4-amino-2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 134

K tert-butyl (2-(3 -chloro-5 -(1-(1 -methoxyisoquinolin-5 -yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamido)pyridin-2-yl)-2H-1 ,2,3-triazol-4-yl)carbamate (180 mg, 0.27 mmol) and conc. HCl (2 ml) was added to i-PrOH (4 ml), stirred at 60°C for 2 hours.

The mixture was concentrated under reduced pressure to give the crude product as a brown oil, which was purified by preparative HPLC (72-42% (v/v) CH3CN and H2O with 0.05% ammonium hydroxide) and lyophilized to dryness to give title compound (64 mg, 44.3%). LCMS (ESI) m/z M+1: 515.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 5.47 (s, 2H), 5.64 (d, J=7.28 Hz, 1H), 7.27 (d, J=7, 28 Hz, 1H), 7.31 (s, 1H), 7.65 (t, J=7.94 Hz, 1H), 7.92 (d, J=7.50 Hz, 1H), 8.42 (d, J=7.94 Hz, 1H), 8.54 (s, 1H), 8.56 (d, J=2.43 Hz, 1H), 8.77 (d, J=2.21 Hz , 1H).

Example 135.

N-(3-Cyano-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 135

A. Ethyl 1-(3-chloro-5-nitropyridin-2-yl)-1H-pyrazole-4-carboxylate, 135a

2,3-Dichloro-5-nitropyridine (500 mg, 2.59 mmol), ethyl 1H-pyrazole-4-carboxylate (435.7 mg, 3.11 mmol) and cesium carbonate (1.01 g, 3.11 mmol) was added to MeCN (10 ml) and stirred at 80°C for 16 hours. The reaction mixture was filtered and the residue was washed with EtOAc (20 ml x 3). The combined organic layers were concentrated under reduced pressure to give the crude product as a yellow solid, which was purified using FCC (petroleum ether/ethyl acetate 100:0 to 70:30) to give the title compound (650 mg, 84.6 %) in the form of a yellow solid.

B. Ethyl 1-(5-amino-3-chloropyridin-2-yl)-1H-pyrazole-4-carboxylate, 135b

Ethyl 1-(3-chloro-5-nitropyridin-2-yl)-1H-pyrazole-4-carboxylate (650 mg, 2.19 mmol) was dissolved in THF (10 ml), Fe (856.5 mg, 15 .34 mmol), NH ₄ Cl (820.4 mg, 15.34 mmol) and H ₂ O (10 ml). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with EtOAc (20 mlx3). The filtrates were concentrated to dryness to give the crude product as a yellow solid, which was purified using FCC (eluent: petroleum ether/ethyl acetate 100/0 to 70/30). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (440 mg, 64.5%) as a yellow oil. LCMS (ESI) m/z M+1: 267.1.

C. Ethyl 1-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2yl)-1H-pyrazol-4-carboxylate , 135s

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Ethyl 1-(5-amino-3-chloropyridin-2-yl)-1H-pyrazole-4-carboxylate (293.93 mg, 0.94 mmol), 1(quinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxylic acid (220 mg, 0.71 mmol) and pyridine (83.77 mg, 1.06 mmol) were dissolved in CH ₂ Cl ₂ (20 ml) and phosphorus oxychloride (162.39, 1.06 mmol). The mixture was stirred at 30°C for 16 hours. Saturated. NaHCO ₃ (40 ml) and extracted using CH ₂ Cl ₂ (40 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow solid, which was purified by FCC (eluent: petroleum ether/ethyl acetate 100/0 to 0/100) . The desired fractions were collected and the solvent was concentrated under reduced pressure to give (120 mg, 22.9%) as a yellow solid. LCMS (ESI) m/z M+1: 556.2.

D. N-(5-Chloro-6-(4-(hydroxymethyl)-1 H-pyrazol-1 -yl)pyridin-3 -yl)-1 -(quinolin-5-yl)-5 - (trifluoromethyl)- 1 H-pyrazole-4-carboxamide, 135

Ethyl 1-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2-yl)1H-pyrazol-4-carboxylate (120 mg, 0.20 mmol) was dissolved in THF (20 ml) and stirred at 0°C, lithium aluminum hydride (III) (68.24 mg, 1.80 mmol) was added in portions. The reaction mixture was stirred at 30°C for 1 hour. H ₂ O (20 ml) was added and extracted with EtOAc (40 ml x 2 ). The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (22-52% (v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to obtain the title compound (35 mg, 33.6%). LCMS (ESI) m/z M+1: 513.9.

^1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (br.s, 1H), 9.08 (br.s, 1H), 8.91 (br.s, 1H), 8 .73 (br.s, 1H), 8.63 (br.s, 1H), 8.35 (br.d, J=7.9 Hz, 1H), 8.09 (br.s, 1H), 7.96 (br.d, J=6.9, 18.2 Hz, 2H), 7.81-7.62 (m, 3H), 4.43 (br.s, 2H).

Example 136.

N-(5-Chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 136

Methyl 2-(3-chloro-5 -(1 -(quinolin-5 -yl)-5 -(trifluoromethyl)-1 H-pyrazole-4-carboxamido)pyridin-2yl)-2H-1,2,3-triazole -4-carboxylate (86 mg, 0.079 mmol) was dissolved in THF (5 ml) at 0° C. LiAlH ₄ (84 mg, 2.21 mmol) was added in portions. The reaction mixture was stirred at 40°C for 18 hours, subsequently H2O (10 ml) was added and the mixture was extracted using EtOAc (20 mlx2). The combined organic layers were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (76-46% (v/v) CH3CN and _H2O with 0. 05% HCl) and lyophilized to dryness to give the title compound (17.3 mg, 5.0%). LCMS (ESI) m/z M+1: 514.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.63 (s, 2H), 7.69-7.83 (m, 2H), 7.94-8.09 (m, 3H) , 8.37 (d, J=8.38 Hz, 1H), 8.63-8.73 (m, 2H), 8.91 (d, J=2.21 Hz, 1H), 9.11 ( dd, J=3.97, 1.54 Hz, 1H), 11.51 (s, 1H).

Example 137.

N-(5-Chloro-6-(4-((dimethylamino)methyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 137

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A. (2-(3-Chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2-yl)2H-1,2,3 -triazol-4-yl)methyl methanesulfonate, 137a

N-(5-Chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide (420 mg, 0.79 mmol) in CH ₂ Cl ₂ (8 ml) was cooled to 0°C. Triethylamine (239.84 mg, 2.37 mmol) was added, subsequently methanesulfonyl chloride (135.75 mg, 1.19 mmol) was added dropwise and stirred at 0°C for 1 hour. The mixture was concentrated, dried and used directly for next stage.

B. N-(5-Chloro-6-(4-((dimethylamino)methyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl) )5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 137

K (2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)pyridin-2-yl)-2H1,2,3-triazole -4-yl)methyl methanesulfonate (250 mg, 0.40 mmol) was added with Me ₂ NH in THF (1M) (20 ml). The mixture was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (84-54% (v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to give the above in the title compound (201 mg, 92.7%). LCMS (ESI) m/z M+1: 514.9.

1H NMR (400 MHz, methanol-d ₄ ) δ ppm 2.99 (s, 6H), 4.64 (s, 2H), 8.17-8.26 (m, 3H), 8.33 -8.41 (m, 1H), 8.48-8.60 (m, 2H), 8.62-8.74 (m, 1H), 8.77 (d, J=2.20 Hz, 1H ), 8.88 (br.s, 1H), 9.29-9.48 (m, 1H).

Example 138.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 138

A. Ethyl 1-(quinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 138a

A solution of 4-hydrazinylquinoline, 60c (300 mg, 1.89 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3oxobutanoate (543.15 mg, 2.26 mmol) in EtOH (5 ml) was stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 50/50). The desired fractions were collected and the solvent was concentrated under reduced pressure to give ethyl 1-(quinolin-4-yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (130 mg, 20.6% yield) as a yellow solid. . LCMS (ESI) m/z M+1: 335.9.

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B. 1-(Quinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 138b

A solution of ethyl 1-(quinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 138a (130 mg, 0.61 mmol), LiOH (16.27 mg, 0.39 mmol) in EtOH/H ₂ O (2/1.2 ml) was stirred at room temperature for 2 hours, 1N HCl solution was added to neutralize the reaction solution. The mixture was extracted using ethyl acetate (5 mlx3). The separated organic layer was dried (Na ₂ SO ₄ ), filtered, and the solvent was concentrated to give 1-(quinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylic acid, 138b (119 mg) as a solid. yellow color. LCMS (ESI) m/z M+1: 308.0.

C. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 138

Phosphorus oxychloride (39.44 µl, 0.42 mmol) was added to a solution of 1-(quinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 138b (67.35 mg, 0.21 mmol), 5-amino-2-(2H-1,2,3triazol-2-yl)nicotinonitrile (59.08 mg, 0.32 mmol) and pyridine (171.12 μl, 2.12 mmol) in CH ₂ Cl ₂ (2 ml). The mixture was stirred at room temperature for 2 hours, 5 ml of H2O was added to the mixture and sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 mlx3). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC (40-70% (v/v) CH3CN and H ₂ O with 0 .05% HCl) and lyophilized to dryness to give the title compound (57 mg, 56.4%). LCMS (ESI) m/z M+1: 475.9.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.33 (d, J=8.16 Hz, 1H), 7.77 (t, J=7.61 Hz, 1H), 7, 91-7.98 (m, 2H), 8.26 (d, J=8.60 Hz, 1H), 8.32 (s, 2H), 8.71 (s, 1H), 8.91 (d , J=2.43 Hz, 1H), 9.13 (d, J=2.43 Hz, 1H), 9.19 (d, J=4.41 Hz, 1H), 11.47 (s, 1H ).

Example 139.

N-(5-Bromo-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 139

A. 3-Bromo-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine, 139a

Solution of 3-bromo-2-chloro-5-nitropyridine (1 g, 4.21 mmol), 1H-1,2,3-triazole (582 mg, 8.42 mmol), K ₂ CO ₃ (1.74 g , 12.64 mmol) in CH3CN (30 ml) was stirred at 50°C for 12 hours. The mixture was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 1:1) . The desired fractions were collected and the solvent was concentrated under reduced pressure to give 3-bromo-5-nitro-2-(2H-1,2,3triazol-2-yl)pyridine, 139a (520 mg, 45.7%) as a solid. yellow color. LCMS (ESI) m/z M+1: 272.1.

B. 5-Bromo-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 139b

Fe (323.50 mg, 5.78 mmol) was added to a solution of 3-bromo-5-nitro-2-(2H-1,2,3-triazole-2

- 239 045333 yl)pyridine, 139a (520 mg, 1.93 mmol) and NH4C1 (515.10 mg, 9.63 mmol) in MeOH (20 ml), THF (20 ml) and H ₂ O (10 ml) . The mixture was stirred at 80°C for 1 hour and subsequently aq. was added to the suspension. NaHCO ₃ to bring the pH of the mixture to 9-10. The resulting mixture was filtered through a layer of diatomite earth and the residue on the filter was washed with CH ₂ Cl ₂ (100 mlx3). The combined filtrates were washed with brine (200 mL), dried over MgSO ₄ and concentrated under reduced pressure to give 1b (310 mg, 67.1%) as a brown solid, which was directly used in the next step. LCMS (ESI) m/z M+H: 242.1.

C. N-(5-bromo-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 139

GL ^Ή

POCl ₃ (232.263 mg, 1.515 mmol) was added to a solution of 5-bromo-6-(2H-1,2,3-triazol-2-yl)pyridin-3amine, 5-bromo-6-(2H-1,2, 3-triazol-2-yl)pyridin-3-amine, 139b (200 mg, 0.83 mmol), 1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (232 .69 mg, 0.76 mmol) and pyridine (149.77 mg 1.89 mmol) in CH2Cl2 (10 ml). The mixture was stirred at room temperature for 2 hours, and subsequently 50 ml of H2O and 50 ml of CH2Cl2 were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (35-65% (v/v) CH3CN and _H2O with 0.05% HCl). The desired fractions were lyophilized to dryness to obtain the title compound (86.8 mg, 20.8% yield) as a white solid. LCMS (ESI) m/z M+1: 528.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s, 1H), 9.01-9.12 (m, 1H), 8.89-8.99 (m, 1H), 8.78-8.86 (m, 1H), 8.64-8.72 (m, 1H), 8.29-8.38 (m, 1H), 8.15 (s, 2H), 7. 90-8.02 (m, 2H), 7.69 (d, J=3.09 Hz, 2H).

Example 140.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrrolo[2,1-f][1,2,4]triazine -4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 140

A. 4-Hydrazinylpyrrolo[2,1-G][1,2,4]triazine, 140a

4-Chloropyrrolo[2,1-1][1,2,4]triazine (200 mg, 1.302 mmol) was dissolved in hydrazine hydrate (8 ml). The reaction mixture was stirred at 40°C for 2 hours. The solvent was removed to give the product as a white solid (200 mg, 100%), which was used directly in the next step.

B. Ethyl 1-(pyrrolo[2,1-£][1,2,4]triazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 140b

4-Hydrazinylpyrrolo[2,1-G][1,2,4]triazine (200 mg, 1.34 mmol) was dissolved in ethanol (10 ml), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro was added -3-oxobutanoate (483.08 mg, 2.01 mmol). The reaction mixture was stirred at 80°C for 2 hours, concentrated under reduced pressure to give the crude product as a white solid, which was purified using FCC (eluent: petroleum ether/ethyl acetate 100/0 to 60/40) to give of the title compound (200 mg, 43.4%) as a white solid. LCMS (ESI) m/z M+1: 326.0.

C. 1-(Pyrrolo[2,1-1][1,2,4]triazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 140c

- 240 045333

Ethyl 1-(pyrrolo[2,1-1][1,2,4]triazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (200 mg, 0.58 mmol) was dissolved in THF (10 ml) and water (10 ml). Sodium hydroxide (46.51 mg, 1.16 mmol) was added. The reaction mixture was stirred at 25°C for 12 hours, adjusted to pH 5 using HCl (2N) and extracted using EtOAc (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude title compound (130 mg, 73.6%) as a yellow solid. LCMS (ESI) m/z M+1: 298.0.

D. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrrolo[2,1-f][1,2,4 ]triazin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide, compound 140

1-(Pyrrolo[2,1-1][1,2,4]triazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (130 mg, 0.43 mmol), 5 -Amino-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile (95.57 mg, 0.51 mmol) and pyridine (203.04 mg, 2.57 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (262.38, 1.71 mmol) was added. The mixture was stirred at 25°C for 4 hours. Saturated. NaHCO ₃ (30 ml) and extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (35-65% (v/v) CH ₃ CN and H2O with 0.05% HCl) and lyophilized to dryness to give the title compound (87.1 mg, 43.5%). LCMS (ESI) m/z M+1: 465.9.

1H NMR (400 MHz, DMSO-d6) δ=11.52 (s, 1H), 9.00 (d, J=2.6 Hz, 1H), 8.78 (d, J=2.6 Hz, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 8.37 (dd, J=1.4, 2.5 Hz, 1H), 8.27 (s, 2H), 7.28 (dd, J=1.3, 4.6 Hz, 1H), 7.20 (dd, J=2.6, 4.4 Hz, 1H).

Example 141.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrazolo[1,5-a]pyrazin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 141

A. 4-Hydrazinylpyrazolo[1,5-a]pyrazine, 141a

4-Chloropyrazolo[1,5-a]pyrazine (300 mg, 1.95 mmol) was dissolved in hydrazine hydrate (10 ml). The reaction mixture was stirred at 25°C for 2 hours. The solvent was removed to give the product as a white solid (300 mg, 100%), which was used directly in the next step.

B. Ethyl 1-(pyrazolo[1,5-a]pyrazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 141b

4-Hydrazinylpyrazolo[1,5-a]pyrazine (300 mg, 2.01 mmol) was dissolved in ethanol (10 ml), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (966, 16 mg, 4.02 mmol).

- 241 045333

The reaction mixture was stirred at 80°C for 2 hours, subsequently concentrated under reduced pressure to obtain the crude product as a yellow solid, which was purified using FCC (eluent: petroleum ether/ethyl acetate 100/0 to 60/40) with obtaining the title compound (500 mg, 61.2%) as a yellow solid.

LCMS (ESI) m/z M+1: 326.0.

C. 1-(Pyrazolo[1,5-a]pyrazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 141c

Ethyl 1-(pyrazolo[1,5-a]pyrazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (500 mg, 1.23 mmol) was dissolved in THF (10 ml) and water (10 ml). Sodium hydroxide (98.4 mg, 2.46 mmol) was added. The reaction mixture was stirred at 25°C for 12 hours, subsequently adjusted to pH 5 using HCl (2 N). The mixture was extracted using EtOAc (50 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude title compound (400 mg, 89.2%) as a yellow solid. LCMS (ESI) m/z M+1: 298.2.

D.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrazolo[1,5-a]pyrazin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 141

1-(Pyrazolo[1,5-a]pyrazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (250 mg, 0.69 mmol), 5-chloro-6-(2H -1,2,3-triazol-2-yl)pyridin-3-amine (161.0 mg, 0.82 mmol) and pyridine (325.52 mg, 4.12 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (420.67, 2.74 mmol) was added. The mixture was stirred at 25°C for 4 hours, then saturated was added. NaHCO ₃ (50 ml) and the mixture was extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (45-75% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to obtain the title compound (22.4 mg, b,b%). LCMS (ESI) m/z M+1: 474.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.42 (s, 1H), 9.05 (dd, J=4.85, 0.88 Hz, 1H), 8.81 (d , J=2.21 Hz, 1H), 8.63 (d, J=2.43 Hz, 1H), 8.60 (s, 1H), 8.37 (d, J=2.43 Hz, 1H ), 8.17 (s, 2H), 7.96 (d, J=4.63 Hz, 1H), 7.11 (dd, J=2.32, 0.77 Hz, 1H).

Example 142.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-d]pyrimidin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 142

A. 4-Hydrazinylthieno[2,3-d]pyrimidine, 142a

A solution of 4-chlorothieno[2,3-d]pyrimidine (450 mg, 2.64 mmol) in hydrazine (5 ml, 98%) was stirred at 80°C for 2 hours. The solid was filtered and washed with 2 ml water . The solid was collected and dried to give 4-hydrazinylthieno[2,3-d]pyrimidine, 142a (400 mg, 91.3% yield) as a white solid. LCMS (ESI) m/z M+1: 166.9.

B. Ethyl 1-(thieno[2,3-d]pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 142b

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Solution of 4-hydrazinylthieno[2,3-d]pyrimidine, 142a (400 mg, 2.41 mmol) and ethyl 2-(ethoxymethylene)4,4,4-trifluoro-3-oxobutanoate (1040 mg, 4.33 mmol) in EtOH (5 ml) was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 70/30). The desired fractions were collected and the solvent was concentrated under reduced pressure to give ethyl 1(thieno[2,3-d]pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 142b (700 mg, 85. 0% yield) as a yellow solid. LCMS (ESI) m/z M+1: 343.1.

C. 1-(Thieno[2,3-0]pyrimidin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, 142c fV o jAV-FiT ⁰ ” )=( , 142c

Solution of ethyl 1-(thieno[2,3-d]pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 142b (120 mg, 0.35 mmol), LiOH-H ₂ O (22.07 mg, 0.53 mmol) in EtOH/H ₂ O (2/1.3 ml) was stirred at room temperature overnight. 1N HCl solution was added to neutralize the reaction solution. The mixture was extracted using ethyl acetate (10 mlx3). The separated organic layer was dried (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated to give 142c (90 mg, 81.7% yield) as a yellow solid. LCMS (ESI) m/z M+1: 314.9.

D. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-d]pyrimidin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 142

Phosphorus oxychloride (53.39 µl, 0.57 mmol) was added to a solution of 1-(thieno[2,3-d]pyrimidin-4yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 142c (90 mg, 0.29 mmol), 5-amino-2-(2H-1,2,3triazol-2-yl)nicotinonitrile (58.65 mg, 0.32 mmol) and pyridine (231.64 μl, 2.86 mmol) in CH ₂ Cl ₂ (2 ml). The mixture was stirred at room temperature for 1 hour, 5 ml of H2O was added to the mixture and sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 mlx3), the combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC (36-66% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (40 mg, 27.9%). LCMS (ESI) m/z M+1: 482.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (d, J=6.17 Hz, 1H), 8.24 (d, J=6.17 Hz, 1H), 8.32 (s, 2H), 8.65 (s, 1H), 8.85 (d, J=2.21 Hz, 1H), 9.07 (d, J=2.21 Hz, 1H), 9.21 (s, 1H), 11.52 (s, 1H).

Example 143.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-c]pyridin-7-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 143

A. 7-Hydrazinylthieno[2,3-c]pyridine, 143a

7-Chlorothieno[2,3-c]pyridine (300 mg, 1.06 mmol) in NH2NH2-H2O (5 ml) was stirred at 26°C for 16 hours. The mixture was extracted with CH ₂ Cl ₂ (20x3 ml) . The solvent was concentrated

- 243 045333 under reduced pressure to obtain the desired compound, which was directly used in the next step without further purification.

B. Ethyl 1-(thieno[2,3-c]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 143b

7-Hydrazinylthieno[2,3-c]pyridine (200 mg, 1.21 mmol) was added to a solution of ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (436.11 mg, 1.82 mmol ) in EtOH (5 ml) and reacted at 80°C for 3 hours. The mixture was concentrated under reduced pressure, subsequently purified using FFS (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate 60:40). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a brown oil. LCMS (ESI) m/z M+1: 341.9.

C. 1-(Thieno[2,3-c]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 143c

ABOUT

NaOH (20.56 mg, 0.51 mmol) was added to a solution of ethyl 1-(thieno[2,3-c]pyridin-7-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (120 mg, 0.34 mmol) in EtOH/H ₂ O=1:1 (5 ml) and reacted at 28°C for 2 hours. The solvent was concentrated under reduced pressure to obtain the desired compound. LCMS (ESI) m/z M+1: 313.9.

D. N-(5-Cyαno-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-c]pyridin-7-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 143

1-(Thieno[2,3-c]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (70 mg, 0.22 mmol), 5-amino-2-(2H -1,2,3-triazol-2-yl)nicotinonitrile (50 mg, 0.27 mmol) and POCl3 (41.18 mg, 0.27 mmol) were dissolved in DCM (2 ml) and pyridine (53.11) was added mg, 0.67 mmol). The mixture was stirred at 25°C for 2 hours, then saturated was added. NH4Cl (20 ml) and the mixture was extracted using CH ₂ Cl ₂ (20 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (54-27% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (46 mg, 49.7%). LCMS (ESI) m/z M+1: 482.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.73 (d, J=5.29 Hz, 1H), 8.09 (d, J=5.29 Hz, 1H), 8 ,25-8.35 (m, 3H), 8.49 (d, J=5.29 Hz, 1H), 8.57 (s, 1H), 8.83 (d, J=2.43 Hz, 1H), 9.05 (d, J=2.43 Hz, 1H), 11.50 (s, 1H).

Example 144.

2-(3-Chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2-yl)-2H1,2,3-triazol-4 -carboxamide, compound 144

2-(3-Chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2-yl)-2H1,2,3-triazol-4 β-carboxylic acid (80 mg, 0.15 mmol), NH ₄ Cl (23.23 mg, 0.43 mmol), HATU (82.56 mg, 0.22 mmol) were dissolved in DMF (4 ml) and DIEA was added (93.54 mg, 0.72 mmol). The mixture was stirred at 25°C for 2 hours, saturated. NH ₄ Cl (20 ml) and extracted using CH ₂ Cl ₂ (20 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (66-36% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to give the title compound (44 mg, 47.5%). LCMS (ESI) m/z

M+1: 529.2.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.74-7.87 (m, 3H), 8.00-8.10 (m, 2H), 8.15 (br.s, 1H), 8.42 (d, J=8.53 Hz, 1H), 8.51 (s, 1H), 8.73-8.81 (m, 2H), 9.01 (d, J=2 .26 Hz, 1H), 9.16 (dd, J=4.27, 1.51 Hz, 1H), 11.64 (s, 1H).

Example 145.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,7-naphthyridin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 145

A. 5-Bromo-8-hydrazinyl-1,7-naphthyridine, 145 a

Vg

A 145a

5-Bromo-8-chloro-1,7-naphthyridine (800 mg, 3.29 mmol) was dissolved in hydrazine hydrate (5 ml). The reaction mixture was stirred at 50°C for 2 hours. The solvent was removed to give the desired product as a yellow oil (785 mg, 100%), which was used directly in the next step.

B. 5-Bromo-1,7-naphthyridine, 145b Br, 145b

5-Bromo-8-hydrazinyl-1,7-naphthyridine (785 mg, 3.29 mmol) was dissolved in water (10 ml) and acetic acid (30 ml). Copper(II) sulfate (524.48 mg, 3.29 mmol) was added and stirred at 70°C for 3 hours. The solvent was removed, 30% NH3-H2O (50 ml) was added and the mixture was extracted with CH ₂ Cl ₂ (50 mlx 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow solid which was purified by FCC (eluent: petroleum ether/ethyl acetate 100/0 to 85/15) to obtain the title compound (420 mg, 59.9%) as a yellow solid. LCMS (ESI) m/z M+1: 208.8.

C. 5-Hydrazinyl-1,7-naphthyridine, 145c nh _2nd , 145c

5-Bromo-1,7-naphthyridine (340 mg, 1.63 mmol), palladium(n)(pi-cinnamyl) chloride dimer (42.13 mg, 0.081 mmol), N-[2-(di-1- Adamantylphosphino)phenyl]morpholine (75.41 mg, 0.16 mmol) and sodium tert-butoxide (624.56 mg, 6.51 mmol) were dissolved in dioxane (10 ml) under N ₂ atmosphere. Hydrazine hydrate (162.84 mg, 3.25 mmol) was added and stirred at 60°C for 3 hours. The mixture was filtered and the solid was washed with 10 ml CH ₂ Cl ₂ . The solvent was partitioned between H ₂ O (10 ml) and CH ₂ Cl ₂ (50x2 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the title compound (260 mg, 99.8%) as a brown solid. LCMS (ESI) m/z M+1: 161.1.

D. Ethyl 1-(1,7-naphthyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 145d

5-Hydrazinyl-1,7-naphthyridine (260 mg, 1.62 mmol) was dissolved in ethanol (10 ml) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (467.8 mg) was added , 1.95 mmol). The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a yellow solid, which was purified using

FCC (eluent: petroleum ether/ethyl acetate 100/0 to 50/50) to give the title compound (100 mg, 17.3%) as a yellow solid. LCMS (ESI) m/z M+1: 337.0.

E. 1-(1,7-Naphthyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 145e

Ethyl (1,7-naphthyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (100 mg, 0.27 mmol) was dissolved in THF (10 ml) and water (10 ml). Lithium hydroxide (64.1 mg, 2.68 mmol) was added. The reaction mixture was stirred at 25°C for 12 hours.

The reaction mixture was adjusted to pH 5 using HCl (2 N), extracted using EtOAc (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude title compound (75 mg, 90.9%) as a yellow solid. LCMS (ESI) m/z M+1: 309.0.

F. No. (5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,7-naphthyridin-5-yl)-5-(trifluoromethyl )1H-pyrazole-4-carboxamide, compound 145

1-(1,7-Naphthyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (75 mg, 0.24 mmol), 5-amino-2-(2H-1,2 ,3-triazol-2-yl)nicotinonitrile (54.36 mg, 0.29 mmol), pyridine (115.49 mg, 1.46 mmol) were dissolved in CH2Cl2 (10 ml) and phosphorus oxychloride (149.25 mg) was added , 0.97 mmol). The mixture was stirred at 25°C for 4 hours, saturated was added. NaHCO ₃ (30 ml) and the mixture was extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (22-52% (v/v) CH3CN and H2O with 0 .05% HCl) and lyophilized to dryness to give the title compound (35 mg, 30.2%). LCMS (ESI) m/z M+1: 477.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.50 (s, 1H), 9.69 (s, 1H), 9.22 (dd, J=1.5, 4.2 Hz , 1H), 9.14 (d, J=2.4 Hz, 1H), 8.95 (s, 1H), 8.90 (d, J=2.4 Hz, 1H), 8.71 (s , 1H), 8.30 (s, 2H), 7.94 (dd, J=4.2, 8.6 Hz, 1H), 7.87-7.82 (m, 1H).

Example 146.

N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 146

A. 5-Nitro-2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridine, 146a

To a solution of 3-chloro-4-fluoronitrobenzene (1.2 g, 6.84 mmol) and 2H-1,2,3-triazole (0.567 g, 8.20 mmol) in anhydrous DMA (5 ml) was added K ₂ CO ₃ (1.89 g, 13.67 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered and washed with ethyl acetate (10 mlx3). The filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 2-chloro-5-nitro-3-(trifluoromethyl)pyridine, 146a (600 mg, 65.6% yield) as a solid.

- 246 045333 yellow.

1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (s, 2H), 9.16 (d, J=2.20 Hz, 1H), 9.68 (d, J=2, 21 Hz, 1H).

B. 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine, 146b

To a solution of 5-nitro-2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridine (550 mg, 1.78 mmol) in MeOH/THF/H ₂ O (5 ml /10 ml/5 ml) iron (593 mg, 10.61 mmol) and ammonium chloride (568 mg, 10.61 mmol) were added. The reaction mixture was stirred at 70°C for 2 hours, saturated was added to the mixture. NaHCO ₃ to adjust the pH to 7 ~ 9. The reaction mixture was filtered and the organic solvent was concentrated. The mixture was extracted using CH ₂ Cl ₂ (10 mlx3). The separated organic layer was dried (MgSO ₄ ), filtered and the solvent was concentrated to give the crude product as a solid. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give ethyl 6-(2H-1,2,3-triazol-2-yl)-5(trifluoromethyl)pyridin-3-amine, 146b (400 mg, 82.2% yield ) in the form of a white solid. LCMS (ESI) m/z M+1: 230.0;

'H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.38 (s, 2H), 7.43 (d, J=2.43 Hz, 1H), 8.04 (s, 2H) , 8.08 (d, J=2.43 Hz, 1H).

C. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methoxyphenyl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide, compound 146

Phosphorus oxychloride (75.85 µl, 0.39 mmol) was added to a solution of 1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b (100 mg, 0.33 mmol) , 6-(2H-1,2,3-triazol-2-yl)-5(trifluoromethyl)pyridin-3-amine (89.51 mg, 0.39 mmol) and pyridine (263.26 μl, 3.26 mmol) in CH ₂ Cl ₂ (2 ml). The mixture was stirred at room temperature for 2 hours, 5 ml of H ₂ O was added to the mixture and sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 mlx3), the combined organic extracts were dried over anhydrous MgSO ₄ , filtered and concentrated to dryness under reduced pressure to obtain the crude product, which was purified using preparative HPLC (42-72% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (120 mg, 70.9%). LCMS (ESI) m/z M+1: 518.9.

'H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.66 (m, 1H), 7.68-7.72 (m, 1H), 7.94-8.02 ( m, 2H), 8.22 (s, 2H), 8.35 (d, J=7.94 Hz, 1H), 8.63 (s, 1H), 8.91 (d, J=1.98 Hz, 1H), 9.08 (d, J=2.65 Hz, 1H), 9.19 (s, 1H), 11.45 (s, 1H).

Example 147.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrrolo[1,2-a]pyrazin-1-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 147

A. N'-(pyrrolo[1,2-a]pyrazin-1-yl)pivalohydrazide, 147a

A mixture of 1-chloropyrrolo[1,2-a]pyrazine (200 mg, 1.31 mmol) and pivalohydrazide (346.47 mg, 2.62 mmol) in MeCN (20 ml) was stirred at 80 °C for 24 h. The solvent was removed to obtain a crude product, the crude product was purified by FCC (petroleum ether/ethyl acetate=100:070:30). The solvent was concentrated to give the crude product (200 mg, 61.5%).

B. 1-Hydrazinylpyrrolo[1,2-a]pyrazine, 147b

- 247 045333

ICVNH n ^NHa 4 ^x , 147b

A mixture of Na-(pyrrolo[1,2-a]pyrazin-1-yl)pivalohydrazide (0.18 g, 0.73 mmol) and HCl in dioxane (1 ml) in CH ₂ Cl ₂ (10 ml) was stirred at room temperature for 1 hour. The solvent was removed to obtain the product as a white solid (133.85 mg, 100%).

C. Ethyl 1-(pyrrolo[1,2-a]pyrazin-1-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxylate, 147c

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (348.25 mg, 1.45 mmol), 1-hydrazinylpyrrolo[1,2-a]pyrazine (133.85 mg , 0.73 mmol), DIEA (0.468 g, 3.63 mmol) and ethanol (20 ml) were stirred at 80°C for 1 hour. The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product, which was purified using FCC (petroleum ether:ethyl acetate=100/0-70/30) to give the title compound (0.15 g, 58.7%) as a yellow oil. LCMS (ESI) m/z M+1: 325.0.

D. 1-(Pyrrolo[1,2-a]pyrazin-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 147d

Sodium hydroxide (34.05 mg, 0.85 mmol) was added to a solution of ethyl 1-(pyrrolo[1,2-a]pyrazin-1-yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (160 mg , 0.43 mmol) in THF/H ₂ O=1:1 (10 ml). The mixture was reacted at room temperature for 2 hours, the solvent was concentrated under reduced pressure, and 20 ml of H ₂ O was added to the mixture. The mixture was acidified using 1M hydrogen chloride to pH 5 and extracted using ethyl acetate (20 mlx3). The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the product as a yellow solid (100 mg, 79.3%).

E. ^(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrrolo[1,2-a]pyrazin-1-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 147

1-(Pyrrolo[1,2-a]pyrazin-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.34 mmol), 5-chloro-6-(2H -1,2,3-triazol-2-yl)pyridin-3-amine, (66.04 mg, 0.34 mmol) and pyridine (0.14 ml, 1.69 mmol) were dissolved in CH ₂ Cl ₂ ( 5 ml) and phosphorus oxychloride (0.12 ml, 1.35 mmol) was added. The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and the mixture was extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC (38-68% (v/v) CH3CN and H ₂ O with 0 .05% HCl) and lyophilized to dryness to give the title compound (66 mg, 40.6%). LCMS (ESI) m/z M+1: 473.9;

^1H NMR (400 MHz, methanol-04) δ ppm 8.78 (1H, s), 8.70 (1H, d, J=2.20 Hz), 8.34 (1H, s), 8.32 (1H, d, J=4.85 Hz), 8.03 (2 H, s), 7.88 (1H, s), 7.47 (1H, d, J=4.85 Hz) , 6.99-7.07 (1H, m), 6.87 (1H, d, J=4.19 Hz).

Example 148.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrrolo[1,2-a]pyrazin-1-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 148

- 248 045333

1-(Pyrrolo[1,2-a]pyrazin-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (180 mg, 0.18 mmol, 30% purity), 5-amino- 2-(2H-1,2,3-triazol-2-yl)nicotinonitrile (33.94 mg, 0.18 mmol) and pyridine (43.26 mg, 0.55 mmol) were dissolved in CH ₂ Cl ₂ (3 ml) and phosphorus oxychloride (41.93 mg, 0.27 mmol) was added. The mixture was stirred at 25°C for 16 hours, saturated was added. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (43-63% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (11 mg, 12.9%). LCMS (ESI) m/z M+1: 454.9.0;

^1H NMR (400 MHz, methanol^) δ ppm 9.07 (br.s, 1H), 8.90 (s, 1H), 8.31-8.39 (m, 2H), 8, 15 (br.s, 2H), 7.89 (d, J=1.32 Hz, 1H), 7.48 (d, J=4.63 Hz, 1H), 7.04 (dd, J=4 ,19, 2.65 Hz, 1H), 6.87 (d, J=4.19 Hz, 1H).

Example 149.

N-(5-Cyano-6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide , connection 149

A. 1-(Quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide, 149a

HATU (2.79 g, 7.32 mmol) was added to a solution of 1-(quinolin-5-yl)-5-(trifluoromethyl)-III-pyrazole-4carboxylic acid, 3b (1.5 g, 4.88 mmol) , NH ₃ /dioxane (19.53 ml, 9.77 mmol) and DIEA (1.26 g, 9.77 mmol) in CH ₂ Cl ₂ . The mixture was stirred at rt for 16 hours, 50 ml of H2O and 50 ml of ethyl acetate were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO ₄ and the filtrate was concentrated under reduced pressure. The residue was purified using FCC (petroleum ether/ethyl acetate=100:5-100:50) to obtain the title compound (1 g, 63.8%) as a yellow solid.

B. 5-Bromo-3-methyl-2-(2H-tetrazol-5-yl)pyridine, 149b

To a stirred solution of 5-bromo-3-methylpicolinonitrile (3.43 g, 17.39 mmol) in DMF (30 ml) was added zinc (II) chloride (2.37 g, 17.39 mmol) and sodium azide (1, 47 g, 22.61 mmol). The reaction mixture was stirred at 95°C for 16 hours. The solution was directly used in the next step.

C. 5-Bromo-3-methyl-2-(2-methyl-2H-tetrazol-5-yl)pyridine, 149c

To a stirred solution of 5-bromo-3-methyl-2-(2H-tetrazol-5-yl)pyridine (2 g, 8.33 mmol) in DMF (30 ml) was added potassium carbonate (5.76 g, 41.66 mmol) and iodomethane (5.20 g, 36.66 mmol). The reaction mixture was stirred at 25°C for 2 hours and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the crude product, which was purified using FCC (petroleum ether:ethyl acetate=100:0-60:40) to obtain the title compound (480 mg, 23.1%) as a white solid colors.

D. 5-Bromo-3-(bromomethyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine, 149d

- 249 045333

Benzoic peroxyanhydride (28.60 mg, 0.12 mmol) was added to a solution of 5-bromo-3-methyl-2-(2methyl-2H-tetrazol-5-yl)pyridine (0.3 g, 1.18 mmol) and 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (185.67 mg, 0.65 mmol) in acetonitrile (10 ml). The mixture was stirred at 80°C under N ₂ for 4 hours. The solvent was concentrated under reduced pressure and extracted with acetate (30 ml x 2). The combined organic layers were concentrated under reduced pressure to obtain the crude product. The crude product was purified using FCC (petroleum ether:ethyl acetate=100:0-70:30) to obtain the title compound (326 mg, 24.5%) as a white solid. LCMS (ESI) m/z M+1: 333.8.

E. 5-Bromo-2-(2-methyl-2H-tetrazol-5-yl)nicotinonitrile, 149e

Diiodine (333.84 mg, 1.32 mmol) was added to a solution of 5-bromo-3-(bromomethyl)-2-(2-methyl-2H-tetrazol5-yl)pyridine (296.00 mg, 0.26 mmol) in ammonium hydrate (5 ml). The mixture was stirred at 60°C for 16 hours. The solvent was concentrated under reduced pressure and extracted using acetate (30 mlx2). The combined organic layers were concentrated under reduced pressure to obtain the crude product. The crude product was purified using FCC (petroleum ether:ethyl acetate=100:0-70:30) to obtain the title compound (160 mg) as a white solid. LCMS (ESI) m/z M+1: 267.0.

F. N-(5-Cyano-6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 149

Mixture of 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)nicotinonitrile (160.0 mg, 0.31 mmol), 1-(quinolin-5yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide (188.76 mg, 0.62 mmol) and sodium 2-methylpropan-2-olate (118.47 mg, 1.23 mmol) were dissolved in dioxane (10 ml) and tris(dibenzylideneactone)dipalladium ( 0) (56.44 mg, 0.062 mmol) and (9,9-dimethyl-9H-xanthene-4,5diyl)bis(diphenylphosphine) (35.67 mg, 0.062 mmol). The mixture was stirred at 100°C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (2646% (v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to give the title compound (28 mg, 17.7%). LCMS (ESI) m/z M+1: 490.9;

^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.46 (1H, s), 9.27 (1H, d, J=2.43 Hz), 9.04 (1H, d, J=2.43 Hz), 8.84 (1H, d, J=2.43 Hz), 8.63 (1H, s), 8.32 (1H, d, J=8.38 Hz), 7 .93-7.99 (1H, m), 7.89-7.93 (1H, m), 7.64-7.69 (1H, m), 7.58-7.63 (1H, m) , 4.50 (3H, s).

Example 150 and example 151.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[3,2-b]niridin-7-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 150

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylfuro[3,2-b]pyridin-7-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 151

- 250 045333

A. Mixture of 7-chloro-2-methylfuro[3,2-b]pyridine with 7-chlorofuro[3,2-b]pyridine, 150a

A mixture of 7-chloro-2-iodofuro[3,2-b]pyridine (180 mg, 0.66 mmol), dicyclohexyl(2',b'-diisopropoxy[1,1'-biphenyl]-2-yl)phosphine ( 30 mg, 0.064 mmol), methylboric acid (50 mg, 0.84 mmol) and K ₃ PO ₄ (628 mg, 1.93 mmol) in dioxane (6 ml) and H ₂ O (1.5 ml) diacetoxypalladium was added (7.23 mg, 0.032 mmol) under N2 and heated at 100°C for 10 hours. The mixture was extracted using

EtOAc (10 mlx3). The combined organic layers were dried over MgSO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude product. The residue was further purified by column chromatography (eluent: petroleum ether/EAAc = 100:0-50:50). The desired fraction was collected and the solvent was removed to give the desired product as a brown oil. (80 mg, 35% yield).

B. Mixture of 7-hydrazinyl-2-methylfuro[3,2-b]pyridine and 7-hydrazinylfuro[3,2-b]pyridine, compound 150b

A mixture of 7-chloro-2-methylfuro[3,2-b]pyridine and 7-chlorofuro[3,2-b]pyridine (80 mg, 0.23 mmol) and hydrazine hydrate (95 mg, 1.9 mmol) was heated at 50°C overnight. The solvent was removed under reduced pressure and the product was directly used in the next step.

C. A mixture of ethyl 1-(2-methylfuro[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate and ethyl 1-(furo[3,2-b] pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxylate, 150c

A mixture of 7-hydrazinyl-2-methylfuro[3,2-b]pyridine and 7-hydrazinylfuro[3,2-b]pyridine (65 mg, 0.21 mmol) was dissolved in ethanol (20 ml) and ethyl 2-( ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (111.96 mg, 0.50 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a brown oil, which was purified using FCC (eluent: petroleum ether/ethyl acetate 100/0 to 50/50) to give of the title compound (50 mg, 35% yield) as a brown oil.

D. Mixture of 1-(2-methylfuro[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid and 1-(furo[3,2-b]pyridine -7-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxylic acid, 150d

HE is he

A mixture of ethyl 1-(2-methylfuro[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate and ethyl 1-(furo[3,2-b]pyridin- 7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (50 mg, 0.075 mmol) was dissolved in THF (5 ml) and water (1 ml). Lithium hydroxide (62.95 mg, 1.5 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. THF was removed and the resulting residue was washed with ether (5 ml). 3M HCl was added to the aqueous layer to adjust the pH of the mixture to 1 and the aqueous phase was extracted using EtOAc (5 mlx3). The organic layers were dried over MgSO ₄ , filtered and the filtrates concentrated to give the product as a brown oil (50 mg).

E. N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[3,2-b]pyridin-7-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 150

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, And

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylfuro[3,2-b]pyridin-7-yl) -5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, 151

A mixture of 1-(2-methylfuro[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid and 1-(FURo[3,2-b]pyridin-7 -yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxylic acid (50 mg, 0.082 mmol), 5-amino-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile (15 .3 mg, 0.082 mmol) and pyridine (19.5 mg, 0.25 mmol) were dissolved in CH ₂ Cl ₂ (3 ml) and phosphorus oxychloride (18.9 mg, 0.12 mmol) was added. The mixture was stirred at 25°C for 16 hours. Saturated. NaHCO ₃ (20 ml) and the mixture was extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (22-52% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title N-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-1-(furo[3 ,2-b]pyridin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 150 (5 mg, 13%). LCMS (ESI) m/z M+1: 465.9.

¹ H NMR (400 MHz, methanol^) δ ppm 9.07 (br.s, 1H) 8.89 (d, J=2.43 Hz, 1H) 8.79 (d, J=5, 51 Hz, 1H) 8.47 (s, 1H) 8.34 (d, J=2.43 Hz, 1H) 8.14 (s, 2H) 7.71 (d, J=5.29 Hz, 1H ) 7.28 (d, J=2.43 Hz, 1H); And

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylfuro[3,2-b]pyridin-7-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 151 (4 mg, 10%).

1H NMR (400 MHz, methanol^) δ ppm 9.06 (s, 1H), 8.90 (d, J=2.65 Hz, 1H), 8.71 (d, J=5.73 Hz, 1H), 8.48 (s, 1H), 8.14 (s, 2H), 7.68 (d, J=5.73 Hz, 1H), 6.98 (d, J=1.10 Hz, 1H), 2.61 (d, J=0.88 Hz, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 480.0.

Example 152.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)niridin-3-yl)-1-(4-fluoro-2-methoxyphenyl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 152

Phosphorus oxychloride (48.54 μl, 0.52 mmol) was added to a solution of 1-(quinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, (80 mg, 0.26 mmol), 5-amino-2-(2H-1,2,3-triazol-2yl)benzonitrile (53.04 mg, 0.29 mmol) and pyridine (210.61 µl, 2.60 mmol) in CH2Cl2 (2 ml) . The mixture was stirred at room temperature for 1 hour, subsequently 5 ml of H ₂ O was added to the mixture. Saturated. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 mlx3). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC (35-65% (v/v) CH3CN and H ₂ O with 0 .05% HCl) and lyophilized to dryness to give the title compound (45 mg, 36.2%). LCMS (ESI) m/z M+1: 475.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.34 (d, J=8.16 Hz, 1H), 7.76 (t, J=7.28 Hz, 1H), 7, 90 (d, J=4.41 Hz, 1H), 7.92-7.98 (m, 1H), 8.11-8.16 (m, 1H), 8.22 (d, J=2, 21 Hz, 1H), 8.24 (s, 1H), 8.26-8.28 (m, 2H), 8.43 (d, J=2.20 Hz, 1H), 8.67 (s, 1H), 9.18 (d, J=4.63 Hz, 1H), 11.22 (s, 1H).

Example 153.

1-(Benzo[d]thiazol-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 153

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A. 7-Hydrazinylbenzo[th]thiazole, 153 a

A mixture of palladium(P)(picinnamyl) chloride dimer (24.2 mg, 0.047 mmol) and N-[2-(di-1adamantylphosphino)phenyl]morpholine (43.31 mg, 0.093 mmol) in dioxane (2.5 ml) was purged with argon (4x). The resulting clear yellow solution was stirred at room temperature under argon for 10 minutes. 7-bromobenzo[th]thiazole (200 mg, 0.93 mmol) and t-BuONa (179.56 mg, 1.87 mmol) were added to the mixture and purged with argon (4x).

The resulting yellow reaction mixture was stirred at room temperature for 5 min and subsequently treated with hydrazine (93.53 mg, 1.87 mmol) via syringe and purged with argon (4x). The mixture was then stirred at 50°C under argon for 2 hours. The mixture was filtered and washed with ethyl acetate (20 ml). The filtrate was concentrated under reduced pressure to give 7-hydrazinylbenzo[y]thiazole (150 mg, crude product) as a black solid.

B. Ethyl 1-(benzo[th]thiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 153b

A solution of 7-hydrazinylbenzo[y]thiazole, 153a (150 mg, 0.91 mmol) and ethyl 2-(ethoxymethylene)-4,4,4trifluoro-3-oxobutanoate (327 mg, 1.36 mmol) in EtOH (20 ml ) was stirred at 80°C for 3 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 70/30). The desired fractions were collected and the solvent was concentrated under reduced pressure to obtain the title compound (130 mg, 42.0% yield) as a yellow solid.

C. 1-(Benzo[th]thiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 153c

Solution of ethyl 1-(benzo[th]thiazol-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 153b (130 mg, 0.38 mmol), LiOH H ₂ O (23.98 mg, 0.57 mmol) in EtOH/H ₂ O (2/1.2 ml) was stirred at room temperature overnight. 1N HCl solution was added to neutralize the reaction solution. The mixture was extracted using ethyl acetate (10 mlx3). The separated organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give the title compound (100 mg, 83.8% yield) as a white solid.

D. 1-(Benzo[d]thiazol-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)1H-pyrazole-4-carboxamide, compound 153

Phosphorus oxychloride (39.71 µl, 0.43 mmol) was added to a solution of 1-(benzo[th]thiazol-7-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 153c (66.73 mg , 0.21 mmol), 5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine (50 mg, 0.26 mmol) and pyridine (172.28 μl, 2, 13 mmol) in CH ₂ Cl ₂ (2 ml). The mixture was stirred at room temperature for 1 hour and 5 ml of H ₂ O was added to the mixture. Satur. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 mlx3). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (35-65% (v/v) CH3CN and H ₂ O with

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0.05% HCl) and lyophilized to dryness to give the title compound (180 mg, 60.6%).

LCMS (ESI) m/z M+1: 490.9.

1H NMR (400 MHz, methanol-d ₄ ) δ ppm 7.69 (d, J=7.72 Hz, 1H), 7.76-7.81 (m, 1H), 8.06 (s , 2H), 8.32 (d, J=8.16 Hz, 1H), 8.38 (s, 1H), 8.72 (d, J=1.76 Hz, 1H), 8.80 (s , 1H), 9.36 (s, 1H).

Example 154.

N-(6-(4-Amino-2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide, compound 154

To a solution of 2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin2-yl)-2H-1,2,3-triazole -4-carboxylic acid, compound 109 (160 mg, 0.29 mmol) in DMF (5 ml), added DPPA (95.92 mg, 0.35 mmol) and TEA (118.83 μl, 0.87 mmol) in an N2 atmosphere. The mixture was stirred at 80°C overnight. The mixture was concentrated to give the crude product, which was purified by preparative HPLC (40-70% (v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to give the title compound (45 mg, 30.8%). LCMS (ESI) m/z M+1: 499.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 5.51 (s, 2H), 7.33 (s, 1H), 7.59-7.64 (m, 1H), 7.66- 7.71 (m, 1H), 7.91-8.01 (m, 2H), 8.33 (d, J=8.60 Hz, 1H), 8.58-8.62 (m, 2H) , 8.79 (d, J=2.21 Hz, 1H), 9.06 (d, J=2.43 Hz, 1H), 11.23 (br.s, 1H).

Example 155.

1-(1-Aminoisoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 155

A. Ethyl 1-(2-chloro-4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 155a

A solution of 4-bromoisoquinoline-1-amine (5.5 g, 24.656 mmol), hexane-2,5-dione (3.377 g, 29.59 mmol) and p-TSA (93.8 mg, 0.49 mmol) in toluene (50 ml) was refluxed for 36 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (3.3 g, 42.7% yield) as a white solid. LCMS (ESI) m/z M+1: 302.9.

B. 1-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-hydrazinyl isoquinoline, 155b

Mixture of ethyl 1-(2-chloro-4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 155a (2.6 g, 8.63 mmol), hydrazine (864.30 mg, 17. 27 mmol), dimer of palladium(P) chloride (pi-cinnamyl) (134.17 mg, 0.26 mmol) and N-[2-(di-1-adamantylphosphino)phenyl]morpholine (240.14 mg, 0. 52 mmol) and t-BuONa (2486.21 mg, 25.90 mmol) in dioxane (50 ml) under N2 atmosphere were stirred at 60°C for 10 hours. After filtration through a layer of diatomaceous earth, the mixture was partitioned between H2O (50 ml ) and CH ₂ Cl ₂ (100x3 ml). The organic layer was separated, dried over MgSO ₄ , filtered and the filtrate was concentrated to give the title compound as a brown oil. LCMS (ESI) m/z M+1: 253.

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C. Ethyl 1-(1 -(2,5-dimethyl-1 H-pyrrol-1 -yl)isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxylate, 155c

Solution of 1-(2,5-dimethyl-1H-pyrrol-1-yl)-4-hydrazinyl isoquinoline, 155b (3.3 g, 8.63 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro- 3-oxobutanoate (2.90 g, 12.09 mmol) in EtOH (50 ml) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate from 100 /0 to 50/50). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product (3.5 g, 94.6% yield) as a yellow solid. LCMS (ESI) m/z M+1: 429.

D. Ethyl 1-(1 -(2,5-dimethyl-1 H-pyrrol-1 -yl)isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate, 155d

Solution of ethyl 1-(1 -(2,5-dimethyl-1H-pyrrol-1-yl)isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, 4c (3.4 g, 7.94 mmol) and hydroxylamine hydrochloride (13.24 g, 190.47 mmol) in EtOH (120 ml) were refluxed for 2 days. The solvent was removed and the residue was made alkaline by adding sat. NaHCO ₃ solution (100 ml). The mixture was extracted using EtOAc (100 mlx3). The combined organic layers were collected, dried over MgSO ₄ , filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (1.6 g, 57.6% yield) as a brown solid. LCMS (ESI) m/z M+1: 350.9.

E. A mixture of ethyl 1-(1-((tert-butoxycarbonyl)amino)isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxylate and ethyl 1-(1-((di-tert-butoxycarbonyl) amino)isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxylate, 155e

Solution of ethyl 1-(1-(2,5-dimethyl-1H-pyrrol-1-yl)isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, 155d (600 mg, 1.71 mmol ) and Boc ₂ O (1121.47 mg, 5.14 mmol), DMAP (10.46 mg, 0.086 mmol) and TEA (715.22 μl, 5.14 mmol) in THF (5 ml) were stirred at room temperature during the night. The mixture was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 50/50). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (650 mg, 68.9% yield) as a yellow solid.

F. A mixture of 1-(1-((tert-butoxycarbonyl)amino)isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylic acid; 1-(1-((di-tert-butoxycarbonyl)amino)isoquinolin-4-yl)-5-(trifluoromethyl)-1H-

- 255 045333 pyrazole-4-carboxylic acid, 155f

A solution of a mixture of ethyl 1-(1-((tert-butoxycarbonyl) amino)isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxylate and ethyl 1-(1-((di-tert-butoxycarbonyl) amino)isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate, 4e (420 mg, 0.42 mmol) and LiOH (35.22 mg, 0.84 mmol) in THF/H ₂ O (2/1, 0.75 ml) was stirred at room temperature for 2 hours. 1N HCl solution was added to neutralize the reaction solution. The mixture was extracted using ethyl acetate (10 mlx3). The separated organic layer was dried (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated to give the title compound (400 mg, crude) as a white solid.

G. A mixture of tert-butyl (4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1H -pyrazol-1-yl)isoquinolin-1-yl)carbamate and di-tert-butyl (4-(4-((5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3 -yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-yl)carbamate, 155g

Phosphorus oxychloride (63.18 μL, 0.68 mmol) was added to the solution of 1-(1-((tert-butoxycarbonyl)amino)isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxylic acid; 1-(1((di-tert-butoxycarbonyl)amino)isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 155f (150 mg, 0.15 mmol), 5-chloro -6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (86.18 mg, 0.44 mmol) and pyridine (274.09 μl, 3.39 mmol) in CH ₂ Cl ₂ (4 ml). The mixture was stirred at room temperature for 1 hour. 5 ml of water was added to the mixture. Added sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 mlx3). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. LCMS (ESI) m/z M+1: 544.2.

N.

1-(1-Aminoisoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 155

A mixture of tert-butyl (4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5 (trifluoromethyl)-1H-pyrazole -1-yl)isoquinolin-1-yl)carbamate and di-tert-butyl(4-(4-((5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl )carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-yl)carbamate, 155d (180 mg, 012 mmol) and HCl in dioxane (4N, 1.3 ml) in CH ₂ Cl ₂ (2.6 ml) was stirred at room temperature for 2 hours. Water (5 ml) was added to the mixture. Added sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 mlx3). The combined organic extracts were dried over anhydrous Mg2SO4, filtered and the filtrate was concentrated

- 256 045333 to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (14-44% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to give the title compound ( 100 mg, 70.2%). LCMS (ESI) m/z M+1: 499.9.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.04 (d, J=8.16 Hz, 1H), 7.87 (t, J=7.50 Hz, 1H), 7, 97-8.03 (m, 1H), 8.16 (s, 2H), 8.33 (s, 1H), 8.64-8.75 (m, 3H), 8.90 (d, J= 2.20 Hz, 1H), 9.57 (br.s, 2H), 11.48 (s, 1H).

Example 156.

1-(1-Aminoisoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 156

A. A mixture of tert-butyl (4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1H -pyrazol-1-yl)isoquinolin-1-yl)carbamate and di-tert-butyl (4-(4-((5-cyano-6-(2H1,2,3-triazol-2-yl)pyridin-3 -yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1yl)carbamate, 156a

Phosphorus oxychloride (97.104 μL, 1.042 mmol) was added to a solution of a mixture of 1-(1-((tertbutoxycarbonyl)amino)isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid and 1-( 1((di-tert-butoxycarbonyl)amino)isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 155f (220 mg, 0.22 mmol), 5-amino-2- (2H-1,2,3-triazol-2-yl)nicotinonitrile (145.46 mg, 0.71 mmol) and pyridine (421.29 μl, 5.21 mmol) in CH ₂ Cl ₂ (2 ml). The mixture was stirred at room temperature for 1 hour. Water (5 ml) was added to the mixture. Added sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 mlx3). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to obtain the crude product (300 mg). LCMS (ESI) m/z M+1: 535.1.

B. 1-(1-Aminoisoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide, compound 156

A mixture of tert-butyl (4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1H-pyrazole -1-yl)isoquinolin-1-yl)carbamate and di-tert-butyl (4-(4-((5-cyano-6-(2H1,2,3-triazol-2-yl)pyridin-3-yl )carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1yl)carbamate, 156a (300 mg, 0.20 mmol) and HCl in dioxane (4N, 1.3 ml) in CH ₂ Cl ₂ (2.6 ml) was stirred at room temperature for 2 hours. Water (5 ml) was added to the mixture. Added sat. NaHCO3 to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 mlx3). The combined organic extracts were dried over anhydrous Mg2SO4, filtered and the filtrate concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (25-55% (v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to obtain the title compound (115 mg, 49.3%). LCMS (ESI) m/z M+1: 491.1;

1H NMR (400 MHz, acetonitrile-b ₃ ) δ ppm 9.06 (br.s, 1H), 8.83 (d, J=1.76 Hz, 1H), 8.47 (d, J =8.38 Hz, 1H), 8.38 (s, 1H), 8.11 (br.s, 2H), 7.98-8.05 (m, 2H), 7.86-7.95 ( m, 1H), 7.69 (s, 1H), 7.21 (d, J=8.38 Hz, 1H).

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Example 157.

Ν-(5-Χλορ-6-( 1 -methyl-1 H-pyrazol-3 -yl)pyridin-3 -yl)-1-(1 -oxo-1,2-dihydroisoquinolin-5-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 157

A. 5-Chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine, 157a

Pd ₂ (dba) ₃ (176.56 mg, 0.19 mmol) and Xphos (183.83 mg, 0.39 mmol) were added to a solution of 6-bromo-5chloropyridin-3-amine (800 mg, 3.86 mmol ), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazole (1203.52 mg, 5.78 mmol) and K3PO4 (2.456 g, 11.57 mmol) in dioxane/H ₂ O (6/1, 20 ml) in an atmosphere of N ₂ . The mixture was stirred at 100°C overnight. The reaction mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 157a (530 mg, 59.0% yield) as a yellow solid. LCMS (ESI) m/z M+1: 209.1.

B. Ν-(5-Χλορ-6-(1 -methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)- 5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 157

Phosphorus oxychloride (115.35 µl, 1.24 mmol) was added to a solution of 1-(1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (400 mg, 1.24 mmol), 5chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine (344.28 mg, 1.49 mmol) and pyridine (1000.9 μl, 12.38 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at room temperature for 1 hour. Water (5 ml) was added to the mixture and sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 mlxE). The combined organic extracts were dried over anhydrous Mg2SO4, filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (29-59% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to obtain the title compound (190 mg, 29.0%). LCMS (ESI) m/z M+1: 513.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 3.94 (s, 3H), 5.67 (d, J=7.28 Hz, 1H), 6.78 (d, J=2, 21 Hz, 1H), 7.30 (t, J=6.50 Hz, 1H), 7.68 (t, J=7.83 Hz, 1H), 7.80 (d, J=2.20 Hz , 1H), 7.95 (d, J=7.28 Hz, 1H), 8.42-8.48 (m, 2H), 8.56 (s, 1H), 8.88 (d, J= 1.98 Hz, 1H), 11.13 (s, 1H), 11.64 (br.d, J=5.51 Hz, 1H).

Example 158.

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1Hpyrazol-4-carboxamide, compound 158

Phosphorus oxychloride (6.64 g, 43.3 mmol) was added to a solution of 1-(1-oxo-1,2-dihydroisoquinolin-5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (7.60 g, 21.7 mmol), 2-(trifluoromethyl)pyridin4-amine (3.51 g, 21.7 mmol) in pyridine (50 ml). The mixture was stirred at room temperature for 2 hours, saturated was added. NaHCO ₃ (500 ml). The mixture was extracted using CH ₂ Cl ₂ (500 mlx3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and

- 258 045333 the filtrate was concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC (5-60% (v/v) CH3CN and H2O with 0.05% HCl). The desired fraction was collected and the pH was adjusted to 7-8 with aqueous NaHCO ₃ (10%). The organic solvent was concentrated under reduced pressure to form a white solid. The solid was collected and washed with water (3x300 ml) and dried to give the title compound (5.90 g, 58.1%). LCMS (ESI) m/z M+1: 467.9;

^1H NMR (400 MHz, DMSO-d6) δ ppm 5.66 (d, J=7.28 Hz, 1H), 7.25-7.32 (m, 1H), 7.67 (t , J=7.83 Hz, 1H), 7.94 (d, J=7.28 Hz, 1H), 7.99 (dd, J=5.62, 1.65 Hz, 1H), 8.26 (d, J=1.76 Hz, 1H), 8.44 (d, J=8.16 Hz, 1H), 8.56 (s, 1H), 8.70 (d, J=5.51 Hz , 1H), 11.35 (s, 1H), 11.64 (br.d, J=5.29 Hz, 1H).

Example 159.

1-(2-Amino-[1,2,4]triazolo[1,5-α]pyridin-5-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2 -yl)pyridin-3yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 159

A. 5 -Bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-[1,2,4]triazolo[1,5-a]pyridine, 159а Вг / , 159а

Hexane-2,5-dione (428.6 mg, 3.76 mmol) was added to a solution of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin2-amine (400 mg, 1.88 mmol) and acetic acid (215 μl) in toluene (5 ml). The mixture was stirred at 155°C for 12 hours. The mixture was concentrated to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 40/60). Collect the eluent and concentrate the solvent under reduced pressure to obtain 5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-[1,2,4]triazolo[1,5-a]pyridine as yellow solid (500 mg, 91%). LC-MS: (ES, m/z): [M+1] ⁺ 292.9.

B. 2-(2,5-Dimethyl-1H-pyrrol-1-yl)-5-hydrazinyl-[1,2,4]triazolo[1,5-a]pyridine, 159b ^h Sh / , 159b

5-Bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-[1,2,4]triazolo[1,5-a]pyridine (500 mg, 1.72 mmol) in hydrazine monohydrate (1 ml) was stirred at 80°C overnight. The solid was filtered and washed with water (2 mlx3). The solid was collected and dried to obtain 2-(2,5-dimethyl-1Hpyrrol-1-yl)-5-hydrazinyl-[1,2,4]triazolo[1,5-a]pyridine as a white solid ( 416 mg, crude product).

C. Ethyl 1-(2-(2,5 - dimethyl-1 H-pyrrol-1 -yl)-[1,2,4]triazolo[1,5-a]pyridin-5 -yl)-5 -( trifluoromethyl)1H-pyrazole-4-carboxylate, 159c

Ethyl (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (824.8 mg, 3.43 mmol) was added to the solution of 2-(2,5-dimethyl-1H-pyrrole -1-yl)-5-hydrazinyl-[1,2,4]triazolo[1,5-a]pyridine (416 mg, 1.72 mmol) in ethanol (5 ml). The mixture was stirred at 80°C overnight. The mixture was concentrated to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 0/100). The eluent was collected and the solvent was concentrated under reduced pressure to give ethyl 1-(2-(2,5-dimethyl-1H-pyrrol-1-yl)[1,2,4]triazolo[1,5-a]pyridin-5- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate as a yellow solid (650 mg, 90%). LC-MS: (ES, m/z): [M+1] ⁺ 419.1.

D. 1-(2-(2,5-Dimethyl-1H-pyrrol-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxylic acid, 159d

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HE

Lithium hydroxide monohydrate (49.7 mg, 1.2 mmol) was added to ethyl 1-(2-(2,5-dimethyl-1H-pyrrol1-yl)-[1,2,4]triazolo[1,5-a ]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (330 mg, 0.79 mmol) in ethanol/water (2:1, 3 ml) and stirred the mixture at rt in for 2 hours. The mixture was concentrated to obtain the crude product. The crude product was dissolved in 2 ml water and 1M HCl was added to adjust the pH to 6~7. The mixture was extracted using ethyl acetate (10 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated to give 1 -(2-(2,5-dimethyl-1H-pyrrol-1-yl)-[1,2,4]triazolo [1, 5-a]pyridin-5-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxylic acid as a white solid (307 mg, crude product).

E. N-(5-Cyano-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(2-(2,5-dimethyl-1H-pyrrole-1 -yl)[1,2,4]triazolo[1,5-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, 159e

To a solution of 1 -(2-(2,5-dimethyl-1H-pyrrol-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxylic acid (300 mg, 0.77 mmol), 5-amino-2-(2H-1,2,3-triazol-2yl)nicotinonitrile, 7b (172 mg, 0.922 mmol) and pyridine (622 µl, 7.69 mmol) in dichloromethane (2 ml) was added dropwise POCl ₃ (143.3 µl, 1.54 mmol). The reaction mixture was stirred at 20°C for 1 hour. Water (5 ml), saturated aqueous NaHCO ₃ solution (20 ml) were added to the mixture and the pH was adjusted to

7-8. The mixture was extracted using dichloromethane (5 mlx3). The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered, and the filtrates were concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 100/0 to 0/100) to give N-(5-cyαno-6-(2H-1,2,3-triazol-2-yl) pyridin-3-yl)-1-(2-(2,5-dimethyl-1Hpyrrol-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4-carboxamide (260 mg, 60%) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.16 (s, 6H), 5.86 (s, 2H), 7.94 (d, J=6.61 Hz, 1H), 8 .03 (t, J=8.27 Hz, 1H), 8.25 (d, J=9.04 Hz, 1H), 8.31 (s, 2H), 8.74 (s, 1H), 8 .89 (d, J=2.43 Hz, 1H), 9.08 (d, J=2.43 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 558.9.

F. 1 -(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-X-(5-cyano-6-(2H-1,2,3-triazole -2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide, compound 159

A solution of N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(2,5-dimethyl-1H-pyrrol-1- yl)[1,2,4]triazolo[1,5-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide (200 mg, 0.357 mmol) in TFA (2 ml) and dioxane/water mixtures (4:1, 4 ml) were stirred at 70°C for 5 hours. Saturated. NaHCO ₃ to the mixture to adjust the pH to 7 ~ 8. The aqueous phase was extracted using ethyl acetate (5 mlx3). The separated organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by preparative high performance liquid chromatography (25-55% (v/v) CH ₃ CN and H2O with 10 mM NH ₄ HCO ₃ ) to give 1 -(2-amino-[1,2,4]triazolo[ 1,5-a]pyridin-5-yl)-H-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)5-(trifluoromethyl)-1H -pyrazole-4-carboxamide (12 mg, 7% yield).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.46 (dd, J=5.95, 2.20 Hz, 1H), 7.65-7.74 (m, 2H), 8, 31 (s, 2H), 8.77 (s, 1H), 8.93 (d, J=2.20 Hz, 1H), 9.17 (d, J=2.43 Hz, 1H), 11, 55 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 558.9.

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Example 160.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-fluoro-1-(quinolin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, conc. 160

A. Ethyl 3-fluoro-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 160a

Ethyl 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 13b (1 g, 2.98 mmol) was dissolved in acetonitrile (8 ml) and silver(II) fluoride was added ( 2.18 g, 14.9 mmol). The reaction mixture was kept in the dark with stirring at 60°C for 16 hours. The reaction mixture was filtered through a pad of diatomaceous earth and washed with CH3CN (200 ml), the filtrates were concentrated under reduced pressure to obtain the crude product, which was purified using preparative high performance liquid chromatography . The pure fractions were collected and the solvent was concentrated under reduced pressure, lyophilized to dryness to give ethyl 3-fluoro-1(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate as a yellow solid (30 mg ). LC-MS: (ES, m/z): [M+1]+ 354.0.

B. 3-Fluoro-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 160b

Ethyl 3-fluoro-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (30 mg, 0.035 mmol) was dissolved in THF (2 ml) and water (2 ml) was added and lithium hydroxide (8.41 mg, 0.35 mmol). The reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain 3-fluoro-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid as white solid (30 mg, 73.5%). LC-MS: (ES, m/z): [M+1]+ 325.9.

C. N-(5 -Chloro-6-(2H-1,2,3 -triazol-2 -yl)pyridin-3 -yl)-3-fluoro-1 -(quinolin-5 -yl)-5 -( trifluoromethyl)1H-pyrazole-4-carboxamide, com. 160

To a solution of 3-fluoro-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (30 mg, 30% HPLC purity, 0.026 mmol), 5-chloro-6 -(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 1j (7.6 mg, 0.038 mmol) and pyridine (133.8 mg, 1.69 mmol) in dichloromethane (10 ml ) POCl ₃ (86.5 mg, 0.56 mmol) was added dropwise. The mixture was stirred at 25°C for 3 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was subsequently purified by preparative HPLC (37-57% (v/v) CH3CN and H2O with 0.05% HCl) to give N-(5-chloro-6-(2H-1,2,3-triazol- 2yl)pyridin-3-yl)-3-fluoro-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide (2.5 mg, 18.7%).

1H NMR (400 MHz, acetonitrile-I3) δ ppm 9.75 (br.s, 1H), 9.06 (d, J=2.8 Hz, 1H), 8.82 (d, J= 2.3 Hz, 1H), 8.63 (d, J=2.3 Hz, 1H), 8.37 (d, J=8.5 Hz, 1H), 8.02 (s, 2H), 7 .96-7.91 (m, 1H), 7.90-7.84 (m, 2H), 7.63 (dd, J=4.1, 8.7 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 502.9.

Example 161.

N-(2,5-Dimethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-okso-1,2-dihydroisoquinolin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 161

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A. 3-Bromo-6-methyl-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine, 161a

O .-.Yn-r^Br ° W

3-Bromo-2-chloro-6-methyl-5-nitropyridine (4.0 g, 15.9 mmol) and 1H-1,2,3-triazole (1.43 g, 20.7 mmol) were dissolved in acetonitrile (30 ml) and potassium carbonate (3.30 g, 23.9 mmol) was added. The reaction mixture was stirred at 60°C for 2 hours. Saturated. NH ₄ Cl (100 ml) and the reaction mixture was extracted using EtOAc (200 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a purple oil. The oil was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 85/15). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a purple solid (2.5 g, 55.3% yield).

B. 2,5-Dimethyl-3-nitro-6-(2H-1,2,3-triazol-2-yl)pyridine, 161b

3-Bromo-6-methyl-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine (1.0 g, 3.52 mmol) and methylboric acid (316.1 mg, 5.28 mmol) was dissolved in dioxane (20 ml), palladium diacetate (79.0 mg, 0.35 mmol), Xantphos (407.4 mg, 0.70 mmol) and potassium carbonate (973 mg, 7.04 mmol) were added mmol) and purged the reaction mixture with N2 for 1 min. The reaction mixture was stirred at 100°C for 16 hours, subsequently filtered and the residue washed with EtOAc (50 mlx3). The combined filtrates were concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 40/60). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (700 mg, 90.7%).

C. 2,5-Dimethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 161c

2,5-Dimethyl-3-nitro-6-(2H-1,2,3-triazol-2-yl)pyridine (200 mg, 3.19 mmol), iron (1.07 g, 19.2 mmol) and NH ₄ Cl (1.03 g, 19.2 mmol) were added to a mixture of THF (20 ml) and water (20 ml).

The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with EtOAc (50 mlx3). The combined filtrates were concentrated to dryness to give the crude product as a yellow oil. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 40/60). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow oil (360 mg, 59.6%).

1H NMR (400 MHz, chloroform-d) δ ppm 7.82 (s, 2H), 6.91 (s, 1H), 3.78 (br.s, 2H), 2.42 (s, 3H), 2.20 (s, 3H).

D. N-(2,5-Dimethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5- yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 161

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To a solution of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (213.2 mg, 0.66 mmol), 2,5- dimethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (150 mg, 0.79 mmol) and pyridine (522.5 mg, 6.61 mmol) in CH ₂ Cl ₂ (15 ml) POCl ₃ (304 mg, 1.98 mmol) was added dropwise. The mixture was stirred at 25°C for 4 hours and at 40°C for 3 hours.

Added 30 ml sat. NaHCO ₃ and extracted using CH ₂ Cl ₂ (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was subsequently purified by preparative HPLC (33-63% (v/v) CH3CN and _H2O with 0.05% HCl) to give the product (190 mg, 57.4%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.60 (br.d, J=5.7 Hz, 1H), 10.44 (s, 1H), 8.50 (s, 1H), 8.42 (d, J=7.9 Hz, 1H), 8.11 (s, 2H), 8.02 (s, 1H), 7.95-7.89 (m, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.28 (dd, J=6.1, 7.2 Hz, 1H), 5.67 (d, J=7.3 Hz, 1H ), 2.47 (br.s, 3H), 2.19 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 495.0.

Example 162 and Example 163.

N-(6-(2H-[1,2,3]Triazolo[4,5-c]pyridin-2-yl)-5-chloropyridin-3-yl)-1 -(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 162

And

N-(6-(1H-[1,2,3]Triazolo[4,5-c]pyridin-1-ul)-5-chloropyridin-3-yl)-1-(quinolin-5-ul)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 163

A. A mixture of 2-(3-chloro-5-nitropyridin-2-yl)-2H-[1,2,3]triazolo[4,5-c]pyridine and 1-(3-chloro-5nitropyridin-2-yl) )- 1H-[1,2,3]triazolo[4,5-c]pyridine, 162a

3H-[1,2,3]Triazolo[4,5-c]pyridine (0.62 g, 5.18 mmol) was added to a mixture of 2,3-dichloro-5 nitropyridine (1 g, 5.18 mmol) and potassium carbonate (3.58 g, 25.9 mmol) in acetonitrile (20 ml).

The mixture was stirred at rt for 3 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the crude product as a yellow solid. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 - petroleum ether/ethyl acetate=0:1). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (580 mg, 40%).

B. A mixture of 6-(2H-[1,2,3]triazolo[4,5-c]pyridin-2-yl)-5-chloropyridin-3-amine and 6-(1H[1,2,3]triazolo [4,5 -с]pyridin-1 -yl)-5-chloropyridin-3-amine, 162b

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Iron (0.535 g, 9.58 mmol) and ammonium chloride (0.512 g, 9.58 mmol) were added to a mixture of 2-(3-chloro-5nitropyridin-2-yl)-2H-[1,2,3]triazolo[ 4,5-c]pyridine and 1-(3-chloro-5-nitropyridin-2-yl)-1H[1,2,3]triazolo[4,5-c]pyridine (530 mg, 0.958 mmol) in THF (20 ml), water (10 ml) and methanol (10 ml). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with EtOAc (20 mlx2). Combined concentrated filtrates

triried to dryness to obtain the crude product as a brown solid. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a brown oil (330 mg, 69.8%).

C. N-(6-(2H-[1,2,3]triazolo[4,5-c]pyridin-2-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 162

and N(6-(1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 163

POCl ₃ (0.49 ml, 5.36 mmol) was added to a mixture of 6-(2H-[1,2,3]triazolo[4,5-c]pyridin-2-yl)-5chloropyridin-3-amine and 6 -(1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-5-chloropyridin-3-amine (330 mg, 1.34 mmol), 1-(quinoline-5- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b (493.9 mg, 1.61 mmol) and pyridine (0.54 ml, 6.70 mmol) in dichloromethane (5 ml).

The reaction mixture was stirred at 20°C for 2 hours. Saturated solution was added to the mixture. NaHCO ₃ solution (20 ml). The mixture was extracted using ethyl acetate (30 mlx2). The organic layers were concentrated under reduced pressure to give the crude product, which was purified by reverse phase HPLC (27-57% (v/v) CH3CN and _H2O with 0.05% HCl) to give N-(6( 2H-[1,2,3]triazolo[4,5-c]pyridin-2-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 162 (340 mg, 47.3%).

1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (1H, s), 9.87 (1H, s), 9.06-9.12 (2H, m), 8.87 ( 1H, d, J=2.20 Hz), 8.77 (1H, d, J=5, 95 Hz), 8.75 (1H, s), 8.36 (1H, d, J=8.60 Hz), 8.07 (1H, d, J=5.51 Hz), 7.98-8.03 (1H, m), 7.94-7.98 (1H, m), 7.69-7 .76 (2 N, m). LC-MS: (ES, m/z): [M+1]+ 535.9; and N-(6-(1H[1,2,3]triazolo[4,5-c]pyridin-1-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5 -(trifluoromethyl)-1Hpyrazole-4-carboxamide, compound 163 (70 mg, 9.4%).

1H NMR (400 MHz, DMSO-d6) δ ppm 11.77 (1H, s), 9.53 (1H, d, J=0.88 Hz), 9.08-9.18 (2H, m), 8.88 (1H, d, J=2.21 Hz), 8.78 (1H, s), 8.70 (1H, d, J=5.95 Hz), 8.37-8, 44 (2H, m), 7.98-8.09 (2H, m), 7.83-7.89 (1H, m), 7.75-7.82 (1H, m). LC-MS: (ES, m/z): [M+1]+ 535.9.

Example 164 and Example 165.

N-(6-(2H-[1,2,3]Triazolo[4,5-b]pyridin-2-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 164

and N-(6-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)- 5-264 045333 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 165

A. A mixture of 2-(3-chloro-5-nitropyridin-2-yl)-2H-[1,2,3]triazolo[4,5-b]pyridine and 3-(3-chloro-5nitropyridin-2-yl) )-3H-[1,2,3]triazolo[4,5-b]pyridine, 164a

1H-[1,2,3]Triazolo[4,5-c]pyridine (3.5 g, 18.14 mmol) was added to a mixture of 2,3-dichloro-5 nitropyridine (2.18 g, 18.14 mmol ) and potassium carbonate (7.5 g, 54.41 mmol) in acetonitrile (50 ml).

The mixture was stirred at rt for 12 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow solid. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate=70:30). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (4.2 g, 83.7%).

B. A mixture of 6-(2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-5-chloropyridin-3-amine and 6-(3H[1,2,3]triazolo [4,5-b]pyridin-3-yl)-5-chloropyridin-3-amine, 164b

Iron (2.02 g, 36.1 mmol) and ammonium chloride (1.93 g, 36.1 mmol) were added to a mixture of 2-(3-chloro-5nitropyridin-2-yl)-2H-[1,2, 3]triazolo[4,5-b]pyridine and 3 -(3-chloro-5-nitropyridin-2-yl)-3H[1,2,3]triazolo[4,5-b]pyridine (4,0 g, 7.23 mmol) in THF (40 ml), water (10 ml) and methanol (20 ml). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with EtOAc (20 mlx3). The combined filtrates were concentrated to dryness to give the crude product as a brown solid. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 10:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a brown oil (3.2 g, 86.1%).

C. N-(6-(2H-[1,2,3]Triazolo[4,5-b]pyridin-2-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 164

and N-(6-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 165

POCl ₃ (239 mg, 1.56 mmol) was added to a mixture of 6-(2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-5chloropyridin-3-amine and 6-( 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-5-chloropyridin-3-amine (200 mg, 0.39 mmol), 1-(quinolin-5-yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b (143.5 mg, 0.47 mmol) and pyridine (185 mg, 2.34 mmol) in dichloromethane (8 ml). The reaction mixture was stirred at 20°C for 4 hours. Saturated solution was added to the mixture. NaHCO ₃ solution (10 ml). The mixture was extracted using dichloromethane (20 mlx3). The organic layers were concentrated under reduced pressure to give the crude product, which was purified by reverse phase HPLC (35-65% (v/v) CH3CN and _H2O with 0.05% HCl) to give N-(6- (2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-5chloropyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 164 (35.7, 16.9%).

- 265 045333 ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (s, 1H), 9.06 (br.s, 1H), 8.98 (s, 1H), 8, 84 (b.d., J=3.7

Hz, 1H), 8.78 (s, 1H), 8.63 (s, 1H), 8.35 (br.d, J=8.2, 16.5 Hz, 2H), 8.01-7 .88 (m, 2H), 7.76-7.59 (m, 3H). LCMS: (ES, m/z): [M+1]+ 535.9; and N-(6-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-5-chloropyridin-3-yl)-1(quinolin-5-yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 165 (21 mg, 9.6%).

1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (s, 1H), 9.08 (dd, J=2.2, 3.5 Hz, 1H), 9.02 (d, J=2.2 Hz, 1H), 8.84-8.75 (m, 3H), 8.68 (s, 1H), 8.35 (d, J=8.2 Hz, 1H), 8, 02-7.94 (m, 2H), 7.73-7.68 (m, 2H), 7.64 (dd, J=4.6, 8.4 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 535.9.

Example 166.

N-(3-Chloro-4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl)-1-(quinolin-5-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 166

A. 2-(4-Bromo-2-chlorobenzylidene)hydrazine-1-carboxamide, 166a

A solution of 4-bromo-2-chlorobenzaldehyde (5.0 g, 22.78 mmol), sodium acetate (3.74 g, 45.57 mmol), hydrazinecarboxamide (1.71 g, 22.78 mmol) in methanol (50 ml) and water (50 ml) were stirred at 50°C for 5 hours. The mixture was cooled to temperature and filtered. The solid was washed with ethyl acetate (10 mlx3). The solid was dried to give the product as a white solid (3 g, 47.6%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.63 (br.s, 2H), 7.54 (dd, J=8.60, 1.76 Hz, 1H), 7.75 (d, J=1.98 Hz, 1H), 8.12-8.19 (m, 2H), 10.55 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 277.9.

B. 5-(4-Bromo-2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, 166b

Bromine (931.5 μl, 18.1 mmol) was added dropwise to a solution of 2-(4-bromo-2chlorobenzylidene)hydrazine-1-carboxamide (2.0 g, 7.23 mmol) in acetic acid (15 ml). The mixture was stirred at 80°C for 3 hours. The mixture was cooled to room temperature, TMEV (60 ml) was added to the mixture and stirred for 10 minutes. The mixture was filtered and the solid was dried to give the product as a white solid (1 g, 50%). LC-MS: (ES, m/z): [M+1]+ 275.9.

C. 5-(4-Bromo-2-chlorophenyl)-2,4-bis((2-(trimethylsilyl)ethoxy)methyl)-2,4-dihydro-3H-1,2,4-triazol3-one, 166c

Sodium hydride (437.1 mg, 10.93 mmol) was added portionwise to a solution of 5-(4-bromo-2-chlorophenyl)-2,4dihydro-3H-1,2,4-triazol-3-one (1.0 g, 3.64 mmol) in DMF (10 ml) at 0°C. After stirring at 0°C for 1 hour, (2-(chloromethoxy)ethyl)trimethylsilane (2.579 mL, 14.57 mmol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature overnight. Water (20 ml) was added to the reaction mixture and the aqueous phase was extracted using ethyl acetate (30 ml x 3). The separated organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 50/50). The eluent was collected and the solvent was concentrated under reduced pressure to give the product as a colorless oil (400 mg, 21% yield).

^1H NMR (400 MHz, chloroform-d) δ ppm -0.05 - -0.02 (m, 9 N), -0.01-0.01 (m, 9 N), 0.80 -0.87 (m, 2H), 0.94-1.00 (m, 2H), 3.52-3.59 (m, 2H), 3.68-3.74 (m, 2H), 4 .95 (s, 2H), 5.25 (s, 2H), 7.40 (d, J=8.16 Hz, 1H), 7.54 (dd, J=8.27, 1.87 Hz, 1H), 7.70 (d, J=1.76 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 536.2.

D. 1-(Quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide, 166d

HBTU (1.65 g, 4.35 mmol) was added to 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylic acid, 3b (0.89 g, 2.90 mmol) , ammonium chloride (775 mg, 14.5 mmol) and DIEA (2.46 ml, 14.5 mmol) in DMF (15 ml). The reaction mixture was stirred at room temperature for 4 hours. Water (20 ml) was added to the reaction mixture. The aqueous layer was extracted using ethyl acetate (30 mlx3). The organic layer was concentrated to obtain the crude product. The crude product was purified by chromatography (eluent: petroleum ether/ethyl acetate 100/0 to 0/100). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (600 mg, 65% yield). LC-MS: (ES, m/z): [M+1]+ 307.0.

E. N-(3-Chloro-4-(5-oxo-1,4-bis((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-1,2,4-triazol-3yl )phenyl)-1 -(quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, 166e

Pd(OAc) ₂ (15.95 mg, 0.071 mmol) and Xantphos (41.1 mg, 0.071 mmol) were added to the solution of 5-(4-bromo2-chlorophenyl)-2,4-bis((2-(trimethylsilyl) ethoxy)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (380 mg, 0.71 mmol), 1-(quinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide (293 mg, 0.92 mmol) and cesium carbonate (810 mg, 2.49 mmol) in dioxane (5 ml) under N ₂ atmosphere. The mixture was stirred at 100°C overnight. The mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by silica gel flash column chromatography (eluent: petroleum ether/ethyl acetate 100/0 to 0/100). The eluent was collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (480 mg, 76% yield). LCMS: (ES, m/z): [M+1]+ 760.1.

F. Ν-(3-Χλορ-4-( 1 -(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl)-1 -(quinoline- 5 yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, 166f

N-(3-Chloro-4-(5-oxo-1,4-bis((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-1,2,4-triazol-3yl)phenyl )-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (400 mg, 0.45 mmol) in TFA/DCM (1:2, 1.5 ml) was stirred at room temperature for 3 hours. The mixture was concentrated to obtain the crude product, which was used directly in the next step. LC-MS: (ES, m/z): [M+1]+ 531.0

G.

N-(3-Chloro-4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl)-1-(quinolin-5-yl)-5-267 045333 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 166

N-(3 -Chloro-4-( 1 -(hydroxymethyl)-5 -oxo-4,5 -dihydro-1H-1,2,4-triazol-3 -yl)phenyl) -1 -(quinolin-5 yl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (386 mg, 0.525 mmol) and TEA (1061 mg, 10.49 mmol) in methanol (5 ml) were stirred at 50°C for 3 hours. The mixture concentrated to give the crude product. The crude product was purified by preparative high performance liquid chromatography (20-50% (v/v) CH3CN and _H2O with 0.05% HCl) to give the product as a white solid (120 mg, 45.5% yield) .

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.58-7.71 (m, 3H), 7.77 (dd, J=8.60, 1.98 Hz, 1H), 7 .88-7.93 (m, 1H), 7.94-8.00 (m, 1H), 8.06 (d, J=1.98 Hz, 1H), 8.33 (d, J=8 ,38 Hz, 1H), 8.54 (s, 1H), 9.06 (dd, J=4.08, 1.65 Hz, 1H), 10.93 (br.s, 1H), 11.77 (us.s, 2H). LC-MS: (ES, m/z): [M+1]+ 489.9.

Example 167.

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-1Hpyrazol-4-carboxamide, compound 167

To a solution of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (345.9 mg, 0.888 mmol) and 5-(trifluoromethyl)pyridine -3-amine (120 mg, 0.74 mmol) in pyridine (3 ml) was added dropwise with POCl ₃ (227 mg, 1.48 mmol).

The mixture was stirred at 25°C for 4 hours and at 40°C for 3 hours. Saturated solution was added. NaHCO ₃ to adjust the pH to 7-8 and the mixture was extracted using ethyl acetate (30 mlx2). The combined organic layers were dried over MgSO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was subsequently purified by preparative HPLC (37-57% (v/v) CH3CN and _H2O with 0.05% HCl) to give 1(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol4-carboxamide (130 mg, 37%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 5.67 (d, J=7.28 Hz, 1H), 7.26-7.31 (m, 1H), 7.68 (t , J=7.94 Hz, 1H), 7.94 (d, J=7.50 Hz, 1H), 8.44 (d, J=7.94 Hz, 1H), 8.53 (s, 1H ), 8.60 (s, 1H), 8.75 (s, 1H), 9.12 (s, 1H), 11.18 (s, 1H), 11.64 (br.d, J=4, 63 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 467.9.

Example 168.

N-(5-Chloro-6-(5-(hydroxymethyl)-1H-1,2,3-triazol-1 -yl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinoline-5- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 168

A. A mixture of methyl 2-(3-chloro-5-nitropyridin-2-yl)-2H-1,2,3-triazol-4-carboxylate and methyl 1-(3chloro-5-nitropyridin-2-yl)-1H -1,2,3-triazole-5-carboxylate, 168a

- 268 045333

Potassium carbonate (10.0 g, 72.5 mmol) was added to a solution of 2,3-dichloro-5-nitropyridine (7.0 g, 36.3 mmol) and methyl 1H-1,2,3-triazole-4- carboxylate (4.61 g, 36.3 mmol) in MeCN (30 ml).

The mixture was reacted at 60°C for 16 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate=40:60). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (8.8 g, 42.8 yield).

B. Methyl 2-(5-amino-3-chloropyridin-2-yl)-2H-1,2,3-triazole-4-carboxylate, 168b

_H2N

168b and

Methyl 1-(5-amino-3-chloropyridin-2-yl)-1H-1,2,3-triazole-5-carboxylate, 168c

A mixture of methyl 2-(3-chloro-5-nitropyridin-2-yl)-2H-1,2,3-triazole-4-carboxylate and methyl 1-(3-chloro-5-nitropyridin-2-yl)-1H-1 ,2,3-triazole-5-carboxylate (8.8 g, 15.5 mmol) was added to a mixture of iron (8.66 g, 155.1 mmol), NH ₄ Cl (8.30 g, 155.1 mmol ) in THF (30 ml) and water (15 ml). The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give the crude product as a brown oil, the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2:1 ethyl acetate). The desired fractions were collected and the solvent was concentrated under reduced pressure to give methyl 2-(5-amino-3-chloropyridin-2-yl)-2H-1,2,3-triazole-4-carboxylate as a yellow solid, 168c ( 1.80 g, 45.7%).

1H NMR (400 MHz, chloroform-d) δ ppm 3.98 (s, 3H), 4.21 (s, 2H), 7.16 (d, J=2.51 Hz, 1H), 7 .90 (d, J=2.51 Hz, 1H), 8.26-8.33 (m, 1H). LC-MS: (ES, m/z): [M+1]+ 254.0;

and methyl 1-(5-amino-3-chloropyridin-2-yl)-1H-1,2,3-triazole-5-carboxylate as a yellow oil, 168d (1.10 g, 28.0%),

1H NMR (400 MHz, chloroform-d) δ ppm 3.99 (s, 3H), 4.33 (br.s, 2H), 7.20 (d, J=2.51 Hz, 1H) , 7.91 (d, J=2.76 Hz, 1H), 8.48 (s, 1H), 8.46-8.53 (m, 1H). LC-MS: (ES, m/z): [M+1]+ 254.0.

D.

Methyl

1-(3 -chloro-5 -(1-(1 -methoxyisoquinolin-5-yl)-5 -(trifluoromethyl)-1 H-pyrazol-4 carboxamido)pyridin-2-yl)-1H-1,2,3 -triazole-5-carboxylate, 168e

To a solution of 1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1.10 g, 3.26 mmol), methyl 1-(5-amino-3- chloropyridin-2-yl)-1H-1,2,3-triazole-5-carboxylate (910 mg, 3.59 mmol) and pyridine (774 mg, 9.79 mmol) in CH ₂ Cl ₂ (20 ml) were added dropwise POCl ₃ (600 mg, 3.91 mmol). The mixture was stirred at 25°C for 2 hours, and 20 ml of sat. _NaHCO3 . The reaction mixture was extracted using CH ₂ Cl ₂ (30 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was subsequently purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1 - ethyl acetate) to give the product (1.10 g, 52.1%). LC-MS: (ES, m/z): [M+1]+ 573.1.

E. Ν-(5-Χλορ-6-(5-(hydroxymethyl)-1H-1,2,3-triazol-1 -yl)pyridin-3-yl)-1-(1-methoxyisoquinolin5-yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide, 168f

LiAlH ₄ (61.6 mg, 1.62 mmol) was slowly added to the solution of methyl 1-(3-chloro-5-(1-(1-269 045333 methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H -pyrazole-4-carboxamido)pyridin-2-yl)-1H-1,2,3triazole-5-carboxylate (300 mg, 0.46 mmol) in THF (10 ml) at 0°C, the mixture was stirred for 2 h at room temperature. Water (61 μL) was added to the mixture at 0°C and the mixture was stirred for 10 min. NaOH (61 μL, 15% in water) was added to the mixture at 0°C and the mixture was stirred for 10 min. Additional water (183 μL) was added to the mixture at 0°C and the mixture was stirred for 10 min. MgSO ₄ was added to the mixture and the mixture was filtered. The filtrate was concentrated to give the crude product as a brown oil (180 mg, 61.2% yield). LC-MS: (ES, m/z): [M+1]+ 545.1.

F. H-(5-Chloro-6-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)pyridin-3-yl)-1-(1-oxo-1,2- Dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 168

N-(5-Chloro-6-(5-(hydroxymethyl)-1H-1,2,3-triazol-1 -yl)pyridin-3-yl)-1-(1-methoxyisoquinolin-5 yl)-5- (trifluoromethyl)-1H-pyrazole-4-carboxamide (180 mg, 0.28 mmol) in isopropanol (4 ml) was added to concentrated HCl (2 ml) and the reaction mixture was stirred at 60°C for 2 hours. The mixture was concentrated under under reduced pressure to obtain the crude product as a yellow oil. The crude product was purified by preparative high performance liquid chromatography (1242% (v/v) CH3CN and _H2O with 0.05% HCl), pure fractions were collected, and the organic solvent was concentrated under reduced pressure, and lyophilized to dryness to give the product as white solid (36 mg, 23.9% yield).

1H NMR (400 MHz, DMSO-d6) δ ppm 4.65 (s, 2H), 5.67 (d, J=7.28 Hz, 1H), 7.31 (t, J=6, 53 Hz, 1H), 7.68 (t, J=7.78 Hz, 1H), 7.96 (d, J=7.28 Hz, 1H), 8.42-8.50 (m, 2H) , 8.54-8.73 (m, 2H), 8.90 (br.s., 1H), 11.2711.47 (m, 1H), 11.65 (br.d, J=5.02 Hz , 1H). LC-MS: (ES, m/z): [M+1]+ 530.9.

Example 169.

N-(5-Chloro-2-methyl-6-(1 -methyl-1 H-pyrazol-3 -yl)pyridin-3 -yl)-1-(1 -oxo-1,2-dihydroisoquinolin-5yl)- 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 169

Iron (0.811 g, 14.5 mmol) and ammonium chloride (0.775 g, 14.5 mmol) were added to a mixture of 2,3-dichloro6-methyl-5-nitropyridine (0.60 g, 2.90 mmol) in methanol ( 20 ml), THF (40 ml) and water (10 ml). The mixture was stirred at 60°C for 2 hours. Ethyl acetate (100 ml) was added to the mixture. The precipitate was collected by filtration. The residue was washed (100x3 ml) with ethyl acetate. The filtrate was collected and concentrated under reduced pressure. 10% NaHCO ₃ (100 ml) was added to the mixture and the mixture was extracted using ethyl acetate (100 ml x 2). The organic layers were dried (Na ₂ SO ₄ ), filtered, and the filtrate was recovered to give the product as a yellow solid. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - petroleum ether/ethyl acetate=0:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (0.45 g, 88% yield).

B. 5 -Chloro-2-methyl-6-(1 -methyl-1 H-pyrazol-3 -yl)pyridin-3-amine, 169b

[1,G-Bis(diphenylphosphino)ferrocene]dichloropalladium(P) complexed with dichloromethane (113 mg, 0.14 mmol) was added to a solution of 5,6-dichloro-2-methylpyridin-3-amine (350 mg, 1. 98 mmol), 1-methyl-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (535 mg, 2.57 mmol) and potassium acetate (582 mg,

- 270 045333

5.93 mmol) in dioxane/water (3:1, 10 ml) under N2 at 100°C overnight. The mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to

0/100). The eluent was collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (315 mg, 72% yield). LC-MS: (ES, m/z): [M+1]+ 222.9.

C. N-(5-Chloro-2-methyl-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5 -yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 169

To a solution of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (175 mg, 0.45 mmol) and 5-chloro-2- methyl 6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine (110 mg, 0.49 mmol) and pyridine (363 μl, 4.49 mmol) in dichloromethane (5 ml) were added drops of POCl ₃ (68.9 mg, 0.45 mmol). The mixture was stirred at 25°C for 2 hours. Water (5 ml) was added, sat. NaHCO3 to adjust the pH to 7-8 and the reaction mixture was extracted using dichloromethane (5 mlx2). The combined organic layers were dried over MgSO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude product. The crude product was subsequently purified by preparative HPLC (30-60% (v/v) CH3CN and _H2O with 0.05% HCl) to give the product as a white solid (105 mg, 44%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.52 (br.s, 3H), 3.93 (s, 3H), 5.69 (br.d, J=7.50 Hz , 1H), 6.75 (d, J=2.21 Hz, 1H), 7.29 (br.s, 1H), 7.67 (t, J=7.83 Hz, 1H), 7.79 (d, J=2.21 Hz, 1H), 7.93 (d, J=7.50 Hz, 1H), 8.09 (s, 1H), 8.44 (d, J=8.38 Hz , 1H), 8.49 (s, 1H), 10.40 (s, 1H), 11.62 (br.s, 1H). LC-MS: (ES, m/z): [M+1]+ 527.9.

Example 170.

N-(5-Chloro-2-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 170

A solution of 2,3-dichloro-6-methyl-5-nitropyridine (1.2 g, 5.80 mmol), 1H-pyrazole (987 mg, 14.5 mmol) and potassium carbonate (2.40 g, 17.4 mmol) in MeCN (20 ml) was stirred at rt overnight and at 40°C for a further 8 hours. The mixture was filtered and the solid was washed with ethyl acetate (20 ml x 3). The filtrate was concentrated to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 50/50). The eluent was collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (650 mg, 47% yield).

1H NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3H), 6.64 (t, J=1.76 Hz, 1H), 7.92 (s, 1H), 8 .49 (d, J=2.65 Hz, 1H), 8.84 (s, 1H).

B. 5-Chloro-2-methyl-6-(1H-pyrazol-1-yl)pyridin-3-amine, 170b

Iron (0.761 g, 13.6 mmol) and ammonium chloride (0.718 g, 13.6 mmol) were added to a mixture of 3-chloro-6methyl-5-nitro-2-(1H-pyrazol-1-yl)pyridine (0.650 g , 2.72 mmol) in methanol (5 ml), THF (10 ml) and water (5 ml). The mixture was stirred at 70°C for 2 hours. 10 ml of sat. was added to the mixture. NaHCO solution, the mixture was filtered and the filtrate was extracted using ethyl acetate (15 mlx3). The organic layer was dried (Na2SO4) and the solvent was removed to give the product as a solid

- 271 045333 yellow (500 mg, 88%).

C. N-(5-Chloro-2-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 170

To a solution of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (146 mg, 0.70 mmol) and 5-chloro-2- methyl 6-(1H-pyrazol-1-yl)pyridin-3-amine (200 mg, 0.58 mmol) in pyridine (5 ml) was added dropwise with POCl ₃ (108 μl, 1.16 mmol). The mixture was stirred at 25°C for 2 hours. Water (5 ml) was added, sat. NaHCO ₃ to adjust the pH to 7-8 and the reaction mixture was extracted using ethyl acetate (20 mlx3). The combined organic layers were dried over MgSO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude product. The crude product was subsequently purified by preparative HPLC (32-62% (v/v) CH3CN and H2O with 0.05% HCl) to give the product as a white solid (160 mg, 53%).

1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (br.s, 3H), 5.68 (d, J=7.72 Hz, 1H), 6.52-6.58 ( m, 1H), 7.277.33 (m, 1H), 7.68 (t, J=7.94 Hz, 1H), 7.81 (d, J=1.32 Hz, 1H), 7.94 ( d, J=7.72 Hz, 1H), 8.27 (d, J=2.21 Hz, 1H), 8.30 (s, 1H), 8.44 (d, J=7.94 Hz, 1H), 8.52 (s, 1H), 10.54 (s, 1H), 11.63 (br.d, J=5.95 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 514.2.

Example 171.

N-(5-Chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 171

A mixture of 1,2-dichloro-4-methyl-5-nitrobenzene (1.0 g, 4.85 mmol), 2H-1,2,3-triazole (0.32 ml, 5.83 mmol), potassium carbonate ( 2.01 g, 14.56 mmol) and potassium fluoride (226 mg, 3.88 mmol) in acetonitrile (10 ml) were stirred at 80°C overnight. The solid was collected by filtration and subsequently washed with 50 ml of ethyl acetate. The solvent was concentrated to give the crude product as a yellow solid. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-50:50). The solvent was concentrated to give the product as a white solid (180 mg, 15.5% yield).

1H NMR (400 MHz, chloroform-d) δ ppm 7.69 (s, 1H), 7.64 (d, J=1.00 Hz, 1H), 7.40 (d, J=1, 25 Hz, 1H), 7.21 (s, 1H) 2.11 (s, 3H).

B. 5-Chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)aniline, 171b

Iron (0.772 g, 13.8 mmol) and ammonium chloride (0.74 g, 13.8 mmol) were added to the 2-(2-chloro-5methyl-4-nitrophenyl)-2H-1,2,3-triazole mixture (660 mg, 2.77 mmol) in methanol (4 ml), THF (6 ml) and water (3 ml). The mixture was stirred at 60°C for 2 hours. Ethyl acetate (50 ml) was added to the mixture. The precipitate was collected by filtration and the residue was washed with ethyl acetate (50x3 ml). The filtrate was collected and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - petroleum ether/ethyl acetate=1:1). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a white solid (0.50 g, 95% yield).

- 272 045333 ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.97 (s, 2H), 7.13 (s, 1H), 6.77 (s, 1H), 5.58 ( s, 2H), 3.33 (s, 2H),

2.48 (br.s, 2H), 2.05 (s, 3H).

C. N-(5-Chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 171

To a solution of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.46 mmol), 5-chloro-2- methyl 4-(2H-1,2,3-triazol-2-yl)aniline (96.8 mg, 0.46 mmol) and pyridine (220 mg, 2.78 mmol) in dichloromethane (10 ml) were added drops of POCl ₃ (285 mg, 1.86 mmol). The mixture was stirred at room temperature for 4 hours. Saturated. NaHCO ₃ to adjust the pH to 9-10 and the reaction mixture was extracted using dichloromethane (30 mlx3). The combined organic layers were dried over MgSO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was subsequently purified by preparative HPLC (35-65% (v/v) CH3CN and _H2O with 0.05% HCl) to give the product as a white solid (131 mg, 54.7%).

1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (br.d, J=5.51 Hz, 1H), 10.35 (s, 1H), 8.36-8.53 ( m, 2H), 8.13 (s, 2H), 7.81-7.95 (m, 2H), 7.59-7.68 (m, 2H), 7.26 (dd, J=7, 17, 6.06 Hz, 1H), 5.66 (br.d, J=7.50 Hz, 1H), 2.27-2.37 (m, 3H). LC-MS: (ES, m/z): [M+1]+ 514.2.

Example 172.

N(5-Chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1 -(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 ( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 172

A. 2-(2-Chloro-5-fluoro-4-nitrophenyl)-2H-1,2,3-triazole, 172a

0^+' ό172a

A mixture of 1-chloro-2,4-difluoro-5-nitrobenzene (3.0 g, 15.5 mmol), 2H-1,2,3-triazole (1.61 ml, 23.3 mmol) and potassium carbonate ( 6.42 g, 46.5 mmol) in acetonitrile (50 ml) was stirred at 30°C for 2 hours. The solid was collected by filtration and washed with 100 ml ethyl acetate and 100 ml dichloromethane. The solvent was concentrated to give the crude product as a yellow solid. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1-1:2). The solvent was concentrated to give the product as a yellow solid (0.6 g, 16%).

1H NMR (400 MHz, chloroform-d) δ ppm 7.79 (br.d, J=10.80 Hz, 1H), 7.95 (s, 2H), 8.32 (br.d, J=7.06 Hz, 1H).

B. 5-Chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)aniline, 172b

_H2N , 172b

Iron (0.692 g, 12.4 mmol) and ammonium chloride (0.661 g, 12.4 mmol) were added to a mixture of 2-(2-chloro-5fluoro-4-nitrophenyl)-2H-1,2,3-triazole (600 mg, 2.47 mmol) in methanol (20 ml), THF (40 ml) and water (10 ml). The mixture was stirred at 60°C for 2 hours. Ethyl acetate (50 ml) was added to the mixture. The precipitate was collected by filtration. The residue was washed with (50x3 ml) ethyl acetate. The filtrate was collected and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - petroleum ether/ethyl acetate=0:1). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a white solid (0.50 g, 81%).

- 273 045333 ¹ H NMR (400 MHz, DMSO-d6) δ ppm 5.93 (s, 2H), 6.93 (d, J=8.60 Hz, 1H), 7.36 (d, J=11.25 Hz, 1H),

7.99-8.04 (m, 2H). LC-MS: (ES, m/z): [M+1]+ 212.9.

C. N-(5-Chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 172

To a solution of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (152 mg, 0.47 mmol) and 5-chloro-2- fluoro-4-(2H-1,2,3-triazol-2-yl)aniline (100 mg, 0.47 mmol) and pyridine (149 mg, 1.888 mmol) in dichloromethane (10 ml) was added dropwise with POCl3 (144 mg, 0.94 mmol). The mixture was stirred at room temperature for 4 hours. Saturated. NaHCO ₃ to adjust the pH to 9-10 and the reaction mixture was extracted using dichloromethane (30 mlx3). The combined organic layers were dried over MgSO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was subsequently purified by preparative HPLC (32-62% (v/v) CH3CN and _H2O with 0.05% HCl) to give the product as a yellow solid (135 mg, 55.4%).

1H NMR (400 MHz, DMSO-d6) δ ppm 5.67 (d, J=7.28 Hz, 1H), 7.27 (dd, J=7.28, 5.95 Hz, 1H) , 7.65 (t, J=7.83 Hz, 1H), 7.86 (d, J=10.58 Hz, 1H), 7.90-7.94 (m, 1H), 8.18 ( s, 2H), 8.24 (d, J=7.50 Hz, 1H), 8.42 (d, J=8.16 Hz, 1H), 8.45 (s, 1H), 10.81 ( s, 1H), 11.60 (br.d, J=5.07 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 518.0.

Example 173.

N-(5-Chloro-6-(4-(methoxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 173

A. Methanesulfonate (2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamido)pyridin-2-yl)-2H-1,2,3 -triazol-4-yl)methyl, 173a

A solution of N-(5-chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5 ( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 136 (420 mg, 0.79 mmol) in DCM (8 ml) was cooled to 0°C, TEA (240 mg, 2.37 mmol) was added and subsequently added dropwise methanesulfonyl chloride (136 mg, 1.19 mmol). The solution was stirred at 0°C for 1 hour. The mixture was concentrated, dried and directly used in the next step.

B. N-(5-Chloro-6-(4-(methoxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 173

Solution of methanesulfonate (2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamido)pyridin-2-yl)-2H-1,2,3- triazol-4-yl)methyl (150 mg, 95% purity, 0.24 mmol) in methanol (20 ml) was stirred at 50°C for 2 hours. The mixture was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified using preparative high performance liquid chromatography (31-61% (v/v) CH3CN and _H2O with 0.05% HCl). Pure fractions were collected and the solvent was concentrated under reduced pressure and lyophilized

- 274 045333 to dryness to obtain the product in the form of a white solid (25 mg, 19.3% yield).

1H NMR (400 MHz, methanol-a ₄ ) δ ppm 3.44 (d, J=0.66 Hz, 3H), 4.67 (s, 2H), 7.61-7.66 (m , 1H), 7.75 (d, J=8.60 Hz, 1H), 7.83 (d, J=7.50 Hz, 1H), 7.94-7.99 (m, 1H), 8 .01 (s, 1H), 8.33 (d, J=8.60 Hz, 1H), 8.39 (s, 1H), 8.72 (dd, J=2.21, 1.32 Hz, 1H), 8.79 (d, J=2.21 Hz, 1H), 9.00 (d, J=3.97 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 528.9.

Example 174.

N-(4-(4-(Aminomethyl)-1H-pyrazol-1-yl)-3-chlorophenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide, compound 174

A. tert-Butyl ((1-(2-chloro-4-nitrophenyl)-1H-pyrazol-4-yl)methyl)carbamate, 174a

Potassium carbonate (350 mg, 2.54 mmol) was added to a solution of 2-chloro-1-fluoro-4-nitrobenzene (245 mg, 1.39 mmol), tert-butyl ((1H-pyrazol-4-yl)methyl) carbamate (250 mg, 1.27 mmol) in MeCN (5 ml), the mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product as a yellow solid, which subsequently purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - petroleum ether/ethyl acetate=1:1). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (440 mg, 98.4% yield). LC-MS: (ES, m/z): [M+1]+ 353.0.

B. tert-Butyl ((1-(4-amino-2-chlorophenyl)-1H-pyrazol-4-yl)methyl)carbamate, 174b

Iron (348.3 mg, 6.24 mmol) and NH ₄ Cl (333.6 mg, 6.24 mmol) were added to the mixture of tert-butyl ((1-(2chloro-4-nitrophenyl)-1H-pyrazole-4 -yl)methyl)carbamate (440 mg, 1.25 mmol) in THF (20 ml), H ₂ O (5 ml), MeOH (5 ml), and the reaction mixture was stirred at 60°C for 2 hours. Reaction the mixture was filtered through a pad of diatomaceous earth and the layer was washed with EtOAc (20 mlx2), the combined filtrates were concentrated to dryness to give the crude product as a brown solid, which was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 20/80). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a brown solid (388 mg, 96.4%). LC-MS: (ES, m/z): [M+1]+ 323.0.

WITH.

tert-Butyl ((1 -(2-chloro-4-( 1 -(quinolin-5-yl)-5 -(trifluoromethyl)-1 H-pyrazol-4 carboxamido)phenyl)-1 H-pyrazol-4-yl )methyl)carbamate, 174c

tert-Butyl ((1-(4-amino-2-chlorophenyl)-1H-pyrazol-4-yl)methyl)carbamate (140 mg, 0.43 mmol), 1(quinolin-5-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b (133.3 mg, 0.43 mmol) and DIEA

- 275 045333 (280.3 mg, 2.17 mmol) was dissolved in DMF (4 ml) and HATU (247.4 mg, 0.65 mmol) was added, the mixture was stirred at 25°C for 3 hours. Saturated. NaHCO ₃ (20 ml) and the reaction mixture was extracted with Na2SO4 product at 612.2.

D.

using CH ₂ Cl ₂ (20 mlx2), the combined organic layers were dried over anhydrous and filtered. The solvent was concentrated under reduced pressure to give provide a brown solid (200 mg, 36.8% yield). LC-MS: (ES, m/z): [M+1]+

N-(4-(4-(aminomethyl)-1H-pyrazol-1-yl)-3-chlorophenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide, compound 174

A mixture of HCl/dioxane (10 ml) was added to tert-butyl ((1-(2-chloro-4-(1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenyl) -1H-pyrazol-4-yl)methyl)carbamate (88 mg, 0.14 mmol), the mixture was stirred at rt for 10 min. The solvent was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (15-45% (v/v) CH3CN and _H2O with 0.05% HCl). The pure fractions were collected and the organic solvent was concentrated under reduced pressure and lyophilized to dryness to give the product as a pale white solid (55 mg 73.9% yield).

1H NMR (400 MHz, methanol-b ₄ ) δ ppm 9.37 (1H, d, J=3.76 Hz), 8.55 (1H, s), 8.52 (1H, s), 8.45 (1H, s), 8.33 (1H, t, J=8.16 Hz), 8.20 (1H, s), 8.18-8.20 (1H, m), 8.17 (1H, s), 8.11-8.16 (1H, m), 7.89 (1H, s), 7.83 (1H, dd, J=8.78, 2.26 Hz), 7, 60 (1H, d, J=8.78 Hz), 4.18 (2H, s). LC-MS: (ES, m/z): [M+1]+ 513.0.

Example 175.

N-(3 -Chloro-4-(4-(hydroxymethyl)-1 H-pyrazol-1 -yl)phenyl)-1 -(quinolin-5 -yl)-5 -(trifluoromethyl)-1Hpyrazol-4-carboxamide, connection 175

A. Ethyl 1-(2-chloro-4-nitrophenyl)-1H-pyrazole-4-carboxylate, 175 a

2-Chloro-1-fluoro-4-nitrobenzene (334 mg, 1.90 mmol) was dissolved in MeCN (10 ml), ethyl 1Hpyrazole-4-carboxylate (222.2 mg, 1.59 mmol) and cesium carbonate ( 568 mg, 1.74 mmol) and stirred at 80°C for 16 hours. The reaction mixture was filtered and the residue was washed with EtOAc (20 mlx3), and the combined organic layers were concentrated under reduced pressure to give the product as a yellow solid. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 70/30). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a white solid (400 mg, 85.3% yield).

Ή NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.58 (d, J=2.5 Hz, 1H), 8.36 (dd, J=2, 5, 8.8 Hz, 1H), 8.26 (s, 1H), 7.97 (d, J=8.8 Hz, 1H), 4.29 (k, J=7.1 Hz, 2H) , 1.30 (t, J=7.2 Hz, 3H).

B. Ethyl 1-(4-amino-2-chlorophenyl)-1H-pyrazole-4-carboxylate, 175b

Ethyl 1-(2-chloro-4-nitrophenyl)-1H-pyrazole-4-carboxylate (400 mg, 1.25 mmol) was dissolved in THF

- 276 045333 (10 ml), added iron (453 mg, 8.12 mmol), NH ₄ Cl (434 mg, 2.12 mmol) and H ₂ O (10 ml), stirred the reaction mixture at 80 ° C for 4 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed with EtOAc (20 mlx3). The filtrates were concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 70/30). The desired fraction was collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (280 mg, 74.2% yield). LC-MS: (ES, m/z): [M+1]+ 266.1.

C. Ethyl 1-(2-chloro-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenyl)-1Hpyrazole-4-carboxylate, 175c

Ethyl 1-(4-amino-2-chlorophenyl)-1H-pyrazole-4-carboxylate (130 mg, 0.49 mmol), 1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4 -carboxylic acid, 3b (100 mg, 0.33 mmol) and pyridine (38.6 mg, 0.49 mmol) were added to DCM (10 ml) and POCl ₃ (74.9 mg, 0.49 mmol) was added dropwise ). The reaction mixture was stirred at 30°C for 16 hours. Saturated solution was added to the mixture. NaHCO ₃ (20 ml) and the reaction mixture was extracted using CH ₂ Cl ₂ (20 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by silica gel flash column chromatography (eluent: petroleum ether/ethyl acetate 100/0 to 40/60 ). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (170 mg, 84.4% yield).

D. N-(3-Chloro-4-(4-(hydroxymethyl)-1H-pyrazol-1-yl)phenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide, compound 175

Ethyl 1-(2-chloro-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenyl)-1Hpyrazole-4-carboxylate (170 mg, 90% purity , 0.28 mmol) was dissolved in THF (10 ml) and stirred at 0°C, LiAlH ₄ (83.4 mg, 2.2 mmol) was slowly added. The reaction mixture was stirred at 40°C for 40 hours. Water (10 ml) was added and the reaction mixture was extracted using EtOAc (10 ml x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrate concentrated under reduced pressure to give the crude product as a yellow oil, which was purified using preparative high performance liquid chromatography (25-55% (v/v) CH3CN and H ₂ O with 0.05% HCl). The pure fractions were collected and the solvent was concentrated under reduced pressure, lyophilized to dryness to give the product as a white solid (34 mg, 24.1% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.12 (br.s, 1H), 9.16 (br.s, 1H), 8.63 (br.s, 1H), 8 .41 (br.d, J=7.0 Hz, 1H), 8.16 (br.s, 1H), 8.11-7.93 (m, 3H), 7.82 (br.s, 3H ), 7.69 (br.s, 1H), 7.60 (br.s, 1H), 4.46 (br.s, 2H). LC-MS: (ES, m/z): [M+1]+ 512.9.

Example 176.

N-(5-Cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)niridin-3-yl)-1-(1-oxo-l,2-dihydroisoquinolin-5yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 176

- 277 045333

A. 5-Bromo-2-hydroxy-6-methylnicotinonitrile, 176a

1-Bromopyrrolidine-2,5-dione (26.54 g, 149.1 mmol) was added dropwise to a solution of 2-hydroxy-6methylnicotinonitrile (10 g, 74.6 mmol) in DMF (120 ml). The mixture was stirred at 70°C for 2 hours. Saturated. NaHCO ₃ solution (100 ml). The mixture was extracted using ethyl acetate (300 mlx3). The separated organic layers were dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give the product as a black solid (14 g, 79% yield). LC-MS: (ES, m/z): [M+1]+ 212.8.

B. 5-Bromo-2-chloro-6-methylnicotinonitrile, 176b

5-Bromo-2-hydroxy-6-methylnicotinonitrile (14 g, 58.65 mmol) in phosphoryl trichloride (101.4 g, 661.2 mmol) was stirred at 80°C overnight. Phosphoryl trichloride was concentrated. Added sat. NaHCO ₃ solution (1000 ml) was added dropwise to the residue to adjust the pH to 7 ~ 8. The aqueous phase was extracted using ethyl acetate (500 ml x 3). The organic phase was dried (MgSO ₄ ), filtered and the filtrate was concentrated to give the product as a black solid (9 g, 66% yield).

C. 5-Bromo-6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, 176c

A solution of 5-bromo-2-chloro-6-methylnicotinonitrile (8.5 g, 36.7 mmol), 2H-1,2,3-triazole (5.07 g, 73.4 mmol) and potassium carbonate (15, 2 g, 110.2 mmol) in acetonitrile (150 ml) was stirred at 40°C overnight. The mixture was filtered and washed with ethyl acetate (200 mlx3). The filtrate was concentrated to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 30/70). The eluent was collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (7 g, 72% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.71 (s, 3H), 8.31 (s, 2H), 8.90 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 264.0.

D. 5-Amino-6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, 176d

Palladium diacetate (170 mg, 0.76 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (438 mg, 0.76 mmol) were added to the 5-bromo-6 solution -methyl-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile (2.0 g, 7.57 mmol), tert-butyl carbamate (1331 mg, 11.36 mmol) and cesium carbonate ( 7.40 g, 22.7 mmol) in dioxane with N ₂ bubbling. The reaction mixture was stirred at 120°C overnight. The mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 0/100). Collect the eluent and concentrate the solvent under reduced pressure to obtain 5-amino-6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile as a yellow solid (300 mg, 18%), LC-MS: (ES, m/z): [M+1] ⁺ 200.8 and tert-butyl (5-cyano-2-methyl-6-(2H-1,2,3-triazol2-yl)pyridine -3-yl)carbamate as a yellow solid (600 mg, 26%).

E. N-(5-Cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline5- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 176

To a solution of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (132 mg, 0.41 mmol) and 5-amino-6- methyl 2-(2H-1,2,3-triazol-2-yl)nicotinonitrile (90 mg, 0.45

- 278 045333 mmol) and pyridine (129 mg, 1.64 mmol) in dichloromethane (20 ml) POCl ₃ (125 mg, 0.82 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. Saturated. NaHCO ₃ solution (20 ml) and the mixture was extracted using dichloromethane (20 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was subsequently purified by preparative HPLC (28-58% (v/v) CH3CN and _H2O with 0.05% HCl) to give the product as a yellow solid (65 mg, 31%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.64 (s, 3H), 5.66 (d, J=7.50 Hz, 1H), 7.24-7.31 (m , 1H), 7.66 (t, J=7.83 Hz, 1H), 7.93 (d, J=7.72 Hz, 1H), 8.29 (s, 2H) 8.42 (d, J=7.94 Hz, 1H), 8.51 (s, 1H), 8.66 (s, 1H), 10.64 (br.s, 1H), 11.61 (br.d, J=5 .07 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 505.9.

Example 177.

N-(5-Cyano-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 177

A. Methyl 2-(3-Cyano-5-nitropyridin-2-yl)-2H-1,2,3-triazole-4-carboxylate, 177a

Potassium carbonate (376.5 mg, 2.72 mmol) was added to a solution of 2-chloro-5-nitronicotinonitrile (500 mg, 2.72 mmol) and methyl 1H-1,2,3-triazole-4-carboxylate (415, 5 mg, 3.27 mmol) in MeCN (10 ml). The mixture was reacted at rt for 3 hours, filtered and the resulting residue was washed with EtOAc (50 mlx3). The filtrates were concentrated under reduced pressure. EtOAc (10 mL) was added, the mixture was stirred at rt for 0.5 h, filtered, collected and dried the resulting solid under reduced pressure to give the product as a yellow solid (550 mg, 73.6% yield).

B. Methyl 2-(5-amino-3-cyanopyridin-2-yl)-2H-1,2,3-triazole-4-carboxylate, 177b

Methyl 2-(3-cyano-5-nitropyridin-2-yl)-2H-1,2,3-triazole-4-carboxylate (550 mg, 2.0 mmol) was dissolved in THF (20 ml), methanol was added ( 10 ml), iron (1.12 g, 20.0 mmol), NH ₄ Cl (1.07 g, 20.0 mmol) and H2O (5 ml), and the reaction mixture was stirred at 60°C for 2 h The mixture was filtered through a pad of diatomaceous earth and the layer was washed with EtOAc (20 ml x3). The combined filtrates were concentrated under reduced pressure to give the crude product, which was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 10:1 to 1:1). The desired fraction was collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (180 mg, 31.2% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.70-8.54 (m, 1H), 8.10 (d, J=2.9 Hz, 1H), 7.48 ( d, J=2.6 Hz, 1H), 6.42 (s, 2H), 3.89 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 245.1.

C. Methyl 2-(3-cyano-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin2-yl)-2H-1,2,3- triazole-4-carboxylate, 177c

Methyl 2-(3-cyano-5-nitropyridin-2-yl)-2H-1,2,3-triazole-4-carboxylate (155 mg, 0.63 mmol), 1(quinolin-5-yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3b (230 mg, 0.75 mmol) and pyridine (297 mg, 3.76 mmol) were added to DCM (10 ml) and POCl ₃ (384 mg, 2.509 mmol). The reaction mixture was stirred at rt for 4 hours. Saturated solution was added. NaHCO3 to adjust the pH to 910, water (30 ml) was added and the mixture was extracted using CH ₂ Cl ₂ (30 mlx3). The combined organic layers were dried over Na2SO4, filtered and the filtrates concentrated under reduced pressure to give the product as a yellow solid (450 mg, 98.7% yield).

LC-MS: (ES, m/z): [M+1]+ 533.9.

D. X-(5-Cyano-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 177

Methyl 2-(3-cyano-5 -(1 -(quinolin-5 -yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamido)pyridin-2yl)-2H-1,2,3-triazole -4-carboxylate (400 mg, 730% purity, 0.55 mmol) was dissolved in THF (10 ml) and the reaction mixture was stirred at 0°C, subsequently LiAlH ₄ (167 mg, 4.4 mmol) was added slowly. The reaction mixture was stirred at 40°C for 10 hours. Water (10 ml) was added and the mixture was extracted using EtOAc (10 ml x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative high performance liquid chromatography. The pure fractions were collected and the solvent was concentrated under reduced pressure, lyophilized to dryness to give the product as a light yellow solid (20 mg, 6.9% yield).

1H NMR (400 MHz, methanol^) δ ppm 9.27 (d, J=3.7 Hz, 1H), 9.07 (br.s, 1H), 8.89 (d, J=2 ,4 Hz, 1H), 8.51-8.43 (m, 2H), 8.39 (d, J=8.4 Hz, 1H), 8.24 (t, J=8.2 Hz, 1H ), 8.13-8.07 (m, 2H), 8.03 (dd, J=5.1, 8.6 Hz, 1H), 4.82 (s, 2H). LC-MS: (ES, m/z): [M+1]+ 506.1.

Example 178.

N-(6-(5-Amino-1H-1,2,3-triazol-1-yl)-5-chloropyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5 yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 178

A.

-(3-Chloro-5 -(1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamido)pyridin-2-yl)-1H-1,2,3-triazole -5-carboxylic acid, 178a

Lithium hydroxide (139 mg, 5.8 mmol) was added to a solution of methyl 1-(3-chloro-5-(1-(1methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido) pyridin-2-yl)-1H-1,2,3triazole-5-carboxylate (750 mg, 1.16 mmol) in THF/H2O (2: 1.6 ml), the mixture was reacted at 25°C for 2 hours The solvent was concentrated under reduced pressure, 1M HCl solution was added to the mixture to adjust the pH to ~5, and a solid formed. The solid was collected by filtration and dried to give the product (600 mg, 88.7% yield). LC-MS: (ES, m/z): [M+1]+ 559.0.

B. tert-Butyl (1 -(3 -chloro-5 -(1-(1 -methoxyisoquinolin-5 -yl)-5-(trifluoromethyl)-1 H-pyrazol-4-carboxamido)pyridin-2-yl)- 1H-1,2,3-triazol-5-yl)carbamate, 178b

- 280 045333 ci nA ν ώ ™ J / °”r)=( /°* i ' _f 178b

To a solution of 1 -(3 -chloro-5 -(1-(1 -methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamido)pyridin-2-yl)-1H-1,2, 3-triazole-5-carboxylic acid (550 mg, 0.94 mmol) in tert-butanol (10 ml) under N ₂ atmosphere was added DPPA (311 mg, 1.13 mmol) and TEA (286 mg, 2.83 mmol). The reaction mixture was stirred at 80°C overnight, saturated was added. NaHCO ₃ (20 ml) and the mixture was extracted using EtOAc (30 ml x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2:1 -ethyl acetate). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (180 mg, 27.9% yield). LC-MS: (ES, m/z): [M+1]+ 630.2.

C. N-(6-(5-Amuho-1H-1,2,3-triazol-1-yl)-5-chloropyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl) )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 178

K tert-butyl (1 -(3 -chloro-5 -(1-(1 -methoxyisoquinolin-5 -yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamido)pyridin-2-yl)-1H-1 ,2,3-triazol-5-yl)carbamate (180 mg, 0.26 mmol) and concentrated HCl (2 ml) was added with isopropanol (4 ml) and stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative high performance liquid chromatography. The pure fractions were collected and the organic solvent was concentrated under reduced pressure, lyophilized to dryness to obtain the product as a white solid (31.2 mg, 22.7% yield).

1H NMR (400 MHz, DMSO-d6) δ ppm 5.63 (d, J=7.28 Hz, 1H), 7.26 (t, J=6.73 Hz, 1H), 7.64 (t, J=7.72 Hz, 1H), 7.83 (s, 1H), 7.92 (d, J=7.94 Hz, 1H), 8.41 (d, J=8.16 Hz , 1H), 8.56 (s, 1H), 8.63 (d, J=1.76 Hz, 1H), 8.84 (d, J=1.76 Hz, 1H), 11.30 (s , 1H), 11.61 (br.d., J=5.29 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 515.9.

Example 179.

N-(5-Chloro-6-(4-cyano-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 179

POCl ₃ (348.6 mg, 2.27 mmol) was added to a solution of 2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamido)pyridine -2-yl)-2H-1,2,3-triazole-4-carboxamide (120 mg, 0.23 mmol) in CH ₃ Cl (8 ml). The mixture was reacted at 80°C for 1 hour, 10% NaHCO ₃ (10 ml) was added and the mixture was extracted using CH2Cl2 (15 ml x 2). The combined organic layers were dried over Na2SO4, filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was purified by preparative high performance liquid chromatography. The pure fractions were collected and the solvent was concentrated under reduced pressure, lyophilized to dryness to obtain the product as a white solid (82 mg, 69.7% yield).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (br.s, 2H), 7.93-8.08 (m, 2H), 8.37 (br.d, J=8 .03 Hz, 1H), 8.69 (br.s., 1H), 8.79 (br.d., J=2.01 Hz, 1H), 8.93-9.04 (m, 2H), 9.10 (br.s, 1H), 11.53 (br.s, 1H). LC-MS: (ES, m/z): [M+1]+ 515.9.

Example 180.

-(1 -Aminoisoquinolin-4-yl)-N-(5 -chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 180

- 281 045333

A solution of sodium nitrite (10.77 g, 156.06 mmol) in water ( 15 ml) at temperatures below 0°C. The reaction mixture was stirred at 0°C for 30 min and a solution of SnC1 ₂ ·2H ₂ O (58.69 g, 260.10 mmol) in HCl (27 ml, 12 mol/L) was added dropwise. The mixture was stirred at room temperature for 12 hours. The mixture was adjusted to pH 12-14 with 20% aqueous sodium hydroxide solution. The mixture was extracted using CH ₂ Cl ₂ (1000 mlx3). The organic layer was dried (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated under reduced pressure to give crude compound 180a (15.8 g, 95.4% yield) as a brown solid, which was directly used in the next step.

B. Ethyl 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 180b

Solution of 4-hydrazinyl isoquinoline, 180a (15.8 g, 99.25 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (35.758 g, 148.88 mmol), triethylamine (30.074 g, 297 .76 mmol) in EtOH (200 ml) was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100:1 to 20:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 180b (16 g, 41.8% yield) as a yellow solid. LCMS (ESI) m/z M+1: 336.0.

C. 4-(4-(Ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinoline 2-oxide, 180c

Solution of ethyl 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 180b (16 g, 41.44 mmol), 3-chloroperoxybenzoic acid (26.817 g, 124.32 mmol) in CH ₂ Cl ₂ (300 ml) was stirred at rt for 16 hours. The reaction mixture was quenched with sat. NaHCO ₃ (1000 ml) and the mixture was extracted using ethyl acetate (500 ml x 3). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give 180c (11 g, 74.4% yield) as a yellow solid. LCMS (ESI) m/z M+1: 352.0.

D. Ethyl 1-(1-chloroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 180d

4-(4-(Ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinoline 2-oxide, 180c (11 g, 30.81 mmol) was added to a solution of POCl ₃ (20 ml, 214.57 mmol) in CHC13 (40 ml). The mixture was stirred at

- 282 045333

80°C for 18 hours. The mixture was diluted with water (1000 ml) and extracted using ethyl acetate (300 mlx3). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 5:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 180d (10 g, 70.6% yield) as a white solid. LCMS (ESI) m/z M+1: 370.0.

1H NMR (400 MHz, chloroform-d) δ ppm 8.44-8.53 (m, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.79- 7.87 (m, 2H), 7.27-7.32 (m, 1H), 4.42 (k, J=7.20 Hz, 2H), 1.42 (t, J=7.17 Hz , 3H).

E. 1-(1-Chloroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 180e

ABOUT

CoN

Cl, 180e

LiOH (1.825 g, 43.49 mmol) was added to a solution of ethyl 1-(1-chloroisoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate, 180d (10 g, 21.75 mmol) and THF (100 ml) in water (100 ml). The mixture was stirred at rt for 1 hour. 5% KHSO4 was added to the mixture to adjust the pH to 3-4. Water (1000 ml) and ethyl acetate (1000 ml) were added to the mixture. The organic layer was washed with brine (500 ml), dried over MgSO4 and concentrated under reduced pressure to give 180e (9.7 g, >100% yield) as a white solid, which was directly used in the next step. LCMS (ESI) m/z M+1: 341.9.

F. N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-chloroisoquinolin-4-yl)-5 (trifluoromethyl)-1 H-pyrazole-4-carboxamide, 180f

POCl ₃ (302.082 mg, 1.97 mmol) was added to a solution of 1-(1-chloroisoquinolin-4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxylic acid, 180e (350 mg, 0.99 mmol) , 5-chloro-2-methyl-6-(2H-1,2,3-triazol-2yl)pyridin-3-amine (206.504 mg, 0.99 mmol), pyridine (194.795 mg, 2.46 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at rt for 2 hours. Water (50 ml) and CH ₂ Cl ₂ (50 ml) were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 0:100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 180f (310 mg, 58.2% yield) as a white solid. LCMS (ESI) m/z M+1: 532.9.

G. 1-(1-Aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 180

Solution No.(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-chloroisoquinolin-4-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, 180f (290 mg, 0.54 mmol), NH3-H2O (3 ml) in dioxane (3 ml) was stirred at 120°C for 5 hours. The mixture was concentrated under reduced pressure with yielding a crude product which was purified by preparative HPLC (20-50% (v/v) CH3CN and _H2O with 0.05% HCl). The pure fractions were collected and the solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the title compound (100.5 mg, 34.1% yield) as a yellow solid. LCMS (ESI) m/z M+1: 513.9;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.71 (s, 1H), 9.01-9.45 (m, 2H), 8.66 (d, J=8.60 Hz , 1H), 8.57 (s, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 8.16 (s, 2H), 7.92-8.00 (m, 1H), 7.82 (t, J=7.61 Hz, 1H), 7.04 (d, J=8.16 Hz, 1H), 2.53 (s, 3H).

- 283 045333

Example 181.

N-(6-(5 -Amino-1 -methyl-1 H-pyrazol-3 -yl)-5-cyanopyridin-3 -yl)-1 -(quinolin-5-yl)-5 (trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 181

To a solution of 3 -(3 -cyano-5-( 1 -(quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamido)pyridin-2-yl)-1-methyl-1H-pyrazol- 5-carboxylic acid (165 mg, 0.31 mmol) in DMF (10 ml) under N2 atmosphere, DPPA (92.2 mg, 0.34 mmol) and TEA (92.5 mg, 0.91 mmol) were added. The reaction mixture was stirred at 80°C for 16 hours and concentrated. The residue was purified by preparative high performance liquid chromatography. The pure fractions were collected, the organic solvent was concentrated under reduced pressure and lyophilized to dryness to give the product as a yellow solid (35 mg, 22.1% yield).

1H NMR (400 MHz, DMSO-d6) δ ppm 11.14 (1H, s), 9.00-9.07 (2H, m), 8.54-8.61 (2H, m), 8.32 (1H, d, J=8.82 Hz), 7.87-7.99 (2H, m), 7.64-7.70 (1H, m), 7.57-7.63 ( 1H, m), 5.93 (1H, s), 3.62 (3H, s). LC-MS: (ES, m/z): [M+1]+ 504.0.

Example 182.

N-(5-Chloro-6-(4-(hydroxymethyl)-1 H-pyrazol-1 -yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin5-yl)-5- (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 182

A. Ethyl 1-(3-chloro-5-(1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamido)pyridin-2-yl)- 1 H-pyrazole-4-carboxylate, 182a

To a solution of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (556 mg, 1.92 mmol) and ethyl 1-(5- amino-3-chloropyridin-2-yl)-1H-pyrazol-4-carboxylate (559 mg, 2.06 mmol) and pyridine (816 mg, 10.3 mmol) in dichloromethane (30 ml) was added dropwise with POCl ₃ ( 791 mg, 5.16 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative high performance liquid chromatography to give the product as a yellow solid (470 mg, 47.8% ). LC-MS: (ES, m/z): [M+1]+ 572.0.

D. N-(5-Chloro-6-(4-(hydroxymethyl)-1 H-pyrazol-1 -yl)pyridin-3 -yl)-1-(1-oxo-1,2dihydroisoquinolin-5-yl)- 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 182

Ethyl 1-(3-chloro-5-(1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamido)pyridin-2-yl)-1H- pyrazole-4-carboxylate (470 mg, 0.82 mmol) was dissolved in THF (25 ml) and cooled to 0°C. LiAlH ₄ (156 mg, 4.11 mmol) was added and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was cooled to 0°C, quenched by adding 0.15 ml H ₂ O, and then 0.15 ml 15 % aq. NaOH and 0.45 ml of H ₂ O. CH ₂ Cl ₂ /MeOH (10/1, 100 ml) and Na ₂ SO ₄ were added, stirred at room temperature for 0.5 h, and the mixture was filtered through layer of diatomaceous earth. The resulting residue was washed with CH ₂ Cl ₂ /MeOH (10/1, 100 mlx2). The filtrate was concentrated to dryness to obtain the crude product, which was purified using preparative high performance liquid chromatography. The pure fractions were collected, concentrated under reduced pressure and lyophilized to dryness to give the product (150 mg, 34.4% yield).

1H NMR (400 MHz, methanol-d4) δ ppm 8.75 (br.s, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.56 (dd, J= 0.8, 8.0 Hz, 1H), 8.34 (s, 1H), 8.15 (s, 1H), 7.88-7.83 (m, 1H), 7.81 (s, 1H ), 7.74-7.65 (m, 1H), 7.26-7.22 (m, 1H), 5.95-5.90 (m, 1H), 4.62 (s, 2H). LC-MS: (ES, m/z): [M+1]+ 529.9.

Example 183.

N-(6-(5-Amino-1-methyl-1H-pyrazol-3-yl)-5-chloropyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin5-yl)-5- (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 183

A. Methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate, 183a

TEA (44.2 ml, 316.7 mmol) was added to a solution of methylhydrazine sulfate (20.3 g, 140.7 mmol) in H ₂ O (100 ml) and MeOH (200 ml) at room temperature and the mixture was stirred for 0 .5 hours at ct. Dimethyl but-2-indioate (20 g, 140.7 mmol) was added to the mixture, and the mixture was stirred for 18 hours at 70°C, followed by stirring at rt for 36 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure yielding the product as a white solid (3.65 g, 16.6% yield).

B. Methyl 1-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-5-carboxylate, 183b

Methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (3.65 g, 23.4 mmol) was dissolved in CH ₂ Cl ₂ (70 ml) and the reaction mixture was cooled to -5°C. TEA (6.52 mL, 46.8 mmol) and trifluoromethanesulfonic anhydride (7.87 mL, 46.8 mmol) were added to the mixture and the mixture was stirred at rt for 1 hour. The mixture was subsequently poured into 60 mL of H2O, and the organic layer was separated and extracted the aqueous layer using CH ₂ Cl ₂ (2x100 ml). The combined extracts were washed with water. The combined organic layers were dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give a brown oil. The brown oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 - petroleum ether/ethyl acetate=1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow oil (6 g, 86.1% yield). LC-MS: (ES, m/z): [M+1]+ 288.9.

C. Methyl 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate, 183c

Methyl 1-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-5-carboxylate (3.0 g, 10.07 mmol), bis(pinacolate)diboron (2.81 g, 11.08 mmol) and potassium acetate (2.97 g, 30.21 mmol) were added to dioxane (20 ml), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (1:1) (412 mg, 0.50 mmol), dppf (279 mg, 0.50 mmol) under N ₂ and the reaction mixture was stirred at 100° C. for 16 hours under N ₂ . The reaction mixture was filtered and the filtrates concentrated under reduced pressure to give a black oil, which was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 60/40). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a white solid (2.5 g, 93.3% yield).

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D. Methyl 3-(5-amino-3-chloropyridin-2-yl)-1-methyl-III-pyrazole-5-carboxylate, 183d

Methyl 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate (1.0 g, 3.76 mmol), 5,6-dichloropyridin-3-amine (0.61 g, 3.76 mmol) and potassium carbonate (1.56 g, 11.3 mmol) were added to the dioxane/water mixture (9:1, 20 ml) and purged reaction mixture N ₂ . [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (0.31 g, 0.38 mmol) was added and the reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was filtered, the filtrates concentrated under reduced pressure to give a black oil, which was purified using silica gel flash column chromatography (petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a black solid (560 mg, 46.5% yield). LC-MS: (ES, m/z): [M+1]+ 267.0.

E. Methyl 3 -(3-chloro-5-(1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamido)pyridin-2-yl)-1-methyl-1 N-pyrazole-5-carboxylate, 183e

To a solution of 1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (315.4 mg, 0.94 mmol), methyl 3-(5-amino-3- chloropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (300 mg, 0.94 mmol) and pyridine (0.38 ml, 4.68 mmol) in CH ₂ Cl ₂ (10 ml) were added dropwise POCl ₃ (0.34 ml, 3.74 mmol). The mixture was stirred at 25°C for 2 hours, 20 ml of sat. NaHCO ₃ and the mixture was extracted using CH ₂ Cl ₂ (30 mlx 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil. The crude product was subsequently purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 - ethyl acetate) to give the product as a brown oil (340 mg, 48.1%). LC-MS: (ES, m/z): [M+1] ⁺ 586.1.

F. 3-(3-Chloro-5-(1-(1-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4-carboxamido)-pyridin-2-yl)-1-methyl -1H-pyrazole-5-carboxylic acid, 183f

Sodium hydroxide (27.0 mg, 0.67 mmol) was added to the solution of methyl 3-(3-chloro-5-(1-(1methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido )pyridin-2-yl)-1-methyl-1Hpyrazole-5-carboxylate (340 mg, 0.45 mmol) in THF/H2O (3:1.8 ml), the mixture was stirred at room temperature for 3 hours. Solvent concentrated under reduced pressure and water was added to the mixture (10 ml). The mixture was adjusted to pH 5 using 1M HCl and extracted using ethyl acetate (20 mlx3). The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the product as a brown oil (250 mg, 78.4% yield). LC-MS: (ES, m/z): [M+1] ⁺ 572.0.

G. tert-Butyl (3 -(3-chloro-5-(1-(1-methoxyisoquinolin-5-yl)-5 -(trifluoromethyl)-1 H-pyrazol-4-carboxamido)pyridin-2-yl)- 1 -methyl-1 H-pyrazol-5 -yl)carbamate, 183 g

To a solution of 3 -(3 -chloro-5-( 1-(1 -methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4- 286 045333 carboxamido)pyridin-2-yl)-1- methyl 1H-pyrazole-5-carboxylic acid (200 mg, 0.28 mmol) in tert-butanol (8 ml) under N2 was added DPPA (85.4 mg, 0.31 mmol) and TEA (85.6 mg, 0 85 mmol), the reaction mixture was subsequently stirred at 80°C for 5 hours. The solvent was removed under reduced pressure to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 - ethyl acetate). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a brown oil (150 mg, 78.2% yield). LC-MS: (ES, m/z): [M+1]+ 643.1.

N. N-(6-(5-Amuho-1-methyl-1 H-pyrazol-3-yl)-5-chloropyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 183

Concentrated HCl (2 ml) was added to the solution of tert-butyl (3-(3-chloro-5-(1-(1methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)pyridin- 2-yl)-1-methyl-1Hpyrazol-5-yl)carbamate (120 mg, 0.18 mmol) in isopropanol (4 ml), the mixture was subsequently stirred at rt for 1 hour. The solvent was concentrated under reduced pressure to give the crude product as a yellow solid which was purified using preparative high performance liquid chromatography. The pure fractions were collected and the organic solvent was concentrated under reduced pressure and the solid was lyophilized to give the product as a pale yellow solid (72 mg, 73.3% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.61 (1H, br.d., J=5.73 Hz), 11.16 (1H, s), 8.86-8, 92 (1H, m), 8.53 (1H, s), 8.44 (1H, s), 8.41 (1H, d, J=8.16 Hz), 7.91 (1H, d, J =7.72 Hz), 7.64 (1H, t, J=7.72 Hz), 7.23-7.29 (1H, m), 6.18 (1H, s), 5.62 (1H , d, J=7.28 Hz), 3.67 (3H, s). LC-MS: (ES, m/z): [M+1]+ 528.9.

Example 184.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-4- yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 184

A. 8-Fluoro-4-hydrazinyl isoquinoline, 184a {Pd(cinnamyl)Cl} ₂ (34.4 mg, 0.066 mmol) and Mor-DalPhos (61.5 mg, 0.13 mmol) in dioxane (5 ml) were stirred at rt for 10 min under N ₂ atmosphere, sodium tert-butoxide (255 mg, 2.65 mmol) and 4-bromo-8-fluoroisoquinoline (300 mg, 1.33 mmol) were added to the mixture at rt with stirring for 5 min under N2 and treat the mixture with hydrazine monohydrate (133 mg, 2.65 mmol) at 50°C for 2 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product as a brown solid (240 mg), which was directly used in the next step.

B. Ethyl 1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 184b

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (1.63 g, 6.77 mmol), 8-fluoro-4-hydrazinyl isoquinoline (800 mg, 4.52 mmol) and ethanol (20 ml) were stirred at 80°C for 1 hour and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure and subsequently purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-80:20) to give the product as a brown oil (820 mg,

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47.6%). LC-MS: (ES, m/z): [M+1]+ 353.9.

C. 4-(4-(Ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-8-fluoroisoquinoline 2-oxide, 184c <E _____

184c m-CPBA (791.6 mg, 4.59 mmol) was added to a solution of ethyl 1-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (700 mg, 92.6 % purity, 1.84 mmol) in DCM (5 ml). The mixture was reacted at 30°C for 2 hours, 40 ml of sat. Na ₂ CO ₃ solution and extracted the mixture using 50 ml CH ₂ Cl ₂ . The organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate=60:40). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow oil (675 mg, 99.6% yield). LC-MS: (ES, m/z): [M+1]+ 369.9.

D. Ethyl 1-(1-chloro-8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 184d

ABOUT "___

POCl ₃ (5 ml) was added to a solution of 4-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-8-fluoroisoquinoline 2-oxide (650 mg, 1.76 mmol) in chloroform (15 ml). The mixture was reacted at 70°C for 2 hours. Saturated solution was added to the mixture. Na ₂ CO ₃ solution (30 ml) and the mixture was extracted using 30 ml CH ₂ Cl ₂ .

The organic layer was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate=85:15). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a colorless oil (400 mg, 58.6% yield).

E. 1-(1-Ethoxy-8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 184e

Lithium hydroxide (124 mg, 5.16 mmol) was added to a solution of ethyl 1-(1-chloro-8-fluoroisoquinolin-4yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (400 mg, 1.03 mmol ) in an ethanol/water mixture (1:1, 10 ml). The mixture was reacted at 23°C for 2 hours and the solvent was concentrated under reduced pressure. A 1M HCl solution was added to the mixture to adjust the pH to ~5 and the mixture was extracted using EtOAc (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude product as a brown oil (335 mg, 44.5% yield). LC-MS: (ES, m/z): [M+1]+ 370.0.

F. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-ethoxy-8-fluoroisoquinolin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, 184f/, 184f

To a solution of 1-(1-ethoxy-8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (280 mg, 50.6% purity, 0.38 mmol), 5- chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-αmine, 1j (75.1 mg,

- 288 045333

0.38 mmol) and pyridine (91 mg, 1.15 mmol) in CH ₂ Cl ₂ (5 ml) was added dropwise POCl ₃ (70.6 mg, 0.46 mmol). The mixture was stirred at 25°C for 2 hours, 10 ml of sat. NaHCO ₃ and the mixture was extracted using CH ₂ Cl ₂ (15 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude product as a brown oil (258 mg, 68.8%). LC-MS: (ES, m/z): [M+1]+ 547.0.

G. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoro-1-oxo-1,2-dihydroisoquinoline- 4yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 184

Concentrated HCl (2 ml) was added to a solution of N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin3-yl)-1-(1-ethoxy-8-fluoroisoquinoline-4 -yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (75 mg, 0.14 mmol) in isopropanol (4 ml) and the mixture was reacted at 60°C for 2 hours. The solvent was concentrated under reduced pressure to give the crude compound, which was purified by preparative high performance liquid chromatography to give the product as a white solid (15 mg, 21% yield).

1H NMR (400 MHz, DMSO-d6) δ ppm 6.48 (d, J=8.16 Hz, 1H), 7.33 (dd, J=11.69, 8.16 Hz, 1H) , 7.73 (td, J=8.16, 4.85 Hz, 1H), 7.88 (d, J=6.39 Hz, 1H), 8.16 (s, 2H), 8.50 ( s, 1H), 8.64 (d, J=2.20 Hz, 1H), 8.82 (d, J=2.21 Hz, 1H), 11.22 (s, 1H), 11.83 ( d, J=6.62 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 518.9.

Example 185.

N-(5-Bromo-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 185

To an ice-bath cooled suspension of 6-methyl-5-nitropyridin-2-ol (10 g, 64.9 mmol) in DMF (100 mL) was added portionwise N-bromosuccinimide (13.9 g, 77.9 mmol) under atmosphere N ₂ . The reaction mixture was stirred at 67°C overnight, cooled to 0°C and 500 ml of water was added to the mixture. The resulting solid was collected by filtration to give the product as a yellow solid (9.2 g, 60.9% yield).

B. 3-Bromo-2-chloro-6-methyl-5-nitropyridine, 185b

3-Bromo-6-methyl-5-nitropyridin-2-ol (9.2 g, 36.7 mmol) in POCl ₃ (56.2 g, 366.7 mmol) was stirred at 80°C overnight. The mixture was slowly poured into water (800 ml) and a solid formed. The solid was collected and dried to give the desired product (7.5 g, 81.4% yield).

C. 3-Bromo-6-methyl-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine, 185c

A solution of 3-bromo-2-chloro-6-methyl-5-nitropyridine (7.5 g, 29.83 mmol), 2H-1,2,3-triazole (3.09 g, 44.74 mmol) and carbonate potassium (12.37 g, 89.48 mmol) in acetonitrile (40 ml) was stirred at 40°C overnight. The mixture was filtered and washed with ethyl acetate (30 mlx3). The filtrate was concentrated to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 20/80). The eluent was collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (5 g, 59% yield).

1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (s, 3H), 8.28 (s, 2H), 9.05 (s, 1H).

D. 5-Bromo-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 185d

3-Bromo-6-methyl-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine (4.0 g, 14.1 mmol) was added to the iron mixture (7.86 g , 140.8 mmol), NH ₄ Cl (7.53 g, 140.8 mmol) in THF (20 ml) and water (7 ml). The reaction mixture was stirred at 60°C for 2 hours and filtered. The filtrate was concentrated under reduced pressure to give the crude product as a brown oil which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30:70-80:20). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (2.3 mg, 64.3% yield). LC-MS: (ES, m/z): [M+1]+ 256.0.

E. N-(5-Bromo-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline- 5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 185

To a solution of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (190 mg, 0.58 mmol) and 5-bromo-2- methyl 6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (147 mg, 0.58 mmol) and pyridine (137 mg, 1.74 mmol) in dichloromethane (10 ml) POCl ₃ (106 mg, 0.69 mmol) was added dropwise. Added sat. NaHCO ₃ (10 ml) and the mixture was extracted using CH ₂ Cl ₂ (15 mlx2). The combined organic layers were dried over Na2SO4, filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil. The brown oil was purified by preparative high performance liquid chromatography (35-65% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to yield the product as a white solid (125.5 mg, 38.3 %).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.51 (s, 3H), 5.65 (d, J=7.06 Hz, 1H), 7.27 (dd, J=7 ,28, 5.95 Hz, 1H), 7.65 (t, J=7.94 Hz, 1H), 7.92 (d, J=7.72 Hz, 1H), 8.16 (s, 1H ), 8.15 (s, 1H), 8.41 (d, J=7.72 Hz, 1H), 8.51 (d, J=5.73 Hz, 2H), 10.59 (s, 1H ), 11.62 (br.d., J=5.51 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 561.1.

Example 186.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-cyano-1-(quinolin-5-yl)-1H-pyrazol-4carboxamide , connection 186

A. Ethyl 1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate, 186a

Combine ethyl 4-pyrazolecarboxylate (500 mg, 3.6 mmol), 5bromoquinoline (816 mg, 3.9 mmol), RockPhos G3 catalyst (150 mg, 0.18 mmol), K ₃ PO ₄ ( 1.52 g, 7.1 mmol), and 1,4-dioxane (20 ml). The flask was refluxed and pumped and filled with N2 several times. The reaction mixture was refluxed for 5 hours, cooled and concentrated. The reaction mixture was partitioned between water and CH ₂ Cl ₂ . The aqueous layer was extracted once using CH ₂ Cl ₂ . The combined organic layers were washed once with 1 M NaOH. The organic layers were dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated to give the crude product, which was purified by flash chromatography (cartridge

- 290 045333 g silica gel, gradient 30-70% EtOAc/hexanes). Yield=375 mg (35%). MS (ESI): m/z 268 [M+H]+.

^1H NMR (400 MHz, CDC13) δ ppm 9.00 (dd, J=4.2, 1.6 Hz, 1H), 8.3 (s, 1H), 8.28-8.24 (m, 1H), 8.24 (s, 1H), 7.80 (dd, J=8.6, 7.5 Hz, 1H), 7.62 (dd, J=7.5, 1.0 Hz, 1H), 7.48 (dd, J=8.7, 4.2 Hz, 1H), 4.38 (k, J=7.2 Hz, 2H), 1.40 (t, J=7 ,2 Hz, 3H).

B. Ethyl 5-cyano-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate, 186b

Ethyl 1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate (100 mg, 0.37 mmol) was added to a 4 ml vial and

THF (1 ml). TMPMgCl-LiCl (0.56 mL of 1 M solution in THF/toluene, 0.56 mmol) was added and the reaction mixture was allowed to stir for 1 h at rt. Solid rtoluenesulfonyl cyanide (102 mg, 0.56 mmol) was added in one dose. The reaction mixture was left stirring overnight and subsequently poured into a saturated aqueous NH4Cl solution. The mixture was diluted with water and extracted twice with EtOAc. MeOH was added to dissolve the precipitate and the homogeneous organic layer was dried (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated to obtain the crude product. The crude product was dissolved in warm CH ₂ Cl ₂ and subsequently filtered. The filtrate was both concentrated and further purified by flash chromatography (12 g silica gel cartridge, 5-60% EtOAc/hexanes gradient). Yield=69 mg (63%). MS (ESI): m/z 293 [M+H]+.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.05 (dd, J=4.2, 1.7 Hz, 1H), 8.37 (dd, J=8.6, 1.0, 1.0 Hz, 1H), 8.33 (s, 1H), 7.92-7.87 (m, 1H), 7.88 (dd, J=8.6, 7.5 Hz, 1H), 7.73 (dd, J=7.4, 1.1 Hz, 1H), 7.51 (dd, J=8.6, 4.2 Hz, 1H), 4.46 (k, J=7, 1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).

C. 5-Cyano-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid, 186c

N „IX yv ^ν Α , _1θ6ο

Ethyl 5-cyano-1-(quinolin-5-yl)-1H-pyrazol-4carboxylate (56 mg, 0.19 mmol), ΕϊΟΗΗ ₂ Ο (24 mg, 0.58 mmol) was added to a 15 ml round bottom flask ), THF (2 ml) and water (2 ml). The reaction mixture was left stirring for 30 min at rt. THF was removed under reduced pressure and the remaining aqueous layer was acidified to precipitate acid. The solid product was allowed to dry. Yield=34 mg (67%). MS (ESI): m/z 265 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 13.75 (bs, 1H), 9.06 (ddd, J=3.7, 1.7, 1.7 Hz, 1H), 8, 49 (d, J=1.6 Hz, 1H), 8.41 (bd, J=8.4 Hz, 1H), 8.07 (ddd, J=7.4, 1.5, 1.5 Hz , 1H), 8.03-7.94 (m, 2H), 7.66 (ddd, J=8.6, 4.1, 1.6 Hz, 1H).

D. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-cyano-1-(quinolin-5-yl)-1H-pyrazole -4carboxamide, compound 186

5-Cyano-1-(quinolin-5-yl)-1H-pyrazol-4-carboxylic acid (33 mg, 0.12 mmol), 5-chloro-6-(2H-1, 2,3-triazol-2-yl)pyridin-3-amine (29 mg, 0.15 mmol), pyridine (60 µl, 0.75 mmol) and CH2Cl2 (3 ml). POCl3 (46 µl, 0.5 mmol) was added and the reaction mixture was left to stir overnight. The reaction mixture was concentrated, redissolved in DMSO (2.5 ml) and treated with 1 drop of sat. NaHCO ₃ solution to neutralize the acid. The mixture was purified by reverse phase preparative HPLC (C18 silica gel column, 50x250 mm, gradient 10100% ACN/H2O with 0.05% TFA, 80 ml/min). Yield=21 mg (38%). MS (ESI): m/z 442 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 11.14 (s, 1H), 9.09 (dd, J=4.1, 1.6 Hz, 1H), 8.91 (d, J=2.3 Hz, 1H), 8.81 (s, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.36 (ddd, J=8.4, 1.0 , 1.0 Hz, 1H), 8.20 (s, 2H), 8.10 (dd, J=7.4, 1.3 Hz, 1H), 8.03 (dd, J=8.4, 7.5 Hz, 1H), 8.02-7.97 (m, 1H), 7.70 (dd, J=8.6, 4.2 Hz, 1H).

Example 187.

5-Chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-1H-pyrazol-4carboxamide , connection 187

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A. Ethyl 5-chloro-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate, 187a

This compound was prepared using the procedure for 186b using ethyl 1 (quinolin-5-yl)-1H-pyrazol-4-carboxylate (100 mg, 0.37 mmol), TMPMgCl-LiCl (0.49 mL 1M solution in THF /toluene, 0.49 mmol) and hexachloroethane (133 mg, 0.56 mmol). Purification was carried out by flash chromatography (cartridge with 12 g of silica gel, gradient 5-40% EtOAc/hexanes). Yield=78 mg (69%). MS (ESI): m/z 302 [M+H]+.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.33 (dd, J=8.6, 1.0, 1.0 Hz, 1H), 8.25 (s, 1H), 7.85 (dd, J=8.6, 7.4 Hz, 1H), 7.73 (ddd, J=8.6, 1 ,7, 0.9 Hz, 1H), 7.63 (dd, J=7.4, 1.1 Hz, 1H), 7.46 (dd, J=8.6, 4.2 Hz, 1H) , 4.40 (k, J=7.1 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).

B. 5-Chloro-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid, 187b ^{C| N} 1, 187b

This compound was prepared using the procedure for 186c using ethyl 5chloro-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate (72 mg, 0.24 mmol), ΓϊΟΗΗ ₂ Ο (30 mg, 0.72 mmol), THF (2 ml) and water (2 ml). Yield=48 mg (74%). MS (ESI): m/z 274 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 13.08 (bs, 1H), 9.04 (dd, J=4.2, 1.7 Hz, 1H), 8.32 (s, 1H), 8.30 (dd, J=8.4, 1.1, 1.1 Hz, 1H), 7.97 (dd, J=8.5, 7.4 Hz, 1H), 7.88 (dd, J=7.3, 1.2 Hz, 1H), 7.75-7.70 (m, 1H), 7.63 (dd, J=8.6, 4.2 Hz, 1H).

C. 5-Chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-1H-pyrazole -4carboxamide, compound 187

The title compound was prepared using the procedure for 186d using 5-chloro-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid (41 mg, 0.15 mmol), 5-chloro-6 -(2H1,2,3-triazol-2-yl)pyridin-3-amine (35 mg, 0.18 mmol), pyridine (72 µl, 0.90 mmol), CH2Cl2 (3 ml), and POCl ₃ ( 56 µl, 0.60 mmol). The mixture was purified by reverse phase preparative HPLC (C18 silica gel column, 50x250 mm, gradient 10-100% ACN/H2O with 0.05% TFA, 80 ml/min). Yield=36 mg (53%). MS (ESI): m/z 451 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1H), 9.06 (dd, J=4.2, 1.7 Hz, 1H), 8.90 (d, J=2.3 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H), 8.66 (s, 1H), 8.33 (ddd, J=8.5, 1.1 , 1.1 Hz, 1H), 8.19 (s, 2H), 8.00 (dd, J=8.5, 7.4 Hz, 1H), 7.91 (dd, J=7.4, 1.2 Hz, 1H), 7.78-7.73 (m, 1H), 7.67 (dd, J=8.6, 4.2 Hz, 1H).

Example 188.

-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-1 -(quinolin-5 -yl)-1 H-pyrazol-4carboxamide , connection 188

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A. Ethyl 5-bromo-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate, 188a

This compound was prepared using the procedure for 186b using ethyl 1(quinolin-5-yl)-1H-pyrazole-4-carboxylate (100 mg, 0.37 mmol), TMPMgCl-LiCl (0.49 mL 1M solution in THF /toluene, 0.49 mmol) and 1,2-dibromotetrachloroethane (183 mg, 0.56 mmol). Purification was carried out by flash chromatography (cartridge with 12 g of silica gel, gradient 5-40% EtOAc/hexanes). Yield=69 mg (53%). MS (ESI): m/z 346, 348 [M+H] ⁺ .

1H NMR (400 MHz, CDCl3) δ ppm 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.33 (dd, J=8.6, 1.0, 1 ,0 Hz, 1H), 8.27 (s, 1H), 7.85 (dd, J=8.6, 7.4 Hz, 1H), 7.66 (ddd, J=8.5, 1, 7, 0.9 Hz, 1H), 7.63 (dd, J=7.4, 1.1 Hz, 1H), 7.46 (dd, J=8.6, 4.2 Hz, 1H), 4.41 (k, J=7.1 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).

B. 5-Bromo-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid, 188b

This compound was prepared using the procedure for 186c using ethyl 5-bromo1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate (64 mg, 0.18 mmol), ΕϊΟΗΗ ₂ Ο (23 mg, 0.56 mmol), THF (2 ml) and water (2 ml). Yield=46 mg (78%). MS (ESI): m/z 318, 320 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ ppm 13.00 (bs, 1H), 9.04 (t, J=2.9 Hz, 1H), 8.31 (s, 1H), 8 .30 (dd, J=8.4, 1.1 Hz, 1H), 7.97 (dd, J=8.5, 7.4 Hz, 1H), 7.85 (dd, J=7.4 , 1.2 Hz, 1H), 7.62 (d, J=2.9 Hz, 2H).

C. 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-1H-nirazole -4carboxamide, compound 188

The title compound was prepared using the procedure for 186d using 5-bromo-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid (43 mg, 0.14 mmol), 5-chloro-6 -(2H1,2,3-triazol-2-yl)pyridin-3-amine (32 mg, 0.16 mmol), pyridine (65 µl, 0.81 mmol), CH ₂ Cl ₂ (3 ml) and POCl ₃ (50 µl, 0.54 mmol). The mixture was purified by reverse phase preparative HPLC (C18 silica gel column, 50x250 mm, gradient 10-100% ACN/H2O with 0.05% TFA, 80 ml/min). Yield=40 mg (60%). MS (ESI): m/z 495, 497 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.81 (s, 1H), 9.06 (t, J=2.9 Hz, 1H), 8.90 (d, J=2 ,3 Hz, 1H), 8.69 (d, J=2.3 Hz, 1H), 8.65 (s, 1H), 8.32 (dd, J=8.6, 1.1 Hz, 1H ), 8.19 (s, 2H), 8.00 (dd, J=8.6, 7.4 Hz, 1H), 7.88 (dd, J=8.6, 1.2 Hz, 1H) , 7.66 (d, J=3.0 Hz, 2H).

Example 189.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyridin-3-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 189

A. Di-tert-butyl 1-(imidazo[1,2-a]pyridin-3-yl)hydrazine-1,2-dicarboxylate, 189a

- 293 045333

A mixture of imidazo[1,2-a]pyridine (2.0 g, 16.9 mmol) and di-tert-butyl diazene-1,2-dicarboxylate in

CH3CN (50 ml) was refluxed for 2 days. The solvent was removed and the residue was purified by silica gel column chromatography (eluent: petroleum ether/EtOAc=100:0-0:100).

The desired fraction was collected and the solvent was removed to give the product as a yellow solid (700 mg, 11.2%). LC-MS: (ES, m/z): [M+1]+ 349.0.

B. 3-Hydrazinylimidazo[1,2-a]pyridine, 189b

Di-tert-butyl 1-(imidazo[1,2-a]pyridin-3-yl)hydrazine-1,2-dicarboxylate in 4M HCl in MeOH (30 ml) was stirred at rt for 1 hour. The solvent was removed to give white solid, which was directly used in the next step.

C. Ethyl 1-(imidazo[1,2-a]pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 189c

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (722 mg, 3.0 mmol), 3-hydrazinylimidazo[1,2-a]pyridine (370 mg, 2 .0 mmol) and ethanol (20 ml) were stirred at rt for 2 hours. The resulting solution was concentrated to dryness under reduced pressure, partitioned between EtOAc (30 ml) and aq. NaHCO ₃ (20 ml). The organic layer was separated, washed with water (10 ml), dried over MgSO ₄ , filtered and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-100:0) to give the product as a gray solid (120 mg, 18.3%). LC-MS: (ES, m/z): [M+1]+ 324.9.

D. 1-(Imidazo[1,2-a]pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 189d

Sodium hydroxide (44 mg, 1.1 mmol) was added to a solution of ethyl 1-(imidazo[1,2-a]pyridin-3-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (120 mg, 0 .37 mmol) in EtOH/H ₂ O (1:1.2 ml). The mixture was reacted at 28°C for 2 hours. 10% HCl was added to the mixture to adjust the pH to ~5. The mixture was extracted using ethyl acetate, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to obtain the desired compound (100 mg, 90.5% yield). LC-MS: (ES, m/z): [M+1]+ 297.0.

E. No. (5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 189

1-(Imidazo[1,2-a]pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (67.5 mg, 0.22 mmol), 5-amino-2- (2H-1,2,3-triazol-2-yl)nicotinonitrile (50 mg, 0.27 mmol), pyridine (53.1 mg, 0.67 mmol) were dissolved in CH ₂ Cl ₂ (2 ml) and added phosphorus oxychloride (41.2 mg, 0.27 mmol). The mixture was stirred at 25°C for 3 hours, saturated was added. NaHCO3 (20 ml) and the mixture was extracted using CH ₂ Cl ₂ (20 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (20-50% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (40 mg, 37.6%).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.22-7.33 (m, 1H), 7.68 (br.t., J=7.28 Hz, 1H), 7.84 -7.95 (m, 1H), 8.18-8.40 (m, 4H), 8.76 (s, 1H), 8.90 (s, 1H), 9.14 (br.s, 1H ), 11.63 (s, 1H). LC-MS: (ES, m/z): [M+1]+

- 294 045333

464.9.

Example 190.

N-(5-Ethynyl-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 190

A. 5-Ethynyl-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 190a

Pd(PPh ₃ ) ₄ (109 mg, 0.095 mmol) was added to a solution of 5-bromo-2-methyl-6-(2H-1,2,3-triazol-2yl)pyridin-3-amine (200 mg, 0. 79 mmol), trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethynyl)silane (338 mg, 1.73 mmol), K3PO4 (109 mg, 0.095 mmol) in THF (8 ml) at 90°C with N2 bubbling for 12 hours. The reaction mixture was filtered through a pad of diatomaceous earth and washed with EtOAc (10 ml x 2). The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate=40:60). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a brown oil (20 mg, 12.8% yield). LC-MS: (ES, m/z): [M+1]+ 200.2.

B. N-(5-Ethynyl-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline5- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 190

To a solution of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (24.3 mg, 0.075 mmol) and 5-ethynyl-2- methyl 6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (15 mg, 0.075 mmol) and pyridine (17.9 mg, 0.23 mmol) in dichloromethane (2 ml) POCl ₃ (13.9 mg, 0.090 mmol) was added dropwise. Added sat. NaHCO ₃ (5 ml) and the mixture was extracted using CH ₂ Cl ₂ (10 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil, which was purified by preparative high performance liquid chromatography (26-56% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to give the product as a white solid (14.8 mg, 38.5%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.56 (s, 3H), 4.43 (s, 1H), 5.67 (br.d., J=6.84 Hz, 1H), 7.28 (br.s., 1H), 7.66 (br.t., J=7.83 Hz, 1H), 7.92 (br.d., J=7.06 Hz, 1H ), 8.14 (s, 2H), 8.30 (s, 1H), 8.42 (br.d., J=7.94 Hz, 1H), 8.51 (s, 1H), 10, 55 (s, 1H), 11.61 (br.d., J=4.41 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 505.0.

Example 191.

N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(isoquinolin-4-yl)-5 -(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 191

A. 1-(Isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 191a

- 295 045333

A mixture of ethyl 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (750 mg, 2.24 mmol) in conc. HCl (12 M, 25 ml) was stirred at 130°C for 2 hours. The solvent was removed under reduced pressure to give the crude product as a yellow solid (700 mg, 95.5%), which was used directly in the next step. LCMS (ESI) m/z M+1: 307.8.

B. N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 191

POCl ₃ (112.3 mg, 0.732 mmol) was added to a mixture of 1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxylic acid (120 mg, 0.37 mmol), 5-chloro- 2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin3-amine (76.77 mg, 0.37 mmol), pyridine (144.83 mg, 1.83 mmol) in CH ₂ Cl ₂ (5 ml) at rt. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with 10 ml of sat. K2CO3 aq. and the mixture was extracted using CH ₂ Cl ₂ (20 mlx3). The organic layer was separated and concentrated under reduced pressure. The product was purified by preparative high performance liquid chromatography (40-70% (v/v) CH3CN and H2O with 0.05% HCl). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the desired product as a pale yellow solid (55 mg, purity: 99.145%, yield: 29.85%). LCMS (ESI) m/z M+1: 498.9.

¹ H NMR (400 MHz, chloroform-d) δ ppm 2.59 (s, 3H), 7.31 (d, J=8.60 Hz, 1H), 7.61 (s, 1H), 7.68-7.79 (m, 2H), 7.88 (s, 2H), 8.11 (d, J=7.72 Hz, 1H), 8.24 (s, 1H), 8.58 (s, 1H), 8.90 (s, 1H), 9.39 (s, 1H).

Example 192.

X-(5-Chloro-6-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol4- carboxamide, compound 192

A. X-(5-Chloro-6-(hydrazinecarbonyl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamide, 192a

Methyl 3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)picolinate (120 mg, 0.25 mmol) and hydrazine monohydride (25.3 mg, 0.50 mmol) in ethanol (1 ml) was stirred at 80°C overnight. The mixture was concentrated to give the crude product (120 mg), which was used directly in the next step.

B. N-(5-Chloro-6-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 192

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Mixture

N-(5-chloro-6-(hydrazinecarbonyl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide (100 mg, 0.21 mmol), triethoxymethane (105 μl, 0.63 mmol) and acetic acid (6.3 μl, 0.11 mmol) in toluene (2 ml) were stirred at 100°C for 4 hours. The mixture was concentrated to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (30-60% (v/v) CH3CN and H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a white solid (45 mg, 43% yield).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.57-7.62 (m, 1H), 7.64-7.69 (m, 1H), 7.89-7.99 (m , 2H), 8.32 (d, J=8.38 Hz, 1H), 8.57 (s, 1H), 8.62 (d, J=1.98 Hz, 1H), 8.99 (d , J=1.98 Hz, 1H), 9.04 (dd, J=4.08, 1.65 Hz, 1H), 9.45 (s, 1H). LCMS (ESI) m/z M+1: 485.9.

Example 193.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-ul)-1-(imidazo[1,2-a]pyridin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 193

A. Ethyl 1-(6-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 193 a

A solution of 2-bromo-6-hydrazinopyridine (3.0 g, 16.0 mmol) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3oxobutanoate (5.75 g, 23.9 mmol) in EtOH ( 150 ml) was stirred at 80°C overnight and subsequently cooled to rt. The solvent was removed under reduced pressure to give a yellow oil. The yellow oil was purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 100/0 - petroleum ether/EtOAc 80/20). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the desired product as a yellow solid (5.7 g, yield: 98.1%).

B. Ethyl 1-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, 193b

Pd(OAc) ₂ (93.3 mg, 0.415 mmol) and Xantphos (238 mg, 0.412 mmol) in dioxane (75 ml) were stirred at rt for 10 min under a nitrogen atmosphere. Subsequently, ethyl 1-(6-bromopyridin-2-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (3.0 g, 8.24 mmol), C ₂ CO ₃ (8.05 g, 24 .7 mmol) and tert-butyl carbamate (1.16 g, 9.89 mmol) at room temperature. The reaction mixture was subsequently allowed to warm at 90°C overnight and then cooled to rt. The reaction mixture was filtered through a layer of diatomaceous earth. The filtrate was concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 100/0 - petroleum ether/EtOAc 80/20). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the desired product as a white solid (3.09 g, yield: 93.7%).

C. 1-(6-((T-butoxycarbonyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 193 s

A mixture of ethyl 1-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate and LiOH H ₂ O (628 mg, 15.0 mmol) in THF /MeOH/H ₂ O (1:1:1, 60 ml) was stirred at rt for 2 hours. The organic solvent was removed under reduced pressure. 2N HCl was added to adjust the pH of the mixture to 4~5, subsequently extracted using EtOAc (50 mlx3). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give the crude product as a white solid (1.8 g,

- 297 045333 yield: 96.8%).

D. tert-Butyl (6-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)1H -pyrazol-1-yl)pyridin-2-yl)carbamate, 193 d

POCl ₃ (824 mg, 5.37 mmol) was added to a mixture of 1-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1 g , 2.69 mmol), 5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-amine (525 mg, 2.69 mmol), pyridine (1.06 g, 13. 4 mmol) in CH ₂ Cl ₂ (30 ml) at rt. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was slowly quenched with 30 ml of sat. K ₂ CO ₃ aq. and extracted using CH ₂ Cl ₂ (50 mlx3). The organic layer was separated and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 100/0 - petroleum ether/EtOAc 0/100). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the desired product as a brown solid (850 mg, purity: 98.4%, yield: 70.8%). LCMS (ESI) m/z M+1: 450.0 (M-100).

E. 1-(6-Aminopyridin-2-yl)-N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide, 193e

A solution of tert-butyl (6-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1H-pyrazole -1-yl)pyridin-2-yl)carbamate α (1.76 g, 3.20 mmol) in HCl/MeOH (4M, 50 ml) was stirred at rt for 2 hours. The solvent was removed under reduced pressure to give the crude product in the form of a red solid. The red solid was purified by preparative high performance liquid chromatography (15-55% (v/v) CH3CN and _H2O with 0.1% TFA). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. Added sat. Added aq. K ₂ CO ₃ to adjust pH to ~12, subsequently extracted using EtOAc (50 mlx2). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the desired product as a yellow solid (1.4 g, purity: 97.2%, yield: 94.6%). LCMS (ESI) m/z M+1: 449.9.

1H NMR (400 MHz, chloroform-d) δ ppm 4.57 (br.s, 2H), 6.54 (d, J=8.16 Hz, 1H), 6.90 (d, J= 7.72 Hz, 1H), 7.57 (t, J=8.05 Hz, 1H), 7.81 (s, 1H), 7.87 (s, 2H), 7.977 (s, 1H), 8 .42 (d, J=2.21 Hz, 1H), 8.68 (d, J=2, 43 Hz, 1H).

F. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 193

-(6-Aminopyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-1 Hpyrazole -4-carboxamide (1.48 g, 2.70 mmol, 97.2% purity) was taken into i-PrOH (40 ml) under N ₂ atmosphere. Bromoacetaldehyde diethyl acetal (1.07 g, 5.41 mmol) was added to the suspension, followed by aq. HBr (48%, 2.5 ml). The reaction mixture was stirred at 90°C overnight and cooled to rt. The solvent was removed under reduced pressure and subsequently purified by preparative high performance liquid chromatography (30-60% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the desired product as an off-white solid (290 mg, purity: 96.7%, yield: 21.9%). LCMS (ESI) m/z M+1: 473.9.

¹ H NMR (400 MHz, chloroform-d) δ ppm 7.01 (d, J=7.06 Hz, 1H), 7.08 (s, 1H), 7.37 (dd, J=9 .04, 7.28 Hz, 1H), 7.63 (d, J=1.10 Hz, 1H), 7.81 (d, J=9.04 Hz, 1H), 7.96 (s, 2H ), 8.30 (s, 1H), 8.67 (d, J=2.21 Hz, 1H), 8.83 (d, J=2.43 Hz, 1H), 9.48 (s, 1H ).

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Example 194.

N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyridin-5- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 194

A. 5-Hydrazinylimidazo[1,2-a]pyridine, 194a

A mixture of {Pd(cinnamyl)Cl} ₂ (131 mg, 0.254 mmol) and Mor-DalPhos (235 mg, 0.508 mmol) in dioxane (100 ml) was deaerated using argon (4x). The resulting clear yellow solution was stirred at room. temp, in argon atmosphere for 10 min. 5bromimidazo[1,2-a]pyridine (1 g, 5.08 mmol) and t-BuONa (975 mg, 10.2 mmol) was added to the mixture and the mixture was deaerated using argon (4x). The resulting yellow reaction mixture was stirred at room. temp, for 5 min and subsequently treated with NH2NH2-H2O (98%, 504 μL, 10.2 mmol) via syringe. The reaction mixture was deaerated using argon (4x). Subsequently, the mixture was stirred at 50° C. under argon for 2 hours. The mixture was filtered through a pad of diatomaceous earth and washed with ethyl acetate/MeOH (v/v 20/1, 100 ml). The filtrate was collected and concentrated to give the crude product as a brown solid (750 mg, crude). This substance was directly used in the next step.

B. Ethyl 1-(imidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 194b

A solution of 5-hydrazinylimidazo[1,2-a]pyridine (750 mg crude, 5.06 mmol) and ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (1.82 g, 7.59 mmol) in EtOH (50 ml) was stirred at 80°C for 1 h and subsequently cooled to rt. The solvent was removed under reduced pressure to obtain a black oil. The product was purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 100/0 - petroleum ether/EtOAc 20/80). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the desired product as a brown solid (850 mg, purity: 98.0%, yield: 50.7%). LCMS (ESI) m/z M+1: 325.1.

C. 1-(Imidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 194c

A mixture of ethyl 1-(imidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1.2 g, 3.70 mmol) in conc. HCl (12M, 25 ml) was stirred at 130°C for 2 hours. The solvent was concentrated under reduced pressure to give the crude product as a dark yellow solid (1.1 g, purity: 96.5%, yield: 96.8 %). LCMS (ESI) m/z M+1: 296.9.

D. 5-Chloro-2-methyl-3-nitropyridine 1-oxide, 194d

A mixture of 5-chloro-2-methyl-3-nitropyridine (3.0 g, 17.4 mmol) and mCPBA (85%, 7.06 g, 34.8 mmol) in CH ₂ Cl ₂ (60 ml) was stirred at ct for 72 hours. The reaction mixture was quenched using 60 ml of sat. aq. Na ₂ SO ₃ . Added sat. aq. K2CO3 to adjust pH 9 ~ 10 and extracted the mixture using CH ₂ Cl ₂ (100 mlx3). The organic layer was separated, dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated to give a yellow solid. The solid was purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 100/0 - 299 045333 petroleum ether/EtOAc 0/100). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the desired product as a yellow solid (2.4 g, yield: 73.2%).

¹ H NMR (400 MHz, chloroform-d) δ ppm 2.65 (s, 3H), 7.71 (d, J=1.54 Hz, 1H), 8.46 (d, J=1 ,54 Hz,

1H).

E. 2,3-Dichloro-6-methyl-5-nitropyridine, 194e ° ² Un CJci

Cl, 194e

POCl ₃ (24.9 ml, 267 mmol) was added to a mixture of 5-chloro-2-methyl-3-nitropyridine 1-oxide (2.4 g, 12.7 mmol) in CHCl ₃ (80 ml). The reaction mixture was stirred under reflux for 6 hours. The reaction mixture was cooled to rt, then slowly added to 200 ml of sat. aq. K2CO3 and extracted using CH ₂ Cl ₂ (200 mlx3). The organic layer was separated, dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated to give a brown solid. The solid was purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 100/0 - petroleum ether/EtOAc 80/20). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the desired product as a yellow solid (1.1 g, yield: 41.8%).

^1H NMR (400 MHz, chloroform-d) δ ppm 2.86 (s, 3H), 8.43 (s, 1H).

F. 3-Chloro-6-methyl-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine, 194f ^2” Cl, 194f

1H-1,2,3-Triazole (550 mg, 7.97 mmol) was added to a solution of 2,3-dichloro-6-methyl-5-nitropyridine (1.1 g, 5.31 mol) and K2CO3 (2, 20 g, 15.9 mmol) in CH3CN (60 ml). The mixture was stirred at 40°C for 2 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the layer was washed using EtOAc (50 mlx3). The filtrate was concentrated under reduced pressure to obtain the crude product as a black solid (1.2 g, yield: 94.2%).

G. 5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 194g, _194d

Mixture of 3-chloro-6-methyl-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine (crude 1.2 g), iron powder (1.40 g, 25, 0 mmol) and NH ₄ Cl (1.34 g, 25.0 mmol) in MeOH/THF/H ₂ O (1:1:1, 60 ml) was stirred at 70°C for 2 hours. The reaction mixture was filtered through layer of diatomaceous earth and washed the layer using EtOAc (50 mlx2). The filtrate was washed with 50 ml sat. aq. K2CO3 and separated. The organic layer was dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated to give a brown solid. The solid was purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 100/0 - petroleum ether/EtOAc 0/100). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the desired product as a yellow solid.

¹ H NMR (400 MHz, chloroform-d) δ ppm 2.44 (s, 3H), 3.97 (br.s, 2H), 7.13 (s, 1H), 7.88 (s , 2H).

H. N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2a]pyridin-5- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 194

POCl ₃ (0.364 ml, 3.91 mmol) was added to a mixture of 1-(imidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxylic acid (600 mg, 1 .96 mmol, 96.5% purity), 5-chloro-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine (410 mg, 1.96 mmol), pyridine (0.786 ml, 9.77 mmol) in CH ₂ Cl ₂ (20 ml) at rt. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched using 30 ml of sat. aq. K ₂ CO ₃ and extracted the mixture using CH ₂ Cl ₂ (50 mlx3). The organic layer was separated and concentrated under reduced pressure. The product was purified by preparative high performance liquid chromatography (30-60% (v/v) CH3CN and H2O with 0.05%

- 300 045333 ammonium hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the desired product as a pale yellow solid (435 mg, purity: 100%, yield: 45.6%). LCMS (ESI) m/z M+1:

487.9.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.54 (s, 3H), 7.35-7.44 (m, 2H), 7.48 (dd, J=9.04, 7.28 Hz, 1H), 7.72 (d, J=1.10 Hz, 1H), 7.90 (d, J=9.04 Hz, 1H), 8.17 (s, 2H), 8 .43 (s, 1H), 8.68 (s, 1H).

Example 195.

N-(5-Chloro-2-ethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyridin-5- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 195

A. 2-Bromo-5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 195a No.=\

ΥγΜ h ₂ nU _ci , _195a

NBS (2.73 g, 15.3 mmol) was added to a mixture of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (3 g, 15.3 mmol) in CH3CN (300 ml) at 0°C, the mixture was subsequently stirred at rt for 1 hour. The reaction mixture was quenched using 100 ml of sat. aq. NaHCO ₃ and subsequently extracted using EtOAc (100 mlx3). The organic layer was combined, washed with 50 ml sat. aq. NaCl, dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain a brown sticky residue. The residue was concentrated and purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 100/0 - petroleum ether/EtOAc 50/50). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the product as a yellow solid (4.00 g, yield: 95.0%).

B. 5-Chloro-2-ethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 195b ζγγ-,ί n^A'a _195b

A mixture of ZnEt ₂ / toluene (1 M, 0.546 ml, 0.546 mmol) and Pd(dppf)Cl ₂ (40.0 mg, 0.055 mmol) under N2 atmosphere. The reaction mixture was stirred at 90°C for 1.5 hours. The reaction mixture was quenched using 10 ml of sat. aq. NaHCO ₃ , the mixture was subsequently filtered through a pad of diatomaceous earth and washed with 20 ml EtOAc. The filtrate was extracted using EtOAc (20 mlx2). The organic layer was separated, dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated to give a brown residue. The residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 50/50). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the product as a yellow solid (70 mg, yield: 86%).

¹ H NMR (400 MHz, chloroform-d) δ ppm 1.29 (t, J=7.61 Hz, 3H), 2.71 (k, J=7.50 Hz, 2H), 3, 96 (br.s, 2H), 7.10 (s, 1H), 7.87 (s, 2H).

C. N-(5-Chloro-2-ethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyridin- 5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 195

POCl ₃ (0.58 ml, 0.626 mmol) was added to a mixture of 1-(imidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxylic acid (96.1 mg , 0.313 mmol, 96.5% purity), 5-chloro-2-ethyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine (70 mg, 0.313 mmol), pyridine (124 mg, 1.57 mmol) in CH ₂ Cl ₂ (5 ml) at rt. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched using 20 ml of sat. aq. K ₂ CO ₃ and extracted using CH ₂ Cl ₂ (20 mlx3). The organic layer was separated and concentrated under reduced pressure. The product was purified by preparative high performance liquid chromatography (35-65% (v/v) CH ₃ CN and H ₂ O with 0.05%

- 301 045333 ammonium hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the desired product as an off-white solid (95 mg, purity: 99%, yield: 60%). LCMS (ESI) m/z M+1: 501.9.

^1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.23 (m, 3H), 2.81-2.93 (m, 2H), 7.38 (s, 2H) , 7.48 (t, J=8.20 Hz, 1H), 7.72 (s, 1H), 7.89 (d, J=8.20 Hz, 1H), 8.17 (s, 2H) , 8.40 (s, 1H), 8.65 (s, 1H), 9.83 (s, 1H).

Example 196.

N-(2,5-Diethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 196

A. 2,5-Diethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 196a

^{Р1 Р2} , 196а

A mixture of ZnEt ₂ / toluene (1 M, 2.55 ml, 2.55 mmol) and Pd(dppf)Cl ₂ (80.0 mg, 0.109 mmol) under N2 atmosphere. The reaction mixture was stirred overnight at 110°C. LCMS analysis showed the formation of 45.4% P2 in the reaction mixture and only traces of formed P1. The reaction mixture was quenched using 10 ml sat. aq. NH ₄ Cl, filtered through a pad of diatomaceous earth and washed with 30 ml EtOAc. The filtrate was washed with 20 ml sat. aq. NaHCO ₃ , the organic layer was subsequently separated, dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated to give a sticky brown residue. The residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to give the product as a sticky yellow residue (crude 125 mg). Displayed 1H NMR ~ 10% 5-chloro-2ethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine.

Ή NMR (400 MHz, chloroform-d) δ ppm 1.04 (t, J=7.61 Hz, 3H), 1.26-1.31 (m, 3H), 2.48 (k, J=7.64 Hz, 2H), 2.68-2.77 (m, 2H), 3.81 (br.s, 2H), 6.93 (s, 1H), 7.82 (s, 2H ).

B. N-(2,5-Diethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyridin-5- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 196

POCl ₃ (0.103 ml, 1.11 mmol) was added to a mixture of 1-(imidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxylic acid (170 mg, 0.552 mmol), 2,5-diethyl-6-(2H-1,2,3-triazol-2-yl)pyridin3-amine (crude 120 mg), pyridine (218 mg, 2.76 mmol) in CH2Cl2 (5 ml) at CT. The reaction mixture was stirred at rt for 1 hour. The reaction mixture was quenched using 20 ml of sat. aq. K2CO3 and extracted using CH ₂ Cl ₂ (20 mlx3). The organic layer was separated and concentrated under reduced pressure. The product was purified by preparative high performance liquid chromatography (35-65% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the desired product as a pale yellow solid, which was further purified by SFC (column: Chiralcel OJ 250x30 5u; conditions: 0.1% NH3H2O MEON, flow rate (ml/min) 65). The pure fractions were collected and the organic solvent was concentrated under reduced pressure, subsequently lyophilized to dryness to obtain the desired product as a white solid (105 mg, purity: 100%, yield: 38.8%). LCMS (ESI) m/z M+1: 496.0.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.99 (t, J=7.61 Hz, 3H), 1.19 (t, J=7.50 Hz, 3H), 2 ,50-2.55 (m, 2H), 2.83 (k, J=7.50 Hz, 2H), 7.40 (d, J=7.28 Hz, 2H), 7.44-7, 53 (m, 1H), 7.72 (d, J=1.10 Hz, 1H), 7.90 (dd, J=9.04, 0.88 Hz, 1H), 8.00 (s, 1H ), 8.12 (s, 2H), 8.66 (s, 1H), 10.52 (s, 1H).

- 302 045333

Example 197.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrazolo[1,5-a]pyridin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 197

A. 4-Hydrazinylpyrazolo[1,5-a]pyridine, 197a

A mixture of {Pd(cinnamyl)Cl} ₂ (131 mg, 0.254 mmol) and Mor-DalPhos (235 mg, 0.508 mmol) in dioxane (100 ml) was deaerated using argon (4x). The resulting clear yellow solution was stirred at rt under argon for 10 min. 4bromopyrazolo[1,5-a]pyridine (1.00 g, 5.08 mmol) and t-BuONa (975 mg, 10.2 mmol) were added to the mixture and the mixture was deaerated using argon (4x). The resulting yellow reaction mixture was stirred at rt for 5 min and subsequently treated with NH2NH2-H2O (98%, 0.502 mL, 10.2 mmol) via syringe. The reaction mixture was deaerated using argon (4x). Subsequently, the mixture was stirred at 50° C. under argon for 3 hours. The mixture was filtered through a pad of diatomaceous earth and washed with ethyl acetate (200 ml). The filtrate was collected and concentrated to give the crude product as a dark yellow solid (750 mg). It was directly used in the next stage.

B. Ethyl 1-(pyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 197b

A solution of 4-hydrazinylpyrazolo[1,5-a]pyridine (750 mg crude) and ethyl 2-(ethoxymethylene)-4,4,4trifluoro-3-oxobutanoate (1.84 g, 7.59 mmol) in EtOH (100 ml) was stirred at 80°C for 1 hour, subsequently cooled to rt. The solvent was removed under reduced pressure to obtain the crude product as a brown solid. The solid was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 50/50). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to give the product as a yellow solid (1.11 g, 67.4% yield in two steps). LCMS (ESI) m/z M+1: 324.9.

C. 1-(Pyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 197c

A mixture of ethyl 1-(pyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (650 mg, 1.96 mmol) in conc. HCl (12 M, 50 ml) was stirred at 130°C for 1 hour. The solvent was removed under reduced pressure to give the crude product as a pale yellow solid (600 mg, purity: 98.8%, quantitative yield). LCMS (ESI) m/z M+1: 296.9.

D. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrazolo[1,5-a]pyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 197

POCl ₃ (0.0755 ml, 0.81 mmol) was added to a mixture of 1-(pyrazolo[1,5-a]pyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (120 mg , 0.405 mmol), 5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-amine (79.2 mg, 0.405 mmol), pyridine (160 mg, 2.03 mmol) in CH ₂ Cl ₂ (5 ml) at rt. Reak

- 303 045333 the reaction mixture was stirred at rt for 1 hour. The reaction mixture was quenched using 20 ml of sat. aq. K ₂ CO ₃ and extracted using CH ₂ Cl ₂ (20 mlx3). The organic layer was separated and concentrated under reduced pressure. The product was purified by preparative high performance liquid chromatography (40-70% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the desired product as a yellow solid (80 mg, purity: 97%, yield: 40%). LCMS (ESI) m/z M+1: 473.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 6.34 (dd, J=2.43, 0.88 Hz, 1H), 7.08 (t, J=7.28 Hz, 1H) , 7.58 (d, J=7.28 Hz, 1H), 8.13 (d, J=2.43 Hz, 1H), 8.17 (s, 2H), 8.55 (s, 1H) , 8.64 (d, J=2.43 Hz, 1H), 8.83 (d, J=2.21 Hz, 1H), 8.96 (d, J=7.06 Hz, 1H).

Example 198.

N-(5 -Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(pyrazolo [1,5-a]pyridin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 198

POCl ₃ (0.076 ml, 0.81 mmol) was added dropwise to a solution of 1-(pyrazolo[1,5-a]pyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (120 mg , 0.405 mmol), 5-chloro-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine (0.085 g, 0.405 mmol) and pyridine (0.164 ml, 2.03 mmol ) in CH ₂ Cl ₂ (5 ml). The reaction mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the mixture. The aqueous layer was extracted with CH2Cl2 (10 mlx3). The separated organic layer was dried (Na ₂ SO ₄ ), filtered and the solvent was concentrated to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (35-65% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the desired product as a white solid (89.2 mg, purity: 98.4%, yield: 44.4%). LCMS (ESI) m/z M+1: 487.9.

^1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H) 6.36 (dd, J=2.43, 0.88 Hz, 1H) 7.08 (t, J =7.17 Hz, 1H) 7.54-7.58 (m, 1H) 8.13 (d, J=2.43 Hz, 1H) 8.17 (s, 2H) 8.43 (s, 1H ) 8.52 (s, 1H) 8.96 (d, J=7.06 Hz, 1H).

Example 199.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylimidazo[1,2-a]pyridin-5-yl) -5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 199

A. 5-Hydrazinyl-2-methylimidazo[1,2-a]pyridine, 199a

A mixture of {Pd(cinnamyl)Cl} ₂ (49.1 mg, 0.095 mmol) and Mor-DalPhos (87.9 mg, 0.19 mmol) in dioxane (40 ml) was deaerated using argon (4x). The resulting clear yellow solution was stirred at room temperature under argon for 10 minutes. 5-Bromo-2-methylimidazo[1,2-a]pyridine (400 mg, 1.9 mmol) and t-BuONa (364.3 mg, 3.79 mmol) were added to the mixture and the mixture was deaerated using argon (4x). The resulting yellow reaction mixture was stirred at rt for 5 min and subsequently treated with NH ₂ NH ₂ -H ₂ O (0.188 ml, 3.79 mmol) via syringe. The reaction mixture was deaerated using argon (4x). Subsequently, the mixture was stirred at 50°C under argon for 2 hours. The mixture was filtered through a pad of diatomaceous earth and washed with ethyl acetate (50 ml). The filtrate was collected and concentrated to give the crude product as a yellow residue (250 mg crude), which was directly used in the next step.

- 304 045333

B. Ethyl 1-(2-methylimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 199b

A solution of 5-hydrazinyl-2-methylimidazo[1,2-a]pyridine (250 mg crude, 1.54 mmol) and ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (555.3 mg , 2.31 mmol) in EtOH (30 ml) was stirred at 80°C for 1 hour, subsequently cooled to rt. The solvent was removed under reduced pressure to obtain the crude product as a dark brown residue. The residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 100/0 - petroleum ether/EtOAc 0/100). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to give the product as a black oil, which was further purified by preparative high performance liquid chromatography (40-70% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide ). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the desired product as a yellow solid (100 mg, yield: 19.2%).

C. 1-(2-Methylimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 199c

F

Vf o b ^N '

I, 199s

A mixture of ethyl 1 -(2-methylimidazo[1,2-a]pyridin-5-yl)-5 -(trifluoromethyl)-1 H-pyrazole-4-carboxylate (100 mg, 0.30 mmol) in conc. HCl (12 M, 5 ml) was stirred at 130°C for 1 hour. The solvent was removed under reduced pressure to give the crude product as a pale yellow solid (100 mg crude, purity: 100%), which was used directly at the next stage. LCMS (ESI) m/z M+1: 310.9.

D. No. (5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylimidazo[1,2-a]pyridin-5-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 199

POCl ₃ (98.9 mg, 0.65 mmol) was added to a mixture of 1-(2-methylimidazo[1,2-a]pyridin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ( 100 mg, 0.32 mmol, 100% purity), 5-chloro-6-(2H1,2,3-triazol-2-yl)pyridin-3-amine (63.05 mg, 0.32 mol) and pyridine (127.49 mg, 1.61 mmol) in CH ₂ Cl ₂ (3 ml) at rt. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched using 20 ml of sat. aq. K ₂ CO ₃ and extracted using CH ₂ Cl ₂ (20 mlx3). The organic layer was separated and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography (40-70% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the desired product as a pale yellow solid (65 mg, purity: 99.7%, yield: 41.2%). LCMS (ESI) m/z M+1: 488.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.32 (s, 3H), 7.10 (s, 1H), 7.33 (dd, J=7.17, 0.99 Hz, 1H), 7.397.44 (m, 1H), 7.74-7.78 (m, 1H), 8.17 (s, 2H), 8.65 (d, J=2.21 Hz, 1H ), 8.68 (s, 1H), 8.83 (d, J=2.43 Hz, 1H), 11.27 (br.s, 1H).

Example 200.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(imidazo[1,2-a]pyridin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 200

- 305 045333

POCl ₃ (82.83 mg, 0.54 mmol) was added to a mixture of 1-(imidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxylic acid (80 mg , 0.27 mmol), 5-amino-2-(2H-1,2,3-triazol-2yl)nicotinonitrile (50.28 mg, 0.27 mmol) and pyridine (106.82 mg, 1.35 mmol ) in CH2Cl2 (2 ml). The reaction mixture was stirred at 20°C for 1 hour. Saturated solution was added to the mixture. NaHCO ₃ solution (20 ml). The mixture was extracted using 30 ml of ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified by preparative high performance liquid chromatography (26-56% (v/v) CH ₃ CN and H ₂ O with 0.05% ammonium hydroxide). The pure fractions were collected and the solvent was concentrated under reduced pressure. The aqueous layer was concentrated to dryness to obtain the product as a light yellow solid (45.6 mg, purity: 99.9%, yield: 36.3%). LCMS (ESI) m/z M+1: 465.0.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.38-7.52 (m, 3H), 7.71 (d, J=1.1 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H), 8.30 (s, 2H), 8.75 (s, 1H), 8.89 (d, J=2.4 Hz, 1H), 9.11 (d, J=2.4 Hz, 1H), 11.27 (br.s, 1H).

Example 201.

Ν-(5-Χλορ-6-(2Η-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-chloroimidazo[1,2-a]pyridin-5-yl) -5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 201

To a stirred solution of N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2a]pyridin-5-yl)- 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (70 mg, 0.15 mmol) in MeCN (2 ml) was added NCS (39.46 mg, 0.30 mmol). The mixture was stirred at 60°C for 4 hours. The mixture was purified by preparative high performance liquid chromatography (40-70% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the product as a light yellow solid (65.6 mg, purity: 98.5%, yield: 86.0%). The structure was originally designated as such; NMR does not distinguish the Cl atom at the 2 and 3 positions of imidazopyridine. LCMS (ESI) m/z M+1: 507.9.

^1H NMR (400 MHz, DMSO-d6) δ ppm 6.10 (br.s, 1H), 7.51-7.63 (m, 2H), 7.85 (s, 1H), 8 .00 (dd, J=1.3, 8.8 Hz, 1H), 8.19 (s, 2H), 8.62 (s, 1H), 8.69 (d, J=2.3 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H).

Example 202.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluorimidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 202

A. 3,6-Difluoro-2-hydrazinylpyridine, 202a

Hydrazine hydrate (3.071 g, 60.12 mmol) was added to an ice-cold solution of 2,3,6-trifluoropyridine (4 g, 30.06 mmol) in EtOH (50 mL). The reaction mixture was warmed to rt and subsequently refluxed for 2 hours. Then cooled to rt, the reaction mixture was diluted with water (50 ml) and extracted with CH ₂ Cl ₂ (2x100 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from EtOH to give the product as a light yellow solid (3 g, yield:

68.8%).

B. 2-Bromo-3,6-difluoropyridine, 202b

Br ₂ (2.13 ml, 41.35 mmol) was added dropwise to a stirred solution of 3,6-difluoro-2hydrazinylpyridine (3 g, 20.67 mmol) in CHCl ₃ (45 ml) at room temperature. The mixture was stirred at 60°C for 1 hour. The mixture was cooled at 0°C and saturated NaHCO ₃ solution (200 ml) was added dropwise. CH ₂ Cl ₂ (200 ml) was added, the organic layer was separated, dried (Na ₂ SO ₄ ), filtered and the solvents were concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (petroleum ether: EtOAc=1:0 ~ 9:1) to give the product as a yellow oil (1.7 g, yield: 42.4%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 6.92 (td, J=3.1, 8.7 Hz, 1H), 7.55 (td, J=6.2, 8, 6 Hz, 1H).

C. 2-Bromo-3-fluoro-6-hydrazinylpyridine, 202c

2-Bromo-3,6-difluoropyridine (2.7 g, 13.92 mmol) was dissolved in MeCN (50 ml) and hydrazine hydrate (1.422 g, 27.84 mmol) was added. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product as a yellow solid (2.868 g, yield: 100%).

D. Ethyl 1-(6-bromo-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 202d

2-Bromo-3-fluoro-6-hydrazinylpyridine (2.8 g, 13.59 mmol) was dissolved in EtOH (60 ml), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate ( 6.529 g, 27.18 mmol) and stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 80/20). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the compound as a yellow solid (2 g, yield: 38.5%).

Ή NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.41 (m, 3H), 4.37-4.41 (m, 2H), 7.63-7.67 (m , 2H), 8.11 (s, 1H).

E. Ethyl 1 -(6-((tert-butoxycarbonyl)amino)-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, 202e

Pd(OAc) ₂ (58.755 mg, 0.26 mmol) and Xantphos (151.428 mg, 0.26 mmol) in dioxane (50 ml) were stirred at rt for 10 min under a nitrogen atmosphere. Subsequently, ethyl 1-(6-bromo-5fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2 g, 5.23 mmol), C ₂ CO ₃ (5.116 g, 15. 70 mmol) and tert-butyl carbamate (0.736 g, 6.28 mmol) at room temperature. The reaction mixture was subsequently left to warm at 90°C overnight and then cooled to rt. The reaction mixture was filtered through a layer of diatomaceous earth. The filtrate was concentrated under reduced pressure and subsequently purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 100/0 - petroleum ether/EtOAc 80/20). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the desired product as a yellow solid (1800 mg, yield: 82.2%).

F. 1-(6-((T-butoxycarbonyl)amino)-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylic acid, 202f

BocHN '202f

To a mixture of ethyl 1-(6-((tert-butoxycarbonyl)amino)-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxylate (1800 mg, 4.30 mmol) in MeOH (15 ml) and H ₂ O (15 ml), LiOH·H ₂ O (361.11 mg, 8.61 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was concentrated

- 307 045333 dry. Water/EtOAc (100 ml/100 ml) was added to the residue. The pH of the mixture was adjusted to ~5 with HCl (1M in water). The organic layer was concentrated to dryness to give product (1500 mg, yield:

89.3%) in the form of a yellow solid.

G. tert-Butyl (6-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)1H- pyrazol-1-yl)-3-fluoropyridin-2-yl)carbamate, 202g

POCl ₃ (1178.60 mg, 7.69 mmol) was added to a mixture of 1-(6-((tert-butoxycarbonyl)amino)-5fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1500 mg, 3.84 mmol), 5-chloro6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (751.78 mg, 3.84 mmol) and pyridine (1520 .0 mg, 19.22 mmol) in CH ₂ Cl ₂ (30 ml). The reaction mixture was stirred at 20°C for 1 hour. Saturated solution was added to the mixture. K ₂ CO ₃ solution (100 ml). The mixture was extracted using 100 ml of ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ and subsequently filtered. The filtrates were concentrated under reduced pressure to give the crude product as a brown oil. The crude material was purified by flash column chromatography on a silica gel column (petroleum ether:ethyl acetate=1:1 ~ 0:1). The desired fraction was collected and the solvent was concentrated under reduced pressure to obtain the product as a yellow solid (2000 mg, yield: 91.6%).

H. 1-(6-Amino-5-fluoropyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl)-1 H-pyrazole-4-carboxamide, 202h

N=\ , compound 202h tert-Butyl (6-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-1Hpyrazol-1-yl)-3-fluoropyridin-2-yl)carbamate (2000 mg, 3.522 mmol) and HCl/MeOH (60 ml, 4M) were stirred at 30°C for 1 hour. The mixture was concentrated to dryness. Saturated aqueous K ₂ CO ₃ (100 ml) was added to the residue. The mixture was extracted using EtOAc (100 mlx3). The combined organic layers were dried over Na2SO4, filtered and the filtrate concentrated to dryness to give a crude orange gum. The crude product was purified by preparative high performance liquid chromatography (20-505% (v/v) CH3CN and _H2O ). The pure fractions were collected and the solvent was concentrated under reduced pressure. The residue was extracted using EtOAc (100 mlx3).

The combined organic layers were concentrated to dryness to give the product as a light yellow solid (800 mg, yield: 48.6%). LCMS (ESI) m/z M+1: 467.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.83 (br.s, 2H), 6.95 (dd, J=2.6, 8.2 Hz, 1H), 7.37 -7.45 (m, 1H), 7.95 (s, 2H), 8.04 (s, 1H), 8.49 (d, J=2.4 Hz, 1H), 8.75 (d, J=2.2 Hz, 1H).

I. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluorimidazo[1,2-a]pyridin-5- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 202

1-(6-Amino-5-fluoropyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide (800 mg, 1.71 mmol) was dissolved in i-PrOH (20 ml) under N ₂ atmosphere. 2-bromo-1,1-diethoxyethane (674.08 mg, 3.42 mmol) followed by HBr (2 mL, 48% in water) was added to the suspension. The resulting mixture was subsequently refluxed for 12 hours and cooled to room temperature. The solvent was removed under reduced pressure. The residue was purified by preparative high performance liquid chromatography (30-60% (v/v) CH3CN and H ₂ O with 0.05% ammonium hydroxide). The pure fractions were collected and the solvent was concentrated under reduced pressure. The residue was lyophilized to dryness to obtain the product as a light yellow solid (422.2 mg, purity: 100%, yield: 50.2%). LCMS (ESI) m/z M+1: 491.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.40-7.47 (m, 1H), 7.47-7.51 (m, 1H), 7.53 (dd, J=1 ,2, 3.2 Hz, 1H), 7.76 (d, J=1.1 Hz, 1H), 8.17 (s, 2H), 8.65 (d, J=2.2 Hz, 1H ), 8.69 (s, 1H), 8.83 (d, J=2.2 Hz, 1H), 11.4211.07 (m, 1H).

- 308 045333

Example 203.

N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluorimidazo[1,2-a]pyridin- 5-yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 203

A. tert-Butyl (6-(4-((5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl )-1H-pyrazol-1-yl)-3-fluoropyridin-2-yl)carbamate, 203a

POCl ₃ (1.571 g, 10.25 mmol) was added to a mixture of fluoropyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic

1-(6-((tert-butoxycarbonyl)amino)-5-acid (2 g, 5.12 mmol), 5-chloro-2methyl-6-(2H-1,2,3-triazol-2-yl)pyridin- 3-amine (1.074 g, 5.12 mmol) and pyridine (2.027 g, 25.62 mmol) in CH ₂ Cl ₂ (50 ml).The reaction mixture was stirred at 20°C for 1 hour. Saturated. K2CO3 solution (120 ml). The mixture was extracted using 100 ml of ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified by flash column chromatography on silica gel (petroleum ether:ethyl acetate=1:1 ~ 0:1) The desired fraction was collected and the solvent was concentrated under reduced pressure to obtain the product as a yellow solid (1.4 g, purity: 58.3%, yield: 27. 4%). LCMS (ESI) m/z M+Na+: 604.0 (M+23).

B. 1-(6-Amino-5-fluoropyridin-2-yl)-N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3- yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, 203b

tert-Butyl (6-(4-((5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)- 1H-pyrazol-1-yl)-3-fluoropyridin-2-yl)carbamate (1.4 g, 1.40 mmol) and HCl/MeOH (50 ml, 4 M) were stirred at 30°C for 1 h. The mixture was concentrated to dryness. Saturated aqueous K2CO3 (100 ml) was added to the residue. The mixture was extracted using EtOAc (100 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness to give the product (1.1 g, crude) as an orange gum.

C. N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluorimidazo[1,2-a] pyridin-5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 203

1-(6-Amino-5-fluoropyridin-2-yl)-N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide (1.1 g, 2.28 mmol) was taken into i-PrOH (20 ml) under N2. 2-bromo-1,1-diethoxyethane (899.85 mg, 4.57 mmol) followed by HBr (2 mL, 48% in water) was added to the suspension. The resulting mixture was subsequently refluxed for 12 hours and cooled to room temperature. The solvent was removed under reduced pressure. The residue was purified by preparative high performance liquid chromatography (30-60% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the solvent was concentrated under reduced pressure. The residue was lyophilized to dryness to give the product as a light solid.

- 309 045333 yellow. (302 mg, purity: 99.2%, yield: 26.0%). LCMS (ESI) m/z M+1: 505.9.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H), 7.40-7.49 (m, 2H), 7.52 (d, J=2.0 Hz , 1H), 7.77 (d, J=1.1 Hz, 1H), 8.17 (s, 2H), 8.42 (s, 1H), 8.67 (s, 1H), 9.73 -10.40 (m, 1H).

Example 204.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluorimidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 204

A. Ethyl 1-(6-amino-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 204a

Ethyl 1-(6-((tert-butoxycarbonyl)amino)-5-fluoroniridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate (0.9 g, 2.15 mmol) and HCl/MeOH (18 ml, 4 M) was stirred at 30°C for 1 hour. The mixture was concentrated to dryness. Saturated aqueous K2CO3 (50 ml) was added to the residue. The mixture was extracted using EtOAc (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness to give the product as an orange gum (650 mg, yield: 94.9%).

B. Ethyl 1-(8-fluorimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 204b

Ethyl 1-(6-amino-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (650 mg, 2.043 mmol) was dissolved in EtOH (20 ml) under N ₂ . 2-bromo-1,1-diethoxyethane (805.057 mg, 4.085 mmol) followed by HBr (2 mL, 48% in water) was added to the suspension. The resulting mixture was subsequently refluxed for 12 hours and cooled to room temperature. The solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (petroleum ether:ethyl acetate=10:1 ~ 1:1). The pure fractions were collected and the solvent was concentrated under reduced pressure to obtain the product as a light yellow solid (320 mg, yield: 45.8%).

¹ H NMR (400 MHz, chloroform-d) δ ppm 1.40 (t, J=7.2 Hz, 3H), 4.42 (k, J=7.1 Hz, 2H), 6, 91 (dd, J=4.0, 7.9 Hz, 1H), 7.04 (dd, J=8.0, 9.4 Hz, 1H), 7.12 (s, 1H), 7.70 (s, 1H), 8.30 (s, 1H).

C. 1-(8-Fluorimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 204c

A mixture of ethyl 1-(8-fluorimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (320 mg, 0.935 mmol) in concentrated HCl (6.064 ml) was stirred at 130°C for 2 hours. The solvent was concentrated under reduced pressure to give the product as a yellow solid (300 mg, crude).

D. X-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluorimidazo[1,2-a]pyridin-5- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 204

- 310 045333

POC13 (292.81 mg, 1.91 mmol) was added to a mixture of 1-(8-fluoromidazo[1,2-a]pyridin-5-yl)-5(trifluoromethyl)-III-pyrazole-4-carboxylic acid (300 mg, 0.96 mmol), 5-amino-2-(2H-1,2,3-triazol-2yl)nicotinonitrile (177.76 mg, 0.96 mmol) and pyridine (377.63 mg, 4.77 mmol) in CH ₂ Cl ₂ (10 ml). The reaction mixture was stirred at 20°C for 1 hour. Saturated solution was added to the mixture. NaHCO ₃ solution (20 ml). The mixture was extracted using 30 ml of ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified by preparative high performance liquid chromatography (30-60% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the solvent was concentrated under reduced pressure. The residue was lyophilized to dryness to give the product as a light yellow solid. (182 mg, purity: 99.2%, yield: 39.2%). LCMS (ESI) m/z M+1: 482.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.38-7.51 (m, 2H), 7.53 (dd, J=1.1, 3.1 Hz, 1H), 7, 76 (d, J=1.1 Hz, 1H), 8.29 (s, 2H), 8.68 (s, 1H), 8.85 (d, J=2.6 Hz, 1H), 9, 06 (d, J=2.4 Hz, 1H), 11.32 (br.s, 1H).

Example 205.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-fluorimidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 205

A. tert-Butyl (6-bromo-5-fluoropyridin-2-yl)carbamate, 205a

6-Bromo-5-fluoropicolinic acid (2000 mg, 9.09 mmol) was dissolved in t-BuOH (60 ml). Subsequently, DPPA (2576.9 mg, 9.36 mmol) and DIEA (1292.5 mg, 10.00 mmol) were added. The reaction mixture was stirred at 100°C for 12 hours under N ₂ atmosphere. The solvent was concentrated. The residue was purified by flash column chromatography on silica gel (gradient eluent: EtOAc/petroleum ether 1/20 to 1/5). The product fractions were collected and the solvent was concentrated to obtain the desired product as a colorless gum (1.6 g, yield: 60.5%).

1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (s, 9H), 7.21 (br.s, 1H), 7.39 (dd, J=6.9, 8.9 Hz, 1H), 7.88 (dd, J=3.1, 8.8 Hz, 1H).

B. tert-Butyl (5-fluoro-6-hydrazinylpyridin-2-yl)carbamate, 205b

A mixture of {Pd(cinnamyl)Cl} ₂ (26.69 mg, 0.052 mmol) and Mor-DalPhos (47.78 mg, 0.10 mmol) in dioxane (20 ml) was deaerated using argon (4x). The resulting clear yellow solution was stirred at rt under argon for 10 min. Tert-butyl (6bromo-5-fluoropyridin-2-yl)carbamate (300 mg, 1.03 mmol) and t-BuONa (198.07 mg, 2.06 mmol) were added to the mixture and the mixture was deaerated using argon (4x). The resulting yellow reaction mixture was subsequently treated with NH2NH2-H2O (105.28 mg, 98%, 2.06 mmol) via syringe. The reaction mixture was deaerated using argon (4x). Subsequently, the mixture was stirred at 50°C under argon for 2 hours. The mixture was filtered and the filter residue was washed with CH ₂ Cl ₂ /MeOH (20/1, 20 ml). The filtrate was collected and concentrated to obtain the crude product, which was directly used in the next step (249.6 mg, yield: 100%).

C. Ethyl 1-(6-((tert-butoxycarbonyl)amino)-3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, 205c

- 311 045333

tert-Butyl (5-fluoro-6-hydrazinylpyridin-2-yl)carbamate (249 mg, 1.03 mmol) was dissolved in EtOH (10 ml), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro- 3-oxobutanoate (493.74 mg, 2.06 mmol) and stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 80/20). The desired fractions were collected and the solvent was concentrated under reduced pressure to obtain the product as a yellow solid (150 mg, yield: 34.9%). LCMS (ESI) m/z M+1: 362.9 (M-55).

1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.2 Hz, 3H), 1.52 (s, 9H), 4.38 (k, J=7, 1 Hz, 2H), 7.22 (s, 1H), 7.60-7.68 (m, 1H), 8.15-8.21 (m, 2H).

D. Ethyl 1-(6-amino-3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 205d

Ethyl 1-(6-((tert-butoxycarbonyl)amino)-3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate (0.150 g, 0.36 mmol) and HCl/MeOH (3 ml, 4 M) was stirred at 30°C for 1 hour. The mixture was concentrated to dryness. The residue was directly used in the next step (120 mg, yield: 94.4%).

E. Ethyl 1-(6-fluorimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 205e

Ethyl 1-(6-amino-3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (120 mg, 0.34 mmol) was dissolved in EtOH (2 ml) under N2. 2-bromo-1,1-diethoxyethane (133.35 mg, 0.68 mmol) followed by HBr (0.2 mL, 48% in water) was added to the suspension. The resulting mixture was subsequently heated at 80°C for 12 hours and cooled to room temperature. The solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (petroleum ether:ethyl acetate=10:1 ~ 1:1). The pure fractions were collected and the solvent was concentrated under reduced pressure to obtain the product as a light yellow solid (130 mg, purity: 86.4%, yield: 97.0%). LCMS (ESI) m/z M+1: 342.9.

F. 1-(6-Fluorimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 205f

A mixture of ethyl 1 -(6-fluorimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (130 mg, 0.33 mmol) in concentrated HCl (2, 13 ml) was stirred at 130°C for 2 hours. The solvent was concentrated under reduced pressure to give the product as a yellow solid (120 mg, crude).

G. N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-fluorimidazo[1,2-a]pyridin-5- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 205

POCl ₃ (117.12 mg, 0.76 mmol) was added to a mixture of 1-(6-fluoroimidazo[1,2-a]pyridin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ( 120 mg, 0.38 mmol), 5-chloro-6-(2H-1,2,3-triazol-2-312 045333 yl)pyridin-3-amine (74.71 mg, 0.38 mmol) and pyridine (151.05 mg, 1.91 mmol) in CH ₂ Cl ₂ (3 ml). The reaction mixture was stirred at 20°C for 1 hour. Saturated solution was added to the mixture. K2CO3 solution (100 ml). The mixture was extracted using 100 ml of ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ and subsequently filtered. The filtrates were concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified by preparative high performance liquid chromatography (35-65% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the solvent was concentrated under reduced pressure. The residue was lyophilized to dryness to obtain the product as a light yellow solid (86.9 mg, purity: 100%, yield: 46.3%). LCMS (ESI) m/z M+1: 491.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.61 (s, 1H), 7.68 (dd, J=8.8, 9.7 Hz, 1H), 7.80 (d , J=1.3 Hz, 1H), 8.05 (dd, J=4.6, 10.1 Hz, 1H), 8.17 (s, 2H), 8.65 (d, J=2, 4 Hz, 1H), 8.79 (s, 1H), 8.82 (d, J=2.2 Hz, 1H), 11.30 (br.s, 1H).

Example 206.

1-(2-Methylimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1Hpyrazol-4-carboxamide, compound 206

POCl ₃ (98.85 mg, 0.65 mmol) was added to a mixture of 1-(2-methylimidazo[1,2-a]pyridin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ( 100 mg, 0.32 mmol), 2-(trifluoromethyl)pyridin-4amine (52.26 mg, 0.32 mmol) and pyridine (127.49 mg, 1.61 mmol) in CH ₂ Cl ₂ (3 ml) at CT The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched using 20 ml of sat. aq. K2CO3 and extracted using CH ₂ Cl ₂ (20 mlx3). The organic layer was separated and concentrated under reduced pressure. The product was purified by preparative high performance liquid chromatography (35-65% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the desired product as a white solid. (80 mg, purity: 99.5%, yield: 54.3%). LCMS (ESI) m/z M+1: 454.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H), 7.08 (s, 1H), 7.32 (d, J=7.06 Hz, 1H), 7 .41 (dd, J=9.04, 7.28 Hz, 1H), 7.75 (d, J=9.04 Hz, 1H), 7.94 (dd, J=5.73, 1.76 Hz, 1H), 8.21 (d, J=1.76 Hz, 1H), 8.65 (s, 1H), 8.69 (d, J=5.29 Hz, 1H), 11.29 ( s, 1H).

Example 207.

1-(7-Methylpyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1Hpyrazol-4-carboxamide, compound 207

A. 1-Amino-5-bromo-2-methylpyridinium-1-2,4-dinitrophenolate, 207a

5-Bromo-2-methylpyridine (5 g, 29.07 mmol) was dissolved in CH ₂ Cl ₂ (30 ml) and added to the mixture of O-(2,4dinitrophenyl)hydroxylamine (6.366 g, 31.97 mmol). The reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a black solid (11 g), which was used directly in the next step.

B. Ethyl 4-bromo-7-methylpyrazolo[1,5-a]pyridine-3-carboxylate, 207b

1-Amino-5-bromo-2-methylpyridinium-1-2,4-dinitrophenolate (3.989 g, 10.75 mmol) was dissolved in DMF (20 ml) and subsequently ethyl propiolate (1.054 g, 10.75 mmol) was added and K ₂ CO ₃ (2.971 g, 21.50 mmol). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was concentrated

- 313 045333 under reduced pressure to obtain the crude product in the form of a black solid. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 85/15). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow oil (0.9 g, purity: 85.2%%, yield: 25.2%). LCMS (ESI) m/z M+1: 285.0.

C. 4-Bromo-7-methylpyrazolo[1,5-a]pyridine, 207c

Ethyl 4-bromo-7-methylpyrazolo[1,5-a]pyridine-3-carboxylate (800 mg, 2.53 mmol, 85.2% purity) and HBr (48%, 5 ml) were stirred at 100°C in for 16 hours. The reaction mixture was adjusted to pH 6 using 5N NaOH and extracted using EtOAc (30 mlx3). The combined organic layers were concentrated under reduced pressure to give the crude product as a yellow oil. The oil was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 90/10). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (500 mg, 93.6% yield).

D. 4-(2-(Diphenylmethylene)hydrazinyl)-7-methylpyrazolo[1,5-a]pyridine, 207d 0/5 ^N -NH fo ^CH h, 207d

Pd(OAc) ₂ (46.80 mg, 0.21 mmol) and BINAP (259.62 mg, 0.42 mmol) were suspended in dioxane (15 ml) and bubbled with N2 for 3 min. 4-bromo-7-methylpyrazolo[1,5-a]pyridine (440 mg, 2.09 mmol), (diphenylmethylene)hydrazine (818.25 mg, 4.17 mmol) and C ₂ CO ₃ (1.358 g, 4.17 mmol) and purged with N2 for 1 min. The reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was filtered and the residue was washed with EtOAc (50 mlx5). The filtrates were concentrated under reduced pressure to give the crude product as a brown oil. The oil was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 70/30). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (600 mg, purity: 75.7%, yield: 66.7%). LCMS (ESI) m/z M+1: 327.0.

E. 4-Hydrazinyl-7-methylpyrazolo[1,5-a]pyridine, 207e ^H2 %n f ^Sn h, 207e

4-(2-(Diphenylmethylene)hydrazinyl)-7-methylpyrazolo[1,5-a]pyridine (550 mg, 1.28 mmol, 75.7% purity) was dissolved in dioxane (5 ml) and conc. HCl (12 M, 0.5 ml). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a black solid (350 mg). The crude product was used in the next step without further purification.

F. Ethyl 1-(7-methylpyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 207f

4-Hydrazinyl-7-methylpyrazolo[1,5-a]pyridine (350 mg, 1.76 mmol, HCl salt) was dissolved in EtOH (10 ml), ethyl 2-(ethoxymethylene)-4,4,4- was added trifluoro-3-oxobutanoate (423.16 mg, 1.76 mmol) and Et ₃ N (356.57 mg, 3.52 mmol) and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give crude product in the form of black oil. The crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 100/0 to 85/15). The desired fraction was collected and the solvent was concentrated under reduced pressure to give the product as a yellow oil (400 mg, purity: 98.8%, yield: 66.3%). LCMS (IER)

- 314 045333 m/z M+1: 339.2.

G. 1-(7-Methylpyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

207g

Ethyl 1-(7-methylpyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (400 mg, 1.18 mmol) was dissolved in THF/H2O=1 /1 (10 ml) and LiOH (56.64 mg, 2.37 mmol) was added. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was adjusted to pH 5 using 2N HCl and extracted using EtOAc (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude product as a yellow solid (350 mg, purity: 97.2%, yield: 92.7%). LCMS (ESI) m/z M+1: 311.0.

H. 1-(7-Methylpyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 207

POCl ₃ (0.07 mL, 0.75 mmol) was added dropwise to a solution of 1-(7-methylpyrazolo[1,5-a]pyridin-4yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (120 mg, 0.38 mmol, 97.2% purity), 2(trifluoromethyl)pyridin-4-amine (60.9 mg, 0.38 mmol) and pyridine (0.15 ml, 1.88 mmol) in CH2C12 (6 ml). The reaction mixture was stirred at room temperature for 1.5 hours. Water (5 ml) was added to the mixture. The aqueous layer was extracted using CH2C12 (15 mlx3). The separated organic layer was dried (Na2SO4), filtered and the solvent was concentrated to give the crude product. The crude product was purified by preparative high performance liquid chromatography (35-68% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the product as a white solid (61.8 mg, purity: 98.1%, yield: 35.5%). LCMS (ESI) m/z M+1: 454.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (s, 3H) 6.36 (d, J=2.43 Hz, 1H) 7.02 (d, J=7.94 Hz , 1H) 7.53 (d, J=7.50 Hz, 1H) 7.95 (dd, J=5.40, 1.65 Hz, 1H) 8.15 (d, J=2.21 Hz, 1H) 8.21 (d, J=1.54 Hz, 1H) 8.51 (s, 1H) 8.69 (d, J=5.51 Hz, 1H) 11.24 (br.s, 1H) .

Example 208.

1-(Imidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol4-carboxamide, compound 208

POC13 (149.87 mg, 0.98 mmol) was added to a mixture of 1-(imidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxylic acid (150 mg, 0.49 mmol, 96.5% purity), 2-(trifluoromethyl)pyridin-4amine (79.22 mg, 0.49 mmol) and pyridine (193.28 mg, 2.44 mmol) in CH2Cl2 (3 ml) . The reaction mixture was stirred at 20°C for 1 hour. Saturated solution was added to the mixture. K2CO3 solution (5 ml). The mixture was extracted using 5 ml of ethyl acetate. The combined organic layers were dried over Na2SO4 and subsequently filtered. The filtrates were concentrated under reduced pressure to give the crude product as a brown oil. The crude oil was purified by preparative high performance liquid chromatography (30-55% (v/v) CH3CN and H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the solvent was concentrated under reduced pressure. The residue was lyophilized to dryness to obtain the product as a light yellow solid (60.2 mg, purity: 99.3%, yield: 27.8%). LCMS (ESI) m/z M+1: 440.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.36 (d, J=0.7 Hz, 1H), 7.39-7.43 (m, 1H), 7.45-7, 51 (m, 1H), 7.71 (d, J=1.3 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.96 (dd, J=1.9 , 5.4 Hz, 1H), 8.22 (d, J=1.5 Hz, 1H), 8.67 (s, 1H), 8.70 (d, J=5.5 Hz, 1H), 11.28 (br.s, 1H).

Example 209.

1-(8-Fluorimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1Hpyrazol-4-carboxamide, compound 209

- 315 045333

POC13 (117.12 mg, 0.76 mmol) was added dropwise to a solution of 1-(8-fluorimidazo[1,2-a]pyridin-5yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ( 120 mg, 0.38 mmol), 2(trifluoromethyl)pyridin-4-amine (61.92 mg, 0.38 mmol) and pyridine (151.05 mg, 1.91 mmol) in CH ₂ Cl ₂ (5 ml ). The reaction mixture was stirred at room temperature for 2 hours. Water (2.5 ml) was added to the mixture. The pH was adjusted to about 7 by gradual addition of NaHCO ₃ (aq). The aqueous phase extra-

gyrated using CH ₂ Cl ₂ (5 mlx3). The separated organic layer was dried (Na ₂ SO ₄ ), filtered and the solvent concentrated to give the crude product, which was purified using preparative high performance liquid chromatography (35-65% (v/v) CH3CN and H ₂ O with 0.05% ammonium hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the product as a white solid (110 mg, purity: 99.0%, yield: 62.2%). LCMS (ESI) m/z M+1: 458.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.41-7.46 (m, 1H), 7.46-7.49 (m, 1H), 7.51 (d, J=3 ,1 Hz, 1H), 7.76 (s, 1H), 7.96 (dd, J=1.9, 5.4 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H ), 8.68 (s, 1H), 8.71 (d, J=5.5 Hz, 1H), 11.25 (br.s, 1H).

Example 210.

1-(7-(3-G hydroxyazetidin-1-yl)thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-N-(2(trifluoromethyl)pyridin-4-yl)- 1 H-pyrazole-4-carboxamide, compound 210

A. 4-(5-(Trifluoromethyl)-4-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)-1H-pyrazol-1-yl)thieno[2,3c]pyridine-6-oxide, 210a

m-CPBA (0.566 g, 3.28 mmol) was added to a solution of 1-(thieno[2,3-c]pyridin-4-yl)-5(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4- yl)-1H-pyrazole-4-carboxamide (0.5 g, 1.09 mmol) in CH2C12 (10 ml). The mixture was stirred at 50°C for 4 hours. The solution was washed with saturated aqueous Na2SO3 (30 ml), saturated aqueous NaHCO3 (30 ml) and brine (50 ml). The extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated to obtain a crude oil. The oil was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to give the product as a white solid (0.35 g, 66.7%).

B. 1-(7-Chlorothieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1Hpyrazol-4-carboxamide, 210b

4-(5-(Trifluoromethyl)-4-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)-1H-pyrazol-1-yl)thieno[2,3c]pyridine 6-oxide (180 mg, 0 .38 mmol) was added to a mixture of POC13 (0.34 ml, 3.75 mmol) in CHC13 (10 ml). The mixture was stirred at 60°C for 2 hours. The mixture was cooled to rt and added to the stirred solution (50 ml). Subsequently, the mixture was made alkaline using NaHCO ₃ and then extracted with CH2C12 (50 mlx2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and subsequently filtered. The filtrates were concentrated under reduced pressure to give the crude product as a brown oil. The brown oil was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1:0 - petroleum

- 316 045333 ether/ethyl acetate = 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a colorless oil (0.15 g, 81.3%).

C. 1-(7-(3-G hydroxyazetidin-1-yl)thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-N-(2(trifluoromethyl)pyridin-4-yl )-1 H-pyrazole-4-carboxamide, compound 210

Na ₂ CO ₃ (53.88 mg, 0.51 mmol) was added to a solution of 1-(7-chlorothieno[2,3-c]pyridin-4-yl)-5(trifluoromethyl)-X-(2-(trifluoromethyl )pyridin-4-yl)-1H-pyrazol-4-carboxamide (100 mg, 0.20 mmol) and azetidin-3-ol hydrochloride (33.42 mg, 0.31 mmol) in DMA (4 ml). The mixture was stirred at 80°C for 16 hours. Water (20 ml) was added to the mixture and extracted with ethyl acetate (30 mlx2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the crude product as a yellow solid, which was purified by preparative HPLC (26-56% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure and lyophilized to dryness to give the product as a brown solid. (76 mg, 70.7%). LCMS (ESI) m/z M+1: 528.9.

1H NMR (400 MHz, DMSO-d6) δ ppm 4.07 (2H, dd, J=9.15, 4.30 Hz), 4.51-4.57 (2H, m), 4, 60-4.67 (1H, m), 6.89 (1H, d, J=5.51 Hz), 7.81 (1H, br.d, J=3.75 Hz), 8.01 (1H , s), 8.09 (1H, d, J=5.29 Hz), 8.14 (1H, d, J=1.76 Hz), 8.34 (1H, s), 8.56 (1H , d, J=5.51 Hz).

Example 211.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylimidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 211

The title compound was prepared according to Example 205 by substituting appropriate reagents, starting materials, and purification methods and adjusting reaction temperatures, timing, and other variables or parameters.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.346 (br.s, 1H), 8.833 (d, J=2.21 Hz, 1H), 8.614-8.684 (m, 2H), 8.171 ( s, 2H), 7.808-7.888 (m, 1H), 7.487 (s, 1H), 7.328-7.392 (m, 2H), 1.787 (s, 3H). LCMS (ESI): m/z - 487.9 [M+H]+.

By following the procedures described in Examples 3 or 4 above and selecting and substituting appropriate reagents, starting materials and purification methods and adjusting reaction temperatures, times and other variables or parameters as necessary or desired, which should be understandable to those skilled in the art area, received the following compounds.

Example 70.

X-(5-Cyano-6-ethoxypyridin-3-yl)-1 -(quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, compound 81

1H NMR (400 MHz, chloroform-d) δ ppm 1.46 (t, J=7.06 Hz, 2H), 4.50 (k, J=7.06 Hz, 2H), 7.48 (dd, J=8.49, 4.30 Hz, 1H), 7.59-7.66 (m, 2H), 7.70 (br.s, 1H), 7.82-7.87 (m , 1H), 8.20 (s, 1H), 8.34-8.38 (m, 1H), 8.43 (br.s, 2H), 9.03 (br.d, J=2.65 Hz, 1H). LCMS (ESI): m/z - 487.9 [M+H]+.

- 317 045333

Example 71.

N-(5-Cyano-6-methoxypyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide, compound 85

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.99 (s, 3H), 7.55-7.61 (m, 1H), 7.62-7.68 (m, 1H ), 7.85-7.91 (m, 1H), 7.92-7.98 (m, 1H), 8.31 (d, J=8.38 Hz, 1H), 8.46-8, 56 (m, 2H), 8.69 (d, J=2.65 Hz, 1H), 9.03 (dd, J=4.08, 1.65 Hz, 1H), 10.93 (br.s , 1H). LCMS (ESI): m/z - 439.0 [M+H]+.

Example 72.

No.(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 49

^1H NMR (400 MHz, DMSO-d6) δ ppm 7.26 (d, J=8.38 Hz, 1H), 7.83-7.88 (m, 1H), 7.90-7 .96 (m, 1H), 8.37 (d, J=7.94 Hz, 1H), 8.63 (s, 1H), 8.78 (s, 1H), 8.80 (d, J= 1.98 Hz, 1H), 9.25 (d, J=1.98 Hz, 1H), 9.60 (s, 1H), 11.58 (br.s, 1H). LCMS (ESI): m/z - 476.9 [M+H]+.

Example 73.

N-(3 -Chloro-4-(3 -methyl-1H-1,2,4-triazol-1 -yl)phenyl)-1 -(isoquinolin-4-yl)-5 -(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 55

¹ H NMR (400 MHz, methanol-d4) δ ppm 2.41 (s, 3H), 7.44 (d, J=8.38 Hz, 1H), 7.60 (d, J=8 .60 Hz, 1H), 7.84-8.01 (m, 3H), 8.17-8.26 (m, 2H), 8.36-8.43 (m, 2H), 8.72 ( br.s, 1H), 9.49-9.66 (m, 1H), 9.60 (br.s, 1H). LCMS (ESI): m/z - 498.0 [M+H]+.

Example 74.

Ν-(5-Χλορ-6-( 1 -methyl-1 N-imidazol-2-yl)pyridin-3 -yl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4- carboxamide, compound 98

¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 3.70 (s, 3H), 7.12 (s, 1H), 7.27 (s, 1H), 7.39 (d, J=8.16 Hz, 1H), 7.84-7.89 (m, 1H), 7.90-7.95 (m, 1H), 8.34 (d, J=8.16 Hz, 1H ), 8.42 (s, 1H), 8.60 (d, J=1.98 Hz, 1H), 8.65 (s, 1H), 8.91 (d, J=1.98 Hz, 1H ), 9.52 (s, 1H). LCMS (ESI): m/z - 497.9 [M+H]+.

Example 75.

N-(8-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(isoquinolin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 97

¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (s, 3H), 4.77 (s, 2H), 7.26 (d, J=8.38 Hz, 1H), 7.45 (br.s, 1H), 7.64 (s, 1H), 7.81-7.89 (m, 1H), 7.89-7.98 (m, 1H), 8.37 ( d, J=8.38 Hz, 1H), 8.52 (s, 1H), 8.76 (s, 1H), 9.60 (s, 1H), 10.71 (br.s, 1H). LCMS (ESI): m/z - 501.9 [M+H]+.

- 318 045333

Example 76.

N-(6-(4-Aminobutoxy)-5-cyanopyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamide, compound 84

1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 9.62 (s, 1H), 8.81 (d, J=2.4 Hz, 1H), 8 .78 (s, 1H), 8.73 (s, 1H), 8.61 (d, J=2.4 Hz, 1H), 8.38 (br.d, J=8.2 Hz, 1H) , 8.09-7.89 (m, 4H), 7.89-7.82 (m, 1H), 7.28 (br.d, J=8.2 Hz, 1H), 4.41 (br .t, J=6.1 Hz, 2H), 2.84 (br.d, J=6.0 Hz, 2H), 1.87-1.63 (m, 4H). LCMS (ESI): m/z - 496.1 [M+H]+.

Example 77.

X-(5-Fluoro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 61

1H NMR (400 MHz, DMSO-d6) δ ppm 7.28 (br.d, J=8.38 Hz, 1H), 7.84-7.96 (m, 3H), 8.03 ( d, J=3.09 Hz, 1H), 8.37 (br.d, J=7.94 Hz, 1H), 8.54-8.73 (m, 2H), 8.78 (s, 1H ), 8.96 (s, 1H), 9.61 (s, 1H), 11.41 (br.s, 1H). LCMS (ESI): m/z - 500.9 [M+H]+.

Example 78.

Methyl 6-chloro-4-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)picolinate, compound 74

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.89 (s, 3H), 7.26 (d, J=8.38 Hz, 1H), 7.80-7.88 (m , 1H, 7.897.97 (m, 1H), 8.11 (s, 1H), 8.30-8.40 (m, 2H), 8.61 (s, 1H), 8.77 (s, 1H), 9.59 (s, 1H), 11.33 (br.s, 1H).LCMS (ESI): m/z - 475.9 [M+H]+.

Example 79.

Ν-(5-Χλορ-6-(( 1 -methylpiperidin-4-yl)oxy)pyridin-3-yl)-1 -(isoquinolin-4-yl)-5 -(trifluoromethyl)1H-pyrazole-4-carboxamide , connection 45

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.70-1.81 (m, 2H), 1.98 (br.s, 2H), 2.26 (s, 3H), 2 .33 (br.s, 2H), 2.48-2.52 (m, 34 N), 2.67 (br.s, 2H), 5.08 (br.d, J=4.41 Hz, 1H), 7.27 (d, J=8.38 Hz, 1H), 7.82-7.90 (m, 1H), 7.90-7.98 (m, 1H), 8.29 (d , J=2.21 Hz, 1H), 8.35-8.42 (m, 2H), 8.55 (s, 1H), 8.76 (s, 1H), 9.61 (s, 1H) , 10.80 (s, 1H). LCMS (ESI): m/z - 531.0 [M+H]+.

Example 80.

X-(4-Aminobutyl)-3-chloro-5-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamido)picolinamide, compound 72

- 319 045333

1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (br.s, 4 H), 2.73-2.85 (m, 2H), 3.19-3.33 (m, 2H), 7.30 (d, J=8.16 Hz, 1H), 7.84-7.90 (m, 1H), 7.95 (br.t, J=7.06 Hz, 3H), 8.39 (d, J=8.16 Hz, 1H), 8.50 (d, J=1.98 Hz, 1H), 8.68 (br.t, J=5.84 Hz, 1H), 8.79 (d, J=7.94 Hz, 1H), 8.95-9.02 (m, 1H), 8.97 (d, J=1.98 Hz, 1H), 9.64 (s , 1H), 11.53 (s, 1H). LCMS (ESI): m/z - 532.0 [M+H]+.

Example 81.

X-(2-Cyanopyridin-4-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 77

^1H NMR (400 MHz, DMSO-d6) δ ppm 11.30 (br.s, 1H), 9.62 (s, 1H), 8.79 (s, 1H), 8.70 (br.s. .d, J=5.5 Hz, 1H), 8.61 (s, 1H), 8.39 (br.d, J=8.3 Hz, 1H), 8.28 (s, 1H), 8 .02-7.91 (m, 2H), 7.91-7.84 (m, 1H), 7.29 (br.d, J=8.5 Hz, 1H). LCMS (ESI): m/z - 531.0 [M+H]+.

Example 82.

X-(5-Chloro-6-(1H-imidazol-1-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol4-carboxamide, compound 70

¹ H NMR (400 MHz, chloroform-d) δ ppm 7.20 (s, 1H), 7.34 (d, J=7.94 Hz, 1H), 7.63 (s, 1H), 7.74-7.84 (m, 2H), 8.14-8.21 (m, 2H), 8.30 (s, 1H), 8.55 (d, J=2.21 Hz, 1H) , 8.61 (s, 1H), 8.75 (d, J=2.21 Hz, 1H), 9.08 (s, 1H), 9.46 (s, 1H). LCMS (ESI): m/z - 483.9 [M+H]+.

Example 83.

N-(5-Chloro-6-(4-methylpiperazin-1-carbonyl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide, compound 48

1H NMR (400 MHz, methanol-d4) δ ppm 2.99 (s, 3H), 3.15-3.29 (m, 2H), 3.32-3.44 (m, 2H), 3.47-3.64 (m, 2H), 3.66-3.79 (m, 2H), 7.65 (br.d, J=8.60 Hz, 1H), 8.14 (br. t, J=7.61 Hz, 1H), 8.23-8.32 (m, 1H), 8.52 (s, 1H), 8.56 (d, J=1.76 Hz, 1H), 8.67 (br.s, J=8.16 Hz, 1H), 8.90 (s, 1H), 9.05 (br.s, 1H), 9.99 (br.s, 1H). LCMS (ESI): m/z - 543.9 [M+H]+.

Example 84.

X-(5-Cyanopyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 82

- 320 045333

1H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (br.s, 1H), 9.66 (br.s, 1H), 9.18 (br.s, 1H), 8, 80 (br.d., J=16.3 Hz, 2H), 8.70 (br.d., J=17.0 Hz, 2H), 8.40 (b.d., J=7.7 Hz, 1H ), 8.02-7.79 (m, 2H), 7.30 (br.d, J=7.9 Hz, 1H). LCMS (ESI): m/z - 409.1 [M+H]+.

Example 85.

1-(Isoquinolin-4-yl)-N-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 73

1H NMR (400 MHz, methanol^) δ ppm 2.60 (s, 3H), 7.38 (d, J=8.16 Hz, 1H), 7.81-7.96 (m, 3H ), 8.04 (d, J=1.54 Hz, 1H), 8.33 (d, J=7.94 Hz, 1H), 8.40 (s, 1H), 8.63 (s, 1H ), 9.51 (s, 1H). LCMS (ESI): m/z - 531.0 [M+H]+.

Example 86.

N-(5-Cyano-6-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide , connection 80

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (br.s, 1H), 10.82 (br.s, 1H), 9.62 (br.s, 1H), 8 ,89-8.51 (m, 4H), 8.38 (br.s, 1H), 8.04-7.73 (m, 2H), 7.28 (br.s, 1H), 5.45 -5.09 (m, 1H), 3.50-3.31 (m, 2H), 3.21-2.97 (m, 2H), 2.75 (br.d, J=12.3 Hz , 3H), 2.35-2.11 (m, 3H), 2.01 (br.s, 1H). LCMS (ESI): m/z - 522.0 [M+H]+.

Example 87.

N-(5-Cyano-6-(4-methylpiperazin-1-carbonyl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 96

1H NMR (400 MHz, methanol^) δ ppm 2.99 (s, 3H), 3.18-3.28 (m, 1H), 3.31-3.35 (m, 1H), 3 .35-3.79 (m, 5 N), 4.18 (br.s, 1H), 7.40 (d, J=8.16 Hz, 1H), 7.83-7.97 (m, 2H), 8.35 (d, J=8.16 Hz, 1H), 8.46 (s, 1H), 8.648.74 (m, 1H), 8.78 (d, J=2.21 Hz, 1H), 9.14 (d, J=2.21 Hz, 1H), 9.58 (br.s, 1H). LCMS (ESI): m/z - 535.0 [M+H]+.

Example 88.

X-(6-Cyano-5-fluoropyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 41

^1H NMR (400 MHz, methanol^) δ ppm 7.56-7.64 (m, 1H), 8.03-8.13 (m, 1H), 8.16-8.25 (m , 1H), 8.508.57 (m, 2H), 8.57-8.63 (m, 1H), 8.75-8.82 (m, 1H), 8.94-8.98 (m, 1H ), 9.89 (s, 1H). LCMS (IER): m/z - 427.0

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[M+N]+.

Example 89.

N-(6-(2H-1,2,3-Triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 71

1H NMR (400 MHz, chloroform-d) δ ppm 7.34 (d, J=8.16 Hz, 1H), 7.74-7.84 (m, 2H), 7.92 (s, 2H), 8.10-8.19 (m, 3H), 8.27 (s, 1H), 8.57-8.62 (m, 2H), 8.64 (d, J=2.65 Hz , 1H), 9.45 (s, 1H). LCMS (ESI): m/z 451.0 [M+H]+.

Example 90.

N-(6-(4-(4-Aminobutyl)piperazine-1-carbonyl)-5-cyanopyridin-3-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4- carboxamide, compound 101

1H NMR (400 MHz, methanol-d ₄ ) δ ppm 1.72 (br.s, 4H), 2.64-2.87 (m, 4H), 2.98 (br.s, 2H) , 3.49-3.70 (m, 1H), 3.58 (br.s, 1H), 3.76-4.09 (m, 1H), 3.92 (br.s, 1H), 4 .66 (br.s, 2H), 7.39 (d, J=8.16 Hz, 1H), 7.837.96 (m, 2H), 8.34 (d, J=8.16 Hz, 1H) , 8.45 (s, 1H), 8.64 (s, 1H), 8.78 (d, J=2.20 Hz, 1H), 9.12 (d, J=1.76 Hz, 1H) , 9.52 (s, 1H). LCMS (ESI): m/z -592.0 [M+H]+.

Example 91.

Ν-(5-ΧλοΡ-6-( 1 H-imidazol-2-yl)pyridin-3-yl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazol4-carboxamide, compound 104

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.07-7.33 (m, 2H) 7.75-7.96 (m, 3H), 8.37 (br.d, J =7.94 Hz, 2H), 8.71 (br.d, J=1.76 Hz, 2H), 8.79 (d, J=11.47 Hz, 1H), 9.20 (br.d , J=1.76 Hz, 1H), 9.61 (s, 1H), 11.77 (s, 1H). LCMS (ESI): m/z - 477.0 [M+H]+.

Example 92.

Methyl 4-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)picoline, compound 75

1H NMR (400 MHz, methanol-d^ δ ppm 4.15 (s, 3H) 7.64 (d, J=8.38 Hz, 1H) 8.08-8.16 (m, 1H) 8.228.29 (m, 1H) 8.58-8.69 (m, 3H) 8.80 (d, J=6.61 Hz, 1H) 8.90-8.97 (m, 1H) 9.03 (br.s, 1H) 9.96 (br.s, 1H) LCMS (ESI): m/z - 442.0 [M+H]+.

Example 106.

N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide, compound 106

1H NMR (400 MHz, chloroform-d) δ ppm 7.32 (br.d, J=7.94 Hz, 1H), 7.60 (s, 1H), 7.71-7.90 ( m, 4H), 8.14-8.19 (m, 2H), 8.21 (s, 1H), 8.59 (s, 1H), 9.44 (s, 1H). LCMS (ESI): m/z -483.8 [M+H]+.

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Example 107.

N-(5-Chloro-6-(2-oxopyrrolidin-1 -yl)pyridin-3-yl)-1 -(isoquinolin-4-yl)-5 -(trifluoromethyl)-1Hpyrazol-4-carboxamide, compound 107

1H NMR (400 MHz, DMSO-d6) δ ppm 2.09-2.21 (m, 2H), 2.46 (br.s, 2H), 3.81 (s, 2H), 7, 27 (d, J=8.38 Hz, 1H), 7.81-7.89 (m, 1H), 7.90-7.97 (m, 1H), 8.31-8.40 (m, 1H), 8.41-8.47 (m, 1H), 8.56-8.61 (m, 1H), 8.708.82 (m, 2H), 9.56-9.66 (m, 1H) , 11.06-11.12 (m, 1H). LCMS (ESI): m/z - 501.0 [M+H]+.

Example 212.

X-(2-Methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 -(quinolin-5 -yl)-5 -(trifluoromethyl)-1Hpyrazole-4-carboxamide, compound 212

1H NMR (400 MHz, DMSO-d6) δ ppm 2.96 (br.t, J=6.62 Hz, 2H), 3.04 (s, 3H) 3.53-3.56 (m , 2H), 7.30 (d, J=8.16 Hz, 1H), 7.75 (d, J=3.09 Hz, 2H), 7.89 (dd, J=8.16, 1, 98 Hz, 1H), 7.94-7.98 (m, 1H), 7.99-8.05 (m, 1H), 8.23 (d, J=1.98 Hz, 1H), 8, 37 (d, J=8.38 Hz, 1H), 8.54 (s, 1H), 9.12 (t, J=2.87 Hz, 1H), 10.71 (s, 1H). LCMS: (ES, m/z): [M+1]+ 466.0.

Example 213.

N-(3-(Methylsulfonyl)-4-(1H-1,2,3-triazol-1 -yl)phenyl)-1 -(quinolin-5 -yl)-5 -(trifluoromethyl)-1Hpyrazol-4-carboxamide , connection 213

1H NMR (400 MHz, methanol-d4) δ ppm 3.24 (s, 3H), 7.69 (d, J=8.60 Hz, 1H), 7.95 (s, 1H), 8 ,15-8.23 (m, 2H), 8.32-8.38 (m, 3H), 8.48 (s, 1H), 8.53 (d, J=8.82 Hz, 1H), 8.61 (d, J=8.82 Hz, 1H), 8.66 (d, J=2.21 Hz, 1H), 9.38 (d, J=4.41 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 528.2.

Example 214.

N-(4-Methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 214

1H NMR (400 MHz, DMSO-d6) δ ppm 10.66 (1H, s), 9.06-9.18 (1H, m), 8.51 (1H, s), 8.38 ( 1H, d, J=8.38 Hz), 8.00-8.07 (1H, m), 7.91-7.99 (1H, m), 7.73-7.81 (2H, m) , 7.60 (1H, d, J=2.21 Hz), 7.37 (1H, dd, J=8.60, 2.21 Hz), 7.00 (1H, d, J=8.60 Hz), 4.63 (2H, s), 3.26 (3H, s). LC-MS: (ES, m/z): [M+1]+ 468.0.

Example 215.

N-(3-(Methylsulfonyl)-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide , connection 215

- 323 045333

¹ H NMR (400 MHz, methanol-d4) δ ppm 3.53 (s, 3H), 7.77 (d, J=8.60 Hz, 1H), 8.00 (s, 2H), 8.10 (dd, J=8.60, 5.07 Hz, 1H), 8.16 (d, J=7.50 Hz, 1H), 8.27-8.34 (m, 2H), 8 .44-8.53 (m, 3H), 8.64 (d, J=1.98 Hz, 1H), 9.33 (d, J=3.97 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 528.1.

Example 216.

N-(2-Methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)-1 -(quinolin-5 -yl)-5 -(trifluoromethyl)-1 H-pyrazole4-carboxamide, compound 216

1H NMR (400 MHz, DMSO-d6) δ ppm 3.51 (s, 3H), 3.99 (br.s, 18H), 6.59 (d, J=7.06 Hz, 1H) , 7.41 (d, J=7.28 Hz, 1H), 7.64-7.74 (m, 3H), 7.90-8.03 (m, 2H), 8.07 (br.d , J=7.72 Hz, 1H), 8.34 (br.d, J=8.38 Hz, 1H), 8.56 (s, 1H), 8.63 (s, 1H), 9.08 (br.s, 1H), 10.86 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 464.0.

Example 217.

N-(3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 217

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.78 (s, 1H), 10.56 (s, 1H), 9.08-9.01 (m, 1H), 8.47 (s, 1H), 8.31 (d, J=8.4 Hz, 1H), 7.99-7.93 (m, 1H), 7.90-7.86 (m, 1H), 7. 69-7.64 (m, 1H), 7.63-7.59 (m, 1H), 7.51 (d, J=2.2 Hz, 1H), 7.19 (dd, J=2, 2, 8.8 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 4.53 (s, 2H). LC-MS: (ES, m/z): [M+1]+ 453.9.

Example 218.

N-(5-Methyl-6-(3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 218

1H NMR (400 MHz, methanol-d ₄ ) δ ppm 2.34 (s, 3H), 3.36 (s, 3H), 6.69 (d, J=3.01 Hz, 1H), 6.74 (d, J=2.76 Hz, 1H), 7.66 (dd, J=8.53, 4.27 Hz, 1H), 7.78 (d, J=8.03 Hz, 1H ), 7.85 (d, J=7.28 Hz, 1H), 7.96-8.02 (m, 1H), 8.29 (d, J=2.01 Hz, 1H), 8.32 -8.39 (m, 2H), 8.72 (d, J=2.51 Hz, 1H), 9.03 (dd, J=4.27, 1.51 Hz, 1H). LCMS: (ES, m/z): [M+1]+ 494.0.

Example 219.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylbenzo[d]oxazol-4-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 219

¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.5 Hz, 1H), 8, 54 (s, 1H), 8.32 (s, 2H), 8.01-7.93 (m, 1H), 7.64-7.53 (m, 2H), 2.65 (s, 3H) . LC-MS: (ES, m/z): [M+1]+ 479.9.

Example 220.

1-(2-Chloroquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H

- 324 045333 pyrazole-4-carboxamide, compound 220

1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H), 9.08 (d, J=2.43 Hz, 1H), 8.85 (d, J=2, 43 Hz, 1H), 8.55 (s, 1H), 8.25-8.36 (m, 4H), 8.05-8.13 (m, 1H), 8.01 (t, J=7 ,17 Hz, 1H), 7.87-7.93 (m, 1H). LC-MS: (ES, m/z): [M+1]+ 509.9.

Example 221.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-chloroquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 221

1H NMR (400 MHz, methanol-d4) δ ppm 7.60-7.64 (m, 1H), 7.73 (d, J=8.60 Hz, 1H), 7.83 (d, J=7.28 Hz, 1H), 7.96-8.01 (m, 1H), 8.04 (s, 2H), 8.23 (d, J=8.60 Hz, 1H), 8, 40 (s, 1H), 8.72 (d, J=2.20 Hz, 1H), 8.79 (d, J=2.21 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 518.9.

Example 222.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 222

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.98 (s, 1H), 8.78 (d, J=2.20 Hz, 1H), 8.63 (s, 1H), 8.60 (d, J=2.21 Hz, 1H), 8.53 (s, 1H), 8.16 (s, 2H). LC-MS: (ES, m/z): [M+1]+ 475.9.

Example 223.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,6-naphthyridin-4-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 223

1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1H), 9.39-9.43 (m, 1H), 9.10-9.15 (m, 1H), 8.89-8.95 (m, 3H), 8.71-8.76 (m, 1H), 8.31 (s, 2H), 8.14-8.20 (m, 1H), 8. 03-8.10 (m, 1H). LC-MS: (ES, m/z): [M+1]+ 476.9.

Example 224.

N-(5-Cyano-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide, compound 224

1H NMR (400 MHz, DMSO-d6) δ ppm 11.08-11.18 (m, 1H), 10.83-10.99 (m, 1H), 9.05 (br.s, 1H ), 8.738.82 (m, 1H), 8.56-8.64 (m, 1H), 8.44-8.55 (m, 1H), 8.27-8.38 (m, 1H), 7.94-8.02 (m, 1H), 7.88-7.93 (m, 1H), 7.59-7.71 (m, 2H), 4.07-4.21 (m, 2H ), 3.52-3.64 (m, 4H), 3.16 (br.d, J=9.92 Hz, 2H), 2.75-2.87 (m, 3H). LCMS: (ES, m/z): [M+1]+ 507.0.

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Example 225.

N-(1 -Methyl-1 H-pyrazolo[3,4-b]pyridin-5 -yl)-1 -(quinolin-5 -yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamide, compound 225

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.09 (s, 1H), 9.21 (d, J=4.0 Hz, 1H), 8.81 (d, J=2 ,0 Hz, 1H), 8.71-8.62 (m, 2H), 8.47 (d, J=8.6 Hz, 1H), 8.14 (s, 1H), 8.11 (t , J=8.0 Hz, 1H), 8.06-8.02 (m, 1H), 7.99 (br.d, J=8.4 Hz, 1H), 7.87 (dd, J= 4.5, 8.5 Hz, 1H), 4.04 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 438.0.

Example 226.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methyl-1-oxo-1,2-dihydroisoquinolin-5yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 226

1H NMR (400 MHz, DMSO-d6) δ ppm 11.24 (1H, s), 8.82 (1H, d, J=2.21 Hz), 8.64 (1H, d, J= 2.20 Hz), 8.53 (1H, s), 8.45 (1H, d, J=8.16 Hz), 8.16 (2H, s), 7.93 (1H, d, J= 7.06 Hz), 7.66 (1H, t, J=7.94 Hz), 7.56 (1H, d, J=7.50 Hz), 5.71 (1H, d, J=7, 72 Hz), 3.50 (3H, s). LC-MS: (ES, m/z): [M+1]+ 514.9.

Example 227.

N-(5-Chloro-6-(5-Cyano-1H-1,2,3-triazol-1 -yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 227

1H NMR (400 MHz, methanol-d ₄ ) δ ppm 7.97 (dd, J=8.60, 5.07 Hz, 1H), 8.06 (d, J=7.50 Hz, 1H ), 8.188.23 (m, 1H), 8.28 (d, J=8.60 Hz, 1H), 8.42-8.47 (m, 2H), 8.77 (d, J=2, 21 Hz, 1H), 8.85 (d, J=2.20 Hz, 1H), 9.21 (s, 1H), 9.23 (dd, J=4.85, 1.32 Hz, 1H) . LC-MS: (ES, m/z): [M+1]+ 509.9.

Example 228.

2-(2-Chloro-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenyl)-2H-1,2,3triazole-4-carboxylic acid, connection 228

1H NMR (400 MHz, DMSO-d6) δ ppm 11.27 (s, 1H), 9.12 (s, 1H), 9.03 (br.d, J=2.21 Hz, 1H) , 8.63 (s, 1H), 8.30 (br.d, J=8.38 Hz, 1H), 8.25 (s, 1H), 7.86-7.97 (m, 3H), 7.74 (d, J=8.60 Hz, 1H), 7.58-7.68 (m, 2H). LC-MS: (ES, m/z): [M+1]+ 527.8.

Example 229.

N-(1H-Pyrazolo[3,4-b]pyridin-5-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 229

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.99 (s, 1H), 9.13 (br.d, J=2.9 Hz, 1H), 8.76 (d, J =1.8 Hz, 1H), 8.66 (s, 1H), 8.62 (s, 1H), 8.39 (d, J=8.6 Hz, 1H), 8.16 (s, 1H ), 8.07-8.00 (m, 1H), 7.99-7.94 (m, 1H), 7.85-7.70

- 326 045333 (m, 2H). LC-MS: (ES, m/z): [M+1]+ 424.0.

Example 230.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyridin-8-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 230

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.35 (br.t, J=7.06 Hz, 1H), 7.90-7.95 (m, 2H), 8.32 (s, 2H), 8.34 (s, 1H), 8.70 (s, 1H), 8.94 (d, J=2.43 Hz, 1H), 8.97 (d, J=6, 84 Hz, 1H), 9.18 (d, J=1.98 Hz, 1H), 11.49 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 465.0.

Example 231.

1-(Benzo[d][1,2,3]thiadiazol-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 231

1H NMR (400 MHz, DMSO-d6) δ ppm 11.32 (s, 1H), 8.85 (s, 1H), 8.73-8.64 (m, 2H), 8.61 ( s, 1H), 8.17 (s, 2H), 8.11-7.95 (m, 2H). LC-MS: (ES, m/z): [M+1]+ 491.9.

Example 232.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylthieno[3,2-b]pyridin-7-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 232

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.66 (s, 3H), 7.49 (s, 1H), 7.59 (d, J=4.85 Hz, 1H), 8.31 (s, 2H), 8.67 (s, 1H), 8.84 (d, J=5.07 Hz, 1H), 8.88 (d, J=2.21 Hz, 1H), 9.11 (d, J=2.20 Hz, 1H), 11.54 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 495.9.

Example 233.

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,5-a]pyridin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 233

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.19 (dd, J=9.15, 6.95 Hz, 1 H), 7.42 (d, J=6.84 Hz, 1H), 7.968.04 (m, 2H), 8.20 (s, 2H), 8.57 (s, 1H), 8.73 (d, J=1.98 Hz, 1H), 8.84 ( s, 1H), 8.95 (d, J=2.21 Hz, 1H), 11.60 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 473.9.

Example 234.

-(3 -Chloro-5 -(1 -(quinolin-5 -yl)-5-(trifluoromethyl)-1 H-pyrazol-4-carboxamido)pyridin-2-yl)-1H1,2,3-triazol-4 -carboxylic acid, compound 234

- 327 045333 ¹ H NMR (400 MHz, methanol^) δ ppm 8.09 (dd, J=8.53, 5.02 Hz, 1H), 8.15 (d, J=7.28 Hz , 1H), 8.29 (t,

J=8.16 Hz, 1H), 8.44-8.53 (m, 3H), 8.78 (d, J=2.26 Hz, 1H), 8.88 (d, J=2.26 Hz, 1H), 8.99 (s, 1H), 9.32 (br.d,

J=5.02 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 528.8.

Example 235.

N-(5-Methoxy-6-(1H-1,2,3-triazol-1 -yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5 -(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 235

1H NMR (400 MHz, DMSO-d6) δ ppm 11.22 (s, 1H), 9.02-9.11 (m, 1H), 8.60-8.66 (m, 1H), 8.53-8.57 (m, 1H), 8.48-8.52 (m, 1H), 8.32-8.37 (m, 1H), 8.25-8.29 (m, 1H), 7.90-8.02 (m, 3H), 7.62-7.73 (m, 2H), 3.85-3.92 (m, 3H). LC-MS: (ES, m/z): [M+1]+ 480.9.

Example 236.

N-(4-Aminobutyl)-3-cyano-5-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamido)picolinamide, compound 236

1H NMR (400 MHz, methanol-a4) δ ppm 1.65-1.87 (m, 3H), 1.69-1.82 (m, 1H), 3.00 (br.s, 2H ), 3.42-3.57 (m, 1H), 3.48 (br.s, 1H), 7.57 (d, J=8.38 Hz, 1H), 8.06 (t, J= 7.39 Hz, 1H), 8.13-8.21 (m, 1H), 8.47-8.53 (m, 1H), 8.57 (d, J=8.38 Hz, 1H), 8.74 (d, J=2.43 Hz, 1H), 8.93 (s, 1H), 9.20 (d, J=2.43 Hz, 1H), 9.85 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 523.0.

Example 237.

2-Cyano-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)benzoic acid, compound 237

1H NMR (400 MHz, DMSO-d6) δ ppm 7.55-7.60 (m, 1H), 7.62-7.67 (m, 1H), 7.86-7.90 (m , 1H), 7.917.97 (m, 1H), 7.99-8.04 (m, 1H), 8.06-8.11 (m, 1H), 8.23 (s, 1H), 8. 30 (d, J=8.38 Hz, 1H), 8.53 (s, 1H), 9.03 (dd, J=4.08, 1.65 Hz, 1H), 11.08 (s, 1H ). LC-MS: (ES, m/z): [M+1]+ 451.9.

Example 238.

N-(4-(4-(Aminomethyl)-1H-pyrazol-1-yl)-3-methylphenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide, compound 238

1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 3H), 3.99 (br.d, J=5.51 Hz, 2H), 7.33 (d, J= 8.60 Hz, 1H), 7.76 (br.d, J=8.60 Hz, 1H), 7.78-7.87 (m, 4H), 7.98-8.02 (m, 1H ), 8.04-8.09 (m, 1H), 8.12 (s, 1H), 8.36 (br.s, 2H), 8.43 (d, J=8.60 Hz, 1H) , 8.60 (s, 1H), 9.16 (d, J=2.65 Hz, 1H), 10.89 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 492.0.

Example 239.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1H-indazol-4-yl)-5 ( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 239

- 328 045333

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.14 (s, 3H), 7.33 (d, J=7.28 Hz, 1H), 7.58 (t, J=7 ,83 Hz, 1H), 7.84 (s, 1H), 7.93 (d, J=8.60 Hz, 1H), 8.30 (s, 2H), 8.53 (s, 1H), 8.86 (d, J=2.21 Hz, 1H), 9.08 (d, J=2.43 Hz, 1H), 11.36 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 479.0.

Example 240.

-Fluorocarbonyl-N-(5-methyl-6-(1 -methyl-1 H-tetrazol-5 -yl)pyridin-3 -yl)-1 -(quinolin-5-yl)-1 Npyrazol-4-carboxamide, connection 240

1H NMR (400 MHz, DMSO-d6) δ ppm 11.37 (1H, s), 9.00-9.08 (2H, m), 8.68 (1H, s), 8.37 ( 1H, s), 8.31 (1H, d, J=8.38 Hz), 7.92-8.00 (1H, m), 7.85-7.92 (1H, m), 7.60 -7.70 (2H, m), 4.19 (3H, s), 2.52 (3H, s). LC-MS: (ES, m/z): [M+1]+ 480.0.

Example 241.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1H-pyrazolo[3,4-b]pyridin- 4-yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 241

1H NMR (400 MHz, DMSO-d6) δ ppm 4.17 (s, 3H), 7.49 (d, J=5.07 Hz, 1H), 8.12 (s, 1H), 8 .32 (s, 2H), 8.65 (s, 1H), 8.83 (d, J=4.85 Hz, 1H), 8.87 (d, J=1.98 Hz, 1H), 9 .10 (d, J=2.21 Hz, 1H), 11.44 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 479.9.

Example 242.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-b]pyridazin-6-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 242

1H NMR (400 MHz, DMSO-06) δ ppm 7.85 (d, J=9.70 Hz, 1H), 8.12 (s, 1H), 8.19 (s, 2H), 8 .54-8.60 (m, 2H), 8.63-8.72 (m, 2H), 8.89 (d, J=2.21 Hz, 1H), 11.55 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 474.9.

Example 243.

Ν-(5-ΧλοΡ-6-(2Η- 1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(1-methoxyisoquinolin-5 -yl)-5 (trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 243

Ή NMR (400 MHz, DMSO-d6) δ ppm 4.10 (s, 3H), 6.56 (d, J=6.17 Hz, 1H), 7.78-7.85 (m, 1H), 8.06 (d, J=6.39 Hz, 1H), 8.10 (d, J=5.95 Hz, 1H), 8.18 (s, 2H), 8.45 (d, J=8.16 Hz, 1H), 8.56 (s, 1H), 8.66 (d, J=2.21 Hz, 1H), 8.83 (d, J=2.21 Hz, 1H) , 11.25 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 514.9.

- 329 045333

Example 244.

2-(2-Chloro-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)phenyl)-2H-1,2,3triazol-4-carboxamide, compound 244

1H NMR (400 MHz, DMSO-d6) δ ppm 11.14 (s, 1H), 9.00-9.08 (m, 1H), 8.95 (s, 1H), 8.58 ( s, 1H), 8.31 (d, J=8.38 Hz, 1H), 8.21 (d, J=1.98 Hz, 1H), 8.04 (s, 1H), 7.93- 7.99 (m, 1H), 7.85-7.92 (m, 2H), 7.74 (d, J=8.60 Hz, 1H), 7.59-7.69 (m, 2H) , 7.59-7.69 (m, 1H). LC-MS: (ES, m/z): [M+1]+ 526.9.

Example 245.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylbenzo[d]thiazol-4-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 245

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.35 (s, 1H), 9.10 (d, J=2.2 Hz, 1H), 8.88 (d, J= 2.2 Hz, 1H), 8.52 (s, 1H), 8.32 (br.s, 1H), 8.30 (s, 2H), 7.70 (d, J=7.3 Hz, 1H), 7.63-7.51 (m, 1H), 2.77 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 496.0.

Example 246.

-(3 -Chloro-5 -(1 -(quinolin-5 -yl)-5-(trifluoromethyl)-1 H-pyrazol-4-carboxamido)pyridin-2-yl)-1H1,2,3-triazol-4 -carboxamide, compound 246

¹ H NMR (400 MHz, methanol-04) δ ppm 7.65 (dd, J=8.49, 4.30 Hz, 1H), 7.76 (d, J=8.82 Hz, 1H ), 7.84 (d, J=7.28 Hz, 1H), 7.95-8.01 (m, 1H), 8.34 (d, J=8.60 Hz, 1H), 8.41 (s, 1H), 8.77 (d, J=2.43 Hz, 1H), 8.84-8.87 (m, 1H), 9.01 (dd, J=4.19, 1.54 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 527.9.

Example 247.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylbenzo[d]thiαzol-7-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 247

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.81 (s, 3H), 7.59-7.73 (m, 2H), 8.14 (d, J=7.72 Hz , 1H), 8.29 (s, 2H), 8.53 (s, 1H), 8.83 (d, J=2.43 Hz, 1H), 9.06 (br.s, 1H), 11 .37 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 495.9.

Example 248.

N-(6-(5-(Aminomethyl)-1H-1,2,3-triazol-1 -yl)-5-chloropyridin-3 -yl)-1 -(quinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 248

- 330 045333

1H NMR (400 MHz, methanol-d4) δ ppm 4.05 (s, 2H), 4.60 (br.s, 2H), 7.61-7.68 (m, 1H), 7, 75 (d, J=7.72 Hz, 1H), 7.83 (d, J=7.28 Hz, 1H), 7.94-8.01 (m, 1H), 8.31-8.35 (m, 2H), 8.39 (s, 1H), 8.73 (d, J=2.43 Hz, 1H), 8.83 (d, J=2.21 Hz, 1H), 9.00 (d, J=4.41 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 513.9.

Example 249.

Methyl 1-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2yl)-1H-1,2,3-triazol- 4-carboxylate, compound 249

1H NMR (400 MHz, chloroform-d) δ ppm 4.03 (s, 3H), 7.48-7.53 (m, 1H), 7.61-7.68 (m, 2H), 7.87 (t, J=7.94 Hz, 1H), 8.05 (s, 1H), 8.28 (s, 1H), 8.38 (d, J=9.26 Hz, 1H), 8.61 (s, 1H), 8.67 (s, 1H), 8.80 (s, 1H), 9.05 (d, J=3.97 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 542.9.

Example 250.

X-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyrimidin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 250

1H NMR (400 MHz, methanol-d4) δ ppm 9.28 (d, J=4.63 Hz, 1H), 9.02-9.21 (m, 1H), 8.89-8, 93 (m, 1H), 8.65-8.71 (m, 1H), 8.32-8.39 (m, 1H), 8.11-8.25 (m, 3H), 7.96- 8.03 (m, 1H). LC-MS: (ES, m/z): [M+1]+ 465.9.

Example 251.

N-(5-Methoxy-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5 -(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 251

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.25 (s, 1H), 9.05-9.12 (m, 1H), 8.63-8.68 (m, 1H) , 8.50-8.57 (m, 1H), 8.31-8.38 (m, 1H), 8.21-8.30 (m, 1H), 8.03-8.10 (m , 1H), 7.92-8.02 (m, 2H), 7.65-7.75 (m, 1H), 3.80-3.87 (m, 1H). LC-MS: (ES, m/z): [M+1]+ 481.0.

Example 252.

1-(Benzo[d]thiazol-4-yl)-N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 252

^1H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (1H, s), 9.49 (1H, s), 8.53 (1H, s), 8.48 (1H, dd , J=8.28, 1.00 Hz), 8.45 (1H, s), 8.20 (2H, s), 7.79-7.83 (1H, m), 7.69-7, 75 (1H, m), 2.57 (3H, s). LC-MS: (ES, m/z): [M+1]+ 504.9.

- 331 045333

Example 253.

N-(5-Chloro-6-(5-(methoxymethyl)-1H-1,2,3-triazol-1 -yl)pyridin-3 -yl)-1 -(quinolin-5 -yl)-5 (trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 253

Ή NMR (400 MHz, methanol^) δ ppm 3.44 (s, 3H), 4.66 (s, 2H), 7.64 (dd, J=8.60, 4.19 Hz, 1H ), 7.75 (d, J=8.38 Hz, 1H), 7.83 (d, J=7.28 Hz, 1H), 7.97 (dd, J=8.60, 7.28 Hz , 1H), 8.33 (d, J=8.60 Hz, 1H), 8.40 (s, 1H), 8.44 (s, 1H), 8.74 (d, J=2.43 Hz , 1H), 8.83 (d, J=2.21 Hz, 1H), 9.00 (dd, J=4.30, 1.65 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 529.0.

Example 254.

Y-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methyl[1,2,4]triazolo[1,5- a]pyridin-5-yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 254

1H NMR (400 MHz, DMSO-d6) δ ppm 11.39 (s, 1H), 9.08 (d, J=2.4 Hz, 1H), 8.86 (d, J=2, 4 Hz, 1H), 8.67 (s, 1H), 8.30 (s, 2H), 8.04 (d, J=9.0 Hz, 1H), 7.86 (dd, J=7, 4, 8.9 Hz, 1H), 7.72 (d, J=6.4 Hz, 1H), 3.34 (s, 131H), 2.44 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 480.0.

Example 255.

3-(3-Cyano-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)pyridin-2-yl)-1methyl-1H-pyrazole-5-carboxylic acid acid, compound 255

1H NMR (400 MHz, methanol-d4) δ ppm 9.08 (1H, d, J=2.20 Hz), 9.00 (1H, br.d, J=3.75 Hz), 8 .71 (1H, d, J=1.98 Hz), 8.38 (1H, s), 8.33 (1H, d, J=8.38 Hz), 7.96 (1H, t, J= 8.05 Hz), 7.83 (1H, d, J=7.72 Hz), 7.71-7.78 (1H, m), 7.64 (1H, dd, J=8.38, 4 .19 Hz), 7.51 (1H, s), 4.27 (3H, s). LC-MS: (ES, m/z): [M+1]+ 533.0.

Example 256.

Methyl 2-(2-chloro-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)phenyl)-2H1,2,3-triazol-4-carboxylate, connection 256

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.11 (s, 1H), 9.27 (s, 1H), 9.04 (dd, J=4.08, 1.65 Hz , 1H), 8.57 (s, 1H), 8.31 (d, J=8.60 Hz, 1H), 8.21 (d, J=2.21 Hz, 1H), 7.93-7 .98 (m, 1H), 7.84-7.92 (m, 2H), 7.76 (d, J=8.60 Hz, 1H), 7.64-7.68 (m, 1H), 7.58-7.63 (m, 1H), 3.86 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 541.9.

Example 257.

N-(5-Cyano-6-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 257

- 332 045333

1H NMR (400 MHz, DMSO-d6) δ ppm 11.29-11.48 (1H, m), 9.20 (1H, d, J=2.51 Hz), 9.01-9, 09 (1H, m), 8.78 (1H, d, J=2.26 Hz), 8.65 (1H, s), 8.27-8.37 (2H, m), 7.96-8 .03 (1H, m), 7.89-7.95 (1H, m), 7.66-7.73 (1H, m), 7.59-7.65 (1H, m), 4.29 (3H, s). LC-MS: (ES, m/z): [M+1]+ 489.9.

Example 258.

Methyl 3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)picolinate, compound 258

^1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3H), 7.57-7.60 (m, 1H), 7.63-7.67 (m, 1H) , 7.89-7.98 (m, 2H), 8.31 (d, J=8.60 Hz, 1H), 8.50 (d, J=1.98 Hz, 1H), 8.55 ( s, 1H), 8.85 (d, J=2.21 Hz, 1H), 9.04 (dd, J=4.19, 1.76 Hz, 1H), 11.19 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 475.9.

Example 259.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridin- 7-yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 259

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.68 (s, 3H), 8.11 (d, J=5.51 Hz, 1H), 8.24-8.32 (m , 3H) 8.46 (s, 1H), 8.64 (s, 1H), 8.86 (d, J=2.65 Hz, 1H), 9.08 (d, J=2.65 Hz, 1H), 11.39 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 479.9.

Example 260.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1 -methyl-1 H-indazol-7-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 260

¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.41 (br.s, 1H), 9.08 (d, J=2.4 Hz, 1H), 8.87 (d, J =2.4 Hz, 1H), 8.57 (s, 1H), 8.36-8.20 (m, 3H), 8.06 (d, J=8.2 Hz, 1H), 7.62 (d, J=7.3 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 3.43 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 479.0.

Example 261.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoroquinolin-8-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 261

1H NMR (400 MHz, methanol^) δ ppm 8.92 (dd, J=4.30, 1.65 Hz, 1H), 8.80 (d, J=2.21 Hz, 1H), 8.71 (d,

- 333 045333

J=2.20 Hz, 1H), 8.64 (dd, J=8.60, 1.54 Hz, 1H), 8.36 (s, 1H), 8.02 (s, 2H), 7, 98 (dd, J=8.38, 5.29 Hz, 1H), 7.677.74 (m, 1H), 7.47-7.57 (m, 1H). LC-MS: (ES, m/z): [M+1]+ 502.9.

Example 262.

N-(5-Cyano-6-(2H-1,2,3-Ίriazol-2-yl)pyridin-3-yl)-1-(1H-pyrazolo[4,3-b]pyridin-7-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 262

1H NMR (400 MHz, DMSO-d6) δ ppm 11.40 (1H, s), 9.12 (1H, d, J=2.65 Hz), 8.88 (1H, d, J= 2.43 Hz), 8.69-8.77 (1H, m), 8.66 (1H, s), 8.56 (1H, s), 8.30 (2H, s), 7.62 ( 1Н, d, J=4.63 Hz). LC-MS: (ES, m/z): [M+1]+ 466.0.

Example 263.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoroisoquinolin-1-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 263

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.68 (br.d, J=8.16 Hz, 1H), 7.93 (t, J=7.50 Hz, 1H), 8.09 (t, J=7.39 Hz, 1H), 8.26-8.34 (m, 3H), 8.64 (s, 2H), 8.88 (d, J=2.65 Hz , 1H), 9.09 (d, J=2.43 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 493.9.

Example 264.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 264

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.33 (br.s, 1H), 8.85 (d, J=2.43 Hz, 1H), 8.60-8.70 (m, 2H), 8.50 (s, 1H), 8.34 (d, J=8.16 Hz, 1H), 8.16 (s, 2H), 8.04 (td, J=7, 72, 1.10 Hz, 1H), 7.89-7.98 (m, 1H), 7.30 (d, J=8.38 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 568.9.

Example 265.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(1-methyl-1H-pyrazolo[3,4-b]pyridine -3-yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 265

1H NMR (400 MHz, DMSO-d6) δ ppm 4.16 (s, 3H), 7.43 (dd, J=8.16, 4.41 Hz, 1H), 8.24 (dd, J=8.16, 1.32 Hz, 1H), 8.30 (s, 2H), 8.59 (s, 1H), 8.75 (dd, J=4.30, 1.21 Hz, 1H ), 8.85 (d, J=2.43 Hz, 1H), 9.08 (d, J=2.43 Hz, 1H), 11.47 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 480.0.

Example 266.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1H-indazol-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 266

- 334 045333

1H NMR (400 MHz, DMSO-d6) δ ppm 4.14 (s, 3H), 7.29-7.34 (m, 1H), 7.54-7.59 (m, 1H), 7.63 (d, J=8.16 Hz, 1H), 7.82 (d, J=8.60 Hz, 1H), 8.30 (s, 2H), 8.55 (s, 1H), 8.85 (d, J=2.65 Hz, 1H), 9.08 (d, J=2.65 Hz, 1H), 11.41 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 479.0.

Example 267.

Methyl 3-(3-cyano-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2yl)-1-methyl-1H-pyrazol-5- carboxylate, compound 267

1H NMR (400 MHz, methanol-d ₄ ) δ ppm 9.30 (1H, dd, J=5.18, 1.43 Hz), 9.10 (1H, d, J=2.43 Hz ), 8.72 (1H, d, J=2.65 Hz), 8.48 (1H, d, J=8.82 Hz), 8.45 (1H, s), 8.43 (1H, d , J=8.60 Hz), 8.27 (1H, t, J=8.05 Hz), 8.13 (1H, d, J=7.06 Hz), 8.06 (1H, dd, J =8.60, 5.07 Hz), 7.53 (1H, s), 4.28 (3H, s), 3.94 (3H, s). LC-MS: (ES, m/z): [M+1]+ 546.9.

Example 268.

N-(5-Cyano-6-( 1 -methyl-1 H-pyrazol-3 -yl)pyridin-3 -yl)-1 -(8-fluoroquinolin-5 -yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide, compound 268

1H NMR (400 MHz, DMSO-d6) δ ppm 11.37 (br.s, 1H), 9.13 (br.d, J=13.6 Hz, 2H), 8.67 (br.s., 1H). d, J=18.3 Hz, 2H), 8.08-7.55 (m, 5H), 6.86 (br.s, 1H), 3.96 (br.s, 3H). LC-MS: (ES, m/z): [M+1]+ 507.0.

Example 269.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,5-naphthyridin-4-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 269

¹ H NMR (400 MHz, chloroform-d) δ ppm 7.81 (dd, J=8.71, 4.08 Hz, 1H), 7.85 (d, J=4.63 Hz, 1H ), 8.04 (s, 2H), 8.29 (s, 2H), 8.59 (d, J=8.82 Hz, 1H), 8.84 (d, J=2.43 Hz, 1H ), 8.98 (d, J=2.65 Hz, 1H), 9.00 (d, J=2.87 Hz, 1H), 9.23 (d, J=4.19 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 476.9.

Example 270.

N-(5-Chloro-6-(5-((dimethylamino)methyl)- 1H-1,2,3-triazol-1 -yl)pyridin-3-yl)-1 -(quinolin-5-yl)- 5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 270

- 335 045333

¹ H NMR (400 MHz, methanol-d4) δ ppm 2.97 (s, 6 H), 4.61 (s, 2H), 8.08 (dd, J=8.71, 5.18 Hz, 1H), 8.13 (d, J=7.50 Hz, 1H), 8.27 (t, J=8.05 Hz, 1H), 8.45-8.53 (m, 3H), 8.74 (s, 1H), 8.77 (d, J=2.21 Hz, 1H), 8.91 (d, J=2.21 Hz, 1H), 9.28-9.32 (m , 1H). LC-MS: (ES, m/z): [M+1]+ 541.9.

Example 271.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-methylbenzo[d]oxazol-7 -yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 271

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.64 (s, 3H), 7.52-7.59 (m, 1H), 7.61-7.67 (m, 1H) , 7.95 (d, J=7.72 Hz, 1H), 8.32 (s, 2H), 8.57 (s, 1H), 8.88 (d, J=2.43 Hz, 1H) , 9.09 (d, J=2.21 Hz, 1H), 11.41 (br.s, 1H). LC-MS: (ES, m/z): [M+1]+ 479.9.

Example 272.

N-(6-(4-(Aminomethyl)-2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 272

1H NMR (400 MHz, DMSO-d6) δ ppm 4.09 (s, 2H), 7.58-7.61 (m, 1H), 7.63-7.67 (m, 1H), 7.88-7.98 (m, 2H), 8.14 (s, 1H), 8.30 (d, J=8.38 Hz, 1H), 8.66 (s, 1H), 8.70 (d, J=1.98 Hz, 1H), 8.91 (d, J=2.20 Hz, 1H), 9.019.06 (m, 1H). LC-MS: (ES, m/z): [M+1]+ 514.0.

Example 273.

X-(5-Chloro-6-(1 -methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1 -(8-fluoroquinolin-5-yl)-5 -(trifluoromethyl)1H-pyrazole -4-carboxamide, compound 273

1H NMR (400 MHz, DMSO-d6) δ ppm 3.92 (s, 3H), 6.77 (d, J=2.21 Hz, 1H), 7.65 (d, J=8, 60 Hz, 1H), 7.73-7.86 (m, 3H), 7.96 (dd, J=8.38, 4.41 Hz, 1H), 8.49 (d, J=1.98 Hz, 1H), 8.64 (s, 1H), 8.92 (d, J=2.20 Hz, 1H), 9.09 (dd, J=4.19, 1.54 Hz, 1H), 11.25 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 516.2.

Example 274.

1-([1,2,4] T riazolo [1,5-a]pyridin-5-yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl) pyridin-3-yl)-5 (trifluoromethyl)-1H-pyrazol-4-carboxamide, compound 274

^1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (d, J=6.62 Hz, 1H), 7.94 (dd, J=8.93, 7.39 Hz, 1H ), 8.20 (dd, J=8.93, 0.99 Hz, 1H), 8.31 (s, 2H), 8.61 (s, 1H), 8.69 (s, 1H), 8 .86 (d, J=2.43 Hz, 1H), 9.07 (d, J=2.43 Hz, 1H), 11.38 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 465.9.

- 336 045333

Example 275.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyrazin-5-yl)-3 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 275

1H NMR (400 MHz, methanol^) δ ppm 9.40 (s, 1H), 9.07 (br.s, 1H), 8.91 (d, J=2.43 Hz, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.15 (br.s, 3H), 7.90 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 466.0.

Example 276.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,7-naphthyridin-4-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 276

1H NMR (400 MHz, DMSO-d6) δ ppm 7.38 (d, J=5.73 Hz, 1H), 8.21 (d, J=4.41 Hz, 1H), 8.31 (s, 2H), 8.74 (s, 1H), 8.78 (br.d, J=5.73 Hz, 1H), 8.91 (d, J=2.43 Hz, 1H), 9 .14 (d, J=2.43 Hz, 1H), 9.36 (d, J=4.41 Hz, 1H), 9.66 (s, 1H), 11.48 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 476.9.

Example 277.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 277

1H NMR (400 MHz, chloroform-d) δ ppm 7.18 (dd, J=9.03, 2.76 Hz, 1H), 7.63 (d, J=7.53 Hz, 1H) , 7.73 (t, J=8.28 Hz, 1H), 7.87 (t, J=8.03 Hz, 1H), 7.96 (s, 2H), 8.16 (s, 1H) , 8.19 (s, 1H), 8.24 (s, 1H), 8.54 (d, J=2.26 Hz, 1H), 8.78 (d, J=2.26 Hz, 1H) . LC-MS: (ES, m/z): [M+1]+ 502.9.

Example 278.

1-(2-Aminobenzo[d]thiazol-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 278

1H NMR (400 MHz, DMSO-d6) δ ppm 7.18 (d, J=7.72 Hz, 1H), 7.42 (t, J=7.94 Hz, 1H), 7.54 (d, J=7.50 Hz, 1H), 7.68 (s, 2H), 8.16 (s, 2H), 8.48 (s, 1H), 8.63 (d, J=2, 43 Hz, 1H), 8.84 (d, J=2.20 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 505.9.

Example 279.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isothiazolo[5,4-b]pyridin-3-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 279

1H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (dd, J=8.16, 4.39 Hz, 1H), 8.20 (s, 2H), 8.61-8, 74 (m, 3H), 8.87 (s, 1H), 9.05 (br.d, J=3.26 Hz, 1H), 11.52 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 491.8.

- 337 045333

Example 280.

N-(5-Cyano-6-(1H-pyrrol-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 280

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.37 (1H, s), 9.08 (1H, br.s), 9.03 (1H, br.s), 8.78 ( 1Н, br.s), 8.64 (1Н, s), 8.34 (1Н, br.d, J=7.94 Hz), 7.96-8.02 (1Н, m), 7.90 -7.96 (1H, m), 7.69 (2H, br.s), 7.55 (2H, br.s), 6.37 (2H, br.s). LC-MS: (ES, m/z): [M+1]+ 474.0.

Example 281.

X-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methoxyisoquinolin-5-yl)-5 (trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 281

1H NMR (400 MHz, DMSO-d6) δ ppm 4.12 (s, 3H), 6.58 (d, J=6.17 Hz, 1H), 7.83 (t, J=7, 94 Hz, 1H), 8.06-8.14 (m, 2H), 8.32 (s, 2H), 8.47 (d, J=8.38 Hz, 1H), 8.59 (s, 1H), 8.89 (d, J=2.43 Hz, 1H), 9.09 (d, J=2.65 Hz, 1H), 11.34 (br.s, 1H). LC-MS: (ES, m/z): [M+1]+ 505.9.

Example 282.

-(2-Aminobenzo[d]thiazol-7 -yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-5 (trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 282

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.25 (d, J=7.72 Hz, 1H), 7.45 (t, J=7.94 Hz, 1H), 7, 52-7.57 (m, 1H), 8.30 (s, 2H), 8.55 (s, 1H), 8.86 (d, J=2.21 Hz, 1H), 9.09 (d , J=2.43 Hz, 1H), 11.49 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 497.2.

Example 283.

N-(6-(1H-1,2,3-Triazol-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-1 -(quinolin-5-yl)-5 -(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 283

1H NMR (400 MHz, DMSO-d6) δ ppm 7.69-7.75 (m, 2H), 7.95-8.04 (m, 3H), 8.36 (d, J=8 ,16 Hz, 1H), 8.69 (d, J=3.31 Hz, 2H), 8.95 (d, J=1.98 Hz, 1H), 9.10 (dd, J=3.53 , 1.98 Hz, 1H), 9.25 (d, J=2.21 Hz, 1H), 11.59 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 518.9.

Example 284.

1-(Benzo[d]isoxazol-3-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 284

- 338 045333 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.49 (1H, s), 8.83 (1H, d, J=2.01 Hz), 8.74 (1H , s), 8.66 (1H, d,

J=2.01 Hz), 8.20 (2H, s), 7.98-8.05 (2H, m), 7.89 (1H, t, J=7.91 Hz), 7.63 ( 1H, t, J=7.53 Hz). LC-MS: (ES, m/z): [M+1]+ 474.9.

Example 285.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-chloroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 285

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.34 (d, J=8.38 Hz, 1H), 7.96-8.07 (m, 2H), 8.18 (s , 2H), 8.47 (d, J=8.16 Hz, 1H), 8.70-8.75 (m, 2H), 8.77 (s, 1H), 8.94 (d, J= 2.21 Hz, 1H), 11.57 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 518.8.

Example 286.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1H-indazol-7-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 286

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.30 (1H, s), 9.11 (1H, d, J=2.21 Hz), 8.88 (1H, d, J =2.43 Hz), 8.55 (1H, s), 8.23-8.35 (3H, m), 8.02 (1H, d, J=8.16 Hz), 7.50 (1H , d, J=7.28 Hz), 7.27 (1H, t, J=7.72 Hz). LCMS: (ES, m/z): [M+1]+ 464.9.

Example 287.

X-(5-Bromo-6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 287

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.49 (s, 1H), 9.07 (br.s, 1H), 8.93-9.00 (m, 1H), 8 .81-8.89 (m,

1H), 8.65-8.73 (m, 1H), 8.55-8.63 (m, 1H), 8.30-8.37 (m, 1H), 7.97 (br.d, J=0.88 Hz, 3H), 7.63-7.75 (m, 2H). LC-MS: (ES, m/z): [M+1]+ 528.8.

Example 288.

N-(5-Chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 288

- 339 045333

1H NMR (400 MHz, DMSO-d6) δ ppm 11.36 (s, 1H), 9.10 (dd, J=1.4, 4.1 Hz, 1H), 9.00 (d, J=2.2 Hz, 1H), 8.64 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.33 (d, J=0.7 Hz, 1H) , 7.97 (dd, J=4.2, 8.4 Hz, 1H), 7.82 (dd, J=8.3, 10.3 Hz, 1H), 7.77 (dd, J=4 ,2, 8.6 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.49 (d, J=0.7 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 502.9.

Example 289.

X-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 289

1H NMR (400 MHz, DMSO-d6) δ ppm 11.35 (br.s, 1H), 9.07 (d, J=2.65 Hz, 1H), 8.86 (d, J= 2.65 Hz, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.34 (d, J=8.38 Hz, 1H), 8.29 (s, 2H) , 8.00-8.07 (m, 1H), 7.90-7.97 (m, 1H), 7.29 (d, J=8.16 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 493.9.

Example 290.

1-(Benzo[d]isothiazol-3-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 290

1H NMR (400 MHz, DMSO-d6) δ ppm 7.60-7.67 (m, 1H), 7.76 (t, J=7.61 Hz, 1H), 8.04 (d, J=8.16 Hz, 1H), 8.16 (s, 2H), 8.39 (d, J=8.38 Hz, 1H), 8.60-8.66 (m, 2H), 8, 83 (d, J=2.21 Hz, 1H), 11.42 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 491.0.

Example 291.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-ul)-1-(2-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 291

¹ H NMR (400 MHz, chloroform-d) δ ppm 8.94 (d, J=2.43 Hz, 1H), 8.78 (d, J=2.43 Hz, 1H), 8, 20 (s, 1H), 8.14 (d, J=8.60 Hz, 1H), 8.09 (s, 1H), 7.97 (s, 2H), 7.81 (t, J=8 .05 Hz, 1H), 7.67 (t, J=8.27 Hz, 1H), 7.56 (d, J=7.06 Hz, 1H), 7.12 (dd, J=9.15 , 2.54 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 494.0.

Example 292.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[2,3-d]pyrimidin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 292

¹ H NMR (400 MHz, DMSO-d6) δ ppm=11.51 (s, 1H), 9.00 (s, 2H), 8.78 (d, J=2.2 Hz, 1H) , 8.58 (s, 1H), 8.39 (d, J=2.2 Hz, 1H), 8.27 (s, 2H), 7.32 (d, J=2.0 Hz, 1H) . LC-MS: (ES, m/z): [M+1]+ 466.9.

- 340 045333

Example 293.

1-(Benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 293

1H NMR (400 MHz, DMSO-d6) δ ppm 11.18 (s, 1H), 8.98 (dd, J=0.9, 8.2 Hz, 1H), 8.84 (d, J=2.2 Hz, 1H), 8.62 (s, 1H), 8.42 (d, J=2.2 Hz, 1H), 8.13-8.08 (m, 1H), 8. 06-8.00 (m, 1H), 7.79 (d, J=2.2 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H), 3.93 (s, 3H ). LC-MS: (ES, m/z): [M+1]+ 505.1.

Example 294.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(thiazolo[5,4-d]pyrimidin-7-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 294

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.42 (br.s, 1H), 9.79 (s, 1H), 9.38 (s, 1H), 9.05 ( d, J=2.6 Hz, 1H), 8.84 (d, J=2.4 Hz, 1H), 8.64 (s, 1H), 8.30 (s, 2H). LC-MS: (ES, m/z): [M+1]+ 483.9.

Example 295.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylimidazo[1,2-a]pyridin-3-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 295

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.51 (s, 1H), 9.09 (d, J=2.2 Hz, 1H), 8.87 (d, J=2 ,4 Hz, 1H), 8.71 (s, 1H), 8.29 (s, 2H), 8.12 (br.d, J=6.6 Hz, 1H), 7.79 (br.d , J=9.3 Hz, 1H), 7.65 (br.t, J=7.6 Hz, 1H), 7.347.12 (m, 1H), 2.28 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 478.9.

Example 296.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinazolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 296

1H NMR (400 MHz, DMSO-d6) δ ppm 11.20-11.63 (m, 1H), 9.43 (s, 1H), 9.05-9.10 (m, 1H), 8.83-8.88 (m, 1H), 8.66-8.71 (m, 1H), 8.17-8.33 (m, 4H), 8.01-8.08 (m, 1H ), 7.89-7.96 (m, 1H). LC-MS: (ES, m/z): [M+1]+ 476.9.

Example 297.

1-(Benzo[d]thiazol-4-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 297

- 341 045333

1H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (1H, s), 9.45 (1H, s), 8.65 (1H, s), 8.49 (1H, s) , 8.44 (1H, dd, J=7.94, 1.10 Hz), 8.28 (2H, s), 7.75-7.82 (1H, m), 7.64-7.73 (1H, m), 2.62-2.66 (3H, m). LC-MS: (ES, m/z):

[M+1]+ 496.1.

Example 298.

1-(Benzo[d]thiazol-4-yl)-N-(5-cyano-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 298

1H NMR (400 MHz, chloroform-d) δ ppm 9.08 (1H, s), 8.66 (1H, s), 8.22 (1H, s), 8.18 (1H, dd, J=7.50, 1.76 Hz), 7.97 (1H, s), 7.92 (2H, s), 7.73 (1H, s), 7.58-7.69 (2H, m ), 2.47 (3H, s). LC-MS: (ES, m/z): [M+1]+ 495.1.

Example 299.

N-(6-(4-Amino-2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1-(benzo[d]thiazol-4-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 299

¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.15 (1H, s), 9.45 (1H, s), 8.78 (1H, d, J=2.21 Hz), 8.57 (1H, d, J=2.21 Hz), 8.52 (1H, s), 8.44 (1H, dd, J=8.16, 1.10 Hz), 7.76-7 .81 (1H, m), 7.64-7.72 (1H, m), 7.31 (1H, s). LC-MS: (ES, m/z): [M+1]+ 506.1.

Example 300.

1-(Benzo[d]thiazol-4-yl)-N-(2,5-dimethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)1H-pyrazole-4-carboxamide, compound 300

^1H NMR (400 MHz, chloroform-d) δ ppm 9.08 (1H, s), 8.60 (1H, br.s), 8.23 (1H, br.s), 8.18 (1H, dd, J=7.50, 1.54 Hz), 7.88 (2H, s), 7.73 (1H, br.s), 7.59-7.68 (2H, m), 2.62 (3H, br.s), 2.43 (3H, s). LC-MS: (ES, m/z): [M+1]+ 485.0.

Example 301.

1-(Benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 301

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.98 (s, 1H), 8.97 (d, J=8.2 Hz, 1H), 8.57 (s, 1H), 8.28 (d, J=7.3 Hz, 1H), 8.20 (s, 2H), 8.12-8.07 (m, 1H), 8.06-7.99 (m, 1H) , 7.88 (d, J=10.4 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 508.8.

Example 302.

K-(5-Chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 302

- 342 045333

^1H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 9.72 (s, 1H), 8.90 (s, 1H), 8.56 (s, 1H ), 8.24 (d, J=7.28 Hz, 1H), 8.17 (s, 2H), 7.93 (td, J=8.16, 5.51 Hz, 1H), 7.86 (d, J=10.36 Hz, 1H), 7.68 (dd, J=10.36, 7.72 Hz, 1H), 7.14 (d, J=8.60 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 519.9.

Example 303.

1-(Benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-2-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 303

1H NMR (400 MHz, DMSO-d6) δ ppm 10.65 (s, 1H), 8.98 (d, J=8.4 Hz, 1H), 8.61 (s, 1H), 8 .32 (s, 1H), 8.26 (d, J=2.2 Hz, 1H), 8.13-8.07 (m, 1H), 8.06-7.99 (m, 1H), 7.81 (s, 1H), 6.55 (s, 1H), 2.53 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 504.9.

Example 304.

N-(5-Chloro-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 304

1H NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s, 1H), 9.06 (t, J=2.54 Hz, 1H), 8.89 (s, 1H), 8 ,60-8.75 (m, 2H), 8.33 (d, J=8.38 Hz, 1H), 7.88-8.03 (m, 3H), 7.68 (d, J=2 .65 Hz, 2H), 2.34 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 499.0.

Example 305.

N-(5-Methyl-6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1 Npyrazol-4- carboxamide, compound 305

1H NMR (400 MHz, DMSO-d6) δ ppm 11.16 (1H, s), 9.03-9.10 (1H, m), 8.92 (1H, s), 8.62 ( 1H, s), 8.33 (1H, d, J=8.38 Hz), 8.29 (1H, d, J=1.76 Hz), 7.95-8.03 (1H, m), 7.88-7.94 (1H, m), 7.64-7.72 (2H, m), 4.44 (3H, s), 2.55 (3H, s). LC-MS: (ES, m/z): [M+1]+ 480.0.

Example 306.

1-(Benzo[d]thiazol-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 306

- 343 045333

1H NMR (400 MHz, DMSO-d6) δ ppm 11.26 (1H, s), 9.48 (1H, s), 8.88 (1H, d, J=2.43 Hz), 8 .68 (1H, d,

J=2.21 Hz), 8.54 (1H, s), 8.47 (1H, dd, J=8.05, 0.99 Hz), 8.19 (2H, s), 7.82 ( 1H, dd, J=7.61, 0.99 Hz), 7.68-7.75 (1H, m). LC-MS: (ES, m/z): [M+1]+ 490.9.

Example 307.

X-(5-Chloro-6-(2H-tetrazol-5-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 307

1H NMR (400 MHz, DMSO-d6) δ ppm 11.35 (1H, s), 9.05 (2H, br.s), 8.61 (2H, s), 8.32 (1H, br.d, J=8.16 Hz), 7.87-8.02 (2H, m), 7.60-7.73 (2H, m). LC-MS: (ES, m/z): [M+1]+ 485.9.

Example 308.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 308

1H NMR (400 MHz, DMSO-d6) δ ppm 11.36 (s, 1H), 9.13-9.05 (m, 2H), 8.87 (d, J=2.6 Hz, 1H), 8.59 (s, 1H), 8.29 (s, 2H), 7.97 (dd, J=4.3, 8.5 Hz, 1H), 7.82 (dd, J=8 ,4, 10.4 Hz, 1H), 7.77 (dd, J=4.2, 8.6 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 493.9.

Example 309.

X-(5-Chloro-6-(2H-1,2,3-triazol-4-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 309

1H NMR (400 MHz, DMSO-d6) δ ppm 11.46 (s, 1H), 9.09-9.16 (m, 1H), 9.02 (d, J=2.20 Hz, 1H), 8.72 (s, 1H), 8.57 (d, J=1.98 Hz, 1H), 8.33-8.43 (m, 2H), 7.93-8.06 (m , 2H), 7.72-7.84 (m, 2H). LC-MS: (ES, m/z): [M+1]+ 484.9.

Example 310.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylthieno[3,2-b]pyridin-7-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 310

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.46-3.47 (m, 3H), 7.70 (d, J=4.85 Hz, 1H), 7.97 ( d, J=0.88 Hz, 1H), 8.32 (s, 2H), 8.68 (s, 1H), 8.88 (d, J=2.65 Hz, 1H), 8.94 ( d, J=4.85 Hz, 1H), 9.10 (d, J=2.43 Hz, 1H), 11.54 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 495.9.

Example 311.

1-(Benzo[d]oxazol-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 311

- 344 045333

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.84-11.15 (m, 1H), 11.50 (br.s, 1H), 9.15 (br.s, 1H) , 8.92 (s,

2H), 8.62 (s, 1H), 8.31 (s, 2H), 8.10 (br.d, J=3.8 Hz, 1H), 7.69 (br.s, 2H). LC-MS: (ES, m/z): [M+1]+ 465.9.

Example 312.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoronaphthalen-1-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 312

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.59 (1H, s), 9.20 (1H, d, J=2.01 Hz), 8.95 (1H, d, J=2.01 Hz), 8.70 (1H, s), 8.33 (2H, s), 8.24 (1H, br.d, J=8.28 Hz), 7.88 (1H, dd, J=8.16, 4.64 Hz), 7.72-7.83 (2H, m), 7.58 (1H, br.t, J=9.16 Hz), 7.17 (1H , br.d, J=8.03 Hz). LC-MS: (ES, m/z): [M+1]+ 492.9.

Example 313.

Methyl 2-cyano-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)benzoate, compound 313

1H NMR (400 MHz, DMSO-d6) δ ppm 3.91 (s, 3H), 7.62-7.72 (m, 2H), 7.90-8.02 (m, 2H), 8.15-8.21 (m, 2H), 8.32-8.39 (m, 2H), 8.60 (s, 1H), 9.07 (dd, J=3.97, 1.76 Hz, 1H), 11.29 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 451.9.

Example 314.

-(Benzo[d] [1,2,3]thiadiazol-7-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin- 3-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 314

1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1H), 8.99 (d, J=8.4 Hz, 1H), 8.70 (s, 1H), 8 .63 (s, 1H), 8.32 (s, 2H), 8.15-8.08 (m, 1H), 8.07-8.01 (m, 1H), 2.67 (s, 3H ). LC-MS: (ES, m/z): [M+1]+ 496.9.

Example 315.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[3,2-d]pyrimidin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 315

1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (d, J=5.73 Hz, 1H), 8.32 (s, 2H), 8.62-8.74 (m, 2H), 8.83 (d, J=2.43 Hz, 1H), 9.05 (d, J=2.21 Hz, 1H), 9.22 (s, 1H), 11.59 (br. s, 1H). LC-MS: (ES, m/z): [M+1]+ 482.9.

Example 316.

1-(Benzo[d]thiazol-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide, compound 316

- 345 045333

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.27 (s, 1H), 9.46 (s, 1H), 9.07 (d, J=2.4 Hz, 1H), 8.86 (d, J=2.6 Hz, 1H), 8.53-8.42 (m, 2H), 8.30 (s, 2H), 7.80 (d, J=6.6 Hz , 1H), 7.74-7.64 (m, 1H). LC-MS: (ES, m/z): [M+1]+ 481.9.

Example 317.

X-(5-Chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 317

^1H NMR (400 MHz, DMSO-d6) δ ppm 10.44 (s, 1H), 9.76 (s, 1H), 8.94 (s, 1H), 8.62 (s, 1H ), 8.15-8.20 (m, 2H), 7.97 (td, J=8.21, 5.40 Hz, 1H), 7.89 (s, 1H), 7.67-7, 76 (m, 2H), 7.17 (d, J=8.38 Hz, 1H), 2.38 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 516.0.

Example 318.

N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-methylpyrazolo[1,5-a]pyridin- 4yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 318

1H NMR (400 MHz, DMSO-d6) δ ppm 10.65 (s, 1H), 8.54 (s, 1H), 8.44 (s, 1H), 8.19 (s, 2H) , 8.17 (d, J=2.2 Hz, 1H), 7.54 (d, J=7.3 Hz, 1H), 7.04 (d, J=7.7 Hz, 1H), 6 .41 (d, J=2.2 Hz, 1H), 2.80 (s, 3H), 2.56 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 502.2.

Example 319.

-(Pyrazolo [1,5-a]pyridin-4-yl)-5 -(trifluoromethyl)-X-(2-(trifluoromethyl)pyridin-4-yl)-1Hpyrazol-4-carboxamide, compound 319

1H NMR (400 MHz, DMSO-d6) δ ppm 6.32 (dd, J=2.21, 0.66 Hz, 1H), 7.07 (t, J=7.17 Hz, 1H) , 7.56 (d, J=7.28 Hz, 1H), 7.94 (dd, J=5.51, 1.98 Hz, 1H), 8.11 (d, J=2.43 Hz, 1H), 8.21 (d, J=1.76 Hz, 1H), 8.53 (s, 1H), 8.67 (d, J=5.73 Hz, 1H), 8.94 (d, J=7.06 Hz, 1H), 11.28 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 440.9.

Example 320.

1-(8-Fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4carboxamide, compound 320

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.12 (d, J=8.38 Hz, 1H), 7.69 (dd, J=10.36, 7.94 Hz, 1H ), 7.94 (td, J=8.21, 5.40 Hz, 1H), 8.01 (br.s, 1H), 8.27 (br.s, 1H), 8.64-8, 72 (m, 2H), 8.92 (s, 1H), 9.73 (s, 1H), 11.43 (br.s, 1H). LC-MS: (ES, m/z): [M+1]+ 469.9.

Example 321.

N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(thieno[2,3-c]pyridin-4- yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 321

- 346 045333

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.61 (1H, s), 9.52 (1H, s), 8.65 (1H, s), 8.57 (1H, s ), 8.43 (1H, s), 8.34 (1H, d, J=5.51 Hz), 8.16-8.18 (2H, m), 7.14-7.21 (1H, m), 2.55 (3H, s). LC-MS: (ES, m/z): [M+1]+ 505.1.

Example 425.

N-(5-Cyαno-6-(2H-1,2,3-triazol-2-yl)niridin-3-yl)-1-(pyrazolo[1,5-α]pyrazin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 425

1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H), 9.02-9.09 (m, 2H), 8.84 (d, J=2.43 Hz, 1H), 8.62 (s, 1H), 8.37 (d, J=2.43 Hz, 1H), 8.30 (s, 2H), 7.96 (d, J=4.63 Hz, 1H), 7.11 (dd, J=2.32, 0.99 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 465.9.

Example 449.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 449

LCMS (ESI): mass calculated for C21H12C1F3N8O - 484.1, obtained m/z - 485.3 [M+H]+.

1H NMR (400 MHz, DMSO-06) δ ppm 7.09 (d, J=6.1 Hz, 1H), 7.89-7.95 (m, 1H), 8.12 (d, J=6.9 Hz, 1H), 8.20 (s, 2H), 8.48 (d, J=8.5 Hz, 1H), 8.61 (s, 1H), 8.64 (d, J=5.7 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.88 (d, J=2.0 Hz, 1H), 9.56 (s, 1H) , 11.28 (br.s, 1H)

Example 450.

No.(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4- carboxamide, compound 450

LCMS (ESI): mass calculated for C ₂₁ H ₁₂ ClF ₃ N ₈ O - 484.1, obtained m/z - 485.3 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.34 (d, J=8.1 Hz, 1H), 7.77 (td, J=7.6, 1.0 Hz, 1H ), 7.91 (d, J=4.5 Hz, 1H), 7.95 (ddd, J=8, 4, 7.0, 1.6 Hz, 1H), 8.20 (s, 2H) , 8.26 (d, J=8.5 Hz, 1H), 8.66 (s, 1H), 8.69 (d, J=2, 0 Hz, 1H), 8.87 (d, J= 2.4 Hz, 1H), 9.19 (d, J=4.5 Hz, 1H), 11.24-11.35 (m, 1H).

Following the procedure described in Example 59 above, and selecting and replacing appropriate reagents, starting materials and purification methods and adjusting reaction temperatures, times and other variables or parameters as necessary or desired, which should be understandable to those skilled in the art, the following compounds were obtained.

Example 93.

N-(3-Chloro-4-methoxyphenyl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 10

- 347 045333

1H NMR (400 MHz, DMSO-d6) δ ppm 3.92 (s, 3H), 6.94 (d, J=8.61 Hz, 1H), 7.51 (d, J=8, 22 Hz, 1H),

7.65 (d, J=7.43 Hz, 1H), 7.69-7.85 (m, 4 N), 8.06 (d, J=8.22 Hz, 1H), 8.18 ( s, 1H), 8.66 (d, J=5.87 Hz, 1H), 8.74 (s, 1H). LCMS (ESI): m/z - 446.9 [M+H]+.

Example 94.

X-(3-Chloro-4-( 1 H-pyrazol-1 -yl)phenyl)-1 -(isoquinolin-8-yl)-5-(trifluoromethyl)-1 I-pyrazol-4carboxamide, compound 12

1H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (s, 1H), 8.92 (s, 1H), 8.74 (d, J=6.1 Hz, 1H), 8 .63 (s, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.34 (d, J=6.1 Hz, 1H), 8.17-8.11 (m, 2H), 8.11-8.05 (m, 2H), 7.83 (dd, J=2.2, 8.7 Hz, 1H), 7.73 (d, J=1.4 Hz, 1H ), 7.59 (d, J=8.8 Hz, 1H), 7.62-7.57 (m, 1H), 6.56-6.46 (m, 1H). LCMS (ESI): m/z 482.9 [M+H]+.

Example 95.

X-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1I-pyrazole-4carboxamide, compound 13

1H NMR (400 MHz, DMSO-d6) δ ppm 7.97 (br.s, 2H), 8.07 (d, J=4.70 Hz, 1H), 8.29 (br.s, 1H), 8.61 (br.s, 2H), 8.67 (d, J=5.09 Hz, 1H), 8.81 (br.s, 1H), 9.26 (br.s, 1H ), 11.61 (br.s, 1H). LCMS (ESI): m/z 477.0 [M+H]+.

Example 96.

N-(4-(2-Aminopyrimidin-4-yl)-3-chlorophenyl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole, compound 14

1H NMR (400 MHz, DMSO-d6) δ ppm 11.27 (s, 1H), 8.91 (s, 1H), 8.74 (d, J=6.1 Hz, 1H), 8 .67 (s, 1H), 8.49 (d, J=6.3 Hz, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.33 (d, J=6, 1 Hz, 1H), 8.17-8.10 (m, 2H), 8.09-8.04 (m, 1H), 7.92 (dd, J=2.0, 8.6 Hz, 1H ), 7.74 (d, J=8.6 Hz, 1H), 7.24 (d, J=6.3 Hz, 1H), 4.46 (br.s, 15H), 5.16-3 .77 (m, 1H), 3.91 (br.s, 1H), 5.16-3.77 (m, 1H). LCMS (ESI): m/z - 509.9 [M+H]+.

Example 97.

X-(5-Chloro-6-(1I-pyrazol-1-yl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1I-pyrazol4-carboxamide, compound 15

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.54 (br.s, 1H), 7.78 (s, 1H), 8.09-8.29 (m, 3H), 8 ,40-8.53 (m, 2H), 8.61-8.70 (m, 1H), 8.65 (br.s, 1H), 8.77 (br.s, 2H), 8.91 (br.s, 1H), 9.00-9.14 (m, 1H), 9.06 (br.s, 1H), 11.54 (br.s, 1H). LCMS (ESI): m/z - 483.9 [M+H]+.

Example 98.

N-(5-Chloro-6-(1,1-dioxidoizothiazolidin-2-yl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide, connection 20

- 348 045333

1H NMR (400 MHz, chloroform-d) δ ppm 8.78 (s, 1H), 8.66 (d, J=5.3 Hz, 1H), 8.55 (d, J=2, 2 Hz, 1H), 8.53 (br.s, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.25 (s, 1H), 8.07 (d, J= 8.4 Hz, 1H), 7.86-7.82 (m, 1H), 7.82-7.79 (m, 1H), 7.67 (d, J=7.1 Hz, 1H), 4.11 (t, J=7.1 Hz, 2H), 3.28 (t, J=7.5 Hz, 2H), 2.67-2.61 (m, 2H). LCMS (ESI): m/z - 536.9 [M+H]+.

Example 99.

N-(5-Chloro-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 30

1H NMR (400 MHz, methanol^) δ ppm 2.46-2.49 (m, 1H), 2.48 (s, 2H), 7.87 (d, J=7.28 Hz, 1H ), 7.98 (dd, J=8.27, 7.39 Hz, 1H), 8.04 (dd, J=5.95, 0.88 Hz, 1H), 8.26 (d, J= 8.60 Hz, 1H), 8.41 (s, 1H), 8.62 (d, J=5.73 Hz, 1H), 8.66 (s, 1H), 8.70 (d, J= 2.43 Hz, 1H), 8.80 (d, J=2.43 Hz, 1H), 8.87 (s, 1H). LCMS (ESI): m/z 498.9 [M+H] ⁺ .

Example 100.

N-(3-Chloro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1 -(isoquinolin-8-yl)-5 -(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 31

1H NMR (400 MHz, methanol-d ₄ ) δ ppm 2.44 (s, 3H), 7.87 (d, J=7.28 Hz, 1H), 7.95-8.02 (m , 1H), 8.04 (d, J=5, 95 Hz, 1H), 8.09 (s, 1H), 8.27 (d, J=8.38 Hz, 1H), 8.43 (s , 1H), 8.63 (d, J=5.73 Hz, 1H), 8.66 (s, 1H), 8.75 (d, J=2.43 Hz, 1H), 8.85 (d , J=2.43 Hz, 1H). LCMS (ESI): m/z - 498.9 [M+H] ⁺ .

Example 101.

X-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 19

1H NMR (400 MHz, methanolO δ ppm 8.14 (s, 2H), 8.20 (d, J=7.50 Hz, 1H), 8.36 (t, J=7.94 Hz, 1H), 8.52 (s, 1H), 8.56 (d, J=8.38 Hz, 1H), 8.64 (d, J=6, 17 Hz, 1H), 8.77 (d, J=6, 17 Hz, 1H), 8.92 (d, J=2.65 Hz, 1H), 9.10 (br.s, 1H), 9.28 (s, 1H).LCMS (ESI) : m/z - 476.0 [M+H] ⁺ .

Example 102.

N-(5-Chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 22

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.93 (d, J=2.2 Hz, 1H), 8.67 (d, J=5.9 Hz, 1H), 8, 60 (s, 1H), 8.588.53 (m, 2H), 8.33 (d, J=0.8 Hz, 1H), 8.29 (dd, J=1.7, 7.3 Hz, 1H ), 8.08-8.04 (m, 1H), 8.00-7.94 (m, 2H), 7.50 (s, 1H). LCMS (ESI): m/z - 531.0 [M+H] ⁺ .

- 349 045333

Example 103.

N-(3-Chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound eleven

1H NMR (400 MHz, chloroform-d) δ ppm 7.61-7.69 (m, 3H), 7.79-7.86 (m, 2H), 7.91 (s, 2H), 8.02-8.11 (m, 3H), 8.24 (s, 1H), 8.69 (d, J=5.67 Hz, 1H), 8.75 (s, 1H). LCMS (ESI): m/z -531.0 [M+H] ⁺ .

Example 104.

N-(3-Chloro-4-(1H-1,2,3-triazol-1-yl)phenyl)-1 -(isoquinolin-8-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamide, connection 18

1H NMR (400 MHz, chloroform-d) δ ppm 7.63-7.70 (m, 3H), 7.80-7.87 (m, 2H), 7.90 (s, 1H), 8.01-8.11 (m, 3H), 8.15 (s, 1H), 8.26 (s, 1H), 8.70 (d, J=5.67 Hz, 1H), 8.76 (s, 1H). LCMS (ESI): m/z - 483.9 [M+H]+.

Example 105.

N-(3 -Chloro-4-(3 -methyl-1H-1,2,4-triazol-1 -yl)phenyl)-1 -(isoquinolin-8-yl)-5 -(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 29

1H NMR (400 MHz, methanol^) δ ppm 2.58 (s, 3H), 7.70 (d, J=8.61 Hz, 1H), 7.91 (dd, J=8.61 , 2.15 Hz, 1H), 8.21-8.28 (m, 2H), 8.40 (t, J=7.92 Hz, 1H), 8.48 (s, 1H), 8.60 (d, J=8.41 Hz, 1H), 8.70-8.75 (m, 1H), 8.768.82 (m, 1H), 9.40 (s, 1H), 9.56 (s, 1H). LCMS (ESI): m/z - 497.9 [M+H] ⁺ .

By following the procedure described in Example 180 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as needed or desired, within the understanding of those skilled in the art, was obtained the following connections.

Example 322.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(dimethylamino)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 322

1H NMR (400 MHz, DMSO-d6) δ ppm 11.43 (s, 1H), 8.89 (d, J=2.21 Hz, 1H), 8.69 (d, J=2, 21 Hz, 1H), 8.61 (s, 1H), 8.33 (d, J=8.60 Hz, 1H), 8.21 (s, 1H), 8.16 (s, 2H), 7 .76-7.83 (m, 1H), 7.63-7.72 (m, 1H), 7.00 (d, J=7.94 Hz, 1H), 3.29 (s, 6H). LC-MS: (ES, m/z): [M+1] ⁺ 527.9.

Example 323.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(methylamino)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 323

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.54 (s, 1H), 8.95 (d, J=2.21 Hz, 1H), 8.74 (d, J=2 ,21 Hz, 1H), 8.70 (s, 2H), 8.26 (s, 1H), 8.20 (s, 2H), 7.89-7.96 (m, 1H), 7.78 -7.86 (m, 1H), 7.03 (d, J=8.16 Hz, 1H), 3.18 (br.d, J=2.65 Hz, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 513.9.

- 350 045333

Example 324.

K-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoro-1-(methylamino)isoquinolin-4-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 324

1H NMR (400 MHz, methanol^) δ ppm 3.33 (d, J=1.76 Hz, 3H), 6.98 (br.d, J=8.82 Hz, 1H), 7, 61-7.70 (m, 1H), 7.93-8.01 (m, 1H), 8.04 (s, 2H), 8.14 (d, J=1.54 Hz, 1H), 8 .43 (s, 1H), 8.71 (d, J=2.20 Hz, 1H), 8.80 (br.s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 532.0.

Example 325.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoro-1-(methylamino)isoquinolin-4-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 325

1H NMR (400 MHz, DMSO-d6) δ ppm 3.13 (s, 3H), 6.76 (d, J=8.16 Hz, 1H), 7.56 (dd, J=13, 34, 8.05 Hz, 1H), 7.83 (td, J=8.16, 5.29 Hz, 1H), 8.23 (s, 1H), 8.28 (s, 2H), 8, 54 (br.d, J=10.80 Hz, 1H), 8.65 (s, 1H), 8.91 (d, J=2.43 Hz, 1H), 9.16 (d, J=2 .43 Hz, 1H), 11.57 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 522.9.

Example 326.

1-(8-Aminoquinolin-5-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 326

1H NMR (400 MHz, methanol-d4) δ ppm 9.07 (d, J=2.4 Hz, 1H), 8.90 (d, J=2.6 Hz, 1H), 8.83 -8.76 (m, 1H), 8.31 (s, 1H), 8.13 (s, 2H), 7.51-7.48 (m, 2H), 7.45 (d, J=8 .2 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 491.0.

Example 327.

1-(1-Aminoisoquinolin-4-yl)-K-(5-chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 327

1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 9.45 (br.s, 2H), 8.73 (d, J=8.16 Hz, 1H) , 8.56 (s, 1H), 8.32 (s, 1H), 8.27 (d, J=7.28 Hz, 1H), 8.21 (s, 2H), 7.99-8, 06 (m, 1H), 7.85-7.93 (m, 2H), 7.09 (d, J=8.16 Hz, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 517.0.

Example 328.

1-(1 - Aminoisoquinolin-5 -yl)-K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 328

- 351 045333

1H NMR (400 MHz, methanol^) δ ppm 9.07 (s, 1H), 8.91 (s, 1H), 8.67 (d, J=8.60 Hz, 1H), 8, 42 (s, 1H), 8.07-8.17 (m, 3H), 7.93 (t, J=8.16 Hz, 1H), 7.68 (br.d, J=7.28 Hz , 1H), 6.45 (d, J=6.84 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 491.0.

Example 329.

1-(2-Aminoquinolin-4-yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 329

1H NMR (400 MHz, methanol^) δ ppm 9.07 (br.s, 1H), 8.90 (s, 1H), 8.46 (s, 1H), 8.37 (d, J =8.38 Hz, 1H), 8.15 (br.s, 2H), 7.96-8.02 (m, 1H), 7.90 (d, J=8.38 Hz, 1H), 7 .74 (t, J=7.83 Hz, 1H), 6.99 (s, 1H). LCMS: (ES, m/z): [M+1]+ 490.9.

Example 330.

1-(1-Aminoisoquinolin-5-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 330.

1H NMR (400 MHz, methanol-d ₄ ) δ ppm 6.25 (d, J=6.17 Hz, 1H), 7.65-7.70 (m, 1H), 7.79 (d , J=6.17 Hz, 1H), 7.83 (d, J=7.50 Hz, 1H), 8.04 (s, 2H), 8.37 (s, 1H), 8.42 (d , J=8.38 Hz, 1H), 8.73 (d, J=2.20 Hz, 1H), 8.81 (d, J=2.21 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 499.9.

Example 331.

-(2-Aminoquinolin-5-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1 Npyrazole -4-carboxamide, compound 331

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.16 (d, J=9.70 Hz, 1H), 7.60 (d, J=9.48 Hz, 1H), 7, 69 (d, J=7.06 Hz, 1H), 7.89-7.98 (m, 2H), 8.17 (s, 2H), 8.67 (s, 1H), 8.70 (d , J=2.20 Hz, 1H), 8.92 (d, J=2.20 Hz, 1H), 11.46 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 499.9.

Example 332.

-(2-Aminoquinolin-5-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide, compound 332

- 352 045333

1H NMR (400 MHz, DMSO-d6) δ ppm 7.14-7.21 (m, 1H), 7.62 (d, J=9.70 Hz, 1H), 7.67-7, 74 (m, 1H), 7.90-7.99 (m, 2H), 8.30 (s, 2H), 8.71 (s, 1H), 8.93 (d, J=2.43 Hz , 1H), 9.18 (d, J=2.21 Hz, 1H), 11.61 (br.s, 1H). LC-MS: (ES, m/z): [M+1]+ 490.9.

Example 333.

1-(1-Aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-5 (trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 333

1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 9.54 (br.s, 1H), 8.72 (d, J=8.38 Hz, 1H) , 8.56 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 8.01 (t, J=7.94 Hz, 1H), 7.87 (t, J=7.72 Hz, 1H), 7.76 (s, 1H), 7.05 (br.d, J=8.16 Hz, 1H), 6.73 (s, 1H), 3.90 (s, 3H), 2.49 (br.s, 3H). LC-MS: (ES, m/z): [M+1]+ 526.9.

Example 334.

1-(1-Aminoisoquinolin-4-yl)-N-(2,5-dimethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide, compound 334

1H NMR (400 MHz, DMSO-d6) δ ppm 10.59 (s, 1H), 9.69 (br.s, 2H), 8.78 (d, J=8.2 Hz, 1H) , 8.62 (s, 1H), 8.35 (s, 1H), 8.13 (s, 2H), 8.08-8.02 (m, 2H), 7.91 (t, J=7 .7 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 2.50 (br.s, 2H), 2.50-2.49 (m, 1H), 2.23 (s, 3H).

LC-MS: (ES, m/z): [M+1]+ 494.0.

Example 335.

1-(1-Aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 335

1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 8.98 (br.s, 2H), 8.65 (d, J=8.38 Hz, 1H) , 8.56 (s, 1H), 8.22 (s, 1H), 8.15 (s, 2H), 7.90-7.96 (m, 1H), 7.86 (s, 1H), 7.80 (t, J=7.39 Hz, 1H), 7.66 (s, 1H), 7.04 (br.d, J=8.16 Hz, 1H), 2.36 (s, 3H ). LC-MS: (ES, m/z): [M+1]+ 512.9.

Example 336.

1-(1-Aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)-5(trifluoromethyl)-1H-pyrazole -4-carboxamide, compound 336

1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H), 6.55 (dd, J=2.43, 1.76 Hz, 1H), 6.94 (d, J=8.38 Hz, 1H), 7.50 (s, 2H), 7.57-7.63 (m, 1H), 7.69-7.75 (m, 1H), 7.80 (d , J=1.10 Hz, 1H), 7.97 (s, 1H), 8.26 (d, J=1.98 Hz, 1H), 8.29-8.37 (m, 2H), 8 .46 (s, 1H), 10.53 (br.s, 1H). LC-MS: (ES, m/z): [M+1]+ 513.1.

Example 337.

1-(1-Aminoisoquinolin-4-yl)-N-(5-cyano-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-353 045333 (trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 337

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.50 (s, 1H), 9.09-9.43 (m, 2H), 8.67 (d, J=8.16 Hz, 1H), 8.56 (s, 1H), 8.22-8.30 (m, 1H), 8.27 (s, 2H), 8.14 (s, 1H), 8.05 (s , 1H), 7.95-8.01 (m, 1H), 7.84 (t, J=7.61 Hz, 1H), 7.05 (br.d, J=8.38 Hz, 1H) , 2.47 (br.s, 3H). LC-MS: (ES, m/z): [M+1]+ 504.1.

Example 338.

1-(1-Aminoisoquinolin-4-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 338

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.89 (s, 1H), 9.32 (br.s, 2H), 8.70-8.75 (m, 1H), 8.66 (d, J=8.60 Hz, 2H), 8.32 (s, 2H), 8.30 (s, 1H), 7.96-8.02 (m, 1H), 7.85 (t, J=7.61 Hz, 1H), 7.07 (d, J=8.16 Hz, 1H), 2.68 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 505.1.

Example 339.

1-(1-Aminoisoquinolin-4-yl)-5-(trifluoromethyl)-X-(2-(trifluoromethyl)pyridin-4-yl)-1 H-pyrazol-4carboxamide, compound 339

1H NMR (400 MHz, DMSO-d6) δ ppm 7.05 (d, J=7.94 Hz, 1H), 7.84-7.91 (m, 1H), 7.97-8, 03 (m, 2H), 8.28 (d, J=1.76 Hz, 1H), 8.31 (s, 1H), 8.63 (s, 1H), 8.66-8.74 (m , 2H), 9.37 (br.s, 2H), 11.42 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 467.1.

Example 377.

1-(1-Aminoisoquinolin-4-yl)-N-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide, compound 377

1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 9.23-10.37 (m, 2H), 9.07 (d, J=1.98 Hz, 1H), 8.77 (d, J=8.38 Hz, 1H), 8.66 (s, 1H), 8.58 (d, J=2.21 Hz, 1H), 8.35 (s, 1H), 7.97-8.05 (m, 1H), 7.83-7.91 (m, 1H), 7.02 (d, J=7.94 Hz, 1H), 2.60 (d , J=1.54 Hz, 3H). LC-MS: (ES, m/z): [M+1]+ 480.9.

Example 340.

1-(1-Aminoisoquinolin-4-yl)-N-(2-cyanopyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 340

1H NMR (400 MHz, DMSO-d6) δ ppm 7.06 (d, J=8.16 Hz, 1H), 7.86-7.92 (m, 1H), 7.99-8, 08 (m, 2H), 8.35 (d, J=3.53 Hz, 2H), 8.66-8.72 (m, 2H), 8.76 (br.d, J=8.60 Hz , 1H), 9.64 (br.s, 2H), 11.59 (s, 1H). LCMS: (ES, m/z): [M+1]+ 424.0.

Example 341.

1-(1-Aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl) 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 341

- 354 045333

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.36 (s, 3H), 2.53 (s, 3H), 6.97 (br.d, J=8.16 Hz, 1H ), 7.56-7.73 (m, 1H), 7.81 (br.s, 1H), 7.93 (s, 1H), 8.08 (br.s, 1H), 8.00- 8.10 (m, 1H), 8.11-8.26 (m, 1H), 8.38 (s, 1H), 8.46 (br.s, 1H), 8.51 (s, 1H) , 10.63 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 527.9.

Example 342.

1-(1-Aminoisoquinolin-4-yl)-5-(trifluoromethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-1 H-pyrazol-4carboxamide, compound 342

1H NMR (400 MHz, DMSO-d6) δ ppm 6.92 (d, J=8.16 Hz, 1H), 7.51 (s, 2H), 7.56-7.65 (m, 1H), 7.677.78 (m, 1H), 7.98 (s, 1H), 8.41 (br.s, 1H), 8.48 (s, 1H), 8.61 (s, 1H), 8.76 (s, 1H), 9.13 (s, 1H), 11.14 (br.s, 1H). LC-MS: (ES, m/z): [M+1]+ 466.9.

Example 343.

1-(1-Aminoisoquinolin-4-yl)-N-(5-bromo-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 343

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.71 (s, 1H), 9.36 (br.s, 2H), 8.68 (d, J=8.38 Hz, 1H ), 8.58 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.11-8.18 (m, 2H), 7.94-8.02 ( m, 1H), 7.84 (t, J=7.72 Hz, 1H), 7.04 (d, J=8.38 Hz, 1H), 2.51 (s, 3H).

LC-MS: (ES, m/z): [M+1]+ 557.9.

Following the procedures described in Example 112 or 113 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as necessary or desired, within the understanding of those skilled in the art , the following compounds were obtained:

Example 344.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-oxo-1,2-dihydroquinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 344

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.61 (d, J=9.70 Hz, 1H), 7.08 (d, J=9.70 Hz, 1H), 7, 38 (d, J=7.72 Hz, 1H), 7.55 (d, J=8.16 Hz, 1H), 7.64-7.73 (m, 1H), 8.17 (s, 2H ), 8.53 (s, 1H), 8.65 (s, 1H), 8.83 (s, 1H), 11.26 (s, 1H), 12.18 (br.s, 1H). LC-MS: (ES, m/z): [M+1]+ 501.1.

Example 345.

N-(5-Chloro-6-methoxypyridin-3-yl)-1-(1-oxo-1, 2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide, compound 345

¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.94 (s, 3H), 5.65 (d, J=7.28 Hz, 1H), 7.25-7.32 (m , 1H), 7.67 (t, J=7.83 Hz, 1H), 7.90-7.96 (m, 1H), 8.27 (d, J=2.43 Hz, 1H), 8 .38-8.47 (m, 3H), 10.74 (s, 1H), 11.62 (br.s, 1H).

- 355 045333

LC-MS: (ES, m/z): [M+1]+ 463.9.

Example 346.

N-(5-Cyanopyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamide, compound 346

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.64 (br.d, J=5.1 Hz, 1H), 11.31 (s, 1H), 9.14 (d, J =2.4 Hz, 1H), 8.79 (d, J=1.5 Hz, 1H), 8.68-8.63 (m, 1H), 8.60 (s, 1H), 8.43 (d, J=7.9 Hz, 1H), 7.94 (d, J=7.3 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.32-7 .25 (m, 1H), 5.66 (d, J=7.3 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 425.1.

Example 347.

X-(2-Methylpyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 347

1H NMR (400 MHz, DMSO-d6) δ ppm 2.69 (s, 3H), 5.66 (d, J=7.50 Hz, 1H), 7.25-7.31 (m, 1H), 7.67 (t, J=7.94 Hz, 1H), 7.94 (d, J=7.50 Hz, 1H), 8.09 (dd, J=6.73, 2.09 Hz, 1H), 8.21 (d, J=1.76 Hz, 1H), 8.43 (d, J=7.94 Hz, 1H), 8.63 (d, J=6, 84 Hz, 1H), 8.71 (s, 1H), 11.65 (br.d, J=5.51 Hz, 1H), 11.98 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 414.3.

Example 348.

N-(6-Methyl-5-(trifluoromethyl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide, connection 348

1H NMR (400 MHz, DMSO-d6) δ ppm 11.61 (br.d, J=5.51 Hz, 1H), 11.05 (s, 1H), 8.99 (d, J= 1.98 Hz, 1H), 8.50 (s, 2H), 8.40 (d, J=7.94 Hz, 1H), 7.91 (dd, J=7.61, 0.99 Hz, 1H), 7.64 (t, J=7.83 Hz, 1H), 7.26 (dd, J=7.28, 5.95 Hz, 1H), 5.62 (d, J=7.28 Hz, 1H), 2.59 (d, J=1.54 Hz, 3H). LC-MS: (ES, m/z): [M+1]+ 481.9.

Example 349.

1-(1-Oxo-1,2-dihydroisoquinolin-5-yl)-N-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 349

1H NMR (400 MHz, DMSO-d6) δ ppm 5.66 (d, J=7.28 Hz, 1H), 7.29 (br.d, J=6.84 Hz, 1H), 7 ,63-7.75 (m, 3H), 7.93 (d, J=6.84 Hz, 1H), 8.44 (d, J=7.94 Hz, 1H), 8.47-8, 54 (m, 3H), 10.93 (br.s, 1H), 11.64 (br.s, 1H). LC-MS: (ES, m/z): [M+1]+ 399.9.

Example 350.

X-(2-Cyclopropylpyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide, compound 350

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.16 (m, 2H), 1.27-1.37 (m, 2H), 2.38 (br.s, 1H), 5.63 (d, J=7.28 Hz, 1H), 7.27 (dd, J=7.28, 6.17 Hz, 1H), 7.65 (t, J=7.94 Hz, 1H), 7.87-7.97 (m, 2H), 8.03 (br.s, 1H), 8.42 (d, J=7.94 Hz, 1H), 8.53 (d , J=6.61 Hz, 1H), 8.67 (br.s, 1H), 11.63 (br.d, J=5.51 Hz, 1H), 11.83 (br.s, 1H) . LC-MS: (ES, m/z): [M+1]+ 440.2.

- 356 045333

Example 351.

-Chloro-N,N-dimethyl-5 -(1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)-1 H-pyrazole-4carboxamido)picolinamide, compound 351

1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (br.d, J=5.3 Hz, 1H), 11.13 (s, 1H), 8.82 (d, J= 1.8 Hz, 1H), 8.52 (s, 1H), 8.43 (dd, J=2.8, 4.8 Hz, 2H), 7.94 (d, J=7.5 Hz, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.29 (t, J=6.5 Hz, 1H), 5.65 (d, J=7.3 Hz, 1H) , 3.02 (s, 3H), 2.78 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 505.1.

Example 352.

-Chloro-N-methyl-5 -(1-(1 -oxo-1,2-dihydroisoquinolin-5 -yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxamido)picolinamide, compound 352

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.64 (br.d, J=5.7 Hz, 1H), 11.24 (s, 1H), 8.86 (d, J =2.0 Hz, 1H), 8.61-8.52 (m, 2H), 8.47-8.38 (m, 2H), 7.94 (d, J=6.6 Hz, 1H) , 7.67 (t, J=7.8 Hz, 1H), 7.35-7.23 (m, 1H), 5.66 (d, J=7.3 Hz, 1H), 2.78 ( d, J=4.9 Hz, 3H). LC-MS: (ES, m/z): [M+1]+ 490.9.

Example 428.

X-(5-Cyano-6-methoxypyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide, compound 428

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.58 (br.s, 1H), 10.85 (br.s, 1H), 8.65 (d, J=1.98 Hz , 1H), 8.49 (d, J=1.98 Hz, 1H), 8.44 (s, 1H), 8.40 (d, J=8.16 Hz, 1H), 7.90 (d , J=7.72 Hz, 1H), 7.63 (t, J=7.83 Hz, 1H), 7.25 (d, J=7.50 Hz, 1H), 5.61 (d, J =7.28 Hz, 1H), 3.97 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 455.0.

Example 446.

X-(5-Cyano-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 446

1H NMR (400 MHz, DMSO-d6) δ ppm 2.48 (s, 3H), 5.69 (d, J=7.06 Hz, 1H), 7.30 (dd, J=7, 28, 6.17 Hz, 1H), 7.68 (t, J=7.83 Hz, 1H), 7.94 (d, J=7.72 Hz, 1H), 8.07 (s, 1H) , 8.17 (s, 1H), 8.29 (s, 2H), 8.45 (d, J=7.72 Hz, 1H), 8.51 (s, 1H), 10.44 (s, 1H), 11.63 (br.d, J=6.17 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 504.9.

Example 353.

N-(5-Chloropyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxamide, compound 353

1H NMR (400 MHz, DMSO-d6) δ ppm 5.63 (d, J=7.50 Hz, 1H), 7.27 (br.d, J=7.50 Hz, 1H), 7 .65 (t, J=7.83 Hz, 1H), 7.89-7.94 (m, 1H), 8.34 (t, J=2.21 Hz, 1H), 8.38-8, 43 (m, 2H), 8.47 (s, 1H), 8.77 (d, J=2.21 Hz,

- 357 045333

1H), 10.96 (br.s, 1H), 11.61 (br.s, 1H). LC-MS: (ES, m/z): [M+1]+ 433.9.

Example 354.

N-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide, connection 354

1H NMR (400 MHz, DMSO-d6) δ ppm 11.61 (br.d, J=5.51 Hz, 1H), 11.57 (s, 1H), 9.24 (d, J= 1.76 Hz, 1H), 8.78 (d, J=1.98 Hz, 1H), 8.56 (s, 1H), 8.41 (d, J=7.94 Hz, 1H), 7 .92 (d, J=6.84 Hz, 1H), 7.64 (t, J=7.83 Hz, 1H), 7.26 (t, J=6.50 Hz, 1H), 5.61 (d, J=7.28 Hz, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 492.9.

Example 355.

Methyl 3-chloro-5-(1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamido)picolinate, compound 355

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.64 (br.d, J=5.3 Hz, 1H), 11.27 (s, 1H), 8.88 (d, J =2.0 Hz, 1H), 8.56 (s, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.44 (d, J=8.0 Hz, 1H), 7.95 (d, J=7.3 Hz, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.29 (t, J=6.5 Hz, 1H), 5, 65 (d, J=7.3 Hz, 1H), 3.90 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 491.9.

Example 356.

N-(2-Cyanopyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)-1 H-pyrazole-4carboxamide, compound 356

1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (br.d, J=4.8 Hz, 1H), 11.44 (s, 1H), 8.67 (d, J= 5.5 Hz, 1H), 8.59 (s, 1H), 8.44 (d, J=7.8 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H), 8 .01 (dd, J=2.0, 5.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.67 (t, J=7.9 Hz, 1H) , 7.29 (br.t, J=6.4 Hz, 1H), 5.66 (d, J=7.3 Hz, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 425.1.

Example 357.

N-(2-(2-Methoxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazol- 4-carboxamide, compound 357

1H NMR (400 MHz, DMSO-06) δ ppm 11.64 (br.d, J=5.5 Hz, 1H), 10.26 (s, 1H), 8.58 (s, 1H) , 8.46-8.39 (m, 3H), 7.93 (d, J=7.5 Hz, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.29 ( t, J=6.5 Hz, 1H), 5.72 (br.d, J=7.3 Hz, 1H), 4.634.55 (m, 2H), 3.79-3.70 (m, 2H ), 3.30 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 541.9.

Example 358.

N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-oxo-1,2-dihydroquinoline-4- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 358

- 358 045333 ¹ H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (1H, br.s), 10.65 (1H, s), 8.59 (1H, s), 8, 40 (1H, s), 8.16 (2H, s), 7.57-7.69 (1H, m), 7.45 (1H, d, J=8.16 Hz), 7.21 (1H , t, J=7.72 Hz), 6.92 (1H, s), 6.85 (1H, d, J=7.94

Hz), 2.53 (3H, s). LC-MS: (ES, m/z): [M+1]+ 514.9.

Example 359.

N-(5-Chloro-2-methyl-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinoline- 5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, compound 359

1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3H), 2.51 (s, 3H), 5.65 (d, J=7.50 Hz, 1H), 7 .27 (t, J=6, 62 Hz, 1H), 7.65 (t, J=7.94 Hz, 1H), 7.86-7.96 (m, 2H), 8.34-8, 45 (m, 2H), 8.51 (s, 1H), 10.58 (s, 1H), 11.61 (br.d, J=4.85 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 528.9.

Example 360.

X-(2-Methoxypyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole4-carboxamide, compound 360

1H NMR (400 MHz, DMSO-d6) δ ppm 3.89 (s, 3H), 5.63 (d, J=7.28 Hz, 1H), 7.21-7.30 (m, 1H), 7.367.44 (m, 2H), 7.63 (t, J=7.83 Hz, 1H), 7.90 (d, J=7.50 Hz, 1H), 8.13 (d, J=5, 95 Hz, 1H), 8.40 (d, J=7.94 Hz, 1H), 8.55 (s, 1H), 11.22 (br.s, 1H), 11.62 ( br.d, J=5.29 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 429.9.

Example 361.

N-(2-Morpholinopyridin-4-yl)-1 -(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide, compound 361

1H NMR (400 MHz, DMSO-d6) δ ppm 3.59-3.67 (m, 4H), 3.75-3.83 (m, 4H), 5.67 (d, J=7 ,28 Hz, 1H), 7.30 (dd, J=7.28, 5.95 Hz, 1H), 7.42 (dd, J=6.95, 1.65 Hz, 1H), 7.68 (t, J=7.94 Hz, 1H), 7.86 (d, J=1.54 Hz, 1H), 7.95 (dd, J=7.50, 1.10 Hz, 1H), 8 .07 (d, J=6.84 Hz, 1H), 8.45 (d, J=7.94 Hz, 1H), 8.73 (s, 1H), 11.63-11.74 (m, 2H). LC-MS: (ES, m/z): [M+1]+ 485.0.

Example 362.

N-(5-Chloro-2-methyl-6-(4-methyl-1H-1,2,3-triazol-1 -yl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinoline- 5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 362

1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H), 2.59 (s, 3H), 5.70 (d, J=7.53 Hz, 1H), 7 .31 (t, J=6.65 Hz, 1H), 7.69 (t, J=7.78 Hz, 1H), 7.76 (s, 1H), 7.95 (d, J=7, 78 Hz, 1H), 8.45 (d, J=8.78 Hz, 1H), 8.53 (d, J=11.80 Hz, 2H), 10.64 (s, 1H), 11.65 (b.d., J=5.27 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 528.9.

Example 363.

N-(5-(2H-1,2,3-Triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide, compound 363

- 359 045333

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 5.68 (d, J=7.28 Hz, 1H), 7.31 (dd, J=7.28, 5.95 Hz, 1H), 7.68 (t, J=7.83 Hz, 1H), 7.96 (d, J=7.50 Hz, 1H), 8.25 (s, 2H), 8.45 (d, J=7.94 Hz, 1H), 8.57 (s, 1H), 8.94 (d, J=2.21 Hz, 1H), 8.99 (t, J=2.09 Hz, 1H) , 9.04 (d, J=2.20 Hz, 1H), 11.15 (s, 1H), 11.65 (br.d, J=5.51 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 466.9.

Example 364.

1-(Thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4carboxamide, compound 364

A. Methyl 4-bromothieno[2,3-c]pyridine-2-carboxylate, 364a

Vg.

Oh, 364a

To a solution of 3,5-dibromoisonicotinaldehyde (15 g, 56.63 mmol) in THF (80 ml) was added methyl 2 mercaptoacetate (6.4 g, 60.3 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour. Subsequently, the mixture was warmed to 25°C and stirred for another 1 hour and C ₂ CO ₃ (18.45 g, 56.63 mmol) was added to the mixture. The mixture was then stirred at rt for 16 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the crude product as a yellow solid. The crude product was purified using FCC (petroleum ether/ethyl acetate=100:0-80:20). The solvents were concentrated to give the crude products as a pale yellow solid (15 g, 97.3%).

B. 4-Bromothieno[2,3-c]pyridine-2-carboxylic acid, 364b

Vg

o, 364b

Lithium hydroxide (2.640 g, 110.246 mmol) was added to a solution of methyl 4-bromothieno[2,3-e]pyridine 2-carboxylate (15 g, 55.123 mmol) in THF/H ₂ O=1:1 (20 ml). The mixture was reacted at room temperature for 4 hours. The solvent was concentrated under reduced pressure and 30 ml of H ₂ O was added to the mixture. The mixture was acidified with 1M hydrogen chloride to pH 5 and filtered and washed the solid with H ₂ O (30 mlx2). The solid was dried under reduced pressure to give the product as a white solid (12 g, 84.3%).

C. 4-Bromothieno[2,3-c]pyridine, 364c

4-Bromothieno[2,3-c]pyridine-2-carboxylic acid (11.9 g, 46.11 mmol) was added to oxydibenzene (120 ml). The mixture was stirred at 230°C for 8 hours. The mixture was purified using FCC (petroleum ether/ethyl acetate=100:0-0:100). The solvents were concentrated to give the crude product as a pale gray solid (8 g, 81.0%).

D. 4-Hydrazinylthieno[2,3-c]pyridine, 364d

Palladium(P)chloride dimer (pi-cinnamyl) (363.0 mg, 0.70 mmol) and 4-(2-(gi((3S,5S,7S)-agamantan-1yl)phosphino)phenyl)morpholine (649 .7 mg, 1.40 mmol) was added to dioxane (15 ml) and the reaction mixture was immediately deaerated using N ₂ . The resulting solution was stirred at rt in an N ₂ atmosphere for 10 minutes. Sodium 2-methylpropan2-olate (2.69 g, 28.03 mmol) and 4-bromothieno[2,3-c]pyridine (3 g, 14.01 mmol) were subsequently added to the reaction vessel. The vessel was sealed and air was removed using N ₂ . The resulting reaction mixture was stirred at rt for 5 min, subsequently treated with hydrazine hydrate (701.5 mg, 4.01 mmol)

- 360 045333 using a syringe. The reaction mixture was stirred at 50° C. under N2 for 1.5 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product as a brown oil (8 g).

E. Ethyl 1-(thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 364e

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (5.815 g, 24.21 mmol), 4-hydrazinylthieno[2,3c]pyridine (8 g, 48.421 mmol) and ethanol (20 ml) were stirred at 80°C for 2 hours. The resulting solution was concentrated to dryness under reduced pressure to give the crude product, which was purified using FCC (petroleum ether:ethyl acetate=100/0-70/30) to obtain the title compound (6 g, 35.2%) as a yellow solid. LCMS (ESI) m/z M+1: 342.2.

F. 1-(Thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 364f

Ya'Ta, 364f

Lithium hydroxide (679.7 mg, 28.38 mmol) was added to a solution of ethyl 1-(thieno[2,3-c]pyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate (5 g , 14.19 mmol) in THF/H ₂ O=1:1 (20 ml). The mixture was stirred at room temperature for 4 hours. The solvent was concentrated under reduced pressure and 30 ml of H ₂ O was added to the mixture. The pH of the solution was adjusted to 5 by adding 1 M hydrochloric acid and extracted using ethyl acetate (40 ml x 3). The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ , filtered, and the filtrates were concentrated to give the product as a white solid. (4.6 g, 97.1%).

G. 1-(Thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol4-carboxamide, compound 364

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (2.25 g, 6.74 mmol), 2-(trifluoromethyl) pyridine-4-amine (1.092 g, 6.74 mmol) and pyridine (2.72 ml, 33.70 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (2.47 ml, 26.96) was added mmol). The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (30 ml) and the reaction mixture was extracted using CH2Cl2 (40 mlx2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC (35-60% (v/v) CH3CN and H ₂ O with 0 .05% TFA). The pure fractions were collected and the pH of the mixture was adjusted to > 7 by adding aq. _NaHCO3 .

The organic solvent was concentrated under reduced pressure until a white solid precipitated out of the solution. The white solid was collected and dried under reduced pressure to give the product (1.6 g, 51.9%). LCMS (ESI) m/z M+1: 457.9.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.15 (1H, d, J=5.73 Hz), 7.96 (1H, dd, J=5.40, 1.87 Hz), 8.22 (1H, d, J=1.76 Hz), 8.34 (1H, d, J=5.51 Hz), 8.56 (1H, s), 8.65 (1H, s), 8.69 (1H, d, J=5.73 Hz), 9.52 (1H, s), 11.26 (1H, br.s).

Example 447.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-c]pyridin-4-yl)-5 -(trifluoromethyl)1H-pyrazole-4-carboxamide, compound 447

By following the procedure described in Example 364 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as needed or desired, within the understanding of those skilled in the art, was obtained compound 447. LCMS (ESI): mass calculated for

- 361 045333

C19H10CIF3N8OS - 490.1 obtained m/z - 491.2 [M+H]+.

^1H NMR (400 MHz, DMSO-d6) δ ppm 7.18 (d, J=5.3 Hz, 1H), 8.16 (s, 2H), 8.35 (d, J=5 .7 Hz, 1H), 8.51 (s, 1H), 8.66 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.71-8.75 (m , 1H), 9.52 (s, 1H)

Example 365 and Example 366.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(tetrahydrofuran-2-yl)isoquinolin-4-yl)5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 365

1-(1,5-Bis(tetrahydrofuran-2-yl)isoquinolin-4-yl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 366

A mixture of THF (1800 mg, 25 mmol), CH3CN (2.5 ml), H2O (2.5 ml), N-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin- 3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (242.5 mg, 0.5 mmol), TFA (0.038 ml, 0.5 mmol) and ammonium persulfate (228 mg, 1 mmol) were weighed into a 10 ml vial. (IR[DF(CF ₃ )PPY] ₂ (DTBPY))PF ₆ (11.2 mg, 0.01 mmol) was then added. The reaction mixture was degassed for 15 min and the vessel was sealed. The reaction mixture was stirred under blue LED irradiation at rt for 1 hour. The reaction mixture was poured into water and extracted using DCM. The organic layer was dried over MgSO ₄ , filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-5 µm, 30x250 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN) to give compound 365 (44 mg, 16%) and compound 366 ( 46 mg, 15%).

Compound 365. LCMS (ESI): mass calculated for C ₂₅ H ₁₈ ClF ₃ N ₈ O ₂ . _554.1 , obtained m/z 555.1 [M+H]+.

1H NMR (400 MHz, chloroform-d) δ ppm 2.08-2.25 (m, 2H), 2.49 (br.s, 2H), 4.01-4.12 (m, 1H ), 4.124.26 (m, 1H), 5.79 (t, J=7.1 Hz, 1H), 7.21-7.26 (m, 1H), 7.65-7.77 (m, 2H), 7.93 (s, 2H), 8.23 (s, 1H), 8.44 (br.s, 1H), 8.53 (s, 1H), 8.62 (d, J=2 .4 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H), 9.22 (s, 1H).

Compound 366. LCMS (ESI): mass calculated for C ₂₉ H ₂₄ ClF ₃ N ₈ O ₃ . _624.2 , resulting m/z 625.2 [M+H]+.

1H NMR (400 MHz, chloroform-d) δ ppm 1.74-1.84 (m, 1H), 1.91-2.07 (m, 2H), 2.07-2.25 (m , 2H), 2.342.44 (m, 1H), 2.44-2.62 (m, 2H), 3.92-4.00 (m, 1H), 4.02-4.11 (m, 2H ), 4.19 (br.s, 1H), 5.01 (k, J=6.5 Hz, 1H), 5.77 (br.t, J=6.9 Hz, 1H), 7.21 (d, J=6.9 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.94 (s, 2H), 8.22 (s, 1H), 8.43 (br.s, 1H), 8.52 (s, 1H), 8.54 (d, J=2.4 Hz, 1H), 8.75 (d, J=2.0 Hz, 1H), 8 .81 (us.s, 1H).

By following the procedure described in Example 365 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as needed or desired, within the understanding of those skilled in the art, was obtained the following connections.

Example 367.

1-(1-(1,4-Ddioxan-2-yl)isoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 367

LCMS (ESI): mass calculated for C ₂₅ H ₁₈ ClF ₃ N ₈ O ₃ . _570.1 , obtained m/z - 571.1[M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.70 (td, J=11.6, 2.8 Hz, 1H), 3.85 (dd, J=11.8, 2, 0 Hz, 1H), 3.92 (dd, J=11.6, 2.2 Hz, 1H), 4.09 (td, J=11.5, 2.6 Hz, 1H), 4.21 ( d, J=6.1 Hz, 2H), 5.44-5.52 (m, 1H) 7.27 (d, J=8.5 Hz, 1H), 7.84-7.91 (m, 1H), 7.92-7.99 (m, 1H), 8.19 (s, 2H), 8.60-8.67 (m, 2H), 8.69 (d, J=2.0 Hz , 1H), 8.76 (s,

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1H), 8.86 (d, J=2.0 Hz, 1H), 11.29 (br.s, 1H).

Example 368.

Ν-(5-Χλορ-6-(2Η- 1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1-ethoxyethyl)isoquinolin-4-yl)-5 ( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 368

LCMS (ESI): mass calculated for C ₂₅ H ₂₀ ClF ₃ N ₈ O ₂ _ _556.1 , obtained m/z - 557.2 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=6.9 Hz, 3H), 1.66 (d, J=6.5 Hz, 3H), 3.36 -3.47 (m, 1H), 3.48-3.67 (m, 1H), 5.34 (k, J=6.5 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.82-7.89 (m, 1H), 7.90-7.98 (m, 1H), 8.19 (s, 2H), 8.63 (s, 1H), 8 .70 (d, J=2.4 Hz, 1H), 8.74 (s, 1H), 8.80 (d, J=8.5 Hz, 1H), 8.86 (d, J=2, 0 Hz, 1H), 11.36 (br.s, 1H).

Example 369.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(5-oxopyrrolidin-2-yl)isoquinolin-4-yl )5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 369

LCMS (ESI): mass calculated for C ₂₅ H ₁₇ ClF ₃ N ₉ O ₂ _ _567.1 , obtained m/z - 568.1 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.09 (br.s., J=13.8 Hz, 1H), 2.32 (br.s., 2H), 2.65-2 .86 (m, 1H), 5.82 (dd, J=8.3, 3.9 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.89 (td, J=7.6, 1.0 Hz, 1H), 7.86-7.92 (m, 1H), 7.93-7.99 (m, 1H), 7.93-8.00 (m, 1H), 8.08 (s, 1H), 8.19 (s, 2H), 8.56 (d, J=8.5 Hz, 1H), 8.64 (s, 1H), 8.69 ( d, J=2.4 Hz, 1H), 8.78 (s, 1H), 8.88 (d, J=2.4 Hz, 1H), 11.32 (br.s, 1H).

Example 370.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(4-oxotetrahydrofuran-2-yl)isoquinolin4-yl)- 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 370

LCMS (ESI): mass calculated for C ₂₅ H ₁₆ ClF ₃ N ₈ O ₃ _ _568.1 , obtained m/z - 569.1[M+H]+.

1H NMR (400 MHz, DMSO-06) δ ppm 2.96-3.08 (m, 1H), 4.17 (s, 1H), 4.07 (br.s, 1H), 4, 13 (s, 1H), 6.50 (s, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.90-7.95 (m, 1H), 7.98 (dd , J=8.1, 1.2 Hz, 1H), 8.19 (s, 2H), 8.64 (s, 1H), 8.68 (d, J=2.0 Hz, 1H), 8 .70 (s, 1H), 8.80 (s, 1H), 8.87 (d, J=2.0 Hz, 1H), 11.29 (s, 1H).

Example 371.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1-hydroxyethyl)isoquinolin-4-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 371

LCMS (ESI): mass calculated for C ₂₃ H ₁₆ ClF ₃ N ₈ O ₂ . _528.1 , obtained m/z - 529.2 [M+H]+.

1H NMR (400 MHz, DMSO-06) δ ppm 1.64 (d, J=6.5 Hz, 3H), 5.61 (br.s, 1H), 5.66-5.74 ( m, 1H), 5.69 (br.d, J=11.0 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 7.81-7.87 (m, 1H ), 7.89-7.94 (m, 1H), 8.19 (s, 2H), 8.61 (s, 1H), 8.68 (d, J=2.0 Hz, 1H), 8 .72 (s, 1H), 8.77 (br.s, 1H), 8.86 (d, J=2.0 Hz, 1H), 11.30 (br.s, 1H).

Example 372.

No.(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(tetrahydrofuran-2-yl)quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 372

- 363 045333

LCMS (ESI): mass calculated for C ₂₅ H ₁₈ ClF ₃ N ₈ O ₂ _ _554.1 , obtained m/z - 555.2 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.92-2.14 (m, 2H), 2.41-2.49 (m, 1H), 3.60 (dpt, J=6 ,1 Hz, 1H), 3.87-3.99 (m, 1H), 3.99-4.15 (m, 1H), 5.06-5.19 (m, 1H), 7.63 ( d, J=9.0 Hz, 1H), 7.72-7.78 (m, 1H), 7.85-7.90 (m, 1H), 7.92-7.99 (m, 1H) , 8.19 (s, 2H), 8.27 (d, J=8.1 Hz, 1H), 8.59 (s, 1H), 8.68 (d, J=2.4 Hz, 1H) , 8.86 (d, J=2.4 Hz, 1H), 11.27 (br.s, 1H).

Example 373.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-((N-methylformamido)methyl)isoquinolin-4yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 373

LCMS (ESI): mass calculated for C ₂₄ H ₁₇ ClF ₃ N ₉ O - 555.1, obtained m/z - 556.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.75-3.10 (m, 3H), 5.24 (br.d, J=3.7 Hz, 1H), 5.37 ( s, 1H), 7.29 (dd, J=8.3, 3.1 Hz, 1H), 7.85-8.01 (m, 2H), 8.19 (s, 2H), 8.24 -8.36 (m, 1H), 8.52 (dd, J=8.3, 3.5 Hz, 1H), 8.62 (s, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.76 (d, J=12.6 Hz, 1H), 8.86 (d, J=2.4 Hz, 1H), 11.29 (br.s, 1H).

Example 374.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(1-hydroxyethyl)quinolin-4-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 374

LCMS (ESI): mass calculated for C ₂₃ H ₁₆ ClF ₃ N ₁₃ O ₂ _ _528.1 , obtained m/z - 529.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.5 Hz, 3H), 5.02 (dd, J=6.5, 4.5 Hz, 1H) , 5.79 (d, J=4.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.71 (ddd, J=8.2, 7.0, 1 .0 Hz, 1H), 7.89-7.95 (m, 2H), 8.16-8.21 (m, 3H), 8.65 (s, 1H), 8.69 (d, J= 2.0 Hz, 1H), 8.87 (d, J=2.0 Hz, 1H), 11.28 (br.s, 1H).

Example 375.

1-(2-Acetylquinolin-4-yl)-N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide, compound 375

LCMS (ESI): mass calculated for C ₂₃ H ₁₄ ClF ₃ N ₈ O ₂ _ _526.1 , obtained m/z - 527.2 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.86 (s, 3H), 7.43 (d, J=8.1 Hz, 1H), 7.91 (td, J=7, 6, 1.0 Hz, 1H), 8.04-8.09 (m, 1H), 8.20 (s, 2H), 8.29 (s, 1H), 8.41 (d, J=8 .5 Hz, 1H), 8.67-8.70 (m, 2H), 8.87 (d, J=2.4 Hz, 1H), 11.27 (s, 1H).

Example 376.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-(1-hydroxyethyl)thieno[2,3-c]pyridine -4yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 376

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LCMS (ESI): mass calculated for C ₂₁ H ₁₄ ClF ₃ N ₈ O ₂ S - 534.1, obtained m/z - 535.1 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.55 (d, J=6.5 Hz, 3H), 5.17 (cd, J=6.6, 4.5 Hz, 1H ), 6.21 (d, J=4.1 Hz, 1H), 7.09 (d, J=5.7 Hz, 1H), 8.19 (s, 2H), 8.28 (d, J =5.3 Hz, 1H), 8.54-8.59 (m, 2H), 8.67 (d, J=2.0 Hz, 1H), 8.85 (d, J=2.0 Hz , 1H), 11.26 (br.s, 1H).

Example 378.

1-(1-Acetylisoquinolin-5-ul)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 378

LCMS (ESI): mass calculated for C ₂₃ H ₁₄ ClF ₃ N ₈ O ₂ - _526.1 , obtained m/z - 527.2 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.83 (s, 3H), 7.28 (d, J=5.9 Hz, 1H), 7.99 (dd, J=8 ,9, 7.3 Hz, 1H), 8.18 (d, J=6.9 Hz, 1H), 8.19 (s, 2H), 8.64 (s, 1H), 8.69 (d , J=2.4 Hz, 1H), 8.74 (d, J=6.1 Hz, 1H), 8.88 (d, J=2.1 Hz, 1H), 9.03 (dt, J =8.8, 1.1 Hz, 1H), 11.24 (br.s, 1H).

Example 379.

1-(1-(Azetudin-2-yl)isoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 379

A.

tert-Butyl

2-(4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1H-pyrazol- 1 -yl)isoquinolin-1 -yl)azetidine-1-carboxylate, compound 379a

A mixture of tert-butyl azetidine-1-carboxylate (236 mg, 1.5 mmol), CH ₃ CN (2.5 ml), H ₂ O (2.5 ml), N-(5chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide (242.5 mg, 0.5 mmol) , TFA (0.038 ml, 0.5 mmol) and ammonium persulfate (228 mg, 1 mmol) were weighed into a 10 ml vial. (IR[DF(CF ₃ )PPY] ₂ (DTBPY))PF ₆ (11.2 mg, 0.01 mmol) was then added. The reaction mixture was degassed for 15 min and the vessel was sealed. The reaction mixture was stirred under blue LED irradiation at rt for 1 hour. The reaction mixture was poured into water and extracted using DCM. The organic layer was dried over MgSO ₄ , filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobile phase: 0.25% NH ₄ HCO ₃ in water, CH ₃ CN) to give compound 379a (240 mg, 75% ). LCMS (ESI): mass calculated for C ₂₉ H ₂₅ ClF ₃ N ₉ O ₃ - _639.2 , obtained m/z - 640.2 [M+H]+.

B. 1-(1 -(Azetudin-2-ul)isoquinolin-4-yl)-N-(5 -chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 379

- 365 045333

A mixture of tert-butyl 2-(4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1H -pyrazol-1-yl)isoquinolin-1-yl)azetidine-1-carboxylate (240 mg, 0.375 mmol), TFA (2 ml) and DCM (6 ml) were stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness . The residue was dissolved in water and made alkaline using K ₂ CO ₃ . The aqueous layer was extracted using DCM and the organic layer was dried over MgSO ₄ , filtered and the filtrate was concentrated. The residue was dissolved in diisopropyl ether and the solid was collected by filtration, filtered and dried to give the product (74 mg, 35.5%). LCMS (ESI): mass calculated for C ₂₄ H ₁₇ ClF ₃ N ₉ O - 539.1, obtained m/z -540.2 [M+H]+.

^1H NMR (400 MHz, DMSO-d6) δ ppm 2.55-2.79 (m, 1H), 2.89-3.05 (m, 1H), 3.54-3.62 ( m, 1H), 3.673.79 (m, 1H), 5.81 (br.t, J=7.7 Hz, 1H), 7.30 (br.d, J=8.1 Hz, 1H), 7.81-7.90 (m, 1H), 7.91-7.99 (m, 1H), 8.20 (s, 2H), 8.29 (br.d, J=8.5 Hz, 1H), 8.63 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.81 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 11.28 (br.s, 1H).

By following the procedure described in Example 379 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as needed or desired, within the understanding of those skilled in the art, was obtained the following connections.

Example 380.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(pyrrolidin-2-yl)isoquinolin-4-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 380

LCMS (ESI): mass calculated for C ₂₅ H ₁₉ ClF ₃ N ₉ O - 553.1, obtained m/z - 554.2 [M+H]+.

^1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-2.01 (m, 3H), 2.44-2.50 (m, 1H), 2.98-3.07 ( m, 1H), 3.263.28 (m, 1H), 5.23 (br.s, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.83-7.92 (m , 1H), 7.92-8.01 (m, 1H), 8.19 (s, 2H), 8.59 (br.d, J=7.7 Hz, 1H), 8.63 (s, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.74 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 11.27 (br. s, 1H).

Example 381.

1-(2-(Azetidin-2-yl)quinolin-5-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 381

LCMS (ESI): mass calculated for C ₂₄ H ₁₇ ClF ₃ N ₉ O - 539.1, obtained m/z - 540.2 [M+H]+.

1H NMR (400 MHz, DMSO-06) δ ppm 2.31-2.47 (m, 1H), 2.64-2.81 (m, 1H), 3.54-3.66 (m , 1H), 3.73 (k, J=8.0 Hz, 1H), 5.15 (t, J=7.9 Hz, 1H), 7.65 (d, J=9.0 Hz, 1H ), 7.82-8.03 (m, 3H), 8.18-8.22 (m, 2H), 8.27 (d, J=8.5 Hz, 1H), 8.61 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.88 (d, J=2.0 Hz, 1H).

Example 382.

1-(2-(Azetidin-2-yl)quinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 382

LCMS (ESI): mass calculated for C ₂₄ H ₁₇ ClF ₃ N ₉ O - 539.1, obtained m/z - 540.2 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.32-2.45 (m, 1H), 2.72 (ddt, J=14.9, 8.2, 4.1, 4, 1 Hz, 1H), 3.353.38 (m, 1H), 3.69-3.82 (m, 1H), 5.21 (t, J=8.1 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.70 (ddd, J=8, 2, 7.0, 1.0 Hz, 1H), 7.91 (ddd, J=8.4, 7.0, 1.2 Hz, 1H), 8.07 (s, 1H), 8.15-8.20 (m, 3H), 8.67 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.88 (d, J=2.4 Hz, 1H), 11.29 (br.s, 1H).

- 366 045333

Example 383.

tert-Butyl 2-(5-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)1 H -pyrazol-1 -yl)isoquinolin-1 -yl)azetidine-1-carboxylate, compound 383

LCMS (ESI): mass calculated for C ₂₉ H ₂₅ ClF ₃ N ₉ O ₃ 639.2, obtained m/z - 640.2 [M+H]+.

Example 384.

1-(1-(Azetidin-2-yl)isoquinolin-5-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 384

LCMS (ESI): mass calculated for C ₂₄ H ₁₇ ClF ₃ N ₉ O - 539.1, obtained m/z - 540.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.67 (br.s, 1H), 3.03-3.15 (m, 1H), 3.80 (td, J=9.1 , 5.9 Hz, 1H), 3.99-4.16 (m, 1H), 6.22 (br.t, J=7.9 Hz, 1H), 7.10 (d, J=6, 1 Hz, 1H), 7.92-8.00 (m, 1H), 8.17 (s, 1H), 8.20 (s, 2H), 8.38 (d, J=8.5 Hz, 1H), 8.63 (s, 1H), 8.67 (d, J=6.1 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.88 (d, J=2.4 Hz, 1H), 11.29 (br.s, 1H).

Example 385.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(hydroxymethyl)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 385

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 α-carboxamide (242.5 mg, 0.5 mmol), TFA (0.038 ml, 0.5 mmol) and BPO (302 mg, 1 mmol) were weighed in MeOH (2.5 ml) in a 10 ml vial. (IR[DF(CF ₃ )PPY] ₂ (DTBPY))PF ₆ (11.2 mg, 0.01 mmol) was then added. The reaction mixture was degassed for 15 min and the vessel was sealed. The reaction mixture was stirred under blue LED irradiation at rt for 1 hour. The reaction mixture was poured into water and extracted using DCM. The organic layer was dried over MgSO ₄ , filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN) to give compound 385 (12 mg, 4.7%). LCMS (ESI): mass calculated for C ₂₂ H ₁₄ ClF ₃ N ₈ O ₂ . _514.1 , resulting m/z - 515.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 5.17 (d, J=5.7 Hz, 2H), 5.60-5.70 (m, 1H), 7.26 (d, J=8.1 Hz, 1H), 7.82-7.89 (m, 1H), 7.90-7.97 (m, 1H), 8.19 (s, 2H), 8.58 (d , J=8.1 Hz, 1H), 8.63 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.71 (s, 1H), 8.87 (d , J=2.0 Hz, 1H), 11.28 (br.s, 1H).

Example 386.

4-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)quinoline -2-carboxamide, compound 386

- 367 045333

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide (485 mg, 1 mmol), iron(II) sulfate heptahydrate (139 mg, 0.5 mmol), formamide (450.5 mg, 10 mmol) and H ₂ SO ₄ (147 mg, 1.5 mmol) stirred in CH ₃ CN (5 ml) and water (5 ml) at 50°C. Hydrogen peroxide (0.486 mL, 0.35 g/mL, 5 mmol) was added slowly. The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was poured into water, the pH of the mixture was adjusted to alkaline with K ₂ CO ₃ and the reaction mixture was extracted using DCM/MeOH (90/10). The organic layer was concentrated. The resulting residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobile phase: 0.5% NH ₄ Ac in water + 10% CH3CN, CH3CN) to obtain compound 386 (65 mg, 12 .3%). LCMS (ESI): mass calculated for C ₂₂ H ₁₃ ClF ₃ N ₉ O ₂ . _527.1 , resulting m/z - 528.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.42 (d, J=8.1 Hz, 1H), 7.87 (ddd, J=8.4, 7.0, 1.2 Hz, 1H), 7.998.08 (m, 2H), 8.19 (s, 2H), 8.33 (d, J=8.5 Hz, 1H), 8.35 (s, 1H), 8, 48 (d, J=1.6 Hz, 1H), 8.67-8.70 (m, 2H), 8.87 (d, J=2.0 Hz, 1H), 11.27 (br.s , 1H).

By following the procedure described in Example 386 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as needed or desired, within the understanding of those skilled in the art, was obtained the following connections.

Example 387.

4-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)isoquinoline -1-carboxamide, compound 387

LCMS (ESI): mass calculated for C ₂₂ H ₁₃ ClF ₃ N ₉ O ₂ . _527.1 , resulting m/z - 528.1[M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.32 (d, J=8.1 Hz, 1H), 7.87-7.93 (m, 1H), 7.95-8, 01 (m, 1H), 8.02 (br.s, 1H), 8.20 (s, 2H), 8.43 (br.s, 1H), 8.66 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.85 (s, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.90 (d, J=8.5 Hz , 1H), 11.29 (s, 1H).

Example 388.

5-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)quinoline -2-carboxamide, compound 388

WITH? ?

N- ^N ^LF /=0

_H2N

LCMS (ESI): mass calculated for C ₂₂ H ₁₃ ClF ₃ N ₉ O ₂ . _527.1 , resulting m/z - 528.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.82 (d, J=8.5 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 8.02 -8.05 (m, 1H), 8.06-8.11 (m, 1H), 8.20 (s, 2H), 8.28 (d, J=8.5 Hz, 1H), 8, 37-8.45 (m, 2H), 8.62 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.87 (d, J=2.0 Hz, 1H ), 11.27 (br.s, 1H).

Example 389.

5-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)isoquinoline -1-carboxamide, compound 389

LCMS (ESI): mass calculated for C ₂₂ H ₁₃ ClF ₃ N ₉ O ₂ . _527.1 , resulting m/z - 528.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.16-7.21 (m, 1H), 7.95 (dd, J=8, 7, 7.5 Hz, 2H), 8, 16 (d, J=6.5 Hz, 1H), 8.19 (s, 2H), 8.36 (s, 1H), 8.62 (s, 1H), 8.64 (d, J=6 ,1 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.4 Hz, 1H), 9.12-9.18 (m, 1H ), 11.27 (br.s, 1H).

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Example 390.

4-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-III-pyrazol-1yl)- N-methylisoquinoline-1-carboxamide, compound 390

LCMS (ESI): mass calculated for C ₂₃ H ₁₅ ClF ₃ N ₉ O _2-541 , 1, obtained m/z - 542.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.93 (d, J=4.9 Hz, 3H), 7.32 (d, J=8.5 Hz, 1H), 7.90 (ddd, J=8.4, 7.0, 1.2 Hz, 1H), 7.98 (ddd, J=8, 2, 7.0, 1.4 Hz, 1H), 8.20 (s , 2H), 8.66 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.86 (s, 1H), 8.87 (d, J=2.0 Hz , 1H), 8.95 (dd, J=8.3, 1.0 Hz, 1H), 9.01 (k, J=4.5 Hz, 1H), 11.29 (s, 1H).

Example 391.

4-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)thieno [2,3-c]pyridine-7-carboxamide, compound 391

LCMS (ESI): mass calculated for C ₂₀ H11ClF ₃ N ₉ O ₂ S - 533, obtained m/z - 534.1 [M+H]+.

1H NMR (600 MHz, DMSO-d6) δ ppm 7.21 (d, J=5.6 Hz, 1H), 8.14 (br.s, 1H), 8.20 (s, 2H) , 8.43 (d, J=5.6 Hz, 1H), 8.60 (br.s, 1H), 8.64 (s, 1H), 8.68 (d, J=2.3 Hz, 1H), 8.81 (s, 1H), 8.86 (d, J=2.3 Hz, 1H), 11.28 (br.s, 1H).

Example 392.

4-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)- N-methylthieno[2,3-c]pyridine-7-carboxamide, compound 392

LCMS (ESI): mass calculated for C ₂₁ H ₁₃ ClF ₃ N ₉ O ₂ S - 547.1, obtained m/z - 548 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.93 (d, J=4.8 Hz, 3H), 7.21 (d, J=5.7 Hz, 1H), 8.19 (s, 2H), 8.44 (d, J=5.5 Hz, 1H), 8.64 (s, 1H), 8.68 (d, J=2.2 Hz, 1H), 8.81 (s, 1H), 8.86 (d, J=2.2 Hz, 1H), 9.24 (k, J=4.5 Hz, 1H), 11.28 (br.s, 1H).

Example 393.

4-(4-((5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1Hpyrazol-1 -yl)thieno[2,3-c]pyridine-7-carboxamide, compound 393

LCMS (ESI): mass calculated for C ₂₁ H ₁₃ ClF ₃ N ₉ O ₂ S - 547.1, obtained m/z - 548 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.58 (s, 3H), 7.24 (d, J=5.7 Hz, 1H), 8.13 (br.s, 1H) , 8.19 (s, 2H), 8.40-8.48 (m, 2H), 8.58 (s, 1H), 8.67 (s, 1H), 8.80 (s, 1H).

Example 394.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(difluoromethyl)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 394

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Mixture of N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide (242 mg, 0.5 mmol), zinc difluoromethanesulfinate (400 mg, 1.35 mmol), water (1 ml) and DCM (2.5 ml) were stirred at rt. TFA (0.038 mL, 0.5 mmol) was added. tert-Butyl hydroperoxide (322 mg, 2.5 mmol) was added slowly. The reaction mixture was stirred for 16 hours. Additional zinc difluoromethanesulfinate (400 mg, 1.35 mmol) and t-butyl hydroperoxide (322 mg, 2.5 mmol) were added. The reaction mixture was stirred for 3 hours. The reaction mixture was poured into water, the mixture was made alkaline by adding Na ₂ CO ₃ and the mixture was extracted using DCM (20 mlx2). The organic layer was dried over MgSO ₄ , filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 30x150 mm, mobile phase: 0.25% NH4HCO3 in water, MeOH). The crude fractions were concentrated and the residue was stirred in diisopropyl ether, the solid was collected by filtration and subsequently dried to give compound 394 (39 mg, 14.6%). LCMS (ESI): mass calculated for C ₂₂ H ₁₂ ClF ₅ N ₈ O - 534.1, obtained m/z - 535.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.42 (d, J=8.1 Hz, 1H), 7.62 (t, J=53.3 Hz, 1H), 7.95 -8.01 (m, 1H), 8.01-8.07 (m, 1H), 8.16 (s, 2H), 8.58 (br.d, J=8.1 Hz, 1H), 8.64 (s, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H) 8.92 (s, 1H).

By following the procedure described in Example 394 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as needed or desired, within the understanding of those skilled in the art, was obtained the following connections.

Example 395.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(difluoromethyl)quinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 395

LCMS (ESI): mass calculated for C ₂₂ H ₁₂ ClF ₅ N ₈ O - 534.1, obtained m/z - 535.1 [M+H]+.

1H NMR (600 MHz, DMSO-d ₆ ) δ ppm 7.21 (t, J=54.7 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7, 98 (d, J=8.9 Hz, 1H), 8.06-8.09 (m, 1H), 8.09-8.13 (m, 1H), 8.20 (s, 2H), 8 .45 (d, J=8.1 Hz, 1H), 8.64 (s, 1H), 8.69 (d, J=2.3 Hz, 1H), 8.88 (d, J=2, 3 Hz, 1H), 11.31 (s, 1H).

Example 396.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-(difluoromethyl)quinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 396

LCMS (ESI): mass calculated for C ₂₂ H ₁₂ ClF ₅ N ₈ O - 534.1, obtained m/z - 535.1 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 5.96-6.33 (m, 1H), 7.91-7.96 (m, 1H), 8.01 (dd, J= 4.3, 2.6 Hz, 1H), 8.03-8.10 (m, 1H), 8.20 (s, 2H), 8.50 (dd, J=8.1, 1.2 Hz , 1H), 8.66 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.88 (d, J=2.0 Hz, 1H), 9.24 (d , J=4.5 Hz, 1H), 11.25 (br.s, 1H).

Example 397.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-(difluoromethyl)quinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 397

LCMS (ESI): mass calculated for C ₂₂ H ₁₂ ClF ₅ N ₈ O - 534.1, obtained m/z - 535.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.73-7.77 (m, 1H), 7.79-8.12 (m, 3H), 8.20 (s, 2H), 8.26 (d, J=7.7

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Hz, 1H), 8.64 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.87 (d, J=2.4 Hz, 1H), 9.17 ( dd, J=4.3, 1.8 Hz, 1H), 11.27 (br.s,

1H).

Example 398.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-(difluoromethyl)thieno[2,3-c]pyridin-4 -yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 398

WITH· ?

^N ' ^N J o UN _K A II UF /=n F ⁿ L ' ^N y NF

LCMS (ESI): mass calculated for C ₂₀ H1oClF ₅ N ₈ OS - 540, obtained m/z - 541 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.26-7.57 (m, 1H), 7.32 (d, J=5.3 Hz, 1H), 8.20 (s, 2H), 8.50 (d,

J=5.7 Hz, 1H), 8.65 (s, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.85-8.88 (m, 2H), 11, 27 (s, 1H).

Example 399.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(difluoromethyl)thieno[2,3-c]pyridin-4 -yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 399

LCMS (ESI): mass calculated for C ₂₀ H ₁₀ ClF ₅ N ₈ OS - 540, obtained m/z - 541.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.39-7.69 (m, 2H), 8.19 (s, 2H), 8.63 (s, 1H), 8.68 ( d, J=2.4 Hz, 1H), 8.82 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 9.61-9.75 (m, 1H), 11.26 (br.s, 1H).

Example 400.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(difluoromethyl)isoquinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 400

LCMS (ESI): mass calculated for C ₂₂ H ₁₂ ClF ₅ N ₈ O - 534.1, obtained m/z - 535.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.28 (d, J=5.7 Hz, 1H), 7.55 (t, J=53.5 Hz, 1H), 8.04 (dd, J=8.5, 7.7 Hz, 1H), 8.19 (s, 2H), 8.25 (d, J=7.3 Hz, 1H), 8.63 (s, 1H) , 8.66-8.74 (m, 3H), 8.87 (d, J=2.0 Hz, 1H), 11.28 (br.s, 1H).

Example 401.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(difluoromethyl)quinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 401

LCMS (ESI): mass calculated for C ₂₂ H ₁₂ ClF ₅ N ₈ O - 534.1, obtained m/z - 535.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.14-7.46 (m, 2H), 7.89 (t, J=7.5 Hz, 1H), 8.06 (t, J=7.7 Hz, 1H), 8.20 (s, 2H), 8.26 (s, 1H), 8.35 (d, J=8.5 Hz, 1H), 8.68-8, 73 (m, 2H), 8.86-8.91 (m, 1H), 11.27 (s, 1H).

Example 402.

Ν-(5-ΧλοΡ-6-(2Η- 1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1,1-difluoroethyl)isoquinolin-4-yl)- 5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 402

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LCMS (ESI): mass calculated for C ₂₃ H ₁₄ ClF ₅ N ₈ O - 548.1, obtained m/z - 549.1 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.31 (t, J=19.9 Hz, 3H), 7.38 (d, J=7.7 Hz, 1H), 7 .95-8.01 (m, 1H), 8.01-8.08 (m, 1H), 8.17-8.27 (m, 2H), 8.64 (s, 1H), 8.63 -8.67 (m, 1H), 8.66 (br.s, 1H), 8.68 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.87 ( d, J=2.4 Hz, 1H), 8.93 (s, 1H), 11.30 (s, 1H).

Example 403.

1-(1 -(Azetidin-3 -yl)isoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 403

A.

tert-Butyl

3-(4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1H-pyrazol- 1 -yl)isoquinolin-1 -yl)azetidine-1-carboxylate, 403a

Mixture of 1-tert-butoxycarbonyl azetidin-3-yl)-trifluoroborohydride (289 mg, 1.1 mmol), N-(5-χλορ6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1E-pyrazole-4carboxamide (242 mg, 0.5 mmol), silver nitrate (34 mg, 0.2 mmol), ammonium persulfate ( 1141 mg, 5 mmol) and TFA (0.0383 ml, 0.5 mmol) were stirred in dioxane (5 ml) and water (5 ml) in a sealed tube. The reaction mixture was stirred at rt for 4 hours. The reaction mixture was poured into a 1:1 mixture of sat. aq. NaHCO ₃ /5% aq. Na ₂ S ₂ O ₃ and extracted the aqueous layer using DCM (3x). The combined organic layers were dried over MgSO ₄ , filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 30x150 mm, mobile phase: 0.25% NH4HCO3 in water, MeOH) to give compound 403a (16 mg, 5%). LCMS (ESI): mass calculated for C ₂₉ H ₂₅ ClF ₃ N ₉ O ₃ . _639.2 , resulting m/z 640.2 [M+H]+.

B. 1-(1-(Azetidin-3-yl)isoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 403

A mixture of tert-butyl 3-(4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1H -pyrazol-1-yl)isoquinolin-1-yl)azetidine-1-carboxylate (16 mg, 0.025 mmol) and TFA (0.134 ml, 1.75 mmol) in DCM (0.5 ml) were stirred for 3 h. The reaction mixture was concentrated to dryness. The reaction mixture was poured into water and made alkaline by adding Na ₂ CO ₃ , subsequently extracted using DCM (2x). The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 30x150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN) to give compound 403 (7 mg, 52%). LCMS (ESI): mass calculated for C ₂₄ H ₁₇ ClF ₃ N ₉ O - 539.2, obtained m/z -540.2 [M+H]+.

1H NMR (400 MHz, chloroform-d) δ ppm 4.11 (br.t, J=8.1 Hz, 2H), 4.32 (br.s, 2H), 4.90 (sq. , J=8.0 Hz, 1H), 7.30 (d, J=7.3 Hz, 1H), 7.67-7.79 (m, 2H), 7.96 (s, 2H), 8 .04 (d, J=7.7 Hz, 1H), 8.26 (s, 1H), 8.55 (d, J=2.4 Hz, 1H), 8.61 (s, 1H), 8 .78 (d, J=2.4 Hz, 1H).

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Example 404.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(methoxymethyl)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 404

Mixture of methoxyacetic acid (135 mg, 1.5 mmol), N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin3-yl)-1-(isoquinolin-4-yl) )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (242 mg, 0.5 mmol), silver nitrate (17 mg, 0.1 mmol), ammonium persulfate (342 mg, 1.5 mmol) and TFA (0.0383 ml, 0.5 mmol) was stirred in DMSO (5 ml) and water (5 ml) in a sealed tube. The reaction mixture was stirred at rt for 16 hours. Additional methoxyacetic acid (135 mg, 1.5 mmol), silver nitrate (17 mg, 0.1 mmol) and ammonium persulfate (342 mg, 1.5 mmol) was added. The reaction mixture was stirred for 16 hours. The reaction mixture was poured into water, made basic with Na ₂ CO ₃ and extracted with DCM (2x). The combined organic layers were dried over MgSO ₄ , filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 30x150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN). The pure fractions were collected, concentrated and the residue was stirred in diisopropyl ether, the solid was collected by filtration and subsequently dried to give compound 404 (21 mg, 8%). LCMS (ESI): mass calculated for C ₂₃ H ₁₆ ClF ₃ N ₈ O ₂ . ₅₂₈ , 1/resulting m/z - 529.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 3.42 (s, 3H), 5.10 (br.s, 2H), 7.28 (d, J=8.5 Hz, 1H) , 7.82-7.91 (m, 1H), 7.91-7.99 (m, 1H), 8.19 (s, 2H), 8.52 (d, J=8.5 Hz, 1H ), 8.64 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.74 (s, 1H), 8.87 (d, J=2.0 Hz, 1H ), 11.28 (br.s, 1H).

Example 405.

4-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)quinoline -1-oxide, compound 405

Solution of X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide (2425 mg, 5 mmol) in DCM (150 ml) was stirred at rt. m-CPBA (1295 mg, 7.5 mmol) was added in portions. Stirring was continued for 16 hours. Additional m-CPBA (1295 mg, 7.5 mmol) was added in portions. Stirring was continued for 4 hours. Additional m-CPBA (1295 mg, 7.5 mmol) was added in portions. Stirring was continued for 16 hours. The reaction mixture was poured into 100 ml of water, and treated with sodium sulfite (4726 mg, 37.7 mmol), and stirred for 15 minutes, and then NaHCO ₃ (3150 mg, 37.5 mmol) was added. . Stirring was continued for 5 minutes. DCM/MeOH (100 ml, 90/10) was added and stirring was continued for 10 min. The precipitate was collected by filtration. The aqueous layer was extracted using DCM/MeOH (100 ml, 90/10, 3x). The combined organic layers were concentrated. The resulting residue was boiled in CH3CN, cooled and the resulting precipitate was collected by filtration, subsequently dried to give crude compound 405 (6.3 g, 251%), which was used as is in the next step. LCMS (ESI): mass calculated for C ₂₁ H ₁₂ ClF ₃ N ₈ O ₂ . ₅₀₀ , 1, obtained m/z 501.1 [M+H]+.

By following the procedure described in Example 405 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as needed or desired, within the understanding of those skilled in the art, was obtained the following connections.

Example 406.

4-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)isoquinoline -2-oxide, compound 406

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LCMS (ESI): mass calculated for C ₂₁ H ₁₂ ClF ₃ N ₈ O ₂ 500.1, obtained m/z 501.1 [M+H]+.

Example 407.

5-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)isoquinoline 2-oxide, compound 407

LCMS (ESI): mass calculated for C ₂₁ H ₁₂ ClF ₃ N ₈ O ₂ 500.1, obtained m/z 501.1 [M+H]+.

Example 408.

5-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)quinoline 1-oxide, compound 408

LCMS (ESI): mass calculated for C ₂₁ H ₁₂ ClF ₃ N ₈ O ₂ 500.1, obtained m/z 501.1 [M+H]+.

Example 409.

4-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)thieno [2,3-c]pyridine 6-oxide, compound 409

LCMS (ESI): mass calculated for C ₁₉ H ₁₀ ClF ₃ N ₈ O ₂ S - 506, obtained m/z - 507 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.05 (d, J=5.7 Hz, 1H), 8.18 (d, J=5.0 Hz, 1H), 8.19 (s, 2H), 8.62 (s, 1H), 8.67 (d, J=2.4 Hz, 1H), 8.77 (d, J=1.6 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H), 9.36 (s, 1H), 11.23 (s, 1H).

Example 410.

4-(4-((5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1Hpyrazol-1 -yl)thieno[2,3-c]pyridine 6-oxide, compound 410

LCMS (ESI): mass calculated for C ₂₀ H ₁₂ ClF ₃ N ₈ O ₂ S - 520, obtained m/z - 521.1 [M+H]+.

Example 411.

N(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-cyanoisoquinolin-5-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide, compound 411

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Mixture of 5-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1Hpyrazol-1-yl) isoquinoline 2-oxide (501 mg, 1 mmol), trimethylsilyl cyanide (119 mg, 1.2 mmol) and DBU (305 mg, 2 mmol in THF (3 ml) were stirred at 50°C for 1 hour. The reaction mixture was poured into water and extracted using ethyl acetate. The organic layer was dried over MgSO ₄ , filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobile phase: 0.25% NH solution ₄ HCO ₃ in water, CH3CN) to give compound 411 (330 mg, 65%) LCMS (ESI): mass calculated for C ₂₂ H ₁₁ ClF ₃ N ₉ O -509.1, obtained m/z - 510, 1[M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.50 (dd, J=5.7, 0.8 Hz, 1H), 8.15 (dd, J=8.5, 7, 7 Hz, 1H), 8.19 (s, 2H), 8.32 (d, J=6.9 Hz, 1H), 8.57 (dt, J=8.4, 0.9 Hz, 1H) , 8.64 (s, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.81-8.84 (m, 1H), 8.87 (d, J=2.4 Hz, 1H), 11.26 (br.s, 1H).

By following the procedure described in Example 411 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as needed or desired, within the understanding of those skilled in the art, was obtained the following connections.

Example 412.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-cyanoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 412

LCMS (ESI): mass calculated for C ₂₂ H _n ClF ₃ N ₉ O - 509.1, obtained m/z - 510.1 [M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.44 (d, J=8.5 Hz, 1H), 7.97 (ddd, J=8.3, 7.1, 0, 8 Hz, 1H), 8.12 (ddd, J=8.4, 7.2, 1.4 Hz, 1H), 8.20 (s, 2H), 8.39 (d, J=8.5 Hz, 1H), 8.63 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.72 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 11.29 (br.s, 1H).

Example 413.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-cyanoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 413

WITH· ?

I ^N '4 oE h

Ν

LCMS (ESI): mass calculated for C ₂₂ H11ClF ₃ N ₉ O - 509.1, obtained m/z - 510.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.89-7.97 (m, 1H), 8.14-8.19 (m, 3H), 8.20 (s, 2H), 8.44-8.51 (m, 1H), 8.63 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.87 (d, J=2.0 Hz , 1H), 11.20 (br.s, 1H).

Example 414.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-cyanoisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 414

LCMS (ESI): mass calculated for C ₂₂ H ₁₁ ClF ₃ N ₉ O - 509.1, obtained m/z - 510.1 [M+H]+.

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1H NMR (400 MHz, DMSO-d6) δ ppm 7.47-7.55 (m, 1H), 8.08-8.17 (m, 2H), 8.20 (s, 2H), 8.44-8.53 (m,

1H), 8.68-8.74 (m, 2H), 8.87 (d, J=2.4 Hz, 1H), 9.09 (s, 1H), 11.29 (br.s, 1H ).

Example 415.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-cyanothieno[2,3-c]pyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 415

LCMS (ESI): mass calculated for C ₂₀ H9ClF ₃ N9OS 515, obtained m/z - 516 [M+H]+.

Example 416.

N-(5-Chloro-2-methyl-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(7-cyanothieno[2,3-c]pyridin- 4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 416

LCMS (ESI): mass calculated for C ₂₁ H ₁₁ ClF ₃ N ₉ OS - 529, obtained m/z - 530[M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.57 (s, 3H), 7.43 (d, J=5.3 Hz, 1H), 8.19 (s, 2H), 8.44 (s, 1H), 8.58 (d, J=5.3 Hz, 1H), 8.67 (s, 1H), 8.95 (s, 1H).

Example 417, Example 418 and Example 419.

i(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxyquinolin-4-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide, compound 417

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-oxo-1,2-dihydroquinolin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 418

And

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-2-oxo-1,2-dihydroquinoline-4- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 419

Mixture of 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1Hpyrazol-1-yl) quinoline 1-oxide (501 mg, 1 mmol), tosyl anhydride (980 mg, 3 mmol), Na ₂ CO ₃ (318 mg, 3 mmol) in MeOH (10 ml) was stirred at rt for 16 hours. DMF (10 ml). Additional tosyl anhydride (980 mg, 3 mmol) and Na ₂ CO ₃ (318 mg, 3 mmol) were added and stirring continued for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (2x). The organic layer was washed with water, dried over MgSO ₄ and the filtrate was concentrated. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN) to give compound 418 (73 mg, 15%), compound 419 ( 48 mg, 9%) and compound 417 (80 mg, 16%).

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Compound 418. LCMS (ESI): mass calculated for C ₂₁ H ₁₂ ClF ₃ N ₈ O ₂ _ ₅₀₀ , 1, obtained m/z 501.1 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.85 (d, J=8.1 Hz, 1H), 6.97 (s, 1H), 7.24 (t, J=7 .5 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 8.19 (s, 2H), 8. 64 (s, 1H), 8.68 (d, J=2.3 Hz, 1H), 8.87 (d, J=2.3 Hz, 1H), 10.93 (br.s, 1H).

Compound 419. LCMS (ESI): mass calculated for C ₂₂ H ₁₄ ClF ₃ N ₈ O ₂ - _514.1 , obtained m/z 515.2 [M+H]+.

1H NMR (600 MHz, DMSO-d ₆ ) δ ppm 3.74 (s, 3H), 6.89 (dd, J=8.1, 1.3 Hz, 1H), 7.14 (s , 1H), 7.34 (ddd, J=8.0, 7.0, 1.2 Hz, 1H), 7.73-7.76 (m, 1H), 7.77-7.81 (m , 1H), 8.19 (s, 2H), 8.63 (s, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.85 (d, J=2.1 Hz , 1H), 11.24 (br.s, 1H).

Compound 417. LCMS (ESI): mass calculated for C ₂₂ H ₁₄ ClF ₃ N ₈ O ₂ _ _514.1 , obtained m/z 515.2 [M+H]+.

1H NMR (600 MHz, DMSO-d6) δ ppm 4.09 (s, 3H), 7.15 (dd, J=8.4, 1.0 Hz, 1H), 7.52-7, 56 (m, 2H), 7.83 (ddd, J=8.4, 7.0, 1.4 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 8.20 (s, 2H), 8.65 (s, 1H), 8.68 (d, J=2.3 Hz, 1H), 8.86 (d, J=2.3 Hz, 1H), 11.01 (us.s, 1H).

By following the procedure described in Example 417 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as needed or desired, within the understanding of those skilled in the art, was obtained the following connections.

Example 420.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxyquinolin-5-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 420

LCMS (ESI): mass calculated for C ₂₂ H ₁₄ ClF ₃ N ₁₃ O ₂ - _514.1 , obtained m/z - 515.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 4.05 (s, 3H), 7.17 (d, J=9.4 Hz, 1H), 7.47 (d, J=9, 4 Hz, 1H), 7.70 (d, J=7.3 Hz, 1H), 7.83-7.92 (m, 1H), 8.08 (d, J=8.5 Hz, 1H) , 8.19 (s, 2H), 8.57 (s, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.4 Hz, 1H) , 11.25 (br.s, 1H).

Example 421.

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methoxyisoquinolin-4-yl)-5 (trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 421

LCMS (ESI): mass calculated for C ₂₂ H ₁₄ ClF ₃ N ₈ O ₂ _ _514.1 , obtained m/z - 515.1 [M+H]+.

1H NMR (400 MHz, chloroform-d) δ ppm 4.22 (d, J=1.2 Hz, 3H), 7.13 (d, J=8.1 Hz, 1H), 7.62 -7.68 (m, 1H), 7.69-7.76 (m, 1H), 7.95 (d, J=1.2 Hz, 2H), 8.11 (s, 2H), 8. 22 (s, 1H), 8.35 (d, J=8.5 Hz, 1H), 8.49-8.55 (m, 1H), 8.73-8.79 (m, 1H).

Example 422.

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-ethoxyisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 422

LCMS (ESI): mass calculated for C ₂₃ H ₁₆ ClF ₃ N ₁₃ O ₂ _ _528.1 , obtained m/z - 529.1 [M+H]+.

1H NMR (400 MHz, chloroform-d) δ ppm 1.56 (t, J=7.1 Hz, 3H), 4.67 (k, J=6.9 Hz, 2H), 7.12 (d, J=8.1 Hz, 1H), 7.60-7.68 (m, 1H), 7.68-7.75 (m, 1H), 7.96 (s, 2H), 8. 09 (s, 1H), 8.23 (s, 1H), 8.31 (br.s, 1H), 8.38 (d,

- 377 045333

J=8.1 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.78 (s, 1H).

Example 448.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-hydroxyisoquinolin-4-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide, compound 448

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-chloroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide (1000 mg, 1.9 mmol), iPrOH (30 ml) and HCl 37% in water (15 ml) were stirred at 60°C for 4 hours. The reaction mixture was concentrated to dryness and the residue was dissolved in 50 ml DXM. The solution was poured into 50 ml of water. The mixture was made alkaline with Na ₂ CO ₃ and stirred for 15 minutes. The layers were separated and the aqueous layer was extracted using DCM. The organic layer was dried over MgSO ₄ , filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (eluent: DCM/MEON 5/95) to give compound 448 (600 mg, 62%). LCMS (ESI): mass calculated for C ₂₁ H ₁₂ ClF ₃ N ₈ O ₂ 500.1, obtained m/z - 501.1 [M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 6.78 (d, J=8.1 Hz, 1H), 7.58-7.65 (m, 1H), 7.74-7 .82 (m, 1H), 7.86 (s, 1H), 8.18 (s, 2H), 8.29 (dd, J=8.1, 0.8 Hz, 1H), 8.51 ( s, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.84 (d, J=2.0 Hz, 1H), 11.53 (br.s, 1H).

Example 423.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 423

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-hydroxyisoquinolin-4-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide (190 mg, 0.307 mmol, ₈₁ % purity) _C2CO3 (100 mg, 0.307 mmol) and iodomethane (43.6 mg, 0.307 mmol) in DMA (2 ml) were stirred at rt for 4 hours. The reaction mixture was poured into 20 ml of water. The mixture was extracted using 3x ethyl acetate and the organic layer was washed with 20 ml of water, dried over MgSO ₄ , filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN). Pure fractions were collected and concentrated. The residue was dissolved in water and extracted using ethyl acetate. The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated. The residue was stirred in diisopropyl ether, the solid was collected by filtration, subsequently filtered and dried to give compound 423 (155 mg, 98%). LCMS (ESI): mass calculated for C ₂₂ H ₁₄ ClF ₃ N ₈ O ₂ . _514.1 , resulting m/z - 515.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 3.60 (s, 3H), 6.82 (d, J=8.1 Hz, 1H), 7.65 (t, J=7, 6 Hz, 1H), 7.79 (t, J=7.1 Hz, 1H), 8.19 (s, 2H), 8.23 (s, 1H), 8.34 (d, J=7, 7 Hz, 1H), 8.55 (s, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.4 Hz, 1H), 11.26 (us.s, 1H).

Example 424.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-chlorothieno[2,3-c]pyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 424

Mixture of 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1Hpyrazol-1-yl) thieno[2,3-c]pyridine 6-oxide (2900 mg, 5.72 mmol) and POCl ₃ (100 ml) were stirred at 60°C for 16 hours. The reaction mixture was concentrated to dryness and dissolved in 150 ml DCM. The solution was added dropwise to 150 ml of water. The mixture was made alkaline with Na ₂ CO ₃ and subsequently varied

- 378 045333 sewed for 15 minutes. The layers were separated and the aqueous layer was extracted using DCM. The organic layer was dried and concentrated. The residue was purified by silica gel flash column chromatography (DCM/MEON 2/98 to 95/5) to give the crude compound (2.55 mg, 85%). A portion of the crude compound (150 mg) was purified by preparative CA {(stationary phase: Chiralpak Daicel IC 20x250 mm, mobile phase: CO ₂ , EtOH+0.4 iPrNH ₂ ) to obtain compound 424 (104 mg). LCMS (ESI): mass calculated for C ₁₉ H ₉ Cl ₂ F ₃ N ₈ OS - 524, obtained m/z - 525[M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6) δ ppm 7.29 (d, J=5.3 Hz, 1H), 8.18 (s, 2H), 8.45 (d, J=5 ,3 Hz, 1H), 8.61 (s, 1H), 8.64 (s, 1H), 8.67 (d, J=2.4 Hz, 1H), 8.85 (d, J=2 .0 Hz, 1H), 11.27 (br.s, 1H).

By following the procedure described in Example 424 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as needed or desired, within the understanding of those skilled in the art, was obtained the following connections.

Example 426.

N-(5-Chloro-2-methyl-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(7-chlorothieno[2,3-c]pyridin- 4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 426

LCMS (ESI): mass calculated for C ₂₀ H ₁₁ Cl2F ₃ N ₈ OS - 538, obtained m/z - 539 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.57 (s, 3H), 7.31 (d, J=5.3 Hz, 1H), 8.19 (s, 2H), 8.43-8.49 (m, 2H), 8.61 (s, 1H), 8.63 (s, 1H), 10.63 (br.s, 1H).

Example 427.

(R)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1 -(3-hydroxypyrrolidin-1 yl)isoquinoline- 4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 427

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-chloroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide (250 mg _, 0.48 mmol), (R)-3-hydroxypyrrolidine (87 mg, 0.96 mmol) and _C2CO3 (314 mg, 0.96 mmol) in DMSO (2 ml ) was stirred at 80°C for 4 hours. The reaction mixture was poured into water and extracted using ethyl acetate. The organic layer was washed with water, dried over MgSO ₄ , filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN) to give compound 427 (90 mg, 33%). LCMS (ESI): mass calculated for C ₂₅ H ₁₉ ClF ₃ N ₉ O ₂ . ₅₆₉ , 1, obtained m/z - 570.2 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.91-2.00 (m, 1H), 2.00-2.11 (m, 1H), 3.68 (br.d, J =11.4 Hz, 1H), 3.85 (ddd, J=10.8, 7.9, 2.8 Hz, 1H), 4.10 (br.d, J=10.2 Hz, 2H) , 4.39-4.48 (m, 1H), 5.04 (d, J=3.3 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 7.58 ( t, J=7.7 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 8.10 (s, 1H), 8.19 (s, 2H), 8.43 ( d, J=8.5 Hz, 1H), 8.50 (br.s, 1H), 8.67 (d, J=2.4 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H), 11.25 (br.s, 1H).

By following the procedure described in Example 427 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as needed or desired, within the understanding of those skilled in the art, was obtained the following connections.

Example 429.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(methylthio)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 429

LCMS (ESI): mass calculated for C ₂₂ H ₁₄ ClF ₃ N ₈ OS - 530.1 obtained m/z - 531.1 [M+H]+.

- 379 045333

1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (s, 3H), 7.21 (d, J=8.1 Hz, 1H), 7.82-7.88 (m, 1H), 7.91-7.97 (m, 1H), 8.19 (s, 2H), 8.34 (d, J=8.5 Hz, 1H), 8.60 (s, 1H), 8.65 (s, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.85 (d, J=2.4

Hz, 1H), 11.27 (br.s, 1H).

Example 430.

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-(3-hydroxyazetidin-1-yl)thieno [2,3c ]pyridin-4-yl)-5-(trifluoromethyl)-1 H-pyrazol-4-carboxamide, compound 430

LCMS (ESI): mass calculated for C ₂₂ H ₁₅ ClF ₃ N ₉ O ₂ S - 561.1, obtained m/z - 562 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.12 (dd, J=9.3, 4.4 Hz, 2H), 4.55-4.62 (m, 2H), 4 .67 (br.d, J=6.2 Hz, 1H), 5.82 (br.s, 1H), 6.94 (d, J=5.5 Hz, 1H), 8.07 (s, 1H), 8.14 (d, J=5.3 Hz, 1H), 8.18 (s, 2H), 8.48 (s, 1H), 8.66 (d, J=2.0 Hz, 1H), 8.84 (d, J=2.0 Hz, 1H), 11.14 (br.s, 1H).

Example 431.

(8)-N(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-(3-hydroxypyrrolidin-1-yl)thieno[ 2,3c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 431

LCMS (ESI): mass calculated for C ₂₃ H ₁₇ ClF ₃ N ₉ O ₂ S - 575, obtained m/z - 576 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.93-2.03 (m, 1H), 2.04-2.18 (m, 1H), 3.82 (br.d, J =11.0 Hz, 1H), 3.90-4.06 (m, 3H), 4.46 (br.s, 1H), 5.10 (d, J=3.7 Hz, 1H), 6 .87 (d, J=5.3 Hz, 1H), 8.02 (s, 1H), 8.11 (d, J=5.3 Hz, 1H), 8.19 (s, 2H), 8 .47 (s, 1H), 8.66 (d, J=2.4 Hz, 1H), 8.84 (d, J=2.0 Hz, 1H), 11.23 (br.s, 1H) .

Example 432.

(R)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-(3-hydroxypyrrolidin-1-yl)thieno [2,3c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 432

LCMS (ESI): mass calculated for C ₂₃ H ₁₇ ClF ₃ N ₉ O2S - 575.1, obtained m/z - 576.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.93-2.03 (m, 1H), 2.04-2.21 (m, 1H), 2.10 (m, J=13 ,0, 8.7, 8.7, 4.3 Hz, 1H), 3.82 (br.d, J=11.0 Hz, 1H), 3.90-4.07 (m, 3H), 4.46 (br.s, 1H), 5.10 (br.d, J=2.8 Hz, 1H), 6.87 (d, J=5.3 Hz, 1H), 8.02 (s , 1H), 8.11 (d, J=5.3 Hz, 1H), 8.19 (s, 2H), 8.48 (s, 1H), 8.66 (d, J=2.0 Hz , 1H), 8.85 (d, J=2.4 Hz, 1H), 11.21 (br.s, 1H).

Example 433.

N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(7-(3 - hydroxyazetidin-1 yl)thieno[ 2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 433

LCMS (ESI): mass calculated for C ₂₃ H ₁₇ ClF ₃ N ₉ O ₂ S - 575.1, obtained m/z - 576.1 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.57 (s, 3H), 3.33 (dd, J=10.4, 9.2 Hz, 1H), 4.13 (br .dd, J=8.5, 4.5 Hz, 2H), 4.58 (br.t, J=7.5 Hz, 2H), 4.65-4.73 (m, 1H), 6, 97 (d, J=5.3 Hz, 1H), 8.07 (s, 1H), 8.14 (d, J=5.3 Hz, 1H), 8.19 (s, 2H), 8. 43 (s, 1H), 8.53 (s, 1H).

Example 434.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-methylthieno[2,3-c]pyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 434

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N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-chlorothieno[2,3-c]pyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide (131 mg, 0.25 mmol), methylboric acid (60 mg, 1 mmol) and K3PO4 (212 mg, 1 mmol) were suspended in dioxane (20 ml) and water (3 ml). PdCl ₂ (dppf)-CH ₂ Cl ₂ (20.5 mg, 0.025 mmol) was added and nitrogen gas was bubbled through the reaction mixture for 15 minutes, subsequently heated at 100°C overnight. The reaction mixture was poured into 20 ml water, extracted with ethyl acetate (3x) and washed the organic layer with 10 ml water. The organic layer was subsequently dried over MgSO ₄ , filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 30x150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN) to give compound 434 (15 mg, 12%). LCMS (ESI): mass calculated for C ₂₀ H ₁₂ ClF ₃ N ₈ OS 504.1, obtained m/z - 505.1 [M+H]+.

By following the procedure described in Example 434 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures, times, and other variables or parameters as needed or desired, within the understanding of those skilled in the art, was obtained the following connections.

Example 435.

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-cyclopropylthieno[2,3-c]pyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 435

LCMS (ESI): mass calculated for C ₂₂ H ₁₄ ClF ₃ N ₈ OS - 530.1, obtained m/z - 531 [M+H]+.

The following compounds were obtained by enantiomer separation using preparative SFC (stationary phase: Chiralpak Diacel AD 20x250 mm, mobile phase: CO2, EtOH with 0.1% triethylamine). The pure fractions were collected, concentrated and the residues were stirred in diisopropyl ether, the solid was collected by filtration and subsequently dried to obtain the pure enantiomers (steric centers were designated arbitrarily).

Example 436.

(R)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(tetrahydrofuran-2-yl)isoquinolin-4yl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 436

LCMS (ESI): mass calculated for C ₂₅ H ₁₈ ClF ₃ N ₈ O ₂ _ _554.1 , obtained m/z - 555.2 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.01-2.18 (m, 2H), 2.31-2.43 (m, 1H), 2.56-2.71 (m , 1H), 3.60 (spt, J=6.0 Hz, 1H), 3.89-4.05 (m, 2H), 5.82 (t, J=6.9 Hz, 1H), 7 .26 (d, J=8.1 Hz, 1H), 7.83-7.89 (m, 1H), 7.907.97 (m, 1H), 8.19 (s, 2H), 8.61- 8.66 (m, 2H), 8.69 (d, J=2.0 Hz, 1H), 8.74 (s, 1H), 8.87 (d, J=2.4 Hz, 1H).

Example 437.

(S)-N-(5-Chloro-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(1-(tetrahydrofurαn-2-yl)isoquinolin-4yl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 437

LCMS (ESI): mass calculated for C ₂₅ H ₁₈ ClF ₃ N ₈ O ₂ _ _554.1 , obtained m/z - 555.2 [M+H]+.

- 381 045333 ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.01-2.20 (m, 2H), 2.31-2.42 (m, 1H), 2.54-2 .72 (m, 1H), 3.553.68 (m, 1H), 3.89-4.08 (m, 2H), 5.82 (t, J=6.9 Hz, 1H), 7.26 ( d, J=8.1 Hz, 1H), 7.83-7.89 (m, 1H), 7.90-7.98 (m,

1H), 8.19 (s, 2H), 8.61-8.66 (m, 2H), 8.69 (d, J=2.4 Hz, 1H), 8.74 (s, 1H), 8.87 (d, J=2.4 Hz, 1H).

Example 438.

(R)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(4-oxotetrahydrofuran-2yl)isoquinoline-4 -yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 438

LCMS (ESI): mass calculated for C ₂₅ H ₁₆ ClF ₃ N ₈ O ₃ . ₅₆₈ , 1, obtained m/z - 569 [M+H]+.

Example 439.

(*S)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(4-oxotetrahydrofuran-2yl)isoquinoline- 4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 439

LCMS (ESI): mass calculated for C ₂₅ H ₁₆ ClF ₃ N ₁₃ O ₃ . ₅₆₈ , 1, obtained m/z - 569 [M+H]+.

Example 440.

(R)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(tetrahydrofuran-2-yl)quinolin-5 -yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 440

LCMS (ESI): mass calculated for C ₂₅ H ₁₈ ClF ₃ N ₈ O ₂ . _554.1 , resulting m/z - 555.1 [M+H]+.

Example 441.

(S)-N-(5-Chloro-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(2-(tetrahydrofuran-2-yl)quinolin-5 -yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 441

LCMS (ESI): mass calculated for C ₂₅ H ₁₈ ClF ₃ N ₈ O ₂ . _554.1 , obtained m/z - 555.2 [M+H]+.

Example 442.

(*R)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1-hydroxyethyl)isoquinoline-4- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 442

LCMS (ESI): mass calculated for C ₂₃ H ₁₆ ClF ₃ N ₈ O ₂ . _528.1 , obtained m/z - 529.2[M+H]+.

- 382 045333

Example 443.

(S)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-ul)pyridin-3-yl)-1-(1-(1-hydroxyethyl)isoquinolin-4-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 443

LCMS (ESI): mass calculated for C ₂₃ H ₁₆ ClF ₃ N ₈ O ₂ . _528.1 , resulting m/z - 529.1[M+H]+.

Example 444 (*R)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1-hydroxyethyl)isoquinoline- 5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 444

LCMS (ESI): mass calculated for C ₂₃ H ₁₆ ClF ₃ N ₈ O ₂ . ₅₂₈ , 1, obtained m/z - 529 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (d, J=6.5 Hz, 3H), 5.52-5.74 (m, 2H), 6.93 (d, J=6.1 Hz, 1H), 7.88 (m, J=8.5, 7.7 Hz, 1H), 8.09 (d, J=6.9 Hz, 1H), 8.20 ( s, 2H), 8.53 (d, J=6.1 Hz, 1H), 8.61 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.88 ( d, J=2.0 Hz, 1H), 11.18-11.52 (m, 1H), 11.29 (s, 1H).

Example 445 (*S)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1-hydroxyethyl)isoquinoline- 5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 445

LCMS (ESI): mass calculated for C ₂₃ H ₁₆ ClF ₃ N ₈ O ₂ . ₅₂₈ , 1, obtained m/z - 529 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (d, J=6.5 Hz, 3H), 5.52-5.74 (m, 2H), 6.93 (d, J=6.1 Hz, 1H), 7.88 (m, J=8.5, 7.7 Hz, 1H), 8.09 (d, J=6.9 Hz, 1H), 8.20 ( s, 2H), 8.53 (d, J=6.1 Hz, 1H), 8.61 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.88 ( d, J=2.0 Hz, 1H), 11.18-11.52 (m, 1H), 11.29 (s, 1H).

Biological examples.

In vitro assays include assays that determine cell morphology, protein expression and/or cytotoxicity, enzyme inhibition activity and/or subsequent functional consequences of treating cells with compounds of the invention. Alternative or additional in vitro assays can be used to quantify the ability of an inhibitor to bind to protein or nucleic acid molecules within a cell.

Inhibitory binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/target molecule complex, and determining the amount of radiolabel bound. Alternatively or additionally, inhibitor binding can be determined by performing a competition experiment in which novel inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands. Detailed conditions of exemplary systems for assaying compounds of formula (I) of the present invention as MALT1 inhibitors are provided in the biological examples below.

Such analyzes are illustrative and are not intended to limit the scope of the invention. A practitioner of the art will appreciate that modifications can be made to traditional assays to develop equivalent or different assays that can be used for comparative assessment of the activity or other characteristics of compounds and/or compositions as described herein.

In vitro assays

Biological example 1.

Biochemical analysis of MALT1 protease activity.

The protease activity of MALT1 was assessed in an in vitro assay using a tetrapeptide in ca.

- 383 045333 as a substrate and full-length MALT1 protein (Strep-MALT1(1-824)-His) purified from insect cells infected with baculovirus. The LRSR tetrapeptide was coupled to AMC (7-amino-4methylcoumarin) to produce a quenched fluorescent substrate for MALT1 protease (SM Biochemicals). Cleavage of AMC from the arginine residue resulted in an increase in coumarin fluorescence measured at 460 nm (excitation wavelength 355 nm). The final assay buffer consisted of 10 nM FL MALT1 protein, 200 μM Ac-LRSR-AMC, 50 mM Tris pH 7.5, 0.6 M citrate, 1 mM DTT, 1 mM EDTA, 0.05% BSA, and 1. 5% DMSO. Test compounds were applied 50 nL in 100% DMSO to a well of a black 384-Proxiplate (Perkin Elmer). Concentrations of test compounds were varied from 30 μM to 0.5 nM using 11 dilution steps (1:3). Background signal was measured in control wells containing assay buffer without enzyme, which served as minimal signal (MS) control. Maximum signal control (MS) values were obtained using the reaction with the enzyme but without the addition of compound. The compounds were preincubated with the MALT1 enzyme for 50 min at RT. Next, the substrate was added and fluorescence was measured on a Labsystems fluoroskan fluorescence scanner at an excitation wavelength of 355 nm and an emission wavelength of 460 nm, which corresponded to time point 0. The reaction mixture was then incubated for 4 h at RT and fluorescence was measured. To calculate _IC50 , the value at time point 0 was subtracted from the value at time point 4 h to account for possible autofluorescence of compounds.

The enzymatic reaction was linear over an incubation period of 4 h. By characterizing the Ac-LRSR-AMC substrate, a Michaelis constant value of K _M 200 μm was determined.

IC ₅₀ values were calculated using the following formula (Z initial must be > 0.5):

LC=median of minimum signal control values = minimum signal control: reaction without cells HC=median of maximum signal control values = maximum signal control: reaction with cells without connection % Effect=100-[(sample-LC)/(HC-LC)x100 ] % Control=(sample/NS)x100% Controlmin=(sample-LC)/(NS-LC)\100

The best fit curve was constructed using the least sum of squares method to plot the dependence of the %Controlmin value on the concentration of the compound. From this the IC ₅₀ value (the concentration of inhibitor causing 50% inhibition) can be obtained. In addition, an estimate of the slope of the graph was obtained in the form of the Hill coefficient.

Calculation of IC ₅₀ :

DATAi = LB + UB LB + e _t +exp(HILL*(LCONC-IC50)) with UB=upper limit;

LB=lower limit.

Used in Lexis Dose Response Curve Fitting version 1.0. The resulting data is shown in table. 2.

table 2

Connection no. MALT1_Biochemical activity (Ac-LRSRamc) IC50 (µM) Connection no. MALT1_Biochemical activity (Ac-LRSRamc) IC50 (µM) 1 0.389 227 1.148 2 0.012 228 1.122 3 0.191 229 1.122 4 0.200 230 1,072 5 0.214 231 0.891

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6 0.091 232 0.891 7 0.041 233 0.871 8 0.013 234 0.851 9 0.065 235 0.776 eleven 0.977 236 0.724 12 4,073 237 0.676 13 6,026 238 0.676 14 4,571 239 0.661 15 4,169 240 0.631 16 0.724 241 0.562 17 0.141 242 0.437 18 2,291 243 0.417 19 0.229 244 0.398 20 9,550 245 0.389 21 1.445 246 0.380 22 0.661 247 0.347 23 0.089 248 0.331 24 0.074 249 0.331 25 0.072 250 0.316 26 0.631 251 0.302 27 0.035 252 0.282 28 0.068 253 0.282 29 2.455 254 0.282 thirty 5,012 255 0.275 31 8,913 256 0.240 32 0.019 257 0.234 33 1,096 258 0.229 34 0.009 259 0.219 35 0.813 260 0.204 36 0.063 261 0.195 37 1.445 262 0.191 38 0.020 263 0.191 39 0.759 264 0.166 40 0.048 265 0.166

- 385 045333

41 0.891 266 0.158 42 0.162 267 0.155 43 0.060 268 0.155 44 0.083 269 0.155 45 0.398 270 0.145 46 0.056 271 0.145 47 0.011 272 0.145 48 0.631 273 0.145 49 0.155 274 0.141 50 0.020 275 0.138 51 0.045 276 0.138 52 0.035 277 0.132 53 0, 100 278 0.129 54 0.275 279 0.126 55 0.182 280 0.126 56 0.257 281 0.123 57 0.043 282 0.123 58 0.141 283 0.123 59 0.031 284 0.120 60 11,482 285 0.112 61 0.102 286 0.110 62 0.059 287 0.095 63 0.295 288 0.095 64 1, 148 289 0.091 65 0.060 290 0.081 66 0.069 291 0.081 67 2,042 292 0.079 68 0.151 293 0.076 69 0.060 294 0.076 70 0.479 295 0.074 71 1.585 296 0.072 72 0.407 297 0.251 73 0.724 298 1,349 74 0.372 299 0.105

- 386 045333

75 27,542 300 4,169 76 8,318 301 0.141 77 0.417 302 0.054 78 0.055 303 0.282 79 0.098 304 0.062 80 0.724 305 0.062 81 0.123 306 0.058 82 0.676 307 0.058 83 0.034 308 0.058 84 0.214 309 0.055 85 0.132 310 0.052 86 0.071 311 0.050 87 0.141 312 0.049 88 0.107 313 0.043 89 0.041 314 0.039 90 0.021 315 0.033 91 0.015 316 0.037 92 0.019 317 0.065 93 0.060 318 0.083 94 0.019 319 0.107 95 0.117 320 0.069 96 0.759 321 0.021 97 0.209 322 0.214 98 0.200 323 0.174 99 0.011 324 0.117 100 0.037 325 0.055 101 2,692 326 0.045 102 0.042 327 0.079 103 1.514 328 2,570 104 0.204 329 0.661 105 0.058 330 0.646 106 0.447 331 0.501 107 1,288 332 0.417 108 0.023 333 0.245

- 387 045333

109 0.010 334 0.417 110 0.019 335 0.174 111 0.010 336 0.214 112 0.017 337 0.141 113 0.011 338 0.058 114 0.011 339 0.117 115 0.012 340 0.209 116 0.015 341 0.025 117 0.013 342 0.115 118 0.015 343 0.020 119 0.013 344 1,230 120 0.030 345 0.093 121 0.022 346 0.275 122 0.013 347 0.933 123 0.013 348 0.195 124 0.020 349 13,490 125 0.013 350 1.259 126 0.015 351 0.068 127 0.015 352 0.044 128 0.016 353 0.115 129 0.016 354 0.052 130 0.017 355 0.010 131 0.017 356 0.123 132 0.019 357 0.977 133 0.019 358 0.019 134 0.020 359 0.028 135 0.021 360 2,692 136 0.021 361 12,303 137 0.023 362 0.138 138 0.023 363 26, 303 139 0.023 364 0.098 140 0.024 365 0.060 141 0.025 366 8,913 142 0.026 367 0.110

- 388 045333

143 0.026 368 0.331 144 0.028 369 0.155 145 0.028 370 0.107 146 0.032 371 0.069 147 0.030 372 1.995 148 0.032 373 0.138 149 0.029 374 0.087 150 0.008 375 0.355 151 0.214 376 0.024 152 0.018 377 0.457 153 0.012 378 0.447 154 0.019 379 0.501 155 0.019 380 0.447 156 0.022 381 4,898 157 0.023 382 0.331 158 0.074 383 10,000 159 0.105 384 5,888 160 0.389 385 0.054 161 0.282 386 0.107 162 0.363 387 0.030 163 0.224 388 1.995 164 0.282 389 0.186 165 0.245 390 0.102 166 0.229 391 0.007 167 0.110 392 0.026 168 0.107 393 0.012 169 0.072 394 0.095 170 0.135 395 3,467 171 0.071 396 0.447 172 0.069 397 0.214 173 0.059 398 0.060 174 0.059 399 0.316 175 0.047 400 0.209 176 0.045 401 0.056

- 389 045333

177 0.044 402 0.178 178 0.042 403 0.871 179 0.042 404 0.091 180 0.026 405 0.044 181 0.038 406 0.076 182 0.035 407 0.021 183 0.035 408 0.112 184 0.032 409 2,291 185 0.018 410 0.071 186 0.3θ0 411 0.033 187 0.178 412 0.022 188 0.115 413 0.288 189 0.078 414 0.019 190 0.170 415 0.054 191 0.036 416 2,570 192 0.025 417 0.174 193 0.041 418 0.550 194 0.076 419 0.015 195 0.324 420 0.010 196 3.162 421 0.020 197 0.015 422 0.011 198 0.026 423 0.054 199 0.110 424 0.072 200 0.040 425 0.389 201 0.028 426 0.013 202 0.051 427 0.009 203 0.162 428 0.011 204 0.035 429 0.030 205 0.195 430 0.013 206 1.738 431 0.017 207 0.331 432 0.098 208 0.316 433 0.170 209 0.224 434 0.214 210 0.072 435 0.170

- 390 045333

211 0.035 436 1.318 212 10,965 437 1,778 213 10,000 438 0.071 214 6,026 439 0.178 215 5,754 440 1.585 216 5, 370 441 0.977 217 4,898 442 0.062 218 3,467 443 0.013 219 2,692 444 0.058 220 2.138 445 0.079 221 2,042 446 0.032 222 1,698 447 0.447 223 1,698 448 1,288 224 1,660 449 0.023 225 1,230 450 0.010 226 1,202

Biological example 2.

PMA-induced IL2 production in Jurkat cells.

Jurkat cells were grown in complete RPMI 1640 medium supplemented with 10% fetal bovine serum, 10 mM HEPES, 100 U/ml penicillin, and 100 μg/ml streptomycin. Before analysis, serial 2- to 4-fold dilutions in DMSO were made for the compounds. In each well, 10 μl of compound diluted in DMSO was further diluted with 240 μl of complete RPMI1640 medium. Jurkat cells were collected by centrifugation at 1200 rpm for 5 min, washed once with RPMI 1640 medium and suspended in fresh complete RPMI 1640 medium at a concentration of 1.25 x 106 cells/ml. Jurkat cells (2x105 cells) in a volume of 160 μl were seeded into each well of 96-well flat-bottom plates. 20 μl of compound diluted in complete RMPI 1640 medium was added to each well and incubated with Jurkat cells for 30 min at 37°C in a 5% CO2 incubator. 20 µl of diluted PMA/Ionomycin solution (81 nM/1.3 µM respectively, ebioscience, cat. no. 00-4970-93) in complete RMPI 1640 medium was added to each well. After incubation at 37°C in a 5% incubator CO2 supernatants were collected for 20 h. IL-2 concentration was determined by ELISA (IL2 Duoset, R&D Systems, cat. no. DY202). Colorimetric intensity at 450 nm was read by a Spectramax plate scanner and analyzed by Softmax Pro software. Cell viability was determined using a Cell Titer Glo kit (Promega, cat. no. G7571) using a Victor Luminescence scanner (Victor 3 V 4202938 from Perkin Elmer).

The resulting data is presented in table. 3.

Biological example 3.

Mesoscale analysis of human IL6/IL10.

NF _K B signaling regulates the secretion of several cytokines, including IL6 and IL10. The secretion of IL6 and IL10 cytokines by TMD8 or OCI-LY3 ABC-DLBCL cells was measured using a Mesoscale assay. Inhibition of NF _K B signaling using MALT1 or BTK inhibitors results in decreased IL6/10 secretion.

TMD8 or OCI-LY3 cells were grown in RPMI-1640 medium (Sigma Aldrich) supplemented with 10% fetal bovine serum (HyClone), 1 mM sodium pyruvate (Invitrogen), 2 mM L-glutamine (Sigma Aldrich), and 1% PenStrep (Sigma Aldrich). The number of cell passages should not exceed 30. The cell concentration during cultivation should be maintained at 0.5-2.5 million per ml, and 50 µM of fresh beta-mercaptoethanol should be added to them every 2-3 days. Betamercaptoethanol was not used in the Mesoscale assay.

For the Mesoscale assay, 100,000 TMD8 or OCI-LY3 cells were seeded per well of black clear-bottom 96-well plates (Corning #3904), and test compounds were added in 9 serial dilutions (1:2) ranging from 15 µM to 58. 6 nM (final DMSO concentration - 0.3%). To determine the maximum signal (maximum signal control (MS)), control wells with DMSO were used. Treatment with the BTK inhibitor RN486 at a dose range of 30 nM to 131 pM (9 1:2 dilutions) served as a positive control for NFKB pathway inhibition and was used to determine maximum inhibition (minimum signal (LC) control). Compounds and cells were incubated for 24 h at 37°C and 5% CO2 (assay volume was 150 μl). After 24 h of incubation, 50 μl of the supernatant was transferred to an MSD plate (V-Plex Proinflamation Panel 1 (human), Mesoscale (MSD)) and incubated for 2 h with vigorous shaking (600 rpm) at room temperature. temperature After incubation, the plates were washed 3 times with PBS+0.05% Tween-20 and 25 μl of detection antibody solution (IL6 & IL10 antibodies in diluent 3 (MSD)) was added per well and incubated for 2 hours with vigorous shaking (600 rpm). min) at room temperature. After washing 3 times with PBS+0.05% Tween-20, the plates were incubated with 150 μl of 2x Read Buffer T and read with a SECTOR imaging device. The resulting data is presented in table. 3.

Table 3

Connection no. Human IL6 analysis Mesoscale (TMD-8) IC50 (µM) Human IL10 Mesoscale Assay (TMD-8) IC50 (µM) Human IL6 Mesoscale Assay (OCI-LY3) IC50 (µM) Human IL10 Mesoscale Assay (OCI-LY3) IC50 (µM) Products IL-2 in Jurkat PMA IC50 (µM) 1 0.31 2 0.052 0.028 0.059 3 0.219 0.138 0.16 4 0.339 0.214 0.36 5 0.282 0.14 6 0.112 0.023 7 0.166 0.13 8 0.032 0.0052 9 0.195 0.039 eleven ~13.5 0.68 16 1.479 17 0.794 0.17 19 1,950 0.41 21 > 15 22 > 15 1.86

- 392 045333

23 0.107 0.81 24 0.093 0.129 0.74 25 0.174 0.21 26 0.575 0.79 27 0.105 28 0.141 0.2 32 0.017 0.014 0.002 33 7,413 1.047 34 ~0.011 0.007 0.016 35 6,026 2,884 3.24 36 0.135 0.141 0.27 38 0.046 0.014 0.021 39 1,950 0.955 1.97 40 0.030 0.035 0.095 41 ~2.09 0.851 0.30 42 0.117 ~0.11 0.011 43 0.102 0.081 0.054 45 0.355 0.204 0.073 46 ~0.046 0.032 0.022 47 ~0.048 ~0.01 0.009 48 ~0.83 ~2.14 0.45 49 ~0.083 0.076 0.018 50 0.107 0.047 0.031 51 0.062 0.126 0.096 52 0.079 0.091 0.13 53 0.200 0.240 0.38 54 0.110 0.269 0.37 55 ~0.093 0.195 0.13 56 0.490 0.275 57 0.081 0.085 58 0.331 0.288 59 0.068 0.074 61 0.263 0.224 62 0.112 0.085

- 393 045333

63 2,042 1.445 65 0.282 0.120 66 0.331 0.132 68 0.417 0.257 69 0.058 0.063 70 1,096 0.891 72 0.851 1,380 73 0.417 0.339 74 1,380 1,380 78 0.081 0.112 79 ~0.34 0.251 81 0.135 0.138 82 0.240 0.295 83 0.032 0.043 84 0.148 0.355 85 0.095 0.120 86 0.037 0.148 87 0.251 0.324 88 0.331 0.209 89 0.074 0.095 90 0.098 0.135 91 0.151 0.155 92 0.102 0.132 93 0.447 0.501 94 0.089 0.105 95 0.646 0.302 96 1.047 0.676 97 0.575 0.257 98 0.468 0.417 99 0.068 0.047 100 0.251 0.155 102 0.110 0.186 103 > 15 > 15 104 > 15 > 15

- 394 045333

105 0.851 0.813 106 1.259 0.617 107 3,467 1.175 108 > 0.302 > 0.302 109 0.028 0.031 110 0.025 0.024 111 0.107 0.089 112 0.115 0.098 113 0.170 0.079 114 0.034 0.029 115 0.054 0.046 0.013 0.010 116 0.013 0.025 0.018 0.018 117 0.012 0.012 118 0.017 0.012 119 0.072 0.040 120 0.102 0.085 121 0.058 0.050 122 0.052 0.056 123 0.389 0.182 124 0.021 0.015 125 0.046 0.024 126 0.021 0.043 127 0.029 0.026 128 0.095 0.105 0.027 0.036 129 0.120 0.123 0.018 0.014 130 0.214 0.166 131 0.056 0.021 132 0.141 0.095 133 0.126 0.054 134 0.058 0.046 135 0.098 0.083 136 0.045 0.031 137 0.170 0.200 0.026 0.017 138 0.245 0.126

- 395 045333

139 0.050 0.036 140 0.072 0.028 141 0.051 0.039 142 0.107 0.017 143 0.098 0.056 144 0.052 0.049 145 0.126 0.047 146 0.331 0.132 147 0.200 0.085 148 0.105 0.112 149 0.912 2,630 150 0.457 0.178 151 0.224 0.200 152 0.110 0, 100 0.034 0.040 153 0.141 0.162 0.054 0.081 154 0.098 0.095 155 0.093 0.068 156 2,512 2,344 157 1,778 0.912 158 > 1.514 0.380 159 > 15,136 0.955 160 0.095 0.093 161 > 15,136 > 15,136 162 0.437 0.309 163 0.095 0.071 164 1,660 165 0.447 0.339 166 0.457 0.479 167 0.191 0.174 168 0.123 0.044 169 0.166 0.182 170 0.339 0.112 171 0.091 0.060 172 0.204 0.158

- 396 045333

173 0.550 0.240 174 0.251 0.112 175 > 3, 02 0.204 176 0.117 0.095 177 0.933 0.363 178 0.589 0.427 179 0.288 0.174 180 0.079 0.081 181 0.141 0.110 182 7,586 2,512 183 6, 607 2.138 184 4,266 1,000 185 0.186 0.162 186 1, 122 0.891 187 0.162 0.112 188 0.046 0.050 189 0.107 0.063 0.039 0.027 190 0.186 0.093 191 0.022 0.013 192 0.046 0.042 193 0.117 0.079 194 0.078 0.098 0, 100 0.068 195 0.107 0.071 196 0.083 0.041 197 0.123 0.085 198 0.115 0.091 199 0.295 200 0.380 0.282 201 0.117 0.120 202 5,012 2,951 203 5, 623 2,692 204 0.525 1.148 205 > 15,136 1.905 206 6,166 3,890

- 397 045333

207 0.525 0.513 208 > 15,136 8,710 209 1.479 1.122 210 0.417 0.380 211 1,660 2,291 212 1.023 0.513 213 > 15,136 > 15,136 214 2,042 2.239 215 12,303 2,089 216 0.912 0.339 217 0.537 0.269 218 0.174 0.087 219 0.102 0.126 220 0.851 0.468 221 0.331 0.331 222 3.311 0.575 223 0.759 1.175 224 0.575 0.832 225 0.407 0.794 226 0.257 0.093 227 6,457 0.550 228 0.692 0.813 229 0.912 0.331 230 1.413 0.759 231 0.724 0.851 232 0.145 0.182 233 0.331 0.240 234 0.263 0.141 235 0.708 1, 122 236 1,380 0.427 0.380 0.309 237 0.275 0.182 238 0.032 0.050 0.044 0.035 239 0.324 0.562 240 0.398 0.135

- 398 045333

241 0.049 0.069 0.051 0.037 242 0.065 0.054 243 0.363 0.339 0.120 0.129 244 0.741 0.245 0.174 0.155 245 0.708 0.141 246 0.135 0.063 247 > 1.5136 1,778 248 1.514 0.468 249 0.148 0.148 250 0.269 0.407 251 2,188 2.239 252 0.158 0.123 253 > 15,136 12,589 254 0.081 0.079 255 0.059 0.041 256 0.257 0.240 257 > 3.2 0.646 258 0.589 0.316 259 0.145 0.151 260 > 3, 02 > 3, 02 > 3, 02 > 3, 02 261 0.794 0.479 262 0.182 0.129 263 > 0.302 > 0.302 264 0.123 0.036 265 > 1.5136 0.120 266 0.186 0.178 267 0.035 0.056 268 0.158 0.229 0.095 0.063 269 0.083 0.085 270 0.170 0.098 271 0.112 0.095 272 0.126 0.087 273 0.085 0.066 274 2,754 3.162

- 399 045333

275 0.240 0.234 276 0.186 0.117 277 0.170 0.095 0.089 0.087 278 0.141 0.219 279 3.715 2,754 280 5.495 2,399 281 2,570 3,020 282 0.741 0.417 283 0.851 0.550 284 0.589 0.724 285 0.229 0.204 286 0.200 0.200 287 0.229 0.234 288 0.251 0.091 289 0.132 0.123 290 0.186 0.110 291 0.110 0, 100 292 0.151 0.115 293 0.447 0.251 294 1.585 0.871 295 1.259 0.724 296 0.182 0.069 297 0.135 0.115 298 0.050 0.025 299 0.537 0.309 300 0.525 0.339 301 0.501 0.417 302 0.102 0.059 303 0.234 0.174 0.251 0.275 304 3.311 3.236 305 > 15,136 7,943 306 > 3.02 > 3.02 > 3.02 2,630 307 0.447 0.427 308 0.219 0.166

- 400 045333

309 0.151 0.117 310 0.646 0.490 311 0.034 0.037 312 8,318 2.455 313 7,244 4,169 314 1.023 0.692 315 0.447 0.339 0.095 0.132 316 0.251 0.182 317 0.072 0.066 318 0.162 0.138 319 0.020 0.018 320 0.182 0.093 321 0.066 0.049 322 0.562 0.708 0.148 0.135 323 0.195 0.141 324 0.040 0.016 325 0.646 0.794 326 0.105 0.089 327 0.129 0, 100 328 0.741 0.589 329 1,660 1.445 330 0.021 0.025 331 0.309 0.339 332 0.048 0.044 333 0.155 0.123 334 0.186 0.251 335 0.132 0.060 336 0.209 0.117 337 0.209 0.182 338 0.045 0.031 339 0.107 0.087 340 0.295 0.229 341 0.479 0.389 342 0.162 0.132

- 401 045333

343 0.069 0.037 344 0.052 0.052 345 0.079 0.058 346 0.457 0.224 347 0.043 0.031 348 0, 100 0.068 349 0.079 0.060 350 0.204 0.182 351 0.078 0.046 352 0.129 0.087 353 0.692 0.537 354 0.457 0.437 355 0.912 0.407 356 0.295 0.209 357 0.015 0.015 358 0.123 0.126 359 0.098 0.091 360 0.020 0.020 361 1.259 0.617 362 3,467 1.175 363 > 0.302 > 0.302 364 0.028 0.031 365 0.025 0.024 366 0.107 0.089 367 0.115 0.098 368 0.170 0.079 369 0.034 0.029 370 0.054 0.046 0.013 0.010 371 0.013 0.025 0.018 0.018 372 0.012 0.012 373 0.017 0.012 374 0.072 0.040 375 0.102 0.085 376 0.058 0.050

- 402 045333

377 0.052 0.056 378 0.389 0.182 379 0.021 0.015 380 0.046 0.024 381 0.021 0.043 382 0.029 0.026 383 0.095 0.105 0.027 0.036 384 0.120 0.123 0.018 0.014 385 0.214 0.166 386 0.056 0.021 387 0.141 0.095 388 0.126 0.054 389 0.058 0.046 390 0.098 0.083 391 0.045 0.031 392 0.170 0.200 0.026 0.017 393 0.245 0.126 394 0.050 0.036 395 0.072 0.028 396 0.051 0.039 397 0.107 0.017 398 0.098 0.056 399 0.052 0.049 400 0.126 0.047 401 0.331 0.132 402 0.200 0.085 403 0.105 0.112 404 0.912 2,630 405 0.457 0.178 406 0.224 0.200 407 0.110 0, 100 0.034 0.040 408 0.141 0.162 0.054 0.081 409 0.098 0.095 410 0.093 0.068

- 403 045333

411 2,512 2,344 412 413 > 1.514 0.380 414 > 15,136 0.955 415 0.095 0.093 416 > 15,136 > 15,136 417 418 419 420 421 422 423 424 425 0.339 0.112 426 0.091 0.060 427 428 0.550 0.240 429 430 > 3, 02 0.204 431 432 0.933 0.363 433 434 435 436 437 7,586 2,512 438 6, 607 2.138 439 4,266 1,000 440 0.186 0.162 441 442 443 0.046 0.050 444 0.107 0.063 445 446 447 448 449 0.078 0.098 450

1,778 0.912 0.437 0.309 0.095 0.071 1,660 0.447 0.339 0.457 0.479 0.191 0.174 0.123 0.044 0.166 0.182 0.204 0.158 0.251 0.112 0.117 0.095 0.589 0.427 0.288 0.174 0.079 0.081 0.141 0.110 1, 122 0.891 0.162 0.112 0.039 0.027 0.186 0.093 0.022 0.013 0.046 0.042 0.117 0.079 0, 100 0.068 0.107 0.071

Biological example 4.

Proliferation assays.

To analyze antiproliferative effects, MALT1 inhibitory compounds were tested in 4-day proliferation assays using three different DLBCL cell lines. Two ABC-DLBCL cell lines with activating mutations in the classical _NFK B pathway (OCI-Ly3 (CARD11, MYD88 & A20 mutations), TMD8 (CD79B & MYD88 mutations), which are essentially sensitive to inhibition of the _NFK B pathway, were evaluated. Cell line GCB-DLBCL (OCI-Ly7), which was found to lack active NF _K B signaling, served as a negative control to exclude compounds with common cytotoxic effects.

OCI-Ly3 cells were grown in RPMI-1640 medium (Sigma Aldrich) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich), and 1% PenStrep (Sigma Aldrich). TMD8 cells were grown in RPMI-1640 medium (Sigma Aldrich) supplemented with 10% fetal bovine serum (HyClone), 1 mM sodium pyruvate (Invitrogen), 2 mM L-glutamine (Sigma Aldrich), and 1% PenStrep (Sigma Aldrich). The cell concentration during culture should be maintained at 0.52.5 million per ml, and 50 µM of fresh beta-mercaptoethanol should be added every 2-3 days. Beta-mercaptoethanol was not used in the proliferation assay. OCI-Ly7 cells were grown in IMDM medium (ThermoFisher) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich), and 50 μg/ml gentamicin. The number of cell passages should not exceed 30 (in the case of OCI-Ly3 cells, passage numbers less than 10 were used).

To evaluate antiproliferative effects, 400 nl of the test compounds were applied to a well of 96-well plates (Costar, cat. no. 3904). 10,000 TMD8 cells, 10,000 OCILy3 cells, or 2,000 OCI-Ly7 cells were seeded in 100 μl of medium per well and incubated for 4 days at 37°C and 5% CO2. The number of cells to be seeded was chosen based on growth curves to ensure linear cell growth. After 4 days of incubation, 50 μl of CellTiterGLO reagent (Promega) was added to each well, and luminescence was measured with an Envision instrument after 10 min of incubation at room temperature.

IC ₅₀ values were calculated using the following formula (Z initial must be > 0.5):

LC=median of minimum signal control values =minimum signal control: reaction without cells

NS=median of maximum signal control values =maximum signal control: reaction with cells without connection % Effect= 100-(sample-LC)/(NS-LC)x 100% Control=(sample/NS)x100% Control _min =(sample -LC)/(HC-LC)x 100

The best fit curve was constructed using the least sum of squares method to plot the dependence of the %Control value on the concentration of the compound. From this the IC ₅₀ value (the concentration of inhibitor that causes 50% cytotoxicity) can be obtained. In addition, an estimate of the slope of the graph was obtained in the form of the Hill coefficient.

Calculation of IC ₅₀ :

DATA, = LB + UB LB + e _t 1 +exp(HILL*(LCONC-IC50)) with UB=upper limit;

LB=lower limit.

The resulting data is presented in table. 4.

- 405 045333

Table 4

Connection no. Antiproliferative effect: OCI-LY-3 IC50 (µN) Antiproliferative effect: TMD-8 IC50 (µM) 2 0.42 13.80 3 ~2.88 9.55 4 ~0.50 ~15.85 5 ~0.78 > 20 6 0.62 9.33 7 0.43 ~14.13 8 0.11 ~7.59 9 ~2.40 10.72 eleven ~9.55 12.59 16 0.58 10.72 17 ~4.37 9.33 19 1.10 > 20 21 ~12.88 > 20 22 ~0.31 16.98 23 3.39 8.32 24 ~1.95 ~10 25 3.31 ~14.13 26 4.79 8.71 27 1.95 13.80 28 1.51 6.61 32 0.11 4.90 33 > 20 > 20 34 ~0.22 ~12.02 35 10.72 10.96 36 1.91 7.94 38 1.15 3.80 39 ~1.12 14.45 40 0.15 6.17 41 1.58 > 20 42 0.56 6.17 43 ~0.26 4.68

- 406 045333

45 0.34 ~9.33 46 0.63 9.33 47 ~0.19 8.13 48 0.30 16.22 49 0.41 5.01 50 0.09 7.08 51 0.20 ~6.61 52 0.21 5.01 53 1.07 ~13.49 54 0.46 8.71 55 0.54 5.25 56 0.54 > 20 57 0.22 ~8.91 58 0.50 4.47 59 0.14 6.76 61 1.26 ~14.12 62 0.23 10.00 63 ~1.15 >7.94 65 0.26 10.23 66 0.81 ~8.71 68 0.37 ~ 19.05 69 0.43 ~ 16.22 70 ~1.35 ~13.81 72 1.66 > 20 73 1.95 ~11.48 74 2.45 > 20 78 ~0.49 7.59 79 ~2.34 8.32 81 ~1.35 11.48 82 ~1.58 6.31 83 0.51 ~8.32 84 1.7 > 20 85 1.66 > 20 86 0.78 ~11.22

- 407 045333

87 1.7 ~13.80 88 1.35 ~12.02 89 0.74 > 20 90 0.52 ~3.89 95 3.8 ~7.94 96 7.08 ~15.49 97 3.47 ~5.89 98 5.75 ~10.96 99 0.65 ~3.24 100 1.95 ~5.25 108 1.122 1,660 109 > 19,953 > 19,953 110 0.220 1.445 111 0.284 3.311 112 0.966 6,310 113 0.912 13,804 114 0.193 2,692 115 1.212 19,953 116 0.344 6,918 117 0.211 1.585 118 0.158 0.832 119 0.193 0.355 120 0.325 1,950 121 0.692 1.905 122 0.132 0.162 123 0.395 0.501 124 0.593 0.977 125 0.285 1.023 126 0.135 0.794 127 0.432 11,220 128 0.188 129 0.179 2.455 130 0.417 3,467 131 0.265 2,630

- 408 045333

132 0.571 7,762 133 0.273 3.311 134 1.015 19,953 135 1,308 3,090 136 0.414 2,291 137 0.819 2,399 138 0.447 2,512 139 0.275 1.413 140 1.166 5,370 141 0.505 6,026 142 0.380 0.832 143 0.423 9,550 144 0.482 2,570 145 0.626 4,571 146 0.337 1.023 147 0.966 11,482 148 0.692 3,802 149 0.759 4.365 150 0.282 > 7,943 152 0.411 3,802 153 0.265 3,802 154 0.395 2.239 155 0.302 1,380 156 0.776 5,248 157 1,269 7,079 158 0.567 4,571 167 1.023 4,571 169 1.751 8,913 172 0.504 4,786 173 1.728 2,692 174 0.804 1,698 175 1,084 1,230 176 1,594 > 19,953 177 1,711 6,607

- 409 045333

178 2,802 > 19,953 179 0.763 1,950 181 1,496 > 7,943 182 3,144 5,248 183 3,569 > 19,953 184 0.585 6,026 191 0.866 0.912 192 0.593 4,571 193 0.521 3.631 197 0.295 7,413 198 0.641 3,020 200 1,388 7,413 201 0.782 3.631 202 1.357 2,344 204 1.718 5,888 221 0.912 2,570 302 0.692 0.955 306 0.540 1.514 308 0.617 4,571 310 1,269 311 2,317 3,548 312 0.516 0.501 313 0.939 7,943 314 0.631 1.862 315 1,084 6,761 316 1.454 3,090 326 0.881 3.236 338 1.148 1.445 376 1,072 1.445 385 0.837 1.514 387 0.692 2,188 391 0.505 0.676 405 0.513 4.365 411 0.486 0.871 418 0.464 3.631 419 1.116 5,754 425 0.905 10,965 446 1.065 > 19,953 447 0.313 2,188 448 0.550 5.623 450 0.295 2,818

Biological example 5.

Tumor efficacy study.

OCI-Ly3 tumor cells (DSMZ, cat. no. ACC 761) of human diffuse large cell lymphoma can be cultured in vitro in RPMI medium supplemented with heat-inactivated fetal bovine serum (10% v/v) and 2 mM L-glutamine 200 mM at 37°C in an air atmosphere with 5% CO ₂ . Cells can be subcultured regularly twice a week. Cells in the exponential growth phase can be collected and counted, diluted 1:1 in Matrigel™ (Corning Matrigel™ Matrix Basement Membrane Growth Factor Reduced) for tumor cell engraftment.

- 410 045333

Male NSG (NOD.Cg-Prkdc ^scid Il2rg ^t1wj1 /SzJ) mice can be inoculated subcutaneously with OCI-Ly3 cells (10 x 10 ⁶ cells in a 1:1 mixture of medium:Matrlgel™ in a volume of 200 μl) in the groin region of each animal. The day of tumor inoculation can be referred to as day 0. Tumor size monitoring can be done twice weekly starting on the seventh day after implantation until the average tumor volume reaches 169 ± 42 mm ³ , at which time mice can be randomized into treatment groups based on tumor volume . The compound or vehicle may be administered orally based on body weight (5 ml/kg) once or twice daily until completion of the study. Tumor size and body weight can be recorded twice a week.

The endpoints of the studies are inhibition of tumor growth, maximum tumor burden (individual tumor size equal to 10 wt.% of the body) and weight loss greater than 20% of body weight at the time of treatment. The percentage change in body weight can be calculated using the formula: change in body weight=[(C-I)/I]χ100, where C is the current body weight and I is the body weight at the start of treatment. The size of the tumor can be measured twice a week in two directions using calipers, and the volume can be expressed in mm ³ using the formula: V=0.5axb ² where a and b represent the major and minor diameters of the tumor, respectively. Complete tumor regression (CR) was defined as tumor shrinkage to the point that is undetectable by palpation (20 mm ³ ). Partial tumor regression (PR) was defined as tumors shrinking to at least half the original tumor volume. Determination of CR or PR for at least three or more consecutive tumor measurements was required to be considered stable.

The corresponding study tables provide summary statistics, including the mean and standard error of the mean (SEM) by tumor volume and differences in tumor volume within each group for each time point. Statistical analysis of differences in tumor volume between groups can be performed using two-way analysis of variance (ANOVA) for repeated measures followed by Tukey's test using GraphPad Prism version 6 software.

While the foregoing description sets forth the principles of the present invention with examples given for purposes of illustration, it is to be understood that the practice of the invention is intended to embrace all normal variations, adaptations and/or modifications included within the scope of the following claims and their equivalents.

Claims (39)

1. Compound of formula (I): Formula (I), where R ₁ is selected from the group consisting of i) naphthalen-1-yl, optionally substituted with fluorine or amino group; and ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, cyclopropyl, methoxymethyl, difluoromethyl, 1,1-difluoroethyl, hydroxymethyl, 1-hydroxyethyl, 1- ethoxyethyl, hydroxy, methoxy, ethoxy, fluorine, chlorine, bromine, methylthio, cyano, amino, methylamino, dimethylamino, 4oxotetrahydrofuran-2-yl, 5-oxopyrrolidin-2-yl, 1,4-dioxanyl, aminocarbonyl, methylcarbonyl, methylaminocarbonyl, oxo, 1-(tert-butoxycarbonyl)azetidin-2-yl, N-(methyl)formamidomethyl, tetrahydrofuran-2-yl, 3-hydroxy-pyrrolidin-1-yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin- 3-yl or azetidin-2-yl; R2 is selected from the group consisting of C _1-4 alkyl, 1-methoxyethyl, difluoromethyl, fluorine, chlorine, bromine, cyano and trifluoromethyl; G1 is N or C(R4); G2 is N or C(R3); so that in any case only one of G1 and G2 is N; R3 is independently selected from the group consisting of trifluoromethyl, cyano, Ci_ ₄ alkyl, fluorine, chlorine, bromine, methylcarbonyl, methylthio, methylsulfinyl and methanesulfonyl; or, if G ₁ is N, R3 is further selected from C _1-4 alkoxycarbonyl; R ₄ is selected from the group consisting of - 411 045333 i) hydrogen if G2 is N; ii) Ci-4 alkoxy; iii) cyano; iv)cyclopropyloxy; v) heteroaryl selected from the group consisting of triazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, tetrazolyl, oxadiazolyl, imidazolyl, 2-amino-pyrimidin-4-yl, 2H[1,2,3]triazolo[4, 5-c]pyridin-2-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl, 3H-[1,2,3]triazolo[4,5b]pyridin- 3-yl, 1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl, wherein the heteroaryl is optionally substituted with one or two substituents independently selected from oxo, C1-4 alkyl, carboxy, methoxycarbonyl, aminocarbonyl, hydroxymethyl, aminomethyl, (dimethylamino)methyl, amino, methoxymethyl, trifluoromethyl, amino(C _2-4 alkyl)amino or cyano; vi) 1-methyl-piperidin-4-yloxy; vii) 4-methyl-piperazin-1-ylcarbonyl; viii) (4-aminobutyl)aminocarbonyl; ix) (4-amino)butoxy; x) 4-(4-aminobutyl)piperazin-1-ylcarbonyl; xi) methoxycarbonyl; xii) 5-chloro-6-(methoxycarbonyl)pyridin-3-ylaminocarbonyl; xiii) 1,1-dioxo-isothiazolidin-2-yl; xiv) 3-methyl-2-oxo-2,3-dihydro-1 H-imidazol-1 -yl; xv) 2-oxopyrrolidin-1-yl; xvi) (E)-(4-aminobut-1-ene)-1-yl-aminocarbonyl; xvii) difluoromethoxy; and xviii) morpholin-4-ylcarbonyl; R5 is independently selected from the group consisting of hydrogen, chlorine, fluorine, bromine, methoxy, methylsulfonyl, cyano, C _1-4 alkyl, ethynyl, morpholin-4-yl, trifluoromethyl, hydroxyethyl, methylcarbonyl, methylsulfinyl, 3-hydroxy-pyrrolidin- 1-yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin-3-yl, azetidin-2-yl, methylthio and 1,1-difluoroethyl; or _R4 and R5 may be taken together to form 8-chloro-4-methyl-3-oxo-3,4-dihydro-2Hbenzo[b][1,4]oxazin-6-yl, 8-chloro-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 2-methyl-1-oxo1,2,3,4-tetrahydroisoquinolin-7-yl, 4-methyl-3 -oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 3-oxo3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl , 1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4b]pyridin-5-yl, 2,3-dihydro-[1,4]dioxino[2, 3-b]pyridin-5-yl, 1,3-dioxolo[4,5]pyridin-5-yl, 1oxo-1,3-dihydroisobenzofuran-5-yl, 2,2-dimethylbenzo[d][1,3 ]dioxol-5-yl, 2,3dihydrobenzo[b][1,4]dioxin-6-yl, 1-oxoisoindolin-5-yl or 2-methyl-1-oxoisoindolin-5-yl, 1Nindazol-5-yl; R6 is hydrogen, C _1-4 alkyl, fluorine, 2-methoxyethoxy, chlorine, cyano or trifluoromethyl; R ₇ represents hydrogen or fluorine; provided that the compound of formula (I) is other than the compound in which R ₁ is isoquinolin-8-yl, R 2 is trifluoromethyl, G ₁ is C(R ₄ ), and R ₄ is 2H-1,2 ,3-triazol-2-yl, G2 is N and _R5 is hydrogen; compounds in which R ₁ is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is 1H-imidazol-1-yl, G2 is N, and R ₅ is chlorine ; compounds in which R ₁ represents isoquinolin-8-yl, R2 represents trifluoromethyl, G ₁ represents C(R4), and R4 represents 1H-1,2,3-triazol-1-yl, G2 represents N , and R ₅ represents hydrogen; compounds wherein R ₁ is isoquinolin-8-yl, R 2 is trifluoromethyl, G ₁ is C(R ₄ ), wherein R ₄ is hydrogen, G 2 is N, and R ₅ is fluorine; N-(2-chloro-3-pyridinyl)-5-methyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide; N-(3-chloro-4-methoxyphenyl)-5-methyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide; And 5-methyl-M-3-pyridinyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide; or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof. 2. The compound according to claim 1, wherein R ₁ is selected from the group consisting of i) naphthalen-1-yl, optionally substituted with an amino or fluorine substituent; and ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxymethyl, difluoromethyl, 1,1-difluoroethyl, hydroxymethyl, 1-hydroxyethyl, hydroxy, methoxy, fluorine, chlorine, - 412 045333 bromine, cyano, amino, methylamino, 4-oxotetrahydrofuran-2-yl, 5-oxopyrrolidin-2-yl, 1,4dioxanyl, aminocarbonyl, methylaminocarbonyl, oxo, N-(methyl)formamidomethyl, tetrahydrofuran-2-yl, 3-hydroxy-pyrrolidin-1-yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin-3-yl or azetidin-2-yl. 3. The compound according to claim 1, wherein R1 is selected from the group consisting of i) naphthalen-1-yl, optionally substituted with an amino or fluorine substituent; and ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, difluoromethyl, hydroxymethyl, 1-hydroxyethyl, hydroxy, fluorine, cyano, amino, aminocarbonyl, methylaminocarbonyl, oxo, tetrahydrofuran-2-yl, 3-hydroxypyrrolidin-1-yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin-3-yl or azetidin-2-yl. 4. The compound according to claim 1, wherein R1 is selected from the group consisting of i) naphthalen-1-yl, optionally substituted with an amino or fluorine substituent; and ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from hydroxymethyl, 1-hydroxyethyl, hydroxy, fluorine, cyano, amino or oxo. 5. The compound according to claim 1, wherein R1 is selected from the group consisting of i) naphthalen-1-yl, 4-amino-naphthalen-1-yl, 4-fluoronaphthalen-1-yl or 5-fluoronaphthalen-1-yl; and ii) heteroaryl selected from the group consisting of isoquinolin-1-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-8-yl, quinolin-7-yl, cinnolin-4-yl, imidazo[1 ,2-a]pyrazin-8-yl, phthalazin1-yl, naphthyridin-5-yl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, furo [2,3-c]pyridin-7-yl, quinoxalin-5-yl, 1H-indazolyl, furo[3,2-b]pyridin-7-yl, pyrazolo[1,5-a]pyrazin-4-yl, quinoline -4-yl, quinolin-5-yl, 1-aminoisoquinolin-4-yl, 1-oxo-1,2-dihydroisoquinolin-5-yl, benzo[d]thiazol-7-yl, 1-hydroxyisoquinolin-5-yl , benzo[d][1,2,3]thiadiazol-7-yl, thieno[2,3-c]pyridin-4-yl, pyrazolo[1,5-a]pyridin-4-yl, thieno[3,2- b]pyridin-7-yl, 2-oxo-1,2-dihydroquinolin-4-yl, 1-amino-8-fluoroisoquinolin-4-yl, 8-fluoroisoquinolin-4-yl, 1-cyanoisoquinolin-5-yl, pyrrolo[ 2,1C[1,2,4]triazin-4-yl, 7-(1-hydroxyethyl)thieno[2,3-c]pyridin-4-yl, thieno[2,3-d]pyrimidin-4-yl , thieno[2,3-c]pyridin-7-yl, 1,7-naphthyridin-5-yl, pyrrolo[1,2-a]pyrazin-1-yl, imidazo[1,2-a]pyridin-5-yl , 1-aminocarbonyl-isoquinolin-4-yl, benzo[d]thiazol-4-yl, 8-fluoro-1-hydroxyisoquinolin-4-yl, thieno[3,2-d]pyrimidin-4-yl, 8-fluorimidazo [1,2-a]pyridin-5-yl, 3-methylimidazo[1,2-a]pyridin-5-yl, 1-oxo-quinolin-4-yl, 8-aminoquinolin-5-yl, benzo[d]oxazole -4-yl, 3-methylthieno[3,2-b]pyridin7-yl, 1 -(hydroxymethyl)isoquinolin-4-yl, (3R-hydroxypyrrolidin-1 -yl)isoquinolin-4-yl, hydroxyethyl)isoquinolin-4 -yl, 2-(difluoromethyl)quinolin-4-yl, 8-fluoroquinolin-5-yl, (11hydroxyisoquinolin-4-yl, 1-(tetrahydrofuran-2-yl)isoquinolin-4-yl, 7-(difluoromethyl)thieno [2,3c]pyridin-4-yl, 1-(1-hydroxyethyl)isoquinolin-4-yl, 1-cyanoisoquinolin-4-yl, 1-(1(R)hydroxyethyl)isoquinolin-4-yl, quinazolin-4 -yl, 2-methylimidazo[1,2-a]pyridin-3-yl, thiazolo[5,4d]pyrimidin-7-yl, 6-N-oxido-thieno[2,3-c]pyridin-4-yl , imidazo[1,2-a]pyridin-3-yl, furo[2,3d]pyrimidin-4-yl, 2-fluoroquinolin-5-yl, benzo[d]isothiazol-3-yl, 7-methylpyrazolo[1 ,5-a]pyridin-4-yl, 1-(hydroxyethyl)quinolin-4-yl, 1-(methoxymethyl)isoquinolin-4-yl, 1-fluoroisoquinolin-4-yl, 1(difluoromethyl)isoquinolin-4-yl, 8 -fluoroquinolin-4-yl, 1-(tetrahydrofuran-2(R)-yl)isoquinolin-4-yl, 2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl, 1-(4-oxotetrahydrofuran-2-yl)isoquinolin-4-yl, (aminocarbonyl)quinolin-4-yl , methylimidazo[1,2-a]pyridin-5-yl, 221H-indazol-7-yl, 1-(1,4-dioxan-2-yl)isoquinolin-4-yl, 1-chloroisoquinolin-4-yl, 2-cyanoquinolin-4-yl, 8-fluoro-1(methylamino)isoquinolin-4-yl, benzo[d]isoxazol-3-yl, 2-aminobenzo[d]thiazol-7- yl, 1,7-naphthyridin4-yl, imidazo[1,2-a]pyrazin-5-yl, (M-((methyl)formamido)methyl)isoquinolin-4-yl, [1,2,4]triazolo[ 1,5a]pyridin-5-yl, 2-methylbenzo[d]oxazol-7-yl, ilisoquinolin-4-yl, 1-methyl-1H-indazol-3-yl, 1,5-naphthyridin-4-yl, 5-oxopyrrolidin-21-(1,1-difluoroethyl)isoquinolin-4-yl, 1-(1(*S)hydroxyethyl)isoquinolin-4-yl, pyrazolo[4,3 -b]pyridin-7-yl, methylfuro[3,2-b]pyridin-7-yl, 1 -(methylamino)isoquinolin-4-yl, 4-fluoroisoquinolin-1-yl, 5-fluoroquinolin-8-yl, 6-fluorimidazo[1,2-a]pyridin-5-yl, 1H28-(difluoromethyl)quinolin-5-yl, 1-(4-oxotetrahydrofuran-2H yl)isoquinolin-4-yl, 1-(dimethylamino)isoquinolin-4-yl, 1-methyl-1H-pyrazolo[3,4- c]pyridin-7-yl, 2methyl[1,2,4]triazolo[1,5-a]pyridin-5-yl, 2-methoxyquinolin-4-yl, imidazo[1,2-a]pyrimidin-5- yl, 2(difluoromethyl)thieno[2,3-c]pyridin-4-yl, 1-(1-ethoxyethyl)isoquinolin-4-yl, 2-(azetidin-2-yl)quinolin4-yl, 2-methylbenzo[ d]thiazol-7-yl, 2-acetylquinolin-4-yl, 1-(methylthio)isoquinolin-4-yl, 2-aminoquinolin-5-yl, yl)isoquinolin-4-yl, yl)isoquinolin-4-yl, 1-methoxyisoquinolin-5-yl, imidazo[1,2-b]pyridazin-6-yl, 1-(pyrrolidine-24-(difluoromethyl)quinolin-5-yl, 1-acetylisoquinolin-5-yl, 1-(azetidine -21-ethoxyisoquinolin-4-yl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl, 1 aminoisoquinolin-5-yl, 1-methyl-1H-indazol-4-yl, 2- aminoquinolin-4-yl, 2-oxo-1,2-dihydroquinolin5-yl, 1-(azetidin-3-yl)isoquinolin-4-yl, 2-methylthieno[3,2-b]pyridin-7-yl, benzo [d][1,2,3]thiadiazol4-yl, 1-(1(S)-hydroxyethyl)isoquinolin-5-yl, imidazo[1,2-a]pyridin-8-yl, 2-methyl-1- oxo-1,2- 413 045333 dihydroisoquinolin-5-yl, 2-(tetrahydrofuran-2-yl)quinolin-5-yl, 1-(1(R)-hydroxyethyl)isoquinolin-5-yl, 1,6-naphthyridin-4 -yl, 1H-nirαzolo[3,4-d]pyrimidin-4-yl, 2-aminocarbonyl-quinolin-5-yl, 2-chloroquinolin-5-yl, 2-chloroquinolin-4-yl, 2-cyanoquinolin-5-yl , 2-methoxyquinolin-5-yl, 2methylbenzo[d]oxazol-4-yl, 2-(difluoromethyl)quinolin-5-yl, 2-(azetidin-2-yl)quinolin-5-yl, 1(azetidin-2 -yl)isoquinolin-5-yl, 1,5-bis(tetrahydrofuran-2-yl)isoquinolin-4-yl, 1-oxo-1,2dihydroisoquinolin-4-yl, 2-methyl-1-oxo-1,2 -dihydroisoquinolin-4-yl, 1-(3-hydroxyazetidin-1yl)isoquinolin-4-yl, 8-fluoro-1-(3-hydroxyazetidin-1-yl)isoquinolin-4-yl, (R)-8-fluoro -1-(3hydroxypyrrolidin-1 -yl)isoquinolin-4-yl, (S)-8-fluoro-1-(3-hydroxypyrrolidin-1 -yl)isoquinolin-4yl, 3 -(hydroxyazetidin-1 -yl)thieno [ 2,3-c]pyridin-4-yl, 8-(3-hydroxyazetidin-1-yl)imidazo[1,2a]pyridin-5-yl, 7-(3-hydroxyazetidin-1-yl)pyrazolo[1, 5-a]pyridin-4-yl, 1-(3-hydroxyazetidin-1yl)isoquinolin-5-yl and 1-(1-tert-butoxycarbonyl azetidin-2-yl)isoquinolin-5-yl. 6. The compound of claim 1, wherein R2 is independently selected from the group consisting of methyl, isopropyl, cyano, bromine, chlorine and trifluoromethyl. 7. A compound according to claim 6, wherein R2 is trifluoromethyl. 8. The compound according to claim 1, wherein R3 is independently selected from the group consisting of trifluoromethyl, cyano, methylcarbonyl, methylthio, methylsulfinyl, methanesulfonyl and chlorine; or, if G ₁ is N, R3 is further selected from C1-4 alkoxycarbonyl. 9. A compound according to claim 1, wherein R3 is independently selected from the group consisting of trifluoromethyl, cyano and chlorine. 10. The compound according to claim 1, wherein G2 represents N. 11. The compound according to claim 1, in which R ₅ represents hydrogen, chlorine, fluorine, bromine, cyano, methyl, ethyl or trifluoromethyl; or R4 and _R5 can be taken together to form 8-chloro-4-methyl-3-oxo-3,4dihydro-2H-benzo[b][1,4]oxazin-6-yl or 8-chloro-3 - oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl. 12. The compound according to claim 11, wherein R ₅ represents hydrogen, chlorine or cyano. 13. The compound according to claim 1, wherein R ₆ represents hydrogen or methyl. 14. The compound according to claim 1, wherein R ₇ represents hydrogen. 15. Compound of formula (I): R ₅ Formula (I) where R1 is selected from the group consisting of i) naphthalen-1-yl, 4-fluoronaphthalen-1-yl, 5-fluoronaphthalen-1-yl or 4-aminonaphthalen-1-yl; and ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxymethyl, difluoromethyl, 1,1-difluoroethyl, hydroxymethyl, 1-hydroxyethyl, hydroxy, methoxy, fluorine, chlorine, bromine, cyano, amino, methylamino, 4-oxotetrahydrofuran-2-yl, 5-oxopyrrolidin-2-yl, 1,4dioxanyl, aminocarbonyl, methylaminocarbonyl, oxo, N-(methyl)formamidomethyl, tetrahydrofuran-2-yl , 3-hydroxy-pyrrolidin-1-yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin-3-yl or azetidin-2-yl; R2 is independently selected from the group consisting of methyl, isopropyl, cyano, bromine, chlorine and trifluoromethyl; G1 represents N or C(R ₄ ); G2 represents N or C(R ₃ ); so that in any case only one of G1 and G2 is N; R ₃ is independently selected from the group consisting of trifluoromethyl, cyano, methylcarbonyl, methylthio, methylsulfinyl, methanesulfonyl and chlorine; or, if G1 is N, _R3 is further selected from C1-4 alkoxycarbonyl; R4 is independently selected from the group consisting of i) hydrogen if G2 is N; ii) C1-4 alkoxy; iii) cyano; iv) cyclopropyloxy; v) carboxy; vi) heteroaryl selected from the group consisting of triazolyl, oxazolyl, pyrazolyl, thiazolyl, oxadiazolyl, imidazolyl and 2-aminopyrimidin-4-yl, wherein the heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of C1-4 alkyl , carboxy- - 414 045333 si, methoxycarbonyl, hydroxymethyl, aminocarbonyl, (dimethylamino)methyl, amino, methoxymethyl, trifluoromethyl, amino(C _2-4 alkyl)amino and cyano; vii) 1-methyl-piperidin-4-yloxy; viii) 4-methyl-piperazin-1-ylcarbonyl; ix) (4-aminobutyl)aminocarbonyl; x) (4-amino)butoxy; xi) methoxycarbonyl; xii) 5-chloro-6-(methoxycarbonyl)pyridin-3-ylaminocarbonyl; xiii) 1,1-dioxo-isothiazolidin-2-yl; and xiv) morpholin-4-ylcarbonyl; R ₅ is hydrogen, chlorine, fluorine, bromine, cyano, methyl, ethyl or trifluoromethyl; or R4 and _R5 can be taken together to form 8-chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin6-yl or 8-chloro-3 - oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl; R ₆ represents hydrogen or methyl; R ₇ represents hydrogen; and, provided that the compound of formula (I) is other than a compound in which R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), and R4 is 2H-1,2,3 -triazol-2-yl, G2 is N and R5 is hydrogen; compounds wherein R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C( _R4 ), wherein _R4 is 1H-imidazol-1-yl, G2 is N, and _R5 is chlorine; compounds in which R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is 1H-1,2,3-triazol-1-yl, G2 is N, a R ₅ represents hydrogen; compounds wherein R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is hydrogen, G2 is N, and R5 is fluorine; N-(3-chloro-4-methoxyphenyl)-5-methyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide; And 5-methyl-N-3-pyridinyl-1-(2-quinolinyl)-1 H-pyrazole-4-carboxamide; or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof. 16. Compound of formula (I): Formula (I) where R ₁ is selected from the group consisting of i) naphthalen-1-yl, optionally substituted with an amino or fluorine substituent; and ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, difluoromethyl, hydroxymethyl, 1-hydroxyethyl, hydroxy, fluorine, cyano, amino, aminocarbonyl, methylaminocarbonyl, oxo, tetrahydrofuran-2-yl, 3-hydroxypyrrolidin-1-yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin-3-yl or azetidin-2-yl; R2 is selected from the group consisting of methyl, isopropyl, cyano and trifluoromethyl; G ₁ represents N or C(R ₄ ); G2 represents N or C(R ₃ ); so that in any case only one of G ₁ and G2 is N; R ₃ is independently selected from the group consisting of trifluoromethyl, cyano and chlorine; R ₄ is independently selected from the group consisting of i) hydrogen when G2 is N; ii) C _1-4 alkoxy; iii) cyano; iv) cyclopropyloxy; v) heteroaryl selected from the group consisting of triazolyl, oxazolyl, pyrazolyl, thiazolyl, oxadiazolyl and imidazolyl, wherein the heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of methyl, carboxy, methoxycarbonyl, hydroxymethyl, aminocarbonyl, (dimethylamino )methyl and amino, methoxymethyl; - 415 045333 vi) (4-amino)butoxy; vii) methoxycarbonyl; viii) 5-chloro-6-(methoxycarbonyl)pyridin-3-ylaminocarbonyl; and ix) 1,1-dioxo-isothiazolidin-2-yl; R5 is hydrogen, bromine or cyano; R ₆ represents hydrogen or methyl; R7 is hydrogen; provided that the compound of formula (I) is other than the compound in which R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C( _R4 ), and _R4 is 2H-1,2,3 -triazol-2-yl, G2 is N and R5 is hydrogen; compounds wherein R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is 1H-imidazol-1-yl, G2 is N, and R5 is chlorine; compounds in which R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is 1H-1,2,3-triazol-1-yl, G2 is N, a R5 represents hydrogen; compounds wherein R1 is isoquinolin-8-yl, R2 is trifluoromethyl, G1 is C(R4), wherein R4 is hydrogen, G2 is N, and R5 is fluorine; N-(3-chloro-4-methoxyphenyl)-5-methyl-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide; And 5 -methyl-N-3 -pyridinyl-1 -(2-quinolinyl)-1 H-pyrazole-4-carboxamide; or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof. 17. Compound of formula (I): where R1 is selected from the group consisting of i) naphthalen-1-yl, optionally substituted with an amino or fluorine substituent; and ii) a nine- to ten-membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is optionally independently substituted with one or two substituents selected from hydroxymethyl, 1-hydroxyethyl, hydroxy, fluorine, cyano, amino, oxo, 3hydroxy-pyrrolidin-1-yl, pyrrolidin-2-yl, 3- hydroxyazetidinyl, azetidin-3-yl or azetidin-2yl; R2 is selected from the group consisting of methyl, isopropyl, cyano and trifluoromethyl; G1 represents N or C(R ₄ ); G2 represents N or C(R ₃ ); so that in any case only one of G1 and G2 is N; R ₃ is independently selected from the group consisting of trifluoromethyl, cyano and chlorine; R4 is selected from the group consisting of i) methoxy; ii) heteroaryl selected from the group consisting of 2H-1,2,3-triazol-2-yl, 4-carboxy-2H-1,2,3triazol-2-yl, 4-(hydroxymethyl)-2H-1, 2,3-triazol-2-yl, 4-methyl-2H-1,2,3-triazol-2-yl, oxazol-2-yl, 4-amino-2H-1,2,3-triazol-2- yl, 4-(hydroxymethyl)-1H-pyrazol-1-yl, 4-((dimethylamino)methyl)-2H1,2,3-triazol-2-yl, 4-methoxycarbonyl-2H-1,2,3-triazole -2-yl, 4-aminocarbonyl-2H-1,2,3-triazol-2yl, 1-methyl-1H-pyrazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-methyl-2H -tetrazol-5-yl, 5-amino-1-methyl-1Hpyrazol-3-yl, 4-(hydroxymethyl)-1H-pyrazol-1 -yl, 4-cyano-2H-1,2,3-triazol- 2-yl, 5-amino-1H-1,2,3triazol-1-yl, 2H-1,2,3-triazol-4-yl, 2H-tetrazol-5-yl, 4-(aminomethyl)-1H- pyrazol-1-yl, 4(methoxymethyl)-2H-1,2,3-triazol-2-yl, 2-methyl-2H-tetrazol-5-yl and 4-methyl-1H-1,2,3-triazole -1-silt; and iii) methoxycarbonyl; R5 is hydrogen, chlorine or cyano; R6 is hydrogen or methyl; R ₇ represents hydrogen; with the proviso that the compound of formula (I) is other than N-(3-chloro-4-methoxyphenyl)-5-methyl-1-(2quinolinyl)-1H-pyrazole-4-carboxamide; or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof. 18. Compound of formula (I): - 416 045333 r ₅ Formula (I) where R1 is independently selected from the group consisting of i) naphthalen-1-yl, 4-amino-naphthalen-1-yl, 4-fluoronaphthalen-1-yl or 5-fluoronaphthalen-1-yl; and ii) heteroaryl selected from the group consisting of isoquinolin-1-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-8-yl, quinolin-7-yl, cinnolin-4-yl, imidazo[1 ,2-a]pyrazin-8-yl, phthalazin1-yl, naphthyridin-5-yl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, furo [2,3-c]pyridin-7-yl, quinoxalin-5-yl, 1H-indazolyl, furo[3,2-b]pyridin-7-yl, pyrazolo[1,5-a]pyrazin-4-yl, quinoline -4-yl, quinolin-5-yl, 1-aminoisoquinolin-4-yl, 1-oxo-1,2-dihydroisoquinolin-5-yl, benzo[d]thiazol-7-yl, 1-hydroxyisoquinolin-5-yl , benzo[o1][1,2,3]thiadiazol-7-yl, thieno[2,3-c]pyridin-4-yl, pyrazolo[1,5-a]pyridin-4-yl, thieno[3,2- b]pyridin-7-yl, 2-oxo-1,2-dihydroquinolin-4-yl, 1-amino-8-fluoroisoquinolin-4-yl, 8-fluoroisoquinolin-4-yl, 1-cyanoisoquinolin-5-yl, pyrrolo[ 2,1f][1,2,4]triazin-4-yl, 7-(1-hydroxyethyl)thieno[2,3-c]pyridin-4-yl, thieno[2,3-d]nirimidin-4- yl, thieno[2,3-c]pyridin-7-yl, 1,7-naphthyridin-5-yl, pyrrolo[1,2-a]pyrazin-1-yl, imidazo[1,2-a]pyridin- 5-yl, 1-aminocarbonyl-isoquinolin-4-yl, benzo[d]thiazol-4-yl, 8-fluoro-1-hydroxyisoquinolin-4-yl, thieno[3,2-d]nirimidin-4-yl, 8- fluorimidazo[1,2-a]pyridin-5-yl, 3-methylimidazo[1,2-a]pyridin-5-yl, 1-oxo-quinolin-4-yl, 8-aminoquinolin-5-yl, benzo[d] Oxazol-4-yl, 3-methylthieno[3,2-b]pyridin7-yl, 1-(hydroxymethyl)isoquinolin-4-yl, (3R-hydroxypyrrolidin-1-yl)isoquinolin-4-yl, (1hydroxyethyl)isoquinoline -4-yl, 2-(difluoromethyl)quinolin-4-yl, 8-fluoroquinolin-5-yl, 1-hydroxyisoquinolin-4-yl, 1-(tetrahydrofuran-2-yl)isoquinolin-4-yl, 7-(difluoromethyl) thieno[2,3c]pyridin-4-yl, 1-(1-hydroxyethyl)isoquinolin-4-yl, 1-cyanoisoquinolin-4-yl, 1-(1(R)hydroxyethyl)isoquinolin-4-yl, quinazolin-4-yl 4-yl, 2-methylimidazo[1,2-a]pyridin-3-yl, thiazolo[5,4d]pyrimidin-7-yl, 6-N-oxido-thieno[2,3-c]pyridin-4- yl, imidazo[1,2-a]pyridin-3-yl, furo[2,3d]pyrimidin-4-yl, 2-fluoroquinolin-5-yl, benzo[d]isothiazol-3-yl, 7-methylpyrazolo[ 1,5-a]pyridin-4-yl, 1-(hydroxyethyl)quinolin-4-yl, 1-(methoxymethyl)isoquinolin-4-yl, 1-fluoroisoquinolin-4-yl, 1(difluoromethyl)isoquinolin-4-yl, 8-fluoroquinolin-4-yl, 8-fluoroquinolin-5-yl, 1 -(tetrahydrofuran-2(R)yl)isoquinolin-4-yl, 2-amino-[1,2,4]triazolo[1,5- a]pyridin-5-yl, 1-(4-oxotetrahydrofuran-2yl)isoquinolin-4-yl, 2-(aminocarbonyl)quinolin-4-yl, 1H-indazol-7-yl, 1-(1,4-dioxane -2yl)isoquinolin-4-yl, 2-methylimidazo[1,2-a]pyridin-5-yl, 1-chloroisoquinolin-4-yl, 2-cyanoquinolin-4-yl, 8-fluoro-1-(methylamino)isoquinolin- 4-yl, benzo[d]isoxazol-3-yl, 2-aminobenzo[d]thiazol-7-yl, 1,7-naphthyridin-4-yl, imidazo[1,2-a]pyrazin-5-yl, (N-((methyl)formamido)methyl)isoquinolin-4-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, 2-methylbenzo[d]oxazol-7-yl, 1,5-naphthyridin-4-yl, 5oxopyrrolidin-2-ylisoquinolin-4-yl, 1-methyl-1H-indazol-3-yl, 1-(1,1-difluoroethyl)isoquinolin-4-yl, 1-(1( *S)-hydroxyethyl)isoquinolin-4-yl, 1-(methylamino)isoquinolin-4-yl, 4-fluoroisoquinolin-1yl, 1H-pyrazolo[4,3-b]pyridin-7-yl, 5-fluoroquinolin-8 -yl, 6-fluorimidazo[1,2-a]pyridin-5-yl, 2-methylfuro[3,2-b]pyridin-7-yl, 8-(difluoromethyl)quinolin-5-yl, 1-(4-oxotetrahydrofuran -2Nyl)isoquinolin-4-yl, 1-(dimethylamino)isoquinolin-4-yl, 1-methyl-1H-pyrazolo[3,4-c]pyridin-7-yl, 2methyl[1,2,4]triazolo[ 1,5-a]pyridin-5-yl, 2-methoxyquinolin-4-yl, imidazo[1,2-a]pyrimidin-5-yl, 2(difluoromethyl)thieno[2,3-c]pyridin-4- yl, 1 -(1-ethoxyethyl)isoquinolin-4-yl, 2-(azetidin-2-yl)quinolin4-yl, 2-methylbenzo[d]thiαzol-7-yl, 2-acetylquinolin-4-yl, 1- (methylthio)isoquinolin-4-yl, 2-aminoquinolin-5-yl, 1-methoxyisoquinolin-5-yl, imidazo[1,2-b]pyridazin-6-yl, 1-(pyrrolidin-2yl)isoquinolin-4-yl, 4-(difluoromethyl)quinolin-5-yl, 1-acetylisoquinolin-5-yl, 1-(azetidin-2yl)isoquinolin-4-yl, 1-ethoxyisoquinolin-4-yl, 1-methyl-1H-pyrazolo[3, 4-b]pyridin-4-yl, 1-aminoisoquinolin-5-yl, 1-methyl-1H-indazol-4-yl, 2-aminoquinolin-4-yl, 2-oxo-1,2-dihydroquinolin5-yl, 1- (azetidin-3-yl)isoquinolin-4-yl, 2-methylthieno[3,2-b]pyridin-7-yl, benzo[d][1,2,3]thiadiazol4-yl, 1-(1(S )-hydroxyethyl)isoquinolin-5-yl, imidazo[1,2-a]pyridin-8-yl, 2-methyl-1-oxo-1,2dihydroisoquinolin-5-yl, 2-(tetrahydrofuran-2-yl)quinoline -5-yl, 1-(1(R)-hydroxyethyl)isoquinolin-5-yl, 1,6-naphthyridin-4-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl, 2-aminocarbonyl-quinoline -5-yl, 2-chloroquinolin-5-yl, 2-chloroquinolin-4-yl, 2-cyanoquinolin-5-yl, 2-methoxyquinolin-5-yl, 2-methylbenzo[d]oxazol-4-yl, 2-(difluoromethyl) quinolin-5-yl, 2-(azetidin-2-yl)quinolin-5-yl, 1(azetidin-2-yl)isoquinolin-5-yl, 1,5-bis(tetrahydrofuran-2-yl)isoquinolin-4 -yl, 1-oxo-1,2dihydroisoquinolin-4-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl, 1-(3-hydroxyazetidin-1yl)isoquinolin-4-yl, 8- fluoro-1 -(3 -hydroxyazetidin-1 -yl)isoquinolin-4-yl, (R)-8-fluoro-1 -(3 -hydroxypyrrolidin-1-yl)isoquinolin-4-yl, (S)-8- fluoro-1-(3-hydroxypyrrolidin-1-yl)isoquinolin-4-yl, 3-(hydroxyazetidin-1-yl)thieno[2,3-c]pyridin-4-yl, 8-(3-hydroxyazetidin-1-yl )imidazo[1,2a]pyridin-5-yl, 7-(3-hydroxyazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl, 1-(3-hydroxyazetidin-1yl)isoquinolin-5 -yl and 1-(1-tert-butoxycarbonyl azetidin-2-yl)isoquinolin-5-yl; - 417 045333 R2 represents trifluoromethyl; G1 represents N or QR4); G2 represents N or C(R ₃ ); so that in any case only one of G1 and G2 is N; R ₃ is independently selected from the group consisting of trifluoromethyl, cyano and chlorine; R ₄ is independently selected from the group consisting of 2H-1,2,3-triazol-2-yl, 4-carboxy-2H-1,2,3triazol-2-yl, 4-(hydroxymethyl)-2H-1,2 ,3-triazol-2-yl, 4-methyl-2H-1,2,3-triazol-2-yl, oxazol-2-yl, 1H-imidazol-2-yl, 4-amino-2H-1,2 ,3-triazol-2-yl, 4-(hydroxymethyl)-1H-pyrazol-1-yl, 4((dimethylamino)methyl)-2H-1,2,3-triazol-2-yl, 4-methoxycarbonyl-2H -1,2,3-triazol-2-yl, 4aminocarbonyl-2H-1,2,3-triazol-2-yl, 1-methyl-1H-pyrazol-3-yl and 1,3,4-oxadiazol-2 -ila; R ₅ is hydrogen, bromine or cyano; R6 is hydrogen or methyl; R7 is hydrogen; or an enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form thereof. 19. A connection selected from the group consisting of: N-(2-cyanopyridin-4-yl)-1-(naphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(naphthalen-1-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; 1-(naphthalen-1-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4carboxamide; 1 -(naphthalen-1 -yl)-5-(trifluoromethyl)-N-(5-(trifluoromethyl)pyridin-3 -yl)-1H-pyrazol-4carboxamide; N-(5-cyanopyridin-3-yl)-1-(naphthalen-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(quinolin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4carboxamide; N-(5-chloro-6-methoxypyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylisoquinolin-1-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(3-chloro-4-methoxyphenyl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(3-chloro-4-(1H-pyrazol-1-yl)phenyl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(4-(2-aminopyrimidin-4-yl)-3-chlorophenyl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamide; Ν-(5-χλορ-6-( 1 H-pyrazol-1 -yl)pyridin-3 -yl)-1 -(isoquinolin-8-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-isobutyl-1-(quinolin-5-yl)-1H-pyrazol-4carboxamide ; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-ethyl-1-(quinolin-5-yl)-1H-pyrazol-4carboxamide ; N-(3 -chloro-4-(1 H-1,2,3-triazol-1 -yl)phenyl)-1 -(isoquinolin-8-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamide ; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(5-chloro-6-(1,1-dioxidoizothiazolidin-2-yl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide; Ν-(5-χλορ-6-(1 -methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide ; N-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-chloro-6-methoxypyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-cyano-6-methoxypyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; - 418 045333 No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-isopropyl-1-(quinolin-5-yl)-III-pyrazole -4carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-methylquinolin-5-yl)-5-(trifluoromethyl)-Spirazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-methylquinolin-5-yl)-5-(trifluoromethyl)-Spirazole -4-carboxamide; N-(3-chloro-4-(3 -methyl-1H-1,2,4-triazol-1-yl)phenyl)-1 -(isoquinolin-8-yl)-5-(trifluoromethyl)-1 Hpyrazol- 4-carboxamide; Ν-(5-χλορ-6-(3 -methyl-1H-1,2,4-triazol-1 -yl)pyridin-3 -yl)-1 -(isoquinolin-8-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide; N-(3-chloro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1-(isoquinolin-8-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-methylisoquinolin-8-yl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide; 1-(benzofuran-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(1-methoxyethyl)-1-(quinolin-5-yl)-1H -pyrazole4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-methylisoquinolin-4-yl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-1-(quinolin-5-yl)-1H-pyrazol-4carboxamide ; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(6-cyano-5-fluoropyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-chloro-6-(1,1-dioxidoizothiazolidin-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide; N-(3-chloro-4-(1 H-1,2,3-triazol-1 -yl)phenyl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamide ; methyl 3 -chloro-5-(3 -chloro-5 -(1 -(isoquinolin-4-yl)-5 -(trifluoromethyl)-1 H-pyrazole-4carboxamido)picolinamido)picolinate; N-(5-chloro-6-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)N-pyrazole-4-carboxamide ; N-(5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(5-chloro-6-(4-methylpiperazin-1-carbonyl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)N-pyrazole-4-carboxamide; N(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-III-pyrazol-4carboxamide; N-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(3-chloro-4-(5-methyl-1H-1,2,4-triazol-1 -yl)phenyl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1 Hpyrazol- 4-carboxamide; Ν-(5-χλορ-6-(1 -methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide ; N-(5-chloro-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; N-(5-chloro-6-(5-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; N-(3-chloro-4-(3 -methyl-1H-1,2,4-triazol-1 -yl)phenyl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1 Hpyrazol- 4-carboxamide; Ν-(5-χλορ-6-(2Η- 1,2,3-triazol-2-yl)pyridin-3-yl)-5-(difluoromethyl)-1 -(isoquinolin-1 -yl)-1 Hpyrazol- 4-carboxamide; - 419 045333 N-(5-χΛορ-6-(2Η-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-1-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(4-(2-aminopyrimidin-4-yl)-3-chlorophenyl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamide; N-(3-cyano-4-(2H-1,2,3-triazol-2-yl)phenyl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamide; N-(5-fluoro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(3-cyano-4-(1 H-1,2,3-triazol-1 -yl)phenyl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazol-4carboxamide ; N(5-chloro-6-(thiazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-III-pyrazol-4carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-1-(quinolin-4-yl)-1H-pyrazol-4carboxamide ; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methylisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-fluoroquinolin-7-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1H-indazol-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide ; Ν-(5-χΛορ-6-( 1 H-imidazol-1 -yl)pyridin-3 -yl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(4-aminobutyl)-3-chloro-5-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamido)picolinamide; 1-(isoquinolin-4-yl)-N-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide; methyl 6-chloro-4-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)picolinate; methyl 4-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)picolinate; N-(2-cyanopyridin-4-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(1 -methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1 Hpyrazol-4- carboxamide; N-(5-chloro-6-cyclopropoxypyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-cyano-6-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)1H-pyrazole-4-carboxamide ; N-(5-cyano-6-ethoxypyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-cyanopyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(6-(4-aminobutoxy)-5-cyanopyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamide; N-(5-cyano-6-methoxypyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-cyano-6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(8-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide; N-(5-cyano-6-cyclopropoxypyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-cyano-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide ; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[3,2-c]pyridin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; - 420 045333 No. (5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroquinolin-4-yl)-5-(trifluoromethyl) -Spirazol-4-carboxamide; 1-(cinnolin-4-yl)-M-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-Spirazol-4 -carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[3,2-c]pyridin-4-yl)-5 -(trifluoromethyl)1H-pyrazole-4-carboxamide; N-(8-chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-cyano-6-(4-methylpiperazin-1-carbonyl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(8-chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(isoquinolin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-chloro-6-(1-methyl-III-imidazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-Spirazol-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[2,3-c]pyridin-7-yl)-5 -(trifluoromethyl)1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-1-(1,6-naphthyridin-5 -yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; No.(6-(4-(4-aminobutyl)piperazine-1-carbonyl)-5-cyanopyridin-3-yl)-1-(isoquinolin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide ; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(phthalazin-1 -yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(imidazo[1,2-a]pyrazin-8-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-chloro-6-(III-imidazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-III-pyrazol4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinoxalin-5-yl)-5-(trifluoromethyl)-Spirazol-4 -carboxamide; N-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 -(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide; tert-butyl 2-(5-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)1H- pyrazol-1-yl)isoquinolin-1-yl)azetidine-1-carboxylate; N-(3-(methylsulfonyl)-4-(1 H-1,2,3-triazol-1-yl)phenyl)-1 -(quinolin-5-yl)-5 -(trifluoromethyl)-1 Npyrazol-4 -carboxamide; 1-(1,5-bis(tetrahydrofuran-2-yl)isoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; 1-(1-(azetidin-2-yl)isoquinolin-5-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(3-(methylsulfonyl)-4-(2H-1,2,3-triazol-2-yl)phenyl)-1 -(quinolin-5-yl)-5 -(trifluoromethyl)-1 Npyrazol-4- carboxamide; 1-(2-(azetidin-2-yl)quinolin-5-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(benzo[d]thiazol-4-yl)-N-(2,5-dimethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)1H-pyrazole-4-carboxamide; N-(5-methyl-6-(3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(2,5-diethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(difluoromethyl)quinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylbenzo[d]oxazol-4-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxyquinolin-5-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; 1-(1-aminoisoquinolin-5-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-cyanoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(2-methylimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-M-(2-(trifluoromethyl)pyridin-4-yl)-1Hpyrazol-4-carboxamide; - 421 045333 1-(2-chloroquinolin-4-yl)-N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-chloroquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)niridin-3-yl)-1-(2-(tetrahydrofuran-2-yl)quinolin-5-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 5-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)quinoline -2-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,6-naphthyridin-4-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; (*R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1-hydroxyethyl)isoquinoline-5- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(benzo[d]thiazol-4-yl)-N-(5-cyano-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; (*R)-N-(5 -chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-(tetrahydrofuran-2-yl)quinolin- 5 -yl)5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; N-(5-chloro-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide; N-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; Ν-(5-χλορ-6-(2Η- 1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-methyl-1-oxo-1,2-dihydroisoquinoline-5- yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(5-cyano-1H-1,2,3-triazol-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; 2-(2-chloro-4-( 1 -(quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamido)phenyl)-2H-1,2,3triazole-4-carboxylic acid ; N-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(imidazo[1,2-a]pyridin-8-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; (*S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1-hydroxyethyl)isoquinoline-5- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(2-methylpyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide; 1-(benzo[d][1,2,3]thiadiazol-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylthieno[3,2-b]pyridin-7-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(1 -(azetidin-3 -yl)isoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,5-a]pyridin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(3-chloro-5-( 1 -(quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4-carboxamido)pyridin-2-yl)-1H1,2,3-triazol- 4-carboxylic acid; N-(5-methoxy-6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; Ν-(5-χλορ-6-(2Η-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-oxo-1,2-dihydroquinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-aminobutyl)-3-cyano-5-(1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamido)picolinamide; N-(4-(4-(aminomethyl)-1H-pyrazol-1 -yl)-3 -methylphenyl)-1 -(quinolin-5 -yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide; 1-(2-aminoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1H-indazol-4-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(1-aminoisoquinolin-5-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-methyl-6-(1-methyl-1H-tetrazol-5-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide ; - 422 045333 K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1H-pyrazolo[3,4-b]pyridine -4-yl)-5 (trifluoromethyl)-1H-pyrazol-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-ethoxyisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; 1-(1-(azetidin-2-yl)isoquinolin-4-yl)-K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(2-aminoquinolin-5-yl)-M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(1-acetylisoquinolin-5-yl)-K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-(difluoromethyl)quinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(pyrrolidin-2-yl)isoquinolin-4-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; K-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-b]pyridazin-6-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-K-(2,5-dimethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(1-methoxyisoquinolin-5-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide; 1-(2-aminoquinolin-5-yl)-K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; 2-(2-chloro-4-(1 -(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)phenyl)-2H-1,2,3triazol-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(methylthio)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-fluoro-1-(quinolin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylbenzo[d]thiazol-4-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; 1 -(3-chloro-5-( 1 -(quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazol-4-carboxamido)pyridin-2-yl)-1H1,2,3-triazol- 4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-cyano-1-(quinolin-5-yl)-1H-pyrazol-4carboxamide ; 1-(7-methylpyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-K-(2-(trifluoromethyl)pyridin-4-yl)-1Hpyrazol-4-carboxamide; K-(6-(2H-[1,2,3]triazolo[4,5-c]pyridin-2-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(2-acetylquinolin-4-yl)-M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylbenzo[d]thiazol-7-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; K-(6-(5-(aminomethyl)-1H-1,2,3-triazol-1-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; 1-(2-(azetidin-2-yl)quinolin-4-yl)-K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1-ethoxyethyl)isoquinolin-4-yl)-5 ( trifluoromethyl)-1H-pyrazole-4-carboxamide; methyl 1-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)pyridin-2-yl)1H-1,2,3-triazole -4-carboxylate; 1-(imidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-K-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol4-carboxamide; K-(5-chloro-2-ethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyridin-5- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(difluoromethyl)thieno[2,3-c]pyridin-4 -yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(imidazo[1,2-a]pyrimidin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; K-(5-methoxy-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; - 423 045333 No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxyquinolin-4-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; 1 -(6eH3o[d] [1,2,3]thiadiazol-7-yl)-N-(5-chloro-2-methyl-6-(1 H-pyrazol-1 -yl)pyridin-3 -yl) -5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(2,5-dimethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(benzo[d]thiazol-4-yl)-N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-chloro-6-(5-(methoxymethyl)-III-1,2,3-triazol-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; N-(6-(2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methyl[1,2,4]triazolo[1,5- a]pyridin-5-yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; 3-(3-cyano-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)pyridin-2-yl)-1methyl-1H-pyrazole-5 - carboxylic acid; 1-(benzo[d]thiazol-4-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-5 (trifluoromethyl)- 1H-pyrazole-4-carboxamide; N-(6-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; methyl 2-(2-chloro-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)phenyl)-2H1,2,3-triazol-4-carboxylate; N-(5-cyano-6-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; N(3-chloro-4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl )1H-pyrazole-4-carboxamide; methyl 3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)picolinate; No.(6-(III-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-cyanopyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide; N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1H-pyrazolo[3,4-c]pyridin-7 -yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N(5-chloro-2-methyl-6-(III-pyrazol-1-yl)pyridin-3-yl)-5(trifluoromethyl)-1H-pyrazol-4 -carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(dimethylamino)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-(difluoromethyl)quinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; (*R)-N-(5 -chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1 -(4-oxotetrahydrofuran-2yl)isoquinoline- 4-yl)-5 -(trifluoromethyl)-1 H-pyrazol-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylfuro[3,2-b]pyridin-7-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(difluoromethyl)isoquinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1 -methyl-1 H-indazol-7-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-fluorimidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoroquinolin-8-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1H-pyrazolo[4,3-b]pyridin-7-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoroisoquinolin-1-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; 5-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)isoquinoline -1-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(methylamino)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; (*S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1-hydroxyethyl)isoquinoline-4- yl)-5- 424 045333 (trifluoromethyl)-1H-pyrazole-4-carboxamide; Ν-(5-χΛορ-6-(2Η-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1,1-difluoroethyl)isoquinolin-4-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 5-χΛορ-Ν-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(quinolin-5-yl)-1 H-pyrazol- 4carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methoxyisoquinolin-4-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide; (*S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(4-oxotetrahydrofuran-2yl)isoquinoline- 4-yl)-5 -(trifluoromethyl)-1 H-pyrazol-4-carboxamide; (*S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(tetrahydrofuran-2-yl)isoquinoline- 4yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1H-pyrazolo[3,4-b]pyridine -3-yl)-5 (trifluoromethyl)-1H-pyrazol-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluorimidazo[1,2-a]pyridin- 5-yl)5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1 -methyl-1 H-indazol-3-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(5-oxopyrrolidin-2-yl)isoquinolin-4-yl )5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; methyl 3-(3-cyano-5 -(1 -(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2yl)-1-methyl-1H-pyrazol-5 -carboxylate; N-(5-cyano-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)1H-pyrazol- 4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,5-naphthyridin-4-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(5-chloro-6-(5-((dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylbenzo[d]oxazol-7-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; N-(6-(4-(aminomethyl)-2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)1H-pyrazol- 4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(5-cyano-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide; 1-(benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-([1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridine -3-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-((N-methylformamido)methyl)isoquinolin-4yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(imidazo[1,2-a]pyrazin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,7-naphthyridin-4-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(2-aminobenzo[d]thiazol-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isothiazolo[5,4-b]pyridin-3-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(1H-pyrrol-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(1-methoxyisoquinolin-5-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide; 1-(2-aminobenzo[d]thiazol-7-ul)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-425 045333 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N(6-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide; 1-(benzo[d]isoxazol-3-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N(2-(trifluoromethyl)pyridin-4-yl)-Spirazol-4-carboxamide; Ν-(5-χΛορ-6-(2Η-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(8-fluoro-1 -(methylamino)isoquinolin-4-yl)- 5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 5-6ροΜ-Ν-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(quinolin-5-yl)-1 H-pyrazol- 4carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-cyanoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-chloroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; 1-(pyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1Hpyrazol-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-methylimidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-1Hpyrazol-4-carboxamide; 1-(1-(1,4-dioxan-2-yl)isoquinolin-4-yl)-N-(5 -chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1H-indazol-7-yl)-5-(trifluoromethyl)- 1Hpyrazole-4-carboxamide; 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)quinoline -2-carboxamide; N-(5-chloro-6-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinoline-5- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(1-(4-oxotetrahydrofuran-2-yl)isoquinolin4-yl)- 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(6-(4-amino-2H-1,2,3-triazol-2-yl)-5-χloropyridin-3-yl)-1-(benzo[d]thiazol-4-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2 -yl)pyridin-3yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; (*R)-N-(5 -chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1 -(tetrahydrofuran-2-yl)isoquinoline- 4yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-bromo-6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)-1-(χinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide; N-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-chloro-6-methoxypyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(difluoromethyl)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(methoxymethyl)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(1-hydroxyethyl)χinolin-4-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-methylpyrazolo[1,5-a]pyridin- 4yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; 1-(benzo[d]isothiazol-3-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[2,3-d]pyrimidin-4-yl)-5 - 426 045333 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(imidazo[1,2-a]pyridin-3-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(imidazo[1,2-a]pyridin-5- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)thieno [2,3-c]pyridine 6-oxide; 1 -(6eH3o[d] [1,2,3]thiadiazol-7-yl)-N-(5-chloro-6-(1 -methyl-1 H-pyrazol-3-yl)pyridin-3-yl) -5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thiazolo[5,4-d]pyrimidin-7-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-methylimidazo[1,2-a]pyridin-3-yl) -5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-cyano-6-methoxypyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1 -(1-oxo-1,2-dihydroisoquinolin-5yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide; No.(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinazolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4- carboxamide; N(5-chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide; N-(5-chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; (*R)-N-(5 -chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1 -hydroxyethyl)isoquinoline-4- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-cyanoisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1-hydroxyethyl)isoquinolin-4-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(4-methyl-1H-1,2,3-triazol-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(5-methyl-6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide ; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-(difluoromethyl)thieno[2,3-c]pyridin-4 -yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(tetrahydrofuran-2-yl)isoquinolin-4-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(4-(methoxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; N-(4-(4-(aminomethyl)-1H-pyrazol-1-yl)-3-chlorophenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; 1-(benzo[d]thiazol-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(1-hydroxyisoquinolin-4-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-tetrazol-5-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(difluoromethyl)quinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(8-fluoro-1 -(methylamino)isoquinolin-4-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-4-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide; N-(5-chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(8-fluorosoquinolin-4-ul)-5-(trifluoromethyl)- 427 045333 1H-pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-2-oxo-1,2-dihydroquinolin-4-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; (*R)-N-(5 -chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(3 -hydroxypyrrolidin-1 yl)isoquinoline -4-yl)-5 -(trifluoromethyl)-1 H-pyrazol-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(hydroxymethyl)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylthieno[3,2-b]pyridin-7-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(benzo[d]oxazol-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(3-chloro-4-(4-(hydroxymethyl)-1H-pyrazol-1 -yl)phenyl)-1 -(quinolin-5 -yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide; N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(8-aminoquinolin-5-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)quinoline 1-oxide; N-(5-cyano-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; methyl 2-cyano-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)benzoate; N-(6-(5-amino-1H-1,2,3-triazol-1-yl)-5-chloropyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl)- 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(4-cyano-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(imidazo[1,2-a]pyridin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(benzo[d] [1,2,3]thiadiazol-7-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridine -3-yl)-5 (trifluoromethyl)-1H-pyrazol-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoromidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(6-(5-amino-1-methyl-1H-pyrazol-3-yl)-5-cyanopyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole -4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; N-(5-chloro-6-(4-(hydroxymethyl)-1H-pyrazol-1 -yl)pyridin-3 -yl)-1-(1-oxo-1,2-dihydroisoquinolin5-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(3-methylimidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(6-(5-amino-1 -methyl-1H-pyrazol-3-yl)-5 -chloropyridin-3-yl)-1 -(1-oxo-1,2-dihydroisoquinolin-5 yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(8-fluorimidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[3,2-d]pyrimidin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoro-1-hydroxyisoquinolin-4-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; 1-(benzo[d]thiazol-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(pyrrolo[1,2-a]pyrazin-1-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; 1-(benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; - 428 045333 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)iridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-irazol-1yl)isoquinoline -1-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)iiridin-3-yl)-1-(imidazo[1,2-a]iiridin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; I-(5-chloro-6-(2H-1,2,3-triazol-2-yl)iridin-3-yl)-1 -(pyrrolo[1,2-a]pyrazin-1-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; K-(5-cyano-6-(2-methyl-2H-tetrazol-5-yl)iridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Niirazol-4-carboxamide ; K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)iiridin-3-yl)-1-(1,7-naphthyridin-5-yl)-5-(trifluoromethyl) -1Niirazole-4-carboxamide; 2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-irazol-4-carboxamido)iridin-2-yl)-2H1,2,3-triazol-4 -carboxamide; K-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)iiridin-3-yl)-1-(irazolo[1,5-a]iiridin-4- yl)-5(trifluoromethyl)-1H-irazol-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)iridin-3-yl)-5-(trifluoromethyl)1H- irazole-4-carboxamide; K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)iiridin-3-yl)-1-(thieno[2,3-c]iiridin-7-yl)-5 (trifluoromethyl)-1H-irazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)iiridin-3-yl)-1-(thieno[2,3-d]iirimidin-4-yl)-5 (trifluoromethyl)-1H-irazole-4-carboxamide; K-(5-chloro-6-(1,3,4-oxadiazol-2-yl)iridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-irazol4-carboxamide ; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)iridin-3-yl)-1-(irazolo[1,5-a]irazin-4-yl)-5 (trifluoromethyl)-1H-irazole-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)iiridin-3-yl)-1-(7-(1-hydroxyethyl)thieno[2,3-c]iiridine -4-yl)5-(trifluoromethyl)-1H-irazol-4-carboxamide; K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)iiridin-3-yl)-1 -(iirrolo[2,1-f][1,2,4]triazine -4-yl)-5 (trifluoromethyl)-1H-irazol-4-carboxamide; K-(5-chloro-6-(1-methyl-1H-irazol-3-yl)iiridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl )-1H-irazole-4-carboxamide; methyl 2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-irazol-4-carboxamido)iridin-2-yl)2H-1,2,3-triazole -4-carboxylate; K-(5-chloro-6-(4-((dimethylamino)methyl)-2H-1,2,3-triazol-2-yl)iridin-3-yl)-1-(quinolin-5-yl)- 5(trifluoromethyl)-1H-irazol-4-carboxamide; K-(5-bromo-6-(2H-1,2,3-triazol-2-yl)iiridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-irazol4 -carboxamide; K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)iiridin-3-yl)-1-(quinolin-4-yl)-5-(trifluoromethyl)-1Niirazol-4 -carboxamide; 1 -(benzo[d][1,2,3]thiadiazol-7-yl)-K-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)iridin -3-yl)-5 (trifluoromethyl)-1H-irazol-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)iridin-3-yl)-1-(1-cyanoisoquinolin-5-yl)-5-(trifluoromethyl)1H- irazole-4-carboxamide; K-(5-chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)iridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl )-1H-irazole-4-carboxamide; K-(5-chloro-6-(4-(hydroxymethyl)-1H-irazol-1 -yl)iridin-3-yl)-1 -(quinolin-5-yl)-5 (trifluoromethyl)-1H-irazol- 4-carboxamide; K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)iridin-3-yl)-1-(irazolo[1,5-a]irazin-4-yl)-5 (trifluoromethyl)-1H-irazole-4-carboxamide; K-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)iridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl )-1H-irazole-4-carboxamide; K-(6-(4-amino-2H-1,2,3-triazol-2-yl)-5-chloroiridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl)- 5-(trifluoromethyl)-1H-irazole-4-carboxamide; K-(6-(4-amino-2H-1,2,3-triazol-2-yl)-5-chloroiridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)- 1 Niirazole-4-carboxamide; 1-(1-amino-8-fluoroisoquinolin-4-yl)-K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)iridin-3-yl)-5(trifluoromethyl )-1H-irazol-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)iridin-3-yl)-5-(trifluoromethyl)1H- irazole-4-carboxamide; K-(3-cyano-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-irazol-4carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)iridin-3-yl)-1 -(2-oxo-1,2-dihydroquinolin-4-yl)-5 (trifluoromethyl)-1H-irazole-4-carboxamide; - 429 045333 1-(4-aminonaphthalen-1-yl)-N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methoxyphenyl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; No.(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-P-quinolin-5-yl)-5-(trifluoromethyl)- 1Hpyrazole-4-carboxamide; No.(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-O-quinolin-5-yl)-5-(trifluoromethyl)- 1Hpyrazole-4-carboxamide; N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[3,2-b]pyridin-7-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-bromo-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5- yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrazolo[1,5-a]pyridin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazol- 4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-b]pyridin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-c]pyridin-4-yl)-5 -(trifluoromethyl)1H-pyrazole-4-carboxamide; N-(5-chloro-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; 1 -(6eH3o[d] [1,2,3]thiadiazol-7-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoronaphthalen-1-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-hydroxyisoquinolin-5-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide; 1-(benzo[d]thiazol-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(5-chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinoline-5- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(benzo[d]thiazol-7-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5 -yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(1-amino-8-fluoroisoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; 2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2-yl)-2H1,2,3-triazol-4 -carboxylic acid; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[3,2-b]pyridin-7-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)thieno [2,3-c]pyridine-7-carboxamide; 1-(7-(3-hydroxyazetidin-1-yl)thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-N-(2(trifluoromethyl)pyridin-4-yl)-1H -pyrazole-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(5-bromo-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(4-methyl-1H-1,2,3-triazol-1 -yl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinoline- 5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; - 430 045333 1-(1-aminoisoquinolin-4-yl)-5-(trifluoromethyl)-N(5-(trifluoromethyl)pyridin-3-yl)-III-pyrazol-4carboxamide; 1-(1-aminoisoquinolin-4-yl)-N(5-chloro-2-methyl-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-ethynyl-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(1-oxo-1,2-dihydroisoquinolin-5yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinoline- 5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-methyl-1-oxo-1,2-dihydroisoquinoline-4- yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; (*R)-N-(5 -chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(7-(3 -hydroxypyrrolidin-1 yl)thieno [2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-chlorothieno[2,3-c]pyridin- 4-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide; (*S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(7-(3-hydroxypyrrolidin-1 yl)thieno [2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-cyanothieno[2,3-c]pyridin- 4-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(7-(3-hydroxyazetidin-1 yl)thieno[ 2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; 4-(4-((5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1Hpyrazol-1 -yl)thieno[2,3-c]pyridine-7-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-cyclopropylthieno[2,3-c]pyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-methylthieno[2,3-c]pyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-cyanothieno[2,3-c]pyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)- N-methylthieno[2,3-c]pyridine-7-carboxamide; Ν-(5-χλορ-6-(2Η- 1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-(3-hydroxyazetidin-1-yl)thieno[2,3c ]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-chlorothieno[2,3-c]pyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(2-cyanopyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-chloropyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide; 1-(thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4carboxamide; 1-(8-fluoromidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1Hpyrazol-4-carboxamide; N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; methyl 3-chloro-5-(1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamido)picolinate; 1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4carboxamide; N-(2-cyanopyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide; N-(2-(2-methoxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazol- 4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-c]pyridin-4- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-oxo-1,2-dihydroquinoline-4- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5- yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; (*S)-N-(5-chloro-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(2-(tetrahydrofurαn-2-yl)quinolin- 5-yl)5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; - 431 045333 or their enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt form. 20. A compound according to claim 19, selected from the group consisting of: K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(naphthalene-1-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; 1-(benzofuran-4-yl)-M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; K-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; K-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[3,2-c]pyridin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; K-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[3,2-c]pyridin-4-yl)-5 -(trifluoromethyl)1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[2,3-c]pyridin-7-yl)-5 -(trifluoromethyl)1H-pyrazole-4-carboxamide; methyl-2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2-yl)2H-1,2,3- triazole-4-carboxylate; 2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2-yl)-2H1,2,3-triazol-4 -carboxylic acid; 1-(1-amino-8-fluoroisoquinolin-4-yl)-K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; 1-(1-amino-8-fluoroisoquinolin-4-yl)-K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; K-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5- yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(benzo[d]thiazol-7-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; K-(5-chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinoline-5- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-hydroxyisoquinolin-5-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; 1 -(benzo[d] [1,2,3]thiadiazol-7-yl)-K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(benzo[d][1,2,3]thiadiazol-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(benzo[d] [1,2,3]thiadiazol-7-yl)-K-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridine -3-yl)-5 (trifluoromethyl)-1H-pyrazol-4-carboxamide; K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(5-fluoronaphthalene-1-yl)-5-(trifluoromethyl)-1 Npirazole-4-carboxamide; K-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; K-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; K-(5-chloro-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; - 432 045333 N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-b]pyridin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazol-4 -carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[3,2-b]pyridin-7-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-D-quinolin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-D-quinolin-5-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; 1-(4-aminonaphthalene-1-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N(3-cyano-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(6-(4-amino-2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl)- 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(4-(hydroxymethyl)-1H-pyrazol-1 -yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5 (trifluoromethyl)-1H-pyrazol- 4-carboxamide; N-(5-chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(4-((dimethylamino)methyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(5-bromo-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(pyrrolo[2,1-f][1,2,4]triazine -4-yl)-5 (trifluoromethyl)-1H-pyrazol-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrazolo[1,5-a]pyrazin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-d]pyrimidin-4-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-c]pyridin-7-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 2-(3-chloro-5-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamido)pyridin-2-yl)-2H1,2,3-triazol-4 -carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-1-(1,7-naphthyridin-5 -yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(pyrrolo[1,2-a]pyrazin-1-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide ; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(furo[3,2-b]pyridin-7-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methoxyphenyl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; 1-(benzo[d]thiazol-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1Hpyrazole-4-carboxamide; N-(6-(4-amino-2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)- 1Hpyrazole-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; N-(5-bromo-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; - 433 045333 No. (5-chloro-6-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide; No.(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrazolo[1,5-a]pyridin-4-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrazolo[1,5-a]pyridin-4- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-ul)nuridin-3-yl)-1 -(3-chloroimidazo[1,2-a]pyridin-5-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(thieno[2,3-c]pyridin-4- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(1-aminoisoquinolin-4-yl)-N-(5-bromo-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide; methyl-3-chloro-5-(1 -(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxamido)picolinate; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-oxo-1,2-dihydroquinoline-4- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxo-1,2dihydroisoquinoline- 5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-(1-hydroxyethyl)thieno[2,3-c]pyridine -4-yl)5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)isoquinoline -1-carboxamide; 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)thieno [2,3-c]pyridine-7-carboxamide; 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)- N-methylthieno[2,3-c]pyridine-7-carboxamide; 4-(4-((5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1Hpyrazol-1 -yl)thieno[2,3-c]pyridine-7-carboxamide; 5-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)isoquinoline -2-oxide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-cyanoquinolin-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-cyanoisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-2-oxo-1,2-dihydroquinoline-4- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxyquinolin-5-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methoxyisoquinolin-4-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-ethoxyisoquinolin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-chlorothieno[2,3-c]pyridin- 4-yl)-5(trifluoromethyl)-1H-pyrazol-4-carboxamide; (R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(3-hydroxypyrrolidin-1 yl)isoquinoline- 4-yl)-5 -(trifluoromethyl)-1 H-pyrazol-4-carboxamide; N-(5-cyano-6-methoxypyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(methylthio)isoquinolin-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; K-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-(3-hydroxyazetidin-1-yl)thieno[2,3c ]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; (S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-(3-hydroxypyrrolidin-1-yl)thieno [2,3c]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; (*S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1-hydroxyethyl)isoquinoline-4- yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide; And - 434 045333 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1Hpyrazol-4-carboxamide; or an enantiomer, hydrate or pharmaceutically acceptable salt form thereof. 21. The connection according to claim 20, which is or a hydrate or pharmaceutically acceptable salt form thereof. 22. The connection according to claim 20, which is or a hydrate or pharmaceutically acceptable salt form thereof. 23. The connection according to claim 20, which is or a hydrate or pharmaceutically acceptable salt form thereof. 24. The connection according to claim 19, which is or a hydrate or pharmaceutically acceptable salt form thereof. 25. The connection according to claim 19, which is or a hydrate or pharmaceutically acceptable salt form thereof. 26. The compound according to any one of claims 20-25, where the compound is a hydrate. 27. The connection according to claim 20, which is or a hydrate or pharmaceutically acceptable salt form thereof. 28. A compound according to claim 27, wherein the compound is a hydrate. 29. A compound selected from the group consisting of: - 435 045333 No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-1H-pyrazol-4-carboxamide ; N-(5-χΛορ-6-(2Η-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(isoquinolin-4-yl)-1 H-pyrazol-4carboxamide; N-(2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxamide; N-(5-cyano-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide; 2-cyano-4-(1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)benzoic acid; N-(2-morpholinopyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide; N-(2-methoxypyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxamide; N-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; N-(2-cyclopropylpyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide; 3 -chloro-N,N-dimethyl-5-(1 -(1 -oxo-1,2-dihydroisoquinolin-5 -yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxamido)picolinamide; 3 -chloro-N-methyl-5-(1 -(1 -oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxamido)picolinamide; 1-(1-aminoisoquinolin-4-yl)-N-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide; N-(5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(1 -oxo-1,2-dihydroisoquinolin-5 -yl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide; N-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide; or a hydrate or pharmaceutically acceptable salt form thereof. 30. A pharmaceutical composition comprising a compound according to claims 1 to 29 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and a pharmaceutically acceptable diluent. 31. The pharmaceutical composition according to claim 30, which is a solid dosage form for oral administration. 32. Pharmaceutical composition according to claim 30, which is a syrup, elixir or suspension. 33. A method of treating a disease, wherein said disease is dependent on inhibition of mucosa-associated lymphoid tissue translocation protein 1 (MALT1), comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 29. 34. The method of claim 33, wherein said disease is selected from the group consisting of diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL) and mucosal associated lymphoid tissue (MALT) lymphoma. , rheumatoid arthritis (RA), psoriatic arthritis (PA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma and chronic obstructive pulmonary disease (COPD). 35. A method of treating a disease selected from the group consisting of diffuse B large cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL) and mucosal associated lymphoid tissue (MALT) lymphoma, rheumatoid arthritis (RA), psoriatic arthritis (PA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma and chronic obstructive pulmonary disease (COPD), comprising administering to a subject in need thereof a therapeutically effective amount of a composition according to any one of claims .30-32. 36. Use of a compound according to any one of claims 1 to 29 for the treatment of a disease, wherein said disease is dependent on inhibition of mucosa-associated lymphoid tissue translocation protein 1 (MALT1). 37. Use according to claim 36, wherein said disease is selected from the group consisting of diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL) and mucosal associated lymphoid tissue (MALT) lymphoma, rheumatoid arthritis (RA), psoriatic arthritis (PA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma and chronic obstructive pulmonary disease (COPD). 38. Method of obtaining a compound which is - 436 045333 including stages: (i) reacting (112a) with intermediate (Y1) to produce (112b); then oxidize (112b) to give (112c); (ii) transformations (112c) into (112d); subsequent treatment of (112d) with concentrated hydrochloric acid to obtain (112e); (iii) interaction of (112e) with (Y2) in the presence of an organic solvent; to obtain the specified connection. 39. Method for preparing a compound of formula (Ia) r ₅ -R, Formula (1a) where R1 represents 1-oxo-1,2-dihydroisoquinolin-5-yl; R ₂ represents CF3; G1 represents N; G ₂ represents C(R ₃ ), where R3 represents trifluoromethyl; and R5, R6 and _R7 are hydrogen; including stages: (i) reacting the intermediate of formula x1 (where X is bromine, chlorine or iodine) with benzophenone hydrazine in the presence of a palladium catalyst, ligand and base to produce hydrazine of formula x2; - 437 045333 (ϋ) acid hydrolysis of hydrazine of formula x2 to obtain hydrazine of formula x3; (iii) reacting the intermediate of formula x4 (where R' is _C1.4 alkyl and W is OEt or NMe ₂ ) with hydrazine of formula x3 to produce pyrazole of formula x5; (iv) hydrolysis of pyrazole of formula x5; then converting to a compound of formula (1a) by coupling with an intermediate of formula cb.