OA19506A

OA19506A - Pyrazole derivatives as malt1 inhibitors.

Info

Publication number: OA19506A
Application number: OA1201900306
Authority: OA
Inventors: Tongfei Wu; Tianbao Lu; Brett Douglas Allison; Joseph Kent Barbay; Peter J. Connolly; Maxwell David Cummings; Gaston Diels; James Patrick EDWARDS; Kevin D. Kreutter; Ulrike Philippar; Fang Shen
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2016-12-21
Filing date: 2017-12-20
Publication date: 2020-11-13

Abstract

Disclosed are compounds, compositions and methods for treating of diseases, syndromes, conditions, and disorders that are affected by the modulation of MALT1. Such compounds are represented by Formula (I) as follows: <img file="OA19506A_A0001.tif"/> wherein R1, R2, R3, R4, R5, R6, R5, G1, and G2 are defined herein.

Description

PYRAZOLE DERIVATIVES AS MALTl INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims priority to United States Provisional Patent Application No. 62/437,384, filed December 21, 2016. which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The présent invention relates to novel compounds that are MALTl (mucosaassociated lymphoid tissue lymphoma translocation protein 1 ) inhibitors. These compounds may be useful for the treatment of a disease, syndrome, condition, or disorder, particularly a MALTI-related disease, syndrome, condition, or disorder, including but not Iimited to, cancer and immunological diseases. The invention also relates to pharmaceutical compositions comprising one or more of such compounds, to processes to préparé such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the treatment of cancer and autoimmunological diseases, syndromes, disorders, or conditions associated with MALT 1 inhibitors.

BACKGROUND OF THE INVENTION

MALTl (mucosa-associated lymphoid tissue lymphoma translocation 1) is a key mediator of the classical NFkB signaling pathway. MALTl is the only human paracaspase and transduces signais from the B cell receptor (BCR) and T cell receptor (TCR). MALTl is the active subunit of the CBM complex which is formed upon receptor activation. The CBM complex consists of multiple subunits of three proteins: CARD11 (caspase recruitment domain family member 11 ), BCL10 (B-cell CLL/Lymphoma 10) and MALTL MALTl affects NFkB signaling by two mechanisms: firstly, MALTl fonctions as a scaffolding protein and recruits NFkB signaling proteins such as TRAF6, TAB-TAK1 or ΝΕΜΟ-ΙΚΚα/β; and secondly. MALTl, as a cysteine protease, cleaves and thereby deactivates négative regulators of NFkB signaling, such as RelB, A20 or CYLD. The ultimate endpoint of MALT1 activity is the nuclear translocation of the NFkB transcription factor complex and activation of NFkB signaling (Jaworski et al., Cell Mol Life Science 2016. 73, 459-473).

Constitutive activation of NFkB signaling is the hallmark of ABC-DLBCL (Diffuse 5 Large B cell Lymphoma of the Activated B Cell-Iike subtype), the more aggressive form of DLBCL. DLBCL is the most common form of non-Hodgkin’s lymphoma (NHL), accounting for approximately 25% of lymphoma cases while ABC-DLBCL comprises approximately 40% of DLBCL. NFkB pathway activation is driven by mutations of signaling components, such as CD79A/B, CARD11, MYD88 or A20, in ABC-DLBCL patients (Staudt, Cold Spring Harb Perspect Biol 2010, 2; Lim et al, Immunol Rev 2012, 246, 359-378).

The use of BTK inhibitors, for example Ibrutinib. provides clinical proof-ofconcept that inhibiting NFkB signaling in ABC-DLBCL is efficacious. MALT1 is downstream of BTK in the NFkB signaling pathway and a MAL T1 inhibitor could target 15 ABC-DLBCL patients not responding to Ibrutinib, mamly patients with CARD11 mutations, as well as treat patients that acquired résistance to Ibrutinib.

Small molécule tool compound inhibitors of MALT1 protease hâve demonstrated efficacy in preclinical models of ABC-DLBCL (Fontan et al., Cancer Cell 2012, 22, 812824; Nagel et al., Cancer Cell 2012, 22, 825-837). Interestingly. covalent catalytic site and 20 allosteric inhibitors of MALT1 protease function hâve been described, suggesting that inhibitors of this protease may be useful as pharmaceutical agents (Demeyer et al., Trends Mol Med 2016, 22, 135-150).

The chromosomal translocation creating the API2-MALT1 fusion oncoprotein is the most common mutation identified in MALT (mucosa-associated lymphoid tissue) lymphoma. API2-MALT1 is a potent activator of the NFkB pathway (Rosebeck et al., World J Biol Chem 2016, 7, 128-137). API2-MALT1 mimics ligand-bound TNF receptor, promûtes TRAF2-dependent ubiquitination of RIP1 which acts as a scaffold for activating canonical NFkB signaling. Furthermore, API2-MALT1 has been shown to cleave and generate a stable, constitutively active fragment of NFKB-mducing kinase (NIK) thereby activating the non-canonical NFkB pathway (Rosebeck et al.. Science, 2011, 331, 468472).

In addition to lymphomas, MALT l has been shown to play a critical rôle in innate and adaptive immunity (JawOrski M, étal., Cell Mol Life Sci. 2016). MALTl protease inhibitor can attenuate disease onset and progression of mouse experimental allergie encephalomyelitis, a mouse model of multiple sclerosis (Mc Guire et al., J. Neuroinflammation 2014, 11, 124). Mice expressing catalytically inactive MALTl mutant showed loss of marginal zone B cells and B1 B cells and general immune deficiency characterized as decreased T and B cell activation and prolifération. However. those mice also developed spontaneous multi-organ autoimmune inflammation at the age of 9 to 10 weeks. It is still poorly understood why MALTl protease dead knock-in mice show a break of tolérance while conventional MALTl KO mice do not. One hypothesis suggests the unbalanced immune homeostasis in MALTl protease dead knock-in mice may be caused by incomplète deficiency in T and B cell but severe deficiency of immunoregulatory cells (Jaworski et al., EMBO J. 2014; Gewies et al., Cell Reports 2014; Bomancin et al., J. Immunology 2015; Yu et al., PLOS One 2015). Similarly, MALT deficiency in humans has been 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, 151-158; Punwani et al., J. Clin. Immunol. 2015, 35, 135-146). Given the différence between genetic mutation and pharmacological inhibition, a phenotype of MALTl protease dead knock-in mice might not resemble that of patients treated with MALTl protease inhibitors. A réduction of immunosuppressive T cells by MALTl protease inhibition may be bénéficiai to cancer patients by potentially increasing antitumor immunity.

Thus, MALT 1 inhibitors of the présent invention may provide a therapeutic benefit to patients suffering from cancer and/or immunological diseases.

SUMMARY OF THE INVENTION

The présent invention is directed to compounds of Formula (I)

Formula (I) wherein

Ri is selected from the group consisting of

i) naphthalen-l-yl, optionally substituted with a fluoro or amino substituent; and ii) a heteroaryl of nine to ten members containing one to four heteroatoms selected from the group consisting of O, N, and S; such that no more than one heteroatom is O or S; wherein said. heteroaryl of ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, ethyl. propyl, isopropyl, trifluoromethyl. cyclopropyl. methoxymethyl, difluoromethyl. l,l-difluoroethyl, hydroxymethyl, l -hydroxyethyl, l -ethoxyethyl, hydroxy, methoxy, ethoxy, fluoro, chloro, bromo, methylthio, cyano, amino, methylamino, dimethylamino, 4oxotetrahydrofuran-2-yl, 5-oxopyrrolidm-2-yl, l ,4-dioxanyl, aminocarbonyl, methylcarbonyl, methylaminocarbonyl, oxo, l-(t-butoxycarbonyl)azetidin-2-yl, N(methyl)formamidomethyl, tetrahydroftiran-2-yl, 3-hydroxy-pyrrolidin-1 -yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl, azetidin-3-yl, or azetidin-2-yl;

R? is selected from the group consisting of Ci-4alkyl, l-methoxy-ethyl, difluoromethyl, fluoro, chloro, bromo, cyano, and trifluoromethyl;

Gi is N or C(R4);

G? is N or C(R.O; such that only one of Gi and G? are N m any instance;

R?, is independently selected from the group consisting of tnfluoromethyl, cyano, Ci-₄alkyl, fluoro, chloro, bromo, methylcarbonyl, methylthio. methylsulfinyl, and methanesulfonyk or, when Gi is N, R₃ is further selected from Ci-4alkoxycarbonyl;

Ra is selected from the group consisting of

i) hydrogen, when G? is N;

ii) Ci-₄alkoxy;

lii) cyano;

iv ) cyclopropyloxy;

v) a heteroaryl selected from the group consisting of triazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, tetrazolyl, oxadiazolyl, imidazolyl, 2-aminopyrimidin-4-yl, 2H-[l,2,3]triazolo[4,5-c]pyridin-2-yl, 2H-[l,2,3]triazolo[4,?b]pyridin-2-yl, 3H-[l.2,3]triazolo[4,5-b]pyridin-3-yl, lH-[l,2,3]triazolo[4,5c]pyridin-l-yl. wherein the heteroaryl is optionally substituted with one or two substituents independently selected from oxo, Ci-₄alkyl, carboxy, methoxycarbonyl, aminocarbonyl, hydroxymethyl, aminomethyl, (dimethylamino)methyl, amino, methoxymethyl, trifluoromethyl, amino(C2-₄alkyl)amino. or cyano;

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

vi i ) 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) l, l-dioxo-isothiazolidin-2-yl;

xiv) 3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl;

xv) 2-oxopyrrolidin-l-yl;

xvi) (E)- (4-aminobut-1 -en-1 -yl-aminocarbonyl:

xvii) difluoromethoxy;

and xviii) morpholin-4-ylcarbonyl;

R 5 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, methoxy, methylsulfonyl, cyano, Cwalkyl, ethynyl. morpholin-4-yl, trifluoromethyl. hydroxyethyl, methylcarbonyl, methylsulfinyl, 3-hydroxy-pyrrolidin-l-yl, pyrrolidin-2-yl. 3-hydroxyazetidinyl, azetidin-3-yl, azetidin-2-yl, methylthio, and l,ldifluoroethyl;

or R4 and R> may be taken together to form 8-chloro-4-methyl-3-oxo-3,4-dihydro2//-benzo[#][l,4]oxazin-6-yl, 8-chloro-3-oxo-3_i4-dihydro-2//-benzo[6][l,4]oxazin-6-yl, 2methyl-l-oxo-l,2,3,4-tetrahydroisoquinolin-7-yl, 4-methyl-3-oxo-3,4-dihydro-2Hbenzo[b][l,4]oxazin-6-yl, 3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl, 1-methyl-1Hpyrazolo[3,4-b]pyridin-5-yl, 1 H-pyrazolo[3,4-b]pyridin-5-yl, 2,3-dihydro[ 1,4]dioxino[2,3-b]pyridin-5-yl, 1.3-dioxolo[4,5]pyridine-5-yl, 1 -oxo-1,3dihydroisobenzofuran-5-yl, 2,2-dimethylbenzo[d][ l,3]dioxoI-5-yl, 2,3dihydrobenzo[b][l,4]dioxin-6-yl, l-oxoisoindolin-5-yl, or 2-methyl-1 -oxoisoindolin-5-yl, lH-mdazol-5-yl;

R₆ is hydrogen, Ciualkyl, fluoro. 2-methoxy-ethoxy, chloro, cyano, or trifluoromethyl;

R? is hydrogen or fluoro;

provided that a compound of Formula (I) is other than a compound wherein Ri is isoquinolin-8-yl, R? is trifluoromethyl, Gi is C(Rt) wherein R4 is 2H-] ,2.3-triazol-2-yl, G? is N, and Rs is hydrogen;

a compound wherein Ri is isoquinolin-8-yl, Rais trifluoromethyl, Gi is CfRfl wherein R₄ is 7/Aimidazol-l -yl, G? is N, and R> is chloro;

a compound wherein Ri is isoquinolin-8-yl, R2 is trifluoromethyl. Gi is C(R4) wherein R4 is ///-1,2,3-triazol-l-yl, G2 is N, and R5 is hydrogen;

a compound wherein Ri is isoquinolin-8-yl, R2 is trifluoromethyl, Gi is QRj) wherein R4 is hydrogen, G₂ is N, and R5 is fluoro:

a compound wherein Ri quinolin-4-yl, R₂ is hydrogen, Gi is C(R4) wherein R4 is (2//)-1,2,3-triazol-2-yl, G2 is N, and R5 is chloro;

or an enantiomer, diastereomer, or pharmaceutically acceptable sait form thereof.

The présent invention also provides a pharmaceutical composition comprising, consisting of and/or consisting essentially 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 sait form thereof.

Also provided are processes for making a pharmaceutical composition comprising, consisting of, and/or consisting essentially of admixing a compound of Formula (I), and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent.

The présent invention further provides methods for treating or ameliorating a 20 disease, syndrome, condition, or disorder in a subject, including a mammal and/or human in which the disease, syndrome, or condition is affected by the inhibition of MALT1, including but not limited to, cancer and/or immunelogical diseases, using a compound of Formula (I).

The présent invention also is directed to the use of any of the compounds described 25 herein in the préparation of a médicament wherein the médicament is prepared for treating a disease, syndrome, condition, or disorder that is affected by the inhibition of MALT1, such as cancer and/or immunological diseases.

The présent invention is also directed to the préparation of substituted pyrazole dérivatives that act as an inhibitor of MALT1.

Exemplifying the invention are methods of treating a disease, syndrome, condition, or disorder mediated by MALTE selected from the group consisting of lymphomas, leukemias, carcinomas, and sarcomas, e.g. non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosaassociated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, chonic lymphocytic leukemia (CLL), lymphoblastic T cell leukemia, chonic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erytholeukemia, brain (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endométrial 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, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, rénal cancer, urothélial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor), comprising, consisting of, and/or consisting essentially of, administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described in the présent invention.

In another embodiment, the présent invention is directed to a compound of Formula (I) for use in the treatment of a disease, syndrome, condition, or disorder affected by the inhibition of MALTl, selected from the group consisting of 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, chonic lymphocytic leukemia (CLL), lymphoblastic T cell leukemia. chonic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erytholeukemia, brain (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endométrial 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, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, rénal cancer, urothélial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor).

In another embodiment, the présent invention is directed to a composition comprising a compound of Formula (I) for the treatment of a disease, syndrome, condition, or disorder affected by inhibition of MALT l, selected from the group consisting of 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, chonic lymphocytic leukemia (CLL), lymphoblastic T cell leukemia, chôme myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erytholeukemia, brain (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endométrial 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, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancei, rénal cancer, urothélial cancer, vulval cancer, esophageal cancer, salivary' gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor).

In another embodiment, the présent invention is directed to a composition comprising a compound of Formula (I) for the treatment of a disease, syndiome, condition.

or disorder affected by inhibition of MALT1, selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma.

An embodiment of the présent invention is directed to a composition comprising a compound of Formula (I) for the treatment of immunological diseases that are affected by the inhibition ofMALTL including but not limited to, autoimmune and inflammatory disorders, e.g. arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatits, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic lever, goût, organ or transplact rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopie, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis. Grave s disease, Hashimoto thyroiditis, Sjoergen’s syndrome, blistering disorders, antibodymediated vasculitis syndromes, immune-complex vasculitides, allergie disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fîbrosis, pneumonia, pulmonary diseases including oedema, embolism, fîbrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

In another embodiment, the présent invention is directed to a composition comprising a compound of Formula (I) for the treatment of a disease, syndrome, condition, or disorder affected by inhibition of MALT1, selected from the group consisting of rheumatoid arthritis (RA), psoritic arthritis (PsA), psorisis (Pso), ulcerative colitis (UC), Crohn’s disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

Another embodiment of the présent invention is directed to a pharmaceutical composition comprising a compound of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

With reference to substituents, the term “independently” refers to the situation where when more than one substituent is possible, the substituents may be the same or different from each other.

The term “alkyl” whether used alone or as part of a substituent group, refers to straight and branched carbon chains having 1 to 8 carbon atoms. Therefore, designated numbers of carbon atoms (e.g., C i-s) refer independently to the numbei of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. In substituent groups with multiple alkyl groups such as, (Ci-6alkyl)2amino-, the Ci-ealkyl 10 groups of the dialkylamino may be the same or different.

The tenir “alkoxy” refers to an -O-alkyl group, wherein the terni “alkyl” is as defined above.

The terms “alkenyl” and “alkynyl” refer to straight and branched carbon chains havina 2 to 8 carbon atoms, wherein an alkenyl chain contains at least one double bond 15 and an alkynyl chain contains at least one triple bond.

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

The term “heterocyclyl” refers to a nonaromatic monocyclic or bicyclic ring system 20 having 3 to 10 ring members that include at least 1 carbon atom and from 1 to 4 heteroatoms independently selected from N, O, and S. Included within the terni heterocyclyl is a nonaromatic cyclic ring of 5 to 7 members in which 1 to 2 membeis are N, or a nonaromatic cyclic ring of 5 to 7 members ni which 0, 1 or 2 members aie N and up to 2 members are O or S and at least one member must be either N, O, or S; wherein, 25 optionally, the ring contains 0 to 1 unsaturated bonds, and, optionally, when the ring is of 6 or 7 members. it contains up to 2 unsaturated bonds. The carbon atom. ring members that form a heterocycle ring may be fully saturated or partially saturated. The term “heterocyclyl” also includes two 5 membered monocyclic heterocycloalkyl groups bndged to form a bicyclic ring. Such groups are not considered to be fully aromatic and aie not referred to as heteroaryl groups. When a 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 heterocycle groups include, and are not Iimited to, pyrrolinyl (including 2H-pyrrole. 2-pyrrolinyl or 3-pyrrolinyl). pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyL pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Unless otherwise noted, the heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

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

The tenu “heteroaryl” refers to an aromatic monocyclic or bicyclic aromatic ring System having 5 to 10 ring members and which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S. Included within the term heteroaryl are aromatic rings of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In the case of 5 membered rings, the heteroaryl ring preferably contains one member of nitrogen, oxygen or sulfur and, in addition, up to 3 additional nitrogens. In the case of 6 membered rings, the heteroaryl ring preferably contains from 1 to 3 nitrogen atoms. For the case wherein the 6 membered ring has 3 nitrogens, at most 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. benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl. benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Unless otherwise noted, the heteroaryl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine atoms.

The tenu “carboxy” refers to the group -C(=O)OH.

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

The tenu “oxo” or “oxido” refers to the group (=0).

Whenever the term “alkyl” or “aryl” or either of their prefix roots appear.in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given above for “alkyl” and “aryl.” Designated numbers of carbon atoms (e.g.. Ci-Cô) refer independently to the number of carbon atoms in an alkyl moiety, an aryl moiety, or in the alkyl portion of a larger substituent in which alkyl appears as its prefix root. For alkyl and alkoxy substituents. the designated number of carbon atoms includes ail of the independent members included within a given range specified. For example Ci-ô alkyl would include methyl, ethyl, propyl, butyl. pentyl and hexyl individually as well as sub-combinations thereof (e.g., C1-2, C1-3, Cm, Cm. C2-6, C3-6, C4-6, C5-6, C2-5. etc.).

In general, under standard nomenclature raies used thoughout this disclosure, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. Thus, for example, a “C i-C₆ alkylcarbonyl” substituent refers to a group of the formula:

O

-^-C---C_rC₆ alkyl

The label “R” at a stereocenter désignâtes that the stereocenter is purely of the Rconfîguration as defined in the art; likewise, the label S means that the steieocentei is purelv of the 5-configuration. As used herein, the labels “ *R or at a stereocenter are used to designate that the stereocenter is of pure but unknown absolute configuration. As used herein, the label “RS” refers to a stereocenter that exists as a mixture of the R- and S'-configurations.

A compound containing one stereocenter drawm w'ithout a steieo bond désignation is a mixture of two enantiomers. A compound containing two stereocenters both drawn without stéréo bond désignations is a mixture of four diastereomers. A compound with two stereocenters both labeled “RS” and drawn with stéréo bond désignations is a mixture of tw'o enantiomers with relative stereochemistry as drawn. A. compound with two stereocenters both labeled “ *RS” and drawn with stéréo bond désignations is a mixture of two enantiomers with a single, but unknown, relative stereochemistry.

Unlabeled stereocenters drawn wdthout stéréo bond désignations are mixtures of the R- and S-configurations. For unlabeled stereocenters drawn with stéréo bond désignations, the relative and absolute stereochemistry is as depicted.

Unless otherwise noted, it is intended that the définition of any substituent or variable at a particular location in a molécule be independent of its définitions elsewhere in that molécule, It is understood that substituents and substitution patterns on the compounds of the présent invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

The term “subject” refers to an animal, preferably a mammal, most preferably a human, who lias been the object of treatment, observation or experiment.

The term “therapeutically effective amount” refers to an amount of an active compound or pharmaceutical agent, including a compound of the présent invention, which elicits the biological or médicinal response in a tissue system. animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, including réduction or inhibition of an enzyme or a protein activity, or ameliorating symptioms, alleviatmg conditions, slowing or delaying disease progression, or preventing a disease.

In one embodiment, the term “therapeutically effective amount” refers to the amount of a compound of the présent invention that. when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent, and/ or ameliorate a condition, or a disorder or a disease (i) mediated by MALT1; or (ii) associated with MALT1 activity; or (iii) characterized by activity (normal or abnormal) of MALT1; or (2) reduce or inhibit the activity of MALT1; or (3) reduce or inhibit the expression of MALT1; or (4) modify the protein levels of MALT1.

The term “composition” refers to a product that includes the specified ingrédients in therapeutically effective amounts. as well as any product that results, directly, or indirectly, from combinations of the specified ingrédients in the specified amounts.

The tenu “MALT 1-mediated” refers to any disease, syndrome, condition, or disorder that might occur in the absence of MALT 1 but can occur in the presence of MALT1. Suitable examples of a disease, syndrome, condition, or disorder mediated by MALT1 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, chonic lymphocytic leukemia (CLL), lymphoblastic T cell leukemia, chonic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erytholeukemia, brain (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endométrial 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, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, rénal cancer, urothélial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor).

As used herein, the term MALT1 inhibitor refers to an agent that inhibits or reduces at least one condition, symptom, disorder, and/or disease of MALTE

As used herein, unless otherwise noted. the term “affect” or “affected” (when referring to a disease, syndrome, condition or disorder that is affected by the inhibition of MALT 1 ) includes a réduction in the frequency and / or severity of one or more symptoms or manifestations of said disease. syndrome, condition or disorder; and / or includes the prévention of the development of one or more symptoms or manifestations of said disease. syndrome, condition or disorder or the development of the disease. condition, syndrome or disorder.

As used herein, the term “treat”, “treating”.. or “treatment” of any disease, condition, syndrome or disorder refers, in one embodiment, to ameliorating the disease, condition, syndrome or disorder (i.e. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, “treat”, “treating”, or “treatment” refers to alleviating or ameliorating at lease one physical parameter including those which may not be discernible by the patient. In a further embodiment, “treat”, “treating”, or “treatment” refers to modulating the disease, condition, syndrome or disorder either physically (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In yet another embodiment, “treat”. “treating”, or “treatment” refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome or disorder.

The compounds of the instant invention are: useful in methods for treating or ameliorating a disease, a syndrome, a condition or a disorder that is affected by the inhibition of MALT 1. Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal. and a human in need of such treatment, amelioration and / or prévention, a therapeutically effective amount of a compound of Formula (I). or an enantiomer, diastereomer, solvaté or pharmaceutically acceptable sait thereof.

One embodiment of the présent invention is directed to a method of treating a MALT1- dépendent or MALT 1-mediated disease or condition, in a subject m need thereof, including an animal, a mammal, and a human in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I).

In another embodiment, the MALT 1-dépendent or MALT 1-mediated disease or condition is selected from cancers of hematopoietic origin or solid tumors such as chonic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma, and othei B cell lymphomas.

In particular, the compounds of Formula (I), or an enantiomer, diastereomer, solvaté or pharmaceutically acceptable sait form thereof are useful for treating or ameliorating diseases. syndromes, conditions, or disorders such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma.

More particularly, the compounds of Formula (I). or an enantiomer, diastereomer, solvaté or pharmaceutically acceptable sait form thereof, are useful for treating or ameliorating diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, diastereomer, solvaté or pharmaceutically acceptable sait form thereof as herein defined.

Further, the compounds of Formula (I), or an enantiomer, diastereomer. solvaté or pharmaceutically acceptable sait form thereof, are useful for treating or ameliorating an immunological disease, syndrome, disorder, or condition selected from the group consisting of rheumatoid arthritis (RA), psoritic arthritis (PsA), psorisis (Pso), ulcerative colitis (UC), Crohn’s disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

Embodiments of the présent invention include a compound of Formula (I)

wherein

AA) Ri is

i) naphthalen-l-yl, optionally substituted with a fluoro or amino substituent;

or ii) a heteroaryl of nine to ten members containing one to four heteroatoms selected from the group consisting of O, N, and S; such that no more than one heteroatoni is O or S; wherein said heteroaryl of ii) is optionally independently substituted with one or two substituents selected fiom deuterium, methyl, ethyl. propyl, isopropyl, trifluoi omethyl, methoxymethyl, difluoromethyl, 1,1-difluoroethyl, hydioxymethyl, 1hydroxyethyl, hydroxy, methoxy, fluoro, chloro. bromo. cyano, amino, methvlamino, 4-oxotetrahydrofuran-2-yl, 5-oxopyrrolidin-2-yl, 1,4dioxanyl, aminocarbonyl, methylaminocarbonyl, oxo, N(methyl)formamidomethyl, tetrahydrofuran-2-yl, 3-hydroxy-pyrrohdm-1 -yl, pyrrolidin-2-yl, 3-hydroxyazetidinyl.. azetidin-3-yl. or azetidin-2-yl;

BB) Ri is

i) naphthalen-l-yl, optionally substituted with a fluoro or amino substituent, or ii) a heteroaryl of nine to ten members containing one to four heteroatoms selected from the group consisting of O, N, and S; such that no more than one heteroatom is O or S; wherein said heteroaryl of ii) is optionally independently substituted with one or two substituents selected from deuterium. methyl, difluoromethyl, hydroxymethyl, 1 -hydroxyethyl. hydroxy, fluoro, cyano, amino, aminocarbonyl, methylaminocarbonyl, oxo, tetrahydrofuran-2-yl, 3-hydroxy-pynolidm-l-yl, pyrrolidin — yl, 3 hydroxyazetidinyl, azetidin-3-yl, or azetidin-2-yl;

CC) Ri is i ) naphthalen-1 -yl, optionally substituted with an amino or fluoro substituent;

or ii ) a heteroaryl of nine to ten members containing one to four heteroatoms selected from the group consisting of O, N, and S; such that no moie than one heteroatom is O or S; wherein said heteroaryl of ii) is optionally independently substituted with one or two substituents selected from hydroxymethyl, 1 -hydroxyethyl, hydroxy, fluoro, cyano, amino, 3hydroxyazetidinyl, or oxo;

DD) Ri is

i) naphthalen- 1-yl, 4-amino-naphthalen-l-yl, 4-fluoronaphthalen-l-yl, or 510 fluoronaphthalen-1 -yl ;

or ii) a heteroaryl selected from the group consisting of isoquinolin- 1-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-8-yl, quinohn-7-yl, cinnolin4-yl, imidazo[l,2-a]pyrazin-8-yl, phthalazin-1 -yl, naphthyridm-5-yl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, furo[2,.D-c]pyiidin-/-yl, quinoxalin-5-yl, 177-indazolylfuro[j,2-b]pyridin-7-yl, pyrazolo[l ,5 a]pyrazin-4-yl, quinolin-4-yl, quinolin-5-yl, l-ammoisoquinolin-4-yl, 1oxo-l,2-dihydroisoquinolin-5-yI, benzo[d]thiazol-7-yl, 1hydroxyisoquinolin-5-yl, benzo[d][ 1,2,3]thiadiazol-7-yl, thieno[2,32Q c]pvridin-4-yl, pyrazolo[l,5-a]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 2ox.o-1,2-dihydroquinolin-4-yl, l-amino-8-fluoroisoquinolin-4-yl, 8fluoroisoquinolin-4-yl, 1 -cyanoisoquinolin-5-yl, pyrrolo[2,1 f][ 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-naphthyndm-525 yl, pyrrolo[l,2-a]pyrazin-l-yl. imidazo[l,2-a]pyridin-5-yl, 1aminocarbonyl-isoquinolin-4-yl. benzo[d]thiazol-4-yl, 8-fluoro-1 hydroxyisoquinolin-4-yl, thieno[3,2-d]pyrimidm-4-yl, 8-fluoroimidazo[ 12a]pyridin-5-yl, 3-methylimidazo[T,2-a]pyridin-5-yl, l-oxo-qumohn-4-yl, 8aminoquinolin-5-yl, benzo[d]oxazol-4-yl, 3-methylthieno[3,2-b]pyridin-7 yl, l -(hydroxymethyl )isoquinolin-4-yL (37?-hydroxypyrrolidin-1 yl)isoquinolin-4-yl, (l-hydroxyethyl)isoquinolin-4-yl, 8-fluoroisoquinolin4-yl, 2-(difluoromethyl)quinolin-4-yl, 8-fluoroquinolin-5-yl, 1hydiOxyisoquinolin-4-yl, 1 -(tetrahydrofi.iran-2-yl)isoquinolin-4-yl, 7(difluoromethyl)thieno[2,3 -c]pyridin-4-yl, 1 -( 1 -hydroxyethyl)isoquinolin-4yl, 1 -cyanoisoquinolin-4-yl, 1 -( 1 (Æ)-hydroxyethyl)isoquinolin-4-yl, quinazolin-4-yl. 2-methyliniidazo[l,2-a]pyridin-3-yl, thiazolo[5,4d]pyrimidin-7-yl, 6-.V-oxido-lH-pyrazol-l-yl)thieno[2,3-c]pyridin-4-yl, imidazo[l,2-a]pyridin-3-yl, fmO[2,3-d]pyrimidin-4-yl, 2-fluoroquinolin-5yl, isoquinolin-5-yl, benzo[d]isothiazol-3-yl, 7-methylpyrazolo[1.5a]pyridin-4-yl, 1 -(hydroxyethyl)quinol in-4-yl, 1 (methoxymethyl)isoquinolin-4-yl, l-fluoroisoquinolin-4-yl, 1(difluoromethyl)isoquinolin-4-yl, 8-fluoroquinolin-4-yl, 8-fluoroquinolin-5yl, l-(tetrahydroforan-2(Â)-yl)isoquinoliii-4-yl, 2-amino-[ l,2,4]triazolo[1.5a]pyridin-5-yl, l-(4-oxotetrahydroforan-2-yl)isoqumolin-4-yl, 2(ammocarbonyl)quinolin-4-yl, 1 H-indazol-7-yl, 1 -( 1,4-dioxan-2yl)isoquinolin-4-yl, 2-methylimidazo[ 1,2-a]pyridin-5-yl, 1 chloroisoquinolin-4-yl, 2-cyanoqumolin-4-yl, 8-fluoro-1 (methylamino)isoquinolin-4-yl, benzo[d]isoxazol-3-yl, 2ammobenzo[d]thiazol-7-yl, 2-fluoroquinolin-5-yl, l,7-naphthyridin-4-yl. imidazo[ 1,2-a]pyrazin-5-yl, (N-( methyl)fomiamido)methyl)isoquinolin-4yl, [l,2,4]triazolo[l,5-a]pyridin-5-yl, 2-methylbenzo[d]oxazol-7-yl, 1,5naphthyridin-4-yl, 5-oxopyrrolidin-2-ylisoquinolin-4-yl, 1 -methyl-lHindazol-3-yl, 8-fluoroimidazo[ 1,2-a]pyridin-5-yl, 1 -(tetrahydrofi.iran-2yl)isoquinolin-4-yl, l-(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-l-yl, lH-pyrazolo[4,3b]pyridin-7-yl, 5-fluoroquinolin-8-yl, 6-fluoroimidazo[l,2-a]pyridin-5-yl, 2methylfuro[3,2-b]pyridin-7-yl, 8-(difluoromethyl)quinolin-5-yl, l-(419506 oxotetrahydrofuran-2R-yl )isoqumolin-4-yl, 1 -(dimethylamino)isoquinolin4-yl, 1 -methyl-1 H-pyrazolo[3,4-c]pyridin-7-yI, 2-methyI[l,2,4]triazolo[l,5-a]pyridin-5-yl, 2-methoxyqumolin-4-yl, imidazo[l,2a]pyrimidin-5-yI, 2-(difluoromethyl)thieno[2,3-c]pyridm-4-yl, quinolin-5yl, l-(l-ethoxyethyl)isoquinolin-4-yl, 2-(azetidin-2-yl)quinolin-4-yl, 2methvlbenzo[d]thiazol-7-yl, 2-acetylquinolin-4-yL 1 (methylthio)isoqumolin-4-yl, 2-amirioquinolin-5-yl, 1 -methoxyisoquinolin5-yl, imidazo[l,2-b]pyridazin-6-yl, l-(pyrrolidm-2-yl)isoqumolin-4-yl, 4(difluoromethyl)quinolin-5-yl, l-acetylisoquinolin-5-yl, 2-aminoquinolin-5yl, l-(azetidin-2-yl)isoquinolin-4-yl, l-ethoxyisoqumolin-4-yl, 1-methyl1 H-pyrazolo[3,4-b]pyridin-4-yl. 1 -ammoisoqumolm-5-yl, 1 -methyl-1Hindazol-4-yl, 2-aminoquinolin-4-yl, 2-oxo-l,2-dihydroquinolin-5-yL 1(azetidin-3-yl)isoquinolin-4-yl, 2-methylthieno[3,2-b]pyridin-7-yl, benzo[d][l,2,3]thiadiazol-4-yl, l-(l(Y)-hydroxyethyl)isoquinolin-5-yl, imidazo[l ,2-a]pyridm-8-yl, 2-methyl-l -oxo-1,2-dihydroisoquinolin-5-yl, 2(tetrahydrofuran-2-yl)quinolin-5-yl, ,1-(1 (R)-hydroxyethyI)isoquinolin-5yl, l,6-naphthyridin-4-yl, lH-pyrazolo[3.4-d]pyrimidin-4-yl. 2aminocarbonyl-qumolin-5-yl, 2-chloroquinolin-5-yl, 2-chloroqumolm-4-yl, 2-cyanoquinolin-5-yl, l-aminoisoquinolin-5-yl, 2-methoxyqumolin-5-yl. 2methylbenzo[d]oxazol-4-yl, 2-(difluoromethyl)quinolm-5-yL 2-(azetidin-2yl)qumolin-5-yl, 1 -(azetidm-2-yl)isoqumolin-5-yl, l,5-bis(tetrahydrofuran2-yl)isoquinolin-4-yl, 1 -oxo-1,2-dihydroisoqumolm-4-yl, 2-methyl-l-oxo1,2-dihydroisoqumolin-4-yl, l-(3-hydroxyazetidin-l-yl)isoquinolm-4-yl, 8fluoro-l-(3-hydroxyazetidin-l-yl)isoquinolin-4-yl, (R)-8-fluoro-l-(3hydroxypyrrolidin-l-yl)isoquinolin-4-yl, (S)-8-fluoro-l-(3hydroxypyrrolidin-l-yl)isoquinolin-4-yl, 3-hydroxyazetidin-l-yl)thieno[2,jc]pyridin-4-yl, 8-(3-hydroxyazetidm-l-yl)miidazo[l,2-a]pyndin-5-yl, 7-(3hydroxyazetidin-1 -yDpyrazolot 1,5-a]pyridin-4-yl, 1 -(3-hydroxyazetidin-1 19506 yl)isoquinolin-5-yl, and l-(l-t-butoxycarbonylazetidin-2-yl)isoquinolin-5yi;

EE) Ri is

i) napthalen-1-yl or 4-fluoronaphthaIen-1 -yl, 4-amino-naphthalen-1 -yl or 5- fluoronaphthalen-1 -yl;

or ii) a heteroaryl selected from the group consisting of thieno[3,2-c]pyridin-4-yl, isoquinoIin-4-yl, 8-fluoroquinolin-4-yl, furo[3,2-c]pyridin-4-yl, quinolin-5yl, furo[2,3-c]pyridm-7-yl, benzofuran-4-yl l,7-naphthyridin-5-yl, pyrrolo[l,2-a]pyrazin-l-yl, imidazo[l,2-a]pyridin-5-yl, 1-aminocarbonylisoquinolin-4-yl, pyrrolo[l,2-a]pyrazin-l-yl, benzo[d]thiazol-4-yl, 8-fluorol-hydroxyisoquinolin-4-yl, thieno[3,2-d]pyrimidin-4-yl, 8fluoroimidazo[ l,2-a]pyridin-5-yl, 3-methylimidazo[l,2-a]pyridin-5-yl, 1aminoisoquinolin-4-yl, 1 -oxo-quinolin-4-yl, 8-aminoquinolin-5-yl, benzo[d]oxazol-4-yl, 3-methylthieno[3,2-b]pyridin-7-yl, 1 (hydroxymethyl)isoquinolin-4-yl, (3/?-hydroxypyrrolidin-l-yl)isoquinolin4-yl, (l-hydroxyethyl)isoquinolin-4-yl, 8-fluoroisoquinolin-4-yl, 2(difluoromethyl)quinolin-4-yL 8-fluoroquinolin-5-yl, 1 -hydroxyisoquinolin4-yl, benzo[d]thiazol-4-yl, l-aminoisoquinolin-4-yl, 1-(tetrahydrofuran-2yI)isoquinoIin-4-yl, 7-(difluoromethyl)thieno[2,3-c]pyridin-4-yl, l-( 1hydroxyethyl)isoqumolin-4-yl, l-cyanoisoquinolin-4-yl, 1 -( 1 (A)hydroxyethyl)isoquinolin-4-yl, quinazolin-4-yl. 2-methylimidazo[ 1,2a]pyridm-3-yl, thiazoIo[5,4-d]pyrimidin-7-yl, imidazo[ 1,2-a]pyridin-5-yl. benzo[d][l,2,3]thiadiazol-7-yl, 6-.V-oxido-lH-pyrazol-l-yl)thieno[2,3c]pyndin-4-yl, imidazo[l,2-a]pyridin-3-yl, furo[2.3-d]pyrimidin-4-yl, 2fluoroquinoIin-5-yl, isoquinolin-5-yl, benzo[d]isothiazol-3-yI, 7methylpyrazolo[l,5-a]pyridin-4-yl. 1 -oxo-1,2-dihydroisoquinolin-4-yl, 2methyl-1 -oxo-1,2-dihydroisoquinolin-4-yl, 1 -(3-hydroxyazetidin-1 - yl)isoquinoIin-4-yl, 8-fluoro-l-(3-hydroxyazetidin-l-yl)isoquinolin-4-yl, (R)-8-fluoro-1 -(3-hydroxypyrrolidin-1 -yl)isoquinolin-4-yl, (S )-8-fluoro-1 (3-hydroxypyrrolidin-l-yl)isoquinolin-4-yl, 3-hydroxyazetidin-lyl)thieno[2,3-c]pyridin-4-yl, 8-(3-hydroxyazetidin-l-yl)imidazo[l,2a]pyridin-5-yl, 7-(3-hydroxyazetidin-1-yl)pyrazolo[l,5-a]pyridm-4-yl, l-(3hydroxyazetidin-1 -yl)isoquinolin-5-yl, and l -(hydroxyethyl)quinolin-4-yl;

FF) R? is independently selected from the group consisting of methyl, isopropyi. cyano, bromo, chloro, and trifluoromethyl;

GG) R? is independently selected from the group consisting of methyl, isopropyi, cyano, and trifluoromethyl;

HH) R2 is trifluoromethyl;

II) Ra is independently selected from the group consisting of trifluoromethyl, cyano, methylcarbonyl, methylthio, methylsulfînyl, methanesulfonyl, and chloro: or, when Gi is N, Ra is further selected from Ci-4alkoxycarbonyl;

JJ) Ra is independently selected from the group consisting of trifluoromethyl, cyano, and chloro;

KK) G? is N or QRs), wherein Ra is chloro;

LL) G2 is N;

MM) R4 is selected from the group consisting of

i) hydrogen, when G2 is N;

ii) Cwalkoxy;

iii) cyano;

iv) cyclopropyloxy;

v) carboxy;

vi) a heteroaryl selected from the group consisting of triazolyl, oxazolyl, pyrazolyl, thiazolyl, oxadiazolyl, imidazolyl, and pyrimidin-4-yI, wherein the heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of Ci-₄alkyl, carboxy, methoxycarbonyl, hydroxymethyl, aminocarbonyl, (dimethylamino)methyl, amino, methoxymethyl, trifluoromethyl, amino(C2-4alkyl)amino, and cyano;

vii) l -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) Ra is selected from the group consisting of

i) hydrogen;

ii) C i-₄alkoxy;

iii) cyano;

iv) cyclopropyloxy;

v) a 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)pyridm-3-ylaminocarbonyl;

and ix) l,l-dioxo-isothiazolidin-2-yl:

OO) Ri is selected from the group consisting of i ) methoxy;

ii) a heteroaryl independently selected from the group consisting of 2H-l ,2,3triazol-2-yl, 4-carboxy-2H-l,2,3-triazol-2-yl, 4-(hydroxymethyl)-2H-1,2,3triazol-2-yl, 4-methyl-2H-l,2,3-triazol-2-yl, oxazol-2-yl, 4-amino-2H-1,2,3triazol-2-yl, 4-(hydroxymethyl)-1 H-pyrazol-1 -yl. 4-(hydroxymethyl)-2H1,2,3-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-triazol2-yl, 1 -methyl-1 H-pyrazol-3-yl, l,3,4-oxadiazol-2-yl, 2-methyl-2H-tetrazol5-yl, 5-amino-1 -methyl-1 H-pyrazol-3-yl, 4-(hydroxymethyl)-1 H-pyrazol-1 yl, 4-cyano-2H-l,2,3-triazol-2-yl, 5-amino-lH-l,2,3-triazol-l-yl, 2H-1,2,3triazol-4-yl, 2H-tetrazol-5-yl. 4-(aminomethyl)-l H-pyrazol-1-yl, 4(methoxymethyl)-2H-1.2,3-triazol-2-yl. 2-methyl-2H-tetrazol-5-yl, and 4methyl-1 H-1,2.3-triazol-1 -yl;

and iii) methoxycarbonyl;

PP) Ri is independently selected from the group consisting of 2H-1,2.3-triazol-2-yl, 4carboxy-2H-l,2,3-triazol-2-yl, 4-(hydroxymethyl)-2H-l,2,3-triazol-2-yl, 4-methyl2H-l,2,3-triazol-2-yl, oxazol-2-yl, l/Z-imidazol-2-yl, 4-amino-2H-1,2,3-triazol-2yl, 4-(hydroxymethyl)-1 H-pyrazol-1 -yl, 4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl,

4-((dimethylammo)methyr)-2H-l.2,3-triazol-2-yl, 4-methoxycarbonyl-2H-1,2,3triazol-2-yl, 4-aminocarbonyl-2H-1,2,3-triazol-2-yl, 1 -methyl-lH-pyrazol-3-yl, and l,3,4-oxadiazol-2-yl;

QQ) R₅ is hydrogen, chloro. fluoro. bromo, cyano, methyl, ethyl. or trifluoromethyl; or, R4 and R5 may be taken together to form 8-chloro-4-methyl-3-oxo-3,4-dihydro-2Hbenzo[ô][ 1.4]oxazin-6-yl or 8-chloro-3-oxo-3,4-dihydro-2//-benzo[à][l,4]oxazin6-yl;

RR) R5 is hydrogen, chloro, bromo, cyano, or trifluoromethyl; or, R4 and R 5 may be taken together to form 8-chloro-4-methyl-3-oxo-3,4-dihydro-2/7benzo[à][l,4]oxazin-6-yl or 8-chloro-3-oxo-3,4-dihydro-_W-benzo[è][l,4]oxazin6-yl;

SS) R5 is hydrogen, chloro. bromo, or cyano;

TT) R5 is hydrogen, chloro. or cyano;

UU) Re is hydrogen or methyl;

VV ) R? i s hydrogen;

and any combination of embodiments AA) though VV) above, provided it is understood that combinations 111 which different embodiments of the same substituent would be combined are excluded; such that only one of Gi and G? are N in any instance, and provided that a compound of Formula (I) is other than a compound wherein Ri is isoquinolin-8-yl, R? is trifluoromethyl, Gi is C(R4) wherein R₄ is 2H-\,2,3-triazol-2-yl, G₂ is N, and R 5 is hydrogen;

a compound wherein Ri is isoqumolin-8-yl, R2 is trifluoromethyl· Gi is C(Rj) wherein R4 is 77/-imidazol-l-yl, G2 is N, and R5 is chloro;

a compound wherein Ri is isoquinolin-8-yl, R2 is trifluoromethyl, Gi is C(R₄) wherein R₄ is 1H-} ,2.3-triazol-l-yl, G? is N, and R5 is hydrogen;

a compound wherein Ri is isoquinolin-8-yl, R₂ is trifluoromethyl, Gi is C(Ri) wherein R₄ is hydrogen, G2 is N, and R5 is fluoro;

a compound wherein Ri qumolin-4-yl, R₂ is hydrogen, Gi is C(R₄) wherein R₄ is (277)-1,2,3-triazol-2-yl, G2 is N, and R? is chloro;

Embodiments of the présent invention include a compound of Formula (I)

R₅

Formula (1) wherein

Ri is selected from the group consisting of

i) naphthalen- 1-yl, 4-amino-naphthaIen-1 -yl, or 4-fluoronaphthalen-1 -yl, 5- fluoronaphthalen- 1-yl ;

and ii) a heteroaryl of nine to ten members containing one to four heteroatoms selected from the group consisting of O. N, and S; such that no more than one heteroatom is O or S; wherein said heteroaryl of ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxymethyl, difluoromethyl, IJ-difluoroethyl, hydroxymethyl. 1hydroxyethyl, hydroxy, methoxy, fluoro, chloro. bromo. 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-l-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, bromo, chloro, and trifluoromethyl;

Gi is N or C(R4);

G₂ is N or C(R₃); such that only one of Gi and G₂ is N in any instance;

R₃ is independently selected from the group consisting of trifluoromethyl, cyano, methylcarbonyl, methylthio, methylsulfinyl, methanesulfonyl, and chloro; or. when Gi is N, R₃ is further selected from Ci-4alkoxycarbonyl;

R4 is independently selected from the group consisting of

1) hydrogen, when G₂ is N;

ii) Ci-₄alkoxy;

iii) cyano;

iv) cyclopropyloxy;

v) carboxy;

vi) a 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 Ciualkyl, carboxy. methoxycarbonyl, hydroxymethyl, aminocarbonyl, (dimethylamino)methyl, amino, methoxymethyl, trifluoromethyl. amino(C₂-4alkyl)amino, and cyano;

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

vi i i ) 4-methyl-piperazin-1 -ylcarbonyl;

ix) (4-aminobutyl)aminocarbonyl;

x) (4-amino)butoxy;

xi) methoxycarbonyl;

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

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

and xiv) morpholin-4-ylcarbonyl;

Rs is hydrogen, chloro, fluoro, brome, cyano, methyl, ethyl, or trifluoromethyl; or, R4 and Rs may be taken together to form 8-chloro-4-methyl-3-oxo-3,4-dihydro-2Hbenzo[i>][l,4]oxazin-6-yl or 8-chloiO-3-oxo-3,4-dihydro-2/7-benzo[ô][l,4]oxazin-6-yl;

Rô is hydrogen or methyl ;

R- is hydrogen:

and provided that a compound of Formula (I) is other than a compound wherein Ri is isoquinolin-8-yl, Rc is trifluoromethyl, Gi is C(R4) wherein R4 is 2H-\,2,3-triazol-2-yl, G2 is N, and R? is hydrogen;

a compound wherein Ri is isoquinolin-8-yl, R2IS trifluoromethyl, Gi is CfRi) wherein R4 is 7//-imidazol-l-yl, G? is N, and Rs is chloro;

a compound wherein Ri is isoqumolin-8-yl, R2 is trifluoromethyl, Gi is C(R4) wherein R4 is 1H-1,2,3-triazol-1-yl, G? is N, and Rs is hydrogen;

a compound wherein Ri is isoquinolin-8-yl, R2 is trifluoromethyl, Gi is C(R4) wherein R4 is hydrogen. G? is N. and Rs is fluoro:

a compound wherein Ri quinolin-4-yI, R? is hydrogen, Gi is CiRg) wherein R4 is (272)-1,2,3-triazol-2-yl. G2 is N, and Rs is chloro;

Embodiments of the présent invention include a compound of Formula (I) r₅

Formula (I) wherein

Ri is selected from the group consisting of

i) naphthalen-l-yl, optionally substituted with a fluoro or amino substituent: or ii) a heteroaryl of nine to ten members containing one to four heteroatoms selected from the group consisting of O, N, and S; such that no more than one heteroatom is O or S; wherein said heteroaryl of ii) is optionally independently substituted with one or two substituents selected from deuterium, methyl, difluoromethyl, hydroxymethyl, 1-hydroxyethyl, hydroxy, fluoro, cyano, amino, aminocarbonyl, methylaminocarbonyl, oxo, tetrahydrofuran-2-yl, 3-hydroxy-pyrrolidin-l-yl, pyrrolidm-2-yL 3-hydroxyazetidinyl, azetidin-3-yl, or azetidin-2-yl;

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

Gi is N or CfRA;

G? is N or CfRj); such that only one of Gi and G₂ is N in any instance;

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

R₄ is independently selected from the group consisting of

i) hydrogen;

ii) Ci-₄alkoxy;

iii) cyano;

iv) cyclopropyloxy;

v) a 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;

Rs is hydrogen, chloro, bromo, or cyano;

Rô is hydrogen or methyl;

R? is hydrogen;

provided that a compound of Formula (I) is other than a compound wherein Ri is isoquinolin-8-yl, R? is trifluoromethyl, Gi is C(R₄) wherein R₄ is 2H-\,2,3-triazol-2-yl, G? is N, and R5 is hydrogen;

a compound wherein Ri is isoquinolin-8-yl, R₂ is trifluoromethyl, Gi is C(R₄) wherein R₄ is //f-imidazol-I-yl, G₂ is N, and R5 is chloro;

a compound wherein Ri is isoquinolin-8-yl. R2 is trifluoromethyl, Gi is C(R₄) wherein R4 is 777-l,2,3-triazol-l-yl, G2 is N, and R5 is hydrogen;

a compound wherein Ri is isoquinolin-8-yl, R? is trifluoromethyl, Gi is C(R₄) wherein R₄ is hydrogen. G2 is N. and R5 is fluoro;

a compound wherein Ri quinolin-4-yl, R: is hydrogen, Gi is CÏR4) wherein R₄ is (277)-1,2,3-triazol-2-yl, G2 is N, and R5 is chloro;

Embodiments of the présent invention include a compound of Formula (I)

R₅

Formula (I) wherein

Ri is selected from the group consisting of

i) naphthalen-1-yl, optionally substituted with a fluoro or amino substituent; and ii) a heteroaryl of nine to ten members containing one to four heteroatoms selected from the group consisting of O, N, and S; such that no more than one heteroatom is

O or S; wherein said heteroaryl of ii) is optionally independently substituted with one or two substituents selected from hydroxymethyl, 1-hydroxyethyl, hydroxy. fluoro, cyano, amino, oxo, 3-hydroxy-pyrrolidin-l-yl, pyrrolidin-2-yl, 3hydroxyazetidinyl, azetidin-3-yl, or azetidin-2-yl;

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

Gi is N or C(R4);

G? is N or C(Rs); such that only one of Gi and G2 is N in any instance;

R; is independently selected from the group consisting of trifluoromethyl. cyano, and chloro;

R-ι is selected from the group consisting of

i) methoxy;

ii) a heteroaryl selected from the group consisting of 2H-l,2.3-triazol-2-yl, 4-carboxy2H-l,2,3-triazol-2-yl, 4-(hydroxymethyl)-2H-l,2,3-triazol-2-yl. 4-methyl-2H-1,2,3triazol-2-yl, oxazol-2-yl, 4-amino-2H-1,2,3-triazol-2-yl, 4-( hydroxymethyl)-1Hpyrazol-l-yl, 4-(hydroxymethyl)-2H-l,2,3-triazol-2-yl, 4((dimethylamino)methyl)-2H-1,2,3-triazol-2-yl, 4-methoxycarbonyl-2H-l,2,3triazol-2-yl, 4-aminocarbonyl-2H-1,2,3-triazol-2-yl,l-methyl-lH-pyrazol-3-yl. l.3,4-oxadiazol-2-yl, 2-methyl-2H-tetrazol-5-yl, 5-amino-l-methyl-lH-pyrazol-3yl, 4-(hydroxymethyl)-1H-pyrazol-1-yl, 4-cyano-2H-l.2,3-triazol-2-yl. 5-aminolH-l,2,3-triazol-l-yl, 2H-l,2,3-triazol-4-yl, 2H-tetrazol-5-yl, 4-(aminomethyl)-lHpyrazol-l-yl, 4-(methoxymethyl)-2H-l,2,3-triazol-2-yl, 2-methyl-2H-tetrazol-5-yl, and 4-methyl-1 H-1,2.3-triazol-1 -yl;

and iii) methoxycarbonyl;

R5 is hydrogen, chloro, or cyano;

Rô is hydrogen or methyl;

R- is hydrogen;

or arrenantiomer, diastereomer, or pharmaceutically acceptable sait form thereof.

Embodiments of the présent invention include a compound of Formula (I)

Formula (I) wherein

Ri is independently selected from the group consisting of

i) naphthalen-l-yl, 4-amino-naphthalen-1-yl, 4-fluoronaphthalen-l-yi, or 5fluoronaphthalen-1 -yl; and ii) a heteroaryl selected from the group consisting of isoquinolin-l-yl, isoquinolin-4yl, isoquinolin-5-yl, isoquinolin-8-yl, quinolin-7-yl, cinnolin-4-yl, imidazo[l,2a]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, 1Hindazolylfuro[3,2-b]pyridm-7-yl, pyrazolo[ 1,5-a]pyrazin-4-yl. quinolin-4-yl, quinolin-5-yl. l-aminoisoquinolin-4-yl, 1 -cxo-l,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[l,5-a]pyridin-4-yl, thieno[3,2-b]pyridin-7-yl, 2oxo-1,2-dihydroquinolin-4-yl, l-amino-8-fl.uoroisoquinolin-4-yl, 8fluoroisoquin.oIin-4-yl, l-cyanoisoquinolin-5-yl, pyrrolo[2,l-f][l,2,4]triazin-4-yl, 7(l-hydroxyethyl)thieno[2,3-c]pyridin-4-yL thieno[2,3-d]pyrimidin-4-yl, thieno[2,3c]pyridin-7-yl, l,7-naphthyridin-5-yl, pyrrdo[ I,2-a]pyrazin-l-yL imidazo[l,2a]pyridin-5-yl, 1 -aminocarbonyl-isoquinolin-4-yl, benzo[d]thiazol-4-yl, 8-fluoro1 -hydroxyisoquinolin-4-yl, thieno[3,2-d]pyrimidin-4-yl, 8-fluoroimidazo[l,2a]pyridin-5-yl, 3-methylimidazo[l,2-a]pyridin-5-yl, 1 -oxo-quinolin-4-yl, 8- aminoquinolin-5-yl, benzo[dJoxazol-4-yl, 3-methylthieno[3,2-b]pyridin-7-yl, l(hydroxymethyl)isoquinolin-4-yl, (37?-hydroxypyrrolidin-1 -yl)isoquinolin-4-yl, ( l hydroxyethyl)isoquinolin-4-yl, 8-fluoroisoquinolin-4-yl, 2(difluoromethyl)quinolin-4-yl, 8-fluoroquinolin-5-yl, l -hydroxyisoquinolin-4-yl, l (tetrahydrofuran-2-yl)isoquinolin-4-yl, 7-(difluoromethyl)thieno[2,3-c]pyridin-4-yl, l-(l-hydroxyethyl)isoquinolin-4-yl, l-cyanoisoqumolin-4-yl, l-( 1(7?)hydroxyethyl)isoquinolin-4-yl, quinazolin-4-yl, 2-methylimidazo[ 1,2-a]pyridin-3yl, thiazolo[5,4-d]pyrimidin-7-yl, 6-;V-oxido-lH-pyrazol-l-yl)thieno[2,3-c]pyridin4-yl, imidazo[ 1,2-a]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, l-(difluoromethyl)isoquinolin-4-yl, 8-fluoroquinolin-4-yl, 8-fluoroquinolin-5-yl, l-(tetrdiydrofuran-2(Æ)-yl)isoquinolin-4-yl, 2-ammo[l,2,4]triazolo[l,5-a]pyridin-5-yl, l-(4-oxotetrahydrofuran-2-yl)isoquinolin-4-yl, 2(aminocarbonyI)qxnnolin-4-yl, lH-indazol-7-yl, l-(l,4-dioxan-2-yl)isoquinolin-4yl. 2-methylimidazo[l ,2-a]pyridin-5-yl, 1 -chloroisoquinolin-4-yl, 2-cyanoquinolin4-yL 8-fluoro-l-(methylamino)isoqumolin-4-yl, benzo[d]isoxazol-3-yl, 2aminobenzo[d]thiazol-7-yl, 2-fluoroquinolin-5-yl, l,7-naphthyridin-4-yl, imidazo[1.2-a]pyrazin-5-yl, (N-(methyl)formamido)methyl)isoquinolin-4-yl, [l,2,4]triazolo[l,5-a]pyridin-5-yl, 2-methylbenzo[d]oxazol-7-yL 1,5-naphthyridin4-yl, 5-oxopyrrolidin-2-ylisoquinolin-4-yl, l-methyl-lH-indazol-3-yl, 8fluoroimidazo[l_?2-a]pyTidin-5-yl, l-(tetrahydiOfuran-2-yl)isoquinolin-4-yl, 1 -(4oxotetrahydrofuran-2-yl)isoquinolin-4-yl, 1-(1,1 -difluoroethyl)isoquinolin-4-yl, 1 ( I ( ^A 5)-hydroxyethyl)isoquinolin-4-yl, l-(methylamino)isoquinolin-4-yl, 4fluoroisoquinolin-l-yl, lH-pyTazolo[4,3-b]pyridin-7-yl, 5-fluoroquinolin-8-yl, 6fluoroimidazo[l,2-a]pyridin-5-yl, 2-methylfuro[3,2-b]pyridin-7-yl, 8(difluoromethyl)quinolin-5-yl, 1 -(4-oxotetrahydrofuran-27?-yl)isoquinolin-4-yl, 1 (dimethyIamino)isoquinolin-4-yl, 1 -methyl- lH-pyrazolo[3,4-c]pyridin-7-yl, 2methyl-[ 1,2,4]triazolo[ 1,5-a]pyridin-5-yl, 2-methoxyquinolin-4-yl, imidazof 1,2

a]pyrimidin-5-yl, 2-(difluoromethyl)thieno[2,3-c]pyridm-4-yL quinolin-5-yl, l-(l ethoxyethyl)isoquinolin-4-yl, 2-(azetidin-2-yl)quinolin-4-yl, 2methylbenzo[d]thiazol-7-yl, 2-acetylquinolin-4-yl, l-(methylthio)isoquinolin-4-yl, 2-ammoquinolin-5-yl, l-methoxyisoquinolin-5-yl, imidazo[l ,2-b]pyridazin-6-yl, l(pyrrolidin-2-yl)isoquinolin-4-yl. 4-(difluoromethyl)qumolin-5-yl. I acetylisoquinolin-5-yl, 2-aminoquinolin-5-yl, l-(azetidin-2-yl)isoquinolin-4-yl, 1ethoxyisoquinolin-4-yl, 1 -methyl- lH-pyrazolo[3,4-b]pyridin-4-yl, 1 aminoisoquinolin-5-yl, 1 -methyl-1 H-indazol-4-yl, 2-aminoquinolm-4-yl, 2-oxol,2-dihydroquinolin-5-yl, l-(azetidin-3-yl)isoquinolin-4-yl, 2-methylthieno[3,2b]pyridin-7-yl, benzo[d][l,2,3]thiadiazol-4-yl, l-(l(5)-hydroxyethyl)isoquinolin-5yl, imidazo[l,2-a]pyridin-8-yl, 2-methyl-l-oxo-l,2-dihydroisoqumolin-5-yL 2(tetrahydrofuran-2-yI)quinolin-5-yl,, l-( l(R)’hydroxyethyl)isoquinolin-5-yl, 1,6naphthyridin-4-yl, 1 H-pyrazolo[3,4-d]pyrinndm-4-yl, 2-aminocarbonyl-quinolin-5yl. 2-chloroquinolin-5-yl, 2-chloroquinolin-4-yl, 2-cyanoquinolin-5-yl, 1aminoisoquinolin-5-yl, 2-methoxyquinolin-5-yl, 2-methylbenzo[d]oxazol-4-yl. 2(difluoromethyl)quinolin-5-yL 2-(azetidm-2-yl)quinolin-5-yl, l-(azetidin-2yl)isoqumolin-5-yl, 1,5-bis(tetrahydroftiran-2-yl)isoquinolin-4-yl, 1 -oxo-1,2dihydroisoquinolin-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-l-(3-hydroxypyrrolidin-l-yl)isoquinolm-4-yh (S)8-fluoro-l-(3-hydroxypyrrolidin-l-yl)isoquinolin-4-yl, 3-hydroxyazetidin-1yl)thieno[2.3-c]pyridin-4-yL 8-(3-hydroxyazetidin-l-yl)imidazo[l,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 l-(l-t-butoxycarbonylazetidm-2-yl)isoquinolm-5-yl;

R₂ is trifluoromethyl;

Gi is N or C(R₄);

G? is N or C(R₃); such that only one of Gi and G? is N in any instance;

Rs is independently selected from the group consisting of trifluoromethyl, cyano, and chloro;

R₄ is independently selected from the group consisting of 2H-l,2,3-triazol-2-yl, 4carboxy-2H-1,2,3-triazol-2-yl, 4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl, 4-methyl-2Hl,2,3-triazol-2-yl, oxazol-2-yI, l//-imidazol-2-yl, 4-amino-2H-l,2,3-triazol-2-yl, 4(hydroxymethyl)-1 H-pyrazol-1 -yl, 4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl, 410 ((dimethylamino)methyl)-2H-l,2,3-triazol-2-yl, 4-methoxycarbonyl-2H-l,2,3-triazol-2-yl, 4-aminocarbonyl-2H-l ,2.3-triazol-2-yl,l-methyl-lH-pyrazol-3-yl. and 1.3,4-oxadiazol-2yl;

Rs is hydrogen, chloro, bromo. or cyano;

Rs is hydrogen or methyl;

R? is hydrogen;

Embodiments of the présent invention include a compound of Formula (I)

Formula (I) wherein

Ri is independently selected from the group consisting of

i) napthalen-1 -yl, 4-ammo-naphthalen-1 -yl, 4-fluoronaphthalen-1 -yl, or 5- fluoronaphthalen-1 -yl;

and ii) a heteroaryl selected from the group consisting of thieno[3,2-c]pyridra-4-yl. isoquinolin-4-yl, 8-fluoroquinolm-4-yl, fiiro[3,2-c]pyridin-4-yl, quinolin-5-yl, furo[2,3-c]pyridm-7-yl. benzofuran-4-yl l,7-naphthyridin-5-yl, pyrrolo[l,2a]pyrazin-l-yl, imidazo[l,2-a]pyridin-5-yl, l-aminocarbonyl-isoquinolin-4-yl, pyrrolof l ,2-a]pyrazin-1 -yl, benzo[d]thiazol-4-yl, 8-fluoro-1 -hydroxyisoquinolin-4yl, thieno[3,2-d]pyrimidin-4-yl, 8-fluoroimidazo[l,2-a]pyridin-5-yl, 3methylimidazo[l,2-a]pyridin-5-yl, l-aminoisoquinolin-4-yl, l-oxo-quinolin-4-yl. 8aminoquinolin-5-yl, benzo[d]oxazol-4-yl, 3-methylthieno[3,2-b]pyridin-7-yl, l (hydroxymethyl)isoquinolin-4-yl, (37?-hydroxypynOlidin-1-yl)isoquinolin-4-yl, ( l hydroxyethyl)isoquinolin-4-yl, 8-fluoroisoquinolin-4-yl, 2(difluoromethyl)quinolin-4-yl, 8-fluoroquinolin-5-yl, l-hydroxyisoqumolin-4-yl, benzo[d]thiazol-4-yl. I -aminoisoquinolin-4-yl, l -(tetrahydrofuran-2-yl)isoquinolin4-yl, 7-(difluoromethyl)thieno[2,3-c]pyridin-4-yl, l-( l-hydroxyethyl)isoquinolin-4yl, l-cyanoisoquinolin-4-yl, l-(l(7?)-hydroxyethyl)isoqumolin-4-yl, quinazolin-4yl, 2-methylimidazo[ l ,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-,V-oxido-1 H-pyrazoll-yl)thieno[2,3-c]pyridin-4-yl. imidazo[l,2-a]pyridin-3-yl, furo[2,3-d]pyrimidin-4yl, 2-fluoroquinolin-5-yl, isoquinolin-5-yl, benzo[d]isothiazol-3-yI, 7methylpyrazolo[ 1,5-a]pyridin-4-yl, 1 -oxo-1,2-dihydroisoquinoIin-4-yl, 2-methyl-1 oxo-1,2-dihydroisoquinolin-4-yl, 1 -(3-hydroxyazetidin-1 -yl )isoquinolin-4-yl, 8fluoro-1 -(3-hydroxyazetidin-1 -yI)isoquinolm-4-yl, (R)-8-fluoro-l-(3hydroxypyrrolidm-l-yl)isoquinolin-4-yl, (S)-8-fluoro-l-(3-hydroxypyrrolidin-lyl)isoquinolin-4-yl, 3-hydroxyazetidin-1-yl)thieno[2,3-c]pyridin-4-yl, 8-(3hydroxyazetidin-l-yl)imidazo[l,2-a]pyridin-5-yl, 7-(3-hydroxyazetidin-1- yl)pyrazolo[ l ,5-a]pyridin-4-yl, l -(3-hydroxyazetidin-1-yl)isoquinolin-5-yl and l (hydroxyethyl)quinolin-4-yl;

Ra is trifluoromethyl;

Gi is N or C(R4);

Gi is N or C(R3); such that only one of Gi and G? is N in any instance;

Ri is independently selected from the group consisting of trifluoromethyl, cyano, and chloro;

R4 is independently selected from the group consisting of 2H-l ,2,3-triazol-2-yl, 4carboxy-2H-1,2,3-triazoI-2-yl, 4-(hydroxymethyI)-2H-1,2,3-triazol-2-yl, 4-methyl-2Hl,2.3-triazol-2-yl, oxazol-2-yl, lH-imidazol-2-yl, 4-amino-2H-l,2,3-triazol-2-yl, 4(hydroxymethyl)-lH-pyrazol-l-yl, 4-(hydroxymetliyl)-2H-l,2,3-triazol-2-yl, 4((dimethylamino)methyl)-2H-1,2,3-triazol-2-yI, 4-methoxycarbonyl-2H-1.2,3-triazol-2-yl, 4-aminocarbonyl-2H-l,2,3-triazol-2-yl,l-methyl- lH-pyrazol-3-yl, and l ,3,4-oxadiazol-2yh

R5 is hydrogen, chloro, or cyano;

R<_; is hydrogen or methyl;

R? is hydrogen;

Additional embodiments of the présent invention include compounds of Formula (I) as herein defined, or an enantiomer, diastereomer, solvaté, or a pharmaceutically acceptable sait form thereof, as exemplifîed in the listing in Table I, below.

Table l

Cpd Name

.V-(2-cyanopyridin-4-yl)-1 (naphthalen-1 -yl)-5 (trifluoromethyl)-/77-pyrazole-4carboxamide

A-(5-chloro-6-(277-l,2,3-triazol2-yl)pyridin-3-yl)-1 -(naphthalenl -yl)-5-(trifluoiOmethyl)-7Æpyrazole-4-carboxamide l -(naphthalen-1 -y l)-5 (trifluoromethyl)-A-(2(trifluoromethyl )pyridin-4-yl)777-pyrazole-4-carboxamide l -(naphthalen-1 -yl )-5 (trifluoromethyl )-N-( 5(trifluoromethyl)pyridin-3-yl)777-pyrazole-4-carboxamide

Structure

Cpd i No.	Cpd Name \|
5	N-(5-cyanopyridin-3-yD-1- ( naphtha 1 en-1 -yl )-5 - (trifluoromethyl)-/77-pyrazole-4carboxamide
6	l-(quinolin-5-yl)-5- j (tnfluoromethyl)-N-(2- j (tri fluoro methyl )pyridin-4-yl)- 7H-pyrazole-4-carboxamide
7	N-(5-chloro-6-methoxypyridin3-yl)- l-(quinolin-5-yl)-5(tnfluoromethyl)-///-pyrazole-4carboxamide
8	N-(5-chloro-6-(_W-l,2,3-triazol2-yl)pyndin-3-yl)-1 -(quinolin-5yl )-5-( tri flu orome thy 1)-1Hpyrazole-4-carboxamide
9	N-(5-chloro-6-(2/7-1,2,3-triazol2-yl)pyridin-3-yl)-l-(3- i methylisoquinolin-l-yl)-5- \| (trifluoromethyl)-//7-pyrazole-4\| carboxamide
10	N-(3-chloro-4-methoxyphenyl)l-(isoquinolin-8-yl)-5- (tri fluoro methyl)-/H-pyrazole-4carboxamide

No.

Cpd Name

AA3-chloro-4-(2Æ-l,2.3-triazol2-yl)phenyl)-1 -(isoquinolin-8yl )-5-(trifluoromethyl)- 1Hpyrazole-4-carboxamide

A-(3-chloro-4-( ///-pyrazol-1 yl)phenyl)-1 -(isoquinolm-8-yl)5-(trifluoromethyl)-/7/-pyrazole4-carboxamide

A-(6-cyano-5( trifluoromethyl)pyridin-3-yl )-1 (isoquinolin-8-yl)-5(trifluoromethyl)-///-pyrazole-4carboxamide

AA4-(2-aminopyrimidin-4-yl)-3chlorophenyl)-1 -(isoquinolin-8yl )-5-( trifluoromethy 1)- 1Hpyrazole-4-carboxamide

N-(5-chloro-6-(72/-pyrazol-1 yl)pyridm-3 -yl)-1 -(isoquinolin8 -yl)-5-( tri fluoromethyl)-1Hpyrazole-4-carboxamide

Cpd Name

A-(5-chloro-6-( l-methyl-Z//pyrazol-3-yl)pyridin-3-yl)-1 (isoquinolin-8-yl)-5(trifluoromethyl)-/2/-pyrazole-4carboxamide

A^:-(5-chloro-6-(oxazol-2yl)pyridin-3-yl)-1 -(isoquinolin8-yl)-5-(trifluoromethyl)-///pyrazole-4-carboxamide

A⁷-(5-chloro-6-methoxypyridin3-yl )-1 -(isoquinolin-4-yl)-5(trifluoromethyl )- ///-pyrazole-4carboxamide

A@5-cyano-6-methoxypyridin-3yl)-l-(isoquinolin-4-yl)-5- j (trifluoromethyl)-/H-pyrazole-4- | carboxamide )

A-(5-chloro-6-(2//-1.2,3-triazol2-yl)pyridin-3-yl)-l-(3fluoroquinolin-5-yl)-5(trifluoromethyl)-///-pyrazole-4carboxamide |

I

Cpd Name ïV-(5-chloro-6-(2/7-1,2,3-triazol2-yl)pyridin-3-yl)-5-isopropyl-1 (quinolin-5-yl)-/H-pyrazole-4carboxamide /V-(5-chloro-6-(2Z/-1,2,3-triazol2-yl)pyridin-3-yl)-l-(6methylquinolin-5-yl)-5(trifluoromethyl)-7/7-pyrazole-4carboxamide

A⁷-(5-chloro-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-l-(8methylquinolin-5-yl )-5| ( trifluoromethyl)-/#-pyrazole-4I carboxamide

A-( 3 -chloro-4-(3-methyl -1H1,2,4-triazol-1 -yl)pheny 1)-1 (isoquinolin-8-yl)-5(tnfluoromethyl)-/H-pyrazole-4carboxamide

Cpd Name

30¹

A-(5-chloro-6-(3-methyl-/J7l,2,4-triazol-l-yl)pyridin-3-yl)1 -(isoquinolin-8-yl)-5(trifluoro methyl)-/H-pyrazole-4carboxamide

Æ-(3-chloro-4-(5-methyl-///1,2,4-triazol-1 -yl)phenyl)-1 (isoquinolin-8-yl)-5(trifluoromethyl)-///-pyrazole-4| carboxamide

Aq5-chloro-6-(2//-l,2,3-tnazol2-yl)pyridin-3-yl)-l(isoquinolin-4-yl)-5( trifluoromethyl)-//f-pyrazole-4carboxamide

À^?-(5-chloro-6-(2Fi^r-1.2,3-triazol2-yl)pyridm-3-yl)-l-(4methylisoquinolin-8-yl)-5(trifluoromethyl)-///-pyrazole-4carboxamide l-(benzofuran-4-yl)-A^r-(5-chloro6-(2H-1,2,3-triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl)-J//pyrazole-4-carboxamide |

Cpd No.	Cpd Name
35	Æ-(5-chloro-6-(2Z7-1,2,3-triazol2-yl)pyridin-3-yl)-5-( 1methoxyethyl)-l-(quinolin-5-yl)7/7-pyrazole-4-carboxamide

A-(5-chloro-6-(277-1,2.3-triazol2-yl)pyridin-3-yl)-l-(6methylisoquinolin-4-yl)-5(trifluoromethyl)-777-pyrazole-4carboxamide

A-(5-chloro-6-( 2H-1.1,3-triazol2-yl)pyridin-3-yl)-l-(2methylquinolin-5-yl)-5( trifluoromethyl )-7/7-pyrazole-4carboxamide

i N-(3-chloro-4-(277-l ,2,3-triazolI 2-yl)phenyl)-l-(isoquinolin-4| yl)-5-(trifluoromethyI)-//7| pyrazole-4-carboxamide

Cpd Name

Structure

A⁷-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5-methyl-l (quinolin-5-yl)-///-pyrazole-4carboxamide

AqS-chloiO-ô-fJ/Z-1,2,3-triazol2-yl)pyridm-3-yl)-1 -( 8fluoroquinolin-5-yl)-5(trifluoromethyl )-/Æ-pyrazole-4carboxamide iV-(6-cyano-5-fluoropyndin-3yl)-l-(isoquinolin-4-yl)-5( trifluoromethyl )-7H-pyrazole-4carboxamide

A⁷-(5-chloro-6-( 1,1dioxidoisothiazolidin-2yl)pyridin-3-yl)-1 -(isoquinolin4-yl)-5-(trifluoromethyl)-/FZpyrazole-4-carboxamide

Cpd Name

A-(3-chloro-4-(///-1,2,3-triazoll -yl)phenyl)-1 -(isoquinolin-4yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide

I methyl 3-chloro-5-(3 -chloro-5 ( l-fisoqumolinN-yD-SOri fluoromethyl)-/77-pyrazole-4carboxamido)picolinamido) picolinate

7V-(5-chIoro-6-(( 1 methylpiperidin-4yl)oxy)pyridin-3-yl)-1 (isoquinolin-4-yl)-5(trifluoromethyl)-///-pyrazole-4carboxamide

Λ⁷-(5-Ηί1ογο-6-( /H-pyrazol-1 yl)pyridin-3 -yl)-1 -(isoquinolin4-yl)-5-(trifluoromethyl)-///pyrazole-4-carboxamide /V-(5-cyano-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-1(isoquinolin-4-yl)-5( trifluoromethyl )-/H-pyrazole-4carboxamide

Structure

50·

Cpd No.	Cpd Name
48	7V-(5-chloro-6-(4methylpiperazine-1 carbonyl)pyridin-3-yl)-1 (isoquinolin-4-yl)-5(trifluoromethyl)-///-pyrazole-4carboxamide
49	A-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-l- ( isoquinolin-4-yl)-5- (trifluoromethyl )- / //-pyrazoIe-4carboxamide

A⁷-(5-chloro-6-(oxazol-2yl)pyridin-3-yl)-l-(isoquinolin4-yl)-5-(trifluoromethyl )-///pyrazole-4-carboxamide

N-(3-chloro-4-(5-methyl-///l ,2,4-triazol-1 -yDphenyl)-1 (isoquinolin-4-yl)-5- î (trifluoromethyl)-/H-pyrazole-4- | carboxamide

A^r-(5-chloro-6-( l -methyl-///pyrazol-3-yl)pyridin-3-yl)-1 (isoquinolin-4-yl)-5(trifluoiOmethyl)-/H-pyrazole-4carboxamide

Cpd

No.

Cpd Name ,V-(5-chloro-6-(3-methyl-77ï1,2,4-triazol-1 -yl)pyridin-3-yl)1 -(isoquinolin-4-yl)-5(trifluoromethyl)-72/-pyrazole-4carboxamide

N-(5-chloro-6-(5-methyl-7Z71,2,4-triazol-1 -y l)pyridin-3-yl )l-(isoquinolin-4-yl)-5(trifluoromethyl)-7//-pyrazole-4carboxamide

AY3-chloro-4-(3-methyl-7H1,2,4-triazol-1 -yl)phenyl)-1 (isoquinolin-4-yl)-5(trifluoromethyl)-777-pyrazole-4carboxamide

A-(5-chloro-6-(_W-1,2,3-triazol2-yl)pyridin-3-yl)-5(difluoromethyl )- l-(isoquinolin1 -yl )-//7-pyrazole-4carboxamide

Cpd Mme | Ad5-chloro-6-(2//-l,2,3-triazoli 2-yl)pyridin-3-yl)-li (isoquinolin-l-yl)-5| (trifluoromethyl)-///-pyrazole-4| carboxamide

.V-(4-(2-aminopyrimidin-4-yl)-3chlorophenyl)-1 -(isoquinolin-4yl )-5-( trifluoromethy l)-1H| pyrazole-4-carboxamide

59	ïV-(3-cyano-4-(227-1,2,3-triazol2-yl)phenyl)-1 -(isoquinolin-4yl )-5-( trifluoromethyl)- 1Hpyrazole-4-carboxamide
60	Àd5-chloiO-6-(2H-1.2,3-triazol2-yl )pyridm-3-yl)-1 -(quinolin-5yl)- /H-pyrazo le-4-carboxamide
61	V-(5-fluoro-6-(2H-1,2,3-tnazol- 2-yl)pyTidin-3-yl)-1 (isoquinolin-4-yl)-5- (trifluoromethyl)-///-pyrazole-4) carboxamide

Cpd Name

AA 3-c yano-4-(7 H-1,2,3-tr i azo Il -yOphenyl)-1 -(isoquinolin-4yl)-5-(trifluoromethyl)-7//pyrazole-4-carboxamide

A^;-(5-chloro-6-(thiazol-2yl )pyridin-3-yl)-1 -(isoquinolin4-yl)-5-(trifluoromethyl)-7/Zpyrazole-4-carboxamide |

A-(5-chloro-6-(2/Z-l,2,3-triazol2-yl)pyridin-3-yl)-5-methyl-1 (quinolin-4-yl)-//7-pyrazole-4carboxamide

A-(5-chloro-6-(2/7-l ,2,3-triazol2-yl)pyridin-3-yl)-l-(3methylquinolm-5-yI)-5(tnfluoromethyl)-7H-pyrazole-4carboxamide | A-(5-chloro-6-(2/7-l,2,3-triazolI 2-yl)pyridin-3-yI)-l-(l| methylisoquinolin-4-yl)-5। (trifluoromethyl )-77/-pyrazole-4- j | carboxamide I

Cpd Name

7V-(5-chloro-6-( 277-1,2,3-triazol2-yl)pyridin-3-yl)-I-(6fluoroquinolin-7-yl)-5( tri fluoro methyl )-77/-pyrazole-4carboxamide

Ai-(5-chloro-6-(2J/-L2,3-triazol2-yl)pyridin-3-yl)-1 -(1Hindazol-4-yl)-5( trifluoromethyl )-777-pyrazole-4carboxamide

A-(5-chloro-6-(l,3,4-oxadiazol2-yl)pyridin-3-yl)-l(isoquinolin-4-yl)-5(trifluoromethyl)-777-pyrazole-4- >

carboxamide |

—.......... -.....—i

M(5-chloro-6-(7//-imidazol-l- | yl)pyridin-3-yl)-l-(isoquinolin- | 4-yl)-5-(trifluoromethyl)-7Hpyrazole-4-carboxamide

N-(6-(2H-1,2,3-triazol-2yl)pyridin-3-yl )-1 -(isoquinolin4-yl)-5-(tnfluoromethyl)-777pyrazole-4-carboxamide

Structure

Cpd No.	Cpd Name
72	,V-(4-aminobutyl)-3-chloiO-5-( l (isoquinolin-4-yl)-5- (trifluoromethyl )- //f-pyrazole-4carboxamido)picolinamide
73	l -(isoqumolin-4-yl)-xV-(2- methyl-6- (trifluoromethyl)pyridm-4-yl)-5- \| (trifluoromethyl)-/H-pyrazole-4- \| carboxamide
74	methyl 6-chloro-4-( l - (isoqumolin-4-yl)-5- (trifluoromethyl)-7/7-pyrazole-4carboxamido)picolinate
75	methyl 4-( l-(isoquinolin-4-yl)-5- (trifluoromethyl)-7/7-pyrazole-4- carboxamido)picolinate
76	N-(5-chloro-6-(2//-l,2,3-triazol2-yl)pyridin-3-yl)-l- (isoqiiiiiolin-4-yl)-7H-pyrazole- 4-carboxamide

Structure V o i II V cf₃ H Γ nY j Y' \=/	Cpd No. 77	Cpd Name N-(2-cyanopyridin-4-yl)-l(isoquinolin-4-yl)-5- (trifluoromethyl)-/77-pyrazole-4carboxamide
* C F \ /^z O xz ύ cô ____	78	N-(5-cyano-6-( 1 -methyl-1Hpyrazol-3-yl)pyridin-3-yl)-1 ( isoquinolin-4-yl)-5(trifluoromethyl)-///-pyrazole-4carboxamide
Y KZ F⁰ JS Ou z	79	7V-(5-chloro-6- cyclopiOpoxypyridin-3-yl)-1 - (quinolin-5-yl)-5- (trifluoromethyl)-7/7-pyrazole-4carboxamide
.ÇD U zx ;R Ô^z'—-z \	80'	iV-(5-cyano-6-((lmethylpiperidin-4yl )oxy)pyridin-3-yl)-1 ( isoquinolin-4-yl)-5- (trifluoromethyl)-777-pyrazole-4carboxamide
''^θχ^Ν F y θ cf₃ NC'''Ux-''Υ >Q J ,--. N // A H Γ N-Y )> W	81	V-(5-cyano-6-ethoxypyridin-3- yl )-1 -(quinolin-5-yl)-5- (trifluoiOmethyl)-7/7-pyrazole-4carboxamide

Cpd Name

Structure

A-(5-cyanopyridin-3-yl)-1 (isoquinolin-4-yl)-5( tri fluoro methyl )-1 H-p yrazo le -4carboxamide

A-(5-cyano-6-(_W-l ,2,3-triazol2-yl)pyridin-3-yl)-1 -(quinolin-5yl )-5-( trifluoromethyl)- / Hpyrazole-4-carboxamide

V-(6-(4-aminobutoxy)-5-| cyanopyridin-3-yl)-l-| (isoquinolin-4-yl)-5-| (trifluoromethyl)-/?/-pyrazole-4- | carboxamide

2V-(5-cyano-6-methoxypyridm-3yl)-l-(quinolin-5-yl)-5( trifluoromethyl )- / J7-pyrazole-4carboxamide

ΛΕ(5-ογ3ηο-6-(/Η-1,2,4-Ιη3ζο11 -yl)pyridin-3-yl)-1 -( quinolin-5yl)-5-( trifluoromethyl )-///pyrazole-4-carboxamide

Structure

Cpd I No.	Cpd Name
87	Aq8-chloro-3-oxo-3,4-dihydro2//-benzo[b] [ 1,4]oxazin-6-yl)-1 (isoquinolin-4-yl)-5- (trifluoromethyl)-7H-pyrazole-4carboxamide
88	A'-( 5-cyano-6- cyc lopropoxypyridin-3-yl)-1 - (qumolin-5-yl)-5- (trifluoromethyl)-///-pyrazole-4carboxamide
89	N-(5-cyano-6-( 1 -methyl-7/7pyrazol-3-yl)pyridin-3-yl)-l(quinolin-5-yl)-5- (trifluoro methyl )-7H-pyrazole-4carboxamide
90	I A^r-(5-cyano-6-(277-l,2,3-triazoI2-yl )pyridin-3-yl)-1 -( thieno[3,2c]pyridin-4-yl)-5- (trifluoromethyl)-777-pyrazole-4carboxamide
91	A⁷-(5-chloro-6-(oxazol-2- yl)pyridin-3-yl)-1 -(quinolin-5- \| yl)-5-(trifluoromethyl)-777- I pyrazole-4-carboxamide __________________—----

Structure

Cpd No.	Cpd Name
92	A-(5 -cyan o-6-(2H-1,2,3 -triazo l- 2 -yl)pyridin-3-yl )-1-(8fluoroquinolin-4-yl)-5- ( trifluoromethyl)-//-f-pyrazole-4carboxamide
93	1-(cmnolin-4-yl)-jV-(5-cyano-6(2H-L2,3-triazol-2-yl)pyridin-3- yl )-5-( trifluoromethyl)- 1Hpyrazole-4-carboxamide
94	N-(5-cyano-6-(2//-l,2,3-triazol2-yl)pyridin-3-yl)-1 -( furo[3.2c]pyridin-4-yl)-5- ( trifluoromethyl)-///-pyrazole-4carboxamide
95	N-(8-chloro-4-methyl-3-oxo-3,4- dihydro-2/Z- benzo[b][l,4]oxazin-6-yl)-l- j (quinolin-5-yl)-5- ( trifluoromethyl )-7H-pyrazole-4carboxamide
96	A-(5-cyano-6-(4- methylpiperazme-1 - carbonyl)pyridin-3-yI)-1 - (isoquinolin-4-yl)-5- ( trifluoromethyl)-/Æ-pyrazole-4- carboxamide [_______________________________________________________

Structure

Cpd No.	Cpd Name
97 I	M(8-chloro-4-methyl-3-oxo-3,4- : dihydro-2H- benzo[b] [ 1,4]oxazin-6-yl )-1 (isoquinolin-4-yl)-5- (trifluoromethyl)-/H-pyrazole-4carboxamide
98	À-(5-chloro-6-( 1 -methyl-/Himidazol-2-yl )pyridin-3-yl)-1 (isoquinolin-4-yl)-5- ( trifluoromethyl)-/H-pyrazole-4carboxamide
99	A^r-(5-cyano-6-(2H-1,2.3-triazol2-yl)pyridin-3-yl)-l-(furo[2,3c]pyridin-7-yl)-5- (trifluoromethyl)-/H-pyrazole-4- j carboxamide 1
100	N-(5-cyano-6-(2 H-1,2,3-triazol2-yl)pyridin-3-yl)-l-( 1,6naphthyridin-5 -yl)-5 (trifluoromethyl)-/H-pyrazole-4carboxamide
101	y-(6-(4-(4- \| aminobutyl)piperazine-l- I carbonyl)-5-cyanopyridin-3-yl)- 1 l-(isoqumolin-4-yl)-5- 1 (trifluoromethyl)-/H-pyrazole-4-

| carboxamide

Structure

CN

CF,

N I N /^N

N'N /^N N'^N

NC

N

N-N

N

CF

ÇF,

Cpd No.

102

103

104

105

Cpd Name

AM5-cyano-6-(22/-l,2,3-triazol2-yl)pyridin-3-yl)-1 -(phthalazinl-yl)-5-(trifluoromethyl)-7/2pyrazole-4-carboxamide jV-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 (imidazo[l,2-a]pyrazin-8-yl)-5(trifluoromethyl)-7H-pyrazole-4carboxamide

Λ^Γ-(5-υι1θΓθ-6-(7//-ίηιίά3ζο1-2yl)pyridin-3-yl)-l-(isoquinolin4-yl)-5-(trifluoromethyl)-7//pyrazole-4-carboxamide

A⁷-(5-cyano-6-(2/7-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(quinoxalin5-yl)-5-(trifluoromethyl)-/Hpyrazole-4-carboxamide

u. T y h ϋ \ ^u )—IX. u.

106

N-(5-chIoro-6- (difluoromethoxy)pyridin-3-yl)- 1 -(isoqumolin-4-yl)-5- (trifluoromethyl)-1 H-pyrazole-4carboxamide

Structure	Cpd No.	Cpd Name
U Q / ° M zz \=o m Z /ΰ	107	N-(5-chloro-6-(2-oxopyrrolidin1 -yl)pyridin-3-yl)-1 ( isoquinolin-4-yl)-5- (trifluoro methyl )-1 H-pyrazole-4carboxamide
I O.O o # - z-z & IZ y=o /17 > Y-n 1 τι	108	methyl2 -( 3 -chl oro-5-( 1 - (qumolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4- carboxamido)pyridin-2-yl)-2H- 1,2,3-triazole-4-carboxylate
θγ° ο Λ 11 “\ ^z-z IZ 7° /Ty^{11 S}Z^X^Jn 1 Tl _ζ^ΥγΥ	109	2-(3-chloro-5-( 1 -(quinolin-5-yl)- 5-( trifluoromethyl)-1 H-pyrazole4-carboxamido)pyridin-2-yl)2H-1,2,3-triazole-4-carboxylic acid
r^N· /^N=\ L n—z \ W 7 .--x n I Y~N Y-n // 7 Cl Ύ Î ' f ^FF Y	110	1 -( 1 -amino-8-fluoroisoquinolin4-yl)-N-(5-chloro-6-(2H-1,2,3triazol-2-yDpyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
LL / 'N ro γ/'Ί >1 Z Z-_z çIa ] P LL Ο^Λζ7 z O ,z ^zt?	111	1 -( 1 -amino-8-fluoroisoquinolin4-yl)-N-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide

Structure	Cpd i No.	Cpd Naine
Ο ί ιΓ ^ζοΧ ο ζ-ζ \	112	N-(5-chloro-2-methyl-6-(2Hi,2,3-triazol-2-yl)pyridin-3-yl)1 -( 1 -oxo-1,2-dihydroisoquinolin5-yI)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
X Ο b ΙΖ 5=0 Ο m ζ Ζ I τι ¢0 ο	113	N-(5-cyano-6-(2H-1,2,3-triazoI2-yl)pyridm-3-yl)-1 -( 1 -oxo-1,2dihydroisoquinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
b Ο b ΙΖ Οο A 7¹ 'z^x ν'n 55 ____	114	1 -(benzo[d] thiazol-7-yl)-N-( 5cyano-6-(2H-1.2,3-triazol-2- yl)pyridin-3-yl)-5- (trifluoro methyl)-1 H-pyrazole-4carboxamide
AN /—v ¹HO N'^Nv-^N-x .- F Il η o F^/ Cl^b<ÿ>b bl /'F __ ^u N^S^A ΓΑ H 1 n—b b b=b <0° —NH	115	N-(5-chloro-6-(4- (hydroxymethyl)-2H-1,2,3triazol-2-yl)pyridin-3-yl)-l -( 1 oxo-1,2-dihydroisoquinolin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
O bbx 00 u_ 1 llO Z_vOA/ o=/ zx V Z-Z L. °	116	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridm-3-yl)-1 -( 1 hydiOxyisoquinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide

Structure	Cpd No.	Cpd Name \|
o \ Z—Z u zz 4 A F z M-/ Z \Π I Tl ço m	117	N-(5-chloro-6-(2H-1,2,3-triazol- 2-yl)pyndin-3-yl)-1 -( 8- fluoroisoquinolin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
An N'^N-_v-ⁿ F F JA o y-F N 'MJ /Γ ^Na H Γ N—\ 7 ^N d-	118	N-(5-cyano-6-(2H-l,2,3-triazol- 2-yl)pyridtn-3-yl)-1 -(8- fluoroisoquinolm-4-yl)-5- (trifluoromethyl)-1 H-pyrazole-4- carboxamide
/^N N'^NvA\ F ^F J A o \af 0vA CC ^H L ^N \ / 'N S. .N N	119	l-(benzo[d][l,2,3]thiadiazol-7yl)-N-(5-cyano-6-( 2H-1.2.3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
C M , ’ „ F Π A ° \Cf ci-^X_nA / ^H c a—\ / ^^n/ r\ ^Sx -C N	120	1 -(benzo[d][ 1,2,3]thiadiazol-7yl)-N-(5-chloro-6-(2H-1,2,3triazol-2-yl )pyridin-3 -yl)-5 ( trifluoromethyl)-1 H-pyrazole-4carboxamide

Structure	Cpd iNo.	Cpd Name
Cf* Cl /9 ^F\/ nA H A' Λ—Λ A N	121	1 -(benzo[d][ 1,2.3]thiadiazol-7yl)-N-(5-chloro-2-methyl-6-(2Hl,2,3-triazol-2-yl)pyridin-3-yl)5-( trifluoromethyl)-1 H-pyrazole4-carboxamide
AN N'^Nx^N jf H ^CF3 nc^AA 0/ N V==\ // \ h nA ^x> A' \=/ V/ ^F	122	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(5fluoronaphthalen-1 -y l)-5( trifluoromethyl)-1 H-pyrazole-4carboxamide
/^N N'^Nx,N y y o J/ / ^F3 üAa ^H L ^N~\ N A/ VA ^F	123	N-(5-chloro-2-methyl-6-(2Hl,2,3-triazol-2-yl)pyridin-3-yl)l-(8-fluoroisoquinolin-4-yl)-5( trifluoromethyl)-1 H-pyrazole-4carboxamide
Ω θ z-z Ά rC AAo <- m ω Ou Tl	124	N-( 5-cyano-2-methyl-6-(2H1,2,3-triazol-2-yl)pyridin-3-yl)1 -(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
LL 1 LL - Λ Z /A< u- \ /J O=/ ZI ^ZA z-z L ÿ ^u	125	N-(5-chloro-6-(4-methyl-2H- 1.2,3-triazol-2-yl)pyridin-3-yl)- 1 -(quinolin-5-yl)-5- ( trifluoromethyl )-1 H-pyrazole-4carboxamide

Structure	Cpd No. i	Cpd Name 1
/-N Ovfy _F F j η o nuf N^OO /F~f. ^H L ^N \ ^Nyy X^s	126	N-(5-cyano-6-(2H-l,2,3-triazol2-yDpyridin-3-yl)-l-(thieno[2,3b]pyridin-4-yl)-5- ( trifluoromethyl )-1 H-pyrazole-4carboxamide
O °X Λ / ^zyx 1Z >_oox y /O I Π Ou O ___	127	N-(5-chloro-6-(oxazol-2yl)pyridin-3 -yl )-1-(1 -oxo-1.2dihydroisoquinolin-5-yl)-5( trifluoromethyl)-1 H-pyrazole-4carboxamide
N /^n III N'^NvJ_{x f} F uO^F N^ y> / χ ^H L ^N \ ^Nu' y=/ ^sX	128	N-(5-cyano-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-l-(thieno[3,2b]pyridin-7-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
o \ Z~Z O IZ >o OO 'z / n I H Ou iy O	129	N-(3-chloro-4-(2H-1,2,3-triazol2-yl)phenyl)-1 -( 1 -oxo-1,2dihydroisoquinolin-5-yl)-5( trifluoromethyl)-1 H-pyrazoie-4carboxamide
N An III N'U Jx _F F Γ π o \Uf Nx 11 II Γ N 'U. /AA ^H L ⁿO / yy o^^N D	130	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-l-(2-Dquinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide

Structure ÇP i Cpd Naine î No. I

X'N F F J / ⁰ T ^F H ρ-Π D	131	N-(5-chloro-6-(2H-l,2,3-triazol2-yj)pyridin-3-yl)-1-(,2- Dquinolin-5-yl)-5- ( trifluoromethyl )-1 H-pyrazole-4carboxamide
Z z+X b IZ 7=o O-Z _zJL 00 z I w	132	1 -(4-aminonaphthalen-1 -yl)-N(5-cyano-6-(2H-l,2,3-triazol-2yl)pyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
X û b IZ 7=0 zO z \~“n	133	N-(3-cyano-4-(2H-1,2,3-triazol2-yl)phenyl)-l-(quinolin-5-yl)-5( trifluoromethyl)-1 H-pyrazole-4carboxamide
An H₂nX > N'^NxX _f F Il η o y-F ^Cl » y-<b V NH	134	N-(6-(4-amino-2H-l,2,3-triazol2-yl)-5-chloropyridin-3-yl)-1 -( 1 oxo-1,2-dihydroisoquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
^H°Vy^N N _F T il o y-F ci'^xA A 7 .—. N—FF y=( w	135	N-(5-chloro-6-(4- (hydroxymethyl)- IH-pyrazol-1 yl)pyridin-3-yl)-Î-(quinolin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide

Structure	Cpd No.	Cpd Name
N r—γ ¹ HO N'^Nx/N F J η o γ ciYA..Â / + _ts H ΥΝ-/Λ Y /=( v_/	136	N-(5-chloro-6-(4- ( hyd roxymethyl)-2H-1,2,3- triazol-2-yl)pyridin-3-yl)-l(quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
/^N —N N'Yk _f F \ J Ί 0 ^rY ciYnJY .—, h r^N-ZY w	137	N-(5-chloro-6-(4- ((dimethylamino)methyl)-2H- 1.2,3-triazol-2-yl)pyridin-3-yl)- 1 -(quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
γΝ Yx/N F J 1 o r^F N’Y ΓΛ H Γ N-( N Y' /Y	138	N-(5-cyano-6-(2H-l,2,3-triazol2-yl)pyri.din-3-yl)-1 -(quinolin-4yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
/^N N'Yn F A H ^CF3 ⁿYa ^H [ nY a Y' Y=u w	139	N-(5-bromo-6-(2H-1,2,3 -triazol2-yl)pyridm-3-yl)-l-(quinolin-5yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
/ û b IZ Yo Oy Z \~TI ] Tl Vz. b z	140	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 (pyrrolo[2.1 -f][ 1.2,4]triazin-4yl)-5-(trifluoromethyl)- 1Hpyrazole-4-carboxamide

Structure	Cpd No.	Cpd Name
/^N N'^N^/N F J Ί 0 FV ^H U n—i / V' Y-N	141	N-(5-chloro-6-(2H-1,2,3-triazol- 2-yI)pyridin-3-yl)-1 - (pyrazolof 1,5-a]pyrazin-4-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
An N-^N'_V/N _f f J ί o r'F n-^ H N—y N ^N u	142	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(thieno[2,3d]pyrimidin-4-yl)-5- ( trifluoromethyl)-lH-pyrazole-4carboxamide
Z ^Zf7] Y z-^zV _m A \=o z z. F A	143	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-l-(thieno[2,3c]pyridin-7-yl)-5- (trifluoromethyl )-1 H-pyrazole-4carboxamide
\ /^N Z—v ¹ H.N NA./N p F Λ A y=/	144	2-(3-chloro-5-(l-(quinolin-5-yl)5-(trifluoromethyl)-1 H-pyrazole4-carboxamido)pyridin-2-yl)2H-l,2,3-triazole-4-carboxamide
/A N^Nk^N //Y F F VJ /? Vf ^N^ N^\Y __N h VA /r~A i _zN—// \\ Y^Z )=/ Cz	145	N-(5-cyano-6-(2H-1,2,3 -triazol2-yl)pyridin-3-yl)-1 -( 1,7naphthyridin-5 -yl )-5 (trifluoromethyl )-1 H-pyrazole-4carboxamide

Structure	Cpd No.	Cpd Name
Cî^ . F Π i O ^F\/ F N \^\ f/ λ F H T '_N—Y Ά /=( w	146	N-(6-(2H-1,2,3-triazoI-2-yl)-5(trifluoromethyl )pyridm-3-yl)-1 (quinoIin-5-yl)-5- (trifluoromethyl)-1 H-pyrazole-4carboxamide
O _ _z__z M iz 4=0 7 A n K? X ”	147	N-(5-chloro-6-(2H-1,2,3-triazol- 2-yr)pyridin-3-yl)-1 - (pyrrolo[l,2-a]pyrazin-l-yl)-5- (trifluoromethyl )-1 H-pyrazole-4carboxamide
F r=N ^F\V^F 4 n^/'s T ^N ^N \ 1 l! \ ^H L # N^/	148	N-(5-cyano-6-(2H-1,2,3-triazol- 2-yl)pyridin-3-yl)-1 - (pyrrolo[ 1,2-a]pyrazin-l-yl)-5(tri fluoro methyl )-1 H-pyrazole-4carboxamide
2/ Z Z^z Z ^x\ fj ΞΖ \=o zdw Z 1	149	N-(5-cyano-6-(2-methyl-2Htetrazol-5-yl )pyridin-3-yl)-1 (quinolin-5-yl)-5- (tri fluoromethyl )-1 H-pyrazole-4carboxamide
u- 1 u—\ Z ^-'^O o=/ ZI Q z-z \. Il	150	N-(5-cyano-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-1 -(furo[3,2b]pyridin-7-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide

Structure	Cpd I No. \|	Cpd Name 1
Γ /<N । ^N A	xz Eo Ew; z I Tl E^^z^	151	N-(5-cyano-6-(2H-1,2.3-triazol2 -y l)p yridin-3 -yl)-1 -(2 methylfuro[3,2-b]pyridin-7-yl)5-( trifluoromethyl)-1 H-pyrazole4-carboxamide
Z b IZ E© ^zx7 Z pu \| ηη n/ z	152	N-(5-cyano-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-1 -(4-fluoro-2methoxyphenyl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
A'-.. ,Z oo LL \| LlY Z^ oE ZI b -Z.--Z. ù_ Cz °	153	l-(benzo[d]thiazol-7-yl)-N-(5chloro-6-(2H-1,2,3-triazol-2yl )pyr idin-3 -yl)-5 - (trifluoromethyl)-1 H-pyrazole-4carboxamide
E u-rt z E^E/ OE^ ZI w z-z ï_ ç ° z CM T	154	N-(6-(4-amino-2H-l,2,3-triazol- 2-yl)-5-chloropyridin-3-yl)-l- (quinolin-5-yl)-5- (trifluoromethyl )-1 H-pyrazole-4carboxamide
r^N< n=, U ^^N~/\ V ^N V^^NH / À—a^N Cl F \\ ' /Γ+α O En^// N f-/ ^N nh₂	155	1 -( 1 -aminoisoquinolin-4-yl)-N(5-chloro-6-(2H-l,2,3-triazol-2yl)pyridin-3-yl)-5- (tri fluoro methyl)-1 H-pyrazole-4carboxamide

Structure	C pd No.	Cpd Name
fi iz V=o z. / z ? QLz z T M	156	1 -( 1 -aminoisoquinolin-4-yl)-N(5-cyano-6-(2H-1 _2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl )-1 H-pyrazole-4carboxamide
\ /'N W L· ^γΝ F F J Ί 0 YY_Fci^'n^ Λ/ .—. Η^Α-ΖΛ ^n r\ —NH	157	N-(5-chloro-6-( 1 -methyl- 1Hpyrazol-3-yl)pyridin-3-yl)-1 -( 1 oxo-1,2-dihydroisoquinolui-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
N^Y F. ,^F Il I 0 \Y rP iï / F'J ''· ’γί? Z λ F ^H Γ 'N—C ? 'Y V=/ 4 / ° —NH	158	1 -( 1 -oxo-1.2-dihydroisoquinolin5-yl)-5-(trifluoromethyl)-N-(2- ( trifluoromethyl)pyridin-4-yl)- 1 H-pyrazole-4-carboxamide
N, 0 ^[\ F _N \ f—y n y 0 fr-J y—NH N=Y ?-\,0 N=\ (/ nh₂	159	l-(2-amino-[l,2,4]triazolo[l,5a]pyridin-5-yl)-N-(5-cyano-6(2H-1,2,3-triazol-2-yl)pyridm-3yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamide
X 1 ü- \ Z \\ // Z£ 0 z—z y. V ^ü	160	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-3-fluoro-1 (quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide

Structure	Cpd No.	Cpd Name
N Z i F V Μ- I n AA o p—4__r. I / N —J H N-—\ / V- / W ‘N / \ / \=O VnF	161	N-(2,5-dimethyl-6-(2H-1,2,3triazol-2-yl)pyridm-3 -yl)-1 -( 1 oxo-1,2-dihydroisoquinol in-5y l)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
_. ci t; 6 m -/Vz=N \ » \ I J IJ n—y h <:C	162	N-(6-(2H-[ 1,2,3]triazolo[4,5c]pyridin-2-yl)-5-chloropyridin3-yl)-l-(quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
n₌n Cl J 'T c f Γγ^Νγ\ o A^{f n}A Ut U r\ O	163	N-(6-( 1 H-[ 1,2,3]triazolo[4,5c]pyridin-1 -yl)-5-chloiOpyridin3-yl)-l-(quinolin-5-yl)-5- ( trifluoromethyl )-1 H-pyrazole-4carboxamide
^F ’⁷ -M F-C/ Γ U Cl _/Ά \ I >N \ O \ H CL U Vt U VUnU^n L i n—/ \, / \ i il VA / \\ /Anh v^n AJ ^λ n—y	164	N-(6-(2H-[l,2,3]triazolo[4,5b]pyridin-2-yl)-5-chloropyridin3-yl)-l-(quinolin-5-yl)-5(trifluoro methyl)-1 H-pyrazole-4carboxamide
zz \ N /g Cl N. 1 \| f n \|\| η o Jr ^FAA AJ ΓΑ h —\_J j—\ 4 N Vj	165	N-(6-(3H-[ 1,2,3]triazolo[4,5b]pyridin-3-yl)-5-chloropyridtn3-yl)-l-(quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
0 A^nh HN J _F F 'nZCl o \p^F H 1 Γ \ L· N vc	166	N-(3-chloro-4-(5-oxo-4,5dihydro-1 H-1,2,4-triazo 1-3 yl)phenyl)-l-(quinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide

Structure	Cpd No.	Cpd Name ’
_F ^F F N f/ λ F ^H 1 N—C A YY W / ³° —NH	167	1 -( 1 -oxo-1,2-dihydroisoquinolin- 5-yl)-5-(trifluoromethyI)-N-(5- (trifluoromethyl)pyridin-3-yl)- 1 H-pyrazole-4-carboxamide
^c\ F N Y Ργ^Ρ Y. L n—# \\ \ 1 Y/ Y YNH \ H A _o Y N=/ ύΥΝ^Υγ ^OH () Y=N	168	N-(5-chloro-6-(5(hydroxymethyl)-1 H-1,2,3triazol-1 -yl)pyridin-3-yl )-1 -(1 oxo-1,2-dihydroisoquinolin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
\ /Y V\/ R F ji Yl Y C1_N Y-Y Λ N H 1 N—1 p ~Y / \ i T° Yh	169	N-(5-chloro-2-methyl-6-( 1 methyl-1 H-pyrazol-3 -y l)pyrid in3-yl)-l-(l-oxo-l,2dihydroisoquinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4carboxamide
/^N Τ,^Ν.. _f J Y o \Yf / — H C1-/T U 4 Τθ —-NH	170	N-( 5-chloro-2-methyl-6-( 1Hpyrazol-1 -yl)pyridin-3-yl)-1 -( 1 oxo-1,2-dihydroisoquinolin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
/7 _C\| \\ 1 / Ν·^^ΝχΥχ F 12 Λ ^F~T^F Y'-Υ a a 1 H f \ // \\ ^'N YY V\ / ° —NH	171	N-( 5-chloro-2-methyl-4-( 2H1,2,3-triazol-2-yl)phenyl)-1 -( 1 oxo-1,2-dihydroisoqumolin-5yl)-5-(trifluoromethyl )-1Hpyrazole-4-carboxamide

Structure	Cpd No.	Cpd Name i
An 4 J N F Il l^ P F—/ A A /~F cr W\ J _, n AA 0 λ ^H La \ / r⁼\ 4 /=° '--NH	172	N-(5-chloro-2-fluoro-4-(2Hl,2,3-triazol-2-yl)phenyI)-l-( 1oxo-1,2-dihydroisoquinolin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
An /—G I —O N'^Nx^N _f Fl i? A-r ^c,'^^anAU H f \ // \ ^ν^ζ )=/ A/	173	N-(5-chloro-6-(4- ( methoxymethyl)-2H-1,2,3triazol-2-yl)pyridin-3-yl )-1 - (quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
A an ^λ—<\ । Cl^A F, ,^F N H A-F \ N—V g ' o	174	N-(4-(4-(aminomethyl)-1Hpyrazol-1 -yl)-3-chlorophenyl)-1 (quinolin-5-yl)-5- (tri fluor omethyl )-1 H-pyrazole-4carboxamide
no z^_XT \ /^-N ^F A 1 il cr Wx A J ,—, H P-ô ^A aa ά N Vv	175	N-(3-chloro-4-(4- (hydroxymethyl)-1 H-pyrazol-1 yl)phenyl)-l-(quinolin-5-yl)-5( trifluoromethyl)- lH-pyrazole-4carboxamide

Structure	Cpd No.	Cpd Name
/^N F Il 0 F-^/ y\A JJ / ^{F N}^OO\ f/—λ \| _zN—F b ^N^Z /==\ 4 / ° é—Nil	176	N-(5-cyano-2-methyl-6-(2Hl,2,3-triazol-2-yl)pyridin-3-yl·)1 -( 1 -oxo-1.2-dihydroisoquinolin5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
/^N /----(\ ¹ TO N^x^N F H i ⁰ ^^OO\ JL O^F N \@ / λ ^H L t A / /=0 v_0	177	N-(5-cyano-6-(4(hydroxymethyl)-2H-1,2,3triazol-2-yl)pyridin-3-yl)-1 (quinolin-5-yl)-5- (trifluoromethyl)-lH-pyrazole-4carboxamide
/C^Z z-A n X t. Z zA ⁿb V“ o_x / \x^Z / ^X -n il /—O ^'Z t: A-/⁷o	178	N-(6-(5-amino-lH-l,2,3-triazolI -yl)-5-chloropyridin-3-yl)-1 -( 1 oxo-1,2-dihydroisoqumolin-5yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamide
Z II □ ^ζΛ \ z-z 0 ΞΖ Z ξ^·-ι1	179	N-(5-chloro-6-(4-cyano-2Hl,2,3-triazol-2-yl)pyridin-3-yl)1 -(quinolin-5-yI)-5- (trifluoromethyl)-lH-pyrazole-4carboxamide
An E ^f 1 γ o ^r\/ ci^><Ax Jl /'f —_N ^N // \\ ^{H N}—\ 7—^NH2 ^N⁷ / \	180	1 -( l-aminoisoquinolin-4-yl)-N(5-chloro-2-methyl-6-(2H-l ,2,3triazol-2-yl)pyridin-3-yl)-5- ( trifluoro methyl)-1 H-pyrazole-4carboxamide

Structure	Cpd , No. 1	Cpd Name j
\, Hz* Y II F F Il I ° ^ίΎ( QZY Gⁿ	181	N-(6-(5-amino-1 -methyl-1Hpyrazol-3-yl)-5-cyanopyridin-3yl)- l-(quinolin-5-yl)-5- ( trifluoromethyl)-lH-pyrazole-4carboxamide
YU , ’ II \| 0 M Y ^!l Yr °Υγ N \=\ (. Y ’—_NH	182	N-(5-chloro-6-(4(hydroxymethyl)-1 H-pyrazol-1 yl )pyridin-3-yl)-1 -( 1 -oxo-1,2dihydroisoqumolin-5-yl)-5(trifluoro methyl)-1 H-pyrazole-4carboxamide
\. Y HiN-J H ^'N UO Y >O '—NH	183	N-(6-(5-amino-1 -methyl-1Hpyrazol-3-yl)-5-chloropyridin-3yÎ)-l-( l-oxo-1,2dihydroisoquinolin-5-yl)-5(trifluoro methyl )-1 H-pyrazole-4carboxamide
Cl F _F Ν^χθΗ ,N \--. fU/ f Y Z N—\ Y- N H Y /Υ/Υγ ^N=/ H Y J / Yn y	184	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-l-(8-fluoro-lhy droxyiso qu inol in-4-yl)- 5 ( trifluoromethyl)-1 H-pyrazole-4carboxamide
Z Y CD \ // Λ Z-Z u Y© My Z Τ'--n I -n Ou ¹ H O	185	N-(5-bromo-2-methyl-6-(2H1.2,3-triazol-2-yl)pyridin-3-yl)1 -( 1 -oxo-1,2-dihydroisoquinolin5-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide

Structure	Cpd No.	Cpd Name \|
N . ’......0 \\ Z/ N V N _Νχ n=\ yyO T n 0/ yr^XH Cl	186	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5-cyano-1 (quinolin-5-yl)-1 H-pyrazole-4carboxamide
°\ n y N=x )>---Ç ; \|l \| —Z /—NH ^N⁷ \—/ Cl	187	5-chloro-N-(5-chloro-6-(2H- 1.2,3-triazol-2-yl)pyridin-3-yl)- 1 -(quinolin-5-yl )-1 H-pyrazole-4carboxamide
Λ=Ν 7 ,Oy ° ^Br ^N u L JY J /--\ Z N y__/J	188	5-bromo-N-(5-chloro-6-(2Hl,2,3-triazol-2-yl)pyridin-3-yl)1 -(quinolin-5-yl)-1 H-pyrazole-4carboxamide
Λ=Ν Z l _c F .N. F / n y y o y^F u 'Oyoy	189	N-(5-cyano-6-(2H-1,2,3-triazol- 2-yl)pyridin-3-yl)-1 - (imidazo[l,2-a]pyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
o JYt 00 LL· \| LL· O Z o=/ \ ^{z:r z} / 2^-2 \\	190	N-(5-ethynyl-2-methyl-6-(2H1.2.3-triazol-2-yl)pyridin-3-yl )l-( 1-oxo- 1,2-dihydroisoquinolm5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-c arboxam ide

Structure	Cpd No.	Cpd Naine . \|
U+n \\ । N^N\.N r A-' f I I P F^/ il /O » iU A i _zn—fi y Ά )=/	191	N-(5-chloro-2-methyl-6-(2Hl,2,3-triazol-2-yl)pyridin-3-yl)1 -(isoquinolin-4-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
Z z' a u© Q IZ o© C T z K/ z \—n JL Ou Z +Z	192	N-(5-chloro-6-(l,3,4-oxadiazol2-yl)pyridin-3-yl)-1 -(quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
/^N \\ 1 N^x^N r N f 1 II p f^/ II cf N a^-U /---s ^H Ο^ν~#Λ ^^n/ V Xz^N	19.5	N-(5-chloro-6-(2H-1,2,3-triazol- 2-yl)pyridin-3-yl)-1 - (imidazo[ 1,2-a]pyridin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
U^N 4 i p T fi O F^/ ^H ooo ) N N-^ O/^N	194	N-(5-chloro-2-methyl-6-(2Hl,2,3-triazol-2-yl)pyridin-3-yl)1 -(imidazo[ 1,2 -a]pyridin-5-yI )-5(trifluoro methyl)-1 H-pyrazole-4carboxamide

Cpd No.

Cpd Name

Structure

195

196

N-(5-chloro-2-ethyl-6-(2H-1,2,3triazoI-2-yl)pyridin-3-yl)-1 (imidazo[ 1,2-a]pyridin-5-yl)-5(trifluoro methyl )-1 H-pyrazole-4carboxamide

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

197

198

N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 (pyrazolo[ 1,5-a]pyridin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4carboxamide

N-(5-chloro-2-methyl-6-(2Hl,2,3-triazol-2-yl)pyridin-3-yl)l-(pyrazolo[ 1.5-a]pyndin-4-yl)5-( trifluoromethyl)-1 H-pyrazole4-carboxamide

Cpd | _r ' I Cpd Name

No. |

Structure

199	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(2methylimidazo[ 1,2-a]pyridin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
200	N-(5-cyano-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-l - (imidazo[ 1,2-a]pyridin-5-yl)-?(trifluoromethyl )-1 H-pyrazole-4carboxamide
201	N-(5-chloro-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-1 -(3chloroimidazo[l,2-a]pyridin-5yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamide
202	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 8fluoroimidazo[ 1,2-a]pyridin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide

Structure ; Çpd iv_ame \a - *

An V n^ⁿ\a_x 1 il 9 ^FV cWA JJ Vf ^H LW N 4^a	203	N-(5-chloro-2-methyl-6-(2H1,2,3-triazol-2-yl)pyridin-3-yl )1 -( 8-fluoroimidazo[ 1,2- aJpyridin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
A^n Q I tVx/N A Y f / li 9 fa n^Vy_nA Jvf /a ^H V>aV^^f N A / \\ An	204	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(8fluoroimidazo[ 1,2-a]pyridin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
r» 4. A z 17 V u. y___lj O=/ zx G F\ ^ü # _zz	205	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-l-(6fluoroimidazo[ 1,2-a]pyridin-5y 1)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
17 N A. F t, T p \A / ° M ργΥΑ J! /a F ^N \_A ^H /AA A AA \\ ^N nJ	206	1 -(2-methylimidazo[ 1,2a]pyridin-5-yl)-5(trifluoromethyl )-N-(2(trifluoromethyl)pyridin-4-yl)1 H-pyrazole-4-carboxamide

Structure	Cpd No.	Cpd Name
n Yx / F II I θ \γί II F^\ N ^Υ_<ίΧ /7 A F H Y\_# Y \—N C	207	1 -(7-methylpyrazolo[ 1.5- a]pyridin-4-yl)-5- (trifluoromethyl)-N-(2(trifluoromethyl)pyridin-4-yl)1 H-pyrazole-4-carboxamide
F N Y R / ii i ° Y^f il / F^l V '^XY /7 X ' H \| \_r // Y F N---y ) N— k/^N	208	l-(imidazo[L2-a]pyridin-5-yl)-5- ( trifluoro niethyl)-N-( 2- ( trifluoromethyl )pyridin-4-yl)- 1 H-pyrazole-4-carboxamide
Ll yK_,z Y Z.,/LL \| LL^/ zy o=/ ZI Z=/ \,Ll ur\ LL	209	1 -(8-fluoroimidazo[ 1.2a]pyridin-5-yl)-5- ( trifluoromethyl)-N-(2- ( trifluoromethyl )pyridin-4-yl)- 1 H-pyrazole-4-carboxamide
z IZ 4 U -n z Λ--Ζ Z \—n 1 ~n Z o z	210	1-(7-(3 -hydroxyazetidin-1 yl)thieno[2,3-c]pyridin-4-yl)-5( tri fluoro methyl )-N-(2(trifluoromethyl)pyridin-4-yl)1 H-pyrazole-4-carboxamide
/Ύ \\ । nⁿ\Y Y Y F 1 il P f-Y Cl-^Y^Y JJ /Y n Y ,—, ^H N^Z Y^Y/N	211	N-(5-chloro-6-(2H- 1,2,3-triazol2-yl)pyridin-3-yl)-l-(3methylimidazo[ 1,2-a]pyridin-5yl)-5-(trifluoromethyl)-lH- pyrazole-4-carboxamide
UU Z y zx \ Y⁰^—z \	212	zV-(2-methyl-l-oxo-l,2,3,4tetrahydroisoquinolin-7-yl )-1 (quinolin-5-yl)-5- ( tri fluoro methyl )-1 H-pyrazole-4carboxamide

Structure	Cpd No.	Cpd Name
0 /A oJ0 N. I ? V^N\A f ^F J 0 ° Af n / λ ^H L· /^N—\ / \\ N A_/	213	N -(3-(methylsulfonyl)-4-( 1H1,2,3-triazol-1 -yl)phenyl )-1 (quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
/ V u. /^r 0=0 zs 0 °A^	_XF x jU ^N \0 ^:N F ψ	214	N-(4-methyl-3-oxo-3,4-dihydro2H-benzo[b] [ 1,4]oxazin-6-yl)-1 (quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
o II A^N O~S— / I I f AN. A. F. A N 00A O A^F H L /^N V-7 Aq / \ A	215	N -(3-(methylsulfonyl)-4-(2H1,2,3-triazol-2-yl)phenyl)-1 (quinolin-5-yl)-5- ( trifluoromethyl )-1 H-pyrazole-4carboxamide
Aa u f I I i o Af 0A* A. Il / I/ ’n^'A' f/ V Ο ^H I N—C p ^A /=0 <Λ N 00	216	N -(2-methyl-1-oxo-1,2dihydroisoquinolin-7-yl)-1 (quinolin-5-yl)-5- (trifluoromethyl)-1 H-pyrazole-4carboxamide

Cpd

Cpd Name

Structure

O O xz 4=0 7¹ X Z Z^'<^ i-----------------	217	N-( 3-oxo-3,4-dihydro-2Hbenzo[b] [ 1,4]oxazin-6-yl )-1 (quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
—4 4 ° 1 T^F ^H L 4 -\ / ^N^Z /=/ 4 N 0 //	218	N -(5-methyl-6-(3-methyl-2-oxo2.3-dihydro-1 H-imidazoi-1 yl)pyridin-3-yl)-1 -(quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
/^N \\ ¹ N^N^>k _f F Il 1 ⁰ \0^F /007 H Γ b 0=4 Ny°	219	N-(5-cyano-6-(2H-l,2,3-triazol- 2-yl)pyridin-3-yl)-1 -(2- methylbenzo[d]oxazol-4-yl)-5(trifluoromethyl)- lH-pyrazole-4carboxamide
/^N \\ / N'^Ny,_N -0 0 F / \=A II Cl N^\ / ^F .__/ ^H / = \ L _zN—ό N ^N^Z \—7	220	l-(2-chloroquinolm-4-yl)-N-(5cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide

Structure	Cpd No.	Cpd Name
Λ=Ν _F / m Fx / F Vⁿe % ? T \~y ye E\ Eu Cl	221	ïV-(5-chloro-6-(2H-l,2,3-triazol- 2-yl)pyridin-3-yl)-1 -(2- chloroquinolin-5-yl)-5- ( trifluoromethyl )-1 H-pyrazole-4carboxamide
/^N \\ ¹ N^N\^N f H η O \Uf ^Cl ' nEEu ^E Q, NH N	222	N-(5-chloro-6-(2H-l,2,3-triazol2-yl)pyTidin-3-yl)-l-(lHpyrazolo[3,4-d]pyrimidin-4-yl)5-( trifluoromethyl)-IH-pyrazole4-carboxamide
u eu YE O IZ Eo // ti fl z_x JE/ z y n 1 t Eu UU^z^	223	N-(5-cyano-6-(2H-l,2,3-triazol- 2-yl)pyridin-3-yl)-1 -( 1,6naphthyrid m-4-yl )-5 - (trifluoromethyl·)-1 H-pyrazole-4carboxamide
'U'^e ^x^-N N F ni o ^FU Il 1 il 7^f n^^UESE/· E^z ?—ç Z N Ez/	224	ïV-(5-cyano-6-(4methylpiperazin-1 -yl)pyridin-3yl)- l-(quinolin-5-yl)-5- (trifluoromethyl)-I//-pyrazole-4carboxamide

Cpd I

Cpd Name

Structure

p ^N \ Π I ^{0 F}Y 'b—Υς JJ F f N YY f/ \ ^H T —y y Υ^Ζ /=4 b N u_f	225	N-(l-methyl-lH-pyrazolo[3,4b]pyridin-5-yl)-1 -(quinolin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
ΛΝ Ci ΥγΥ e P il) ° r^Î Lq II J ___ N D-Y, /\ H î /J—ά à ( / Yo	226	N-(5-chloro-6-(2H-1,2,3-triazol2-yl )pyridin-3-yl)-1 -( 2-methyl-1 oxo-1,2-dihydroisoquinolin-5yl )-5-( trifluoromethyl)- 1Hpyrazole-4-carboxamide
/-C 4 Yb u ^N \\ L Yy YYnY 7 Y ^H Y A=\ Y )yY F '_F // X---N	227	N-(5-chloro-6-(5-cyano-1Hl,2,3-triazol-l-yl)pyridin-3-yl)1 -(quinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
“Y Y Y Y ° ΧΛ-νΥ /ⁿYY CF ¹¹ / % Ys	228	2-(2-chIoro-4-( 1 -(quinolin-5-yl)5-(trifluoromethyD-1 H-pyrazole4-carboxamido)phenyl)-2H1,2.3-triazole-4-carboxylic acid

Structure \|	Cpd \| No. i	Cpd Name \|
z CP xz )=o O T	229	N-( lH-pyrazolo[3,4-b]pyndin-5yl )-1 -(quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
/ij z R O	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)-1 H-pyrazole-4carboxamide
a t'// \ z—z w² ÏZ oC z Ά C jfj	231	1 -(benzo[d][ 1,2,3]thiadiazol-4yl)-N-(5-chloro-6-(2H-l,2,3triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl)-1 H-pyrazole-4carboxamide
^zp) z y^z W \=o rCz z. / z \	232	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-l-(2methylthieno[3,2-b]pyridin-7yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide

Structure	Cpd No.	Cpd Name
/^N ί .A _x N F ^F ii i o y? N Xcii\ f/ \\ ^H X / \ / X N—/ O N	233	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1- ( imidazof l ,5-a]pyridin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
0 Ny W / / \X-Άί, xi HO \X^N\ F I H ^{0 F}Y ciOa Ot /— » γγγ^Λ G	234	l -(3-chloro-5-( l -( quinolin-5-yl)5-( trifluoromethyl)-1 H-pyrazole4-carboxamido )pyridin-2-yl)- l H-1,2,3-triazole-4-carboxylic acid
nOy f jy ° ^Fy oAyt, OL ^F _ ' ⁿ c5^T5 yy Z N Y //	235	N-(5-methoxy-6-(lH-l,2,3triazol-1 -yl)pyridin-3-yl)-1 (quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
ο θ ^FA^F yn yo ^h=ⁿ— ^h y y> x y	236	N-(4-aminobutyl)-3-cyano-5-( 1 (isoquinolm-4-yl)-5(trifhjoromethyl)-lH-pyrazole-4carboxamido)picolinamide
F py/^F 9\ o \| Π f ΛγΠ\ ΑΛνΛλ ^H0 ΚΛΟνγ N	237	2-cyano-4-(l-(quinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamido)benzoic acid

Structure	Cpd No. i	Cpd Name \
/^N /—<\ । / X-X HiN XXX L J Π ° F^/ ^sJVxT5 w	238	N-(4-(4-(aminomethyl)-1Hpyrazol-1 -yl)-3-methylphenyl)l-(quinolin-5-yl)-5- ( tri fluoro methyl)-1 H-pyrazole-4carboxamide
N o 1' Α^αΟα fJ A ^- 1 p o XL—f Y n Nx JJ / \___( Ν^γΑ // \\ ^H T N---(/ ) ⁷⁼¹⁷	239	N-(5-cyano-6-(2H-1,2,3-triazol2-y 1 )pyridin-3-yl)-1 -( 1 -methyllH-indazol-4-yl)-5- (trifluoromethyl)-lH-pyrazole-4carboxamide
F F ZX N—x ^FX U L v /—\ b=^N\ #Όι 'τΧ XU M \ / o	240	N-(5-methyl-6-( 1 -methyl-1Htetrazol-5-yl )pyndin-3-yl)-1 (quinolin-5-yl)-5- (trifluoiO methyl)-1 H-pyrazole-4carboxamide
/X F 4^zXA fi T OAA- 4Αχ. χθ\ ✓X N \ nj—X / X h \ / xx n X— ' r— \ ^N N \ \ L N—- X	241	N-( 5-cyano-6-(2H-1,2,3 -triazol2-yl)pyridin-3-yl)-1 -( 1 -methyllH-pyrazolo[3,4-b]pyridin-4-yl)5-(trifluoromethyl)-1 H-pyrazole4-carboxamide
/ \ ^F n ^x A θ ^τΑ / H ü / ^F N'—'. ¹ *^z Αχ?¹ A_A	242	N-(5-chloro-6-(2H-1,2,3-triazol- 2-yl)pyTⁱdm-3-yl)-l- (imidazo[ 1,2-b]pyridazin-6-yl)5-( trifluoromethyl)-1 H-pyrazole4-carboxamide
Ζχ Cl ° F «Οχχ ^n/ /X_/ χ/Χ ⁰ ^x---N_____________	243	N-(5-chloro-6-(2H-1,2,3-triazol2-yl ipyrid in-3-yl)-1 -( 1 methoxyisoquinolin-5-yl)-5( trifluoromethyl)-1 H-pyrazole-4carboxamide

Structure \|	Cpd i No. \|	Cpd Name
Ύ y n Y%J θ' ^N VY F Γ X1 iî X^e 1 \ / XX w	244	2-(2-chloro-4-(l-(quinolin-5-yl)- 5-(trifluoromethyl)-1 H-pyrazole- 4-carboxamido)phenyl)-2H- 1,2,3-triazole-4-carboxamide
z Y ^z\ // ^x\ z—z (/ xz X^O U Z* Z /	245	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 2 methylbenzo[d]thiazol-4-yl)-5( trifluoromethyl)-1H -pyrazole-4carboxamide
Y /-_N / 11 N HjN y\ F X ΐ ii 7 αΥγΙχ >γ ^F /-\ h ^N XX w	246	1 -(3-chloro-5-(l -(qumolin-S-yl)- 5-(trifluoromethyl)-1 H-pyrazole- 4-carboxamido)pyridin-2-yl)- 1 H-1,2,3-triazole-4-carboxamide
r=^N n / ^v Y \\ * XZ^N^SX S^Y F—X ^ΥλΝ ,N n ^z A // Ύ F F \_Y	247	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(2methylbenzo[d]thiazol-7-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
NA / ^ ψ Cl rA J il ⁰ Y^F H.N^ ^N%lk Jl / » ιΧχχ X\ X/ⁿ	248	N-(6-(5-(aminomethyl)-1Hl,2,3-triazol-l-yl)-5chloropyridin-3-yl)-1 -(quinolm5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

methyl l-(3-chloro-5-(l(quinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamido)pyridin-2-yl)-1Hl ,2,3-triazole-4-carboxylate

N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-l(imidazo[ l ,2-a]pyrimidin-5-yD5-(trifluoromethyl )-1 H-pyrazole4-carboxamide

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

Cpd Name

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

| Structure

Cpd No.

Cpd Name

253

254

256

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

N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(2-methyl[ l ,2,4]triazolo[ l ,5-a]pyridin-5yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide

3-(3-cyano-5-(l-(quinolin-5-yl)5-(trifluoromethyl )-1 H-pyrazole4-carboxamido)pyridin-2-yl)-1 methyl-lH-pyrazole-5carboxylic acid methyl 2-(2-chloro-4-( l (quinolin-5-yl)-5( trifluoromethyl )-lH-pyrazole-4carboxamido)phenyl )-2H-1,2,3triazole-4-carboxylate

N-(5-cyano-6-(2-methyl-2H1.2,3-triazol-4-yl)pyridin-3-yl)1 -(quinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide

Structure	cpd ; No.	Cpd Name
Ο ^XoU\ F F J H Ο A; crVA A / ^H IM > ^A \=/ Aⁿ	258	methyl 3-chloro-5-(l-(qutnoIm5-yl)-5-(trifluoromethyl)-1Hpyrazole-4- carboxamido)picolinate
N AN । । Z l F VU o U GA ΓΑ n A\A 7 H / X,___/ At / \ Ak A N	259	N-(5-cyano-6-(2H-l,2,3-triazol2-yl)pyndin-3-yl)-1 -( 1 -methyllH-pyrazolo[3,4-c]pyridin-7-yl)5-(trifluoromethyl)-1 H-pyrazole4-carboxamide
N V 0_x . A A A-A \r I A A /\\ ¹ ,^N~^N V /A Anh An / \\ ^N nA j AA fA // / F F AA	260	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 -methyllH-indazol-7-yl)-5- (trifluoromethyl)-1 H-pyrazole-4carboxamide
An F i AAA ,^f H Ί O F~A Il ί n Af Ci-^AAr^jA^J^ r, \ ^H l /^N \ /—^F Ai /A ⁿa7	261	N-(5-chloro-6-(2H-1,2,3-triazol- 2-yl)pyTidin-3-yl)-1 -(5fluoroquinolin-8-yl)-5(trifluoromethyl)-lH-pyrazole-4carboxamide

Structure	Cpd No. j	Cpd Name
/^N N^^N^N f ni ° \0^F ^Λαa A ^HNx 0 N	262	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 )-1 H-pyrazole-4carboxamide
F K /^E Ον/ 1 X jV N \\ z0 N'X^k ^H =N / // F X?	263	N-(5-cyano-6-(2H-1,2,3-tiiazol2-yl)pyridm-3-yl)-l-(4fluoroisoqumolin- l-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
Cl 0\ 3 Ά F0/^F L 'N-0 \\ 0 il ^N V/^0 k 1 1 O \=N	264	N-(5-chloro-6-(2H-1,2,3-triazol- 2-yl)pyridin-3-yl)-1 -( 1 fluoroisoquinolin-4-yl)-5(trifluoro methyl )-1 H-pyrazole-4carboxamide
F V / 0^ N-N 0k 4 L An 4^F⁷A/~X/( ^N ΧΛn Vn w F__________	265	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 -methyl1 H-pyrazolo[3.4-b]pyridin-3-yl )5-(trifluoromethyl )-1 H-pyrazole4-carboxamide
fJv^f _n-n n °w X JLA. 5=0 ^N~A \\0 N \ A 007/~™0 /	266	N-(5-cyano-6-(2H-l ,2,3-triazol2-yl )pyridin-3-yl)-1 -( 1 -methyllH-indazol-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
\ o. N~._x, -o^z ^A-% _F / U-J ? A ^N^ x γ\_/Λ ⁿ r=< W	267	methyl 3-(3-cyano-5-(l- (quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamido)pyridin-2-yl )-1 methyl-1 H-pyrazole-5carboxylate

Structure :	Cpd J No. \|	Cpd Name
z Fl J/ HZ X⁰ AJ z, AA-t. z I I Tl Ti	268	N-(5-cyano-6-( 1-methyl-1Hpyrazol-3-yl)pyridin-3-yl)-1 -( 8fkioroquinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
A_x FY-n an Ά \ nA / \—<_x ' I JJ V ^N 0 / yl fA Vⁿ F ^F	269	N-(5-cyano-6-(2H-l,2,3-triazol- 2-yl)pyridin-3-yD-1-(1,5- naphthyridin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
Yv F /' x / n \/^F \ J HO \Af ^{N N}+>F À / ⁷ N Al ΙΛ A^z aa V^N	270	N-(5-chloro-6-(5((dimethylamino)methyl)-1Hl,2,3-triazol-l-yl)pyridin-3-yl)l-(quinolin-5-yl)-5- ( trifluoro methyl)-1 H-pyrazole-4carboxamide
N ^X\_ V A o-WJ a Va N n=/ Y—A^{7 N N} F An o-4^	271	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(2methylbenzo[d]oxazol-7-yl)-5( trifluoro methyl )-1 H-pyrazole-4carboxamide
/^N /-----\\ ¹ H.N ^Ν^^ΝΥ^ΝΝ p ^F ......^uAü (\ N	272	N-(6-(4-(aminomethyl)-2H1,2,3-triazol-2-yl)-5chloropyridin-3-yl)-1 -(quinolin5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide

η

Structure

Cpd No,.	Cpd Name \|
273	N-( 5-chloro-6-( l -methyl-1Hpyrazol-3-yl)pyridin-3-yl)-1 -(8fluoroquinolin-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4carboxamide
274	l-([ l,2,4]triazolo[ l,5-a]pyridin5-yl)-N-(5-cyano-6-(2H-l,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoro methyl )-1 H-pyrazole-4carboxamide
275	N-(5-cvano-6-(2H- 1,2,3-triazol2-yl)pyridm-3-yl)-1 - (imidazo[ 1,2-a]pyrazin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4carboxamide
276	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1,7naphthyridin-4-yl )-5 - ( trifluoromethyl )-lH-pyrazole-4carboxamide

277

N-(5-chloro-6-(2H-l ,2,3-triazol2-yl)pyridin-3-yl)-1 -( 2fluoroquinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide

278 l-(2-aminobenzo[d]thiazol-7-yl)N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-5( trifluoromethyl)-1 H-pyrazole-4carboxamide

Structure	Cpd I No. \|	Cpd Name
Cl F F « _N Z Ο⁷ Z \ A χ ΖΛ \ D Z^N N—A y—NH k_vzx// \\ Ά N A-y j AA o On	279	N-(5-chloro-6-(2H-1,2,3-triazol2-yl )pyridin-3-yl)-1 (isothiazolo[5,4-b]pyridm-3-yl)5-(trifluoromethyl )-1 H-pyrazole4-carboxamide
ΑΛ ⁿ=\ fJ/^F P/^N p-NH )_ ί l A~^ y_z/ ⁿ Οι Z O \^N 4 0 N	280	N-(5-cyano-6-( 1 H-pyrrol-1 yl)pyridin-3-yl)-1 -(quinolin-5yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
/ \ F ⁿ ⁿacⁿa o f-J _F ΟΛΟΛ^Ζ / ^N cr	281	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 methoxyisoquinolin-5-yl)-5(trifluoro methyl )-1 H-pyrazole-4carboxamide
N_x ^xX\ fP^f OP A-oP-z P^AA N—' 0\/N ^S \ o _Nh₂	282	l-(2-aminobenzo[d]thiazol-7-yl)- N-(5-cyano-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-5- ( trifluoromethyl)-lH-pyrazole-4carboxamide
An G । Y/Ν n _F ^F Ii P 04 Z\Z Z / f F^\ ^' 'γ+'Χ // G F ^H L /^N \ / AA Vaⁿ	283	N-(6-( 1 H-1,2,3-triazol-1 -yl)-5( trifluoromethyl)pyridin-3-yl )-1 (quinolin-5-yl)-5- ( trifluoromethyl )-1 H-pyrazole-4carboxamide
F A n/ y Ό Γχ Z^ H ZZ Cl ____	284	l-(benzo[d]isoxazol-3-yl)-N-(5chloro-6-(2H-l,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoro methyl )-1 H-pyrazole-4carboxamide

Structure ;	Cpd No.	Cpd Name I
Y N Cl \\ ¹ 1 *Yr< 1 _c N F F 1 H ° Y F Νχ JL II / /“b h r \—7 y—ci o	285	N-(5-chloro-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 chloroisoquinolin-4-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
/Y N^x^N _F F J i i? Ÿ^F Y H 14 /Y H 1 —Ç \\ HN Ù N	286	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1Hindazol-7-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
«u. U. \| 1 4 ^AY/ z rjj ° \ zx b v	287	N-(5-bromo-6-( 1 H-1,2.3-triazol1 -yl)pyridin-3-yl)-1 -(quinolin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
rjj 0=7 zx Y zY □ 4u°	288	N-(5-chloro-6-(oxazol-2- yl )pyr idin-3 -yl)-1 -( 8- fluoroquinolin-5-yl)-5- (trifluoromethyl )-1 H-pyrazole-4carboxamide
Z—Z yj ü- __i 1 z^Yq z^ T U	289	N-(5-cyano-6-(2H-1.2,3-triazol2-yl)pyridin-3-yD-1 -( 1 fluoroisoquinolin-4-yl)-5( trifluoromethyl)-lH-pyrazole-4carboxamide

100

Structure \|	Cpd i No. \|	Cpd Name \|
/=N vA^N\ fJ _f N Μ, o '0' A oL JL A ⁿ~~s cr n γΜΝ // ) H l /^N \0\ A^N aj	290	l-(benzo[d]isothiazol-3-yl)-N(5-chloro-6-(2H-1.2,3-triazol-2yl)pyridin-3-yl)-5- ( trifluoromethyl )-1 H-pyrazole-4carboxamide
Λ=^Ν F 4 ^FxCF ^N Ai j ? r Α^ΑνΑζ,^α j _Nc H L / \C —N / \ /N j# F	291	N-(5-cyano-6-(2H-l,2,3-triazol2-yl )pyridin-3-yl)-1 -( 2fl uoroqu ino lin- 5 -y 1 )- 5 (trifluoromethyl)-1 H-pyrazole-4carboxamide
/^N ΛΑΟ N—^y	292	N-(5-cyano-6-(2H-1,2,3 -triazol2-yl)pyridin-3-yl)-l-(furo[2.3d]pyrimidin-4-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
\ <\1 F I/o ^F^/ ci^xmA A τ' ^f N fi—λ ^H A /^N—\ / ^Ν^ζ V=/ % <N N	293	1 -(benzo[d][ 1,2.3]thiadiazol-7yl)-N-(5-chloro-6-( 1 -methyl-1Hpyrazol-3-yl)pyridin-3-yl)-5(trifluoro methyl )-1 H-pyrazole-4carboxamide
/^N \\ ¹ _N-N _N F n i ° Ά^F A A n —\ ^H L A \ ^N ^ν^ζ JA ^ν<^⁸	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)-lH-pyrazole- 4-carboxamide

101

Structure	Cpd j No. \|	Cpd Name
z FJ Y Z^zy sz X=o Z„ / X-n z \ 1 T) X Y²·	295	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yI)-l-(2methylimidazo[ 1.2-a]pyridin-3yl)-5-( trifluoromethyl )-1Hpyrazole-4-carboxamide
ZI \\\ \ // ^x\ z—z y!/ sz y 7 Λ JT z jy/ z y’’⁰ yS -= z^	296	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(quinazolin4-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamide
z\ ,UQ no y/^'-z m I ^JJF ru 0=7 0 y ¥ (/ / z z	297	l-(benzo[d]thiazol-4-yl)-N-(5cyano-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
F'N Q ^N X-Fx Z' F J 7 ^{0 F}y <f>^\yx 7 yf N ΧΧ\ A—λ ^H L o \ / y^z ^NX/^S	298	l-(benzo[d]thiazol-4-yl)-N-(5cyano-2-methyl-4-(2H-1,2,3triazol-2-yl)phenyl)-5- (tri fluoro methyl )-1 H-pyrazole-4carboxamide
oVy/ U-F F o^g o z,-, X Y Y z F r FJ/ z, x'	299	N-(6-(4-amino-2H-1.2,3-triazol- 2-yl)-5-chloropyridin-3-yl)-l- (benzo[d]thiazol-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4- 1 carboxamide____________________

102

Structure	Cpd ! No.	Cpd Name
Ο tf / ° 04, i -ri	300	l-(benzo[d]thiazol-4-yl)-N-(2,5dimethyl-6-(2H-1,2,3-triazol-2yl)pyndin-3-yl)-5- (trifluoromethyl)-lH-pyrazole-4carboxamide
. ^z3 xz: \=:O Ου z / CO^_Z Y>> / n \ \ΐ J l·	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 )-1 H-pyrazole-4carboxamide
/Ύ N^NXYX-F F Il 1 o F—J χ J i Y~-f ciOO_nAJ γ-y H y \ Y ? ^4 /=\ V/ ^F	302	N-(5-chloro-2-fluoro-4-(2Hl,2,3-triazol-2-yI)phenyl)-l-(8fluoroisoquinolin-4-y l)-5 (trifluoromethyl )-1 H-pyrazole-4carboxamide
A^N Vk y / / n o f~y_ Π ij /~^F c । ΥγΥ _N Υγγ\ JJ y h n—y / Y / \—-J ^N /\ Y o^N N	303	l-(benzo[d][l,2,3]thiadiazol-7yl)-N-(5-chloro-2-methyl-6-( 1Hpyrazol-1 -yDp yndin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4carboxamide
ΥΝ ci —\\ 1 1 J. p Y^xs R / Il i ° γο ⁿ JJ J ⁹ LJn-ΛΛ γγ Vyⁿ	304	N-(5-chloro-6-(4-methyl-lH- 1.2,3-triazol-1 -yl)pyridin-3-yl)- 1 -(quinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide

103

Structure	Cpd No.	Cpd Name
A —N \ F x Vx p i N % 0 ^lA, I jj / F ___ // \\ H 1 /^N \-=/ An /A / N A	305	N-(5-methyl-6-(2-methyI-2Htetrazol-5-yl)pyridin-3-yl)-1 (quinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
Q \ z-z HZ 0=0 ZA 7 z_x 0/ ^xz /Ί Ζχ/Α Z=\0	306	l-(benzo[d\|thiazol-4-yl)-N-(5chloro-6-(2H-l,2,3-triazol-2yl)pyridin-3-yl)-5- ( trifluoromethyl )-1 H-pyrazole-4carboxamide
Cl n-n \ o 0 Faa\ 5a/a ^N N^Z Ax II ^{F F} AA	307	N-(5-chloro-6-(2H-tetrazol-5yl)pyridin-3-yl)-1 -(quiiiolin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
<\ i Ν^ΝΧχΝ F Il । ° \A^f nAA, 00 ^A VA Aⁿ	308	N-(5-cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 8fluoroquinolin-5-yl)-5(trifluoromethyl )-1 H-p yrazole-4carboxamide
An 0 A F Il j o fA A Λ i / f cr W0,-A / ,—. ^N W\ // w ^H L Fa / 00 v/	309	N-(5-chloro-6-(2H-1,2,3-tnazol4-yl)pyndm-3-yl)-1 -(quinolin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide

104

Structure	Cpd ! No. j	Cpd Name
z A, h. 1 \ A --/ Z /yj ° \ zx zH rX\ yy z	310	N-(5-cyano-6-(2H-] ,23-triazol2-yl)pyridin-3-yl)-1 -(3methylthieno[3.2-b]pyridin-7yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
An F il I ° A^^F /“A ^H L /^N—\ / YY Ν,.γ	311	1 -(benzo[d]oxazol-4-yl)-N-(5cyano-6-(2H-l,2,3-triazol-2- yl)pyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
^zX Z-Z A- IZ A° mz \ n	312	N-(5-cyano-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-1 -(4fluoronaphthalen- l-yl)-5( trifluoromethyl )-1 H-pyrazole-4carboxamide
/x QQ U- T Ü-^J\ Ζ_χ/χχ oA ZI ^o=X / ^z	313	methyl 2-cyano-4-( 1 -(quinolin-5yl)-5-( trifluoromethyl)-1Hpyrazole-4carboxamido)benzoate
An f ^F il 1 ° \A^F N N f/ \\ ^H Γ \—A / ^N⁷ YY ^Sx ->^N ___________________________N	314	1 -(benzo[d][ 1,2.3]thiadiazol-7yl)-N-(5-cyano-2-methyl-6-(2H1,2,3-triazol-2-yl)pyridin-3-yl )5-(trifluoromethyl)-1 H-pyrazole4-carboxamide

105

Structure	Cpd ! No. i	Cpd Name
A=N F / i F v t'A n fZ. N X A 0 ‘ /AF L 1 J X AXmXZ J! n z h \ ^NXx Z ^H Z ^z vz ^N / \ ^S\Z	31:5	N-(5-cyano-6-(2H-1,2,3-triazol2Z)py^ncbⁿ-3-yl)-l-(thieno[3,2d ] pyri midin-4-y 1 ) - 5 (trifluoromethyl )-1 H-pyrazole-4carboxamide
Z^N \\ ¹ FtX\ F Il J 0 X Ad^l II /~^Fn ΑΧ Λ λ ^H L /^N—\ / x^z zO N^S	316	1 -(benzo[d]thiazol-4-yl)-N-(5cyano-6-(2H-1,2,3-triazol-2yj )pyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
Z^N f b A-·-.. AA--Z θ ^{1 F} _-N n X Ί χ ! Z <\ AXn^v ⁿ^ \ Z ^{C1 H} x rV	317	N-(5-chloro-2-methyl-4-(2H- 1,2,3-triazol-2-yl)phenyl)-1 -(8fluoroisoquinolin-4-yl)-5(trifluoro methyl)-1 H-pyrazole-4carboxamide
Z^N \\ ¹ Z Z-. / F H 'l ⁰ X X X II Z^F c> ZA\_mA 7 .—. ^N Z\ Z Z H [ N@ L— X^z Vn A	318	N-(5-chloro-2-methyl-6-(2H- L2,3-triazol-2-yl)pyridin-3-yl)- 1 -(7-methylpyrazolo[ 1,5- a]pyridin-4-yl)-5- (trifluoro methyl )-1 H-pyrazole-4carboxamide
^f Jd ^{0 F}f^F F Χ^'^Χ^^Ν'⁷ΧΧ_χ f/ \\ F ^H \| nZ Xn XJ ---------------------Z--	319	1 -(pyrazolo[ 1,5-a]pyndm-4-yl)5-(trifluoromethyl)-N-(2(trifluoromethyl)pyridin-4-yl)1 H-pyrazole-4-carboxamide

106

Structure SE I Cpd Name . No. i

“Π \πί “n'y IZ E° z^EJ z / ^-n JL H 03 T	320	l-(8-fluoroisoquinolin-4-yl)-5( trifluoromethyl)-N-( 2(trifluoro methyl )pyridin-4-yl)1 H-pyrazole-4-carboxamide
z^ LL \| LL^J Z rp ©E y z-z \_ h ' © E^z	321	N-(5-chloro-2-methyl-6-(2Hl,2.3-triazol-2-yl)pyridm-3-yl)l-(thieno[2,3-c]pyridin-4-yl)-5( trifluoromethyl)- lH-pyrazole-4carboxamide
/==N Cl Z l \| 'F V Jx C / p N M A o ^N A_NAU Γ yA ^N O	322	N-(5-chloro-6-(2H-l ,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 (dimethylamino)isoquinolin-4yl)-5-(trifluoromethyl)-lHpyrazole-4-c arbo xam i de
/=N Cl Z \ i f I o ê^fτ Π Ή / zE / N<xAx,/\/\ // V-NH u v /ⁿAe ⁿ /E	323	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 (methylamino)isoquinolin-4-yl)5 -(tri fluoromethyl)-1 H-pyrazole4-carboxamide
ci ^F F /3 \ F—V ίΐ ï E /E \ X 3/ L /-χ Eu UnE i U λ-/ I U U EVh	324	N-(5-chloro-6-(2H-1,2,3-triazol2-yl )pyridin-3-y 1 )-1 -( 8-fluoro-1 (methylamino)isoquinolin-4-yl)5-(trifluoromethyl)-1 H-pyrazole4-carboxamide
/AN Z l F N χΝ F, / p n e U ° E H J: H / ^-N / n^Έ^ν\,A Έn^hH l /^NE / Λ G // E-f	32:5	N-(5-cyano-6-(2H-1,2.3-triazol2-yl)pyridin-3-yl)-1 -( 8-fluoro-1 (methylammo)isoquinolin-4-yI)5-(trifluoromethyl)-1 H-pyrazole4-carboxamide

107

Structure _XP Cpd Name i >o.

A YyAV* N/ F. 7 ο /Ap A^{N N} F t A	326	l-(8-aminoquinolin-5-yl)-N-(5cyano-6-(2H-1,2,3 -triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-lH-pyrazole-4carboxamide
An nA Y l'A F JJ l P ^FA cA\A, JI F F H >A A L 7~\ Ύνη, N YY O	327	1 -( 1 -aminoisoquinolin-4-yl)-N(5-chloro-2-fluoro-4-(2H-1,2,3triazol-2-yl)phenyl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
z_v Y Z'^Z» 17 >O Va z^ z\—ⁿ Z Z X ____	328	1 -( 1 -aminoisoquinol in-5-yl)-N(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl )-1 H-pyrazole-4carboxamide
A^=bÎ ^F NH, vsa p ^fV^f V V^V \ j W N C=_N / /1	329	l-(2-aminoquinolin-4-yl)-N-(5cyano-6-(2H-1.2,3 -triazol-2yl)pyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
[V /A 'V Y^N L AL Y-NH A A II ^N A-P / W^A / A L il ^NHi ^Cl F F	330	1 -( 1 -aminoisoquinolin-5-yl )-N(5-chloro-6-(2H-l,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-lH-pyrazole-4carboxamide

108

Structure	Cpd No. \|	Cpd Name
/¾ N Cl 7 il n \|\| ⁰ .x 'Fr'Y /=λ ^f1 FF //-^. iy	331	l-(2-aminoquinolin-5-yl)-N-(5chloiO-6-(2H-l,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl )-1 H-pyrazole-4carboxamide
Asn <\ ’ F X .N N^ F, / * y y ⁰ / ^r J \ N = H N—\\ / y \ L N y N H,	332	1 -(2-ammoquinolin-5-yl)-N-(5cyano-6-( 2H-1,2,3 -triazol-2- yl)pyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
\ 71 vlv o y_F il / r^N ΛΧ„ΧΑ // V^NH’ ^C1 h yyF —ⁿ / \ U	333	1 -( 1 -aminoisoquinolin-4-yl )-N(5-chloro-2-methyl-6-( 1 -methyllH-pyrazol-3-yl)pyridin-3-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
Λ=^Ν Z \ F Y .n. .by .x / ^N Y Ί il 7—F Il 1 II / /—^N /AF\Z\A 7 'X _NHz « U /yl —’^N / \ w	334	1 -( 1 -aminoisoquinolin-4-yl)-N(2,5-dimethyl-6-(2H-l,2,3triazol-2-yl)pyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
r-i Z Z ^ζφθ \ ^J—[—/ z 1JJ u ..-	335	1 -( 1 -aminoisoqu inolin-4-yl)-N(5-chloro-2-methyl-4-(2H-1,2,3triazol-2-yl)phenyl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide

109

Structure	Cpel No.	Cpd Name
« η q z-z O IZ \ 7=0 Y < Y< 1 z X l-j	336	l-(l-aminoisoquinolin-4-yl)-N(5-chloro-2-methyl-6-( 1Hpyrazol-1 -yl)pyridin-3-yl)-5( trifluoromethyl)-1 H-pyrazole-4carboxamide
z zO) yJ ΞΖ ' 4° m Ύ^,ζ J tj θφ § to	337	1 -( 1 -aminoisoquinol in-4-yl)-N(5-cyano-2-methyl-4-(2H-1,2,3triazol-2-yl)phenyl)-5- ( trifluoromethyl )-1 H-pyrazole-4carboxamide
A=N Z ' F V ..N. _r, / N AS γ O I J Λ / Y Unh₂ Y ^H U b \=/ ^N / \ Y#	338	1 -( 1 -aminoisoquinolin-4-yl)-N(5-cyano-2-methyl-6-(2H-l,2,3triazol-2-yl)pyridin-3-yl)-5- ( trifluoromethyl )-lH-pyrazole-4carboxamide
CM I Z Y LL 1 u. \ o=/ ZI A~U- U- H	339	1 -( 1 -aminoisoquinolin-4-yl)-5 (trifluoromethyl)-N-(2- ( trifluoromethyl )pyridin-4-yl)- 1 H-pyrazole-4-carboxamide
Z xz b=o Oy 'z PH ii Ou z I ΓΌ	340	1 -( 1 -aminoisoquinolin-4-yl )-N(2-cyanopyridin-4-yl)-5- ( trifluoromethyl)-lH-pyrazole-4carboxamide

110

Structure	Cpd NO. ;	Cpd Name \|
ο z z-z X IZ \ Co A Z /Ti 1 -n CÔ Z T ND	341	1 -( 1 -aminoisoquinolin-4-yl )-N(5-chloro-2-methyl-6-(4-methyl2H-1,2,3-triazol-2-yDpyridin-3yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
F A4 y A F n =00 ^N F H 1 ^N \ / ^NH2 0' 0=(	342	1 -( 1 -aminoisoquinolin-4-yl)-5(trifluoromethyl)-N-( 5(trifluoromethyl)pyridin-3-yl)- 1 H-pyrazole-4-carboxamide
CM Z Z w LL 1 iL^y z o=/ \ zz X z-z L // ' ⁰⁰0/Z	343	1 -( 1 -aminoisoqinnolm-4-yl )-N(5-bromo-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
o A \ Z—Z A IZ A T Z 30/ -n X	344	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1-(2-oxo-1,2dihydroquinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
-=000 F ^F 1 il ° 40 aa_njî/ 00 h k 0-0 k 00 0 0° t—NU	345	N-(5-chloro-6-methoxypyridin3-yl)-1-( 1-oxo-1,2dihydroisoquinolin-5-yl)-5(trifluoro methyl)-1 H-pyrazole-4carboxamide

111

Structure	C pd Νο.	Cpd Name
ζ \ξ ζΖ \=ο r—Λ /ΑΛ / /*Tj Ζ / 1 “Π ζ. /^Α χΛΓ ο	346	N-(5-cyanopyridin-3-yl)-l-( 1οχο-1,2-dihydroisoquinolin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
/—ζ \ 4 æz Α=Ο %Λζ Ζ \ ‘π 1 'Π ζ ο	347	N-(2-methylpyridm-4-yl )-1 -( 1 oxo-1,2-dihydroisoquinolin-5yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
Π \ ΓΠ Π ξ / çy τζ Οο Ο 7 ζ /C/ 'ζ Ι'-π 1 τι Ου “/ι ο	348	N-(6-methyl-5- (tnfluoromethyl)pyridm-3-yl)-1 ( 1 -oxo-1,2-dihydroisoqumolin-5yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
ο ζ\ JO ÇO il \| υ_Α ζ Aj ο ο ΖΙ υ ζ=/	349	1 -( 1 -oxo-1,2-dihydroisoquinolin- 5-yl)-N-(pyridin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
Ο QQ LL ] U-Λ Ζ 0=0 ΖΙ υ ζ=/	350	N-(2-cyclopropylpyridin-4-yl)-1 (1 -oxo-1,2-dihydroisoquinolin-5yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide

112

Cpd

351

3-chloro-N-methyl-5-( 1 -( 1 -oxol,2-dihydroisoquinolin-5-yl)-5(trifluoro methyl )-1 H-pyrazole-4carboxamido)picolinamide

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

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

Cpd Name

3-chloro-N,N-dimethyl-5-( 1 -( 1 oxo-1,2-dihydroisoquinolm-5yl)-5-(trifluoromethyl)-1Hpyrazole-4carboxamido)picolinamide

113

Structure	Cpd No. i	Cpd Name \|
o A \ 2=0 yA IZ /=o Oa z: /n I Tl Ou iv o	355	methyl 3-chloro-5-( 1 -( 1 -oxo-1.2dihydroisoquinolin-5-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamido)picolinate
O F-O U00 Jf / F N'' N '-U r, x H L ^N \ / A' 00 Ah	356	N-(2-cyanopyridm-4-yl)-1 -( 1 oxo-1,2-dihydroisoquinolin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
o 01 Ou LL J llO z_v o=/ zi _n LL ___/ / ~ AVcU LL V=_z	357	N-(2-(2-methoxyethoxy)-5(trifluoromethyl)pyridin-3-yl)-l( 1 -oxo-1,2-dihydroisoquinolm-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-caiboxamide
An ⁿ'ⁿvA _f J ° F-V ci-AA 11 A f _zo n AU .—1/ H \\χ// \ L _NH ^N /A VQ	358	N-(5-chloro-2-methyl-6-(2H- 1.2_!3-triazol-2-yl)pyridin-3-yl)- 1 -(2-oxo-1,2-dihydroquinolm-4yl)-5-(trifluoromethyl)- 1Hpyrazole-4-carboxamide

114

Cpd

Cpd Naine

Structure

o ^11 _ _z__zΛ J=o zMo Z /'“Π 1 -p 00 o	359	N-(5-chloro-2-methyl-6-(4methyl-2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -( 1 -oxo-1,2dihydroisoquinolin-5-yl)-5( trifluoromethyl)- lH-pyrazole-4carboxamide
Y o xx Âï i II ^z LL \| LL, / z zi 0 o /	360	N-(2-methoxypyridin-4-yl)-1 -( 1 oxo-1,2-dihydroisoqumolin-5yl)-5-( trifluoromethyl)- 1Hpyrazole-4-carboxamide
o XX JO Ou LL ] u.Y z /0 ~^zu- yj o=/ ZI Ci D '-o	361	N-(2-morpholinopyridin-4-yl)-l( 1 -oxo-1,2-dihydroisoquinolin-5yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
z .. y O IZ \ Oo Mo Z /Yn 1 Ou lY °	362	N-(5-chloro-2-methyl-6-(4methyl- i H-1,2,3-triazol-1 yr)pyridin-3-yl)-1 -( 1 -oxo-12dihydroisoquinolin-5-yl)-5(trifluoromethyl )- lH-pyrazole-4carboxamide
o xx JkX l· Il ^z LL ] U__\ Z /U Y \\ Il oO ZI z \ vO uj	363	N-(5-(2H-l ,2,3-triazol-2yl)pyridin-3-yl)-1 -( 1 -oxo-1,2dihydroisoquinolin-5-yl)-5( trifluoromethyl)-1 H-pyrazole-4carboxamide

115

Structure	Cpd \| No. \|	Cpd Name
π -Π -n-V Α^ζ Ο χζ j=o Ζ 7Π \| ΤΊ	364	l-(thieno[2,3-c]pyridin-4-yl)-5(trifluoromethyl)-N-(2(trifluoro methyl )pyridin-4-yl)lH-pyrazole-4-carboxamide
Ί ο \ Η ΊJ ίχ. Τ X Ζ ΓΟ ο=/ ζχ X=Z ζ—ζ <7	365	N-(5-chloro-6-(2H-1,2,3-tnazol2-yl)pyridin-3-yl)-1 -( 1(tetrahydrofuran-2yl)isoquinolin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
/7 \\ / CI ^Ν'^ΝνΧ 1 0 F F // y-F N^\ / H AA /=N 0^ A ,-^N---4 V—/ i r >XX 0 '-—^y	366	1 -( 1,5-bis(tetrahydrofuran-2yl)isoquinolin-4-yl)-N-(5-chloro6-(2H-1,2,3-triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
O^J cVAA^Z Γ Γ H ^X z X ^gx5 y—z z—z Ak	367	1 -( 1 -( 1,4-dioxan-2yl)isoquinolin-4-yl)-N-(5-chloro6-(2H-1,2,3-triazol-2-yl)pyridm3-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamide
Ο r VA le J C- /=N / H 1 \. / \___/ A^AA-/ W	368	N-(5-chloro-6-(2H-1.2,3-triazol2-yl)pyridin-3-yl)-1-(1-(1ethoxyethyl)isoquinolin-4-yl)-5(trifluoromethyl )- lH-pyrazole-4carboxamide
Y N _cl ? Xf Xca ¹¹ νΧχχχ	369	N-(5-chloro-6-(2H-1,2,3-triazol2-yl )pyridin-3-yl)-1-( 1 -(5oxopyrrolidin-2-yl)isoquinolin4-y 1)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide

116

Structure \|	Cpd I No. !	Cpd Naine
A N _C1 V^NxA F Il η o n Λ II / + ν ûU \ / °	370	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 -(4oxotetrahydrofu.ran-2yl)isoquinolin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
/Ά Cl ^N vA ^F Il J 0 F-__/ ^N\A Λ /~^F^nAA /=\ / ^H X/pXc N 2---( OH	371	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)py^ridin-3-yl)-l-( 1 -( 1 hydroxyethyl)isoquinolin-4-yl)5-(trifluoromethyl )-1 H-pyrazole4-carboxamide
An ci \\ ’ 1 AxO ^f Il i ° ^FZ ^NxZx Z / ^FnAA ΛΛ ^H U ΔΡζ/ n /—\ w \—o	372	A⁷-(5-chloro-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-1 -(2(tetrahydrofuran-2-yl)qumolin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
A^N Cl \\ 1 i V^N\Zx F Π i f? ^FZ n A A^F nvà /=n h L /^N—4 //—\ ^H ^N⁷ y—K nZ O ⁷ '°	373	N-(5-chloro-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 -((Nmethylformamido)methyl)isoqui nolin-4-yl)-5-(trifluoromethyl)1 H-pyrazole-4-carboxamide

117

Structure	Cpd ) No. I	Cpd Name
/= N Cl Ta ï À X° z \A. Ζχ ^H N—G N 0	374	N-(5-chloro-6-(2H- L2,3-triazol2 -yl)pyridin-3-yl)-1 -(2-( 1 hydroxyethyI)quinolin-4-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
O r ^f \ Ί h ^fAp x° N Jl ! / AA ” Qz	375	l-(2-acetylquinolin-4-yl)-N-(5chloro-6-(2H-1,2,3 -triazol-2yl )pyridin-3 -yl )-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
A z-z zZ îz ^Q IZ Xo zA 'Z Z^-01 Ή *ΧΖ\|/^Ζ y'O I ___	376	N-(5-chloro-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-1 -(7-( 1 hydroxyethyl)thieno[2,3- c]pyridin-4-yl)-5- (trifluoro methyl )-1 H-pyrazole-4carboxamide
AZ F aQ ^F F η\|Χ N-/” ^xXnH₂ ZZ	377	1 -( 1 -aminoisoqumolin-4-yl)-N(6-methyl-5- (trifluoromethyl)pyridin-3-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
/^M Cl 4AÀ n A • 1 ^f N I y NH F—L _F AzA x /zz⁰4 //\ V—·Ν	378	1 -( 1 -acetylisoquinolin-5-yl)-N(5-chloro-6-(2H-l,2,3-triazoI-2- yl)pyridin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide

118

Structure	Cptl No.	Cpd Name
Λ Z—Z AU zzz	379	1 -( 1 -(azetidin-2-yl)isoquinolin4-yl)-N-(5-chloro-6-(2H-l,24triazol-2-yl )pyridin-3 -yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
A U u.,__! Z l~~M ^xz - UJ z= S-V^ Z—Z A^	380	N-(5-chloro-6-(2H-1,24-triazol2-yl)pyridin-3-yl)-1 -( 1 (pyrrolidin-2-yl)isoquinolm-4yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
A=N Cl _c / l I f V MU /X _n F—4 N Μ θ /^^F ^N .. VA j L fi X 7X4 ⁿ A VJ HN—	381	1-(2-( azetidin-2-yl)quinolin-5yl)- N-(5-chloro-6-(2H-l,24triazol-2-yl)pyridin-3-yl )-5 - (trifluoromethyl )-1 H-pyrazole-4carboxamide
4¾ N _C\| <\ ¹ ï V^N\Jx F XV ii । ° ^F—/L OVk Λ v / A? A/ N /—\ U/	382	1-(2-( azetidin-2-yl)quinolin-4yl)-N-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyndin-3-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide

119

Structure	Cpd No. :	Cpd Name \
I A Qu x Γ * AJ Z—Z Y ' Z—Z Jz	383	/er/-butyl 2-(5-(4-((5-chloro-6(2H-1.2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5- ( trifluoromethyl)-1 H-pyrazol-1 yl )isoquinolin-1 -yl)azetidine-1 carboxylate
Cl rY Λά Q T ^7 u ^N 4aa x FI Y A A ' /'u Ac nA^x t / ° A /. 1 y A/'N ^H	384	1 -( 1 -(azetidin-2-yl)isoquinolin5-yl)-N-(5-chloro-6-(2H-1,2,3tnazol-2-yl)pyridin-3-yl)-5(trifluoromethyl Y1 H-pyrazole-4carboxamide
AV Cl N^NxJx ^f il i ° ^fA n A, U / f ^A^>k A\ ^H XI A N )--Ç OU	385	N-(5-chloro-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 (hydroxymethyl)isoquinolin-4yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
J* J nⁿxJu ^F °, J i 9 SQ V-nh, n _-A IJ / F / n” A Ux ^H L. /^N—I /^N^n^z v—/	386	4-(4-((5-chloro-6-(2H-1,2,3- triazol-2-yl)pyridin-3- yl)carbamoyl)-5- (trifluoromethyl)-l H-pyrazol-1 - yl)quinoline-2-carboxamide
O u Va ^f Il i ° f-J n, A, II Af ^-ΆΑα, aⁿ\ /P ^H C M\ n >—ς nh₂	387	4-(4-( (5-chloro-6-(2H-1,2,3triazoI-2-yl)pyridin-3yl)carbamoyl)-5- ( trifluoromethyl)-1 H-pyrazol-1 vl)isoquinoline-1 -carboxamide

120

Structure	Cpd No. i	Cpd Name
F Cl _FE^F AU \ θ i Æ U AZ ? Th ⁿ lEs ^Vn MEo h₂n	388	5-(4-((5-chloro-6-(2H-1.2,3triazol-2-yl)pyridin-3yl)carbamoyl)-5- ( trifluoromethyl)-1 H-pyrazol-1 yl)quinoline-2-carboxamide
/an Cl <\ ' I \-^NU> Y] F /U / AA _nhF^J I / F YeE\_N_AA Y / Y/ A b\ A—n nh₂	389	5-(4-((5-chloro-6-(2H-1.2,3triazol-2-yl)pyridin-3yl)carbamoyl)-5- (tri fluoro methyl )-1 H-pyrazol-1 yDisoquinoline-1 -carboxamide
^Y z-z z/ pY IZ E° Y T z. aj i υΧχ z Ά© I ___	390	4-(4-((5-chloro-6-(2H-l ,2,3triazol-2-yl)pyridin-3yl)carbamoyl)-5- ( trifluoromethyl)-1 H-pyrazol-1 yl)-N-methylisoquinoline-1 carboxamide
?Έ Cl V^A 71 η o F-y N M U /F ΈΑΕ /=N. P ^H L Y/H N NH₂ Y^s	391	4-(4-((5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)carbamoyl)-5- (trifliioro methyl )-1 H-pyrazol-1 yl)thieno[2,3-c]pyridine-7carboxamide
/Έ Cl V 1 U1Y /=n o ^H L Ύ /A F—\ NH E?s ^/	392	4-(4-((5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)carbamoyl)-5- (trifluoromethyl )-1 H-pyrazol-1 yl)-N-methylthieno[2,3c]pyridine-7-carboxamide

121

Cpd Name

Structure

Cpd No.

y y F II η o f-J N X II FF I nXF\ /=n o ^{1 H} L -^N a FF N FF NH₂ FF	393	4-(4-((5-chloro-2-methyl-6-(2H- l,2,3-triazol-2-yl)pyridm-3- yl)carbamoyl)-5- ( trifluoromethyl)-1 H-pyrazol-1 yl )thieno[2,3-c]pyridme-7carboxamide
/Y Cl V^N _VX F ii η o fx n II Ff /=\ / ^H L z^NX /U ^N o ^F	394	N-(5-chloro-6-(2H-l,2,3-triazol2-yl )pyridin-3-yl)-1 -(1 (difluoromethyl)isoquinolin-4yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
Z. ,X Çu “ T IN u. y___!j o=g zs ô-X~^ F=z z—z o	395	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-l-(2(difluoromethyl)quinolin-5-yl )5-(trifluoromethyl )- IH-pyrazole4-carboxamide
v—* zu Vf ² zz 7=0 O T •z τι -n x / 1 ÔO	396	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-l-(4( difluoromethyl )qu ino lin-5 -yl )5-(trifluoromethyl )-1 H-pyrazole4-carboxamide

122

Structure	Cpd ; No.	Cpd Name \|
/0 _C1 N -0 0 F N /-=0. F il 1 ° ^H~0 ^NV 0. Il 0F '000 /=\ F ^H Aⁿ~v_/X Aⁿ	397	N-(5-chloro-6-(2H-1,2,3-triazol2-yl )pyridin-3-yl)-l -(8(difluoromethyl)quinolm-5-yl)5-(trifluoromethyl )-1 H-pyrazole4-caiboxamide
0 f¹ ^X0N_x 0 F N F Il i ° ^F=0 N 0 II / ^F N00 0^Νχ 7 ¹¹ X xC_X~4 0/	398	N-( 5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-l-(7(difluoromethyl)thieno[2,3c]pyridin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
/0 Cl 0N Xx F N 0==0 F lï 1 ° ^F0( N ^1 II (0 F H 0 \,_/ \ U /Λ/ N )---/ 0 S [00-	399	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(2(difluoromethyl)thieno[2,3c]pyridin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
/=N Cl 00 J (L t NH FÀ _c 1 / F Î0 0N F	400	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 (difluoromethyl)isoquinoliii-5yl)-5-(tnfluoromethyl)-lHpyrazole-4-carboxamid

123

Structure	Cpd ! No.	Cpd Name
/A Cl N A V F F A A A KAA /A ^H N0 N ' n	401	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridm-3-yl)-1 -(2(difluoromethyl)quinolin-4-yl)5-( trifluoromethyl)-1 H-pyrazole4-carboxamide
u. x zAy^zV œ A A A ^z Lu H___IJ ZI ^A~/ Z—Z /0	402	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1-(1-(1,1difluoroethyl)isoqumolin-4-yl)5-( trifluoromethyl)-1 H-pyrazole4-carboxamide
G r V ^-N 1 ^K Va ^F il i ° ^faL N -f II /Ά UU /=\ A ^H L ^/N—\\ A—\/^NH N 2 (	403	1 -( 1 -(azetidin-3-yl)isoquinolin4-yl)-N-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridm-3-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
O Zj η IX 1 u. Λ___!j zx ûA^V Az ζ—z u	404	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1-( 1 (methoxymethyl)isoquinolin-4yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide

124

Structure	Cpd No.	Cpd Name
Y* Cl ^VnA y ^NY A y^f _ n γ#, UY ^H L· /^N—v χ-θ’ Y' \—z	405	4-(4-((5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)carbamoyl)-5- ( trifluoromethyl )-1 H-pyrazol-1 yDquinoline 1-oxide
bx «x /x. Z Xp X> LL \| u-U z yO oY zz ô-Y^ z-z Çz	406	4-(4-((5-chloro-6-(2H-1.2,3triazol-2-yl)pyridin-3yl)carbamoyl)-5- (trifluoromethyl )-1 H-pyrazol-1 yl)isoquinoline 2-oxide
^C‘A · ^N''4^nhF-U _F ⁰ Y )—\ G // ^N⁺b-	407	5-(4-((5-chloro-6-(2H-l,2,3- tnazol-2-yl)pyridin-3- yl)carbamoyl)-5- ( trifluoromethyl)-1 H-pyrazol-1 yl)isoquinoline 2-oxide
b +’ Y\/^Z Çu LL \| u_Y z bO oY zz /=z z-z A'z	408	5-(4-((5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)carbamoyl)-5- (trifluoromethyl )-1 H-pyrazol-1 yl)quinoline 1-oxide

125

Structure	Cpd ! No. \|	Cpd Mime
O0 Cl \..^N O F N Χυχχ F Il / 0 fY Ο- Υ Y /F / ^H L /^N—k # Ç_s	409	4-(4-((5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3yl)carbamoyl)-5- (trifluoromethyl )-1 H-pyrazol-1 yl)thieno[2,3-c]pyridine 6-oxide
θ'ζΥ<^ΜnX? LL \| LL Y Z IN LL V__!J O=/ ZI Ü--F^_ z-z Ç'z	410	4-(4-((5-chloro-2-mcthyl-6-(2Hl,2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5- ( trifluoromethyl)-1 H-pyrazol-1 yl)thieno[2,3-c]pyridine 6-oxide
F? _VY y-z / I ri? z y— cj II ^z _______	411	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 cyanoisoquinolin-5-yl)-5(tri fluoro methyl)-1 H-pyrazole-4carboxamide
z—z xz 2=0 Γ0 J Z / -n 1 Oil xx Z χ z	412	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-l-(2cyanoquinolin-4-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
FO Z il ' ^Z Z / zrA Q S TZ r y~A y 4 —-/O J^⁷	413	N-(5-chloro-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-1 -(2cyanoquinolin-5-yl)-5(tnfluoromethyl)-1 H-pyrazole-4carboxamide

126

I Structure i	1 Cpd Name No. \| . 1
An ci VA Il η o fa N /4 U / F /=^NX ^H L ^N \\ /)—~^N Z Va	414	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 cyanoisoquinolin-4-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
An ci Τι η o fa nZ 11 Zf /=n H I N—G /)—=^N	415	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridm-3-yl)-1 -(7cyanothieno[2,3-c]pyridin-4-yl)5-( trifluoromethyl)-IH-pyrazole4-carboxamide
z ii z Az LL \| z rij oZ ZI ô-Z~^_ /Z z-z Çz	416	N-(5-chloro-2-methyl-6-(2Hl,2.3-triazol-2-yl)pyridin-3-yl)l-(7-cyanothieno[2,3-c]pyridin4-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
A Z—Z AA 22 Pzz z z·” Z ¹	417	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(2methoxyqumolm-4-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
I Graz zx LL 1 U—J Z A oZ ZI ô-Z~7 V^zz-z a	418	N-(5-chloro-6-(2H-1,2,3-triazol2-yI )pyridin-3-yl)-1 -( 2-oxo-1,2dihydroquinolin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4carboxamide

127

128

Structure	Cpd No.	Cpd Name j
Λ f π η o fC n_vA h Vf / VAJ, H I NA )=o V' /=\	423	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(2-methyl-1 oxo-1,2-dihydroisoquinolin-4yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
V^NyA F N.A i/ CF ^WX /=N ^H I N—(y /ACl	424	N-(5-chloro-6-(2H-1,2,3-tnazol2-yl)pyridin-3-yl)-1 -(7chlorothieno[2,3-c]pyridin-4-yl)5-( trifluoromethyl)-1 H-pyrazole4-carboxamide
jzj z^W u- \| ^z TM '^z LL W___/J OH ZT 4 z-z \, // ' 4 ^z	425	N-(5-cyano-6-(2H-l,2,3-triazol2-yl)pyridin-3-yl)-l- (pyrazolof 1,5-a]pyrazin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
Λ ? ⁿ'ⁿvL ^f ii η o fU n.A II Vf n Ό-Α /V. I h I nA Λ—ci a yj V^s	426	N-(5-chloro-2-methyl-6-(2Hl,2,3-triazol-2-yl)pyridin-3-yl)l-(7-chlorothieno[2,3-c]pyridin4-yl )-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
A _CI An I N W, F il η o f./ N ,-J. M’F ^nAA /=n /^,-oh ^H L /^N—w //—^N j	427	(R)-N-(5-chloro-6-(2H-1,2,3triazol-2-yr)pyridin-3-yl)-1 -( 1 - (3-hydroxypyrrolidin-1 - yl)isoquinolin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide

129

Structure	Cpd No.	Cpd Name ^s
h 0 9 A Il I H / f ^z ' - //x N^x H ^N—\ / z/ / \ / Xo Z- N H	428	N-(5-cyano-6-methoxypyridin-3yl)-1-( 1-oxo-1,2dihydroisoquinolin-5-yl)-5- ( trifluoromethyl)-lH-pyrazole-4carboxamide
O r XZ F il 7 o F-Z n ^A II /^F n'-'A^A z=\ H A \·__/ \__c A A \	429	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -( 1 - (methylthio)isoquinoIin-4-yl)-5(trifluoromethyl )-1 H-pyrazole-4carboxamide
<A ?' N'^NA. f ii η o fJ n M il Z^F 'ZZ-X /=^N. zX H L ^N \\ // \/^OH Z' Zf z^s	430	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(7-(3hydroxyazetidin-1 -yl)thieno[2,3c]pyridin-4-yl)-5- (trifluoromethyl)-l H-pyrazole-4carboxamide
ZN Cl XZ ^f Τι η o fX N_x X M Z^F nu N'Z /Z^OH ^H L ^N # ^N J Z' A/^s	431	(S)-N-(5-chloro-6-(2H-I,2,3triazol-2-yl)pyridin-3-yl)-l-(7(3-hydroxypyrrolidin-1 yl)thieno[2,3-c]pyridin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
A ?' N'^NAx F ii η o fZ n_xA 11 Zf _ni, /=n /-v ^H u/-A^A x^s	432	(R)-N-(5-chloro-6-(2H-l,2,3triazol-2-yl)pyridin-3-yl)-1 -(7(3-hydiOxypyrrolidin-1 yl)thieno[2,3-c]pyridin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
/Z Cl N'^NA F Il η o fX n_xz ii Z^F AA x ^{1 H} L ^N \\ z^N\z ^OH 4^3	433	N-(5-chloro-2-methyl-6-(2Hl,2.3-triazol-2-yl)pyridin-3-yl)1 -( 7-( 3 -hy droxyaze tidin-1 yl)thieno[2,3-c]pyridin-4-yl)-5( trifluoromethyl)-1 H-pyrazole-4carboxamide

130

Structure	Cptl No.	Cpd Name
y Ν'Υ,Ο F Τη o f-O J U / F /=n ^H Z ^N~i y ^N / \ FF	434	N-(5-chloro-6-(2H-1,2,3-triazol- 2-yl )pyridin-3-yl)-1 -( 7methylthieno[2,3-c]pyridin-4yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
y çi Ογό F ί ] o F-F NF II FF ^rAJ, 7=n ^H Z y /JF n Y—y FF	435	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1-(7cyclopropylthieno[2,3-c]pyridin4-yl)-5-(trifluoromethyl)-1 Hpyrazole-4-carboxamide
Oï ¹ N ' V..F Il i ^{0 F}-F n A. Il F^F ' 2-/0. /=N 0 FF	436	(*R)-N-(5-chloro-6-(2H-l,2.3- triazol-2-yl )pyridm-3-yl)-1 -( 1- (tetrahydrofuran-2- yl)isoquinolin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
Cz pO z 7=° Yf 7 ''z y2~Ti J m xFff w 1 O o	437	(*S)-N-(5-chloro-6-(2H-1.2,3triazol-2-yl)pyridin-3-yl)-1 -( 1 ( tetrahydrofuran-2yl)isoquinolin-4-yl)-5- (trifluoro methyl )-1 H-pyrazole-4carboxamide
F N Cl OfOx F p η ^{0 f}F N J II F^f ^H tbyyzA n y—< '-^N \ / °	438	(*R)-N-(5-chloro-6-(2H-1,2.3triazol-2-yl)pyridin-3-yl)-l-(l(4-oxotetrahydrofùran-2yl)isoquinolin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide

131

Cpd

Cpd Name

Structure

A CI VaA _F 0) ^{0 F}A N II 0F AU A\ _z0 AA Q	439	(’ S)-N-( 5-chloro-6-(2H-1.2,3triazol-2-yl)pyridin-3-yl)-1 -( 1 (4-oxotetrahydrofuran-2yl)isoquinolin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide
/A Cl n-aX 7 7 η o ^fâ ⁿG 1 V^F ⁿ AA. AA ^H L /ⁿaa N /— \ w	440	(*R)-N-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-1 -(2(tetrahydrofuran-2-yl)quinoIin-5yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
An ci ii η o fA N A A / ^F n AA AA ^H L '^N A ? N 00 U^N Va	441	CS)-N-(5-chloro-6-(2H-l,2,3triazol-2-yl)pyridin-3-yl)-l-(2( tetrahydrofuran-2 - y 1) qu i nol in- 5 yl )-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide
<V ? 0x0 F II η o f0 n A il Uf AAX /A / ^H U >A //A N y—Y OH 4a	442	( 'R)-N-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-l-( 1( 1 -hydroxyethyl)isoquinolin-4- yl )-5-( trifluoromethyl)-1H- pyrazole-4-carboxamide

132

Structure	Cpd No.	Cpd Name
A Y ci V I N F Il I ° Ά A A. U / F ^n^A /=\ ? ^H U T ~A_/A\ N /—/ OH	443	(*S)-N-(5-chloro-6-(2H-l,23triazol-2-y l)pyrid in-3 -yl)-1 -( 1 ( 1 -hydroxyethyl)isoquinolin-4yl )-5-( trifluorometh yl)-1Hpyrazole-4-carboxamide
Y Cl UA ΥΊ _f n A / NH F—A_c I / ^FθΧΑχΛ A A. p^h \\ // *r\ W-n ^x	444	(*2?)-N-(5-chloro-6-(2Y-l,2,3triazoI-2-yl)pYdin-3 -yl)-1 -( 1 ( 1 -hydroxyethyl)isoquinolin-5yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
Cl F Y A A^F ίϊΊ C _Z ^N y J N H / Α ''Ί^Χ' A \ A AA \ T //W Va	445	(*S)-N-(5-chloro-6-(2H-l,2,3triazol-2-yl)pyridin-3-yl)-1 -( 1 ( 1 -hydroxyethyl)isoquinolin-5yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamide
N Y^n III V\A N AA\ f Ai ° fA a 1 / ^F Y AA Z \--NH	446	N-(5-cyano-2-methyl-4-(2H- 1.2.3-triazol-2-yl)pbenyl)-1 -( 1 oxo-l,2-dihydroisoquinolin-5yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide
_ΖΆΑ VO U. Y LL Y Z TA '^z LL. W___IJ oA zx T z-z C^z °	447	N-(5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-l-(thieno[2,3c]pyridin-4-yl)-5- ( trifluoromethyl)-1 H-pyrazole-4carboxamide

133

In a further embodiment, the invention is directed to a compound of Formula (I)

Formula (I) selected from the group consisting of

134

7V-(2-cyanopyridin-4-yl)-l-(naphthalen-l-yl)-5-( trifluoromethyl)-///-pyrazole-4carboxamide;

A-(5-chloro-6-(27/-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(naphthalen-l-yl)-5-( trifluoromethyl)7Æ-pyrazole-4-carboxamide:

l-(naphthalen-l-yl)-5-(trifluoromethy4)-A'-(2-(tnfluoromethyl)pyridm-4-yl)-7H-pyrazole4-carboxamide;

l-(naphthalen-l-yl)-5-(trifluoromethyl)-A-(5-(trifluoromethyl)pyridin-3-yl)-7//-pyrazole4-carboxamide;

A^r-(5-cyanopyTidin-3-yl)-l-(naphthalen-l-yl)-5-( trifluoromethyl)-77/-pyrazole-410 carboxamide;

l-(quinolm-5-yl)-5-(trifluoromethyl)-A⁷-(2-(trifluoromethyl)pyridin-4-yl)-7?7-pyrazole-4carboxamide;

AH5-chloro-6-methoxypyridin-3-yl)-l-(quinolin-5-yl)-5-(trifluoromethyl)-777-pyrazole-4carboxamide;

jV-(5-chloro-6-(2if-1.2.3-tfiazol-2-yl)pyridin-3-yl)-]-(quinolin-5-yl)-5-( trifluoromethyl)7//-pyrazole-4-carboxamide;

A-(5-chloro-6-(22M,2.3-triazol-2-yl)pyridin-3-yl)-l-(3-methylisoquinolin-l-yl)-5(trifluoromethyl)-777-pyrazole-4-carboxamide;

A^r-(3-chloro-4-methoxyphenyl)-l-(isoqumolin-8-yl)-5-(trifluoromethyl)-///-pyrazole-420 carboxamide;

A43-chloro-4-(2H-l,2,3-triazol-2-yl)phenyl)-l-(isoquinolin-8-yl)-5-(trifluoromethyl)-7/7pyrazole-4-carboxamide;

_iV-(3-chloro-4-(7H-pyrazol-l-yl)phenyl)-l-(isoqulnolin-8-yl·)-5-(trifluolΌmethyl)'-7A7pyrazole-4-carboxamide;

A⁷-(6-cyaiio-5-(trifluoromethyl)pyridin-3-yl)-l-(isoquinolin-8-yl )-5-( trifluoromethyl)-///pyrazole-4-carboxamide;

A⁷-(4-(2-aminopyrimidin-4-yl)-3-chlorophenyl)-l -(isoquinolin-8-yl)-5-(trifluoromethyl)7Z/-pyrazole-4-carboxamide;

135 /V-(5-chloro-6-(/Æ-pyrazol-l-yl)pyridin-3-yl)-I-(iso^ trifluoromethyl)-IHpyrazole-4-carboxamide; jV-(5-chloro-6-(2 H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-isobutyl-1 -(quinolin-5-yl)-/Hpyrazole-4-carboxamide;

y-(5-_Chloro-6-(2/7-1.2,3-triazol-2-yl)pyridin-3-yl)-5-ethyl-1 -(quinolin-5-yl)-7Æ-pyrazole4-carboxamide;

N-(3-chloro-4-(l H-1,2,3-triazol- l-yl)phenyl)-l-( isoquinolm-8-yl)-5-(trifluoromethyl)-/77pyrazole-4-carboxamide;

A-(5-cyano-6-(2//-1,2,3-triazol-2-yl)pyTidin-3-yl)-l-(isoquinoIin-8-yl)-5-( trifluoromethyl)10 777-pyrazole-4-carboxamide;

iV-(5-chloro-6-( 1,1 -dioxidoisothiazolidin-2-yl)pyridm-3-yl)-1 -(isoquinolin-8-yl)-5( trifluoromethyl )-7H-pyrazole-4-carboxamide;

A-(5-chloro-6-( 1 -methyl-77/-pyrazol-3-yl)pyridin-3-yl)-1 -(isoquinolin-8-yl)-5( trifluoromethyl)-7//-pyrazole-4-carboxamide;

A-(5-chloro-6-(oxazol-2-yl)pyridiii-3-yl)-l-(isoquinolin-8-yl)-5-(trifluoromethyl)-7Hpyrazole-4-carboxamide;

AA5-chloro-6-methoxypyridin-3-yl)-l-(isoquinolin-4-yl)-5-(trifluoromethyl)-72/-pyrazole4-carboxamide;

A^r-(5-cyano-6-methoxypyndin-3-yl)-l-(isoquinolin-4-yl)-5-(trifluoiOmethyl)-7/7-pyrazole20 4-carboxamide;

AU5-chloro-6-(27/-l,2,3-triazol-2-yl)pyridjn-3-yl)-l-(3-fluoroquijiolin-5-yl)-5(trifluoiOmethyl)-72/-pyrazole-4-carboxamide;

A^?-(5-chloro-6-(277-l,2,3-triazol-2-yl)pyridin-3-yl)-5-isopropyl-l-(quinolin-5-yl)-777pyrazole-4-carboxamide:

iV-fS-chloro-ô-UÆ-l^J-triazol^-yllpyridm-S-yll-Hô-methylquinolin-S-yO-S( trifluoromethyl )-7/7-pyrazole-4-carboxamide;

A⁷-(5-chloro-6-(277-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(8-methylqumolin-5-yl)-5(trifluoromethyl)-777-pyrazole-4-carboxamide;

136

Aⁱ-(3-chloro-4-(3-rnethyl-//f-1.2,4-triazol-l-yl)phenyl)-l-(isoquinolin-8-yI)-5(trifluoromethyl )-7//-pyrazole-4-carboxamide;

A45-chloro-6-(3-methyl-/H-l;2,4-triazol-l-yl)pyridm-3-yl)-l-(isoqumolm-8-yl)-5(trifluoromethyl )-/Z/-pyrazole-4-carboxamide:

M(3-_chloro-4-(5-methyl-//f-l,2,4-triazol-l-yl)pheiiyl)-l-(isoqumolin-8-yl)-5(trifluoromethyI)-777-pyrazole-4-carboxamide;

A^r-(5-chloro-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(isoquinoiin-4-yl)-5(trifluoromethyl)-/77-pyrazole-4-carboxamide;

A-(5-chIoro-6-(27/-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(4-methylisoquinoIin-8-yl)-510 ( trifluoromethyl )-7À/-pyrazole-4-carboxamide;

l-(benzoftiran-4-yl)-A-(5-chloro-6-(22/-L2,3-triazol-2-yI)pyridin-3-yl)-5(tri fluoro methyl )-/H-pyrazole-4-carboxamide ;

Λ^5-chloro-6-(2Æ-l,2,3-triazol-2-yl·)pyridm-3-yl)-5-(l-methoxyethyl)-l-(qulnolin-5-yl)7//-pyrazole-4-carboxamide;

A^r-(5-chloro-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(6-methylisoquinoliii-4-yl)-5(trifluoromethyl )-/Æ-pyrazole-4-carboxamide:

A/5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(2-methylquinolin-5-yl)-5( trifluoromethyl )-7Æ-pyrazole-4-carboxam ide;

AX3-chloro-4-(2//-1.2,3-triazol-2-yl)phenyl)-l-(isoquinolm-4-yl)-5-(trifluoromethyl)-/f720 pyrazole-4-carboxamide;

AC(5-chloro-6-(2/M,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-l-(quinoIin-5-yl)-7/A pyrazole-4-carboxamide;

ïV-(5-chloro-6-(27/-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoroquinoliii-5-yl)-5(trifluoromethyl)-/Z/-pyrazole-4-carboxamide;

_xV-(6-cyano-5-fluoropyridin-3-yl)-l-(isoquinolin-4-yl)-5-(trifluoromethyl)-7//-pyrazole-4carboxamide;

A^r-(5-chloro-6-(l J-dioxidoisothiazolidin-2-yl)pyridin-3-yl)-l-(isoquinolm-4-yl)-5(trifluoromethyl)- 7Æ-pyrazole-4-carboxamide;

137

A⁷-(3-chloro-4-( ZH-l,2,3-triazol-l-yl)phenyl)-l-(isoquinolin-4-yl)-5-(trifluoromethyl)-ZHpyrazole-4-carboxamide:

methyl 3-chloro-5-(3-chloro-5-(l-(isoquinolin-4-yl)-5-(trifluoromethyl)-///-pyrazole-4carboxamido)picolinamido)picolinate;

,V-(5-chloro-6-((l-methylpiperidiii-4-yl)oxy)pyridin-3-yl)-l-(isoquiiiolin-4-yl)-5(trifluoromethyl)-ZH-pyrazole-4-carboxamide;

/V-(5-chloro-6-(/H-pyrazol-l-yl)pyridin-3-yl)-l-(isoquinolin-4-yl )-5-( trifluoromethyl)-ZHpyrazole-4-carboxamide;

A/5-cyano-6-(2H-l,2,3-tnazol-2-yl)pyridm-3-yl)-l-(isoquinolin-4-yl)-5-(trifluoiOmethyl)/H-pyrazole-4-carboxamide;

À/5-chloiO-6-(4-methylpiperazine-l-carbonyl)pyridin-3-yl)-l-(isoqumolin-4-yl)-5(trifluoromethyl)-ZH-pyrazole-4-carboxamide;

A46-cyaiio-5-(trifluoromethyl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5-(trifluoromethyl)-ZHpyrazole-4-carboxamide;

/V-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-l-(ïsoquinolin-4-yl)-5-(trifluoromethyl)-/Hpyrazole-4-carboxamide;

xV-(3-chloro-4-(5-methyl-/H-1,2,4-triazol-1 -yl)phenyl)-1 -( isoquinolin-4-yl)-5(trifluoromethyl)-/H-pyrazole-4-carboxamide;

,V-(5-chloro-6-(l-methyl-/H-pyrazoI-3-yl)pyridin-3-yl)-l-(isoquinolm-4-yl)-5(trifluoromethyl)-/H-pyrazole-4-carboxamide;

ïV-(5-chloiO-6-(3-methyl-/H-1.2,4-triazol-l-yl)pyridin-3-yl)-l-(isoqumolm-4-yl)-5(trifluoromethyl)-/H-pyrazole-4-carboxamide;

V45-diloro-6-(5-methyl-/H-l,2,4-triazol-l-yl)pyridin-3-yl)-l-(isoquinoliii-4-yl)-5( trifluoromethyl )-/H-pyrazole-4-carboxamide;

/V-(3-chloro-4-(3-methyl-/H-l,2,4-triazol-l-yl)phenyl)-l-(isoquinolin-4-yl)-5(trifluoromethyl)-/H-pyrazole-4-carboxamide;

H-(5-chloro-6-(2H-L2.3-triazol-2-yl)pyridin-3-yl)-5-(difluoromethyl)-l-(ïsoqumolm-l-yl)ZH-pyrazole-4-carboxamide;

138 /V-(5-chloro-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(isoquinolin-l-yl)-5(trifluoiOmethyl)-///-pyrazole-4-carboxamide;

A4 4-(2-ammopyrimidin-4-yl)-3-chlorophenyl)-l-(isoquinolin-4-yl)-5-( trifluoromethyl)///-pyrazole-4-carboxamide:

A43-cyano-4-(2YL2,3-triazol-2-yl)phenyl)-l-(isoquÎnolin-4-yl)-5-( trifluoromethyl)-///pyrazole-4-carboxamide;

A^r-(5-chloro-6-(2//-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(quinolin-5-yl)-7J/-pyrazole-4carboxamide;

A^r-(5-fluoro-6-(27/-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(isoquinolm-4-yl)-5-(trifluoromethyl)10 7#-pyrazole-4-carboxamide;

/V-(3-cyano-4-(//7-l,2,3-triazol-l-yl)phenyl)-l-(isoquinolin-4-yl)-5-(trifluoromethyl)-//7pyrazole-4-carboxamide;

N-(5-chloro-6-(thiazol-2-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5-( trifluoromethyl)-///pyrazole-4-carboxamide;

A^r-(5-chloro-6-(2//-1.2.3-triazol-2-yl)pyridin-3-yl)-5-methyl-l-(quinolin-4-yl)-///pyrazole-4-carboxamide;

2V-(5-chloro-6-(2//-L2,3-triazol-2-yl)pyridin-3-yr)-l-(3-methylquinolin-5-yl)-5(trifluoromethyl)-7//-pyrazole-4-carboxamide;

A-(5-chloro-6-(2Z/-1.2,3-triazol-2-yl)pyridin-3-yl)-1 -( 1 -methylisoquinolin-4-yl)-520 (trifluoromethyl)-77/-pyrazole-4-carboxamide;

AY5-chloro-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(6-fhioroquinolm-7-yl)-5( trifluoromethyl )-7//-pyrazole-4-carboxamide;

xV-(5-chloro-6-(2//-l ,2,3-triazol-2-yl)pyridin-3-yl)-l-(7//-indazol-4-yl)-5(trifluoromethyl)-/Z/-pyrazole-4-carboxamide;

,V-(5-chloro-6-( 1,3,4-oxadiazol-2-yl)pyridin-3-yl )-1 -(isoqumolin-4-yl)-5-(trifluoromethyl)7//-pyrazole-4-carboxamide:

A-(5-chloro-6-(72/-imidazol-l-yl)pyridin-3-yl)-l-(isoqumolin-4-yl)-5-(trifluoromethyl)72/-pyrazole-4-carboxamide;

139

Ν-(β-(2Η-1,2.3 -triazol-2-yl )pyridi η-3-yl)-1 -(isoqumolin-4-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide;

A44-aminobutyl)-3-chloro-5-(l-(isoquinolin-4-yl)-5-(trifluoiOmethyl)-//7-pyrazole-4carboxamido)picolinamide;

l-(isoquinolin-4-yl)-A42-methyl-6-(trifluoromethyl)pyridin-4-yl)-5-(tnfluoromethyl)-///pyrazole-4-carboxamide;

methyl 6-chloro-4-( 1 -(isoquinolin-4-yl)-5-(trifluoromefhyl)-7//-pyrazole-4carboxamido)picolinate;

methyl 4-(l -(isoquinolin-4-yl)-5-(trifluoromethyl)-///-pyrazole-4-carboxamido)picolinate _JV-(5-chloro-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-7/7-pyrazole-4carboxamide;

A^z-(2-cyanopyridin-4-yl)-l-(isoquinoliii-4-yl)-5-( trifluoromethyl)-///-pyrazole-4carboxamide;

A45-cyano-6-(l-methyl-7H-pyrazol-3-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-515 (trifluoromethyl)-///-pyrazole-4-carboxamide;

7V-(5-chloro-6-cyclopropoxypyridin-3-yl)-l-(quiiioliii-5-yl)-5-( trifluoromethyl)-///pyrazole-4-carboxamide;

A^r-(5-cyano-6-((l-methylpiperidin-4-yl)oxy)pyridin-3-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl)-///-pyrazole-4-carboxamide;

7V-(5-cyano-6-ethoxypyridin-3-yl)-l-(quinolin-5-yl)-5-(trifluoromethyl)-7//-pyrazole-4carboxamide;

A45-cyanopyridin-3-yl)-l-(isoqumolin-4-yl)-5-(trifluoiOmethyl)-7Z/-pyrazole-4carboxamide;

7V-(5-cyano-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5-( trifluoromethyl)25 7//-pyrazole-4-carboxamide;

A^L(6-(4-ammobutoxy)-5-cyanopyridm-3-yl)-l-(isoqumolin-4-yl )-5-( trifluoromethyl)-7//pyrazole-4-carboxamide;

A^r-(5-cyano-6-methoxypyridin-3-yl)-l-(quinolin-5-yl)-5-(trifluoromethyl)-///-pyrazole-4carboxamide;

140 jV-(5-cyano-6-( 1H-1,2,4-triazol-1 -yl)pyridin-3-yl)-1 -(quinoJin-5-yl)-5-(trifluoromethyl )777-pyrazole-4-carboxamide;

A48-chloro-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl )-/Æ-pyrazole-4-carboxamide;

_zV-(5-cyano-6-cyclopiOpoxypyridin-3-yl)-l-(quinolin-5-yl )-5-( trifluoromethyl)-/77pyrazole-4-carboxamide;

A-(5-cyano-6-( 1 -methyl-7/7-pyrazol-3-yl)pyridin-3-yl )-1 -(qumolin-5-yl)-5(trifluoromethyl)-777-pyrazole-4-carboxamide;

AA-cyano-6-(277-l,2,3-triazol-2-yl)pyTidin-3-yl)-l-(thieno[3,2-c]pyridin-4-yl)-510 (trifluoromethyl )-7H-pyrazole-4-carboxamide;

A^z-(5-chloro-6-(oxazol-2-yl)pyridm-3-yl)-l-(quinolin-5-yl)-5-(trifluoiOmethyl)-7//pyrazole-4-carboxamide;

A^z-(5-cyano-6-(227-1,2,3-triazol-2-yI)pyridin-3-yl)-1 -(8-fluoroquinolin-4-yl)-5(trifluoromethyl)-7H-pyrazole-4-carboxamide:

]-(cinnolin-4-yl)-05-cyano-6-(27M,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)777-pyrazoIe-4-carboxamide:

A^r-(5-cyano-6-(277-1.2,3-triazol-2-yl)pyridm-3-yl)-l-(furo[3,2-c]pyridin-4-yl)-5(trifluoromethyl)-7/7-pyrazole-4-carboxamide;

ïV-(8-chloro-4-methyl-3-oxo-3,4-dihydro-277-benzo[b] [ 1,4]oxazin-6-yl )-1 -( quinolin-5-yl )20 5-( trifluoromethyl)-7/7-pyrazole-4-carboxamide:

iV-(5-cyano-6-(4-methylpiperazine-l-carbonyl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5( trifluoromethyl )-727-pyrazole-4-carboxamide;

A^z-(8-chloro-4-methyl-3-oxo-3,4-dihydiO-277-benzo[b][l,4]oxazin-6-yl)-l-(isoquinolin-4yl)-5-(trifluoiOmethyl)-7/Z-pyrazole-4-carboxamide;

xV-(5-chloro-6-(l-methyl-/77-imidazol-2-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl )-777-pyrazole-4-carboxamide;

A⁷-(5-cyano-6-(27/-l,2.3-triazol-2-yl)pyridin-3-yl)-l-(finO[2.3-c]pyridin-7-yl)-5( trifluoromethyl)- 7Æ-pyrazole-4-carboxamide;

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

iV-(6-(4-(4-aminobutyl)piperazine-l-carbonyl)-5-cyanopyridin-3-yl)-l-(isoqumolin-4-yl)5-(trifluoromethyl)-7//-pyrazole-4-carboxamide;

xV-(5-cyano-6-(2Z7-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(phthalazin-1 -yl)-5-(trifluoromethyl)7//-pyrazole-4-carboxamide;

iV-(5-cyano-6-(27/-1.2,3-tnazol-2-yl)pyTidin-3-yl)-l-(imidazo[l,2-a]pyrazm-8-yl)-5(trifluoromethyl)-7/7-pyrazole-4-carboxamide;

À^r-(5-chloro-6-(7Z7-imidazol-2-yl)pyridin-3-yl)-l-(isoqumolm-4-yl)-5-(trifluoromethyl)10 77/-pyrazole-4-carboxamide;

7V-(5-cyano-6-(277-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(quinoxalin-5-yl)-5-(trifluoromethyl)7 77-pyrazole-4-carboxamide;

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

/m-butyl 2-(5-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyI)-5(trifluoromethyl)-1 H-pyrazol-1 -yl)isoquinolin-1 -yDazetidine-1 -carboxylate;

N -( 3-(methylsulfonyl )-4-( 1 H-1.2,3 -triazol-1 -yl )phenyl)-1 -(quinolin-5-yl)-5( trifluoromethyl)-! H-pyrazol e-4-carboxamide;

l-(l,5-bis(tetrahydrofuran-2-yl)isoquinolin-4-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-220 yl)pyridin-3-yl )-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

Aq4-methy1-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazm-6-yl)-l-(qumolm-5-yl)-5( trifluoromethyl )-lH-pyrazole-4-carboxamide;

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

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

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

142 l-(2-(azetidm-2-yl)quinolin-5-yl)- V^r-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridm-3-yl)-5( trifluoromethyl )-lH-pyrazole-4-carboxamide;

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

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

AX5-methyl-6-(3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)pyridm-3-yl)-l-(quinolin5-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxamide;

AM2,5-diethyl-6-(2H-l,2,3-triazol-2-yl)pyndin-3-yl)-l-(imidazo[l,2-a]pyridm-5-yl)-510 ( trifluoromethyl)- lH-pyrazole-4-carboxamide;

N-(5-chloro-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(2-(difluoromethyl)quinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-methoxyquinolm-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide:

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

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-cyanoquinolin-5-yl)-520 (trifluoromethyl)- lH-pyrazole-4-carboxamide;

l-(2-methylimidazo[l,2-a]pyridm-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridm4-yl)-lH-pyrazole-4-carboxamide;

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

jV-(5-chloro-6-(2H-I,2,3-triazol-2-yl)pyridm-3-yl)-l-(2-chloroqumolin-5-yl)-5( trifluoromethyl )-lH-pyrazole-4-carboxamide;

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

143

5-(4-((5-chloro-6-(2H-l,2.3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-lHpyrazol-1-yl )quinolme-2-carboxamide;

A'-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl')-l-(lH-pyrazolo[3,4-d]pyrimidin-4-yl)5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide;

AA5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-l-(l,6-naphthyridin-4-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

AU5-cyano-6-(4-methylpiperazin-l-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5-( trifluoromethyl )177-pyrazole-4-carboxamide;

(*R)-N-(5-chloro-6-( 2/7-1.2,3-triazol-2-yl)pyridin-3-yl )-1-(1-(l-hydroxyethyl)isoquinolin10 5-yl)-5-(trifluoromethyl)-l/7-pyrazole-4-carboxamide;

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

(*A)-N-(5-chloro-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-(tetrahydro&ran-2yl)quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-chloro-6-(2-oxopyrrolidm-l-yl)pyridm-3-yl)-l-(isoquinolin-4-yl)-5( tri fluoromethyl )-1 H-pyrazole-4-carboxamide;

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

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yO-1 -(2-methyl-1 -oxo-1,220 dihvdroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide,

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

2-(2-chloro-4-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamido)phenyl)2H-l,2,3-triazole-4-carboxylic acid;

N-(lH-pyrazolo[3,4-b]pyridin-5-yl)-l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamide;

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

144 (*S)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(l-hydroxyethyl)isoqumolm5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(2-methylpyridin-4-yl )-1-( 1 -oxo-l,2-dihydroisoquinolm-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamide;

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

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

l-(l-(azetidin-3-yl)isoquinolin-4-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-510 ( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

N-(5-cliloro-6-(2H-L2.3-triazol-2-yl)pyridin-3-yl)-]-(imidazo[l,5-a]pyridin-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide;

l-(3-chloro-5-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazolc-4-carboxamido)pyridin2-yl)-lH-l,2,3-triazole-4-carboxylic acid;

N-(5-methoxy-6-( l H-1,2,3-triazol- l-yl)pyridm-3-y!)-1 -(quinolin-5-yl)-5-(trifluoromethyl)1 H-pyrazole-4-carboxamide;

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

N-(4-aminobutyl)-3-cyano-5-(l-(isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-420 carboxamido)picolinamide;

2-cyano-4-(l-(qumolm-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamido)benzoic acid

N-(4-(4-(ammomethyl)-lH-pyrazol-l-yl)-3-methylphenyl)-l-(quinolin-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide;

l-(2-aminoquinolin-4-yl)-N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-525 (trifluoromethyl)- lH-pyrazole-4-carboxamide;

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

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

145

N-(5-methyl-6-(l -methyl- lH-tetrazol-5-yl)pyridin-3-yl )-l-(quinolin-5-yl)-5(tnfluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazo 1-2-yl)pyridin-3-yl)-l-(l-methyl-!H-pyrazolo[3,4-b]pyridin4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-chloro-6-(2H-l,2,3-triazoI-2-yl)pyridin-3-yl)-l-(T-ethoxyisoquinolm-4-yl)-5( trifluoromethyl)-! H-pyrazole-4-carboxamide;

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

l-(2-ammoquinoliii-5-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-510 ( trifluoromethyl )-lH-pyrazole-4-carboxamide;

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

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

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

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

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(imidazo[l,2-b]pyridazin-6-yl)-520 ( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

N-(5-chloiO-6-(2H-l,2,3-triazol-2-yl)pyTidin-3-yl)-l-(l-methoxyisoquinolin-5-yl)-5(trifluoiOmethyl)-lH-pyrazole-4-carboxamide;

1 -(2-aminoquinolm-5-yl)-N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide:

2-(2-chloro-4-(l-(quinolin-5-yl)-5-(trifluoiOmethyl)-l H-pyrazole-4-carboxamido)phenyl)2H-l,2,3-triazole-4-carboxamide;

146

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

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

N-(5-cyano-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(2-methylbenzo[d]thiazol-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide;

-(3-chloro-5-( 1 -(quinolin-5-yl )-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamido )pyridin2 -yl) -1 H-1,2,3 -triazole-4-carboxamide;

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5-cyano-l-(quinolin-5-yl)-lH-pyrazole4-carboxamide;

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

N-(6-(2H-[l,2,3]triazolo[4.5-c]pyridin-2-yl)-5-chloropyridin-3-yl)- l-(quinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

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

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

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

N-(5-chloro-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(l-ethoxyethyl)isoquinolm-4-yl)5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide;

methyl l-(3-chloro-5-(l-(quinolin-5-yl)-5-(trifluoromethyl)-IH-pyrazole-4carboxamido)pyridin-2-yl)-1 H-1,2,3-triazole-4-carboxylate

-(imidazo[ 1.2-a]pyridiii-5-yl )-5-( trifluoromethyl)-N-(2-(trifluorornethyl)pyridin-4-yl )-1Hpyrazole-4-carboxamide;

147

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

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-(difluoromethyl)thieno[2,3c]pyridm-4-yl)-5-(trifluoromethyl)-IH-pyrazole-4-carboxamide;

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

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

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(2-methoxyquinoIin-4-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

l-(benzo[d][l, 2.3]thiadiazol-7-yl)-N-(5-chloro-2-methyl-6-(l H-pyrazol-l-yl)pyridin-3-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

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

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

N-(6-(2H-[l,2,3]triazolo[4,5-b]pyridin-2-yD-5-chloropyridin-3-yI)-l-(quinolin-5-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

3-(3-cyano-5-( 1 -(quinolin-5-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamido)pyridin2-yl)-l-methyl-lH-pyrazole-5-carboxylic acid;

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

-( 1 -aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-( 1 -methyl-1 H-pyrazol-3-yl)pyridin3 -yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

148

N-(6-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-5-chloropyridin-3-yl)-l-(quinolin-5-yI)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide;

methyl 2-(2-chloro-4-( 1 -(quinolm-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxamido)phenyl)-2H-l,2,3-triazole-4-carboxylate;

N-(5-cyano-6-(2-methyl-2H-l,2.3-triazol-4-yl)pyridm-3-yl)-l-(quinolm-5-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

methyl 3-chloro-5-( 1 -(quinolm-5-yI)-5-(trifluoromethyl)-lH-pyrazole-410 carboxamido)picolinate;

N-(6-(lH-[l,2,3]triazolo[4,5-c]pyridin-l-yl)-5-chloropyridin-3-yl)-l-(qumolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-cyanopyridin-3-yl)-l-(l-oxo-1,2-dihydroisoquinolin-5-yl )-5-( trifluoromethyl)-! Hpyrazole-4-carboxamide;

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-methyl-lH-pyrazolo[3,4-c]pyridin7-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

-( 1 -aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-( IH-pyrazol-1 -yl)pyridin-3-yl)-5( trifluoromethyl)-1 H-pyrazoIe-4-carboxamide;

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(dimethylamino)isoquinolin-4-yl)20 5-( trifluoromethyl)- lH-pyrazole-4-carboxamide;

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

(*R)-N-(5-chloiO-6-(2H-l,2,3-triazol-2-yl)pyTidin-3-yl)-l-(l-(4-oxotetrahydiOfuran-2yl)isoquinolin-4-yl)-5-( trifluoromethyl)-IH-pyrazole-4-carboxamide;

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

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

149

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

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

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

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

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yr)-l-(4-fluoroisoquinolin-l-yl)-510 ( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

5-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-lHpyrazol-1-yl )isoquinoline-1-carboxamide;

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

(*S)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(l-(l-hydroxyethyl)isoquinolin4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

5-chloro-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(qiünolin-5-yl)-lH- pyrazole-4-carboxamide;

-( 1 -aminoisoqumolin-4-yl)-N-(5-chloro-2-methyl-4-(2H-l ,2,3-triazol-2-yl)phenyI)-5( trifluoromethyl )-lH-pyrazole-4-carboxamide;

N-(5-chloro-6-(2H-l,2,3-tnazol-2-yl)pyridin-3-yl)-l-(l-methoxyisoquinolin-4-yl)-5(trifluoromethyl )-lH-pyrazole-4-carboxamide;

(*S)-N-(5-chloiO-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(4-oxotetrahydiOfuran-2yl)isoqumolin-4-yl )-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

CS)-N-(5-chloro-6-(2H- L2,3-tnazol-2-yl)pyridin-3-yl)-1 -( 1 -(tetrahydrofuran-2yl)isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

150

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-( l-fluoroisoquinolin-4-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide;

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-methyl-lH-pyrazolo[3,4-b]pyridin3-yl)-5-(trifluoromethyI)-1 H-pyrazole-4-carboxamide;

N-(5-chloro-2-rnethyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoroirnidazo[l,2a]pyridin-5-yl)-5-( trifluoromethyl)- lH-pyrazole-4-carboxamide;

N-(5-cyano-6-(2H-l ,2.3-triazol-2-yl)pyridin-3-yl)-l-( 1 -methyl-IH-indazo l-3-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-( l-(5-oxopyrrolidin-2-yl)isoquinolin4-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxamide;

methyl 3-(3-cyano-5-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)pyridin-2-yl)-l-methyl-lH-pyrazole-5-carboxylate;

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

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

N-(5-chloiO-6-(5-((dimethylamino)methyl)-lH-l,2.3-triazol-l-yl)pyridin-3-yl)-l(quinolin-5-yl )-5-( trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

N-(6-(4-(aminomethyl)-2H-l,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide;

N-(5-chloro-6-( l-methyl-lH-pyrazol-3-yl)pyridin-3-yl)-l-(8-fluoroquiiiolin-5-yl)-5( trifluoromethyl )-lH-pyrazole-4-carboxamide;

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

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

151

1-([1,2,4]triazolo[l,5-a]pyridm-5-yl)-N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyndin-3-yl Y (trifluoromethyl )-lH-pyrazole-4-carboxamide;

N-(5-chloiO-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-((Nmethylformamido)methyl)isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamide;

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

N-(5-chloro-2-methyl-6-(l H-pyrazol-l-yl)pyridin-3-yl)-l-(l-oxo-1,2-dihydroisoquinolin5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyTidin-3-yl)-l-(2-fluoroqumolm-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

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

N-(5-cyano-6-(lH-pynOl-l-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide;

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

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

N-(6-( lH-1.2,3-triazol-l-yl)-5-(tnfluoromethyl)pyridin-3-yl)-l-(quinoIin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

-(1 -oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin4-yl)-1 H-pyrazole-4-carboxamide;

152

N-(5-chloro-6-(2H- 1.2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fhioro-1 (methylamino)isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

N-(5-chloiO-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-cyanoquinolin-4-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

l-(pyTazolo[L5-a]pyridin-4-yl)-5-(trifluorometliyl)-N-(2-(trifluoromethyI)pyridin-4-yl)10 1 H-pyrazole-4-carboxamide;

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

l-( 1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(5-(trifluoromethyl)pyridin3-yl)-1 H-pyrazole-4-carboxamide;

]-(l-(l,4-dioxan-2-yl)isoquinolin-4-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

4-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-lH20 pyrazol-1 -yl)quinoline-2-carboxamide;

N-(5-chloro-6-(5-(hydroxymethyI)-lH-l,2,3-triazol-l-yl)pyridin-3-yl)-l-(l-oxo-l,2dihvdroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide:

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyTidin-3-yl)-l-(l-(4-oxotetrahydroftiran-2yl)isoquinolin-4-yl )-5-( trifluoromethyl)- lH-pyrazole-4-carboxamide,

N-(6-(4-amino-2H-lΛ3-triazol-2-yl·)-5-chloropyridm-3-yl)-l-(benzo[d]thiazol-4-yl)-5( trifluoro methyl)-1 H-pyrazole-4-carboxamide;

l-(2-ammo-[l,2,4]triazolo[l,5-a]pyridin-5-yl)-N-(5-cyano-6-(2H-l,2,3-triazol-2yl)pyridin-3-yl )-5-( trifluoromethyl)-lH-pyrazole-4-carboxamide;

153 (^<!R)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl )-1-(1 -( tetrahydrofuran-2yl)isoquinolin-4-yl)-5-( trifluoromethyl)- lH-pyrazole-4-carboxamide;

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

N-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-]-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)I H-pyrazole-4-carboxamide;

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

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

N-(5-cyano-6-(2H-l,23-triazol-2-yl)pyridin-3-yl)-l-(l-fluoroisoquinolin-4-yl)-5( trifluoromethyl )-1 H-pyrazole-4-carboxamide;

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

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

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

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

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

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

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

N-(5-cyano-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(furo[2,3-d]pyrimidin-4-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide;

154

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

N-(5-chloro-2-methyI-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(imidazo[l,2-a]pyridin-5yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxamide:

4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )carbamoyl )-5-( trifluoromethyl)-1Hpyrazol-l-yl)thieno[2,3-c]pyridine 6-oxide;

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

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

N-(5-cyano-6-(2H-1,2.3-triazol-2-yl)pyridm-3-y4)-l-(2-methylimidazo[ 1,2-a]pyndm-3-yI)5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide;

N-(5-cyano-6-methoxypyridin-3-yl)-l -(1-oxo- 1,2-dihydro isoquinolin-5-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide:

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

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinazolin-4-yl)-5-( trifluoromethyl)-

H-pyrazole-4-carboxamide;

N-(5-chloro-2-methyl-4-(2H-l,2,3-triazol-2-yl)phenyl )-l-(8-fluoroisoquinolin-4-yl)-520 (trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

(*R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -( 1 -( 1 -hydroxyethyl)isoquinolin4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

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

155

N-(5-chloro-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(l-hydroxyethyl)isoquinolin-4-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

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

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

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(7-(difluoromethyl)thieno[2,310 c]pyridm-4-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-chloro-6-(2H-k2,3-triazol-2-yDpyridin-3-yl)-l-(l-(tetrahydrofuran-2-yl)isoqumolm4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

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

l-(l-aminoisoquinolin-4-yl)-N-(5-cyano-2-methyl-6-(2H-l,2.3-triazol-2-yl)pyridin-3-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

l-(benzo[d]thiazol-4-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-520 (trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

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

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

156

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

N-(5-chloro-6-(2H-l,2,3-triazol-4-yl)pyTidm-3-yl)-l-(qumolm-5-yl)-5-(trifluoromethyl)1 H-pyrazole-4-carboxamide;

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

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

(*R)-N-(5-diloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-( l-(3-hydroxypynOlidin-l10 yl)isoquinolin-4-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

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

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

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(4-fluoronaphthalen-l-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

N-(3-diloro-4-(4-(hydroxymethyl)-lH-pyrazol-l-yl)phenyl)-I-(quinolin-5-yl)-520 ( trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

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

4-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-! Hpyrazol-1 -yOquinoline 1 -oxide:

N-(5-cyano-6-(4-(hydroxymethyD-2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(quinolin-5-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide;

157 methyl 2-cyano-4-( 1 -(quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxamido)benzoate;

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

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

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridm-3-yD-1-( imidazof k2-a]pyTidm-5-yl )-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

l-(benzo[d][l,2,3]thiadiazol-7-yl)-N-(5-cyano-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

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

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

N-(5-chloro-6-(4-(hydroxymethyl)-1 H-pyrazol-1 -yl )pyridin-3-yl)-l -( 1 -oxo-1,2dihydroisoquinolm-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-chloro-6-(2H-L2_?3-triazol-2-yI)pyridin-3-yI)-] -(3-methylimidazo[l,2-a]pyridin-5yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

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

N-(5-cyano-6-(2H-l ,2,3-triazoI-2-yl)pyridin-3-yl)-l-(thieno[3.2-d]pyrimidin-4-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

158

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

l-(benzo[d]fhiazol-4-yl)-N-(5-cyano-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

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

N-(6-(2H-l ,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)-1 -(quinolin-5-yl)-510 (trifluoromethyl)-1 H-pyrazole-4-carboxamide;

l-(benzo[d][l,2,3]thiadiazol-7-yl)-N-(5-chloro-6-(2H-1.2,3-triazol-2-yl)pyridm-3-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide;

4-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-! Hpyrazol-1 -yl )isoquinoline-1 -carboxamide;

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

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(pyrrolo[l,2-a]pyrazin-l-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

N-(5-cyano-6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)-l-(quinolm-5-yI)-520 (trifluoromethyl)-1 H-pyrazole-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yI)-1 -( 1.7-naphthyridin-5-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

2-(3-chloro-5-(l-(quinolin-5-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxamido)pyridin2-yl)-2H-1,2,3-triazole-4-carboxamide;

N-(5-chloiO-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(pyrazolo[l,5-a]pyridin-4yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

159

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

N-(5-cyano-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[2,3-d]pyrimidin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(pyrazolo[l,5-a]pyrazin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide;

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(7-(l-hydroxyethyl)thieno[2,3c]pyridin-4-yl )-5-( trifluoromethyl)- lH-pyrazole-4-carboxamide;

N-(5-cyano-6-(2H-1,2,3-tnazol-2-yl)pyridm-3-yl)-1 -(pyrrolo[2.1 -f] [ 1,2,4]tnazm-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-chloro-6-( 1-methyl-1 H-pyrazol-3-yl)pyridin-3-yl)-1-( I-oxo-1,2-dihydroisoqumolin5-yl)-5-(trifluoromethyl)-l H-pyrazole-4-carboxamide;

methyl2-(3-chloro-5-(T-(qumolm-5-yr)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)pyridin-2-yl)-2H-l,2,3-triazole-4-carboxylate;

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

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

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

l-(benzo[d][l,2,3]thiadiazol-7-yl)-N-(5-chloro-2-methyl-6-(2H-l,2,3-triazol-2-yI)pyridin3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

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

160

N-(5-chloro-6-(4-(hydroxymethyl)-l H-pyrazol- l-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-cyano-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(pyrazolo[l,5-a]pyrazin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide:

N-(5-cyano-2-methyI-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(8-fluoroisoquinoIin-4-yl)5-(tnfluoromethyl)-lH-pyrazole-4-carboxamide;

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

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

l-(l-ammo-8-fluoroisoqumolin-4-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

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

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

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

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

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

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-Dquinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-cyano-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(2-D-quinolin-5-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

161

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

N-(5-cyano-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[3,2-b]pyridin-7-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxarnide;

N-(5-bromo-2-methyl-6-( 2H-1,2,3-triazol-2-yl)pyridin-3-yl)-l -( 1 -oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide:

N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -( 1 -oxo-1,2dihydroisoqumolin-5-yl)-5-(tnfluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(pyrazolo[l,5-a]pyridin-4-yl)-510 (trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-l -(1-oxo- l,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide:

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[2,3-b]pyridin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide:

N-(5-chloiO-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[2.3-c]pyridm-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide;

N-(5-chloro-6-(4-methyl-2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolm-5-yl)-520 ( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

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

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

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

162

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridiii-3-yl)-l-(l-hydroxyisoquinolin-5-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide;

l-(benzo[d]thiazol-7-yl)-N-(5-chloro-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-chloro-6-(4-(hydroxymethyl)-2H-1,2.3-triazol-2-yl)pyridin-3-yl)-1 -( 1 -oxo-1,2dihydroisoqumolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

l-(benzo[d]thiazol-7-yl)-N-(5-cyano-6-(2H-l,2.3-triazol-2-yl)pyridin-3-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(T-oxo-1.2-dihydroisoquinolm-5-yl)10 5-(trifluoromethyl)-lH-pyrazole-4-carboxamide:

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

2-i3-chloro-5-(l-(qumolin-5-yl)-5-(trifluoiOmethyl)-lH-pyrazole-4-carboxamido)pyridin2-yl)-2H-l,2,3-triazole-4-carboxylic acid;

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

4-(4-((5-_chl_oro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-! Hpyrazol-l-yl)thieno[2,3-c]pyridine-7-carboxamide;

I-(7-(3-hydroxyazetidin-l-yl)thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-N-(220 (trifluoromethyl )pyridin-4-yl)-lH-pyrazole-4-carboxamide;

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

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

N-(5-chloro-2-methyl-6-(4-methyl-1 H-1,2,3-triazol-1 -yl)pyridin-3-yl)-1 -( 1 -oxo-1,2dihydroisoquinoliii-5-yl)-5-(trifluoiOmethyl)-lH-pyrazole-4-carboxaniide;

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

163

N-(.2-methoxypyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-l Hpyrazole-4-carboxamide;

l-(l-ammoisoquinolin-4-yI)-5-(trifluoromethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-lHpyrazole-4-carboxamide;

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

N-(5-ethynyl-2-methyl-6-(2H-1,2,3-tnazol-2-yl )pyridin-3-yl)-1 -( 1 -oxo-1,2dihydroisoqumolin-5-yl)-5-(tnfluoromethyl)-lH-pyrazole-4-carboxamide;

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

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yI )-1 -(2-methyl-1 -oxo-1.2dihydroisoquinolin-4-yl)-5-(trifluoromethyl)-lH-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)-lH-pyrazole-4-carboxamide;

N-(5-chloiO-2-methyl-6-(2H-l,2.3-triazol-2-yl)pyridm-3-yl)-l-(7-chlorothieno[2,3c]pyridin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

N-(5-chloro-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(7-cyanothieno|2,3c]pyridin-4-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

4-(4-((5-chloro-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(tnfluoromethyl)-lH-pyrazol-l-yl)thieno[2,3-c]pyridme-7-carboxamide;

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyTidin-3-yl)-l-(7-cyclopropylthieno[2,3-c]pyridin-4y l)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide;

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

164

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(7-cyanothieno[2,3-c]pyridm-4-yl)-5(trifluoromethyl )-lH-pyrazole-4-carboxamide;

4-(4-((5-chIoro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)carbamoyl)-5-(trifluoromethyl)-lHpyrazol-1 -yl )-N-methylthieno[2,3-c]pyridine-7-carboxamide;

N-(5-chloiO-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(7-(3-hydroxyazetidin-lyl)thieno[2,3-c]pyridm-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

l-(l-ammoisoquinolin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoiOmethyl)pyndin-4-yl)-lH10 pyrazole-4-carboxamide;

N-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)-l-(l-oxo-l,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl )- lH-pyrazole-4-carboxamide;

l-( 1-oxo-I,2-dihydroisoquinolin-5-yl)-N-(pyridin-4-yl)-5-( trifluoromethyl)-IH-pyrazole4-carboxamide;

N-(2-cvclopropylpvridin-4-vl)-1 -( 1 -oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoiomethyl)1 H-pyrazole-4-carboxamide;

3-chloro-N,N-dimethyl-5-( 1 -( 1 -oxo-1,2-dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamido)picolinamide l-(l-aminoisoquinolin-4-yl)-N-(2-cyanopyridin-4-yl )-5-( trifluoromethyl)-lH-pyrazole-420 carboxamide;

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

l-(l-aminoisoquinolin-4-yl)-N-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5(tnfluoromethyl)-lH-pyrazole-4-carboxamide;

N-(5-chloropyridm-3-yl)-l-(1-oxo-L2-dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-! Hpyrazole-4-carboxamide;

l-(thieno[2,3-c]pyridm-4-yl)-5-(trifluoromethyI)-N-(2-(trifluoromethyl)pyridin-4-yl)-lHpyrazo le-4-c arb oxamide ;

165 l-(8-fluoroimidazo[1.2-a]pyridin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin4-yl)-1 H-pyrazole-4-carboxamide;

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

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

l-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-lHpyrazole-4-carboxamide;

N-(2-cyanopyridin-4-yl )-1-( 1-oxo-1,2-dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-1H10 pyrazole-4-carboxamide;

N-(2-(2-methoxyethoxy)-5-(trifluoiOmethyl)pyridin-3-yl )-1 -(1-oxo-1.2dihydroisoquinoIin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide;

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

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

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

(A-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yI)-l-(2-(tetrahydrofuran-220 yl)quinolin-5-yl)-5-( trifluoromethyl)- lH-pyrazole-4-carboxamide;

or a pharmaceutically acceptable sait form thereof.

For use in medicine, salts of compounds of Formula (I) refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the préparation of compounds of Formula (I) or of their pharmaceutically acceptable sait forms thereof. Suitable pharmaceutically acceptable salts of compounds of Formula (I) include acid addition salts that can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as, hydrochloric acid, sulfuric

166 acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of Formula (I) carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali métal salts such as, sodium or potassium salts; alkaline earth métal salts such as, calcium or magnésium salts; and salts formed with suitable organic ligands such as, quatemary ammonium salts. Thus, représentative 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, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, V-methylglucamine ammonium sait, oleate, pamoate (embonate). palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stéarate, sulfate, subacetate. succinate, tannate, tartrate, teoclate. tosylate, triethiodide, and va le rate.

Représentative acids and bases that may be used in the préparation of 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, (+)-camphoric acid, camphorsulfonic acid, (+)-(1 S)-camphor-10-sulfonic acid, capric acid, caproïc acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1.2disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, salactaric acid, gentisic acid, glucoheptonic acid, D-glucomc acid, D-glucoronic acid, L-glutamic acid, α-οχο-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)L-malic acid, malomc acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2sulfonic acid, naphthalene-l,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid.

167

L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, ptoluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, 5 diethylamine, 2-(diethylammo)-ethanol, ethanolamine, ethylenediamine, Λ-methylglucamine, hydrabamine, ZH-imidazole, L-lysine, magnésium hydroxide, 4-(2hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)pyrrolidine, sodium hydroxide, triethanolamine, tromethamme, and zinc hydroxide.

Embodiments of the présent invention include prodrugs of compounds of Formula 10 (I). In general, such prodrugs will be functional dérivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treating or preventing embodiments of the présent invention, the term “administering” encompasses the treatment or prévention of the various diseases, conditions, syndromes and disorders described with the compound specifïcally disclosed or with a compound that may not be 15 specifïcally disclosed, but which couverts to the specified compound in vivo after administration to a patient. Conventional procedures for the sélection and préparation of suitable prodrug dérivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard. Elsevier, 1985.

Where the compounds according to embodiments of this invention hâve at least one 20 chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that ail such isomers and mixtures thereof are encompassed within the scope of the présent invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorph and as such are intended to be included in the présent invention. In 25 addition, some of the compounds may form solvatés with water (i.e., hydrates) or common organic solvents, and such solvatés are also intended to be encompassed within the scope of this invention. The skilled artisan will understand that the term compound as used herein, is meant to include solvated compounds of Formula (I).

168

Where the processes for the préparation of the compounds according to certain embodiments of the invention give rise to mixture of stereoisomers. these isomers may be separated by conventional techniques such as, préparative chromatography. The compounds may be prepared in racemic form. or individual enantiomers may be prepared either by enantiospecifïc synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques such as, the formation of diastereomeric pairs by sait formation with an optically active acid such as, (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and régénération of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides. followed by chomatographic séparation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

One embodiment of the présent invention is directed to a composition, including a pharmaceutical composition, comprising, consisting of, and/or consisting essentially of the (+)-enantiomer of a compound of Formula (I) wherein said composition is substantially free from the (-)-isomer of said compound. In the présent context, 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 calculated as „ _z ( mass (+) - e nantiomer ) . „ % (+ ) - enantiomer =---------------;------ x lUO (mass(+) -enantiomer ) + (mass(-) - enantiomer )

Another embodiment of the présent invention is a composition, including a pharmaceutical composition, comprising, consisting of, and consisting essentially of the ()-enantiomer of a compound of Formula (I) wherein said composition is substantially free from the (+)-isomer of said compound. In the présent context, substantially free from 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

169

about 1 % of the (+)-isomer calculated as % (-) - enantiomer (mass (-) - enantiomer ) (mass (+) - enantiomer ) + (mass(-) - enantiomer )

It is intended that within the scope of the présent invention, any one or more element(s), in particular when mentioned in relation to a compound of Formula (I), shall comprise ail isotopes and isotopic mixtures of said element(s), either naturally' occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope *H, ‘H (D), and Ή (T). Similarly, references to carbon and oxygen include within their scope respectively ¹²C. ^I3C and ¹⁴C and ¹⁶O and ¹⁸O. The isotopes may be radioactive or non- radioactive. Radiolabelled compounds of formula (I) may comprise one or more radioactive isotope(s) selected from the group of Ή, ⁿC, ¹⁸F, ¹²²I, ¹²'T V, ‘A, ''Br, ^,6Br, ⁷⁷Br and ⁸²Br. Preferably, the radioactive isotope is selected from the group of ²H, Ή, “C 15 and ¹⁸F.

During any of the processes for préparation of the compounds of the various embodiments of the présent invention, it may be necessary and/or désirable to protect sensitive or reactive groups on any of the molécules concemed. This may be achieved by means of conventional protecting groups such as those described in Protective Groups in

Organic Chemistry, Second Edition, J.F.W. McOmie, Plénum 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. The protecting groups may be removed at a convenient subséquent stage using methods known from the art.

Even though the compounds of embodiments of the présent invention (including their pharmaceutically acceptable salts and pharmaceutically acceptable solvatés) can be administered alone, they will generally be administered in admixture with a

170 pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and/or a pharmaceutically acceptable diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice. Thus, particular embodiments of the présent invention are directed to pharmaceutical and veterinary 5 compositions comprising compounds of Formula (I) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or pharmaceutically acceptable diluent.

By way of example, in the pharmaceutical compositions of embodiments of the présent invention, the compounds of Formula (I) may be admixed with any suitable 10 binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), and combinations thereof.

Solid oral dosage forms such as, tablets or capsules, containing the compounds of the présent invention may be administered m at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release 15 formulations.

Additional oral forms in which the présent inventive compounds may be administered include élixirs, solutions, syrups, and suspensions; each optionally containing flavoring agents and coloring agents.

Alternatively, compounds of Formula (I) can be administered by inhalation 20 (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 dusting powder. For example, they can be incorporated into a cream comprising, consisting of, and/or consisting essentially of an aqueous émulsion of polyethylene glycols or liquid paraffm. They can also be incorporated, at a concentration of between about 1 % and about 10 % by 25 weight of the cream, into an ointment comprising, consisting of, and/or consisting essentially of a wax or soft paraffin base together with any stabilizers and preservatives as may be required. An alternative means of administration includes transdermal administration by using a skin or transdermal patch.

The pharmaceutical compositions of the présent invention (as well as the

171 compounds of the présent invention alone) can also be injected parenterally, for example, intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally, or intrathecally. In this case, the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.

For parentéral administration, the pharmaceutical compositions of the présent invention are best used in the form of a stérile aqueous solution that may contain other substances, for example, enough salts and monosaccharides to make the solution isotonie with blood.

For buccal or sublingual administration, the pharmaceutical compositions of the 10 présent invention may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.

By way of further example, pharmaceutical compositions containing at least one of the compounds of Formula (I) as the active ingrédient can be prepared by mixing the compound(s) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable 15 diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques. The carrier, excipient, and diluent may take a wide variety of forms depending upon the desired route of administration (e.g.. oral, parentéral, etc.). Thus, for liquid oral préparations such as, suspensions, syrups, élixirs and solutions, suitable carriers, excipients and diluents include water, glycols, oils, alcohols, 20 flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral préparations such as, powders, capsules, and tablets. suitable carriers, excipients and diluents include starch.es, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral préparations also may be optionally coated with substances such as, sugars, or be enterically coated so as to modulate the major site of 25 absorption and disintegration. For parentéral administration, the carrier, excipient and diluent will usually include stérile water, and other ingrédients may be added to increase solubility and préservation of the composition. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives such as, solubilizers and preservatives.

172

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 particular amount or range therein, in particular from about 1 mg to about 1000 mg, or any particular amount or range therein, or, more particularly, from about 10 mg to 5 about 500 mg, or any particular amount or range therein, of active ingrédient in a regimen of about 1 to about (4x) per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for a compound of Formula (f) will vary as will the diseases, syndromes, conditions, and disorders being treated.

For oral administration, a pharmaceutical composition is preferably provided m the 10 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 présent invention is directed to a pharmaceutical composition for oral administration, comprising a compound of Formula (I) in an amount of from about 25 mg to about 500 mg.

Advantageously, a compound. of Formula (I) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, thee and (4x) daily.

Optimal dosages of a compound of Formula (I) to be administered may be readily determined and will vary with the particular compound used, the mode of administration, 20 the strength of the préparation, and the advancement of the disease, syndrome, condition or disorder. In addition, factors associated with the particular subject being treated. including subject gender. âge, weight. diet and time of administration, will resuit in the need to adjust the dose to achieve an appropriate therapeutic level and desired therapeutic effect. The above dosages are thus exemplary of the average case. There can be, of course, individual 25 instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.

Compounds of Formula (I) may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a compound of Formula (I) is required for

173 a subject in need thereof.

In an embodiment, cancers that may benefit from a treatment with MALTl inhibitors of the présent invention include, but are not limited to, lymphomas, leukemias, carcinomas, and sarcomas, e.g. non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma 5 (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, Burkitf s lymphoma, multiple myeloma, chonic lymphocytic leukemia (CLL), lymphoblastic T cell leukemia. chonic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic 10 large cell leukemia, megakaryoblastic leukemia. acute megakaryocytic leukemia, promyelocytic leukemia, erytholeukemia, brain (gliomas). glioblastomas. breast cancer, colorectal/colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endométrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder 15 cancer, head&neck cancer, testicular cancer. Ewing’s sarcoma, rhabdomyosarcoma, medulloblastoma. neuroblastoma, cervical cancer, rénal cancer, urothélial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor).

In another embodiment, MALTl inhibitors of the présent invention may be used 20 for the treatment of immunological diseases including, but not limited to, autoimmune and inflammatory disorders. e.g. arthitis, inflammatory bowel disease. gastritis, ankylosing spondylitis, ulcerative colitis. pancreatits, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephitis, rheumatic fever, goût, organ or transplact rejection, chonic allograft rejection, acute or chonic graft-versus-host disease, 25 dermatitis including atopie, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjoergen’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergie disorders, asthma, bronchitis, chôme obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis,

174 sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

In another embodiment of the présent invention, the compounds of the présent invention may be employed in combination with one or more other médicinal agents, more 5 particularly with other anti-cancer agents, e.g. chemotherapeutic, anti-proliferative or immunomodulating agents, or with adjuvants in cancer therapy, e.g. immunosuppressive or anti-inflammatory agents.

Possible combinations of the compounds of the présent invention may include, but are not Iimited to, BTK (Bruton’s tyrosine kinase) inhibitors such as ibrutinib, SYK 10 inhibitors, PKC inhibitors, PI3K pathway inhibitors, BCL family inhibitors, J AK inhibitors, PIM kinase inhibitors, rituximab or other B cell antigen-binding antibodies, as well as immune cell redirection agents (e.g. blinatumomab or CAR T-cells) and immunomodulatory agents such as daratumumab, anti-PDl antibodies, and anti-PD-Ll antibodies.

GENERAL SYNTHETIC METHODS

Représentative compounds of the présent invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the schemes and examples that follow. Since the schemes are an illustration, the invention 20 should not be construed as being Iimited by the Chemical reactions and conditions described in the schemes and examples. Compounds analogous to the target compounds of these examples can be made according to similar routes. The disclosed compounds are useful as pharmaceutical agents as described herein. The various starting materials used in the schemes and examples are commercially available or may be prepared by methods well 25 within the skill of persons versed in the art.

Abbreviations used in the instant spécification, particularly tire schemes and examples, are as follows:

ACN acetonitrile

175

AcOH	acetic acid
BINAP	2,2’-bis(diphenylphosphino)-l,l'-binaphthalene
Boc	?er/-butyl carbamate
BuLi	butyllithium
5 Cbz	benzyl carbamate
DCM	dichloromethane
DMA	dimethylacetamide
DME	ethylene glycol dimethyl ether
DMF	d ime thylformamide
10 DMSO	dimethyl sulfoxide
EA	ethyl acetate
Et	ethyl
EtjO	diethyl ether
EtOAc	ethyl acetate
15 EtOH	ethyl alcohol
FCC	flash column chromatography
h	hour(s)
HATU	O-(7-azabenzotriazol-l-yl)-ALV.A^rLV’-tetramethyluronium
	hexafluorophosphate
20 HCHO	formaldéhyde
HCl	hydrochloric acid
HPLC	high performance liquid chromatography
KCN	potassium cyanide
LCMS	high pressure liquid choatography with mass spectrometer
25 LDA	lithium diisopropylamide
LiOH	lithium hydroxyde
Me	methyl
MeCN	acetonitrile
MeOH	methyl alcohol

176

mg min	milligram minute
NaCN	sodium cyanide
NaOH	sodium hydroxide
5 NaOtBu	sodium tert-butoxide
NH₄C1	ammonium chloride
Pd/C	palladium on charcoal
Pd2(dba)3	tris(dibenzylideneacetone)dipalladium
Pd(dppf)Ch	[1,1 '-bis(diphenylphosphino )ferrocene]dichloropalladium
10 Pd(OAc)₂	palladium diacetate
Pd(PPh₃)₄	tetrakis(triphenylphosphine)palladium
PPh₃	triphenyl phosphine
p-TsOH	para-toluenesulfonic acid
rt or RT	room température
15 TB AF	tetrabutyl ammonium fluoride
TMSI	iodotrimethylsilane
t-Bu	tert-butyl
TFA	trifluoroacetic acid
TF AA	trifluoroacetic anhydride
20 THF	tetrahydrofuran
TLC	thin layer chromatography
Xantphos	4,5-Bis(diphenylphosphino)-9.9-dimethylxanthene
Xphos	2-dicyclohexylphosphino-2',4',6'-triisopropy!biphenyl

Compounds of Formula (la) wherein R? is hydrogen. may be prepared according to the process outlined in Scheme 1.

Scheme 1

177

r₁-nhnh₂1E

1. Hydrolysis

Re

Amide Coupling,

or 1G, base

A carboxylic acid of formula (IA) may be treated with carbonyldiimidazole followed by addition of a mono-ester of malonic acid of formula (IB), wherein R' is Cigalkyl, and a base, such as isopropylmagesium chloride, to yield a ketoester of formula (1C).

Condensation with triethyl orthoformate in acetic anhydride or with l.l-dimethoxy-/VAdimethylmethanamine may yield a 2-ethoxymethylidene-3-oxo ester (or 2((dimethylamino)methylidene-3-oxo ester) of formula (ID). A compound of formula (ID) may be reacted with a hydrazine of formula (1E) to provide a pyrazole of formula (1F). Hydrolysis of the ester group may be effected via by treatment with aqueous sodium hydroxide in the présence of an alcohol co-solvent, to provide the corresponding carboxylic acid intermediate, which, subsequently, may be converted to a compound of Formula (I) upon amide coupling with a compound of formula (IG). The amide coupling may be carried out. for example, in the presence of phosphorus oxychloride in pyridine to afford the corresponding acid chloride, followed by treatment with a compound of formula ( 1 G), m the presence of a base. In one embodiment, the amide coupling réaction is carried out in the presence of a suitable amide coupling reagent such as HATU, in the presence ot a base such as. but not limited to. diisopropylethyl amine.

178

Alternatively, the pyrazole ester of formula (1F) may be directly converted to a compound of Formula (I) via treatment with a compound of formula (IG) and a base, such as potassium terz-butoxide.

An altemate route to compounds of Formula (la) wherein R? is hydrogen. is illustrated in Scheme 2.

Scheme 2

Aniline (IG) may be coupled with a lithium acetoacetate of formula (2A) in the presence of coupling reagent such as BOP, a base such as DIPEA, and a solvent such as WP. to provide a compound of formula (2B). A compound of formula (2B) may then be reacted with DMF-DMA (2C) in the presence of an acid, such as TsOH, or reacted with triethoxymethane (2D) in AcOH to afford a compound of formula (2E) or (2F), respectively. A compound of formula (2E) or (2F) may then be treated with a hydrazine of formula (1E) to afford a compound of Formula (I).

Scheme 3 illustrâtes the préparation of certain hydrazine intermediates of formula

179 (1E), useful for the préparation of compounds of Formula (I) of the présent invention.

Scheme 3

PATH

H₂

Pt/C

1. NaNO₂, HCl

3A

Z = C or N

PATH 3

3I

R₁-NH₂

3B

O t-BuO. ,N. JL „ Y ' N Ot-Bu

O

R_rB(OH)₂

3E

Cu catalyst _Z-^A i°l

PATH 4 n l _____

A-„Z

-------* R_rNHNH₂

2. SnCI₂ or ascorbic acid 1E

3C P*·^{1 cat}· phosphine ligand

X = Br, Cl, I base

HCl, H₂O

deprotection

R_rNHNH₂

1E

R₁-NHNH₂

1E

POCIa/DMF or

POBr₃/DMF or

TFAA/TBAF or

TMSI

NH₂NH₂

NHNH₂

3G

At least one A is N X = halogen Z = CH or N

1E-1

PATH 5

NH₂NH₂ —----- R₁-NHNH₂

Pd cat.

phosphine ligand base ^1E’²

X = Cl, Br, I Z = C or N

180

Λ heteroaryl amine of formula (3B) may be converted to a heteroaryl diazonium sait via treatment with sodium nitrite under acidic conditions. This intennediate may be reduced, using a reductant such as tin (II) chloride or ascorbic acid, to form the hydrazine of formula (1E). For heteroaryl amines of formula (3B) that are not commercially available, 5 they may be accessed by réduction of the heteronitroarene (3A) using hydrogen and Pt/C or other conventional nitro-reducing conditions (path one).

Ri-substituted chlorides, bromides, and iodides may undergo a palladium catalyzed Buchwald Hartwig coupling with benzophenone hydrazine, in the presence of a ligand, such as Xantphos, and a base, such as sodium zm-butoxide, to form a hydrazine of formula (3D). Acidic hydrolysis may afford the hydrazine of formula (1E) (path two).

Ri-substituted boronic acids may also serve as a precursor to compounds of formula (1E) by the route shown in path three. A boronic acid of formula (3E) may undergo a Cu^-catalyzed (such as Cu(OAc)2, TEA in CH2CI2) addition to di-zmbutylazodicarboxylate to afford an intennediate of formula (3F), which may be 15 deprotected under acidic conditions to yield the compound of formula (1E). Heteroaryl hydrazines of formula (1 E-l). having a nitrogen atom in the ortho- or para- position with respect to the hydrazine functionality, may be prepared via direct displacement of a halogen with hydrazine or hydrazine hydrate. (Hetero) haloarenes of formula (3G) that are not commercially available may be prepared from their corresponding (hetero)arenes (31), 20 with an oxidant such as mCPBA, to form the N-oxide (3J) (or (3K)) that may then be converted to (hetero) haloarene 3G via treatment with POCE and DMF. POBrs/DMF, TFAA/TBAF, or TMSI (path four). Alternatively. halogenated (hetero)arenes of formula (3H) may undergo palladium-catalyzed cross-coupling with hydrazine to directly furnish intennediate (1E-2) (path five).

Scheme 4 illustrâtes multiple pathways available for the synthesis of intennediate (1G-1), wherein Gi is C(Ri).

181

Compound (B-l) may be reacted with a compound of formula RiH in the presence of a base, such as CS2CO3, in a solvent, such as DMF, to yield a compound of formula (4B).

Alternatively, a compound of formula (4C) may be treated with a Crossing coupling reagent. such as a boron reagent of formula (4D) or a tin reagent of formula R/SnfBujj, m the presence of a palladium catalyst, including but not limited to, Pd(dppf)Cb or Pd(PPhs)4; in a suitable solvent or solvent system such as DMF, dioxane/water, or the like; to produce a compound of formula (4B). Another suitable pathway includes the reaction of a compound of formula (4C) with a compound of formula RtH, in the presence of a coupling reagent such as Cul. with a base such as CszCOj, and in a solvent such as DMF. to afford a compound of formula (4B). A compound of formula (4B) may be reduced to a compound of formula (1G-1) using a reducing agent such as Zn or Fe in the presence of NH4CI, in a solvent such as MeOH.

Scheme 5 illustrâtes the préparation of certain compounds of Formula (I) wherein Re is other than hydrogen.

182

Scheme 5

RockPhos G3

K3PO4 dioxane

TMPMgOLÎCI

R,l·

THF, rt reflux

Scheme 6 illustrâtes the préparation of certain compounds of Formula (I) of the présent invention.

Scheme 6

183

Rja L

In the instance when L is H. alkylation of compounds of formulae 6A, 6C and 6E 5 may occur via formation of a radical from Ria-L, generated by treatment with ammonium persulfate and (IR[DF(CF3)PPY]2(DTBPY))PFe, m a mixture of water and CH3CN or DMSO and TFA, under irradiation with blue LED.

Altematively. in the instance when L is H, alkylation of compounds of formulae 6A, 6C and 6E may occur via formation of a radical from Ria-L, generated by treatment 10 with BPO and (IR[DF(CF3)PPY]2(DTBPY))PFe in MEOH and TFA, under irradiation with blue LED.

When L is H, alkylation of compounds of formulae 6A, 6C and 6E may occur via formation of a radical from Ria-L, generated by treatment with iron(II)sulfate heptahydrate 15 and hydrogen peroxide, in a mixture of water and CH3CN or DMSO and H2SO4.

184

When L is a zinc sulfonate. alkylation of compounds of formulae 6A, 6C and 6E may occur via formation of a radical from Ria-L, generated by treatment with tert-butyl hydroperoxide, in a mixture of water and DCM and TFA.

Likewise, when L is -COOH or a BFs-salt, alkylation of compounds of formulae 5 6A. 6C and 6E may occur via formation of a radical from Ria-L. generated by treatment with ammonium persulfate and silver nitrate, in a mixture of water and DCM or CH3CN or DMSO or dioxane and TFA.

Compounds of formulae 6A, 6C and 6E may also be converted to their corresponding N-oxides via treatment with an oxidizing agent such as m-CPBA in DCM or 10 THF. Said N-oxides by optionally be converted to their corresponding ortho -CN dérivatives using trimethylsilyl cyanide and DBU, in a solvent such as THF. Said Noxides may also be converted to their alkoxy or cycloalkoxy dérivatives by the action of tosylanhydride, NajCOs and an appropriately substituted alkyl-OH or cycloalkyl-OH reagent.

Alternatively. the N-oxides of compounds of formulae 6A, 6C and 6E may be converted to their corresponding ortho-chloro dérivatives by the action of POCh, optionally in a solvent such as CHCh. which may be used as an intermediate for the préparation of Ci-6alkylthio, Ci-6cycloalkylthio, and sulfur-linked heterocyclic rings of the présent invention. Similarly, the ortho-chloro dérivatives may be reacted with appropriately substituted amines to afford Ci-ealkylamino, Ci.6cycloalkylamino, or Nlinked heterocyclic rings of the présent invention. Or, the ortho-chloro dérivatives may undergo a Suzuki-type reaction in a subséquent step, with an appropriately substituted corresponding alkyl- or cycloalkyl-boronic acid to form a compound of Formula (I).

Spécifie Examples

In the foilowing Examples, some synthesis products are listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term “residue” does not lirait the physical State in which the product was isolated and may 30 include, for example, a solid. an oil, a foam, a gum, a syrup, and the like.

185

Examine 1 l-(Benzofuran-4-yl)-tV-(5-chloro-6-(2/7-I,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-l//-pyrazole-4-carboxamide, Cpd 34

A. l-Bromo-3-(2.2-diethoxyethoxy)benzene, la

Sodium hydride in minerai 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 résultant mixture was stirred for 10 min at 0 °C. 2-Bromo-l,ldiethoxyethane (31 mL, 0.21 mmol) was added to the mixture at 0 °C, and the resulting mixture was stirred at 120 °C for 16 h before cooling to room température. The resulting solution was poured into water and extracted wdth ethyl acetate. The organic extracts were dried over anhydrous Na₂SO4, filtered. and concentrated to dryness under reduced pressure to afford the crude product, which was purified by FCC ( petroleum ether: ethyl acetate = 10:1 ) to afford compound la (50 g, 99%) as a colorless oil. ^!H NMR (400 MHz, CDCL) 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 (le)

186 il 1 v=y ^Br lb le

Polyphosphonc acid (PPA) (175 g, 519 mmol) was added to a solution consisting of l-bromo-3-(2,2-diethoxyethoxy)benzene, la (50.0 g, 173 mmol) and toluene (200 mL) at room température under an Ar<_g) atmosphère. The resulting mixture was stirred at 110 °C for 4 h before cooling to room température. The resulting mixture was quenched with cooled water and extracted with ethyl acetate. The organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. which was purified by FCC (petroleum ether: ethyl acetate = 20:1) to give a mixture of compounds lb and le (21 g, 6224) as a colorless' oil. ’H NMR (400 MHz, CDCL) δ ppm

7.70 (s, 1 H), 7.68 (d, .7 = 2.0 Hz, 1H),7.61 (d,J=2.0Hz, 1H), 7.47 (d, J= 8.0 Hz, 2H),

7.43 _ 7.34 (_1Ώ, 2H), 7.18 (t, J= 8.0 Hz, IH), 6.83 (d, J= 1.2 Hz, 1H), 6.76 (d, J= 1.2 Hz, 1H).

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

A mixture consisting of compounds lb and le (21 g, 53 mmol), (diphenylmethylene)hydrazine (13 g, 64 mmol), palladium(II) acetate (1.2 g, 5.3 mmol), Xphos (5.1 g, Il mmol), sodium hydroxide (4.3 g. 0.11 mol), and /-AmOH (150 mL) was stirred at 100 °C for 16 h before cooling to room température. The suspension was filtered and the pad was washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure to afford a crude product, which was purified by FCC (petroleum ether: ethyl acetate = 10:1) to afford compound Id (5.8 g, 17%) as a brown oil. LCMS (ESI): mass calcd. for C21H16N2O 312.13, m/z found 313.1 [M+H]⁺. ’H NMR (400 MHz, CDCh)

187 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=8.4Hz, 1H), 6.98 - 6.95 (m, 1H), 6.90 (d, J = 8.0 Hz, 1H). LCMS (ESI) m/z M+l: 313.0.

D. Benzofuran-4-ylhydrazine dihydiOchloride, le

Conc. HCl (50 mL) was added to a solution consisting of l-(benzofuran-4-yl)-2(diphenylmethylene)hydrazine, Id (4.8 g, 15 mmol) and EtOH (5 mL). The resulting mixture was stirred at room température for 16 h, concentrated to dryness under reduced pressure to afford a residue, which was added into water (10 mL). The resulting mixture was basified with 2 M NaOH to pH 13, and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were dried over anhydrous NazSCU, filtered, and the filtrate concentrated to dryness under reduced pressure to afford a crude product le (1.1 g. crude), which was used in the foilowing reaction without further purification.

E. Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If

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 h. The brown mixture was concentrated to afford ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate. If (38 g, 97.1%) as a brown oil, which was used in the foilowing réaction without further purification. Ή NMR (400 MHz,

188

CDCh) δ ppm l .23 - 1.33 (m, 3 H) 1.40 (dt, J=14.18. 7.19 Hz, 3 H) 4.19 - 4.36 (m, 4 H) 7.66 - 7.87 (m, 1 H).

F. Ethyl l-(benzofuran-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate, 1g

A solution consisting of ethyl 2-(ethoxymethylene)-4.4,4-trifluoro-3-oxobutanoate, If (1.43 g, 5.97 mmol), benzofuran-4-ylhydrazine dihydrochloride, le (1.10 g. 4.98 mmol), triethylamine (1.39 mL, 9.95 mmol), and éthanol (20 mL) was stirred at 80 °C for 16 h before cooling to room température. 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 NaiSCU. filtered, and concentrated to dryness under reduced pressure to afford the crude product, which was purified by FCC (petroleum ether: ethyl acetate = 3:1) to afford compound 1g (250 mg, 15 %) as a yellow oil. LCMS (ESI): mass calcd. for C15H11F3N2O3 324.07, m/z found 324.9 i Μ · 111 . ‘H 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 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+l: 324.9.

G. l-(Benzofuran-4-yl)-5-(trifIuoromethyl)-lH-pyrazole-4-carboxylic acid, Ih

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 l-(benzofuran-4-yl)-5-(trifluoromethyl)lH-pyrazole-4-carboxylate, 1g (250 mg, 0.771 mmol) and éthanol (10 mL). The mixture

189 was stirred at room température for 16 h. The resulting solution was concentrated to dryness under reduced pressure to afford 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 then dried under reduced pressure to afford compound Ih (200 mg, 88%) as a yellow solid. LCMS (ESI): mass calcd. for C13H7F3N2O3 296.04, m/z found 337.9 [M+H+CH₃CN]⁺. ‘H NMR (400 MHz, DMSOF) 5 ppm 13.40 (br.s., 1H), 8.32 (s, 1H), 8.14 (d, J=2.4Hz, 1H), 7.87 (d,./ = 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-(222-1,2,3-triazol-2-yl)pyridine, li

Cl

A mixture of 2,3-dichloro-5-nitropyridine (50 g, 259.08 mmol), 12/-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 mL x 2) and brine (500 mL), dried over anhydrous NazSCfi, filtered, and concentrated to dryness under reduced pressure. The residue was triturated with DCM (100 mL), filtered, and the solid was collected to afford compound li (40 g, 68%) as an off-white solid. LC-MS: (ES, m/z): [M+1 ]⁺ 225.9. *H NMR (400 MHz, DMSO-X) δ ppm 9.40 (d, J=2.0Hz, 1H), 9.15 (d, J=2.0Hz, 1H), 8.33 (s, 2H).

I. 5-Chloro-6-(22/-l,2,3-triazol-2-yi)pyridin-3-amine, Ij

Cl

3-Chloro-5-nitro-2-(22/-1,2,3-triazol-2-yl)pyridine, li (20 g, 88.656 mmol), MeOH (500 mL) and Pt/C (2 g, 5%, 0.513 mmol ) were added to a 1000 mL hydrogénation bottle.

190

The résultant mixture was stirred under a H? atmosphère (30 psi) at 25 °C for 20 h. The suspension was filtered though a pad of diatomaceous earth and the filter cake was washed with ethyl acetate (100 mL). The filtrate was concentrated to dryness under reduced pressure to afford a crude product. which was purified by préparative reverse phase HPLC (0% to 50% (v/v) CHsCN and water with 0.05% NH3), followed by lyophilization to dryness to afford compound Ij (10.4 g, 60 %) as an off-white solid. LC-MS: (ES. m/:)·. | M l Γ 196.1; Ή NMR (400 MHz, DMS0X₆) δ ppm 8.05 (s, 2H), 7.83 (d, J = 2.0 Hz, 1H), 7.21 (d. .T = 2.4 Hz, 1H), 6.19 (s. 2H).

J. 1 -(Benzofuran-4-yl)-A-(5-chloro-6-(2//-l ,2.3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)- 177-pyrazole-4-carboxamide, Cprl 34

POCI3 (112 mg. 0.729 mmol) was added dropwise to solution consisting of 1(benzofuran-4-yl)-5-(trifluoromethyl)-l/7-pyrazole-4-carboxylic acid, Ih (180 mg, 0.608 mmol), 5-chloro-6-(2//-l ,2,3-triazol-2-yl)pyridin-3-amine, Ij (131 mg, 0.668 mmol), and pyridine (5 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The resulting mixture was diluted with sat. aqueous NaHCO?(10 mL) and extracted with ethyl acetate (15 mL x 3). The organic extracts were dried over anhydrous NagSCU, filtered, and the filtrate concentrated to dryness under reduced pressure to give a crude residue, which was purified by FCC (petroleum ether: ethyl acetate = 1:1) to afford crude compound 34 (180 mg). Further purification by préparative reverse phase HPLC (43% to 73% (v/v) CH3CN and water with 0.05% NH3) afforded compound 34. which was then suspended in water (10 mL). frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 34 ( 166.10 mg, 57 %). LCMS (ESI): mass calcd. for C20H11CIF3N7O2 473.06, m/z found

191

473.9 [M+H]\ ‘H NMR (400 MHz, CDCh) 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, 1 H), 6.63 (d, J= 1.6 Hz, 1H).

Example 2

A%5-Chloro-6-(2/ï-l,2,3-triazol-2-yl)pyridiii-3-yl)-l-(naphthalen-l-yl)-5 (trifluoromethyl)- l//-pyrazole-4-carboxamide, Cpd 2

A. Ethyl l-(naphthalen-l-yl)-5-(trifhjoromethyl)-l#-pyrazole-4-carboxylate, 2a

Ethyl 2-(ethoxymethyIene)-4,4,4-trifluoro-3-oxobutanoate, lf (200 mg, 0.833 mmol) was added to a solution consisting of naphthalen-l-ylhydrazine (162 mg, 0.833 mmol), triethylamine (168 mg, 1.67 mmol) and éthanol (5 mL). The mixture was heated to reflux at 80 °C for 16 h. The resulting mixture was concentrated to dryness under reduced pressure to give a crude residue, which was purified by préparative high performance liquid chromatography using Phenomenex Gemini 150 x 25 mm x 10 pm ( 50% to 80% (v/v) ACN and water with 0.05% NH?) to afford compound 2a. Compound 2a was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 2a (129.80 mg, 47 %). LCMS (ESI): mass calcd. for C17H1JF5N2O2 334.293, m/z found 335.1 (Mil). Ή NMR (400 MHz, CDCh) δ ppm 8.26

192 (s, 1H), 8.04 (d, J =8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.59 - 7.50 (m, 4H), 7.19 (d. J =

8.0Hz, 1 H), 4.42 (q,J=7.2Hz, 2H), 1.41 (t, J= 7.2 Hz, 3H). LCMS (ESI) m/z M+l:

335.0.

B. 1 -(Naphthalen-l-yl)-5-(trifluoromethyl)-lÆ-pyrazole-4-carboxylic acid, 2b

A solution consisting of ethyl l-(naphthalen-l-yl)-5-(trifluoromethyl)-l/7-pyrazole4-carboxylate, 2a (1.20 g, 3.59 mmol), LiOH (452 mg, 10.8 mmol) and a water: EtOH mixture ( 12 mL, 1:2) was stirred at room température for 16 h. The solution was neutralized to about pH 7 with 4 M HCl, extracted with ethyl acetate (30 mL x 3), and dried over anhydrous Na2SO4. The extracts were concentrated to dryness under reduced pressure to afford compound 2b ( 1.00 g, 78 %), which was used in the foilowing reaction without further purification. LCMS (ESI): mass calcd. For C15H9F3N2O2 306.239, m/z found 306.9 [M+H]+ Ή NMR (400 MHz, DMSO-U) δ ppm 13.43 (br.s., 1H), 8.38 (s, 1H). 8.21 (d, J= 8.0 Hz, 1H), 8.12 (d,./ = 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. A^r-(5-Chloro-6-(2H-1,2,3-triazoI-2-yl)pyridin-3-yl)-l -(naphthalen-1 -yl )-5(trifluoromethyl)-lZ7-pyrazole-4-carboxamide, Cpd 2

193

POCh (90.1 mg, 0.588 mmol) was added dropwise to a solution consisting of 1 (naphthalen-l-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylic acid, 2b (150 mg, 0.490 mmol), 5-chloro-6-(2Z/-l,2,3-triazol-2-yl)pyridin-3-amine, Ij (105 mg, 0.539 mmol) and pyridine (2 mL). The mixture was stirred at 0 °C for 1 h. The resulting mixture was 5 concentrated to dryness under reduced pressure to give a crude product, which was purified by préparative reverse phase HPLC (46% to 76% (v/v) ACN and water with 0.05% NHs) to afford compound 2, which was then suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 2 (102.30 mg, 43 %). LCMS (ESI): mass calcd. for C22H13CIF3N7O483.833, m/z found 10 484.1 j M H | . Ή NMR (400 MHz, DMSO-A) δ ppm 9.08 (br.s., IH), 8.86 (d. J= 2.0 Hz.

IH), 8.69 (d, J = 2.0 Hz, IH), 8.57 (s, IH), 8.25 (d, J = 8.4 Hz, IH). 8.20 (s, 2H). 8.15 (d, J = 7.2 Hz, IH), 7.79 (d, J = 8.0 Hz, IH), 7.76 - 7.62 (m, 3H). 7.13 (d, J = 8.0 Hz, IH). LCMS (ESI) m/z MJ: 483.9.

Example 3

A⁷-(5-Chloro-6-(2/7-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolm-5-yl)-5-(trifluoromethyi)17/-pyrazole-4-carboxamide, Cpd 8

194

A. Ethyl l-(quinolin-5-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylate, 3a

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 5 If (905 mg, 3.77 mmol), 5-hydrazmylquino)me (500 mg, 3.14 mmol), and éthanol (20 mL) was stirred at 80 °C for 16 h before cooling to room température. The resulting solution was concentrated to dryness under reduced pressure, and then purified by FCC (petroleum ether: ethyl acetate = 1:1) to afford compound 3a (530 mg, 84 %) as a brown solid. LCMS (ESI): mass calcd. for C16H12F3N3O2 335.09, m/z found 335.8 j M I i | . ^lH NMR (400

MHz, CDCb) 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, ./ = 4.4, 8.8 Hz, 1H), 4.43 (q,./= 6.8 Hz, 2H), 1.42 (t, J= 7.2 Hz, 3H). LCMS (ESI) m/z M+l : 335.8.

B. l-(Quinolin-5-yl)-5-(trifluoromethyl)-177-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)1//-pyrazole-4-carboxylate, 3a (1.00 g, 2.98 mmol) in éthanol (10 mL). The resulting solution was stirred at room température for 16 h, 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 was washed with water (10 mL) and dried under reduced pressure to afford compound 3b (910 mg, 99 %) as a yellow solid. LC-MS (ESI); mass calcd. for C14H8F3N3O2 307.06, m/z found 308.0

195 |\l - H j . Ή NMR (400 MHz. DMSO-Λ) δ ppm 9.03 (s, 1H). 8.40 (s. 1 H). 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+L 308.0.

l-(Quinolin-5-yl )-5-( trifluoromethyl)-l//-pyrazole-4-carbonyl chloride, 3c

Oxalyl dichloride (0.0830 mL, 0.976 mmol) was added to solution consisting of 1( quinolin-5-yl)-5-( trifluoromethyl)-l//-pyrazole-4-carboxylic acid, 3b (200 mg, 0.651 mmol), dichloromethane (15 mL), and DMF (catalytic amount). The solution was stirred at room température for 1 h. The resulting solution was concentrated to dryness to afford compound 3c (200 mg, crude), wdiich was used in the follow'ing reaction without further purification.

D. A⁷-(5-Chloro-6-( 2//-1,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)-l//-pyrazole-4-carboxamide, Cpd 8

A solution consisting of l-(quinolin-5-yl)-5-(trifluoromethyl)-l/7-pyrazole-4carbonyl chloride. 3c (200 mg, 0.614 mmol), 5-chloro-6-(2/f-L2,3-triazol-2-yl)pyridin-3amine, Ij (144 mg, 0.737 mmol), and pyridine (10 mL) was stirred at 90 °C for 1 h before cooling to room température. The mixture was concentrated to dryness under reduced pressure, which was then purified by préparative HPLC using a Kromasil 150 x 25 mm x 10 μηι column ( 32% to 62% (v/v) CHsCN and water with 0.05% NHs) to afford

196 compound 8 (149.20 mg. 50 %) as a white solid. LCMS (ESI): mass calcd. for CziHnClFsNsO 484.08, m/z found 485.1 [M+H]C Ή NMR (400 MHz, CDCh) 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

AM3-chloro-4-(2H-L2,3-triazol-2-yl)phenyl)-l-(isoqumolm-4-yl)-5-(trifluoromethyl)-12L pyrazole-4-carboxamide, Cpd 38

A. 4-Hydrazinylisoquinoline, 4a

NH

NH₂ ,4a

To a stirring solution of isoquinolin-4-amine (5.0 g, 34.68 mmol) in HCl (50 mL, 5N) at 0° C was added a solution of sodium nitrite (NaNCL, 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 (SnCh.2 Η?Ο. 19.56 g, 86.70 mmol) in concentrated hydrochloric acid (5 mL) was added dropwise. The mixture was stirred at room température for 2 h. The mixture was adjusted to about pH 12-14 with 20 % aqueous sodium hydroxide. At that time, the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic extracts were washed with brine (300 mL). The organic portion was dried over NaiSO^ filtered, and the filtrate concentrated under reduced pressure. The résultant crude product was purified by flash chromatography (petroleum ether/ ethyl acetate = 100:0 to ethyl

197 acetate/ methanol = 90:10) to afford compound 4a ( 1.15 g, 20.8%) as a brown solid, which was used in the following reaction without further purification.

B. Ethyl 1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate. 4b

A mixture of 4-hydrazinylisoquinoline, 4a (1.15 g, 7.224 mmol) and ethyl (Z)-2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate. If (2.08 g. 8.669 mmol) in EtOH (30 mL) was stirred at 80 °C for 16 h. The resulting solution was cooled to room température and concentrated to dryness under reduced pressure to afford a crude product. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate= 100:0 to 70:30) to afford compound 4b (1.77 g, 72.98 %) as a yellow solid. LCMS (ESI) m/z M+l: 335.9; Ή NMR (400 MHz, CDCh) δ ppm 1.41 (t, J=7.06 Hz, 3 H) 4.42 (q, J=7.06 Hz, 2 H) 7.31 (d, J=8.38 Hz. 1 H) 7.70 - 7.80 (m, 1 H) 8.12 (dd, J=7.28, 1.10 Hz, 1 H) 8.28 (s, 1 H) 8.58 (s, 1 H) 9.41 (s, 1 H).

l-(Isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 4c

A solution of ethyl l-(isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxvlate, 4b (500 mg, 1.49 mmol) in concentrated hydrochloric acid (5 mL) was stirred at 130 °C for 3 h. The solvent was concentrated under reduced pressure to afford compound 4c (465.61 mg. 100 %) as a yellow solid. LCMS (ESI) m/z M+l: 307.9.

198

D. 2-(2-Chloro-4-nitrophenyl)-2H-l,2,3-triazole, 4d

Cl

To a solution of 3-chloro-4-fluoronitrobenzene (1.2 g, 6.836 mmol) and 2H-1,2.3triazole (0.567 g, 8.203 mmol) in anhydrous DMA (5 mL) was added K2CO3 ( 1.89 g, 13.7 5 mmol). The reaction mixture was stirred at 55 °C ovemight. The reaction was concentrated to give a crude oil. The crude product was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 20/80) to give compound 4d (1 g. 65.1 %) as a yellow solid. ’H NMR (400 MHz, CDCh) δ ppm 7.88 8.02 (m, 3H). 8.28 (dd, .1=8.93, 2.54 Hz, 1H), 8.49 (d, J=2.21 Hz, 1H).

E. 3-Chloro-4-(2H-l,2,3-triazol-2-yl)aniline, 4e

Cl

To a solution of 2-(2-chloiO-4-mtrophenyl)-2H-l,2,3-triazole, 4d (1 g, 4.45 mmol) in MeOH 11ΙΓ water (5 mL/10 mL/5 mL) was added Fe(0) (1.243 g, 22.26 mmol) and 15 ammonium chloride (1.191 g, 22.26 mmol). The reaction mixture was stirred at 60 °C for

h. The reaction was filtered and the organic solvent was concentrated under reduced pressure. Water (10 mL) was added and the mixture w^ras extracted with ethyl acetate (15 mL x 3). The organic extracts were dried over MgSOg, filtered, and the filtrate was concentrated under reduced pressure to afford a crude product which was purified by flash 20 column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 0/100) to afford 3-chloro-4-(277-l,2,3-triazol-2-yl)amline, 4e (0.7 g, 80.8 24) as a yellow solid. ‘H NMR (400 MHz, CDCh) 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.

A^T-(3-Chloro-4-(2/7-1,2,3-triazol-2-yl)phenyl)-1 -(isoquinolin-4-yl)-5(trifluoromethyl)- l//-pyrazole-4-carboxamide, Cpd 38

To a solution of l-(isoquinolin-4-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylic acid, 4c (60 mg, 0.195 mmol), 3-chloro-4-(2//-l,2,3-triazol-2-yl)anilme. 4e (45.6 mg, 0.234 mmol) and pyridine (77.2 mg, 0.98 mmol) in dichloromethane (5 mL) was added

POCL (89.8 mg, 0.59 mmol) dropwise. The reaction mixture was stirred at 20 °C for l h. Saturated aqueous NaHCCh (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic extracts were washed with brine, dried over Na?SO₄, filtered, and the filtrâtes concentrated under reduced pressure to afford a yellow oil. The yellow oil was purifïed by column chromatography over silica gel (petroleum ether/ ethyl acetate = 10: l to petroleum ether/ ethyl acetate = 0: l) to afford compound 38 (35 mg, 35.8 %) as a white solid. 'H NMR (400 MHz, CDCL) δ ppm 7.34 (d, J=8.4l Hz, l H), 7.58 - 7.68 (m, 2 H). 7.72 - 7.84 (m, 2 H), 7.89 (s, 2 H). 7.96 - 8.06 (m, 2 H), 8.15 (d, J=7.43 Hz, 1 H), 8.24 (s, 1 H), 8.60 (s, 1 H), 9.44 (s, 1 H); LCMS (ESI) m z M+l: 483.9.

Example 5

M-(3-Cyano-4-(227- L2,3-triazol-2-yl)phenyl )-1 -( isoquinolin-4-yl)-5-(trifluoromethyl )-1Hpyrazole-4-carboxamide, Cpd 59

A. 5-Nitro-2-(22/-l,2,3-triazol-2-yl)benzonitrile, 5a

200

2-Fluoro-5-nitrobenzonitrile (500 mg, 3.01 mmol), 2//-l,2,3-triazole (228.68 mg, 3.311 mmol) and K2CO3 (832.02 mg, 6.02 mmol) were added to THF ( K) mL) and stirred at 25 °C for 16 h. 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 afford a crude residue as a yellow solid which was purified by flash column chromatography over silica gel (petroleum ether/ ethyl acetate, 100:0 to 50:50) to afford 5-mtro-2-(2/7-L2,3-triazol-2-yl)benzonitrile, 5a ( 140 111g, 21.6 %) as a white solid. ‘H NMR (400 MHz, CDCh) 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-(2Zf-l,2,3-triazol-2-yl)benzonitrile, 5b

5-Nitro-2-(227-L2,3-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), NH4CI (348.04 mg, 6.507 mmol) and water (8 mL) were added. The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with ethyl acetate (20 mL x 3). Water (50 mL) was added and the organic layer was separated, dried over Na₂SO₄, filtered, and the filtrate concentrated to dryness to give crude compound 5b (140 mg) as yellow solid. which was used in the following reaction without further purification. LCMS (ESI) m/z Μ 1: 186.1.

C. N-(3-Cyano-4-(2H-l,2,3-triazol-2-yl)phenyl)-l-(isoquinolm-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 59

5-Amino-2-(2//-l,2,3-triazoI-2-yl)benzonitrile , 5b (67.03 mg, 0.21 mmol), l(isoqumolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid. 4c (66.95 mg, 0.315 mmol), and pyridine (74.84 mg, 0.946 mmol) were dissolved in dichloromethane (j mL), and POCh (48.36 mg, 0.315 mmol) was added to the mixture. The mixture was stirred at 25 °C for 16 h. Saturated aqueous NH4CI (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic extracts were dried over Na₂SO₄, filtered and the filtrâtes were concentrated under reduced pressure to afford a yellow oil. The oil was purified by flash column chromatography over silica gel (Petroleum ether/ ethyl acetate from 100:0 to 40/60) to afford compound 59 (38 mg, 36.3 %) as a white solid. ‘H NMR (400 MHz, DMSO-X) 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 (br d, J=5.5 Hz, 1H). LCMS (ESI) m/z M+l: 475.0.

Example 6

A⁷-(5-Chloro-6-(oxazol-2-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5-( trifluoromethyl )-l Hpyrazole-4-carboxamide, Cpd 50

A. 2-(3-Chloro-5-nitropyridin-2-yl)oxazole, 6a

202

2,3-Dichloro-5-nitropyridine (216 mg, 1.119 mmol) and 2-(tnbutylstannyl)oxazole (400.1 mg, l.l 19 mmol) were dissolved in DMF (3 mL) and purged with Lb. Pd(PPh3)4 (129 mg, 0.112 mmol) was added and the reaction was stirred at 110 °C for 16 h. The combined reaction mixture was concentrated under reduced pressure to afford a crude black oil. The oil was purified by flash, column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30) to afford 2-(3-chloro-5-nitropyridin-2-yl)oxazole, 6a (150 mg, 59.4 %) as a yellow solid. ‘H NMR (400 MHz, CDCh) 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+l: 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 ), andNHjCl (208.6 mg, 3.90 mmol) were added to a mixture of THF (5 mL) and water (1 mL). The reaction mixture was stirred at 80 ^CC for 3 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was w-ashed with ethyl acetate (20 mL x 3). The combined filtrâtes were concentrated to dryness to give a crade yellow oil as product. The crade product was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 50/50 to 0/100) to afford 5-chloro-6-(oxazol-2-yl)pyridin-3-amme , 6b (50 mg, 65.5 %) as a yellow oil, which was used in the following reaction without further purification.

203

C. N-(5-Chloro-6-(oxazoI-2-yl)pyridin-3-yl)-l-(isoquinolm-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 50

POCh (78.4 mg, 0.5 l l mmol ) was added to a mixture of 5-chloro-6-(oxazol-2yI)pyridin-3-amine , 6b (50 mg, 0.256 mmol ), l-(isoqumolin-4-yl )-5-( trifluoromethyl)lH-pyrazole-4-carboxylic acid, 4c (62.8 mg, 0.204 mmol). and pyridine (TOI mg, 1.278 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at 20 °C for 16 h. Water (20 mL) was added to the mixture. The mixture was extracted with dichloromethane (30 mL). The organic layer was concentrated under reduced pressure to afford a crade product, which was purified by préparative reverse phase HPLC (water (0.05% HCl):MeCN from 76 % to 46 %) and lyophilized to give A^r-(5-chloro-6-(oxazol-2yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5-(trifluoromethyl)-lJï-pyrazole-4-carboxamide, compound 50 (28 mg, 22.6 %) as a white solid. ^lH NMR (400 MHz, METHANOL-cL) δ ppm 7.50 (s, l H), 7.65 (d, J=8.38 Hz, I H), 8.11 - 8.21 (m, 2 H), 8.27 (t, J=7.20 Hz, 1 H), 8.53 (s. 1 H), 8.60 - 8.70 (m. 2 H), 8.97 (br s, 1 H). 9.05 (s. 1 H), 9.98 (s, 1 H); LCMS (ESI) m/z M+l: 484.9.

Example 7

AA-cyano-6-(2JY-lA-triazol-2-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5-(trifluoromethyl)IÆ-pyrazole-4-carboxamide, Cpd 47

204

A. 5-Nitro-2-(2H-1,2,3-triazol-2-yl)nicotinomtrile, 7a

N=A

A mixture of 2-chloro-5-nitronicotinonitrile (600 mg, 3.27 mmol), 1,2,3-triazole (270 mg, 3.92 mmol) and K2CO3 (1.35 g, 9.8 mmol) in CH3CN (10 mL) was stirred at 30 °C for 2 h. A yellow solid was collected by filtration and was washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to give a crude product which was washed with dichloromethane (10 mL). The solid was dried under reduced pressure to give 5-nitro-2-(2/f-l,2,3-triazol-2-yl)mcotinonitrile, 7a (0.4 g, 56.6 %) as a white solid. Ή NMR (400 MHz, DMSO-U) δ ppm 8.44 (s, 2 H), 9.43 (d, J=2.35 Hz, 1 H), 9.59 (d, J=2.35 Hz, 1 H).

B. 5-Amino-2-(2//-l,2.3-triazol-2-yl)nicotinonitrile, 7b

N U /

N ,7b

A solution of 5-nitro-2-(2/7-1,2,3-triazol-2-yl)nicotinonitrile, 7a (353 mg 1.6 mmol), Fe(0), (456 mg, 8.2 mmol) and NH₄C1 (437 mg, 8.2 mmol) in THF/MeOH/water (4:2:1, 35 mL) was stirred at 60 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product as a yellow oil. Water (20 mL) was added to the yellow oil. The mixture was extracted with ethyl acetate (30 x 3 mL), dried over MgSO₄, filtered and the filtrate concentrated under reduced pressure to afford 5-ammo-2-(2//-l,2,3-triazol-2-yl)nicotinonitrile, 7b (200 mg, 65.7 %) as a white solid, which was used m the foilowing reaction without further purification. ‘H NMR (400 MHz. METHANOL-Λ) δ ppm 7.46 (d, J=3.09 Hz, 1 H), 8.00 (s, 2 H). 8.10 (d, J=3.09 Hz, 1 H).

205

C. A/5-Cyano-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl)- 177-pyrazole-4-carboxamide, Cpd 47

POCh (82.36 mg, 0.537 mmol) was added to a mixture of 5-amino-2-(2/7-1,2,3triazol-2-yl)nicotinonitrile, 7b (50 mg, 0.269 mmol), l-(isoquinolin-4-yl)-5(trifluoromethyl)-lÆ-pyrazole-4-carboxylic 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 w^;as extracted with dichloromethane (30 mL). The organic layer was concentrated under reduced pressure to afford a crude product. The crude product was purified by préparative high-performance liquid chromatography (water (0.05% HCl):MeCN from 84:16 to 66:44). The pure fractions were collected, the organic solvents concentrated under reduced pressure, and the mixture Ivophilized to dryness to afford compound 47 (29 mg, 22.7 %) as a yellow solid. 'H NMR (400 MHz, METHANOL-Λ) δ ppm 7.51 (d, J=8.82 Hz, 1 H), 7.97 - 8.03 (m, 1 H), 8.07 8.16 (m, 3 H), 8.47 - 8.51 (m, 2 H), 8.85 (s, 1 H), 8.91 (d, J=2.43 Hz, 1 H), 9.08 (br s, 1 H). 9.75 (s, 1 H); LCMS (ESI) m/z M+l: 476.0.

Example 8

W-(5-chloro-6-(l-methyl-l/7-pyrazol-3-yl)pyridin-3-yI)-l-(isoquinolin-4-yl)-5 (trifluoromethyl)-17ï-pyrazole-4-carboxamide, Cpd 52

6-Bromo-5-chloropyridin-3-amine (383.87 mg, 1.85 mmol), l-methyl-3-(4,4,5.55 tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (350 mg, 1.682 mmol) andNaiCO? (356.58 mg, 3.364 mmol) were added to dioxane/water (9:1. 6 mL) and purged with Ni. Pd(dppf)Ch( 123.09 mg, 0.168 mmol) was added and the reaction was stirred at 120 °C for 16 h. The reaction mixture was filtered though a pad of diatomaceous earth and the. pad was washed with ethyl acetate (20 mL x 3). The combined filtrâtes were concentrated to dryness to give a crade black oil. The black oil was purified by préparative reverse phase HPLC. The pure fractions were collected, the organic solvents concentrated under reduced pressure, and the mixture lyophilized to dryness to afford 5-chloro-6-( 1-methyl-lHpyrazol-3-yl)pyridin-3-amine, 8a (150 mg, 42.7 %, yield) as a yellow oil. LCMS (ESI) m/z M+l: 209.1.

B. A⁷-(5-Chloro-6-(l-methyl-lH-pyrazol-3-yl)pyndin-3-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 52

207

To a solution of ethyl l-(isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate, 4b (106.95 mg, 0.335 mmol), 5-chloro-6-( l-methyl-l/Tpyrazol-3-yl)pyridin3-amine, 8a (70 mg, 0.335 mmol) and pyridine (132.69 mg, 1.677 mmol) in dichloromethane (5 mL) was added POCh (102.88 mg, 0.671 mmol) dropwise. The reaction mixture was stirred at 20 °C for l h. A solution of saturated aqueous NaHCOj (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with brine and dried over Na/SCh. The mixture was filtered, and the filtrâtes concentrated under reduced pressure to afford a crude product as a yellow oil. The crude product was purifïed by flash column chromatography over silica sel (dichloromethane: MeOH = from 100:0 to 80:20) to afford a residue, which was further purified by préparative reverse phase HPLC. The pure fractions were collected, the organic solvents concentrated under reduced pressure, and the mixture lyophilized to dryness to give A-(5-chloro-6-( 1 -methyl-17f-pyrazol-3-yl)pyridin-3-yl)-l-(isoquinolin-4yl)-5-(trifluoromethyl)-lFpyrazole-4-carboxamide, compound 52 (45 mg, 26.7 %) as a yellow solid. ‘H NMR (400 MHz. DMSOF) δ ppm 11.03 (br s, 1H), 9.60 (s, 1H), 8.83 (d, ./=2.0 Hz. 1H), 8.77 (s, 1H), 8.58 (s, 1H), 8.42 (d, 7=2.0 Hz. 1H), 8.36 (d, 7=8.2 Hz, 1H), 7.96 - 7.89 (m, 1H). 7.88 - 7.82 (m, 1H), 7.77 (d, 7=2.2 Hz, 1H), 7.27 (d, 7=8.4 Hz, 1H). 6.75 (d, 7=2.0 Hz, 1H), 3.91 (s, 3H). LCMS (ESI) m/z M+l: 497.9.

Example 9

A-(5-chloro-6-(27/-L2,3-triazol-2-yl)pyridin-3-yl)-l-(isoqumolm-4-yl)-5(trifluoromethyl)- H7-pyrazole-4-carboxamide. Cpd 32

A 20 mL vial equipped with a stirbar was charged with ethyl l-(isoqumolin-4-yl).25 5-(trifluoromethyl)-l/Apyrazole-4-carboxylate, 4b (67 mg, 0.2 mmol), 5-chloro-6-(277L2.3-triazol-2-yl)pyndin-3-amine. Ij (39.9 mg. 0.204 mmol), and THF (0.67 mL, 0.3 M,

208

0.201 mmol). The resulting solution was treated with 1.01 M KOtBu/THF (0.32 mL, 1.01 M, 0.323 mmol) in one portion at room température and then stirred for 25 min. The reaction was then partitioned between 5 M NH4CI (1 mL) and ethyl acetate (2 mL), and the organic layer was dried over Na2SO4, fïltered, and the filtrate concentrated to dryness to provide a beige foam (78 mg). The foam w^ras purified by flash column chromatography on a 12 g Silicycle HP column (10 - 100% EtOAc in heptane over 25 CVs, then isocratic EtOAc) to provide compound 32 as a foam (27.4 mg, 28 %). ’H NMR (400 MHz, CDCL) δ ppm 9.45 (s, 1H), 8.80 (d, 7=2.53 Hz, 1H), 8.66 (br s, 1H), 8.49-8.59 (m, 2H), 8.25 (s, 1H), 8.16 (dd, 7=1.52, 7.07 Hz, 1H), 7.92-8.00 (ni, 2H), 7.71-7.83 (m, 2H); MS m/e 485.0 (M+H).

Example 10

A-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(isoquinolin-1 -yl )-5( trifluoromethyl )- lÆ-pyrazole-4-carboxamide, Cpd 57

A 2-5 mL Biotage microwave vial equipped with a stirbar was charged with 1 - chloroisoquinoline (341.8 mg, 2.089 mmol) and hydrazine (0.66 mL. 1.021 g ml- 21.028 mmol) at room température, and the vial was evacuated/flushed with Argon (4x) and the reaction was stirred at 150 °C for 20 min. The resulting dark yellow homogeneous solution was allowed to cool to room température, at which time a precipitate formed.

209

This was taken up in a 3:l water/CH.?CN mixture (2 mL) and the solids were collected by filtration. The yellow filter cake was washed with water (2 mL x 3) and then dissolved in DCM (6 mL). The DCM mixture was dried over Na₂SO₄, filtered, and the filtrate concentrated to provide compound 10a as a yellow solid (189 mg, 57 %).

B. A%5-Chloro-642H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(isoquinolin-l-yl)-5(trifluoromethyl)- 17/-pyrazole-4-carboxamide. Cpd 57

A 4 mL vial equipped with a with stirbar was charged with 110 hydrazinylisoquinoline, 10a (45.5 mg, 0.286 mmol), THF (0.41 mL, 0.7 M, 0.287 mmol), and 0.5 M ethyl 2-(ethoxymethylene)-4,4.4-trifluoro-3-oxobutanoate, If/THF (0.57 mL, 0.5 M, 0.285 mmol). and the reaction was stirred at room température for 10 min, followed by 90 min of stirring at 70 °C. The reaction was then charged with calcium sulfate (183 mg, 1.34 mmol) and stirred at 70 °C for 10 min. The réaction was then cooled to room température, treated with 5-chloro-6-(2A/-l,2,3-triazol-2-yl)pyridin-3-amine, Ij (56.6 mg, 0.288 mmol) and 1.01 M KOtBu/THF (0.42 mL, 1.01 M, 0.424 mmol) in single portions at room température, and the resulting dark reaction was stirred at room température for 30 mm. The dark réaction was then partitioned between 5 M NH₄C1 (1 mL) and ethyl acetate ( 1 mL), and the organic layer was dried over Na₂SO₄, filtered, and the filtrate concentrated under reduced pressure. The résultant residue was purified by flash column chromatography (50 - 100% EtOAc in heptane over 10 CVs) followed by ( L1 acetone/heptane; isocratic) to afford compound 57 (21.3 mg, 15 %). ^lH NMR (400 MHz, CDCh) δ ppm 8.77 (d, .7=2,02 Hz. 1H), 8.50-8.53 (m, 2H). 8.26 (s, 1H), 7.91-8.02 (m, 4H), 7.83 (ddd, 7=2.78, 5.56, 8.34 Hz. 1 H), 7.67-7.72 (m, 2H); MS m/e 485.1 (M+H).

210

Example 11

N-(3-cyano-4-( 1H-1,2.3-triazol-1 -yl )pheny 1 )-1 -( isoquinolin-4-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide, Cpd 62

A. 5-Nitro-2-(lE/-L2,3-triazol-l-yl)benzonitrile, lia

N'N l A pAA o₂nZZ-_cn , _Iia

2-Fluoro-5-nitrobenzonitrile (500 mg, 3.01 mmol), triazole (228.7 mg, 3.31 mmol) and K2CO3 (832.0 mg, 6.02 mmol) were added to THF (10 mL) and stirred at 25 °C for 16 h. The reaction mixture was filtered and the residue was washed with ethyl acetate (30 mL x 3). The combined organic layers were concentrated under reduced pressure to afford a crude yellow solid. The crude solid was purified by flash column chromatography over silica gel (petroleum ether/ ethyl acetate from 100:0 to 50:50) to afford 5-nitro-2-(lHl,2.3-triazol-l-yl)benzonitrile, lia (500 mg, 77.2 %) as a yellow solid. ^lH NMR (400 MHz, CDCH) 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-( 1/7-1,2,3-triazol-l-yl)benzonitrile, 11b

5-Nitro-2-(l//-I,2,3-triazol-l-yl)benzonitrile, lia (500 mg, 2.32 mmol) was dissolved in THF (10 mL), to which Fe(0) ( 1297.7 mg, 23.24 mmol), NH4CI (1243.0 mg,

211

23.24 mmol) and water (10 mL) were added. The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with ethyl acetate (20 mL x 3). Water (30 mL) was added and the organic layer was separated, dried over Na₂SO₄, filtered and the filtrate concentrated to dryness to give crude 5-amino-2-(lH- L2,3-triazol-l-yl)benzonitrile, 11b (460 mg, 104.4 %, crude) as a yellow solid. LCMS (ESI) m/z M+L 185.9.

C. ;V-(3-cyano-4-(T/Z-l,2,3-triazol-l-yl)phenyl)-I-(isoquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 62

l-(Isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid. 4c (75.1 mg, 0.23 mmol). 5-amino-2-(l.H-L2,3-triazol-l-yl)benzomtrile, 11b (66.4 mg, 0.35 mmol), and pyridine (83.1 mg, 1.05 mmol) were dissolved in dichloromethane (3 mL), and POCh (53.7 mg, 0.35 mmol) was added. The mixture was stirred at 25 °C for 16 h. Sat. aqueous NH₄C1 (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered and the filtrâtes were concentrated under reduced pressure to afford 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%) at the end: A: (32%) and B (68%)). The pure fractions were collected, concentrated under reduced pressure, and lyophilized to dryness to afford compound 62 (35 mg, 29 %) as a white solid. LCMS (ESI) m/z M+l: 185.9; Ή NMR (400 MHz, DMSO0) δ ppm 11.48 (s, 1H), 9.69 (s, 1H), 8.86 (s, 1H), 8.77 (br d, >4.0 Hz, 2H), 8.53 (brd, >1.3 Hz, 1H), 8.43 (br d, >8.3 Hz, 1H), 8.31 (br d, >8.8 Hz, HT), 8.07 (s, 1H), 8.03 - 7.96 (m, 1H), 7.96 - 7.87 (m, 2H), 7.35 (br d, >8.5 Hz, 1 H).

212

Example 12 yV-(5-cyano-6-(l-methyl- lH-pyrazol-3-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 78

A. 5-Amino-2-chloronicotinonitrile, 12a

2-Chloro-5-nitronicotinonitrile (500 mg, 2.72 mmol) was dissolved in THF (10 mL), to which was added Fe (0) (1521.2 mg, 27.24 mmol), NH4CI (1457.1 mg, 27.24 mmol) and water (10 mL). The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was fïltered though a pad of diatomaceous earth and the pad w^ras washed with ethyl acetate (20 mL x 3). Water (50 mL) w’as added and the organic layer was separated. dried over Na2SO4. fïltered and the filtrate was concentrated to dryness to give a crude yellow solid. The crude solid w^as purified by flash column chromatography over silica gel (petroleum ether/ ethyl acetate from 100/0 to 80/20) to afford 5-amino-2chloronicotinonitrile, 12a (270 mg. 64.5 %) as a yellow solid. *H NMR (400 MHz, CDCL0 δ ppm 7.73 (d, J=2.8 Hz, 1 H), 7.04 (d, J=2.8 Hz, 1H), 4.96 (br s. 2H).

B. 5-Amino-2-(l-methyl- 177-pyrazol-3-yl)nicotinonitrile, 12b

213

5-Amino-2-chloiOmcotinonitrile, 12a (100 mg, 0.65 mmol), 1-methyl-3-(4,4,5,5tetramethyI-l,3,2-dioxaborolan-2-yl)-lÆ-pyrazole (135.5 mg, 0.65 mmol) and Na2CCh (138.0 mg, 1.30 mmol) were added to a dioxane/water mixture (9:1,6 mL) and the reaction was purged with N?. Pd(dppf)Ch (47.6, 0.065 mmol) was added and the reaction was stirred at 100 °C for 16 h. The reaction mixture was concentrated to dryness to give a crude black oil. The crude oil was purified by flash column chromatography over silica gel (dichloromethane / MeOH from 100/0 to 90/10) to afford 5-amino-2-(l-methyl-l/7pyrazol-3-yl)nicotinonitrile, 12b (100 mg, 51.3 %) as a black solid. LCMS (ESI) m/z Ml: 200.1.

C. AM5-cyano-6-(l-methyl-lH-pyrazoI-3-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl)-l/f-pyrazole-4-carboxamide, Cpd 78

l-(Isoquinolin-4-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylic acid, 4c (70 mg, 0.22 mmol), 5-amino-2-(l-methyl-lE^pyrazol-3-yl)mcotinonitrile, 12b (97.8 mg, 0.33 mmol), and pyridine (74.5 mg, 0.98 mmol) were dissolved in dichloromethane (3 mL), and POCh (50.0 mg, 0.32 mmol ) was added. The mixture was stirred at 25 °C for 16 h. Sat. aqueous NaHCOs (20 mL) was added and the mixture extracted with dichloromethane (20 mL x 2). The combined organic layers were dried over NaîSO#, filtered, and the filtrâtes were concentrated under reduced pressure to afford a crude yellow oil. The oil was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: A/B (75%/25%

214 to 48%/52 %). The pure fractions concentrated under reduced pressure and lyophilized to dryness to give compound 78 (50 mg, 46 %) as a yellow solid. LCMS (ESI) m/z M+l: 489.0. ‘H NMR (400 MHz, DMSO0) 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, JH), 7.99 - 7.91 (m, 1H), 7.90 5 7.80 (m, 2H), 7.29 (br d. J=8.2 Hz. 1H), 6.85 (d, J=1.8 Hz, LH), 3.94 (s, 3H).

Example 13

A+(5-cyano-6-(l -methyl- lH-pyrazol-3-yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 89

A. 5-Hydrazinylquinoline, 13a

NH nh₂, 13a

To a stirring solution of isoquinolin-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?, 2.51 g, 36.42 mmol) m water at 0° C. The reaction mixture was stirred at 0 °C for 30 min and a solution of tin (Π) chloride dihydrate (SnCh.2 H?O, 13.695 g, 60.69 mmol) dissolved in concentrated hydrochloric acid (6.5 mL) was added dropwise. The mixture was stirred at room température for 2 h. The mixture was adjusted to pH 12-14 with 20% aqueous sodium hydroxide. The mixtuie was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (300 mL). The organic layers were dried over Na/SCL. filtered, and the filtrate concentrated under reduced pressure. The resulting crude product was pmified by flash

215 chromatography (petroleum ether/ ethyl acetate=100:0 to ethyl acetate/ méthane 1=90:10) to afford compound 13a (1.5 g, 39 %) as a brown solid.

B. Ethyl l-(quinolin-5-yl)-5-(tnfluoromethyl)-lH-pyrazole-4-carboxylate, 13b

A solution of 5-hydrazinylquinoline, 13a (1.5 g, 9.42 mmol) and ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate. If (2.716 g, 11.31 mmol) in EtOH (40 mL) was stirred at 80 °C for 16 h. The résultant solution was cooled to room température and concentrated to dryness under reduced pressure to afford a crude product. which was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate, 100:0 to 70:30) to afford crude compound 13b (2.56 g, 80.9 %) as a yellow solid. LCMS (ESI) m/z M+l : 336.4. Ή NMR (400 MHz, CDCh) δ ppm 1.34 - 1.47 (m, 3 H), 4.36 - 4.48 (m, 2 H), 7.41 - 7.50 (m, 1 H), 7.55 - 7.67 (m, 2 H), 7.77 - 7.86 (m, 1 H). 8.25 (s, 1 H), 8.29 - 8.38 (m, 1 H), 8.96 - 9.06 (m, 1 H).

C. AY-cyano-ô-f 1 -methyl-1 Æ-pyrazol-3-yl )pyridin-3-yl)-1 -(quinolin-5-yl)-5- ( trifluoromethyl)-l/f-pyrazole-4-carboxamide. Cpd 89 /

l-(Quinolin-5-yl)-5-(trifluorornethyl)-lH-pyrazole-4-carboxylic acid, 3b (102.2 mg, 0.33 mmol), 5-amino-2-(l-methyl-lH-pyrazol-3-yl)nicotinonitrile, 12b (150 mg, 0.50 mmol), and pyridine (118.47 mg, 1.50 mmol) were dissolved in dichloromethane (3 mL),

216 and POCh (76.496 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h. Sat. aqueous NaHCCh (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic layers were dried over Na2SO4. filtered, and the filtrâtes were concentrated under reduced pressure to afford a crude yellow oil. The oil was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: AB (75%/25% to 45%/55 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 89 (85 mg, 52 %) as a yellow solid. LCMS (ESI) m/z M+l: 489.1; ΉNMR (400 MHz, DMSO-U) 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).

Example 14 ïV-(5-Chloro-6-( 1 H-pyrazol-l-yl)pyridin-3 -yl)-l-(isoquinolin-4-yl)-5-( trifluoromethyl)-IHpyrazole-4-carboxamide, Cpd 46

3-Chloro-5-nitro-2-( lH-pyrazol-l-yl)pyridine, 14a

2,3-Dichloro-5-nitropyridine ( 1g, 5.18 mmol). pyrazole (529 mg, 7.77 mmol). and

Cs2CO3(5.06 g. 15.50 mmol) were added to DMF (15 mL) and stirred at 20 °C for 16 h.

The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude yellow oil. The yellow oil was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=l :0 to petroleum ether/ ethyl acetate=10:1 ) to give compound 14a (511 mg, 43.907 %) as a yellow solid. LCMS (ESI) m/z M+l : 224.8;

217 ’H NMR (400 MHz, CDCh) δ ppm 6.57 (d, J=1.76 Hz, 1 H), 7.90 (s, 1 H), 8.37 - 8.46 (m, 1 H), 8.42 (d, J=2.65 Hz, 1 H), 8.71 (d, J=2.21 Hz.l H), 9.21 (d, J=2.21 Hz, 1 H).

B. 5-Chloro-6-(lH-pyrazol-l-yî)pyridin-3-amine, 14b

3-Chloro-5-nitro-2-(lH-pyrazol- l-yl)pyridine, 14a (500 mg, 2.26 mmol) was added to a mixture of Fe (0) (621.6 mg, 11.13 mmol), NH₄C1 (595.4 mg, 11.13 mmol) in MeOH (10 mL), water (5 mL), and THF (20 mL). The reaction was stirred at 60 °C for 1 h. The réaction mixture was filtered, and the fîltrate was concentrated under reduced pressure to give a crude yellow oil. The crude oil was purified by column chromatography over silica gel (petroleum ether, ethyl acetate=l:O to petroleum ether/ ethyl acetate=O: 1) to give compound 14b (300 mg, 69.2 %) as a yellow solid. ^!H NMR (400 MHz, CDCL) δ ppm 6.44 (s. 1 H), 7.15 (d. J=2.35 Hz, 1 H). 7.75 (s. 1 H), 7.85 - 7.91 (m, 2 H).

C. A%5-chloro-6-(lH-pyrazol-l-yl)pyridin-3-yl)-l-(isoqumolin-4-yl)-5(trifluoromethyl)-lH-pyrazo!e-4-carboxamide, Cpd 46

POCL (78.8 mg, 0.514 mmol ) was added to a mixture of 5-chloro-6-(lH-pyrazoll-yl)pyridin-3-amine, 14b (50 mg,0.26 mmol ), l-(isoquinolin-4-yl)-5-(trifluoromethyl)20 lH-pyrazole-4-carboxylic acid, 4c (63.1 mg, 0.21 mmol), and pyridine (101.6 mg, 1.3 mmol) m dichloromethane (5 mL). The reaction mixture was stirred at 20 °C for 16 h. Water (20 mL) was added to the mixture. The mixture was extracted with dichloromethane (30 mL). The organic layer was concentrated under reduced pressure to

218 afford a crude product which was purified by reverse phase HPLC (A: water (0.05% HCl). B: MeCN; then: A B (57%/43% to 27%/73 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 46 (55 mg, 44 %) as a pale white solid. LCMS (ESI) m/z M+l : 483.9; Ή NMR (400 MHz. METHANOLX) δ ppm 6.57 (t. J=2.09 Hz. 1 H), 7.38 (d, J=8.60 Hz, 1 H), 7.78 - 7.95 (m, 3 H), 8.16 (d. J=2.43 Hz, 1 H), 8.33 (d. J=8.16 Hz, 1 H), 8.41 (s, i H). 8.61 - 8.66 (m, 2 H), 8.77 (d, J=2.21 Hz, 1 H), 9.51 (s, 1 H).

Example 15 AN3-Chloro-4-(5-methyl-]H-l,2,4-triazol-l-yl)phenyl)-l-(isoquinolin-4-yl)-5(trifluoromethyl)-l//-pyrazole-4-carboxamide. Cpd 51

2-Chloro-l-fluoro-4-nitrobenzene (1.6 g, 9.11 mmol), 5-methyl-l/7-l,2,4-triazole (1.14g, 13.7 mmol) and CsjCOj (8.9 g, 27.3 mmol) were added to DMF ( 15 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture xvas fïltered and the filtrate was concentrated under reduced pressure to give a crude yellow⁷ oil. The crude oil was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=7:3 to Petroleum ether/ ethyl acetate=3:7) to afford compound 15a ( 1.5 g, 69 %) as a yellow⁷solid. ‘H NMR (400 MHz, CDCh) δ ppm 2.38 - 2.56 (m. 1 H), 2.39 - 2.44 (m, 1 H), 2.51 (s, 2 H), 7.60 - 7.67 (m, 1 H), 7.90 (d, J=8.82 Hz, 1 H), 8.02 (s, 1 H). 8.23 - 8.33 (m, 1 H), 8.43 - 8.50 (m, 1 H), 8.69 (s. 1 H).

219

B. 3-Cbloro-4-(5-methyI-lH-l,2,4-triazol-l-yl)amlme, 15b z=\ h₂n

Cl ,15b l-(2-Chloro-4-mtrophenyl)-5-methyl-lH-l,2,4-triazole, 15a (1500 mg, 2.26 mmol) was added to the mixture of Fe (0) (877 mg. 15.71 mmol), NH4CI (840 mg, 15.71 mmol) in MeOH (10 mL), water (5 mL), and THF (20 mL). The reaction was stirred at 60 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude yellow oil. The crude oil was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=l : 1 to petroleum ethcr ethyl acetate=0:1 ) afford compound 15b (1200 mg, 91.5 %) as a yellow solid. ^[H NMR (400 MHz, CDCh) δ ppm 2.90 (s, 3 H), 6.52 - 6.61 (m, 1 H), 6.69 - 6.77 (m, 1 H), 7.06 (d, J=8.61 Hz, 1 H), 7.16 (d, J=8.61 Hz, 1H), 7.87 (s, 1 H), 7.96 (s, 1 H). 8.15 (s, 1 H).

C . AX3-chloro-4-(5-methyl-177-1,2,4-triazol-l-yl)phenyl)-l-(isoquinolin-4-yl )-5(trifluoromethyl)-127-pyrazole-4-carboxamide, Cpd 51

POChfl 10.23 mg, 0.719 mmol ) was added to a mixture of3-chloro-4-(5-methyll#-l,2,4-triazol-l-yl)aniline. 15b (150 mg, 0.36 mmol ), 1 -(isoquinolin-4-yl)-5(trifluoiOmethyl)-lÆ-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 h. Water (20 mL) was added to the mixture. The mixture was extracted with dichloromethane (30 mL). The organic layer was concentrated under reduced pressure to afford a crade product, which was purified by reverse phase HPLC (A; water (0.05% HCl). B: MeCN; then: AB (62%/38% to 32%/68 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound compound 51 (31 mg, 17 %) as a pale white solid. LCMS (ESI) m z M+l: 497.9; ^!H NMR (400 MHz,

220

METHANOLA) δ ppm 2.50 (s, 3 H), 7.48 (d, J=8.38 Hz, l H), 7.64 (d, J=8.82 Hz, l H), 7.84 (dd, J=8.60, 2.20 Hz, l H), 7.92 - 7.98 (m, IH), 8.00 - 8.06 (m. 1 H), 8.22 (d. .1=2.20 Hz, 1 H), 8.39 - 8.48 (m, 2 H), 8.67 (br s, 1 H), 8.82 (br s, 1 H), 9.01 (s. 1 H), 9.53 - 9.91 (m, 1 H), 9.72 (br s. 1 H).

Example 16

A-(5-cyano-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5-(trifluoromethyl)lH-pyrazole-4-carboxamide, Cpd 83

POCh (49.4 mg, 0.32 mmol ) was added to a mixture of 5-ammo-2-(2/f-l,2,3triazol-2-yl)nicotinonitrile, 7b (30 mg, 0.161 mmol), l-(quinolin-5-yl)-5-(trifluoromethyl)l/7-pyrazole-4-carboxylic acid, 3b (49.5 mg,0.16 mmol), and pyridine (63.7 mg, 0.81 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at 20 °C for 2 h.

Water (20 mL) was added to the mixture. The mixture was extracted with dichloromethane (30 mL). The organic layers were concentrated under reduced pressure to afford a crude product, which was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: A/B (67%/33% to 37%/63 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 83 (33 mg, 42 %) as a white solid. LCMS (ESI) m/z M+l : 475.9. Ή NMR (400 MHz. METHANOLA) δ ppm 8.07 - 8.21 (m, 4 H), 8.32 (t, J=8.03 Hz, 1 H), 8.48 - 8.57 (m, 3 H), 8.94 (d, J=2.26 Hz, 1 H), 9.10 - 9.18 (m, 1 H), 9.35 (d, J=4.02 Hz, 1 H).

Example 17

M( 5-cyano-6-( 1 H-1,2,4-triazol-1 -yl)pyridin-3-yl )-1 -(qumolm-5-yI)-5-(trifluorom lH-pyrazoIe-4-carboxamide, Cpd 86

221

A. 5-Nitro-2-(l/7-L2,4-triazol-l-yl)nicotinonitrile, 17a

K2CO3 (564.7 mg, 4.09 mmol) was added to a solution of 2-chloro-5nitronicotinonitrile (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 give a crude yellow oil. The crude oil was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=10:l to petroleum ether/ ethyl acetate=l:2) to afford compound 17a (200 mg, 67.9 %) as a yellow solid. ^lH NMR (400 MHz, CDCI3) δ ppm 8.31 (s, 1 H), 9.02 (d, J=2.51 Hz, 1 H), 9.28 (s, 1 H), 9.48 (d, J=2.51 Hz, 1 H).

B. 5-Amino-2-( ÏH-1,2,4-triazol-1 -yl)nicotinonitrile, 17b

5-Nitro-2(l/7-l,2,4-triazol-l-yl)nicotmonitrile. 17a (100 mg, 0.46 mmol) was added to a mixture of Fe(0) (206.7 mg, 3.7 mmol), NH4CI (198.0 mg, 3.70 mmol) in THF (4 mL), and water (1 mL). The reaction was stirred at 60 °C for 1 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with ethyl acetate (20 mL x 3). The combined filtrâtes were concentrated to dryness to give a crude yellow solid. The crude solid was purified by flash column chromatography over silica gel

222 (petroleum ether/ethyl acetate from 50/50 to O/l 00) to afford compound 17b (55 mg, 64 %) as a yellow solid. ^JH NMR (400 MHz, CDCb) δ ppm 4.08 - 4.17 (m, 2 H), 7.35 - 7.42 (m, 1 H), 7.39 (d, J=2.65 Hz, 1 H), 8.17 (s, 1 H). 8.93 (s, 1 H).

C. M(5-cyano-6-( 1 H-1,2,4-triazol-1 -y l)pyridin-3-yl)-1 -(quinolin-5-yl)-5(trifluoromethyO-l/f-pyrazoleFcarboxamide, Cpd 86

POCh (82.4 mg, 0.54 mmol ) was added to a mixture of 5-amino-2-(ÏH-1,2,4triazol-l-yl)nicotmonitrile, 17b (50 mg, 0.269 mmol), l-(quinolin-5-yl)-510 (trifluoromethyl)-l//-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 h. Water (20 mL) was added to the mixture. The mixture was extracted with dichloromethane (30 mL). The organic layer was concentrated under reduced pressure to afford a crude product, which was purifïed by reverse phase HPLC (A: water (0.05% HCl), 15 B: MeCN; then: A/B (65%/35% to 35%/65 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 86 (84 mg, 66 %) as a white solid. LCMS (ESI) m/z M+l : 475.9; ‘H NMR (400 MHz, METHANOL-Λ) δ ppm 8.16 - 8.24 (m. 2 H), 8.31 - 8.39 (m, 2 H), 8.50 (s, 1 H), 8.55 (d, J=8.82 Hz, 1 H), 8.64 (d, J=8.60 Hz, 1 H), 8.88 (d. J=2.43 Hz, 1 H). 9.09 (d, J=2.65 Hz. 1 H), 9.35 - 9.43 (m, 2

H).

Example 18 /V-(5-Chloro-6-cyclopropoxypyridin-3-yl )-1 -(quinolin-5-yI)-5-( trifluoromethyl)-1/7pyrazole-4-carboxamide. Cpd 79

223

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 température. The mixture was stirred at 40 °C for 1 h. 2,3-Dichloro-5-mtiOpyridine in THF (20 mL) was added to the mixture at 0 °C. The mixture was stirred at room température for 1 h. The reaction mixture was quenched with water (50 mL). The mixture was extracted with ethyl acetate (200 mL x 3). The organic layer was dried over Na₂SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (Petroleum ether/ethyl acetate from 100/0 to 90/10) to afford 3-chloro-2-cyclopropoxy-5nitropyridine, 18a (9 g, 53 %) as a yellow solid.

B. 5-Chloro-6-cyclopropoxypyridm-3-amine, 18b

3-Chloro-2-cyclopropoxy-5-nitropyridine, 18a (18 g, 76.79 mmol) was dissolved in a mixture of 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 h. Ethyl 20 acetate (200 mL) was added to the mixture. A precipitate was removed by filtration. The precipitate was washed with ethyl acetate ( 100 mL). and the filtrate was concentrated under reduced pressure. A 10% NaHCOs solution (100 mL) was added to the mixture and

224 the mixture was extracted with ethyl acetate (100 mL x 2). The organic portion was dried overNa2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a crude yellow oil. The crade product was purified by column chromatography over silica gel (petroleum ether/' ethyl acetate=10:1 to petroleum ether/ ethyl acetate= 1:2) to afford compound 18b (12 g. 78.3 %) as a yellow oil. ’H NMR (400 MHz. CDCh) δ ppm 0.78 (d. J=4.52 Hz, 4 H), 3.43 (br. s., 2 H), 4.22 (quin, J=4.58 Hz, 1 H), 7.10 (d, J=2.76 Hz, 1 H), 7.62 (d, J=2.51 Hz, 1 H).

C. /V-(5-chloro-6-cyclopropoxypyridin-3-yl)-l-(quinolin-5-yl)-5-(trifluoromethyl)lH-pyrazole-4-carboxamide. Cpd 79

HATU (111.6 mg. 0.294 mmol) was added to a mixture of 5-chloro-6cyclopropoxypyridi.n-3-amine, 18b (58.7 mg, 0.29 mmol), l-(quinolin-5-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 3b (75.1 mg, 0.245 mmol) and DIEA (94.85 mg, 0.73 mmol) m DMF (3 mL). The mixture was stirred at room température for 2 h. Water (10 mL) was added to the mixture and the mixture was extracted with ethyl acetate (30 mL x 2). The organic layer was separated, dried over NaiSCU, filtered and the filtrate concentrated to dryness to give a crude yellow solid. The crade solid was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=10:l to petroleum ether/ ethyl acetate=0:1 ) to give compound 79 (90 mg, 76 %) as a white solid. LCMS (ESI) m/z M+l : 473.9. Ή NMR (400 MFIz, DMSO-î/Q δ ppm 0.73 (br s, 2 H), 0.77 - 0.83 (m, 2 H), 4.33 (dt, J=6.21,3.04 Hz, 1 H), 7.56 - 7.63 (m, 1 H), 7.65 - 7.71 (m, 1 H), 7.87 - 7.93 (m, I H), 7.95 - 8.00 (m, 1 H), 8.29 (d. J=2.26 Hz, 1 H), 8.33 (d, J=8.28 Hz, 1 H), 8.45 (d, J=2.51 Hz, 1 H), 8.51 (s, 1 H), 9.06 (dd, J=4.39, 1.38 Hz, 1 H), 10.80 (s, 1 H).

225

Example 19 /V-(5-Chloro-6-(l,3,4-oxadiazol-2-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 69

A. Methyl 5-amino-3-chloropicolinate, 19a

O

A stirring solution of 5-amino-2-bromo-3-chloropyridine (800 mg, 3.856 mmol), dppf (213.8 mg, 0.386 mmol) and NEts (1.17 g, 11.6 mmol) in MeOH (4 mL) and toluene (20 mL) was carbonylated at 70 °C (35 psi) with PdidppfiCh.CHgCL (314.9 mg, 0.386 mmol) as a catalyst for 16 h. After uptake of CO ( 1 equiv), the catalyst was removed by filtration, and the filtrate was concentrated to give a crade product. The crude product was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30) to afford methyl 5-amino-3-chloropicolinate, 19a (400 mg, 56 %) as a red solid. Ή NMR (400 MHz, CDCh) δ ppm 3.95 (s. 3 H), 4.20 (br s, 2 H), 7.02 (d, J=2.43 Hz, 1 H), 8.01 (d, J=2.43 Hz, 1 H).

B. Methyl 3-diloro-5-(l-(isoqumolin-4-yT)-5-(trifluoromethyl)-l.H-pyrazole-4carboxamido )picolinate, 19b

226

To a solution of methyl 5-amino-3-chloropicolinate, 19a (270 mg, 1.45 mmol), 1(isoquinolin-4-yl)-5-(trifluoromethyl)-lE/-pyrazole-4-carboxylic acid, 4c (387.9 mg, 1.206 mmol) and pyridine (388 pL, 4.82 mmol) in dichloromethane (3 mL), POCh (221 pL, 2.41 5 mmol) was added dropwise. The reaction mixture was stirred at 20 °C for 1 h. Sat. aqueous NaHCO? (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic extracts were washed with brine and dried over Na2SÛ4, filtered. and the fïltrate was concentrated under reduced pressure to afford a crude yellow oil. The crade product was purified by column chromatography over silica gel 10 (petroleum ether/ ethyl acetate=10:l to petroleum ether/ ethyl acetate=O:l) to give methyl 3-chloro-5-(l-(isoqumolin-4-yl)-5-(trifluoromethyl)-l#-pyrazole-4-carboxamido) picolinate. 1.9b (190 mg, 33 %) as a yellow solid. LCMS (ESI) m/zM+l: 475.9.

C. ïV-(5-ChloiO-6-(hydrazinecarbonyl)pyridin-3-yl)-1 -(isoquinolin-4-yl)-515 (trifluoromethyl)-lH-pyrazole-4-carboxamide, 19c

227

To a solution of methyl 3-chloro-5-( l-(isoquinolin-4-yl)-5-(tnfluoromethyl)-lHpyrazole-4-carboxamido)picolinate, 19b (170 mg, 0.36 mmol) in EtOH (5 mL) was added 85 % NH2NH2.H2O (2 mL) at room température. The mixture was heated to 80 °C and stirred for 4 h. 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 compound 19c (160 mg, 83 %) as a red solid. LCMS (ESI) m/z M+l : 476.0.

D. ïV-(5-chloro-6-(l,3,4-oxadiazol-2-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5( trifluoromethyl)-l//-pyrazole-4-carboxamide, Cpd 69

To a solution of M-(5-chloiO-6-(hydrazinecarbonyl)pyridin-3-yl)-l-(isoquinolin-4yl )-5-(trifluoromethyl)-l//-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 température. The mixture was heated to 100 °C for 2 h. The solvent 15 was concentrated to afford a crude yellow oil. The crude oil was purified by column. chromatography over silica gel (petroleum ether/ ethyl acetate=10:1 to ethyl acetate / methanol=5:1) to afford compound 69 (26.8 mg, 17 %) as a white solid, LCMS (ESI) m/z M+l: 485.9; Ή NMR (400 MHz, CDCh) δ ppm 7.34 (d, J=7.72 Hz, 1 H), 7.75 - 7.83 (m, 2 H), 8.16 (d, J=8.16 Hz, 1 H), 8.29 (s, 2 H) 8.60 (s, 2 H), 8.75 (d, J=3.97 Hz, 2 H), 9.45 (s. 1 H).

228

Example 20 jV-(5-Chloro-6-(3-methyl-IH-1,2,4-triazol-1-yl)pyridin-3-yl)-1-(isoquinolin-4-yl )-5(trifluoromethyl )-l//-pyrazole-4-carboxamide, Cpd 53 and

N-( 5-Chloro-6-(5-methyl-IH -1,2,4-triazol-1 -yl )pyridin-3-yl)-1 -(isoquinolin-4-yl)-5(trifluoromethyl)-l//-pyrazole-4-carboxamide, Cpd 54

Cpd 53

Cpd 54

A. 3-Chloro-2-(3-methyl-l//-l,2,4-triazol-l-yl)-5-nitropyridine (20a) and 3-chloro-2(5-methyl-1H-1,2,4-triazol-1 -yl)-5-nitropyridine (20a-1 )

2,3-Dichloro-5-nitropyridme (2 g, 10.36 mmol), 3-methyl-lH-l,2,4-triazole (1.722 g, 20.73 mmol) and CS2CO3 (6.798 g, 20.73 mmol) were added to DMF (30 mL) and the reaction was stirred at rt for 12 h. The reaction mixture was quenched with water (200 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The organic layer was dried over Na2SO₄, fïltered, and the filtrate concentrated under reduced pressure. The cnide residue was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100:0 to 50:50) to afford a mixture of compounds 20a and 20a-1 (780 mg, 31 %) as a white solid.

229

B. 5-Chloro-6-(3-methyl-lH-L2,4-triazol-l-yl)pyridm-3-amine (20b) and 5-chloro6-(5-methyl-\H-1,2,4-triazol-l-yl)pyridin-3-amine (20b-l )

20b 20b-l

A mixture of3-chloro-2-(3-methyl-1/7-1,2,4-triazol-l-yl)-5-nitropyridine, 20a and 5 3-chloro-2-(5-methyl-l//-l,2,4-triazol-l-yl)-5-nitropyridine, 20a-l (780 mg, 1.63 mmol) was dissolved in MeOH (20 mL), and Zn (0) (1.058 g, 16.28 mmol) and aqueous NH4CI (20 mL) were added. The reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad washed with ethyl acetate (20 mL x 3). Water (50 mL) was added and the organic layer was separated. dried over

Na2SO₄, filtered and the filtrate was concentrated to dryness to give a crude mixture of compounds 20b and 20b-l (400 mg, 59 %) as a yellow solid. ’H NMR (400 MHz, METHANOL-tL) δ ppm 2.43 (s, 3 H), 2.85 (d, J=0.66 Hz, 1 H), 2.99 (s, 1 H), 7.21 - 7.23 (m. 1 H), 7.82 (d, J=2.65 Hz, 1 H) ,7.86 (dd. J=4.85, 2.43 Hz, 1 H). 8.02 (s, 1 H), 8.61 8.65 (m. 1 H), 8.63 (s, 1 H).

C. A-(5-Chloro-6-(3-methyl-l/7-L2,4-triazol-l-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)5-(trifluoromethyl)- l/7-pyrazole-4-carboxamide, Cpd 53 and

Aq5-chloro-6-(5-methyl-l/7-L2,4-triazol-l-yl)pyndin-3-yl)-l-(isoquinolin-4-yl)20 5-(trifluoromethyl)-1/7 -pyrazole-4-carboxamide, Cpd 54

230

Cpd 54

A mixture of compounds 5-chloro-6-(3-methyl-l//-l,2,4-triazolTyl)pyridin-3amine. 20b and 5-chloro-6-(5-methyl-l/f-L2,4-triazol-l-yl)pyridin-3-amine, 20b-l (100 mg, 0.31 mmol). l-(isoquinolin-4-yl)-5-(trifluoromethyl)-l7T^r-pyrazole-4-carboxylic acid, 5 4c (263.0 mg, 0.63 mmol), and pyridine (62.0 mg, 0.78 mmol) were dissolved in dichloromethane ( 10 mL), and POCh (96.2 mg, 0.63 mmol) was added. The mixture was stirred at rt for 2.5 h. Sat. aqueous NH4CI (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic layers were dried over NacSCU, filtered, and the filtrâtes were concentrated under reduced pressure to afford 10 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 pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford a mixture of compounds 53 and 54 (90 mg). The mixture was separated by Supercritical Fluid Chromatography (0. l% NH3H2O: MEOH. Mobile phase: A: CO2 B: O.UôNHsFhO: MEOH; A/B 75/25).

Cpd 53: A-(5-chloro-6-(3-methyl-lH-l,2,4-triazol-l-yl)pyndin-3-yl)-l(isoquinolin-4-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxamide, (37.8 mg, 24.1%) as a white solid. LCMS (ESI) m/z M+l: 498.9. ^lH NMR (400 MHz. DMSO-V) δ ppm 2.34 2.40 (m, 3 H). 7.27 - 7.30 (m, 1 H), 7.81 - 7.90 (m, 1 H), 7.90 - 7.97 (m, 1 H), 8.33 - 8.41 (m, 1 H), 8.66 - 8.72 (m, 1 H), 8.74 - 8.82 (m, 2 H), 8.86 - 8.98 (m, 2 H), 9.60 (s, 1 H).

Cpd 54: JV-(5-chloro-6-(5-methyl-\H-1,2,4-triazol-1 -yl)pyridin-3-yl)-1 (isoquinolin-4-yl)-5-(trifluoromethyl)-127-pyrazole-4-carboxamide (18.4 mg, 11.7%) as a white solid. LCMS (ESI) m/z M+l : 499.0. ‘H NMR (400 MHz, DMSOA) δ ppm 2.34 2.37 (m, 3 H), 7.23 - 7.32 (m, 1 H), 7.82 - 7.90 (m, 1 H), 7.91 - 7.98 (m, 1 H), 8.06 - 8.12

231 (m, 1 H), 8.33 - 8.41 (m, 1 H), 8.59 - 8.64 (m. 1 H), 8.65 - 8.70 (m, 1 H), 8.75 - 8.81 (m, 1

H), 8.85 - 8.90 (m, 1 H), 9.58 - 9.64 (m, 1 H).

Example 21 ,-V-(3-chloro-4-( lH-l,2.3-triazol-l-yl)phenyl)-l-(isoqumolin-4-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamide, Cpd 18

A. l-(2-Chloro-4-nitrophenyl)-lH-l,2,3-triazoIe, 21a

Cl

To a solution of 3-chloro-4-fluoronitrobenzene (1.2 g. 6.836 mmol) and 2H-1.2.3triazole (0.567 g, 8.203 mmol) in anhydrous DMA (5 mL) was added K2CO3 (1.89 g. 13.672 mmol). The reaction mixture was stirred at 55 °C ovemight. The réaction was concentrated to give a crude product as an oil. The crude product was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 20/80 to afford l-(2-chloro-4-nitrophenyl)-lH-L2.3-triazole, 21a (400 mg, 26.1 %) as a yellow solid. ‘H NMR (400 MHz, CDCI3) δ ppm 7.92 - 8.00 (m, 2 H). 8.20 (s, 1 H), 8.35 (dd, J=8.71, 2.32 Hz, 1 H), 8.51 (d, J=2.43 Hz, 1 H)

B. 3-ChloiO-4-(lH-L2,3-triazol-l-yl)aniline. 21b

Cl

232

To a solution of l-(2-chloro-4-mtrophenyI)-l/f-l,2,3-triazole, 21a (400 mg. 1.781 mmol) in MeOH/THF/water (5 mL/ΊΟ 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 h. The reaction was filtered and the organic solvent was concentrated. Water (10 mL) was added and the mixture was extracted with ethyl acetate ( 15 mL x 3). The separated organic layer was dried over MgSO₄, filtered, and the filtrate was concentrated under reduced pressure to give a crude solid. The crude solid was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100 0 to 0/100 to afford 3-chloro-4-(l//-l ,2,3-triazol-l-yl)aniline, 21b (300 mg, 86.6 %) as a yellow solid.

Ή NMR (400 MHz. CDCh) δ ppm 4.03 (br. s., 2 H), 6.66 (dd, J=8.41, 2.15 Hz, 1 H), 6.82 (d, J= 1.96 Hz, 1 H), 7.32 (d, J=8.61 Hz, 1 H), 7.85 (d, J=14.09 Hz, 2 H)

C. A⁷-(3-Chloro-4-(\H- l,2,3-triazol-l-yl)phenyl)- l-(isoquinolin-4-yl)-5(trifluoromethyl)-l H-pyrazole-4-carboxamide, Cpd 18

To a solution of l-(isoquinolin-4-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylic acid (50 mg, 0.16 mmol), 3-chloro-4-( lf/-L2,3-triazol- l-yl)aniiine, 21b (37 mg, 0.19 mmol) and pyridine (63 mg, 0.8 mmol) in dichloromethane (2 mL), was added POCL (49.4 mg, 0.32 mmol) dropwise to the mixture. The reaction mixture was stirred at 20 °C for 1 h. Water (5 mL) was added and the reaction mixture was extracted with dichloromethane (5 mL x 3). The combined organic extracts were washed with brine and dried over Na. SO filtered, and the filtrâtes were concentrated under reduced pressure to afford a crude yellow oil. The crude oil was purified by reverse phase HPLC (A: water (0.05% ammonia hydroxide v/v), B: MeCN; then; A/B (60%/40% to 70%/30 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford

233 compound 18 (30 mg. 39 %) as a white solid. LCMS (ESI) m/z M+1: 483.9; 'H NMR (400 MHz, CDCh) δ ppm 7.37 (d, J=8.38 Hz, 1 H), 7.61 - 7.69 (m, 2 H), 7.75 - 7.85 (m, 2 H). 7.90 (s. 1 H), 7.96 (s, 1 H), 8.03 (s, 1 H), 8.12 - 8.20 (m, 2 H), 8.27 (s, 1 H), 8.64 (s. 1 H), 9.46 (s. 1 H).

Example 22

AU5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[3,2-c]pyridm-4-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 90

4-Hydrazinylthieno[3,2-c]pyridine, 22a

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 h. The mixture was extracted with dichloromethane (30 mL x 2). The organic portion was concentrated under reduced pressure to afford a crude product (120 mg, 82 %) as a yellow solid.

B. Ethyl l-(thieno[3,2-c]pyridin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate,

22b

234

A solution of 4-hydrazinylthieno[3,2-c]pyridine, 22a (120 mg, 7.26 mmol) and ethyl 2-(ethoxymethyIene)-4,4,4-trifluoro-3-oxobutanoate, If (227 mg, 0.944 mmol) in EtOH (50 mL) was stirred at 80 °C for 16 h. The résultant solution was cooled to room température and concentrated to dryness under reduced pressure to afford a crude product, which was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=lOO:O to 70:30) to afford compound 22b (120 mg, 48 %) as a yellow solid. LCMS (ESI) m/z M+l: 341.9.

C. l-(Thieno[3,2-c]pyridin-4-yl)-5-(trifluoromethyl)-I//-pyrazole-4-carboxylic acid,

A solution of ethyl l-(thieno[3,2-c]pyridin-4-yl)-5-(trifluoromethyl)- 1/7-pyrazole4-carboxylate, 22b (120 mg, 0.352 mmol) in concentrated hydrochloric acid (3 mL) was stirred at 130 °C for 3 h. The solvent was concentrated under reduced pressure to afford a crude product ( 110 mg, 100 %) as a yellow solid, which was used in the following reaction without further purification. LCMS (ESI) m/z M+l: 313.8.

D. AA5-Cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[3,2-c|pyridin-4-yl)-5(trifluoromethyl)-17/-pyrazole-4-carboxamide, Cpd 90

N A

To a solution of l-(thieno[3,2-c]pyridin-4-yl)-5-(trifluoromethyl)-l//-pyrazole-4carboxylic acid, 22c (90 mg, 0.29 mmol), 5-amino-2-(2H-L2,3-triazol-2-yl)nicotinonitrile,

235

7b (45.6 mg, 0.23 mmol) and pyridine (l 15.9 pL, 1.44 mmol) in dichloromethane (5 mL), was added POCh (52.6 pL, 0.575 mmol) dropwise to the mixture. The reaction mixture was stirred at 20 °C for l h. Sat. aqueous NaHCO? (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic extracts were washed with brine, dried over Na2SÛ4, filtered, and the filtrâtes were concentrated under reduced pressure to afford a crude yellow oil. The crade oil was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=lO:l to petroleum ether/ ethyl acetate=0: l) to afford compound 90 (71.2 mg, 51 %) as a white solid. LCMS (ESI) m/z M+l: 481.9. ‘H NMR (400 MHz, DMSO-O δ ppm 7.45 (d, J=5.51 Hz, 1 H), 8.11 (d, 10 J=5.51 Hz, 1 H), 8.30 (s, 2 H), 8.39 (d, J=5.51 Hz, 1 H), 8.46 (d, J=5.51 Hz, 1 H), 8.60 (s,

H), 8.88 (d, J=2.43 Hz, 1 H), 9.11 (d, J=2.43 Hz, 1 H), 11.46 (s. 1 H).

Example 23

N-(5-ChIoro-6-(2/f-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(6-methylquinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 27

A.

5-Hydrazmyl-6-methylqumoline, 23a

A solution of 6-methylquinolin-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 added slowly, then stirred at 0 °C for 1 h. L-

236 ascorbic acid (935 mg, 5.31 mmol) was then added to the réaction mixture over 10 min. The mixture was warmed to room température and stirred for l h before heating at 80 °C for 30 min. Water (4 mL) was added. The suspension was cooled to 0 °C and stirred for 2 h. The resulting mixture was basified to pH 10 with 4 M aq. NaOH, extracted with ethyl acetate (30 mL x 3), and dried over anhydrous Na₂SO₄. The mixture was filtered and the filtrate concentrated to dryness under reduced pressure to afford a crude product, which was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 30:70) to afford compound 23a ( 150 mg. 17 %). Ή NMR (400 MHz, DMSO-X) δ ppm 8.93 - 8.89 (m, 1 H), 8.75 8.72 (ra, 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 10 4.60 (m, 1 H), 2.52 - 2.50 (m, 2 H), 2.42 (s, 3H).

B. Ethyl 1 -(6-methylqumolin-5-yl)-5-(trifluoiOmethyl)-l 77-pyrazole-4-carboxylate, 23b

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (130 mg, 0.541 mmol), 5-hydrazinyl-6-methylquinoline, 23a (113 mg, 0.541 mmol) and éthanol (5 mL) was refluxed at 80 °C for 16 h before cooling to room température. The mixture was concentrated to dryness under reduced pressure to afford the crude product, 20 which was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 50:50) to give compound 23b (130 mg, 60 %). *H NMR (400 MHz, CDCh) δ ppm 8.91 (d, J = 3.2 Hz, 1H), 8.31 (s, 1H), 8.20 (d,J=9.2Hz, 1H), 7.66 (d, J= 8.8 Hz 1H), 7.42 - 7.29 (m, 2H), 4.41 (q, .7= 6.8 Hz, 2H), 2.21 (s, 3H), 1.40 (t,J=7.2 Hz, 3H).

C. l-(6-Methylquinolin-5-yl)-5-(trifluoromethyl)-177-pyrazole-4-carboxylic acid, 23c

237

A solution consisting of ethyl l-(6-methylquinolm-5-yl)-5-(trifluoromethyl)-] Hpyrazoie-4-carboxylate. 23b ( 100 mg, 0.286 mmol), NaOH (34.4 mg, 0.859 mmol) and water:EtOH (3 mL, l :2) was stirred at room température for 16 h. The solution was concentrated under reduced pressure, neutralized to pH 7 with 4 N aq. HCl, and a solid, compound 23, was collected by filtration (90 mg, crude), which was used in the following réaction without further purification. LCMS (ESI): Rt = 0.65 min, mass calcd. for C15H10F3N3O2 321.254, m/z found 322.0 [M+H]'

D. H-(5-Chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yT)-l-(6-methylquinoIin-5-yl)-5(trifluoromethyl)- IH-pyrazole-4-carboxamide, Cpd 27

POCk (45.8 mg, 0.299 mmol) was added dropwise to a solution consisting of 1 -(6methylquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 23c (80.0 mg, 0.249 mmol), 5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-amine, Ij (97.4 mg, 0.498 mmol) and pyridine (5 mL). The mixture was stirred at 0 °C for 1 h. The résultant mixture was poured into sat. aqueous NaHCCh (10 mL), extracted with ethyl acetate (10 mL x 3). dried over anhydrous Na/SCL and concentrated under reduced pressure to give a crude product, which was purified by préparative high performance liquid chromatography using Boston Green ODS 150 x 30 mm x 5 μηι (27% to 57% (v/v) ACN and water with 0.05% HCl) to afford compound 27. The product was suspended in water (10 mL), the mixture frozen using dry-· ice/acetone, and then lyophilized to dryness to give compound 27 (23.0

238 mg, 18 %). LCMS (ESI): mass calcd. for CîzHuCIFsNsO 498.848, m/z found 499.0 [M+H] \ ‘H NMR (400 MHz, DMSOA) 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 (ni, 2H), 8.32 (d, J= 8.8 Hz, 1H), 8.21 (s, 2H), 7.98 (d, J= 8.8 Hz, 1H), 7.74 (dd, 4.4, 8.4 Hz, 1H), 7.61 (d. J = 8.4 Hz. 1H), 2.24 (s, 5 3 H).

Example 24

AX5-Chloro-6-methoxypyridin-3-yl)-l-(quinolin-5-yl)-5-( trifluoromethyl)- lH-pyrazole-4carboxamide, Cpd 7

A.

l-(Quinolin-5-yI)-5-( trifluoromethyl)-l/f-pyrazole-4-carbonyl chloride, 24a rr F

Cl

, 24a

Oxalyl dichloride (0.0830 mL, 0.976 mmol) was added to solution consisting of 1(quinolm-5-yl)-5-(trifluoromethyl)-177-pyrazole-4-carboxylic acid. 3b (200 mg, 0.651 mmol), dichloromethane ( 15 mL). and DMF (catalytic amount). The résultant solution was stirred at room température for 1 h. The résultant solution was concentrated to dryness to afford compound 24a (200 mg, crude), which was used in the following reaction without further purification.

239

B. N-{5-Chloro-6-methoxypyridin-3-yl)-1 -(quinolin-5-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide, Cpd 7

O. N c

A solution consisting of l-(quinolin-5-yl)-5-(trifluoromethyl)-17/-pyrazole-4carbonyl chloride. 24a (200 mg, 0.614 mmol), 5-chloro-6-methoxypyridin-3-amine ( 117 mg, 0.737 mmol), and pyridine (10 mL) was stirred at 90 °C for 1 h before cooling to room température. The résultant mixture was concentrated to dryness under reduced pressure to give the crude product, w'htch was purified by reverse phase HPLC (38% to 68% (v/v) CH3CN and water with 0.05% NH3) to afford compound 7 (74.80 mg, 27 %) as a brown solid. LCMS (ESI): mass calcd. for C20H13CIF3N5O2 447.07, m/z found 448.1 [M H| . ‘H NMR (400 MHz, CDCh) 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. 1 H), 7.66 - 7.59 (m, 2H), 7.47 (dd. J = 4.4,8.4 Hz, 1H), 4.04 (s, 3H).

Example 25 l-(Quinolin-5-yl )-5-( trifluoromethyl)-ïV-(2-(trifluoromethyI)pyridin-4-yl)-lZ/-pyrazole-4carboxamide, Cpd 6

A solution consisting of l-(quinolin-5-yl)-5-(trifluoromethyl)-l/7-pyrazole-4carbonyl chloride, 24a (200 mg, 0.614 mmol), 2-(trifluoromethyl)pyridin-4-amine (119 mg, 0.737 mmol), and pyridine (10 mL) was stirred at 90 °C for 1 h before cooling to room température. The résultant mixture was concentrated to dryness under reduced pressure to

240 give the crude product. which was purified by reverse phase HPLC (43% to 63% (v/v) CHsCN and water with 0.05% NH3) to afford compound 6 (107.30 mg, 39 %) as a white solid. LCMS (ESI): mass calcd. for CzoHnFeNsO 451.09, m/z found 452.1 [M+H]\ ’H NMR (400 MHz, CDCI3) δ ppm 9.04 (dd, 7= 1.6, 4.4 Hz, IH), 8.71 (d,7= 5.6 Hz, 1H),

8.37 (d, 7= 8.4 Hz. 1 H), 8.23 (s. IH). 8.16 (s, 1H). 8.01 (d, 7= 2.0 Hz. 1H), 7.88 - 7.81 (m, 2H), 7.67 - 7.57 (m, 2H), 7.49 (dd,7 = 4.4, 8.4 Hz, 1H).

Example 26 ïV-(5-ChloiO-6-(2/f-l,2,3-triazol-2-yl)pyridin-3-yD-l-(8-methylquinolin-5-yl)-510 (tnfluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 28

A. 5-Hydrazinyl-8-methylquinoline, 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-methylquinolin-5-amine (100 mg, 0.632 mmol) and concentrated hydrochloric acid (4 mL) at a température between -10 °C and 0 °C. The mixture was stirred at a température between -10 °C and 0 °C for 1.5 h. A solution consisting of SnCb (285 mg, 1.26 mmol) and concentrated hydrochloric acid (0.5 mL) was added dropwise at a température between -10 °C and 0 °C, then the mixture was stirred at room température for 16 h before filtration. The collected solid was washed with MeOH (2 mL x 2) to give compound 26a (90 mg, crade), which was used in the following reaction without further purification. LCMS (ESI): mass calcd. for C10H11N3 173.214,m/z

241 .

found 174.2 [M+H]L Ή NMR (400 MHz, DMSOF) δ ppm 10.72 (br. s., 2H), 9.82 - 9.31 (m, 1H), 9.14 (d, 7= 4.4 Hz, 1H). 9.05 (d, 7= 8.4 Hz, 1H), 7.98- 7.85 (m, 1H), 7.80 (d,7 = 7.6 Hz, 1H), 7.17 (d, 7= 8.0 Hz, 1H), 2.71 (s, 3H).

B. Ethyl l-(8-methylquinolin-5-yl)-5-(trifluoromethyl)- l//-pyrazole-4carboxylate, 26b

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (87.8 mg, 0.366 mmol), 5-hydrazinyl-8-methylquinoline, 26a (90.0 mg, 0.366 mmol) and éthanol (3 mL) was refluxed at 80 °C for 16 h before cooling to room température. The mixture was concentrated to dryness under reduced pressure to afford a crude product, which was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 70:30) to afford compound 26b (90 mg, 70 %). *H NMR (400 MHz, CDCh) δ ppm 9.06 - 8.98 (m, 1H), 8.24 (s, 1H), 7.66 (d,7= 8.0 Hz, 1H), 7.58 - 7.43 (m, 3H), 4.41 (d,7= 6.8 Hz, 2H), 2.90 (s, 3H), 1.41 (t, 7 =7.2 Hz, 3H).

C. l-(8-Methylquinolin-5-yl)-5-(trifluoromethyl)-l/f-pyrazole-4-carboxylic acid. 26c

,26c

A solution of ethyl l-(8-methylquinolin-5-yl)-5-(trifluoromethyl)-l//-pyrazole-4carboxylate, 26b (70 mg, 0.20 mmol), NaOH (24.0 mg, 0.601 mmol) and water: EtOH (3 mL. 1:2) was stirred at room température for 16 h. The reaction mixture was neutralized to pH 7 with 4 M aq. HCl, and then concentrated to dryness under reduced pressure to give

242 the crude compound 26c (110 mg, crude), which was used in the foilowing reaction without further purification. LCMS (ESI): mass calcd. for C15H10F3N3O2 321.254, m/z found 322.0 [M+H]⁺.

D. yV-(5-Chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-methylquinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 28

POCI3 (52.7 mg, 0.344 mmol) was added dropwise to a solution of ethyl l-(8methylquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate, 26c (100 mg, 0.286 mmol), 5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine, Ij (112 mg, 0.573 mmol) and pyridine (3 mL). The mixture was stirred at 0 °C for 1 h. T he résultant mixture was poured into sat. aqueous NaHCO? (10 mL), extracted with ethyl acetate (10 mL x 3), dried over anhydrous NaaSCh, filtered, and the filtrate concentrated under reduced pressure to give a crude product, which was purified by reverse phase HPLC (48% to 78% (v/v) ACN and water with 0.05% NH3) to afford pure compound 28. The compound was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to give compound 28 (39.20 mg, 27 %). LCMS (ESI): mass calcd. for C22H14CIF3N8O 498.848, m/z found 498.9 [M+H]⁺. ^lH NMR (400 MHz. DMSO-U) δ ppm 9.08 (dd, J= 1.6, 4.0 Hz. 1H), 8.86 (d,J= 2.4 Hz, 1H). 8.68 (à,J=2A 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

A^r-(5-Chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(3-methylquinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 65

243

A, 3-Methyl-5-nitroquinoline (27a) and 3-methyl-8-nitroquinoline (27a-l)

27a

HNO3 (4.72 mL. 105 mmol) was added dropwise to a mixture consisting of 3methylquinoline (5.0 g. 35 mmol) and H2SO4 (5 mL) at 0 °C, and the reaction mixture was stirred at room température for 1 h. The résultant mixture was neutralized to pH 7 with 1 M aq. NaOH, extracted with ethyl acetate (30 mL x 3), and the extracts were concentrated under reduced pressure and purified by FCC (petroleum ether: ethyl acetate = 100:0 to 50:50) to afford a mixture of compounds 27a and 27a-l (4 g, 30 %). LCMS (ESI): mass calcd. for C10HSN2O2 188.18, m/z found 189.0 [M+H]⁺.

B. 3-Methylquinolin-5-amine, 27b

A mixture of 3-methyl-5-nitroquinoline (27a) and 3-methyl-8-nitroquinoline (27a1) (3.50 g, 9.30 mmol), MeOH (30 mL) and dry' Pd/C (350 mg, 5%) was added to a 500 mL hydrogénation bottle. The mixture was stirred under a H2 (30 psi) atmosphère at room température for 16 h. The suspension was filtered though a pad of diatomaceous earth and the pad was washed with MeOH (100 mL). The filtrate was concentrated to dryness under reduced pressure to give crude compound 27b, which was purified by FCC (ethyl acetate:

244 methanol = 100:0 to 95:5) to afford compound 27b (300 mg, 20 %). 'H NMR (400 MHz, DMSO-Λ) 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 /^NHNH₂[f T 2 HCl ,27c

A solution of sodium nitrite (131 mg, 1.90 mmol) and water (1 mL) was added dropwise to a solution of 3-methylquinolin-5-amine, 27b (200 mg, 1.26 mmol) and concentrated hydrochloric acid (1 mL) at a température between -10 °C and 0 °C. The mixture was stirred at a température between -10 °C and 0 °C for 1.5 h. A solution consisting of SnCh (571 mg. 2.53 mmol) and concentrated hydrochloric acid (1 mL) was added dropwise at a température between -10 °C and 0 °C, then the mixture was stirred at room température for 16 h. The suspension was filtered to give compound 27c (200 mg, crude), which was used in the next step without purification. LCMS (ESI): mass calcd. for C10H11N3 173.214,m/z found 174.0 [M+H]⁺.

D. Ethyl l-(3-methylquinolin-5-yl)-5-(trifluoromethyl)-137-pyrazole-4-carboxylate, 27d

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (195 mg, 0.813 mmol), 5-hydrazinyl-3-methylquinoline, 27c (200 mg, 0.813 mmol), triethylamine (164 mg, 1.63 mmol), and éthanol (2 mL) was stirred at 80 °C for 16 h

245 before cooling to room température. The reaction was concentrated to dryness under reduced pressure to give crude product, which was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 60:40) to give compound 27d ( 100 mg, 35 %). ’H NMR (400 MHz, CDCh) δ ppm 8.85 (d. .7 = 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 (q, J= 7.2 Hz, 2H), 2.48 (s, 3H), 1.42 (t, J= 7.2 Hz, 3H).

E. 2V-(5-Chloro-6-(2H-l,2.3-triazol-2-yl)pyridin-3-yl)-l-(3-methylquinolin-5-yl)-5(trifluoromethyl)- l/7-pyrazole-4-carboxamide, Cpd 65

A solution consisting of 5-chloro-6-(277-L2,3-triazol-2-yl)pyridin-3-amine, Ij (44.8 mg, 0.229 mmol) and THF (0.5 mL) was added to potassium rerr-butoxide in THF (0.687 mL, 0.687 mmol, 1 M) at 0 °C, then a solution consisting of ethyl l-(3methylquinolin-5-yl)-5-(trifluoromethyl)-l/7-pyrazole-4-carboxylate, 27d (60.0 mg, 0.229 mmol) and THF (0.5 mL) was added. The résultant mixture was stirred at room température for 16 h. The reaction mixture was concentrated under reduced pressure to give a cnide product, which was purified by reverse phase HPLC (41% to 71% (v/v) ACN and water with 0.05% NH?) to afford pure compound 65. The product was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 65 (45.40 mg, 40 %). LCMS (ESI): mass calcd. for C22H14CIF3N8O 498.848, m/z found 499.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-î/₆) δ ppm 11.28 (br.s., 1H), 8.93 (d,J=2.0Hz, 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).

246

Example 28

A^r-(5-Chloro-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoroquinolin-5-yl)-5(trifluoromethyl)-l//-pyrazole-4-carboxamide, Cpd 40

A. 8-Fluoro-5-hydrazinylquinoline,'28a

Y^.nhnh₂ff T 2HCI Ô ,23a

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-fluoroquinolin-5-amine (150 mg, 0.925 mmol) and conc. hydrochloric acid (4 mL, 36 %) at a température between -10 °C and 0 °C. The mixture was stirred at a température between -10 °C and 0 °C for 1.5 h. A solution of SnCh (417 mg, 1.85 mmol) and conc. hydrochloric acid ( 1 mL) was added dropwise at a température between -10 °C and 0 °C and the réaction was stirred at room température for 16 h. The mixture was filtered. The résultant solid was washed with MeOH ( 1 mL x 2) and dried under reduced pressure to afford compound 28a (220 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI): mass calcd. for C9H8FN3 177.178, m/z found 178.1 [M+H]L

B. Ethyl l-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-l/Z-pyrazole-4-carboxylate, 28b

247

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (207 mg, 0.864 mmol), 8-fluoro-5-hydrazinylquinoline HCl sait, 28a (360 mg, 0.864 mmol), triethylamine (175 mg, 1.73 mmol), and éthanol (5 mL) was refluxcd at 80 °C for 16 h before cooling to room température. The reaction was concentrated to dryness under reduced pressure to afford a crude product, which was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 70:30) to give compound 28b (100 mg, 33 %). 'H NMR (400 MHz, CDCh) δ ppm 9.06 (dd, J= 1.6,4.0 Hz, 1H), 8.25 (s, 1H). 7.61 - 7.48 (m, 4H), 4.41 (q, J= 7.2 Hz, 2H), 1.41 (t, J= 7.2 Hz, 3H).

C. l-(8-Fluoroquînolin-5-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylic acid, 28c

28c

A solution of ethyl l-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-l?/-pyrazole-4carboxylate, 28b (100 mg, 0.283 mmol), NaOH (34.0 mg, 0.849 mmol) and water: EtOH (3 mL, 1:2) was stirred at room température for 16 h. The solution was neutralized to pH 7 with 4 M aq. HCl, and then concentrated to dryness under reduced pressure to give compound 28c (120 mg, crude), which was used in the following reaction without further purification. LCMS (ESI): mass calcd. for C14H7F4N3O2 325.218, in/z found 325.9 [M+H]T

248

D.

A^r-(5-Chloro-6-(2//-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoroquinolin-5-yl)-5(trifluoromethyl)-l//-pyrazole-4-carboxamide, Cpd 40

POCh (56.6 mg, 0.369 mmol) was added dropwise to a solution of 1 -(8fluoroquinolin-5-yl)-5-(trifluoromethyl)-l/7-pyrazole-4-carboxylic acid, 28c (100 mg, 0.307 mmol), 5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-amine, Ij (120 mg, 0.615 mmol) and pyridine (5 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by reverse phase HPLC (38% to 68% (v/v) ACN and water with 0.05% NH;) to afford pure compound 40. Compound was suspended in water (10 mL), the mixture frozen using dry ice/acetone. and then lyophilized to dryness to give compound 40 (20.10 mg, 13 %). LCMS (ESI): mass calcd. for CaiHuGFjNsO 502.812,m/z found 502.9 [M+Hf. Ή NMR (400 MHz, DMSOA) δ ppm 11.28 (br.s., 1 H), 9.13 (dd, J = 1.6,4.0 Hz, IH), 8.87 (d,J = 2.0 Hz, IH), 8.69 (d, J= 2.0 Hz, IH), 8.60 (s, IH), 8.20 (s, 2H), 8.00 (dd, J = 4.4, 8.4 Hz, IH), 7.87 - 7,78 (m, 2H), 7.67 (d, J= 8.4 Hz, IH).

Example 29

Æ-(5-Chloro-6-(2/7-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(3-fluoroquinolin-5-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 25

249

A. 3-Fluoro-5-hydrazinylquinoline, 29a /Gx/NHNH₂JT 2HCI nYL

F ,29a

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-fluoroquinolin-5-amine (150 mg, 0.925 mmol) and concentrated hydrochloric acid (4 mL, 36%) at -10 °C - 0 °C. The mixture was stirred at a température between -10 °C and 0 °C for 1.5 h. A solution of SnCh (417 mg, 1.85 mmol) and concentrated hydrochloric acid (1 mL) was added dropwise at a température between -10 °C and 0 °C. The mixture was stirred at room température for 16 h. The mixture was filtered. The résultant solid was washed with MeOH (1 mL x 2) and dried under reduced pressure to afford compound 29a (220 mg, crude), which was used in the foilowing reaction without further purification. LCMS (ESI): mass calcd. for C9H8FN3 177.178, m/z found 178.1 [M+H]⁺.

B. Ethyl l-(3-fluoroquinolin-5-yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxylate, 29b

E p ^F \ U

Ç y—N

Y ^NY F ,29b

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (211 mg, 0.880 mmol),3-fluoro-5-hydrazmylquinoline, 29a (220 mg, 0.880 mmol), triethylamine (178 mg, 1.76 mmol), and éthanol (5 mL) was refluxed at 80 °C for 16 h before cooling to room température. The reaction mixture was concentrated to dryness under reduced pressure to afford crude compound 29b, which was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 70:30) to give compound 29b (160 mg, 51 %). 'H NMR (400 MHz, CDCls) δ ppm 8.94 - 8.89 (m. 1H). 8.34 (d, J= 8.4 Hz, 1H), 8.28 (s.

250

1H), 7.83 - 7.76 (m, 1H), 7.65 (d, J= Ί2 Hz, 1H), 7.25 - 7.19 (m. 1H), 4.43 (q, J= 7.2 Hz, 2H), 1.42 (t, J =7.2 Hz, 3 H).

C. l-(3-Fluoroquinolin-5-yl)-5-(trifluoromethyl)- 177-pyrazole-4-carboxylic acid, 29c 0 °L 0^00°h

N /) \\ //

F . 29c

A solution consisting of ethyl l-(3-fluoroquinolin-5-yl)-5-(trifluoromethyl)-l/7pyrazole-4-carboxylate. 29b (160 mg, 0.453 mmol), NaOH (54.3 mg, 1.54 mmol) and water: EtOH (3 mL, 1:2) was stirred at room température for 16 h. The solution was neutralized to pH 7 with 4 M aq. HCl, and the résultant solid was collected by filtration to afford compound 29c (150 mg, crude), which was used in the following reaction without further purification. LCMS (ESI): mass calcd. for C14H7F4N3O2 325.218, m/z found 325.9 [M^Hf.

A-(5-Chloro-6-(2.£M,2,3-triazol-2-yl)pyridin-3-yl)-l-(3-fluoroquinolin-5-yl)-5(trifluoromethyl)-177-pyrazole-4-carboxamide, Cpd 25

POCI3 (5.7 mg, 0.037 mmol) was added dropwise to a solution of l-(3fluoroquinolin-5-yl)-5-(trifluoromethyl)-l/7-pyrazole-4-carboxylic acid, 29c (160 mg, 0.492 mmol), 5-chloro-6-(2.£M,2,3-triazol-2-yl)pyridin-3-amine, Ij (192 mg, 0.984 mmol) and pyridine (5 mL). The mixture was stirred at 0 °C for 1 h. The résultant mixture was

251 poured into sat. aqueous NaHCO? (10 mL), extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na?SO4, fïltered, and the filtrate concentrated under reduced pressure to give the crude compound 25, which was purified by reverse phase HPLC (42% to 72% (v/v) ACN and H2O with 0.05% NH?) to afford pure compound 25. The product was suspended in water ( 10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to give compound 25 (53.60 mg, 21 %). LCMS (ESI): mass calcd. for C21H11CIF4N8O 502.812, m/z found 502.9 [M+H]⁺. ‘H NMR (400 MHz, DMSO-4,) δ ppm 11.24 (br.s., IH), 9.14 (d, J= 2.8 Hz, IH), 8.88 (d, J= 2.4 Hz, IH), 8.70 (d, J= 2.0 Hz, IH), 8.61 (s, IH), 8.40 (d,<7=7.6 Hz. 1H),8.21 (s, 2H), 8.03 - 7.96 (m, 2H). 7.52-7.49 (m, IH).

Example 30 ïV-(5-Chloro-6-(27/-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(6-methylisoquinolin-4-yl)-5(trifluoromethyl)-17/-pyrazole-4-carboxamide, Cpd 36

A mixture 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 /err-butoxide (325 mg, 3.38 mmol), and toluene (3 mL) was heated to 100 °C and stirred for 20 h under a N2 atmosphère before cooling to room température. The mixture was fïltered and concentrated to give a black oil, which was

252 purified by FCC (petroleum ether: ethyl acetate = 30 :70) to afford compound 30a (280 mg, 37 %) as a yellow solid. LCMS (ESI): mass calcd. for C23H19N3 337.4, m/z found 338.0 [M+Hf.

B. 4-Hydrazinyl-6-methylisoquinoline hydrochloride, 30b

HCl N—\ NH₂ (f y—NH

30b

A mixture of 4-(2-(diphenylmethylene)hydrazinyI)-6-methylisoquinoline, 30a (260 mg. 0.771 mmol), conc. hydrochloride (10 mL, 12 M in water, 43 mmol), and EtOH (1 mL) was stirred for 20 h at room température. The solid was collected by filtration, washed with DCM (3 mL x 2), and dried under reduced pressure to afford compound 30b (145 mg, 76 %) as a yellow solid, which was used in the following reaction without further purification. LCMS (ESI): Mass calcd. for C10H11N3 173.2, m/z found 174.1 [M+H]⁺.

C. Ethyl l-(6-methyIisoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate, 30c

A mixture of 4-hydrazinyl-6-methylisoquinoline hydrochloride, 30b ( 145 mg, 0.589 mmol), ethyl 2-(ethoxymethylene)-4.4,4-trifluoro-3-oxobutanoate, If (200 mg, 0.707 mmol), triethylamine (0.246 mL, 1.77 mmol), and EtOH (5 mL) was heated to 90 °C and stirred for 20 h before cooling to room température. The mixture was concentrated under reduced pressure to afford a yellow oil, which was purified by FCC (ethyl acetate: petroleum ether = 40: 60) to afford compound 30c (96 mg, 47 %) as a yellow solid. LCMS (ESI): mass calcd. for C17H14F3N3O2 349.3, m/z found 350.1 [M+H]⁺.

253

D. À⁷-(5-Chloro-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(6-methylisoquinolin-4-yl)-5(trifluoromethyl)-17Z-pyrazole-4-carboxamide, Cpd 36

Ethyl l-(6-methylisoquinolin-4-yl)-5-(trifluoromethyl)-17/-pyrazole-4-carboxylate, 30c (90.0 mg, 0.258 mmol) in THF (0.5 mL) and 5-chloro-6-(2H-l,2,3-triazol-2yl)pyridin-3-amine, Ij (50.4 mg, 0.258 mmol) in THF (0.5 mL) were added into a suspension of potassium /e/7-butoxide (43.4 mg, 0.386 mmol) in THF (2 mL) at 0 °C. The mixture was stirred at room température for 20 h before evaporating under reduced pressure to give a yellow solid, which was purified by reverse phase HPLC (CH3CN in Basic water (0.05% ΝΗ3Ή2Ο) from 45% to 75%, v/v). The résultant residue was resuspended in water (50 mL) and the resulting mixture was lyophilized to dryness to remove the solvent residue completely. Compound 36 (40.40 mg. 31 %) was obtained as an off-white solid. LCMS (ESI): mass calcd. for C22H14CIF3N8O 498.8, m/z found 498.9 [M+H]⁺. 'H NMR (400 MHz, DMSO-Λ) 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-(2Z/-L2.3-triazol-2-yl)pyridin-3-yl)-l-(3-methylisoquinolin-l-yl)-5(trifluoromethyl)-17/-pyrazole-4-carboxamide, Cpd 9

254

A. 3-Methylisoquinoline 2-oxide, 31a

,31a

3-Chloroperoxybenzoic acid (2.53 g, 14.7 mmol) was added in portions into a mixture consisting of 3-methylisoquinoline (1.91 g, 13.3 mmol) and DCM (10 mL). The résultant mixture was stirred for 2 days at room température before diluting with DCM (100 mL), washing with aqueous NaHCCh (70 mL x 2) and brine (70 mL), drying over anhydrous Na2SO4, filtering, and the filtrate concentrating under reduced pressure to afford compound 31a (1.4 g, 66 %) as a yellow solid, which was used in the following reaction without further purification. LCMS (ESI): mass calcd. for C10H9NO 159.2, m/z found 160.0 [M+H]⁺.

B. l-Chloro-3-methylisoquinoline, 31b

Cl ,31b

To a stirred solution of 3-methylisoquinoline 2-oxide, 31a (1.40 g. 8.80 mmol) in anhydrous CH2CI2 (5 mL) at 0 °C was added phosphorus oxychloride (0.902 mL. 9.67 mmol) followed by dropwise addition of DMF (0.338 mL, 4.40 mmol) under an Argon atmosphère. The resulting reaction mixture was warmed to room température and stirred

255 for 20 h. Saturated aqueous sodium carbonate solution was added to the reaction mixture slowly 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 Na2SÛ4, filtered and the filtrate concentrated under reduced pressure to afford a crude compound 31b, which was purified by flash column chromatography (ethyl acetate: pretroleum ether = 20: 80) to afford compound 31b (670 mg, 43 %) as a yellow oil. LCMS (ESI): mass calcd. for CioHsCIN 177.6, m/z found 177.9 [M+H]⁺.

C. l-Hydrazmyl-3-methylisoquinoline, 31c

NH

NH₂ ,31c

A mixture of l-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 before cooling to room température. The mixture was concentrated to give a yellow solid, which was dissoived into ethyl acetate (100 mL), washed with water (100 mL x 2), dried . over anhydrous Na₂SO4, filtered, and the filtrate was concentrated under reduced pressure to afford compound 31c (715 mg, 98 %) as a yellow solid. The crude product was used directly without further purification. LCMS (ESI): mass calcd. for C10H11N3 173.2, m/z found 174.0 [M+H]⁺.

D. Ethyl l-(3-methylisoquinolin-l-yl)-5-(trifluoromethyl)-lZ7-pyrazole-4-carboxylate, 31d

256

A mixture of l-hydrazinyl-3-methylisoquinoline, 31c (710 mg, 4.10 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (1.27 g, 4.51 mmol), and EtOH (15 mL) was heated to 90 °C and stirred for 20 h before cooling to room température. The mixture was concentrated under reduced pressure to afford a yellow solid, which was treated with MeOH (5 mL) and stirred for 15 min. The solid was collected by filtration, washed with MeOH (3 mL x 2), and dried under reduced pressure at room température to afford compound 31d (823.2 mg, 56 %). LCMS (ESI): mass calcd. for C17H14F3N3O2 349.3, m/z found 350.0 [M+H]⁺. Ή NMR (400 MHz, CDCh) 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 (q, J= 7.2 Hz, 2H), 2.73 (s, 3H), 1.42 (t,.7= 7.2 Hz, 3H).

E. l-(3-Methylisoquinolin-l-yl)-5-(trifluoromethyl)-l/7-pyrazole-4-carbo.xylic acid, 31e

A mixture of ethyl l-(3-methylisoquinolin-l-yl)-5-(trifluoromethyl)-177-pyrazoIe4-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) was stirred for 20 h atroom température. The pH of the mixture was adjusted to 2 with 6 N aq. HCl. The organic solvents were removed under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic layers were combined and dried over anhydrous Na₂SO4, filtered, and the filtrate concentrated under reduced pressure to afford compound 31e (140 mg, 69 %) as a yellow solid. LCMS (ESI): mass calcd. for C15H10F3N3O2 321.2, m/z found 322.0 [M+H]⁺.

257

F. A'-(5-Chloro-6-(277-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(3-methylisoquinolin-l-yl)-5(trifluoromethyl)-l/7-pyrazole-4-carboxamide, Cpd 9

Phosphorus oxychloride (0.049 mL, 0.52 mmol) was added dropwise into a solution consisting of l-(3-methylisoquinolin-l-yl)-5-(trifluoromethyl)-l/7-pyrazole-4carboxylic acid, 31e (140 mg, 0.436 mmol), 5-chloro-6-(2/7-l,2,3-triazol-2-yl)pyrïdin-3amine, Ij (93.8 mg, 0.479 mmol), and pyridine (2 mL). The mixture was stirred at 0 °C for 1 h before concentrating to dryness under reduced pressure to give crude product, which was purified by préparative HPLC using a Phenomenex Gemini C18 150 x 25 mm x

5 pin column ( 502-0 to 8024 (v/v) CH?CN and water with 0.05% NH?) to afford pure compound 9. Compound was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 9 (96.10 mg, 44 %) as a white solid. LCMS (ESI): mass calcd. for C22H14CIF3N8O 498.8, m/z found 498.9 [M+Hf. Ή NMR (400 MHz, DMSOY) 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=8.4Hz, 1 H), 8.04 (s, 1H), 7.90 (m, 1 H), 7.73 (m, 1H), 7.60 (d, 8.4 Hz, 1H), 2.68 (s, 3H).

Example 32

A^r-(5-chloro-6-(2/M,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-methylisoquinolin-4-yl)-520 (trifluoromethyl )-l/7-pyrazole-4-carboxamide, Cpd 66

258

A. 4-(2-(Diphenylmethylene)hydrazinyl)-1 -methylisoquinoline, 32a

,32a

A mixture consisting of 4-bromo-l-methylisoquinoline (800 mg, 3.60 mmol), (diphenylmethylene)hydrazine (707 mg, 3.60 mmol), BINAP (224 mg, 0.360 mmol), palladium(II) acetate (80.9 mg, 0.360 mmol), Z-BuONa (1.04 g, 10.8 mmol), and 1,4dioxane (20 mL) was stirred at 100 °C for 16 h before cooling to room température. The suspension was filtered though a pad of diatomaceous earth and the pad was washed with ethyl acetate (30 mL). The filtrate was concentrated to dryness under reduced pressure to give a crude product, which was added into water (15 mL). The résultant mixture was extracted with ethyl acetate (20 mL x 3). The combined organic extracts were dried over anhydrous NazSOj, filtered, and the filtrate was concentrated to dryness under reduced pressure to afford crude compound 32a, which was purified by FCC (petroleum ether: ethyl acetate = 4:1) to afford compound 32a (500 mg, 41 %) as a brown oil. LCMS (ESI): mass calcd. for C23H19N3 337.16, m/z found 337.9 [M+H]⁺. Ή NMR (400 MHz, CDCfi) δ ppm 8.74 (s, 1 H), 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

,32b

Conc. HCl (5 mL) was added to a solution consisting of 4-(2-(diphenyhnethylene) hydrazinyl)-l-methylisoquiuoline, 32a (500 mg, 1.48 mmol) and EtOH (2 mL). The résultant solution was stirred at room température for 16 h. The résultant mixture was added into dichloromethane (20 mL), filtered and the pad was washed with

259 dichloromethane (10 mL). The organic solution was concentrated to dryness under reduced pressure to afford compound 32b (940 mg, crude), which was used in the following reaction without further purification. LCMS (ESI): mass calcd. for C10H11N3 173.10, m/z found 174.1 [M+H]\

C. Ethyl l-(l-methylisoquinolin-4-yl)-5-(trifluoromethyl)-I77-pyrazole-4-carboxylate, 32c

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (984 mg, 4.10 mmol), 4-hydrazinyl-l-methylisoquinoline, 32b (840 mg, 3.41 mmol), triethylamine (0.950 mL, 6.83 mmol), and éthanol (20 mL) was stirred at 80 °C for 16 h before cooling to room température. The résultant solution was concentrated to dryness under reduced pressure to afford a crude product, which was added into water (10 mL). The résultant mixture was extracted with ethyl acetate (20 mL x 3). The combined organic extracts were dried over anhydrous Na?SO4, filtered, and the filtrated concentrated to dryness under reduced pressure to afford compound 32c, which was purified by FCC (petroleum ether: ethyl acetate = 4:1) to afford compound 32c (250 mg, 21 %) as a brown solid. LCMS (ESI): mass calcd. for C17H14F3N3O2 349.10. m/z found 349.9 [M+H]⁺. Ή NMR (400 MHz. CDCh) 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 (q.J= 7.2 Hz. 2H), 3.07 (s,3H), 1.41 (t, J = 7.2 Hz, 3H).

D. A⁷-(5-Chloro-6-(27/-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-methylisoquinolin-4-yl)-5(trifluoromethyl)-lE/-pyrazole-4-carboxamide, Cpd 66

260

A solution consisting of 5-chloro-6-(27/-l,2,3-triazoI-2-yl)pyridin-3-amine, Ij (193 mg, 0.988 mmol) and THF (1 mL), and a solution consisting of ethyl l-( 1 methylisoquinolin-4-yl)-5-(trifluoromethyl)-177-pyrazole-4-carboxylate, 32c (230 mg, 0.658 mmol) and THF (1 mL) were added to a solution consisting of potassium tcrtbutoxide (1.98 mL, 1.98 mmol, 1 M in THF) at 0 °C. The résultant mixture was stirred at room température for 16 h. The résultant mixture was added water (5 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic extracts were dried over anhydrous NajSCL, filtered, and the filtrate was concentrated to dryness under reduced pressure to afford a crude product, which was purified by préparative HPLC using a Kromasil 150 x 25 mm x 10 μηι column (35% to 65% (v/v) CHjCN and water with 0.05% NH.;) to afford pure compound 66. The product was suspended in water (10 mL), the mixUire frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 66 (126.40 mg, 38 %). LCMS (ESI): mass calcd. for C-HnClNsO 444.12, m/z found 449.0 [M+H]⁺. *H NMR (400 MHz, DMSOF) 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).

Example 33

2V-(5-cliloro-6-methoxypyridm-3-yl)-l-(isoquinolin-4-yl)-5-(trifluoromethyl)-l//-pyrazole4-carboxamide, Cpd 23

Cl

261

A. Ethyl l-(isoquinolin-4-yl)-5-(trifluoromcthyl)-lH-pyrazolc-4-carboxylate, 33a

A 20 mL vial with stirbar was charged with 4-chloroisoquinoline (103.6 mg, 0.633 mmol), palladium(II)(pi-cinnamyl) chloride dimer (9.1 mg, 0.0176 mmol), n-[2-(di-ladamantylphosphino)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) under air at room température. The dark yellow mixture was quickly bubbled with Argon gas for 1 min, and the vial was then sealed and stirred at 100 °C under an Argon atmosphère overnight (14 h). The reaction was then cooled to room température and treated with ethyl 2-(ethoxymethylene)-4,4.4-trifluoro-3-oxobutanoate, lf(0.123 mL, 1.235 g^zmL, 0.633 mmol) and stirred at 100 °C under air (sealed). After 20 min at 100 °C, the reaction was concentrated at 46 °C under reduced pressure to give a light green residue. This was taken up in THF (3 mL) and stirred at 60 °C for 5 min to maximize dissolution of compound 33a from the reaction mixture, and the reaction mixture was then cooled to room température. The amber solution in THF (assumed 0.2 M) was split into two (4 mL) vials and used in the next step immediately without further purification or characterization.

B.

/V-(5-chloro-6-methoxypyridin-3-yl)-l-(isoquinolin-4-yl)-5-(trifluoromcthyl)-lHpyrazole-4-carboxamide. Cpd 23

Cl

A solution of crude ethyl l-(isoquinolin-4-yl)-5-(trifluoromcthyl)-lH-pyrazolc-4carboxylate, 33a in THF, (Step A, assumed 106 mg, 0.316 mmol) was treated with 519506

262 chloro-6-methoxypyridin-3-amine (52.7 mg. 0.332 mmol) and the mixture was stirred until it was homogeneous. The mixture was then treated with KOtBu (56 mg, 0.499 mmol) in one portion, and the resulting dark reddish reaction was stirred at room température under air (sealed) for 45 min. About 100 mg of thiol-functionalized silica gel (1.2 mmol/g, -3 eq) was then added, and the reaction stirred at room température for another 45 min. The mixture was then fïltered and concentrated to provide a dark residue (136 mg) that was dissolved in a co-solvent (0.14 mL DMSO / 0.2 mL DCM), and purified by flash column chromatography (10 to 100% EtOAc in heptane over 24 CVs). Concentration from MeOH provided compound 23 as a white foam (11.6 mg, 8 % overall from 3 steps). ’H NMR (400 MHz, CDCI3) δ ppm 9.43 (s, IH), 8.54 (s, IH), 8.08-8.26 (m, 5H), 7.77 (quind, 2H), 7.34 (br d, 7=7.58 Hz, IH), 4.03 (s, 3H); MS m/e 448.0 (M+H).

Example 34 N-(5-cyano-6-methoxypyridin-3-yl)-l-(isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole4-carboxamide, Cpd 24 .

CN

A solution of crude ethyl l-(isoquinolin-4-yl)-5-(trifluoromethyl)-l/f-pyrazole-4carboxylate, 33a in THF, (assumed 106 mg, 0.316 mmol) was treated as described in Example 33, Step B, substituting 5-amino-2-methoxynicotinonitrile (47.4 mg, 0.318 mmol) for 5-chloro-6-methoxypyridin-3-amine, and the reaction was quenched with solid NH4CI rather than thiol-functionalized silica gel. Purification by flash column chromatography provided, following concentration from MeOH, compound 24 (18 mg, 13% overall in 3 steps) Ή NMR (400 MHz, CDCI3) δ ppm 9.45 (s, IH), 8.61 (s, IH), 8.45 (s, 2H), 8.24 (s, IH), 8.17 (d, 7=7.58 Hz, IH), 7.74-7.83 (m, 2H), 7.69 (s, IH), 7.28-7.37 (m, IH), 4.08 (s, 3H). MS m/e 439.2 (M+H).

263

Example 35

A^r-(5-cyano-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l,6-naphthyridin-5-yl)-5(trifluoromethyl)-l//-pyrazole-4-carboxamide, Cpd 100

A. 5-Hydrazinyl-l,6-naphthyridine, 35a ^'NH

MAY ύ J J ,35a

A solution of 5-chloro-l,6-naphthyridinè (150 mg, 0.91 mmol) was added into hydrazine hydrate (3 mL), the mixture was heated to 80 °C and stirred for 16 h. The mixture afforded compound 35a as a solid, collected by filtration. (100 mg, 42 %). LCMS (ESI) m/z M+l: 161.1.

B. Ethyl l-(l,6-naphthyridin-5-yI)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylate,

35b

A solution consisting of 5-hydrazinyl-l,6-naphthyridine, 35a (100 mg, 0.38 mmol) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (119.5 mg, 0.50 mmol) in éthanol (5 mL) was stirred at 80 °C for 4 h, The résultant solution was cooled to room • 264 température and concentrated to dryness under reduced pressure to afford crude compound 35b. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate= 100:0 to 70:30) to afford compound 35b as a yellow solid (100 mg, 85.5 %). LCMS (ESI) m/z M+l: 337.1.

C. l-(l,6-Naphthyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 35c

To a solution of ethyl l-(l,6-naphthyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate, 35b (90 mg, 0.27 mmol) in water (1 mL) and éthanol (ImL) was addedNaOH (12.85 mg, 0.32 mmol) at room température. The mixture was stirred for 3 h. 2N HCl (aq) was added to the mixture until the solution was adjusted to pH 2. The solvent was removed under reduced pressure to afford crude compound 35c as a white solid (82.5 mg, 100 %). LCMS (ESI) m/zM+l: 308.8.

D. A-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -( 1,6-naphthyridin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 100

Phosphoryl trichloride (49.4 mg. 0.32 mmol) was added to a mixture of 1-(1.6naphthyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 35c (82 mg, 0.27 mmol), 5-amino-2-(2//-l,2,3-triazol-2-yl)nicotinonitrile. 7b (59.4 mg, 0.32 mmol), and pyridine (107 pL, 1.33 mmol) in dichloromethane at room température. The reaction was . 265 stirred at room température for 2 h. Sat. aqueous NH4CI (aq) (lOmL) was added to the mixture. The mixture was extracted with dichloromethane (30 mL). The organic extracts were washed with water (5 mL), and brine (10 mL), dried over Na₂SO₄, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=IOO:O to ethyl acetate/ methanol =90:10). The solvent was removed under reduced pressure to afford compound 100 as a white solid (56.4 mg, 43 %). LCMS (ESI) m/z M+l : 447.0. Ή NMR (400 MHz, CDCh) δ ppm 7.63 (dd, J=8.60, 4.19 Hz, 1 H), 8.03 (s, 2 H), 8.15 (s, 1 H), 8.16 - 8.22 (m, 2 H), 8.27 (s, 1 H), 8.73 (d. >5.73 Hz, 1 H). 8.83 (d, J=2.65 Hz, 1 H), 8.96 (d, J=2.65 Hz, 1 H), 9.21 (dd, J=4.30, 1.65 Hz, 1 H).

Example 36 jV-(5-cyano-6-(27ï-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(fi.nO[2,3-c]pyridin-7-yl)-5(trifluoromethyl)-l/f-pyrazole-4-carboxamide, Cpd 99

7-Hydrazinylfuro[2,3-c]pyridine, 36a

7-Chlorofuro[2,3-c]pyridine (300 mg, 1.95 mmol) was dissolved in éthanol (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 afford crude compound 36a as a yellow solid. Compound 36a was purified by flash column

266 chromatography over silica gel (dichloromethane/MeOH from 100/0 to 80/20) to afford compound 36a as a yellow solid (250 mg, 83.9 %). LCMS (ESI) m/z M+l : 150.1.

B. Ethyl l-(furo[2,3-c]pyridin-7-yl)-5-(trifluoromethyl)-177-pyrazole-4carboxylate, 36b

,36b

7-Hydrazinylfuro[2.3-c]pyridine, 36a (250 mg, 1.64 mmol) was dissolved in éthanol (10 mL), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (788 mg, 3.28 mmol) was added and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford a cnide yellow oil. The oil was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 80/20) to afford compound 36b as a yellow oil (360 mg, 68 %). LCMS (ESI) m/z M+l : 325.9.

C.

l-(Furo[2,3-c]pyridin-7-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylic acid, 36c

Concentrated HCl (4.7 mL) was added to ethyl l-(furo[2,3-c]pyridin-7-yl)-5( trifluoromethyl)-177-pyrazole-4-carboxylate, 36b (170 mg, 0.52 mmol) and the reaction mixture was stirred at 130 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford compound 36c as a yellow solid (160 mg, 98 %), which was used in the following reaction without further purification. LCMS (ESI) m/z M+L 297.9.

267

D. ;V-(5-Cyano-6-(2//-l ,2,3-triazol-2-yl)pyridin-3-yl)- l-(furo[2,3-c]pyridin-7-yl)-5( trifluoromethyl)-l/7-pyrazole-4-carboxamide, Cpd 99

l-(Furo[2.3-c]pyridin-7-yI)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylic acid, 36c (160 mg, 0.51 mmol), 5-amino-2-(2//-l,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 phosphoryl trichloride (78.8 mg, 0.51 mmol) was added. The mixture was stirred at 25 °C for 16 h. Sat. aqueous NaHCOj (20 mL) was added and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic layers were dried over Na₂SO4, filtered, and the filtrate was concentrated under reduced pressure to afford crude compound 99 as a yellow oil. The oil was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: A/B (65%/35% to 40%/60 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 99 as a yellow solid (65 mg, 41 %). LCMS (ESI) m/z M+l: 465.9; Ή NMR (400 MHz, DMSO0) δ ppm 11.41 (s, 1H), 9.06 (d, >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, >2.4 Hz, 1H), 8.29 (s, 2H), 7.95 (dd, J=0.9, 5.7 Hz, 1H), 7.13 (dd, >0.9, 2.2 Hz, 1H).

Example 37 '

ÏV-(5-cyano-6-(2Z/-l,2,3-triazol-2-yI)pyridin-3-yl)-l-(furo[3,2-c]pyridin-4-yl)-5(trifluoromethyl)-l//-pyrazole-4-carboxamide, Cpd 94

268

A. 4-Hydrazinylfuro[3,2-c]pyridine, 37a hn'^NH2

37a

A mixture of 4-chlorofiiro[3,2-c]pyridine (200 mg, 1.30 mmol) in hydrazine (6.52 g, 130 mmol) was stirred at 80 °C for 12 h. The reaction mixture was extracted with dichloromethane (30 mL x 2). The organic layer partitioned and concentrated to afford compound 37a as a yellow solid (0.15 g, 77 %).

B. Ethyl I-(furo[3,2-c]pyridin-4-yl)-5-(trifluoromcthyI)-IH-pyrazole-4carboxylate, 37b

A solution consisting of4-hydrazinylfuro[3,2-c]pyridine, 37a (150 mg, 1.01 mmol) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (314 mg, I.3I mmol) in éthanol (5 mL) was stirred at 80 °C for 3 h. The résultant solution was cooled to room température and concentrated to dryness under reduced pressure to afford the crude product. The crude product was purified by column chromâtography over silica gel

269 (petroleum ether/ ethyl acetate=100:0 to 70:30) to afford crude compound 37b as a yellow solid (170 mg, 51 %). LCMS (ESI) m/z M+l: 325.9.

C. l-(Furo[3.2-c]pyridin-4-yl)-5-(trifluoromethyl)- l//-pyrazolc-4-carboxylic acid,

37c

A mixture of ethyl l-(furo[3,2-c]pyridin-4-yl)-5-(trifluoroniethyl)-lH-pyrazole-4carboxylate, 37b (170 mg, 0.52 mmol) in concentrated HCl (4.4 mL) was stirred at 110 °C for 5 h. The solvent was removed under reduced pressure to afford compound 37c as a yellow solid ( 155 mg, 100 %). LCMS (ESI) m/z M+l : 297.9.

D. JV-(5-Cyano-6-(2/M ,2,3-triazol-2-yl)pyridin-3-yl)- l-(furo[3,2-c]pyridin-4-yl)-5(trifluoromethyl)-l/7-pyrazole-4-carboxamide, Cpd 94

Phosphoryl trichloride (61.6 pL, 0.67 mmol) was added to the mixture of 1(furo[3,2-c]pyridin-4-yl)-5-(trifluoromethyl)-l/7-pyrazole-4-carboxylic acid, 37c (100 mg, 0.34 mmol), 5-amino-2-(2//-l,2,3-triazol-2-yl)nicotinonitrile, 7b (75.2 mg, 0.40 mmol), and pyridine (135 pL, Γ.68 mmol) in dichloromethane at 0 °C. The reaction was stirred at room température for 2 h. Sat. aqueous NH4CI (aq) (10 mL) was added to the mixture.

The mixture was extracted with dichloromethane (30 mL). The organic extracts were washed with water (5 mL). and brine (10 mL), dried overNa2SO4, filtered, and the filtrate

270 concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: A/B (65%/35% to 35%/65 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 94 as a white solid (73.6 mg, 46 %). LCMS (ESI) m/z M+l: 447.0; Ή NMR (400 MHz, DMSO-e/e) δ ppm 7.13 (d, J=1.32 Hz. 1 H), 7.94 - 7.99 (m, 1 H), 8.30 (s, 2 H), 8.33 (d, J=2.21 Hz, 1 H), 8.49 (d, J=5.73 Hz, 1 H), 8.55 (s, 1 H), 8.85 (d, J=2.43 Hz, 1 H), 9.07 (d, J=2.43 Hz, 1 H), 11.45 (s, 1 H).

Example 38 l-(Cinnolin-4-yl)-A-(5-eyano-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)l/f-pyrazole-4-carboxamide, Cpd 93

A. 4-Hydrazinylcinnoline, 38a

A vial with stirbar was charged with 4-chlorocinnoline (212 mg, 1.288 mmol) and hydrazine (0.4 mL, 1.021 g/mL, 12.745 mmol), and the mixture was evacuated and flushed with argon (4.x). Within 1-2 min at room température, the reaction mixture became a homogeneous amber solution and spontaneously warmed, becoming an orange paste. The reaction was then heated at 110 °C for 5 min. The reaction was allowed to cool to room température, water (8 mL) was added to the resulting paste, and the mixture was filtered.

271

The fîlter cake was washed with water (4 mL x 2) and dried under reduced pressure to afford compound 38a as a yellow powder (142.1 mg, 69 %).

B. Ethyl l-(cinnolin-4-yl)-5-(trifluoromethyl)-lJf-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, If (244 mg, 1.02 mmol) in éthanol (5 mL) was stirred at 80 °C for 3 h. The résultant solution was cooled to room température and concentrated to dryness under reduced pressure to afford crade compound 38b. The 10 crade product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate= 100:0 to 70:30) to afford crade compound 38b as a yellow solid (90 mg, 53 %). LCMS (ESI) m/z M+l:336.9. *H NMR (400 MHz, CDCh) δ ppm 1.42 (t, J=7.17 Hz, 3 H), 4.43 (q, J=7.28 Hz, 2 H), 7.54 (d, J=8.60 Hz, 1 H), 7.87 (t, J=7.61 Hz, 1 H), 7.99 (td, J=7.72, 1.10 Hz, 1 H), 8.33 (s, 1 H), 8.74 (d, J=8.60 Hz, 1 H), 9.33 (s, I H).

C. l-(Cinnolin-4-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylic acid, 38c

A mixture of ethyl l-(cinnoIin-4-yl)-5-(trifluoromethyl)-l//-pyrazole-420 carboxylate, 38b (90 mg, 0.27 mmol) in concentrated HCl (2.23 mL) was stirred at 110 °C for 5 h. The solvent was removed under reduced pressure to give compound 38c as a yellow solid (82 mg, 100 %). LCMS (ESI) m/z M+l:308.9.

272

D. l-(Cinnolin-4-yl)-jV-(5-cyano-6-(2J/-l,2,3-triazoI-2-yl)pyridin-3-yl)-5(trifluoromethyl)- l//-pyrazolc-4-carboxamidc, Cpd 93

ΝΛ

Phosphoryl trichloride (163.2 mg, 1.01 mmol) was added to a mixture of 1(cinnolin-4-yl)-5-(trifhioromethyl)-l //-pyrazole-4-carboxylic acid, 38c (82 mg, 0.27 mmol), 5-aniino-2-(2JZ-l,2,3-triazol-2-yl)nicotinonitrile, 7b (59.4 mg, 0.32 mmol), and pyridine (126 mg, 1.60 mmol) in dichloromethane at 0 °C. The reaction was stirred at room température for 2 h. Sat. NH4CI (aq) (10 mL) was added to the mixture. The mixture was extracted with dichloromethane (30 mL x 2). The organic extracts were washed with water (5 mL), and brine (10 mL), dried overNa2SÛ4, fïltered, and the fîltrated concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: A/B (62%/38% to 32%/68 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 93 as a pale yellow solid (20 mg, 16 %). LCMS (ESI) m/z M+l: 477.0; 'H NMR (400 MHz, DMSO-Jù) δ ppm 7.58 (d, >8.38 Hz, 1 H), 8.01-8.10 (m, 1 H), 8.15 (t, >7.50 Hz, 1 H), 8.29 (s, 2 H), 8.71 (s, 1 H), 8.74 (d, >8.60 Hz, 1 H), 8.87 (d, >2.65 Hz, 1 H), 9.09 (d, >2.65 Hz, 1 H), 9.77 (s, 1 H), 11.37 (s, 1 H).

Ex amp le 39 yV-(5-cyano-6-(2J/-L2,3-triazol-2-yI)pyridin-3-yl)-l-(8-fluoroquinolin-4-yl)-5(trifluoromethyl)-17/-pyrazole-4-carboxamide, Cpd 92

273

A. 8-Fluoro-4-hydrazinylquinoline, 39a

Ah

ÔQ

F , 39a

4-ChIoro-8-fluoroquinoline (300 mg, 1.65 mmol) was dissolved in éthanol (5 mL), hydrazine hydrate (292 mg, 5.0 mmol) was added and the reaction was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford crude compound 39a as a yellow solid. The solid was purified by flash column chromatography over silica gel (dichloromethane/MeOH from 100/0 to 80/20) to afford compound 39a as a yellow solid (350 mg, 82 %). LCMS (ESI) m/z M+L 178.1.

B. Ethyl l-(8-fluoroquinolin-4-yI)-5-(trifluoromethyl)-l/7-pyrazole-4-carboxylate,

A solution consisting of 8-fluoro-4-hydrazinylquinoline, 39a (350 mg, 1.35 mmol) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (648 mg, 2.70 mmol) in éthanol (10 mL) was stirred at 80 °C for 16 h. The résultant solution was cooled to room

274 température and concentrated to dryness under reduced pressure to afford a crude product. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=100:0 to 80:20). The solvent was removed under reduced pressure to afford compound 39b as a yellow solid (780 mg, 61 %).

C. l-(8-Fluoroquinolin-4-yl)-5-(trifluoromcthyl)-lH-pyrazole-4-carboxylic acid, 39c

A mixture of ethyl l-(8-fluoroquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate. 39b (150 mg, 0.43 mmol) in concentrated HCl (10 mL) was stirred at 130 °C for 4 h. The solvent was concentrated under reduced pressure to afford compound 39c as a yellow solid (140 mg, 100 %). LCMS (ESI) m/z M+l: 325.9.

D. A'-(5-Cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoroquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 92

Phosphoryl trichloride (81.2 mg, 0.53 mmol) was added to a mixture of l-(8fluoroquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 39c (150 mg, 0.46 mmol), 5-amino-2-(2H-l,2,3-triazol-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 was stirred at room température for 2 h. Sat. NH4CI (aq) (10 mL) was added to the mixture. The

275 mixture was extracted with dichloromethane (30 mL x 2). The organic layer was washed with water (5 mL), and brine (10 mL), dried over Na₂SÛ4, filtered, and the filtrate concentrated under reduced pressure. The résultant residue was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: A/B (57%/43% to 27%/73 %). The pure 5 fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 92 as a yellow solid (54 mg, 31 %). LCMS (ESI) m/z M+l: 493.9; ’H NMR (400 MHz, DMSO-U) 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 ïV-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5-(trifluoromethyl)-l/fpyrazole-4-carboxamide, Cpd 91

Phosphoryl trichloride (38.5 mg, 0.25 mmol) was added to a mixture of 1(quinolin-5-yl)-5-(trifluoromethyl)-l/f-pjTazole-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. The reaction was stirred at room température for 16 h. Sat. NaHCOs (aq) (20 mL) was added to the mixture. The mixture was extracted with dichloromethane (20 mL x 2). The organic layer was washed with water (5 mL), dried over Na₂SO4, filtered, and the filtrate concentrated under reduced pressure. The résultant residue was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: A/B (64%/36% to 34%/66 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 91 as a yellow solid (40 mg, 49 %). LCMS (ESI) m/z M+l : 484.9; *H NMR (400 MHz, DMSO19506

276 de) 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, IH), 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

A⁷-(5-cyano-6-cyclopropoxypyridm-3-yl)-l-(quinoIin-5-yI)-5-(trifluoromethyI)-l//pyrazole-4-carboxamide, Cpd 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 température ovemight. The mixture was concentrated to dryness and dissolved in ethyl acetate (5 mL). Water (10 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (10 mL x 3). 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 flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 60/40) to afford compound 41a as a yellow solid (310 mg, 92 %). Ή NMR (400 MHz, DMSO- de) δ ppm 0.85 - 0.90 (m, 4 H),

4.52 - 4.58 (m, 1 H), 9.18 (d, J=2.76 Hz. 1 H) ,9.35 (d, J=2.76 Hz, 1 H).

B. 5-Amino-2-cyclopropoxynicotinonitriIe, 41b

277

41b

Fe (0) (422 mg, 7.56 mmol) and NH4CI (404 mg, 7.56 mmol) was added to a solution of 2-cyclopropoxy-5-nitronicotinonitrile, 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 h. The mixture was filtered. Sat. aqueous NaHCOs was added to adjust the pH of the reaction mixture to 7-8. The mixture was extracted with ethyl acetate (10 mL x 3). The organic extracts were dried over MgSO4. filtered. and the filtrate was concentrated under reduced pressure to afford compound 41b as a yellow solid (280 mg, 87 %). LCMS (ESI) m/z M+l: 175.8.

C. N-(5-Cyano-6-cyclopropoxypyridin-3-yl)-l-(quinolin-5-yl)-5-(trifluoromcthyl)-l//pyrazole-4-carboxamide, Cpd 88

2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3.3-tetramethyluronium hexafluorophosphate (186 mg, 0.49 mmol) was added to a solution of l-(quinolin-5-yl)-5-(trifluoromethyl)-l//pyrazole-4-carboxylic acid. 3b (100 mg, 0.325 mmol). 5-amino-2cyclopropoxynicotinonitrile, 41b (97.1 mg, 0.46 mmol) and triethylamine (142 pL, 0.81 mmol) in DMF (2 mL). The reaction mixture was stirred at room température for 1 h. Water (5 mL) was added to the mixture. The aqueous portion was extracted with dichloromethane (5 mL x 3). The separated organic layer was dried over MgSQj, filtered, and the filtrate was concentrated under reduced pressure to afford a crude product. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: A/B (74%/26% to 44%/56 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 88 as a white solid (90 mg, 43 %).

278

LCMS (ESI) m/z M+l: 465.0; Ή NMR (400 MHz. DMSO/ό) δ ppm 0.75 - 0.80 (m, 2 H), 0.81 - 0.87 (m. 2 H), 4.39 (tt, >6.12, 3.14 Hz. 1 H), 7.63 - 7.73 (m, 2 H), 7.91 - 7.95 (m, 1 H), 7.96 - 8.02 (m, 1 H), 8.34 (d. >8.38 Hz, 1 H), 8.52 - 8.58 (m, 2 H), 8.75 (d, >2.43 Hz.

I H). 9.08 (dd, >4.08. 1.65 Hz, 1 H), 11.01 (brs, 1 H).

Example 42 ïV-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(phthalazin-1 -yl)-5-(trifluoromethyl) lH-pyrazole-4-carboxamide, Cpd 102

A. 1-Hydrazinylphthalazine, 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 h. The mixture was extracted with dichloromethane (50 mL x 2). The organic layer was concentrated under reduced pressure to afford a crude product. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=100:0 to 0:100) to afford crude compound 42a as a yellow solid (0.25 g, 73.3 %).

B. Ethyl l-(phthalazin-l-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate, 42b

279

A solution consisting of 1-hydrazinylphthalazine, 42a (250 mg, 1.56 mmol) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (750 mg, 3.12 mmol) in éthanol (5 mL) was stirred at 80 °C for 3 h. The résultant solution was cooled to room température and concentrated to dryness under reduced pressure to afford a crude product. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=100:0 to 70:30) to afford crude compound 42b as a yellow solid (160 mg, 27.4 %). LCMS (ESI) m/z M+l: 336.9.

C. l-(Phthalazin-l-yl)-5-(trifluoromethyl)-l/f-pyrazole-4-carboxylic acid, 42c

A mixture of ethyl l-(phthalazin-l-yl)-5-(trifluoromethyl)-l//-pyrazole-4carboxylate, 42b (160 mg, 0.43 mmol) in concentrated HCl (3.5 mL) was stirred at 110 °C for 5 h. The solvent was removed under reduced pressure to afford compound 42c as a yellow solid (140 mg, 100 %). LCMS (ESI) m/z M+l: 308.9.

D. À^r-(5-cyano-6-(27/-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(phthalazin-l-yl)-5( trifluoromethyl)-l//-pyrazole-4-carboxamide, Cpd 102

280

Phosphoryl trichloride (218.2 mg, 1.42 mmol) was added to the mixture of 1(phthalazin-l-yl)-5-(trifluoromethyl)-lÆ-pyrazole-4-carboxylic acid, 42c (130 mg, 0.36 mmol), 5-amino-2-(2Z/-l,2,3-triazol-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 was stirred at room température for 2 h. Water (20 mL) was added to the mixture. The mixture was extracted with dichloromethane (20 mL x 2). The organic portion was concentrated under reduced pressure to afford a crude product. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: A/B (65%/35% to 35%/65

%). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 102 as a white solid (15 mg, 9 %). LCMS (ESI) m/z M+l: 477.0; Ή NMR (400 MHz, DMSO-Λ) δ ppm 7.81 (d, J=8.38 Hz, 1 H), 8.14 - 8.25 (m, 2 H), 8.44 (d, J=7.72 Hz, 1 H). 8.73 (s, 1 H), 8.89 (d, J=2.43 Hz. 1 H), 9.12 (d. J=2.43 Hz, 1 H). 9.98 (s. 1 H), 11.45 (s, 1 H).

Example 43

Methyl 3-chloro-5-(3-chloro-5-(l-(isoquinolin-4-yl)-5-(trifluoromethyl)-l#-pyrazole-4carboxamido)picolinamido)picolinate. Cpd 44

A. Methyl 5-amino-3-chloropicolinate, 43a

O h₂n , 43a

A mixture of 6-bromo-5-chloropyridin-3-amine (500 mg, 2.41 mmol), 1J* bis(diphenylphosphino)ferrocene (134 mg, 0.24 mmol) and triethylamine (732 mg, 7.23 mmol) m MeOH (3 mL) and toluene (15 mL) was heated at 70 °C under a CO (35 psi) atmosphère with dichloro[LT-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (catalyst, 197 mg, 0.24 mmol), and the mixture was stirred ovemight. After uptake of CO ( 1 equiv), the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 50/50) to afford compound 43a as a red solid (300 mg, 67 %). ΉNMR (400 MHz, CDCh) δ ppm 3.96 (s, 3 H), 4.14 - 4.24 (m, 2 H), 7.03 (d, J=2.26

Hz, 1 H), 8.03 (d, J=2.51 Hz. 1 H).

B. Methyl 3-chloro-5-(3-chloro-5-( l-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H- pyrazole-4-carboxamido)picolinamido)picolinate, Cpd 44

282

Phosphoryl trichloride (29.8 mg, 0.32 mmol) was added dropwise to a solution of l-(isoquinolin-4-yl)-5-(trifluoromethyl)-177-pyrazole-4-carboxylic acid, 4c (50 mg, 0.16 mmol), methyl 5-amino-3-chloropicolinate, 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 température for l h. Water (5 mL) was added to the mixture. The aqueous portion was extracted with dichloromethane (5 mL x 3). The separated organic extracts were dried over MgSÛ4, filtered, and the filtrate concentrated under reduced pressure to afford a crude product. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), l() B: MeCN; then: A/B (55%/45% to 25%/75 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 44 as a white solid (22 mg, 21 %). LCMS (ESI) m/z M+l: 629.8: Ή NMR (400 MHz. DMSO-Λ) δ ppm 3.90 (s, 3 H), 7.30 (d, J=8.38 Hz, 1 H), 7.84 - 8.00 (m, 2 H), 8.39 (d, J=8.16 Hz, 1 H), 8.58 (dd, J=10.69, 1.87 Hz, 2 H), 8.68 (s, 1 H), 8.81 (s, 1 H), 9.01 (dd, J=10.03, 1.87 Hz, 2 H), 9.64 (s, l H), 11.36 (d, J=19.40 Hz, 2 H).

Examp te 44 _iV-(5-Chloro-6-(277-L2,3-triazol-2-yl)pyridin-3-yl)-5-ethyl-l-(quinolin-5-yl)-l/7-pyrazole4-carboxamide, Cpd 17

283

A. 3-(Ethoxymethylene)-1 -methoxyhexane-2,4-dione, 44a

A solution consisting of ethyl 3-oxopentanoate (LO g, 6.9 mmol), triethoxymethane (3.1 g, 21 mmol), and acetic anhydride (20 mL) was stirred at 135 °C for 16 h before cooling to room température. The résultant mixture was concentrated to dryness under reduced pressure to afford crude compound 44a ( 1.8 g, crude), which was used in the following reaction without further purification. U NMR (400 MHz, CDCh) δ ppm 7.69 7.54 (m, 1H), 4.33-4.15 (m, 4H), 2.70 (dd, J= 7.6, 13.2 Hz, 214), 1.41 - 1.26 (m, 6H), 1.13 - 1.05 (m, 3H).

A solution consisting of 5-aminoquinoline (LO g, 6.9 mmol) and concentrated hydrochloric acid (5 mL) was stirred at 0 °C (ice/water) for 10 min. A solution consisting 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 réaction mixture over 10 min. The résultant mixture was warmed

284 to room température and stirred for 50 min. The reaction mixture was then heated at 80 ^CC for 20 min and water (4 mL) was added. The suspension was again cooled to 0 °C (ice/water) and stirred for 2 h. A solid was collected by filtration and washed with methanol to afford compound 44b (870 mg, 79 %). *H NMR (400 MHz. DMSO-t/o) δ ppm 10.01 (br. s., IH). 9.28 - 9.13 (m, 2H), 8.06 - 7.86 (m, 3H), 7.33 - 7.20 (m, IH).

C. Ethyl 5-ethyl-l-(quinolin-5-yl)-lH-pyrazole-4-carboxylate, 44c

A solution consisting of 3-(ethoxymethylene)-l-methoxyhexane-2,4-dione, 44a (755 mg, 3.77 mmol), 5-hydrazinylquinoline, 44b (500 mg, 3.14 mmol), and éthanol ( 15 mL) was stirred at 80 °C for 16 h before cooling to room température. The résultant solution was concentrated to dryness under reduced pressure to afford a crude product, w'hich was purified by FCC (dichloromethane: methanol = 10:1) to afford 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), followed by a gradient up to 5% solvent A and 95% solvent B). *H NMR (400 MHz, DMSO-Jô) δ ppm 9.17 - 9.11 (ni, IH), 8.40 (d, J= 8.4 Hz, IH), 8.17 (s, IH), 8.06 (t, J= 8.0 Hz, IH), 7.93 (d, J=7.6Hz, IH), 7.83 - 7.78 (m. IH), 7.77 - 7.71 (m, IH), 4.30 (q, J= Ί 2 Hz, 2H), 2.78 - 2.68 (m. 2H), 1.33 (t, J = Ί2 Hz, 3H), 0.92 (t. J =7.6 Hz, 3H).

D.

5-Ethyl-1 -(qumolin-5-yI)-lH-pyrazole-4-carboxylic acid, 44d

285

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-l-(quinolin-5-yl)-l7f-pyrazole4-carboxylate, 44c (700 mg, 2.37 mmol) and éthanol (10 mL). The résultant solution was stirred at room température for 16 h. The résultant solution was concentrated to dryness under reduced pressure to afford a crude product, which was poured into water (3 mL) and acidified with 3N HCl to pH 5. A precipitate was removed by filtration, the filter cake was washed with w^rater (3 mL), and then dried under reduced pressure to afford compound 44d (400 mg, 63 %) as a brown solid. LCMS (ESI): Rt = 0.54 min, mass calcd. for CisHisNsCh 267.10, m/z found 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 up to 5% solvent A and 95% solvent B) afforded compound 44d. Ή NMR (400 MHz, DMSOF) δ ppm 12.55 (br. s., IH), 9.02 (d, J= 2.4 Hz, 1H), 8.27 (d, J =8.8 Hz, IH), 8.10 (s, IH), 7.97 - 7.91 (m, 1H), 7.82 (d, 7= 7.2 Hz, 1H), 7.63 - 7.53 (m, 2H), 2.77 - 2.65 (m, 2H), 0.88 (t,7= 7.6 Hz, 3H).

E. A'-(5-Chloro-6-(2Zf-L2,3-triazol-2-yl)pyridin-3-yr)-5-ethyl-l-(quinoIin-5-yI)-l/3^rpyrazole-4-carboxamide, Cpd 17

POCh (172 mg, 1.12 mmol) was added dropwise to a solution consisting of 5ethyl-1 -(quinoIin-5-yl)-l/Z-pyrazole-4-carboxylic acid, 44d (250 mg, 0.935 mmol), 5chloro-6-(2//-l,2,3-triazol-2-yl)pyridin-3-amine, Ij (201 mg, 1.03 mmol). and pyridine (5 mL) at 0 °C. The résultant mixture w^ras stirred at 0 °C for 1 h. To the résultant mixture was added sat. aqueous NaHCCh (10 mL) and the mixture was extracted with ethyl acetate (15 mL x 3). The organic extracts were dried over anhydrous NUtSOt, filtered. and the filtrate was concentrated to dryness under reduced pressure to give a crude product. The

286 crade material was purified by reverse phase HPLC (40% to 50% (v/v) CH3CN and water with 0.05% NH3) to afford compound 17 (100 mg). Compound 17 was further purified by reverse phase HPLC (30% to 60% (v/v) CH3CN and water with 10 mM NH4HCO3) to afford pure compound 17, which was suspended in water (10 mL), frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 17 (56.50 mg, 13 %). LCMS (ESI): Rt = 4.51 min, mass calcd. for CgzHnClNsO 444.12, m/z found 445.0 [M+H]T *H NMR (400 MHz, CDCI3) δ ppm 9.02 (dd, 7 = 1.6.4.4Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H). 8.54 (d, 7= 2.4 Hz, 1 H), 8.34 (d, 7= 8.4 Hz, lH),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, 7= 7.6 Hz, 3H).

Ex amp le 45

A-(5-Chloro-6-( 1H-1,2,3-triazol-2-yDpyridin-3-yl)-1 -( lH-indazol-4-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 68

A. 4-(2-( Diphenylmethylene)hydrazinyl)-1 H-indazole, 45a

A mixture consisting of 4-bromo-lH-indazole (1.50 g. 0.760 mmol), (diphenylmethylene)hydrazine (1.49 g. 7.61 mmol), f-BuONa (2.19 g, 22.8 mmol), Pd2(dba)3 (697 mg. 0.760 mmol). Xantphos (440 mg, 0.760 mmol), and 1,4-dioxane (20 mL) was stirred at 110 °C for 24 h under a N? atmosphère. The mixture was cooled to room température, filtered and the filtrate was concentrated to dryness under reduced pressure to give a residue. which was purified by FCC (petroleum ether: ethyl acetate =

287

1:2) to afford compound 45a (1 g, 42 %). *H NMR (400 MHz, CDCk) δ ppm 10.37 (br s, 1H), 8.52 (s, 1H), 7.95 (s, 1H), 7.67 - 7.56 (m, 5H), 7.42 - 7.33 (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-l H-indazole, 45b h₂nhn~J^nh

V , 45b

A mixture consisting of 4-(2-(diphenylmethylene)hydrazinyl)-l H-indazole, 45a (800 mg, 2.56 mmol), conc. HCl (10 mL), and éthanol (5 mL) was stirred at room température for 16 h. The éthanol was removed under reduced pressure and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The extracts were concentrated to dryness under reduced pressure to afford compound 45b (450 mg, 95 %). 'H NMR (400 MHz, DMSOA) 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 l-(lH-indazol-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate. 45c

A mixture consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, cpd If (39.0 mg, 0.160 mmol), 4-hydrazinyl-1 H-indazole, 45b (30.0 mg, 0.160 mmol), triethylamine (18.0 mg, 0.180 mmol), and éthanol (3 mL) was stirred at 80 °C for 16 h. The mixture was cooled to room température and concentrated to dryness under reduced pressure to give a residue, which was purified by FCC (petroleum ether: ethyl acetate = 2:1) to afford impure compound 45c (550 mg). The post-chromatographic product (550 mg) was further purified by préparative HPLC (32% to 62% (v/v) CHjCN and water with 0.05% NH3) to afford compound 45c, which was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 45c (260

288 mg, 33 %). Ή NMR (400 MHz, CDCh) δ ppm 11.01 (br s. 1 H), 8.24 (s. 1 H), 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 (q, J= 7.2 Hz, 2H), 1.41 (t, J= 7.2 Hz, 3H).

D. N-(5-Chloro-6-( 2//-1,2,3-triazol-2-yl)pyridin-3-yl)-l-(12/-indazol-4-yi)-5( trifluoromethyl)-l/Z-pyrazole-4-carboxamide. Cpd 68 \=N

A solution consisting of 5-chloro-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-amme, Ij (79.6 mg, 0.410 mmol) and THF ( 1 mL) was added dropwise to a solution of z-BuOK (1.02 mL, 1.02 mmol, 1 M in THF) at 0 °C. Then a solution consisting of ethyl indazol-4-yl)-5-(tnfluoromethyl)-l//-pyrazole-4-carboxylate, 45c (20.0 mg, 0.0600 mmol), and THF (1 mL) was added dropwise. The mixture was warmed to room température and stirred for 16 h before quenching with water and extracting w^rith ethyl acetate (50 mL x 3). The combined extracts were dried over anhydrous Na?SO4, filtered, and the filtrate concentrated to dryness under reduced pressure to give a residue, which was purified by reverse phase HPLC (26% to 56% (v/v) CH3CN and water with 0.05% NH3) to afford pure compound 68. The product was suspended m water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 68 (70 mg, 44 %). *H NMR (400 MHz, DMSO0) δ ppm 13.63 (br s, 1H), 11.29 (br s, 1H), 8.86 (d, J= 2.4 Hz,

1H), 8.68 (d, 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,./ = 7.6 Hz, 1H).

289

Example 46 l -(Naphthalen-1 -yl)-5-(tnfluoromethyl )-AX2-(trifluoromethyl)pyTidin-4-yl)- l/f-pyrazole4-carboxamide, Cpd 3

POCh (90.1 mg, 0.588 mmol) was added dropwise to a solution consisting of 1(naphthalen-l-yl)-5-(trifluoromethyD-lÆ-pyrazole-4-carboxylic acid, 2b (150 mg, 0.490 mmol), 2-(trifluoromethyl)pyridin-4-amine (87.3 mg, 0.539 mmol) and pyridine (3 mL). The mixture was stirred at 0 °C for 1 h. The resulting mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by préparative high performance liquid chromatography using Kromasil 150 x 25 mm x 10 pm (55% to 55% (v/v) ACN and water with 0.05% NH3) to afford pure compound 3. The product was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to afford compound 3 (76.90 mg, 35 %). 'H NMR (400 MHz, DMSO-Λ) δ ppm 11.28 (br.s., IH), 8.72 (d, 7 = 6.0 Hz, IH), 8.56 (s, IH), 8.25 (d, 7= 6.4 Hz, 2H), 8.15 (d, 7= 7.6 Hz, IH), 7.99 (d, 7 = 4.8 Hz, IH), 7.83 - 7.76 (m, IH), 7.75 - 7.60 (m, 3H), 7.12 (d,7 = 8.0 Hz. IH).

Example 47

1-(Naphthalen-l-yl)-5-( tri fluoromethyl)-A-(5-(trifluoiOmethyl)pyridin-3-yl)-l/f-pyrazole4-carboxamide, Cpd 4

290

POCh (120 mg. 0.784 mmol) was added dropwise to a solution consisting of 1(naphthalen-l-yl)-5-(trifluorometliyl)-lH-pyrazole-4-carboxylic acid, 2b (200 mg, 0.653 mmol), 5-(trifluoromethyl)pyridiii-3-amine (116 mg, 0.718 mmol) and pyridine (3 mL). The mixture was stirred at 0 °C for 1 h. The résultant mixture was concentrated to dryness under reduced pressure to give a crade product, which was purified by reverse phase HPLC (54% to 84% (v/v) ACN and water with 0.05% NH?) to afford pure compound 4. The product was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 4 (81.70 mg, 28 %). LCMS (ESI): Rt = 4.32 min, mass calcd. for C21H12F6N4O450.337, m/z found 451.1 [M+H]⁺. *H NMR (400 MHz, DMSO-Λ) 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).

Ex ample 48

A-(5-Cyanopyridin-3-yl)-l-(naphthalen-l-yl)-5-(trifluoromethyl)-l.ff-pyrazole-4carboxamide, Cpd 5

POCh (22.9 mg, 0.149 mmol) was added dropwise to a solution consisting of 1(naphthalen-l-yl)-5-(trifluoromethyl)-127-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 h. The resulting mixture was washed with water (20 mL), extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na₂SO4, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crade product was purified by reverse phase HPLC (46% to 76% (v/v) ACN and water with 0.05% NHs) to afford pure compound 5 (74.90 mg, 28 %). LCMS (ESI): Rt = 5.12 min, mass calcd. for C21H12F3N5O 407.348, m/z found 408.1 [M+Hf. ^lH NMR (400 MHz,

291

DMSOU) 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, 1 H), 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 jV-(5-Chloro-6-(2Z7-1,2,3-triazol-2-yl)pyridin-3-yl )-5-( difluoromethyl)-1 -(isoquinolin-1 yl)-l//-pyrazole-4-carboxamide, Cpd 56

A 4 mL vial with stirbar was charged with 1-hydrazinylisoquinoline, 10a (44.9 mg,

0.282 mmol), THF (0.56 mL, 0.5 M, 0.28 mmol), ethyl 2-(ethoxymethylene)-4,4-difluoro3-oxobutanoate/THF (0.56 mL, 0.5 M. 0.28 mmol), and the resulting amber homogeneous solution was stirred at room température (capped) for 10 min, followed by stirring at 70 °C for 1 h. The reaction was then cooled to room température and treated with calcium sulfate (184 mg, 1.352 mmol) and stirred (capped) for 10 min. The reaction was then cooled to room température, treated with 5-chIoro-6-(2.H-1,2,3-triazol-2-yl)pyridin-3-amme, Ij (55.7 mg, 0.284 mmol) and 1.01 M KOtBu/THF (0.42 mL, 0.424 mmol). and the resulting dark réaction was stirred at room température for 3 h. The mixture was partitioned with 5 M NHæl (1 mL) and ethyl acetate (1 mL). The organic layer was dried overNaiSOi, filtered, and the filtrate concentrated to provide 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 over 10 CVs, then isocratic) to provide impure compound 56 (43 mg) as a beige solid. This was crystallized from MeOH (1 mL) to provide, after washing the crystals with MeOH (2 x 0.5 mL), compound as an off-white powder (31.3 mg, 24 %). ’H

NMR (400 MHz, CDCh) δ ppm 8.72-8.75 (m. 1H). 8.55-8.57 (m, 1H), 8.51 (d, ,7=5.56 Hz,

292

IH). 8.39-8.44 (m, IH), 8.34 (s, IH), 7.97-8.02 (m. 2H), 7.96 (s, 2H), 7.88-7.91 (m, 1H).

7.80-7.87 (m, IH), 7.67-7.73 (m, IH), 7.40 (t, 7=53.1 Hz, IH); MS m/e 467.1 (M+H).

Example 50

A7-(5-chloro-6-(2/7-l,2,3-triazol-2-yl)pyridin-3-yl)-5-isopropyI-l-(quinolin-5-yl)-lHpyrazole-4-carboxamide, Cpd 26

A. Ethyl 2-(ethoxymethylene)-4-methyl-3-oxopentanoate. 50a

OEt ^OEi . 50a

A solution consisting of ethyl 4-methyl-3-oxopentanoate (500 mg. 3.16 mmol), triethoxymethane (1.41 mg, 9.48 mmol) and Ac?O (5 mL) was stirred at 130 °C for 16 h before cooling to room température and concentrating to dryness under reduced pressure to afford compound 50a (550 mg, crude), which was used in the following reaction without further purification.

B. Ethyl 5-isopropyl-l-(quinolin-5-yl)-lH-pyrazole-4-carboxylate. 50b

293

A solution consisting of ethyl 2-(ethoxymethylene)-4-methyl-3-oxopentanoate, 50a (550 mg, 2.57 mmol), 5-hydrazinylqumoline, 13a (408 mg, 2.57 mmol) and éthanol (5 mL) was stirred at 80 °C for 16 h before cooling to room température and concentrating to dryness under reduced pressure to give a crude product, which was purified by FCC (dichloromethane: methanol = 100:0 to 90:10) to afford compound 50b (450 mg, 57 %). LCMS (ESI): Rt = 0.75 min, mass calcd. for CisHwNjOz 309.362, m/z found 310.0 [M+H]⁺. The compound was fiirther purified 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 up to 5% solvent A and 95% solvent B).

C. 5-Isopropyl-l-(quinolin-5-yl)-l#-pyrazole-4-carboxylic acid, 50c

50c

A solution consisting of ethyl 5-isopiOpyl-I-(quinolin-5-yl)-lEf-pyrazole-4carboxylate, 50b (450 mg, 1.46 mmol), LiOH (183 mg, 4.36 mmol) and water: EtOH (6 mL, 1:2) was stirred at room température for 16 h. The solution was neutralized to pH 7 with 4 M aq. HCl, and a solid was collected by filtration to afford compound 50c (280 mg, crude), which was used in the next step without purification. LCMS (ESI): Rt = 0.62 min, mass calcd. for C16H15N3O2 281.309, m/z found 282.0 [M+H] .

D. Æ-(5-chloro-6-(2//-l,2,3-triazol-2-yl)pyridm-3-yl)-5-isopropyl-l-(quinolm-5-yl)lH-pyrazole-4-carboxamide, Cpd 26

294

POCh (183 mg, IJ 9 mmol) was added dropwise to a solution consisting of 5isopropyl-l-(quinolin-5-yl)-l/7-pyrazole-4-carboxylic acid, 50c (280 mg, 0.995 mmol), 5chloro-6-( 2/7-1,2,3-triazol-2-yl)pyridin-3-amine, Ij (389 mg, 1.99 mmol) and pyridine (5 mL). The mixture was stirred at 0 °C for l h. The résultant mixture was poured into sat. aqueous NaHCCh (10 mL), extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na₂SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product, which was purified by reverse phase HPLC (40% to 70% (v/v) ACN and H₂O with 0.05% NH;) to afford pure compound 26. Compound 26 was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 26 (48.60 mg, 10 %). LCMS (ESI): Rt = 4.79 min, mass calcd. for C>11 i A ΊΧ 4 ) 458.903, m/z found 459.0 i \ 1 H | . ‘H NMR (400 MHz, DMSO-Λ) δ ppm 10.70 (s, 1H), 9.04 (dd,J= 1.6,4.4Hz, 1H), 8.91 (d,J=2.8Hz, 1 H), 8.72 (d, J = 2.0 Hz, 1H). 8.48 (s. 1 H), 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, .7= 4.4, 8.4 Hz, 1H),7.51 (d,J=8.0Hz, 1H), 3.10 - 3.00 (m, 1H). 1.28 -1.13 (m, 6H).

Example 51

Aⁱ-(5-Chloro-6-(277-L2,3-triazol-2-yl)pyridin-3-yl)-5-isobutyl-l-(quinolin-5-yl)-l/7pyrazole-4-carboxamide, Cpd 16

A. Ethyl 2-(ethoxymethylene)-5-methyl-3-oxohexanoate, 51a । O O

OEt _; 5i_a

A solution consisting of ethyl 5-methyl-3-oxohexanoate (500 mg, 2.90 mmol), triethoxymethane (1.29 mg, 8.71 mmol) and Ac?O (5 mL) was stirred at 130 °C for 16 h. The reaction was cooled to room température and concentrated to dryness under reduced pressure to afford crude compound 51a (580 mg. 88 %), which was used in the foilowing step without purification.

B. Ethyl 5-isobutyl-l-(quinolin-5-yl)-lH-pyrazole-4-carboxylate, 51b ,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 éthanol ( 10 mL) was refluxed at 80 °C for 16 h before cooling to room température and concentrating to dryness under reduced pressure to afford crude compound 51b, which was purified by FCC (dichloromethane: methanol = 100:0 to 95:5) to afford compound 51b (330 mg, 54 %). ‘H NMR (400 MHz, DMSO-Je) δ ppm 9.22 - 9.15 (m, IH), 8.49 - 8.41 (m. IH), 8.20 (s, IH), 8.14 - 8.06 (m, IH), 7.97 (d, J= 6.8 Hz, 2H), 7.85 - 7.77 (m, IH), 4.29 (d,./= 6.8 Hz. 2H), 2.74 (d, J = 7.2 Hz, 2H). 1.61 - 1.48 (m, IH), 1.31 (t. J= 6.8 Hz. 3H), 0.70 - 0.50 (m, 6H).

C. 5-Isobutyl-14quinolin-5-yl)-lH-pyrazole-4-carboxylic acid, 51c

296

A solution consisting of ethyl 5-isobutyl-l-(quinolin-5-yl)-l//-pyrazole-4carboxylate, 51b (200 mg, 0.618 mmol), LiOH (77.9 mg, 1.86 mmol) and water: EtOH (6 mL, l :2) was stirred at room température for 16 h. The reaction mixture was neutralized to pH 7 with 4 N aq. HCl, extracted with ethyl acetate (10 mL x 3), dried over anhydrous NacSCU, and fïltered. The filtrate was concentrated to dryness under reduced pressure to give crude compound 51c (160 mg), which was used in the follow’ing reaction without further purification.

D. Aⁱ-(5-ChloiO-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-5-isobutyl-l-(quinolin-5-y[)l//-pyrazole-4-carboxamide, Cpd 16

POCk (74.8 mg, 0.488 mmol) was added dropwise to a solution consisting of 5isobutyl-l-(quinolin-5-yl)-l//-pyrazole-4-carboxylic acid, 51c (140 mg, 0.474 mmol), 5chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-amine. Ij (87.4 mg, 0.447 mmol) and pyridine (5 mL). The mixture was stirred at 0 °C for 1 h. The résultant mixture was washed wdth water (20 mL), extracted with ethyl acetate ( 10 mL x 3), dried over anhydrous Na₂SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product, which was purified by reverse phase HPLC (40% to 70% (v/v) ACN and water with 0.05% NH₃) to afford pure compound 16. Compound 16 was suspended in water (10 mL), the mixture frozen using dry' ice/acetone, and then lyophilized to dryness to give compound 16 (24.30 mg, 11 %). LCMS (ESI): Rt = 3.66 min, mass calcd. for C24H21CIN8O 472.93, m/z found 473.0 [M+Hf. Ή NMR (400 MHz, DMSO-X) 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).

297

Example 52 ïV-(5-Chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-l-(quinolin-5-yl)-IHpyrazole-4-carboxamide, Cpd 39

A. Ethyl 2-(ethoxymethylene)-3-oxobutanoate, 52a

O o Y , 52a

A solution consisting of ethyl 3-oxobutanoate (10.0 g, 76,8 mmol), tnethylorthoformate (38.3 g, 230 mmol), and acetic anhydride (100 mL) was stirred at 135 °C for 18 h. The mixture was concentrated to dryness under reduced pressure to give compound 52a (21 g, crude), which was used m the foilowing reaction without further purification. *H NMR (400 MHz, CDCh) 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-l-(quinolin-5-yl)-lH-pyrazole-4-carboxylate, 52b

298

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 éthanol (15 mL) was stirred at 80 °C for 16 h. The mixture was concentrated to dryness under reduced pressure to give a crade residue. which was purified by FCC (petroleum ether: ethyl acetate = 2:1 to 1:2) to afford compound 52b (520 mg, 23 %). *H NMR (400 MHz, CDCh) δ ppm 9.02 - 8.97 (m, IH), 8.32 - 8.27 (m, IH), 8.16 (s, IH), 7.83 (dd, 7= 7.2, 8.4 Hz, 1 H), 7.67 (d, 7= 8.4 Hz, IH), 7.56 (dd, 7= 1.2,7.2 Hz, IH), 7.44 (dd, 7= 4.0, 8.4 Hz. IH), 7.27 (s, IH), 4.40 - 4.34 (m, 2H), 2.38 (s, 3H), 1.43 - 1.39 (m. 3H).

C. AX5-Chloro-6-(2Yl,2,3-triazol-2-yl)298rimethy-3-yl)-5-methyI-l-(qiiinolm-5-yl)1//-pyrazole-4-carboxamide, Cpd 39

A solution consisting of 5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine, Ij (194 mg, 0.990 mmol) and THF (2 mL) was added dropwise to a solution of /-BuOK (3.3 mL, 3.3 mmol, 1 M in THF) at 0 °C. A solution consisting of ethyl 5-methyl-l-(quinolin-5-yl)l//-pyrazole-4-carboxylate, 52b (186 mg, 0.660 mmol) and THF (2 mL) was added dropwise. The mixture was warmed to room température and stirred for 16 h before quenching with water and extracting with ethyl acetate (50 mL x 3). The combined organic extracts were dried over anhydrous NajSO#, filtered, and the filtrate concentrated to dryness under reduced pressure to give crude compound 39, which was purified by reverse phase chromatography (33% to 43% (v/v) CH3CN and water with 0.05% NH?) to afford pure compound 39. The product was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dry ness to afford compound 39 (61.3 mg, 22 %). LCMS (ESI): Rt = 4.16 min, mass calcd. for CjiHisCINsO 430.850, m/z

299 found 431.0 .Mil). Ή NMR (400 MHz, CDCh) δ ppm 9.02 (dd. J= l.6, 4.0 Hz, IH), 8.77 (d, J= 2.4 Hz, HT), 8.56 (d, J = 2.4 Hz, IH), 8.33 (d, J = 8.4 Hz, IH), 8.15 (s, IH), 7.99 (s, IH), 7.95 (s, 2H), 7.89 - 7.83 (m, IH), 7.67 (d, J = 8.4 Hz, HT), 7.60 (d, J= 7.2 Hz. IH), 7.47 (dd. 7= 4.4, 8.4 Hz. I H), 2.47 (s, 3H).

Example 53

N-( 5-Chloro-6-(2Æ-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(1-methoxyethyD-1 - (quinolin-5-yl)l//-pyrazole-4-carboxamide, Cpd 35

A. Ethyl 4-methoxy-3-oxopentanoate. 53a

Bis(17f-imidazol-l-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 température for 3 h. In a separate flask, isopropylmagnesium chloride (HO mL, 144 mmol, L3 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 température for 3 h. This solution was added dropwise to the acyl imidazole solution at 0 °C and the resulting mixture was stirred at room température for l h. The reaction mixture was quenched with aqueous citric acid (25 mL, 10 wt.%) and extracted with ethyl acetate (100 mL x 3). The combined organic extracts were washed with sat. aqueous NaHCOs, dried over anhydrous NazSCU, filtered,

300 and concentrated to dryness under reduced pressure to give a residue, which was purified by FCC (petroleum ether: ethyl acetate = 10 :l ) to afford compound 53a (3.6 g, 43 %). ^lH NMR (400 MHz, CDCh) 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), triethylorthoformate (9.19 g. 1.72 mmol ), and acetic anhydride (30 mL) was stirred at 135 °C for 18 h. The mixture was cooled to room température and concentrated to dryness under reduced pressure to give compound 53b (5.4 g), which was used in the following reaction without further purification. *H NMR (400 MHz. CDCh) δ ppm 7.70(s, 0.5H), 7.58 (s, 0.5H), 4.30-4.21 (m, 4H), 3.60 (q,./= 7.2 Hz, 1H), 3.35, 3.32 (s, 3H), 1.38 - 1.29 (m, 9H).

C. Ethyl 5-(l-methoxyethyl)-l-(quinolin-5-yl)-lH-pyrazole-4-carboxylate, 53c

A 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 éthanol (12 mL) was stirred at 80 °C for 16 h. The mixture was cooled to room température and concentrated to dryness under reduced pressure to give a residue, which was purified by FCC (dichloromethane: methanol = 10:1) to afford

301 compound 53c (300 mg. 35 %). ’H NMR (400 MHz, CDCh) δ ppm 9.00 - 8.93 (m, IH), 8.28 (d, J= 8.4 Hz, IH), 8.17 (s, IH), 7.80 (dd, J= 7.2, 8.4 Hz, IH), 7.65 (br d, J= 7.2 Hz. IH), 7.62 - 7.56 (m, IH), 7.41 (dd, J= 4.0, 8.4 Hz, IH), 5.29 - 5.14 (m, IH), 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-( l-Methoxyethyl)-l-(quinolin-5-yl)-U7-pyrazole-4-carboxylic acid, 53d

A mixture consisting of ethyl 5-(l-methoxyethyl)-l-(qumolin-5-yl)-l/Lpyrazole-4carboxylate, 53c (265 mg, 0.840 mmol), aq. NaOH (2.44 mL, 2.44 mmol, 1 M), and éthanol (3 mL) was stirred at room température for 16 h. 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?SO4, fïltered, and the filtrate concentrated to dryness under reduced pressure to afford compound 53d (120 mg, 50 %). ^lH NMR (400 MHz, CD?.OD) δ ppm 8.97 (dd, 7= 1.6, 4.4 Hz, IH), 8.28 (d, 7= 8.4 Hz, IH), 8.19 (s, IH), 7.93 (dd, J = 12. 8.4 Hz, IH), 7.80 (d, 7= 6.4 Hz, IH), 7.71 (d. 7 = 8.0 Hz. IH), 7.60 (dd, 7= 4.4, 8.4 Hz, IH), 5.36 - 5.24 (m, IH). 3.32 (s, 3H), 1.37 - 1.29 (m, 3H).

E. A-(5-Chloro-6-(2/L1,2,3-triazol-2-yl)pyridin-3-yl)-5-( 1 -methoxyethyl)-1 (quinolin-5-yl)-l//-pyrazole-4-carboxamide, Cpd 35

302

POCh (0.1 mL) was added to a mixture consisting of 5-(l-methoxyethyl)-l(quinolin-5-yl)-lH-pyrazole-4-carboxylic acid, 53d (120 mg, 0.40 mmol), 5-chloro-6-(2Æl,2,3-triazol-2-yl)pyridin-3-amme, Ij (78.95 mg, 0.40 mmol), and pyridine (3 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h before quenching with aq. NaHCOj. The mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic extracts were dried overNa?SO₄, filtered, and the filtrate concentrated to dryness under reduced pressure to afford a residue, which was purified by reverse phase HPLC (16% to 46% (v/v) CH3CN and water with 0.05% NH4HCO3) to afford pure compound 35. Compound 35 was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 35 (29.1 mg, 15 %). LCMS (ESI): Rt = 4.61 min, mass calcd. for C23H19CIN8O2 474.902, m/z found 475.0 | VI · 11 ] . *H NMR (400 MHz, CDCh) ô 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 (q, J =

6.4 Hz, 0.5H), 4.30 (q, Τ= 6.4 Hz, 0.6H), 3.54 (s, 1,4H), 3.25 (s, 1.7H), 1.68 (d,J= 6.8

Hz. L6H), 1.42 (d,.7 = 6.8 Hz, 1.4H).

Example 54

A%5-Chloro-6-(2H-L2,3-triazol-2-yl)p>Tidm-3-yl)-l-(4-methylisoquinolin-8-yl)-520 (trifluoromethyl)-177-pyrazole-4-carboxamide. Cpd 33

A.

8-(2-(Diphenylmethylene)hydrazinyl)-4-methylisoquinoline, 54a

303

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 ru/7-butoxide (389 mg, 4.05 mmol), and 1,4-dioxane (5 mL). The mixture was heated at 100 °C for 16 h before cooling to room température. The résultant mixture was filtered, and the filtrate concentrated under reduced pressure to give crude compound 54a, which was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 70:30) to afford compound 54a (250 mg, 55 %). ‘H NMR (400 MHz, DMSO-fy) 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

A solution consisting of 8-(2-(diphenylmethylene)hydrazinyl)-4methylisoquinoline, 54a (250 mg, 0.741 mmol), conc. HCl (4 mL) and EtOH (2 mL) was stirred at room température for 16 h. The réaction 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 following reaction without further purification.

304

C. Ethyl l-(4-methylisoquinolm-8-yl)-5-( trifluoromethyl)- l7/-pyrazole-4carboxylate, 54c

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (150 mg, 0.650 mmol), 8-hydrazinyl-4-methylisoquinoline, 54b (160 mg, 0.650 mmol), triethylamine (132 mg, 1.30 mmol), and éthanol (5 mL) was stirred at 80 °C for 16 h before cooling to room température and concentrating to dryness under reduced pressure to afford crude compound 54c, which was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 70:30) to give compound 54c (110 mg, 48 %). ^!H NMR (400 MHz, CDCh) δ ppm 8.54 (s, IH), 8.27 (s, IH), 8.16 (d, J= 8.4 Hz, IH), 7.96 (t, J = 7.6 Hz, IH), 7.82 (dd, J= Ί 2, 8.4 Hz, IH), 7.60 (d, J= Ί2 Hz, IH), 4.42 (q, J = 7.2 Hz, 2H), 2.69 (s, 3H), 1.41 (t, J= 7.2 Hz, 3H).

D. A-(5-Chloro-6-(2/Z-L2,3-triazol-2-yl)pyridin-3-yI)-l-(4-methylisoqiimolm8-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxamide, Cpd 33

A solution consisting of 5-chloro-6-(2ELl,2,3-triazol-2-yl)pyridin-3-amine, lj (56.0 mg, 0.286 mmol) and THF (1 mL) were added to potassium tert-butoxide (0.8 mL, 0.8 mmol, 1 M in THF) at 0 °C, then a solution consisting of ethyl 1 -(4-methylisoquinolin8-yT)-5-(trifluoromethyl)-l/7pyrazole-4-carboxylate, 54c (100 mg, 0.286 mmol) and THF (1 mL) was added. The résultant mixture was stirred at room température for 16 h. The

305 reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by préparative high performance liquid chromatography using Phenomenex Gemini 150 x 25 mm x 5 pm ( 45% to 75% (v/v) ACN and water with 0.05% NH?) to afford pure compound 33. The product was suspended in water (10 mL). the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 33 (31.50 mg, 22 %). LCMS (ESI): Rt = 4.46 min, mass calcd. for CjzHuClFsNgO 498.848, m/z found 499.0 [M+H]⁺. ‘H NMR (400 MHz, DMSO-î/ô) δ ppm 8.84 (d, J= 2.4 Hz, IH), 8.69 (d, J=2.0Hz, IH), 8.58 (s. IH), 8.55 (s, IH), 8.45 (s. 1 H), 8.37 (d, J = 8.4 Hz, IH), 8.19 (s. 2H), 8.06 - 7.96 (m, 2H), 2.71 (s, 3H).

Example 55

A%8-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-l-(quinolin-5-yl)5-(trifluoromethyl)-lH-pyrazoIe-4-carboxamide. Cpd 95

A. 2-Chloro-A^z-(3-chloro-2-hydroxy-5-nitrophenyl)acetamide, 55a

O __pi

HN \ O

HO% En⁺

E^ bCl , 55a

Chloroacetyl chloride ( 1.98 g, 17.5 mmol) was added to a solution of 2-amino-6chloro-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 h. Water (50 mL) and dichloromethane (50 mL) were added to the mixture. The organic layer was partitioned and washed with brine (50 mL), dried over MgSO₄, filtered, and the filtrate concentrated

306 under reduced pressure to afford compound 55a as a yellow oil (4.0 g, 94.9 %), which was used in the foilowing reaction without further purification.

B. 8-Chloro-6-nitro-2H-benzo[b][l,4]oxazin-3(4H)-one, 55b

Sodium methoxide (896.8 mg. 16.6 mmol) was added to a solution of 2-chloro-ïV(3-chloro-2-hydroxy-5-nitrophenyl)acetamide, 55a (4.0 g, 15.1 mmol) in methanol (40 mL). The mixture was stirred at 80 °C for 16 h. Water (150 mL) and dichloromethane (100 mL) were added to the mixture. The organic layer was partitioned, washed with brine 10 (100 mL), dried over MgSO₄, filtered, and the filtrate concentrated under reduced pressure to afford compound 55b as a yellow oil. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=10:l to petroleum ether/ ethyl acetate=l T) to afford compound 55b as a yellow solid (2.5 g, 73 %). 'H NMR (400 MHz, METHANOL^) δ ppm 4.84 (s, 2 H). 7.72 (d, J=2.65 Hz. 1 H), 7.98 (d. J=2.65 Hz, 15 1 H).

C. 8-Chloro-4-methyl-6-nitro-2H-benzo[b][l ,4]oxazm-3(4H)-one. 55c

Cl . 55c lodomethane (931 mg, 6.56 mmol) was added to a mixture of 8-chloro-6-nitro-2H20 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 h. The solvent was concentrated under reduced pressure. A crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=10:l to petroleum ether/

307 ethyl acetate=l : l) to afford compound 55c as a white solid (0.3 g, 56.5 %). ^lH NMR (400 MHz, CDCh) δ ppm 3.44 (s, 3 H), 4.85 (s, 2 H), 7.78 (d, J=2.51 Hz, l H), 8.04 (d, J=2.51 Hz, 1 H).

D. 6-Amino-8-chloro-4-methyl-2H-benzo[b][L4]oxazin-3(4H)-one, 55d °\ / A

O A ANH₂

Zinc (804 mg, 12.37 mmol) was added to a solution of 8-chloro-4-methyl-6-nitro2H-benzo[b][l,4]oxazin-3(4H)-one, 55c (300 mg, 1.24 mmol) m aqueous NH4CI (2 mL) and methanol (2 mL). The mixture was stirred at rt for 16 h. To the suspension was added 10 aqueous NaHCCh to adjust the pH to 9-10, and the mixture was fïltered though a pad of diatomaceous earth. The fîlter cake was washed with dichloromethane (30 mL x 3). The combined filtrâtes were washed with brine ( 100 mL), dried over MgSO₄, fïltered, and the filtrate concentrated under reduced pressure to afford compound 55d as a brown solid. The crude product was purified by column chromatography over silica gel (petroleum 15 ether/ ethyl acetate=2:l to petroleum ether/ ethyl acetate=0:1 ) to afford compound 55d as a yellow solid (200 mg, 76.1 %). ’H NMR (400 MHz, CDCL) δ ppm 3.31 (s, 3 H), 4.61 (s, 2 H), 6.23 (d, J=2.43 Hz, 1 H), 6.42 (d, J=2.43 Hz, 1 H).

E. _;V-(8-ChloiO-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][L4]oxazin-6-yD-l20 (quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 95

Cl l-(Quinolin-5-y4)-5-(trifluoiOmethyl)-lH-pyrazole-4-carboxylic acid, 3b ( 120 mg.

0.39 mmol), 6-amino-8-chloro-4-methyl-2H-benzo[b][l ,4]oxazin-3(4H)-one. 55d ( 100

308 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 h. Sat. aqueous NH₄Cl (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic layers were dried over NacSCL, filtered, and the filtrâtes were concentrated under reduced pressure to afford compound 95 as a crude brown oil. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: A/B (70%/30% to 40%/60 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 95 as a pale white solid ( 139 mg, 71 %). LCMS (ESI): m/z 501.9 [M+Hf. 0 NMR (400 MHz, DMSO-J0) δ ppm 3.27 (s, 3 H), 4.77 (s, 2 H), 7.47 (s, 1 H), 7.57 - 7.63 (m, 1 H), 7.64 - 7.70 (m, 2 H). 7.87 - 7.92 (m, 1 H), 7.93 - 7.99 (m, 1 H), 8.31 (d, J=8.60 Hz, 1 H), 8.50 (s. 1 H), 9.04 (d, J=2.65 Hz, 1 H), 10.74 (s, 1 H).

Example 56

A-(4-(2-Aminopyrimidin-4-yl)-3-chlorophenyl)-l-(isoquinolin-4-yl )-5-( trifluoromethyl)lH-pyrazole-4-carboxamide, Cpd 58

A. 4-(2-Chloro-4-nitrophenyl)pyrimidin-2-amine. 56a

A mixture of 2-(2-chloro-4-nitrophenyl)-4,4,5,5-tetramethyl-L3,2-dioxaborolane (250 mg, 0.882 mmol), 2-amino-4-chloropyrimidine (126 mg, 0.97 mmol) and césium carbonate (862 mg, 2.65 mmol) in dioxane/water (4:1 ) was stirred at rt. PdiPPhshCL was

309 added under N? at rt. The reaction mixture was stirred at 80 °C ovemight. The mixture was filtered though a pad of diatomaceous earth and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with water (10 mL). The organic laver was separated and concentrated under reduced pressure. The résultant residue was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from lOO/O to 0/100) to afford compound 56a as a yellow solid (155 mg, 70 %). LCMS (ESI): m/z 250.9 [M+H]\ ‘H NMR (400 MHz, CDCh) δ ppm 5.17 (br s, 2 H), 6.99 (d, J=5.07 Hz, l H), 7.78 (d, J=8.38 Hz, l H), 8.21 (dd, J=8.49, 2.09 Hz, l H), 8.36 (d, J=2.20 Hz, 1 H), 8.43 (d, J=5.07 Hz, 1 H).

B. 4-(4-Amino-2-chlorophenyl)pyrimidin-2-amine, 56b

4-(2-Chloro-4-nitropheiiyl)pyrimidin-2-amine, 56a (132 mg, 0.53 mmol), Fe(0) (294 mg, 5.27 mmol) , and NH4CI (282, 5.27 mmol) were added to a mixture of THF (5 mL) and water ( 1 mL). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with ethyl acetate (20 mL x 3). The combined filtrâtes were concentrated to dryness to give crude compound 56b as a yellow solid. The crude compound was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 50/50 to 0/100) to afford compound 56b as a yellow solid (85 mg, 73 %). ^!H NMR (400 MHz, CDCh) δ ppm 3.76 - 3.88 (m, 2 H), 4.98 (br s. 2 H), 6.57 (dd. J=8.27, 2.32 Hz, 1 H), 6.68 (d, J=2.21 Hz. 1 H), 6.96 (d. ,1=5.07 Hz, 1 H). 7.41 (d, J=8.38 Hz, 1 H), 8.22 (d. ,1=5.29 Hz, 1 H).

C. AM4-(2-Aminopyrimidin-4-yl)-3-chlorophenyl)-l-(isoquinolin-4-yl)-5(trifluoromethyl)- l#-pyrazole-4-carboxamide, Cpd 58

310

4-(4-Amino-2-chlorophenyl)pyrimidin-2-amine, 56b (80 mg, 0.36 mmol), 1(isoquinolin-4-yl)-5-(trifluoromethyD-lH-pyTazole-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 h. Sat. aqueous NH4CI (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic layers were dried over Na2SO₄, filtered, and the filtrâtes were concentrated under reduced pressure to afford crude compound 58 as a yellow oil. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: ΑΊ3 (82%/18% to 52%/48 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 58 as a pale w'hite solid (20.1 mg, 11 %). LCMS (ESI): m/z 510.0 (MH). ’H NMR (400 MHz, METHANOL-Λ) δ ppm 7.46 (d, J=6.61 Hz, 1 H), 7.57 (d, J=8.60 Hz, 1 H), 7.83 - 7.89 (m, 2 H), 8.02 - 8.07 (m, 1

H), 8.12 - 8.19 (m. 2 H). 8.39 (d, J=6.62 Hz, 1 H), 8.46 (s, 1 H), 8.55 (d, J=8.38 Hz, 1 H),

8.91 (s. 1 H), 9.83 (s, 1 H).

Example 57

A%8-Chloro-3-oxo-3,4-dihydiO-2Æ-benzo[b][l,4]oxazin-6-yl)-l-(isoquinolin-4-yl)-5(tnfluoromethyl)-l/7-pyrazole-4-carboxamide. Cpd 87

A. 6-Amino-8-chloro-2//-benzo[b][ l ,4]oxazin-3(4//)-one, 57a

O y—NH b—<f y—nh₂ ,57a

Zinc (0) (426.5 mg, 6.56 mmol) was added to a solution of8-chloro-6-nitro-2Hbenzo[b][L4]oxazin-3(4//)-one. 55b (150 mg, 0.66 mmol) in aqueous NH4CI (2 mL) and MeOH (2 mL). The mixture was stirred at rt for 16 h. To the suspension was added aqueous NaHCOa to adjust the pH to 9-10, and the mixture was fïltered though a pad of diatomaceous earth. The fïlter cake was washed with dichloromethane (30 mL x 3). The combined filtrâtes were washed with brine (100 mL), dried over MgSOi. fïltered, and the filtrate concentrated under reduced pressure to afford compound 57a as a brown solid. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=2:l to petroleum ether, ethyl acetate=O:l) to afford compound 57a as a yellow solid (90 mg, 69.1 %). U NMR (400 MHz, CDCh) δ ppm 3.57 (br s, 2 H), 4.61 (s, 2 H), 6.05 (d, J 2.43 Hz, l H), 6.39 (d, J=2.43 Hz, l H), 7.90 - 8.05 (m, l H).

B. A-(8-Chloro-3-oxo-3,4-dihydiO-2H-benzo[b][l,4]oxazm-6-yl)-l-(isoquinolin-4yl)-5-(tnfluoromethyl)-lÆ-pyrazole-4-carboxamide, Cpd 87 ,Ν_χ F ^F l-(Isoquinolin-4-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylic acid. 4c (100 mg, 0.29 mmol). 6-amino-8-chloro-2//-benzo[b][L4]oxazin-3(4//)-one, 57a (57.1 mg, 0.29 mmol), HATU (164.1 mg, 0.43 mmol) and DIEA (185.9 mg, 1.44 mmol) were dissolved in DMF (2 mL). The mixture was stirred at 25 °C for 3 h. Sat. aqueous NH4CI (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The

312 combined organic layers were dried over NazSOi, filtered, and the filtrâtes were concentrated under reduced pressure to afford crude compound 87 as a yellow oil. The crude product was purified by reverse phase HPLC (A: water (0.05% HCl), B: MeCN; then: A/B (95%/5% to 65%/35 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 87 as a pale white solid (54 mg, 38 %). LCMS (ESI): m/z 487.9 (M+H)⁺. ‘H NMR (400 MHz, METHANOL-Y) δ ppm 4.68 (s, 2 H), 7.36 (d, J=2.21 Hz, 1 H), 7.43 (d, J=2.43 Hz, 1 H), 7.55 (d, J=8.38 Hz. 1 H), 8.00 - 8.08 (m, 1 H), 8.11 - 8.19 (m, 1 H), 8.37 (s, 1 H), 8.54 (d. J=8.16 Hz, 1 H), 8.90 (s, I H), 9.82 (s, 1 H).

Example 58

A-(5-ChloiO-6-(l,l-dioxidoisothiazolidin-2-yl)pyndin-3-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl)-Uï-pyrazole-4-carboxamide, Cpd 42

A. 2-(3-Chloro-5-nitropyridin-2-yl)isothiazolidine 1,1-dioxide, 58a

(iy25)-Nl,N2-Dimethylcyclohexane-l,2-diamine (46.1 mg, 0.30 mmol) and copper lodide (56.3 mg, 0.30 mmol) were added to a mixture of 2,3-dichloro-5nitropyridine (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) under N2. The reaction

313 mixture was stirred at 100 °C for 16 h. The mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic extracts were dried over NazSO-i, filtered, and the filtrate concentrated under reduced pressure. The résultant crude product was purified by flash chromatography (petroleum ether/ ethyl acetate=100:0 to petroleum ether- ethyl acetate=50:50) to afford compound 58a as a white solid (600 mg. 73 %).

B. 2-(5-Amino-3-chloropyndm-2-yl)isothiazolidine 1,1-dioxide, 58b

H₂N

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 NHrCl (925 mg, 17.29 mmol) were 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 h. The reaction mixture was filtered though a pad of diatomaceous earth, and the pad was washed with ethyl acetate (20 mL x 3). The combined filtrâtes were concentrated to dryness to give crude compound 58b as a yellow oil (530 mg, 99 %).

C. AX5-chloro-6-(Ll-dioxidoisothiazolidin-2-yI)pyridin-3-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide. Cpd 42

Phosphoryl trichloride (0.052 mL, 0.57 mmol) was added to a solution of 1(isoquinolin-4-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylic acid. 4c (60 mg, 0.19 mmol), 2-(5-amino-3-chloropyridin-2-yl)isothiazolidine Ll-dioxide, 58b (60.6 mg, 0.245 mmol), and pyridine (0.091 mL, 1.13 mmol) in dichloromethane at room température. The

314 mixture was stirred for 2 h. The mixture was poured into water (10 mL), and the mixture was extracted with dichloromethane (20 mL x 2). The separated organic layer was dried overNa2SO4, filtered, and the filtrate concentrated under reduced pressure to afford a crude product. The crude product was purified by reverse phase HPLC (0.05% ammonia hydroxide v/v): B: MeCN; then: A/B (65%/35% to 35%/65 %). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 42 as a white solid (35.6 mg, 35 %). LCMS (ESI): m/z 536.9 [M+H] \ ^JH NMR (400 MHz, CDCh) δ ppm 2,53 - 2.60 (m, 2 H), 3.19 (br t, J=7.50 Hz, 2 H), 4.05 (br t, J=6.84 Hz. 2 H). 7.29 (br d. J=7.94 Hz. 1 H), 7.73 (dt, J=13.40, 6.64 Hz, 2 H). 7.94 (br s, 1 H), 8.09 (br d, J=8.16 Hz, 1 H), 8.19 (s. 1 H), 8.29 (br s, 1 H), 8.44 (br s, 1 H). 8.55 (s, 1 H). 9.38 (s, 1 H).

Example 59

A^T-(5-chloro-6-(2H-l,2.3-triazol-2-yl)pyridm-3-yl)-l-(isoqumolin-4-yl)-lH-pyrazole-4carboxamide, Cpd 76

A. Ethyl l-(isoquinolin-4-yl)-lH-pyrazole-4-carboxylate, 59a

A solution consisting of ethyl 2-formyl-3-oxopropanoate (90.5 mg, 0.628 mmol). 4-hydrazinylisoquinoline, 4a (100 mg, 0.628 mmol) and 2-propanol (2 mL) was stirred at 80 °C overnight before cooling to room température and concentrating to dryness under reduced pressure to give the crude product, which was purified by FCC (petroleum ether:

315 ethyl acetate = 100:0 to 80:20) to give compound 59a (140 mg, 84 %). LCMS (ESI): Rt = 0.70 min, mass calcd. for C15H13N3O2 267.283, m/z found 268.0 [M+H] '.

B. NM5-Chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(isoquinolin-4-yl)-lH5 pyrazole-4-carboxamide, Cpd 76

A solution consisting of 5-chloro-6-(2H-L2,3-triazol-2-yl)pyridm-3-amine, lj (87.8 mg, 0.449 mmol) and THF (1 mL) were added to 1 M potassium /err-butoxide in

THF (1.35 mL, 1.35 mmol) at 0 °C. then a solution consisting of ethyl 1 -(isoquinolin-4yl)-1 H-pyrazole-4-carboxylate. 59a (120 mg, 0.449 mmol) and THF ( 1 mL) was added. The résultant mixture was stirred at room température for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by préparative reverse phase HPLC (30% to 60% (v/v) ACN and H2O with 0.05% NH?). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 76 (69.3 mg, 36 %). LCMS (ESI): Rt = 4.36 min, mass calcd. for CjoHbCINsO 416.823, m/z found 416.9 [M+Hf. ‘H NMR (400 MHz, DMSO-^) δ 10.74 (br.s., IH), 9.52 (s, IH), 9.01 (s, IH), 8.88 (d, J=2.4Hz, IH). 8.76 (s, IH), 8.70 (d. J=

2.4 Hz, IH), 8.54 (s, IH), 8.35 (d. J= 8.0 Hz, IH), 8.19 (s, 2H), 7.98 - 7.92 (m, 2H), 7.89 7.84 (m. IH).

Example 60 ïV-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-l-(quinolin-4-yl)-lHpyrazole-4-carboxamide, Cpd 64

316

A. 7-ChloiO-4-methoxyquinoline, 60a

Cl , 60a

4,7-DichloroquinoIine (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 température. The mixture was stirred at 80 °C for 12 h before quenching with water and extracting with ethyl acetate (200 mL x 3). The combined organic extracts were dried over anhydrous NazSCh, filtered, and the filtrate concentrated to dryness under reduced pressure to give a residue, which was purified by FCC (petroleum ether: ethyl acetate = 2:1 to 1:2) to afford compound 60a (4.1 g, 70 %). “H NMR (400 MHz. CDCL) δ ppm 8.73 (d, .J = 5.2 Hz, 1H), 8.11 (d.J=8.8Hz. 1H), 8.01 (d,J=2.0 Hz, 1H), 7.43 (dd, J = 2.0, 8.8 Hz, 1H), 6.71 (d../=5,2Hz, 1H), 4.03 (s, 3H).

B. 4-Methoxyqumoline. 60b

A mixture consisting of 7-chloiO-4-methoxyquinoline, 60a (4.10 g, 21.1 mmol), dry Pd/C (400 mg, 10 wt.%, 0.377 mmol), and methanol (100 mL) was stirred at roomtemperature for 16 h under H2 (15 psi). The mixture was filtered through a pad of

317 diatomaceous earth and the pad was washed with methanol (50 mL). The filtrate was concentrated to dryness under reduced pressure to give 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 NUSCL. filtered. and the filtrate concentrated to dryness under reduced pressure to give a crude product, which was purified by FCC (petroleum ether: ethyl acetate = 1:3) and further purified by reverse phase HPLC (10% to 40% (v/v) CHsCN and HiO with 0.05% NH3). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 60b (1.1 g, 33 %). ’H NMR (400 MHz, CDCh) δ 8.74 (d,J= 5.2 Hz, IH), 8.22 - 8.15 (m, IH), 8.03 (d. J= 8.4 Hz, IH), 7.73 - 7.65 (m, IH), 7.51 - 7.47 (m, IH), 6.72 (d, J= 5.2 Hz. IH), 4.03 (s, 3H).

C. 4-Hydrazinylquinoline, 60c

NH₂

A mixture consisting of 4-methoxyquinoline, 60b (1.00 g, 6.28 mmol), hydrazine hydrate (10 mL, 85 wt.%), and éthanol (5 mL) was refluxed for 16 h. Then the éthanol was removed under reduced pressure and the résultant aqueous mixture was filtered to afford compound 60c (713 mg, 71 %), which was dried under reduced pressure. *H NMR (400 MHz, DMSO-A) δ ppm 8.37 (d, J = 5.2 Hz, 1 H), 8.10 (d, .7= 8.4 Hz, IH), 7.74 (d, J = 8.4 Hz, IH), 7.56 (1.,/=7.6 Hz, IH), 7.34 (t, J= 7.6 Hz, 1 H). 6.83 (d, J= 5.2 Hz, IH), 4.37 (brs, IH).

D.

Ethyl 5-methyl-1 -(quinolin-4-yl)-1 H-pyrazole-4-carboxylate. 60d

318

A mixture consisting of ethyl 2-(ethoxymethyIene)-3-oxobutanoate, 52a (418 mg. 2.25 mmol), 4-hydrazmylquinoline, 60c (220 mg, 1.12 mmol), and éthanol (8 mL) was stirred at 80 °C for 16 h. The mixture was cooled to room température and concentrated to dryness under reduced pressure to give a residue, which was purified by FCC (petroleum 5 ether: ethyl acetate = 2:1 ) to afford compound 60d (320 mg, 51 %). U \ M R (400 MHz, CDCh) δ ppm 9.08 (d, J = 4.8 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 7.83 - 7.79 (m, 1H), 7.61 -7.57 (m, HT), 7.46 (d, J = 8.0 Hz, 1H), 7.40 (d,J = 4.4 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H). 1.41 (t. J= 7.2 Hz. 3H).

E. A-(5-chloro-6-(2/L1,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-1 -(quinolin-4-yl)-l Hpyrazole-4-carboxamide, Cpd 64

A solution consisting of 5-chloro-6-(2ZZ-L2,3-triazol-2-yl)pyridin-3-amine, Ij (229 mg, 1.17 mmol) and THF (1 mL) was added dropwise to a solution of /-BuOK (3.2 mL,

3.2 mmol, 1 M in THF) at 0 °C. Then a solution consisting of ethyl 5-methyl-l-(quinolin4-yl)-l//-pyrazole-4-carboxylate, 60d (300 mg, 1.07 mmol) and THF ( 1 mL) was added dropwise. The résultant mixture was wanned to room température and stirred for 16 h before quenching with water and extracting with ethyl acetate (50 mL x 3). The combined extracts were dried over anhydrous NarSCL, filtered, and the filtrate concentrated to dryness under reduced pressure to give a residue, which was purified by préparative reverse phase HPLC (30% to 60% (v/v) CHsCN and HiO with 0.05% NH₃). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 64 (153 mg, 33 %). LCMS (ESI): Rt = 4.52 min, mass calcd. for CziHisCINsO 430.850, m/z found 431.0 [M+H]⁺. ‘H NMR (400 MHz, DMSO-Λ) δ 10.66 (s, 1H), 9.14 (d,J=4.4Hz, 1H), 8.92 (d, J=2.4Hz, 1H), 8.71 (d,J=2.4Hz, IH), 8.57 (s, 1H), 8.23 (d,

319

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 ïV-(5-ch]oro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolm-5-yl)-lH-pyrazole-4carboxamide, Cpd 60

A. Ethyl l-(quinolin-5-yl)-l//-pyrazole-4-carboxylate, 61a

Copper(II) acetate (1.43 g, 7.88 mmol) was added to a mixture consisting of ethyl lH-pyrazoIe-4-carboxylate (368 mg, 2.63 mmol), quinolin-5-ylboronic acid (500 mg, 2.89 mmol), molecular sieve (4 A, 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 O₂ (1 atm„ balloon) at room température for 16 h. The suspension was fïltered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (100 mL). The filtrate was washed with water (100 mL x 2), dried over anhydrous Na₂SO₄, fïltered, and the filtrate concentrated to dryness under reduced pressure to afford a crude product, which was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 70:30) to give compound 61a (160 mg, 23 %). Ή NMR (400 MHz, CDCh) 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=4A, 8.4 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H).

320

B. A^r-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(quinolin-5-yl)- IH-pyrazole4-carboxamide, Cpd 60

, Cpd 60

A solution consisting of 5-chloro-6-(2//-l,2,3-triazol-2-yl)pyridin-3-amine, Ij ( 102 mg, 0.524 mmol) and THF ( l mL) were added to l M potassium rert-butoxide in THF (1.57 mL, l,57 mmol) at 0 °C, then a solution consisting of ethyl l-(quinolin-5-yl)-l/fpyrazole-4-carboxylate, 61a (140 mg, 0.524 mmol) and THF ( l mL) was added. The résultant mixture was stirred at room température for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by préparative reverse phase HPLC (30% to 60% (v/v) ACN and H2O with 0.05% NH3). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford compound 60 (104.50 mg, 49 %). LCMS (ESI): Rt = 4.01 min, mass calcd. for C20H13CIN8O 416.823, m/z found 417.0 | Μ 11 ] . Ή NMR (400 MHz, DMSO-7₆) δ 9.04 (dd, 7 = 1.6, 4.0 Hz, IH), 8.96 (s, IH), 8.88 A.J IA Hz, IH), 8.70 (d, 7= 2.4 Hz, IH), 8.50 (s. IH), 8.33 - 8.28 (m, IH), 8.24 (d,7= 8.4 Hz, IH), 8.19 (s. 2H), 7.98 - 7.92 (m, IH), 7.89 - 7.85 (m, IH), 7.68 (dd, 7= 4.0, 8.4 Hz. 1 H).

Example 61 _yV-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-1 -(2-methylquinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 37

A. Ethyl I-(2-methylquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate, 61a

A mixture of 5-chloro-2-methylquinoline (200 mg, 1.12 mmol), hydrazine hydrate (0.111 mL, 98 %. 2.25 mmol). palladium) II )(pi-cinnamyl) chloride dimer (16 mg. 0.030 mmol), A-[2-(di-l-adamantylphosphino)phenyl]morpholine (42 mg, 0.090 mmol), sodium te/7-butoxide (216 mg, 2.25 mmol), and toluene (11 mL, 0.1 M, 1.1 mmol) was bubbled with Argon for 1 mm, sealed, and stirred at 100 °C for 2.5 h before cooling to room température and treating with ethyl 2-)ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (270 mg. 1.13 mmol) in one portion under air. The reaction was then sealed under air and stirred at 100 °C for 40 min. then at 90 °C for another 20 h before cooling to room température. The mixture was filtered and concentrated under reduced pressure to give a yellow oil, which was purified by FCC (petroleum ether: ethyl acetate = 40: 60) to afford compound 61a (210 mg, 16 %). LCMS (ESI): Rt = 0.75 min, mass calcd. for C17H14F3N3O2 349.3. m/z found 350.0 [M+H]*.

322

B. A-(5-ChlotO-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-methylquinolin-5-yl)-5( trifluoromethyl)-l/7-pyrazole-4-carboxamide, Cpd 37

Ethyl l-(2-methylquinolin-5-yI)-5-(trifluoiOmethyl)-lH-pyrazole-4-carboxyIate, 61a (210 mg, 0.180 mmol) in THF (1 mL) and 5-chloro-6-(2H-l ,2,3-triazol-2-yl)pyridin3-amine. Ij (i 17 mg, 0.601 mmol) in THF (1 mL) were added into a suspension of potassium zer/-butoxide (101 mg, 0.902 mmol) in THF (3 mL) at 0 °C. The mixture was stirred at room température for 20 h before concentrating under reduced pressure to afford a yellow solid, which was purified by préparative reverse phase HPLC (42% to 72% (v/v) CH3CN and H2O with 0.05 % NHs) from 42% to 72%, v/v) and lyophilized to afford compound 37 (12.0 mg, 13 %). LCMS (ESI): Rt = 4.34 min. mass calcd. for C22Hi₄C1F₃N₈O 498.093, m/z found 499.0 [M+H]⁺. Ή NMR (400MHz, DMSO-U) δ 11.30 (br s, 1H), 8.86 (d, 7= 2.4 Hz, 1H), 8.68 (d, 7 = 2.0 Hz, 1H), 8.58 (s, 1H), 8.23 (d. 7 = 8.8 Hz, 1H), 8.20 (s, 2H), 7.92 (dd,7= 7.2, 8.4 Hz, 1H), 7.83 (d,7= 7.2 Hz. 1 H), 7.59 7.53 (m, 1H). 7.52 - 7.47 (m, 1 H), 2.72 (s, 3H).

Example 62 jV-(5-Chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(6-fluoroquinolin-7-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 67

323

A. 5-Bromo-6-fluoroquinoline, 62a and 7-Bromo-6-fluoroquinoline, 62a-l

F Br F

Water (l 1.38 mL) was added to a solution consisting of 3-bromo-4-fluoroamline ( 10 g, 53 mmol), sodium 3-nitrobenzenesulfonate (21 g, 95 mmol), and propane-1,2,3-triol ( 14 g, 0.15 mol). The résultant mixture was carefully treated with concentrated H2SO4 (2l.l mL), and then heated to 150 °C with stirring for 2 h before cooling to room température. The résultant mixture was carefully neutralized with 5 N sodium hydroxide. filtered through a pad of diatomaceous earth, and the pad was washed with dichloromethane (50 mL). The résultant mixture was extracted with dichloromethane (100 mL x 3) and the combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated to give a crade product, which was purified by FCC (petroleum ether:

ethyl acetate = 3:1) to afford the compounds 62a and 62a-l (9.5 g, 80 %). LCMS (ESI): Rt = 0.64, 0.68 min, mass calcd. for CgHsBrFN 224.96, m/z found 227.6 [M+H] \ Ή NMR (400 MHz, CDCh) 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).

324

B. 5-(2-(Diphenylmethylene)hydrazinyI)-6-fluoroquinoIine, 62b and 7-(2(Diphenylmethylene)hydrazinyl)-6-fluoroquinoline, 62b-l

A mixture of 5-bromo-6-fluoroquinoline, 62a and 7-bromo-6-fluoroquinoline, 62a-l ( 10 g, 22 mmol), (diphcnylmethylene)hydrazine (4.3 g, 22 mmol), 2,2'bis(diphenylphosphino)-l,T-binaphthyl (1.4 g, 2.2 mmol), palladium(II) acetate (0.50 g, 2.2 mmol), /-BuONa (6.4 g, 66 mmol), and 1,4-dioxane (150 mL) was stirred at 100 °C for 16 h. The suspension was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (30 mL). The filtrate was concentrated to dryness under reduced pressure to give a crude product, which was added into water (30 mL). The résultant mixture was 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 afford the crude product, which was purified by FCC (petroleum ether: ethyl acetate = 3:1 ) to afford compounds 62b and 62b-l (5 g, 33 %). LCMS (ESI): Rt = 0.68 min, mass calcd. for C22H16FN3 341.13, m/z found 341.9 ΐ Μ 111 .

C. 6-Fluoro-5-hydrazinylquinoline, 62c and 6-Fluoro-7-hydrazinylquinoline. 62c-l

Concentrated HCl (10 mL) was added to a solution consisting of 5-(2(diphenylmethylene)hydrazinyl)-6-fluoroquinoline. 62b and 7-( 219506

325 (diphenylmethylene)hydrazmyl)-6-fluoroqumoline, 62b-1 (5.0 g, 7.3 mmol) and EtOH (3 mL). The résultant solution was stirred at room température for 16 h. The résultant mixture was treated with water (30 mL) and extracted with dichloromethane (30 mL x 3). The aqueous phase was basified with 5 M NaOH to pH 12. The suspension was filtered and the collected solids were washed with water (20 mL) and dried under reduced pressure to afford compounds 62c and 62c-1 ( l .2 g, 46 %). LCMS (ESI): Rt = L24 min, mass calcd. for CgHsFNs 177.07, m/z found 178.1 (M H | .

D. Ethyl l-(6-fluoroquinoliii-7-yl)-5-(trifluoiOmethyl)-lÆ-pyrazole-4-carboxylate,

62d

F , 62d

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, lf( l .79 g, 7.45 mmol), 6-fluoro-5-hydraziiiylquinoline and 6-fluoro-7-hydrazinylquinoline, 62c and 62c-l(l.l0 g, 6.21 mmol), and éthanol (20 mL) was stirred at 80 °C for 16 h before cooling to room température. The résultant solution was concentrated to dryness under reduced pressure to afford the crude product. This was purified by FCC (eluent: petroleum ether: ethyl acetate = 3: l) to afford the title compound ( 1.3 g, 59%). LCMS (ESI): Rt = 3.90 min, mass calcd. for C16H11F4N3O2 353.08, m/z found 353.9 j M+Hp. ‘H NMR (400 MHz, CDCh) 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, ,/ = 4.2, 8.4 Hz, 1 H), 4.41 (q, J= 7.2 Hz, 2H), 1.41 (t, J= 7.2 Hz, 3H).

E. A^L(5-Chloro-6-(2//-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(6-fluoroquinolin-7-yI)-5(trifluoromethyl)-I//-pyrazole-4-carboxamide, Cpd 67

326

A solution consisting of 5-chloro-6-(2H-l,2,3-triazoI-2-yl)pyridm-3-arnine, Ij (249 mg, 1.27 mmol) and THF (l mL), and a solution consisting of ethyl 1-(6-fluoroquinolin-75 yl)-5-(trifluoromethyl)-lJ/-pyrazole-4-carboxylate, 62d (300 mg, 0.849 mmol) and THF (1 mL) were added to a solution consisting of potassium /m-butoxide (2.55 mL, 2.55 mmol, 1 M in THF) at 0 °C. The résultant mixture was stirred at room température for 16 h. The résultant mixture was added water (5 mL) and extracted with ethyl acetate (15 mL x 3).

The combined organic extracts were dried over anhydrous NaiSO?, filtered, and the filtrate 10 concentrated to dryness under reduced pressure to afford a crude product, which was purified by préparative reverse phase HPLC (35% to 55% (v/v) CHjCN and H2O with 10 mM NH4HCO3) and lyophilized to afford compound 67 (70.7 mg. 17 %). LCMS (ESI): Rt = 5.05 min, mass calcd. for C21H11CIF4N8O 502.07, m/z found 502.9 [M+H] \ ’H NMR (400 MHz, DMSOY) δ 10.81 (br.s., IH). 9.06 (d, .7= 4.0 Hz, IH), 8.85 (d, J= 2.4 15 Hz, IH), 8.67 (d, 7= 2.4 Hz, IH), 8.59 (s, IH). 8.53 (d, 7= 8.4 Hz, IH), 8.50 (d, 7= 7.2

Hz, IH), 8.25 - 8.17 (m, 3H), 7.76 (dd,7 = 4.2, 8.4 Hz, IH).

Example 63

A^;-(5-Chloro-6-( 1 -methyl- l/f-pyrazol-3-yl)pyridm-3-yl)-1 -(isoquinolin-8-yl)-5(trifluoromethyl)-I//-pyrazole-4-carboxamide, Cpd 21

A. 8-HydrazinyIisoquinoline, 63a

H N nh₂ , 63a

To a stirring solution of isoquinolin-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) 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) w^;as added dropwise. The mixture was stirred at room température for 2 h. The mixture was adjusted to pH 12-14 with 20% aqueous sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was dried over NaaSCU, filtered, and the filtrate concentrated in under reduced pressure. The resulting crude product was purified by flash chromatography (petroleum ether,' ethyl acetate= 100:0 to ethyl acetate/ methnol=90:10) to give compound 63a (2.83 g, 60 %) as a brown solid.

B. Ethyl l-(isoquinolin-8-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate₅ 63b

A solution consisting of 8-hydrazinylisoquinoline, 63a (2.83 g, 17.8 mmol) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate. If (5.12 g, 21.3 mmol) in

328 éthanol (42 mL) was stirred at 80 °C for 16 h. The résultant solution was cooled to room température and concentrated to dryness under reduced pressure to afford a crade product, which was then purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=lOO:O to 70:30) to afford compound 63b as a yellow solid (3.14 g, 53 %). MS m/e 335.9 (M+H).

C. l-(Isoquinolin-8-yl)-5-(trifluoromethyl)-l77-pyrazole-4-carboxylic acid, 63c

F \ AOH

NaOH (375 mg, 9.4 mmol) was added to a solution of ethyl l -(isoquinolin-8-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate, 63b (3.14 g, 9.4 mmol) in methanol (5 mL) and water (15 mL) at room température. The mixture was stirred for 4 h. The solvent was concentrated under reduced pressure to afford compound 63c as a yellow solid (3.093 g 100 %). 'H NMR (400 MHz, DMSO-Λ) 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. A+(5-Chloro-6-(1 -methyl- 1/f-pyrazol-3-yl)pyridin-3-yl)-1-(ïsoquinolin-8-yl)-5- (trifluoromethyl)-l//-pyrazole-4-carboxamide, Cpd 21 /

—N

To a solution of 1 -(isoquinolin-8-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid, 63c (95 mg, 0.29 mmol), 5-chloro-6-(l -methyl- lH-pyrazol-3-yl)pyridin-3-amine, 8a

329 (60 mg. 0.29 mmol) and pyridine (132.7 mg, 1.7 mmol) in dichloromethane (5 mL) was added POCh (l02.9 mg, 0.67 mmol) dropwise. The reaction mixture was stirred at 20 °C for l h. A solution of saturated aqueous NaHCOs (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic phases were washed w'ith brine and dried over NaiSCU. The mixture was fïltered, and the filtrâtes concentrated under reduced pressure to afford a crude product as a yellow oil. The crude product w^ras purified by préparative HPLC to afford compound 21 as a white solid (55 mg, 38 %). ‘H NMR (400 MHz, DMSOA δ ppm 11.02 (s, 1H), 8.82 (d, J=2.2 Hz, 1H), 8.67 (d, J=5.7 Hz. 1H), 8.60 (s, IH), 8.54 (s, 1H), 8.42 (d, J=2.3 Hz, IH), 8.29 (d, J=7.4 Hz, 1H), 8.08 10 8.03 (m. IH), 8.00 - 7.93 (m, 2H), 7.77 (d, J=2.2 Hz. IH), 6.75 (d. J=2.2 Hz, IH), 3.92 (s,

3H). MS m/e 498.1 (M+H).

Example 64

A⁷-(2-Cyanopyridin-4-yl)-1 -(naphthalen-1 -yl)-5-(trifluoiOmethyl)- lH-pyrazole-415 carboxamide, Cpd 1

POCh (0.3 mL) was added dropwise to a solution consisting of 1-(naphthalen-1yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid 2b (150 mg, 0.490 mmol), 4aminopicolinonitrile (64.2 mg. 0.539 mmol) and pyridine (5 mL). The mixture w^ras stirred 20 at 0 °C for l h. The resulting mixture was concentrated under reduced pressure to give a crude product, which was purified by préparative HPLC (40% to 70% (v/v) ACN and H2O with 0.05% NH3) to afford compound 1. Compound 1 was concentrated to dryness under reduced pressure (101.30 mg, 51 %). LCMS (ESI): Rt = 5.45 min, mass calcd. for C21H12F3N5O 407.348, m/z found 408.0 [M+H]L *H NMR (400 MHz, DMSO-c/0) δ ppm 25 11.31 (s, IH), 8.71 (d, .7=5.2 Hz, lH),8.56(s, lH),8.30(s, 1 H), 8.26 (d, .7= 8.0 Hz, IH),

330

8.15 (d, .7 =8.0 Hz, 1 H), 8.00 (d. J = 4.0 Hz, IH), 7.83 - 7.77 (m. 1 H), 7.76 - 7.62 (m, 3H),

7.14 (d, J = 8.0 Hz, IH).

Example 65

A-(5-Cyano-6-(2/7-L2,3-triazol-2-yl)pyridin-3-yl)-l-(imidazo[1,2-a]pyrazin-8-yl)-5( trifluoromethyl)- l/f-pyrazole-4-carboxamide, Cpd 103

8-Chloroimidazo[l,2-a]pyrazine (400 mg, 2.6 mmol) and tert-butyl hydrazinecarboxylate (516.4 g, 3.9 mmol) were dissolved in THF (8 mL), sodium hydride (312.5 mg, 7.8 mmol) was added, and the mixture stirred at 30 °C for 16 h. Saturated aqueous NH4CI (10 mL) was added and the mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were dried over NaiSOi. filtered. and the filtrâtes concentrated under reduced pressure to afford a crude product as a black oil. The cnide product was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 30/70). The solvent was concentrated under reduced pressure to afford compound 65a as a yellow solid (220 mg, 28 %). LCMS (ESI): m/z 250.1 [M+H] \

331

B. 8-Hydrazinylimidazo[l,2-a]pyrazine, 65b

to7-Butyl 2-(imidazo[l,2-a]pyrazin-8-yl)hydrazine-l-carboxylate, 65a (220 mg,

0.72 mmol) was suspended in dichloromethane (5 mL) and HCl/dioxane (10 mL) was added. The reaction mixture was stirred at 30 °C for 1 h, then concentrated under reduced pressure to afford compound 65b as a yellow solid. The solid was used for the next step without further purification.

C. Ethyl 1 -(imidazo[ 1,2-a]pyrazin-8-yl)-5-( trifluoromethyl)-1 /f-pyrazole-4carboxylate, 65c

8-Hydrazinylimidazo[l ,2-a]pyrazine, 65b (160 mg, 1.1 mmol) and triethylamine (325.6 mg, 3.2 mmol) were dissolved in éthanol (3 mL), ethyl 2-(ethoxymethylene)-4,4,415 trifluoro-3-oxobutanoate, If (515.3 mg, 2.15 mmol ) was added and the mixture stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford a crude brown solid. The solid was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 20/80). The solvent was concentrated under reduced pressure to afford compound 65c as a yellow oil (160 mg, 41 %). LCMS (ESI):

m/z 326.0 · Μ 111 /

D. 1 -(Imidazo[ 1,2-a]pyrazm-8-yI)-5-(trifluoromethyl)- 12/-pyrazole-4-carboxylic acid,

65d

332

Lithium hydroxide monohydrate (183.4 mg, 4.4 mmol) was added to ethyl 1(imidazo[l,2-a]pyrazin-8-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate, 65c (160 mg, 0.44 mmol) and the mixture stirred at 30 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford a crude yellow solid, which was used for the next step without further purification (160 mg).

E. A'-(5-Cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(imidazo[L2-a]pyrazm-8-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 103

E

To a solution of l-(imidazo[l,2-a]pyrazin-8-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylic acid, 65d (115 mg, 0.39 mmol), 5-ammo-2-(2H-1.2,3-triazol-2yl)mcotinonitrile, 7b (47.9 mg, 0.26 mmol) and pyridine (91.5 mg, 1.2 mmol) in dichloromethane (3 mL) was added POCI3 (59.1 mg, 0.39 mmol) dropwise. The reaction mixture was stirred at 20 °C for 16 h. A solution of saturated aqueous NaHCO? (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with brine and dried over NazSOr. The mixture was filtered, and the filtrâtes concentrated under reduced pressure to afford a crude product as a yellow oil. The crude product was purified by préparative HPLC to afford compound

103 as a white solid (5 mg, 4 %). Ή NMR (400 MHz, METHANOL-cL) δ ppm 9.04 (br s.

333

IH). 8.89 (d, J=2.6 Hz. IH), 8.86 (d. J=4.6 Hz, IH), 8.50 - 8.43 (m. 2H), 8.19 (d, J=4.6 Hz,

IH), 8.16 (s, IH), 8.13 (s, 2H). LCMS (ESI): m/z 465.9 [M+Hf.

Example 66

A45-Cyano-6-(22M,2,3-triazol-2-yl)pyridin-3-yI)-l-(quinoxalin-5-yl)-5-( trifluoromethyl)lH-pyrazole-4-carboxamid. Cpd 105

A. Di-/m-butyl l-(quinoxalin-5-yl)hydrazine-l,2-dicarboxylate, 66a

5-Bromoquinoxaline (300 mg, 1.44 mmol) and di-tert-butyl hydrazine-1,2dicarboxylate (500 mg, 2.15 mmol) were dissoived in DMF (5 mL). Cul (27.5 mg, 0.14 mmol) and K5PO4 (609.3 mg, 2.87 mmol) were added and purged with N2, cyclohexaneL3-diamine (32.8 mg, 0.29 mmol) was added and the reaction mixture was stirred at 110 °C for 16 h. The réaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with EtOAc (20 mL x 3). The filtrate was concentrated under reduced pressure to afford a crude produce as a brown oil. The crude product was purified by column chromatography over silica gel (petroleum ether, ethyl acetate= 100:0 to petroleum ether, ethyl acetate=50:50), and the solvents were removed under reduced pressure to afford compound 66a as a brown oil (0.3 g, 58 %). LCMS (ESI): m/z 383.0 [M+H] .

334

B. 5-HydrazinyIquinoxaline, 66b

H₂N, ² NH ôô ,66b

Di-/m-butyl l-(quinoxalin-5-yl)hydrazine-1,2-dicarboxyIate. 66a (300 mg, 0.48 mmol) in HCl in dioxane (10 mL) was mixed at 28 °C for 2 h. The solvent was 5 concentrated under reduced pressure to afford compound 66b.

C. Ethyl 1 -(quinoxalm-5-yl)-5-(trifhiorornethyl)- lW-pyrazole-4-carboxylate, 66c

5-Hydrazinylquinoxaline, 66b (200 mg, 1.0 mmol) was dissolved in éthanol (5 mL), ethyl 2-(ethoxymethylene)-4,4.4-trifluoro-3-oxobutanoate, lf (336.4 mg, 1.53 mmol) was added and the mixture stirred at 80 °C for 3 h. The reaction, mixture was concentrated under reduced pressure to afford a crude product as a brown solid. The solid was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 50 50). and the solvent was concentrated under reduced pressure to afford compound

66c as a yellow oil (155 mg, 26 %). LCMS (ESI): m/z 336.9 [M+H]\

D. l-(Quinoxalin-5-yl)-5-(trifluoromethyl)-IH-pyrazole-4-carboxylic acid, 66d

335

Lithium hydroxide monohydrate (92 mg, 2.2 mmol) was added to ethyl 1(quinoxalin-5-yl)-5-(trifluoromethyl)-l/7-pyrazole-4-carboxylate, 66c (125 mg, 0.37 mmol) and stirred at 30 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford a crude product as a yellow solid. The crude product was used for the 5 next step without further purification (95 mg).

E. _iV-(5-cyano-6-(2/7-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinoxalin-5-yl)-5(tnfluoromethyl)-lH-pyTazole-4-carboxamid, Cpd 105

To a solution of l-(quinoxalin-5-yl)-5-(trifluoromethyl)-l//-pyrazole-4-carboxylic acid, 66d (56.2 mg, 0.30 mmol), 5-amino-2-(2H-l ,2,3-triazol-2-yl)nicotinonitrile, 7b (100 mg, 0.30 mmol) and pyridine (119 mg, 1.5 mmol) in dichloromethane (5 mL) was added POCh (92.5 mg, 0.60 mmol) dropwise. The reaction mixture was stirred at 20 °C for 16 h. A solution of saturated aqueous NaHCCL (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with brine and dried over NaiSCL. The mixture was filtered, and the filtrâtes concentrated under reduced pressure to afford a crude product as a yellow oil. The crude product was purified by préparative HPLC to afford the compound 105 as a white solid (21 mg. 15 %). ‘H NMR (400 MHz, DMSO-Y) δ ppm 8.04-8.11 (m, 1 H), 8.19-8.23 (m, 1 H), 8.29 (s,

2 H), 8.39 (d, J=8.38 Hz, 1 H), 8.56 (s, 1 H). 8.87 (d, J=2.43 Hz, 1 H), 8.97 (d, J=1.54 Hz,

H). 9.05 - 9.12 (m, 2 H), 11.29 (s, 1 H). LCMS (ESI): m/z 477.0 | Μ 111 .

336

Example 67

N-(5-Chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-lH-pyrazole-4carboxamide. Cpd 76

A solution consisting of 5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amme, lj (87.8 mg, 0.449 mmol) and THF (l mL) were added to l M potassium ZerZ-butoxide in THF ( 1.35 mL, 1.35 mmol) at 0 °C, then a solution consisting of ethyl l-(isoquinolin-4- yI)-lH-pyrazole-4-carboxylate, 59a (120 mg, 0.449 mmol) and THF ( 1 mL) was added. The résultant mixture was stirred at room température for 16 h. The réaction mixture was concentrated under reduced pressure to give a crude product. which was purified.by préparative reverse phase HPLC (30% to 60% (v/v) ACN and H2O with 0.05% NH?) and lyophilized to give compound 76 (69.3 mg, 36 %). LCMS (ESI): Rt = 4.36 min, mass calcd. for C20H13CIN8O 416.823, nvz found 416.9 [M+H]L ‘H NMR (400 MHz, DMSOi/₆) δ ppm 10.74 (br.s., 1H), 9.52 (s, 1H), 9.01 (s, 1H), 8.88 (d,7=2.4 Hz. 1H), 8.76 (s, 1H), 8.70 (d,7= 2.4 Hz, 1H), 8.54 (s, 1H), 8.35 (d.7= 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-l,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-l-(quinolin-4-yl)-lHpyrazole-4-carboxamide, Cpd 64

337

A solution consisting of 5-chloro-6-(2Zl,2,3-triazol-2-yl)pyridm-3-amine, Ij (229 mg, l, 17 mmol) and THF ( l mL) was added dropwise to a solution of z-BuOK (3.2 mL,

3.2 mmol, l M in THF) at 0 °C. Then a solution consisting of ethyl 5-methyl-l-(quinolin-

4-yl)-l/7-pyrazole-4-carboxylate, 60d (300 mg, 1.07 mmol) and THF (1 mL) was added dropwise. The résultant mixture was warmed to room température and stirred for 16 h before quenching with water and extractiiig with ethyl acetate (50 mL x 3). The combined extracts were dried over anhydrous Na2SO4, filtered, and the filtrate concentrated to dryness under reduced pressure to give a residue, which was purified by préparative reverse phase HPLC (30% to 60% (v/v) CHjCN and H2O with 0.05% NH3) and lyophilized to afford compound 64 (153 mg. 33 %). LCMS (ESI): Rt = 4.52 min, mass calcd. for C^iHuClNsO 430.850, m/z found 431.0 [M+H]’. 'H NMR (400 MHz, DMSOΛ) δ ppm 10.66 (s, 1H), 9.14 (d, ./= 4.4 Hz, 1 H). 8.92 (d, ./= 2.4 Hz, 1H). 8.71 (d, ./= 2.4

Hz, 1H), 8.57 (s, 1H), 8.23 (d, J=8.4Hz, 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-( 2/7-1,2,3-triazol-2-yl)pyridin-3-yl)-l-(qinnolm-5-yl)-lÆ-pyrazole-4carboxamide, Cpd 60

338

A solution consisting of 5-chloiO-6-(2H-l ,2,3-triazol-2-yl)pyfidin-3-amme, Ij (102 mg, 0.524 mmol) and THF (1 mL) were added to 1 M potassium im-butoxide in THF ¢1.57 mL, 1.57 mmol) at 0 °C, then a solution consisting of ethyl 1 -(quinolin-5-yl)-\Hpyrazole-4-carboxylate, 61a (140 mg, 0.524 mmol) and THF (1 mL) was added. The résultant mixture was stirred at room température for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by préparative reverse phase HPLC (30% to 60% (v/v) ACN and H2O with 0.05% NH?) to afford compound 60 ( 104.50 mg, 49 %). LCMS (ESI): Rt = 4.01 mm, mass calcd. for C2oHi?C1N₈0 416.823, m/z found 417.0 [M+Hp. 'H NMR (400 MHz, DMSO-Y) δ 9.04 (dd.7= 1.6, 4.0 Hz. IH), 8.96 (s. IH), 8.88 (d, 7 = 2.4 Hz, IH), 8.70 (d,7= 2.4 Hz, IH), 8.50 (s, IH), 8.33 - 8.28 (m, IH), 8.24 (d, 7= 8.4 Hz, IH), 8.19 (s, 2H), 7.98 - 7.92 (m, IH), 7.89 - 7.85 (m, IH), 7.68 (dd, 7= 4.0, 8.4 Hz, IH).

Example 70

Methyl 2-(3-chloro-5-( l-(quinolm-5-yl)-5-(trifluoiOmethyl)-lH-pyrazole-4carboxamido)pyridin-2-yl)-2H-L2,3-triazole-4-carboxylate, Cpd 108

A. Mixture of methyl l-(3-chloro-5-nitropyridin-2-yl)-lH-L2,3-triazole-5-carboxylate compound with methyl 2-(3-chloro-5-nitropyridin-2-yl)-2H-1,2,3-triazole-4carboxylate, 70a

339

Potassium carbonate (7249.14 mg, 52.45 mmol) was added to a solution of 2,3dichloro-5-nitropyridine (7249.14 mg, 17.48 mmol) and methyl lh-l,2,3-triazole-4carboxylate (2000 mg, 15.76 mmol) in MeCN (20 mL). The mixture was reacted at 60°C for 12 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give the crude product as yellow oil. which was purified by FFS (petroleum ether/ ethyl acetate=100:0 to petroleum ether/ ethyl acetate=40:60). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as yellow solid.

B. Methyl 2-(5-amino-3-chloropyridin-2-yl)-2H-L2,3-triazole-4-carboxylate. 108b

Mixture of methyl l-(3-chloro-5-nitropyridin-2-yl)-IH-l,2,3-triazole-5carboxylate and methyl 2-(3-chloiO-5-nitropyridin-2-yl)-2H-L2,3-triazole-4carboxylate (2500 mg, 4.41 mmol) was added to a solution of Fe (1230 mg. 22.04 mmol) and NH4CI (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 pad was washed with EtOAc (50 mLx 2). The combined filtrâtes were concentrated to dryness to give crude as yellow solid, which was purified by FFS (petroleum ether/ ethyl acetate=50:50 to petroleum ether/ ethyl acetate=0:100). The desired fractions were collected and the solvent was concentrated under reduced pressure. Ή NMR (400 MHz. CHLOROFORM-d) δ ppm 3.98 (s, 3 H). 4.17 (br s, 2 H), 7.17 (d. J=2.43 Hz, 1 H), 7.91 (d, J=2.65 Hz, 1 H), 8.30 (s, 1 H).

340

C. Methyl 2-(3-chloro-5-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4 carboxamido)pyridin-2-yl)-2H-l,2,3-triazole-4-carboxyIate, Cpd 108

l-(Quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (240.87 mg, 5 0.77 mmol). methyl 2-(5-amino-3-chloropyridin-2-yl)-2H-l ,2,3-triazoIe-4-carboxylate (200 mg, 0.79 mmol), POCI3 (142.24 mg, 0.93 mmol) were dissolved m DCM (8 mL), and pyridine (183.44 mg, 2.32 mmol) was added. The mixture was stirred at 25 °C for 1 h, sat. NaHCOs (30 mL) was added and extracted with CH2CI2 (30 mL x 2). The combined organic layers were dried over Na:2SO4, filtered and the filtrâtes were concentrated under 10 reduced pressure to afford a brown oil, which was purified by FFS (petroleum ether/ ethyl acetate=50:50 to petroleum ether/ ethyl acetate=0:100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as yellow solid. ‘H NMR (400 MHz, DMSO-d₆) δ ppm 3.90 (s, 3 H), 7.58 - 7.62 (m, 1 H), 7.64 - 7.69 (m, 1 H), 7.90 - 7.99 (m, 2 H), 8.32 (d, J=8.38 Hz, 1 H), 8.59 (s, 1 H), 8.69 (s, 1

H), 8.71 (d, J=2.21 Hz, 1 H), 8.87 (d, J=2.43 Hz, 1 H), 9.05 (dd, J=3.97, 1.54 Hz, 1 H),

11.32 ts. 1 H). LCMS (ESI) m/z M+L 543.2.

341

Example 109

2-(3-chloro-5-(I-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamido)pyridin2-yl)-2H-l,2,3-triazole-4-carboxylic acid, Cpd 109

NaOH (63.528 mg, 1.588 mmol) was added to a solution of methyl 2-(3-chloro-5(1-(quinolin-5-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxamido)pyridin-2-yl)-2H-1,2,3triazole-4-carboxylate, cpd 108 (445 mg, 0.794 mmol) in EtOH/H2O=l :1 (5 mL) was reacted at 18 °C for 2 h. The solvent was concentrated under reduced pressure, IM HCl solution was add to the mixture to adjust the pH to ~5 and solid formed. The solid was collected to afford the product. ’H NMR (400 MHz, DMSO-de) δ ppm 7.58 - 7.62 (m, 1 H), 7.64 - 7.69 (m, I H), 7.90 - 7.99 (m, 2 H), 8.32 (d, J=7.94 Hz, 1 H), 8.58 (d, J=11.47 Hz, 2 H), 8.70 (d, J=2.21 Hz, 1 H), 8.87 (d, J=2.21 Hz, 1 H), 9.05 (dd, J=3.97, 1.54 Hz, 1 H), 11.34 (s, 1 H). LCMS (ESI) m/z M+L 542.9.

Example 110 l-(l-amino-8-fluoroisoqumolin-4-yl)-N-(5-chIoro-6-(2H-L2,3-triazol-2-yl)pyridm-3-yl)-5(trifluoromethyl)-IH-pyrazole-4-carboxamide, Cpd 110

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A. 8-Fluoro-4-hydrazmylisoquinoline. 110a

H₂N ΛηΓ f^Z '=n noa

A mixture of palladium (II) (pi-cinnamyl) (103.14 mg, 0.20 mmol) chloride dimer and N-[2-(di-l-adamantylphosphino) phenyl] morpholine (184.6 mg, 0.40 mmol) in dioxane (20 mL) was evacuated with argon (4x). The resulting clear yellow solution w^;as stirred at room temp under argon 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 yellow⁷ réaction was stirred at room température for 5 min and then treated with hydrazine (398.63 mg, 7.96 mmol) via syringe and purged with argon (4x). Then the mixture was stirred at 55 °C under argon for 2 h. The reaction mixture was fïltered. The filtrate w⁷as concentrated under reduced pressure to give the crude product as a brown solid.

B. Ethyl 1 -(8-fluoroisoquinoIin-4-yl)-5-(trifluoiOmethyl)-1 H-pyrazole-4-carboxylate, 110b

8-Fluoro-4-hydrazinylisoquinoline (700 mg, 3.95 mmol) w⁷as 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 h. The mixture was concentrated under reduced pressure, then was purified by FFS (petroleum ether/ ethyl acetate= 100:0 to petroleum ether/ ethyl acetate=80:20). The desired fractions were collected and the solvent

343

was concentrated under reduced pressure to give the product as brown oil. LCMS (ESI) m/z M+l : 353.9.

C. 4-(4-(Ethoxycarbonyl)-5-( trifluoromethyl)-1 H-pyrazol-l-yl)-8-fluoroisoquinoline

2-oxide, 110c

m-CPBA (700 mg. 3.95 mmol) was added to a solution of ethyl l-(8fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate (800 mg. 2.25 mmol) in DCM ( 10 mL) was reacted at 30 °C for 2 h. The mixture was added to 40 mL sat.NaiCOs solution, extracted with 50 mL CH2CI2, the organic layer was concentrated under reduced pressure and purified by FFS (petroleum ether/ ethyl acetate=100:0 to 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+l : 370.0.

D. Ethyl 1 -( 1 -chloro-8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxylate, llOd

344

POCh (5 mL) was added to a solution of 4-(4-(ethoxycarbonyl)-5(trifluoromethyl)-IH-pyrazol- I-yl)-8-fluoroisoquinoline 2-oxide, (720 mg, 1.95 mmol) in CHCh ( 15 mL) was reacted at 70 °C for 2 h. The mixture was added to 30 mL sat.NaiCO? solution, extracted with 30 mL CfLCL, the organic layer was concentrated under reduced pressure, then purified by FFS (petroleum ether/ ethyl acetate=lOO:O to petroleum ether/ ethyl acetate=85:15). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as colorless oil. LCMS (ESI) m/z Ml 388.0.

E. l-(l-Chloro-8-fluoroisoquinolin-4-yl)-5-( trifluoromethyl)-! H-pyrazole-4carbo.xylic acid, 110e

LiOH (70.415 mg, 2.940 mmol) was added to a solution of ethyl l-(thieno[2,3c]pyridin-7-yl)-5- (trifluoromethyl)-lH-pyrazole-4-carboxylate (240 mg, 0.59 mmol) in THF/H2O= 1:1 (10 mL) was reacted at 23 °C for 2 h. The solvent was concentrated under reduced pressure, IM HCl solution was add to the mixture to adjust the pH to ~5 and EtOAc (30mL x 3) was added to the mixture. The combined organic layers were dried over NazSOg, filtered and the filtrâtes were concentrated under reduced pressure to afford the product as a brown oil. LCMS (ESI) m/z M+L 359.9.

345

F. N-(5-Chloro-6-(2H-l,2,3-triazoI-2-yl)pyridin-3-yl )-1-( l-chloro-8fluoroisoquinolin-4-yl)-5-(trifluoiOmethyl)-lH-pyrazole-4-carboxamide, IlOf

, IlOf l-(l-ChloiO-8-fluoiOisoquinolin-4-yl)-5-( trifluoromethyl)-lH-pyrazole-45 carboxylic acid (210 mg, 0.22 mmol), 5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine (107.93 mg, 0.55 mmol), POC1₃ (96.69 mg, 0.63 mmol ) were dissolved in DCM (5 mL), and pyridine (124.7 mg, 1.58 mmol) was added. The mixture was stirred at 25 °C for 1 h, sat.NaHCO? (10 mL) was added and extracted with CH2CI2 (15 mLx 2). The combined organic layers were dried over NajSOg, filtered and the filtrâtes were concentrated under reduced pressure to afford the product as a brown oil. LCMS (ESI) m/z M+l : 536.9.

l-( l-amino-8-fluoroisoquinolin-4-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 110

N-(5-Chloro-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-chloiO-8-fluoroisoquinolin-4-yl)5-(tnfluoromethyl)-lH-pyrazole-4-carboxamide (200 mg, 0.18 mmol) in NH3.H2O (12 mL) was reacted at 80 °C for 16 h. The solvent was concentrated under reduced pressure the give the crude compound, which was purified by préparative HPLC (77 % to 57 % ( v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (29 mg. 31.5%). LCMS (ESI) m/z M+L 518.0. Ή NMR (400 MHz, DMSOd6) δ ppm 6.77 (d, J=8.53 Hz, 1 H), 7.56 (dd, J=12.92, 7.91 Hz, 1 H). 7.81 - 7.91 (m, 1 H).

346

8.20 (s, 2 H), 8.22 (s, l H). 8.61 (s, l H), 8.70 (d. J=2.01 Hz, l H), 8.89 (d, J=2.01 Hz, l H), H.36 (s, l H).

Example 111 l-( l-amino-8-fluoiOisoquinolin-4-yl)-N-(5-cyano-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 111

A. l-(l-chloro-8-fluoroisoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3 -triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide. 111a

-( 1 -chloro-8-fluoroisoquinolin-4-yl)-5-( trifluoromethyl)-1 H-pyrazole-4carboxylic acid, cpd 110e (230 mg, 0.588 mmol), 5-amino-2-(2H-l,2,3-triazol-2yl)nicotinonitrile (109.474 mg, 0.588 mmol), POCh ( 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 h, sat. NaHCO? (10 mL) was added and extracted with CH2CI2 (15 mL x 2). The combined organic layers were dried over NazSCU, filtered and the filtrâtes were concentrated under reduced pressure to afford crude as brown oil which was purified by FFS (petroleum ether/ ethyl acetate=10:1 to ethyl acetate). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as colorless oïl. LCMS (ESI) m/z M+l : 528.1

347

B. l-(l-amino-8-fluoroisoquinolin-4-yl)-N-(5-cyano-6-(2H-l,2.3-triazol-2-yl)pyridin3-y 1)-5-(.trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 111

-( 1 -Chloro-8-fluoroisoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide (140 mg, 0.262 mmol) in NH3.H2O ( 10 mL) was stirred at 60°C for 2 h. The solvent was concentrated under reduced pressure the give the crude compound. which was purified by préparative HPLC (83 % to 53 % (v/v) CHaCN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (50.0 mg, 37.6%). *H NMR (400 MHz, DMSO-d6) δ ppm 6.79 (d, J=8.28 Hz, 1 H), 7.60 (dd, J=12.92. 7.91 Hz, 1 H), 7.90 (td, J=8.16, 5.27 Hz, 1 H), 8.27 (s, 1 H). 8.32 (s, 2 H), 8.64 (s, 1 H), 8.91 (d, J=2.51 Hz, 1 H), 9.15 (d, J=2.26 Hz. 1 H). LCMS (ESI) m/z \H: 508.9. 11.51 (s. 1 H).

Example 112

N-( 5-chloro-2-methyl-6-(2H-1,2,3 -tnazol-2-y l)pyridin-3-yl)-1 -( 1 -oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-!H-pyrazole-4-carboxamide, Cpd 112

A. 5-hydrazinylisoquinoline, 112a

348

,ΝΗ ^η2^ν , 112a

Το a stirring solution of isoquinolin-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 H?O (85 mL) 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 température for 3 h. The mixture was adjusted to pH 12-14 with 20% aqueous sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was dried (NajSOi), filtered, and concentrated under reduced pressure to afford the title product as a yellow solid (27 g, 81.5% yield).

B. Ethyl l-(isoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxyIate. 112b

A solution consisting of 5-hydrazinylisoquinoline (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 h. The résultant solution was cooled to room température and concentrated to dryness under reduced pressure to afford the crade product. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate= 100:0 to 70:30). The solvent was concentrated to get the title product as yellow solid (22 g, 38.7% yield). LCMS (ESI) m/z M+l: 336.0.

C. 5-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-lH-pyrazol-l-yI)isoquinoline 2-oxide, 112c

To a cooled (0 °C) solution of ethyl l-(isoquinolin-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylate (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 a half-saturated aqueous solution of sodium bisfulfite (100 mL) to destroy excess oxidant. The mixture was then twice washed with half-saturated aqueous potassium carbonate (100 mL), and brine (100 mL). The extracts were dried over magnésium sulfate, filtered and concentrated to afford a crude oil that was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to

20/80). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to give title product as yellow solid (2 g, 63.6% yield). LCMS (ESI) m/z M+l: 351.9.

Ethyl l-(l-chloroisoquinolin-5-yI)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate, 112d

A solution consisting of POCh (16.6 g, 108.2 mmol) and 5-(4-(ethoxycarbonyl)-5(trifluoromethyl)-lH-pyrazol-l-yDisoquinoline 2-oxide (19 g, 54.1 mmol) in CHCh (40 mL) was stirred at 60 °C for 3 h. The resulting solution was cooled to room température and concentrated to dryness under reduced pressure to afford the crude product. The crude

350 product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate= 100:0 to 70:30). The solvent was concentrated to get the title product as a yellow solid (12 g, 60.0% yield). LCMS (ESI) m/z M+l: 369.9

E. 1-(1-Oxo-L2-dihydroisoquinoIin-5-yl)-5-( trifluoromethyl)-! H-pyrazole-4- carboxylic acid, 112e

A mixture of ethyl l-( l-chIoroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate (12 g, 32.546 mmol) in concentrated HCl (20 mL) was stirred at 120 °C for 3 h. The solvent concentrated under reduced pressure to give the product as a yellow solid (11g, 83% yield). LCMS (ESI) m/z M+H: 324.1.

F. N-(5-chloro-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-( 1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 112

POCL (5.26 g, 30.3 mmol) was added to a solution of l-(l-oxo-l,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (7.0 g, 17.2 mmol), 5-chloro-2-methyl-6-(2H-l,2,3-triazol-2-yI)pyridin-3-amine (3.96 g, 18.9 mmol) in pyridine (20 mL). The mixture was stirred at rt for 3h, 50 mL sat. NaHCCh (500 mL) added to the mixture, extracted with CH/CL (500 mL x 2). The organic layer was washed with brine (200 mL). dried over MgSOi and concentrated under reduced pressure to afford the crude product, which was purified by préparative HPLC (5% to 60% (v/v) CHjCN and

351

H2O with 0.05% HCl) and concentrated to dryness to afford the title compound (5.7 g.

64.4% yield) as a white solid. LCMS (ESI) m/z M+l : 515.2. ‘H NMR (400 MHz, DMSOd6) δ ppm 2.54 (s, 3 H), 5.67 (d, J=7.50 Hz, 1 H), 7.28 (dd, J=7.17, 5.84 Hz, 1 H), 7.66 (t, J=7.83 Hz, 1 H), 7.93 (dd, J=7.61. 0.99 Hz, 1 H), 8.14 - 8.20 (m, 2 H), 8.43 (t. J=3.97 Hz, 2 H), 8.51 (s, 1 H), 10.59 (s, 1 H), 11.61 (br d, J=5.29 Hz, 1 H).

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)-lH-pyrazole-4-carboxaniide, Cpd 113

lodomethane (9.50 g, 66.95 mmol) was added to a solution of 5-bromoisoquinolinl(2H)-one (5 g, 22.32 mmol), AggCO? (18.46 g. 66.95 mmol) in Cl L( N (100 mL). The mixture was stirred at 40°C for 16 h. The mixture was fïltered and washed with ethyl acetate (100 mLx 3). The filtrate was collected and concentrated under reduced pressure, and the crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 100:1 to 10:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford 113a (2 g. 37.6% yield) as a white oil.

352

B. 5-hydrazmyl-l-methoxyisoqumoline, 113b

The 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 under argon for 10 min. cpd 113a (2 g, 8.401 mmol) and t-BuONa ( 1612.896 mg, 16.801 mmol) w^;as added to the mixture and the mixture was purged with argon (4x). The resulting yellow' reaction was stirred at room temp for 5 min and w'as then treated with hydrazine hydrate (858.230 mg, 16.801 mmol) via syringe. The reaction was purged with argon (4x). Then the mixture was stirred at 50 °C under argon for 4 h, The mixture was fïltered and washed w'ith ethyl acetate (50 mLx 3). The filtrate w'as collected and concentrated to afford crude cpd 113b (1.6 g) as a yellow’ solid which was used directly for the next step.

C. Ethyl 1-(l-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate, 113c

A solution of 5-hydrazinyl-l-methoxyisoquinoline, cpd 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 h. The mixture was concentrated under reduced pressure, the crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 100:0 to 10:1).

353

The desired fractions were collected and the solvent was concentrated under reduced pressure to afford cpil 113c (2.2 g, 71.2% yield) as a yellow' solid. LCMS (ESI) m/z M+L 365.9.

D. 1 -( 1 -hydroxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid,

113d

Ethyl 1 -( 1 -methoxyisoquinolm-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxylate, cpd 113c (l g, 2.74 mmol) was added to HCl (10 mL). The mixture was stirred at 130 °C for 3h and concentrated under reduced pressure to afford cpd 113d (530 mg, 55.5% yield) as brown solid which used directly for the next step. LCMS (ESI) m/z M il: 323.9.

E. N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl )-1-( 1-oxo- L215 dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazoIe-4-carboxamide, Cpd 113

l-( 1-Oxo-l,2-dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-lH-pyrazole-4carboxylic acid, cpd 113d (170 mg, 0.37 mmol), 5-amino-2-(2H-l,2,3-triazol-2yDnicotinonitrile, (69.15 mg, 0.37 mmol), pyridine (0.15 mL. 1.86 mmol) were dissolved

354 in CH2CI2 (ΙΟ mL), and phosphores oxychloride (0.14 mL. 1.49 mmol) was added. The mixture was stirred at 25 °C for 2 h. Sat.NaHCO₃ (20 mL) was added and extracted with CH2CI2 (30 mL x 2). The combined organic extracts were dried over anhydrous Na₂SO4, filtered, and concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (35% to 65% (v/v) CH₃CN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound (46 mg, 24.6%). LCMS (ESI) m/zM+l:49L9. 'HNMR (400 MHz, DMSO-d6) 6 ppm 11.62 (I H, brd, J=5.51 Hz), 11.30 (1 H, s), 9.06 (1 H, d, J=2.65 Hz), 8.85 (1 H, d, J=2.43 Hz), 8.53 (1 H, s), 8.42 ( 1 H, d, J=7.94 Hz), 8.29 (2 H, s), 7.89 - 7.98 (1 H, m), 7.66 (I H, t. J=7.94 Hz), 7.28 (1 H, dd, J=7.28, 6.17 Hz), 5.64 (1 H. d, J=7.28 Hz).

Example 114 l-(benzo[d]fhiazol-7-yl)-N-(5-cyano-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 114

7-bromobenzo[d]thiazole (300 mg, 1.40 mmol), palladium(ïi)(pi-cmnamyl) chloride dimer (36.3 mg, 0.07 mmol), N-[2-(di-l-adamantylphosphino)phenyl]morpholine (64.97 mg, 0.14 mmol) and sodium tert-butoxide (269.35 mg, 2.80 mmol) was dissoived m dioxane (20 mL) under N₂ atmosphère. Hydrazine hydrate (140.30 mg, 2.80 mmol) was added and stirred at 50°C for 2 h. The combined mixture was filtered and the solid was

355 washed by 10 mL ethyl acetate. The solvent was concentrated under reduced pressure to afford the title compound (200 mg, 86.4 %) as brown solid.

B. ethyl l-(benzo[d|thiazoI-7-yl)-5-( trifluoromethyl )-lH-pyrazole-4-carboxylate,

114b

7-hydrazinylbenzo[d]thiazole (200 mg, 1.21 mmol) was dissolved in éthanol (5 mL), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (436.11 mg, 1.82 mmol) was added. The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure to afford the crude product as yellow solid, which was purified by FCC (eluent: petroleum ether/ethyl acetate from 100/0 to 70/30) to afford the title compound (195 mg, 43.6%) as white solid. LCMS (ESI) m/z M+l: 342.0.

C. l-(benzo[d]thiazol-7-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 114c

Ethyl 1 -(benzo[d]thiazol-7-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate ( 195 mg, 0.53 mmol) was dissolved in THF (10 mL) and water (10 mL) sodium hydroxide (31.64 mg, 0.79 mmol) was added. The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was adjusted to pH=5 using HCl (2 N), extracted with EtOAc (30 mL x 20 2). The combined organic layers were dried over NagSOn filtered and the filtrâtes were concentrated under reduced pressure to afford crude the title compound (140 mg. 81.8%) as brown solid. LCMS (ESI) m/z M+l: 313.9.

356

D. l-(benzo[d]thiazol-7-yl)-N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H-py^;razole-4-carboxamide, Cpd 114

l-(benzo[d]thiazol-7-yl)-5-(trifluoiOmethyl)-1 H-pyrazole-4-carboxylic acid ( 140 mg, 0.37 mmol), 5-ammo-2-(2H-l ,2,3-triazol-2-yl)nicotinonitrile (81.71 mg, 0.44 mmol), pyridine (173.59 mg, 2.20 mmol) were dissolved in CHzCh ( 10 mL), and phosphorus oxychloride (224.33 mg, 1.46 mmol) was added. The mixture was stirred at 25 °C for 4 h. Sat.NaHCOs (40 mL) was added and extracted with CH₂C1₂ (40 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered and the filtrâtes were concentrated under 10 reduced pressure to afford the crude product as brown oil, which was purified by préparative HPLC (25% to 55% (v/v) CH3CN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound (49.0 mg, 27.8%). LCMS (ESI) m/z M+l : 481.9. ’H NMR (400MHz, DMSO-d6) δ = 11.52 (s, IH). 9.00 (d, J=2.6 Hz. 1 H). 8.78 (d, J=2.6 Hz, IH), 8.63 (s, IH), 8.60 (s, IH), 8.37 (dd, J= 1.4, 2.5 Hz. IH), 8.27 (s, 2H), 7.28 (dd, 15 J=1.3, 4.6 Hz. IH), 7.20 (dd, J=2.6, 4.4 Hz. IH).

Example 115

N-(5-chloiO-6-(4-(hydroxymethyI)-2H-l,2,3-triazol-2-yl)pyridin-3-yl)-1-( 1-oxo-1,2dihyd.roisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 115

357

A. 5-hydrazinyl-I-methoxyisoquinoline, 115a

,NH ^h2ⁿ , 115a

The mixture of {Pd(cmnamyl)Cn 2 (457 mg, 0.88 mmol) and Mor-DalPhos (818 mg, 1.76 mmol) in dioxane (50 mL) was evacuated with argon (4x). The resulting clear yellow solution was stirred at room temp under argon for 10 min. 5-Bromo-lmethoxyisoquinoline (4.2 g, 17.6 mmol) and sodium fôr/-butoxide (3.39 g, 35.3 mmol) was added to the mixture and the mixture was evacuated with argon (4x). The resulting yellow reaction was stirred at room temp for 5 min and was then treated with hydrazine (1.77 g, 35.3 mmol) via syringe. Then the mixture was stirred at 50 °C under argon for 2 h.

The précipita te was fïltered, washed with ethyl acetate (200 mL) and the dried under reduced pressure to afford the product (3.4 g).

B. ethyl 1 -( 1 -methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxylate, 115b

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoiO-3-oxobutanoate, If (8.89 g, 37,0 mmol), 5-hydrazinyl-l-methoxyisoquinoline (3.4 g, 18.5 mmol), and éthanol (200 mL) was stirred at 80 °C for 3 h before cooling to room température. The resulting solution was concentrated to dryness under reduced pressure, and then purified by 20 column chromatography over silica gel (petroleum ether/ ethyl acetate= 100:0 to 70:30) to afford product as w’hite solid (5.4 g, 80%).

358

C. I -( l -methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid, 115c

, 115c

Sodium hydroxide (1.15g, 28.7 mmol) was added to a solution of ethyl 1-(1methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate (3.0 g, 8.2 mmol) in THF HsO (2:1, 15 mL), and the mixture was heated at 23^CC for 2 h. The solvent was concentrated under reduced pressure, IM HCl solution was added to the mixture to adjust the pH to -5. and the mixture extracted with EtOAc(30 mL x 3). The combined organic layers were dried overNASCL, filtered and the filtrâtes were concentrated under reduced pressure to afford the product as a yellow solid (2.5 g, 90.3% yield). LC-MS: (ES, 0): iM 1 f 338.0.

D. methyl 2-(3-chIoro-5-(l-( l-methoxyisoqumolm-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamido)pyridin-2-yl)-2H-L2,3-triazole-4-carboxyIatee, 115d

, 115d

-(! -methoxyisoquinolin-5-yl)-5-( trifluoromethyl)-!H-pyrazole-4-carboxylic acid (1000 mg, 2.97 mmol), methyl 2-(5-amino-3-chloropyridin-2-yl)-2H-L2,3-triazole-4carboxylate (827.30 mg, 3.26 mmol), POCI3 (545.58 mg, 3.56 mmol ) were dissolved in DCM (6 mL), and pyridine (703.63 mg, 8.90 mmol) was added. The mixture was stirred at 25 °C for 1 h, sat.NaHCO.3 ( 10 mL) was added and extracted with CH2CI2 (15 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered and the filtrâtes were

359 concentrated under reduced pressure to afford a crude product as a brown oil, which was purified by FFS (petroleum ether/ ethyl acetate=50:50 to petroleum ether/ ethyl acetate=O: 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+l : 573.1.

E. N-(5-chloro-6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(l methoxyisoquinolin-5-yl)-5-(trifluoromethyl )- lH-pyrazole-4-carboxamide. 115e

Methyl 2-(3-chloro-5-( l-( 1 -methoxyisoquinolm-5-yl)-5-(trifluoromethyl)-1H10 pyrazole-4-carboxamido)pyridin-2-yl)-2H-l,2,3-triazole-4-carboxylatee (250 mg, 0.38 mmol) was dissolved in THF (5 mL) at 0 °C, LiAlH₄ (49.85 mg. 1.31 mmol) was added slowly. The reaction mixture was stirred at room température for 2 h. Water (80 uL) was added to the mixture at 0 °C and the mixture was stirred for 10 min. NaOH (80 uL, 15% in water) was added to the mixture at 0 °C and the mixture was stirred for 10 min. Water (240 uL) 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+l: 545.0.

360

C. N-(5-chloro-6-(4-(hydroxymethyl)-2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-oxol ,2-dihydroisoquinolin-5-yl)-5-(trifluorometliyl)-1 H-pyrazole-4-carboxamide, Cpd 115

N-(5-ChloiO-6-(4-(hydroxymethyl)-2H-1.2,3-triazol-2-yl)pyridin-3-yl)-1 -( 1 methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide (200 mg, 0.33 mmol), and con.HCl (4 mL) was added i-PrOH (8 mL), stirred at 60 °C for 2 h. The mixture was concentrated under reduced pressure to afford crude product as a brown oil, which was purified by préparative HPLC (75 % to 45 % (v/v) CH?CN and H2O with

0.05% HCl) and lyophilized to dryness to afford the title compound (108 mg, 62.4%).

LCMS (ESI) m/z M+l: 530.9. Ή NMR (400 MHz, DMSO-d6) δ ppm 4.63 (s, 2 H), 5.63 (d, >7.06 Hz, 1 H), 7.28 (dd, >7.39, 5.84 Hz, 1 H), 7.65 (t. >7.83 Hz, 1 H), 7.94 (d, >7.50 Hz, 1 H), 8.05 (s, 1 H), 8.42 (d, >7.94 Hz, 1 H), 8.52 (s, 1 H), 8.63 (d, >2.20 Hz, 1 H), 8.81 (d, >2.21 Hz, 1 H), 11.22 (s, 1 H), 11.62 (br d, >5.95 Hz, 1 H).

Example 116

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-l -( 1 -hydroxyisoquinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 116

361

A. N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(] -methoxyisoquinolin-5-yl)5-(trifluoromethyl)- lH-pyrazole-4-carboxamide, 116a

-(l-Methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (200 mg, 0.587 mmol), 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (117.16 mg,

0.60 mmol), POCh (108.05 mg, 0.71 mmol ) were dissolved in DCM (8 mL), and pyridine (139.35 mg, 1.76 mmol) was added. The mixture was stirred at 25 °C for 1 h, sat. NaHCO? (20 mL) was added and extracted with CH2CI2 (30 mL x 2). The combined organic layers were dried over Na;SO4, filtered and the filtrâtes were concentrated under reduced pressure 10 to afford crude product as a brown oil, which was purified by préparative HPLC (50% to 20?b (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (142 mg, 46.7%). LCMS (ESI) m/z M+l: 514.9. Ή NMR (400 MHz, DMSOd6) Ô ppm 4.10 (s, 3 H), 6.56 (d, J=6.17 Hz, 1 H), 7.78 - 7.85 (m, 1 H), 8.06 (d, J=6.39 Hz, 1 H), 8.10 (d, J=5.95 Hz, 1 H), 8.18 (s, 2 H), 8.45 (d, J=8.16 Hz, 1 H), 8.56 (s, l H), 8.66 (d, J=2.21 Hz, 1 H). 8.83 (d, J=2.21 Hz. 1 H), 11.25 (s, 1 H).

B. N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -( 1 -hydroxyisoquinolin-5-yl)5-(tniluoromethyl )- lH-pyrazole-4-carboxamide, Cpd 116

362

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(l-methoxyisoquinolin-5-yl)5-( trifluoromethyl)-lH-pyrazole-4-carboxamide (70 mg, 0,14 mmol), and con.HCl (4 mL) was added i-PrOH (8 mL), stirred at 60°C for 2 hrs. The mixture was concentrated under reduced pressure to afford crude as yellow oil, which was purified by préparative HPLC (84 % to 54 % (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (47 mg, 69.4%). LCMS (ESI) m/z M+l: 500.9. 'HNMR (400 MHz, DMSO-d6) δ ppm 5.63 (d, J=7.50 Hz, l H), 7.27 (dd, J=7.17, 6.06 Hz, l H), 7.65 (t, J=7.83 Hz, l H), 7.93 (d, J=7.06 Hz, l H), 8.16 (s, 2 H), 8.41 (d, J=7.94 Hz, l H), 8.53 (s, l H), 8.64 (d, J=2.2l Hz, l H), 8.82 (d, J=2.20 Hz, l H), H.25 (s, l H), H.62 (br d, J=5.73 Hz, l H).

Example 117

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoroisoquinolin-4-yl)-5( trifluoromethyl)-lH-pyrazoIe-4-carboxami de, Cpd 117

A. 4-bromo-8-fhioroisoquinoline, 117a

F

Br , H7a

To a solution of 8-fluoroisoquinoline (0.5 g, 3.40 mmol) in CCL ( 15 mL) was added l-bromopyriOlidine-2,5-dione (604.78 mg, 3.40 mmol) and (E)-3,3'-(diazene-l,2diyl)bis(2-methylpropanenitrile) (55.8 mg, 0.34 mmol).The mixture was stirred at 80°C for 3 h. The solvent was concentrated under reduced pressure to give crude product, which was purified by FCC(petroleum ether/ ethyl acetate=l :0 to petroleum ether/ ethyl

363 acetate= 1 : l ) to afford the title compound (0.21 g. 27.1%) as a yellow oil. LCMS (ESI) m/z M+l : 225.9. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 9.44 ( 1 H, s), 8.78 (1 H, s), 7.93 (1 H, br d, J=8.38 Hz), 7.74 (I H, td, J=7.94, 5.51 Hz), 7.27 - 7.36 (1 H, m).

B. 8-fluoro-4-hydrazinylisoquinoline. 117b

Palladium(ll)(pi-cinnamyl) chloride dimer (23.81 mg, 0.046 mmol) and 4-(2(di((3S,5S,7S)-adamantan-l-yl)phosphino)phenyl)morpholine (42.62 mg, 0.092 mmol) was added to dioxane (8 mL), immediately evacuated with Ni. The resulting solution was stirred at room temp under Ni for 10 min. Then was charged with sodium 2-methylpropan2-olate (176.69 mg, 1.84 mmol) and 4-bromo-8-fluoroisoquinoline (210 mg, 0.92 mmol). sealed, and evacuated with Ne. The resulting mixture was stirred at room temp for 5 min and was then treated with hydrazine hydrate (92.04 mg, 1.84 mmol) via syringe. The mixture was stirred at 50 °C under N? for 1.5 hrs, filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow- solid (260 mg). The mixture was directly used for next step.

C. Ethyl l-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-lH-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-hydrazinylisoquinoline (260 mg. 1.47 mmol) and éthanol (10 mL) was stirred at 80 °C for 2 h. The résultant solution was concentrated to dryness

364 under reduced pressure to afford the crude product, which was purified by FCC (petroleum ether: ethyl acetate = 100/0 to 70 30) to afford the title compound (0.22 g, 42.4%) as a yellow solid. LCMS (ESI) m/z Ml: 354.0.

D. l-(8-fhioroisoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 117d

Sodium hydroxide (37.36 mg. 0.93 mmol) was added to a solution of ethyl l-(8fluoroisoquinolin-4-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxylate (220 mg, 0.62 mmol) in THF/ Η2θ=3: l(12 mL). The mixture was stirred at room température for 3 h. The solvent was concentrated under reduced pressure and 20 mL H2O was added to the mixture, The mixture was acidified using IM hydrochloric to pH=5 and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous MgSOi and filtered. The filtrâtes were concentrated under reduced pressure to afford product as a yellow solid (160 mg. 79.0%).

E. N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yI)-l-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 117

-(8-Fhioroisoquinolm-4-yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxylic acid (80 mg, 0.25 mmol), 5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-amine (48.12 mg, 0.25

365 mmol), pyridine (O.IO mL, 1.23 mmol) were dissoived in CH2CI2 (l0 mL), and phosphores oxychloride (0.090 mL, 0.98 mmol) was added. The mixture was stirred at 25 °C for 2 h, Sat.NaHCOs (20 mL) was added and extracted with CH2CI2 (30 mLx 2). The combined organic extracts were dried over anhydrous Na/SCL. filtered, and concentrated to dryness 5 under reduced pressure to afford the crude product, which was purified by préparative

HPLC (43% to 73% (v/v) CH3CN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound (35 mg. 28.2 %). LCMS (ESI) m/z M+l: 502.9. ^!H NMR (400 MHz, DMSO-d6)5ppm 11.33 (I H, s), 9.73 (1 H, s), 8.93 (1 H, s), 8.85 (1 H, d, J=1.98 Hz), 8.67 (1 H, d, J=2.21 Hz), 8.65 (1 H, s), 8.17 (2 H, s), 7.90 - 7.98 (1 H, m), 7.69 (1 H, 10 dd, 1=10.36, 8.38 Hz), 7.12(1 H, d, J=8.60 Hz).

Example 118

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl)- JH-pyrazoie-4-carboxamide, Cpd 118

l-(8-Fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (80 mg, 0.25 mmol), 5-amino-2-(2H-l,2,3-triazol-2-yl)nicotinonitrile, (45.8 mg, 0.25 mmol), pyridine (0.10 mL, 1.23 mmol) were dissoived in CH2CI2 ( 10 mL), and phosphores oxychloride (0.090 mL, 0.98 mmol) was added. The mixture was stirred at 25 °C for 2 h, 20 Sat.NaHCOs (20 mL) was added and extracted with CH2CI2 (30 mL x 2). The combined organic extracts were dried over anhydrous Na₂SO4, filtered, and concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (43% to 63% (v/v) CH3CN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound (36 mg, 29.1 %). LCMS (ESI) m/z M+l: 493.9. ‘H NMR (400

MHz, DMSO-d6) δ ppm 11.40 (1 H, s), 9.73 (1 H. s), 9.09 (1 H. d, J=2.43 Hz), 8.93 (1 H,

366

s), 8.87 ( l H. d, J=2.43 Hz), 8.65 (1 H, s) 8.29 (2 H, s), 7.89 - 7.99 ( 1 H. m), 7.64 - 7.72 (1 H, m), 7.12(1 H, d, J=8.38 Hz).

Example 119 l-(benzo[d][l,2.3]thiadiazol-7-yl)-N-(5-cyano-6-(2H-l,2.3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 119

A. 7-hydrazinylbenzo[d][L2,3]thiadiazole, 119a

H

JA'^Nnh₂\;s ^N=N , H9a

To a stirring solution of benzo[d][I,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) below -20° C. The reaction mixture was stirred at rt for 0.5 hr. Then cooled to -20 °C, tin(ii) chloride dihydrate (5.97 g, 26.45 mmol) was added portions to the mixture and stirred for 1 h. The reaction mixture was basified with 3 M NaOH and the aqueous extracted with EtOAc (200 mL x 3). The combined organic layers were dried over NacSOi, fïltered and the filtrâtes were concentrated under reduced pressure to afford crude (2.5 g) as brown solid, which was used for the next step without further purification. LCMS (ESI) m/z M+l: 167.1.

367

B.

Ethyl l-(benzo[d][l,2,3]thiadiazol-7-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate, 119b

, 119b

7-Hydrazinylbenzo[d][l ,2.3]thiadiazole (2.5 g. 5.71 mmol) was dissolved in éthanol (30 mL), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (3.28 g, 13.64 mmol) was added and stirred at 70°C for 2 h before cooling to room-temperature. The combined mixture was concentrated under reduced pressure to afford crude product as yellow oil, which was purified by FCC (eluent: petroleum ether/ethyl acetate from 100/0 to 85/15) to afford the title compound (1.2 g, 61.4%) as a yellow solid. LCMS (ESI) m/z Ml :342.9.

C. l-(benzo[d][l,2,3]thiadiazol-7-yI)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 119c

Ethyl l-(benzo[d][ 1,2,3]thiadiazol-7-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate (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 h. The reaction mixture was adjust to pH=5 using HCl (2 N), extracted with CTLCL/MeOH (10/L 60 mLx 5). The combined organic layers were dried overNagSCL. filtered and the filtrâtes were concentrated under reduced pressure to afford crude title compound (900 mg, 81.0%) as a yellow solid. LCMS (ESI) m/z M+l: 315.1.

368

D. l-(benzo[d][l,2,3]thiadiazol-7-yl)-N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3yl )-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 119

1 -( Benzo[d][ 1,2,3]thiadiazoI-7-yl)-5-(trifIuoiOmethyl)-1 H-pyrazole-4-carboxylic acid (300 mg, 0.95 mmol), 5-amino-2-(2H-l ,2,3-tnazol-2-yl)nicotinomtrile. (229.0 mg, 1.23 mmol), pyridine (449.05 mg, 5.68 mmol) were dissolved in CH2CI2 (30 mL), and phosphorus oxychloride (435.23, 2.84 mmol) was added. The mixture was stirred at 25 °C for 2 h. Sat.NaHCCh (20 mL) was added and extracted with CH2CI2 (50 mL x 2). The combined organic layers were dried over Na2SO₄, filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as yellow oil, which was purified by préparative HPLC (45% to 75% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (200 mg, 43.1%). LCMS (ESI) m/z M I : 483.0. Ή NMR (400MHz, DMSO-d6) ό= 11.47 (s, 1H), 9.08 (d, J=2.4 Hz, 1H), 8.99 (d, J=8.4 Hz, JH), 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).

369

Example ] 20 l-(benzo[d][l,2,3]thiadiazol-7-yl)-N-(5-chloiO-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, Cpd 120

Y _ZS N l-(Benzo[d][l,2,3]thiadiazol-7-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (100 mg, 0.28 mmol), 5-chloro-6-(2H-l ,2,3-triazol-2-yl)pyridm-3-amine, (53.95 mg, 0.28 mmol). pyridine (130.9 mg, 1.66 mmol) were dissolved in CH2CI2 ( 10 mL), and phosphoms oxychloride (126.87, 0.83 mmol) was added. The mixture was stirred at 25 °C for 2 h. Sat.NaHCO? (20 mL) was added and extracted with CH2CI2 (50 mLx 2). The combined organic layers were dried over NaiSCU, fïltered and the filtrâtes were concentrated under reduced pressure to afford the crude product as yellow oil, which was purified by préparative HPLC (45% to 75% (v/v) CH ( N and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (18 mg, 13.2%). LCMS (ESI) m/z Ml: 492.0. *H NMR (400MHz, DMSO-d6) δ= 11.43 (s, IH), 8.99 (d, J=8.2 Hz. IH), 8.84 (d, J=2.2Hz, IH), 8.66 (d, J=2.2 Hz, IH), 8.64 (s, IH), 8.20 (s, 2H), 8.15 - 8.10 (m, IH),

8.06 - 8.00 (m, IH).

370

Example I2l l-(benzo[d][L2,3]thiadiazol-7-yl)-N-(5-chloiO-2-methyl-6-(2H-l,2.3-triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 121

l-(Benzo[d][l ,2.3]thiadiazoI-7-yl)-5-( trifluoromethyl )-lH-pyrazole-4-carboxylic acid (149.93 mg, 0.47 mmol), 5-chloro-2-methyl-6-(2H-L2,3-triazol-2-yl)pyridin-3-amine, (109.09 mg, 0.52 mmol), pyridine (224.52 mg, 2.84 mmol) were dissolved in CH2CI2 ( 10 mL), and phosphorus oxychloride (217.62 mg, 1.42 mmol) was added. The mixture was stirred at 25 °C for 2 h. Sat.NaHCO.3 (20 mL) was added and extracted with CH2CI2 (50 mL x 2). The combined organic layers were dried overNa^SOa, filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a yellow oil, which was purified by préparative HPLC (45% to 75% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (102 111g, 42.4%). LCMS (ESI) m/z M+l : 505.9. Ή NMR (400MHz, DMSO-d6) δ= 10.73 (s, IH). 8.98 (d, J=8.2 Hz. IH), 8.63 (s, IH), 8.47 (s. IH), 8.19 (s, 2H), 8.13 - 8.09 (m. IH). 8.06 - 8.01 (m, IH), 2.56 (s. 3H).

Example 122

N-(5-cyano-6-(2H-L2,3-triazoI-2-yl)pyridin-3-yl)-l-(5-fluoronaphthalen-l-yl)-5(trifluoromethyl)-] H-pyrazole-4-carboxamide, Cpd 122

371

A. (5-fluoronaphthalen-l-yl)hydrazine, 122a

A mixture of {Pd(cinnamyl)Cl}2(l 1.51 mg, 0.022 mmol) and Mor-DalPhos (20.60 mg, 0.044 mmol) m dioxane (2 mL) was evacuated with argon (4x). The resulting clear yellow solution was stirred at room temp under argon for 10 min. l-Bromo-5fluoronaphthalene (100 mg, 0.44 mmol) and t-BuONa (85.31 mg, 0.89 mmol) was added to the mixture and the mixture was evacuated with argon (4x). The resulting yellow mixture was stirred at room temp for 5 min and was then treated wdth hydrazine hydrate (45.40 mg, 0.889 mmol) via syringe. The reaction mixture was evacuated with argon (4x). Then the mixture was stirred at 50°C under argon for 4hrs. The mixture was filtered and washed with ethyl acetate (5 mL x 3). The fdtrate was collected and concentrated to afford crude product (100 mg, >100% yield) as a brown solid which was used directly for the next step.

B. Ethyl 1 -(5-fluoronaphthalen-1 -yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate, 122b

A solution of (5-fluoronaphthalen-l-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 h. The

372 mixture was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 20: l to l : l ). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford 122b (100 mg, 46.7% yield) as a yellow solid. LCMS (ESI) m/z M+1 : 352.9.

l-(5-fluoronaphthalen-l-yl )-5-( trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 122c

A solution of ethyl 1-(5-fluoronaphthalen-l-yl)-5-(trifluoromethyl)-IH-pyrazole -4carboxylate, 122b (100 mg. 0.27 mmol), LiOH (22.23 mg, 0.53 mmol) in MeOH (10 mL), THF (10 mL) and water ( 10 mL) was stirred at rt for 3h. To the mixture was added 5% KHSO4 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 MgSCL, filtered, and the filtrate concentrated under reduced pressure to afford 122c (90 mg, 94Λ%> yield) as a yellow solid used for the next step directly. LCMS (ESI) m/z M+H: 324.8

D. N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridm-3-yl)-l-(5-fluoronaphthalen-l-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 122

POCh (76.46 mg, 0.50 mmol) was added to a solution of 1 -(5-fluoronaphthalen-1 yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 122c (90 mg, 0.25 mmol), 5-amino2-(2H-l,2,3-triazol-2-yl)nicotinonitrile (46.42 mg, 0.25 mmol). pyridine (49.30 mg 0.62

373 mmol) in CH^Ch ( ΙΟ mL). The mixture was stirred at rt for 2 h, 50 mL water and 50 mL CH2CI2 were added to the mixture. The organic layer was washed with brine (50 mL), dried over MgSCU, fïltered, and the filtrate concentrated under reduced pressure to afford the crude product, which was purified by préparative HPLC (47% to 77% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (33.5 mg 26.5% yield) as a white solid. LCMS (ESI) m/z M+l : 492.9. ^JH NMR (400 MHz, DMSO-d6) δ ppm 9.08 (d, J=2.43 Hz, l H), 8.86 (d, J=2.43 Hz, 1 H), 8.58 (s, 1 H), 8.32 (d, J=8.38 Hz. 1 H), 8.28 (s. 2 H), 7.90 (d, J=7.28 Hz, 1 H), 7.74 - 7.83 (m, 1 H), 7.60 (td, J=8.10, 5.62 Hz, 1 H), 7.49 (dd, J=10.47, 7.61 Hz, 1 H), 6.93 (d, J=8.38 Hz, 1 H).

Example 123

N-(5-chIoro-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoroisoquinolin-4-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 123

A mixture of i Pd(cinnamyl)Cl}2 (68.76 mg, 0.13 mmol) and Mor-DalPhos ( 123.06 mg, 0.27 mmol) in dioxane (10 mL) was evacuated with argon (4x). The resulting clear yellow solution was stirred at room temp under argon for 10 min. 4-bromo-820 fluoroisoquinoline (600 mg, 2.65 mmol) and t-BuONa (509.63 mg, 5.31 mmol) was added to the mixture and the mixture was evacuated with argon (4x). The resulting yellow reaction w⁷as stirred at room temp for 5 min and was then treated wùth hydrazine hydrate (271.18 mg, 5.31 mmol) via syringe. The reaction mixture wus evacuated with argon (4x).

374

Then the mixture was stirred at 50 °C under argon for 2 h. The mixture was filtered and washed with ethyl acetate (50 mL x 3), the filtrate was collected and concentrated to afford crude 123a (510 mg, >100% yield) as a brown solid, used directly for the next step.

B. Ethyl l-(8-fluoroisoquinolin-4-yl)-5-(trifhioromethyl)-lH-pyrazole-4-carboxylate, 123b

A solution of 8-fluoro-4-hydrazinylisoquinoline, 123a (510 mg, 2.88 mmol), ethyl 2-(ethoxymethylene)-4,4.4-trifluoro-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 h. The mixture was concentrated under reduced pressure, the crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 20:1 to 5:1 ). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford 123b (510 mg, 40.7% yield) as a yellow solid. LCMS (ESI) m/z M+l: 353.9.

C. l-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid.

123c

A solution of ethyl l-(8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)- IH-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 h. The mixture was added 5% KHSO4 to adjust pH 3-4. Water (100 mL) and ethyl acetate (100 mL) were added to the mixture. The

375 organic layer was washed with brine (50 mL), dried over MgSO-t and concentrated under reduced pressure to afford 123c (420 mg) as a yellow solid , used directly for the next step.. LCMS (ESI) m/z M+H: 325.9 .

D. N-(5-chloro-2-methyl-6-(2H-L2.3-tnazol-2-yI)pyridin-3-yl)-l-(8fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 123

POCL (198.02 mg, 1.29 mmol) was added to a solution of l-(8-fluoroisoquinolin4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxyIic acid, 123c (210 mg, 0.65 mmol), 5chloro-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine (162.44 mg, 0.78 mmol), pyridine (127.69 mg 1.61 mmol) in CH2CI2 (10 mL). The mixture was stirred at rt for 3h, 50 mL H2O and 50 mL CH2CI2 were added to the mixture. The organic layer was washed with brine (50 mL), dried over MgSCL. filtered, and the filtrate concentrated under reduced pressure to afford the crude product, which was purified by préparative HPLC (37% to 67% (v/v) CH3CN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound (86.0 mg 25.8% yield) as a white solid. LCMS (ESI) m/z M+l: 516.9. 'H NMR (400 MHz. DMSO-d6) δ ppm 10.66 (s, 1 H), 9.72 (s. 1 H), 8.91 (s, 1 H), 8.62 (s, 1 H), 8.42 (s, 1 H), 8.16 (s, 2 H), 7.94 (td, J=8.10, 5.62 Hz, 1 H), 7.68 (dd, J=10.36, 7.94 Hz, 1 H), 7.13 (d, J=8.38 Hz, 1 H), 2.54 (s, 3 H).

Example 124 N-(5-cyano-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoroisoquinolin-4-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 124

376

POCh (94.27 mg, 0.62 mmol) was added to a solution of l-(8-fluoroisoquinolin -4yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (100 mg, 0.31 mmol), 5-amino-6methyl-2-(2H-l,2,3-triazol-2-yl)nicotinonitrile (73.87 mg, 0.37 mmol), pyridine (60.81 mg 0.77 mmol) in CHiCh ( 10 mL). The mixture was stirred at rt for 3h, 50 mL IbO and 50 mL CH2CI2 were added to the mixture. The organic layer was washed with brine (50 mL), dried over MgSCL and concentrated under reduced pressure to afford the crude product, which was purified by préparative HPLC (30% to 60% (v/v) CH?CN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound (37.6 mg 24.1% yield) as a white solid. LCMS (ESI) m/z M+l : 507.9. Ή NMR (400 MHz, DMSO-d6) δ ppm 10.71 (s. 1 H), 9.72 (s, 1 H), 8.91 (s, 1 H), 8.64 (d, J= 15.88 Hz, 2 H), 8.29 (s, 2 H). 7.90 - 7.98 (m, 1 H), 7.64 - 7.72 (m, 1 H), 7.13 (d, J=8.60 Hz, 1 H), 2.64 (s, 3 H).

Example 125

N-(5-chloro-6-(4-methyI-2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, 125

A. mixture of 3-chloro-2-(4-methyl-2H-1,2,3-triazol-2-yl)-5-nitropyridine and 3chloro-2-(4-methyl-lH-l,2,3-triazol-l-yl)-5-nitropyridine, 125a

377

A solution of 4-methyl-IH-l,2,3-triazole (500 mg, 6.02 mmol), 2,3-dichloro-5nitropyridine (1277.42 mg, 6.62 mmol), K2CO3 (2491.22 mg, 18.05 mmol) in CH3CN (5 5 mL) was stirred at rt for 12 h. The mixture was concentrated under reduced pressure, the crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 20:1 to 1:1 ). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford 125a (1.1 g, 76.3%) as a yellow solid. LCMS (ESI) m/z Μ 1: 239.7.

B. mixture of 5-chloro-6-(4-methyl-2H-L2,3-triazol-2-yl)pyridin-3-amine and 5chloro-6-(4-methyl-1 H-1,2,3-triazol-1 -yl)pyridm-3-amine, 125b

Zn ( 1491.96 mg, 22.95 mmol) was added to a solution of mixture of 3-chloro-2-(415 methyl-2H-L2,3-triazol-2-yl)-5-nitiOpyridine and 3-chloro-2-(4-methyl-lH-L2,3-triazoll-yl)-5-nitropyridine, 125a (1.1 g, 2.30 mmol) in aqNH₄Cl (30 mL) and H2O (30 mL). The mixture was stirred at rt for 16 h. To the suspension was added aq NaHCO₃ to adjust to pH 9%0, and the mixture was filtered through a pad of diatomaceous earth. The filter cake was washed with CH2CI2 (100 mLx3). The combined filtrâtes were washed with brine (200 mL), dried over MgSO₄ and concentrated under reduced pressure to afford mixture of

5-chloro-6-(4-methyl-2H-L2,3-triazol-2-yl)pyridin-3-amine and 5-chloro-6-(4-methyl-lH1,2,3-triazol-l-yl)pyridin-3-amine, 125b ( 1 g) as a brown solid, used directly for the next step. LCMS (ESI) m/z M+H; 209.7

378

C. N-(5-chloro-6-(4-methyl-2H-],2.3-rriazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yD-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 125

POCh ( 182.86 mg, 1.19 mmol) was added to a solution of 125b (300 mg. 0.72 mmol), l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (183.19 mg, 0.60 mmol), pyridine (117.91 mg 1.49 mmol) inCHiCh (10 mL). The mixture was stirred at rt for 2h, 50 mL H2O and 50 mL CH2CI2 were added to the mixture. The organic layer was washed with brine (50 mL), dried over MgSCL and concentrated under reduced pressure to afford the crude product, which was purified by préparative HPLC (35% to 65% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (208 mg 69.8% yield) as a white solid. LCMS (ESI) m/z M+l: 499.0. 'H NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s, 1 H), 9.06 (t, J=2.54 Hz, 1 H), 8.89 (s, 1 H), 8.60 8.75 (m, 2 H). 8.33 (d, J=8.38 Hz, 1 H), 7.88 - 8.03 (m, 3 H), 7.68 (d. J=2.65 Hz, 2 H), 2.34 (s, 3 H).

Example 126

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[2,3-b]pyridin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 126

A. 4-hydrazinylthieno[2,3-b]pyridine, 126a

379

A solution of 4-chlorothieno[2,3-b]pyridine (600 mg, 3.54 mmol) in hydrazine (5 mL, 98%) was stirred at l00°C overnight. The solid was filtered and washed by 2 mL water. The solid was collected and dried to afford 126a (550 mg, 88.2% yield) as a white 5 solid. LCMS (ESI) m/z M+l: 165.9.

B. ethyl 1 -(thieno[2,3-b]pyridin-4-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxylate.

126b

o A solution of 4-hydrazinylthieno[2,3-b]pyridine (300 mg. 1.70 mmol), ethyl 2- (ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (613.23 mg, 2.55 mmol), in EtOH (5 mL) was stirred at 80 ^CC for 3 h. The mixture was concentrated under reduced pressure, the crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 100/0 to 20/80). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford 126b (500 mg, 86.1 % yield) as a yellow solid.

C. l-(thieno[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid,

126c

380

A solution of ethyl l-(thieno[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)-lH-pyrazole4-carboxylate, 126b ( 150 mg, 0.44 mmol), LiOH (18.44 mg, 0.44 mmol) in EtOH 110 (2/1, 2 mL) was stirred at room température ovemight. IN HCl solution was added to neutralize the réaction solution. The mixture was extracted with ethyl acetate (5 mLx 3).

The separated organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated to afford 126c (137 mg, crude product) as a yellow solid. LCMS (ESI) m/z M+l: 313.9.

D. N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[2,3-b]pyndin-4-yT)-5(trifluoromethyl·)- lH-pyrazole-4-carboxamide, Cpd 126

Phosphorus oxychloride (41.66 uL, 0.45 mmol) was added to a solution of 1(thieno[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 126c (70 mg, 0.22 mmol), 5-amino-2-(2H-l,2,3-triazol-2-yl)nicotinomtrile (62.40 mg, 0.34 mmol·).

pyridine ( 180.73 uL, 2.24 mmol) in CH2CI2 (2 mL). The mixture was stirred at room température for 2 h, 5 mL H2O was added to the mixture. Sat. NaHCOa was added to adjust the pH of reaction mixture to 7~8. The mixture was extracted with CH2CI2 (5 mL x 3). The combined organic extracts were dried over anhydrous Mg2SO4, filtered, and concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (42% to 72% (v/v) CH?CN and H_ZO with 0.05% HCl) and lyophilized to dryness to afford the title compound (50 mg, 46.4%). LCMS (ESI) m/z M+l: 481.9. Ή NMR (400 MHz. DMSO-d6) δ ppm 7.17 (d, J=6.17 Hz, 1 H), 7.73 (d,

J=5.07 Hz, 1 H), 8.13 (d, J=6.17 Hz, 1 H), 8.31 (s, 2 H), 8.62 (s, 1 H), 8.84 (d, J=4.85 Hz, 1 H), 8.87 (d, J=2.43 Hz, 1 H), 9.08 (d, J=2.43 Hz, 1 H), 11.36 (s, 1 H).

381

Example 127

N-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(1 -oxo-1,2-dihydroisoquinolin-5-yl)-5 ( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 127

A. 5-bromo-3-chloropicolinoyl chloride, 127a

O n Jk k T ^ClBr'Y^CI . i?7a

5-bromo-3-chloropicolinic acid (15 g, 63.44 mmol) was suspended in CEECb (250 mL) and stirred at 0 °C. oxalyl chloride (15 mL, 176.09 mmol) was added dropwise then DM F (drops ) added. The reaction mixture was stirred at 0 °C for 1 h and stirred at 20 °C for 1 h. The yellow solution was concentrated under reduced pressure to afford the compound ( 17 g) as a yellow solid.

B. 5-bromo-3-chloro-N-(2,2-dimethoxyethyl)picolinamide, 127b

O °^x , 127b

5-Bromo-3-chloropicolinoyl chloride (17 g, 66.69 mmol) was dissolved in CH2CI2 (250 mL) and added dropwise to the mixture of 2,2-dimethoxyethanamine (14.02g, 133.39 mmol) and TEA (13.50 g, 133,39 mmol) at 0 °C. The mixture was stirred at 0 °C for 1.5 h. H2O (300 mL) was added and extracted with CH2CI2 (300 mL x 3). The combined organic layers were dried over NagSCL, fïltered and the filtrâtes were concentrated under reduced pressure to afford crude as a brown oil, which was purified by flash column chromatography over silica gel (eluent: CHiCb/ethyl acetate from 100/0 to 80/20). The

382 desired fractions were collected and the solvent was concentrated under reduced pressure to afford the title compound (16 g, 74. l%) as a yellow⁷ solid.

C. 5-bromo-3-chloro-N-(2-oxoethyl)picolinamide, 127c

O

Λ.Λχκ⁰Af N LL ^H

Br Al , 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 h. The reaction mixture was adjust to pH 7.5 using sat. Na! KO., extracted with EtOAc (200 mL x 3). The combined organic layers were dried over NaeSCU, fïltered and the filtrâtes were concentrated under reduced pressure to afford crude (12 g, 87.5%) as a yellow⁷ solid. LCMS (ESI) m/z M+1: 278.8.

D. 2-(5-bromo-3-chloropyridin-2-yl)oxazole, 127d n x^Nr Br^A^CI , 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) added. The reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was poured into water (800 mL), stirred at rt for 0.5 h, then extracted with EtOAc (400 mL x 3). The combined organic layers were dried over NajSOa. fïltered, and the filtrâtes were concentrated under reduced pressure to afford a black oil. The black oil w⁷as purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 70/30) to afford the title compound (1.5 g, 13.3%) as a yellow solid. LCMS (ESI) m/z Ml: 258.9.

E. tert-butyl (5-chloro-6-(oxazol-2-yl)pyridin-3-yl)carbamate, 127e

383 °0

3ocH00''CI . 127e

2-(5-Bromo-3;chloropyridin-2-yl)oxazole (1.5 g, 5.78 mmol) and rm-butyl carbamate (1.35 g, 11.56 mmol) were dissolved in dioxane (30 mL), Pd?(dba)3 (264.67 mg, 0.29 mmol), Xantphos (333.48 mg, 0.58 mmol) and césium carbonate (3.77 g, 11.56 mmol) were added and purged with Ni for 1 min. The réaction mixture was stirred at 90 °C for 16 h. The combined mixture was filtered through a pad of diatomaceous earth and tire pad was washed with EtOAc (50 mL x 3). The filtrâtes w^rere concentrated under reduced pressure to afford a crude product as a yellow oil, which was purified by flash column chromatography over silica gel (petroleum ether/ ethyl acetate from 100/0 to 40/60). The desired fraction was collected and the solvent was concentrated under reduced pressure to afford the title compound (970 mg, 61.4%) as a yellow solid. LCMS (ESI) m/z M+l : 296.1.

F. 5-chloro-6-(oxazol-2-yl)pyridin-3-amine, 127f

7er/-Butyl (5-chloro-6-(oxazol-2-yl)pyridin-3-yl)carbamate (970 mg, 3.28 mmol) was dissolved in CFLCL (5 mL) and HCl/dioxane (5.4 mL, 21.6 mmol) was added. The reaction mixture was stirred at 30 °C for 4 h. The reaction mixture was concentrated under reduced pressure to afford crude as a yellow oil, and adjust to pH 8 using sat .NaiCCh, extracted with CFLCL (50 mL x 2). The combined organic layers were dried over Na?SO4, filtered and the filtrâtes were concentrated under reduced pressure to afford the product (650 mg, 95.4%) as a yellow oil. LCMS (ESI) m/z M+l: 196.1.

G. N-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl )-1-(1 -oxo- l,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide Cpd 127

384

l -( 1 -Oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl )-1 H-pyrazole-4carboxylic 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 CH2CI2 (40 mL), and phosphorus oxychloride (940.66 mg, 6.14 mmol) was added. The mixture was stirred at 25 °C for 3 h, sat. NaHCO; (20 mL) was added and extracted with CH2CI2 (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a yellow oil, which was purified by préparative HPLC (34% to 54% (v/v) CH3CN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound (240 mg, 23.2%). LCMS (ESI) m/z M+l: 500.9. ‘H NMR (400MHz. DMSO-d6) δ= 11.64 (br d. >5.3 Hz, 1H), 11.29 (s, 1H), 8.97 (s, 1 H), 8.63 - 8.53 (m, 2H), 8.44 (d, >8.2 Hz, 1H), 8.34 (s, 1H), 7.95 (d, >7.7 Hz, 1H), 7.67 (t, >7.9 Hz, 1H), 7.51 (s, 1H), 7.30 (t, >6.6 Hz, 1H), 5.66 (d, >7.3 Hz, 1H).

Example 128

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[3,2-b]pyridin-7-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 128

N

385

A. 7-hydrazinylthieno[3,2-b]pyridine. 128a h₂n

7-chlorothieno[3,2-b]pyridine (180 mg, 1.06 mmol) Π1ΝΗ2ΝΗ2.Η2Ο (7 mL) was reacted at 26°C for 16 h. The mixture was extracted with 20 x 3 mL CH2CI2. the solvent was concentrated under reduced pressure the give the desired compound.

B. ethyl l-(thieno[3,2-b]pyridm-7-yl)-5-(trifluoromethyl)-lH-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) was reacted at 80°C for 3 h. The mixture was concentrated under reduced pressure, then was purified by FFS (petroleum ether/ ethyl acetate= 100:0 to petroleum ether/ ethyl acetate=60:40). The desired fractions were collected and 15 the solvent was concentrated under reduced pressure to give the product as brown oil. LCMS (ESI) m/z M+l: 342.2.

386

C. l-(thieno[3,2-b]pyridin-7-yl)-5-(trifluoromethyI)-lH-pyrazole-4-carboxylic acid, 128c

NaOH (25.23 mg, 0.63 mmol) was added to a solution of ethyl l-(thieno[3,25 b]pyridin-7-yl) -5-(trifluoromethyl)-lH-pyrazole-4-carboxyIate (75 mg, 0.21 mmol) in EtOH/H20=l:l (3 mL) was reacted at 28°C for 2 h. The solvent was concentrated under reduced pressure the give the desired compound.. LCMS (ESI) m/z M+l : 314.2

D. N-(5-cyano-6-(2H-l,2,3-triazoL2-yl)pyridin-3-yI)-l-(thieno[3,2-b]pyridin-7-yl)-510 ( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 128

l-(Thieno[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (65 mg. 0.19 mmol), 5-ammo-2-(2H-L2,3-triazol-2-yl)nicotmonitrile (42.76 mg, 0.23 mmol), POCh (35.21 mg, 0.23 mmol ) were dissolved in DCM (2 mL), and pyridine (45.41 mg, 0.57 mmol) was added. The mixture was stirred at 25 °C for 2 h, sat.NELCl (20 mL) was added and extracted with CELCb (20 mL x 2). The combined organic layers were dried over NaiSCU, filtered and the filtrâtes were concentrated under reduced pressure to afford crade as a yellow oil, which was purified by préparative HPLC (73% to 43% (v/v) CHsCN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (46 mg, 49.7%). LCMS (ESI) m/z M+l: 481.9. ‘HNMR (400 MHz, DMSO-d6) δ ppm

387

7.67 (br d, J=4.63 Hz, l H), 7.75 (d, J=5.5 l Hz. I H), 8.21 - 8.38 (m. 1 H), 8.23 - 8.37 (m.

H), 8.74 (s, 1 H), 8.87 - 8.96 (m, 2 H), 9.14 (d, J=2.21 Hz, 1 H). 11.66 (s, 1 H).

Example 129

N-(3-chloro-4-(2H-l,2,3-triazol-2-yl)phenyl)-l-( 1-oxo-1,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 129

A.

2-(2-chloro-4-nitrophenyl)-2H-1,2,3-triazole, 129a

2-Chloro-l-fluoro-4-nitrobenzene (3 g, 17.09 mmol), lH-l,2,3-triazole ( 1.30g,

18.80 mmol) and potassium carbonate (3.54 g, 25.63 mmol) were added to DMF (50 mL) and stirred at 55 °C for 3 hr. The reaction mixture was concentrated under reduced pressure to afford crude as a yellow solid. Sat.NH₄Cl (100 mL) was added and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na?SO₄, filtered and the filtrâtes were concentrated under reduced pressure to afford crude as a yellow solid, which was purified by FCC (eluent: petroleum ether/ethyl acetate from 100/0 to 60/40) to afford the title compound ( 1.9 g, 49.5%) as a yellow solid. NMR (400M1iz,

CHLOROFORM-d) δ = 8.49 (d, ,1=2.5 Hz, IH), 8.28 (dd, J=2.5, 8.8 Hz, IH), 7.97 (s. 2H),

7.93 (d. J=8.8 Hz, IH). 7.95 - 7.91 (m, IH).

B. 3-Chloro-4-(2H-L2,3-triazol-2-yl)aniline, 129b

388

2-(2-Chloro-4-nitrophenyl)-2H-l,2,3-triazole (1.9 g, 8.46 mmol) was dissolved in THF (20 mL), Fe (2.83 g, 50.76 mmol), NHiCl (2.72 g, 50.76 mmol) and H2O (20 mL) were added. The reaction mixture was stirred at 80 °C for 3 hr. The reaction mixture was filtered through a pad of Diatomaceous earth and the pad was washed with EtOAc (30 mL><3). The filtrâtes were concentrated to dryness to give crude as a yellow solid, which was purified by FCC (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 afford ( L5 g, 89.5%) as a yellow solid. LCMS (ESI) m/z M+1: 194.8.

N-(3-chloro-442H-L2,3-triazol-2-yl)phenyl)-l-(l-oxo-l,2-dihydroisoquinolin-5 yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, 129

-( 1 -oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxylic acid (300 mg, 0.77 mmol), 3-chloiO-4-(2H-l,2,3-triazol-2-yl)aniline (182.95 mg, 0.92 mmol) and pyridine (608.89 mg, 7.70 mmol) were dissolved in CH2CI2 (15 mL), and phosphorus oxychloride (354.09 mg, 2.31 mmol) was added. The mixture was stirred at 25 °C for 3 h. sat.NaHCCb (20 mL) was added and extracted with CH2CI2 (50 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a yellow oil, which was purified by préparative HPLC (40% to 40% (v/v)· CH3CN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound (135 mg, 34.8%). LCMS (ESI) m/z M+l : 499.9. Ή NMR (400MHz, DMSO-d6) δ= 11.64 (br d, J=5.5 Hz, 1H), 11.02 (s, 1 H),

389

8.52 (s, IH), 8.44 (d, J=8.2 Hz, IH), 8.17 (d, J=2.0 Hz. IH), 8.15 (s. 2H), 7.94 (d. J=7.5 Hz, IH), 7.86 (dd, J=2.l, 8.7 Hz, IH), 7.71 (d, J=8.8 Hz, IH), 7.67 (t, J=7.8 Hz, IH), 7.30 (t, J=6.6 Hz, IH), 5.67 (d, J=7.1 Hz, IH).

Example 130

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-D-quinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 130

A. 2-D-quinoline, 130a

A solution of quinoline-2-carboxyIic acid (1.5 g, 8.66 mmol) , silver(I) carbonate (238.85 mg, 0.87 mmol) and deuteroxide (9 mL) in DMSO(45 m L) was stirred at 140°C for 16 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give the crude product as colorless oil, which was purified by FCC (petroleum ether: ethyl acetate=100:0 to petroleum ether/ ethyl acetate=0:100) to afford the title compound (0.88 g, 78.049 %) as a colorless oil.

B. 5-bromo-2D-quinoline, 130b

Br , 130b

390 l-BiOmopyrrolidine-2,5-dione(L203 g, 6.76 mmol) was added to a solution of 2-Dquinoline(0.88 g, 6.76 mmol) in conc.fLSO-t (15 mL). The reaction mixture was poured onto 75 mL crushed ice, pH was adjusted to 9.0 using coned aqNHs, the alkaline slurry was then extracted with ethyl acetate (3 x 30 mL). The combined organic fractions were washed with LO M NaOH then water. dried (MgSOj), filtered, concentrated to give crude product, which was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 0:100) to afford relatively high purity product. which was purified by préparative HPLC ( 10% to 40% (v/v) CHjCN and H2O with 0.05% ammonia hydroxide) and lyophilized to dryness to afford the title compound (390 mg, 27.6 %). ‘H NMR (400 MHz. DMSO-d6) ô ppm 8.70 (l H. d, J=8.78 Hz), 8.18 (l H, d. J=8.53 Hz). 8.09 (1 H, d. J=7.53 Hz), 7.77 - 7.87 (2 H. m).

C. 2-D-5-hydrazinylquinoline. 130c

Palladium(ll)(pi-cinnamyl) chloride dimer (24.78 mg, 0.048 mmol) and 4-(2(di((3S,5S,7S)-adamantan-l-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 N? for 10 min, and then charged with sodium 2-methylpropan2-oIate (183.88 mg, 1.91 mmol) and 5-bromo-2-D-qumolme(200 mg, 0.96 mmol). The reaction vessel was sealed, and purged with N₂. The resulting reaction was stirred at room temp for 5 mm and was then treated with hydrazine hydrate (95.78 mg, 1.91 mmol) via syringe. The reaction was stirred at 50 °C under N2 for 1.5 h. The mixture was filtered, the filtrate was concentrated under reduced pressure to give the crude product as a yellow solid ( 140 mg, 91.4%) which directly used for the next step without further purification.

391

D. ethyl l-(2-D-quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate, 130d ⁰f~~ y-d

Ua

NVF

IF

D U aJ , _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 éthanol (10 mL) was stirred at 80 °C for 2 h. The résultant solution w^ras concentrated to dryness under reduced pressure to afford the crude product, which was purified by FCC (petroleum ether: ethyl acetate = 100/0 to 50/50) to afford the title compound (0.26 g, 87.7%) as a yellow solid. LCMS (ESI) m/z M+l: 336.9.

E. l-(2-Dquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 130e

Sodium hydroxide (45.96 mg. 1.15 mmol) was added to a solution of ethyl l-(2-Dquinolm-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate (260 mg, 0.77 mmol) in THF/ H2O 3:1 (12 mL). The mixture was reacted at room température for 16 h, the solvent was concentrated under reduced pressure and 20 mL H2O was added to the mixture. The mixture was acidifîed by IM hydrochloric to pH 5 and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous MgSO₄, and fïltered. The filtrâtes were concentrated under reduced pressure to afford the product as a white solid (200 mg, 84.695%).

392

F. N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridm-3-yl)-l-(2-D-quinoIin-5-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, Cpd 130

l-(2-D-quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (100 mg, 5 0.32 mmol), 5-amino-2-(2H-l,2,3-triazol-2-yl)nicotinonitrile, (60.40 mg, 0.32 mmol), pyridine (0.13 mL, 1.62 mmol) were dissolved in CH2CI2 (10 mL), and phosphorus oxychloride (0.12 mL, 1.30 mmol) was added. The mixture was stirred at 25 °C for 2 h, sat.NaHCCh (20 mL) was added and the mixture extracted with CH2CI2 (30 mL x 2). The combined organic extracts were dried over anhydrous NajSO#, filtered, and the filtrate 10 concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (21% to 51% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (45 mg. 28.8 %). LCMS (ESI) m/z M+l: 477.0. ‘H NMR (400 MHz, METHANOL-d4) δ ppm 12.20 (1 H, s), 9.93 (1 H, d, J=2.51 Hz), 9.71 (1 H. d, J=2.51 Hz), 9.43 (1 H, s), 9.12 - 9.18 (3 H, m), 8.73 - 8.84 (2 H.

m), 8.42 - 8.53 (2 H, m).

Example 131

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(2-Dquinolin-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 131

393

l-(2-D-quinolm-5-yl)-5-(trifluoromethyl)-IH-pyrazole-4-carboxyIic acid (240.00 mg. 0.78 mmol). 5-chloro-6-(2H-l ,2,3-triazol-2-yI)pyridin-3-amine, (152.31 mg, 0.78 mmol), pyridine (0.31 mL, 3.89 mmol) were dissolved in CH2CI2 (10 mL), and phosphorus 5 oxychloride (0.285 mL, 3.12 mmol) was added. The mixture was stirred at 25 °C for 2 h, sat. NaHCOs (20 mL) was added and extracted with CH2CI2 (30 mL x 2). The combined organic extracts were dried over anhydrous Na2SO₄, filtered, and concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (25% to 55% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to 10 afford the title compound (183 mg, 48.4 %). LCMS (ESI) m/z M+l: 485.9. Ή NMR (400 MHz, DMSO-d6) δ ppm 11.40 (l H, s), 8.91 (l H, d, J=2.01 Hz), 8.72 (1 H. d, J=2.0I Hz). 8.66 (1 H, s), 8.36 ( 1 H, d. J=8.28 Hz), 8.21 (2 H, s), 7.93 - 8.05 (2 H, m), 7.64 - 7.74 (2 H, m).

Example 132 l-(4-aminonaphthalen-l-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 132

394

A. (4-nitronaphthalen-l-yl)hydrazme, 132 a

O₂N—Y V-nh ^nh2

FF , 132a

A solution of 1 -fluoro-4-nitronaphthalene (670 mg, 3.51 mmol) in iPrOH(20 mL) was added N2H4.H2O (460 mg, 9.19 mmol) and heated to 60 °C for 2 hrs. After cooled to RT, the solid was collected, washed with H₂O (5 mL) and EtOH (5 mL), and then dried under vacuo to give product as a yellowish solid (500 mg,70.2%).

B. ethyl l-(4-nitronaphthalen-l-y 1)-5-(trifluoromethyl)-1 H-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 éthanol (30 mL) was stirred at 25 °C for 2 h. The résultant solution was concentrated to dryness under reduced pressure to afford the crude product, which was purified by FCC (petroleum ether: ethyl acetate = 100/0 to 0/100) to afford the title compound (0.8 g, 85.7%) as a yellow oil. LCMS (ESI) m/z M+l: 380.0.

C. 1-(4-nitronaphthalen-l-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 132c

, 132c

Sodium hydroxide (126.54 mg, 3.16 mmol) was added to a solution of ethyl 1-(4nitronaphthalen-I-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate (800 mg, 2.11 mmol)

395 in THF/ H2O l: l (20 mL). The mixture was stirred at room température for 16 h, the solvent was concentrated under reduced pressure and 20 mL H?O was added to the mixture. The mixture was acidified using l M hydrochloric to pH 5 and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over 5 anhydrous MgSCU, filtered, the filtrâtes were concentrated under reduced pressure to afford product as a yellow solid (630 mg, 85.0%). LCMS (ESI) m/z M+l : 352.0.

D. N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yD-1-(4-nitronaphthalen-1-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide. Cpd 132d

]-(4-Nitronaphthalen-l-yl)-5-(trifluoromethyl)-IH-pyrazole-4-carboxylic acid (400 mg, l. 14 mmol), 5-amino-2-(2H-l,2,3-triazol-2-yl)mcotinonitrile, (212.02 mg, l. 14 mmol), pyridine (0.46 mL, 5.69 mmol) were dissolved in CH2CI2 (20 mL), and phosphorus oxychloride (0.42 mL, 4.56 mmol) was added. The mixture was stirred at 25 °C for 2 h, 15 sat. NaHCOs (20 mL) was added and extracted with CH2CI2 (30 mL x 2). The combined organic extracts were dried over anhydrous NasSCL. filtered. and the filtrate concentrated to dryness under reduced pressure to afford the crude product. which was purified by FCC (petroleum ether: ethyl acetate = 100/0 to 0/100) to afford the title compound (0.41 g, 61.7%) as a yellow' solid. LCMS (ESI) m/z M+1: 520.1.

396

E. 1 -(4-Aminonaphthalen-1 -yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -y l)-5 (trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 132

ΙΟ

Fe (196.27 mg, 3.52 mmol) and NH4CI (188.0 mg, 3.52 mmol) were added to the mixture of N-(5-cyano-6-(2H-l ,2,3-triazol-2-yl)pyridi.n-3-yl)-l-(4-nitronaphthalen-l-yl)-5 (trifluoromethyl )-lH-pyrazole-4-carboxamide (410 mg, 0.70 mmol) in THF (20 mL), H2O (10 mL), MeOH ( 10 mL). The reaction was stirred at 70 °C for 2 h, fïltered through a pad of diatomaceous earth, and the pad was washed with EtOAc (20 mL x 2). The combined filtrâtes were concentrated to dryness to give a crude brown solid, which was purified by préparative HPLC (35% to 65% (v/v) CH?CN and H2O with 0.05% ammonia hydroxide) and lyophilized to dryness to afford the title compound (220 mg. 63.4 %). LCMS (ESI) m/z M+1:490.0. Ή NMR (400 MHz, DMSO-d6) δ ppm 11.39(1 H, s), 9.10(1 H, d, J=2.20 Hz), 8.88 ( 1 H, d, J=2.43 Hz), 8.49 (1 H. s) 8.30 (2 H, s), 8.15 - 8.24 ( 1 H, m), 7.44 - 7.53 (2 H, m), 7.40(1 H. d, J=7.94 Hz), 6.86 - 6.93 (1 H, m), 6.78 (1 H, d. .1=8.16 Hz).

Example 133

N-(3-cyano-4-(2H-L2.3-triazol-2-yl)phenyl)-l-(quinolin-5-yl)-5-(trifh.ioromethyl)-lHpyrazole-4-carboxamide, Cpd 133

A. 5-nitro-2-(2H-l,2,3-triazol-2-yl)benzonitrile, 133a

397

Q, 133a

2-Fluoro-5-nitrobenzonitrile (500 mg. 3.01 mmol), lH-l,2,3-triazole (228.68 mg.

3.31 mmol) and potassium carbonate (832.02 mg, 6.02 mmol) were added to MeCN (10 mL) and stirred at 25 °C for 16 h. 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 afford a crude yellow solid, which was purified by FCC (petroleum ether/ ethyl acetate from 100:0 to 70:30) to afford the title compound (600 mg. 92.6%) as a white solid. Ή NMR (400MHz, CHLOROFORM-d) δ = 8.72 (d, >2.6 Hz, IH), 8.55 (dd, >2.4. 9.0 Hz, IH), 8.42 (d, >9.3 Hz, IH). 8.03 (s, 2H).

B. 5-ammo-2-(2H-l ,2,3-triazol-2-yl)benzonitrile, 133 b h₂n

N 133b

5-Nitro-2-(2H-1.2,3-triazol-2-yl)benzonitrile (600 mg, 2.79 mmol) was dissolved in THF (10 mL), Fe ( 1.25 g, 22.31 mmol), NH4CI (1.19 g, 22.31 mmol) and H2O (10 mL) were added. The reaction mixture was stirred at 80 °C for 4 h, filtered through a pad of diatomaceous earth and the pad was washed with EtOAc (20 mL^:<3). The filtrâtes were concentrated to dryness to give crude product as a yellow solid, which was purified by FCC (eluent: petroleum ether/ethyl acetate from 100/0 to 50/50). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford the title compound (440 mg. 82.1%) as a yellow oil. LCMS (ESI) m/z M+l: 186.1. 'H NMR (400MHz, DMSO-d6) δ = 8.08 (s. 2H), 7.57 (d. >8.8 Hz, IH), 6.99 (d, >2.6 Hz, IH). 6.94 (dd. >2.6, 8.8 Hz, IH), 5.98 (s, 2H).

C. N-(3-cvano-4-(2H-l,2,3-triazol-2-yl)phenvl)-l -(quinolin-5-yl)-5-( trifluoromethyl)25 lH-pyrazole-4-carboxamide, Cpd 133

5-Amino-2-(2H-l,2,3-triazol-2-yl)benzonitrile (l ΙΟ.98 mg, 0.58 mmol), l(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (120 mg, 0.39 mmol) and pyridine (45.7 mg, 0.58 mmol) wcrc dissolved in CH2CI2 (IO mL), and phosphorus oxychloride (88.58 mg, 0.58 mmol) was added. The mixture was stirred at 25 °C for 16 h, sat.NaHCO? (20 mL) was added and extracted with CH2CI2 (.50 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a yellow solid. which was purified by préparative HPLC (35% to 65% (v/v) CH?CN and H₂O with 0.05% HCl) and lyophilized

IO to dryness to afford the title compound (87 mg, 47.8%). LCMS (ESI) m/zM+l: 474.9. *H NMR (400MHz, DMSO-d6) δ ppm 11.22 (s, IH), 9.11 (dd, J=1.9. 3.9 Hz, IH), 8.62 (s, IH), 8.44 (d, J=2.2 Hz, IH), 8.37 (d, J=8.2 Hz, IH), 8.28 (s, 2H), 8.26 - 8.21 (m, IH), 8.17 - 8.11 (m, IH), 8.05 - 7.98 (m, IH), 7.98 - 7.94 (m, IH), 7.76 - 7.68 (m, 2H).

Example 134

N-(6-(4-amino-2H-l,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-l-(1-oxo-1,2dihydroisoquinoIin-5-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 134

399

2-(3-chloro-5-( l -( l -methoxyisoquinolin-5-yl)-5-(trifhioromethyl )-1 H-pyrazole-4carboxamido)pyridin-2-yl)-2H-L2,3-triazole-4-carboxylic acid, 134a

134a

NaOH (72.62 mg. 1.82 mmol) was added to a solution of methyl 2-(3-chloro-5-(I5 (1 - methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamido)pyridin-2yl)-2H-l,2.3-triazole-4-carboxylate (600 mg, 0.91 mmol) in THF/H₂O 1:1 (10 mL) was reacted at 23 °C for 2 h. The solvent was concentrated under reduced pressure. IM HCl solution was add to the mixture to adjust to pH 5 and a solid formed. The solid was collected to afford the product. LCMS (ESI) m/z M+l: 530.9.

B. rm-butyl(2-(3-chloro-5-( l-(l-methoxyisoquinolin-5-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamido)pyridin-2-yl)-2H-L2,3-triazol-4-yl)carbamate, 134b

To a solution of 2-(3-chloro-5-( l-(l-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)15 1 H-pyrazole-4-carboxamido)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 ul, 2.47 mmol) were added under N: atmosphère. The mixture was stirred at 80 °C ovemight, sat. NaHCOs (20 mL) was added and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered and the filtrâtes were concentrated under reduced pressure to afford crude as a brown oil. The crude product was purified by column

400 chromatography over silica gel (petroleum ether/ ethyl acetate=2:l to petroleum ether.

ethyl acetate=l :2). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid. LCMS (ESI) m/z M+l : 630.0.

C. N-(6-(4-ammo-2H-l ,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-l-( l-oxo-l.2dihydiOisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 134

A J HN—^J /ezï-Butyl (2-(3-chloro-5-(l-(l-methoxyisoquinolin-5-yl)-5-(trifluoiOmethyl)-lH10 pyrazole-4-carboxamido)pyridin-2-yl)-2H-l,2,3-triazol-4-yl)carbamate (180 mg, 0.27 mmol), and conc. HCl (2 mL) was added i-PrOH (4 mL), stirred at 60°C for 2 h. The mixture was concentrated under reduced pressure to afford crude product as a brown oil, which was purified by préparative HPLC (72 % to 42 % (v/v) CHjCN and H?O with 0.05% ammonia hydroxide) and lyophilized to dryness to afford the title compound (64 mg, 44.3%). LCMS (ESI) m/z M+l : 515.9. *H NMR (400 MHz, DMSO-d6) δ ppm 5.47 (s, 2 H), 5.64 (d, J=7.28 Hz, l H), 7.27 (d, J=7.28 Hz, l H), 7.31 (s, l H), 7.65 (t, J=7.94 Hz, l H), 7.92 (d, J=7.50 Hz. I H), 8.42 (d. .1=7.94 Hz, 1 H), 8.54 (s, 1 H), 8.56 (d, J=2.43 Hz, I H), 8.77 (d, J=2.21 Hz, 1 H).

401

Example 135

N-(3-cyano-4-(2H-l,2,3-triazol-2-yl)phenyl)-l-(quinolin-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamide, Cpd 135

A. ethyl l-(3-chloro-5-nitropyridin-2-yl)-lH-pyrazoIe-4-carboxylate, 135a

2,3-Dichloro-5-nitropyridine (500 mg, 2.59 mmol), ethyl lH-pyrazole-4-carboxylate (435.7 mg, 3.11 mmol) and césium carbonate (1.01 g, 3.11 mmol) were added to MeCN (10 mL) and stirred at 80 ^CC for 16 h. The reaction mixture was fïltered and the residue was washed with EtOAc (20 mL x 3). The combined organic layers were concentrated under reduced pressure to afford crade product as a yellow solid, which was purified by FCC (petroleum ether/ethyl acetate from 100:0 to 70:30) to afford the title compound (650 mg, 84.6%) as a yellow solid.

B. ethyl l-(5-amino-3-chloropyridin-2-yl)-lH-pyrazoIe-4-carboxylate, 135b

Ethyl l-(3-chloro-5-nitropyridin-2-yl)-lH-pyrazole-4-carboxylate (650 mg, 2.19 mmol) was dissolved in THF ( 10 mL), Fe (856.5 mg, 15.34 mmol), NH4CI (820.4 mg,

15.34 mmol) and H2O (10 mL) were added. The reaction mixture was stirred at 80 °C for 2

402

h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with EtOAc (20 mL x 3). The filtrâtes were concentrated to dryness to give crude as a yellow solid, which was purified by FCC (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 afford the title compound (440 mg, 64.5%) as a yellow oil. LCMS (ESI) m/z M+l: 267. L

C. Ethyl l-(3-chIoro-5-(l-(quinolin-5-yl)-5-( trifluoromethyl)-1H-pyrazole-4carboxamido)pyridin-2-yl)-l H-pyrazole-4-carboxylate, 135c

, 135c

Ethyl l-(5-amino-3-chloropyridin-2-yl)-lH-pyrazole-4-carboxylate (293.93 mg, 0.94 mmol), l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (220 mg, 0.71 mmol) and pyridine (83.77 mg, 1.06 mmol) were dissolved in CHgCh (20 mL), and phosphorus oxychloride ( 162.39, 1.06 mmol) was added. The mixture was stirred at 30 °C for 16 h. Sat. NaHCO? (40 mL) was added and extracted with CH2CI2 (40 mL x 2). The combined organic layers were dried over Na₂SO4, filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a yellow’ solid, which w’as purified by FCC (eluent: petroleum ether/ethyl acetate from 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford (120 mg, 22.9%) as a yellow solid. LCMS (ESI) m/z M+l: 556.2.

403

D. N-(5-chloro-6-(4-(hydroxymethyl)-lH-pyrazol-l-yl)pyridin-3-yl)-l-(quinolin-5yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, 135

Ethyl l-(3-chloro-5-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)pyridin-2-yl)-lH-pyrazole-4-carboxylate (120 mg, 0.20 mmol) was dissolved in THF (20 mL) and stirred at 0 °C, aluminum(III) lithium hydride (68.24 mg, 1.80 mmol) was added in. portions. The reaction mixture was stirred at 30 °C for 1 h. H?O (20 mL) was added and extracted with EtOAc (40 mL x 2). The combined organic layer was dried over NaiSO-i, filtered and the flltrate was concentrated under reduced pressure to afford the crude product, which was purified by préparative HPLC (22% to 52% (v/v) CH?CN and

H?O with 0.05% HCl) and lyophilized to dryness to afford the title compound (35 mg, 33.6%). LCMS (ESI) ni / Μ I : 513.9. Ή NMR (400MHz, DMSO-d6) \ ppm 11.56 (br s. IH). 9.08 (br s, IH), 8.91 (br s. IH), 8.73 (br s, IH), 8.63 (br s, IH), 8.35 (br d, J=7.9 Hz, IH). 8.09 (br s, IH), 7.96 (br dd, J=6.9, 18.2 Hz, 2H), 7.81 - 7.62 (m, 3H), 4.43 (br s, 2H).

404

Example 136

N-(5-chloro-6-(4-(hydroxymethyl)-2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 136

Methyl 2-(3-chloro-5-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)pyridin-2-yl)-2H-l,2.3-triazole-4-carboxyIate (86 mg. 0.079 mmol) was dissolved in THF (5 mL) at 0 °C, LiAlH₄ (84 mg, 2.21 mmol) was added in portions. The reaction mixture was stirred at 40 °C for 18 h, then H2O (10 mL) was added and the mixture extracted with EtOAc (20 mL x 2). The combined organic layers were dried over

NazSOj, filtered and the filtrate was concentrated under reduced pressure to afford the crade product as a yellow oil, which was purified by préparative HPLC (76% to 46% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound ( 17.3 mg, 5.0 %). LCMS (ESI) m/z M+1: 514.9. ’H NMR (400 MHz, DMSO-d6) ô ppm 4.63 (s. 2 H), 7.69 - 7.83 (m, 2 H), 7.94 - 8.09 (m, 3 H), 8.37 (d, J=8.38 Hz, 1 H), 8.63 -

8.73 (m. 2 H), 8.91 (d.J=2.21Hz, 1 H), 9.11 (dd, .1=3.97, 1.54 Hz, 1 H), 11.51 (s. 1 H).

Example 137

N-(5-chloro-6-(4-((dimethylamino)methyl)-2H-L2,3-triazol-2-yl)pyridin-3-yl)-I(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 137

405

A. (2-(3-chloro-5-( I -(quinolin-5-yl)-5-( trifluoromethyl)-1 H-pyrazole-4carboxamido)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)pyridm-3-yl )-1 -(quinolin5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide (420 mg, 0.79 mmol) in CH2CI2 (8 mL) was cooled to 0 °C. Triethylamine (239.84 mg, 2.37 mmol) was added, then methanesulfonyl chloride (135.75 mg, 1.19 mmol) was added dropwise and stirred at 0 °C 10 for 1 h. The mixture concentrated, dried. and used directly for the next step.

B. N-(5-chloro-6-(4-((dimethylamino)methyl)-2H-l .2,3-triazol-2-yl)pyridin-3-yl)-l(quinolin-5-yl)-5-(trifluorornethyl)-1 H-pyrazole-4-carboxamide. Cpd 137

(2-(3-Chloro-5-( 1 -(quinolin-5-yl)-5-( trifluoromethyl)-lH-pyrazole-4carboxamido)pyridm-2-yl)-2H-l,2,3-triazol-4-yl)methyl methanesulfonate (250 mg, 0.40

406 mmol) was added Me₂NH in THF (IM) (20 mL). The mixture was concentrated under reduced pressure to afford a crude product as a yellow oil, which was purified by préparative HPLC (84% to 54% (v/v) CHsCN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (201 mg, 92.7 %). LCMS (ESI) m/zM+l: 514.9.

Ή NMR (400 MHz, METHANOL-d4) δ ppm 2.99 (s, 6 H). 4.64 (s. 2 H). 8.17 - 8.26 (m, 3 H), 8.33 - 8.41 (m. I H), 8.48 - 8.60 (m, 2 H), 8.62 - 8.74 (m, l H), 8.77 (d, J=2.20 Hz, l H), 8.88 (br s, 1 H), 9.29 - 9.48 (m, 1 H).

Example 138

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-1 -(quinolin-4-yl)-5-(trifluoromethyl)lH-pyrazole-4-carboxamide. Cpd 138

A. ethyl l-(quinolin-4-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxylate, 138a

A solution of 4-hydrazinylquinoline, 60c (300 mg, 1.89 mmol), ethyl 2(ethoxvmethylene)-4,4,4-trifluoiO-3-oxobutanoate (543.15 mg, 2.26 mmol), m EtOH (5 mL) was stirred at 80 °C for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (petroleum 20 ether/ ethyl acetate from 100/0 to 50/50). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford ethyl 1 -(quinolin-4-yl)-519506

407 (trifluoromethyl)-lH-pyrazole-4-carboxylate (130 mg, 20.6% yield) as a yellow solid.

LCMS (ESI) m/z M+l: 335.9.

B. l-(quinolin-4-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 138b

E F

Y n O KYoH

N y—N

Æ ,138b

A solution of ethyl l-(quinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate, 138a ( 130 mg, 0.61 mmol), LiOH ( 16.27 mg, 0.39 mmol) in EtOH /H2O (2/1, 2 mL) was stirred at room température for 2 h, IN HCl solution was added to neutralize the reaction solution. The mixture was extracted with ethyl acetate (5 mL x 3). The separated organic layer was dried (NasSOn filtered, and the solvent was concentrated to afford l-(quinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 138b (119 mg) as a yellow solid. LCMS (ESI) m/z M+L 308.0.

C. N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 138

Phosphorus oxychloride (39.44 uL, 0.42 mmol) was added to a solution of 1(quinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 138b (67.35 mg, 0.21 mmol), 5-amino-2-(2H-l,2,3-triazol-2-yl)nicotinonitrile (59.08 mg, 0.32 mmol), pyridine (171.12 uL, 2.12 mmol) in CH2CI2 (2 mL). The mixture was stirred at room température for 2 h, 5 mL LLO was added to the mixture and sat. NaHCCh was added to adjust the pH

408 of reaction mixture to 7-8. The mixture was extracted with CH2O2 (5 mL x 3). The combined organic extracts were dried over anhydrous MgzSCL, filtered, and the filtrate concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (40% to 70% (v/v) CH3CN and HT) with 0.05% HCl) and lyophilized to dryness to afford the title compound (57 mg, 56.4%). LCMS (ESI) m/z Ml: 475.9. Ή NMR (400 MHz, DMSO-d6) δ ppm 7.33 (d, J=8.16 Hz, 1 H), 7.77 (t, J=7.61 Hz, 1 H), 7.91 - 7.98 (m, 2 H), 8.26 (d, J=8.60 Hz, 1 H), 8.32 (s, 2 H), 8.71 (s, 1 H), 8.91 (d, J=2.43 Hz, 1 H), 9.13 (d, J=2.43 Hz, 1 H), 9.19 (d, J=4.41 Hz, 1 H), 1 1.47 (s, 1 H).

Example 139

N-(5-bromo-6-(2H-1,2.3-triazol-2-yl)pyridin-3-yl)-1 -(quinoIin-5-yl)-5-(trifluoromethyl)lH-pyrazole-4-carboxamide, Cpd 139

A. 3-bromo-5-nitro-2-(2H-l ,2,3-triazol-2-yl)pyridine. 139a

A solution of 3-bromo-2-chloro-5-nitropyridine (1 g, 4.21 mmol), lH-l,2,3-triazole (582 mg, 8.42 mmol), K2CO3 (1.74 g, 12.64 mmol) in CH3CN (30 mL) was stirred at 50 °C for 12 h. The mixture was concentrated under reduced pressure, the crude product was purified by column chromatography over silica gel (petroleum ether,· ethyl acetate from 20:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford 3-bromo-5-nitro-2-(2H-l,2,3-triazol-2-yl)pyridine, 139a (520 mg, 45.7%) as a yellow solid. LCMS (ESI) m/z M+l: 272.L

409

B. 5-bromo-6-(2H-I,2,3-triazol-2-yl)pyridin-3-amine, 139b

N=\ h₂n AA_Br , _139b

Fe (323.50 mg, 5.78 mmol) was added to a solution of 3-bromo-5-nitro-2-(2Hl,2,3-triazol-2-yl)pyridine, 139a (520 mg, 1.93 mmol) andNHjCl (515.10 mg, 9.63 mmol) m MeOH (20 mL), THF (20 mL) and HtO (10 mL). The mixture was stirred at 80 °C for Ih, and then aq. NaHCOi was added to the suspension to adjust the mixture to pH 9-10. The resulting mixture was fïltered through a pad of diatomaceous earth and the fîlter cake w’as washed with CH2CI2 ( 100 mL><3). The combined filtrâtes were w'ashed with brine (200 mL), dried over MgSO₄ and concentrated under reduced pressure to afford 1b (310 mg, 67.1%) as a brown solid, which was used directly in the next step. LCMS (ESI) m/z M+H: 242.1

C. N-(5-bromo-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 139

POCh (232.263 mg, 1.515 mmol) was added to a solution of 5-bromo-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine, 5-bromo-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine, 139b (200 mg, 0.83 mmol), 1-(quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (232.69 mg, 0.76 mmol), pyridine (149.77 mg 1.89 mmol) in CH2CI2 (10 mL). The mixture was stirred at rt for 2 h, then 50 mL H2O and 50 mL CH2CI2 were added to the mixture. The organic layer was washed with brine (50 mL), dried over MgSO₄ fïltered, and the filtrate concentrated under reduced pressure to afford the crude product. which was

410 purified by préparative HPLC (35% to 65% (v/v) CHsCN and H2O with 0.05% HCl). The desired fractions were lyophilized to dryness to afford the title compound (86.8 mg 20.8% yield) as a white solid. LCMS (ESI) m/z Μ · 1: 528.9. Ή NMR (400 MHz. DMSO-d6) δ ppm 11.45 (s, 1 H), 9.01 - 9.12 (m, 1 H). 8.89 - 8.99 (m, 1 H), 8.78 - 8.86 (m, 1 H), 8.64 5 8.72 (m, 1 H). 8.29 - 8.38 (m, 1 H), 8.15 (s, 2 H), 7.90 - 8.02 (m, 2 H), 7.69 (d, J=3.09 Hz,

H).

Examole 140

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)-510 (trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 140

A. 4-hydrazinylpyrrolo[2,1 -f] [ 1,2,4] triazine. 140a

Γ^Ν

N 0ΝΗ

N A nh₂

VU , 140a

4-Chloropyrrolo[2,l-f][l,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 h. The solvent was removed to afford product as a white solid (200 mg, 100%), which w⁷as used directly for the next step.

411 ethyl 1 -(pyrrolo[2,1 -f][ 1,2,4]triazin-4-yl )-5-( trifluoromethyl)-1 H-pyrazole-4carboxylate, 140b

4-Hydrazinylpyrrolo[2,l-f][ l,2,4]triazine (200 mg, 1.34 mmol) was dissolved in éthanol (10 mL). ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (483.08 mg, 2.01 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h, concentrated under reduced pressure to afford the crude product as a white solid, which was purified by FCC (eluent: petroleum ether/ethyl acetate from 100/0 to 60/40) to afford the title compound (200 mg, 43.4%) as a white solid. LCMS (ESI) m/z M+l: 326.0.

C. l-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 140c

Ethyl 1 -(pyrrolo[2,1 -f][ 1,2,4]triazin-4-yl)-5-( trifluoromethyl)-1 H-pyrazole-4carboxylate (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 °C for 12 h, adjusted to pH 5 using HCl (2 N), and extracted with EtOAc (30 mL x 2). The combined organic layers were dried overNa2SO4, fïltered, and the filtrâtes were concentrated under reduced pressure to afford crude the title compound (130 mg, 73.6%) as a yellow⁷ solid. LCMS (ESI) m/z M+l: 298.0.

412

D. N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(pynOlo[2,l-f|[L2,4]triazm-4yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 140

-(Pyrrolo[2, l-f][ 1,2,4]triazin-4-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (130 mg, 0.43 mmol), 5-amino-2-(2H-l,2,3-triazol-2-yl)nicotinonitrile (95.57 mg, 0.51 mmol), pyridine (203.04 mg, 2.57 mmol) were dissolved in CH₂Ch (10 mL), and phosphorus oxychloride (262.38, 1.71 mmol) was added. The mixture was stirred at 25 °C for 4 h, sat.NaHCOj (30 mL) was added and extracted with CH2CI2 (30 mL x 2). The combined organic layers were dried over Na/SOu filtered, and the filtrâtes were concentrated under reduced pressure to afford the crade product as a yellow oil, which was purified by préparative HPLC (35% to 65% (v/v) CH3CN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound (87.1 mg, 43.5%). LCMS (ESI) m/z M+l: 465.9. *H NMR (400MHz, 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-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(pyrazolo[L5-a]pyrazin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 141

413

4-hydrazmylpyrazolo[ 1,5-a]pyrazine, 141a

^NH2, 141a 4-Chloropyrazolo[l,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 h. The solvent was removed to afford product as a white solid (300 mg, 100%), which was used directly for the next step.

B. ethyl 1 -(pyrazolo[l,5-a]pyrazin-4-yl)-5-( trifluoromethyl)- lH-pyrazole-410 carboxylate, 141b

4-Hydrazinylpyrazolo[l,5-a]pyrazine (300 mg, 2.01 mmol) was dissolved in éthanol ( 10 mL), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (966.16 mg, 4.02 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h, then concentrated under reduced pressure to afford a crude product as a yellow solid, which was purified by FCC (eluent: petroleum ether/ethyl acetate from 100/0 to 60/40) to afford the title compound (500 mg, 61.2%) as a yellow solid. LCMS (ESI) m/z M+l: 326.0.

C. l-(pyrazolo[L5-a]pyrazin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid,

141c

, 141c

414

Ethyl 1 -(pyrazolo[ 1.5-a]pyrazin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxyiate (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 h. then adjusted to pH 5 using HCl (2 N). The mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na^SOr, filtered, and the filtrâtes were concentrated under reduced pressure to afford the crude the title compound (400 mg, 89.2%) as a yellow solid. LCMS (ESI) m/z M+l: 298.2.

D. N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(pyrazolo[L5-a]pyrazin-4-yl)5-(trifluoromethyl)-l H-pyrazole-4-carboxamide. Cpd 141

-(Pyrazolo[ 1,5-a]pyrazin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (250 mg, 0.69 mmol), 5-chloro-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-amine (161.0 mg, 0.82 mmol), pyridine (325.52 mg, 4.12 mmol) were dissolved in CH2CI2 (10 mL), and phosphorus oxychloride (420.67, 2.74 mmol) was added. The mixture was stirred at 25 °C for 4 h, then sat. NaHCOi (50 mL) was added and the mixture extracted with CH2CI2 (30 mL x 2). The combined organic layers were dried over NuSOi. filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a yellow oil, which was purified by préparative HPLC (45% to 75% (v/v) CH3CN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound (22.4 mg, 6.6%). LCMS (ESI) m'z M+l : 474.9. Ή NMR (400 MHz, DMSO-d6) δ ppm 11.42 (s, 1 H), 9.05 (dd, J=4.85, 0.88 Hz, 1 H), 8.81 (d, J=2.21 Hz, 1 H), 8.63 (d, J=2.43 Hz, 1 H). 8.60 (s, 1 H), 8.37 (d, J=2.43 Hz, 1 H), 8.17 (s, 2 H). 7.96 (d, J=4.63 Hz, 1 H), 7.11 (dd, J=2.32, 0.77 Hz, 1 H).

415

Example 142

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yI)-l-(thieno[2,3-d]pyrimidm-4-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 142

4-hydrazinylthieno[2,3-d]pyrimidine, 142a ² NH

N ° ,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 h. The solid was filtered and washed by 2 mL water.

The solid was collected and dried to afford 4-hydrazinylthieno[2,3-d]pyrimidine, 142a (400 mg, 91.3% yield) as a white solid. LCMS (ESI) m z M+l: 166.9.

B. ethyl l-(thieno[2,3-d]pyrimidin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate, 142b

, 142b

A solution of 4-hydrazinylthieno[2,3-d]pyrimidine. 142a (400 mg, 2,41 mmol), 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 h. The mixture was concentrated under reduced pressure, the crade product was purified by column chromatography over silica gel (petroleum ether/

416 ethyl acetate from 100/0 to 70/30). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford ethyl l-(thieno[2,3-d]pyrimidin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxylate, 142b (700 mg, 85.0% yield) as a yellow solid. LCMS (ESI) m/z M+l: 343.1.

C. l-(thieno[2,3-d]pyrimidin-4-yl)-5-(trifluoromethyI)-lH-pyrazole-4-carboxylic acid, 142c

A solution of ethyl l-(thieno[2,3-d]pyrimidin-4-yl)-5-(trifluoromethyl)-lH10 pyrazole-4-carboxylate. 142b (120 mg, 0.35 mmol), LiOH.HiO (22.07 mg, 0.53 mmol) in EtOH /H₂O (2/1, 3 mL) was stirred. at room température overnight. IN HCl solution was added to neutralize the reaction solution. The mixture was extracted with ethyl acetate ( 10 mL x 3). The separated organic layer was dried (NaiSOQ, filtered, and the filtrate was concentrated to afford 142c (90 mg, 81.7% yield) as a yellow' solid. LCMS (ESI) m/z

M+l: 314.9.

N-(5-cyano-6-(2H-1,2.3 -triazol-2-yl)pyridin-3-yl)-l-(thieno[2,3-d]pyrimidin-4-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 142

Phosphorus oxychloride (53.39 uL, 0.57 mmol) was added to a solution of 1(thieno[2.3-d]pyrirnidin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 142c (90 mg, 0.29 mmol), 5-amino-2-(2H-l,2,3-triazol-2-yl)nicotinonitrile (58.65 mg, 0.32 mmol),

417 pyridine (231.64 uL, 2.86 mmol) in CH2CI2 (2 mL). The mixture was stirred at room température for 1 h, 5 mL H₂0 was added to the mixture and sat. NaHCCh was added to adjust the pH of reaction mixture to 7-8. The mixture was extracted with CH2CI2 (5 mL x 3), the combined organic extracts were dried over anhydrous Mg-SOi. filtered, and the filtrate concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (36% to 66% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (40 mg, 27.9%). LCMS (ESI) m/z M+l: 482.9. Ή NMR (400 MHz, DMSO-d6) δ ppm 7.78 (d, J=6.17 Hz, 1 H), 8.24 (d, J=6.17 Hz, 1 H), 8.32 (s, 2 H), 8.65 (s, 1 H), 8.85 (d, J=2.21 Hz, 1 H), 9.07 (d, J=2.21 Hz, 10 1 H). 9.21 (s, 1 H), 11.52 (s, 1 H).

Example 143

N-(5-cyaiio-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[2,3-c]pyridin-7-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 143

A. 7-hydrazmylthieno[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 h. The mixture was extracted with CH2CI2 (20 x 3 mL). The solvent was concentrated under reduced pressure the give the desired compound, used directly for the next step without further purification.

418

B. ethyl l -(thieno[2,3-c]pyridin-7-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate.

143b

7-Hydrazmylthieno[2,3-c]pyridine (200 mg, 1.21 mmol) was added to a solution of 5 ethyl 2-(ethoxymethylene)-4,4,4-trifluoiO-3-oxobutanoate (436.11 mg, 1.82 mmol) in

EtOH (5 mL) and was reacted at 80 °C for 3 h. The mixture was concentrated under reduced pressure, then was purified by FFS (petroleum ether/ ethyl acetate= 100:0 to 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) 10 m z M+l: 341.9.

C. l-(thieno[2,3-c]pyridin-7-yl)-5-(trifluoromethyl )-lH-pyrazole-4-carboxylic acid,

143c

NaOH (20.56 mg. 0.51 mmol) was added to a solution of ethyl 1 -(thieno[2,3c]pyridin-7- yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate (120 mg, 0.34 mmol) in EtOH H₂O=1 :1 (5 mL) w'as reacted at 28 °C for 2 h. The solvent was concentrated under reduced pressure the give the desired compound. LCMS (ESI) m/z M+l: 313.9.

419

D. N-(5-cyano-6-(2H-L2,3-triazoI-2-yl)pyridm-3-yl)-l-(thieno[2,3-c]pyridin-7-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 143

-(Thieno[2,3-c]pyridin-7-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (70 mg, 0.22 mmol), 5-amino-2-(2H-l,2,3-triazol-2-yl)nicotinonitrile (50 mg, 0.27 mmol),

POCl? (41.18 mg, 0.27 mmol ) were dissolved in DCM (2 mL), and pyridine (53.11 mg, 0.67 mmol) was added. The mixture was stirred at 25 °C for 2 h, then sat.NH4Cl (20 mL) was added and the mixture extracted with CHrCh (20 mL x 2). The combined organic layers were dried over NagSOr, filtered and the filtrâtes w*ere concentrated under reduced pressure to afford crude as a yellow oil, which was purified by préparative HPLC (54% to 27% (v/v) CH.;CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (46 mg. 49.7%). LCMS (ESI) m/z M+l : 482.1. ¹H NMR (400 MHz, DMSOd6) δ ppm 7.73 (d, J=5.29 Hz. 1 H), 8.09 (d, J=5.29 Hz, 1 H). 8.25 - 8.35 (m, 3 H), 8.49 (d, J=5.29 Hz, 1 H), 8.57 (s, 1 H). 8.83 (d, J=2.43 Hz, 1 H), 9.05 (d, J=2.43 Hz, 1 H), 11.50 (s,

1 H).

Example 144

2-(3-chloro-5-( l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamido)pyridin2-yl)-2H-l,2,3-triazole-4-carboxamide, Cpd 144

420

2-(3-Chloro-5-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)pyridin-2-yl)-2H-l,2,3-triazole-4-carboxylic acid (80 mg, 0.15 mmol), NH4CI (23.23 mg, 0.43 mmol), HATU (82.56 mg, 0.22 mmol ) were dissolved in DMF (4 mL), and DIEA (93.54 mg, 0.72 mmol) was added. The mixture was stirred at 25 °C for 2 h, sat.NFLCl (20 mL) was added and extracted with CH2CI2 (20 mL x 2). The combined organic layers were dried over NagSOj, fïltered and the filtrâtes were concentrated under reduced pressure to afford a crude product as a yellow oil, which was purified by préparative HPLC (66% to 36% (v/v) CH?CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (44 mg, 47.5%). LCMS (ESI) m/z Mi: 529.2. ^!H

NMR (400 MHz. DMSO-d6) δ ppm 7.74 - 7.87 (m, 3 H), 8.00 - 8.10 (m, 2 H), 8.15 (br s. 1 H), 8.42 (d, 1=8.53 Hz, 1 H), 8.51 (s, 1 H), 8.73 - 8.81 (m. 2 H), 9.01 (d, J=2.26 Hz, 1 H). 9.16 (dd, J=4.27, 1.51 Hz, 1 H). 11.64 (s, 1 H).

Example 145

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l -( 1,7-naphthyridin-5-yl)-5(trifluoromethyl)- IH-pyrazole-4-carboxamide, Cpd 145

5-bromo-8-hydrazinyl-1,7-naphthyridine, 145a

5-Bromo-8-chloro-L7-naphthyridine (800 mg. 3.29 mmol) was dissolved in hydrazine hydrate (5 mL). The reaction mixture was stirred at 50 °C for 2 h. The solvent

421 was removed to afford the desired product as a yellow oil (785 mg, 100%), which was used directly for the next step.

B. 5-bromo-1,7-naphthyridine. 145b

Br % N , 145b

5-Bromo-8-hydrazinyl-I,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 h. The solvent was removed, 30%) NH3.H2O (50 mL) was added and the mixture was extracted with CH2CI2 (50 mL x 2). The combined organic layers were dried over NazSCL. filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a yellow solid, which was purified by FCC (eluent: petroleum ether/ethyl acetate from 100/0 to 85/15) to afford the title compound (420 mg, 59.9%) as a yellow solid. LCMS (ESI) m/z Ml: 208.8.

C. 5-hydrazinyl-l ,7-naphthyridine, 145c

NH₂N H % ^N , 145c

5-Bromo-L7-naphthyridine (340 mg, 1.63 mmol), palladium(ii)(pi-cinnamyl) chloride dimer (42.13 mg, 0.081 mmol), N-[2-(di-l-adamantylphosphino)phenyl] morpholine (75.41 mg, 0.16 mmol) and sodium ter/-butoxide (624.56 mg, 6.5 1 mmol) was dissolved in dioxane (10 mL) under N? atmosphère. Hydrazine hydrate (162.84 mg, 3.25 mmol) was added and stirred at 60 °C for 3 h. The mixture was filtered and the solid was washed with 10 mL CH2CI2. The solvent was partioned between FLO ( 10 mL) and CH2CI2 (50 x 2 mL). The combined organic layers were dried overNa2SO₄, filtered and the filtrâtes were concentrated under reduced pressure to afford the title compound (260 mg, 99.8%) as brown solid. LCMS (ESI) m/z M+l: 161.1.

422

D. ethyl l-(l,7-naphthyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate,

145d

5-Hydrazinyl-l,7-naphthyridine (260 mg, 1.62 mmol) was dissolved m éthanol ( 10 mL), and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (467.8 mg, 1.95 mmol) was added. The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford the crude product as a yellow solid, which was purified by FCC (eluent; petroleum ether/ethyl acetate from 100 0 to 50/50) to afford the title compound (100 mg, 17.3%) as a yellow solid. LCMS (ESI) m/z

M+l: 337.0.

E.

-( 1,7-naphthyndin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 145e

, 145e

Ethy 1 -( 1,7-naphthyridin-5-yl)-5-(trifluoromethyl)-1 H-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 h. The reaction mixture was adjusted to pH 5 using HCl (2 N), extracted with EtOAc (30 mL x 2). The combined organic layers were dried over NYSCh, filtered and the filtrâtes were concentrated under reduced pressure to afford crude the title compound (75 mg, 90.9%) as a yellow solid. LCMS (ESI) m/z M+I: 309.0.

423

F. N-(5-cyano-6-(2H-L2,3-triazol-2-yI)pyridin-3-yl)-l-(l,7-naphthyridin-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 145

1 -(l,7-Naphthyridin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (75 mg, 0.24 mmol). 5-amino-2-(2H-1.2.3-triazol-2-yl)nicotinomtrile (54.36 mg, 0.29 mmol), pyridine (115.49 mg, 1.46 mmol) were dissolved in CH₂Ch ( 10 mL), and phosphorus oxychloride (149.25 mg, 0.97 mmol) was added. The mixture was stirred at 25 °C for 4 h, sat. NaHCO? (30 mL) was added and the mixture was extracted with CH2CI2 (30 mL x 2).

The combined organic layers were dried over Na₂SO4, filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a yellow oil, which was purified by préparative HPLC (22% to 52% (v/v) CH3CN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound (35 mg, 30.2%). LCMS (ESI) m/z M l : 477.0. Ή NMR (400MHz, DMSO-d6) 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, 1 H), 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, IH), 7.87 - 7.82 (m, 1H).

Example 146

N-(6-(2H-1,2,3-tnazol-2-yl)-5-( trifluoromethyl )pyridin-3-yl)-l-(qumolin-5-yl)-520 (trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 146

424

A. 5-nitro-2-(2H-l,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridme. 146a

O₂N

F ,146a

To a solution of 3-chloro-4-fluoronitrobenzene (1.2 g. 6.84 mmol) and 2H-1.2,3triazole (0.567 g, 8.20 mmol) in anhydrous DMA (5 mL) was added K2CO3 (1.89 g, 13.67 mmol). The reaction mixture was stirred at room température for 2 h. The mixture was fïltered and washed with ethyl acetate (10 mL x 3). The filtrate was concentrated to dryness to give a crude product. The crude product was purified by a flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100 0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford 2-chloro-5-nitro-3-(trifluoromethyl)pyridine, 146a (600 mg, 65.6% yield) as a yellow solid. ‘H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (s, 2 H). 9.16 (d, J=2.20 Hz, 1 H), 9.68 (d, J=2.21 Hz, 1 H).

B. 6-(2H-l,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine, 146b h₂n

F ^F ,146b

To a solution of 5-nitro-2-(2H-l,2,3-tnazol-2-yl)-3-(trifluoromethyl)pyridme (550 mg, 1.78 mmol) in MeOH/THF/H2O (5 mL10 mL/5 mL) was added iron (593 mg, 10.61 mmol) and ammonium chloride (568 mg, 10.61 mmol). The reaction mixture w^ras stirred at 70 °C for 2 h, sat. NaHCOs was added to the mixture to adjust the pH to 7~9. The reaction was fïltered and the organic solvent was concentrated. The mixture was extracted with CH2CI2 (10 mL x 3). The separated organic layer was dried (MgSCL), fïltered, and the solvent was concentrated to give a crade product as solid. The crude product was purified by a flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate

425 from 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford ethyl 6-(2H-l,2,3-triazol-2-yl)-5(trifluoromethyl)pyridin-3-amine, 146b (400 mg, 82.2% yield) as a white solid. LCMS (ESI) m/z M+l: 230.0; Ή NMR (400 MHz, DMSO-d6) δ ppm 6.38 (s, 2 H), 7.43 (d, J=2.43 Hz, 1 H), 8.04 (s. 2 H), 8.08 (d. J=2.43 Hz, 1 H).

C. N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(4-fhioro-2-methoxyphenyl)5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 146

Phosphorus oxychloride (75.85 uL, 0.39 mmol) was added to a solution of 1(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 3b (100 mg, 0.33 mmol), 6-(2H-L2,3-triazol-2-yl)-5-( trifluoromethyl )pyridin-3-amine (89.51 mg, 0.39 mmol), pyridine (263.26 uL. 3.26 mmol) in CH/Cb (2 mL). The mixture was stirred at room température for 2 h, 5 mL H₂O was added to the mixture and sat. NaHCOs was added to adjust the pH of the reaction mixture to 7-8. The mixture was extracted with CH2CI2 (5 mL x 3), the combined organic extracts were dried over anhydrous MgSO₄, filtered, and concentrated to drvncss under reduced pressure to afford the crude product. which was purified by préparative HPLC (42% to 72% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (120 mg, 70.9%). LCMS (ESI) m/z M+l : 518.9. Ή NMR (400 MHz. DMSO-d6) 8 ppm 7.62 - 7.66 (m, 1 H), 7.68 7.72 (m, 1 H), 7.94 - 8.02 (m, 2 H), 8.22 (s, 2 H), 8.35 (d, J=7.94 Hz, 1 H), 8.63 (s, 1 H), 8.91 (d. J=1.98 Hz, 1 H), 9.08 (d, J=2.65 Hz, 1 H), 9.19 (s, 1 H), 11.45 (s, 1 H).

426

Example 147

N-(5-chloro-6-(2H-L2,3-triazol-2-yr)pyridin-3-yl)-l-(pyrrolo[L2-a]pyrazin-l-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 147

A. N'-(pyrrolo[ 1,2-a]pyrazin-1 -yl)pivalohydrazide, 147a

147a

The mixture of l-chloropyrrolo[L2-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 give the crude product, the crode product was purified by FCC (petroleum ether/ ethyl acetate=100:0 to 70:30). The solvent was concentrated to get the crude product (200 mg, 61.5%).

B. l-hydrazinylpyrrolo[l,2-a]pyrazine, 147b

147b

The mixture ofN’-(pyrrolo[l,2-a]pyrazin-l-yl)pivalohydrazide (0.18 g, 0.73 mmol) and HCl in dioxane ( 1 mL) in CH2CI2 (10 mL) was stirred at room température for 1 h. The solvent was removed to give the product as a white solid (133.85 mg, 100%).

427

C.

ethyl l -(pyrrolo[ l ,2-a]pyrazm-1 -yl)-5-( trifluoromethyl)-1 H-pyrazole-4carboxylate, 147c

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (348.25 mg, 1.45 mmol), l-hydrazinylpyrrolo[I,2-a]pyrazine (133.85 mg, 0.73 mmol), DIEA (0.468 g, 3.63 mmol) and éthanol (20 mL) was stirred at 80 °C for 1 h. The résultant solution was concentrated to dryness under reduced pressure to afford the crude product, which was purified by FCC (petroleum ether: ethyl acetate = 100/0 to 70/30) to afford the title compound (0.15 g. 58.7%) as a yellow oil. LCMS (ESI) m/z M+l: 325.0.

D. 1 -(pyrrolo[ 1,2-a]pyrazin-1 -yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid,

147d

Sodium hydroxide (34.05 mg, 0.85 mmol) was added to a solution of ethyl 1(pyrrolo[l,2-a]pyrazin-l-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate (160 mg. 0.43 mmol) in THF/ H:O=1:1(10 mL). The mixture was reacted at room température for 2 h, the solvent was concentrated under reduced pressure and 20 mL ILO was added to the mixture. The mixture was acidified using IM hydrochloric to pH 5 and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous MgSO₄, and filtered. The filtrâtes were concentrated under reduced pressure to afford the product as a yellow solid (100 mg, 79.3%).

428

E. N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyndin-3-yl)-l-(pyrrolo[L2-a]pyrazm-l-yl)5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 147

1 -(Pyrrolo[ 1,2-a]pyrazin-l-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid ( 100 mg, 0.34 mmol), 5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine, (66.04 mg, 0.34 mmol), pyridine (0.14 mL, 1.69 mmol) were dissolved in CHrCb (5 mL), and phosphorus oxychloride (0.12 mL, 1.35 mmol) was added. The mixture was stirred at 25 °C for 2 h. Sat. NaHCO?, (20 mL) was added and the mixture extracted with CH2CI2 (30 mL x 2). The combined organic extracts were dried over anhydrous Na2SO₄. filtered. and the filtrate concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (38% to 68% (v/v) CH;,CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (66 mg, 40.6%). LCMS (ESI) m/z M+l: 473.9; *H NMR(400MHz, METHANOL-d4) δ ppm 8.78 (1 H, s), 8.70 (1 H, d.

J=2.20 Hz). 8.34 (1 H, s), 8.32 (1 H, d, J=4.85 Hz), 8.03 (2 H, s), 7.88 (1 H, s), 7.47 (1 H, d, J=4.85 Hz), 6.99 - 7.07 (1 H. m), 6.87 ( 1 H, d. J=4.19 Hz).

Example 148

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(pyrrolo[l,2-a]pyrazin-l-yl)-520 (trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 148

429 l -( PyrroΙο[ l ,2-a]pyrazin-1 -yl)-5-(trifluoromethyl)-1 H-pyrazoIe-4-carboxylic acid (180 mg, 0.18 mmol, 30% pure), 5-amino-2-(2H-l,2,3-triazol-2-yl)nicotinonitrile (33.94 mg, 0.18 mmol), pyridine (43.26 mg, 0.55 mmol) were dissolved in CH2CI2 (3 mL), and phosphorus oxychloride (41.93 mg, 0.27 mmol) was added. The mixture was stirred at 25 °C for 16 h, sat. NaHCO.3 (20 mL) was added and extracted with CH2C12 (30 mL x 2). The combined organic layers were dried over Na₂SO4, filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a yellow oil, which was purified by préparative HPLC (43% to 63% (v/v) CHsCN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound ( 11 mg, 12.9%). LCMS (ESI) m/z

M+l: 454.9.0; ‘H NMR (400 MHz, METHANOL-d4) δ ppm 9.07 (br s, 1 H), 8.90 (s, 1 H), 8.31 - 8.39 (m, 2 H), 8.15 (br s. 2 H), 7.89 (d. .1=1.32 Hz, 1 H), 7.48 (d,J=4.63 Hz, 1 H), 7.04 (dd, J=4.19, 2.65 Hz, 1 H), 6.87 (d, 1=4.19 Hz, 1 H).

Example 149

N-(5-cyano-6-(2-methyI-2H-tetrazol-5-yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 149

A. l-(quinolin-5-yl)-5-( trifluoromethyl)- lH-pyrazole-4-carboxamide, 149a

HATU (2.79 g, 7.32 mmol) was added to a solution of l-(quinolin-5-yl)-5(trifluoromethyl)-177-pyrazole-4-carboxylic acid, 3b (1.5 g, 4.88 mmol). NHa/dioxane (19.53 mL, 9.77 mmol), DIEA (1.26 g, 9.77 mmol) in CH₂C1₂. The mixture was stirred at rt for 16 h. 50 mL H₂O and 50 mL ethyl acetate were added to the mixture. The organic

430 layer was washed with brine (50 mL), dried over MgSOa and the fiitrate concentrated under reduced pressure. The residue was purified by FCC (petroleum ether/ ethyl acetate=100:5 to 100:50) to afford the title compound (1 g, 63.8%) as a yellow solid.

B. 5-bromo-3-methyl-2-(2H-tetrazol-5-yl)pyridine. 149b n=n N A '^NHίΓ ί^^ν _J49b

To a stirring 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 h. The solution was used directly for the next step.

C. 5-bromo-3-methyI-2-(2-methyl-2H-tetrazol-5-yl)pyridine, 149c n=n

N A , 149c

To a stirring 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 h and filtered. The fiitrate was concentrated to dryness under reduced pressure to afford the crude product, which was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 60:40) to afford the title compound (480 mg, 23.1%) as a white solid.

D. 5-bromo-3-(bromomethyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine. 149d

431

Benzoic peroxyanhydride (28.60 mg, 0.12 mmol) was added to a solution of 5bromo-3-methyl-2-(2-methyl-2H-tetrazol-5-yl)pyridme (0.3 g, 1.18 mmol) and 1,3dibromo-5,5-dimethylimidazolidine-2,4-dione (185.67 mg, 0.65 mmol) in acetonitrile (10 mL). The mixture was stirred at 80 °C under N₂ for 4 h. 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 give crude product. The crude product was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 70:30) to afford the title compound (326 mg, 24.5%) as a white solid. LCMS (ESI) m/z M+l: 333.8.

E. 5-biOmo-2-(2-methyl-2H-tetrazol-5-yl)nicotinonitrile, 149e

N0 N X Î |^NN ,149e

Diiodine (333.84 mg, 1.32 mmol) w⁷as added to a solution of 5-bromo-3(bromomethyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridme (296.00 mg, 0.26 mmol) in ammonia hydrate (5 mL). The mixture was stirred at 60 °C for 16 h. The solvent w⁷as concentrated under reduced pressure and extracted with acetate (30 mL x 2). The combined organic layers were concentrated under reduced pressure to give cnide product. The cnide product was purified by FCC (petroleum ether: ethyl acetate = 100:0 to 70:30) to afford the title compound (160 mg) as a white solid. LCMS (ESI) m/z M+l : 267.0.

F. N-(5-cyano-6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)-1 -(quinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4-carboxamide, Cpd 149

To a mixture of 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)nicotinonitrile (160.0 mg, 0.31 mmol), 1 -(quinolin-5-yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxamide (188.76

432 mg, 0.62 mmol), and sodium 2-methylpropan-2-olate ( l 18.47 mg, 1.23 mmol) were dissolved m dioxane ( 10 mL) was added tris(dibenzylideneactone)dipalladium(0) (56.44 mg, 0.062 mmol) and (9.9-dimethyl-9H-xanthene-4,5-diyI)bis(diphenylphos phine) (35.67 mg, 0.062 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was 5 filtered, the filtrate was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by préparative HPLC (26% to 46% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (28 mg, 17.7%).

LCMS (ESI) m/z Ml : 490.9; ‘H NMR (400 MHz, DMSO-d6) δ ppm 11.46 ( 1 H, s), 9.27 (1 H, d, J-2.43 Hz), 9.04 (1 H, d, J=2.43 Hz), 8.84 (1 H, d, J=2.43 Hz), 8.63 ( 1 H, s), 8.32 10 (1 H, d, J=8.38 Hz), 7.93 - 7.99(1 H. m), 7.89 - 7.93 ( 1 H, m), 7.64 - 7.69 (1 H, m), 7.58 7.63 (1 H. ni), 4.50 (3 H, s).

Example 150 and Example 151

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(furo[3,2-b]pyridin-7-yl)-515 (trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 150

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-methylfuro[3,2-b]pyridin-7-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 151

433

A. mixture of 7-chIoro-2-methylfuro[3,2-b]pyridine with 7-chlorofuro[3,2-b]pyridine, 150a

A mixture of 7-chloro-2-iodofiiro[3,2-b]pyridine (180 mg, 0.66 mmol). dicycloliexyl(2',6^,-diisopropoxy-[Ll'-biphenyl]-2-yl)phosphine (30 mg, 0.064 mmol), methylboronic acid (50 mg, 0.84 mmol), and K3PO4 (628 mg, 1.93 mmol) in dioxane (6 mL) and H2O ( 1.5 mL) was added diacetoxypalladium (7.23 mg, 0.032 mmol) under N2 and heated to 100 °C for 10 h. The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were dried o\er MgSO4, .fïltered and the filtrâtes were concentrated under reduced pressure to afford the crude product. The residue was further purified by column chromatography (eluent: petrol ether/EtOAc= 100:0 to 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[3,2b]pyridine, Cpd 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 to 50 °C ovemight. The solvent was removed under reduced pressure and directly used for the next step.

434

Mixture of ethyl l -(2-methylfuiO[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylate and ethyl l-(fuiO[3,2-b]pyridin-7-yl)-5-(trifluoiOmethyl) l H-pyrazole-4-carboxylate, 150c

A mixture of 7-hydrazinyl-2-methylfuro[3,2-b]pyridine and 7-hydrazinylfuro[3,2b]pyridine (65 mg, 0.21 mmol) was dissolved in éthanol (20 mL), and ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (111.96 mg, 0.50 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h. The réaction mixture was concentrated under reduced pressure to afford the crude product as a brown oil. which was purified by

FCC (eluent: petroleum ether/ethyl acetate from 100/0 to 50/50) to afford the title compound (50 mg, 35% yield) as a brown oil.

D. Mixture of l-(2-methylfuiO[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylic acid and l-(furo[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-lH-pyrazole-4 carboxylic acid, 150d

A mixture of ethyl l-(2-methylfuro[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylate and ethyl l-(furo[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-!Hpyrazole-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

435 stirred at 25 °C for l h. THF was removed, and the résultant residue was washed wâth ether (5 mL). To the aqueous layer waas added 3M HCl to adjust the mixture to pH i, and the aqueous phase was extracted with EtOAc (5 mL x 3). The organic layers were dried over MgS0₄, fïltered and the filtrâtes concentrated to afford the product as a brown oil (50 mg).

E. N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyndin-3-yI)-l-(furo[3,2-b]pyridin-7-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 150

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(2-methylfuro[3,2-b]pyridin-710 yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, 151

N

A । />

A mixture of l-(2-methylfuro[3,2-b]pyridin-7-yl)-5-(trifluoromethyl)-lH-pyrazole4-carboxylic acid and 1 -(furo[3,2-b]pyridin-7-yI)-5-(trifluoromethyl)-1 H-pyrazole-4carboxylic acid (50 mg, 0.082 mmol), 5-amino-2-(2H-1.2,3-triazol-2-yl)nicotinomtrile (15.3 mg. 0.082 mmol), and pyridine (19.5 mg, 0.25 mmol) were dissolved in CH2CI2 (3 mL), and phosphorus oxychloride ( 18.9 mg, 0.12 mmol) w'as added. The mixture was stirred at 25 °C for 16 h. Sat. NaHCO; (20 mL) was added and the mixture wus extracted with CH2CI2 (30 mL x 2). The combined organic layers were dried over Na2SO₄, fïltered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a

436 yellow oil, which was purified by préparative HPLC (22% to 52% (v/v) CHjCN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title N-(5-cyano-6-(2H-L2.3triazol-2-yl)pyridin-3-yl)-l-(furo[3,2-b]pyridin-7-yl)-5-( trifluoromethyl)-! H-pyrazole-4carboxamide. Cpd 150 (5 mg, 13%). LCMS (ESI) m/z M+1: 465.9. IH NMR (400 MHz, METHANOL-d₄) δ ppm 9.07 (br s, I H) 8.89 (d, J=2.43 Hz, 1 H) 8.79 (d, J=5.51 Hz. 1 H) 8.47 (s. 1 H) 8.34 (d, J=2.43 Hz, IH) 8.14 (s, 2 H) 7.71 (d, J=5.29 Hz, 1 H) 7.28 (d. J=2.43 Hz, 1 H); and

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(2-methylfuro[3,2-b]pyridin-7y! )-5-( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 151 (4 mg, 10%). 'H NMR (400 MHz, METHANOL-d4) δ ppm 9.06 (s. 1 H), 8.90 (d. J=2.65 Hz, 1 H), 8.71 (d, J=5.73 Hz, 1 H), 8.48 (s, 1 H), 8.14 (s, 2 H), 7.68 (d, J=5.73 Hz, 1 H), 6.98 (d, J=1.10 Hz, 1 H), 2.61 (d, J=0.88 Hz, 3 H). LC-MS: (ES, m/z)·. [M+l]⁺ 480.0.

Example 152

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(4-fluoro-2-methoxyphenyl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 152

Phosphorus oxychloride (48.54 uL, 0.52 mmol) was added to a solution of 1( quinolin-4-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxylic acid. (80 mg, 0.26 mmol), 5amino-2-(2H-L2,3-triazol-2-yl)benzonitrile (53.04 mg. 0.29 mmol), pyridine (210.61 uL.

2.60 mmol) in CH2CI2 (2 mL). The mixture was stirred at room température for 1 h, then 5 mL H2O was added to the mixture. Sat. NaHCO?, was added to adjust the pH of reaction mixture to 7-8. The mixture was extracted with CH2CI2 (5 mL x 3). The combined organic extracts were dried over anhydrous Mg₂SO₄, filtered, and the filtrate concentrated to dryness under reduced pressure to afford the crude product, which was purified by

437 préparative HPLC (35% to 65% (v/v) CH3CN and H?0 with 0.05% HCl) and lyophilized to dryness to afford the title compound (45 mg, 36.2%). LCMS (ESI) m/z M+l : 475.0. 'H NMR (400 MHz, DMSO-d6) δ ppm 7.34 (d, J=8.16 Hz, 1 H), 7.76 (t, J=7.28 Hz, 1 H), 7.90 (d, J=4.41 Hz, 1 H), 7.92 - 7.98 (m, 1 H), 8.11 - 8.16 (m, 1 H), 8.22 (d, J=2.21 Hz, 1

HL 8.24 (s, 1 H), 8.26 - 8.28 (m, 2 H), 8.43 (d. .1=2.20 Hz, 1 H), 8.67 (s. 1 H), 9.18 (d, J=4.63 Hz, 1 H), 11.22 (s, 1 H).

Example 153 l-(benzo[d]thiazol-7-yl)-N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-510 (trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 153

A. 7-hydrazinylbenzo[d]thiazole, 153a

A mixture of palladium(II)(pi-cinnamyl) chloride dimer (24.2 mg, 0.047 mmol) and

N-[2-(di-l-adamantylphosphino)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 température under argon for 10 min. 7-Bromobenzo[d]thiazole (200 mg, 0.93 mmol) and t-BuONa (1 79.56 mg, 1.87 mmol) were added to the mixture and purged with argon (4x). The resulting yellow réaction was stirred at room température for 5 min and then treated with hydrazine (93.53 mg, 1.87 mmol) via synnge and purged with argon (4x).

Then the mixture was stirred at 50 °C under argon for 2 h. The mixture was filtered and

438 washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to afford 7-hydrazinylbenzo[d]thiazole (150 mg, crude product) as a black solid.

B. ethyl l-(benzo[d]thiazol-7-yl)-5-(trifluoromethyI)-lH-pyrazole-4-carboxylate.

153b , 153b

A solution of 7-hydrazinylbenzo[d]thiazole. 153a (150 mg, 0.91 mmol). ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (327 mg, 1.36 mmol) in EtOH (20 mL) was stirred at 80 °C for 3 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 100/0 to 70/30). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford the title product (130 mg, 42.0 % yield) as a yellow solid,

C. 1 -(benzo[d]thiazol-7-yl )-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 153c

A solution of ethyl 1 -(benzo[d]thiazoI-7-yl)-5-(trifluoromethyl)-] H-pyrazole-4carboxylate, 153b (130 mg, 0.38 mmol), L1OH.H2O (23.98 mg, 0.57 mmol) in EtOH /Ή2Ο ¢2/1, 2 mL) was stirred at room température ovemight. IN HCl solution was added to neutralize the reaction solution. The mixture was extracted with ethyl acetate (J0 mL x 3). The separated organic layer was dried (MgSO₄), filtered, and the filtrate was concentrated to afford the title product (100 mg, 83.8% yield) as a white solid.

439

D. l-(benzo[d]thiazol-7-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5( trifluoromethyl)-l H-pyrazole-4-carboxamide, Cpd 153

N ,

Phosphores oxychloride (39.71 uL, 0.43 mmol) was added to a solution of 1(benzo[d]thiazol-7-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 153c (66.73 mg, 0.21 mmol), 5-chloiO-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine (50 mg, 0.26 mmol), pyridine (172.28 uL. 2.13 mmol) in CH2CI2 (2 mL). The mixture was stirred at room température for 1 h and 5 mL H2O ?vas added to the mixture. Sat. NaHCCh was added to adjust the pH of the reaction mixture to 7-8. The mixture was extracted with CH2CI2 (5 mL x 3). The combined organic extracts were dried over anhydrous Mg₂SO4, filtered, and the fiitrate concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (35% to 65% (v/v) CH3CN and H?O with 0.05% HCl) and lyophilized to dryness to afford the title compound (180 mg, 60.6%). LCMS (ESI) m/z M+1: 490.9. ‘H NMR (400 MHz, METHANOL-d4) δ ppm 7.69 (d, J=7.72 Hz, 1 H), 7.76 - 7.81 (m, 1 H), 8.06 (s. 2 H), 8.32 (d, .1=8.16 Hz, I H). 8.38 (s, 1 H), 8.72 (d, J=1.76 Hz, 1 H), 8.80 (s, 1 H), 9.36 (s, 1 H).

Example 154

N-(6-(4-amino-2H-1,2,3-triazol-2-yI)-5-chloropyridin-3-yl)- l-(quinolm-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 154

To a solution of 2-(3-chloro-5-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole4-carboxamido)pyridin-2-yl)-2H-l,2,3-triazole-4-carboxylic acid, Cpd 109 ( 160 mg, 0.29 mmol) in DMF (5 mL). DPPA (95.92 mg, 0.35 mmol) and TEA (118.83 ul, 0.87 mmol) were added under N2 atmosphère. The mixture was stirred at 80 °C overnight. The mixture was concentrated to give a crude product. which was purified by préparative HPLC (40% to 70% (v/v) CH/CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (45 mg, 30.8%). LCMS (ESI) m/z M+l: 499.9. ‘H NMR (400 MHz, DMSO-d6) δ ppm 5.51 (s, 2 H), 7.33 (s, 1 H), 7.59 - 7.64 (m, 1 H), 7.66 - 7.71 (m, 1 H),

7.91 - 8.01 (m, 2 H), 8.33 (d, J=8.60 Hz. 1 H), 8.58 - 8.62 (m. 2 H), 8.79 (d. J=2.2I Hz, 1

H), 9.06 (d. J=2.43 Hz, 1 H). 11.23 (br s, 1 H).

Example 155 l-(l-aminoisoqumolin-4-yl)-N-(5-chIoro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yI)-515 (trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 155

A.

ethyl 1 -(2-chloro-4-fluorophenyl )-5 -(trifluoromethyl)-1 H-pyrazole-4-carboxylate, 155a

441

Br

N

A solution of 4-bromoisoquinolin-l-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 heated to reflux for 36 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford the title product (3.3 g, 42.7% yield) as a white solid. LCMS (ESI) m/z M+l : 302.9.

B. l-(2,5-dimethyl-lH-pyrrol-l-yl)-4-hydrazinylisoquinoline, 155b

N ,155b

A mixture of ethyl l-(2-chloro-4-fluorophenyl)-5-(trifluoromethyl )-lH-pyrazole-4carboxylate, 155a (2.6 g, 8.63 mmol), hydrazine (864.30 mg, 17.27 mmol), palladium(II)(pi-cinnamyl) chloride dimer (134.17 mg, 0.26 mmol) and N-[2-(di-l15 adamantylphosphino)phenyl]morpholine (240.14 mg, 0.52 mmol) and t-BuONa (2486.21 mg, 25.90 mmol) in dioxane (50 mL) with N2 atmosphère was stirred at 60 °C for 10 h. After filtering through diatomaceous earth, the mixture was partitioned between Η?Ο (50 mL) and CH2CI2 ( 100 x 3 mL). The organic layer was separated, dried over MgSCU filtered and the filtrate concentrated to give the title product as a brown oil. LCMS (ESI) m/z Ml: 253.

442

C. ethyl l-(1-(2,5-dimethyl-lH-pyrrol-1 -yl)isoqumolin-4-yl)-5-(trifluoromethyl)- 1Hpyrazole-4-carboxylate, 155c

A solution of l-(2,5-dimethyl-lH-pyrrol-l-yl)-4-hydrazinylisoqumolme, 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 température for 2 h. The mixture was concentrated under reduced pressure, the crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 100. 0 to 50/50). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford the product (3.5 g, 94.6% yield) as a yellow solid. LCMS (ESI) m/z M+L 429.

D.

ethyl 1 -(l-(2.5-dimethyl- IH-pyrrol-l -yl)isoquinolin-4-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxylate, 155d

A solution of ethyl 1 -(1-(2,5-dimethyl-IH-pyrrol-I-yl)isoquiiiolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxylate, 4c (3.4 g, 7.94 mmol) and hydroxylamine

443 hydrochloride (13.24 g. 190.47 mmol) in EtOH (120 mL) was heated to reflux for 2 days. The solvent was removed and the residue was made basic by the addition of sat. NaHCO? solution (100 mL). The mixture was extracted with EtOAc ( 100 mL x 3). The combined organic layers were collected, dried over MgSO₄, filtered and the filtrate concentrated to give a crude product. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford the title product ( 1.6 g, 57.6% yield) as a brown solid. LCMS (ESI) m/z M+l : 350.9.

E. mixture of ethyl l-(l-((tert-butoxycarbonyl)amino)isoquinolin-4-yl)-5(trifluoromcthyl)-lH-pyrazole-4-carboxylate and ethyl 1 -(l-((di-teitbutoxycarbonyl)amino)isoquinolm-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate, 155e

A solution of ethyl l-(l-(2,5-dimethyl-lH-pyrrol-l-yl)isoquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxylate. 155d (600 mg, 1.71 mmol) and Boc₂O (1 121.47 mg, 5.14 mmol), DMAP ( 10.46 mg, 0.086 mmol) and TEA (715.22 ul, 5.14 mmol) in THF (5 mL) was stirred at room température overnight. The mixture was concentrated to give a crade product. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 100/0 to 50/50). The

444 desired fractions were collected and the solvent was concentrated under reduced pressure to afford the title product (650 mg, 68.9% yield) as a yellow solid.

F.

Mixture of 1 -( 1 -((tert-butoxycarbonyl)ammo)isoquinolin-4-y])-5-(trifluoromethyl)1 H-pyrazole-4-carboxylic acid; l-(l-((di-tert-butoxycarbonyl)amino)isoquinolin-4yl)-5-(trifluoromethyl)-!H-pyrazole-4-carboxylic acid, 155f

HO HO

, 155f

A solution of mixture of ethyl l-(l-((tert-butoxycarbonyl)amino)isoquinolin-4-yl)5-(trifluoromethyl)-!H-pyrazole-4-carboxylate and ethyl l-( 1 -((di-tertbutoxycarbonyl)amino)isoquinolm-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate, 4e (420 mg, 0.42 mmol), LiOH (35.22 mg, 0.84 mmol) m THF /H₂O (2/1. 0.75 mL) was stirred at room température for 2 h. IN HCl solution was added to neutralize the reaction solution. The mixture was extracted with ethyl acetate (10 mL x 3). The separated organic layer was dried (NacSCU). fïltered. and the filtrate was concentrated to afford the title product (400 mg, crade product) as a white solid.

G. Mixture of icrv-butyl (4-(4-((5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-(trifluoromethyl)-!H-pyrazol-l-yl)isoquinolin-l-yl)carbamate and di-^rt-butyl (4-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5( trifluoromethyl)-! H-pyrazol-l-yl)isoquinolin-!-yl)carbamate, 155g

445

Phosphorus oxychloride (63.18 uL, 0.68 mmol) was added to a solution of mixture of l -( l-((tert-butoxycarbonyl)amino)isoquinolin-4-yl)-5-(trifluoromethyl)- lH-pyrazole-4carboxylic acid; l-( l -((di-tert-butoxycarbonyl)amino)isoquinolin-4-yl)-55 ( trifluoromethyl)-lH-pyrazole-4-carboxyIic acid. 155f ( 150 mg, 0.15 mmol), 5-chloro-6(2H-L2,3-triazol-2-yl)pyridin-3-amine (86.18 mg, 0.44 mmol), pyridine ¢274.09 uL. 3.39 mmol) in CH2CI2 ¢4 mL). The mixture was stirred at room température for 1 h. 5 mL water was added to the mixture. Sat. NaHCOs was added to adjust the pH of reaction mixture to 7~8. The mixture was extracted with CH2CI2 (5 mL x 3). The combined organic extracts were dried over anhydrous Mg₂SO4, filtered. and the filtrate concentrated to dryness under reduced pressure to afford the crude product. LCMS (ESI) m/z M+l: 544.2.

H. l-(l-aminoisoquinolin-4-yl)-N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 155 ^N X c¹

NX O

Z^F

446

A mixture of mixture of Ze/7-butyl (4-(4-((5-chloro-6-(2H-I,2,3-triazol-2yl)pyridin-3-yl )carbamoyl)-5-(trifluoiOmethyl)-1 H-pyrazol-1-yl)isoquinolin-1 yl)carbamate and di-fô/7-butyl (4-(4-(( 5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3yl)carbamoyl )-5-( trifluoromethyl)-1 H-pyrazol-1 -yl)isoquinolin-1 -yl)carbamate. 155g ( 180 mg, 012 mmol) and HCl in dioxane (4N, 1,3 mL) in CH^CL (2.6 mL) was stirred at room température for 2 h. Water (5 mL) was added to the mixture. Sat. NaHCCh was added to adjust the pH of reaction mixture to 7~8. The mixture was extracted with CH₂CT (5 mL x 3). The combined organic extracts were dried over anhydrous Mg ,SO u filtered, and the filtrate concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (14% to 44% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized, to dryness to afford the title compound (100 mg, 70.2%). LCMS (ESI) m/z M+L 499.9. Ή NMR (400 MHz, DMSO-d6) δ ppm 7.04 (d, J=8.16 Hz, 1 H), 7.87 (t, J=7.50 Hz, 1 H), 7.97 - 8.03 (m, 1 H), 8.16 (s, 2 H), 8.33 (s, 1 H), 8.64 - 8.75 (m, 3 H), 8.90 (d, J=2.20 Hz, 1 H), 9.57 (br s. 2 H), 11.48 (s, 1 H).

Example 156 l-( 1 -aminoisoquinolin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 156

A. Mixture of /e/7-butyl (4-(4-((5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-320 yl)carbamoyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)isoquinolin-l-yl)carbamate and di-zA-butyl (4-(4-((5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl )-1 H-pyrazol-1 -yl)isoquinolin-1 -yDcarbamate, 156a

447

Phosphorus oxychloride (97.104 uL, 1.042 mmol) was added to a solution of mixture of 1 -( 1 -((tert-butoxycarbonyl)amino)isoquinolin-4-yl)-5-(trifluoroinethyl)-1Hpyrazole-4-carboxylic acid and l-( l-((di-tert-butoxycarbonyl)ammo)isoquinolin-4-yl)-55 (trifluoromethyl)-lH-pyrazole-4-carboxylic acid. 155f (220 mg, 0.22 mmol), 5-amino-2(2H-l,2,3-triazol-2-yl)nicotinonitrile (145.46 mg. 0.71 mmol), pyridine (421.29 uL, 5.21 mmol) in CH2CI2 (2 mL). The mixture was stirred at room température for 1 h. Water (5 mL) was added to the mixture. Sat. NaHCO? was added to adjust the pH of the reaction mixture to 7-8. The mixture was extracted with CH₂CL (5 mL x 3). The combined organic extracts were dried over anhydrous Mg-SO;. filtered. and the filtrate concentrated to dryness under reduced pressure to afford the crude product (300 mg). LCMS (ESI) m/z Ml: 535.1.

B. l-( l-aminoisoquinolin-4-yl)-N-(5-cyano-6-(2H-I,2,3-triazol-2-yl)pyridm-3-yI)-515 (trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 156

448

A mixture of /m-butyl (4-(4-((5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-(trifluoromethyl)-1 H-pyrazol-1 -yl)isoquinolin-1 -yl)carbamate and άί-tertbutyl (4-(4-((5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-lH-pyrazol-l-yl)isoquinolin-l-yl)carbamate, 156a (300 mg, 0.20 mmol) and HCl in dioxane (4N, 1.3 mL) in CH2CI2 (2.6 mL) was stirred at room température for 2 h. Water (5 mL) was added to the mixture. Sat. NaHCCh was added to adjust the pH of the reaction mixture to 7~8. The mixture was extracted with CH2CI2 (5 mL x 3). The combined organic extracts were dried over anhydrous Mg2SO4. filtered. and the filtrate concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (25% to 55% (v/v) CH3CN and H2O with 0.05% HCl) and lyophilized to dryness to afford the title compound (115 mg, 49.3%). LCMS (ESI) m/z M+l: 491.1; ‘H NMR (400 MHz, ACETONITRILE-d₃) δ ppm 9.06 (br s, 1 H). 8.83 (d, J=1.76 Hz, 1 H), 8.47 (d, J=8.38 Hz, 1 H), 8.38 (s, 1 H), 8.11 (br s, 2 H), 7.98 - 8.05 (m, 2 H). 7.86 - 7.95 (m. 1 H), 7.69 (s, 1 H), 7.2 1 (d, J=8.38 Hz, 1 H).

Example 157 N-(5-chloro-6-( 1 -methyl-lH-pyrazol-3-yl)pyridin-3-yl)-l-(1-oxo-1,2-dihydroisoquinolm5-yl )-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 157

A. 5-chloro-6-(l-methyl-lH-pyrazol-3-yl)pyridin-3-amine, 157a

449

Pd₂(dbaL (176.56 mg, 0.19 mmol) and Xphos ( 183.83 mg, 0.39 mmol) were added to a solution of 6-bromo-5-chloropyridin-3-amine (800 mg, 3.86 mmol), l-methyl-3(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (1203.52 mg, 5.78 mmol) and K5PO4 (2.456 g, 11.57 mmol) in dioxane/H₂O (6 1.20 mL) under an N; atmosphère. The mixture was stirred at 100 °C ovemight. The reaction solution was fïltered and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 100/0 to 0 100). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford 157a (530 mg, 59.0% yield) as a yellow solid. LCMS (ESI) m/z M+l: 209.1.

B. N-(5-chloro-6-( 1 -methyl- lH-pyrazol-3-yl)pyridin-3-yl )-1-(1 -oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyTazole-4-carboxamide, Cpd 157 /

Phosphorus oxychloride (115.35 uL, 1.24 mmol) was added to a solution of 1-(115 oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (400 mg, 1.24 mmol), 5-chloro-6-( 1 -methyl-lH-pyrazol-3-yl)pyridin-3-amine (344.28 mg, 1.49 mmol), pyridine (1000.9 uL, 12.38 mmol) in CH2CI2 (10 mL). The mixture was stirred at room température for 1 h. Water (5 mL) was added to the mixture and sat. NaHCOs was added to adjust the pH of the reaction mixture to 7-8. The mixture was extracted w'ith

CH2CI2 (5 mL x 3). The combined organic extracts were dried over anhydrous Mg₂SO₄, fïltered, and concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (29% to 59% (v/v) CH3CN and H₂O with 0.05% HCl) and lyophilized to dryness to afford the title compound (190 mg, 29.0%). LCMS (ESI) m/z M+l: 513.9. ’H NMR (400 MHz, DMSO-d6) δ ppm 3.94 (s, 3 H), 5.67 (d.

450

1=7.28 Hz, ] H), 6.78 (d, J=2.21 Hz, 1 H), 7.30 (t, >6.50 Hz. 1 H), 7.68 (t, >7.83 Hz, 1 H), 7.80 (d, >2.20 Hz, 1 H), 7.95 (d, >7.28 Hz, 1 H), 8.42 - 8.48 (m, 2 H), 8.56 (s, 1 H), 8.88 (d, >1.98 Hz, 1 H), 11.13 (s, 1 H), 11.64 (brd,J=5.51 Hz, 1 H).

Example 158 l-( 1-oxo- l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoiOmethyl)pyridin4-yl)-lH-pyrazole-4-carboxamide, Cpd 158

Phosphorus oxychloride (6.64 g, 43.3 mmol) was added to a solution of l-(l-oxo10 1,2-dihydroisoquinolin-5-yT)-5-(trifluoromethyl)- lH-pyrazole-4-carboxylic acid (7.60 g,

21.7 mmol), 2-(trifluoromethyl)pyridin-4-amine (3.51 g, 21.7 mmol) in pyridine (50 mL). The mixture was stirred at room température for 2 h, sat. NaHCO; (500 mL) was added. The mixture was extracted with CH2CI2 (500 mL x 3). The combined organic extracts were dried over anhydrous Na2SO₄, filtered, and the filtrate concentrated to dryness under reduced pressure to afford the crade product, which was purified by préparative HPLC (5% to 60% (v/v) CH3CN and H2O with 0.05% HCl). The desired fraction was collected and adjusted to pH 7-8 with aqueous NaHCO? (10%). The organic solvent was concentrated under reduced pressure and a white solid was formed. The solid was collected and washed with water (3 x 300 mL) and dried to afford the title compound (5.90 g,

58.1%). LCMS (ESI) m/z M+l: 467.9; Ή NMR (400 MHz, DMSO-d6) δ ppm 5.66 (d, >7.28 Hz, 1 H), 7.25 - 7.32 (m, 1 H), 7.67 (t, J=7.83 Hz, 1 H), 7.94 (d, J=7.28 Hz, 1 H), 7.99 (dd. >5.62. 1.65 Hz, 1 H). 8.26 (d, >1.76 Hz, 1 H), 8.44 (d, >8.16 Hz. 1 H), 8.56 (s, 1 H), 8.70 (d. >5.5 1 Hz, 1 H), 1 1.35 (s, 1 H), 11.64 (br d. >5.29 Hz, 1 H).

Example 159

451

-(2-amino-[ 1,2,4]triazolo[ 1,5-a]pyridin-5-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-( trifluoromethyl)-IH-pyrazole-4-carboxamide, Cpd 159

A.

5-bromo-2-(2.5-dimethyl-lH-pyiTol-l-yl)-[l,2,4]triazolo[l,5-a]pyridine, 159a

, 159a

Hexane-2,5-dione (428.6 mg, 3.76 mmol) was added to a solution of 5-bromo[l,2,4]triazolo[ L5-a]pyridin-2-amme (400 mg, 1.88 mmol) and acetic acid (215 pL) in toluene (5 mL). The mixture was stirred at 155 °C for 12 h. The mixture was concentrated 10 to give a crude product. The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 40/60). The eluant was collected and the solvent was concentrated under reduced pressure to give 5-bromo-2-(2,5dimethyl-lH-pyrrol-l-yl)-[L2,4]triazolo[L5-a]pyridine as a yellow solid (500 mg, 91%). LC-MS: (ES, m/z): |M · I | 292.9 15

B. 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-hydrazinyl-[l,2,4]triazolo[l,5-a]pyridine, 159b H₂N. * MU , 159b

5-Bromo-2-(2,5-dimethyl-lH-pyriOl-l-yl)-[l,2,4]triazolo[l,5-a]pyridine (500 mg, 1.72 mmol) in hydrazine monohydrate ( 1 mL) was stirred at 80 °C overnight. The solid

452 was filtered and washed with water (2 mL x 3). The solid was collected and dried to afford 2-(2,5-dimethyl-1 H-pyrrol-1 -yl)-5-hydrazinyl-[ l ,2,4] triazolo[ l ,5-a]pyridine as a white solid (416 mg, cnide product).

C. ethyl l-(2-(2,5-dimethyl-lH-pyrrol-l-yl)-[ 1.2,4]triazolo[1.5-a]pyridin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxylate. 159c

Ethyl (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, If (824.8 mg, 3.43 mmol) was added to a solution of2-(2,5-dimethyl-l H-pyrrol-l-yl)-5-hydrazinyl10 [L2.4]triazolo[l,5-a]pyridine (416 mg, 1.72 mmol) in éthanol (5 mL). The mixture was stirred at 80 °C overnight. The mixture was concentrated to give a cnide product. The cnide product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 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-lH15 pyrrol-l-yl)-[L2,4Jtriazolo[L5-a]pyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate as a yellow solid (650 mg, 90%). LC-MS: (ES. m/z): [M+l]* 419.1.

D. 1 -(2-( 2,5-dimethyl-1 H-pyrrol-1 -yl)-[l ,2,4]triazolo[ 1,5-a]pyridin-5-yl)-5( trifluoromethyl)- lH-pyrazole-4-carboxylic acid, 159d

453

Lithium hydroxide monohydrate (49.7 mg, L2 mmol) was added to ethyl 1-(2-(2,5dimcthyl-lH-pyrrol-l-yl)-[l,2,4]triazolo[ l,5-a]pyridm-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylate (330 mg, 0.79 mmol) in ethanol/water (2:1, 3 mL) and the mixture was stirred at rt for 2 h. The mixture was concentrated to give a crude product. The crude product was dissolved in 2 mL water and IM HCl was added to adjust the pH to 6~7. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over Na/SOi, filtered and the filtrâtes were concentrated to give 1-(2-(2,5-dimethyl1 H-pytTol-1 -yI)-[ 1,2.4]triazolo[ 1,5-a]pyridin-5-yl )-5-( trifluoromethyl)-1 H-pyrazole-4carboxylic acid as a white solid (307 mg, crude product).

E. N-(5-cyano-6-( 2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-(2,5-dimethyl-1 H-pyrrol-1 yl )-[ 1,2,4|triazolo[ l,5-a]pyridin-5-yl)-5-( trifluoromethyl)-1 H-pyrazole-4earboxamide, 159e

To a solution of 1-(2-(2.5-dimethyl-lH-pyrrol-l-yl)-[l,2,4]triazolo[l,5-a]pyridin-5yl)-5-(trifluoromethyl)-lH-pyrazoIe-4-carboxylic acid (300 mg, 0.77 mmol), 5-amino-2(2//-1,2,3-tnazol-2-yl)nicotinonitrile, 7b (172 mg, 0.922 mmol) and pyridine (622 pL,

7.69 mmol) in dichloromethane (2 mL) was added POCh ( 143.3 pL, 1.54 mmol) dropwise.

The reaction mixture was stirred at 20 °C for 1 h. Water (5 mL) was added to the mixture,

454 saturated aqueous NaHCO? (20 mL) was added and the pH was adjusted to 7-8. The mixture was extracted with dichloromethane (5 mL x 3). The combined organic extracts were washed with brine, dried over MgSO₄, filtered, and the filtrâtes concentrated under reduced pressure to afford the crude product. The crude product was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 10()/() to 0/100) to afford N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridm-3-yD-1-(2-(2,5-dimcthyl-1 H-pyrroll -yl)-[ 1,2,4]triazolo[ 1,5-a]pyridin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide (260 mg. 60 %) as a yellow solid. Ή NMR (400 MHz, DMSO-d6) δ ppm 2.16 (s. 6 H), 5.86 (s, 2 H), 7.94 (d. >6.61 Hz, 1 H), 8.03 (t. >8.27 Hz, 1 H), 8.25 (d. >9.04 Hz, 1 H). 8.31 (s, 2 H), 8.74 (s, 1 H), 8.89 (d, >2.43 Hz, 1 H), 9.08 (d. >2.43 Hz, 1 H). LC-MS: (ES, m/z): [M+l] 558.9.

F. l-(2-amino-[ L2,4]triazolo[L5-a]pyridin-5-yl)-N-(5-cyano-6-(2H-L2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 159

A solution ofN-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(2-(2,5dimethyl-lH-pyrrol-l-yl)-[l,-,4]triazolo| L5-a]pyridin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide (200 mg, 0.357 mmol) in TFA (2 mL) and dioxane/water (4:1, 4 mL) was stirred at 70 °C for 5 h. Sat. NaHCOa was added to the mixture to adjust the pH to 7-8. The aqueous phase was extracted with ethyl acetate (5 mL x 3). The separated organic layer was dried (MgSO₄), filtered, and the filtrate concentrated to give a crude product. The crude product was purified by préparative high-performance liquid chromatography (25% to 55% (v/v) CH3CN and H₂O with 10 mM NH4HCO3) to give 1(2-amiiio-[L2,4]triazolo[1.5-a]pyridin-5-yl)-N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide (12 mg, 7% yield). 'H NMR (400

455

MHz, DMSO-d6) δ ppm 7.46 (dd, >5.95, 2.20 Hz, 1 H), 7.65 - 7.74 (m, 2 H), 8.31 (s, 2 H), 8.77 (s, 1 H), 8.93 (d, >2.20 Hz, 1 H), 9.17 (d, >2.43 Hz, 1 H), 11.55 (s, 1 H). LCMS: (ES, m/z): [M +11 558.9.

Example 160

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-3-fluoro-l-(quinolin-5-yl)-5(trifluoromethyl)-! H-pyrazole-4-carboxamide, Cpd 160

ethyl 3-fluoro-l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate, 160a

, 160a

Ethyl l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate, 13b (1 g, 2.98 mmol) was dissolved in acetonitrile (8 mL) and silver (II) fluoride (2.18 g, 14.9 mmol) was added. The reaction mixture was kept in a dark place with stirring at 60 °C for 16 h. The reaction was filtered though diatomaceous earth and washed with CHsCN (200 mL), the filtrâtes were concentrated under reduced pressure to afford a crude product which was purified by préparative 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-l-(quinolin-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylate as a yellow solid (30 mg). LC-MS: (ES, m/z): IΜ · 11 354.0.

B. 3-fluoro-l-(quinohn-5-yl)-5-(tnfluoromethyl)-lH-pyrazole-4-carboxylic acid, 160b

456

Ethyl 3-fluoro-l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazoIe-4-carboxylate (30 mg, 0.035 mmol) was dissoived in THF (2 mL) and water (2 mL) and lithium hydroxide (8.41 mg, 0.35 mmol) were added. The reaction mixture was stirred at 30 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford 3-fluoro-l-(quinolin-5yl )-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid as a white solid (30 mg, 73.5%). LC-MS: (ES, m/z): [M+l]⁺ 325.9.

C. N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-3-fluoro-l-(qumolin-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide. Cpd 160

To a solution of 3-fluoro-l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylic acid (30 mg, 30% pure by HPLC, 0.026 mmol), 5-chloro-6-(2//-L2.3-triazol-2yl)pyridin-3-amine, Ij (7.6 mg, 0.038 mmol), and pyridine (133.8 mg, 1.69 mmol) in dichloromethane (10 mL) was added POCh (86.5 mg, 0.56 mmol) dropwise. The mixture was stirred at 25 °C for 3 h. Sat. NaHCOa (20 mL) was added and extracted with CH2CI2 (30 mL x 2). The combined organic layers were dried over Na₂SO4, filtered and the filtrâtes were concentrated under reduced pressure to afford crude product as a yellow oil. The crude product was then purifïed by préparative HPLC (37% to 57% (v/v) ( Tl ( \ and H₂O with 0.05%HCl) to afford N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-3fluoro-l-(quinolin-5-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxamide (2.5 mg, 18.7 %).

457

Ή NMR (400MHz, ACETONITRILE-d3) δ ppm 9.75 (br s, IH), 9.06 (d. J=2.8 Hz, IH), 8.82 (d, J=2.3 Hz, IH). 8.63 (d, J=2.3 Hz. IH), 8.37 (d, J=8.5 Hz. IH), 8.02 (s, 2H), 7.96 7.91 (m. IH), 7.90 - 7.84 (m, 2H), 7.63 (dd. J=4.1, 8.7 Hz, IH). LC-MS: (ES. m/zY [M+l] 502.9.

Example 161

N-(2.5-dimethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-oxo-l,2-dihydroisoquinolin-5yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 161

3-Bromo-2-chloro-6-methyl-5-nitropyridine (4.0 g, 15.9 mmol) and IH-1,2,3triazole (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

h. Sat. NH4CI (100 mL) was added and the reaction mixture extracted with EtOAc (200 mL x 3). The combined organic layers were dried over NagSOg. filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a purple oil. The oil was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 85/15). The desired fractions were collected and the

458 solvent was concentrated under reduced pressure to afford product as purple solid (2.5 g,

55.3%, yield).

B. 2,5-dimethyl-3-nitro-6-(2H-l,2,3-triazol-2-yl)pyridine. 161b

3-Bromo-6-methyl-5-nitiO-2-(2H-l,2,3-triazol-2-yl)pyridine (1.0 g, 3.52 mmol) and methylboronic acid (316.1 mg, 5.28 mmol) were 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 and the reaction mixture purged with N? for 1 min. The reaction mixture was stirred at 100 °C for 16 h, then filtered, and the residue was washed with EtOAc (50 mL x 3). The combined filtrâtes were concentrated under reduced pressure to afford crude product as a brown oil. The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 40/60). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford the product as a yellow solid (700 mg, 90.7%).

C. 2,5-dimethyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine, 161c

2,5-Dimethyl-3-nitro-6-(2H-l,2,3-triazol-2-yl)pyridine (200 mg. 3.19 mmol), iron ( 1.07 g, 19.2 mmol), NH4CI ( 1.03 g, 19.2 mmol) were added to the mixture of THF (20 mL) and water (20 mL). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with EtOAc (50 mL x 3). The combined filtrâtes were concentrated to dryness to give the crude

459 product as a yellow oil. The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from lOO/O to 40/60). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford product as a yellow oil (360 mg, 59.6%). ’H NMR (400MHz, CHLOROFORM-d) δ ppm

7.82 (s, 2H), 6.91 (s, IH), 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-yI)pyridin-3-yl)-1 -( l -oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 161

H

To asolution of l-(l-oxo-l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylic acid (213.2 mg, 0.66 mmol), 2,5-dimethyl-6-(2H-l,2,3-triazol-2yl)pyrid.in-3-amine (150 mg, 0.79 mmol) and pyridine (522.5 mg, 6.61 mmol) in CH2CI2 (15 mL) was added POCI3 (304 mg, 1.98 mmol) dropwise. The mixture was stirred at 25 °C for 4 h and at 40 °C for 3 h. 30 mL sat.NaHCOs w^:as added and extracted with CH2CI2 (30 mL x 3). The combined organic layers were dried over Na₂SO4, fïltered and the filtrâtes were concentrated under reduced pressure to afford crade product as a yellow oil. The crude product was then purified by préparative HPLC (33% to 63% (v/v) CH3CN and H₂O with 0.05%HCl) to afford product ( 190 mg, 57.4 %). *H NMR (400MHz, DMSO-d6) δ ppm 11.60 (br d, J=5.7 Hz, IH). 10.44 (s, IH), 8.50 (s, IH), 8.42 (d, J=7.9 Hz, IH), 8.11 (s, 2H), 8.02 (s, 1 H). 7.95 - 7.89 (m, IH), 7.65 (t. J=7.9 Hz, IH), 7.28 (dd, J=6.1. 7.2 Hz,

IH), 5.67 (d, J=7.3 Hz, IH), 2.47 (br s, 3H), 2.19 (s, 3H). LC-MS: (ES, m/z): [M+l]⁺495.0.

460

Example 162 and Example 163

N-(6-(2H-[l,2,3]triazolo[4,5-c]pyridm-2-yl)-5-chloiOpyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 162

and

N-(6-(lH-[l,2,3]triazolo[4,5-c]pyridin-l-yl)-5-chloropyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 163

A. Mixture of2-(3-chloro-5-nitropyridm-2-yl)-2H-[ 1,2,3 |triazolo[4,5-c]pyridine and l-(3-chloro-5-nitropyridin-2-yl)-lH-| 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 h. The reaction mixture

461 was filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow solid. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=l:O to petroleum ether/ ethyl acetate=O:l). 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. mixture of 6-(2H-[L2,3]triazolo[4,5-c]pyridin-2-yl)-5-chloropyridin-3-amine and 6-( lH-[l,2,3]triazolo[4,5-c]pyridin-l-yl)-5-chloropyridin-3-amine. 162b

Iron (0.535 g, 9.58 mmol) and ammonium chloride (0.512 g, 9.58 mmol) were added to the mixture of 2-(3-chloro-5-nitropyridin-2-yI)-2H-| l,2.3]triazolo|4,5-c]pyridme and l-(3-chloro-5-nitropyridin-2-yl)-lH-|1,2,3Jtriazolo[4,5-c]pyridine (530 mg, 0.958 mmol) in THF (20 mL), water (10 mL) and methanol ( 10 mL). The réaction was stirred at 80 °C for 2 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with EtOAc (20 mL x 2). The combined filtrâtes were concentrated to dryness to give a crude product as a brown solid. The crade product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford product as a brown oil (330 mg, 69.8%).

C. N-(6-(2H-[l,2.3]triazolo[4,5-c]pyridin-2-yl)-5-chloropyridm-3-yl )-l -(quinolin-5yl )-5-( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 162

and N-(6-( lH-[l.2,3]triazolo[4,5-c]pyridin-l-yl)-5-chloiOpyridin-3-yl)-l-(quinolin5-y 1)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 163

POCh (0.49 mL, 5.36 mmol ) was added to a mixture of 6-(2H-[ 1.2,3 ]triazolo[4,5c]pyridin-2-yl)-5-chloropyridin-3-amine and 6-( lH-[ l,2,3]triazolo[4,5-c]pyridin-l-yl)-5chIoropyridin-3-amine (330 mg, 1.34 mmol), l-(quinolin-5-yl)-5-(trifluoromethyl)-I/7pyrazole-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 h. Sat. NaHCOs solution (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (30 mL x 2). The organic layers were concentrated under reduced pressure to afford a crude product, which was purified by reverse phase HPLC (27% to 57% iv vi CILCN and H₂O with 0.05 % HCl) to afford N-(6-(2H-[ 1,2,3]triazolo[4.5-c]pyridin-2-yl)5-chloropyridm-3-yl)-l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 162 (340 mg, 47.3%). Ή NMR (400 MHz, DMSO-d6) δ ppm 11.73 (1 H, s), 9.87 (1 H. s), 9.06 - 9.12 (2 H, m), 8.87 (1 H, d, J=2.20 Hz), 8.77 (1 H. d, J=5.95 Hz), 8.75 (1 H, s), 8.36 (1 H, d, J=8.60 Hz), 8.07 (1 H, d, J=5.51 Hz), 7.98 - 8.03 (1 H, m), 7.94 - 7.98 (1 H, m). 7.69 - 7.76 (2 H, m). LC-MS: (ES, m/z): | Μ · 11 535.9; and

N-(6-( 1 H-[ 1.2,3]triazolo[4,5-c]pyridin-l-yl )-5-chloropyridin-3-yl)-l-(quinolin-5yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 163 (70 mg, 9.4%). ‘H NMR

463 ¢400 MHz, DMSO-d6) δ ppm 11.77 (I H, s), 9.53 ¢1 H, d, J=0.88 Hz), 9.08 - 9.18 ¢2 H, m), 8.88 (1 H, d, J=2.21 Hz), 8.78 ¢1 H, s), 8.70 (1 H, d, J=5.95 Hz), 8.37 - 8.44 (2 H. m), 7.98 - 8.09 (2 H, m), 7.83 - 7.89 (1 H, m), 7.75 - 7.82 (1 H, m). LC-MS: (ES, m/z): [M+l]⁺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-( qumolin-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 164

and N-(6-(3H-[L2,3]triazolo[4,5-b]pyridin-3-yJ)-5-chloropyridin-3-yl)-l-(quinolin-5-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 165

A. Mixture of 2-(3-chloro-5-mtiOpyndin-2-yl)-2H-[l,2,3]tnazolo[4,5-b]pyridme and

3-(3-chloro-5-nitropyridin-2-yl)-3H-[L2,3]triazolo[4,5-b]pyridine, 164a

lH-[L2,3]triazolo[4,5-c]pyridine (3.5 g, 18.14 mmol) was added to a mixture of 2,3-dichloro-5-nitropvridine (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 h. The réaction mixture was fïltered. The filtrate was concentrated under reduced pressure to give the crade product as a yellow solid. The crade product was purified by column chromatography over

464 silica gel (petroleum ether/ ethyl acetate= 100:0 to 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. mixture of 6-(2H-[l ,2,3]triazolo[4,5-b]pyridin-2-yl)-5-chloropyridin-3-amine and 6-(3H-[L2,3]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-5-nitropyridin-2-yl)-2H-[l,2,3]triazolo[4,5-b]pyridine and 3-(3chloro-5-nitiOpyridin-2-yD-3H-[l,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 was stirred at 80 °C for 2 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with EtOAc (20 mL x 3). The combined filtrâtes were concentrated to dryness to give crude product as a brown solid. The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 10:1 to 1:1). The desired fractions w'ere collected and the solvent was concentrated under reduced pressure to afford the product as a brown oil (3.2 g, 86.1%).

C. N-(6-(2H-[l,2,3]triazolo|4,5-b]pyridin-2-yl)-5-chIoropyridin-3-yl)-l-(quinolin-5yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 164 and N-(6-(3H-[ 1,2,3]triazolo[4,5-b]pyridin-3-yl)-5-chloropyridin-3-yl)-l -(quinolin5-yl)-5-(trifluoromethyl )- lH-pyrazole-4-carboxamide, Cpd 165

POCk(239 mg, 1.56 mmol ) was added to a mixture of 6-(2H-[l,2.3]triazolo[4,5b]pyridin-2-yl)-5-chloropyridin-3-amine and 6-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-5chloropyridin-3-amine (200 mg, 0.39 mmol), l-(quinolin-5-yl)-5-(trifluoromethyl)-\H5 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 h. Sat.

NaHCOj solution (10 mL) was added to the mixture. The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were concentrated under reduced pressure to afford a crude product, which was purified by reverse phase HPLC (35% to

65% (v/v) CHjCN and H₂O with 0.05%HCl) to afford N-(6-(2H-[ 1,2,3]triazolo[4,5b]pyridin-2-yl)-5-chloropyridin-3-yl)-l-(quinolm-5-yl)-5-( trifluoromethyl)-lH-pyrazole-4carboxamide, Cpd 164 (35.7, 16.9%). Ή NMR (400MHz, DMSO-d6) δ ppm 11.44 (s, 1H), 9.06 (br s. 1H), 8.98 (s. 1H), 8.84 (br d, >3.7 Hz, 1H), 8.78 (s, 1H), 8.63 (s. 1H), 8.35 (br dd, >8.2, 16.5 Hz, 2H), 8.01 - 7.88 (m, 2H), 7.76 - 7.59 (m, 3H). LC-MS: (ES, m/z): [Ml] 535.9; and

N-(6-(3H-[L2,3]triazolo[4,5-b]pyridin-3-yl)-5-chloiOpyridin-3-yl)-l-(quinolin-5yl)-5-(trifluoromethyI)-lH-pyrazole-4-carboxamide, Cpd 165 (21 mg, 9.6%). 'H NMR (400MHz. DMSO-d6) δ ppm 11.51 (s, 1 H). 9.08 (dd, >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, >8.2 Hz, 1H), 8.02 - 7.94 (m, 2H),

7.73 - 7.68 (m, 2H), 7.64 (dd, >4.6. 8.4 Hz, 1H). LC-MS: (ES, m/z): [M+l]' 535.9.

Example 166

N-(3-chloro-4-(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)phenyl)-l-(quinolin-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 166

466

2-(4-bromo-2-chlorobenzylidene)hydrazine-l -carboxamide, 166a

, 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, 22.78mmol) in methanol (50 mL) and water (50 mL) was stirred at 50 °C for 5 h. The mixture was cooled to température and filtered. The solid was w'ashed with ethyl acetate (10 mL x 3). The solid w⁷as dried to give the product as a white solid (3 g, 47.6%). ’H NMR (400 MHz, DMSO-d6) δ ppm 6.63 (brs, 2 H), 7.54 (dd, J=8.60, 1.76 Hz, 1 H), 7.75 (d,J=1.98 Hz, 1 H), 8.12 - 8.19 (m, 2 H), 10.55 (s, 1 H). 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

Br

, 166b

Bromine (931.5 uL, 18.1 mmol) was added dropwise to a solution of 2-(4-bromo2-chlorobenzylidene)hydrazine-I-carboxamide (2.0 g, 7.23 mmol) in acetic acid (15 mL). The mixture was stirred at 80 °C for 3 h. The mixture was cooled to room température, TMEB (60 mL) was added to the mixture and stirred for 10 min. The mixture was filtered

467 and the solid was dried to give the product as a white solid (l g, 50%). LC-MS: (ES. m/z): [M+l] 275.9

C. 5-(4-bromo-2-chlorophenyl)-2,4-bis((2-(trimethylsilyl)ethoxy)methyl)-2.4-dihydiO3H-l.2,4-triazol-3-one, 166c

/ ,166c

Sodium hydride (437.1 mg, 10.93 mmol) was added in portion to solution of5-(4bromo-2-chlorophenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (1.0 g, 3.64 mmol) m DMF (10 mL) at 0 °C. After stirring at 0 °C for 1 h, (2-(chloromethoxy)ethyl)trimethylsilane (2.579 mL. 14.57 mmol) was added dropwise to the mixture. The reaction was stirred at room température ovemight. Water (20 mL) was added to the reaction and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The separated organic layer was dried (MgSCU), fïltered, and the filtrate was concentrated to give a crude product. The crude product w^ras purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 50/50). The eluent was collected and the solvent w’as concentrated under reduced pressure to give the product as a colorless oil (400 mg, 21% yield). Ή NMR (400 MHz, CHLOROFORM-d) δ ppm -0.05 - -0.02 (m, 9 H), -0.01 - 0.01 (m, 9 H), 0.80 - 0.87 (m, 2 FI), 0.94 - 1.00 (m, 2 H), 3.52 - 3.59 (m, 2 H), 3.68 - 3.74 (m, 2 H), 4.95 (s, 2 H), 5.25 (s, 2 H), 7.40 (d, J=8.16 Hz, 1 H), 7.54 (dd. .1=8.27. 1.87 Hz, 1 H). 7.70 (d, J= 1.76 Hz, 1 H). LC-MS: (ES, m/z): [M+l]' 536.2

D. 1-(quinolin-5-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxamide, 166d

468 y=z f

N f .166d

HBTU ( 1.65 g, 4.35 mmol) was added to the mixture of l-(quinolin-5-yl)-5(trifluoromethyl)-lÆ-pyrazole-4-carboxylic acid. 3b (0.89 g, 2.90 mmol), ammonium chloride (775 mg, 14.5 mmol), DIEA (2.46 mL, 14.5 mmol) in DMF (15 mL). The reaction mixture was stirred at room température for 4 h. Water (20 mL) was added to the reaction solution. The aqueous layer was extracted with ethyl acetate (30 mL x 3). The organic layer was concentrated to give a crude product. The crude product was purifïed by chromatography (eluent:petroleum ether/ethyl acetate from 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+l]^: 307.0.

E. N-(3-chloiO-4-(5-oxo-L4-bis((2-(trimethylsilyl)ethoxy)methyl)-4_!5-dihydro-lHL2.4-tnazoI-3-yl)phenyl)-l-(quinolin-5-yl)-5-( trifluoromethyl)- lH-pyrazole-4carboxamide, 166e

Pd (OAc)2 ( 15.95 mg, 0.071 mmol) and Xantphos (41.1 mg. 0.071 mmol) were added to a solution of 5-(4-bromo-2-chlorophenyl)-2,4-bis((2(trimethylsilyl)ethoxy)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (380 mg, 0.71 mmol).

469 l-(quinoIin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide (293 mg, 0.92 mmol) and césium carbonate (8 K) mg, 2.49 mmol) in dioxane (5 mL) under N₂ atmosphère. The mixture was stirred at 100 °C overnight. The mixture was filtered and the filtrate concentrated to give a crude product, which was purified by flash column chromatography 5 over silica gel (eluent: petroleum ether/ethyl acetate from 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). LC-MS: (ES, m/z): [M+l]⁺ 760.1.

F. N-(3-chloro-4-( I-(hydroxymethyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-310 yl)phenyl)-1 -( quinolm-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, 166f

N-(3-Chloro-4-(5-oxo-1,4-bis((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1HL2.4-triazol-3-yl)phenyl)-l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamide (400 mg, 0.45 mmol) in TFA/DCM (1:2, 1.5 mL) was stirred at room température for 3 h. The mixture was concentrated to give a crude product which was used directly for the next step. LC-MS: (ES, m/zj. [M+l]” 531.0

G. N-(3-chloro-4-(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)phenyl)-I-(quinolin-5-yl)5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 166

470

N-(3-Chloro-4-( l-(hydlΌxymethyI)-5-oxo-4,5-dihydlΌ-lH-l,2.4-triazol-3yl)phenyl)- 1-(quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide (386 mg, 0.525 mmol) and TEA ( 1061 mg, 10.49 mmol) in methanol (5 mL) was stirred at 50 °C for 5 3 h. The mixture was concentrated to give a crude product. The crude product was purified by préparative high-performance liquid chromatography (20% to 50% (v/v) CH3CN and H?O with 0.05% HCl) to give the product as a white solid (120 mg, 45.5% yield). *H NMR (400 MHz, DMSO-d6) δ ppm 7.58 - 7.71 (m, 3 H), 7.77 (dd, J=8.60, 1.98 Hz, 1 H), 7.88 7.93 (m, 1 H), 7.94 - 8.00 (m, 1 H), 8.06 (d, J=1.98 Hz, 1 H), 8.33 (d, J=8.38 Hz, 1 H), 10 8.54 (s, 1 H). 9.06 (dd, J=4.08, 1.65 Hz, 1 H). 10.93 (br s, 1 H), 11.77 (br s, 2 H). LC-MS:

(ES, m/z): [M+1 i 489.9

Example 167

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(5-(trifluoromethyl)pyridin15 3-yl)-lH-pyrazole-4-carboxamide, Cpd 167

To a solution of 1-(1 -oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)- 1Hpyrazole-4-carboxylic acid (345.9 111g, 0.888 mmol) and 5-(trifluoromethyl)pyridin-319506

471 amine (120 mg, 0.74 mmol) in pyridine (3 mL) was added POCh (227 mg, 1.48 mmol) dropwise. The mixture was stirred at 25 °C for 4 h and at 40 °C for 3 h. Sat. NaHCCh was added to adjust the pH to 7-8 and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over MgSCL. filtered and the filtrâtes were concentrated under reduced pressure to afford crude product as a yellow oil. The crude product was then purified by préparative HPLC (37% to 57% (v/v) CH3CN and H2O with 0.05% HCl) to afford l-( l-oxo-l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(5(trifluoiOmethyl)pyridin-3-yl)-lH-pyrazole-4-carboxamide (130 mg, 37 %). '11 WR (400 MHz, DMSO-d6) δ ppm 5.67 (d, J=7.28 Hz, 1 H), 7.26 - 7.31 (m. 1 H), 7.68 (t, J=7.94 Hz. 1 H), 7.94 (d, J=7.50 Hz, 1 H), 8.44 (d, J=7.94 Hz, 1 H), 8.53 (s, 1 H), 8.60 (s, 1 H), 8.75 (s. 1 H), 9.12 (s, 1 H), 11.18 (s, 1 H), 11.64 (br d, J=4.63 Hz, 1 H). LC-MS: (ES. m/z): [M+l]’ 467.9

Example 168

N-(5-chloiO-6-(5-(hydroxymethyl)-l H-1,2,3-triazol-1-yl )pyridin-3-yl)-1-( 1-oxo-1.2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 168

A. mixture of methyl 2-(3-chloro-5-nitropyridin-2-yl )-2H-1,2,3-triazole-4-carboxylate and methyl l-(3-chloro-5-nitropyridin-2-yl)-lH-L2,3-triazole-5-carboxylate, 168a

472

Potassium carbonate (10.0 g, 72.5 mmol) was added to a solution of 2,3-dichIoro-5nitropyridine (7.0 g. 36.3 mmol) and methyl lH-l,2,3-triazole-4-carboxylate (4.61 g, 36.3 mmol) in MeCN (30 mL). The mixture was reacted at 60 °C for 16 h. 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 column chromatography over silica gel (petroleum ether/ ethyl acetate= 100:0 to petroleum ether/ ethyl acetate=40:60). The pure fractions were collected and the solvent w⁷as concentrated under reduced pressure to give the product as a yellow⁷ solid (8.8 g, 42.8 yield).

B. methyl 2-(5-amino-3-chloropyridin-2-yl)-2H-l ,2,3-triazole-4-carboxylate. 168b

and methyl l-(5-ammo-3-chloropyridin-2-yl)-lH-I,2,3-triazole-5-carboxylate, 168c

A mixture of methyl 2-(3-chIoro-5-nitropyridin-2-yl)-2H-1,2,3-triazole-4carboxylate and methyl l-(3-chloro-5-nitropyridin-2-yl)-lH-L2,3-triazole-5-carboxylate (8.8 g, 15.5 mmol) was added to a mixture of iron (8.66 g, 155.1 mmol), \H ·( 1 (8.30 g, 155.1 mmol) in THF (30 mL) and w⁷ater (15 mL). The reaction was stirred at 60 °C for 2 h.

The réaction mixture w⁷as filtered, the filtrate was concentrated under reduced pressure to

473 give the crude product as a brown oil, the crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=2:l to 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-l,2,3-triazole-4-carboxylate as a yellow solid, 168c ( 1.80 g. 45.7%). ^!H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.98 (s, 3 H), 4.21 (s. 2 H), 7.16 (d, J=2.51 Hz, 1 H), 7.90 (d, J=2.51 Hz, 1 H), 8.26 - 8.33 (m, 1 H). LC-MS: (ES. m/z): [M+l]* 254.0; and methyl l-(5-amino-3-chloropyridin-2-yl)-lH-L2,3-triazole-5-carboxylate as a yellow oil, 168d (1.10 g, 28.03+), ’H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.99 (s,

3 H), 4.33 (br s, 2 H), 7.20 (d, J=2.51 Hz, 1 H), 7.91 (d, J=2.76 Hz, 1 H), 8.48 (s, 1 H),

8.46 - 8.53 (m, 1 H). LC-MS: (ES, m/z): [Μ +1 f 254.0

D. methyl l-(3-chloro-5-(1-(1 -methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamido)pyridin-2-yl)-lH-l,2,3-triazole-5-carboxylate, 168e

To a solution of l-( l-methoxyisoquinolin-5-yl)-5-(trifluoromethyl )-lH-pyrazole-4carboxylic acid (1.10 g, 3.26 mmol), methyl l-(5-amino-3-chloropyridin-2-yl)-l H-l ,2.3triazole-5-carboxylate (910 mg. 3.59 mmol) and pyridine (774 mg, 9.79 mmol) in CH2CL (20 mL) was added POCh (600 mg. 3.91 mmol) dropwise. The mixture was stirred at 25 °C for 2 h, and 20 mL sat. NaHCCh was added. The reaction mixture was extracted with

CH2CI2 (30 mL x 2). The combined organic layers were dried over Na₂SO4, filtered and the filtrâtes were concentrated under reduced pressure to afford crude product as a yellow oil. The crade product was then purified by column chromatography over silica gel

474 (petroleum ether/ ethyl acetate = l:l to ethyl acetate) to afford the product (l.10 g. 52.1 %). LC-MS: (ES, m/z): [M+l]⁺ 573.1.

E. N-(5-chloro-6-(5-(hydroxymethyl)-lH-l,2,3-triazol-l-yl)pyridin-3-yl)-l-(lmethoxyisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, 168f

LiAlFL (61.6 mg, 1.62 mmol) was added to a solution of methyl l-(3-chloro-5-(l(l-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamido)pyridin-2yl)-lH-L2,3-triazole-5-carboxylate (300 mg, 0.46 mmol) in THF (10 mL) at 0 °C slowly, the mixture was stirred for 2 h at room température. Water (61 uL) was added to the mixture at 0 °C and the mixture was stirred for 10 min. NaOH (61 uL, 15% in water) was added to the mixture at 0 °C and the mixture was stirred for 10 min. Additional water (183 uL) was added to the mixture at 0 °C and the mixture was stirred for 10 min. MgSCh 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): ; XI 1 | 545.1

F. N-(5-chloro-6-(5-(hydroxymethyl)-1 H-1,2,3-triazol-1 -yl )pyridin-3-yl)-l -( 1-oxoL2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-! H-pyrazole-4-carboxamide. Cpd 168

475

N-(5-Chloro-6-(5-(hydroxymethyl)-1 H-1,2,3-triazol-1 -yl )pyridin-3-y l)-1 -( 1 methoxyisoquinolm-5-yl )-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide (180 mg, 0.28 mmol) in isopropanol (4 mL) was added to concentrated HCl (2 mL) and the reaction was stirred at 60 °C for 2 h. The mixture was concentrated under reduced pressure to afford the crude product as a yellow oil. The crude product was purified by préparative highperformance liquid chromatography (12% to 42% (v/v) CH?CN 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 white solid (36 mg, 23.9% yield). Ή NMR (400 MHz, DMSO-d6) δ ppm 4.65 (s, 2 H), 5.67 (d, J=7.28 Hz, 1 H), 7.31 (t, J=6.53 Hz, 1 H), 7.68 (t, J=7.78 Hz, 1 H), 7.96 (d, J=7.28 Hz, 1 H), 8.42 - 8.50 (m, 2 H). 8.54 - 8.73 (m, 2 H), 8.90 (br s, 1 H), 11.27 - 11.47 (m, 1 H), 11.65 (brd, J=5.02 Hz, 1 H). LC-MS: (ES, m/z): |M+11 530.9.

Example 169

N-(5-chloro-2-methyl-6-( 1 -methyl-1 H-pyrazol-3-yl )pyridin-3-yl)-1 -( 1 -oxo-1,2dihydroisoquinolin-5-yl )-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 169

A. 5,6-dichloro-2-methylpyridin-3-amine, 169a

Iron (0.811 g, 14.5 mmol) and ammonium chloride (0.775 g, 14.5 mmol) were added to a mixture of 2,3-dichloro-6-methyl-5-nitiOpyridine (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 h. Ethyl acetate (100 mL) was added to the mixture. The precipitate was collected by

476 filtration. The residue was washed by (100 x 3 mL) ethyl acetate. The filtrate was collected and concentrated under reduced pressure. 10% NaHCCh (100 mL) was added to the mixture and the mixture was extracted with ethyl acetate (100 mL x 2). The organic layers were dried (NazSOfl, filtered. and the filtrate removed to afford the product as a yellow solid. The crude product was purified by column chromatography over silica gel (petroleum ether, ethyl acetate=10:l to 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-( l-methyl-lH-pyrazol-3-yl)pyridin-3-amine, 169b

[1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium( II), complexed with dichloromethane (113 mg, 0.14 mmol) was added to a solution of 5,6-dichloro-2methylpyridin-3-amine (350 mg, 1.98 mmol), l-methyl-3-(4,4.5,5-tetramethyl-1,3.215 dioxaborolan-2-yl)-lH-pyrazole (535 mg, 2.57 mmol) and potassium acetate (582 mg, 5.93 mmol) in dioxane/water (3:1, 10 mL) under N₂ atmosphère at 100 °C ovemight. The mixture was filtered. and the filtrate was concentrated to give a crude product. The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 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): IM+1 ! 222.9.

C. N-( 5-chloro-2-methyl-6-( 1 -methyl-1 H-pyrazol-3-y l)pyridin-3-yl )-1-(1 -oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 169

477

° \ /) HN-X

To a solution of l-( l-oxo-l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylic acid (175 mg, 0.45 mmol) and 5-chloro-2-methyl-6-(l-methyl-lHpyrazol-3-yl)pyridm-3-amine (l 10 mg, 0.49 mmol) and pyridine (363 pL, 4.49 mmol) in dichloromethane (5 mL) was added POCh (68.9 mg, 0.45 mmol) dropwise. The mixture was stirred at 25 °C for 2 h. Water (5 mL) was added, sat. NaHCOs was added to adjust the pH to 7-8 and the reaction mixture was extracted with dichloromethane (5 mL x 2). The combined organic layers were dried over MgSO₄, filtered and the filtrâtes were concentrated under reduced pressure to afford crude product. The crude product was then purified by préparative HPLC (30% to 60% (v/v) CH3CN and H2O with 0.05%HCl) to afford product as a white solid ( 105 mg, 44%). *H NMR (400 MHz, DMSO-d6) δ ppm 2.52 (br s, 3 H), 3.93 (s, 3 H), 5.69 (br d, J=7.50 Hz, l H), 6.75 (d, J=2.21 Hz, l H), 7.29 (br s, l H), 7.67 (t, J=7.83 Hz, l H), 7.79 (d, J=2.21 Hz, l H), 7.93 (d, J=7.50 Hz, l H), 8.09 (s, l H), 8.44 (d, J=8.38 Hz, l H), 8.49 (s, l H), 10.40 (s, l H), 11.62 (brs, 1 H). LC15 MS: (ES, m/z): [M 11 527.9

Example 170

N-(5-chloro-2-methyl-6-( 1 H-pyrazol-1 -yl)pyridin-3-yl)-l -( 1 -oxo-1,2-dihydroisoquinolin5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 170

478

A. 3-chloro-6-methyl-5-nitro-2-( lH-pyrazol-l-yl)pyridine, 170a

A solution of 2,3-dichloro-6-methyl-5-mtropyridine (1.2 g. 5.80 mmol), 1H5 pyrazole (987 mg, 14.5 mmol) and potassium carbonate (2.40 g, 17.4 mmol) in MeCN (20 mL) was stirred at rt ovemight and at 40 °C for another 8 h. The mixture was filtered and the solid was washed with ethyl acetate (20 mL x 3). The filtrate was concentrated to give a crude product. The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 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). ‘H NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3 H), 6.64 (t. >1.76 Hz, 1 H), 7.92 (s, 1 H), 8.49 (d. >2.65 Hz, 1 H). 8.84 (s. 1 H).

B. 5-chloro-2-methyl-6-( lH-pyrazol-l-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-6-methyl-5-nitro-2-(lH-pyrazol-l-yl)pyridine (0.650 g,

2.72 mmol) in methanol (5 mL), THF (10 mL) and water (5 mL). The mixture was stirred 20 at 70 °C for 2 h. 10 mL Sat. NaHCO3 solution was added to the mixture, the mixture was filtered, and the filtrate was extracted with ethyl acetate (15 mL x 3). The organic layer was dried (NazSCL) and the solvent removed to afford the product as a yellow solid (500 mg, 88%).

479

C. N-(5-chloro-2-methyl-6-( l H-pyrazol-1 -yl)pyridin-3-yl)-1 -( l -oxo-1.2dihydroisoquinolm-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 170

To a solution of l-(l-oxo-1.2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylic acid (146 mg, 0.70 mmol) and 5-chloro-2-methyI-6-( 1 H-pyrazol-1yl)pyridin-3-amine (200 mg, 0.58 mmol) in pyridine (5 mL) was added POCh (108 uL, 1.16 mmol) dropwise. The mixture was stirred at 25 °C for 2 h. Water (5 mL) was added, sat. NaHCOs was added to adjust the pH to 7-8 and the réaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over MgSO₄, filtered and the filtrâtes were concentrated under reduced pressure to afford crude product. The crade product was then purified by préparative HPLC (32% to 62% (v/v) CTECN and HzO with ().()5%HC1) to afford the product as a white solid (160 mg, 53%). 'H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (br s, 3 H). 5.68 (d, J=7.72 Hz, 1 H), 6.52 - 6.58 (m, 1 H), 7.27 - 7.33 (m, 1 H), 7.68 (t, J=7.94 Hz, I H), 7.81 (d, J=1.32 Hz, 1 H), 7.94 (d, J=7.72 Hz. 1 H), 8.27 (d, J=2.21 Hz, 1 H), 8.30 (s, 1 H), 8.44 (d, J=7.94 Hz. 1 H), 8.52 (s, I H), 10.54 (s, 1 H), 11.63 (br d, J=5.95 Hz, 1 H). LC-MS: (ES, m/z): JM 11 514.2

Example 171 N-(5-chloiO-2-methyl-4-(2H-l,2,3-triazol-2-yl)phenyl)-l-( 1-oxo-l,2-dihydiOisoquinolin-5yl)-5-(trifluoromethvl)-lH-pyrazole-4-carboxamide, Cpd 171

480

A. 2-(2-chloro-5-methyl-4-nitrophenyl)-2H-1,2,3-triazole, 171a

The mixture of L2-dichloiO-4-methyl-5-nitrobenzene (1.0 g, 4.85 mmol), 2H-1,2,3triazole (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) was stirred at 80 °C overnight. The solid was collected by filtration and then was washed wdth 50 mL ethyl acetate. The solvent was concentrated to give the crude product as a yellow solid. The cnide product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=100:0 to 50:50). The solvent was concentrated to afford the product as a white solid (180 mg. 15.5% yield). Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69 (s. 1 H), 7.64 (d. J=1.00 Hz, 1 H), 7.40 (d, J= 1.25 Hz, 1 H), 7.21 (s, 1 H) 2.11 (s, 3 H).

B. 5-chloro-2-methyl-4-(2H-l,2,3-triazol-2-yl)aniline, 171b

bon (0.772 g, 13.8 mmol) and ammonium chloride (0.74 g, 13.8 mmol) were added to a mixture of 2-(2-chloro-5-methyl-4-nitrophenyl)-2H-L2,3-triazole (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 h. Ethyl acetate (50 mL) was added to the mixture. The precipitate was collected by filtration, and the residue was washed with ethyl acetate (50 x 3 mL). The filtrate was

481 collected and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=10:1 to 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). *H NMR (400 MHz, DMSO-d6) δ ppm 7.97 (s. 2 H), 7.13 (s, 1 H), 6.77 (s, 1 H), 5.58 (s, 2 H), 3.33 (s, 2 H), 2.48 (br s, 2 H), 2.05 (s, 3 H).

C. N-(5-chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl )-1 -( 1 -oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 171

To a solution of l-( 1 -oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)- 1Hpyrazole-4-carboxylic acid (150 mg, 0.46 mmol) and 5-chloro-2-methyl-4-(2H-1,2,3triazol-2-yl)aniline (96.8 mg, 0.46 mmol) and pyridine (220 mg, 2.78 mmol) in dichloromethane (10 mL) was added POC1₃ (285 mg, 1.86 mmol) dropwise. The mixture was stirred at room température for 4 h. Sat. NaHCOs was added to adjust the pH to 9-10, and the reaction mixture was extracted with dichloromethane (30 mL x 3). The combined organic layers were dried over MgSO₄, filtered and the filtrâtes were concentrated under reduced pressure to afford crude product as a yellow’ oil. The crude product was then purified by préparative HPLC (35% to 65% (v/v) CH3CN and H2O with 0.05%HCl) to afford product as a white solid (131 mg, 54.7%). *H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (br d, J=5.51 Hz, 1 H), 10.35 (s, 1 H), 8.36 - 8.53 (m, 2 H), 8.13 (s, 2 H), 7.81 - 7.95 (m, 2 H), 7.59 - 7.68 (m. 2 H), 7.26 (dd, J=7.17, 6.06 Hz, 1 H), 5.66 (br d, J=7.50 Hz, 1 H), 2.27 - 2.37 (m. 3 H). LC-MS: (ES. m/z): | Μ ~ 1 I 514.2

482

Example 172

N-(5-chloro-2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1 -( l -oxo-1,2-dihydroisoquinolin-5yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 172

A. 2-(2-chloro-5-fluoro-4-nitrophenyl)-2H-l,2,3-triazole, 172a

A mixture of l-chloro-2,4-difluoro-5-nitrobenzene (3.0 g, 15.5 mmol), 2H-1,2,3triazole (1.61 mL, 23.3 mmol), and potassium carbonate (6.42 g, 46.5 mmol) m acetonitrile (50 mL) was stirred at 30 °C for 2 h. 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 crade product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=10:l to 1:2). The solvent was concentrated to afford the product as a yellow solid (0.6 g, 16%). ^!H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79 (br d, >10.80 Hz, 1 H), 7.95 (s, 2 H), 8.32 (br d, J=7.06

Hz, 1 H).

5-chloro-2-fluoro-4-(2H-l ,2,3-triazol-2-yDaniline, 172b

483

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-5-fluoiO-4-nitrophenyl)-2H-l,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 h. Ethyl acetate (50 mL) was added to the mixture. The precipitate was collected by filtration. The residue was washed with (50 x 3 mL) ethyl acetate. The filtrate was collected and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=10:l to petroleum ether/ ethyl acetate=0:1 ). The pure fractions were collected and the solvent was concentrated under reduced pressure to afford the product as a white solid (0.50 g, 81%).

IH NMR (400 MHz, DMSO-d6) δ ppm 5.93 (s, 2 H), 6.93 (d, J=8.60 Hz. 1 H), 7.36 (d. J=11.25 Hz, 1 H), 7.99 - 8.04 (m, 2 H). LC-MS: (ES, m/z): [M+l]’ 212.9

C. N-(5-chloro-2-fluoiO-4-(2H-L2,3-triazol-2-yl)phenyl)-l-( 1 -oxo-1,2dihydroisoquinolin-5-yl )-5-(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 172

To a solution of l-(l-oxo-l,2-dihydiOisoquinolin-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylic acid (152 mg, 0.47 mmol) and 5-chloro-2-fluoro-4-(2H-1,2,3triazol-2-yl)aniline (100 mg, 0.47 mmol) and pyridine (149 mg. 1.888 mmol) in dichloromethane (10 mL) was added POCh (144 mg. 0.94 mmol) dropwise. The mixture was stirred at room température for 4 h. Sat. NaHCOj was added to adjust the pH to 9-10 and the reaction mixture was extracted with dichloromethane (30 mL x 3). The combined organic layers were dried over MgSOj, filtered and the filtrâtes were concentrated under reduced pressure to afford crude product as a yellow oil. The crude product was then purified by préparative HPLC (32% to 62% (v/v) CH?CN and HjO with 0.05%HCl) to afford product as a yellow solid ( 135 mg, 55.4%). 'H NMR (400 MHz. DMSO-d6) δ ppm

484

5.67 (d, J=7.28 Hz. I H), 7.27 (dd, J=7.28. 5.95 Hz, l H), 7.65 (t, J=7.83 Hz. I H), 7.86 (d. J=10.58 Hz, l H), 7.90 - 7.94 (m, 1 H), 8.18 (s, 2 H), 8.24 (d. J=7.50 Hz, 1 H), 8.42 (d, J=8.16Hz, 1 H), 8.45 (s, 1 H). 10.81 (s, 1 H), 11.60 (br d, J=5.07 Hz, 1 H). LC-MS: (ES, m/z): [M+l]’ 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)-lH-pyrazole-4-carboxamide, Cpd 173

A. (2-(3-chloro-5-(l-(quinolin-5-yl)-5-(trifluoromethyl)-l H-pyrazole-4carboxamido)pyridin-2-yl)-2H-l .2,3-triazol-4-yl(methyl methanesulfonate. 173a

A solution of N-(5-chloro-6-(4-(hydroxymethyl)-2H-l,2,3-triazol-2-yl)pyridin-3yl )-1-( qumolin-5-yl)-5-(tnfluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 136 (420 mg.

0.79 mmol) in DCM (8 mL) was cooled to 0 °C, TEA (240 mg, 2.37 mmol) w⁷as added and then methanesulfonyl chloride (136 mg, 1.19 mmol) was added dropwise. The solution was stirred at 0 °C for 1 h. The mixture was concentrated, dried, and used directly for the next step.

485

B. N-(5-chloro-6-(4-(methoxymethyl)-2H-l,2.3-triazol-2-yl)pyridin-3-yl)-l-(quinolin5-yl)-5-(tnfluoiOmethyl)-lH-pyrazole-4-carboxarnide, Cpd 173

A solution of (2-(3-chloro-5-( 1 -(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-45 carboxamido)pyridin-2-yl)-2H-l,2.3-triazol-4-yl)methyl methanesulfonate (150 mg. 95% pure, 0.24 mmol) in methanol (20. mL) was stirred at 50 ^CC for 2 h. The mixture was concentrated under reduced pressure to afford crude product as a yellow oil which was purified by préparative high-performance liquid chromatography (31% to 61% (v/v) CH?CN and H₂O with 0.05%HCl). The pure fractions were collected and the solvent w⁷as 10 concentrated under reduced pressure, lyophilized to dryness to give product as a white solid (25 mg, 19.3 % yield). ’H NMR (400 MHz. METHANOL-d4) δ ppm 3.44 (d, J=0.66 Hz, 3 H), 4.67 (s, 2 H), 7.61 - 7.66 (m, 1 H), 7.75 (d, J=8.60 Hz, 1 H), 7.83 (d, >7.50 Hz, 1 H), 7.94 - 7.99 (m, 1 H), 8.01 (s, 1 H), 8.33 (d, >8.60 Hz, 1 H), 8.39 (s, 1 H), 8.72 (dd, >2.21, 1.32 Hz, 1 H), 8.79 (d, >2.21 Hz, 1 H), 9.00 (d, J=3.97 Hz. 1 H). LC-MS: (ES, 15 m/z): ΜΠ 528.9

Example 174

N-(4-(4-(aminomethyl)-1 H-pyrazol-1 -yl)-3-chlorophenyl)-1 -(quinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 174

486

A. rm-butyl (( l-(2-chloro-4-nitrophenyl)-lH-pyrazol-4-yl)methyl)carbamate, 174a

Potassium carbonate (350 mg, 2.54 mmol) was added a solution of 2-chloro-1 5 fluoro-4-nitrobenzene (245 mg, 1.39 mmol), zm-butyl (( lH-pyrazol-4yl)methyl)carbamate (250 mg, 1.27 mmol) in MeCN (5 mL), the mixture was stirred at 80 °C for 12 h. The reaction mixture was fïltered, and the filtrate was concentrated under reduced pressure to give the crade product as a yellow' solid, which was then purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=10:l to petroleum ether/ ethyl acetate=l : 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+l]' 353.0

B. /m-butyl (( l-(4-amino-2-chlorophenyl)-lH-pyrazol-4-yl)methyl)carbamate, 174b

, 174b

487

Iron (348.3 mg. 6.24 mmol ) and NH4CI (333.6 mg. 6.24 mmol) were added to the mixture of rerr-butyl (( I-(2-chloro-4-nitrophenyl)-lH-pyrazol-4-yl)methyl)carbamate (440 mg, 1.25 mmol) in THF (20 mL), H2O (5 mL), MeOH (5 mL), the réaction mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with EtOAc (20 mL x 2). the combined filtrâtes were concentrated to dryness to give a crude product as a brown solid which was purified by flash column chromatography over 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 afford product as a brown solid (388 mg, 96.4%). LC-MS: (ES, m/z): [Μ- Π 323.0

C. rm-butyl (( l -(2-chloro-4-( l -(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)phenyl)-1 H-pyrazoI-4-yl)methyl)carbamate, 174c rm-Butyl (( 1 -(4-amino-2-chlorophenyl)-1 H-pyrazol-4-yl)methyl)carbamate ( 140 mg, 0.43 mmol). l-(Quinolin-5-yl)-5-(trifluoromethyl)-l/7-pyrazole-4-carboxylic acid, 3b (133.3 mg, 0.43 mmol), DIEA (280.3 mg, 2.17 mmol) were dissoived in DMF (4 mL), and HATU (247.4 mg, 0.65 mmol) was added, the mixture was stirred at 25 °C for 3 h. Sat. NaHCO? (20 mL) was added and the reaction mixture was extracted with CH2CI2 (20 mL x 2), the combined organic layers were dried over anhydrous Na SO:. and filtered. The solvent was concentrated under reduced pressure to afford product as a brown solid (200 mg, 36.8% yield). LC-MS: (ES, m/z): [M+l g 612.2

488

D, N-(4-(4-(aminomethyl)-l H-pyrazol-l-yl)-3-chlorophenyI)-l-(quinolin-5-yI)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 174

HCl/dioxane (10 mL) was added to ze/7-butyl (( l-(2-chloro-4-(l-(quinoiin-5-yl)-55 (trifluoromethyl)-lH-pyrazole-4-carboxamido)phenyl)-lH-pyrazoI-4-yl)methyl)carbamate (88 mg. 0.14 mmol), the mixture was stirred at rt 10 min. The solvent was concentrated under reduced pressure. The residue purified by préparative high-performance liquid chromatography (15% to 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). 'H NMR (400 MHz, METHANOL-d4) δ ppm 9.37 (1 H. d, J=3.76 Hz), 8.55 (1 H, s), 8.52 ( 1 H, s), 8.45(1 H. s), 8.33(1 H, t, J=8.16 Hz), 8.20 (1 H, s), 8.18 - 8.20 ( 1 H, m), 8.17 ( 1 H, s), 8.11 - 8.16 (1 H, m), 7.89 (1 H, s), 7.83 (1 H, dd, J=8.78. 2.26 Hz), 7.60 (1 H, d, J=8.78 Hz). 4.18(2 H, s). LC-MS: (ES, m/z); |M%L 513.0

Example 175

N-(3-chloro-4-(4-(hydroxymethyl)-1 H-pyrazol-1 -yl)phenyl )-1 -( quinolin-5-yl )-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 175

489

A. ethyl l-(2-chloro-4-nitrophenyl)-lH-pyrazole-4-carboxylate, 175a

2-Chloro-l-fluoro-4-nitrobenzene (334 mg, 1.90 mmol) was dissolved in MeCN (10 mL), ethyl lH-pyrazole-4-carboxylate (222.2 mg, 1.59 mmol) and césium carbonate (568 mg, 1.74 mmol ) were added. and stirred at 80 °C for 16 h. 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 afford the product as a yellow solid. The crude product was purified by flash column chromatography over 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 afford product as a white solid (400 mg, 85.3% yield). Ή NMR (400MHz, 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 (q. ,1=7.1 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).

B. ethyl l-(4-amino-2-chlorophenyl)-lH-pyrazole-4-carboxylate, 175b

Ethyl l-(2-chloro-4-nitrophenyl)-lH-pyrazole-4-carboxylate (400 mg, 1.25 mmol) was dissolved in THF (10 mL), iron (453 mg, 8.12 mmol), NH4CI (434 mg, 2.12 mmol) and H2O (10 mL) w'ere added, the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with EtOAc (20 mLx3). The filtrâtes were concentrated under reduced pressure to afford crude product as a yellow oil which was purified by flash column chromatography over

490 silica gel (petroleum ether/ ethyl acetate from |OO 0 to 70/30 ). The desired fraction was collected and the solvent was concentrated under reduced pressure to afford product as a yellow solid (280 mg, 74.2% yield). LC-MS: (ES, m/z): ! M ! | 266.i

C. ethyl l-(2-chloro-4-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido )phenyl )-1 H-pyrazole-4-carboxylate, 175c

Ethyl l-(4-amino-2-chlorophenyl)-lH-pyrazole-4-carboxylate ( 130 mg, 0.49 mmol), l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-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 (74.9 mg, 0.49 mmol) was added dropwise. The reaction mixture was stirred at 30 °C for 16 h. Sat. NaHCOs (20 mL) w'as added and the reaction mixture extracted with CH2CI2 (20 mL x 2). The combined organic layers were dried over NaiSOi, filtered and the filtrâtes were concentrated under reduced pressure to afford cnide product as a yellow oil which w'as purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100'0 to 40/60). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford product as a yellow solid ( 170 mg, 84.4% yield).

D. N-(3-chloro-4-(4-(hydroxymethyl)-lH-pyrazol-l-yl)phenyl)-l-(quinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4-carboxamide, Cpd 175

491

Ethyl l-(2-chloro-4-(l-(quinolin-5-yl)-5-( trifluoromethyl)-lH-pyrazole-4carboxamido)phenyl)-l H-pyrazole-4-carboxylate (170 mg, 90% pure, 0.28 mmol) was dissolved in THF (10 mL) and stirred at 0 °C, LiAlH₄ (83.4 mg, 2.2 mmol) was added slowly. The reaction mixture was stirred at 40 °C for 40 h. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to afford the crade product as a yellow oil which was purified by préparative highperformance liquid chromatography (25% to 55% (v/v) CH3CN and H₂O with 0.05% HCl). The pure fractions were collected and the solvent was concentrated under reduced pressure, lyophilized to dryness to give product as a white solid (34 mg, 24.1% yield). *H. NMR (400MHz, DMSO-d6) 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/zY [M+lf 512.9

Example 176

N-(5-cyano-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(1-oxo-1,2 dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 176

A. 5-bromo-2-hydroxy-6-methylnicotinonitrile, 176a

492

l-Bromopyrrolidine-2,5-dione (26.54 g, 149.1 mmol) was added dropwise to a solution of 2-hydroxy-6-methylnicotinonitrile (10 g, 74.6 mmol) in DMF (120 mL). The mixture was stirred at 70 C for 2 h. Sat. NaHCCL solution ( 100 mL) was added to the mixture. The mixture was extracted with ethyl acetate (300 mL x 3). The separated organic layers were dried (MgSO₄), filtered, and the filtrate was concentrated to afford the product as a black solid (14 g, 79% yield). LC-MS: (ES, m/zY [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. The phosphoryl trichloride was concentrated. Sat. NaHCOs solution (1000 mL) was added dropwise to the residue to adjust the pH to 7~8. The aqueous phase was extracted with ethyl acetate (500 15 mL x 3). The organic phase was dried (MgSO₄), filtered, and the filtrate was concentrated to afford 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), 2H1,2,3-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 mL x 3). The filtrate was concentrated to afford a crude product.

493

The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/Ό 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). ‘H NMR (400 MHz, DMSO-d6) δ ppm 2.71 (s, 3 H), 8.31 (s, 2 H), 8.90 (s, l H). LC-MS: (ES, m/z): [M+l]⁺ 264.0

D. 5-amino-6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinomtrile, 176d

H₂N

N . 176d

Palladium diacetate (170 mg, 0.76 mmol) and (9,9-dimethyl-9H-xanthene-4,5diyl)bis(diphenylphosphane) (438 mg, 0.76 mmol) were added to a solution of 5-bromo-6methyl-2-(2H-l,2,3-triazol-2-yl)nicotinonitrile (2.0 g, 7.57 mmol), to7-butyl carbamate ( 1331 mg, 11.36 mmol) and césium carbonate (7.40 g, 22.7 mmol) in dioxane under N? bubbling. The reaction was stirred at 120 ^CC ovemight. The mixture w⁷as filtered and the filtrate was concentrated to give a crude product. The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 0/T00). The eluent was collected and the solvent was concentrated under reduced pressure to give 5-amino-6-methyl-2-(2H-l,2,3-triazol-2-yl)mcotinonitrile as a yellow solid (300 mg, 18%). LC-MS: (ES, m/z): [M+l]’ 200.8 and reri-butyl (5-cyano-2-methyl-6-(2HL2.3-triazol-2-yl)pyridin-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 -( l -oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)- l H-pyrazole-4-carboxamide. Cpd 176 N Y ¹ T

F \

494

To a solution of l-(l -oxo- L2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)- IHpyrazole-4-carboxylic acid (132 mg, 0.41 mmol) and 5-amino-6-methyl-2-(2H-1,2,3triazol-2-yl)nicotinonitrile (90 mg, 0.45 mmol) and pyridine (129 mg, 1.64 mmol) in dichloromethane (20 mL) was added POCh (125 mg, 0.82 mmol) dropwise. The mixture w'as stirred at room température for 2 h. Sat. NaHCOs solution (20 mL) was added to the mixture and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over Na2SO₄, fïltered and the filtrâtes were concentrated under reduced pressure to afford crude product as a yellow oil. The crude product was then purified by préparative HPLC (28% to 58% (v/v) CHsCN and H2O with 0.05%HCl) to afford the product as a yellow solid (65 mg, 31%). *H NMR (400 MHz. DMSO-d6) δ ppm 2.64 (s, 3 H), 5.66 (d. J=7.50 Hz, 1 H), 7.24 - 7.31 (m, 1 H), 7.66 (t, J=7.83 Hz, 1 H), 7.93 (d, J=7.72 Hz, 1 H), 8.29 (s, 2 H) 8.42 (d, J=7.94 Hz, 1 H), 8.51 (s, 1 H), 8.66 (s, 1 H), 10.64 (br s, 1 H), I L61 (br d. J=5.07 Hz, 1 H). LC-MS: (ES, m/z): [M+l] 505.9

Example 177

N-(5-cyano-6-(4-(hydroxymethyl)-2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 177

A. methyl 2-(3-cyano-5-nitropyridin-2-yl)-2H-l ,2,3-triazole-4-carboxylate, 177a

Potassium carbonate (376.5 mg, 2.72 mmol) was added to a solution of 2-chloro-5nitronicotinonitrile (500 mg, 2.72 mmol) and methyl iH-l,2,3-triazole-4-carboxylate

495 (415.5 mg, 3.27 mmol) in MeCN (10 mL). The mixture was reacted at rt for 3 h, filtered and the résultant residue was washed with EtOAc (50 mL x 3). The filtrâtes were concentrated under reduced pressure. EtOAc (10 mL) was added, the mixture stirred at rt for 0.5 h, filtered, and the résultant solid was collected and dried under reduced pressure to afford the product as a yellow solid (550 mg, 73.6% yield).

B. methyl 2-(5-ammo-3-cyanopyridin-2-yl)-2H-l,2,3-triazole-4-carboxylate, 177b N

J h₂n—FJ—K I —n ^ΝγΌ\ ο .177b

Methyl 2-(3-cyano-5-nitropyridin-2-yl)-2H-l,2,3-triazole-4-carboxylate (550 mg, 2.0 mmol) was dissolved in THF (20 mL) and methanol (10 mL), iron (1.12 g, 20.0 mmol), NH4CI ( 1.07 g, 20.0 mmol) and H₂O (5 mL) were added. and the reaction mixture was stirred at 60 °C for 2 h. The mixture was filtered through a pad of diatomaceous earth and the pad was washed with EtOAc (20 mL x 3). The combined filtrâtes were concentrated under reduced pressure to afford crude product which was purified by flash column. chromatography over silica gel (petroleum ether/ ethyl acetate from 10:1 to 1:1). The desired fraction was collected and the solvent was concentrated under reduced pressure to afford the product as a yellow solid (180 mg, 31.2% yield). *H NMR (400MHz, DMSOd6) δ ppm 8.70 - 8.54 (m, IH), 8.10 (d, J=2.9 Hz, IH), 7.48 (d, J=2.6 Hz, IH), 6.42 (s, 2H), 3.89 (s, 3H). LC-MS: (ES, m/z): [M+l]⁺ 245.1

C. methyl 2-(3-cyano-5-(l-(quinolm-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)pyridm-2-yl)-2H-l,2,3-triazole-4-carboxylate, 177c

496

Methyl 2-(3-cyano-5-nitropyridin-2-yl)-2H-l,2,3-triazole-4-carboxylate ( 155 mg, 0.63 mmol), l-(quinolin-5-yl)-5-(trifluoromethyl)-l2/-pyrazole-4-carboxylic acid, 3b (230 mg, 0.75 mmol) and pyridine (297 mg, 3.76 mmol) were added to DCM (10 mL), POCk (384 mg, 2.509 mmol) was added dropwise. The réaction mixture was stirred at rt for 4 h.

Sat. NaHCO? was added to adjust the pH to 9-10, water (30 mL) was added. and the mixture was extracted with CHgCL (30 mL x 3). The combined organic layers were dried ovc · Na₂SO4. filtered and the filtrâtes were concentrated under reduced pressure to afford product as a yellow’ solid (450 mg, 98.7% yield). LC-MS: (ES, m/z): [M+l]⁺ 533.9

D. N-(5-cyano-6-(4-(hydiOxymethyl)-2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 177

Methyl 2-(3-cyano-5-( l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-415 carboxamido)pyridin-2-yl)-2H-l,2,3-triazole-4-carboxylate (400 mg, 730% pure, 0.55 mmol) was dissolved in THF (10 mL) and the reaction was stirred at 0 ^CC, then LiA1H4 (167 mg, 4.4 mmol) was added slowly. The reaction mixture was stirred at 40 ^CC for 10 h. Water ( 10 mL) was added and the mixture extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na2SO₄, filtered and the filtrate was concentrated under reduced pressure to afford the crude product as a yellow oil which was purified by

497 préparative high-performance liquid chromatography. The pure fractions were collected and the solvent was concentrated under reduced pressure, lyophilized to dryness to give product as a light yellow solid (20 mg, 6.9% yield). Ή NMR (400MHz, METHAN0L-d4) δ ppm 9.27 (d, J=3.7 Hz, IH), 9.07 (br s. IH), 8.89 (d, J=2.4 Hz. IH), 8.51 - 8.43 (m, 2H).

8.39 (d, J=8.4 Hz, IH), 8.24 (t, J=8.2 Hz, IH), 8.13 - 8.07 (m, 2H), 8.03 (dd, J=5.1, 8.6 Hz,

IH), 4.82 (s, 2H). LC-MS: (ES, m/z): | Μ 1 | 506.1

Example 178

N-(6-(5-amino-l H-l ,2,3-triazol-l -yl)-5-chloropyridin-3-yl)-1 -( 1 -oxo-1.2dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 178

A. l-(3-chloro-5-( 1 -( 1 -methoxyisoquinolin-5-yl)-5-(trifluoromethyl )-lH-pyrazole-4carboxamido)pyridin-2-yl)-lH-L2.3-triazole-5-carboxylic acid, 178a

O

Lithium hydroxide (139 mg, 5.8 mmol) was added to a solution of methyl l-(3chloro-5-( l-( l-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)pyridin-2-yl)-lH-L2,3-triazole-5-carboxylate (750 mg, 1.16 mmol) m

THF/HcO (2:1,6 mL), the mixture was reacted at 25 °C for 2 h. The solvent was

498 concentrated under reduced pressure. IM 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 afford the product (600 mg, 88.7% yield). LC-MS: (ES, m/z): [M+l]⁺ 559.0

B. /m-butyl (l-(3-chloro-5-(l-(l-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-]Hpyrazole-4-carboxamido)pyridin-2-yI)-lH-L2,3-triazol-5-yl)carbamate, 178b

To a solution of l-(3-chloro-5-(l-(l-methoxyisoquinolin-5-yl)-5-(trifluoromethyl)lH-pyrazole-4-carboxamido)pyridin-2-yl)-lH-L2,3-triazole-5-carboxylic acid (550 mg, 0.94 mmol) in rert-butanol (10 mL) under N2 was added DPPA (3 1 1 mg, 1.13 mmol) and TEA (286 mg, 2.83 mmol). The reaction mixture was stirred at 80 °C overnight. sat. NaHCOa (20 mL) was added, and the mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were dried over NazSOr, filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a brown oil. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=2:l to 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): ÏM+11 630.2

C. N-(6-(5-amino-lH-l,2,3-triazol-l-yl)-5-chloropyridin-3-yl)-l-( 1 -oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyD- lH-pyrazole-4-carboxamide, Cpd 178

499

zm-Butyl ( l -(3-chloro-5-( l -( l -methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamido)pyridm-2-yl)-l H-1,2,3-triazol-5-yl)carbamate ( 180 mg, 0.26 mmol) and concentrated HCl (2 mL) was added isopropanol (4 mL) and stirred at 60 °C for 2 h. The mixture was concentrated under reduced pressure to afford a crude product as a yellow oil, which was purified by préparative high-performance liquid chromatography. The pure fractions were collected and the organic solvent was concentrated under reduced pressure, lyophilized to dryness to give the product as a white solid (31.2 mg, 22.7 % yield). ^!H NMR (400 MHz, DMSO-d6) δ ppm 5.63 (d, J=7.28 Hz, l H), 7.26 (t, J=6.73

Hz, 1 H), 7.64 (t, J=7.72 Hz. 1 H), 7.83 (s, 1 H). 7.92 (d, J=7.94 Hz, 1 H), 8.41 (d. J=8.16 Hz, 1 H), 8.56 (s, 1 H), 8.63 (d, J=L76 Hz, 1 H), 8.84 (d, J=1.76 Hz, 1 H), 11.30 (s, 1 H), 11.61 (brd, J=5.29 Hz, 1 H). LC-MS: (ES, m/z): |M^: H 515.9

Example 179

N-(5-chloiO-6-(4-cyano-2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 179

POCL (348.6 mg, 2.27 mmol) was added to a solution of 2-(3-chloro-5-(l(quinolin-5-yl)-5-(trifluoromethyl)-l H-pyrazole-4 -carboxamido)pyridin-2-yl)-2H-1,2,320 triazole-4-carboxamide (120 mg, 0.23 mmol) in CHsCl (8 mL). The mixture was reacted at 80 °C for 1 h, 10 %NaHCO? (10 mL) was added, and the mixture extracted with CHjCL

500 (15 mL x 2). The combined organic layers were dried over Na2SO₄, filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a yellow oil. The crude product was purified by préparative high-performance liquid chromatography. The pure fractions were collected and the solvent was concentrated under 5 reduced pressure, lyophilized to dryness to give product as a white solid (82 mg. 69.7 % yield). *H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (br s, 2 H), 7.93 - 8.08 (m, 2 H), 8.37 (br d, J=8.03 Hz. I H), 8.69 (br s, l H), 8.79 (br d, J=2.01 Hz, I H), 8.93 - 9.04 (m, 2 H), 9. K) (br s, l H), 11.53 (br s, l H). LC-MS: (ES, m/ζγ. [M+1 Γ 515.9

H)

Example 180 l-(l-aminoisoquinolin-4-yl)-N-(5-chIoro-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)5-(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 180

To a stirring solution of isoquinolin-4-amine (15 g, 104.04 mmol) in HCl (150 mL, 5 mol/L) at 0° C was added a solution of sodium nitrite (10.77 g, 156.06 mmol) in water (15 mL) at below 0° C. The reaction mixture was stirred at 0° C for 30 min and a solution of SnCh.2H2O (58.69 g. 260.10 mmol) dissolved in HCl (27 mL, 12 mol/L) was added dropwise. The mixture was stirred at room température for 12 h. The mixture was adjusted to pH 12-14 with 20% aqueous sodium hydroxide. The mixture was extracted with CH2CI2 (1000 mL x 3). The organic layer was dried (Na2SO₄), filtered, and the filtrate concentrated

501 under reduced pressure to afford cnide 180a (15.8 g. 95.4% yield) as a brown solid, used directly for the next step.

B. ethyl 1 -(isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate, 180b

A solution of 4-hydrazinylisoquinoline. 180a ( 15.8 g, 99.25 mmol), ethyl 2(efhoxymethylene)-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 h. The mixture was concentrated under reduced pressure. The cnide product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 100:1 to 20:1 ). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford 180b (16 g, 41.8% yield) as a yellow solid. LCMS (ESI) m/z M+l: 336.0.

C. 4-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-l H-pyrazol-l-yl)isoquino]ine 2-oxide, 15 180c

A solution of ethyl l-(isoquinolin-4-yl)-5-(trifluoromethyI)-lH-pyrazole-4carboxylate. 180b (16 g, 41.44 mmol). 3-chlorobenzopeiOxoic acid (26.817 g, 124.32 mmol) in CH2CI2 (300 mL) was stirred at rt for 16 h. The reaction mixture was quenched with sat. NaHCOs (1000 mL) and the mixture was extracted with ethyl acetate (500 mL x 3). The organic layers were combined, dried over Na₂SO4, filtered and the filtrate

502 concentrated under reduced pressure to afford 180c (11 g. 74.4% yield) as a yellow solid.

LCMS (ESI) m/z M+l: 352.0.

D. ethyl 1-(1 -chloroisoquinolin-4-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxylate,

180d

4-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1 H-pyrazol-l-yl)isoqumoline 2-oxide, 180c (11 g, 30.81 mmol) was added to a solution of POCk (20 mL, 214.57 mmol) in

C) CHCk (40 mL). The mixture was stirred at 80 °C for 18 h. The mixture was diluted with water (1000 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were dried (MgSO₄), filtered, and concentrated. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 20:1 to 5:1 ). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford 180d (10 g, 70.6% yield) as a white solid. LCMS (ESI) m/z M+l : 370.0. ‘H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.44 - 8.53 (m, 1 H), 8.37 (s, 1 H), 8.29 (s, 1 H), 7.79 - 7.87 (m, 2 H), 7.27 - 7.32 (m, 1 H), 4.42 (q, J=7.20 Hz, 2 H), 1.42 (t, J=7.17 Hz. 3 H)

E. l-(l-chloroisoquinolin-4-yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxylic acid, 180e

LiOH (l .825 g, 43.49 mmol) was added to a solution of ethyl l-(lchioroisoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate, 180d ( 10 g, 21.75 mmol). THF ( 100 mL) in water ( 100 mL). The mixture was stirred at rt for l h. The mixture was added 5% KHSO₄ to adjust pH 3-4. Water ( 1000 mL) and ethyl acetate ( [000 111L) were added to the mixture. The organic layer was washed with brine (500 mL), dried over MgSO₄ and concentrated under reduced pressure to afford 180e (9.7 g. >100% yield) as a white solid which was used directly for the next step. LCMS (ESI) m/z Μ · 1: 341.9.

F. N-(5-chloiO-2-methyl-6-(2H-l,2.3-triazol-2-yl)pyridin-3-yl)-l-(l-chIoroisoquinolin-4yl )-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide, 180f

POCh (302.082 mg, 1.97 mmol) uns added to a solution of l-(l-chloroisoquinolin4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 180e (350 mg, 0.99 mmol), 515 chloro-2-methyl-6-(2H-L2.3-triazol-2-yl)pyridin-3-amine (206.504 mg, 0.99 mmol), pyridine (194.795 mg, 2.46 mmol) in CH2CI2 (10 mL). The mixture was stirred at rt for 2 li. Water (50 mL) and CH2CI2 (50 mL) were added to the mixture. The organic layer was washed with brine (50 mL), dried over MgSO₄, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate from 20:1 to 0:100). The desired fractions were

504 collected and the solvent was concentrated under reduced pressure to afford 180f (310 mg, 58.2% yield) as a white solid. LCMS (ESI) m/z M+l : 532.9.

G. l-(l-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-(2H-l,2,3-triazol-25 yDpyridin-3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 180

H₂N .A, solution of N-(5-chloro-2-methyl-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-( 1 chloiOisoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide. 180f (290 mg, 0.54 mmol). ΝΉ3.Η2Ο (3 mL) in dioxane (3 mL) was stirred at 120 °C for 5 h. The mixture was concentrated under reduced pressure to afford the crude product, which was purified by préparative HPLC (20% to 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 afford the title compound (100.5 mg, 34.1% yield) as a yellow solid. LCMS (ESI) m/z M+l: 513.9; *H NMR (400 MHz, DMSO-d6) δ ppm 10.71 (s, 1 H), 9.01 - 9.45 (m, 2 H), 8.66 (d, J=8.60 Hz, 1 H), 8.57 (s, 1 H), 8.39 (s, 1 H), 8.25 (s, 1 H), 8.16 (s, 2 H), 7.92 - 8.00 (m, 1 H), 7.82 (t, J=7.61 Hz, 1 H), 7.04 (d, J=8.16 Hz, 1 H), 2.53 (s, 3 H).

Example 181

N-(6-(5-amino-1 -methyl-1 H-pyrazol-3-yl)-5-cyanopyridin-3-yl)-1 -(quinolin-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 181

505

To a solution of 3-(3-cyano-5-( l -(quinolin-5-yl)-5-( trifluoromethyl)-1 H-pyrazole4-carboxamido)pyridin-2-yl)-l-methyl-lH-pyrazole-5-carboxylic acid (165 mg, 0.31 mmol) in DMF (10 mL) under N2 was added DPPA (92.2 mg, 0.34 mmol) and TEA (92.5 mg, 0.91 mmol). The reaction mixture was stirred at 80 °C for 16 h and concentrated. The residue was purified by préparative 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. l% yield). X NMR (400 MHz, DMSO-d6) δ ppm 11.14 (l H, s), 9.00 - 9.07 (2 H, m). 8.54 - 8.6I (2 H, m).

l() 8.32 (l H, d. J=8.82 Hz), 7.87 - 7.99 (2 H. m), 7.64 - 7.70 (1 H, m), 7.57 - 7.63 (1 H, m),

5.93 ( 1 H, s), 3.62 (3 H, s). LC-MS: (ES, m/z): U H 504.0

Example 182

N-(5-chloro-6-(4-(hydroxymethyl)-1 H-pyrazol-1 -yI)pyridin-3-yl)-1 -( 1 -oxo-1.2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 182

A. ethyl 1 -(3-chloro-5-( 1 -( 1 -oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamido)pyridin-2-yl)-lH-pyrazolc-4-carboxylate, 182a

506

To a solution of l-(l-oxo-L2-dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-IHpyrazole-4-carboxylic acid (556 mg, l .92 mmol) and ethyl l-(5-amino-3-chloropyridin-25 yl)-1H-pyrazole-4-carboxylate (559 mg, 2.06 mmol) and pyridine (816 mg, 10.3 mmol) in dichloromethane (30 mL) was added POCh (791 mg, 5.16 mmol) dropwise. The mixture was stirred at room température for 3 h. The réaction mixture was concentrated under reduced pressure to afford the crude product as a yellow oil which was purified by préparative high-performance liquid chromatography to afford the product as a yellow solid (470 mg, 47.8%). LC-MS: (ES, m/z): [M+l]” 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)-lH-pyrazole-4-carboxamide. Cpd 182

Ethyl 1 -(3-chloro-5-( 1 -( 1 -oxo-1,2-dihydroisoquinolin-5-yi)-5-(trifluoromethyl)lH-pyrazole-4-carboxamido)pyridm-2-yl)-lH-pyrazole-4-carboxylate (470 mg, 0.82 mmol) was dissolved in THF (25 mL) and cooled to 0 ^CC. LiAlFL (156 mg, 4.11 mmol) was added and the réaction mixture was stirred at 0 °C for 2 h. The reaction mixture was cooled to 0 °C, quenched by addition of 0.15 mL of H₂O, followed by 0.15 mL of 15% aqueous NaOH and 0.45 mL of H₂O. CH₂Cl₂/MeOH (10/1, 100 mL) and Na₂SO₄ was

507 added, stirred at room température for 0.5 h, and the mixture was fïltered through diatomaceous earth. The résultant residue was washed wnth CHeCb/MeOH ( 10/l, 100 mL x 2). The filtrate was concentrated to dryness to give crude product winch was purified by préparative high-performance liquid chromatography. The pure fractions were collected, 5 concentrated under reduced pressure and lyophilized to dryness to afford the product (150 mg, 34.4% yield). Ή NMR (400MHz, METHANOL-d4) δ ppm 8.75 (br s. IH), 8.62 (d, J=2.4 Hz, IH), 8.56 (dd, J=0.8, 8.0 Hz. IH), 8.34 (s. IH), 8.15 (s. IH), 7.88 - 7.83 (m, IH). 7.81 (s. IH), 7.74 - 7.65 (m, IH), 7.26 - 7.22 (m, lH), 5.95 - 5.90 (m, IH), 4.62 (s, 2H). LC-MS: (ES, m/z): | Μ ' I ] 529.9

Example 183

N-(6-(5-amino-l-methyl-IH-pyr azol-3-yl)-5-chloiOpyridin-3-yl)-l-(l-oxo-1,2dihydroisoquinolin-5-yI)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 183 /

⁰⁼\ J

HN—^J

A. methyl 3-hydroxy-l-methyl-lH-pyrazole-5-carboxylate, 183a

HO _; 183a

TEA (44.2 mL, 316.7 mmol) was added to a solution of methylhydrazine sulfate (20.3 g, 140.7 mmol) in H:O (100 mL) and MeOH (200 mL) at room température, and the mixture was stirred for 0.5 h at rt. Dimethyl but-2-ynedioate (20 g, 140.7 mmol) was added to the mixture, the mixture was stirred for 18 h at 70 °C, followed by stirring at rt for 36 h. The reaction mixture was fïltered, and the filtrate concentrated under reduced pressure to give the product as a white solid (3.65 g, 16.6% yield).

508

B. methyl l-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-lH-pyrazole-5-carboxyIate, 183b

Methyl 3-hydroxy-l-methyl-lH-pyrazole-5-carboxylate (3.65 g, 23.4 mmol) was dissolved in CH2CI2 (70 mL) and the reaction 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 h. The mixture was then poured into 60 mL H?O, the organic layer was separated, and the aqueous layer was extracted with CH₂Cb (2 x 100 mL). The combined extracts were washed with water. The combined organic layers were dried (MgSCL), fïltered, and the filtrate concentrated to a brown oil. The brown oil was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=10: 1 to petroleum ether/ ethyl acetate=l:l). 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+lp 288.9

C. methyl l-methyl-3-(4,4,5,5-tetrâmethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-5carboxylate, 183c n'V

JL //—\ χ--⁷ _o_ , 183c

Methyl l-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-lH-pyrazole-5-carboxylate (3.0 g, 10.07 mmol), bis(pinacolate)diboro (2.81 g, 11.08 mmol), and potassium acetate (2.97 g, 30.21 mmol) were added to dioxane (20 mL). [Ll'-Bis(diphenylphosphino)

509 ferrocene]dichloropalladium(n) (1:1)(412 mg, 0.50 mmol), dppf (279 mg, 0.50 mmol) were added to the mixture under N₂, and the reaction mixture was stirred at 100 °C for 16 h under N₂. The reaction mixture was filtered, and the filtrâtes were concentrated under reduced pressure to afford a black oil which was purified by flash column chromatography over silica gel (petroleum ether/ ethyl acetate from 100/0 to 60/40 ). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford the product as a white solid (2.5 g, 93.3% yield).

D. methyl 3-(5-amino-3-chloropyridin-2-yl)-1 -methyl-1 H-pyrazole-5-carboxylate,

Methyl 1 -methyl-3-(4,4,5,5-tetramethyl-1.3,2-dioxaborolan-2-yl)-1 H-pyrazole-5carboxylate (1.0 g. 3.76 mmol), 5,6-dichIoropyridin-3-amine (0.61 g, 3.76 mmol) and potassium carbonate (1.56 g, 11.3 mmol) were added to dioxane/water (9:1,20 mL) and the réaction was purged with N₂. [1,1 ’-bis(diphenylphosphino)ferrocene] dichloropalladium (Π) (1:1) (0.31 g, 0.38 mmol) was added and the réaction stirred at 100 °C for 12 h. The reaction mixture was filtered, the filtrâtes were concentrated under reduced pressure to afford a black oil which w'as purified by flash column chromatography over silica gel (petroleum ether/ ethyl acetate from 100/0 to 0/100 ). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford the product as a black solid (560 mg, 46.5% yield). LC-MS: (ES, m/z)·. [M+l]⁺ 267.0

E. methyl 3-(3-chloro-5-( 1 -( 1 -methoxyisoquinoIin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamido)pyridin-2-yl)-1 -methyl-1 H-pyrazole-5-carboxylate, 183e

510

To a solution of 1 -( 1 -methoxyisoqumolin-5-yl)-5-( trifluoromethyl )-lH-pyrazole-4carboxylic acid (315.4 mg, 0.94 mmol), methyl 3-(5-amino-3-chloropyridin-2-yl)-lmethyl-lH-pyrazole-5-carboxylate (300 mg, 0.94 mmol) and pyridine (0.38 mL, 4.68 mmol) in CH2CI2 (10 mL) was added POCI3 (0.34 mL, 3.74 mmol) dropwise. The mixture was stirred at 25 °C for 2 h, 20 mL sat. NaHCOj was added and the mixture was extracted with CH2CI2 (30 mL x 2). The combined organic layers were dried over Na₂SO4, filtered and the filtrâtes were concentrated under reduced pressure to afford crude product as a brown oil. The crude product was then purified by column chromatography over silica gel (petroleum ether/ ethyl acetate = 1:0 to ethyl acetate) to afford product as a brown oil (340 mg, 48.1 %). LC-MS: (ES, m/z): [M+l]” 586.1

F. 3-(3-chloro-5-( 1 -( 1 -methoxyisoquinolin-5-yl)-5-(trifluoro methyl )-l H-pyrazole-4carboxamido)pyridin-2-yl)-l-methyl-lH-pyrazole-5-carboxylic acid, 183f

, 183f

Sodium hydroxide (27.0 mg, 0.67 mmol) was added to a solution of methyl 3-(3chloro-5-( l-( 1 -methoxyisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)pyridin-2-yl)-1 -methyl-1 H-pyrazole-5-carboxylate (340 mg, 0.45 mmol) in

511

THF/H2O (3:1,8 mL), the mixture was stirred at room température for 3 h. The solvent was concentrated under reduced pressure and water (10 mL) was added to the mixture. The mixture was adjusted to pH 5 using IM HCl, and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous MgSO₄, filtered. the filtrâtes were concentrated under reduced pressure to afford product as a brown oil (250 mg, 78.4% yield). LC-MS: (ES, m/z): [M+l]' 572.0

G. zm-butyl (3-(3-chloro-5-(l-(l-methoxyisoquinolin-5-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamido)pyridin-2-yl)-1 -methyl- lH-pyrazol-5-yl)carbamate, 183g

To a solution of 3-(3-chloro-5-(l-(l-methoxyisoquinoIin-5-yl)-5-(trifluoromethyl)lH-pyrazole-4-carboxamido)pyridin-2-yl)-l -methyl- lH-pyrazole-5-carboxylic acid (200 mg, 0.28 mmol) in /ez7-butanol (8 mL) under N₂ was added DPPA (85.4 mg, 0.31 mmol) and TE A (85.6 mg, 0.85 mmol), then the reaction mixture was stirred at 80 °C for 5 h. The solvent was removed under reduced pressure to give the crude product as a brown oil. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=l:O to 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+l]' 643.1

H. N-(6-(5-amino-1 -methyl-1 H-pyrazol-3-yl)-5-chloropyridin-3-yl)-1 -( 1 -oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 183

512

Concentrated HCl (2 mL) was added to a solution of tezŸ-butyl (3-(3-chloro-5-(l( 1 -methoxyisoquinolin-5-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamido)pyridin-2yl)-l-methyl-lH-pyrazol-5-yl)carbamate (120 mg, 0.18 mmol) m isopropanol (4 mL), then 5 the mixture was stirred at rt for 1 h. The solvent was concentrated under reduced pressure to give the crude product as a yellow solid which was purified by préparative highperformance liquid chromatography. The pure fractions were collected and the organic solvent was concentrated under reduced pressure, the solid lyophilized to afford the product as pale yellow solid (72 mg, 73.3% yield). *H NMR (400 MHz, DMSO-d6) δ ppm 10 11.61 (1 H, brd. J=5.73 Hz), 11.16(1 H, s), 8.86-8.92 (1 H. m), 8.53 (1 H, s), 8.44(1 H,

s), 8.41 (1 H, d, J=8.16 Hz), 7.91 (1 H, d. ,1=7.72 Hz), 7.64 (1 H, t, J=7.72 Hz), 7.23 - 7.29 (1 H, m), 6.18 (1 H. s), 5.62 (1 H, d, J=7.28 Hz), 3.67 (3 H, s). LC-MS: (ES. m/z): jM I | 528.9

Examplc 184

N-(5-chloiO-6-(2H-l,2.3-tiiazol-2-yl)pyridm-3-yl)-l-(8-fluoro-1-oxo-1,2dihydroisoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 184

513

A. 8-fluoro-4-hydrazinylisoquinoline, 184a

H₂N

F ,184a {Pd(cinnamyl)Cl}2 (34.4 mg, 0.066 mmol) and Mor-DalPhos (61.5 mg, 0.13 mmol) in dioxane (5 mL) was stirred at rt for 10 min under N’, sodium te/ï-butoxide (255 mg, 2.65 mmol) and 4-bromo-8-fluoroisoquinoline (300 mg, 1.33 mmol) was added to the mixture at rt with stirring for 5 min under N2, and the mixture was treated with hydrazine monohydrate (133 mg, 2.65 mmol) at 50 °C for 2 h under N2. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give the crude product as a brown solid (240 mg), used directly for the next step.

B. ethyl 1 -(8-fluoroisoquinolin-4-yl)-5-( trifluoromethyl)-! H-pyrazole-4-carboxyiate,

184b

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate,

If (1.63 g, 6.77 mmol), 8-fluoro-4-hydrazinylisoquinoline (800 mg, 4.52 mmol), and éthanol (20 mL) was stirred at 80 °C for 1 h before cooling to room température. The resulting solution was concentrated to dryness under reduced pressure, and then purified by column chromatography over silica gel (petroleum ether/ ethyl acetate=100:0 to 80:20) to afford the product as a brown oil (820 mg, 47.6%). LC-MS: (ES, m/z): [M+l]* 353.9

C. 4-(4-(ethoxycarbonyl)-5-( trifluoromethyl)- !H-pyrazol-l-yl)-8-fluoroisoquinoline

2-oxide, 184c

514

m-CPBA (791.6 mg, 4.59 mmol) was added to a solution of ethyl l-(8fluoiOisoquinolin-4-yl)-5-(tnfluoromethyl)-lH-pyrazole-4-carboxylate (700 mg, 92.6% pure, 1.84 mmol) in DCM (5 mL). The mixture was reacted at 30 °C for 2 h, 40 mL sat.

NaiCOs solution was added to the mixture, and the mixture was extracted with 50 mL CH2CI2. The organic layer was concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate= 100:0 to 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+l] 369.9

D. ethyl l-(l-chloro-8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylate, 184d

POCh (5 mL) was added to a solution of 4-(4-(ethoxycarbonyl)-5(trifluoromethyl)-lH-pyrazol-l-yl)-8-fluoroisoquinoline 2-oxide (650 mg. 1.76 mmol) in chloroform (15 mL). The mixture was reacted at 70 °C for 2 h. Sat. LZCO? solution (30 mL) was added to the mixture, and the mixture was extracted with 30 mL CH2CI2. The organic layer was concentrated under reduced pressure, the crude product was purified by

515 column chromatography over silica gel (petroleum ether/ ethyl acetate=100:0 to 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. l-( l-ethoxy-8-fluoroisoquinolin-4-yl)-5-( trifluoromethyl)- lH-pyrazole-4carboxylic acid. 184e

F O.

Lithium hydroxide (124 mg, 5.16 mmol) was added to a solution of ethyl 1-(110 chloro-8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate (400 mg, .03 mmol) in ethanol/water (1:1, 10 mL). The mixture was reacted at 23 °C for 2 h and the solvent was concentrated under reduced pressure. 1M HCl solution was added to the mixture to adjust the pH to ~5 and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over NazSOg, filtered and the filtrâtes were concentrated under reduced pressure to afford crude product as a brown oil (335 mg, 44.5 % yield). LC-MS: (ES, m/z): |M · I | 370.0

F. N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(l-ethoxy-8- fluoiOisoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, 184f

516

To a solution of l-(l-ethoxy-8-fluoroisoquinolin-4-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylic acid (280 mg, 50.6% purity, 0.38 mmol), 5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine, Ij (75.1 mg, 0.38 mmol) and pyridine (91 mg, 1.15 mmol) m

CH2CI2 (5 mL) was added POCI3 (70.6 mg, 0.46 mmol) dropwdse. The mixture was stirred at 25 °C for 2 h, 10 mL sat. NaHCOs w’as added and the mixture aextracted with CH2CI2 ( 15 mL x 2). The combined organic layers were dried over Na SO i. filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a brown oil (258 mg, 68.8 %). LC-MS: (ES, m/z): [M+l]⁺ 547.0

G. N-(5-chloro-6-(2H-1,2,3-triazol-2-yl )pyridm-3-yl )-1 -(8-fluoro-1 -oxo-1,2dihydroisoquinolin-4-yl)-5-(trifluoromethyl )-1 H-pyrazole-4-carboxamide, Cpd 184

Concentrated HCl (2 mL) was added to a solution of N-(5-chloro-6-(2H-l,2,315 triazol-2-yl)pyridin-3-yl)-l-(l-ethoxy-8-fluoiOisoquinolin-4-yl)-5-( trifluoromethyl)-! Hpyrazole-4-carboxamide (75 mg, 0.14 mmol) m isopropanol (4 mL), and the mixture was rcacted at 60 °C for 2 h. The solvent was concentrated under reduced pressure to afford the crude compound. which was purified by préparative high-performance liquid chromatography to afford the product as a white solid (15 mg, 21 % yield). ’H NMR (400

517

MHz, DMSO-d6) δ ppm 6.48 (d, >8.16 Hz, 1 H), 7.33 (dd, >11.69, 8.16 Hz, 1 H), 7.73 (td. >8.16. 4.85 Hz, 1 H), 7.88 (d, >6.39 Hz, 1 H), 8.16 (s, 2 H), 8.50 (s, 1 H), 8.64 (d, >2.20 Hz. 1 H), 8.82 (d, >2.21 Hz. 1 H), 11.22 (s, 1 H), 11.83 (d, >6.62 Hz, 1 H). LCMS: (ES, wz): [MH| 518.9

Example 185

N-(5-bromo-2-methyl-6-(2H-1,2.3-triazol-2-y0pyrid in-3-yl )-1-( 1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 185

A. 3-bromo-6-methyl-5-nitropyTidin-2-ol, 185a

To an ice-bath cooled suspension of 6-methyl-5-nitropyridin-2-ol (10 g, 64.9 mmol) in DMF (100 mL) was added N-bromosuccinimide (13.9 g, 77.9 mmol) portionwise under N2. The reaction mixture was stirred at 67 °C overnight, cooled to 0 °C, and 500 mL water was added to the mixture. The résultant solid was collected by filtration to afford the product as a yellow solid (9.2 g, 60.9% yield).

B. 3-bromo-2-ch1oro-6-methyl-5-nitropyridine, 185b

cr

518

3-Bromo-6-methyl-5-nitropyTÎdin-2-ol (9.2 g, 36.7 mmol) in POCh (56.2 g, 366.7 mmol) was stirred at 80 °C overnight. The mixture was slowly poured into water (800 mL) and a solid was formed. The solid was collected and dried to afford the desired product (7.5 g, 8 1.4% yield).

C. 3-bromo-6-methyl-5-nitro-2-(2H-L2,3-triazol-2-yl)pyridine, 185c

NA J, ?

O^Mbi

Cr , 185c

A solution of 3-bromo-2-chloro-6-methyl-5-nitropyridine (7.5 g, 29.83 mmol), 2H1,2,3-triazole (3.09 g, 44.74 mmol) and potassium carbonate (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 mL x 3). The filtrate was concentrated to afford a crude product. The crude product was purified by flash column chromatography over 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). ‘H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (s, 3 H), 8.28 (s, 2 H), 9.05 (s, 1 H).

D. 5-bro mo-2-methy 1-6-( 2H- L2,3-triazol-2-yL)pyridm-3-amine, 185d

3-BiOmo-6-methyl-5-nitro-2-(2H-L2.3-triazol-2-yl)pyridine (4.0 g, 14.1 mmol) was added to the mixture of iron (7.86 g, 140.8 mmol). NH4CI (7.53 g, 140.8 mmol) in THF (20 mL) and water (7 mL). The reaction mixture was stirred at 60 °C for 2 h and filtered. The filtrate was concentrated under reduced pressure to give the crude product as a brown oil which was purified by column chromatography over silica gel (petroleum ether/

519 ethyl acetate=30:70 to 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 g, 64.3% yield). LC-MS: (ES, m/z): [M+l]' 256.0

E. N-(5-bromo-2-methyl-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-yl)-l-( 1-oxo-1.2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 185

To a solution of l-( 1-oxo-l,2-dihydroisoqumolin-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylic acid (190 mg, 0.58 mmol) and 5-bromo-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine (147 mg, 0.58 mmol) and pyridine (137 mg, 1.74 mmol) in dichloromethane (10 mL) w’as added POCh (106 mg, 0.69 mmol) dropwise. Sat. NaHCOj ( 10 mL) w’as added and the mixture extracted with CHeCh (15 mL x 2). The combined organic layers were dried over NajSOa, fïltered, and the filtrâtes were concentrated under reduced pressure to afford the crude product as a brown oil. The brown oil was purified by préparative high-performance liquid chromatography (35% to 65% (v/v) CHsCN and H/O with 0.05% HCl) and lyophilized to dryness to afford the product as a w'hite solid (125.5 mg, 38.3%). Tl NMR (400 MHz, DMSO-d6) δ ppm 2.51 (s, 3 H), 5.65 (d, J=7.06 Hz, 1 H), 7.27 (dd, J=7.28, 5.95 Hz, 1 H), 7.65 (t, J=7.94 Hz. 1 H), 7.92 (d, J=7.72 Hz. 1 H). 8.16 (s, 1 H), 8.15 (s, 1 H), 8.41 (d, J=7.72 Hz, 1 H), 8.51 (d, J=5.73 Hz, 2 H), 10.59 (s, 1 H), 11.62 (brd, J=5.51 Hz, 1 H). LC-MS: (ES, m/z): [M+l]⁺ 561.1

Example 186

N-(5-Chloro-6-(2H-l,2.3-triazol-2-yl)pyridin-3-yl)-5-cyano-l-(quinolin-5-yl)-lHpyrazole-4-carboxamide, Cpd 186

A. Ethyl l-(quinolin-5-yl)-lH-pyrazole-4-carboxylate, 186a

In a 100 mL round-bottom flask was combined ethyl 4-pyrazolecarboxylate (500 mg, 3.6 mmol), 5-bromoquinoline (816 mg, 3.9 mmol), RockPhos G3 catalyst ( 150 mg, 0.18 mmol), K5PO4 ( 1.52 g, 7.1 mmol), and 1,4-dioxane (20 mL). The flask was fitted with a reflux condenser and pumped and backfilled with N₂ several times. The reaction was heated at reflux for 5 h, cooled, and concentrated. The reaction mixture was partitioned between water and CH2CI2. The aqueous layer was extracted once with CH2CI2. The combined organic layers were washed once with 1 M NaOH. The organic layers were dried (NazSOj), fïltered, and the filtrate concentrated to afford the crude product, which was purified by flash chromatography (40 g silica gel cartridge. gradient 30-70% EtOAc/hex). Yield = 375 mg (35%). MS (ESI): m/z 268 [M+Hp. ‘H NMR (400 MHz,

CDCh) δρρηι 9.00 (dd, 7= 4.2, 1.6 Hz, IH), 8.3 (s, 1 H), 8.28-8.24 (m, lH),8.24(s, IH), 7.80 (dd, 7 = 8.6. 7.5 Hz, IH), 7.62 (dd,7=7.5, 1.0 Hz, IH), 7.48 (dd,7= 8.7, 4.2 Hz. IH). 4.38 (q, 7 = 7.2 Hz, 2H). 1.40 (t,7= 7.2 Hz, 3H).

B. Ethyl 5-cyano-l-(quinolin-5-yl)-lH-pyrazole-4-carboxylate, 186b

To a 4 mL vial were added ethyl l-(quinolin-5-yl)- lH-pyrazole-4-carboxylate (100 mg, 0.37 mmol) and THF (l mL). TMPMgCl’LiCl (0.56 mL of a l M solution in THF/toluene. 0.56 mmol) was added, and the reaction was allowed to stir for l h at rt. Solid p-toluenesulfonyl cyanide (102 mg. 0.56 mmol) was added in one portion. The reaction was allowed to stir overnight and then was poured into 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 (Na2SO₄). filtered, and the filtrate concentrated to afford the crude product. The crude product was dissoived in warm CH2CI2. then filtered. The filrate and concentrated and further purified by flash chromatography (12g silica gel cartridge, gradient 5-60% EtOAc,·hex). Yield = 69 mg (63%). MS (ESI): m/z 293 ΐ M · H | . ‘H NMR (400 MHz. CDCk) δ ppm 9.05 (dd, .J = 4.2. 1.7 Hz, IH), 8.37 (ddd, 7= 8.6, 1.0. 1.0 Hz, IH), 8.33 (s, IH). 7.92-7.87 (m. IH), 7.88 (dd. 7= 8.6, 7.5 Hz. IH), 7.73 (dd. 7= 7.4, 1.1 Hz, IH), 7.51 (dd. 7= 8.6. 4.2 Hz, IH), 4.46 (q, 7= 7.1 Hz, 2H), 1.45 (t,7= 7.1 Hz, 3H).

C. 5-Cyano-l-(qumolin-5-yl)-lH-pyrazole-4-carboxylic acid. 186c

To a 15mL round bottom flask were added ethyl 5-cyano-l-(quinolin-5-yl)-lHpyrazoIe-4-carboxylate (56 mg, 0.19 mmol), LiOH«H2O (24 mg, 0.58 mmol), THF (2 mL), and water (2 mL). The reaction was allowed to stir for 30 mm at rt. THF was removed under reduced pressure, and the remaining aqueous layer was acidified to precipitate the

522 acid. The solid product was allowed to dry. Yield = 34 mg (67%). MS (ESI): m/z 265 [M+Hf. *H NMR (400 MHz. DMSO-d₆) δ ppm 13.75 (bs, 1H), 9.06 (ddd, J= 3.7, 1.7, I.7 Hz, IH), 8.49 (d. J = l.6Hz, IH), 8.41 (bd, J =8.4 Hz, IH), 8.07 (ddd, J = 7.4, 1.5, 1.5 Hz, IH), 8.03-7.94 (m. 2H), 7.66 (ddd. .7 = 8.6, 4.1, 1.6 Hz, IH).

D. N-(5-Chloro-6-(2H-1,2,3-triazoI-2-yl)pyridin-3-yl)-5-cyano-l-(quinolin-5-yl)-1Hpyrazole-4-carboxamide, Cpd 186

To a 10 mL round bottom flask were added 5-cyano-l-(quinolin-5-yl)-lHpyrazole-4-carboxylic acid (33 mg, 0.12 mmol), 5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm3-amine (29 mg, 0.15 mmol). pyridine (60 uL, 0.75 mmol), and CH₂C1₂ (3 mL). POCT, (46 pL, 0.5 mmol) was added, and the reaction was allowed to stir ovemight. The reaction was concentrated, redissolved in DMSO (2.5 mL), and treated with 1 drop of saturated NaHCO? solution to neutralize the acid. The mixture was purified by reversed-phase préparative HPLC (Cl8 silica column, 50x250 mm, gradient 10%-100% ACN H?O with 0.05% TFA, 80 niL/min). Yield = 21 mg (38%). MS (ESI): m/z 442 [M+H]T *H NMR (400 MHz, DMSO-de) δ ppm 11.14 (s, IH), 9.09 (dd, J= 4.1, 1.6 Hz, IH), 8.91 (d. .7=2.3 Hz, IH), 8.81 (s, IH), 8.72 (d, .7=2.3 Hz, IH), 8.36 (ddd, J = 8.4, 1.0, 1.0 Hz, IH), 8.20 (s, 2H). 8.10 (dd, J= 7.4. 1.3 Hz, IH), 8.03 (dd,.7= 8.4. 7.5 Hz, IH), 8.02-7.97 (m. IH), 7.70 (dd, ./= 8.6, 4.2 Hz, IH).

Example 187

5-Chloro-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-lHpyrazole-4-carboxamide, Cpd 187

523

A. Ethyl 5-chloro-l-(quinolin-5-yl)-lH-pyrazole-4-carboxylate, 187a

This compound was made using the procedure of 186b using ethyl l-(quinolm-5yl)-lH-pyrazole-4-carboxylate (100 mg, 0.37 mmol), TMPMgCbLiCl (0.49 mL of a 1 M solution in THF/toluene, 0.49 mmol), and hexachloroethane (133 mg, 0.56 mmol).

Purification was accomplished by flash chromatography (12 g silica gel cartridge, gradient 5-40% EtOAc/hex). Yield = 78 mg (69%). MS (ESI): m/z 302 [M+H]'. Ή NMR (400

MHz, CDCh) δ ppm 9.01 (dd,J = 4.2, 1.7 Hz, 1H), 8.33 (ddd, 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, ./=8.6,4.2 Hz, 1H), 4.40 (q,.7= 7.1 Hz, 2H), 1.42 (t,<7=7.2 Hz, 3H).

B. 5-ChloroT-(qumoIin-5-yl)-lH-pyrazole-4-carboxylic acid, 187b

This compound was made using the procedure of 186c using ethyl 5-chIoro-l(quinolin-5-yl)-lH-pyrazole-4-carboxylate (72 mg, 0.24 mmol), LiOH«H2O (30 mg, 0.72

524 mmol), THF (2 mL), and water (2 mL). Yield = 48 mg (74%). MS (ESI): m/z 274 [M+H]⁺. Ή NMR (400 MHz, DMSO-de) δ ppm 13.08 (bs, IH), 9.04 (dd, J = 4.2, 1.7 Hz, IH), 8.32 (s, IH). 8.30 (ddd. J = 8.4, LL l.l Hz, IH), 7.97 (dd, J = 8.5. 7.4 Hz, IH). 7.88(dd,J = 7.3, 1.2 Hz. IH), 7.75-7.70 (m, IH). 7.63 (dd, J= 8.6. 4.2 Hz, IH).

C. 5-Chloro-N-(5-chloro-6-( 2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(quinolm-5-yl)-1Hpyrazole-4-carboxamide. Cpd 187

The title compound was made using the procedure of 186d using 5-chloro-l(quinolin-5-yl)-lH-pyrazole-4-carboxylic acid (41 mg, 0.15 mmol), 5-chloro-6-(2H-L2,3triazol-2-yl)pyridin-3-amine (35 mg, 0.18 mmol), pyridine (72 uL, 0.90 mmol), CH2CI2 (3 inL), and POCh (56 pL, 0.60 mmol). The mixture was purified by reversed-phase préparative HPLC (Cl8 silica 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]T Ή NMR (400 MHz, DMSO-dt,) δ ppm 10.82 (s, IH), 9.06 (dd, J= 4.2, 1.7 Hz, IH), 8.90 (d, J= 2.3 Hz, IH), 8.69 (d,.7=2.2 Hz, IH), 8.66 (s, IH), 8.33 (ddd, J= 8.5, 1.1. 1.1 Hz, IH), 8.19 (s, 2H). 8.00 (dd, J = 8.5, 7.4 Hz, IH), 7.91 (dd, J= 7.4, 1.2 Hz, IH), 7.78-7.73 (m. IH), 7.67 (dd, J = 8.6. 4.2 Hz, IH).

Example 188

5-BiOmo-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-lH pyrazole-4-carboxamide, Cpd 188

525

A. Ethyl 5-bromo-l-(quinolin-5-yl)-lH-pyrazole-4-carboxylate, 188a

This compound was made using the procedure of 186b using ethyl l-(quinolin-5yl)-l H-pyrazole-4-carboxylate (100 mg, 0.37 mmol), TMPMgChLiCl (0.49 mL ofa 1 M solution in THF/toluene, 0.49 mmol), and 1,2-dibromotetrachloroethane ( 183 mg, 0.56 mmol). Purification was accomplished by flash chromatography (12 g silica gel cartridge, gradient 5-40% EtOAc/hex). Yield = 69 mg (53%). MS (ESI): m/z 346, 348 [M+HJ’. ’H

NMR (400 MHz, CDCh) δ ppm 9.01 (dd,7=4.2, 1.7 Hz. IH), 8.33 (ddd,7= 8.6, 1.0, 1.0 Hz, IH), 8.27 (s, IH). 7.85 (dd, 7= 8.6, 7.4 Hz, IH), 7.66 (ddd, 7= 8.5, 1.7,0.9 Hz, IH), 7.63 (dd,7=7.4, 1.1 Hz, IH), 7.46 (dd,7 = 8.6, 4.2 Hz, IH), 4.41 (q,7=7.1 Hz. 2H), 1.42 (t.7= 7.2 Hz. 3H).

B. 5-Bromo-l-(quinolin-5-yl)-lH-pyrazole-4-carboxylic acid, 188b

This compound was made using the procedure of 186c using ethyl 5-bromo-l(quinolin-5-yl)-lH-pyrazole-4-carboxylate (64 mg, 0.18 mmol), LiOH’H₂O (23 mg, 0.56

526 mmol). THF (2 mL), and water (2 mL). Yield = 46 mg (78%). \IS (ESI): m/z 318, 320 [M+H]L ‘H NMR (400 MHz, DMSO-d₆) δ ppm 13.00 (bs, 1 H), 9.04 (t, J = 2.9 Hz, IH), 8.31 (s, IH). 8.30 (dd, J= 8.4. 1.1 Hz, IH), 7.97 (dd, J = 8.5. 7.4 Hz, IH), 7.85 (dd, J = 7.4, 1.2 Hz. IH), 7.62 (d,</= 2.9 Hz, 2H).

C. 5-Bromo-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-lHpyrazole-4-carboxamide. Cpd 188

The title compound was made using the procedure of186d using 5-bromo-l(quinolin-5-yl)-lH-pyrazole-4-carboxylic acid (43 mg, 0.14 mmol), 5-chloro-6-(2H-l,2,3triazoI-2-yl)pyridin-3-amine (32 mg. 0.16 mmol), pyridine (65 pL, 0.81 mmol), CH2CI2 (3 mL), and POCh (50 pL, 0.54 mmol). The mixture was purified by reversed-phase préparative HPLC (Cl8 silica column, 50x250 mm, gradient l()%-100% ACNÆLO with 0.05% TFA, 80 mL/min). Yield = 40 mg (60%). MS (ESI): m/z 495. 497 [M+H]”. ’H NMR (400 MHz. DMSO-dû) δ ppm 10.81 (s, IH), 9.06 (t, J= 2.9 Hz, IH), 8.90 (d, J= 2.3 Hz, IH), 8.69 (d, J= 2.3 Hz, IH), 8.65 (s, IH). 8.32 (dd, ./= 8.6. 1.1 Hz, IH), 8.19 (s, 2H). 8.00 (dd, J = 8.6. 7.4 Hz, IH), 7.88 (dd, .7= 8.6, 1.2 Hz, IH), 7.66 (d. J= 3.0 Hz, 2H).

Example 189 N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(imidazo[L2-a]pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 189

527

A. di-zm-butyl l -(imidazo[ l ,2-a]pyridin-3-yl)hydrazine-l ,2-dicarboxylate, 189a

X o °o

N-NH

Y Y O° x y ? o ^N /v / \ , 189a

A mixture of imidazo[l,2-a]pyridine (2.0 g. 16.9 mmol) and di-zm-butyl diazene1,2-dicarboxylate in CHaCN (50 mL) was heated to reflux for 2 days. The solvent was removed and the residue was purified by column chromatography over silica gel (eulent: petrol etherÆtOAc=100:0 to 0:100). The desired fraction was collected and the solvent was removed to afford the product as a yellow solid (700 mg, 11.2%). LC-MS: (ES, m/z):

| M + 1 f 349.0

B. 3-hydrazinylimidazo[l,2-a]pyridine, 189b

HN-NH₂

N ,189b

Di-rm-butyl l-(imidazo[l,2-a]pyridin-3-yl)hydrazine-l,2-dicarboxylate in 4M HCl in MeOH (30 mL) was stirred at rt for 1 h. The solvent was removed to afford a white solid that was used directly for the next step.

528

C. ethyl l -(imidazo[l,2-a]pyridin-3-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxylate, 189c

A solution consisting of ethyl 2-(ethoxymethylene)-4.4,4-trifluoro-3-oxobutanoate, 5 If (722 mg, 3.0 mmol). 3-hydrazinylimidazo[l,2-a|pyridine (370 mg, 2.0 mmol). and éthanol (20 mL) was stirred at rt for 2 h. The resulting solution was concentrated to dryness under reduced pressure, partioned between EtOAc (30 mL) and aq. Vil ICO (20 mL). The organic layer was separated, washed with water (10 mL), dried over MgSO4, fïltered and the filtrate concentrated to afford the crude product. The crude product was purified by' column chromatography over silica gel (petroleum ether/ ethyl acetate=l 00:0 to 100:0) to afford the product as gray solid (120 mg, 18.3%). LC-MS: (ES, m/z): [M+lp 324.9.

D. l-(imidazo[ l,2-a]pyridin-3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid.

189d

Sodium hydroxide (44 mg, 1.1 mmol) was added to a solution of ethyl 1(imidazo[L2-a]pyridin-3-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate (120 mg, 0.37 mmol ) in EiOl 1 I LO (1:1,2 mL). The mixture was reacted at 28 °C for 2 h. 10% HCl solution was add to the mixture to adjust the pH to -5. The mixture was extracted with ethyl acetate, dried over MgSO4, fïltered, and the filtrate concentrated under reduced

529 pressure the give the desired compound (100 mg, 90.5 % yield). LC-MS: (ES, m/z): ) Μ 1 ] 297.0.

E, N-( 5-cyano-6-(2H-1,2.3-triazol-2-yl)pyridin-3-yl )-l -(imidazo[ 1,2-a]pyridin-3-yl)5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 189

l-(Imidazo[L2-a]pyndin-3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (67.5 mg, 0.22mmol), 5-amino-2-(2H-l,2,3-triazol-2-yl)nicotinomtrile (50 mg, 0.27 mmol), pyridine (53.1 mg, 0.67 mmol) were dissolved in CH2CI2 (2 mL), and phosphorus oxychloride (41.2 mg, 0.27 mmol) was added. The mixture was stirred at 25 °C for 3 h, satNaHCOs (20 mL) was added and the mixture extracted with CH2CI2 (20 mL x 2). The combined organic layers were dried over Na₂SO4, filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a yellow oil, which was purified by préparative HPLC (20% to 50% (v/v) CH3CN and H?O with 0.05% HCl) and lyophilized to dryness to afford the title compound (40 mg, 37.6%). ’H NMR (400 MHz, DMSO-d6) δ ppm 7.22 - 7.33 (m, 1 H), 7.68 (br t, J=7.28 Hz. 1 H). 7.84 - 7.95 (m, 1 H), 8.18-8.40 (m,4H), 8.76 (s, 1 H), 8.90 (s, 1 H), 9.14(brs, 1 H), 11.63 (s, 1 H). LC-MS: (ES. m/z): [M+lf 464.9.

Example 190

N-(5-ethynyl-2-methyl-6-(2H-l,2,3-triazol-2-yi)pyridin-3-yl)-l-(l-oxo-1.2dibydroisoquinolin-5-yl)-5-(trifluoromethyr)-lH-pyrazole-4-carboxamide, Cpd 190

530

A. 5-ethynyl-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, 190a

Pd(PPh3)4 (109 mg, 0.095 mmol) was added to a solution of 5-bromo-2-methyl-6(2H-L2,3-triazol-2-yl)pyridin-3-amine (200 mg, 0.79 mmol), trimethyl((4,4,5,5tetramethyl-l,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 under N2 bubbling for 12 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with EtOAc ( 10 mL x 2). The filtrate was concentrated under reduced pressure to afford crade product which was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate= 100:0 to petroleum ether/ ethyl acetate=40:60). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford the product as a brown oil (20 mg, 12.8 % yield). LC-MS: (ES, m/): |M 11 200.2 .

B. N-(5-ethynyl-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyndin-3-yl)-l-(1-oxo-1,2dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 190

531

To a solution of l-(l-oxo-L2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylic acid (24.3 mg, 0.075 mmol) and 5-ethynyl-2-methyl-6-(2H-l,2,3triazol-2-yI)pyridin-3-amine (15 mg, 0.075 mmol) and pyridine ( 17.9 mg, 0.23 mmol) in dichloromethane (2 mL) was added POCh (13.9 mg, 0.090 mmol) dropwise. Sat. NaHCOs (5 mL) was added and the mixture extracted with CTLCb (10 mL x 2). The combined organic layers were dried over Na/SCL. filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a brown oil which was purified by préparative high-performance liquid chromatography (26% to 56% (v/v) CH3CN and H;O with 0.05% HCl) and lyophilized to dryness to afford the product as a white solid (14.8 mg, 38.5%). Ή NMR (400 MHz, DMSO-d6) δ ppm 2.56 (s, 3 H). 4.43 (s, 1 H), 5.67 (br d, J=6.84 Hz, 1 H), 7.28 (br s, 1 H), 7.66 (br t, J=7.83 Hz, 1 H), 7.92 (br d, J=7.06 Hz, 1 H), 8.14 (s, 2 H), 8.30 (s, 1 H), 8.42 (br d, J=7.94 Hz, 1 H), 8.51 (s, 1 H), 10.55 (s, 1 H), 11.61 (br d, J=4.41 Hz, 1 H). LC-MS: (ES. m/z): [M+l]’ 505.0

Example 191 iV-(5-chloro-2-methyl-6-(22/-l,2,3-triazol-2-yl)pyridin-3-yl)-1-( isoquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 191

532

A mixture of ethyl l-(isoquinolin-4-yl )-5-( trifluoromethyl)-l//-pyrazole-4carboxylate (750 mg, 2.24 mmol) in conc. HCl (12 M, 25 mL) was stirred at 130 °C for 2 h. The solvent was removed under reduced pressure to give the crude product as a yellow solid (700 mg, 95.5%). which was used directly for the next step. LCMS (ESI) m/z M+L 307.8.

B. N-(5-chloro-2-methyl-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 191

POCh (112.3 mg, 0.732 mmol) was added to a mixture of l-(isoquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (120 mg, 0.37 mmol), 5-chloro-2-methyl6-(2//-1,2,3-triazoI-2-yl)pyridin-3-amine (76.77 mg, 0.37 mmol). pyridine (144.83 mg, 1.83 mmol) in CH2CI2 (5 mL) at rt. The reaction mixture was stirred at room température for 1 h. The reaction mixture was quenched with 10 mL sat. K2CO3 aq, and the mixture extracted with CH₂C1₂ (20 mL x 3). The organic layer was separated and concentrated under reduced pressure. It was purified by préparative high-performance liquid chromatography (40% to 70% (v/v) CH3CN andH₂O 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 give the desired product as a pale yellow solid (55 mg, purity: 99.145%, yield: 29.85%). LCMS (ESI) m/z M+l: 498.9. 'H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.59 (s, 3 H), 7.31 (d, J=8.60 Hz. 1 H), 7.61 (s, 1 H), 7.68 .- 7.79 (m, 2 H), 7.88 (s, 2 H). 8.11 (d, J=7.72 Hz. 1 H), 8.24 (s, 1 H), 8.58 (s, 1 H), 8.90 (s, 1 H). 9.39 (s, 1 H).

533

Example 192

N-(5-chloro-6-(L3,4-oxadiazol-2-yl)pyridin-3-yD-l-(quinolin-5-yl)-5-(trifluoromethyI)lH-pyrazole-4-carboxamide, Cpd 192

A. N-(5-chloro-6-(hydrazmecarbonyl)pyridin-3-yl)-l-(quinolin-5-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, 192a

Methyl 3-chloro-5-( l-(quinolin-5-yl )-5-( trifluoromethyl)-lH-pyrazole-410 carboxamido)picolinate (120 mg, 0.25 mmol) and hydrazine monohydride (25.3 mg, 0.50 mmol) in éthanol (1 mL) was stirred at 80 °C ovemight. The mixture was concentrated to give a crude product (120 mg) which was used directly for the next step.

B. N-(5-chloro-6-(l,3.4-oxadiazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-515 (trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 192

534

A mixture of N-(5-chloro-6-(hydrazinecarbonyI)pyridin-3-yl)-l -(quinolin-5-yl )-5(trifluoromethyl)-lH-pyrazole-4-carboxamide ( 100 mg, 0.21 mmol), triethoxymethane ( ] 05 pL, 0.63 mmol ) and acetic acid (6.3 pL, 0.11 mmol) in toluène (2 mL) was stirred at l()0 °C for 4 h. The mixture was concentrated to give a crude product. The crude product 5 was purified by préparative high-performancc liquid chromatography (30% to 60% (v/v) CHsCN and H₂O with 0.05 % ammonia 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). ‘H NMR (400 MHz. DMSO-d6) δ ppm 7.57 - 7.62 (m, l H), 7.64 7.69 (m, l H), 7.89 - 7.99 (m. 2 H), 8.32 (d, J=8.38 Hz, l H), 8.57 (s, l H), 8.62 (d, J=l.98 K) Hz, l H). 8.99 (d, J=1.98 Hz, l H), 9.04 (dd, J=4.08, 1.65 Hz, l H), 9.45 (s, l H). LCMS (TSTimz M+l: 485.9

Example 193

A%5-chloro-6-(2H-L2,3-triazol-2-yl)pyridm-3-yl)-l-(imidazo[l,2-i?]pyndm-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide. Cpd 193

A.

ethyl 1 -(6-bromopyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate, 193a

A solution of 2-bromo-6-hydrazinopyridine (3.0 g, 16.0 mmol) and ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (5.75 g, 23.9 mmo) in EtOH (150 mL)

535 was stirred at 80 °C ovemight then cooled to rt. The solvent was removed under reduced pressure to afford a yellow oil. The yellow oil was purified by flash column chromatography over silica gel (eluent: petroleum ether/EtOAc 100/0 to petroleum ether/EtOAc 80/20). The desired fractions were collected and the solvent w^ras concentrated to dryness under reduced pressure to afford the desired product as a yellow solid (5.7 g, yield: 98.1%).

B. ethyl 1 -( 6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-5-(trifhioromefhyl)-1Hpyrazole-4-carboxylate, 193b

Pd(OAc)2 (93.3 mg, 0.415 mmol) andXantphos (238 mg, 0.412 mmol) in dioxane (75 mL) w’ere stirred at rt for 10 min under nitrogen. Ethyl l-(6-bromopyridin-2-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxylate (3.0 g, 8.24 mmol), Cs₂CO? (8.05 g, 24.7 mmol) and tert-butyl carbamate (1.16 g, 9.89 mmol) are then added at room température. The réaction mixture is then allowed to heat at 90 °C ovemight and then cooled to rt. The réaction mixture was fïltered though a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure. It was purified by flash column chromatography over silica gel (eluent: petroleum ether/EtOAc 100 0 to petroleum ether/EtOAc 80/20). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to give the desired product as a white solid (3.09 g, yield: 93.7%).

C. 1-(6-(( tert-butoxycarbonyl)amino)pyridm-2-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylic acid, 193c

536

A mixture of ethyl l -(6-((zm-butoxycarbonyl )amino)pyridin-2-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxylate and LiOH.HaO (628 mg, 15.0 mmol) in THF/MeOH H₂O ( l : l : l, 60 mL) was stirred at rt for 2 h. The organic solvent was removed under reduced pressure. 2N HCl was added to adjust the mixture to pH 4~5, then it was extracted with EtOAc (50 mL x 3). The organic layer was separated, dried over NajSOj. filtered and the filtrate concentrated under reduced pressure to give the crude product as a white solid (1.8 g, yield: 96.8%).

D. tert-butyl (6-(4-((5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-l H-pyrazol-l-yl)pyridin-2-yl)carbamate, 193d

POCh (824 mg. 5.37 mmol) was added to a mixture of l-(6-((te/7butoxycarbonyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid ( l g, 2.69 mmol), 5-chloro-6-(2H-l,2,3-tnazol-2-yl)pyridin-3-amine (525 mg, 2.69 mmol). pyridine ( 1.06 g. 13.4 mmol) in CHrChQO mL) at rt. The reaction mixture was stirred at room température for 1 h. The réaction mixture was slowly quenched with 30 mL sat. K2CO3 aq, and extracted with CH2CI2 (50 mL x 3). The organic layer was separated and concentrated under reduced pressure. The résultant residue was purified by flash column chromatography over silica gel (eluent: petroleum ether EtOAc 100/0 to petroleum ether/'EtOAc 0/100). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to give the desired product as a brown solid (8?0 mg, purity: 98.4%. yield: 70.8%). LCMS (ESI) m/z M+l: 450.0 (M-100).

537

E. l-(6-aminopyridin-2-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, 193e

A solution of zm-butyl (6-(4-((5-chloro-6-(2//-l,2,3-triazol-2-yl)pyridin-35 yl)carbamoyl)-5-(trifluoromethyl)-lZ/-pyrazol-l-yl)pyridin-2-yl)carbamate (1.76 g, 3.20 mmol) in HCl/MeOH (4M, 50 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure to afford the crude product as a red solid. The red solid was purified by préparative high-performance liquid chromatography ( 15% to 55% ( v v) CHjCN and H2O with 0.1% TFA). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. Sat. K2CO3 aq was added to adjust pH ~12, then it was extracted with EtOAc (50 mL x 2). The organic layer was separated, dried overNa2SO4, 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+L 449.9. 'H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.57 (br s. 2 H), 6.54 (d, J=8.16 Hz, 1 H),

6.90 (d, J=7.72 Hz, 1 H), 7.57 (t. J=8.05 Hz, 1 H), 7.81 (s, 1 H), 7.87 (s, 2 H), 7.977 (s, 1

H), 8.42 (d, J=2.21 Hz. 1 H), 8.68 (d. J=2.43 Hz, 1 H).

F. N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(imidazo[l,2-a]pyridin-5-yl)5-(trifhioromethyl)-lH-pyrazole-4-carboxamide, Cpd 193

538 l-(6-Aminopyridin-2-yl)-2V-(5-chIoro-6-( 2//-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-l//-pyrazole-4-carboxamide ( 1.48 g, 2.70 mmol, 97.2% purity) is taken up in i-PrOH (40 mL) under N₂. Bromoacetaldehyde diethyl acetal (1.07 g, 5.41 mmol) is added to the suspension followed by HBr aq. (48%. 2.5 mL). The reaction mixture was stirred at 90 °C ovemight and cooled to rt. The solvent was removed under reduced pressure and then purified by préparative high-performance liquid chromatography (30% to 60% (v/v) CH/CN and H₂O with 0.05% ammonia 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 give the desired product as off-white solid (290 mg, purity: 96.7 %, yield: 21.9%). LCMS (ESI) m/z M+l: 473.9. 'H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.01 (d, J=7.06 Hz, 1 H), 7.08 (s, 1 H), 7.37 (dd, 1=9.04. 7.28 Hz, 1 H), 7.63 (d, 1=1.10 Hz, 1 H), 7.81 (d, J=9.04 Hz, 1 H), 7.96 (s, 2 H), 8.30 (s, 1 H), 8.67 (d, J=2.21 Hz, 1 H). 8.83 (d, 1=2.43 Hz. 1 H), 9.48 (s, 1 H).

Example 194

A-(5-chloro-2-methyl-6-(2/7-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(imidazo[l,2-i7]pyridin-5yI)-5-(trifluoromethyl)-l//-pyrazole-4-carboxamide, Cpd 194

A. 5-hydrazinylimidazo[I,2-a]pyridine, 194a

NH nh₂ , 194a

539

The mixture of {Pd(cinnamyl)Clh ( 13 l mg. 0.254 mmol) and Mor-DalPhos (235 mg, 0.508 mmol) in dioxane (100 mL) was evacuated with argon (4x). The resulting clear yellow solution was stirred at room temp under argon for 10 min. 5-Bromoimidazo[l,2C7]pyridine (l g, 5.08 mmol) and t-BuONa (975 mg, 10.2 mmol) were added to the mixture and the mixture was evacuated with argon (4x). The resulting yellow reaction was stirred at room temp for 5 min and was then treated with NH2NH2.H2O (98%, 504 pL, 10.2 mmol) via syringe. The reaction was evacuated with argon (4x). Then the mixture was stirred at 50 °C under argon for 2 h. The mixture was filtered though 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 crude product as a brown solid (750 mg. crude). It was used directly in the next step.

B. ethyl l -(imidazo[ l ,2-alpyridin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxylate, 194b

A solution of 5-hydrazinylimidazo[l,2-</]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 then cooled to rt. The solvent was removed under reduced pressure to give a black oil. It was purified by flash column chromatography over silica gel (eluent: petroleum ether/EtOAc 100/0 to petroleum ether/EtOAc 20/80). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to give the desired product as a brown solid (850 mg, purity: 98.0%, yield: 50.7%). LCMS (ESI) m/zM+l: 325.1.

540 l-(imidazo[ L2-a]pyndin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 194c

OH , 194c

The mixture of ethyl l-(imidazo[L2-c?]pyridin-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxylate (1.2 g, 3.70 mmol) in conc. HCl (12M, 25 mL) was stirred at 130 °C for 2 h. 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 Ml: 296.9.

D. 5-chloro-2-methyl-3-nitropyridine 1-oxide, 194d o₂n

Cl , 194d

A mixture of 5-chIoro-2-methyl-3-nitropyridine (3.0 g, 17.4 mmol) and mCPBA (85%, 7.06 g. 34.8 mmol) in CH2Q2 (60 mL) was stirred at rt for 72 h. The reaction mixture was quenched with 60 mL sat. NazSOs aq. Sat. K2CO3 aq was added to adjust the mixture pH to 9~ 10 and the mixture was extracted with CH2CI2 (100 mL x 3). The organic layer was separated, dried over NarSCU, filtered and the filtrate concentrated to afford a yellow solid. The solid was purified by flash column chromatography over silica gel (eluent: petroleum ether/EtOAc 100/0 to petroleum ether/EtOAc 0/100). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to afford the desired product as a yellow solid (2.4 g, yield: 73.2%). ^!H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.65 (s, 3 H), 7.71 (d, J=1.54 Hz, 1 H), 8.46 (d, J= 1.54 Hz, 1 H).

541

E. 2,3-dichloro-6-methyl-5-nitropyridine, 194e

Cl cl ,194e

POCh (24.9 mL. 267 mmol) was added to a mixture of 5-chloro-2-methyl-3nitropyridine 1-oxide (2.4 g, 12.7 mmol) in CHCh (80 mL). The reaction mixture was stirred at reflux for 6 h. The réaction mixture was cooled to rt, then slowly added to 200 mL sat. K2CO3 aq. and extracted with CH2CI2 (200 mL x 3). The organic layer was separated. dried over Na₂SO4. filtered and the fiitrate concentrated to afford a brown solid. The solid was purified by flash column chromatography over silica gel (eluent: petroleum ether/EtOAc 100/0 to petroleum ether/EtOAc 80/20). The desired fractions were collected 10 and the solvent was concentrated to dryness under reduced pressure to afford the desired product as a yellow⁷ solid (1.1 g, yield: 41.8%). *H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.86 (s. 3 H). 8.43 (s, 1 H).

F. 3-chloro-6-mcthyl-5-mtro-2-(2H-1,2,3-triazol-2-yl)pyridine, 194f

O₂N Cl _194f lH-l,2,3-tnazole (550 mg, 7.97 mmol) was added to a solution of 2,3-dichIoro-6methyl-5-nitropyridine (1.1 g, 5.31 mol.) and K2CO3 (2.20 g, 15.9 mmol) iu ( H CN (60 mL). The mixture was stirred at 40 °C for 2 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with EtOAc (50 mL x 3). The fiitrate 20 was concentrated under reduced pressure to give the crude product as a black solid ( 1.2 g, yield: 94.2%).

542

G. 5-chloiO-2-methyl-6-(2H-l,2.3-triazol-2-yl)pyridm-3-amine, 194g

N^\ 00/

H₂N A0+_C| ,

A mixture of 3-chIoro-6-methyl-5-nitro-2-(2//-1,2,3-triazol-2-yl)pyridine (crude

1.2 g), iron powder (1.40 g, 25.0 mmol) and NH4CI (1.34 g, 25.0 mmol) 111

MeOH/THFÆLO ( 1:1:1, 60 mL) was stirred at 70 °C for 2 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad washed with EtOAc (50 mL x 2). The filtrate was w'ashed with 50 mL sat. K2CO3 aq. and separated. The organic layer was dried over Na₂SO4, filtered and the filtrate concentrated to afford a brown solid. The solid was purified by flash column chromatography over silica gel (eluent: petroleum ether,-EtOAc 100/0 to petroleum cther EtOAc 0/100). The desired fractions were collected and the solvent w^;as concentrated to dryness under reduced pressure to afford the desired product as a yellow⁷ solid. *H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.44 (s, 3 H), 3.97 (br s, 2 H), 7.13 (s, 1 H), 7.88 (s, 2 H).

H. N-(5-chloro-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(imidazo[l,2

a]pyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 194

POCh (0.364 mL, 3.91 mmol) was added to a mixture of l-(imidazo[L2-<7]pyridin5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (600 mg, 1.96 mmol, 96.5% purity), 5-chloro-2-methyl-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-amine (410 mg. 1.96 mmol). pyridine (0.786 mL, 9.77 mmol) in CH2CI2 (20 mL) at rt. The reaction mixture was stirred at room température for 1 h. The reaction mixture was quenched with 30 mL sat. K2CO3 aq, and the mixture extracted with CH2CI2 (50 mL x 3). The organic layer was separated

543 and concentrated under reduced pressure. It was purified by préparative high-performance liquid chromatography (30% to 60% (v/v) CH3CN and H2O with 0.05% ammonia hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to give the desired product as a pale yellow solid (435 mg, purity: 100%, yield: 45.6%). LCMS (ESI) m/z M+l: 487.9. Ή NMR (400 MHz, DMSO-d6) δ ppm 2.54 (s, 3 H), 7.35 - 7.44 (m, 2 H), 7.48 (dd, J=9.04, 7.28 Hz, 1 H), 7.72 (d, J= L10 Hz, I H), 7.90 (d, J=9.04 Hz, 1 H), 8.17 (s, 2 H), 8.43 (s, 1 H), 8.68 (s, 1 H).

Example 195 iV-(5-chloro-2-ethyl-6-(2//-L2,3-triazol-2-yl)pyridin-3-yl)-l-(imidazo[L2-iz]pyridin-5-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 195

A. 2-bromo-5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine, 195a βχΠ a⁷ h₂n Ax_cl _ _195a

NBS (2.73 g, 15.3 mmol) was added to a mixture of 5-chloro-6-(23/-1,2,3-triazol-2yl)pyridin-3-amine (3 g, 15.3 mmol) 111 CH3CN (300 mL) at 0 °C, then the mixture was stirred at rt for 1 h. The reaction mixture was quenched with 100 mL sat. NaHCOa aq, and then extracted with EtOAc (100 mL x 3). The organic layer was combined, washed with 50 mL of sat NaCl aq., dried over Na₂SO4, filtered and the filtrate concentrated under reduced pressure to give a brown. sticky residue. It was concentrated and purified by flash column chromatography over silica gel (eluent: petroleum ether/EtOAc 100/0 to petroleum ether/EtOAc 50/50). The desired fractions were collected and the solvent was concentrated

544 to dryness under reduced pressure to give the product as a yellow solid (4.00g, yield:

95.0%).

B. 5-chloro-2-ethyl-6-(2H-L2,3-triazol-2-yl)pyridin-3-amine, 195b /aaa h₂n , _195b

To a solution of 2-bromo-5-chloro-6-(2Zf-1.2,3-triazol-2-yl)pyridin-3-amine (100 mg, 0.364 mmol) in dioxane (3 mL) was added ZnEtVtoluene ( 1 M, 0.546 mL, 0.546 mmol) and Pd(dppf)Cl₂ (40.0 mg, 0.055 mmol) under N₂. The reaction mixture was stirred at 90 °C for 1.5 h. The reaction mixture was quenched with 10 mL sat. NaHCCL aq, then the mixture was filtered though a pad of diatomaceous earth and washed with 20 mL EtOAc. The filtrate was extracted with EtOAc (20 mL x 2). The organic layer was separated, dried over Na₂SÛ4, filtered and the filtrate concentrated to give a brown residue. It was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/() to 50/50). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to give product as a yellow solid (70 mg, yield: 86%). 'H NMR (400 MHz, CHLOROfORM-d) δ ppm 1.29 (t, J=7.61 Hz. 3 H), 2.71 (q, J=7.50 Hz, 2 H), 3.96 (br s, 2 H), 7.10 (s, 1 H), 7.87 (s, 2 H).

C. N-(5-chloro-2-ethyl-6-(2H-l,2.3-triazol-2-yr)pyridin-3-yl)-l-(imidazo[L2a]pyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 195

545

POCh (0.58 mL, 0.626 mmol) was added to a mixture of l-(imidazo[l,2-i7]pyridin5-yl )-5-( trifluoromethyl)-lH-pyrazole-4-carboxylic acid (96.1 mg, 0.313 mmol, 96.5% purity), 5-chloro-2-ethyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amme (70 mg, 0.313 mmol), pyridine (124 mg, 1.57 mmol) in CH2CI2 (5 mL) at rt. The réaction mixture was stirred at room température for 1 h. The reaction mixture was quenched with 20 mL sat. K2CO3 aq. and extracted with CH2CI2 (20 mL x 3). The organic layer was separated and concentrated under reduced pressure. It was purified by préparative high-performance liquid chromatography (35% to 65% ( v/v) CHsCN and H2O with 0.05% ammonia hydroxide).

The pure fractions were collected and the organic solvent was concentrated under reduced 10 pressure. The aqueous layer was lyophilized to dryness to give the desired product as an off-white solid (95 mg. purity: 99%, yield: 60%). LCMS (ESI) m/z M+l: 501.9. *H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.23 (m, 3 H), 2.81 - 2.93 (m, 2 H). 7.38 (s, 2 H), 7.48 (t, J=8.20 Hz, 1 H), 7.72 (s, 1 H), 7.89 (d. J=8.20 Hz, 1 H), 8.17 (s. 2 H), 8.40 (s, 1 H), 8.65 (s. 1 H), 9.83 (s, 1 H).

Example 196 ïV-(2,5-diethyl-6-(2H-1,2,3-triazol-2-yl )pyridin-3-yl)-1 -(imidazo[ 1,2-u]pyndin-5-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 196

A. 2,5-diethyl-6-(2H-1.2,3-triazol-2-yl)pyridin-3-amme, 196a

546

To a solution of 2-bromo-5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine (200 mg, 0.729 mmol) in dioxane (6 mL) was added ZnEtj, toluene (l M, 2.55 mL, 2.55 mmol) and Pd(dppf)Ch (80.0 mg, 0.109 mmol) under N?. The reaction mixture was stirred at 110 °C ovemight. LCMS showed 45.4% P2 formed in the reaction mixture, but only trace PI formed. The reaction was quenched by 10 mL sat. aq. NH4CI. filtered though a pad of diatomaceous earth and washed w^rith 30 mL EtOAc. The filtrate was washed with 20 mL sat. NaHCOi aq., then the organic layer was separated, dried over Na₂SO4, filtered and the filtrate concentrated to give a brown sticky residue. The residue was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 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 yellow sticky residue (crude 125 mg). 'H NMR reflected — 10? 0 5-chloro-2-ethyl-6-(2H-L2.3-triazol-2-yT)pyridin-3-amine. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04 (t, J=7.61 Hz, 3 H), 1.26 - 1.31 (m, 3 H), 2.48 (q, J=7.64Hz, 2 H). 2.68 - 2.77 (m, 2 H). 3.81 (br s. 2 H), 6.93 (s, 1 H), 7.82 (s, 2 H).

B.

N-(2.5-diethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-l -(ïmidazo[ 1,2-a]pyridin-5yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 196

POCI3 (0.103 mL. 1.11 mmol) was added to a mixture of 1 -(imidazo[ 1,2-<7]pyridin

5-yl)-5-(tnfluoromethyl)-l//-pyrazole-4-carboxylic acid (170 mg, 0.552 mmol). 2,5diethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (crude 120 mg), pyridine (218 mg, 2.76 mmol) in CH2CI2 (5 mL) at rt. The reaction mixture was stirred at rt for 1 h. The réaction mixture was quenched with 20 mL sat. K2CO3 aq, and extracted with CH₂Ch (20 mL x 3). The organic layer was separated and concentrated under reduced pressure. It was purified by préparative high-performance liquid chromatography (35% to 65% (v/v) CH3CN and

547

H₂O with 0.05% ammonia hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to give the desired product as a pale yellow solid which was further purified by' SFC (Column: Chiralcel OJ 250 x 30 5u: Condition: 0.1% NH3H2O MEOH, Flow Rate(mL/min) 65). The pure fractions were collected and the organic solvent was concentrated under reduced pressure, then lyophilized to dryness to give the desired product as a white solid (l05 mg, purity: 100%, yield: 38.8%). LCMS (ESI) m/z M+l: 496.0. ^lH NMR (400 MHz. DMSO-d6) δ ppm 0.99 (t, J=7.61 Hz, 3 H), 1.19 (t, J=7.50 Hz, 3 H), 2.50 - 2.55 (m, 2 H), 2.83 (q, J=7.50 Hz, 2 H), 7.40 (d, J=7.28 Hz, 2 H), 7.44 - 7.53 (m. 1 H), 7.72 (d, J=1.10 Hz, 1 H). 7.90 (dd. .1=9.04. 0.88 Hz, 1 H). 8.00 (s. 1 H), 8.12 (s. 2 H), 8.66 (s, 1 H), 10,52 (s. 1 H).

Example 197 ïV-(5-chloro-6-(2/f-L2,3-triazol-2-yl)pyridin-3-yl)-l-(pyrazolo[L5-i7]pyridin-4-yl)-5(trifluoromethyl)-lÆ-pyrazole-4-carboxamide, Cpd 197

A. 4-hydrazinylpyrazolo[ L5-a]pyridine, 197a

, 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 evacuated with argon (4x). The resulting clear yellow solution was stirred at rt under argon for 10 min. 4-BromopyTazolo[L5-«]pyridine (1.00 g, 5.08 mmol) and t-BuONa (975 mg, 10.2 mmol) were added to the mixture and the

548 mixture was evacuated with argon (4x). The resulting yellow reaction was stirred at rt for 5 min and was then treated with NH2NH2.H2O (98%, 0.502 mL, 10.2 mmol) via syringe. The reaction was evacuated with argon (4x). Then the mixture was stirred at 50 °C under argon for 3 h. The mixture was filtered though a pad of diatomaceous earth and washed with ethyl acetate (200 mL). The filtrate was collected and concentrated to give a crude product as a dark yellow solid (750 mg). It was used directly for the next step.

B. ethyl l-(pyrazolo[L5-a]pyridin-4-yl)-5-(trifluoromethyl)-l H-pyrazole-4carboxylate, 197b

A solution of 4-hydrazinylpyrazolo[l,5-r/]pyridine (750 mg crude) and ethyl 2(ethoxyniethylene)-4,4,4-trifluoro-3-oxobutanoate (1.84 g, 7.59 mmol) in EtOH (100 mL) was stirred at 80 °C for 1 h then cooled to rt. The solvent was removed under reduced pressure to give the crude product as a brown solid. The solid was purified by flash column chromatography over 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 give product as a yellow solid (1.11 g, 67.4% yield in two steps). LCMS (ESI) m/z M+l: 324.9.

C. I -(pyrazolof 1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, . 197c

549

A mixture of ethyl l-(pyrazolo[L5-a]pyridin-4-yl)-5-( trifluoromethyl)-IHpyrazole-4-carboxylate (650 mg, I.96 mmol) in conc. HCl ( 12 M, 50 mL) was stirred at 130 °C for l h. The solvent was removed under reduced pressure to give the crude as a pale yellow solid (600 mg. purity: 98.8%. quantitative yield). LCMS (ESI) m/z M+l: 296.9.

D. N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(pyrazolo[ L5-a]pyridin-4-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 197

POCh (0.0755 mL, 0.81 mmol) was added to a mixture of l-(pyrazolo[ 1.5a]pyridin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (120 mg, 0.405 mmol), 5-chloiO-6-(2//-L2,3-triazol-2-yl)pyridin-3-amine (79.2 mg. 0.405 mmol), pyridine (160 mg, 2.03 mmol) in CH2Q2 (5 mL) at rt. The reaction mixture was stirred rt for 1 h. The reaction mixture was quenched with 20 mL sat. K2CO3 aq, and extracted with CH2CI2 (20 mL x 3). The organic layer was separated and concentrated under reduced pressure. It was purified by préparative high-performance liquid chromatography (40% to 70% (v/v) CH3CN and H2O with 0.05% ammonia hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure, The aqueous layer was lyophilized to dryness to give the desired product as a yellow solid (80 mg, purity: 97%>, yield: 40%). LCMS (ESI) m/z M+l: 473.9. ^fH NMR (400 MHz. DMSO-d6) δ ppm 6.34 (dd, J=2.43, 0.88 Hz, 1 H), 7.08 (t, J=7.28 Hz, 1 H), 7.58 (d, J=7.28 Hz, 1 H), 8.13 (d, J=2.43 Hz, 1 H), 8.17 (s, 2 H), 8.55 (s, 1 H), 8.64 (d, J=2.43 Hz, 1 H), 8.83 (d, J=2.21 Hz, 1 H), 8.96 (d, J=7.06 Hz, 1 H).

550

Example 198

A-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-l-(pyrazolo[ l ,5-<7]pyridin-4-yl)-5 (trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 198

POCh (0.076 mL, 0.81 mmol) was added dropwise to a solution of 1- (pyrazolo[ 1,5-tf]pyridin-4-yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxylic acid (120 mg, 0.405 mmol), 5-chloro-2-methyl-6-(2H-L2,3-triazol-2-yl)pyridin-3-amine (0.085 g, 0.405 mmol) and pyridine (0.164 mL, 2.03 mmol) in CH₂C1₂ (5 mL). The reaction mixture was stirred at room température for 2 h. Water (5 mL) was added to the mixture. The aqueous was extracted with CH2CI2 (10 mL x 3). The separated organic layer was dried (Na:>SO₄), filtered, and the solvent was concentrated to give a crude product. The crude product was purified by préparative high-performance liquid chromatography (35% to 65% (v/v) CHsCN and H2O with 0.05% ammonia hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to give the desired product as a white solid (89.2 mg, purity: 98.4%, yield: 44.4%). LCMS (ESI) m/z M+l: 487.9. ‘H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3 H) 6.36 (dd, J=2.43, 0.88 Hz, 1 H) 7.08 (t. J=7.1 7 Hz, 1 H) 7.54 - 7.58 (m, 1 H) 8.13 (d, J=2.43 Hz, 1 H) 8.17 (s, 2 H) <8.43 (s, 1 H) 8.52 (s, 1 H) 8.96 (d, J=7.06 Hz, 1 H).

551

Example 199

Aq5-chloro-6-(2H-l,2.3-tnazol-2-yl)pyridm-3-yl)-l-(2-methylimidazo[l,2-<:z]pyridin-5yl)-5-(trifluoiOmethyD-l/7-pyrazole-4-carboxamide, Cpd 199

A. 5-hydrazinyl-2-methylimidazo[l,2-a]pyridine, 199a

NH

NH₂ . 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 evacuated with argon (4x). The resulting clear yellow solution was stirred at rt under argon for 10 min. 5-Bromo-2-methylimidazo[ 1.210 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 evacuated with argon (4x). The resulting yellow reaction was stirred at rt for 5 min and was then treated with NH2NH2.H2O (0.188 mL, 3.79 mmol) via syringe. The reaction was evacuated with argon (4x). Then the mixture was stirred at 50 °C under argon for 2 h. The mixture was filtered though 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 used directly for the next step.

552

B. ethyl l -(2-methylimidazo[ l ,2-a]pyridin-5-yl)-5-(trifluoromethyl)- lH-pyrazole-4carboxylate, 199b

I ,199b

A solution of 5-hydrazinyl-2-methylimidazo[l,2-<7] pyridine (250 mg crude, 1.54 5 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 h then cooled to rt. The solvent was removed under reduced pressure to give the crude product as dark brown residue. The residue was purified by flash column chromatography over silica gel (eluent: petroleum ether/EtOAc 100/0 to petroleum ether/EtOAc 0/100). The desired fractions were collected 10 and the solvent was concentrated to dryness under reduced pressure to give the product as a black oil, which was further purified by préparative high-performance liquid chromatography (40% to 70% (v/v) CTLCN and ELO with 0.05% ammonia hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to give the desired product as a 15 yellow solid (100 mg, yield: 19.2%).

C. l-(2-methylimidazo[L2-a]pyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazoIe-4carboxylic acid, 199c

, 199c

A mixture of ethyl 1 -(2-methylimidazo[l,2-«]pyTidin-5-yl)-5-(trifluoromethyl)-\Hpyrazole-4-carboxylate (100 mg, 0.30 mmol) in conc. HCl (1 2 M, 5 mL) was stirred at 130

553 °C for 1 h. The solvent was removed under reduced pressure to give the crude product as pale yellow solid (100 mg crude, purity: 100%), which was used directly for the next step. LCMS (ESI) m/z M+l: 310.9.

D. N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yD-l-(2-methylimidazo[L2

a]pyTidin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 199

POCh (98.9 mg, 0.65 mmol) was added to a mixture of I -(2-methylimidazo[ 1,2if]pyridin-5-yl)-5-(trifluoromethyl)-13/-pyrazole-4-carboxylic acid (100 mg, 0.32 mmol, 10 100% purity), 5-chloro-6-(2/M,2,3-triazol-2-yl)pyridin-3-amine (63.05 mg, 0.32 mol), pyridine (127.49 mg, 1.61 mmol) in CH2CI2 (3 mL) at rt. The reaction mixture was stirred at room température for 1 h. The reaction mixture was quenched with 20 mL sat. K2CO3 aq, and extracted with CH2CI2 (20 mL x 3). The organic layer was separated and concentrated under reduced pressure. The resulting residue was purified by préparative high-performance liquid chromatography (40% to 70% (v/v) CH3CN and H2O with 0.05% ammonia hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to give the desired product as a pale yellow solid (65 mg, purity: 99.7%, yield: 41.2%). LCMS (ESI) m/z M+l : 488.1. ‘H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3 H), 7.10 (s, 1 H), 20 7.33 (dd, J=7.17, 0.99 Hz, 1 H), 7.39 - 7.44 (m, 1 H), 7.74 - 7.78 (m, 1 H), 8.17 (s, 2 H),

8.65 (d, J=2.21 Hz, 1 H), 8.68 (s, 1 H), 8.83 (d, J=2.43 Hz, 1 H), 11.27 (br s, 1 H).

554

Example 200

N-(5-cyano-6-(2H-L2,3-triazoI-2-yl)pyridin-3-yl)-1 -(imidazo[L2-a]pyridin-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 200

POCh (82.83 mg. 0.54 mmol) was added to a mixture of l -(imidazo[ l ,2-ii]pyndin5-yl)-5-(trifluoromethyl)-lH-pyTazole-4-carboxylic acid (80 mg, 0.27 mmol). 5-amino-2(2H-l,2,3-tnazol-2-yl)nicotinonitrile (50.28 mg. 0.27 mmol) and pyridine ( 106.82 mg.

1.35 mmol) in CH2CI2 (2 mL). The reaction mixture was stirred at 20 °C for 1 h. Sat.

NaHCOj solution (20 mL) was added to the mixture. The mixture was extracted with 30 mL ethyl acetate. The combined organic layers were dried over Na2SO₄ and fïltered. The filtrâtes were concentrated under reduced pressure to afford crude product as a brown oil. The crude product was purified by préparative high-performance liquid chromatography (26% to 56% (v/v) CHiCN and H2O with 0.05% ammonia hydroxide). The pure fractions were collected and the solvent was concentrated under reduced pressure. The aqueous layer wus concentrated to dryness to give product as a light yellow solid (45.6 mg, purity: 99.9%, yield: 36.3%). LCMS (ESI) m/z M+l: 465.0. ‘H NMR (400 MHz, DMSO-d6) δ ppm 7.38 - 7.52 (m, 3H), 7.71 (d, J= 1.1 Hz, IH), 7.90 (d, J=9.0 Hz, IH), 8.30 (s, 2H), 8.75 (s, IH), 8.89 (d, J-2.4 Hz, IH), 9.11 (d, J=2.4 Hz, IH), 1 1.27 (br s, IH).

555

Example 201

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(3-chloroimidazo[l,2-a]pyridin-5-yl)5-(trifluoromethyl)-lH-pyTazole-4-carboxamide, Cpd 201

To a stirred solution of A'-(5-chloro-6-(2/7-1,2,3-triazol-2-yl)pyridin-3-yl)-l (imidazo[l,2-n]pyridin-5-yl)-5-(trifluoromethyl)-l/f-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 h. The mixture was purified by préparative high-performance liquid chromatography (40% to 70% (v/v) CH3CN and H₂O with 0.05% ammonia hydroxide).

The pure fractions were collected and the solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to give the product as a light yellow solid (65.6 mg, purity: 98.5%, yield: 86.0%). The structure is first assigned as such, NMR could not distinguish the position of the Cl at 2 or 3 position of the imidazopyridine. LCMS (ESI) m/z M+l: 507.9. ‘H NMR (400 MHz, DMSO-d6) δ ppm 6.10 (br s, JH), 7.51

- 7.63 (m, 2H), 7.85 (s, IH), 8.00 (dd, J=1.3, 8.8 Hz, IH). 8.19 (s, 2H), 8.62 (s, IH), 8.69 (d, J=2.3 Hz, 1 H), 8.81 (d, J=2.3 Hz. IH).

556

Example 202

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoroimidazo[l,2-a]pyridin-5-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 202

A. 3.6-difluoro-2-hydrazinylpyridine. 202a

H₂NHN 0 F _202a

To an ice-cold solution of 2,3,6-tnfluoropyridine (4 g, 30.06 mmol) in EtOH (50 mL) was added hydrazine hydrate (3.071 g, 60.12 mmol). The reaction mixture was warmed up to r.t. and then heated at reflux for 2 h. After it was cooled to r.t., the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic layers were dried over anhydrous Na₂SÛ4, filtered, and the filtrate concentrated under reduced pressure. The residue w^ras re-crystallized from EtOH to obtain the product as a light yellow⁷ solid (3 g, yield: 68.8%).

B. 2-bromo-3,6-difluoropyridine, 202b

F,202b

Br₂ (2.13 mL, 4I.35 mmol) w⁷as added dropwise to a stirred solution of 3,6difluoro-2-hydrazinylpyridine (3 g, 20.67 mmol) in CHCL (45 mL) at room température. The mixture w⁷as stirred at 60 °C for I h. The mixture was cooled at 0 °C and a saturated solution of NaHCOs (200 mL) was added dropwise. CH2CI2 (200 mL) w^zas added, the organic layer was separated, dried (NacSCL). filtered and the solvents concentrated under

557 reduced pressure. The residue was purified by flash column chromatography over silica gel (petroleum ether: EtOAc=l :0-9:1) to yield the product as a yellow oil (1.7 g, yield: 42.4%). Ή NMR (400 MHz, DMSO-d6) δ ppm 6.92 (td, J=3.1, 8.7 Hz, IH), 7.55 (td, J=6.2. 8.6 Hz, IH).

C. 2-bromo-3-fluoro-6-hydrazinylpyridme, 202c

Br N NHNH₂ 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 h. The reaction mixture was concentrated under reduced pressure to afford crade as a yellow solid (2.868 g, yield: 100%).

D. ethyl 1 -(6-bromo-5-fluoropyridin-2-yI)-5-( trifluoromethyl )-l H-pyrazole-4- carboxylate, 202d f₃c θ . 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) was added and stirred at 60 °C for 2 h. The mixture was concentrated under reduced pressure to afford crude product. The crade product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100 0 to 80/20). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford compound as a yellow solid (2 g, yield: 38.5%). ^lH 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, IH).

558

E. ethyl ] -(6-((tert-butoxycarbonyl)amino)-5-fluoropyridin-2-yl )-5-(trifluoromethyl)- l H-pyrazole-4-carboxylate, 202e

BocHN ,202e

PdfOAc): (58.755 mg, 0.26 mmol) and Xantphos (l51.428 mg, 0.26 mmol) in dioxane (50 mL) were stirred at rt for 10 min under nitrogen. Ethyl l-(6-bromo-5fluoropyridin-2-yl)-5-(trifluoromethyl)-I H-pyrazol e-4-carboxylate (2 g, 5.23 mmol), CS2CO3 (5.116 g, 15.70 mmol) and tert-butyl carbamate (0.736 g, 6.28 mmol) were then added at room température. The reaction mixture was then allowed to heat at 90 °C overnight and before cooling to rt. The reaction mixture was filtered though a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure, then purified by flash column chromatography over silica gel (eluent: petroleum ether/EtOAc 100 0 to petroleum ether/EtOAc 80/20). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to give the desired product as a yellow solid ( 1800 mg, yield: 82.2%).

F. I -( 6-((tert-butoxycarbonyl)amino)-5-fluoropyridin-2-yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxylic acid, 202f

BocHN _ 202f

To a mixture of ethyl l-(6-((ze/7-butoxycarbonyl)amino)-5-fluoropyridin-2-yl)-5(trifluoromethyl)- lH-pyrazoIe-4-carboxyiate ( 1800 mg, 4.30 mmol) in MeOH ( 15 mmL) and H₂O ( 15 mL) was added LÎOH.H2O (36l.l Img, 8.61 mmol) at 0 °C. The mixture was stirred at 0 °C for l h. The mixture was concentrated to dryness. To the residue was added water/EtOAc (100 mL/100 mL). HCl (1 M in water) was used to adjust the pH of the mixture to pH~5. The organic layer was concentrated to dryness to give the product (1500 mg, yield: 89.3%) as a yellow solid.

559

G. tert-butyl (6-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yI)pyridin-3-yl)carbamoyI)-5(trifluoromethyl)-!H-pyrazol-l-yl)-3-fluoropyridin-2-yl)carbamate, 202g

POCh (l 178.60 mg, 7.69 mmol) was added to a mixture of \ butoxycarbonyl )amino)-5-fluoropyridin-2-yl)-5-( trifluoromethyl)- lrt-pyrazole-4carboxylic acid (1500 mg, 3,84 mmol), 5-chIoro-6-(2Æ-l,2.3-triazol-2-yl)pyridin-3-amine (751.78 mg. 3.84 mmol) and pyridine ( 1520.0 mg, 19.22 mmol) in CH2Q2 (30 mL). The reaction mixture was stirred at 20 °C for 1 h. Sat.KiCCh solution (100 mL) was added to the mixture. The mixture was extracted with 100 mL ethyl acetate. The combined organic layers were dried over NaiSCU, then filtered. The filtrâtes were concentrated under reduced pressure to afford a crude product as a brown oil. The crude material was purified by flash column chromatography over silica gel column (petroleum ethecethyl acetate=l :1-0:1). The desired fraction was collected and the solvent was concentrated under reduced pressure to afford the product as a yellow solid (2000 mg, yield: 91.6%).

H. l-(6-amino-5-fluoropyridin-2-yl)-N-(5-chloro-6-(2H-l,2.3-tnazol-2-yI)pyridin-3yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, 202h

^H2^N , cpd 202h

Tert-butyl (6-(4-((5-chloro-6-(2//-1.2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5( trifluoromethyl)-l//-pyrazol-l-yl)-3-fluoropyridin-2-yI)carbamate (2000 mg. 3.522 mmol) and HCl/MeOH (60 mL, 4M) were stirred at 30 ^CC for 1 h. The mixture was concentrated to dryness. To the residue was added saturated aqueous K2CO3 (100 mL).

560

The mixture was extracted with EtOAc ( 100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the fiitrate was concentrated to dryness to give a crude orange gum. The crude product w^ras purified by préparative high-performance liquid chromatography (20% to 505% (v/v) CH3CN and H2O). The pure fractions were collected and the solvent was concentrated under reduced pressure. The residue was extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated to dryness to give product as a light yellow' solid (800 mg, yield: 48.6%). LCMS (ESI) m/z M+l: 467.9. NMR (400 MHz, DMSO-d6) δ ppm 4.83 (br s, 2H), 6.95 (dd, J=2.6, 8.2 Hz, IH), 7.37 7.45 (m, IH), 7.95 (s, 2H), 8.04 (s, IH), 8.49 (d, J=2.4 Hz, IH), 8.75 (d, J=2.2 Hz, IH).

I. N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-1 -(8-fluoroimidazo[ l ,2a]pyridin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 202

l-(6-amino-5-fluoropyridin-2-yl)-2V-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide (800 mg, L7l mmol) was dissolved in i-PrOH (20 mL) under N₂. 2-Bromo-Ll-diethoxyethane (674.08 mg, 3.42 mmol) was added to the suspension followed by HBr (2 mL, 48% in water). The resulting mixture was then refluxed for 12 h and cooled down to room température. The solvent was removed under reduced pressure. The residue was purified by préparative high-performance liquid chromatography (30% to 60% (v/v) CH3CN and H?.O with 0.053+ ammonia 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 (422.2 mg, purity: 1003% yield: 50.2%). LCMS (ESI) m/z M+l: 491.9. Il NMR (400 MHz, DMSO-d6) δ ppm 7.40 - 7.47 (m, IH). 7.47 - 7.51 (m, IH), 7.53 (dd, J=1.2, 3.2 Hz,

561

1H). 7.76 (d, 1=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), 11.42- 11.07(m, 1H).

Example 203 .V-(5-chloro-2-methyl-6-(277-1,2,3-triazoI-2-yl)pyridin-3-yl)-l-(8-fluoroimidazo[ 1,2«]pyridin-5-yl)-5-(trifluoromethyl)-lFZ-pyrazole-4-carboxamide, Cpd 203

A. tert-butyl (6-(4-((5-chloiO-2-methyI-6-(2H-l,2,3-triazol-2-yl)pyridm-310 yl)carbamoyl)-5-(trifluoromethyl)-1 H-pyrazol-1 -yl)-3-fluoropyridin-2yl)carbamate, 203a

POCk (1.571 g, 10.25 mmol) was added to a mixture of l-(6-((tertbutoxycarbonyl)amino)-5-fluoropyridin-2-yl)-5-( trifluoromethyl)- lf7-pyrazole-415 carboxylic acid (2 g, 5.12 mmol), 5-chloro-2-methyl-6-(2//-l,2.3-triazol-2-yl)pyridin-3amine (1.074 g. 5.12 mmol) and pyridine (2.027 g, 25.62 mmol) in CH2CI2 (50 mL). The reaction mixture was stirred at 20 °C for 1 h. Sat.K₂CCh (120 mL) solution was added to the mixture. The mixture was extracted with 100 mL ethyl acetate. The combined organic layers were dried over Na₂SO4 and filtered. The filtrâtes were concentrated under reduced pressure to afford crude as a brown oil. The crude was purified by flash column

562 chromatography over silica gel (petroleum ether: ethyl acetate=l:1-0:1). The desired fraction was collected and the solvent was concentrated under reduced pressure to afford 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. l-(6-amino-5-fluoropyridin-2-yl)-N-(5-chloro-2-niethyl-6-(2H-l,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, 203b

^h2ⁿ ,203b

Tert-butyl (6-(4-((5-chloiO-2-methyl-6-(27/-l ,2,3-triazol-2-yl)pyridin-310 yl)carbamoy! )-5-(trifluoromethyl)-1 H-pyrazol-1 -yl)-3-fluoropyridin-2-yl)carbamate ( 1.4 g, 1.40 mmol) and HCI/MeOH (50 mL, 4 M) were stirred at 30 °C for 1 h. The mixture was concentrated to dryness. To the residue was added saturated aqueous K2CO3 (100 mL). The mixture was extrated with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO₄, filtered and the filtrate was concentrated to dryness to give the product ( L1 g, crude) as an orange gum.

C.

N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-1-(8fluoroimidazo[ 1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, cpd 203

563

I-(6-Amino-5-fluoropyridin-2-yl)-7V-(5-chloro-2-methyl-6-(2Æ-L2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-lZ/-pyrazole-4-carboxamide ( l.l g, 2.28 mmol) was taken up in i-PrOH (20 mL) under N₂. 2-Bromo-Ll-diethoxyethane (899.85 mg, 4.57 mmol) was added to the suspension followed by HBr (2 mL, 48% in water). The resulting 5 mixture was then refluxed for 12 h and cooled to room température. The solvent was removed under reduced pressure. The residue was purified by préparative highperformance liquid chromatography (30% to 60% (v/v) CfLCN and H₂O with 0.05% ammonia 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 l() light yellow solid. (302 mg, purity: 99.2%, yield: 26.0%). LCMS (ESI) m/z M+l: 505.9. Ή NMR (400 MHz. DMSO-d6) δ ppm 2.53 (s, 3H), 7.40 - 7.49 (m, 2H), 7.52 (d. J=2.0 Hz, IH), 7.77 (d, J=l.I Hz, IH), 8.17 (s, 2H), 8.42 (s, IH), 8.67 (s, IH), 9.73 - 10.40 (m, IH).

Example 204

A-(5-cyano-6-(2//-l ,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fIuoroimidazo[L2-<7]pyridin-5-yI)5-(trifluoromethyl)-lif-pyrazole-4-carboxamide, Cpd 204

564

A. ethyl l -(6-ammo-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxylate, 204a

Ethyl l-(6-((ft77-butoxycarbonyl)amino)-5-fluoropyridin-2-yl)-5-(trifluoromethyl)5 l//-pyrazole-4-carboxylate (0.9 g, 2.15 mmol) and HCl/MeOH (18 mL, 4 M) were stirred at 30 °C for 1 h. The mixture was concentrated to dryness. To the residue was added saturated aqueous K2CO3 (50 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over NazSO^ filtered and the filtrate was concentrated to dryness to give the product as an orange gum (650 mg, yield: 94.9%).

B. ethyl 1 -( 8-fluoroimidazo[ 1,2-a]pyridin-5-yl)-5-( trifluoromethyl)-1 H-pyrazole-4carboxylate, 204b

Ethyl l-(6-amino-5-fluoropyridin-2-yl)-5-( trifluoromethyl)-l//-pyrazole-415 carboxylate (650 mg, 2.043 mmol) was dissoived in EtOH (20 mL) under N?. 2-BromoL1 -diethoxyethane (805.057 mg, 4.085 mmol) was added to the suspension followed by HBr (2 mL, 48% in water). The resulting mixture was then refluxed for 12 h and cooled to room température. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel (petroleum ether: ethyl acetate=10:1-1:1). The pure fractions were collected and the solvent was concentrated under reduced pressure to afford the product as a light yellow solid (320 mg, yield: 45.8%). 'H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (t. J=7.2 Hz, 3H), 4.42 (q.

565

J=7.l Hz. 2H), 6.91 (dd. J=4.0, 7.9 Hz, IH), 7.04 (dd, J=8.0, 9.4 Hz, IH). 7.12 (s. IH).

7.70 (s, IH), 8.30 (s, IH).

C. I-(8-fluoroimidazo[l,2-a]pyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxylic acid, 204c

. 204c

The mixture of ethyl l-(8-fluoroimidazo[l,2-a]pyridin-5-yI)-5-(trifluoromethyl)lH-pyrazole-4-carboxylate (320 mg, 0.935 mmol) in concentrated HCl (6.064 mL) was stirred at 130 °C for 2 h. The solvent was concentrated under reduced pressure to afford the product as a yellow' solid (300 mg, crude).

D. N-(5-cyano-6-(2H-l,2.3-triazol-2-yl)pyridiii-3-yl)-l-(8-fluoroimidazo[ L2a]pyridm-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 204

POCL (292.81 mg, l.9l mmol) was added to a mixture of l-(8-fluoroimidazo[ 1,2<7]pyridin-5-yl)-5-(trifluoromethyl)-17/-pyrazole-4-carboxylic acid (300 mg, 0.96 mmol), 5-amino-2-(2Z7-L2,3-triazol-2-yl)nicotinonitrile (177.76 mg. 0.96 mmol) and pyridine (377.63 mg, 4.77 mmol) in CH2CI2 (10 mL). The reaction mixture was stirred at 20 °C for 1 h. Sat.NaHCO? solution (20 mL) was added to the mixture. The mixture was extracted with 30 mL ethyl acetate. The combined organic layers were dried over NaiSCL, filtered.

566 and the filtrâtes concentrated under reduced pressure to afford crude product as a brown oil. The crude product was purified by préparative high-performance liquid chromatography (30% to 60% (v/v) CH3CN and H2O with 0.05% ammonia 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, punty: 99.2%, yield: 39.2%). LCMS (ESI) m/z M+l: 482.9. ‘H NMR (400 MHz, DMSO-d6) δ ppm 7.38 - 7.51 (m, 2H), 7.53 (dd, J= l. I, 3.1 Hz, IH), 7.76 (d, J=l.l Hz, IH), 8.29 (s, 2H), 8.68 (s, IH), 8.85 (d, J=2.6 Hz, IH), 9.06 (d, J=2.4 Hz, IH), 11.32 (br s, IH).

Example 205

A-(5-chloro-6-(2£f-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(6-fluoroimidazo[ 1,2-i?]pyridin-5-yl)

5-(trifluoromethyl)-l//-pyrazole-4-carboxamide, Cpd 205

,4. rc/7-butyl (6-bromo-5-fluoropyridin-2-yl)carbamate, 205a

H ,205a

6-Bromo-5-fluoropicolinic acid (2000 mg, 9.09 mmol) was dissolved in r-BuOH (60 mL). Then 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 h under N2. The solvent was concentrated. The residue was purified by flash column chromatography over silica gel (gradient eluent: EtOAc/petrol ether from 1/20 to 1/5). The product fractions were collected and the solvent was concentrated to give the desired product as a colorless gum

567 ( l .6 g, yield: 60.5%). Ή NMR (400 MHz, DMSO-d6) δ ppm l.50 (s, 9H), 7.21 (br s. I H), 7.39 (dd, J=6.9, 8.9 Hz, IH), 7.88 (dd, J=3.1, 8.8 Hz, IH).

B. tert-butyl (5-fluoro-6-hydrazinylpyridin-2-yl)carbamate, 205b

The 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 evacuated with argon (4x). The resulting clear yellow solution was stirred at rt under argon for 10 min. Tert-butyl (6-bromo-5fluoropyndin-2-yl)carbamate (300 mg, 1.03 mmol) and z-BuONa (198.07 mg, 2.06 mmol) was added to the mixture and the mixture was evacuated with argon (4x). The resulting yellow⁷ reaction was then treated with NH₂NH₂.H₂O (105.28 mg, 98%, 2.06 mmol) via syringe. The reaction was evacuated with argon (4x). Then the mixture was stirred at 50 °C under argon for 2 h. The mixture was fïltered and the fîlter cake was washed wath CH₂Cl₂/MeOH (20/1, 20 mL). The filtrate was collected and concentrated to give the crude product which w⁷as used directly for the next step (249.6 mg, yield: 100%).

C. ethyl l-(6-((tert-butoxycarbonyl)amino)-3-fluoropyridin-2-yl )-5-(trifluoromethyl)-

H-pyrazole-4-carboxylate, 205c F /=0 F ^F

O /V , 205c

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) was added and stirred at 80 °C for 12 h. The mixture was

568 concentrated under reduced pressure to afford cnide product. The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 80/20). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford product as a yellow solid ( 150 mg. yield: 34.9%). LCMS (ESI) m/z M+l: 362.9 (M-55). Ή NMR (400 MHz. DMSO-d6) δ ppm 1.38 (t, J=7.2 Hz, 3H), 1.52 (s, 9H), 4.38 (q, J=7.1 Hz, 2H), 7.22 (s, IH), 7.60 - 7.68 (m, IH), 8.I5 - 8.21 (m, 2H).

D. ethyl l-(6-amino-3-fluoropyridin-2-yl)-5-(trifluoromethyl)-!H-pyrazole-4carboxylate, 205d

Ethyl l-(6-((ter/-butoxycarbonyl)arnino)-3-fluoropyridin-2-yl)-5-(trifluoromethyl)lH-pyrazole-4-carboxylate (O.l 50 g. 0.36 mmol) and HCl-MeOH (3 mL, 4 M) were stirred at 30 °C for l h. The mixture was concentrated to dryness. The residue was used directly for the next step ( 120 mg. yield: 94.4%).

E. ethyl l-(6-fluoroimidazo[ l,2-a]pyridm-5-yI)-5-( trifluoromethyl)-lH-pyrazole-4carboxylate, 205e

Ethyl l -(6-amino-3-fluoiOpyridin-2-yl)-5-(trifluoromethyl)-IH-pyrazole-4carboxvlate ( 120 mg, 0.34 mmol) was dissolved in EtOH (2 mL) under N?. 2-Bromo-I, l diethoxyethane ( 133.35 mg, 0.68 mmol) was added to the suspension followed by HBr (0.2

569 mL. 48% in water). The resulting mixture was then heated to 80 °C for 12 h and cooled to room température. The solvent was removed under reduced presure. The residue was purified by flash column chromatography over silica gel (petroleum ether:ethyl acetate=lO:l~l:l). The pure fractions were collected and the solvent was concentrated under reduced pressure to afford the product as a light yellow solid (130 mg, purity;

86.4%, yield: 97.0%). LCMS (ESI) m/z M+l: 342.9.

F. l-(6-fluoroimidazo|T, 2-a]pyridin-5-yl)-5-( trifluoromethyl)-l H-pyrazole-4carboxylic acid, 205f

The mixture of ethyl l-(6-fluoroimidazo[l,2-u]pyridin-5-yl)-5-(tnfluoromethyl)lH-pyrazole-4-carboxylate (I30 mg ,0.33 mmol) in concentrated HCl (2.13 mL) was stirred at 130 °C for 2 h.. The solvent was concentrated under reduced pressure to give the product as a yellow solid (120 mg, crude).

G. N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(6-flnoroimidazo[ 1.2a]pyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 205

POCh (117.12 mg, 0.76 mmol) was added to a mixture of l-(6-fluoroimidazo[ 1.220 u]pyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (120 mg, 0.38 mmol), 5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-amine (74.71 mg, 0.38 mmol) and pyridine

570 ( 15 J .05 mg, l .91 mmol) in CH2CI2 (3 mL). The reaction mixture was stirred at 20 °C for l h. Sat.K₂CO3 solution ( 100 mL) was added to the mixture. The mixture was extracted with 100 mL ethyl acetate. The combined organic layers were dried over Na2SO4, then filtered. The filtrâtes were concentrated under reduced pressure to afford crude product as a brown oil. The crude product was purified by préparative high-performance liquid chromatography (35% to 65% (v/v) CH3CN and LLO with 0.05% ammonia hydroxide). The pure fractions were collected and the solvent was concentrated under reduced pressure. The residue was lyophilized to dryness to afford the product as a light yellow solid (86.9 mg, purity: 100%, yield: 46.3%). LCMS (ESI) m/z M+l: 491.9. U NMR (400

MHz. DMSO-d6) δ ppm 7.61 (s, IH), 7.68 (dd. J=8.8, 9.7 Hz, IH), 7.80 (d. J=1.3 Hz, IH), 8.05 (dd, J=4.6, 10.1 Hz, IH), 8.17 (s, 2H), 8.65 (d, J=2.4 Hz, IH), 8.79 (s, IH), 8.82 (d, J=2.2 Hz, IH), 11.30(brs, IH).

Example 206

1 -(2-methylimidazo[ 1,2-u]pyTidin-5-yl)-5-(trifluoromethyl)-A^z-(2-( trifluoromethyl)pyridin4-yl)-lH-pyrazole-4-carboxamide. Cpd 206

POCI3 (98.85 mg, 0.65 mmol) was added to a mixture of l-(2-methylimidazo[l,2u]pyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid ( 100 mg, 0.32 mmol), 20 2-(trifluoromethyl)pyridm-4-amine (52.26 mg, 0.32 mmol), pyridine (127.49 mg, 1.61 mmol) in CH2CI2 (3 mL) at rt. The reaction mixture was stirred at room température for 1 h. The reaction mixture was quenched with 20 mL sat. K2CO3 aq, and extracted with CH2CI2 (20 mL x 3). The organic layer was separated and concentrated under reduced pressure. It was purified by préparative high-performance liquid chromatography (35% to 25 65% (v/v) CH3CN and H?O with 0.05% ammonia hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous

571 layer was lyophilized to dryness to give the desired product as a white solid. (80 mg, purity: 99.5 %, yield: 54.3 %). LCMS (ESI) m/z M+l: 454.9. ‘H NMR (400 MHz, DMSOd6) δ ppm 2.32 (s, 3 H), 7.08 (s, 1 H), 7.32 (d, J=7.06 Hz, 1 H). 7.41 (dd, J=9.04, 7.28 Hz, 1 H), 7.75 (d. J=9.04 Hz, 1 H). 7.94 (dd. J=5.73. 1.76 Hz, 1 H), 8.21 (d, J=1.76 Hz, 1 H),

8.65 (s. 1 H), 8.69 (d. J=5.29 Hz, 1 H), 11.29 (s, 1 H).

Example 207 l-(7-methylpyrazolo[l ,5-a]pyndm-4-yl)-5-(tnfluoromethyl)-.V-(2(trifluoromethyl)pyridin-4-yl)- lZ7-pyrazole-4-carboxamide, Cpd 207

A. l-amino-5-bromo-2-methylpyridin-l-ium 2,4-dinitrophenolate, 207a

5-Bromo-2-methylpyridine (5 g, 29.07 mmol) was dissolved in CH2CI2 (30 mL) and ()-(2,4-dinitrophenyI)hydroxylamine (6.366 g 31.97 mmol) was added to the mixture.

The reaction mixture was stirred at 30 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford crude product as black solid (T 1 g), which was used directly for the next step.

B.

ethyl 4-bromo-7-methylpyrazolo[ 1,5-aJpyridine-3-carboxylate, 207b

^ch3 ,207b

572 l-Amino-5-bromo-2-methylpyridin-l-ium 2,4-dinitrophenolate (3.989 g, 10.75 mmol) was dissolved in DMF (20 mL), and then ethyl propiolate (1.054 g, 10.75 mmol) and K2CO3 (2.971 g, 21.50 mmol) were added. The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure to afford the crude product as a black solid. The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ethenethyl acetate from 100/0 to 85/15). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford product as a yellow oil (0.9 g, purity: 85.2%%, yield: 25.2%). LCMS (ESI) m/z M+l: 285.0

C. 4-bromo-7-methyIpyrazolo[ L5-a]pyridine. 207c

Br

^CH3 ,207c

Ethyl 4-bromo-7-methylpyrazolo[l,5-r/]pyTidine-3-carboxylate (800 mg, 2.53 mmol, 85.2% purity) and HBr (48%, 5 mL) was stirred at 100 °C for 16 h. The reaction mixture was adjusted to pH 6 using 5 N NaOH, and extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated under reduced pressure to afford crude product as a yellow oil. The oil was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from IOOO to 90/10). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford product as a yellow solid (500 mg, 93.6% yield).

573

D. 4-(2-(diphenylmethylene)hydrazinyl)-7-methylpyrazolo[l ,5-aJpyridine, 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-75 methylpyrazolo[ l,5-z/Jpyridine (440 mg, 2.09 mmol), (diphenylmethylene)hydrazine (818.25 mg, 4.17 mmol) and CS2CO3 (1.358 g, 4.17 mmol) were added and purged with N₂for 1 min. The reaction mixture xvas stirred at 120 °C for 16 h. The reaction mixture was filtered and the residue was washed with EtOAc (50 mL x 5). The filtrâtes were concentrated under reduced pressure to afford crude product as a brown oil. The oil was purified by flash column chromatography over 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 afford product as a yellow solid (600 mg, purity: 75.7%, yield: 66.7%). LCMS (ESI) m/z M+l: 327.0

E. 4-hydrazinyl-7-methylpyrazolo[l,5-a]pyridine, 207e

4-(2-(Diphenylmethylene)hydrazinyl)-7-methylpyrazolo[ 1,5-it]pyridine (550 mg,

1.28 mmol. 75.7% purity) was dissolved in dioxane (5 mL) and conc. HCl (12 M, 0.5 mL) was added. The reaction was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure to afford a crude product as a black solid (350 mg). The crude product was used for the next step without further purification.

574

F. ethyl l -(7-methylpyrazolo[l ,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxylate, 207f

, 207f

4-Hydrazinyl-7-methylpyrazolo[l,5-<7]pyridine (350 mg, 1.76 mmol, HCl sait) was dissolved in EtOH ( 10 mL), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (423.16 mg, 1.76 mmol) and EtsN (356.57 mg, 3.52 mmol) were added and stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the crude product as a black oil. The crude product was purified by flash column chromatography over silica gel (petroleum ether/ ethyl acetate from 100/0 to 85 15). The desired fraction was collected and the solvent was concentrated under reduced pressure to afford product as a yellow oil (400 mg, purity: 98.8%, yield: 66.3%). LCMS (ESI) m/z M+l: 339.2

G. I -(7-methylpyrazolo[ l ,5-a]pyridin-4-yl)-5-(trifluoromethyl )-1 H-pyrazole-4carboxylic acid, 207g

Ethyl l -( 7-methylpyrazolo[ 1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxylate (400 mg, 1.18 mmol) was dissolved in THE H2O I ! (10 mL) and LiOH (56.64 mg, 2.37 mmol) added. The reaction mixture was stirred at rt for 16 h. The reaction mixture was adjusted to pH 5 using 2 N HCl and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na₂SO4, filtered and the filtrâtes were concentrated under reduced pressure to afford the crude product as a yellow solid (350 mg, purity: 97.2%. yield: 92.7%). LCMS (ESI) m/z M+L 311.0

575

H. I -(7-methylpyrazolo[ l ,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4carboxylic acid, Cpd 207

POCh (0.07 mL, 0.75 mmol) was added dropwise to a solution of l-(7methylpyrazolo[L5-«]pyridin-4-yl)-5-(trifluoromethyl)-l/7-pyrazole-4-carboxyüc 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 CH2CI2 (6 mL). The reaction mixture was stirred at room température for 1.5 h. Water (5 mL) was added to the mixture. The aqueous 10 was extracted with CH2CI2 (15mL x 3). The separated organic layer was dried (NazSCh), filtered, and the solvent was concentrated to give a crude product. The crude product was purified by préparative high-performance liquid chromatography (35% to 68% (v/v) CH3CN and H2O with 0.05% ammonia hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to give product as a white solid product (61.8 mg, purity: 98.1%, yield: 35.5%). LCMS (ESI) m/z Μ- 1: 454.9. ‘H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (s, 3 H) 6.36 (d, J=2.43 Hz, 1 H) 7.02 (d, J=7.94 Hz, 1 H) 7.53 (d, J=7.50 Hz, 1 H) 7.95 (dd. J=5.40. 1.65 Hz, 1 H) 8.15 (d, J=2.21 Hz, 1 H) 8.21 (d. J=L54 Hz, 1 H) 8.51 (s, 1 H) 8.69 (d, J=5.51 Hz, 1 H) 11.24 (br s, 1 H).

576

Example 208 l -( imidazo[ l ,2-a]pyridin-5-yl)-5-(trifluoiOmethyl)-A-(2-(trifluoromethyl)pyridin-4-yl)-\Hpyrazole-4-carboxamide, Cpd 208

POCh (149.87 mg, 0.98 mmol) was added to a mixture of l-(imidazo[l ,2n]pyridin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid ( 150 mg, 0.49 mmol, 96.5% purity), 2-(trifluoromethyl)pyridin-4-amine (79.22 mg, 0.49 mmol) and pyridine (193.28 mg, 2.44 mmol) in CH2CI2 (3 mL). The réaction mixture was stirred at 20 °C for 1 h. Sat.KgCOs solution (5 mL) was added to the mixture. The mixture was extracted with 5 10 mL ethyl acetate. The combined organic layers were dried over NaaSOj, then fïltered. The filtrâtes were concentrated under reduced pressure to afford a crude product as a brown oil. The crude oil was purified by préparative high-performance liquid chromatography (30% to 55% (v/v) CHjCN and H₂O with 0.05% ammonia hydroxide). The pure fractions were collected and the solvent was concentrated under reduced pressure. The residue was lyophilized to dryness to give product as a light yellow solid (60.2 mg, purity: 99.3%, vield: 27.8%). LCMS (ESI) m/z M+l: 440.9. ΉNMR (400 MHz, DMSO-d6) δ ppm 7.36 (d, J=0.7 Hz, IH), 7.39 - 7.43 (m, IH), 7.45 - 7.51 (m, IH), 7.71 (d, J=1.3 Hz, IH), 7.90 (d, J=8.8 Hz, IH), 7.96 (dd. J=1.9, 5.4 Hz, IH), 8.22 (d, J=1.5 Hz, IH), 8.67 (s. IH), 8.70 (d, J=5.5 Hz, IH), 11.28 (br s, IH).

577

Example 209 l-(8-fluoroimidazo[l,2-a]pyridin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin

4-yl)-lH-pyrazole-4-carboxamide, Cpd 209

POCh (l 17.12 mg, 0.76 mmol) was added dropwise to a solution of l-(8fluoroimidazo[ l ,2-o]pyridin-5-yI)-5-(trifluoromethyl)-1 H-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, l.9l mmol) in CH2CI2 (5 mL). The reaction mixture was stirred at room température for 2 h. Water (2.5 mL) was added to the mixture. The pH was adjusted to about 7 by progressively addingNaHCO? (aq). The aqueous phase was extracted with CH2CI2 (5 mL x 3). The separated organic layer was dried (NacSOi), filtered, and the solvent was concentrated to give a crude product which was purified by préparative highperformance liquid chromatography (35% to 65% (v/v) CHsCN and H2O with 0.05% ammonia hydroxide). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to afford the product as a white soild (l 10 mg, purity: 99.0%, yield: 62.2%). LCMS (ESI) m/z M+l: 458.9. Ή NMR (400 MHz, DMSO-d6) δ ppm 7.41 - 7.46 (m, IH), 7.46 - 7.49 (m, IH). 7.51 (d, J=3.1 Hz, IH). 7.76 (s. IH). 7.96 (dd. J=L9, 5.4 Hz, lH), 8.22 (d. .1=2.0 Hz. IH). 8.68 (s. IH), 8.71 (d. J=5.5 Hz, IH), 11.25 (br s. IH).

Example 210 l-(7-(3-hydroxyazetidin-l-yl)thieno[2,3-c|pyridin-4-yl )-5-( tri fluoromethyl)-N-(2( trifluoromethyl)pyridin-4-yT)- lH-pyrazole-4-carboxamide, Cpd 210

578

A. 4-(5-(trifluoromethyl)-4-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)-l H-pyrazoll -yl)thieno[2.3-c]pyridine 6-oxide, 210a

m-CPBA(0.566 g, 3.28 mmol) was added to a solution of l-(thieno[2.3-c]pyridin4-yl )-5-( trifluoiOmethyl)-N-(2-(tnfluoromethyl)pyridin-4-yD-lH-pyrazole-4-carboxamide (0.5 g, 1.09 mmol) in CHjCh ( 10 mL). The mixture was stirred at 50 °C for 4 h. The solution was washed with saturated aqueous solution ofNaiSCL (30 mL), saturated aqueous NaHCO? (30 mL), and brine (50 mL). The extracts were dried over anhydrous NarSCh. filtered and the filtrate concentrated to afford a crude oil. The oil was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/'0 to 0/100). The desired fractions were collected and the sol vent was concentrated to dryness under reduced pressure to afford the product as a white solid (0.35 g, 66.7%).

B. 1 -(7-chlorothieno [2,3-c | pyndin-4-y l)-5 -(trifl uoromethyl )-N-(2(trifluoromethyl)pyrÎdin-4-yl)-lH-pyrazole-4-carboxa.mide, 210b

579

4-(5-(Trifluoromethyl)-4-((2-(trifluoromethyl)pyridin-4-yl)carbamo H-pyrazoll-yl)thieno|2,3-c]pyridine 6-oxide (180 mg , 0.38 mmol) was added to the mixture of POCh (0.34 mL , 3.75 mmol) in CHCh (10 mL). The mixture was stirred ai 60 °C for 2 h. The mixture was cooled to rt and was added to a stirring aqueous solution (50 mL). Then the mizXture was made basic using NaHCOa, followed by extraction with CH2CI2 (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, then filtcrcd. The filtrâtes were concentrated under reduced pressure to afford a crude product as a brown oil. The brown oil was purified by flash column chromatography over silica gel (petroleum ether/ ethyl acetate=l :0 to petroleum ether/ ethyl acetate=l : l). The

H) 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-hydroxyazetidin-1 -yl)thieiio|2,3-c]pyridiii-4-yl)-5-(trifluoromethyl)-N-(2(trifluoiOinethyl)pyridin-4-yl)-lH-pyrazole-4-carboxamide, Cpd 210

NaiCO? (53.88 mg, 0.51 mmol) was added to a solution of l-(7-chIorothicno|2,3c|pyridin-4-yl)-5-(trifluoiOmethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-lH-pyrazole-4carboxamide (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 h. Water (20 mL) was added to the mixture, and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO4, and fïltered. The filtrâtes were concentrated under reduced pressure to afford a crude product as a yellow solid, which was purified by préparative HPLC (26% to 56% (v/v) CH?CN and H2O with 0.05% ammonia 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+l: 528.9. 1H NMR (400 MHz. DMSO19506

580 d6) δ ppm 4.07 (2 H, dd, J=9.15, 4.30 Hz), 4.51 - 4.57 (2 H, m), 4.60 - 4.67 ( I H. m), 6.89 (l H, d, .1=5.51 Hz), 7.81 (1 H, br d, J=3.75 Hz), 8.01 (1 H, s), 8.09 (1 H, d, .1=5.29 Hz),

8.14 (1 H, d, .1=1.76 Hz), 8.34 (1 H, s), 8.56 (1 H, 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-5y!)-5-(trifluoromethyl)-!H-pyrazole-4-carboxamide, Cpd 211

The title prepared according to Example 205 by substituting the appropriate reagents, starting materials, and purification methods, and adjusting reaction températures, times and other variables or parameters. 41 NMR (400 MHz, DMSO-d6) δ ppm 11.346 (brs, 1 H), 8.833 (d, J=2.21 Hz, 1 H), 8.614 - 8.684 (m, 2 H), 8.171 (s, 2 H), 7.808 - 7.888 (m, 1 H), 7.487 (s, 1 H), 7.328 - 7.392 (m, 2 H), 1.787 (s, 3 H). LCMS (ESI): m/z 487.9 [Μ+ΗΓ

Following the procedures described in Examples 3 or 4, above, and selecting and substituting the appropriate reagents, starting materials, and purification methods, and adjusting reaction températures, times and other variables or parameters, as needed or désirable, as would be readily recognized by those skilled in the art, the following compounds were prepared.

Example 70

N-(5-cyano-6-ethoxypyridin-3-yl)-l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamide, Cpd 81

581

‘H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46 (t. 1=7.(.)6 Hz, 2 H). 4.50 (q, J=7.06 Hz, 2 H), 7.48 (dd, J=8.49, 4.30 Hz, 1 H), 7.59 - 7.66 (m, 2 H), 7.70 (br s, 1 H), 7.82 - 7.87 (m. 1 H), 8.20 (s, 1 H). 8.34 - 8.38 (m, 1 H), 8.43 (br s. 2 H), 9.03 (br d, 1=2.65

Hz, 1 H). LCMS (ESI): m/z 487.9 [M+H]

Example 71

N-(5-cyano-6-methoxypyridin-3-yl)- l-(quinolin-5-yl)-5-( trifluoromethyl)-1 H-pyrazole-4carboxamide, Cpd 85

‘H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H), 7.55 - 7.61 (m, 1 H), 7.62 7.68 (m. 1 H), 7.85 - 7.91 (m, 1 H), 7.92 - 7.98 (m, 1 H), 8.31 (d, 1=8.38 Hz, 1 H). 8.46 8.56 (m. 2 H), 8.69 (d. ,1=2.65 Hz, 1 H), 9.03 (dd, .1=4.08. 1.65 Hz, 1 H), 10.93 (br s, 1 H). LCMS (ESI): m/z 439.0 | Μ · I i |

Example 72 N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide, Cpd 49

‘H NMR (400 MHz, DMSO-d6) δ ppm 7.26 (d. J=8.38 Hz, l H), 7.83 - 7.88 (m, l H), 7.90 - 7.96 (m, l H), 8.37 (d, J=7.94 Hz, l H), 8.63 (s, l H). 8.78 (s. 1 H), 8.80 (d. J=1.98 Hz, 1 H), 9.25 (d, J=1.98 Hz, 1 H), 9.60 (s, 1 H), 11.58 (br s, 1 H). LCMS (ESI): m/z 476.9 ' M H |

Example 73

N-(3-chloro-4-(3-methyl-lH-l ,2,4-triazol-l -yl)phenyl)-l-(isoqumolin-4-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 55

‘H NMR (400 MHz, METHANOL-d4) δ ppm 2.41 (s, 3 H), 7.44 (d, J=8.38 Hz, 1 H), 7.60 (d, J=8.60 Hz, 1 H), 7.84 - 8.01 (m, 3 H), 8.17 - 8.26 (m, 2 H), 8.36 - 8.43 (m, 2 H), 8.72 (br s, 1 H), 9.49 - 9.66 (m, 1 H). 9.60 (br s, 1 H). LCMS (ESI): m/z 498.0 [M+Hf

Example 74

N-(5-chloro-6-( 1 -methyl-1 H-imidazol-2-yl)pyridin-3-yl)-1 -( isoquinolin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 98

583

Ή NMR (400 MHz, METHANOL-d4) δ ppm 3.70 (s, 3 H), 7.12 (s, l H), 7.27 (s, l H), 7.39 (d, J=8.16 Hz. 1 H), 7.84 - 7.89 (m, 1 H), 7.90 - 7.95 (m. 1 H), 8.34 (d, J=8.16 Hz, 1 H), 8.42 (s. 1 H), 8.60 (d, J=1.98 Hz, 1 H), 8.65 (s, 1 H), 8.91 (d, J=1.98 Hz, 1 H), 9.52 (s, 1 H). LCMS (ESI): m/z 497.9[M+Hf

Example 75

N-(8-chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-l-(isoquinolin-4yl)-5-(trifluoromethyI)-lH-pyrazole-4-carboxamide, Cpd 97

Ή NMR (400 MHz, DMSO-d6) δ ppm 3.28 (s, 3 H), 4.77 (s, 2 H), 7.26 (d, J=8.38

Hz, 1 H), 7.45 (br s, 1 H), 7.64 (s, 1 H), 7.81 - 7.89 (m, 1 H), 7.89 - 7.98 (m, 1 H), 8.37 (d, J=8.38 Hz, 1 H), 8.52 (s, 1 H), 8.76 (s, 1 H), 9.60 (s, 1 H), 10.71 (br s. 1 H). LCMS (ESI): m z 501.9 [M+H]⁺

Example 76

N-(6-(4-aminobutoxy)-5-cyanopyridin-3-yl)-1 -(isoquinolin-4-yl )-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide, Cpd 84

nh₂ 'H NMR (400MHz, DMSO-d6) δ ppm 11.31 (s, IH), 9.62 (s, IH), 8.81 (d, J=2.4 Hz, IH), 8.78 (s, IH). 8.73 (s, IH). 8.61 (d, J=2.4 Hz, IH), 8.38 (br d, J=8.2 Hz, IH), 8.09 - 7.89 (m, 4H), 7.89 - 7.82 (m, 1 H), 7.28 (br d, J=8.2 Hz, IH), 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

N-(5-fluoro-6-(2H-l,2.3-triazol-2-yl)pyndrii-3-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl )-l H-pyrazole-4-carboxamide, Cpd 61 ‘H NMR (400 MHz, DMSO-d6) δ ppm 7.28 (br d, J=8.38 Hz, 1 H), 7.84 - 7.96 (m, 3 H), 8.03 (d, J=3.09 Hz, 1 H), 8.37 (br d, J=7.94 Hz. 1 H), 8.54 - 8.73 (m, 2 H), 8.78 (s. 1 H), 8.96 (s, 1 H), 9.61 (s, 1 H), 11.41 (br s, 1 H). LCMS (ESI): m/z 500.9 |M H|

Example 78

Methyl 6-chloro-4-(l-(isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)picolinate, Cpd 74 ‘H NMR (400 MHz, DMSO-d6) δ ppm 3.89 (s, 3 H), 7.26 (d, J=8.38 Hz, 1 H), 7.80 - 7.88 (m, 1 H. 7.89 - 7.97 (m, 1 H), 8.11 (s, 1 H), 8.30 - 8.40 (m, 2 H), 8.61 (s, I H), 8.77 (s, 1 H). 9.59 (s. 1 H), 11.33 (br s, 1 H). LCMS (ESI): m/z 475.9 AL H |

585

Example 79

N-(5-chloro-6-(( l-methylpiperidin-4-yl)oxy)pyridin-3-yl)-l-(isoquinolm-4-yl)-5( trifluoromethyl )-lH-pyrazole-4-carboxamide, Cpd 45

‘H NMR (400 MHz, DMSO-d6) δ ppm 1.70 - l .81 (m, 2 H), l .98 (br s, 2 H), 2.26 (s, 3 H), 2.33 (br s, 2 H), 2.48 - 2.52 (m, 34 H), 2.67 (br s, 2 H), 5.08 (br d, J=4.41 Hz, l

H), 7.27 (d, J=8.38 Hz. I H), 7.82 - 7.90 (m, l H), 7.90 - 7.98 (m. I H), 8.29 (d, J=2.21 Hz, 1 H), 8.35 - 8.42 (m, 2 H). 8.55 (s, 1 H), 8.76 (s, 1 H), 9.61 (s, 1 H). 10.80 (s, 1 H). LCMS (ESI): m/z 531.0 [M+H]⁺

Example 80

N-(4-aminobutyl)-3-chloro-5-(l-(isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)picolinamide. Cpd 72

Ή NMR (400 MHz, DMSO-d6) δ ppm 1.57 (br s, 4 H), 2.73 - 2.85 (m, 2 H), 3.19 3.33 (m, 2 H). 7.30 (d, J=8.16 Hz, 1 H), 7.84 - 7.90 (m, I H), 7.95 (br t, J=7.06 Hz, 3 H),

8.39 (d, J=8.16 Hz, 1 H), 8.50 (d, J=L98 Hz, 1 H), 8.68 (br t, J=5.84 Hz, 1 H), 8.79 (d,

586

J=7.94 Hz, l H), 8.95 - 9.02 (m, l H), 8.97 (d, >1.98 Hz, 1 H), 9.64 (s, 1 H), 11.53 (s, 1

H). LCMS (ESI): m/z 532.0 [M+H]”

Example 81

N-(2-cyanopyridin-4-yl)-l -(ïsoquinolin-4-y 1)-5-( trifluoromethyl)- lH-pyrazoIe-4carboxamide, Cpd 77

‘H W1H (400MHz, DMSO-d6) δ ppm 11.30 (br s, 1H), 9.62 (s, 1H), 8.79 (s, 1H). 8.70 (br 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, 1 H), 7.29 (br d, J=8.5 Hz, 1H). LCMS (ESI): m/z 53 1.0 [M+H]”

Example 82

N-(5-chloro-6-(lH-imidazol-l-yl)pyndin-3-yl)-l-(isoquinolin-4-yl)-5-( trifluoromethyl)lH-pyrazole-4-carboxamide, Cpd 70

‘H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 (s, 1 H). 7.34 (d, J=7.94 Hz, 1 H), 7.63 (s, 1 H), 7.74 - 7.84 (m. 2 H), 8.14 - 8.21 (m, 2 H), 8.30 (s, 1 H), 8.55 (d. J=2.21 Hz, 1 H), 8.61 (s, 1 H), 8.75 (d, J=2.21 Hz, 1 H), 9.08 (s, 1 H), 9.46 (s, 1 H). LCMS (ESI): m/z 483.9 [M+H]”

587

Example 83

N-(5-chloro-6-(4-methylpiperazine-l-carbonyl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5(trifluoromethyl )-1 H-pyrazole-4-carboxamide, Cpd 48

‘H NMR (400 MHz. METHANOL-d4) δ ppm 2.99 (s, 3 H), 3.15 - 3.29 (m, 2 H),

3.32 - 3.44 (m, 2 H), 3.47 - 3.64 (m, 2 H), 3.66 - 3.79 (m, 2 H). 7.65 (br d. J=8.60 Hz, l H),

8.14 (br t, J=7.61 Hz. I H), 8.23 - 8.32 (m, l H), 8.52 (s, l H), 8.56 (d, J=l .76 Hz. 1 H),

8.67 (br d, J=8.16 Hz, 1 H), 8.90 (s, I H), 9.05 (br s, 1 H), 9.99 (br s. 1 H). LCMS (ESI):

m/z 543.9 ίΜ · II|

Example 84

N-(5-cyanopyridin-3-yl)-1 -(isoquinolin-4-y 1)-5-( trifluoromethyl)-! H-pyrazoIe-4carboxamide, Cpd 82

Ή NMR (400MHz, DMSO-d6) δ ppm 11.44 (br s, IH), 9.66 (br s, IH), 9.18 (br s, IH), 8.80 (br d, J=16.3 Hz, 2H), 8.70 (br d, J=17.0 Hz, 2H), 8.40 (br d, J=7.7 Hz, IH), 8.02 - 7.79 (m. 2H). 7.30 (br d. J=7.9 Hz, IH). LCMS (ESI): m/z 409.1 [M+H]'

588

Example 85 l-(isoquinolin-4-yl)-N-(2-methyl-6-(trifluoromethyl)pyridin-4-yl )-5-( trifluoromethyl)-IHpyrazole-4-carboxamide. Cpd 73

Ή NMR (400 MHz, METHANOL-d4) δ ppm 2.60 (s, 3 H), 7.38 (d, >8.16 Hz, l

H). 7.81 - 7.96 (m, 3 H), 8.04 (d, J=1.54 Hz, l H), 8.33 (d, J=7.94 Hz, l H), 8.40 (s, 1 H), 8.63 (s, 1 H), 9.51 (s, 1 H). LCMS (ESI): m/z 531.0 ; M i 11

Example 86

N-(5-cyano-6-((l-methylpiperidin-4-yl)oxy)pyridin-3-yl)-l-(isoquinolin-4-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 80

‘H NMR (400MHz, DMSO-d6) δ ppm 1.26 (br s, IH), 10.82 (br s, IH), 9.62 (br s, IH). 8.89 - 8.51 (m, 4H), 8.38 (br s, IH), 8.04 - 7.73 (m, 2H), 7.28 (br s, IH), 5.45 - 5.09 (m, IH), 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, IH). LCMS (ESI): m/z 522.0 [M+H]⁺

589

Example 87

N-(5-cyano-6-(4-methylpiperazine-l-carbonyl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5 (trifluoromethyl )-1 H-pyrazole-4-carboxamide, Cpd 96

‘H NMR (400 MHz. METHANOL-d4) δ ppm 2.99 (s, 3 H), 3.18 - 3.28 (m, 1 H), 3.31 - 3.35 (m, 1 H), 3.35 - 3.79 (m, 5 H), 4.18 (br s, 1 H), 7.40 (d, J=8.16 Hz, 1 H), 7.83 7.97 (m. 2 H), 8.35 (d, J=8.16 Hz, 1 H), 8.46 (s. 1 H), 8.64 - 8.74 (m, 1 H), 8.78 (d, J=2.21 Hz, 1 H), 9.14 (d, J=2.21 Hz, 1 H), 9.58 (br s, 1 H). LCMS (ESI): m/z 535.0 [M+H]⁺

Example 88

N-(6-cyano-5-fluoropyridin-3-yl)-l-(isoquinolin-4-yl)-5-(trifluoromethyI)-lH-pyrazole-4carboxamide, Cpd 41

‘H NMR (400 MHz, METHANOL-d4) δ ppm 7.56 - 7.64 (m, 1 H), 8.03 - 8.13 (m, 1 H), 8.16 - 8.25 (m, 1 H), 8.50 - 8.57 (m, 2 H), 8.57 - 8.63 (m, 1 H), 8.75 - 8.82 (m, 1 H), 8.94 - 8.98 (m, 1 H), 9.89 (s, 1 H). LCMS (ESI): m/z 427.0 [M+H]⁺

Example 89

N-(6-(2H-1,2,3-triazol-2-yI )pyridin-3-yl)-1 -(isoqumolin-4-yl)-5-(trifluoromethyl)-lHpyrazoIe-4-carboxamide. Cpd 71

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 7.34 (d, J=8.l6 Hz, l H), 7.74 7.84 (m, 2 H). 7.92 (s, 2 H), 8.10 - 8.19 (m, 3 H), 8.27 (s. I H), 8.57 - 8.62 (m, 2 H), 8.64 (d, J=2.65 Hz, l H), 9.45 (s, l H). LCMS (ESI): m/z 451.0 [M+H]⁺

Example 90

N-(6-(4-(4-aminobutyl)piperazine-l-carbonyl)-5-cyanopyridin-3-yl)-l-(isoquinolin-4-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 101 o

Ή NMR (400 MHz, METHANOL-d4) δ ppm 1.72 (br s, 4 H), 2.64 - 2.87 (m, 4

H), 2.98 (br s, 2 H), 3.49 - 3.70 (m, 1 H), 3.58 (br s, 1 H), 3.76 - 4.09 (m, 1 H), 3.92 (br s, 1

H), 4.66 (br s, 2 H), 7.39 (d, .1=8.16 Hz, 1 H). 7.83 - 7.96 (m, 2 H), 8.34 (d, J=8.16 Hz. 1 H), 8.45 (s, 1 H), 8.64 (s, 1 H), 8.78 (d. 1=2.20 Hz, 1 H), 9.12 (d, J=1.76 Hz, 1 H), 9.52 (s, 1 H). LCMS (ESI): m/z 592.0 [M+H]

Example 91

NM5-chloro-6-(lH-imidazol-2-yl)pyridin-3-yl)-l-(isoquinolm-4-yl)-5-(trifluoromethyl)lH-pyrazole-4-carboxamide, Cpd 104

591

^!H NMR (400 MHz, DMSO-A) δ ppm 7.07 - 7.33 (m, 2 H) 7.75 - 7.96 (m, 3 H), 8.37 (br d, J=1.94 Hz, 2 H), 8.71 (br d, .7=1.76 Hz, 2 H), 8.79 (d, .7= H .47 Hz, 1 H), 9.20 (brd, «7=1.76 Hz, 1 H), 9.61 (s, 1 H), 11.77 (s, 1 H). LCMS (ESI): m/z 477.0 [M+Hf

Example 92

Methyl 4-(l-(isoquinolin-4-yl)-5-(trifluoromethyI)-/77-pyrazole-4-carboxamido)picoIin,

‘H NMR (400 MHz, METHANOL-d4) δ ppm 4.1 5 (s, 3 H) 7.64 (d, J=8.38 Hz, 1

H) 8.08 - 8.16 (m, 1 H) 8.22 - 8.29 (m, 1 H) 8.58 - 8.69 (m, 3 H) 8.80 (d, J=6.61 Hz, I H)

8.90 - 8.97 (m, 1 H) 9.03 (br s, 1 H) 9.96 (br s, 1 H). LCMS (ESI): m/z 442.0 [M+H]”

Example 106

N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-1 -(isoquinoIin-4-yl)-5-(trifluoromethyl )JH-pyrazole-4-carboxamide, Cpd 106

592

Ή NMR ¢400 MHz, CHLOROFORM-d) δ ppm 7.32 (br d, J=7.94 Hz, l H), 7.60 (s, l H). 7.71 - 7.90 (m, 4 H), 8.14 - 8.19 (m, 2 H), 8.21 (s, l H), 8.59 (s. I H), 9.44 (s, l H). LCMS (ESI); m/z 483.8 [M+H]⁺

Example 107

N-(5-cliloro-6-(2-oxopyrrolidin-l-y[)pyridm-3-yl)-l-(isoqumolin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 107

Ή NMR (400 MHz, DMSO-d6) δ ppm 2.09 - 2.21 (m, 2 H), 2.46 (br s, 2 H), 3.81 (s, 2 H), 7.27 (d, J=8.38 Hz, 1 H), 7.81 - 7.89 (m, 1 H), 7.90 - 7.97 (m, 1 H). 8.31 - 8.40 (m, 1 H), 8.41 - 8.47 (m. 1 H), 8.56 - 8.61 (m, 1 H), 8.70 - 8.82 (m, 2 H), 9.56 - 9.66 (m, 1 H), 11.06-11.12(m, 1 H). LCMS (ESI): m/z 501.0 IM H|

Example 212

N-(2-methyl- 1-oxo-1,2,3,4-tetrahydroisoqumoliii-7-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 212

Ή NMR (400 MHz, DMSO-d6) δ ppm 2.96 (br t, J=6.62 Hz, 2 H), 3.04 (s, 3 H) 3.53 - 3.56 (m, 2 H), 7.30 (d, J=8.16 Hz, 1 H), 7.75 (d, J=3.09 Hz. 2 H), 7.89 (dd, J=8.16, 1.98 Hz, 1 H). 7.94 - 7.98 (m. I H), 7.99 - 8.05 (m, 1 H), 8.23 (d, J=L98 Hz, 1 H), 8.37 (d,

593

J=8.38 Hz, l H), 8.54 (s, l H), 9.12 (t, J=2.87 Hz, l H), 10.71 (s, 1 H). LC-MS: (ES, m/z):

j M - 1 | 466.0

Example 213

N-(3-( methylsulfonyl)-4-( 1 H-1.2,3-triazol-1 -yl (phenyl)-1 -(quinolin-5-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 213

Ή NMR (400 MHz, METHANOL-d4) δ ppm 3.24 (s, 3 H), 7.69 (d, J=8.60 Hz. 1 H), 7.95 (s, 1 H), 8.15 - 8.23 (m, 2 H), 8.32 - 8.38 (m, 3 H), 8.48 (s, 1 H), 8.53 (d. J=8.82

Hz, 1 H). 8.61 (d, J=8.82 Hz. 1 H), 8.66 (d. J=2.21 Hz, 1 H), 9.38 (d, J=4.41 Hz, 1 H). LCMS: (ES, m/z): AL C 528.2

Example 214

N-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][L4]oxazm-6-yl)-l-(quinolin-5-yl)-515 (trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 214

^JH NMR (400 MHz, DMSO-d6) δ ppm 10.66 ( 1 H. s). 9.06 -9.18(1 H, m), 8.51(1

H, s), 8.38 (1 H, d, J=8.38 Hz), 8.00 - 8.07 ( 1 H, m), 7.91 - 7.99 ( 1 H, m), 7.73 - 7.81 (2 H,

594

m). 7.60 (l H, d, J=2.21 Hz), 7.37 (l H, dd, J=8.60, 2.21 Hz), 7.00 (l H. d, J=8.60 Hz),

4.63 (2 H, s) 3.26 (3 H, s). LC-MS: (ES, m/z): [M+l]' 468.0

Example 215

N-(3-(methylsulfonyl)-4-(2H-L2,3-triazol-2-yl)phenyl)-I-(quinoIm-5-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 215

O

Ή NMR (400 MHz, METHANOL-d4) δ ppm 3.53 (s, 3 H), 7.77 (d, J=8.60 Hz. 1

H), 8.00 (s, 2 H), 8.10 (dd, J=8.60, 5.07 Hz, 1 H), 8.16 (d, J=7.50 Hz, 1 H), 8.27 - 8.34 (m, 10 2 H), 8.44 - 8.53 (m, 3 H). 8.64 (d, J=1.98 Hz. 1 H), 9.33 (d, J=3.97 Hz. 1 H). LC-MS:

(ES, m/z): [M+l]' 528.1

Exampie 216

N-(2-methyl-1-oxo-l,2-dihydroisoqumolin-7-yl)-l-(qumolin-5-yl)-5-(trifluoromethyl)-lH15 pyrazole-4-carboxamide, Cpd 216

‘HNMR (400 MHz, DMSO-d6) δ ppm 3.51 (s, 3 H), 3.99 (br s. 18 H), 6.59 (d.

J=7.06 Hz, 1 H), 7.41 (d, J=7.28 Hz, 1 H), 7.64 - 7.74 (m, 3 H), 7.90 - 8.03 (m, 2 H), 8.07 (br d. J=7.72 Hz, 1 H), 8.34 (br d, J=8.38 Hz, 1 H), 8.56 (s, 1 H), 8.63 (s, l H), 9.08 (br s, I

H). 10.86 (s, 1 H). LC-MS: (ES, m/z): IM+Il 464.0

595

Example 217

N-(3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-l-(quinolin-5-yl)-5-(trifluorornethyl)lH-pyrazoIe-4-carboxamide, Cpd 217

^!H NMR (400MHz, DMSO-d6) δ ppm 10.78 (s, IH), 10.56 (s, IH), 9.08 - 9.01 (m,

IH), 8.47 (s, IH), 8.31 (d. >8.4 Hz, IH), 7.99 - 7.93 (m, IH), 7.90 - 7.86 (m. IH), 7.697.64 (m, IH). 7.63 - 7.59 (m, JH), 7.51 (d, J=2.2 Hz, IH). 7.19 (dd, >2.2, 8.8 Hz. IH), 6.94 (d, >8.6 Hz, IH), 4.53 (s, 2H). LC-MS: (ES, m/z): IM H 453.9

Example 218

N-(5-methyl-6-(3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)pyridin-3-yl)-l-(quinolin5-yl)-5-( trifluoromethyl)- lH-pyrazole-4-carboxamide. Cpd 218

Ή NMR (400 MHz, METHANOL-d4) δ ppm 2.34 (s, 3 H), 3.36 (s, 3 H), 6.69 (d, 15 J=3.01 Hz, 1 H), 6.74 (d. J=2.76 Hz, 1 H), 7.66 (dd, >8.53, 4.27 Hz, 1 H), 7.78 (d, >8.03

Hz, 1 H). 7.85 (d, J=7.28 Hz. 1 H), 7.96 - 8.02 (m. 1 H), 8.29 (d, >2.01 Hz, 1 H). 8.32 8.39 (m, 2 H), 8.72 (d. >2.51 Hz, 1 H), 9.03 (dd, >4.27, 1.51 Hz, 1 H). LC-MS: (ES, m/z): | M - 1 | 494.0

596

Example 219

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-methylbenzo[d]oxazol-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, cpd 219

Ή NMR (400MHz, DMSO-d6) δ ppm 9.12 (d, J=2.3 Hz, IH), 8.89 (d, J=2.5 Hz, IH), 8.54 (s, IH), 8.32 (s, 2H), 8.01 - 7.93 (m, IH), 7.64 - 7.53 (m. 2H), 2.65 (s, 3H). LCMS: (ES, m/z): [M+l f 479.9

Example 220

1 -(2-chloroquinoIin-4-yl)-N-(5-cyano-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 220

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1 H), 9.08 (d, J=2.43 Hz. 1 H),

8.85 (d, J=2.43 Hz, 1 H), 8.55 (s, 1 H), 8.25 - 8.36 (m, 4 H), 8.05 - 8.13 (m, I H), 8.01 (t, 15 J=7.17 Hz, 1 H), 7.87 - 7.93 (m, 1 H). LC-MS: (ES, m/z): [Μ+1f 509.9

Example 221

N-(5-chloro-6-(2H-L2,3-triazol-2-y4)pyridm-3-yl)-l-(2-chloroquinolin-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 221

Ή NMR (400 MHz. METHANOL-d4) δ ppm 7.60 - 7.64 un. I H), 7.73 (d. J=8.60 Hz, l H). 7.83 (d, J=7.28 Hz. I H), 7.96 - 8.01 (m. I H), 8.04 (s, 2 H), 8.23 (d. J=8.60 Hz, l H), 8.40 (s. I H), 8.72 (d, >2.20 Hz, l H), 8.79 (d, J=2.21 Hz. 1 H). LC-MS: (ES. m/z):

[M+l]” 518.9

Example 222

N-(5-cliloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-( lH-pyrazolo[3,4-d]pyrimidm-4-yl)5-( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 222

‘H NMR (400 MHz, DMSO-d6) δ ppm 8.98 (s, 1 H), 8.78 (d, >2.20 Hz, 1 H), 8.63 (s, 1 H), 8.60 (d, >2.21 Hz, 1 H), 8.53 (s, 1 H), 8.16 (s, 2 H). LC-MS: (ES, m/z): [M+l]”

475.9

Example 223

N-(5-cyano-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-yl )-1-( 1,6-naphthyridin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 223

598

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1 H), 9.39 - 9.43 (m, 1 H), 9.10 9.15 (m, 1 H). 8.89 - 8.95 (m, 3 H), 8.71 - 8.76 (m, 1 H), 8.31 (s, 2 H), 8.14 - 8.20 (m, 1 H), 8.03 - 8.10 (m. 1 H). LC-MS: (ES, m/z): [M+l]’ 476.9

Example 224 N-(5-cyano-6-(4-methylpiperazm-1 -yl)pyridin-3-yl)-1 -( quinolin-5-yl)-5-( trifluoromethyl)lH-pyrazole-4-carboxamide, Cpd 224

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.08 - 11.18 (m, 1 H), 10.83 - 10.99 (m, 1

H), 9.05 (br s, 1 H), 8.73 - 8.82 (m, 1 H), 8.56 - 8.64 (m, 1 H), 8.44 - 8.55 (m, 1 H), 8.27 8.38 (m, 1 H), 7.94 - 8.02 (m, 1 H), 7.88 - 7.93 (m, 1 H), 7.59 - 7.71 (m, 2 H), 4.07 - 4.21 (m, 2 H), 3.52 - 3.64 (m, 4 H), 3.16 (br d, J=9.92 Hz, 2 H), 2.75 - 2.87 (m, 3 H). LC-MS: (ES, m/z): [M+l]’ 507.0

Example 225

N-(l-methyl- lH-pyrazolo[3,4-b]pyridin-5-yl)-l-(quinolin-5-yl)-5-(trifluoromethyl)-l Hpyrazole-4-carboxamide, Cpd 225

599

Ή NMR (400MHz, DMSO-d6) δ ppm 11.09 (s, IH), 9.21 (d, J=4.0 Hz, IH). 8.81 (d, J=2.0Hz, IH), 8.71 -8.62 (m, 2H), 8.47 (d, J=8.6 Hz, IH), 8.14 (s, IH), 8.11 (t, J=8.0 Hz, IH), 8.06 - 8.02 (m, IH), 7.99 (br d, J=8.4 Hz, IH), 7.87 (dd, J=4.5, 8.5 Hz, IH), 4.04 5 (s. 3H). LC-MS: (ES. me): [M+l ]” 438.0

Example 226

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-methyI-l-oxo-1,2dihydiOisoquinolin-5-yl)-5-(tnfluoiOmethyl)-lH-pyrazole-4-carboxamide, Cpd 226

J^F f¹ a .L+%.....

N-k 'H NMR (400 MHz, DMSO-d6) δ ppm 11.24 ( 1 H. s), 8.82 (1 H, d, J=2.21 Hz), 8.64(1 H, d, J=2.20 Hz), 8.53 (1 H, s), 8.45 (1 H, d, J=8.16Hz), 8.16(2 H, s), 7.93 (1 H, d, J=7.06 Hz), 7.66 (1 H, t, J=7.94 Hz), 7.56 (1 H, d, J=7.50 Hz), 5.71 (1 H, d, J=7.72 Hz), 3.50 (3 H, s). LC-MS: (ES. m/z): [M+l]” 514.9

Example 227

N-(5-chloro-6-(5-cyano-lH-L2,3-triazol-l-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 227

600

^lH NMR (400 MHz, METHANOL-d4) δ ppm 7.97 (dd, J=8.60, 5.07 Hz. I H), 8.06 (d, J=7.50 Hz, l H). 8.18 - 8.23 (m, l H). 8.28 (d, J=8.60 Hz. I H), 8.42 - 8.47 (m, 2 H).

8.77 (d, J=2.2l Hz, l H), 8.85 (d, J=2.20 Hz. I H), 9.21 (s, l H), 9.23 (dd, J=4.85, 1.32 Hz, l H). LC-MS: (ES, m/z): N-ü 509.9

Example 228

2-(2-chloro-4-( I-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamido)phenyl)2H-l,2,3-triazole-4-carboxylic acid, Cpd 228

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.27 (s, 1 H), 9.12 (s, 1 H), 9.03 (brd.

J=2.21 Hz, 1 H), 8.63 (s, 1 H), 8.30 (br d, J=8.38 Hz. 1 H), 8.25 (s, 1 H). 7.86 - 7.97 (m. 3

H). 7.74 (d. J=8.60 Hz, 1 H). 7.58 - 7.68 (m, 2 H). LC-MS: (ES, m/z): [M+l]' 527.8

Example 229

N-( lH-pyrazolo[3,4-b]pyridin-5-yl)-l-(quinolin-5-yl)-5-( trifluoromethyl)-lH-pyrazole-4carboxamide, Cpd 229

NH ’H NMR (400MHz, DMSO-d6) δ ppm 10.99 (s, IH), 9.13 (br d, J=2.9 Hz, IH), 8.76 (d, J=l.8 Hz, IH), 8.66 (s, IH), 8.62 (s, IH), 8.39 (d, J=8.6 Hz, IH), 8.16 (s, IH). 8.07 - 8.00 (m, IH), 7.99 - 7.94 (m, IH). 7.85 - 7.70 (m, 2H). LC-MS: (ES, m/z): [M+l] 5 424.0

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)-lH-pyrazole-4-carboxamide, Cpd 230

Ή NMR (400 MHz, DMSO-d6) δ ppm 7.35 (br t, J=7.06 Hz. 1 H), 7.90 - 7.95 (m. 2 H), 8.32 (s, 2 H), 8.34 (s, 1 H), 8.70 (s, 1 H), 8.94 (d, J=2.43 Hz, 1 H), 8.97 (d, J=6.84 Hz, 1 H), 9.18 (d, J=1.98 Hz. 1 H), 1 1.49 (s, 1 H). LC-MS: (ES, m/z): [M+l]⁺ 465.0

Example 231

I-(benzo[d][l,2,3]thiadiazol-4-yl)-N-(5-chloro-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 231

602

^lH NMR (400MHz, DMSO-d6) δ ppm 11.32 (s, IH), 8.85 (s, IH), 8.73 - 8.64 (m,

2H), 8.61 (s, IH), 8.17 (s, 2H), 8.11 - 7.95 (m, 2H). LC-MS: (ES. m/z): [M+l]' 491.9

Example 232

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(2-methylthieno[3,2-b]pyridin-7-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 232

‘H NMR (400 MHz, DMSO-d6) δ ppm 2.66 (s, 3 H), 7.49 (s, 1 H), 7.59 (d. >4.85

Hz, 1 H), 8.31 (s, 2 H), 8.67 (s. 1 H), 8.84 (d. >5.07 Hz, 1 H). 8.88 (d, >2.21 Hz. 1 H), 9.11 (d. >2.20 Hz. 1 H), 11.54 (s, 1 H). LC-MS: (ES, m/z): +11 495.9

Example 233

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(imidazo[L5-a]pyridm-5-yl)-515 (trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 233

603

Ή NMR (400 MHz. DMSO-d6) δ ppm 7.19 (dd, J=9.15, 6.95 Hz. I H), 7.42 (d.

J=6.84 Hz, l H), 7.96 - 8.04 (m, 2 H), 8.20 (s, 2 H), 8.57 (s, l H), 8.73 (d. J=1.98 Hz, l H), 8.84 (s. I H), 8.95 (d, J=2.2l Hz, l H). 11.60 (s, l H). LC-MS: (ES, m/z): IM I f 473.9

Example 234 l-(3-chloro-5-(l-(qumolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamido)pyridin2-yl)-lH-L2,3-triazole-4-carboxylic acid. Cpd 234

'H NMR (400 MHz, METHAN0L-d4) δ ppm 8.09 (dd, J=8.53, 5.02 Hz, l H). 8.15 (d, J=7.28 Hz, 1 H), 8.29 (t, J=8.16 Hz, 1 H), 8.44 - 8.53 (m, 3 H), 8.78 (d, J=2.26 Hz, 1 H), 8.88 (d, J=2.26 Hz, 1 H), 8.99 (s, 1 H), 9.32 (brd, J=5.02 Hz, 1 H). LC-MS: (ES, m/z): 'Μ I | 528.8

Example 235

N-(5-methoxy-6-( IH-1,2,3-tnazol-1 -yl)pyridin-3-yl)-1 -(qumolin-5-yl)-5-(trifluoromethyl·)lH-pyrazole-4-carboxamide, Cpd 235

Ή NMR (400 MHz. DMSO-d6) δ ppm 11.22 (s, 1 H), 9.02 - 9.11 (m, 1 H), 8.60 8.66 (m, 1 H), 8.53 - 8.57 (m, 1 H), 8.48 - 8.52 (m, 1 H), 8.32 - 8.37 (m, 1 H), 8.25 - 8.29 (m, 1 H), 7.90 - 8.02 (m, 3 H). 7.62 - 7.73 (m, 2 H), 3.85 - 3.92 (m, 3 H). LC-MS: (ES, 5 m/-); | N1 i | 480.9

Example 236

N-(4-aminobutyl)-3-cyano-5-(l-(isoquinolin-4-yl)-5-( trifluoromethyl)-1 H-pyrazole-4 carboxainido)picolinamide, Cpd 236

O 'H NMR (400 MHz, METHANOL-d4) δ ppm 1.65 - 1.87 (m, 3 H), 1.69 - 1.82 (m, 1 H), 3.00 (br s, 2 H), 3.42 - 3.57 (m. 1 H), 3.48 (br s. 1 H), 7.57 (d. J=8.38 Hz, 1 H), 8.06 (t. J=7.39 Hz, 1 H). 8.13 - 8.21 (m, 1 H). 8.47 - 8.53 (m, 1 H), 8.57 (d, J=8.38 Hz. 1 H), 8.74 (d, J=2.43 Hz, 1 H), 8.93 (s, 1 H), 9.20 (d, J=2.43 Hz, 1 H), 9.85 (s, 1 H). LC-MS:

(ES. Y): [M+l]Y23.0

Example 237

2-cyano-4-(l-(quinolin-5-yl)-5-(trifluoromethyr)-lH-pyrazole-4-carboxamido)benzoic acid, Cpd 237

605

Ο

*Η NMR (400 MHz, DMSO-d6) δ ppm 7.55 - 7.60 (m, l H), 7.62 - 7.67 (m, l H), 7.86 - 7.90 (m. I H), 7.91 - 7.97 (ni, l H), 7.99 - 8.04 (m, 1 H), 8.06 - 8.11 (m, 1 H), 8.23 (s, 1 H). 8.30 (d, >8.38 Hz, 1 H), 8.53 (s, 1 H), 9.03 (dd, J=4.08, 1.65 Hz, 1 H), 11.08 (s. 1 5 H). LC-MS: (ES, wz): [M+l]⁺451.9

Example 238

N-(4-(4-(aminomethyl)-1 H-pyrazol-1 -yl)-3-methylphenyl)-1 -(quinolin-5-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 238

‘H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 3 H), 3.99 (br d, >5.51 Hz, 2 H), 7.33 (d, >8.60 Hz. 1 H). 7.76 (br d, >8.60 Hz, 1 H), 7.78 - 7.87 (m. 4 H), 7.98 - 8.02 (m, 1 H), 8.04 - 8.09 (m, 1 H), 8.12 (s, 1 H), 8.36 (brs, 2 H), 8.43 (d, >8.60 Hz, 1 H), 8.60 (s, 1 H), 9.16 (d, >2.65 Hz, I H), 10.89 (s, 1 H). LC-MS: (ES, m/z): M ' H 492.0

Example 239

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridm-3-yl)-1 -( 1 -methyl-1 H-indazol-4-yl )-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 239

606

N

*H NMR (400 MHz, DMSO-d6) δ ppm 4.14 (s, 3 H), 7.33 (d, J=7.28 Hz, l H), 7.58 (t. >7.83 Hz, l H). 7.84 (s, l H), 7.93 (d, >8.60 Hz, l H), 8.30 (s, 2 H), 8.53 (s. I H), 8.86 (d, >2.21 Hz. I H). 9.08 (d. >2.43 Hz, I H), 11.36 (s, 1 H). LC-MS: (ES. m/z):

:\1·η 479.0

Example 240

5-fluorocarbonyl-N-(5-methyl-6-(l-methyl-lH-tetrazol-5-yl)pyridin-3-yl)-l-(quinolin-5yl)-lH-pyrazole-4-carboxamide, Cpd 240

’H NMR (400 MHz, DMSO-d6) δ ppm 11.37 (1 H, s), 9.00 - 9.08 (2 H, m), 8.68 (1 H. s), 8.37 (1 H, s), 8.31 (1 H, d. >8.38 Hz), 7.92 - 8.00 (1 H, m), 7.85 - 7.92 (1 H, m), 7.60 - 7.70 (2 H, m), 4.19 (3 H, s), 2.52 (3 H, s). LC-MS: (ES. m/z): [Μ 1 f 480.0

Example 241

N-(5-cyano-6-(2H- L2,3-triazol-2-yl)pyridin-3-yl)-l-(l-methyl- lH-pyrazolo[3,4-b]pyridin4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 241

607

N ^lH NMR (400 MHz, DMSO-d6) δ ppm 4.17 (s, 3 H), 7.49 (d, J=5.07 Hz, l H), 8.12 (s. 1 H), 8.32 (s, 2 H), 8.65 (s, 1 H). 8.83 (d, J=4.85 Hz, 1 H), 8.87 (d, J=1.98 Hz, 1 H), 9.10 (d, J=2.21 Hz, ] H), 11.44 (s. 1 H). LC-MS: (ES, m/z): [M+l] 479.9

Example 242

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(imidazo[L2-b]pyridazin-6-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 242

‘H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (d, J=9.70 Hz, 1 H), 8.12 (s, 1 H). 8.19 (s, 2 H), 8.54 - 8.60 (m, 2 H). 8.63 - 8.72 (m, 2 H), 8.89 (d, J=2.21 Hz. 1 H), 11.55 (s, 1 H). LC-MS: (ES, m/z): [MH 474.9

Example 243

N-(5-chloro-6-(2H- L2,3-triazol-2-yl)pyridin-3-yl)-l-( l-methoxyisoquinolin-5-yl)-5(trifluoromethyl )-1 H-pyrazole-4-carboxamide, Cpd 243

Ή NMR (400 MHz, DMSO-d6) δ ppm 4.10 (s, 3 H), 6.56 (d, J=6.17 Hz, 1 H), 7.78 - 7.85 (m, 1 H), 8.06 (d, J=6.39 Hz, 1 H), 8.10 (d, J=5.95 Hz. 1 H), 8.18 (s, 2 H), 8.45 (d. J=8.16 Hz, 1 H), 8.56 (s. 1 H), 8.66 (d, J=2.21 Hz, 1 H), 8.83 (d, J=2.21 Hz. 1 H), 11.25 (s, 5 1 H). LC-MS: (ES. m/z): LU 514.9

Example 244

2-(2-chloro-4-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamido)phenyl)

2H-1,2,3-triazole-4-carboxamide. Cpd 244 ‘H NMR (400 MHz, DMSO-d6) δ ppm 11.14 (s, 1 H), 9.00 - 9.08 (m, 1 H), 8.95 (s, ] H), 8.58 (s, 1 H). 8.31 (d, J=8.38 Hz, 1 H), 8.21 (d, J=1.98 Hz, 1 H), 8.04 (s, 1 H), 7.93 7.99 (m, 1 H). 7.85 - 7.92 (m, 2 H), 7.74 (d, J=8.60 Hz. 1 H), 7.59 - 7.69 (m. 2 H), 7.59 7.69 (m, 1 H). LC-MS: (ES, m/z): [M+l]’ 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)-1 H-pyrazole-4-carboxamide, Cpd 245

609

^lH NMR (400MHz, DMSO-d6) δ ppm 11.35 (s, IH), 9.10 (d, J=2.2 Hz, IH), 8.88 (d, J=2.2 Hz, IH), 8.52 (s, IH), 8.32 (br s, IH), 8.30 (s, 2H), 7.70 (d, J=7.3 Hz, IH), 7.63 7.51 (m, IH), 2.77 (s, 3H). LC-MS: (ES, m/z): [M+lf 496.0

Example 246 l-(3-chloro-5-(l-(quiiiolm-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamido)pyridm2-y 1 )-1 H-1,2,3 -triazole-4-carboxamide, Cpd 246

‘H NMR (400 MHz, METHANOL-d4) δ ppm 7.65 (dd, J=8.49, 4.30 Hz, 1 H), 7.76 (d, J=8.82 Hz, 1 H), 7.84 (d, J=7.28 Hz, 1 H). 7.95 - 8.01 (m, 1 H), 8.34 (d, J=8.60 Hz, 1 H), 8.41 (s, 1 H), 8.77 (d, J=2.43 Hz, 1 H), 8.84 - 8.87 (m, 1 H), 9.01 (dd, J=4.19, 1.54 Hz, 1 H). LC-MS: (ES, m/z): [Μ -I | 527.9

Example 247

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(2-methylbenzo[d]thiazol-7-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 247

610

NMR (400 MHz, DMSO-d6) δ ppm 2.81 (s, 3 H), 7.59 - 7.73 (m, 2 H), 8.14 (d, J=7.72 Hz, 1 H), 8.29 (s, 2 H), 8.53 (s, 1 H), 8.83 (d, J=2.43 Hz, 1 H), 9.06 (br s, 1 H), 11.37 (s, 1 H). LC-MS: (ES, m/z): [M+l]* 495.9

Example 248

N-(6-(5-(ammomethyl)-lH-L2,3-tnazol-l-yl)-5-chloropyridin-3-yl)-l-(quinolm-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 248

^lH NMR (400 MHz, METHANOL-d4) δ ppm 4.05 (s, 2 H), 4.60 (br s, 2 H), 7.61 7.68 (m, 1 H), 7.75 (d, J=7.72 Hz, 1 H), 7.83 (d, J=7.28 Hz, 1 H), 7.94 - 8.01 (m, 1 H), 8.31 - 8.35 (m, 2 H), 8.39 (s, 1 H), 8.73 (d, J=2.43 Hz, 1 H), 8.83 (d, J=2.21 Hz, 1 H), 9.00 (d, J=4.41 Hz, 1 H). LC-MS: (ES, m/z): [M+l]* 513.9

Example 249 methyl l-(3-chloro-5-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)pyridin-2-yl)-lH-l,2,3-triazole-4-carboxylate, Cpd 249

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 4.03 (s, 3 H), 7.48 - 7.53 (m, i H), 7.6! - 7.68 (m, 2 H), 7.87 (t, >7.94 Hz, l H), 8.05 (s, l H), 8.28 (s, l H), 8.38 (d, >9.26 Hz. I H), 8.61 (s, l H), 8.67 (s, l H). 8.80 (s, 1 H), 9.05 (d, >3.97 Hz. 1 H). LC-MS; (ES, 5 m/~): [M+l]* 542.9

Example 250

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(imidazo[l,2-a]pyrimidin-5-yl)-5 (trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 250 ‘H NMR (400 MHz, METHANOL-d4) δ ppm 9.28 (d. >4.63 Hz, 1 H). 9.02 - 9.21 (m, 1 H), 8.89 - 8.93 (m, 1 H), 8.65 - 8.71 (m, 1 H), 8.32 - 8.39 (m. 1 H), 8.11 - 8.25 (m, 3 H), 7.96 - 8.03 (m, 1 H). LC-MS; (ES, m/-): [M+lf 465.9

Example 251

N-(5-methoxy-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5-( trifluoromethyl)lH-pyrazole-4-carboxamide, Cpd 251

612

’H NMR (400 MHz, DMSO-d6) δ ppm 11.25 (s, 1 H), 9.05 - 9.12 (m, 1 H), 8.63 8.68 (m, 1 H). 8.50 - 8.57 (m, 1 H), 8.31 - 8.38 (m, 1 H), 8.21 - 8.30 (m, 1 H), 8.03 - 8.10 (m, 1 H), 7.92 - 8.02 (m, 2 H). 7.65 - 7.75 (m, I H), 3.80 - 3.87 (m, 1 H). LC-MS: (ES, m/z): Μ Π 481.0

Example 252 l-(benzo[d]thiazol-4-yl)-N-(5-chloro-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide. Cpd 252

^lH NMR (400 MHz, DMSO-d6) δ ppm 10.64 (1 H, s), 9.49 (1 H, s), 8.53 (1 H, s),

8.48 (1 H, dd, J=8.28, 1.00 Hz), 8.45 (1 H, s), 8.20 (2 H, s), 7.79 - 7.83 (1 H. m), 7.69 7.75 (1 H, m), 2.57 (3 H, s). LC-MS: (ES, m/z): |M~H 504.9

Example 253

N-(5-chloro-6-(5-(methoxymethyl)-lH-L2,3-triazol-l-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 253

613

Ή NMR (400 MHz, METHANOL-d4) δ ppm 3.44 (s, 3 H), 4.66 (s, 2 H), 7.64 (dd, J=8.60, 4.19 Hz, 1 H). 7.75 (d, >8.38 Hz, 1 H), 7.83 (d, J=7.28 Hz. 1 H), 7.97 (dd. >8.60, 7.28 Hz, 1 H). 8.33 (d. .1=8.60 Hz, 1 H). 8.40 (s. 1 H) 8.44 (s. 1 H), 8.74 (d, J=2.43 Hz, 1 5 H). 8.83 (d. >2.21 Hz, 1 H), 9.00 (dd, J=4.30, 1.65 Hz, 1 H). LC-MS: (ES. m/z): [M+lf

529.0

Example 254

N-(5-cyano-6-(2H-l ,2.3-triazol-2-yl)pyridin-3-yl)-1 -(2-methyl-[l ,2,4]triazolo[ 1.510 a]pyridm-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 254

N Z

N^N

Ή NMR (400MHz, DMSO-d6) δ ppm 11.39 (s. IH), 9.08 (d, J=2.4 Hz, IH), 8.86 (d, >2.4 Hz, IH). 8.67 (s, IH), 8.30 (s. 2H), 8.04 (d, >9.0 Hz, IH), 7.86 (dd, >7.4, 8.9 Hz, IH), 7.72 (d, >6.4 Hz, 1 H). 3.34 (s. 13 IH), 2.44 (s, 3H). LC-MS: (ES, m/z): [M If 15 480.0

Example 255

3-(3-cyano-5-(l-(qiiinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamido)pyridin2-yl)-l-methyl-lH-pyrazole-5-carboxylic acid, Cpd 255 ‘ H NMR ¢400 MHz, METHANOL-d4) δ ppm 9.08 ¢1 H, d, J=2.20 Hz), 9.00 ( 1 H, br d, J=3.75 Hz), 8.71 ( 1 H, d, J=1.98 Hz), 8.38 (1 H, s), 8.33 (1 H, d, J=8.38 Hz). 7.96 (1 H, t, J=8.05 Hz), 7.83 ¢1 H, d, J=7.72 Hz). 7.71 -7.78 (1 H, m). 7.64(1 H, dd, J=8.38, 4.19 5 Hz), 7.51 (1 H, s) 4.27 (3 H, s). LC-MS: (ES, m/z): [M+lf 533.0

Example 256 methyl 2-(2-chloro-4-(l-(quinolm-5-yI)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)phenyl)-2H-l,2,3-triazole-4-carboxylate. Cpd 256 ‘H NMR (400 MHz, DMSO-d6) δ ppm 11.11 (s, 1 H), 9.27 (s, 1 H). 9.04 (dd, J=4.08, 1.65 Hz. 1 H), 8.57 (s, 1 H). 8.31 (d, J=8.60 Hz, 1 H), 8.21 (d. J=2.21 Hz, 1 H). 7.93 - 7.98 (m, l H), 7.84 - 7.92 (m, 2 H), 7.76 (d, J=8.60 Hz, 1 H), 7.64 - 7.68 (m, 1 H), 7.58 - 7.63 (m, 1 H), 3.86 (s, 3 H). LC-MS: (ES, m/z): [M+lf 541.9

Example 257

N-(5-cyano-6-(2-niethyI-2H-l,2,3-triazol-4-yl)pyridùi-3 Y (trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 257

615

*H NMR (400 MHz, DMSO-d6) δ ppm 11.29 - 11.48 (1 H, m), 9.20 ( i H, d, >2.51 Hz), 9.01 - 9.09 (1 H, m), 8.78 (1 H, d, >2.26 Hz), 8.65 (1 H, s), 8.27 - 8.37 (2 H. m), 7.96 - 8.03 (1 H, m), 7.89 - 7.95 (1 H, m), 7.66 - 7.73 (1 H, m), 7.59 - 7.65 ( l H, m), 4.29 (3 H, 5 s). LC-MS: (ES, m/z): [M+1 ]⁺ 489.9

Example 258 methyl 3-chloro-5-(l-(qu inolin-5-yl)-5-(trifluoromethyl )-lH-pyrazo!e-4carboxamido)picolinate, Cpd 258

*H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3 H), 7.57 - 7.60 (m, 1 H), 7.63 7.67 (m, 1 H), 7.89 - 7.98 (m, 2 H), 8.31 (d, >8.60 Hz, 1 H), 8.50 (d, >1.98 Hz, 1 H), 8.55 (s, 1 H). 8.85 (d, >2.21 Hz, 1 H), 9.04 (dd, >4.19, 1.76 Hz, 1 H), 11.19 (s, 1 H). LCMS: (ES, m/z): [M+I | 475.9

Example 259

N-(5-cyano-6-( 2H-1,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-methyl- lH-pyrazolo[3,4-c]pyridin7-yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxamide. Cpd 259

616

N

N ‘H NMR (400 MHz, DMSO-d6) δ ppm 3.68 (s, 3 H), 8.11 (d, J=5.51 Hz, 1 H), 8.24 - 8.32 (m, 3 H) 8.46 (s, 1 H), 8.64 (s, 1 H), 8.86 (d, J=2.65 Hz, 1 H), 9.08 (d, J=2.65 Hz, 1 H), 11.39 (s. 1 H). LC-MS: (ES, m/z): [M+l]’ 479.9

Example 260

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl )-1-( l-methyl-lH-indazol-7-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 260

N

Ή NMR (400MHz, DMSO-d6) δ ppm 11.41 (br s, IH), 9.08 (d, J=2.4 Hz, IH),

8.87 (d, J=2.4 Hz, IH). 8.57 (s, IH), 8.36 - 8.20 (m, 3H), 8.06 (d, J=8.2 Hz, IH), 7.62 (d, J=7.3 Hz, IH), 7.30 (t, J=7.8 Hz, IH), 3.43 (s, 3H). LC-MS: (ES, m/z): [M+l]’ 479.0

Example 261

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridm-3-yl)-l-(5-fluoroquinolin-8-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxanude, Cpd 261

‘H NMR (400 MHz, METHANOL-d4) δ ppm 8.92 (dd, >4.30, 1.65 Hz, l H), 8.80 (d, >2.21 Hz, 1 H), 8.71 (d, >2.20 Hz. 1 H), 8.64 (dd, >8.60, 1.54 Hz, 1 H), 8.36 (s. 1 H) 8.02 (s. 2 H), 7.98 (dd. >8.38, 5.29 Hz. 1 H), 7.67 - 7.74 (m, 1 H), 7.47 - 7.57 (m, 1 H).

LC-MS: (ES, m/z): [M+l]” 502.9

Example 262

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-( 1 H-pyrazolo[4,3-b]pyridin-7-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 262

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.40 (1 H, s), 9.12 (1 H, d, >2.65 Hz), 8.88 (1 H, d. >2.43 Hz), 8.69 - 8.77 (1 H, m), 8.66 (1 H. s), 8.56 (1 H, s). 8.30 (2 H, s), 7.62 (1 H, d, >4.63 Hz). LC-MS: (ES, m/z): [M+l]” 466.0

Example 263

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridm-3-yl)-l-(4-fluoiOisoquinolin-l-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide. Cpd 263

618

‘H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (br d, J=8.16 Hz, 1 H), 7.93 (t, J-7.50 Hz. 1 H), 8.09 (t, J=7.39 Hz. 1 H), 8.26 - 8.34 (m, 3 H), 8.64 (s, 2 H), 8.88 (d. J=2.65 Hz, 1 H), 9.09 (d, J=2.43 Hz, 1 H). LC-MS: (ES, m/z): [M+l]” 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)-1 H-pyrazoIe-4-carboxamide. Cpd 264

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.33 (br s, 1 H), 8.85 (d, J=2.43 Hz, 1 H),

8.60 - 8.70 (m, 2 H), 8.50 (s, 1 H), 8.34 (d, J=8.16 Hz, 1 H), 8.16 (s, 2 H), 8.04 (td, J=7.72, 1.10 Hz, 1 H), 7.89 - 7.98 (m. 1 H), 7.30 (d. J=8.38 Hz, 1 H). LC-MS: (ES, m/z): [M+l]” 568.9

Example 265

N-(5-cyano-6-(2H-l,2,3-triazol-2-yT)pyridin-3-yl)-I-(l-methyl-lH-pyrazolo[3,4-b]pyridin3-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 265

‘H NMR (400 MHz, DMSO-d6) δ ppm 4.16 (s, 3 H), 7.43 (dd, J-8.16, 4.41 Hz, l H), 8.24 (dd, >8.16. 1.32 Hz, l H), 8.30 (s. 2 H), 8.59 (s, l H), 8.75 (dd, >4.30, l.21 Hz, 1 H), 8.85 (d, >2.43 Hz, 1 H), 9.08 (d, >2.43 Hz, 1 H). 11.47 (s, 1 H). LC-MS: (ES, m/z): ΜΠ 480.0

Example 266

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yI)-l-(l-methyl-lH-indazol-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 266

‘H NMR (400 MHz, DMSO-d6) δ ppm 4.14 (s, 3 H), 7.29 - 7.34 (m, 1 H), 7.54 7.59 (m, 1 H), 7.63 (d, >8.16 Hz, 1 H), 7.82 (d, >8.60 Hz, 1 H), 8.30 (s, 2 H), 8.55 (s, 1 H), 8.85 (d, >2.65 Hz, 1 H), 9.08 (d, >2.65 Hz, 1 H), 11.41 (s, 1 H). LC-MS: (ES, m/z):

jM· 11 479.0

620

Example 267 methyl 3-(3-cyano-5-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)pyndm-2-yl)-l-methyl-lH-pyrazole-5-carboxylate, Cpd 267

Ή NMR (400 MHz, METHANOL-d4) δ ppm 9.30 ( l H, dd. J=5.18, l .43 Hz), 9.10 (l H, d, J=2.43 Hz), 8.72 (1 H. d, J=2.65 Hz). 8.48 (1 H, d, J=8.82 Hz), 8.45 (1 H, s), 8.43 (1 H, d, J=8.60 Hz), 8.27 (1 H, t, J=8.05 Hz), 8.13 (1 H, d, J=7.06 Hz), 8.06 (1 H, dd, J=8.60. 5.07 Hz). 7.53 (1 H, s). 4.28 (3 H, s), 3.94 (3 H, s). LC-MS: (ES, m/z): [M+l]⁺546.9

Example 268

N-(5-cyano-6-( 1-methyl-1 H-pyrazol-3-y l)pyndin-3-yl)-1-( 8-fluoroqumolin-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 268

^LH NMR (400MHz, DMSO-d6) δ ppm 11.37 (br s, IH), 9.13 (br d, J=13.6 Hz, 2H),

8.67 (br d, J=18.3 Hz. 2H), 8.08 - 7.55 (m, 5H), 6.86 (br s, IH), 3.96 (br s, 3H). LC-MS: (ES, m/z): | Μ l j 507.0

621

Example 269

N-(5-cyano-6-(2H-l ,2.3-triazol-2-yl)pyridin-3-yl)-l-( i ,5-naphthyridin-4-yl )-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 269

N'+U Y

N Vn J H w

^lH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.81 (dd, >8.71,4.08 Hz. 1 H),

7.85 (d, >4.63 Hz, 1 H). 8.04 (s, 2 H), 8.29 (s. 2 H), 8.59 (d. J=8.82 Hz, 1 H). 8.84 (d, J=2.43 Hz, 1 H), 8.98 (d, >2.65 Hz, 1 H), 9.00 (d, J=2.87 Hz, 1 H), 9.23 (d, >4.19 Hz, 1 H). LC-MS: (ES, m/z): [M+lf 476.9

Example 270

N-( 5-chloro-6-(5-((dimethylamino)methy 1)-1 H-1,2,3-triazol-1-yl )pyridin-3-yl)-1 (quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 270

M'^N γυυ ^h

Vx ‘H NMR (400 MHz, METHANOL-d4) δ ppm 2.97 (s, 6 H) 4.61 (s, 2 H), 8.08 (dd, 15 >8.71, 5.18 Hz, 1 H), 8.13 (d, >7.50 Hz, 1 H). 8.27 (t, >8.05 Hz, 1 H), 8.45 - 8.53 (m, 3

H), 8.74 (s, 1 H), 8.77 (d, >2.21 Hz, 1 H), 8.91 (d, >2.2 1 Hz, 1 H), 9.28 - 9.32 (m, 1 H). LC-MS: (ES, m/z): [M+1 f 541.9

622

Example 271

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(2-methylbenzo[d]oxazol-7-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 271

'H NMR (400 MHz, DMSO-d6) δ ppm 2.64 (s. 3 H), 7.52 - 7.59 (m, 1 H), 7.61 -

7.67 (m, 1 H), 7.95 (d, J=7.72 Hz. 1 H), 8.32 (s, 2 H), 8.57 (s, 1 H), 8.88 (d, J=2.43 Hz. 1 H). 9.09 (d, J=2.21 Hz, 1 H), 11.41 (br s, 1 H). LC-MS: (ES, m/z): [M+l]* 479.9

Example 272

N-(6-(4-(aminomethyl)-2H-l,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 272

’H NMR (400 MHz, DMSO-d6) δ ppm 4.09 (s, 2 H), 7.58 - 7.61 (m, 1 H), 7.63 7.67 (m, 1 H), 7.88 - 7.98 (m, 2 H), 8.14 (s, 1 H), 8.30 (d, J=8.38 Hz, 1 H), 8.66 (s, 1 H), 15 8.70 (d, J= 1.98 Hz, 1 H), 8.91 (d, J=2.20 Hz, 1 H). 9.01 - 9.06 (m, 1 H). LC-MS: (ES, m/z): i Μ 1 | 514.0

Example 273

N-(5-chloro-6-(l-methyl-lH-pyrazol-3-yl)pyridin-3-yl)-l-(8-fluoroquinolin-5-yl)-520 (trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 273

623

Ή NMR (400 MHz, DMSO-d6) δ ppm 3.92 (s. 3 H), 6.77 (d. >2.21 Hz, l H), 7.65 (d, >8.60 Hz, l H), 7.73 - 7.86 (m, 3 H), 7.96 (dd, >8.38, 4.41 Hz, l H), 8.49 (d, >l.98 Hz. I H), 8.64 (s, l H), 8.92 (d, >2.20 Hz, 1 H), 9.09 (dd. >4.19. 1.54 Hz, 1 H), 1 1.25 (s, 5 1 H). LC-MS: (ES, m/z): [M+l]' 516.2

Example 274 l-(fL2,4]triazolo[l,5-a]pyridin-5-yl)-N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 274

N

‘H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (d, >6.62 Hz, 1 H), 7.94 (dd, >8.93, 7.39 Hz, 1 H), 8.20 (dd, >8.93, 0.99 Hz, 1 H), 8.31 (s, 2 H), 8.61 (s, 1 H), 8.69 (s, 1 H), 8.86 (d, >2.43 Hz, 1 H), 9.07 (d, >2.43 Hz, 1 H), 11.38 (s, 1 H). LC-MS: (ES, nVzY [M+l | 465.9

Example 275

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridiîi-3-yl)-l-(imidazo[l,2-a]pyrazin-5-yl)-3(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 275

624

‘H NMR (400 MHz, METHANOL-d4) δ ppm 9.40 (s, l H), 9.07 (br s, l H), 8.91 (d, J=2.43 Hz, 1 H), 8.59 (s, 1. H), 8.47 (s, 1 H), 8.15 (br s. 3 H), 7.90 (s, 1 H). LC-MS: (ES, m/z): [M+l] 466.0

Example 276

N-(5-cyano-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-yl)-l-( l,7-naphthyridin-4-yl)-5( trifluoromethyl )- lH-pyrazole-4-carboxamide, Cpd 276

*H NMR (400 MHz. DMSO-d6) δ ppm 7.38 (d, J=5.73 Hz, 1 H), 8.21 (d, J-4.41

Hz, 1 H), 8.31 (s, 2 H), 8.74 (s, 1 H), 8.78 (br d, J=5.73 Hz, 1 H), 8.91 (d, J=2.43 Hz, 1 H), 9.14 (d, J=2.43 Hz, 1 H), 9.36 (d, J=4.41 Hz, 1 H), 9.66 (s, 1 H), 11.48 (s, 1 H). LC-MS: (ES, m/z): [M+l]' 476.9

Example 277

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-fluoroquinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 277 ‘H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18 (dd, 1=9.03, 2.76 Hz, 1 H), 7.63 (d. 1=7.53 Hz, 1 H), 7.73 (t, J=8.28 Hz, 1 H), 7.87 (t, 1=8.03 Hz, 1 H), 7.96 (s, 2 H), 8.16 (s, 1 H), 8.19 (s, 1 H), 8.24 (s, 1 H), 8.54 (d, J=2.26 Hz, 1 H), 8.78 (d, J=2.26 Hz, 1

H). LC-MS: (ES, m/z): |\L 11 502.9

Example 278 l-(2-aminobenzo[d]thiazol-7-yl)-N-(5-chloro-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-yl)-5( trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 278 'H NMR (400 MHz, DMSO-d6) δ ppm 7.18 (d, J=7.72 Hz, 1 H), 7.42 (t, J=7.94 Hz, 1 H), 7.54 (d, 1=7.50 Hz. 1 H ),7.68 (s. 2 H), 8.16 (s, 2 H), 8.48 (s, 1 H). 8.63 (d, 1=2.43 Hz, 1 H). 8.84 (d, 1=2.20 Hz. 1 H). LC-MS: (ES, m/z): [M+lf 505.9

Example 279

N-(5-chloro-6-(2H-L2.3-triazol-2-yl)pyridin-3-yl)-l -(isothiazolo[5,4-b]pyridin-3-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide. Cpd 279 ‘H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (dd, >8.16, 4.39 Hz, l H), 8.20 (s, 2 H), 8.61 - 8.74 (m, 3 H), 8.87 (s, l H), 9.05 (br d, J=3.26 Hz, l H), 11.52 (s, l H). LC-MS: (ES, m/z): [M+l] 491.8

Example 280

N-(5-cyano-6-(lH-pyrrol-l-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5-(trifluoromethyl)-lH‘H NMR (400 MHz, DMSO-d6) δ ppm 11.37 (I H, s), 9.08 (1 H, br s), 9.03 (1 H, br s), 8.78 (1 H. br s), 8.64 ( 1 H, s), 8.34 (1 H. br d, J=7.94 Hz), 7.96 - 8.02 (1 H, m), 7.90 - 7.96 (1 H, m), 7.69 (2 H, br s), 7.55 (2 H, br s), 6.37 (2 H, br s). LC-MS: (ES, m/z):

; M : I ] 474.0

Example 281

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyndm-3-yl)-l-(l-methoxyisoqumoIm-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 281

Ή NMR (4(.)0 MHz, DMSO-d6) δ ppm 4.12 (s, 3 H), 6.58 (d, >6.17 Hz, l H), 7.83 (t, J=7.94 Hz, l H), 8.06 - 8.14 (m, 2 H), 8.32 (s, 2 H), 8.47 (d, J=8.38 Hz, 1 H), 8.59 (s. 1 H), 8.89 (d, J=2.43 Hz, 1 H), 9.09 (d, J=2.65 Hz, 1 H), 11.34 (br s, 1 H). LC-MS: (ES, m/z): i NI · 11 505.9

Example 282 l-(2-aminobenzo[d]thiazol-7-yl)-N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 282

Ή NMR (400 MHz, DMSO-d6) δ ppm 7.25 (d, J=7.72 Hz, 1 H), 7.45 (t, J=7.94 Hz. 1 H), 7.52 - 7.57 (m. 1 H). 8.30 (s. 2 H), 8.55 (s, 1 H), 8.86 (d. J=2.21 Hz, 1 H), 9.09 (d, J=2.43 Hz, 1 H). 11.49 (s. 1 H). LC-MS: (ES. m/z): [M H | 497.2

Example 283

N-(6-( 1 H-1,2,3-triazol-l-yl )-5-( trifluoromethyl)pyridin-3-yl)-1 -(quinolin-5-yl )-5( trifluoromethyl)-1 H-pyrazoIe-4-carboxamide, Cpd 283

628

‘H NMR (400 MHz, DMSO-d6) δ ppm 7.69 - 7.75 (m, 2 H), 7.95 - 8.04 (m, 3 H), 8.36 (d, J=8.l6 Hz, 1 H), 8.69 (d, J=3.31 Hz. 2 H), 8.95 (d, J=1.98 Hz, 1 H), 9.10 (dd, J=3.53, 1.98 Hz, 1 H), 9.25 (d, J=2.21 Hz, 1 H). 11.59 (s, 1 H). LC-MS: (ES, m/z): [M+l]’ 5 518.9

Example 284 l-(benzo[d]isoxazol-3-yl)-N-(5-chloro-6-(2H-I,2,3-triazol-2-yl)pyridin-3-yl)-5( trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 284

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.49(1 H, s), 8.83 (1 H, d, J=2.01 Hz),

8.74 (1 H, s), 8.66(1 H, d, J=2.01 Hz), 8.20 (2 H, s), 7.98 - 8.05 (2 H, m), 7.89 (1 H, t,

J=7.91 Hz), 7.63 (1 H, t,J=7.53 Hz). LC-MS: (ES, m/z): |M · I | 474.9

Example 285

N-(5-chloro-6-(2H-L2.3-triazol-2-yl)pyridin-3-yl)-l-(l-chloroisoquinolin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 285

629

’H NMR (400 MHz, DMSO-d6) δ ppm 7.34 (d, J=8.38 Hz, l H), 7.96 - 8.07 (m, 2 H), 8.18 (s, 2 H), 8.47 (d, J=8.16 Hz, 1 H), 8.70 - 8.75 (m, 2 H), 8.77 (s, 1 H), 8.94 (d, J=2.21 Hz, 1 H), 11.57 (s, 1 H). LC-MS: (ES, m/z): i Μ 11 518.8

Example 286

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridm-3-yl)-l-(lH-indazol-7-yn-5-( trifluoromethyl)lH-pyrazole-4-carboxamide, Cpd 286

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.30(1 H, s). 9.11 (1 H,d,J=2.21 Hz),

8.88 (1 H, d, J=2.43 Hz), 8.55 (1 H, s), 8.23 - 8.35 (3 H, m), 8.02 (1 H, d, J=8.16 Hz), 7.50 (1 H, d, J=7.28 Hz), 7.27 ( 1 H, t, J=7.72 Hz). LC-MS: (ES, m/z): [M+l]⁺ 464.9

Example 287

N-(5-bromo-6-(lH-L2,3-triazol-l-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5-(trifluoromethyl)1 H-pyrazole-4-carboxamide, Cpd 287

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.49 (s, 1 H), 9.07 (br s, 1 H), 8.93 - 9.00 (m, 1 H), 8.81 - 8.89 (m, 1 H). 8.65 - 8.73 (m, 1 H), 8.55 - 8.63 (m, 1 H). 8.30 - 8.37 (m, 1 H), 7.97 (br d, J=0.88 Hz, 3 H), 7.63 - 7.75 (m, 2 H). LC-MS: (ES, m/z): [M+l ]' 528.8

Example 288

N-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-l-(8-fluoroquinolin-5-yl)-5-( trifluoromethyl)lH-pyrazole-4-carboxamide, Cpd 288

*H NMR (400MHz, DMSO-d6) δ ppm 11.36 (s. 1H), 9.10 (dd, J=1.4, 4.1 Hz, 1 H),

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. 1 H). LC-MS: (ES, m/z): [M+l]” 502.9

Example 289

N-(5-cyano-6-(2H- L2,3-triazol-2-yl)pyridin-3 -yl)-1 -( 1 -fluoroisoquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 289

'H NMR (400 MHz, DMSO-d6) δ ppm 11.35 (br s, 1 H), 9.07 (d, >2.65 Hz, 1 H), 8.86 (d, >2.65 Hz. 1 H), 8.62 (s, 1 H). 8.50 (s, 1 H), 8.34 (d, >8.38 Hz, 1 H), 8.29 (s, 2 H), 8.00 - 8.07 (m, 1 H), 7.90 - 7.97 (m, 1 H), 7.29 (d, >8.16 Hz, 1 H). LC-MS: (ES, m/z}:

[M+l]’ 493.9

Example 290 l-(benzo[d]isothiazol-3-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 290

'H NMR (400 MHz, DMSO-d6) δ ppm 7.60 - 7.67 (m, 1 H), 7.76 (t, J—7.61 Hz. 1

H), 8.04 (d, >8.16 Hz, 1 H), 8.16 (s, 2 H). 8.39 (d, >8.38 Hz. 1 H), 8.60 - 8.66 (m. 2 H), 8.83 (d, >2.21 Hz. 1 H), 11.42 (s, I H). LC-MS: (ES, m/z): [M+l]’ 491.0

Example 291

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(2-fluoroquinolin-5-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cptl 291 ‘H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.94 (d, >2.43 Hz. 1 H), 8.78 (d, >2.43 Hz, 1 H), 8.20 (s, 1 H), 8.14 (d, >8.60 Hz, 1 H), 8.09 (s, 1 H), 7.97 (s, 2 H), 7.81 (t, >8.05 Hz, 1 H), 7.67 (t, >8.27 Hz, 1 H), 7.56 (d, >7.06 Hz, 1 H), 7.12 (dd, >9.15, 5 2.54 Hz, 1 H). LC-MS: (ES, m/z): [M+lf 494.0

Example 292

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyTidin-3-yl)-l-(furo[2,3-d]pyrimidin-4-yl)-5 (trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 292 ’H NMR (400MHz, DMSO-d6) δ ppm = 11.51 (s, IH), 9.00 (s, 2H), 8.78 (d, >2.2 Hz, IH), 8.58 (s, IH), 8.39 (d, >2.2 Hz, IH), 8.27 (s, 2H), 7.32 (d, >2.0 Hz, IH). LC-MS: (ES, m/z): [M+l]’ 466.9

Example 293 l-(benzo[d][l,2,3]thiadiazol-7-yl)-N-(5-chloro-6-(l-methyl-lH-pyrazol-3-yl)pyridin-3-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 293

Ή NMR (400MHz, DMSO-d6) δ ppm 11.18 (s, IH), 8.98 (dd. J=0.9. 8.2 Hz, 1 H), 8.84 (d, J=2.2 Hz, IH). 8.62 (s, IH), 8.42 (d, J=2.2 Hz, IH), 8.13 - 8.08 (m, IH). 8.06 8.00 (m. IH), 7.79 (d, J=2.2 Hz, IH), 6.76 (d, J=2.2 Hz, IH), 3.93 (s, 3H). LC-MS: (ES, 5 m/z): [M+lf 505.1

Example 294

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(thiazolo[5,4-d]pyrimidin-7-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 2.94

Ή NMR (400MHz, DMSO-d6) δ ppm 11.42 (br s, IH), 9.79 (s, IH), 9.38 (s, IH),

9.05 (d, J=2.6 Hz, 1 H), 8.84 (d, J=2.4 Hz, IH), 8.64 (s, IH), 8.30 (s, 2H). LC-MS: (ES, m/z): Μ 1 | 483.9

Example 295

N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(2-methyIimidazo[l,2-a]pyridin-3-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 295

Ή NMR (400MHz, DMS0-d6) δ ppm l l.5l (s, IH), 9.09 (d, J=2.2 Hz, IH), 8.87 (d, J=2.4 Hz, IH), 8.71 (s, IH), 8.29 (s, 2H), 8.12 (br d, J=6.6 Hz, IH), 7.79 (br d, J=9.3 Hz, IH), 7.65 (br t, J=7.6 Hz, IH), 7.34 - 7.12 (m, IH), 2.28 (s, 3H). LC-MS: (ES, m/z): |M 11 478.9

Example 296

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinazolin-4-yl)-5-( trifluoromethyl)lH-pyrazole-4-carboxamide, Cpd 296

ΙΟ

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.20 - 11.63 (m, 1 H), 9.43 (s, 1 H), 9.05 9.10 (m, I H). 8.83 - 8.88 (m, I H), 8.66 - 8.71 (m, 1 H), 8.17 - 8.33 (m, 4 H), 8.01 - 8.08 (m, 1 H), 7.89 - 7.96 (m, 1 H). LC-MS: (ES, m/z): [M+l]’ 476.9

Example 297 l-(beiizo[d]thiazol-4-yl)-N-(5-cyano-2-methyl-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 297

635

‘H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (1 H, s), 9.45 (1 H, s), 8.65 ( 1 H. s), 8.49 (1 H, s), 8.44 (1 H, dd, J=7.94, 1.10 Hz), 8.28 (2 H, s), 7.75 - 7.82 (1 H, m), 7.64 7.73 (1 H, m). 2.62 - 2.66 (3 H, m). LC-MS: (ES, m/z): [M+lf 496.1

Example 298 l-(benzo[d]thiazol-4-yl)-N-(5-cyano-2-methyl-4-(2H-l,2.3-triazol-2-yl)phenyl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 298

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 9.08 (1 H, s), 8.66 (1 H, s), 8.22 (1

H. s), 8.18 (1 H, dd. J=7.50. 1.76 Hz). 7.97 (1 H, s), 7.92 (2 H, s), 7.73 (1 H, s), 7.58 - 7.69 (2 H, m), 2.47 (3 H, s). LC-MS: (ES, m/z): · Μ - I | 495.1

Example 299

N-(6-(4-amino-2H-L2,3-triazol-2-yl)-5-chloropyridm-3-yl)-l-(benzo[d]thiazol-4-yI)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 299

636

NH₂ ^]H NMR (400 MHz, DMSO-d6) δ ppm 11.15 ( I H, s) 9.45 (1 H, s), 8.78 (1 H, d, J=2.21 Hz), 8.57 (1 H. d, J=2.21 Hz), 8.52 (1 H, s), 8.44 (1 H, dd, J=8.16, 1.10 Hz), 7.76 7.81 (1 H. m), 7.64 - 7.72 (1 H, m), 7.31 (1 H, s). LC-MS: (ES, m/z): [Μ I | 506.1

Example 300 l-(benzo[d]thiazol-4-yl)-N-(2,5-dimethyl-6-(2H-l,2,3-triazoI-2-yI)pyridin-3-yI)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 300

‘H NMR (400 MHz. CHLOROFORM-d) δ ppm 9.08 (1 H, s). 8.60 (1 H, br s), 8.23 (1 H, br s), 8.18(1 H, dd, J=7.50, 1.54 Hz), 7.88 (2 H, s), 7.73(1 H, br s), 7.59 - 7.68 (2 H,

m). 2.62 (3 H, br s), 2.43 (3 H, s). LC-MS: (ES, m/z): [M+l]' 485.0

Example 301 l-(benzo[d][l,2.3]thiadiazol-7-yl)-N-(5-chloro-2-fluoro-4-(2H-L2,3-triazol-2-yl)phenyl)5-(trifluoromethyl)-!H-pyrazole-4-carboxamide, Cpd 301

637

Ή NMR (400MHz, DMSO-d6) δ ppm 10.98 (s, IH), 8.97 (d, J=8.2 Hz, IH), 8.57 (s, IH), 8.28 (d, >7.3 Hz, IH), 8.20 (s, 2H), 8.12 - 8.07 (m, IH), 8.06 - 7.99 (m, IH), 7.88 (d, >10.4 Hz, IH). LC-MS: (ES, m/z): [M ; 11 508.8

Example 302

N-(5-chloro-2-fluoro-4-(2H-L2,3-triazol-2-yl)phenyl)-l-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 302

Ή NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1 H), 9.72 (s, 1 H), 8.90 (s, 1 H),

8.56 (s, 1 H). 8.24 (d, >7.28 Hz, 1 H), 8.17 (s, 2 H), 7.93 (td. >8.16, 5.51 Hz. 1 H), 7.86 (d, >10.36 Hz, 1 H), 7.68 (dd, >10.36, 7.72 Hz, 1 H), 7.14 (d, >8.60 Hz, 1 H). LC-MS: (ES, m/z): ;M - i | 519.9

Example 303 l-(benzo[d][l,2,3] thiadiazol-7-yl)-N-(5-chloro-2-methyl-6-(l H-pyrazol-l-yl)pyridin-3-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 303

638

‘H NMR (400MHz, DMSO-d6) δ ppm 10.65 (s, IH), 8.98 (d, J=8.4 Hz, IH), 8.61 (s. IH), 8.32 (s, IH), 8.26 (d, J=2.2 Hz, IH), 8.13 - 8.07 (m, IH), 8.06 - 7.99 (m. IH), 7.81 (s, IH), 6.55 (s, IH), 2.53 (s, 3H). LC-MS: (ES. m/z): |Μ 11 504.9

Example 304

N-(5-chloro-6-(4-methyl-2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide. Cpd 304

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s. 1 H), 9.06 (t, J=2.54 Hz. 1 H),

8.89 (s. 1 H), 8.60 - 8.75 (m. 2 H), 8.33 (d. .1=8.38 Hz, 1 H). 7.88 - 8.03 (m, 3 H), 7.68 (d, J=2.65 Hz, 2 H), 2.34 (s. 3 H). LC-MS: (ES. m/z): [M+l]* 499.0

Example 305

N-(5-methyl-6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 305

‘H NMR (400 MHz, DMSO-d6) δ ppm 11.16 (I H, s), 9.03 - 9.10 (1 H. m), 8.92 (1 H, s), 8.62 (1 H, s), 8.33 (1 H, d, J=8.38 Hz), 8.29 (1 H, d, J=1.76 Hz), 7.95 - 8.03 (1 H, m), 7.88 - 7.94 (1 H, m), 7.64 - 7.72 (2 H, m), 4.44 (3 H, s), 2.55 (3 H, s). LC-MS: (ES, 5 m/z): [M+l]* 480.0

Example 306 l-(benzo[d]thiazol-4-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 306

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.26 ( 1 H, s), 9.48 (l H, s), 8.88 (1 H, d, J=2.43 Hz), 8.68 (1 H, d, J=2.21 Hz). 8.54 (1 H, s), 8.47 (T H, dd, J=8.05, 0.99 Hz), 8.19 (2 H, s), 7.82 (1 H. dd, J=7.61,0.99 Hz), 7.68 - 7.75 (1 H. m). LC-MS: (ES, m/z): [Μ+1 ]⁺490.9

Example 307

N-(5-chloro-6-(2H-tetrazol-5-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5-(trifh.ioiOmethyl)-lHpyrazole-4-carboxamide, Cpd 307

640

‘H NMR (400 MHz, DMSO-d6) δ ppm 11.35 (l H, s), 9.05 (2 H, br s), 8.61 (2 H, s). 8.32 (] H, br d, J=8.16 Hz), 7.87 - 8.02 (2 H, m), 7.60 - 7.73 (2 H, m). LC-MS: (ES, m/z): 'AI - I | 485.9

Example 308

N-(5-cyano-6-(2H-l,2,3-tiïazol-2-yl)pyridin-3-yl)-l-(8-fluoiOqumolm-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 308

ΙΟ Ή NMR (400MHz, DMSO-d6) δ ppm l1.36 (s, IH), 9.13 - 9.05 (m, 2H), 8.87 (d.

J=2.6 Hz, IH), 8.59 (s, IH), 8.29 (s, 2H), 7.97 (dd, J=4.3, 8.5 Hz, IH), 7.82 (dd, J=8.4, 10.4 Hz, IH), 7.77 (dd. J=4.2, 8.6 Hz, IH), 7.64 (d. J=8.6 Hz, IH). LC-MS: (ES. m/z): \ifi 493.9

Example 309

N-(5-chloro-6-(2H-L2.3-triazol-4-yl)pyridin-3-yl)-l-(quinolin-5-yl)-5-( trifluoromethyl)l H-pyrazole-4-carboxamide, Cpd 309

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.46 (s, l H), 9.09 - 9.16 (m, l H), 9.02 (d, J=2.20 Hz, I H), 8.72 (s, I H), 8.57 (d, J=l .98 Hz, 1 H), 8.33 - 8.43 (m, 2 H), 7.93 8.06 (m, 2 H), 7.72 - 7.84 (m, 2 H). LC-MS: (ES, m/z): [M+l]’ 484.9

Example 310

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(3-methylthieno[3,2-b]pyridin-7-yl)5-( trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 310

‘H NMR (400 MHz, DMSO-d6) δ ppm 3.46 - 3.47 (m, 3 H), 7.70 (d, ,1=4.85 Hz, 1

H), 7.97 (d, J=0.88 Hz, 1 H), 8.32 (s, 2 H), 8.68 (s, 1 H), 8.88 (d, J=2.65 Hz, 1 H), 8.94 (d, J=4.85 Hz, 1 H), 9.10 (d, J=2.43 Hz, 1 H), 11.54 (s, 1 H). LC-MS: (ES, m/z): [M+lf 495.9

Example 311 l-(beiizo[d]oxazol-4-yl)-N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 311

642

Ή NMR (400MHz, DMSO-d6) 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, >3.8 Hz, 1H), 7.69 (br s, 2H). LC-MS: (ES, m/z): [NI 1 | 465.9

Example 312

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-1 -(4-fluoronaphthalen-1 -y l)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 312

*H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (1 H, s), 9.20 (1 H, d, >2.01 Hz),

8.95(1 H, d, >2.01 Hz), 8.70(1 H, s), 8.33 (2 H, s), 8.24(1 H, br d, >8.28 Hz), 7.88(1 H. dd, >8.16, 4.64 Hz), 7.72 - 7.83 (2 H, m), 7.58 ( 1 H, br t, J=9.16 Hz), 7.17 (1 H, br d, >8.03 Hz). LC-MS: (ES, m/z): [M+l]” 492.9

Example 313 methyl 2-cyano-4-(l-(quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4carboxamido)benzoate, Cpd 313

Ή NMR (400 MHz, DMSO-d6) δ ppm 3.91 (s, 3 H), 7.62 - 7.72 (m, 2 H), 7.90 8.02 (m, 2 H), 8.15 - 8.21 (m, 2 H), 8.32 - 8.39 (m, 2 H), 8.60 (s, l H), 9.07 (dd, J=3.97, 1.76 Hz, l H), 11.29 (s, 1 H). LC-MS: (ES, m zY [M+lf 451.9

Example 314 l-(benzo[d][l,2,3]thiadiazol-7-yl)-N-(5-cyano-2-methyl-6-(2H-L2,3-triazol-2-yl)pyridm3-yl)-5-(trifluoromethyl )-1 H-pyrazole-4-carboxamide, Cpd 314

‘H NMR (400MHz. DMSO-d6) δ ppm 10.78 (s. IH), 8.99 (d, J=8.4 Hz. IH), 8.70 (s. IH), 8.63 (s, IH), 8.32 (s, 2H), 8.15 - 8.08 (m, IH), 8.07 - 8.01 (m, IH), 2.67 (s, 3H). LC-MS: (ES, m/z): [M+1 f 496.9

Example 315

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[3,2-d]pyrimidin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 315

‘H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (d, J=5.73 Hz, 1 H), 8.32 (s, 2 H), 8.62 - 8.74 (m, 2 H), 8.83 (d, J=2.43 Hz, 1 H), 9.05 (d, J=2.21 Hz, 1 H), 9.22 (s, 1 H), 11.59 (br s, 1 H). LC-MS: (ES, m/z): [M+l]’ 482.9

Example 316

-(benzo[d]thiazol-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 316

S ‘H NMR (400MHz, DMSO-d6) δ ppm 11.27 (s, IH), 9.46 (s, 1 H), 9.07 (d, J=2.4

Hz, IH), 8.86 (d, J=2.6 Hz, IH), 8.53 - 8.42 (m, 2H), 8.30 (s, 2H), 7.80 (d, J=6.6 Hz, IH), 7.74 - 7.64 (m, IH). LC-MS: (ES, m/z): [M+l]⁺ 481.9

Example 317

N-(5-chloro-2-methyl-4-(2H-l,2,3-triazol-2-yl)phenyl)-l-(8-fluoroisoquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 317

645

‘H NMR (400 MHz, DMSO-d6) δ ppm 10.44 (s. 1 H), 9.76 (s, 1 H), 8.94 (s, 1 H). 8.62 (s, 1 H), 8.15 - 8,20 (m, 2 H), 7.97 (td, J=8.21, 5.40 Hz. 1 H), 7.89 (s, 1 H), 7.67 7.76 (m. 2 H), 7.17 (d. J=8.38 Hz, 1 H), 2.38 (s. 3 H). LC-MS: (ES. m zY [M+l]' 516.0

Example 318

N-(5-chloro-2-methyl-6-(2H-L2,3-triazol-2-yl)pyndm-3-yl)-l-(7-methylpyrazolo[L5a]pyridm-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 318

‘H NMR (400MHz, DMSO-d6) δ ppm 10.65 (s, IH), 8.54 (s, IH), 8.44 (s, IH),

8.19 (s, 2H), 8.17 (d, J=2.2 Hz, IH), 7.54 (d, J=7.3 Hz. IH), 7.04 (d, J=7.7 Hz, IH), 6.41 (d, J=2.2 Hz, IH). 2.80 (s. 3H), 2.56 (s. 3H). LC-MS: (ES, m/zY. [M+l]' 502.2

Example 319

1 -(pyrazolo[ 1,5-a]pyridm-4-yl )-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)lH-pyrazole-4-carboxamide, Cpd 319

646 ^JH NMR (400 MHz, DMSO-d6) δ ppm 6.32 (dd, J=2.21, 0.66 Hz, l H), 7.07 (t, J=7.17Hz, l H), 7.56 (d. J=7.28Hz, l H), 7.94 (dd, J=5.5l, 1.98 Hz, l H), 8. H (d, J=2.43 Hz, l H). 8.21 (d, J=l.76 Hz, 1 H), 8.53 (s, 1 H), 8.67 (d, J=5.73 Hz, 1 H), 8.94 (d. J=7.06 Hz, 1 H). 11.28 (s. 1 H). LC-MS: (ES. m/z): [M+l]⁺ 440.9

Example 320 l-(8-fluoroisoqumolm-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-lH pyrazole-4-carboxamide, Cpd 320

Ή NMR (400 MHz, DMSO-d6) δ ppm 7.12 (d, J=8.38 Hz. 1 H), 7.69 (dd, J=10.36, 7.94 Hz, 1 H), 7.94 (td. J=8.21, 5.40 Hz, 1 H), 8.0.1 (brs, 1 H), 8.27 (br s, 1 H), 8.64 - 8.72 (m, 2 H), 8.92 (s. 1 H), 9.73 (s, 1 H), 11.43 (br s, 1 H). LC-MS: (ES, m/z): 'Μ · 11 469.9

Example 321

N-(5-chloro-2-methyl-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[2,3-c]pyridin-4-yl)

5-( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 321 ^lH NMR (400 MHz, DMSO-d6) δ ppm 10.61 (1 H, s), 9.52 (1 H, s), 8.65 (1 H, s), 8.57 (1 H, s), 8.43 (1 H, s), 8.34 (1 H. d, J=5.51 Hz), 8.16 - 8.18 (2 H, m), 7.14 - 7.21 (T H, m), 2.55 (3 H, s). LC-MS: (ES, m/z): [M+l] 505.1

647

Example 425

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(pyrazolo[l,5-a]pyrazin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 425

‘H NMR ¢400 MHz, DMSO-d6) δ ppm 11.54 (s, 1 H), 9.02 - 9.09 (m, 2 H), 8.84 (d, J=2.43 Hz, 1 H). 8.62 (s, 1 H), 8.37 (d, J=2.43 Hz, 1 H), 8.30 (s, 2 H), 7.96 (d, J=4.63 Hz, 1 H), 7.11 (dd, J=2.32, 0.99 Hz, 1 H). LC-MS: (ES, m/z): [M+l]' 465.9

Example 449

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(isoquinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 449

LCMS (ESI): mass calcd. for C21H12CIF3N8O 484.1 m/z found 485.3 [M+H] . ^!H

NMR (400 MHz, DMSO-X) δ ppm 7.09 (d, J=6A Hz, 1 H) 7.89 - 7.95 (m. 1 H) 8.12 (d, J=6.9 Hz, 1 H) 8.20 (s, 2 H) 8.48 (d, J=8.5 Hz, 1 H) 8.61 (s, 1 H) 8.64 (d, Μ5.Ί Hz, 1 H) 8.69 (d, J=2.0 Hz, 1 H) 8.88 (d, J=2I) Hz, 1 H) 9.56 (s, 1 H) 11.28 (br s, 1 H)

Example 450

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yD-l-(quinolin-4-yl)-5-( trifluoromethyl)lH-pyrazole-4-carboxamide, Cpd 450

648

LCMS (ESI): mass calcd. for C21H12CIF3N8O 484.1 m/z found 485.3 [M+H]’. *H

NMR (400 MHz. DMSO-Y) δ ppm 7.34 (d. 7=8.1 Hz, l H) 7.77 (td, 7=7.6, l.O Hz, l H) 7.91 (d, 7=4.5 Hz, l H) 7.95 (ddd, 7=8.4, 7.0, 1.6 Hz, l H) 8.20 (s, 2 H) 8.26 (d, 7=8.5 Hz, 5 l H) 8.66 (s, l H) 8.69 (d, 7=2.0 Hz, l H) 8.87 (d, 7=2.4 Hz, I H) 9.19 (d, 7=4.5 Hz, l H)

11.24 - 11.35 (m, 1 H)

Following the procedure described in Example 59. and selecttng and substituting the appropriate reagents, starting materials, and purification methods. and adjusting reaction températures, times and other variables or parameters, as needed or désirable, as would be readily recognized by those skilled in the art, the following compounds were prepared.

Example 93

N-(3-chloro-4-methoxyphenyl)-l-(isoquinolin-8-yl)-5-( trifluoromethyl )-/H-pyrazole-4carboxamide, Cpd 10

’H NMR (400MHz, DMSO-d6) δ ppm 3.92 (s, 3 H) 6.94 (d, J=8.61 Hz, 1 H) 7.51 (d, J=8.22 Hz, 1 H) 7.65 (d, J=7.43 Hz, 1 H) 7.69 - 7.85 (m, 4 H) 8.06 (d, J=8.22 Hz, 1 H)

8.18 (s, 1 H) 8.66 (d, J=5.87 Hz, 1 H) 8.74 (s, 1 H). LCMS (ESI): m/z 446.9 | M H |

649

Example 94

A^z-(3-chloro-4-(///-pyrazol-l-yl)phenyl)-l-(isoquinolin-8-yl)-5-(trifluoromethyl)-///pyrazole-4-carboxamide, Cpd 12

‘H NMR (400MHz, DMSO-d6) δ ppm 11.10 (s. IH), 8.92 (s. IH), 8.74 (d, J=6.1 Hz, IH), 8.63 (s, IH), 8.42 (d, J=8.4 Hz, IH), 8.34 (d, J=6.1 Hz, IH), 8.17-8.11 (m, 2H), 8.11 - 8.05 (m, 2H), 7.83 (dd, J=2.2, 8.7 Hz, IH), 7.73 (d, J=1.4 Hz, IH), 7.59 (d, J=8.8 Hz, IH), 7.62 - 7.57 (m, IH), 6.56 - 6.46 (m, IH). LCMS (ESI): m/z 482.9 [M+H]*

Example 95

N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-l-(isoquinolin-8-yl)-5-( trifluoromethyl)-///pyrazole-4-carboxamide, Cpd 13

Ή NMR (400MHz, DMSO-d6) δ ppm 7.97 (br. s., 2 H) 8.07 (d, J=4.70 Hz, 1 H) 8.29 (br. s., 1 H) 8.61 (br. s., 2 H) 8.67 (d, J=5.09 Hz, 1 H) 8.81 (br. s., 1 H) 9.26 (br. s., 1 H) 11.61 (br. s., 1 H). LCMS (ESI): m/z 477.0 ! M ‘ 111

Example 96 /V-(4-(2-aminopyrimidin-4-yl)-3-chloiOphenyl)-l-(isoquinolin-8-yl)-5-(trifluoromethyl)///-pyrazole, Cpd 14

650

Ή NMR (400MHz, DMSO-d6) □ ppm H.27 (s, IH), 8.91 (s, IH), 8.74 (d, J=6.1 Hz, IH), 8.67 (s, IH), 8.49 (d, J=6.3 Hz, IH), 8.42 (d, J=8.4 Hz, IH), 8.33 (d, J=6.1 Hz, IH), 8.17 - 8.10 (m, 2H), 8.09 - 8.04 (m, IH), 7.92 (dd, J=2.0, 8.6 Hz, IH), 7.74 (d, J=8.6 5 Hz, IH), 7.24 (d, J=6.3 Hz. IH), 4.46 (br s. 15H), 5.16 - 3.77 (m. IH), 3.91 (br s, IH), 5.16 - 3.77 (m. IH). LCMS (ESI): m/z 509.9 [M+H]^T

Example 97

N-(5-chloro-6-(7H-pyrazol-l-yl)pyridm-3-yl)-l-(isoquinolin-8-yl)-5-(trifluoromethyl)-ZH10 pyrazole-4-carboxamide. Cpd 15

*H NMR (400MHz, DMSO-d6) δ ppm 6.54 (br. s., 1 H) 7.78 (s, 1 H) 8.09 - 8.29 (m. 3 H) 8.40 - 8.53 (m. 2 H) 8.61 - 8.70 (m, 1 H) 8.65 (br. s., 1 H) 8.77 (br. s., 2 H) 8.91 (br. s., 1 H) 9.00 - 9.14 (m, 1 H) 9.06 (br. s.. 1 H) 11.54 (br. s., 1 H). LCMS (ESI): m/z

483.9 [M+Hf

Example 98

A^r-(5-chloro-6-( l,l-dioxidoisothiazolidin-2-yl)pyridin-3-yl)-l-(isoquinolin-8-yl)-5(trifluoromethyl)-/H-pyrazole-4-carboxamide, Cpd 20

651

Ή NMR (400MHz, CHLOROFORM-d) δ ppm 8.78 (s, IH), 8.66 (d, J=5.3 Hz, IH), 8.55 (d, J=2.2 Hz. IH), 8.53 (br. s.. IH), 8.36 (d, J=2.2 Hz. IH), 8.25 (s. IH), 8.07 (d. J=8.4 Hz. IH), 7.86 - 7.82 (m, IH), 7.82 - 7.79 (m, IH). 7.67 (d, J=7.1 Hz. IH), 4.11 (t, 5 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

UY

Example 99

Aq5-chloro-6-(3-methyl-/Y,2,4-triazol-l-yl)pyridin-3-yI )-1-( isoquinolin-8-yl)-510 (trifluoromethyl)-///-pyrazole-4-carboxamide, Cpd 30

‘H NMR (400 MHz, METHANOL-d4) δ ppm 2.46 - 2.49 (m, 1 H) 2.48 (s. 2 H) 7.87 (d, J=7.28 Hz, 1 H) 7.98 (dd, 1=8.27, 7.39 Hz, 1 H) 8.04 (dd, J=5.95, 0.88 Hz. 1 H) 8.26 (d, 1=8.60 Hz, 1 H) 8.41 (s, 1 H) 8.62 (d, J=5.73 Hz, 1 H) 8.66 (s, 1 H) 8.70 (d, 15 1=2.43 Hz, 1 H) 8.80 (d, J=2.43 Hz, 1 H) 8.87 (s. 1 H). LCMS (ESI): m/z 498.9 [M+H]⁺

Example 100 /V-(3-chloro-4-( 5-methyl- IH-1.2,4-triazol-1 -yl)phenyl)-1 -(isoquinolin-8-yl)-5(trifluoromethyl)-//f-pyrazole-4-carboxamide, Cpd 31

652

‘H NMR (400 MHz. METHANOL-d4) δ ppm 2.44 (s, 3 H) 7.87 (d, J=7.28 Hz, 1 H) 7.95 - 8.02 (m, 1 H) 8.04 (d, J=5.95 Hz, 1 H) 8.09 (s, 1 H) 8.27 (d, J=8.38 Hz, 1 H) 8.43 (s. 1 H) 8.63 (d, J=5.73 Hz, 1 H) 8.66 (s, 1 H) 8.75 (d, J=2.43 Hz, 1 H) 8.85 (d.

J=2.43 Hz, 1 H). LCMS (ESI): m/z 498.9 [M+Hf

Example 101

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(isoquinolin-8-yl)-5-( trifluoromethyl)lH-pyrazole-4-carboxamide, Cpd 19

Ή NMR (400 MHz, METHANOL-d4) δ ppm 8.14 (s, 2 H), 8.20 (d, J=7.50 Hz. 1

H), 8.36 (t, J=7.94 Hz, 1 H), 8.52 (s, 1 H), 8.56 (d, J=8.38 Hz, 1 H), 8.64 (d, J=6.17 Hz, 1

H), 8.77 (d, J=6.17 Hz, 1 H), 8.92 (d, J=2.65 Hz, 1 H), 9.10 (br. s., 1 H), 9.28 (s, 1 H).

LCMS (ESI): m/z 476.0 [M+H]*

Example 102

N-(5-chIoro-6-(oxazol-2-yl)pyridm-3-yl)-l-(ïsoquinolin-8-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamide, Cpd 22

Ή NMR (400MHz, DMSO-d6) δ ppm 8.93 (d, J=2.2 Hz, IH), 8.67 (d, J=5.9 Hz, IH), 8.60 (s, IH), 8.58 - 8.53 (m, 2H), 8.33 (d, J=0.8 Hz, IH), 8.29 (dd, J=l.7, 7.3 Hz, IH), 8.08 - 8.04 (m, IH), 8.00 - 7.94 (m. 2H), 7.50 (s. IH). LCMS (ESI): m/z 531.0 ; Μ I i |

Example 103

N-(3-chloro-4-( 2H-1,2,3-triazol-2-yl)phenyl )-1 -( isoquinolin-8-yl)-5-(trifluoromethyl )-1Hpyrazole-4-carboxamide, Cpd 11

‘H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 - 7.69 (m, 3 H), 7.79 - 7.86 (m, 2 H), 7.91 (s, 2 H), 8.02 - 8.11 (m, 3 H), 8.24 (s, 1 H), 8.69 (d,J=5.67 Hz, 1 H), 8.75 (s, 1 H). LCMS (ESI): m/z 531.0 |M H|

Example 104

N-(3-chloro-4-( 1 H-1,2,3-triazol-1 -yDphenyl)-1 -( isoquinolin-8-yl)-5-(trifluoromethyl )-1Hpyrazole-4-carboxamide, Cpd 18

654

^lH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.63 - 7.70 (m, 3 H), 7.80 - 7.87 (m, 2 H), 7.90 (s. I H), 8.01 - 8.I l (m, 3 H). 8.15 (s, l H), 8.26 (s, l H), 8.70 (d, J=5.67

Hz, l H), 8.76 (s, l H). LCMS (ESI): m/z 483.9 [M+H]^:

Example 105

N-(3-chloro-4-(3-methyl-l H-l ,2,4-triazol-1 -yl)phenyl)-l-(isoquinolin-8-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 29

‘H NMR (400 MHz, METHANOL-d4) δ ppm 2.58 (s, 3 H), 7.70 (d. J=8.61 Hz. I H), 7.91 (dd, J=8.61, 2.15 Hz, 1 H), 8.21 - 8.28 (m, 2 H), 8.40 (t, J=7.92 Hz, 1 H), 8.48 (s, 1 H), 8.60 (d, J=8.41 Hz, 1 H), 8.70 - 8.75 (m, 1 H), 8.76 - 8.82 (m, 1 H), 9.40 (s, 1 H), 9.56 (s, 1 H). LCMS (ESI): m/z 497.9 [M+H]”

Following the procedure described in Example 180, above, selecting and substituting the appropriate reagents, starting materials, and purification methods, and adjusting reaction températures, times and other variables or parameters, as needed or désirable, as would be readily recognized by those skilled in the art, the following compounds were prepared:

Example 322

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(dimethylamino)isoquinolin-4-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 322

655

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.43 (s, l H), 8.89 (d, J=2.2l Hz, l H), 8.69 (d, J=2.2l Hz, l H), 8.61 (s, l H), 8.33 (d, J=8.60 Hz, l H), 8.21 (s, l H). 8.16 (s. 2 H), 7.76 - 7.83 (m. I H), 7.63 - 7.72 (m, l H), 7.00 (d, J=7.94 Hz. I H), 3.29 (s, 6 H). LC5 MS: (ES, m/z): [M+l]' 527.9

Example 323

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yI)-l-(l-(methylamino)isoquinolin-4-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 323

Ή NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s. 1 H), 8.95 (d, J=2.21 Hz, 1 H). 8.74 (d, J=2.21 Hz, 1 H), 8.70 (s, 2 H), 8.26 (s, 1 H), 8.20 (s, 2 H), 7.89 - 7.96 (m, 1 H), 7.78 - 7.86 (m, 1 H), 7.03 (d, J=8.16 Hz, 1 H), 3.18 (br d, J=2.65 Hz. 3 H). LC-MS: (ES. m/z): [M+l]* 513.9

Example 324

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoro-l(methylamino)isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 324

’H NMR (400 MHz, METHANOL-d4) δ ppm 3.33 (d, J=l .76 Hz, 3 H), 6.98 (br d, J=8.82 Hz, l H), 7.61 - 7.70 (m, l H), 7.93-8.01 (m, 1 H), 8.04 (s, 2 H), 8.14 (d, J=1.54 Hz, 1 H), 8.43 (s, 1 H), 8.71 (d, J=2.20 Hz, 1 H), 8.80 (br s, 1 H). LC-MS: (ES, m/z):

| M ! | 532.0

Example 325

N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-fluoro-l(methylamino)isoquinolin-4-yl)-5-( trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 325

HN ^!H NMR (400 MHz, DMSO-d6) δ ppm 3.13 (s, 3 H), 6.76 (d, J=8.16 Hz, 1 H), 7.56 (dd. J=13.34, 8.05 Hz, 1 H), 7.83 (td, J=8.16, 5.29 Hz, 1 H), 8.23 (s, 1 H), 8.28 (s, 2 H), 8.54 (br d, J= 10.80 Hz, 1 H), 8.65 (s, 1 H), 8.91 (d, J=2.43 Hz, 1 H), 9.16 (d. J=2.43 Hz, 1

H), 11.57 (s, l H). LC-MS: (ES, m/z): [M+l]’ 522.9

Example 326 l-(8-aminoquinolin-5-yl)-N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 326

657

‘H NMR (400MHz, METHANOL-d4) δ ppm 9.07 (d, J=2.4 Hz, IH). 8.90 (d, J=2.6

Hz, IH), 8.83 - 8.76 (m, IH), 8.31 (s, IH), 8.13 (s, 2H), 7.51 - 7.48 (m, 2H), 7.45 (d, J=8.2

Hz, IH), 6.96 (d, J=8.2 Hz, IH). LC-MS: (ES, m/z): | M i | 491.0

Example 327 l-(l-aminoisoqumoliii-4-yl)-N-(5-chloro-2-fluoiO-4-(2H-L2,3-triazol-2-yl)phenyl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 327

‘H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1 H), 9.45 (br s, 2 H), 8.73 (d,

J=8.16 Hz, 1 H), 8.56 (s, 1 H), 8.32 (s, 1 H), 8.27 (d, J=7.28 Hz, 1 H), 8.21 (s, 2 H), 7.99 8.06 (m, 1 H). 7.85 - 7.93 (m, 2 H), 7.09 (d, J=8.16 Hz. 1 H). LC-MS: (ES. m z): [M+1 f 517.0

Example 328 l-(l-aminoisoquin.olin-5-yl)-N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridiii-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 328

658

N

^!H NMR (400 MHz, METHANOL-d4) δ ppm 9.07 (s, l H), 8.91 (s, l H), 8.67 (d, J=8.60 Hz, l H), 8.42 (s, l H). 8.07 - 8.17 (m, 3 H), 7.93 (t. J=8.16 Hz, l H), 7.68 (br d. J=7.28 Hz, l H), 6.45 (d, J=6.84 Hz, 1 H). LC-MS: (ES. m/z): [M+l]⁺ 491.0

Example 329 l-(2-aminoquinolin-4-yl)-N-(5-cyano-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 329

‘H NMR (400 MHz, METHANOL-d4) δ ppm 9.07 (br s. I H), 8.90 (s, 1 H), 8.46 (s, 1 H), 8.37 (d. J=8.38 Hz, 1 H), 8.15 (br s, 2 H), 7.96 - 8.02 (m, 1 H), 7.90 (d, J=8.38 Hz, 1 H), 7.74 (t, J=7.83 Hz, 1 H), 6.99 (s, 1 H). LC-MS: (ES. m/z): [M+if 490.9

Example 330 l-( l-aminoisoquinolin-5-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 330

659

X NMR (400 MHz, METHANOL-d4) δ ppm 6.25 (d, J=6.17 Hz, l H), 7.65 - 7.70 (m, l H), 7.79 (d, J=6.l7 Hz, l H), 7.83 (d, J=7.50 Hz, l H), 8.04 (s, 2 H), 8.37 (s, l H), 8.42 (d, J=8.38 Hz, l H), 8.73 (d, J=2.20 Hz, 1 H), 8.81 (d, J=2.21 Hz, 1 H). LC-MS: (ES, 5 m/z): [M+l]⁺ 499.9

Example 331 l-(2-aminoqumolm-5-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 331

‘H NMR (400 MHz, DMSO-d6) δ ppm 7.16 (d, J=9.70 Hz, 1 H), 7.60 (d, J=9.48 Hz, 1 H), 7.69 (d. J=7.06 Hz, 1 H), 7.89 - 7.98 (m, 2 H), 8.17 (s, 2 H), 8.67 (s. 1 H), 8.70 (d, J=2.20 Hz, 1 H), 8.92 (d, J=2.20 Hz, 1 H), 11.46 (s, 1 H). LC-MS: (ES, m/z): [M+l] 499.9

660

Example 332 l-(2-aminoquinolin-5-yl)-N-(5-cyano-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 332

Ή NMR (400 MHz, DMSO-d6) δ ppm 7.14 - 7.21 (m, l H), 7.62 (d, J=9.70 Hz, 1 H), 7.67 - 7.74 (m, 1 H), 7.90 - 7.99 (m, 2 H), 8.30 (s, 2 H), 8.71 (s, 1 H), 8.93 (d, J=2.43 Hz, 1 H), 9.18 (d, J=2.21 Hz, 1 H), 11.61 (br s, 1 H). LC-MS: (ES, m/z): [M+lF 490.9

Example 333

1-(l-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-( 1 -methyl-1 H-pyrazol-3-yl )pyridin

3-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 333

‘H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s. 1 H), 9.54 (br s, 1 H), 8.72 (d, J=8.38 Hz, 1 H), 8.56 (s, 1 H), 8.30 (s, 1 H), 8.05 (s, 1 H), 8.01 (t, J=7.94 Hz, 1 H), 7.87 (t, J=7.72 Hz, 1 H), 7.76 (s, 1 H), 7.05 (br d, J=8.16 Hz, 1 H), 6.73 (s, 1 H), 3.90 (s, 3 H), 2.49 (br s. 3 H). LC-MS: (ES. m/z): [M+l]⁺ 526.9

Example 334

-( 1 -aminoisoquinolin-4-yl)-N-(2,5-dimethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 334

Ή NMR (400MHz, DMS0-d6) δ ppm 10.59 (s, IH), 9.69 (br s, 2H), 8.78 (d, J=8.2 Hz, IH), 8.62 (s. IH), 8.35 (s, IH), 8.13 (s, 2H), 8.08 - 8.02 (m. 2H), 7.91 (t, J=7.7 Hz, IH), 7.10 (d. J=8.4 Hz, IH), 2.50 (br s, 2H), 2.50 - 2.49 (m, IH), 2.23 (s, 3H). LC-MS:

(ES, m/z): IM1| 494.0

Example 335 l-(l-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-4-(2H-L2_?3-triazol-2-yl)phenyl)0 (trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 335 ’H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s. 1 H), 8.98 (br s, 2 H), 8.65 (d, J=8.38 Hz, 1 H), 8.56 (s, 1 H), 8.22 (s, 1 H), 8.15 (s, 2 H), 7.90 - 7.96 (m, 1 H), 7.86 (s, 1 H), 7.80 (t, J=7.39 Hz, 1 H), 7.66 (s, 1 H)„ 7.04 (br d, J=8.16 Hz, 1 H), 2.36 (s, 3 H). LCMS: (ES, m/z): [M 11 512.9

Example 336 l-(l-aminoisoquinolin-4-yl)-N-(5-chloro-2-methyl-6-( 1 H-pyrazol-l-yl)pyridin-3-yl)-5 (trifluoromethyl)- l H-pyrazole-4-carboxamide, Cpd 336 ^lH NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3 H), 6.55 (dd, J=2.43, 1.76 Hz, l H), 6.94 (d. J=8.38 Hz, l H). 7.50 (s, 2 H), 7.57 - 7.63 (m, l H), 7.69 - 7.75 (m, l H), 7.80 (d, J=l. 10 Hz, 1 H), 7.97 (s, 1 H). 8.26 (d, J=1.98 Hz, 1 H), 8.29 - 8.37 (m, 2 H), 8.46 (s, 1 5 H) 10.53 (brs, 1 H). LC-MS: (ES, m/z): [M+l]⁺ 513.1

Example 337 l-(l-ammoisoquinolin-4-yl)-N-(5-cyano-2-methyl-4-(2H-l,2,3-triazol-2-yl)phenyl)-5 (trifluoromethyl)-1 H-pyrazole-4-carboxamide. Cpd 337

NX ^lH NMR (400 MHz, DMSO-d6) δ ppm 10.50 (s. 1 H), 9.09 - 9.43 (m, 2 H), 8.67 (d, J=8.16 Hz, 1 H), 8.56 (s, 1 H), 8.22 - 8.30 (m, 1 H), 8.27 (s. 2 H), 8.14 (s, 1 H), 8.05 (s. 1 H), 7.95 - 8.01 (m, 1 H), 7.84 (t, J=7.61 Hz, 1 H), 7.05 (br d, J=8.38 Hz, 1 H), 2.47 (br s, 3 H). LC-MS: (ES, m/z): |\1+1 Γ 504.1

Example 338

-( I -ammoisoquinolin-4-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl )pyridin-3-yl)

5-(trifluoromethyl)-l H-pyrazole-4-carboxamide, Cpd 338

^lH NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s, 1 H) 9.32 (br s, 2 H), 8.70 - 8.75 (m, 1 H), 8.66 (d, >8.60 Hz, 2 H), 8.32 (s, 2 H), 8.30 (s, 1 H). 7.96 - 8.02 (m, 1 H), 7.85 (t, >7.61 Hz, 1 H), 7.07 (d, >8.16 Hz, 1 H), 2.68 (s, 3 H). LC-MS: (ES, m/z): pi H

505.1

Example 339 l-(l-aminoisoquinolin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yI)-lHpyrazole-4-carboxamide, Cpd 339

Ή NMR (400 MHz, DMSO-d6) δ ppm 7.05 (d, >7.94 Hz, 1 H), 7.84 - 7.91 (m, 1

H), 7.97 - 8.03 (m, 2 H), 8.28 (d, >1.76 Hz, 1 H), 8.31 (s, 1 H), 8.63 (s, 1 H), 8.66 - 8.74 (m, 2 H), 9.37 (br s, 2 H), 11.42 (s, 1 H). LC-MS: (ES, m/z): [M+l]* 467.1

Example 377 l-(l-aminoisoquinolin-4-yl)-N-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide. Cpd 377

664 ‘H NMR (400 MHz, DMSO-d6) δ ppm I l.3l (s, l H), 9.23 - 10.37 (ni, 2 H), 9.07 (d. J=1.98 Hz. I H), 8.77 (d. J=8.38 Hz, l H). 8.66 (s, 1 H), 8.58 (d, J=2.21 Hz, 1 H), 8.35 (s, 1 H), 7.97 - 8.05 (m, 1 H), 7.83 - 7.91 (m, 1 H). 7.02 (d, J=7.94 Hz. 1 H), 2.60 (d, J=1.54 Hz, 3 H). LC-MS: (ES, m/z): [M+1 ]⁺ 480.9

Example 340

-( 1 -aminoisoquinolin-4-yl)-N-(2-cyanopyridin-4-yl)-5-( trifluoromethyl)-1 H-pyrazole-4carboxamide, Cpd 340

’H NMR (400 MHz, DMSO-d6) δ ppm 7.06 (d, J=8.16 Hz, 1 H), 7.86 - 7.92 (m, 1

H), 7.99 - 8.08 (m, 2 H), 8.35 (d, J=3.53 Hz, 2 H), 8.66 - 8.72 (m, 2 H), 8.76 (br d, J=8.60 Hz. 1 H), 9.64 (br s, 2 H), 11.59 (s, 1 H). LC-MS: (ES, m/z): [ Ni 11 424.0

Example 341 l-(l-aminoisoquiiiolin-4-yl)-N-(5-chloro-2-methyl-6-(4-methyl-2H-l,2,3-triazol-2yl)pyridin-3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 341

‘H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 2.53 (s, 3 H), 6.97 (br d, J=8.16 Hz, 1 H), 7.56 - 7.73 (m, 1 H), 7.81 (br s, 1 H), 7.93 (s, 1 H), 8.08 (br s, 1 H), 8.00 20 8.10 (m. 1 H), 8.11 - 8.26 (m. 1 H), 8.38 (s, 1 H), 8.46 (br s, 1 H), 8.51 (s, 1 H), 10.63 (s, 1

H). LC-MS: (ES, m/z): [M+l]⁺ 527.9

665

Example 342 l-(l-ammoisoquinolm-4-yl)-5-(trifluoiOmethyl)-N-(5-(trifluoromethyl)pyridm-3-yl)-lHpyrazole-4-carboxamide, Cpd 342

'H NMR (400 MHz, DMSO-d6) δ ppm 6.92 (d, >8.16 Hz, l H), 7.51 (s. 2 H), 7.56 - 7.65 (m, l H), 7.67 - 7.78 (m, l H), 7.98 (s, l H), 8.41 (br s, l H), 8.48 (s, l H), 8.61 (s, l H), 8.76 (s, l H), 9.13 (s, l H), 11.14 (br s, l H). LC-MS: (ES, m/z): i M - i | 466.9

Example 343 l-(l-aminoisoquinolin-4-yl)-N-(5-bromo-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)5-( trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 343

^lH NMR (400 MHz, DMSO-d6) δ ppm 10.71 (s, 1 H), 9.36 (br s, 2 H), 8.68 (d, >8.38 Hz, 1 H), 8.58 (s, 1 H), 8.50 (s, 1 H), 8.28 (s, 1 H), 8.11 - 8.18 (m, 2 H), 7.94 - 8.02 (m, 1 H), 7.84 (t, >7.72 Hz, 1 H), 7.04 (d, >8.38 Hz, 1 H), 2.51 (s, 3 H). LC-MS: (ES, m/z): [M+l]* 557.9

Foilowing the procedures described in Example 112 or 113, above, selecting and substituting the appropriate reagents, starting materials, and purification methods, and

666 adjusting reaction températures, times and other variables or parameters. as needed or désirable, as would be readily recognized by those skilled in the art, the following compounds were prepared:

Example 344

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-oxo-L2-dihydroquinoIm-5-yI)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 344

‘H NMR (400 MHz, DMSO-d6) δ ppm 6.61 (d, J=9.70 Hz, l H), 7.08 (d, >9.70

Hz. I H), 7.38 (d. >7.72 Hz, i H), 7.55 (d, >8.16 Hz, 1 H), 7.64 - 7.73 (m, 1 H), 8.17 (s, 2 H), 8.53 (s, 1 H), 8.65 (s, 1 H), 8.83 (s. 1 H), 11.26 (s, 1 H), 12.18 (br s, 1 H). LC-MS: (ES, m/z): [M+11 501.1

Example 345

N-(5-chloro-6-methoxypyridin-3-yl )-1-(1 -oxo-1,2-dihydroisoquinolm-5-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 345

‘H NMR (400 MHz, DMSO-d6) δ ppm 3.94 (s, 3 H), 5.65 (d, >7.28 Hz. 1 H), 7.25 - 7.32 (m, 1 H), 7.67 (t, >7.83 Hz, 1 H), 7.90 - 7.96 (m, 1 H), 8.27 (d, >2.43 Hz, 1 H), 8.38 20 8.47 (m, 3 H), 10.74 (s, 1 H), 11.62 (br s, 1 H). LC-MS: (ES, m/z): [M+l]⁺ 463.9

667

Example 346

N-(5-cyanopyridin-3-yl)-1-( l -oxo-L2-dihydroisoquinolm-5-yl)-5-( trifluoromethyl)-1 Hpyrazole-4-carboxamide, Cpd 346

‘HNMR (400MHz, DMSO-d6) δ ppm 11.64 (br d, >5.1 Hz, IH), U.3l(s, IH),

9.14 (d. >2.4 Hz, IH), 8.79 (d, J=l.5 Hz. IH), 8.68 - 8.63 (m, IH). 8.60 (s, IH). 8.43 (d, J=7.9 Hz. IH), 7.94 (d. >7.3 Hz, IH), 7.67 (t. >7.8 Hz, IH), 7.32 - 7.25 (m. IH), 5.66 (d. >7.3 Hz, IH). LC-MS: (ES, m/z): [M+l]” 425.1

Example 347

N-(2-methylpyridin-4-yl)-1 -( l -oxo-1,2-dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-1Hpyrazolc-4-carboxamide, Cpd 347

Ή NMR (400 MHz, DMSO-d6) δ ppm 2.69 (s, 3 H), 5.66 (d, >7.50 Hz, l H), 7.25 15 - 7.31 (m. 1 H), 7.67 (t, >7.94 Hz, 1 H), 7.94 (d, >7.50 Hz, 1 H), 8.09 (dd, >6.73, 2.09

Hz, 1 H), 8.21 (d, >1.76 Hz, 1 H), 8.43 (d, >7.94 Hz, 1 H), 8.63 (d, >6.84 Hz, 1 H), 8.71 (s, 1 H>, 11.65 (br d, >5.51 Hz, 1 H), 11.98 (s, 1 H). LC-MS: (ES, m/z): [M+l]” 414.3

Example 348

N-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)-l-( l-oxo-l,2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 348

NMR (400 MHz, DMSO-d6) δ ppm l l.6l (br d, J=5.51 Hz. 1 H), 1 ! .05 (s, 1 H). 8.99 (d, J=1.98 Hz, 1 H), 8.50 (s, 2 H), 8.40 (d, J=7.94 Hz. 1 H), 7.91 (dd. J=7.61. 0.99 Hz, 1 H), 7.64 (t, J=7.83 Hz, 1 H), 7.26 (dd, J=7.28, 5.95 Hz, 1 H), 5.62 (d, J=7.28 Hz, 1 H), 5 2.59 (d, J=1.54 Hz, 3 H). LC-MS: (ES, m/z): [M+l]' 481.9

Example 349 l-(l-oxoT,2-dihydroisoquinolin-5-yl)-N-(pyridm-4-yl)-5-(trifh.ioromethyl)-lH-pyrazole

4-carboxamide, Cpd 349 ‘H NMR (400 MHz, DMSO-d6) δ ppm 5.66 (d, J=7.28 Hz, 1 H), 7.29 (br d, J=6.84 Hz, 1 H), 7.63 - 7.75 (m, 3H), 7.93 (d, J=6.84 Hz, 1 H), 8.44 (d, J=7.94 Hz, 1 H), 8.47 8.54 (m, 3 H). 10.93 (br s, 1 H). 11.64 (br s, 1 H). LC-MS: (ES, m/z): [M+l]' 399.9

Example 350

N-(2-cyclopropylpyridin-4-yl)-l-(1-oxo-1,2-dihydroisoqu inolin-5-y 1)-5-( trifluoromethyl)1 H-pyrazole-4-carboxamide, Cpd 350

669

Ή NMR (400 MHz, DMSO-d6) δ ppm l.04 - l. 16 (m, 2 H). 1.27 - 1.37 (m, 2 H), 2.38 (br s. I H), 5.63 (d, J=7.28 Hz, l H). 7.27 (dd. J=7.28, 6.]7 Hz, l H), 7.65 (t. J=7.94 Hz, l H), 7.87 - 7.97 (m, 2 H), 8.03 (br s, l H), 8.42 (d, J=7.94 Hz, l H). 8.53 (d, J=6.6l

Hz, l H), 8.67 (brs, l H), H.63 (br d, J=5.5l Hz, 1 H), 11.83 (brs, 1 H). LC-MS: (ES, m/z): IM · 11 440.2

Example 351

3-chloro-N,N-dimethyl-5-(l-(l-oxo-L2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH10 pyrazole-4-ca±oxamido)picolinamide, Cpd 351

‘H NMR (400MHz, DMSO-d6) δ ppm 11.64 (br d, J=5.3 Hz, IH), 11.13 (s, IH), 8.82 (d, J=1.8 Hz, IH), 8.52 (s, IH), 8.43 (dd. J=2.8, 4.8 Hz, 2H), 7.94 (d. J=7.5 Hz, IH), 7.67 (t, J=7.9 Hz, IH), 7.29 (t, J=6.5 Hz, IH), 5.65 (d, J=7.3 Hz, IH), 3.02 (s, 3H), 2.78 (s, 15 3H). LC-MS: (ES, m/z): |M 1 | 505.1

Example 352

3-chloro-N-methyl-5-(l-(T-oxo-L2-dihydroisoquinolin-5-yl)-5-(trifluorornethyl)-lHpyrazole-4-carboxamido)picolinamide, Cpd 352

670 ‘H NMR (400MHz, DMSO-d6) δ ppm 11.64 (br d, >5.7 Hz, IH), 11.24 (s, IH), 8.86 (d. >2.0 Hz, IH). 8.61 - 8.52 (m, 2H), 8.47 - 8.38 (m, 2H), 7.94 (d, J=6.6 Hz, IH), 7.67 (t, >7.8 Hz, IH), 7.35 - 7.23 (m, IH), 5.66 (d, >7.3 Hz, IH), 2.78 (d, >4.9 Hz, 3H). LC-MS: (ES. m/z): [M+l]' 490.9

Example 428

N-(5-cyano-6-methoxypyridin-3-yl)-l -(l-oxo-L2-dihydroisoquinolin-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 428

‘H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (br s, 1 H), 10.85 (br s, 1 H), 8.65 (d, >1.98 Hz, 1 H), 8.49 (d, >1.98 Hz. 1 H), 8.44 (s, 1 H), 8.40 (d, >8.16 Hz, 1 H), 7.90 (d, >7.72 Hz, 1 H), 7.63 (t, >7.83 Hz, 1 H), 7.25 (d, >7.50 Hz. 1 H), 5.61 (d, >7.28 Hz, 1 H), 3.97 (s, 3 H). LC-MS: (ES, m/z): [M+l]' 455.0

Example 446

N-(5-cyano-2-methyl-4-(2H-L2,3-triazol-2-yl)phenyl)-l-( 1-oxo-1,2-dihydroisoquinolin-5yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 446

N

°0 J

HN—^J ‘H NMR (400 MHz, DMSO-d6) δ ppm 2.48 (s, 3 H), 5.69 (d, >7.06 Hz, 1 H), 7.30 (dd, >7.28, 6.17 Hz, 1 H), 7.68 (t, >7.83 Hz, 1 H), 7.94 (d, >7.72 Hz, l H), 8.07 (s, 1 H),

671

8.17 (s, 1 H), 8.29 (s, 2 H), 8.45 (d, J=7.72 Hz, 1 H), 8.51 (s, 1 H), 10.44 (s, 1 H). 11.63 (br d, J=6.17 Hz, 1 H). LC-MS: (ES, m/z): [M+l]’ 504.9

Example 353

N-(5-chloropyridin-3-yl)-1 -( 1 -oxo-1,2-dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-1Hpyrazole-4-carboxamide, Cpd 3S3

Ή NMR (400 MHz, DMSO-d6) δ ppm 5.63 (d. J=7.50 Hz, 1 H), 7.27 (br d. J=7.50 Hz, 1 H). 7.65 (t. J=7.83 Hz, 1 H). 7.89 - 7.94 (m, 1 H), 8.34 (t. J=2.21 Hz, 1 H). 8.38 8.43 (m, 2 H), 8.47 (s, 1 H), 8.77 (d, J=2.21 Hz. 1 H), 10.96 (br s, 1 H), 11.61 (br s, 1 H). LC-MS: (ES, m/z): |M+1 | 433.9

Example 354

N-(6-cyaiio-5-(trifluoromethyl)pyridin-3-yl)-l-(l-oxo-L2-dihydroisoquinolm-5-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 354

’H NMR (400 MHz, DMSO-d6) δ ppm 11.61 (br d, J=5.51 Hz, l H), 11.57 (s, 1 H), 9.24 (d, J=L76 Hz, 1 H), 8.78 (d, J=L98 Hz, 1 H), 8.56 (s, 1 H), 8.41 (d, J=7.94 Hz, 1 H), 7.92 (d. J=6.84 Hz, 1 H), 7.64 (t, J=7.83 Hz, 1 H). 7.26 (t, J=6.50 Hz, 1 H), 5.61 (d, J=7.28 Hz, 1 H). LC-MS: (ES, m/z): [M+l]⁺ 492.9

672

Example 355 methyl 3-chloro-5-( l-( 1-oxo-l,2-dihydroisoqumolin-5-yl)-5-(trifluoromethyl)- 1Hpyrazole-4-carboxamido)picolinate, Cpd 355

‘H NMR (400MHz, DMSO-d6) δ ppm 11.64 (br d. J=5.3 Hz, IH), 11.27 (s, IH), 8.88 (d, J=2.0 Hz, 1 H), 8.56 (s, IH), 8.52 (d, J=2.0 Hz, IH), 8.44 (d, J=8.() Hz, IH), 7.95 (d, J=7.3 Hz, IH), 7.67 (t, J=7.9 Hz. IH), 7.29 (t, J=6.5 Hz. IH), 5.65 (d. J=7.3 Hz, IH), 3.90 (s, 3H). LC-MS: (ES, m/z): [M+lf 491.9

Example 356

N-(2-cyanopyridin-4-y 1)-1 -( 1 -oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide, Cpd 356

U NMR (400MHz, DMSO-d6) δ ppm 11.65 (br d, J=4.8 Hz, IH), 11.44 (s, IH), 8.67 (d, J=5.5 Hz, IH), 8.59 (s, IH), 8.44 (d, J=7.8 Hz, IH). 8.31 (d,J=L8Hz. IH), 8.01 (dd. J=2.0, 5.5 Hz, IH), 7.94 (d, J=7.5 Hz, IH), 7.67 (t, J=7.9 Hz, IH), 7.29 (br t, J=6.4 Hz, IH), 5.66 (d, J=7.3 Hz, IH). LC-MS: (ES, m/z): [M+l]' 425.1

Example 357

N-(2-( 2-methoxyethoxy)-5-( trifluoromethyl)pyridin-3 -yl )-1 -( 1 -oxo-1.2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 357

673

’H NMR (400MHz, DMSO-d6) δ ppm 11.64 (br d, J=5.5 Hz. IH), 10.26 (s, IH), 8.58 (s, IH), 8.46 - 8.39 (m, 3H), 7.93 (d, J=7.5 Hz, IH), 7.67 (t, J=7.9 Hz, IH), 7.29 (t, J=6.5 Hz, IH), 5.72 (br d, J=7.3 Hz, IH), 4.63 - 4.55 (m, 2H), 3.79 - 3.70 (m, 2H), 3.30 (s, 5 3H). LC-MS: (ES, m/z): Nil 541.9

Example 358

N-(5-chloro-2-methyl-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(2-oxo-l,2dihydroquinolin-4-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 358

Ή NMR (400 MHz, DMSO-d6) δ ppm 12.37 ( I H, br s), 10.65 ( 1 H, s), 8.59 ( 1 H, s), 8.40 (1 H. s). 8.16 (2 H, s), 7.57 - 7.69 (1 H, m). 7.45 (1 H, d, J=8.16 Hz), 7.21 (1 H, t, J=7.72 Hz), 6.92 (1 H. s), 6.85 (1 H, d, J=7.94 Hz), 2.53 (3 H, s). LC-MS: (ES, m/z): | M U | 514.9

Example 359

N-(5-chloro-2-methyl-6-(4-methyl-2H-1,2,3-triazoI-2-yl)pyridin-3-yl)-l-( 1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 359

674

^lH NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3 H), 2.51 (s, 3 H), 5.65 (d, >7.50 Hz. I H), 7.27 (t, >6.62 Hz. I H), 7.65 (t, J=7.94 Hz. I H), 7.86 - 7.96 (m. 2 H). 8.34 8.45 (m, 2 H), 8.51 (s, l H), 10.58 (s, 1 H), 11.61 (br d, J=4.85 Hz, 1 H). LC-MS: (ES, m/z): [M+l]* 528.9

Example 360

N-(2-methoxypyridin-4-yl)-l-(l-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-lHpyrazole-4-carboxamide. Cpd 360

Ή NMR (400 MHz, DMSO-d6) δ ppm 3.89 (s, 3 H), 5.63 (d, J=7.28 Hz, 1 H), 7.21 - 7.30 (m, 1 H), 7.36 - 7.44 (m, 2 H), 7.63 (t, >7.83 Hz, 1 H), 7.90 (d, >7.50 Hz, 1 H), 8.13 (d, >5.95 Hz, 1 H), 8.40 (d, >7.94 Hz, 1 H), 8.55 (s, 1 H), 11.22 (br s, 1 H), 11.62 (br d, >5.29 Hz, 1 H). LC-MS: (ES, m/z): [M+l]* 429.9

Example 361

N-(2-morpholinopyridin-4-yl)-l-( 1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)1 H-pyrazole-4-carboxamide, Cpd 361

Ή NMR (400 MHz, DMSO-d6) δ ppm 3.59 - 3.67 (m. 4 H). 3.75 - 3.83 (m, 4 H), 5.67 (d, J=7.28 Hz, 1 H), 7.30 (dd, J=7.28, 5.95 Hz, 1 H), 7.42 (dd, J=6.95, 1.65 Hz, 1 H), 7.68 (t, J=7.94 Hz, 1 H), 7.86 (d, J=1.54 Hz, 1 H), 7.95 (dd, J=7.50, 1.10 Hz, 1 H), 8.07 (d, 5 J=6.84 Hz, 1 H), 8.45 (d, J=7.94 Hz, 1 H), 8.73 (s, 1 H), 11.63 - 11.74 (m, 2 H). LC-MS:

(ES, m/z): [M 1| 485.0

Example 362

N-(5-chloro-2-methyl-6-(4-methyl-1 H-1,2,3-triazol-1-yl)pyridm-3-yl)-1-( 1-oxo-1,2dihydroisoquinolm-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 362 ‘H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3 H), 2.59 (s, 3 H), 5.70 (d, J=7.53 Hz, 1 H), 7.31 (t, J=6.65 Hz, 1 H), 7.69 (t, J=7.78 Hz, 1 H), 7.76 (s, 1 H), 7.95 (d, J=7.78 Hz, 1 H), 8.45 (d, J=8.78 Hz, 1 H), 8.53 (d, J=1L8O Hz, 2 H). 10.64 (s, 1 H), 11.65 (br d, 15 J=5.27 Hz, 1 H). LC-MS: (ES, m/z): [M+l]⁺ 528.9

Example 363

N-(5-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(1-oxo- l,2-dihydroisoquinolin-5-yl) (trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 363

676

X NMR (400 MHz, DMSO-d6) δ ppm 5.68 (d, J=7.28 Hz, l H), 7.31 (dd, J=7.28, 5.95 Hz, l H), 7.68 (t, J=7.83 Hz, l H), 7.96 (d, J=7.50 Hz, 1 H), 8.25 (s, 2 H), 8.45 (d, J=7.94 Hz, 1 H), 8.57 (s, 1 H), 8.94 (d, J=2.21 Hz, 1 H), 8.99 (t, J=2.09 Hz, 1 H), 9.04 (d, 5 J=2.20 Hz, 1 H)„ 11.15 (s, 1 H), 11.65 (brd, J=5.51 Hz, 1 H). LC-MS: (ES, m/z): |M H

466.9

Example 364 l-(thieno[2.3-c]pyridin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-lH10 pyrazole-4-carboxamide, Cpd 364

A. Methyl 4-bromothieno [2,3-c]pyridine-2-carboxylate, 364a

To the 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 h. Then the mixture was warmed to 25 °C and stirred for another 1 h and CS2CO3 (18.45 g, 56.63 mmol) was added to the mixture. Then the mixture was stirred at rt for 16 h. The reaction mixture was fïltered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow⁷ solid. The crude product was

677 purified by FCC (petroleum ether/ ethyl acetate=lOO:O to 80:20). The solvents were concentrated to get the crude products as a pale yellow solid (15 g, 97.3%).

B. 4-bromothieno[2,3-c]pyridine-2-carboxylic acid, 364b

Br nAsA) ,364b

Lithium hydroxide (2.640 g, 1 10.246 mmol) was added to a solution of methyl 4bromothieno[2,3-c]pyridme-2-carboxylate (15 g, 55.123 mmol) in THF/FhOLl (20 mL).The mixture was reacted at room température for 4 h. The solvent was concentrated under reduced pressure and 30 mL H2O was added to the mixture. The mixture was acidized by 1 M hydrochloric to pH=5 and the solid was filtered, washed with H2O (30 mL x 2). The solid was dried under reduced pressure to afford product as a white solid (12 g, 84.3%).

C. 4-bromothieno[2,3-c]pyridine, 364c

Br cpd 364_c

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 h. The mixture was purified by FCC (petroleum ether/ ethyl acetate=100;0 to 0:100). The solvents were concentrated to afford the crude product as a pale gray solid (8 g, 81.0 %).

D. 4-hydrazinylthieno[2,3-c]pyridine, 364d ,NH₂HN ²

Q Z > y λ ]

S , 364d

678

Palladium(ll)(pi-cinnamyl) chloride dimer (363.0 mg, 0.70 mmol) and 4-(2(di((3S,5S,7S)-adamantan-l-yl)phosphino)phenyl)morpholine (649.7 mg, 1.40 mmol) was added to dioxane ( 15 mL), and the reaction, was immediately evacuated with N₂. The resulting solution was stirred at rt under N₂ for K) min. The reaction vessel was then charged with sodium 2-methylpropan-2-olate (2.69 g, 28.03 mmol) and 4bromothieno[2,3-c]pyridine (3 g, 14.01 mmol). The vessel was sealed and evacuated with N₂. The resulting reaction was stirred at rt for 5 min, then treated with hydrazine hydrate (701.5 mg, 4.01 mmol) via syringe. The reaction was stirred at 50 °C under N₂ for l .5 h.

The mixture was filtered, and the fiitrate concentrated under reduced pressure to afford the crude product as a brown oil (8 g).

E. ethyl l-(thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-lH-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). 4hydrazinylthieno[2,3-c]pyridine (8 g, 48.421 mmol) and éthanol (20 mL) was stirred at 80 °C for 2 h. The résultant solution was concentrated to dryness under reduced pressure to afford the crude product, which was purified by FCC (petroleum ether: ethyl acetate = 100/0 to 70/30) to afford the title compound (6 g, 35.2%) as a yellow solid. LCMS (ESI) m/z M+l : 342.2.

679

F. l-(thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid,

364f

Lithium hydroxide (679.7 mg, 28.38 mmol) was added to a solution of ethyl l (thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-]H-pyrazole-4-carboxylate (5 g, 14.19 mmol) in THF/ H₂O=L1 (20 mL). The mixture was stirred at room température for 4 h. The solvent was concentrated under reduced pressure and 30 mL H₂O was added to the mixture. The solution was adjusted to pH 5 by the addition of IM hydrochloric acid, and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine, dried over anhydrous MgSO₄, filtered, and the filtrâtes concentrated under reduced pressure to afford the product as a white solid. (4.6 g, 97.1%).

G. l-(thieno[2,3-c]pyridin-4-yl )-5-( trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4yl)-lH-pyrazole-4-carboxamide, Cpd 364

-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-( trifluoromethyl)-1 H-pyrazole-4carboxylic acid (2.25 g, 6.74 mmol), 2-(trifluoromethyl)pyridm-4-amine (1.092 g, 6.74 mmol), pyridine (2.72 mL, 33.70 mmol) were dissoived in CH₂C1₂ (10 mL), and phosphores oxychloride (2.47 mL, 26.96 mmol) was added. The mixture was stirred at 25 °C for 2 h. Sat.NaHCOa (30 mL) was added and the reaction mixture extracted with

CH₂C1₂ (40 mL x 2). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and the filtrate concentrated to dryness under reduced pressure to afford the crude product, which was purified by préparative HPLC (35% to 60% (v/v) CH?CN and H;O with 0.05% TFA). The pure fractions were collected and the mixture was adjusted to pH > 7 by the addition of aq.NaHCCh. The organic solvent was concentrated under reduced pressure until a white solid precipitated from solution. The white solid was collected and dried under reduced pressure to afford the product ( l .6 g, 51.9%). LCMS (ESI) m/z M+L 457.9. Ή NMR (400 MHz, DMSO-A) 5 ppm 7.15 (l H, d, 7=5.73 Hz), 7.96 (l H, dd, 7=5.40, 1.87 Hz), 8.22 (l H, d,7=1.76 Hz), 8.34(1 H, d,7=5.51 Hz), 8.56 (1 H, s), 8.65 (1 H, s), 8.69(1 H, d,7=5.73 Hz), 9.52(1 H, s), 11.26(1 H, brs).

Example 447

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(thieno[2.3-c]pyridin-4-yl)-5(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 447

Following the procedure described in Example 364, above, selecting and substituting the appropriate reagents, starting materials, and purification methods, and adjusting reaction températures, times and other variables or parameters, as needed or désirable, as would be readily recognized by those skilled in the art, Compound 447 was prepared. LCMS (ESI): mass calcd. for Cwl LCU'AsOS 490.1 m/z found 491.2 [M+H] . Ή NMR (400 MHz. DMSO-A) δ ppm 7.18 (d, 7=5.3 Hz. 1 H) 8.16 (s. 2 H) 8.35 (d, 7=5.7

Hz, 1 H) 8.51 (s, 1 H) 8.66 (s, 1 H) 8.69 (d, 7=2.4 Hz, 1 H) 8.71 - 8.75 (m, 1 H) 9.52 (s. 1 H)

Example 365 and Example 366

N-(5-chloro-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(tetrahydrofuran-2-yr)isoquinolin25 4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 365

681

] -( 1,5-bis(tetrahydrofuran-2-yl)isoqumolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazoI-2yl)pyridin-3-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 366

A mixture of THF (1800 mg, 25 mmol), CH?CN (2.5 mL), H_;O (2.5 mL), N-(5chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(isoquinolin-4-yl)-5-( trifluoromethyl)-! Hpyrazole-4-carboxamide (242.5 mg, 0.5 mmol), TFA (0.038 mL, 0.5 mmol) and ammonium persulfate (228 mg, 1 mmol) was weighted in a 10 mL vial.

(IR[DF(CF?)PPY]2(DTBPY))PF6 (11.2 mg, 0.01 mmol) was successively added. The reaction mixture was degassed for 15 min and the vessel sealed. The reaction was stirred under blue LED irradiation at rt for 1 h. The reaction mixture was poured into water and extracted with DCM. The organic layer was dried over MgSO₄. fïltered and the filtrate was concentrated to dryness. The residue was purified via Prep HPLC (Stationary phase:

RP XBridge Prep C18 OBD- 5 pm. 30x 250 mm, Mobile phase: 0.25% NH4HCO3 solution in water. CH3CN) to afford Cpd 365 (44 mg, 16%) and compound 366 (46 mg, 15%).

Cpd 365. LCMS (ESI): mass calcd. for C25H18CIF3NSO2 554.1, m/z found 555.1 [M+H] 7 Ή NMR (400 MHz, CHLOROFORM-J) δ ppm 2.08 - 2.25 (m, 2 H), 2.49 (br s,

2 H), 4.01 -4.12 (m, 1 H), 4.12 - 4.26 (m, 1 H). 5.79 (t. J=7.1 Hz. 1 H), 7.21 - 7.26 (m, 1

682

H), 7.65 - 7.77 (m, 2 H), 7.93 (s, 2 H), 8.23 (s. I H), 8.44 (br s, l H), 8.53 (s, l H), 8.62 (d, J=2A Hz, l H), 8.75 (d, ./=2.4 Hz, l H), 9.22 (s, l H).

Cpd 366. LCMS (ESI): mass calcd. for C .H.'CIRMO· 624.2, m/z found 625.2 iM H|'. ‘H NMR (400 MHz, CHLOROFORM-ti) δ ppm 1.74 - 1.84 (m. I H), l.9l - 2.07 5 (m, 2 H). 2.07 - 2.25 (m, 2 H), 2.34 - 2.44 (m, l H), 2.44 - 2.62 (m, 2 H). 3.92 - 4.00 (m, l

H), 4.02 - 4.11 (m, 2 H), 4.19 (br s, l H), 5.01 (q, ./=6.5 Hz, l H), 5.77 (br t, J=6.9 Hz, l H), 7.21 (d, J=6.9 Hz, l H), 7.64 (t, <7=8.0 Hz, l H), 7.94 (s, 2 H), 8.22 (s, l H), 8.43 (br s, l H), 8.52 (s, l H), 8.54 (d, <7=2.4 Hz, l H), 8.75 (d, J=2.Q Hz, l H), 8.81 (br s, l H).

Following the procedure described in Example 365, above, selecting and substituting the appropriate reagents, starting materials. and purification methods, and adjusting reaction températures, times and other variables or parameters, as needed or désirable, as would be readily recognized by those skilled in the art, the following compounds were prepared.

Example 367

1-(1-(1,4-dioxan-2-yl)isoqumoliii-4-yl)-N-(5-chloro-6-(2H-l,2,3-tnazol-2-yl)pyndin-3-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 367

LCMS (ESI): mass calcd. for CîsHisCIFjNsO? 570.1, m/z found 571.1 [M+H] . H NMR (400 MHz, DMSO-Λ) δ ppm 3.70 (td. J=11.6, 2.8 Hz, 1 H), 3.8? (dd, J=11.8, 2.0 Hz. 1 H). 3.92 (dd, J=11.6. 2.2 Hz, 1 H), 4.09 (td, .7=11.5, 2.6 Hz, 1 H), 4.21 (d. <7-6.1 Hz, 2 H), 5.44 - 5.52 (m, 1 H) 7.27 (d, <7=8.5 Hz, 1 H), 7.84 - 7.91 (m, 1 H).7.92 - 7.99 (m, 1 H), 8.19 (s, 2 H), 8.60 - 8.67 (m, 2 H), 8.69 (d,<7=2.0 Hz, 1 H), 8.76 (s, 1 H), 8.86 (d, <7=2.0

Hz, 1 H), 11.29 (br s. 1 H).

683

Example 368

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(l-ethoxyethyl)isoquinoIin-4-yl)5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 368

LCMS (ESI): mass calcd. for C25H20CIF3N8O2 556.1 m / found 557.2 \EH| . 'H NMR (400 MHz, DMSO-U) δ ppm 1.12 (t, 7=6.9 Hz, 3 H), 1.66 (d, 7=6.5 Hz, 3 H), 3.36 3.47 (m, 1 H), 3.48 - 3.67 (m, 1 H), 5.34 (q, 7=6.5 Hz, 1 H), 7.27 (d, 7=8.5 Hz, 1 H), 7.82 7.89 (m, 1 H), 7.90 - 7.98 (m, 1 H), 8.19 (s, 2 H), 8.63 (s. 1 H), 8.70 (d, 7=2.4 Hz, 1 H). 8.74 (s. 1 H), 8.80 (d, 7=8.5 Hz, 1 H), 8.86 (d, 7=2.0 Hz, 1 H). 11.36(brs, 1 H).

Example 369

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridm-3-yD-1 -( l-(5-oxopyrrolidin-2-yl)isoquinolin4-yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxamide. Cpd 369

LCMS (ESI): mass calcd. for C25H17CIF3N9O2 567.1 m/z found 568.1 [M+H] ^:. Ή

NMR (400 MHz. DMSO-7₆) δ ppm 2.09 (br d, 7= 13.8 Hz, 1 H), 2.32 (br s, 2 H), 2.65 -

2.86 (m, 1 H), 5.82 (dd, 7=8.3, 3.9 Hz, 1 H), 7.28 (d, 7=8.1 Hz, 1 H), 7.89 (td, 7=7.6, 1.0 Hz. 1 H), 7.86 - 7.92 (m. 1 H). 7.93 - 7.99 (m, 1 H), 7.93 - 8.00 (m, 1 H), 8.08 (s. 1 H), 8.19 (s, 2 H), 8.56 (d. 7=8.5 Hz, 1 H), 8.64 (s. 1 H), 8.69 (d, 7=2.4 Hz, 1 H), 8.78 (s, 1 H).

8.88 (d, 7=2.4 Hz, 1 H), i 1.32 (br s, 1 H).

684

Example 370

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(4-oxotetrahydroftiran-2 yl)isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide. Cpd 370

LCMS (ESI): mass calcd. for C25H16CIF5N8O3 568.1 m/z found 569.1[M+H] . *H NMR (400 MHz, DMSO-Λ) δ ppm 2.96 - 3.08 (m, 1 H), 4.17 (s, 1 H), 4.07 (br s, 1 H), 4.13 (s, 1 H), 6.50 (s, 1 H), 7.30 (d, 7=8.1 Hz, 1 H), 7.90 - 7.95 (m, 1 H), 7.98 (dd, 7=8.1, 1.2 Hz, 1 H), 8.19 (s, 2 H), 8.64 (s, 1 H), 8.68 (d, 7=2.0 Hz, 1 H), 8.70 (s, 1 H), 8.80 (s, 1

H), 8.87 (d, 7=2.0 Hz, 1 H) 11.29 (s, 1 H).

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)-lH-pyrazole-4-carboxamide, Cpd 371

LCMS (ESI): mass calcd. for C23H16CIF3N8O2 528.1 m/z found 529.2 NUI ‘H NMR (400 MHz, DMSO-Λ) δ ppm 1.64 (d, 7=6.5 Hz, 3 H), 5.61 (br s, 1 H), 5.66 - 5.74 (m, 1 H),5.69 (br d, .7= 1 LO Hz, 1 H), 7.24 (d,.7=8.1 Hz, 1 H), 7.81 - 7.87 (m, 1 H),7.897.94 (m, 1 H), 8.19 (s, 2 H), 8.61 (s, 1 H), 8.68 (d, .7=2,0 Hz, 1 H), 8.72 (s, 1 H), 8.77 (br s, 20 1 H), 8.86 (d, 7=2.0 Hz, 1 H). 11.30 (br s, 1 H).

685

Example 372

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(2-(tetrahydrofuran-2-yI)quinolin-5yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 372

LCMS (ESI): mass calcd. for CjsHisCIFjNsO? 554.1 m/z found 555.2[M+H] . ’H

NMR (400 MHz, DMSO-X) δ ppm 1.92 - 2.14 (m, 2 H), 2.41 - 2.49 (m, 1 H), 3.60 (spt, ./=6.1 Hz, IH), 3.87 - 3.99 (m, 1 H), 3.99 - 4.15 (m, 1 H), 5.06 - 5.19 (m, 1 H), 7.63 (d, ./=9.0 Hz. 1 H), 7.72 - 7.78 (m, 1 H), 7.85 - 7.90 (m, 1 H), 7.92 - 7.99 (m, 1 H), 8.19 (s. 2 H), 8.27 (d, J=8.1 Hz, 1 H), 8.59 (s. 1 H), 8.68 (d, J=2A Hz, 1 H). 8.86 (d, J=2A Hz, 1 H),

1 1.27 (br s, 1 H).

Example 373

N-(5-chloro-6-( 2H-L 2,3-triazol-2-yl)pyndin-3-yl)-1-(1-( (Nmethylformamido)methyl)isoquinolin-4-yl)-5-(trifluorornethyl)-lH-pyrazole-4carboxamide, Cpd 373

LCMS (ESI): mass calcd. for C24H17CIF3N9O 555.1 m/z found 556.1 [M+H] . Ή

NMR (400 MHz, DMSO-X) δ ppm 2.75 -3.10 (m, 3 H). 5.24 (br d, J=3J Hz, 1 H), 5.37 (s. 1 H), 7.29 (dd, .7=8.3, 3.1 Hz, 1 H). 7.85 - 8.01 (m, 2 H). 8.19 (s, 2 H), 8.24 - 8.36 (m. 1

686

H), 8.52 (dd, 7=8.3, 3.5 Hz. I H), 8.62 (s. I H), 8.68 (d, 7=2.0 Hz, l H), 8.76 (d, 7=12.6 Hz, 1 H), 8.86 (d, 7=2.4 Hz, 1 H), 11.29 (br s, 1 H).

Example 374

N-(5-chloiO-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-(l-hydroxyethyl)quinolin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 374

LCMS (ESI): mass calcd. for CaaHieCIFaNsO? 528.1 m/z found 529.1 [M+H] . 'H NMR (400 MHz, DMSO-7ô) δ ppm 1.51 (d, 7=6.5 Hz, 3 H), 5.02 (dd, 7=6.5. 4.5 Hz, 1 H), 5.79 (d, 7=4.5 Hz, 1 H), 7.32 (d, 7=8.5 Hz. 1 H), 7.71 (ddd, 7=8.2, 7.0, 1.0 Hz, 1 H), 7.89 7.95 (m, 2 H), 8.16 - 8.21 (m, 3 H), 8.65 (s, 1 H), 8.69 (d. 7=2.0 Hz, 1 H), 8.87 (d, 7=2.0 Hz, 1 H), 11.28 (br s, 1 H).

Example 375 l-(2-acetylquinolin-4-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 375

LCMS (ESI): mass calcd. for C23H14CIF3N8O2 526.1 m/z found 527.2[M+H] . *H NMR (400 MHz, DM St We) δ ppm 2.86 (s, 3 H), 7.43 (d. 7=8.1 Hz, 1 H), 7.91 (td, 7=7.6, 1.0 Hz, 1 H), 8.04 - 8.09 (m, 1 H), 8.20 (s, 2 H). 8.29 (s, 1 H). 8.41 (d, 7=8.5 Hz, 1 H), 8.67 - 8.70 (m, 2 H), 8.87 (d, 7=2.4 Hz, 1 H), 11.27 (s, 1 H).

687

Example 376

N-(5-chloro-6-(2H-l,2,3-triazol-2-yI)pyridm-3-yl)-l-(7-(l-hydroxyethyl)thieno[2,3c]pyridin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 376

LCMS (ESI): mass calcd. for C21H14CIF3N8O2S 534.1, m/z found 535.1 j Μ · 11 Γ. Ή NMR (400 MHz, DMSO-Λ) δ ppm 1.55 (d, J=6.5 Hz, 3 H), 5.17 (qd, J=6.6, 4.5 Hz, l H), 6.2l (d, J=4.l Hz, l H), 7.09 (d, J=5.7Hz, l H), 8.19 (s, 2 H), 8.28 (d,>5.3 Hz, l H), 8.54 - 8.59 (m, 2 H), 8.67 (d, .7=2.0 Hz, l H), 8.85 (d, .7=2.0 Hz. I H), 11.26 (br

IO s, l H).

Example 378 l-(l-acetylisoquinoIin-5-yl)-N-(5-chloro-6-(2H-l,2.3-triazol-2-yl)pyridm-3-y!)-5(trifluoromethyl)-l H-pyrazole-4-carboxamide, Cpd 378

LCMS (ESI): mass calcd. for C23H14CIF3NSO2 526.1, m/z found 527.2 [M+Hf. ‘H NMR (400 MHz. DMSO-Λ) δ ppm 2.83 (s, 3 H), 7.28 (d, J=5.9 Hz, l H). 7.99 (dd, .7=8.9, 7.3 Hz, 1 H), 8.18 (d, .7=6.9 Hz, 1 H), 8.19 (s, 2 H), 8.64 (s, 1 H), 8.69 (d.

688

J=1A Hz, l H). 8.74 (d, 7=6.1 Hz. I H), 8.88 (d, 7=2.1 Hz, 1 H), 9.03 (dt, >8.8. 1.1 Hz, 1

H), 11.24 (br s, 1 H).

Example 379 l-(l-(azetidin-2-yl)isoquinolin-4-yl)-N-(5-chIoro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5 ( trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 379

A. tert-butyl 2-(4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1 H-pyrazol-1 -yDisoquinolin-1 -yl)azetidine-1 -carboxylate. Cpd 379a

A mixture of tert-butyl azetidine-1-carboxylate (236 mg, 1.5 mmol), CHjCN (2.5 mL), H₂O (2.5 mL), A%5-chloro-6-(27AL2,3-triazol-2-yl)pyndin-3-yl)-l-(isoqumolm-4yl)-5-(trifluoromethyl)-/77-pyrazole-4-carboxamide (242.5 mg. 0.5 mmol). TFA (0.038 mL, 0.5 mmol) and ammonium persulfate (228 mg, 1 mmol) was weighted in. a 10 mL vial, (IR[DF(CF3)PPY]2(DTBPY))PFô ( 112 mg, 0.01 mmol) was successively added. The reaction mixture was degassed for 15 mm and the vessel sealed. The reaction was stirred under blue LED irradiation at rt for 1 h. The reaction mixture was poured into water and extracted with DCM. The organic layer was dried over MgSO₄, filtered and the fiitrate was concentrated to dryness. The residue was purified via Prep HPLC (Stationary phase:

RP XBridge Prep C18 OBD-10 um.50 x 150 mm, Mobile phase: 0.25% NH4HCO3

689 solution in water, CHsCN) yielding cpd 379a (240 mg. 75%). LCMS (ESI): mass calcd. for C29H25CIF3N9O3 639.2, m/z found 640.2 [M+H] c

B. l-(l-(azetidin-2-yl)isoquinolin-4-yl)-N-(5-chloro-6-(2H-I,2,3-triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 379

A mixture of tert-butyl 2-(4-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-( trifluoromethyl)-1 H-pyrazol-1 -yl)isoquinolin-1 -yl)azetidine-1carboxylate (240 mg, 0.375 mmol), TFA (2 mL) and DCM (6 mL) was stirred at room température for 3 h. The reaction mixture was concentrated to dryness. The residue was dissolved in water and made basic with K2CO3. The aqueous layer was extracted with DCM, and the organic layer was dried over MgSO4, filtered, and the filtrate and concentrated. The residue was dissolved into diisopropylether, a solid collected by filtrationfiltered off and dried, to afford the product (74 mg, 35.5%). LCMS (ESI): mass calcd. for C24H17CIF3N9O 539.1, m/z found 540.2 [M+H]*. *H NMR (400 MHz, DMSOdA δ ppm 2.55 - 2.79 (m, I H), 2.89 - 3.05 (m, 1 H), 3.54 - 3.62 (m, 1 H), 3.67 - 3.79 (m, 1 H), 5.81 (brt, 07.7 Hz, 1 H), 7.30 (br d, 08.1 Hz. 1 H), 7.81 - 7.90 (m. 1 H), 7.91 -7.99 (m, 1 H), 8.20 (s, 2 H), 8.29 (brd,08.5 Hz, 1 H), 8.63 (s, 1 H), 8.69 (d,02.O Hz. I H), 8.81 (s, 1 H), 8.87 (d, 02.4 Hz. 1 H), 11.28 (br s, 1 H).

Following the procedure described in Example 379, above, selecting and substituting the appropriate reagents, starting materials. and purification methods, and adjusting reaction températures, times and other variables or parameters, as needed or désirable, as would be readily recognized by those skilled in the art, the following 25 compounds were prepared:

690

Example 380

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yI)-l-(l-(pyrrolidin-2-yl)isoqumolm-4-yl)5-( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 380

LCMS (ESI): mass calcd. for C25H19CIF3N9O 553. L m/z found 554.2[M+H] \ ‘H NMR (400 MHz, DMSOF) ô ppm L81 - 2.01 (m, 3 H), 2.44 - 2.50 (m, l H), 2.98 - 3.07 (m, l H), 3.26 - 3.28 (m, l H), 5.23 (br s, l H), 7.28 (d, J=8.5 Hz, l H), 7.83 - 7.92 (m, 1 H), 7.92 - 8.01 (m, 1 H), 8.19 (s, 2 H), 8.59 (br d, J=1.7 Hz, 1 H), 8.63 (s, 1 H), 8.68 (d, 10 J=2.4 Hz, 1 H), 8.74 (s, 1 H), 8.87 (d, JM A Hz, 1 H), 11.27 (br s, 1 H).

Example 381 l-(2-(azetidin-2-yl)quinolin-5-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yDpyridm-3-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 381

LCMS (ESI): mass calcd. for C24H17CIF3N9O 539.1 m/z found 540.2[M+H] . H NMR (400 MHz. DMSOF) δ ppm 2.31 - 2.47 (m, 1 H), 2.64 - 2.81 (m, 1 H), 3.54 - 3.66 (m, 1 H), 3.73 (q, J=8.0 Hz, 1 H), 5.15 (t, JM .9 Hz, 1 H), 7.65 (d, .7=9,0 Hz. 1 H), 7.82 19506

691

8.03 (m. 3 H), 8.18 - 8.22 (m, 2 H), 8.27 (d, 7=8.5 Hz, 1 H), 8.61 (s. 1 H), 8.70 (d, 7=2.4 Hz, 1 H), 8.88 (d, 7=2.0 Hz, 1 H).

Example 382

1 -(2-(azetidin-2-yl)quinolm-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 382

LCMS (ESI): mass calcd. for C24H17CIF3N9O 539.1, m/z found 540.2 [M । H] . 'H NMR (400 MHz, DMSO-A) δ ppm 2.32 - 2.45 (m, 1 H), 2.72 (ddt, 7=14.9, 8.2, 4.1, 4.1

Hz, 1 H). 3.35 - 3.38 (m, 1 H), 3.69 - 3.82 (m, 1 H), 5.21 (t, 7=8.1 Hz, 1 H), 7.32 (d, 7=7.7 Hz, 1 H), 7.70 (ddd. 7=8.2. 7.0, 1.0 Hz, 1 H), 7.91 (ddd, 7=8.4. 7.0, 1.2 Hz, 1 H), 8.07 (s, 1 H), 8.15 - 8.20 (m, 3 H), 8.67 (s, 1 H), 8.69 (d, 7=2.0 Hz, 1 H), 8.88 (d, 7=2.4 Hz, 1 H),

11.29 (brs, 1 H).

Example 383 tert-butyl 2-(5-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1 H-pyrazol-1 -yl )isoquinolin-1 -yDazetidine-1 -carboxylate. Cpd 383

LCMS (ESI): mass calcd. For C29H25CIF3N9O3 639.2 m/z found 640.2[M+H] .

692

Example 384 l-( l-(azetidin-2-yl)isoquinolin-5-yl)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide, Cpd 384

LCMS (ESI): mass calcd. for C24H17CIF3N9O 539.1, m/z found 540.1 [M+H] . ’H NMR (400 MHz, DMSOY) δ ppm 2.67 (br s, l H), 3.03 - 3.15 (m. 1 H), 3.80 (td, 7=9.1, 5.9 Hz, 1 H), 3.99 - 4.16 (m, 1 H), 6.22 (br t, 7=7.9 Hz. 1 H), 7.10 (d, 7=6.1 Hz, 1 H), 7.92 - 8.00 (m, 1 H), 8.17 (s, 1 H), 8.20 (s, 2 H), 8.38 (d, 7=8.5 Hz, 1 H), 8.63 (s, 1 H), 8.67 (d.

7=6.1 Hz, 1 H), 8.69 (d, 7=2.0 Hz, 1 H), 8.88 (d, 7=2.4 Hz, I H), 11.29 (br s, 1 H).

Example 385

N-(5-chloro-6-(2H-I,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(hydroxymethyl)isoquinolin-4-yl)15 5-(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 385

A-(5-chloro-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-yl)-l-(isoquinolm-4-yl)-5(trifluoromethyl)-///-pyrazole-4-carboxamide (242.5 mg. 0.5 mmol), TFA (0.038 mL, 0.5 mmol) and BPO (302 mg, 1 mmol) were weighted in MeOH (2.5 mL) m a 10 mL vial.

(IR[DF(CF₃)PPY]2(DTBPY))PF6 (11.2 mg, 0.01 mmol) was successively added. The

693 réaction mixture was degassed for 15 min and the vessel sealed. The reaction was stirred under blue LED irradiation at rt for l h. The reaction mixture was poured into water and extracted with DCM. The organic layer was dried over MgSÛ4, filtered and the filtrate was concentrated to dryness. The residue was purified via Prep HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD-IO pm, 50 x 150 mm, Mobile phase: 0.25% NH₄HCOs solution in water, CH;CN) to afford cpd 385 (12 mg, 4.7%). LCMS (ESI): mass calcd. for C22H14CIF3N8O2 514.1, m/z found 515.1 [ M H | . ‘H NMR (400 MHz. DMSO-Λ) δ ppm 5.17 (d. 7=5.7 Hz, 2 H), 5.60-5.70 (m, 1 H), 7.26 (d, 7=8.1 Hz, 1 H). 7.82 - 7.89 (m, 1 H), 7.90 - 7.97 (m, 1 H), 8.19 (s. 2 H), 8.58 (d, 7=8.1 Hz, 1 H), 8.63 (s, 1 H), 8.69 (d, 7=2.0 Hz, 1 H). 8.71 (s, 1 H), 8.87 (d, 7=2.0 Hz, 1 H), 11.28 (br s, 1 H).

Example 386

4T4-((5-_chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-lHpyrazol-l-yl)quinoline-2-carboxamide, Cpd 386

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-4-yI)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide (485 mg, 1 mmol), iron (II) sulfate heptahydrate (139 mg, 0.5 mmol), formamide (450.5 mg, 10 mmol) and H2SO4 (147 mg, 1.5 mmol) were stirred in CH3CN (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 h. The reaction mixture was poured into water, the pH of the mixture was made basic with K2CO3, and the réaction mixture extracted with DCM/ MeOH (90/10). The organic layer was concentrated. The résultant residue was putified by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-I0 pm, 50 x 150 mm, Mobile phase: 0.5% NH₄Ac solution in water + 10% CH3CN, CH3CN) to afford cpd 386 (65 mg, 12.3%).

LCMS (ESI): mass calcd. for C22H13CIF3N9O2 527.1, m/z found 528.1 [M+H] . ’H NMR (400 MHz, DMSO-Λ) δ ppm 7.42 (d, J=8.1 Hz, l H), 7.87 (ddd, <7=8.4, 7.0, 1.2 Hz, 1 H), 7.99 - 8.08 (m, 2 H), 8.19 (s, 2 H), 8.33 (d, <7=8.5 Hz, 1 H), 8.35 (s, 1 H), 8.48 (d, <7=1.6 Hz, 1 H), 8.67 - 8.70 (m. 2 H), 8.87 (d, <7=2.0 Hz, 1 H). 11.27 (br s, 1 H).

Following the procedure described in Example 386, above, selecting and substituting the appropriate reagents, starting materials, and purification methods, and adjusting reaction températures, times and other variables or parameters, as needed or désirable, as would be readily recognized by those skilled in the art, the following compounds were prepared:

Example 387

4-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoiOmethyl)-lHpyrazol-l-yl)isoquinoline-l-carboxamide, cpd 387

LCMS (ESI): mass calcd. for C22H13CIF3N9O2 527.1, m/z found 528.1 [M+H]”. ‘H NMR (400 MHz, DMSO-;#! δ ppm 7.32 (d, <7=8.1 Hz, 1 H), 7.87 - 7.93 (m, 1 H), 7.95 - 8.01 (m, 1 H), 8.02 (br s, 1 H), 8.20 (s, 2 H), 8.43 (br s, 1 H), 8.66 (s, 1 H), 8.69 (d, <7=2.4 Hz, 1 H), 8.85 (s, 1 H), 8.87 (d, <7=2.0 Hz, 1 H), 8.90 (d, ,7=8.5 Hz, 1 H), 11.29 (s, 1 H).

Example 388

5-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-lH pyrazol-l-yl)quinoline-2-carboxamide, Cpd 388

695

LCMS (ESI): mass calcd. for C22H13CIF3N9O2 527.1 m/z found 528.1 [M+H] . ‘H NMR (400 MHz, DMSO-Λ) δ ppm 7.82 (d, >8.5 Hz, l H), 7.90 (d, .7=2.0 Hz, l H), 8.02 8.05 (m, l H), 8.06 - 8.11 (m, I H), 8.20 (s, 2 H), 8.28 (d, .7=8.5 Hz, l H), 8.37 - 8.45 (m, 2 5 H), 8.62 (s, l H), 8.69 (d,.7=2.0 Hz, l H), 8.87 (d, >2.0 Hz, l H), ll.27(brs, l H).

Example 389

5-(4-(( 5-chloro-6-(2H-L2,3-triazol-2-y!)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-lHpyrazol-l-yl)isoquinoline-l-carboxamide, Cpd 389

LCMS (ESI): mass calcd. for C22H13CIF3N9O2 527.1, m/z found 528.1 [Μ î H] . ‘H NMR (400 MHz. DMSO-Λ) δ ppm 7.16-7.21 (m, 1 H), 7.95 (dd, .7=8.7, 7.5 Hz. 2 H), 8.16 (d, .7=6.5 Hz, 1 H), 8.19 (s, 2 H), 8.36 (s, 1 H), 8.62 (s, 1 H), 8.64 (d, >6.1 Hz, 1 H), 8.69 (d, .7=2.0 Hz, 1 H), 8.86 (d. >2.4 Hz, 1 H), 9.12 - 9.18 (m, 1 H), 1 1.27 (br s, 1 H).

Example 390 4-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)carbamoyl)-5-(trifluoromethyl)-lHpyrazol-l-yl)-N-methylisoquinoline-l-carboxamide, Cpd 390

696

LCMS (ESI): mass calcd. for C23H15CIF3N9O2 54l.l m/z found 542.1 [M : H] . 'H NMR (400 MHz, DMSO-U) δ ppm 2.93 (d, .7=4.9 Hz, 3 H), 7.32 (d. 7=8.5 Hz, 1 H), 7.90 (ddd, 7=8.4, 7.0, 1.2 Hz, 1 H), 7.98 (ddd, 7=8.2, 7.0, 1.4 Hz. 1 H), 8.20 (s, 2 H), 8.66 (s, 1

H), 8.69 (d, 7=2.4 Hz, 1 H), 8.86 (s, 1 H), 8.87 (d, 7=2.0 Hz. 1 H), 8.95 (dd. 7=8.3, 1.0 Hz.

H). 9.01 (q, 7=4.5 Hz, 1 H), 11.29 (s, 1 H).

Example 391

4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl )-5-(trifluoromethyl)-1H10 pyrazol-l-yl)thieno[2,3-c]pyridine-7-carboxamide, Cpd 391

LCMS (ESI): mass calcd. for C20H11CIF3N9O2S 533. m/z found 534.1 [M+H]*. *H NMR (600 MHz. DMSO-U) δ ppm 7.21 (d, 7=5.6 Hz. 1 H), 8.14 (br s, 1 H), 8.20 (s, 2 H), 8.43 (d, 7=5.6 Hz, 1 H). 8.60 (br s, 1 H), 8.64 (s, 1 H), 8.68 (d, 7=2.3 Hz, 1 H), 8.81 (s, 1 15 H), 8.86 (d, 7=2.3 Hz, 1 H), 11.28 (br s, 1 H).

Example 392

4.(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-lHpyrazol-l-yl )-N-methylthieno[2,3-c]pyndine-7-carboxamide, Cpd 392

LCMS (ESI): mass calcd. for C21H13CIF3N9O2S 547.1 m/z found ^4Nj M H j . Ή NMR (400 MHz, DMSO-Y) δ ppm 2.93 (d, J=4.8 Hz, 3 H), 7.21 (d, ./=5,7 Hz, l H), 8.19 (s, 2 H), 8.44 (d, J=5.5 Hz, l H), 8.64 (s, 1 H), 8.68 (d,.7=2.2 Hz, 1 H), 8.81 (s, 1 H), 8.86 5 (d, J=22 Hz, 1 H), 9.24 (q, J=4.5 Hz, 1 H), 11.28 (br s, 1 H).

Example 393

4-(4-((5-chloro-2-methyl-6-(2H-l ,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1 H-pyrazol-l-yl)thieno[2,3-c]pyndme-7-carboxamide, Cpd 393

LCMS (ESI): mass calcd. for C21H13CIF3N9O2S 547.1 m/z found M8|M II | . ‘H NMR (400 MHz, DMSO-Y) δ ppm 2.58 (s. 3 H), 7.24 (d, <7=5.7 Hz, 1 H), 8.13 (br s, 1 H), 8.19 (s. 2 H), 8.40 - 8.48 (m. 2 H), 8.58 (s, 1 H), 8.67 (s, 1 H), 8.80 (s, 1 H).

Example 394

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(difluoromethyl)isoquinolin-4-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 394

698

A mixture ofA-(5-chloro-6-(2/7-1,2,3-triazol-2-yl)pyridin-3-yl )-1-(isoquinolin-4yl)-5-(trifluoromethyl)-/H-pyrazole-4-carboxamide (242 mg, 0.5 mmol), zinc difluoromethanesulfmate (400 mg. 1.35 mmol), water ( 1 mL), and DCM (z..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 h. Additional zinc difluoromethanesulfmate (400 mg, 1.35 mmol) and tert-butyl hydioperoxide (322 mg, _.5 mmol) were added. The réaction mixture was stirred for 3 h. The reaction mixture was poured into water, the mixture was made basic by the addition of Na2CCh, and the mixture was extracted with DCM (20 mL x 2). The organic layer was dried over MgSO₄, filtered, and the fiitrate concentrated. The residue was purified via Prep HPLC (Stationary- phase. RP XBridge Prep C18 OBD-10 nm. 30 xl50 mm. Mobile phase: 0.25% NH4HCO3 solution m water, MeOH). The pure fractions were concentrated and the residue was stirred in diisopropydether, the solid collected by filtration and then diied to afford cpd 394 (39 mg, 14.6%). LCMS (ESI): mass calcd. for C22H12CIF5NSO 534.1, m/z found 535.1

[M+H]*. ‘H NMR (400 MHz, DMSO-7₆) δ ppm 7.42 (d, 7=8.1 Hz, 1 H). 7.62 (t, 7=53.3 Hz, 1 H), 7.95 - 8.01 (m, 1 H), 8.01 - 8.07 (m, 1 H), 8.16 (s. 2 H), 8.58 (br d, 7=8.1 Hz, 1 H), 8.64 (s, 1 H), 8.75 (d, 7=2.0 Hz, 1 H), 8.77 (d, 7=2.0 Hz, 1 H) 8.92 (s, 1 H).

Foilowing the procedure described in Example 394, above, selecting and substituting the appropriate reagents, starting materials. and purification methods, and adjusting reaction températures, times and other variables or parameters. as needed or désirable, as would be readily recognized by those skilled in the art, the foilowing compounds were prepared:

699

Example 395

N-(5-chloro-6-(2H-l,2,3-triazol-2-yI)pyridin-3-yl)-l-(2-(difluoromethyl)qumolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 395

LCMS (ESI): mass calcd. for C22H12CIF5NSO 534.1 m/z found 535.1 [M+H] . 'H NMR (600 MHz. DMSO-X) δ ppm 7.21 (t, <7=54.7 Hz, 1 H), 7.89 (d, <7=8.8 Hz, 1 H), 7.98 (d, .7=8.9 Hz, 1 H), 8.06 - 8.09 (m, 1 H), 8.09 - 8.13 (m. 1 H), 8.20 (s. 2 H), 8.45 (d, .7=8.1 Hz, 1 H), 8.64 (s, 1 H), 8.69 (d, J=2.3 Hz, 1 H), 8.88 (d, J=2.3 Hz, 1 H), 11.31 (s, 1 H).

Example 396

N-(5-chloro-6-(2H-l,2.3-triazol-2-yl)pyridin-3-yl)-l-(4-(difluoromethyl)quinolin-5-yl)-5(trifluoromethyl)-l H-pyrazole-4-carboxamide, Cpd 396

LCMS (ESI): mass calcd. for C22H12CIF5N8O 534.1 m/z found 535.1 [M+H]'. 'H 15 NMR (400 MHz, DMSO-X) δ ppm 5.96 - 6.33 (m, 1 FI), 7.91 - 7.96 (m, 1 FI), 8.01 (dd, J=4.3, 2.6 Hz, 1 H), 8.03 - 8.10 (m, 1 H), 8.20 (s, 2 H), 8.50 (dd, <7=8.1, 1.2 Hz, 1 H), 8.66 (s, 1 H), 8.69 (d, 7=2.4 Hz, 1 H), 8.88 (d, .7=2,0 Hz, 1 H). 9.24 (d, </=4.5 Hz, 1 H), 11.25 (brs, 1 H).

700

Example 397

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(8-(difluoromethyl)qumolm-5-yl)-5 (trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 397

LCMS (ESI): mass calcd. for C22H12CIF5N8O 534.1 m/z found 535.1 } X1 · 111 . ‘H NMR (400 MHz, DMSO-A) δ ppm 7.73 - 7.77 (m, l H), 7.79 - 8.12 (m, 3 H). 8.20 (s. 2 H), 8.26 (d. 7=7.7 Hz, 1 H), 8.64 (s, I H), 8.69 (d, 7=2.4 Hz, 1 H), 8.87 (d, 7=2.4 Hz, 1 H), 9.17 (dd, 7=4.3, 1.8 Hz, 1 H), 11.27 (br s, 1 H).

Example 398

N-(5-chIoro-6-(2H-l,2,3-triazol-2-yl)pyridm-3-yl)-l-(7-(difluoromethyl)thieno[2,3c]pyridin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamidc, Cpd 398

LCMS (ESI): mass calcd. for C20H10CIF5N8OS 540 m/z found 541 [M ^; H] . H NMR (400.MHz, DMSO-A) δ ppm 7.26 - 7.57 (m, 1 H), 7.32 (d, 7=5.3 Hz, 1 H), 8.20 (s, 2 H), 8.50 (d, 7=5.7 Hz, 1 H), 8.65 (s, 1 H), 8.68 (d, 7=2.4 Hz, 1 H), 8.85 - 8.88 (m, 2 H), 11.27 (s, 1 H).

Example 399

N-(5-chloro-6-(2H-l,2,3-triazoI-2-yl)pyridm-3-yl)-l-(2-(difhjoromethyl)thieno[2,3c]pyridin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 399

701

LCMS (ESI): mass calcd. for CcoHioCIFsNsOS 540 m/z found 541.1 i M -411'. ’H NMR (400 MHz, DMSO-» δ ppm 7.39 - 7.69 (m, 2 H), 8.19 (s. 2 H), 8.63 (s, 1 H), 8.68 (d,.7=2.4 Hz, 1 H), 8.82 (s, 1 H). 8.86 (d, J=2A Hz, 1 H), 9.61 - 9.75 (m, 1 H). 11.26 (br s, 5 1 H).

Example 400

N-(5-chloro-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(difluoromethyl)isoquinolin-5-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 400

LCMS (ESI): mass calcd. for C22H12CIF5N8O 534.1, m/z found >35.1 |M H| . 'H NMR (400 MHz. DMSO-X) δ ppm 7.28 (d, >5.7 Hz, 1 H), 7.55 (t, >53.5 Hz, 1 H), 8.04 (dd. >8.5, 7.7 Hz, 1 H), 8.19 (s. 2 H), 8.25 (d. .7=7.3 Hz, 1 H). 8.63 (s. 1 H), 8.66 - 8.74 (m, 3 H). 8.87 (d, >2.0 Hz, 1 H), 11.28 (br s, 1 H).

Example 401 N-(5-chloro-6-(2H-L2,3-triazol-2-yI)pyridin-3-yl)-l-(2-(difluoromethyl)quinolin-4-yI)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 401

702

LCMS (ESI): mass calcd. for C22H12CIF5N8O 534.1 m/z found 535.1 [M+H] . ^[H NMR (400 MHz, DMSO-0) δ ppm 7.14 - 7.46 (m, 2 H), 7.89 (t, J=1.5 Hz, 1 H), 8.06 (t, 07.7 Hz. 1 H), 8.20 (s, 2 H), 8.26 (s, 1 H), 8.35 (d, 08.5 Hz, 1 H), 8.68 - 8.73 (m. 2 H), 5 8.86-8.91 (m, 1 H), 11.27 (s. 1 H).

Example 402

N-(5-chloro-6-(2H-1,2,3-triazol-2-yDpyridin-3-yl)-1-(1-(1,1 -difluoroethyl)isoquinolin-4yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 402

LCMS (ESI): mass calcd. for C23H14CIF5N8O 548.1 m/z found 549.1 [M+H] . ’H NMR (400 MHz, DMSO0) δ ppm 2.3 1 (t, 019.9 Hz. 3 H), 7.38 (d, 07.7 Hz, 1 H), 7.95 - 8.01 (111, 1 H), 8.01 - 8.08 (m, 1 H), 8.17 - 8.27 (m, 2 H), 8.64 (s, 1 H). 8.63 - 8.67 (111, 1 H), 8.66 (br s, 1 H), 8.68 (s, 1 H), 8.69 (d, 02.0 Hz. 1 H), 8.87 (d, 02.4 Hz, 1 H), 8.93 (s.

1 H), 11.30 (s, 1 H).

Example 403

-(1-( azetidin-3-yl)isoquinolin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl )pyridin-3-yl)-5( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 403

703

A. tert-butyl 3-(4-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1 H-pyrazol-1 -yl)isoquinolin-1 -yl)azetidine-1 -carboxylate, 403a

A mixture of l-tert-butoxycarbonylazetidin-3-yl)-trifluoro-boranuide (289 mg. 1.1 mmol), A45-diloro-6-(2H-1.2,3-triazol-2-yl)pyridm-3-yl)-l-(isoqumolin-4-yl)-5(trifluoromethyl)-/H-pyrazole-4-carboxamide (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) was stirred in dio.xane (5 mL) and water (5 mL) in a sealed tube. The réaction was stirred 10 at rt for 4 h. The reaction mixture was poured into a 1:1 mixture sat aq. Nal K O < 5% aq

Na:S2O3 and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over MgSO₄, filtered, and the filtrate concentrated. The residue was purified via Prep HPLC (Stationary phase: RP XBridge Prep Cl8 OBD-10 μιη,30 x 150 mm. Mobile phase: 0.25% NH4HCO3 solution in water, MeOH) to afford cpd 403a ( 16 mg, 5%). LCMS (ESI): mass calcd. for C29H25CIF3N9O3 639.2, m/z found 640.2 [M+H]'.

B. l-(l-(azetidin-3-yl)isoquinolin-4-yl)-N-(.5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridm3-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 403

704

A mixture of tert-butyl 3-(4-(4-((5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3yl)carbamoyl)-5-( trifluoromethyl)-1 H-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) was stirred for 3 h. The reaction mixture was concentrated to dryness. The reaction mixture was poured into water and made basic by the addition of NaiCOs, then extracted wùth DCM (2x). The organic layer was dried over MgSCL, filtered, and the filtrate concentrated. The residue was purified via Prep HPLC (Stationary phase: RP XBridge Prep Cl8 OBD10 pm, 30 x 150 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to afford cpd 403 (7 mg, 52%). LCMS (ESI): mass calcd. for C24H17CIF3N9O 539.2, m/z found 540.2 [M+H]”. ‘H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.11 (br t, ,7=8.1 Hz, 2 H), 4.32 (br s, 2 H), 4.90 (quin, J=X.O Hz, I H), 7.30 (d, J=7.3 Hz, 1 H), 7.67 - 7.79 (m, 2 H), 7.96 (s, 2 H), 8.04 (d, J=1.7 Hz, 1 H), 8.26 (s, 1 H), 8.55 (d, J=2A Hz, 1 H), 8.61 (s, 1 H).

8.78 (d, J=2.4 Hz, 1 H).

Example 404

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridm-3-yl)-l-(l-(methoxymethyl)isoqumolin-4-yl)5-( trifluoromethyl)-lH-pyrazole-4-carboxamide, Cptl 404

A mixture of methoxyacetic acid (135 mg, 1.5 mmol), A-(5-chloro-6-(2//-L2,3triazol-2-yl)pvridin-3-yl)-1 -(isoquinolin-4-yl)-5-(tiïfluoromethyl)-//7-pyrazole-4

705 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 was stirred at rt for 16 h. Additional methoxvacetic acid (135 mg, 1.5 mmol), silver nitrate (17 mg, 0.1 mmol), and ammonium persulfate (342 mg, 1.5 mmol) were added. The reaction was stirred for 16 h. The reaction mixture was poured into water, made basic withNazCOj and extracted with DCM (2x). The combined organic layers were dried over MgSO₄, filtered, and the filtrate concentrated. The residue was purified via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm. Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The pure fractions were collected, concentrated and the residue was stirred in disiopropylether, the solid collected by filtration and then dried to afford cpd 404 (21mg, 8%). LCMS (ESI): mass calcd. for C23H16CIF3N8O2 528.1, m/z found 529.1 [M+H] . ’H NMR (400 MHz, DMSO-Λ) δ ppm 3.42 (s, 3 H), 5.10 (br s, 2 H), 7.28 (d, 7=8.5 Hz, 1 H), 7.82 - 7.91 (m, 1 H), 7.91 - 7.99 (m, 1 H), 8.19 (s. 2 H), 8.52 (d. 7=8.5 Hz, 1 H), 8.64 (s, 1 H), 8.69 (d, 7=2.4 Hz, 1 H), 8.74 (s. 1 H), 8.87 (d, 7=2.0 Hz, 1 H). 11.28 (br s, 1 H).

Example 405

4-(4-((5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoiOmethyl)-lHpyrazol-l-yl)quinoline 1-oxide, Cpd 405

A solution of N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(quinolin-4-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide (2425 mg, 5 mmol) in DCM (150 mL) was stirred at rt. m-CPBA (1295 mg, 7.5 mmol) was added portion-wise. Stirring was continued for 16 h. Additional m-CPBA (1295 mg, 7.5 mmol) was added portion-wise. Stirring was continued for 4 h. Additional m-CPBA (1295 mg. 7.5 mmol) was added

706 portion-wise. Stirring was continued for 16 h. The reaction mixture was poured into 100 mL water and was treated with sodium sulfite (4726 mg, 37.7 mmol) and stirred for lo min before the addition ofNaHCOs (3! 50 mg, 37.5 mmol). Stirring was continued for 5 min. 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 with DCM/ MeOH (100 mL, 90/10, 3x). The combined organic layers were concentrated. The résultant residue was boiled in CH_?CN, cooled, and the resulting precipitate was collected by filtration, then dried to afford crude cpd 405 (6.3 g, 251%) which was used as such in the next step. LCMS (ESI): mass calcd. for C21H12CIF3N8O2 500.1, m/z found 501.1[M+H] .

Foilowing the procedure described in Example 405, above, selecting and substituting the appropriate reagents, starting materials, and purification methods, and adjusting reaction températures, times and other variables or parameters, as needed or désirable, as would be readily recognized by those skilled in the art, the foilowing 15 compounds were prepared:

Example 406

4-(4-(( 5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-! Hpyrazol-l-yl)isoquinoline 2-oxide, Cpd 406

LCMS (ESI): mass calcd. For C21H12CIF3N8O2 500.1 m/z found 501.1 [M+H] .

Example 407

5-(4.((5-chforo-6-(2H-L2,3-tnazol-2-yl)pyridin-3-yI)carbamoyl)-5-(trifluoromethyl)-lH25 pyrazol-l-yl)isoquinoline 2-oxide, Cpd 407

707

LCMS (ESI): mass calcd. For C21H12CIF3N8O2 500.1 m/z found 501.1 [M+H] .

Example 408

5-(4-((5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-lHpyrazol-l-yl)quinoline 1-oxide. Cpd 408

LCMS (ESI): mass calcd. For C21H12CIF.3N8O2 500.1 m/z found 501.1 [M+H] .

Example 409

4-(4-((5-_chloiO-6-(2H-L2,3-triazol-2-yI)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-lHpyrazol-l-yl)thieno[2,3-c]pyridine 6-oxide, Cpd 409

LCMS (ESI): mass calcd. for C19H10CIF3N8O2S 506 m/z found 507[M+H]L ’H

NMR (400 MHz. DMSO-Λ) δ ppm 7.05 (d,.7=5.7 Hz, 1 H), 8.18 (d. 7=5.0 Hz, 1 H). 8.19

708 (s, 2 H), 8.62 (s, l H), 8.67 (d, 7=2.4 Hz, l H). 8.77 (d, 7=1.6 Hz, 1 H), 8.86 (d, 7=2.0 Hz,

H), 9.36 (s, 1 H), 11.23 (s, 1 H).

Example 410

4-(4-((5-chloro-2-methyl-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-lH-pyrazol-l-yl)thieno[2,3-c]pyridine 6-oxide, Cpd 410

LCMS (ESI): mass calcd. for C2oHi₂C1F3N_s02S 520 m/z found 521.1 [M+H] .

Example 411

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-cyanoisoquinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 411

A mixture of 5-(4-((5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-lH-pyrazol-I-yl)isoquinolme 2-oxide (501 mg, 1 mmol), trimethylsilyl cyanide ( 119 mg, 1.2 mmol) and DBU (305 mg, 2 mmol in THF( 3 mL) was stirred at 50 °C for I h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic laver was dried over MgSO4, filtered, and the filtrate concentrated. The residue was purified via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm,50 x!50 mm. Mobile phase: 0.25% NH4HCO3 solution m water. CH3CN) to afford cpd 411

709 (330 mg, 65%). LCMS (ESI): mass calcd. for C22H11CIF3N9O 509.1, m/z found

510.1 j M H L. ¹H NMR (400 MHz, DMSO-Λ) δ ppm 7.50 (dd, >5.7, 0.8 Hz, 1 H), 8.15 (dd, >8.5, 7.7 Hz, 1 H), 8.19 (s, 2 H), 8.32 (d, >6.9 Hz, 1 H), 8.57 (dt, >8.4, 0.9 Hz, 1 H), 8.64 (s, I H), 8.68 (d,>2.0 Hz, 1 H), 8.81 - 8.84 (m, 1 H), 8.87 (d,>2.4 Hz, 1 H), 5 11.26(brs, 1 H).

Following the procedure described in Example 411, above, selecting and substituting the appropriate reagents, starting materials, and purification methods, and adjusting reaction températures, times and other variables or parameters, as needed or 10 désirable, as would be readily recognized by those skilled in the art, the following compounds were prepared:

Example 412

N-(5-chloro-6-(2H-L2.3-triazol-2-yl)pyridin-3-yl)-l-(2-cyanoquinolin-4-yl)-515 (trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 412

LCMS (ESI): mass calcd. for C22H11CIF3N9O 509.1 m/z found 510.1 [M+H]\ Ή NMR (400 MHz, DMSO-Λ) δ ppm 7.44 (d, >8.5 Hz, 1 H), 7.97 (ddd, >8.3, 7.1, 0.8 Hz, 1 H), 8.12 (ddd. >8.4, 7.2. 1.4 Hz, 1 H). 8.20 (s, 2 H), 8.39 (d, >8.5 Hz, 1 H). 8.63 (s, 1 20 H), 8.69 (d, >2.4 Hz, 1 H), 8.72 (s, 1 H), 8.87 (d, >2.4 Hz. 1 H), 11.29 (br s. 1 H).

Example 413

N-(5-chloro-6-(2H-l,2.3-triazol-2-yl)pyridin-3-yl)-l-(2-cyanoquinolin-5-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 413

710

LCMS (ESI): mass calcd. for C22H11CIF3N9O 509.1 m/z found 510.1 [M+H] . *H NMR (400 MHz, DMSO-» δ ppm 7.89 - 7.97 (m, 1 H), 8.14 - 8.19 (m, 3 H), 8.20 (s, 2 H), 8.44 - 8.51 (m, 1 H), 8.63 (s, 1 H), 8.69 (d, 7=2.4 Hz, 1 H), 8.87 (d, 7=2.0 Hz, 1 H).

11.20(brs, 1 H).

Example 414

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(l-cyanoisoquinolin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 414

LCMS (ESI): mass calcd. for C22H11CIF3N9O 509.1 m/z found 510.1 [M+H] . ^lH

NMR (400 MHz, DMSO-» δ ppm 7.47 - 7.55 (m, 1 H), 8.08 - 8.17 (m, 2 H), 8.20 (s, 2

H), 8.44 - 8.53 (m, 1 H), 8.68 - 8.74 (m, 2 H), 8.87 (d, 7=2.4 Hz, 1 H), 9.09 (s, 1 H), 11.29 (br s. 1 H).

Example 415

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(7-cyanothieno[2,3-c]pyridin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 415

711

LCMS (ESI): mass calcd. For C20H9CIF3N9OS 515, m/z found 5 lo|M · H| .

Example 416

N-(5-chloro-2-methyl-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-I-(7-cyanothieno[2,3c]pyridin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 416

LCMS (ESI): mass calcd. for C21H11CIF3N9OS 529 m/z found 530[M+H] . Ή

NMR (400 MHz, DMSO-Y) δ ppm 2.57 (s, 3 H), 7.43 (d, J=5.3 Hz, 1 H), 8.19 (s, 2 H),

8.44 (s, 1 H), 8.58 (d, J=5.3 Hz, 1 H). 8.67 (s, 1 H), 8.95 (s, 1 H).

Example 417. Example 418. and Example 419

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(2-methoxyquinolin-4-yl)-515 (trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 417

712

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-I-(2-oxo-L2-dihydroquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 418

N-(5-chloro-6-(2H-1.2,3-triazol-2-yl)pyridin-3-yl)-l-( 1 -methyl-2-oxo-1.2dihydroquinoIin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide. Cpd 419

A mixture of 4-(4-((5-chloro-6-(2H-L2,3-triazol-2-yl)pyTidin-3-yl)carbamoyl)-5(trifluoromethyD-lH-pyrazol-l-yl)quinoline 1-oxide (501 mg, 1 mmol), tosylanhydride (980 mg, 3 mmol), NazCOs (318 mg. 3 mmol) in MeOH (10 mL) was stirred at rt for 16 h.

DMF (10 mL) was added. Additional tosylanhydride (980 mg, 3 mmol) and NaiCOa (318 mg, 3 mmol) were added and stirring was continued for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate (2x). The organic layer was washed with water, dried over MgSOa , and the filtrate concentrated. The residue was purified via Prep HPLC (Stationary phase: RP XBridge Prep Cl8 OBD-10 pm.5O x 150 mm, Mobile phase:

0.25% NH4HCO3 solution in water. CH3CN) to afford cpd 418 (73 mg. 15%), cpd 419 (48 mg, 9 %), and cpd 417 (80 mg, 16%).

Cpd 418. LCMS (ESI): mass calcd. for C21H12CIF3N8O2 500.1, m/z found

501.11M 1! | . ‘H NMR (400 MHz, DMSO-A) δ ppm 6.85 (d, 7=8.1 Hz, 1 H), 6.97 (s, 1 H), 7.24 (t, 7=7.5 Hz, 1 H), 7.49 (d, 7=8.1 Hz, 1 H), 7.65 (t, 7=7.7 Hz, 1 H), 8.19 (s, 2 H),

8.64 (s. 1 H), 8.68 (d. 7=2.3 Hz, 1 H), 8.87 (d, 7=2.3 Hz, 1 H). 10.93 (br s, 1 H);

713

Cpd 419. LCMS (ESI): mass calcd. for C22H14CIF3N8O2 514.1, m/z found 515.2[M+H]⁺. ΉNMR (600 MHz, DMSO-Λ) δ ppm 3.74 (s, 3 H), 6.89 (dd, J=8.1, 1.3 Hz, 1 H), 7.14 (s, 1 H), 7.34 (ddd, <7=8.0, 7.0, 1.2 Hz, 1 H), 7.73 - 7.76 (m, 1 H), 7.77 7.81 (m, 1 H). 8.19 (s, 2 H), 8.63 (s. 1 H), 8.67 (d, J=2.3 Hz, 1 H), 8.85 (d, .7=2.1 Hz, 1 H). 11.24 (brs, 1 H);

Cpd 417. LCMS (ESI): mass calcd. for C22H14CIF3N8O2 514.1, m/z found 5 15.2’ M H | . ‘H NMR (600 MHz, DMSO-Λ) δ ppm 4.09 (s, 3 H), 7.15 (dd, J=8A, 1.0 Hz, 1 H), 7.52 - 7.56 (m, 2 H), 7.83 (ddd, <7=8.4, 7.0, 1.4 Hz, 1 H), 7.98 (d, J=8.1 Hz, 1 H), 8.20 (s, 2 H), 8.65 (s, 1 H), 8.68 (d, </=2.3 Hz. 1 H), 8.86 (d, J=23 Hz, 1 H), 1 1.01 (br s, 1 H).

Following the procedure described in Example 417, above, selecting and substituting the appropriate reagents, starting materials, and purification methods, and adjusting reaction températures, times and other variables or parameters, as needed or désirable, as would be readily recognized by those skilled in the art, the following compounds were prepared:

Example 420

N-(5-chloro-6-(2H-L2.3-triazol-2-yl)pyridin-3-yl)-l-(2-methoxyquinolin-5-yD-5(trifluoromethyl)-lH-pyrazole-4-carboxamide. Cpd 420

LCMS (ESI): mass calcd. for C22H14CIF3N8O2 514.1 m/z found 515.1 [M+H]”. ‘H

NMR (400 MHz, DMSO-Λ) δ ppm 4.05 (s, 3 H), 7.17 (d, </=9.4 Hz, 1 H), 7.47 (d, <7=9.4

714

Hz, 1 H), 7.70 (d, 7=7.3 Hz. 1 H), 7.83 - 7.92 (m, 1 H), 8.08 (d. 7=8.5 Hz. 1 H). 8.19 (s. 2 H), 8.57 (s. 1 H). 8.68 (d, 7=2.0 Hz, 1 H), 8.86 (d, 7=2.4 Hz, 1 H), 11.25 (br s. 1 H).

Example 421

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(l-methoxyisoquinolin-4-yl)-5(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 421

LCMS (ESI): mass calcd. for C22H14CIF3NSO2 514.1 m/z found 515.1 [M+H]L Ή NMR (400 MHz, CHLOROFORM-r/) 5 ppm 4.22 (d, 7=1.2 Hz, 3 H), 7.13 (d, 7=8.1 Hz, 1 H), 7.62 - 7.68 (m, 1 H), 7.69 - 7.76 (m, 1 H), 7.95 (d, 7=1.2 Hz. 2 H), 8.11 (s, 2 H), 8.22 (s, 1 H). 8.35 (d, 7=8.5 Hz, 1 H), 8.49 - 8.55 (m, 1 H), 8.73 - 8.79 (m, 1 H).

Example 422

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-ethoxyisoquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 422

LCMS (ESI): mass calcd. for C23H16CIF3N8O2 528.1 m/z found 529.1 [M+Hf. Ή NMR (400 MHz, CHLOROFORM-7) δ ppm 1.56 (t, 7=7.1 Hz, 3 H), 4.67 (q, 7=6.9 Hz, 2 H), 7.12 (d, 7=8.1 Hz, 1 H), 7.60 - 7.68 (m, 1 H), 7.68 - 7.75 (m, 1 H), 7.96 (s, 2 H), 8.09 (s, 1 H). 8.23 (s, 1 H), 8.31 (br s, 1 H), 8.38 (d, 7=8.1 Hz, 1 H), 8.54 (d, 7=2.0 Hz, 1 H), 8.78 (s. 1 H).

715

Example 448

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-hydroxyisoquinolin-4-yl)-5(trifluoromethyl )-1 H-pyrazole-4-carboxamide. Cpd 448

N-( 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-1 -( 1 -chloroisoquinolin-4-yl)-5(trifluoromethyl)-lH-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 h. The reaction mixture was concentrated to dryness and the residue was dissolved in 50 mL DCM. The solution was 10 poured into 50 mL of water. The mixture was made basic with NacCO? and stirred for 1 5 min. The layers were separated and the aqueous layer was extracted with DCM. The organic layer was dried over MgSÜ4, filtered, and the filtrate concentrated. The residue was purified by flash column chromatography over silica gel (eluent: DCM /MEOH ratio 5/95) to afford cpd 448 (600 mg, 62%). LCMS (ESI): mass calcd. For CciHicCIFsNsOc 15 500.1, m/z found 501.1 [M+H]⁺. ^JH NMR (400 MHz, DMSO4) δ ppm 6.78 (d. 08.1 Hz,

H), 7.58 - 7.65 (m, 1 H), 7.74 - 7.82 (m. 1 H), 7.86 (s, 1 H), 8.18 (s, 2 H). 8.29 (dd, 08.1,0.8 Hz. 1 H), 8.51 (s. 1 H), 8.67 (d, 02.0 Hz, 1 H), 8.84 (d, 02.0 Hz, 1 H). 11.53 (brs, 1 H).

Example 423

N-( 5-chloro-6-(2H-1,2,3-triazol-2-yl )pyridin-3-yl )-1 -(2-methyl-1 -oxo-1.2dihydroisoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 423

716

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )-1 -( I -hydroxyisoquinolin-4-yl)5-(trifluoromethyl)-lH-pyrazole-4-carboxamide (190 mg, 0.307 mmol, purity 81%)) Cs2CO₃ (100 mg, 0.307 mmol) and iodomethane (43.6 mg. 0.307 mmol) in DMA (2 mL) were stirred at rt for 4 h. The reaction mixture was poured into 20 mL of water. The mixture was extracted 3 x with ethyl acetate and the organic layer was washed with 20 mL water. dried over MgSO₄, filtered, and the filtrate concentrated. The residue was purified via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 gm, 50 x l?0 mm. Mobile phase: 0.25% NH₄HCO₃ solution in water, CH₃CN). The pure fractions were collected and concentrated. The residue was dissoived in water and extracted with ethyl acetate. The organic layer was dried over MgSO₄, filtered, and the filtrate concentrated. The residue was stirred. in diisopropylether, the solid collected by filtration and then filtered off and dried to afford cpd 423 ( 155 mg, 98%). LCMS (ESI): mass calcd. For C22H14CIF3NSO2 514.1, m/z found 515.1 [M+H]*. Ή NMR (400 MHz, DMSO-» δ ppm

3.60 (s. 3 H), 6.82 (d. 7=8.1 Hz, 1 H), 7.65 (t, 7=7.6 Hz. 1 H), 7.79 (t, 7=7.1 Hz, 1 H), 8.19 (s. 2 H), 8.23 (s, 1 H), 8.34 (d. 7=7.7 Hz. 1 H), 8.55 (s, 1 H), 8.67 (d. 7=2.0 Hz. 1 H), 8.86 (d, 7=2.4 Hz, 1 H), 11.26 (br s, 1 H).

Example 424

N-(5-chloro-6-(2H-L2.3-triazol-2-yl)pyTidin-3-yl)-l-(7-chIoiOthieno[2.3-c]pyridin4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide. Cpd 424

717

A mixture of 4-(4-((5-chloro-6-(2H-I,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-lH-pyrazol-l-yl)thieno[2,3-c]pyridine 6-oxide (2900 mg, 5.72 mmol) and POCh (100 mL) was stirred at 60 °C for 16 h. 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 basic with NaiCOj and then stirred for 15 min. The layers were separated and the aqueous layer was extracted with DCM. The organic layer was dried and concentrated. The residue was purified by flash column chromatography over silica gel (DCM /MEOH ratio from 2/98 to 95/ 5) to afford a crade compound (2.55 mg, 85%). A portion of the crude compound (150 mg) was purified via Prep SFC (Stationary phase: Chiralpak Daicel IC 20 x 250 mm. Mobile phase: CO?, EtOH - 0.4 iPrNH?) to afford cpd 424 (104 mg). LCMS (ESI): mass calcd. for CwHgChFsNsOS 524 m/z found 525[M+H]T ‘H NMR (400 MHz, DMSO-Λ) δ ppm 7.29 (d, >5.3 Hz, 1 H), 8.18 (s, 2 H). 8.45 (d, >5.3 Hz, I H), 8.61 (s, 1 H), 8.64 (s, 1 H), 8.67 (d,>2.4 Hz, 1 H), 8.85 (d,>2.0 Hz. 1 H), 11.27 (br s. 1 H).

Following the procedure described in Example 424, above, selecting and substituting the appropriate reagents, starting materials. and purification methods, and adjusting reaction températures, times and other variables or parameters, as needed or désirable, as would be readily recognized by those skilled in the art. the following compounds were prepared:

Example 426

N-(5-chIoro-2-methyI-6-(2H-L2,3-triazol-2-yl)pyridm-3-yl)-l-(7-chloiOthieno[2.3c]pyridin-4-yl)-5-(trifluoromethyl )-1 H-pyrazoIe-4-carboxamide, Cpd 426

718

LCMS (ESI): mass calcd. for CcoHnCLFsNsOS 538 m/z found 539 [M+H] . *H

NMR (400 MHz, DMSO-X) δ ppm 2.57 (s. 3 H), 7.31 (d. 7=5.3 Hz, 1 H). 8.19 (s. 2 H), 8.43.8.49 (m, 2 H), 8.61 (s. 1 H), 8.63 (s. 1 H), 10.63 (br s. I H).

Example 427 (R)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-( l-(3-hydroxypyrrolidin-lyl)isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 427

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-chloroisoquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide (250 mg, 0.48 mmol), (R)-3hydroxvpyrrolidine (87 mg, 0.96 mmol) and CscCCh ( 314 mg, 0.96 mmol) in DMSO (2 mL) were stirred at 80 °C for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO₄. fïltered. and the filtrate concentrated. The residue was purified via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 μιη,50 xl50 mm. Mobile phase: 0.25% NH4HCO3 solution 111 water, CH3CN) to afford cpd 427 (90 mg, 33%). LCMS (ESI): mass calcd. for C25H19CIF3N9O2 569.1 m/z found 570.2[M+H]⁺. X NMR (400 MHz, DMSO-X) δ ppm 1.91 - 2.00 (m, 1 H),2.00-2.11 (m. 1 H), 3.68 (br d, 7= 11.4 Hz, 1 H),3.85 (ddd. <7=10.8, 7.9, 2.8 Hz. 1 H), 4.10 (br d, 7=10.2 Hz, 2 H), 4.39 - 4.48 (m, 1 H), 5.04 (d, <7=3.3 Hz, 1 H), 6.92 (d, 7=8.5 Hz, 1 H), 7.58 (t, 7=7.7 Hz, 1 H), 7.71 (t. 7=7.6 Hz, 1 H). 8.10 (s, l H),

719

8.19 (s, 2 H). 8.43 (d, >8.5 Hz, 1 H), 8.50 (br s. 1 H), 8.67 (d. >2.4 Hz, 1 H), 8.85 (d, >2.0 Hz. 1 H), 11.25 (br s, 1 H).

Following the procedure described in Example 427, above. selecting and substituting the appropriate reagents, starting materials, and purification methods, and adjustmg reaction températures, times and other variables or parameters, as needed or désirable, as would be readily recognized by those skilled in the art, the following compounds were prepared:

Example 429

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(methylthio)isoquinolin-4-yl)-5(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 429

LCMS (ESI): mass calcd. for C22H14CIF3N8OS 530.1 m/z found 531.1 [M+H] . 'H NMR (400 MHz, DMSO-Y) δ ppm 2.76 (s. 3 H), 7.21 (d. >8.1 Hz, 1 H), 7.82 - 7.88 (m, 1 H), 7.91 - 7.97 (m, 1 H), 8.19 (s, 2 H), 8.34 (d, >8.5 Hz. 1 H), 8.60 (s, 1 H), 8.65 (s, 1 H), 8.68 (d. >2.0 Hz, 1 H). 8.85 (d,>2.4 Hz, 1 H). 11.27 (br s, 1 H).

Example 430

N-(5-chloro-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)-lH-pyrazole-4-carboxamide, Cpd 430

720

LCMS (ESI): mass calcd. for C22H15CIF3N9O2S 561.1 m/z found 562[M+H|g ‘H NMR (400 MHz, DMSO-7₆) δ ppm 4.12 (dd. 7=9.3, 4.4 Hz, 2 H). 4.55 - 4.62 (m, 2 H). 4.67 (br d. 7=6.2 Hz, 1 H), 5.82 (br s. 1 H), 6.94 (d, 7=5.5 Hz, 1 H), 8.07 (s, 1 H), 8.14 (d, 5 7=5.3 Hz, 1 H), 8.18 (s, 2 H), 8.48 (s, 1 H), 8.66 (d, 7=2.0 Hz, 1 H), 8.84 (d, 7=2.0 Hz. 1

H), 11.14 (br s, 1 H).

Example 431 (S)-N-(5-chloro-6-(2H-L2,3-triazoI-2-yl)pyridin-3-yl)-l-(7-(3-hydroxypyrrolidin-l10 yl)thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-l H-pyrazole-4-carboxamide, Cpd 431

LCMS (ESI): mass calcd. For C23H17CIF3N9O2S 575 m/z found 576 [M+H]⁺. 'H NMR (400 MHz, DMSOU) δ ppm 1.93 - 2.03 (m, 1 H) 2.04-2.18 (m, 1 H). 3.82 (br d. 7=11.0 Hz, 1 H), 3.90 - 4.06 (m, 3 H), 4.46 (br s. 1 H), 5.10 (d, 7=3.7 Hz, 1 H), 6.87 (d, 15 7=5.3 Hz. 1 H), 8.02 (s, 1 H), 8.11 (d, 7=5.3 Hz, 1 H), 8.19 (s, 2 H), 8.47 (s, 1 H), 8.66 (d,

7=2.4 Hz, 1 H), 8.84 (d, 7=2.0 Hz. 1 H), 11.23 (br s. 1 H).

Example 432 (R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-( 3-hydroxypyrrolidin-l20 yl)thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 432

721

LCMS (ESI): mass calcd. for C23H17CIF3N9O2S 575.1 m/z found 576.1 [M ; H] . 'H NMR (400 MHz, DMSO-7₆) δ ppm 1.93 - 2.03 (m, 1 H), 2.04 - 2.21 (m, 1 H), 2.10 (m, 7=13.0, 8.7, 8.7, 4.3 Hz, 1 H), 3.82 (br d, 7=1 LO Hz, 1 H), 3.90 - 4.07 (m, 3 H), 4.46 (br s, 1 H), 5.10 (br d, 7=2.8 Hz, 1 H). 6.87 (d, 7=5.3 Hz, I H), 8.02 (s, 1 H), 8.11 (d, 7=5.3 Hz, 1 H), 8.19 (s, 2 H), 8.48 (s, 1 H), 8.66 (d, 7=2.0 Hz, 1 H), 8.85 (d, 7=2.4 Hz, 1 H), 11.21 (br s, 1 H).

Example 433

N-(5-chloro-2-methyl-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(7-(3-hydroxyazetidin-lyl)thieno[2,3-c]pyridin-4-yl)-5-(trifluoromethyT)-lH-pyrazole-4-carboxamide, Cpd 433

LCMS (ESI): mass calcd. For C23H17CIF3N9O2S 575.1 m/z found 576.1 j M H | . ‘H NMR (400 MHz, DMSO-7&) δ ppm 2.57 (s, 3 H), 3.33 (dd,7=10.4, 9.2 Hz, 1 H), 4.13 (br dd, 7=8.5, 4.5 Hz, 2 H), 4.58 (br t, 7=7.5 Hz, 2 H), 4.65 - 4.73 (m, 1 H), 6.97 (d, 7=5.3 Hz, 1 H). 8.07 (s, 1 H), 8.14 (d, 7=5.3 Hz, 1 H), 8.19 (s, 2 H). 8.43 (s. 1 H), 8.53 (s, 1 H).

Example 434

N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(7-methylthieno[2,3-c]pyridin-4-yl)5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 434

722

N-(5-chloiO-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(7-chlorothieno[2,3-c]pyridin4-yl)-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide (I3l mg, 0.25 mmol), methylboronic acid (60 mg, l mmol) and K3PO4 (212 mg, l mmol) were suspended in dioxane (20 mL) and water (3 mL). PdChfdppO.CILCb (20.5 mg, 0.025 mmol) was added and nitrogen gas was bubbled through the reaction mixture for 15 min, then heated at 100 °C ovemight. The reaction mixture was poured into 20 mL of water, extracted with ethyl. acetate (3x) and the organic layer was washed with 10 mL of water. The organic layer was then dried over MgSCU, filtered, and the filtrate concentrated. The residue was purified via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-ΙΟμιη, 30 x l?0 mm. Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to afford cpd 434 (15 mg, 12%). LCMS (ESI): mass calcd. For C20H12CIF3N.SOS 504.1 m/z found 505.1 [M+H]’.

Following the procedure described in Example 434, above, selecting and substituting the appropriate reagents, starting materials, and purification methods, and adjusting reaction températures, times and other variables or parameters, as needed or désirable, as would be readily recognized by those skilled in the art, the following compounds were prepared:

Example 435

N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(7-cyck)propylthieno[2,3-c]pyridin-4yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 435

723

LCMS (ESI): mass calcd. For C22H14CIF3NSOS 530.1 m/z found 531 [M : H] .

The following compounds were prepared via séparation of enantiomers using Prep

SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH with 0.1% triethylamine). The pure fractions were collected, concentrated and the residues were stirred in diisopropylether, the solid collected by filtration, and then dried to give pure enantiomers (the steric centers are arbitrarily sassigned).

IO

Example 436 (*R)-N-(5-_chi_oro-6-(2H-L2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(tetrahydrofuran-2yl)isoqumolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 436

LCMS (ESI): mass calcd. for C25H18CIF3NSO2 >54.1, m/z found 555.2 [M+H]”. ^!H

NMR (400 MHz, DMSO-Λ) δ ppm 2.01 - 2.18 (m, 2 H), 2.31 - 2.43 (m, 1 H), 2.56-2.71 (m, 1 H), 3.60 (spt, <7=6.0 Hz, 1 H), 3.89 - 4.05 (m, 2 H), 5.82 (t, <7=6.9 Hz, 1 H), 7.26 (d, .7=8.1 Hz, 1 H), 7.83 - 7.89 (m, 1 H), 7.90 - 7.97 (m, 1 H), 8.19 (s, 2 H), 8.61 - 8.66 (m, 2 H), 8.69 (d. <7=2.0 Hz, 1 H), 8.74 (s, 1 H), 8.87 (d, <7=2.4 Hz, 1 H).

724

Example 437 (*S)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(tetrahydiOfaran-2yl)isoquinolin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 437

LCMS (ESI): mass calcd. for C25H18CIF3N8O2 554.1, m/z found 555.2 [M+H] . ^lH NMR (400 MHz, DMSO-» δ ppm 2.01 - 2.20 (m, 2 H), 2.31 - 2.42 (m, l H), 2.54 - 2.72 (m, l H), 3.55 - 3.68 (m, l H), 3.89 - 4.08 (m, 2 H), 5.82 (t, 7=6.9 Hz, I H), 7.26 (d, 7=8.1 Hz, l H), 7.83 - 7.89 (m, l H), 7.90 - 7.98 (m, l H), 8.19 (s, 2 H), 8.6I - 8.66 (m, 2 H), 8.69 (d, 7=2.4 Hz, l H), 8.74 (s. I H), 8.87 (d, 7=2.4 Hz, l H).

IO

Example 438 (*R)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(4-oxotetraliydroftiran-2yl)isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 438

LCMS (ESI): mass calcd. for C25H16CIF3N8O3 568.1 m/z found 569 [M=H] .

Example 439 (*S)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(l-(4-oxotetrahydrofuran-2yl)isoquinolin-4-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 439

Cl A

Y

LCMS (ESI): mass calcd. for C25H16CIF3N8O3 568.1 m/z found 569 IM H| .

Example 440 (*R)-N-(5-chloiO-6-(2H-L2,3-triazol-2-yl)pyndin-3-yl)-l-(2-(tetrahydroftiran-2yl)quinolin-5-yl)-5-(trifluoromethyl)-l H-pyrazole-4-carboxamide, Cpd 440

LCMS (ESI): mass calcd. for CgsHisClFiNsOc 554.1 m/z found 55?.l[M+H]L

IO Example 441 (*S)-N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(2-(tetrahydiOfuran-2yl)quinolin-5-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide, Cpd 441

726

LCMS (ESI): mass calcd. for C25H18CIF3N8O2 554.1 m z found 555.2[M+H]

Example 442 (*R)-N-(5-chloiO-6-(2H-L2.3-triazol-2-yi)pyridin-3-yl)-l-( l-(l-hydroxyethyl)isoquinolin4-yl)-5-(trifluoromethyl)-1 H-pyrazoIe-4-carboxamide, Cpd 442

LCMS (ESI): mass calcd. for C23H16CIF3N8O2 528.1 m/z found 529.2 [M+H] .

Example 443 (’S)-N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyridm-3-yl)-l-(l-(l-hydiOxyethyl)isoqumolm4-yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxamide, Cpd 443

LCMS (ESI): mass calcd. for C23H16CIF3N8O2 528.1 m/z found 529.1 j XI 111 .

Example 444 (*R)-N-(5-chloro-6-(2H-L2,3-triazol-2-yl)pyTidin-3-yl)-l-(l-( l-hydroxyethyl)isoqumolin5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 444

727

LCMS (ESI): mass calcd. for CzsHiéClFsNgCh 528.1 m/z found 529[M+H] JH NMR (400 MHz, DMSO-Λ) δ ppm 1.62 (d, 7=6.5 Hz, 3 H), 5.52 - 5.74 (m, 2 H), 6.93 (d, 7=6.1 Hz, 1 H). 7.88 (m, 7=8.5, 7.7 Hz. 1 H), 8.09 (d, 7=6.9 Hz, 1 H). 8.20 (s, 2 H), 8.53 5 (d,7=6.1 Hz, 1 H),8.61 (s, 1 H), 8.69 (d, 7=2.4 Hz. 1 H), 8.88 (d, 7=2.0 Hz, 1 H), 11.18I1.52(m, 1 H), 11.29 (s, 1 H).

Example 445 (*S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-(1 -hydroxyethyl )isoquinolin-

5-yl )-5-( trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 445

Cl N^\ . /A / . Λ .'·

Z °

LCMS (ESI): mass calcd. for CisHieClFsNsOi 528.1 m/z found 529[M+H] .‘H

NMR (400 MHz, DMSO-Λ) δ ppm 1.62 (d, 7=6.5 Hz, 3 H), 5.52 - 5.74 (m, 2 H), 6.93 (d, 7=6.1 Hz, 1 H), 7.88 (m, 7=8.5, 7.7 Hz, 1 H), 8.09 (d, 7=6.9 Hz, 1 H), 8.20 (s, 2 H), 8.53 15 (d, 7=6.1 Hz, 1 H), 8.61 (s, 1 H), 8.69 (d, 7=2.4 Hz, 1 H), 8.88 (d, 7=2.0 Hz, 1 H), 11.18 11.52 (m, 1 H), 11.29 (s. 1 H).

728

Biological Examples

In vitro assays include assays that détermine cell morphology, protein expression, and/or the cytotoxicity. enzyme inhibitory' activity, and/or the subséquent functional conséquences of treatment of cells with compounds of the invention. Alternate or additionai in vitro assays may be used to quantitate the ability of the inhibitor to bind to protein or nucleic acid molécules within the cell.

Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/target molécule complex and determining the amount of radiolabel bound. Alternatively or additionally, inhibitor binding may be determined by running a compétition experiment where new inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands. Detailed conditions of exemplary Systems for assaying a compound of Formula (I) of the présent invention as MALTl inhibitors are set forth in the Biological Examples below.

Such assays are exemplary and not intended to limit the scope of the invention. The skilled practitioner can appreciate that modifications can be made to conventional assays to develop équivalent or other assays that can be employed to comparably assess activity or otherwise characterize compounds and/or compositions as described herein.

In Vitro Assays

Biological Example 1

MALTl Biochemical Protease Assay

MALTl protease activity was assessed in an in vitro assay using a tetrapeptide as substrate and full-length MALTl protein (Strep-MALTl(l-824)-His) purified from baculovirus-infected insect cells. The tetrapeptide LRSR is coupled to AMC (7-amino-4methylcoumarin) and provides a quenched, fluorescent substrate for the MALTl protease (SM Biochemicals). Cleavage of AMC from the Arginine residue results in an increase in coumarin fluorescence measured at 460 nm (excitation 355 nm). The final assay buffer consisted of 10 nM FL MALTl protein, 200 μΜ 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

729 spotted at 50 n.L in 100% DMSO per well of a black 384-Proxiplate (Perkin Elmer). Test compound concentrations ranged from 30 μΜ to 0.5 nM using 11 dilution steps (1:3). Background signal was measured from control wells containing assay buffer without enzyme which functions as low control (LC). High control (HC) values were generated using the reaction with enzyme but no compound treatment. Compounds w-’ere preincubated with MALT1 enzyme for 50 minutes at RT. Substrate was added subsequently and fluorescence was measured in Labsystems fluoroskan at excitation 355 nm and émission 460 nm to determme time 0. The reaction was subsequently incubated for 4 h at RT and fluorescence was measured. For ICso calculations, timepoint 0 was subtracted from the 4 h timepoint to correct for any potential autofluorescence of the compounds. The enzyme reaction was linear during the 4 h incubation period. Characterization of the substrate Ac-LRSR-AMC determined the Michaelis constant Km at 200 μΜ.

ICso values were calculated using the following formula (Z prime should be >0.5):

LC = Médian of the low control values = Low control: Reaction without cells HC = Médian of the High control values = High Control: Reaction with cells without compound %Effect = 100-[(sample-LC) / (HC-LC) x 100] %Control = (sample /HC) x 100 %Controlmin = (sample-LC) / (HC-LC) x 100

A best-fit curve was fïtted by a minimum sum of squares method to the plot of %Controlmin vs. compound concentration, From this an IC50 value (inhibitory concentration causing 50 % inhibition) can. be obtained. An estimate of the slope of the plot in ternis of the Hill coefficient was also obtained.

I C50 Calculation:

DA TAi = LB + UB - LB + s, cxpdlILL NLCONC.-IC50))

With

730

UB = upper bound

LB = lower bound

Used in “Lexis Dose Response Curve Fitting” Version l .0. Résultant data are shown in

Table 2.

Cpd No.	MALUBiochemical activity (Ac-LRSR-amc) IC50 (μΜ)	Cpd No.	MAL TlBiochemical activity (Ac-LRSR-amc) 1C50 (μΜ)
1	0.389	227	1.148
2	0.012	228	1.122
3	0.191	229	1.122
4	0.200	230	1.072
	0.214	231	0.891
6	0.091	232	0.891
7	0.041	233	0.871
8	0.013	234	0.851
9	0.065	235	0.776
11	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
30	5.012	255	0.275
31	8.913	256	0.240
32	0.019	257	0.234
33	1.096	258	0.229

731

Cpd No.	MALTlBiochemical activity (Ac-LRSR-amc) K 50 (μΜ)	Cpd No.	MALTlBiochemical activity (Ac-LRSR-amc) IC50 (μΜ)
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
41	¢).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	0.63 1	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
	0.182	280	0.126
56	0.257	281	0.123
57	0.043	282	0.123
58	0.141	283	0.123
59	0.03 1	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

732

Cpd No.	MALT IBiochemical activity (Ac-LRSR-amc) IC50 (μΜ)	Cpd No.	MALTlBiochemical activity (Ac-LRSR-amc) IC50 (μΜ)
73	0.724	298	1.349
74	0.372	299	0.105
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
109	0.010	334	0.417
110	0.019	335	0.174
111	0.010	336	0.214

733

Cpd No.	MALTlBiochemical activity (Ac-LRSR-amc) IC50 (μΜ)	Cpd No.	MALTlBiochemical activity (Ac-LRSR-amc) IC50 (μΜ) _____
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	¢).015	352	0.044__________
128	0.016	353	0.1 15
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
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__________

734

Cpd No.	MALTIBiochemical activity (Ac-LRSR-amc) 1C50 (μΜ)	Cpd No.	MALTIBiochemical activity (Ac-LRSR-amc) IC50 (μΜ)
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	θ·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
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	0.380	411	0.033
187	0.178	412	0.022
188	0.115	413	0.288
189	0.078	414	0.019

735

Cpd No.	MALTlBiochemical activity (Ac-LRSR-amc) IC50 (μΜ)	Cpd No.	MALTlBiochemical activity (Ac-LRSR-amc) IC50 (μΜ)
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 Ί	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
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

736

Biological Example 2

PMA Induced IL2 Production In Jurkat Cells

Jurkat cells were maintained in complété RPMI 1640 media containing 10% fêtai bovine sérum, lOmM HEPES, 100 umts/mL of penicillin and 100 pg/mL of streptomycin. Prior to the assay, compounds were made 2- to 4-fold serial dilutions in DMSO. A volume of 10 pL of DMSO-diluted compound in each well were further diluted into 240 pL RPMI 1640 complété media. Jurkat cells were harvested by centrifuge at 1200RPM for 5 min. washed one time with RPMI 1640 media, and suspended in fresh complété RPMI

1640 media at concentration of 1.25 x 10⁶ cell/mL. A volume of 160 uL of Jurkat cells (z x 10⁵ cells) were seeded in each well of 96 well plate-bottom plates. A volume of 20 uL of diluted compound in RMPI 1640 complété media were added to each well and incubated with Jurkat cells for 30 mm at 37 °C in a 5% CO2 incubator. A volume 20 pL of diluted PMA / lonomycin (81 nM / 1.3 uM respectively, ebioscience, catalog number 00-4970-93) in RMPI 1640 complété media were added to each well. After incubation at 37 °C in 5% CO2 incubator for 20 h, supernatants were harvested. IL-2 concentration was assessed by ELISA (IL2 Duoset, R&D Systems, catalog number DY202). Colorimétrie intensity at 450 nm was read by Spectramax plate reader and analyzed with Softmax Pro software. Cell viability was assessed by Cell Titer Glo kit (Promega, catalog number G7571) using

Victor Luminescence reader (Victor 3N 4202938 by Perkin Elmer).

Résultant data are shown in Table 3.

Biological Example 3 Human IL6 II. iI Mesoscale Assay

NFkB signaling régulâtes the sécrétion of multiple cytokines, including IL6 and

IL10. Sécrétion of the cytokines IL6 and IL10 by TMD8 or OCI-LN 3 ABC-DLBCL cells was measured using a mesoscale assay. Inhibition of NFkB signaling by MALTl or ΒΤΚ inhibitors results in a decrease of IL6/1Ü sécrétion.

TMD8 or OCI-LY3 cells were propagated in RPMI-1640 (Sigma Aldrich) supplemented with 10% fêtai bovine sérum (HyClone), 1 mM sodium pyruvate

737 (Invitrogen), 2 mM L-glutamine (Sigma Aldrich) and l% PenStrep (Sigma Aldrich). Cell passage number should not exceed 30. Cells should be kept between 0.5 - 2.5 million cells per mL during culturing and cells should be supplemented every 2-3 days with fresh 50 μΜ beta-mercaptoenthanol. No beta-mercaptoethanol was used during the mesoscale assay.

For the Mesoscale assay, 100,000 TMD8 or OCI-LY3 cells were seeded per well into black-colored 96-well plates with clear bottom (Corning #3904) and test compounds were added in 9 dilution steps (1:2) ranging from 15 μΜ to 58.6 nM (final DMSO concentration 0.3%). DMSO control wells were used to déterminé the maximum signal (High Control (HC)). Treatment with the BTK inhibitor RN486 in a dose range from 30 nM to 131 pM (9 dilutions of 1:2) served as a positive control for NFkB pathway inhibition and was used to détermine the maximum inhibition (Low Control (LC)). Compounds and cells were incubated for 24 h at 37 °C and 5% CO₂ (assay volume is 150 pL). After 24 h of incubation 50 pL of the supematant was transferred to a MSD plate (V15 Plex Proinflammation Panel 1 (human) kit, Mesoscale (MSD)) and incubated for 2 h with vigorous shaking (600 rpm) at room température. Foilowing incubation, plates were washed 3x with PBS + 0.05% Tween-20 and 25 pL détection antibody solution (IL6 & IL 10 antibodies in diluent 3 (MSD)) was added per well tollowed by 2 h of incubation with vigorous shaking (600 rpm) at room température. After 3x washes with PBS + 0.05%

Tween-20, plates were incubated with 150 pL 2x Rend Buffer T and read on SECTOR imager. Résultant data are shown in Table 3.

Table 3.

Cpd No.	Human IL6 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL10 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL6 Mesoscale assay (OCI-LY3) IC50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	IL-2 prod h Jurkat PMA 1C50 (pM)
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

738

Cpd No.	Human IL6 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL10 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL6 Mesoscale 3SS3V (OCI-LY3) IC50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	IL-2 prod h Jui kat PMA IC50 (μΜ)
6	0.112				0.023
7	0.166				0.13
8	0.032				0.0052
9	0.195				0.039
11	-13.5				0.68
16	1.479
17	0.794				0.17
19	1.950				0.41
21	>15
22	>15				1.86
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			0.03 1
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

739

Cpd No.	Human IL6 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL10 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL6 Mesoscale assay (OCI-LY3) IC50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	IL-2 prod h Jurkat PMA IC50 (μΜ)
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	¢.).074
61	0.263	0.224
62	0.112	0.085
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		9
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	¢).302
96	1.047	0.676
97	0.575	0.257
98	0.468	0.417
99	0.068	0.047

740

Cpd No.	Human IL6 Mesoscale assay (TMD-8) IC 50 (μΜ)	Human IL10 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL6 Mesoscale assay (OCI-LY3) 1C50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	IL-2 prod h Jm kat PMA IC150 (μΜ)
100	0.251	0.155
102	0.110	0.186
103	>15	>15
104	>15	>15
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	¢).083
136	0.045	0.03 1
137	0.170	0.200	0.026	0.017

741

Cpd No.	Human IL6 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL10 Mesoscale assay (TMD-8) IC50 (μΜ)	Human 1L6 Mesoscale assay (OCI-LY3) IC50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	IL-2 prod h Jurkat PMA IC50 (μΜ)
138	0.245	0.126
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	¢).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
173	0.550	0.240
174			0.251	0.112

742

Cpd No.	Human IL6 Mesoscale assay (TMD-8) 1C50 (μΜ)	Human IL10 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL6 Mesoscale assay (OCI-LY3) IC50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	IL-2 prod h Jurkat PMA IC50 (μΜ)
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
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			]_____________________

743

Cpd No.	Human IL6 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL1Ü Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL6 Mesoscale assay (OCI-LY3) IC50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	IL-2 prod h Jurkat PMA IC50 (μΜ)
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
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

744

Cpd No.	Human IL6 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL10 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL6 Mesoscale assay (OCI-LY3) IC50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	IL-2 prod h Jm kat PMA IC50 (μΜ)
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
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

745

Cpd No.	Human IL6 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL10 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL6 Mesoscale assay (OCI-LY3) IC50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	IL-2 prod h Jurkat PMA IC50 (μΜ)
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
309			0.15 1	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

746

Cpd No.	Human IL6 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL10 Mesoscale assay (TMD-8) IC50 (μΜ)	Human 1L6 Mesoscale assay (OCI-LY3) IC50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	IL-2 prod h Jurkat PMA IC50 (μΜ)
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
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	___

747

Cpd No.	Human IL6 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL10 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL6 Mesoscale assay (OCI-LY3) 1C50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	1L-2 prod h Jurkat PMA IC 50 (μΜ)
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			0.1 15	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
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

748

Cpd No.	Human IL6 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL1Ü Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL6 Mesoscale assay (OCI-LY3) IC50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	IL-2 prod h Jurkat PMA IC50 (μΜ)
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
411	2.512	2.344
412			1.778	0.912
413	>1.514	0.380
414	>15.136	0.955
415	0.095	0.093
416	>15.136	>15.136
417			0.437	0.309
418			0.095	0.071
419			1.660
420			0.447	0.339
421			0.457	0.479
422			0.191	0.174
423			0.123	0.044
424			0.166	0.182
425	0.339	0.112
426	0.091	0.060
427			0.204	0.158
428	0.550	0.240
429			0.251	0.112
430	>3.02	0.204
431			0.117	0.095
432	0.933	0.363
433			0.589	0.427

749

Cpd No.	Human IL6 Mesoscale assay (TMD-8) IC50 (μΜ)	Human IL10 Mesoscale assay (TMD-8) 1C50 (μΜ)	Human 1L6 Mesoscale assay (OCI-LY3) IC50 (μΜ)	Human IL10 Mesoscale assay (OCILY3) IC50 (μΜ)	IL-2 prod h Jurkat PMA IC50 (μΜ)
434			0.288	0.174
435			0.079	0.081
436			0.141	0.110
437	/.586	2.512
438	6.607	2.138
439	4.266	1.000
440	0.186	0.162
441			1.122	0.891
442			0.162	0.112
443	0.046	0.050
444	0.107	0.063	0.039	0.027
445			0.186	0.093
446			0.022	0.013
447			0.046	0.042
448			0.117	0.079
449	0.078	0.098	0.100	0.068
450			0.107	0.071

Biological Example 4

Prolifération Assays

To assess anti-proliferative effects, MALTl inhibitor test compounds were tested in 4-day prolifération assays using three different DLBCL cell lines. Two ABC-DLBCL cell lines with activating mutations in the classical NFkB pathway w'ere evaluated (0CI-Ly3 (CARDl L MYD88 & A20 mutations), TMD8 (CD79B & MYD88 mutations), which are generally sensitive to NFkB pathway inhibition. A GCB-DLBCL cell line (0CI-Ly7), which has not been shown to hâve active NFkB signaling, served as a négative control to exclude compounds wath general cytotoxic effects.

0CI-Ly3 cells were propagated in RPMI-1640 (Sigma Aldrich) supplemented with 10% fêtai bovine sérum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and l% PenStrep

750 (Sigma Aldrich). TMD8 cells were propagated in RPMI-1640 (Sigma Aldrich) supplemented with 10% fêtai bovine sérum (HyClone), 1 mM sodium pyruvate (Invitrogen), 2 mM L-glutamine (Sigma Aldrich) and 1% PenStrep (Sigma Aldrich). Cells should be kept between 0.5 - 2.5 million cells per mL during culturmg and cells should be supplemented every 2-3 days with fresh 50 μΜ beta-mercaptoenthanol. No betamercaptoethanol is used during the prolifération assay. OCI-Ly7 cells were propagated in IMDM (ThermoFisher) supplemented with 10% fêtai bovine sérum (HyClone), 2 mM Lglutamine (Sigma Aldrich) and 50 pg/mL Gentamycin. Cell passage numbers should not exceed 30 (for OCI-Ly3 cells with passage number lower than 10 were used).

To assess anti-proliferative effects, 400 nL of test compounds were spotted per well of 96-well plates (Costar, catalogue number 3904). 10,000 TMD8, 10,000 OCI-Ly3 or 2,000 OCI-Ly7 cells were seeded in 100 pL media per well and incubated for 4 days at 37 °C and 5% CO2. Cell plating numbers were chosen based on growth curves to ensure linear cell growth. After 4 days of incubation 50 pL CellTiterGLO reagent (Promega) were added to each well and luminescence was measured on the Envision after 10 min of incubation at room température.

IC50 values were calculated using the following formula (Z prime should be >0.5):

LC = médian of the low control values = Low control: Reaction without cells

HC = Médian of the High control values = High control: Reaction with cells without compound %Effect = 100 - (sample-LC) / (HC-LC) x 100 %Control = (sample/HC) x 100 %Controlmm = (sample-LC) / (HC-LC) x 100

751

A best-fit curve was fitted by a minimum sum of squares method to the plot of %Control vs compound concentration. From this an IC50 value (inhibitory concentration causing 50 % cytotoxicity) can be obtained. An estimate of the slope of the plot in terms of the Hill coefficient was also obtained.

IC50 Calculation:

DATA, = LB + UB - LB + ε, J +exp(HILL *(LCONC,-IC50))

With

UB = upper bound

LB = lower bound

Résultant data are shown in Table 4.

Table 4.

Cpd No.	Antiproliferation: OCI-LY-3 IC50 (μΜ)	Antiproliferation: TMD-8 1C50 (μΜ)
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
11	—9.55	12.59
16	0.58	10.72
17	-4.37	9.33
19	1.10	>20

752

Cpd No.	Antîproliferation: OC1-LY-3 IC50 (μΜ)	Antiproliferation: TMD-8 IC50 (μΜ)
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
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

753

Cpd No.	Antiproliferation: OCI-LY-3 IC50 (μΜ)	Antiproliferation: TMD-8 K 50 (μΜ)
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

754

Cpd No.	Antiproliferation: OCI-LY-3 IC50 (μΜ)	Antiproliferation: TMD-8 IC50 (μΜ)
84	1.7	>20
85	1.66	>20
86	0.78	11.22
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

755

Cpd No.	Antiproliferation: OCI-LY-3 IC50 (μΜ)	Antiproliferation: TMD-8 IC50 (μΜ)
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
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

756

Cpd No.	Antiproliferation: OCI-LY-3 IC50 (μΜ)	Antiproliferation: TMD-8 IC50 (μΜ)
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
178	2.802	>19.953
179	0.763	1.950
181	1.496	>7.943
182	3.144	5.248

757

Cpd No.	Antiproliferation: OCI-LY-3 IC50 (μΜ)	Antiproliferation: TMD-8 IC50 (μΜ)
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

758

Cpd No.	Antiproliferation: OCI-LY-3 IC50 (μΜ)	Antiproliferation: TMD-8 IC50 (μΜ)
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 Studies 5

The 0CI-Ly3 (DSMZ, catalog number ACC 761) human diffuse large B-cell lymphoma tumor cells may be maintained in vitro in RPMI medium supplemented with heat inactivated fêtai bovine sérum (10% v/v) and 2mM L-Glutamine 200 mM at 37 °C m an atmosphère of 5% CO₂ in air. The cells may be routinely subcultured once weekly.

The cells growing in an exponential growth phase may be harvested and counted, and cell suspension diluted 1:1 in Matrigel™ (Corning Matrigel™ Matrix Basement Membrane Growth Factor Reduced) for tumor cell inoculation.

Male NSG QAOD.Cg-Prkde^sc“' Il2rg^rmifr5SzJ) mice may be subcutaneously inoculated with OCI-Ly3 cells (10x10⁶ cells in 1:1 medium:Matrigel™ in a volume of 200

759 pL) in the inguinal région of each animal. The day of tumor cell inoculation may be denoted as day 0. Tumor measurements may be monitored twice weekly beginning seven days post-implantation, until the mean tumor volume is 169±42 mm \ at which point mice may be randomized by tumor volume into treatment groups. Compound or vehicle may be orally administered according to body weight (5 mL/kg) once or twice daily until study termination. Tumor measurements and body weights may be recorded twice weekly.

The endpoints of the studies are tumor growth inhibition, maximal tumor burden (individual tumor size equaling 10% of body weight), and body weight loss greater than 20% treatment initiation body weight. Percent body weight change may be calculated using the formula: Body weight change = | (< -1 » 11 x 100 where C is the current body weight and I is the body weight at the initiation of treatment. Tumor size may be measured twice weekly in two dimensions using a caliper and the volume may be expressed in mm³using the formula: V=0.5axb² where and b are the long and short diameters of the tumor, respectively. Complété tumor régression (CR) is defined as tumors that are reduced to below the limit of palpation (20 mm³). Paillai tumor régression (PR) is defined as tumors that are reduced by at least half from initial tumor volume. A minimum duration of CR or PR in thee or more successive tumor measurements is required for a CR or PR to be considered durable.

Summary statistics, including mean and the standard error of the mean (SEM), are provided for the tumor volume of différence in tumor volume among each group at each time-point are shown in corresponding study tables. Statistical analysis of différence in tumor volume among the groups may be evaluated using a two-way ANOVA repeated measures test, followed by Tukey post-test, using GraphPad Prism version 6.

While the foregoing spécification teaches the principles of the présent invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses ail of the usual variations, adaptations and/or modifications as corne within the scope of the following claims and their équivalents.

Claims

We claim:

1. The compound

or a pharmaceutically acceptable addition sait or a solvaté thereof.

10
2. The compound of claim 1 wherein the compound is a solvaté.
3. The compound of claim 2 wherein the compound is a hydrate.
4. A pharmaceutical composition comprising a compound of any one of claims 1 to 3 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

15
5. The pharmaceutical composition of claim 4, wherein the composition is a solid oral dosage form.
6. The pharmaceutical composition of claim 4, wherein the composition is a syrup, an élixir or a suspension.
7. The compound of any one of claims 1 to 3 for use in the treatment or prévention of 20 a disease, syndrome, or condition affected by the inhibition of MALT1.
8. The compound according to claim 7 wherein the disease or condition is cancer.
9. Use of a compound as defined in any one of claims 1 to 3 in the manufacture of a médicament for use in the treatment or prévention of a disease, syndrome, or condition

25 affected by the inhibition of MALT 1.

761
10. The use as claimed in claim 9 wherein the disease or condition is cancer.
11. A process for the préparation of a compound that is

(Compound 158) comprising

(112a) o o

(1) reacting (112a) with intermediate (Yl) to yield (112b); then oxidizing (112b) to

10 yield (112c);

(iii) converting (112c) to (112d); subsequently treating (112d) with concentrated hydrochloric acid; to yield (112e); and

762

reacting (112e) with (Y2), in the presence of an organic solvent; to yield Compound 158.