EA046082B1 - PYRAZOLE DERIVATIVES AS MALT1 INHIBITORS - Google Patents

Description

Cross-references to related applications

This application claims benefit from U.S. Patent Application No. 62/686,447, filed June 18, 2018, which is incorporated herein by reference in its entirety.

Scope of the invention

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

Prerequisites for creating the invention

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

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

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

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

The chromosomal translocation generating the API2-MALT1 oncoprotein fusion protein is the most common mutation identified in MALT lymphoma (mucosal 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 the ligand-bound TNF receptor, stimulates TRAF2-dependent ubiquitination of RIP1, which acts as a scaffold for the activation of canonical NFkB signaling. Moreover, API2-MALT1 has been shown to cleave and form a stable, constitutively active fragment of NFKB-inducing kinase (NIK), thereby activating the non-canonical NFkB pathway (Rosebeck et al., Science, 2011, 331, 468-472).

Along with lymphomas, MALT1 has been shown to play an important role in innate and adaptive immunity (Jaworski M., et al., Cell Mol Life Sci. 2016). A MALT1 protease inhibitor may attenuate the onset and progression of experimental allergic encephalomyelitis in mice, a mouse model of multiple sclerosis (Mc Guire et al., J. Neuroinflammation 2014, 11, 124). Mice expressing a catalytically inactive mutant form of MALT1 showed loss of marginal zone B cells and B1 B cells, as well as a general immune deficiency characterized by decreased activation and proliferation of T and B cells. However, these mice also developed spontaneous multiorgan

- 1 046082 new autoimmune inflammation at the age of 9 to 10 weeks. It is still not clear why mice knocked out of the functionally inactive MALT1 protease show breakthrough tolerance, while normal MALT1 knockout mice do not. According to one hypothesis, the imbalance of immune homeostasis in mice knocked out of the functionally inactive protease MALT1 may be caused by an incomplete deficiency of T and B cells, but by a severe deficiency of immunoregulatory cells (Jaworski et al., EMBO J. 2014; Gewies et al., Cell Reports 2014; Bornancin et al., J. Immunology 2015; Yu et al., PLOS One 2015). Similarly, MALT deficiency in humans is associated with combined immunodeficiency disorder (McKinnon et al., J. Allergy Clin. Immunol. 2014, 133, 1458-1462; Jabara et al., J. Allergy Clin. Immunol. 2013, 132, 151-1462). 158; Punwani et al., J. Clin. Immunol. 2015, 35, 135-146). Given the difference between genetic mutation and pharmacological inhibition, the phenotype of functionally inactive MALT1 protease knockin mice may not resemble the phenotype of patients treated with MALT1 protease inhibitors. Reducing the number of immunosuppressive T cells through inhibition of MALT1 protease may be beneficial for cancer patients through the potential to enhance antitumor immunity.

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

Summary of the invention

The present invention relates to compounds of formula (I)

Rj

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

i) phenyl substituted with one to three substituents independently selected from the group consisting of 1-methoxyethyl, Cl. ₄ alkyl, isopropyl, methoxy, chlorine, fluorine, bromine, methanesulfonyl, cyclopropyl, methylthio, trifluoromethyl, amino, methylamino and cyano;

ii) a five to six membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is independently substituted with one to three substituents independently selected from ^alkyl, methoxy, fluorine, chlorine, bromine, cyano, amino, methylamino, methanesulfonyl, methylthio, tetrahydrofuran-2-yl, furan-2 -yl, 5,6-dihydro-1,4-dioxin-2-yl, 1,4-dioxan-2-yl, trifluoromethyl, 3-hydroxyazetidin-1-yl or N-oxido; and iii) a bicyclic ring system selected from the group consisting of 2,2-difluorobenzo[1,3]dioxol-4-yl, [1,3]dioxolo[4,5-b]pyridin-7-yl, 1-oxoisoindolin-4-yl, 1-methyl-1,2,3,4tetrahydroquinolin-8-yl, indolin-4-yl, 1-methylindolin-4-yl, P^dioxolo^^-^pyridin^-yl, 1methyl-1,2,3,4-tetrahydroquinolin-5-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl, benzo^][1,3 ]dioxol-4-yl and 2,3-dihydrobenzoI[1,4]dioxin-5-yl;

R2 is selected from the group consisting of C1. ₄ alkyl, 1-methoxyethyl, difluoromethyl, fluorine, chlorine, bromine, cyano, methylthio, methylsulfonyl and trifluoromethyl;

R ₃ represents hydrogen or methyl;

G represents N or CH;

R ₄ represents a five-membered heteroaryl containing from two to four heteroatoms selected from O and N, or a six-membered heteroaryl containing from one to two N; wherein said R ₄ is optionally independently substituted with one or two substituents selected from the group consisting of amino, fluorine, chlorine, bromine, cyano, Cl. ₄ alkyl and R _a -(C ₁ . ₄ )alkyl; where R _a is independently selected from hydroxy, methoxy, dimethylamino or amino;

R5 is independently selected from the group consisting of hydrogen, chlorine, fluorine, bromine, methoxy, methanesulfonyl, cyano, methyl or trifluoromethyl;

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

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

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

The present invention further provides methods for treating or alleviating a disease

- 2 046082 disease, syndrome, condition or disorder in a subject, including a mammal and/or a human, whose disease, syndrome or condition is dependent on inhibition of MALT1, including, without limitation, cancer and/or immunological diseases, using a compound of formula (I ).

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

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

Examples of the invention are methods of treating a disease, syndrome, condition or disorder mediated by MALT1 selected from the group consisting of lymphoma, leukemia, carcinoma and sarcoma, for example non-Hodgkin lymphoma (NHL), B cell NHL, diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small cell lymphocytic lymphoma (MLL), Waldenström's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain tumors (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer, including non-small cell cancer, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer , sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial cancer, vaginal cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer and GIST (gastrointestinal stromal tumor), the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described in the present invention, consists of or consists essentially of from this introduction.

In another embodiment, the present invention provides a compound of formula (I) for use in the treatment of a disease, syndrome, condition or disorder dependent on MALT 1 inhibition selected from the group consisting of lymphoma, leukemia, carcinoma and sarcoma, for example non-Hodgkin's lymphoma ( NHL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small cell lymphocytic lymphoma (SLL), Waldenström's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell exact leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain tumors (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer, including non-small cell cancer, stomach cancer, endometrial cancer , melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer uterine, kidney cancer, urothelial cancer, vaginal cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer and GIST (gastrointestinal stromal tumor).

In another embodiment, the present invention provides a composition containing a compound of formula (I) for the treatment of a disease, syndrome, condition or disorder dependent on MALT1 inhibition selected from the group consisting of lymphoma, leukemia, carcinoma and sarcoma, for example non-Hodgkin lymphoma ( NHL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small cell lymphocytic lymphoma (SLL), Waldenström's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia ia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain tumors (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer, including non-small cell, gastric cancer, endometrial cancer, melanoma , pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, urinary cancer

- 3 046082 bladder, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial cancer, vaginal cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer cavities and GIST (gastrointestinal stromal tumor).

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

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

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

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

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

Detailed Description of the Invention

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

The term alkyl, used alone or as part of a group of substituents, denotes linear and branched carbon chains having from 1 to 8 carbon atoms. Therefore, the indicated numbers of carbon atoms (eg, C _1-8 ) independently indicate the number of carbon atoms in the alkyl functional group or the alkyl portion of a larger alkyl-containing substituent. In substituent groups with multiple alkyl groups, such as (^-balkylEamino-, C _1-6 alkyl groups, dialkylamino may be the same or different.

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

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

The term cycloalkyl means saturated or partially saturated monocyclic or

- 4 046082 polycyclic hydrocarbon rings having from 3 to 14 carbon atoms. Examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.

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

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

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

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

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

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

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

If the term alkyl or aryl, or any of the prefixes derived from these roots, appears in the name of a substituent (eg, arylalkyl, alkylamino), that name should be interpreted to include the limitations noted above for the terms alkyl and aryl. The specified number of carbon atoms (eg, C ₁ -C ₆ ) refers independently to the number of carbon atoms in the alkyl functional group, aryl functional group, or in the alkyl part of a larger substituent in which the alkyl root is used as a prefix. For alkyl and alkoxy substituents, the stated number of carbon atoms includes all independent members within the specified range. For example, ^^alkyl will include separately methyl, ethyl, propyl, butyl, pentyl and hexyl, as well as subcombinations thereof (for example, C1-2, C1-3, C1-4, _C1.5 , _{C2.6 ,} C _3-6 , C4-6, C5-6, C2-5, etc.). In general, according to the standard rules of nomenclature used throughout this specification, the terminal portion of the specified side chain is described first, followed by the description of adjacent functional groups towards the point of chain attachment. Thus, for example, the name of the substituent C ₁ -C ₆ alkylcarbonyl denotes a group of the formula:

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

- 5 046082

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

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

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

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

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

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

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

The term MALT 1-mediated refers to any disease, syndrome, condition or disorder that would occur in the absence of MALT1, but can occur in the presence of MALT 1. Acceptable examples of a MALT1-mediated disease, syndrome, condition or disorder include, but are not limited to , lymphomas, leukemias, carcinomas and sarcomas, e.g. non-Hodgkin's lymphoma (NHL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosal associated lymphoid tissue lymphoma ( MALT), marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small cell lymphocytic lymphoma (SLL), Waldenström's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML) ) , hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain tumors (gliomas), glioblastomas, breast cancer, colorectal cancer/ colon cancer, prostate cancer glands, lung cancer, including non-small cell cancer, stomach cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, cancer testicular, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial cancer, vaginal cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer and GIST (gastrointestinal stromal tumor).

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

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

- 6 046082 disorder or development of a disease, condition, syndrome or disorder.

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

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

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

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

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

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

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

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

Formula (I) where A) R ₁ is independently selected from the group consisting of:

i) phenyl substituted with one to three substituents independently selected from the group consisting of C1. ₄ alkyl, methoxy, chlorine, fluorine, bromine, cyclopropyl, methylthio, amino, methylamino and cyano;

ii) a five to six membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is independently substituted with one to three substituents independently selected from ^alkyl, methoxy, fluorine, chlorine, bromine, cyano, amino, methylamino, methanesulfonyl, methylthio, furan-2-yl, 5,6 -dihydro-1,4-dioxin-2-yl, 1,4-dioxan-2-yl, trifluoromethyl, 3-hydroxy

- 7 046082 azetidin-1-yl, pyrimidin-2-yl or tetrahydrofuran-2-yl; and a bicyclic ring system independently selected from the group consisting of 2,2di(|)torbenzo[1,3|dioxol-4-yl, [1,3]dioxolo[4,5-b]pyridin-7-yl, 1-oxoisoindolin-4-yl, indolin-4-yl, 1-methylindolin-4-yl, [1,3]dioxolo[4,5-b]pyridin-7-yl, 4-methyl-3,4-dihydro -2H-benzo[b][1,4]oxazin-8-yl, benzo[1.3|dioxol-4-yl and 2,3-dihydrobenzo[b][1,4]dioxin-5-yl;

B) Rj is independently selected from the group consisting of:

i) phenyl substituted with one to three substituents independently selected from the group consisting of methyl, methoxy, chlorine, (toro, bromine and cyano;

ii) a five to six membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is independently substituted with one to three substituents independently selected from C1-4alkyl, fluorine, chlorine, cyano, amino or methylamino; and iii) a bicyclic ring system selected from the group consisting of [1,3]dioxolo[4,5b]pyridin-7-yl, [1,3]dioxolo[4,5-b]pyridin-7-yl and benzo2 [1,3]dioxol-4-yl;

C) Rj is independently selected from the group consisting of

i) phenyl substituted with one to three substituents independently selected from the group consisting of methyl, methoxy, chlorine, fluorine and cyano;

ii) a five to six membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is independently substituted with one to three substituents independently selected from C1-4alkyl, fluorine, chlorine, cyano and amino; and iii) a bicyclic ring system selected from the group consisting of [1,3]dioxolo[4,5b]pyridin-7-yl and benzo[1,3]dioxol-4-yl;

D) R ¹ is independently selected from the group consisting of 2-amino-5-methylpyridin-4-yl, 6-amino-5fluoropyridin-2-yl, benzo[1,3]dioxol-4-yl, 6-amino-5 -fluoro-3-methylpyridin-2-yl, 6-amino-5chloropyridin-2-yl, 6-amino-5-cyanopyridin-2-yl, 2-amino-5-chloropyridin-4-yl, 4-cyano-2 -methylphenyl, 4-chloro-2-methylphenyl, 3-chloropyridin-4-yl, 2-bromo-4-fluorophenyl, 2-chloro-4-fluorophenyl, [1,3]dioxolo[4,5-b]pyridin- 7-yl, 4-fluoro-2-methoxyphenyl, 2-methylphenyl, 2-amino-3-chloropyridin-4yl, 2-chloro-3,4-difluorophenyl, 2-chloro-3-fluorophenyl, 4-fluoro-2- methylphenyl, 6-amino-3-methylpyridin2-yl, 5-fluoro-6-(methylamino)pyridin-2-yl, 3-fluoro-2-methylphenyl, 3,4-difluoro-2-methylphenyl, 4cyanophenyl, 2-methoxypyridine -3-yl, 3-bromo-5-fluoropyridin-2-yl, 3,4-dichloropyridin-2-yl, 2,3dimethylpyridin-4-yl, 3-chloro-2-methylpyridin-4-yl, 3.5 -dichloropyridin-4-yl, 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, 2,2-difluorobenzo[1,3]dioxol-4-yl, 5-chloro-2-methylpyridine -4-yl, 2-chloro-5fluorophenyl, 2-chloro-4,6-difluorophenyl, 2-cyclopropylphenyl, 2-fluoro-6-methylphenyl, 2,6-dichloro-4fluorophenyl, 5-fluoro-2-methylphenyl, 3 -chloro-5-fluoropyridin-2-yl, 4-fluorophenyl, 2-chloro-4-cyanophenyl, 2,4-difluorophenyl, 5-fluoro-3-methylpyridin-2-yl, 2-chlorophenyl, 4-amino-3 -chloropyridin-2-yl, 1methylindolin-4-yl, indolin-4-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl, 1-oxoisoindolin- 4-yl, 2-(methylthio)phenyl, 2-amino-3-methylpyridin-4-yl, 3-methylpyridin-4-yl, 2,4,6trifluorophenyl, 6-amino-3-chloropyridin-2-yl, 6 -amino-4-methylpyridin-2-yl, 6-aminopyridin-2-yl and 5-methyl-2(*R)-(tetrahydrofuran-2-yl)pyridin-4-yl;

E) R ¹ is independently selected from the group consisting of 2-amino-5-methylpyridin-4-yl, 6-amino-5fluoropyridin-2-yl, benzo[d][1,3]dioxol-4-yl, 6- amino-5-fluoro-3-methylpyridin-2-yl, 6-amino-5-chloropyridin-2-yl, 6-amino-5-cyanopyridin-2-yl, 2-amino-5-chloropyridin-4-yl, 4- cyano-2methylphenyl, 4-chloro-2-methylphenyl, 3-chloropyridin-4-yl, 2-bromo-4-fluorophenyl, 2-chloro-4-fluorophenyl, [1,3]dioxolo[4,5-b]pyridine -7-yl, 4-fluoro-2-methoxyphenyl, 2-methylphenyl, 2-amino-3-chloropyridin-4yl, 2-chloro-3,4-difluorophenyl, 2-chloro-3-fluorophenyl, 4-fluoro-2 -methylphenyl, 6-amino-3-methylpyridin2-yl, 5-fluoro-6-(methylamino)pyridin-2-yl, 3-fluoro-2-methylphenyl, 3,4-difluoro-2-methylphenyl and 4cyanophenyl;

F) R ¹ is independently selected from the group consisting of 2-amino-5-methylpyridin-4-yl, 6-amino-5fluoropyridin-2-yl, benzo[d][1,3]dioxol-4-yl, 6- amino-5-fluoro-3-methylpyridin-2-yl, 6-amino-5-chloropyridin-2-yl, 6-amino-5-cyanopyridin-2-yl, 2-amino-5-chloropyridin-4-yl, 4- cyano-2-methylphenyl and 4-chloro-2-methylphenyl;

G) R2 is independently selected from the group consisting of methyl, chlorine, bromine, cyano and trifluoromethyl;

H) R2 is independently selected from the group consisting of methyl and trifluoromethyl;

I) R ₃ represents H;

J) G is N;

K) G represents CH;

L) R4 is a five-membered heteroaryl containing from two to four heteroatoms selected from O and N, or a six-membered heteroaryl containing from one to two N heteroatoms; wherein said R4 is optionally independently substituted with one or two substituents selected from the group consisting of amino, fluorine, chlorine and methyl;

M) R4 is a five- or six-membered heteroaryl independently selected from the group

- 8 046082 consisting of triazolyl, oxazolyl, pyrazolyl, thiazolyl, tetrazolyl, oxadiazolyl, imidazolyl and 2-aminopyrimidin-4-yl;

N) R ₄ is 2H-1,2,3-triazol-2-yl;

O) R ₅ is independently selected from the group consisting of hydrogen, chlorine, fluorine, bromine, cyano, methyl and trifluoromethyl;

P) R ₅ is independently selected from the group consisting of chlorine, cyano, methyl and trifluoromethyl;

Q) R ₅ is independently selected from the group consisting of chlorine and cyano;

and any combination of embodiments A)-Q) described above, provided that it is understood that combinations in which different embodiments of the same substituent are combined are excluded;

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

Embodiments of the present invention include a compound of formula (I) r ₅

-Ri

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

i) phenyl substituted with one to three substituents independently selected from the group consisting of C1. ₄ alkyl, methoxy, chlorine, fluorine, bromine, cyclopropyl, methylthio and cyano;

ii) five to six membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is independently substituted with one to three substituents independently selected from ^alkyl, methoxy, fluorine, chlorine, bromine, cyano, amino, methylamino or tetrahydrofuran-2-yl; and ii i) a bicyclic ring system independently selected from the group consisting of 2,2difluorobenzo[1,3]dioxol-4-yl, P^dioxolo^^-EDpyridin-U-yl, 1-oxoisoindolin-4-yl , indolin-4-yl, 1-methylindolin-4-yl, [1,3]dioxolo[4,5-b]pyridin-7-yl, 4-methyl-3,4-dihydro-2H-benzo^^^ oxazin-3-yl, benzo[1,3]dioxol-4-yl and 2,3-dihydrobenzo[b][1,4]dioxin-5-yl;

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

R ₃ represents hydrogen or methyl;

G represents N or CH;

R ₄ represents a five-membered heteroaryl containing from two to four heteroatoms selected from O and N, or a six-membered heteroaryl containing from one to two N; wherein said R ₄ is optionally independently substituted with one or two substituents selected from the group consisting of amino, fluorine, chlorine and methyl;

R ₅ is independently selected from the group consisting of hydrogen, chlorine, fluorine, bromine, cyano, methyl and trifluoromethyl;

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

Embodiments of the present invention include a compound of formula (I) r ₅

-Ri

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

i) phenyl substituted with one to three substituents independently selected from the group consisting of methyl, methoxy, chlorine, fluorine, bromine and cyano;

ii) a five to six membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is independently substituted with one to three substituents independently selected from O-4alkyl, fluorine, chlorine, cyano, amino and methylamino; and iii) a bicyclic ring system selected from the group consisting of [1,3]dioxolo[4,5^pyridin-7-yl, P^dioxolo^^-EDpyridin^-yl and benzo[1,3]dioxol -4-ila;

R2 is independently selected from the group consisting of methyl, chlorine, bromine, cyano and trifluoromethyl;

R ₃ represents hydrogen;

G represents N or CH;

- 9 046082

R4 is a five-membered heteroaryl containing from two to four heteroatoms selected from O and N, or a six-membered heteroaryl containing from one to two N; wherein said R ₄ is optionally independently substituted with one or two substituents selected from the group consisting of amino, fluorine, chlorine and methyl;

R5 is independently selected from the group consisting of hydrogen, chlorine, fluorine, bromine, cyano, methyl and trifluoromethyl;

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

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

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

i) phenyl substituted with one to three substituents independently selected from the group consisting of methyl, methoxy, chlorine, fluorine and cyano;

ii) a five to six membered heteroaryl containing from one to four heteroatoms selected from the group consisting of O, N and S; such that at most one heteroatom is O or S; wherein said heteroaryl according to claim ii) is independently substituted with one or three substituents independently selected from O-4alkyl, fluorine, chlorine, cyano and amino; and iii) a bicyclic ring system independently selected from the group consisting of [1,3]dioxolo^^-^pyridin^-yl and benzo[1,3]dioxol-4-yl;

R2 is independently selected from the group consisting of methyl, chlorine, bromine, cyano and trifluoromethyl;

R ₃ represents hydrogen;

G represents N or CH;

R ₄ is a five- or six-membered heteroaryl independently selected from the group consisting of triazolyl, oxazolyl, pyrazolyl, thiazolyl, tetrazolyl, oxadiazolyl, imidazolyl and 2-aminopyrimidin-4-yl;

R ₅ is independently selected from the group consisting of chlorine, cyano, methyl and trifluoromethyl;

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

Embodiments of the present invention include a compound of formula (I) *5

Formula (I) wherein R1 is independently selected from the group consisting of 2-amino-5-methylpyridin-4-yl, 6-amino-5fluoropyridin-2-yl, benzo[1,3]dioxol-4-yl, 6 -amino-5-fluoro-3-methylpyridin-2-yl, 6-amino-5-chloropyridin-2-yl, 6-amino-5-cyanopyridin-2-yl, 2-amino-5-chloropyridin-4-yl , 4-cyano-2-methylphenyl, 4-chloro-2-methylphenyl, 3-chloropyridin-4-yl, 2-bromo-4-fluorophenyl, 2-chloro-4-fluorophenyl, [1,3]dioxolo^^- ^pyridin^-yl, 4-fluoro-2-methoxyphenyl, 2-methylphenyl, 2-amino-3-chloropyridin-4-yl, 2-chloro-3,4-difluorophenyl, 2-chloro-3-fluorophenyl, 4-fluoro- 2-methylphenyl, 6-amino-3-methylpyridin-2-yl, 5-fluoro-6-(methylamino)pyridin-2-yl, 3-fluoro-2-methylphenyl, 3,4-difluoro-2-methylphenyl, 4 -cyanophenyl, 2-methoxypyridin-3-yl, 3-bromo-5-fluoropyridin-2-yl, 3,4-dichloropyridin-2-yl, 2,3-dimethylpyridin-4-yl, 3-chloro-2-methylpyridine -4-yl, 3,5-dichloropyridin-4-yl, 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, 2,2-difluorobenzo^][1,3]dioxol-4- yl, 5-chloro-2-methylpyridin-4-yl, 2-chloro-5-fluorophenyl, 2-chloro-4,6-difluorophenyl, 2-cyclopropylphenyl, 2-fluoro-6-methylphenyl, 2,6-dichloro- 4-fluorophenyl, 5-fluoro-2-methylphenyl, 3-chloro-5-fluoropyridin-2-yl, 4-fluorophenyl, 2-chloro-4-cyanophenyl, 2,4-difluorophenyl, 5-fluoro-3-methylpyridin-2- yl, 2-chlorophenyl, 4-amino-3-chloropyridin-2-yl, 1-methylindolin-4yl, indolin-4-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4 ]oxazin-8-yl, 1-oxoisoindolin-4-yl, 2(methylthio)phenyl, 2-amino-3-methylpyridin-4-yl, 3-methylpyridin-4-yl, 2,4,6-trifluorophenyl, 6amino -3-chloropyridin-2-yl, 6-amino-4-methylpyridin-2-yl, 6-aminopyridin-2-yl and 5-methyl-2(*R)(tetrahydrofuran-2-yl)pyridin-4-yl ;

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

R ₃ represents hydrogen;

G represents N or CH;

R ₄ is a five- or six-membered heteroaryl, independently selected from the group with

- 10 046082 consisting of triazolyl, oxazolyl, pyrazolyl, thiazolyl, tetrazolyl, oxadiazolyl, imidazolyl and 2-aminopyrimidin-4-yl;

R ₅ is independently selected from the group consisting of chlorine, cyano, methyl and trifluoromethyl;

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

Embodiments of the present invention include a compound of formula (I) r ₅

-Ri

Formula (I) where R ¹ is selected from the group consisting of 2-amino-5-methylpyridin-4-yl, 6-amino-5-fluoropyridin-2yl, benzo[1,3]dioxol-4-yl, 6 -amino-5-fluoro-3-methylpyridin-2-yl, 6-amino-5-chloropyridin-2-yl, 6-amino-5-cyanopyridin-2-yl, 2-amino-5-chloropyridin-4-yl , 4-cyano-2-methylphenyl, 4-chloro-2-methylphenyl, 3-chloropyridin-4-yl, 2-bromo-4-fluorophenyl, 2-chloro-4-fluorophenyl, [1,3]dioxolo[4, 5-b]pyridin-7-yl, 4-fluoro-2-methoxyphenyl, 2-methylphenyl, 2-amino-3-chloropyridin-4-yl, 2-chloro-3,4difluorophenyl, 2-chloro-3-fluorophenyl, 4-fluoro-2-methylphenyl, 6-amino-3-methylpyridin-2-yl, 5-fluoro-6(methylamino)pyridin-2-yl, 3-fluoro-2-methylphenyl, 3,4-difluoro-2- methylphenyl and 4-cyanophenyl;

R2 is independently selected from the group consisting of methyl, chlorine, bromine, cyano and trifluoromethyl;

R ₃ represents hydrogen;

G represents N or CH;

R ₄ is a five- or six-membered heteroaryl independently selected from the group consisting of triazolyl, oxazolyl, pyrazolyl, thiazolyl, tetrazolyl, oxadiazolyl, imidazolyl and 2-aminopyrimidin-4-yl;

R ₅ is independently selected from the group consisting of chlorine and cyano;

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

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

-Ri

Formula (I) wherein R ¹ is independently selected from the group consisting of 2-amino-5-methylpyridin-4-yl, 6-amino-5fluoropyridin-2-yl, chloropyridin-2-yl, benzo[d][1,3 ]dioxol-4-yl, 6-amino-5-fluoro-3-methylpyridin-2-yl, 6-amino-56-amino-5-cyanopyridin-2-yl, 2-amino-5-chloropyridin-4-yl , 4-cyano-2-methylphenyl and 4-chloro-2-methylphenyl;

R2 is independently selected from the group consisting of methyl, chlorine, bromine, cyano and trifluoromethyl;

R ₃ represents hydrogen;

G represents N or CH;

R ₄ is a five- or six-membered heteroaryl independently selected from the group consisting of triazolyl, oxazolyl, pyrazolyl, thiazolyl, tetrazolyl, oxadiazolyl, imidazolyl and 2-aminopyrimidin-4-yl;

R ₅ is independently selected from the group consisting of chlorine and cyano;

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

Embodiments of the present invention include a compound of formula (I) r ₅

-Ri

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

i) phenyl, optionally substituted with one to three substituents independently selected from the group consisting of 1-methoxyethyl, C^alkyl, methoxy, chlorine, fluorine, bromine, methanesulfonyl, cyclopropyl, methylthio, trifluoromethyl, amino and cyano;

ii) 4-methylpyridazin-3-yl, pyrimidinyl, pyrazinyl or pyridinyl, wherein said pyridinyl is optionally substituted with one to three substituents independently selected from the group,

- 11 046082 consisting of C( _1-4 )alkyl, methoxy, fluorine, chlorine, bromine, cyano, amino, methylamino, tetrahydrofuran-2yl, furan-2-yl, 5,6-dihydro-1,4-dioxin-2 -yl, 1,4-dioxan-2-yl, trifluoromethyl, 3-hydroxyazetidin-1-yl, N-oxido and aminocarbonyl; and iii) a bicyclic ring system independently selected from the group consisting of 2,2-difluorobenzo[1,3]dioxol-4-yl, P^dioxolo^D-^pyridinP-yl, 1-oxoisoindolin-4-yl , 1-methyl-1,2,3,4tetrahydroquinolin-8-yl, 1,2,3,4-tetrahydroisoquinolin-5-yl, indolin-4-yl, 1-methylindolin-4-yl, 1methyl-1,2 ,3,4-tetrahydroquinolin-5-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl, benzo[1,3]dioxol-4- silt and 2,3-dihydrobenzo^][1,4]dioxin-5-yl;

R2 is independently selected from the group consisting of _C1 . ₄ alkyl, 1-methoxyethyl, difluoromethyl, fluorine, chlorine, bromine, cyano, methylthio, methylsulfonyl and trifluoromethyl;

R3 represents hydrogen or Cd-^alkyl;

G represents N or CH;

R ₄ represents 2H-1,2,3-triazol-2-yl;

R ₅ is independently selected from the group consisting of chlorine, bromine, cyano, C( _1-4 )alkyl or trifluoromethyl;

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

Embodiments of the present invention include a compound of formula (I) γ ^; || ? ^R G^ D, AJ' G N

I n N-Rj

Kz D/

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

iv) phenyl, optionally substituted with one to three substituents independently selected from the group consisting of 1-methoxyethyl, methyl, isopropyl, methoxy, chlorine, fluorine, bromine, methanesulfonyl, cyclopropyl, methylthio, trifluoromethyl, amino and cyano;

v) 4-methylpyridazin-3-yl, pyrimidinyl, pyrazinyl or pyridinyl, wherein said pyridinyl is optionally substituted with one to three substituents independently selected from the group consisting of methyl, methoxy, fluorine, chlorine, bromine, cyano, amino, methylamino, tetrahydrofuran-2-yl, furan-2-yl, 5,6-dihydro-1,4-dioxin-2-yl, 1,4-dioxan-2-yl, trifluoromethyl, 3-hydroxyazetidin-1yl, N-oxido and aminocarbonyl; and vi) a bicyclic ring system independently selected from the group consisting of 2,2difluorobenzo^[1,3]dioxol-4-yl, [1,3^ioxolo^D-^pyridinP-yl, 1-oxoisoindolin-4- yl, 1-methyl-1,2,3,4-tetrahydroquinolin-8-yl, 1,2,3,4-tetrahydroisoquinolin-5-yl, indolin-4-yl, 1-methylindolin-4-yl, 1- methyl-1,2,3,4-tetrahydroquinolin-5-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8yl, benzo[1,3]dioxol -4-yl and 2,3-dihydrobenzo[b][1,4]dioxin-5-yl;

R2 is independently selected from the group consisting of difluoromethyl, fluoro and trifluoromethyl;

R ₃ represents hydrogen or methyl;

G represents N or CH;

R ₄ represents 2H-1,2,3-triazol-2-yl;

R ₅ is independently selected from the group consisting of chlorine, bromine, cyano or trifluoromethyl;

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

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

- 12 046082

Table 1

Structure Conn. No. Name N^\ f ₃ c ?if X /=\ X'4 ' ⁴ ' ^C F—< })— NH M vX 1 M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(4-fluoro-2methylphenyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide N^\ _Ν_Λ|ί AX 2 1-(4-Chloro-2-methylphenyl)-M-(5chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide N^\ _,N^ XX F ₃ C o if γ N z^ ^N IA JI X v 'Am ^y X ⁿ ^ ^C| Υ=/ Ch n 3 M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3methylpyridin-2-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide №=Χ _l ,Ν. XX %с ο Α γ ^Ν Ν ^Ζ Λ.. Άγ' Ν 1 \^/ Ν Η 4 M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(pyridin-4yl)-5-(methyl trifluoro)-1Hpyrazol-4-carboxamide 7 ¹ iV ⁿ ζζ И ² =0 5 M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-phenyl-5(trifluoromethyl)-1H-pyrazol-4carboxamide

- 13 046082

zz 0=4. Λ ζ 6 M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3fluoropyridin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide №=% ί XX /=Ν K ^A # ^ ^{CI F} X Χ ^Ν 1 ^Η VJ' 7 M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5fluoropyridin-2-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Ν^\ κΛί F ₃ C ?, f X 4 ,Χ ^ν j η 8 M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(pyridin-2yl)-5-(methyl trifluoro)-1Hpyrazol-4-carboxamide X ζζ Ρ ° o 9 M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(pyrazin-2yl)-5-(methyl trifluoro)-1Hpyrazol-4-carboxamide Ν^Χ ,Ν,- ^Ν φ ^F ₃ c θ g χ X--X'^' ^CI W ^η 10 M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(pyrimidin2-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide Ν^\ ^F ₃ C 9. f Τ /=Ν NC—X )r~ N 1 ⁿ W Ή eleven M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5cyanopyridin-2-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide g^g Г I] h; ^< ? ^Γ χ ^{_ g=} \g-g 12 M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(pyridin-3yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide

- 14 046082

Cl y to GT \ N=4 ,iAtsU 0—ά A— Ν 1 N 13 M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-1-(6methoxypyridin-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Cl №Л Jk^A./ FC θ i |И Ν ³ V Λ. X Ν / 14 M-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2methoxypyridin-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Cl №У JkjL./ h to GT N=\ Хк ⁴ '<\У-NJHN—' 15 X-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(pyrimidin5-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide Cl N^\ JkA ·Α v 2 fif ^N N-h pkA ^H 16 X-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5methylpyridin-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Cl N^\ Jk-Ax ^F * ^c , к П N=\ УХ Qv ^H N ^Z 17 X-(5-Chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5cyanopyridin-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Cl X\ AA/ FC θ ΓΗ N V A. XN /=\ /Wn ^F 4x /Vn ] n 'L·/ 18 X-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4fluorophenyl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide Cl N^\ FC Q Flk N ³ X A. AN /=\ N ^N =—( ₄ A— Ν 1 H 19 X-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4cyanophenyl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide

- 15 046082

Cl N^\ JLA--.A FC θ i lk N F 20 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3fluorophenyl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide Cl#Λ. Х_А.А FC θ l· lk N ³ V A. Λ- N €> ⁿ P ^H N ^Z 21 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3cyanophenyl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide Cl N^\ JkA-,./ FjC ft £|f /= ^N . kA _N 'V p-<J ^H 22 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4methylpyridin-2-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Cl NA Ιί, A o f¥ ^N /=NL''·' -Λ /)- J ^and 23 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5methylpyridin-2-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Cl NA JkA \ h 1 GT μ k,AA,< 4 A ^N - J ^H 'LA 24 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(6methylpyridin-2-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Cl №A fV 0 rV' ^N /=\ λ _5τ ·Ά'Ά' ^{ν n} AAA ^h 25 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5- (difluoromethyl)-1 -(pyridin-4-yl)1H-pyrazol-4-carboxamide Cl №A Jk.A./ F θ pY ^N /=\ < JH LA 26 LG-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5-fluoro-1phenyl-1H-pyrazol-4-carboxamide

- 16 046082

Cl ΝΑ FC θ ΓΐΤ NVA Λ, N /=\ N -4 zb J ^H 27 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(p-tolyl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Cl N^\ FC $ i Г N \ Λ AAN < J ^H 28 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(m-tolyl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Cl N^\ FC θ Γ^ ϊί N ³ VAXN /=4 ,.Α-' Ν L _; HJ ^H 29 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(o-tolyl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide N^\ F _F ,.N ^N 4 ^F Ύ I LjX Br —(( N ] H \=( hr Cl thirty 1 -(5-bromo-3-chloropyridin-2-yl)bG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide N^\ F _F lHA ^f aa iX. zT\ .W ⁿ n=-A Vn ] H 4=/ Cl 31 1-(3-chloro-5-cyanopyridin-2-yl)lG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide N^\ F _F ^ν πΧΛη^^ ^ν Q Cl X 32 1 -(3-Chloro-2-methoxypyride in-4yl)-I-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)- 1H -pyrazole-4carboxamide F _F ^F \ 1 Xjx zr-^ N y— _N 1 η n ^N N 33 1-(3-Cyano-2-methylpyridin-4yl)-I-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide

- 17 046082

N^\ F _F ^f a iXX. Br 34 1-(3-Bromo-5-fluoropyridin-2-yl)lG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide n^\ F _F ,Ν^'Ν ^f A ° DT Z'“ ^N a F—/ ⁴ VN ] H \=< hr \ 35 1-(3-cyano-5-fluoropyridin-2-yl)lG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide N<\ F _F -N ^.- ^N ы fV θ f Y ГмП'й ^m Cl· Cl 36 M-(5-Cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1 -(3,4dichloropyridin-2-yl)-5(trifluoromethyl)-1H-pyrazol- 4carbox Ά z ⁿ a ⁿ ' ⁿ V °\ C=z~ ^cl Fv / N' H j7 V ^N - J ^N 37 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(4-cyano-2methylphenyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide N^\ F _F ⁿ QV^ ^s ^^ ⁿ 38 LG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2-methoxy-3methylpyridin-4-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide n<a F _F ^ ^N 'V ^N N ^{<? N} Pv^ ^{K iN} Cl 39 1-(2-chloropyridin-4-yl)-bG-(5cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide

- 18 046082

'i- 40 1HG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2cyanopyridin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide s ^O7 \-Z. 1 41 M-(5-Cyano-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)-1-(2methoxypyridin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide N^\ f _F ,N nV ^F \ 1 XJX. N y—N 1 H \=Z 42 1HG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-1-(2,3dimethylpyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole -4carboxamide N^\ F _FX NN^/ ^F \ 1 £ X ^x N V- N 1 H У=/ ' Cl 43 1-(3-chloro-2-methylpyridin-4-yl)1HG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide 1- 44 1-(3-Chloropyridin-2-yl)-M-(5cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide N^\ F c fV o XJL g/L— NH 4' ^N 45 1-(3-chloropyridin-4-yl)-bG-(5cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide

- 19 046082

N^\ F _F ,.N - ^N r/ /Оу N'^^N N VN ] H \=Z rr 46 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3cyanopyridin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide N<\ F _F ^F Ύ IAA Χ' ^Α Χ' ^Ζ Χ ({ N ] H Γ\. ' Cl 47 1-(3-chloro-4-methylpyridin-2-yl)M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3 -yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide N^\ PF _F J4^ ^N ~N ci Y ° Ct <C. _; ν^'^{< ί?} Ν N V- NIHW AND Cl 48 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-1-(3,5dichloropyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole -4carboxamide 0-^2) g- ^H , 7 ¹ γγ 7*0 /x 4J 49 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2,3dihydrobenzo[b][1,4]dioxin-5yl)-5- (methyl trifluoro)-1Hpyrazole-4-carboxamide N^\ \=( Br 50 1-(2-bromo-4-fluorophenyl)-M-(5cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide ^ΞΕ V 51 1-(2-chloro-4-fluorophenyl)-M-(5cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide

- 20 046082

0 - zx o=/ ή. □_ ² ΊΟ o^ 7 52 1-([1,3]dioxolo[4,5-b]pyridin7-yl)-M-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4carboxamide N^\ o A 1 Г ^N N ;Γ Ν^4-Λ 0 n4h ^CN D N=/ 53 1-([1,3]dioxolo[4,5-b]pyridin7-yl)-LG-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4carboxamide F _c N=\ Ύ 0 .N 'OnV^n-^X NJ ^{H :} ~N 54 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4-fluoro-2methoxyphenyl)-5 (trifluoromethyl)-1H-pyrazol-4carboxamide N^\ F. FJ* A ^F A 1 DH l\ uV^u '^' ^ ⁿ uI 55 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(o-tolyl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide N3=\ ^F K IJLX SU<7 ” ^CN HzNbl 56 1-(2-amino-3-chloropyridin-4-yl)M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide c? _ ZT ^o=< \ CI X 57 1-(2-amino-3-chloropyridin-4-yl)M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3 -yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide

- 21 046082

f ₃ c 9 f T W ^! 0 0 f'f 58 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2,2difluorobenzo[0][1,3]dioxol-4yl)-5- (methyl trifluoro)-1Hpyrazole-4-carboxamide zz /(.AW cr | jfA ^g z z' Ή 59 1 -(benzo[<1] [1,3]dioxol-4-yl)-I(5-cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-5 - (trifluoromethyl)-1H-pyrazole-4carboxamide ^F Y\ ^F f ^F ? AZ'n'VA.2 G F l ' / NW Cl ^{N=/ H} A N 60 1 -(2-chloro-3,4-difluorophenyl)-I-(5cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide ^f \Lf ⁿ Xi T o J _N fv nAw H ha ci Xwn- A ⁿ A \= _N N 61 1-(2-chloro-3-fluorophenyl)-bH-(5cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide N^\ f,c » f Y ^N f-Wn'V'I! ^cl /=N )А H ₂ N 62 1-(6-amino-5-fluoropyridin-2-yl)M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3 -yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide N^\ Lch/'M F ₃ C 9. f Ύ F—XANJH Wn A h ₂ n 63 1-(6-amino-5-fluoropyridin-2-yl)lG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide

- 22 046082

N^\ F, _F N ^F k ? f T W'N^CN Ff Ml JH X=Z 64 LG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4-fluoro-2methylphenyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide N^\ /-N ^f Va j£c Г VmA ⁿ X / ^N H 0 b 65 1-(3-chloro-4-methoxypyridin-2yl)-M-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)- 1H- pyrazole-4carboxamide ΝίΛ _r . -Ъ .CC J ^{H >N} Γ~\ N 0 Yl 66 1 -(3-chloro-4-methoxypyridin-2yl)-I-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide NA, F _F ,N>^ ^N ~N L'Ha.AA, N^A—N^l H m; Cl 67 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-1-(3,5dichloropyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole -4carboxamide N^X F .Ν^Ν'.μ X fV ?ι ί to ηΧ ^Λ ν ^ΧΑ:ι N ⁷ 'Vn ] H \=/ Cl 68 1-(5-chloro-2-methylpyridin-4-yl)M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide N^\ FFN hl / fA- 0 γ N Av ⁿ Cl 69 1-(3-chloro-2-methylpyridin-4-yl)M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3 -yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide

- 23 046082

N^\ v Λ’Ϊ Cl 70 1-(5-chloro-2-methylpyridin-4-yl)lG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide N^X F ,.A- ^N A fV °uf X „ LAn'- CI fAA ⁿ X h \=i ' Cl 71 1-(2-chloro-4-fluoro-3-methylphenyl)M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5(trifluoromethyl)- Sh-pyrazole-4carboxamide N.A. F JlJ-rf fVLXJA _F4 nV A \=/ rA ' Cl 72 1-(2-chloro-4-fluoro-3-methylphenyl)M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide NA F _F .Nv ^N A fA 0 r 1 /=\ χΛν^^ ¹ F —L /)—N ^H F Cl 73 1-(2-chloro-3,4-difluorophenyl)-bH-(5chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-5(trifluoromethyl)-1H-pyrazole -4carboxamide A? _A zi oA XX o Q 74 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3(methylsulfonyl)phenyl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide N^\ f _/F V ?, £ X o A AAA^ci 44ZrV ^H 0 ⁴ — ^{! N} 75 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(2-methyl-4(methylsulfonyl)phenyl)-5(trifluoromethyl)- 1H- pyrazole-4carboxamide

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N^\ fV 0 Cl V^/ ^N n 76 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2isopropylphenyl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Ν^\ FJ^ ^N - _N ^Z fV l ίΧ F— ¹ i^'VN j η /X 77 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4-fluoro-2,3dimethylphenyl)-5(trifluoromethyl)-1H-pyrazol- 4carboxamide N^X ^F V ° rV ^{x ρ} -£Λ- _ν \ ^Λ η '' ^X ' ^ci F 78 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(3,4difluorophenyl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide N^\ F. _F ^'ν'^Ν F FV 0 f J ы? ^sCl 79 1-(2-chloro-5-fluorophenyl)-bH-(5chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide ΝΛ_ F _F F 0 jQf ΚλΛτ - Cl 80 1-(2-chloro-5-fluorophenyl)-bH-(5cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide N^\ F F—Uf 2 Г L ζΓΑ ,Χγ- N ¹ ^'' ^Xl F—(/ V- N ] H / 81 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4-fluoro-2methoxyphenyl)-5 (trifluoromethyl)-1H-pyrazol-4carboxamide

- 25 046082

Ν γ F _F N -N. _n ' fJZ o r T ,_. \AY''\l ΐφΥ h }=/ F Cl 82 1-(2-chloro-3-fluorophenyl)-bH-(5chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Y F _FZ N _V ^N 4| FY 0 f T _t —s <An'^'' Cl f—N Ύ' hr V g 83 1-(2-bromo-4-fluorophenyl)-bH-(5chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide ΝΑ F _t f NN r FA 0 γ N /=\ /Y-'Y'Arf4 /Vn Th =*n γί 84 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4-fluoro-2,3dimethylphenyl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide N-\ F _F ,Μ'Ν '/ΑΛΑ Y mm H hr N ^Z 85 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3-cyano-4fluorophenyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide N γ F. _F ,ΝγΥ FY ° f Y zt^\ UAy'^'YF—/ U ] η y=J hr N ^Z 86 1-(3-cyano-4-fluorophenyl)-bH-(5cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide NA F _X N ,-ζΐΛ-Α _α F—H \=/ Ύ 87 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(6-fluoro-4methylpyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide

- 26 046082

N^\ F .Ή/ -A 9 Γ;_ _ν ^' ^Λ η + n=<'n^ 88 LG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2methylpyridin-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide F fAf 9 G Ji H Vn ] h )=( hr F F 89 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5(trifluoromethyl)-1 -(2,3,4trifluorophenyl)-1H-pyrazol-4carboxamide Cl ы=\ HN—)—Ν' ^Ν= Ί d>Аь ^N CXfF-V 90 LG-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(2-chloro-6fluorophenyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide EF A-An ^F l 1 XX l ^- \ ^N & y - N ΊΓ H \=Z 91 LG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4methylpyridin-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide F ,,Ν^Α /-Υ1ΧΛ. 4-¼ F 92 LG-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2-fluoro-6methylphenyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide ^Ν Ά F ^CI f VH l /—( KA _N - -' Ci f—('An'·') h \=/ Ά Cl 93 LG-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(2,6-dichloro4-fluorophenyl)-5-(trifluoromethyl)1H-pyrazol- 4-carboxamide

- 27 046082

F _Z N _V N.|/ ^Ci fX ^F 4 ( X /—( k,-^y ^/H ' ^C fA''An ^j J h F 94 1-(2-chloro-4,6-difluorophenyl)-b[-(5chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5(trifluoromethyl)- 1H- pyrazole-4carboxamide F _F N.- ^N X \ 1 Xjx CI^X^Xn'X' η N=< 95 1-(6-chloro-2-methylpyridin-3-yl)M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide Cl _N ^K ΠΝΗ^^Λ yP 96 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5-fluoro-2methylphenyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide F JyV ^f X~ ^f a jol F XX'S H ^XN >=/ X FF 97 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5(trifluoromethyl)-1 -(2,3,4trifluorophenyl)-1H-pyrazol-4carboxamide zX ei n==\ hnYA/S JL Vi hX CX Xf° 98 1-(2-chloro-6-fluorophenyl)-M-(5cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide ^N ^\ F ,Ν-^Νγ <Y> ^F 9 ΓΧ /X fA/ Vn Ί H \=^ F 99 1-(2-chloro-4,6-difluorophenyl)-M-(5cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5(trifluoromethyl)-1H-pyrazole -4carboxamide

- 28 046082

N^\ ^F Y ⁰ r ^N jR 100 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2cyclopropylphenyl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide N^x F vN^z ^N 'N ^Z ^-ojX QXj ^h F 101 LG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2-fluoro-6methylphenyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide N^\ F _z N^> ⁿ -n ^c t> ^F i GT /gCh Χϊ<^Ν''^ ^Ζ ^Ν Ff Vn IH \=/ Cl 102 LG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(2,6-dichloro4-fluorophenyl)-5-(trifluoromethyl)1H-pyrazol- 4-carboxamide •th> ⁿ 1 ϊ*ΛΑ ^ν Ύ>-ν' ^Νϊ ι ζΛ-< ^Ν \ T'Z 103 LG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5-fluoro-2methylphenyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide Λ^Ζ y o^i /ίη n έ. ^{Hn ζ} ο ^ζ 104 LG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(3,4difluorophenyl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide CI _f V 105 1-(3-chloro-5-fluoropyridin-2-yl)M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide

- 29 046082

/ Cl N^\ 1 i X__/ \ / ГЧ Г Y \ о _F ^ ^N 7 ^f 106 1-(3-chloro-5-fluoropyridin-2-yl)M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide N^\ F _F J<_Υ1Λ< Ff W 7 H \=/ Cl 107 1-(2-chloro-4-fluorophenyl)-bH-(5chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide Cl _ΝΛ HN—С$-Л H = ^{N CI} '-Y^V ^N L O XX _f Xf FF _F 108 1-(3-chloro-4-fluorophenyl)-bH-(5chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide SZX' ^ ^/<=N \_ % ^c, YyX _f ^hn m“ ⁿ X F''^' ^F F to 109 1-(3-chloro-4-fluorophenyl)-bH-(5cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide L-, 0% TZ A ^Ω o 110 1-(2-chloro-4-cyanophenyl)-M-(5chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide N^\ F _F <γ o f ΐ /GA F—FX—NJH \=/ 111 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2,4difluorophenyl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide

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N^\ f .nV-n fV CL Z“ ^N MV' ⁰ fV V ⁿ I ^H \=Z Ή 112 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5-fluoro-3methylpyridin-2-yl)-5(trifluoromethyl)- 1H- pyrazole-4carboxamide N fVijuC /-N ..%< N ^>N fV y _N ] H \=/ V 113 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5-fluoro-3methylpyridin-2-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide ъ° ζι ο =( / ^H LX. 114 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4-fluoro-2(trifluoromethyl)phenyl)-5(trifluoromethyl)- 1H- pyrazole-4carboxamide z-z' // < o=< %-<?ζ 115 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4-fluoro-2(trifluoromethyl)phenyl)-5(trifluoromethyl)- 1H- pyrazole-4carboxamide №\ F-V 0 €bj« a Cl 116 1-(2-chlorophenyl)-X-(5-cyano-6(2H-1,2,3-triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide F; f NN FUZ 0 ^ ^Ν γ ^Ν 'Ν ^F Ά \ J ^H 117 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2,4difluorophenyl)-5-(trifluoromethyl)1H-pyrazol-4-carboxamide

- 31 046082

F 'z> _F U 0 λ ^ν -<<-- ^ν ν O' ⁿ \ ^A h' ^A ^ ^CI —< ¢/ X 118 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-1-(2-(1methoxyethyl)phenyl)-5(trifluoromethyl)-1H-pyrazol- 4carboxamide fkiu r ^N A ^H2l/ 4 -' ^ 4, 119 1-(4-amino-3-chloropyridin-2-yl)M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)-1H -pyrazole-4carboxamide zx o =/ v/з LJ-'^Vx .X z z <4 X 120 1-(4-amino-3-chloropyridin-2-yl)1HG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide N==X Lf 0 ✓M* ^F \ 1 £ 1 ^F -Ao h N=/ 121 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(6fluoropyridin-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide nY' ⁿ FC °(LA~ ^{CI 3} X An _ l=y h \ Ar ^N . J N-^. / N H 122 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(6(methylamino)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide N^N^n ^Z F ₃ C ?< f T f^/Α-νΠ ^th \=/ 123 1HG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(6(fluoro)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide

- 32 046082

N^\ jCk ^HN X У ^N 1 ^H / _N =/ 124 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-1-(6(methylamino)pyridin-3-yl)-5(trifluoromethyl)- 1H -pyrazole-4carboxamide N^\ F _F v ° _u Cl KU^-'S! H ₂ M—(' V—NJ η N=/ iX 125 1-(6-aminopyridin-3-yl)-bG-(5chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide Z w jOZ\-η TUH y±o L / =□ 126 1-(4-cyano-2-methylphenyl)-bG-(5cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide Xco 1 127 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(1 -methyl1,2,3,4-tetrahydroquinolin-5-yl)5- (trifluoromethyl)-1H-pyrazole-4carboxamide L ZI □X U\ w<L Z \ 128 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(1methylindolin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide DЪ L-U i T 1 I Г y~N J HN j fti^/ nX Г Η ·\ 129 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(1,2,3,4tetrahydroisoquinolin-5-yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide

- 33 046082

Cf Zz ZI Q =( A Il ~·Τν ² / Z 03 'V'Z ΞΕ 130 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(indolin-4yl)-5-(methyl trifluoro)-1Hpyrazole-4-carboxa N^\ _F ζΛν fV to JUO /=X / h LL ^N / N — 131 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(1 -methyl1,2,3,4-tetrahydroquinolin-8-yl)5- (trifluoromethyl)-1H-pyrazole-4carboxamide N^\ _F ν.Λν O ^F 1 OU / V- N ] ^H —ν'”__Ъ 132 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4-methyl-3,4dihydro-2H-benzo[b] [1.4 ]oxazin8-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide o ζζ'Ά^Χ OJ Z ^J \ /А mО #~Z О >L Za d V kJ 133 LG-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(1oxoisoind olin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide ΣΕ z Xj Z ΤΧη Js=° ъ / A 134 1-(6-aminopyridin-2-yl)-M-(5cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide Vn izv 3° ΙΞ A/A 135 1-(2-cyano-4-fluorophenyl)-bH-(5cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide

- 34 046082

0 i X ζχ ^ο \ b-W ζ u. 1 or 136 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(2-cyano-4fluorophenyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide AV_ Η-ζ ω 4 0JI LjT 137 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2(methylthio)phenyl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide ο /TV '' „Л ^-J Г -π ^ο ^,ζ^Λ.-π )=ο ъ ог- _г W 138 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2(methylsulfonyl)phenyl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide ^H Vn »AAvz ⁿ _F XI XI n ^Г p F MnV nW 139 1-(6-amino-5-cyanopyridin-2yl)-I-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide _ U Z-Z 0 ΙΞ ziQi /' z 140 1-(6-amino-5-cyanopyridin-2yl)-LH-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide nh ₂ ό/Γ° J vm<w Wn ⁿ 141 1-(6-amino-3-methylpyridin-2yl)-I-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide

- 35 046082

N^x F _F h ₂ nif Y ')/ ΐν /Χγ'' ^Γ ^'Ν N 7—N ] H 142 1-(2-amino-5-methylpyridin-4yl)-LG-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide N^\ F _F /NAH fx 0 Г L Λ X .ksX''''N NAN ] H ^=/ H ₂ N ' 143 1 -(2-amino-3 - methylpyridin-4yl)-bG-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide A zi oA oh u? ² J* 0 ¹ 144 1-(6-amino-5-chloropyridin-2-yl)M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3 -yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide N^X L--.A/ / F ₃ C 0 f Y F - A \ί И '^τ^' NN ^r \ Mi 7 h An (A h ₂ n 145 1-(6-amino-5-fluoro-3- methylpyridin-2-yl)-1\G-(5-cyano6-(2H-1,2,3-triazol-2- yl)pyrid in-3 -yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide N^X / ^F 3 ^C 9 f T F - nhx*'' N 1 ^h \ p—Ν TH An tA h ₂ n 146 1-(6-amino-5-fluoro-3methylpyridin-2-yl)-I-(5-chloro-6(2H-1,2,3-triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl )- 1Hpyrazole-4-carboxamide N^=X ^p ₃ e ? f T F _$ \\ k'^'Х^''' N '' ^V ' ¹ '^ CF 3 ^F d A ^N T h An fA h ₂ n 147 N-(6-(2H-1,2,3-triazol-2-yl)-5(trifluoromethyl)pyridin-3-yl)-1 (6-amino-5-fluoropyridin-2-yl)-5(trifluoromethyl )- 1H-pyrazole-4carboxamide

- 36 046082

ΞΕ g ζ K 148 1-(2-amino-5-chloropyridin-4-yl)M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3 -yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide ^Η ί ^Ν . f 'l F Ύ θ _N ' J n ^z Λ X l G X ^<N N ^: / 'N “AXL \ N= H ^Cl Cl 149 1-(2-amino-5-chloropyridin-4-yl)M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3 -yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide N^\. -NH fA/ ^F ο ^ ^Ν γΧ|/ \=n \ 11 LI ^F 4/ ⁿ :jhX 150 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5-fluoro-6(methylamino)pyridin-2-yl)-5(trifluoromethyl )- 1H-pyrazole-4carboxamide ΣΕ ABOUT tl 7· z J Jj zz\z - ,^Z 151 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5-fluoro-6-(3hydroxyazetide in-1 -yl)pyridin2-yl) -5-(trifluoromethyl)-1Hpyrazole-4-carboxamide °Y1 r У/ z ^X ^L-^i ν/Λ y° ΣΕ^ //Xz ^Z XX 152 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5-fluoro-6-(3hydroxyazetide in-1 -yl)pyridin2-yl) -5-(trifluoromethyl)-1Hpyrazole-4-carboxamide Cl N^\ F, LL fV 1 £X /=\ Ό-Ν* })—N 1 H 153 4-(4-((5-chloro-6-(2H-1,2,3-triazol2-yl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)-1H-pyrazol-1 yl)-3 -methylpyridine 1-oxide

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Tsd ⁵ ζτ 0Г about ² 154 1-(2-chloro-5-methyl-4-pyridyl)-lG[5-chloro-6-(triazol-2-yl)-3pyridyl]-5(trifluoromethyl)pyrazole-4carboxamide N^\ FN^ ^N ~N v ^f ° ί 1 f-D K ^{/<< s} ' νΠ-νΧ) ^nd ng ^ν Cl 5 155 1-(2-chloro-3-methylpyridin-4-yl)M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide I _..О g 2¼ fj z 3¼ ¹ 1Г+ 7 ⁵ ° ιζ С/ - о 156 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2-(3hydroxyazetide in-1 -yl)-5methylpyridin-4-yl)- 5(trifluoromethyl)-1H-pyrazole-4carboxamide (G^> U ΖΙ o =/ _w But T j 47 g A h I 157 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(2-(3hydroxyazetide in-1 -yl)-3 methylpyridin-4-yl) -5(trifluoromethyl)-1H-pyrazole-4carboxamide А1Ζ+, уо А 0 158 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3methylpyridin-4-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide ) _{with l} d< A./ _f A~F 0 if γ Ν ^ν ^ν V D JL JL C A^ai ^C| ( rA 159 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4methylpyridazin-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide

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zx chlZ ZX Z 160 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5-fluoro-6methylpyridin-2-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide /7/ zx o 4. vh /\ fAz LI 161 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(5-fluoro-6methylpyridin-2-yl)-5(trifluoromethyl)- 1H- pyrazole-4carboxamide N=X ^F \ c zV'N ^C| fX ^f ? ί Ύ ^and 162 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3,6dichloropyridin-2-yl)-5(trifluoromethyl)-1H-pyrazol- 4carboxamide ^F \ c zM'l/ ci _F Af o [f Ύ q/A ” 163 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3,6dichloropyridin-2-yl)-5(trifluoromethyl)-1H-pyrazol- 4carboxamide N^\ F _F /M'N Cl ^F V ° £1 (4L_n'j'1 4=4 X Vf FF 164 1-(6-chloro-3- (trifluoromethyl)pyridin-2-yl)-bG(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide F _F ci 4 ° f I x V ^N J ^H 4=/ N^ /V ^F FF 165 1-(6-chloro-3- (trifluoromethyl)pyridin-2-yl)-bH(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide

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F c CL/ fL o r T /ha, .A-·'ν·'^ ^χ ά _ν ci—v ⁴ Vn ] h /=/ 166 1-(4-chloro-2-methylphenyl)-C-(5cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3 -yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide 1 z'A 167 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3-fluoro-2methylphenyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide N^\ F _ n An Alik rAWAH ^H )=/ ii^ F 168 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(3,4-difluoro2-methylphenyl)-5-(trifluoromethyl)1H-pyrazol- 4-carboxamide 1 Z/-n Z\L#A )=o TZ / / =0 169 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(4cyanophenyl)-5-(1fluoromethyl)1H-pyrazol-4-carboxamide A Z Α-η )=o X / =rj 170 LG-(5-cyano-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-1-(4fluoro-2-methyl phenyl)-5 (trifluoromethyl)- 1H-pyrazole-4carboxamide NA, F _F f-D/ or Y < Vn YH )=/ and F \ 171 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3-fluoro-2methylphenyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide N^ F _F __,,Νν^Ν'Ν f Y ο Ύ I I 7 ^H ΓΤ ' ^N 172 LG-(5-chloro-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-1-(4fluoro-2-methyl phenyl)-5 (trifluoromethyl)- 1H-pyrazole-4carboxamide

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ΝΑ F F V 0 f T \=( >A F 173 LG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyrid in-3-yl)-5(trifluoromethyl)-1-(2,4,6trifluorophenyl)-1H-pyrazol-4carboxamide NA F _F ^Ν Άν' ^f Y ?L f I AL Tsa^'A ¹ f—c An ] h /A F \ 174 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(3,4-difluoro2-methylphenyl)-5-(trifluoromethyl)1H-pyrazol- 4-carboxamide rj ΓΧ ^Ζ o A z \A Lp ΞΖ / =M 175 1-(6-amino-3-chloropyridin-2-yl)lG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide I Ni 1, 176 1 -(6-amino-4-methylpyridin-2yl)-M-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)- 1H- pyrazole-4carboxamide NA ^F Y iXCk /=\ NA _n ⁿ - pv h ₂ n 177 1-(6-amino-5-cyanopyridin-2yl)-LG-(5-cyano-2-methyl-6-(2H1,2,3-triazol-2-yl)pyridin-3yl)-5-(methyl trifluoro )-1Hpyrazole-4-carboxamide Cf o o4 _ z 178 1-(6-amino-5-cyanopyridin-2yl)-LG-(5-chloro-2-methyl-6-(2H1,2,3-triazol-2-yl)pyridin-3yl)-5-(methyl trifluoro )-1Hpyrazole-4-carboxamide

- 41 046082

Ν γ f ^γΥιί' γ o y 1 F^YyΝγΜ }=Ν Ύ η _ξ ν 179 1-(6-amino-5-fluoropyridin-2-yl)M-(5-chloro-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5( trifluoromethyl)-1H-pyrazole-4carboxamide Ν γ V o <gM< ^F Y II Jl J >Ν Η η ₂ ν 180 1-(6-aminopyridin-2-yl)-bG-(5chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide Ν γ F _F - .; ^Ν - _ν · ^Ν “Ν AIL fA Υν ] η Υν γτ ηΧ 181 1-(6-amino-5-fluoropyridin-2-yl)M-(5-bromo-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5( trifluoromethyl)-1H-pyrazole-4carboxamide Ν γ F _F ργ ^Γ °Τ ί .Yr^N'^'^N F—( ^Ζ W 1 n ΥΝ hr Η _ξ Ν 182 1-(6-amino-5-fluoropyridin-2-yl)lG-(5-cyano-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5( trifluoromethyl)-1H-pyrazole-4carboxamide Cl Ν γ η ₂ ν _c Jr ^F ο < γ ^π Υν V Λ Αγ γτΑ 183 1-(6-amino-3-chloropyridin-2-yl)M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3 -yl)-5(trifluoromethyl)- 1H-pyrazole-4carboxamide , ² Υ--Π χο ъ Ο Ζ-ζ γ 184 1-(6-amino-5-methylpyridin-2yl)-LH-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide

- 42 046082

ι χχ ,z jr ϊ Z Υ-Π 'CX IZ 0 ^Q Y 185 1-(6-amino-3-methylpyridin-2yl)-M-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide p' I zz vh A 186 1-(6-amino-5-fluoro-3methylpyridin-2-yl)-bG-(5-cyano2-methyl-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4carboxamide N<\ F g A/A h ₂ nx ° f I f vn η n V=Z 'X X ^F FF 187 1-(6-amino-3- (trifluoromethyl)pyridin-2-yl)-bG(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide N^X F хЛ-Хм' h ₂ n _f A- ^f ο Ύ ¥ _F >v ΧΛν'ΧΧχι ^F -€fV h 188 1-(6-amino-5-fluoro-3methylpyridin-2-yl)-LH-(5-chloro-2methyl-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4carboxamide N*\ F _F N^z ^N 'N ^Z сй¥' HN \ 189 M-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(6(methylamino)pyridin-2-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide TG »> X 1. 190 1-(6-amino-4-methylpyridin-3yl)-LG-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide

- 43 046082

z κι Z A^'Z Г j z IjX /=° IZ A ² AJ 191 1-(6-amino-4-methylpyridin-3yl)-A-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide N*A F _F Ak h ₂ n ^F V ° Г I \γΥ ^ΛCl ( ^z An η h WH /V ^F FF 192 1-(6-amino-3- (trifluoromethyl)pyridin-2-yl)-bH(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide NA FA/X fY ^f U kX _t _. \ AAAi F ^H )=N h ₂ n 193 1-(6-amino-5-fluoropyridin-2-yl)A-(5-chloro-2-methyl-4-(2H-1,2,3triazol-2-yl)phenyl)-5(trifluoromethyl)- 1H -pyrazole-4carboxamide N^=A f ^n- ⁿ -n ^; fVIaX. /Г~\ /ANH _: N—({ y—N ] ^H N— 194 1-(6-aminopyridin-3-yl)-bG-(5cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide ΞΕ Ή z' vA- ⁴¹ vkA A / =0 195 1-(6-amino-5-fluoropyridin-2-yl)lG-(5-cyano-2-methyl-4-(2H-1,2,3triazol-2-yl)phenyl)-5(trifluoromethyl)-1H -pyrazole-4carboxamide N^A F _F ^f a I XY f/ A /A''N ^*n H ₃ N—( ^z A—NH \=/ 196 1-(6-amino-2-methylpyridin-3yl)-LG-(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide

- 44 046082

N^\ F. F ^F X Ilk /=\ -4 4 ^N J ⁿ JF-N LG H _? N 197 1-(6-amino-5-methylpyridin-2yl)-LG-(5-cyano-2-methyl-6-(2H1,2,3-triazol-2-yl)pyridin-3yl)-5-(methyl trifluoro )-1Hpyrazole-4-carboxamide №Л EFN Г FkV o >''V ^N h ₂ n \ jj L JL <Ο-Λν ^h h ₂ n 198 2-amino-6-(4-((5-chloro-2-methyl-6(2H-1,2,3-triazol-2-yl)pyridin3-yl)carbamoyl)-5- (trifluoromethyl)-1 H-pyrazol-1 yl)nicotinamide N^\ FF ^ ^Ν Ύ ^Ν 'Ν^ ^f AI £X „ch4 nG ^A h ₂ n ⁴ 199 1-(2-amino-3-methylpyridin-4yl)-LH-(5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4carboxamide $ O 4. _ \dU X o 200 1-(6-amino-5-chloropyridin-2-yl)lG-(5-cyano-2-methyl-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-5( trifluoromethyl)-1H-pyrazole-4carboxamide z II ζ'Άι llj ZZ^ ¹ Ή X ⁰ ΞΖ u ^{2 z} V 201 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(6-cyano-2methylpyridin-3-yl)-5(trifluoromethyl)- 1H- pyrazole-4carboxamide N-^\ F ^f X ^f 1IX fVnXs ^Cl / ⁼ N 0r 202 1-(6-bromopyridin-2-yl)-bG-(5chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide

- 45 046082

A ^F T i? J n \ A__I JT ^N |q=/ H Cl 203 (*R)-N-(5-xnop-6-(2H-l,2,3- triazol-2-yl)pyridin-3-yl)-1-(5methyl-2-(tetrahydrofuran-2yl)pyridin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxamide °4'S 'j L ^F + ^F 0 _N ' λ A Ji ίι Ά A D N=^ Η ΌΙ 204 (*S)-N-(5-xaop-6-(2H-l,2,3triazol-2-yl)pyridin-3-yl)-1-(5methyl-2-(tetrahydrofuran-2yl)pyridin-4 -yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide _L· f ¹ a A ^F- T ^{F 0} J ^N 1 KmM JL 'N wa Aww \ AH 205 (*S)-1-(2-(1,4-dioxan-2-yl)-5methylpyridin-4-yl)-LG-(5-chloro-6(2H-1,2,3-triazol-2- yl)pyridin3-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide Pz ^Z 'Z — /=z 1 _o w 206 (*R)-1-(2-(1,4-dioxan-2-yl)-5methylpyridin-4-yl)-LG-(5-chloro-6(2H-1,2,3-triazol-2- yl)pyridin3-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide π Z, z u_ ^x 2vA zz C ^z o 207 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1 -(6-(furan-2yl)pyridin-2-yl)-5(trifluoromethyl )- 1H-pyrazole-4carboxamide Λ JF NyN/ _F W o f γ ?=n 4 An jh VW A 208 M-(5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(6-(5,6dihydro-1,4-dioxin-2yl)pyridin- 2-yl)-5(trifluoromethyl)-1H-pyrazol-4carboxamide

In a further embodiment, the present invention relates to a compound of formula (I)

1 IR ₃ selected from the group consisting of 9 ^R 2 1 1 NR!

- 46 046082

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide;

1-(4-Chloro-2-methylphenyl)-bH-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylpyridin-2-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyridin-4-yl)-5(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-phenyl-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-fluoropyridin-4-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoropyridin-2-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyridin-2-yl)-5(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrazin-2-yl)-5(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrimidin-2-yl)-5(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-cyanopyridin-2-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyridin-3-yl)-5(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-methoxypyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxypyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrimidin-5-yl)-5(trifluoromethyl)-1H-pyrazol- 4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-methylpyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide;

X-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-cyanopyridin-3-yl)-5-47 046082 (trifluoromethyl) -1H-pyrazole-4-carboxamide;

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

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

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

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

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

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

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

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

M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-fluoro-1-phenyl-1H-pyrazol-4carboxamide;

M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(p-tolyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide;

M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(m-tolyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide;

M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(o-tolyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide;

1-(5-bromo-3-chloropyridin-2-yl)-bG-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

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

1-(3-Chloro-2-methoxypyridin-4-yl)-LG-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

1-(3-Cyano-2-methylpyridin-4-yl)-LG-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

1-(3-Bromo-5-fluoropyridin-2-yl)-LG-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

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

M-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-dichloropyridin-2-yl)-5 (trifluoromethyl)- 1H-pyrazole-4-carboxamide;

M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-cyano-2-methylphenyl)-5-48 046082 (trifluoromethyl) -1H-pyrazole-4-carboxamide;

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxy-3-methylpyridin4-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

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

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

X-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxypyridin-4-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide;

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

1-(3-chloro-2-methylpyridin-4-yl)-b1-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

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

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

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

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

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

LG-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,3dihydrobenzo[b][1,4]dioxin-5-yl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

1-(2-bromo-4-fluorophenyl)-bH-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide;

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

-([ 1,3 ] dioxolo[4,5 -b] pyridin-7-yl)-X-(5-chloro-6-(2H-1,2,3 -triazol-2-yl)pyridin 3- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

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

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

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(o-tolyl)-5-(trifluoromethyl)1H-pyrazol-4- carboxamide;

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

1-(2-amino-3-chloropyridin-4-yl)-bG-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-49 046082 yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide;

M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,2difluorobenzo[0][1,3]dioxol-4-yl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

1-(benzo[0][1,3]dioxol-4-yl)-bG-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide;

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

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

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

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

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

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

1-(3-chloro-4-methoxypyridin-2-yl)-LG-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin3-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

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

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

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

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

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

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

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

M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-(methylsulfonyl)phenyl)-5 (trifluoromethyl)-1H-pyrazole -4-carboxamide;

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

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

M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2,3-dimethylphenyl)-5-50 046082 ( trifluoromethyl)-1H-pyrazole-4-carboxamide;

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

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

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

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

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

1-(2-bromo-4-fluorophenyl)-bH-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)-1H- pyrazole-4-carboxamide;

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

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

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

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

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

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

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

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

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

M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-fluorophenyl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

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

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

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

M-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1-(2,3,4

- 51 046082 trifluorophenyl)-1H-pyrazole-4-carboxamide;

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

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

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

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

M-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-fluorophenyl)-5(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,4-difluorophenyl)-5-52 046082 (trifluoromethyl)-1H -pyrazole-4-carboxamide;

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

1-(4-amino-3-chloropyridin-2-yl)-b1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

1-(4-amino-3-chloropyridin-2-yl)-b1-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3·yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide;

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

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

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

L1-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-(methylamino)pyridin-3 yl)-5-(trifluoromethyl )-1H-pyrazole-4-carboxamide;

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

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

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

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

L1-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,2,3,4tetrahydroisoquinolin-5-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide;

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

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

I-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-methyl-3,4-dihydro-2Hbenzo[b][1 ,4]oxazin-8-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

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

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

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

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

I-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(methylthio)phenyl)-5-53 046082 (trifluoromethyl)- 1H-pyrazole-4-carboxamide;

LG-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(methylsulfonyl)phenyl)-5 (trifluoromethyl)-1H-pyrazole -4-carboxamide;

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

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

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

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

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

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

1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-LG-(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide;

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

LG-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(6-amino-5fluoropyridin-2-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide;

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

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

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

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

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

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

1-(2-chloro-5-methyl-4-pyridyl)-lG-[5-chloro-6-(triazol-2-yl)-3-pyridyl]-5(trifluoromethyl)pyrazole-4-carboxamide;

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

LG-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(3-hydroxyazetidin-1-yl)5-methylpyridin-4 -yl)-5-(trifluoromethyl)-1 H-pyrazol-4-carboxamide a;

LG-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(3-hydroxyazetidin-1-yl)

- 54 046082

-methylpyridin-4-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide a;

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

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

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

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

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

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

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

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

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

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

M-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-difluoro-2-methylphenyl)5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide;

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

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

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

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

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

LG-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-difluoro-2-methylphenyl)-5 (trifluoromethyl) -1H-pyrazole-4-carboxamide;

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

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

1-(6-amino-5-cyanopyridin-2-yl)-M-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-55 046082 yl)pyridin-3- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

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

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

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

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

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

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

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

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

1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-LG-(5-cyano-2-methyl-6-(2H-1,2,3-triazol2-yl)pyridin-3- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

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

1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-LH-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2·yl)pyridin- 3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

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

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

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

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

1-(6-amino-5-fluoropyridin-2-yl)-LH-(5-chloro-2-methyl-4-(2H-1,2,3-triazol-2yl)phenyl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

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

1-(6-amino-5-fluoropyridin-2-yl)-LG-(5-cyano-2-methyl-4-(2H-1,2,3-triazol-2yl)phenyl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide;

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

1-(6-amino-5-methylpyridin-2-yl)-14-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2- 56 046082 yl)pyridin-3- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

2-amino-6-(4-((5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)5-(trifluoromethyl)- 1H-pyrazol-1-yl)nicotinamide;

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

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

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

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

(*K)-M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-methyl-2(tetrahydrofuran-2-yl )pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

(*8)-M-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-methyl-2(tetrahydrofuran-2-yl )pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

(*S)-1-(2-(1,4-dioxan-2-yl)-5-methylpyridin-4-yl)-LG-(5-chloro-6-(2H-1,2,3-triazole2 -yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

(*R)-1-(2-(1,4-dioxan-2-yl)-5-methylpyridin-4-yl)-LG-(5-chloro-6-(2H-1,2,3-triazole2 -yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide;

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

LG-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-(5,6-dihydro-1,4-dioxin2-yl )pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

or a pharmaceutically acceptable salt form thereof.

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

Representative acids and bases that can be used to prepare pharmaceutically acceptable salts include acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid , 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(^)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α -oxoglutaric acid, glycolic acid, hippuric acid

- 57 046082 tu, hydrobromic acid, hydrochloric acid, (-)-n-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-l-malic acid, malonic acid, (±) -DLmandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid , phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, ()-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid ; as well as bases, including ammonia, L-arginine, benetamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamine)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, L -lysine, magnesium hydroxide, 4-(2-hydroxyethyl)morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)pyrrolidine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

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

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

One skilled in the art will appreciate that the compounds described herein may exist as tautomers and that other tautomeric configurations of the structures presented herein are possible. It should be understood that all tautomeric forms are covered by the structure, which describes one possible tautomeric configuration of the groups of a compound, even if not specifically stated.

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

One embodiment of the present invention relates to a composition, including a pharmaceutical composition, comprising, and/or essentially consisting of, a (+)-enantiomer of a compound of formula (I), wherein said composition is substantially free of the (-)-isomer of said compound . As used herein, substantially free means the presence of less than about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2%, and even more preferably less than about 1% of the (-)-isomer contained in calculated as %( ₊ ) - enantiomer =----------(4)-enantiomer)------------- _x , ₀₀ (mass (+) - enantiomer) + (mass(-) - enantiomer)

Another embodiment of the present invention is a composition, including a pharmaceutical composition, which contains, consists of, and is essentially composed of a (-)-enantiomer of a compound of formula (I), wherein said composition is substantially free of said (+)-isomer

- 58 046082 connection. As used herein, the expression substantially free means a content of less than about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2%, and even more preferably less than about 1% of the (+)isomer, content which is calculated as (mass (-)- enantiomer) %(-) - enantiomer =---------- ¹ -----—----------—---- --------x 100 (mass (+) - enantiomer) + (mass (-) - enantiomer)

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

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

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

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

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

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

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

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

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

For buccal or sublingual administration, the pharmaceutical compositions of this

- 59 046082 of the invention can be administered in the form of tablets or lozenges, which can be prepared in a traditional way.

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

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

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

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

It is an advantage that the compound of formula (I) can be administered in a single daily dose or that the daily dose can be divided into two, three or four divided doses per day.

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

The compounds of formula (I) may be administered in the form of any of the above-described compositions and in accordance with any of the above-described dosage regimens, or using any compositions and dosage regimens conventional in the art in any case where a patient requires administration of a compound of formula (I ).

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

- 60 046082 head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyelosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial cancer, vaginal cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer, and GIST (gastrointestinal stromal tumor).

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

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

Possible combinations of compounds of the present invention include, but are not limited to, BTK (Bruton's tyrosine kinase) inhibitors such as ibrutinib, SYK inhibitors, PKC inhibitors, PI3K pathway inhibitors, BCL family inhibitors, JAK inhibitors, PIM kinase inhibitors, rituximab or other antibodies that bind with B-cell antigen, as well as immune cell redirection agents (eg, blinatumomab or chimeric antigen receptor T cells (CAR T cells)) and immunomodulatory agents such as daratumumab, anti-PD1 antibodies, and anti-PDL1 antibodies.

The compounds of the present invention have been found to inhibit MALT 1 activity.

In some embodiments, inhibition of MALT1 by a compound of the invention may be useful in the treatment or prevention, particularly the treatment of a non-limiting list of cancers described herein.

The invention relates to compounds of formula (I) or their enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form for use as a medicine.

The invention relates to compounds of formula (I) or their enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form for use in inhibiting MALT 1 activity.

The invention relates to compounds of formula (I) or their enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form for use in the treatment of diseases mentioned herein.

The invention relates to compounds of formula (I) or their enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form for the treatment or prevention, in particular for the treatment of these diseases.

The invention relates to compounds of formula (I) or their enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form for the treatment or prevention, in particular for the treatment of MALT1-mediated diseases or conditions.

The invention relates to compounds of formula (I) or their enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form for the preparation of a drug.

The invention relates to compounds of formula (I) or their enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form for the preparation of a drug for inhibiting MALT1.

The invention relates to compounds of formula (I) or their enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form for the preparation of a medicinal product for the treatment or prevention, in particular for the treatment, of any of the pathological conditions mentioned herein.

The invention relates to compounds of formula (I) or their enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form for the preparation of a medicament for the treatment of any of the pathological conditions mentioned herein.

The invention relates to compounds of formula (I) or their enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form, which can be administered to mammals, preferably humans, for the treatment or prevention of any of the diseases mentioned herein.

In light of the usefulness of the compounds of formula (I) or their enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form, a method of treating warm-blooded animals, including

- 61 046082 people suffering from any of the diseases mentioned herein, or a method for preventing such diseases in warm-blooded animals, including humans.

General synthesis methods

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

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

AcOH acetic acid

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

Vos /7?/7c/7?-butyl carbamate

BuLi butyllithium

Cbz benzyl carbamate

DCM dichloromethane

DMA dimethylacetamide

DME ethylene glycol dimethyl ether

DMF dimethylformamide

DMSO dimethyl sulfoxide

EA ethyl acetate

Et ethyl

Et ₂ O diethyl ether

EE Ac ethyl acetate

EtOH ethyl alcohol

FCC flash column chromatography h hour(s)

HATU O-(7-azabenzotriazol-1-yl)-L', Ν,Ν',N'-tetramethyluronium hexafluorophosphate

HCHO formaldehyde

HC1 hydrochloric acid

HPLC high performance liquid chromatography

KCN potassium cyanide

LCMS high pressure liquid chromatography with mass spectrometry

LDA lithium diisopropylamide

LiOH lithium hydroxide

Me methyl

MeCN acetonitrile

MeOH methyl alcohol mg milligram min minute

NaCN sodium cyanide

NaOH sodium hydroxide

- 62 046082

NaOtBu sodium tert-butoxide

NH4CI ammonium chloride

Pd/C palladium on activated carbon

P02(dba)3s tris(dibinsylideneacetone)dipalladium

Pd(dppf)C12 [1, G-bis(diphenylphosphino)ferrocene]dichloropalladium

Pd(OAc) ₂ palladium diacetate

Pd(PPys)4 tetrakis(triphenylphosphine)palladium

PPh ₃ triphenylphosphine p-TsOH para-toluenesulfonic acid RT or RT room temperature

TBAF tetrabutylammonium fluoride

TMSI iodotrimethylsilane t-Bu tert-butyl

TFU trifluoroacetic acid

TFUA trifluoroacetic anhydride

THF tetrahydrofuran

TLC thin layer chromatography

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

XPhos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

The compounds of formula (I) can be prepared according to the process shown in Scheme 1.

Scheme 1 _ν ^ν ^Λ ν^ _ν ,Gj ,NHNH ₂ η ² Ί (EtO) ₃ CH

F ₃ C OH

_Ac2O

1D

W = OEt or NMc

1. Hydrolysis

Formula 1

Amide bonding or 1G, base

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

In an alternative embodiment, the pyrazole ester of formula (1F) can be directly converted to a compound of formula (I) by treatment with a compound of formula (1G) and a base,

- 63 046082 such as potassium tert-butoxide.

An alternative method for the synthesis of compounds of formula (I) is presented in Scheme 2.

Scheme 2

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

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

Scheme 3

- 64 046082

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

Chloride, bromide or iodide-substituted aryls or heteroaryls can be subjected to palladium-catalyzed Buchwald-Hartwig coupling with benzophenone hydrazine in the presence of a ligand such as Xantphos and a base such as sodium t-butoxide to form the hydrazine of formula (3D). Acid hydrolysis allows one to obtain hydrazine of formula (1E) (path number two).

Aryl- or heteroaryl-substituted boronic acids can also act as precursors for compounds of formula (1E) in the synthetic route represented as route three. A boronic acid of formula (3E) can undergo a Cu ²⁺ catalyzed addition to a di-tert-butyl azodicarboxylate to yield an intermediate of formula (3F), which can be deprotected in an acidic environment to yield a compound of formula (1E). Heteroarylhydrazines of formula (1E) having a nitrogen atom in the ortho or para position relative to the hydrazine functionality can be prepared by direct halogen substitution with hydrazine or hydrazine hydrate (route number four). Alternatively, halogenated (hetero)arenes of formula (3H) can be subjected to palladium-catalyzed cross-coupling with hydrazine to directly produce intermediate (1E) (route number five).

Scheme 4 illustrates several available routes for the synthesis of the intermediate (1G, Q2=CR).

Scheme 4

1G

Compound (4A) can be reacted with a compound of formula RH in the presence of a base such as Cs ₂ CO ₃ in a solvent such as DMF to produce a compound of formula (4B). Alternatively, the compound of formula (4C) can be treated with a cross-linking reagent such as a boron reagent of formula (4D) or a tin reagent of formula RSn(Bu) ₃ ; in the presence of a palladium catalyst, including, without limitation, Pd(dppf)Cl ₂ or Pd(PPh ₃ ) ₄ ; in a suitable solvent or solvent system such as DMF, dioxane/water, etc.; to obtain the compound of formula (4B). Another suitable route involves reacting a compound of formula (4C) with a compound of formula RH in the presence of a coupling reagent such as CuI, a base such as Cs ₂ CO ₃ and a solvent such as DMF to produce a compound of formula (4B) . The compound of formula (4B) can be reduced to the compound of formula (1G) using a reducing reagent such as Zn or Fe, in the presence of NH4Cl, in a solvent such as MeOH.

Alternatively, intermediate 1G can be prepared by Curtius rearrangement of suitable aryl acids (Scheme 5), which can be prepared in the same way as Scheme 4 (replacing _NO2 with acid or ester)

Scheme 5

Acid 5A treated with diphenylphosphoryl azide in the presence of a base in tert-butanol gives the deprotected tert-butoxycarbonyl-protected amino compound 5B in an acidic environment such as HCl or TFA to give intermediate 1G.

- 65 046082

Scheme 6

Formula I Formula IA

In the situation in which L is H, alkylation of compounds of formula I can occur through the formation of a radical from R2-L obtained by treatment with ammonium persulfate and (IR[DF(CF3)PPY]2(DTBPY))PF ₆ in a mixture of water and CH3CN or DMSO and TFA under blue light LED irradiation. The compounds of formula I can also be converted to the corresponding N-oxides by treatment with an oxidizing agent such as m-CPBA in DCM or THF. Said N-oxides of the compounds of formula I can also be converted to the corresponding ortho-chlorine derivatives by the action of POCl3, optionally in a solvent such as CHCl3. Such ortho-chloro derivatives can react with suitably substituted amines to produce the _C1-6 alkylamino, _C1-6 cycloalkylamino or N-linked heterocyclic rings of the present invention.

Specific examples.

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

Intermediate connection 1.

Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT 1

Ethyl 4,4,4-trifluoro-3-oxobutanoate (30 g, 162.9 mmol) was added to a solution of triethoxymethane (72.4 g, 488.8 mmol) in acetic anhydride (50 ml). The mixture was stirred at 135°C for 18 hours. The brown mixture was concentrated to give ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (38 g, 97.1%), as a brown oil , which was used without further purification. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.23-1.33 (m, 3H), 1.40 (dt, J=14.18, 7.19 Hz, 3H), 4.19 -4.36 (m, 4 N), 7.66-7.87 (m, 1 H).

Intermediate 2.

A. 3-Chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine, INT2A

CI /={ Ά

Ν , ΙΝΤ2Α

Mixture of 2,3-dichloro-5-nitropyridine (50 g, 259.08 mmol), 1H-1,2,3-triazole (19.683 g, 284.99 mmol), potassium carbonate (46.549 g, 336.81 mmol) and CH ₃ CN (200 ml) were 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 Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was triturated with DCM (100 ml), filtered and the solid collected to give INT2A (40 g, 68%) as an off-white solid. LC-MS: (ES, m/z): [M+1]+ 225.9. ^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.40 (d, J=2.0 Hz, 1H), 9.15 (d, J=2.0 Hz, 1H), 8 .33 (s, 2H).

B. 5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2

CI/C -¼

Μ Ν ,INT2

3-Chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine, INT2A (20 g, 88.656 mmol), MeOH (500 ml) and Pt/C (2 g, 5 %, 0.513 mmol) was added to a 1000 ml hydrogenation bottle. The resulting mixture was stirred under H ₂ (30 psi) at 25° C. for 20 hours. The suspension was filtered through a pad of diatomaceous earth and the filter residue was washed with ethyl acetate (100 ml). The filtrate was concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative reverse phase HPLC (0-50% (v/v) CH ₃ CN and water with 0.05% NH3) followed by lyophilization to dryness to give compound INT2 (10.4 g, 60%) as an off-white solid. LC-MS: (ES, m/z): [M+1] ⁺ 196.1; 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.05 (s, 2H), 7.83 (d, J=2.0 Hz, 1H), 7.21 (d, J=2 .4 Hz, 1H), 6.19 (s, 2H).

- 66 046082

Intermediate 3.

A. 5-Nitro-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3A % ₊ 0

Ν' *N , INT3A

A mixture of 2-chloro-5-nitropyridine-3-carbonitrile (9.0 g, 49 mmol), 2H-[1,2,3]triazole (3.41 ml, 58.8 mmol) and potassium carbonate (20.32 g, 147 mmol) in acetonitrile (225 ml) was stirred at 30°C for 2 hours. Water and ethyl acetate were added and the organic phase was separated, dried with MgSO ₄ , filtered and the filtrate was concentrated to give the crude product, which was mixed with dichloromethane (30 ml) and filtered to obtain pure 5-nitro-2-[1,2,3]triazol-2-yl-nicotinonitrile (8.3 g, 78.4% yield) as an orange solid. ¹ H NMR (300 MHz, DMSOd ₆ ) δ 8.46 (s, 2H), 9.45 (d, J=2.5 Hz, 1H), 9.61 (d, J=2.5 Hz, 1H ). LC-MS: m/z 217.0 [M+H]+.

B. 5-Amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3

NH ₂

^N N.

N N

U,INT3

To a solution of 5-nitro-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3a (2.0 g, 9.25 mmol), in ethyl acetate (30 ml) was added tin(II) chloride dihydrate in three parts ) (19.2 g, 92.5 mmol, 10 eq.) for 3 hours and the mixture was stirred at room temperature for 24 hours. The mixture was poured into a mixture of water and JaHCO ₃ and diluted with ethyl acetate. The organic layer was separated and washed with brine, then dried over MgSO ₄ and the filtrate was concentrated to obtain a mixture of product and starting material, which was dissolved in ethanol (300 ml). Tin(II) chloride dihydrate (9.6 g, 46.25 mmol, 5 eq.) was added. This mixture was heated to 50°C and stirred for 48 hours until the reaction was complete. The mixture was poured into a mixture of water and HCO ₃ and diluted with ethyl acetate. The organic layer was separated and washed with brine, then dried over MgSO ₄ and the filtrate was concentrated. Flash column chromatography (SiO ₂ , methanol-dichloromethane gradient from 0 to 10%) was used for purification. The pure fractions were combined and concentrated to give pure 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (899 mg, 52% yield) as an orange solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.26 (s, 2H), 7.45 (d, J=2.87 Hz, 1H), 8.09 (d, J= 2.65 Hz, 1H), 8.13 (s, 2H). LC-MS: m/z 187.1 [M+H]+.

Example 1.

\-(5-\lor-6-(211-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)- 1H pyrazole-4-carboxamide, compound 1

A. Ethyl 1-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 1a

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1.55 g, 6.46 mmol), (4-fluoro-2-methylphenyl)hydrazine (950 mg, 5.38 mmol), triethylamine (0.749 ml, 5.38 mmol) and ethanol (20 ml), stirred at 80°C for 16 hours and then cooled to room temperature.

The resulting solution was concentrated to dryness under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=10:1) to give the title compound (1.2 g, 71%) as a brown oil. LCMS (ESI) m/z M+1: 316.9. ^1H NMR (400 MHz, CDC13) δ 8.16 (s, 1H), 7.27-7.21 (m, 1H), 7.08-6.98 (m, 2H), 4.39 (d , J=7.2 Hz, 2H), 2.04 (s, 3H), 1.40 (t, J=7.2 Hz, 3H).

B. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide, compound 1

- 67 046082

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (148 mg, 0.759 mmol), and THF (1 ml), and a solution consisting of ethyl 1-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxylate, compound 1a (200 mg, 0.632 mmol), and THF (1 ml), was added to the solution containing from potassium tert-butoxide (3.16 ml, 3.16 mmol, 1M in THF), at 0°C. The resulting mixture was stirred at room temperature for 16 hours. Water was added to the resulting mixture and the mixture was extracted using ethyl acetate (15 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (42-72% (v/v) CH3CN and H ₂ O with 0.05 % NH3) and lyophilized to dryness to obtain the title compound (143.60 mg, 49%). LCMS (ESI) m/z M+1: 465.9. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.74 (d, J=2.4 Hz, 1H), 8.49 (d, J=2.4 Hz, 1H), 8.37 (br.s , 1H), 8.11 (s, 1H), 7.94 (s, 2H), 7.28-7.25 (m, 1H), 7.11-7.00 (m, 2H), 2, 05 (s, 3H).

Example 2.

1-(4-Chloro-2-methylphenyl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-Spirazole -4-carboxamide, compound 2

A. Ethyl 1-(4-chloro-2-methylphenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 2a

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (0.836 g, 3.48 mmol), (4-chloro-2-methylphenyl)hydrazine (560 mg, 2. 90 mmol), triethylamine (0.404 ml, 2.90 mmol) and ethanol (20 ml), stirred at 80°C for 16 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product, which was added to water (10 ml). The resulting mixture was extracted using ethyl acetate (20 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=10:1) to give the title compound (580 mg , 60%) in the form of a yellow solid. LCMS (ESI) m/z M+1: 332.9. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 7.35 (s, 1H), 7.33-7.28 (m, 1H), 7.19 (d, J= 8.4 Hz, 1H), 4.39 (k, J=7.2 Hz, 2H), 2.04 (s, 3H), 1.40 (t, J=7.2 Hz, 3H).

B. 1-(4-chloro-2-methylphenyl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 2

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (176 mg, 0.902 mmol), and THF (1 ml), and a solution consisting of ethyl 1-(4-chloro-2-methylphenyl)-5-(trifluoromethyl)-1H pyrazole-4-carboxylate, compound 2a (200 mg, 0.601 mmol), and THF (1 ml), was added to the solution, with consisting of potassium tert-butoxide (3.01 ml, 3.01 mmol, 1M in THF), at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was added to water (5 ml) and extracted using ethyl acetate (15 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure from half

- 68 046082 by purifying the crude product, which was purified by preparative HPLC (45-75% (v/v) CH3CN and H2O with 0.05% NH3) and lyophilized to give the title compound (172.30 mg, 59 %) in the form of a brown solid. LCMS (ESI) m/z M+1: 481.8. 1H NMR (400 MHz,

CDCl3) δ 8.75 (d, J=2.4 Hz, 1H), 8.50 (d, J=2.8 Hz, 1H), 8.33 (br.s, 1H), 8.12 ( s, 1H), 7.94 (s, 2H), 7.38 (d, J=2.0 Hz, 1H), 7.35-7.30 (m, 1H), 7.22 (d, J =8.4 Hz, 1H), 2.05 (s, 3H).

Example 3.

N-(5-chloro-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(3-methylpyridin-2-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide

A. Ethyl 1-(3-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 3 a

, connection For

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (2.3 g, 9.7 mmol), 2-hydrazinyl-3-methylpyridine (1.0 g, 8 .1 mmol) and ethanol (20 ml), stirred at 80°C for 16 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=4:1) to give the title compound (1.1 g, 45%) as a brown oil. LCMS (ESI) m/z M+1: 300.0. ¹ H NMR (400

MHz, CDCl3) δ 8.44 (dd, J=1.6, 4.8 Hz, 1H), 8.19 (s, 1H), 7.78-7.73 (m, 1H), 7.42 (dd, J=4.8, 8.0 Hz, 1H), 4.39 (k, J=7.2 Hz, 2H), 2.17 (s, 3H), 1.40 (t, J= 7.2 Hz, 3H).

B. 1-(3-Methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 3b

A solution consisting of lithium hydroxide hydrate (126 mg, 3.01 mmol) and water (5 ml) was added to a solution consisting of ethyl 1-(3-methylpyridin-2-yl)-5-(trifluoromethyl)-1H- pyrazole-4-carboxylate, compound 3a (300 mg, 1.00 mmol), and ethanol (10 ml). The resulting solution was stirred at room temperature for 16 hours. The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product, which was poured into water (3 ml) and acidified with 3 N HCl to pH 5. The resulting mixture was filtered and the residue remained on the filter. washed with 3 ml of water and dried under reduced pressure to obtain the title compound (160 mg, 59%) as a white solid. LCMS (ESI) m/z M+1: 272.1. 1H NMR (400 MHz, DMSO-d ₆ ) δ 13.43 (br.s, 1H), 8.45 (dd, J=1.2, 4.8 Hz, 1H), 8.31 (s, 1H ), 8.01 (d, J=8.0 Hz, 1H), 7.61 (dd, J=4.8, 8.0 Hz, 1H), 2.11 (s, 3H).

S. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylpyridin-2-yl)-5-(trifluoromethyl)III -pyrazole-4-carboxamide, compound 3

POCl ₃ (95.0 mg, 0.619 mmol) was added dropwise to a solution consisting of 1-(3-methylpyridin-2yl^-^trifluoromethyl-fN-pyrazoleA-carboxylic acid, compound 3b (140 mg, 0.516 mmol), 5-chloro -6(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (121 mg, 0.619 mmol), and pyridine (5 ml), at 0° C. The resulting mixture was stirred at 0° C for 1 hour. Saturated NaHCO ₃ (10 ml) was added to the resulting mixture and the mixture was extracted using ethyl acetate (15 ml x 3).The organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated to dryness under reduced pressure to obtain crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=3:1) to give still crude product (200 mg). The product was further purified by preparative HPLC (30-60% (v/v) CH3CN and H ₂ O

- 69 046082 with 0.05% NH3) and lyophilized to give the title compound (120.3 mg, 52%).

LCMS (ESI) m/z M+1: 448.9. 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.20 (br.s, 1H), 8.84 (d, J=2.4 Hz, 1H), 8.66 (d, J=2.4 Hz, 1H), 8.51-8.47 (m, 2H), 8.18 (s, 2H), 8.04 (d, J=7.6 Hz, 1H), 7.63 (dd, J =4.8, 7.6 Hz, 1H), 2.16 (s, 3H).

Example 4.

^(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyridin-4-yl)-5-(trifluoromethyl)-III-pyrazol4- carboxamide, compound 4

A. Ethyl 1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 4a

A mixture consisting of 4-hydrazinylpyridine hydrochloride (1.00 g, 6.87 mmol), triethylamine (0.690 g, 6.87 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1.65 g, 6.87 mmol), and ethanol (12 ml), were stirred at 80°C for 1 hour. The mixture was then cooled to room temperature and concentrated to dryness under reduced pressure to obtain a residue, which was purified using flash column chromatography (petroleum ether:ethyl acetate=8:1) to give the title compound (215 mg, 11%). LCMS (ESI) m/z M+1: 285.8.

B. 1-(Pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 4b

A mixture consisting of ethyl 1-(pyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 4a (210 mg, 0.740 mmol), sodium hydroxide (2.21 ml, 2.21 mmol, 1 M) and ethanol (2 ml), stirred at room temperature for 2 hours. The mixture was neutralized with 1 M HCl to pH 6 and extracted with ethyl acetate (40 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and the filtrate was concentrated to dryness under reduced pressure to give the title compound (180 mg, crude), which was used in the next step without further purification. LCMS (ESI) m/z M+1: 257.7.

C. N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(pyridin-4-yl)-5-(trifluoromethyl)-Spirazole -4-carboxamide, compound 4

POCl ₃ (0.1 ml) was added dropwise to a solution consisting of 1-(pyridin-4-yl)-5-(trifluoromethyl)N-pyrazole-4-carboxylic acid, compound 4b (140 mg, 0.540 mmol), 5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-amine, INT2 (106 mg, 0.540 mmol), and pyridine (4 ml), at 0°C. The mixture was stirred at 0°C for 1 hour, then quenched with sat. NaHCO ₃ and extracted using ethyl acetate (50 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated to dryness under reduced pressure to give a residue, which was purified by preparative TLC (petroleum ether:ethyl acetate=1:1) to give the still crude product (80 mg). The chromatographic product (80 mg) was purified by preparative HPLC (28-58% (v/v) CH3CN and _H2O with 0.05% NH3) and lyophilized to give the title compound (50 mg, 21%). LCMS (ESI) m/z M+1: 434.9. ¹ H NMR (400 MHz, CDO3) δ 8.85 (d, J=6.4 Hz, 2H), 8.74 (d, J=2.4 Hz, 1H), 8.50 (d, J= 1.6 Hz, 1H), 8.13 (s, 1H), 8.11 (s, 1H), 7.95 (s, 2H), 7.48 (d, J=6.0 Hz, 2H) .

Example 5.

^(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-phenyl-5-(trifluoromethyl)-III-pyrazol-4carboxamide, compound 5

- 70 046082

A. Ethyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 5a

, connection 5a

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (9.97 g, 41.5 mmol), phenylhydrazine (5.00 g, 34.6 mmol), triethylamine (4.81 ml, 34.6 mmol) and ethanol (20 ml), stirred at 80°C for 16 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product, which was added to water (10 ml). The resulting mixture was extracted using ethyl acetate (20 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated to dryness under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=5:1) to give the title compound (5 g, 50%) as brown oil. LCMS (ESI) m/z M+1: 284.9. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.56-7.48 (m, 3H), 7.47-7.39 (m, 2H), 4.39 (k, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).

B. N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4carboxamide, compound 5

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (206 mg, 1.06 mmol), and THF (1.5 ml) , and a solution consisting of ethyl 1-phenyl-5-(trifluoromethyl)-III-pyrazole-4carboxylate, compound 5a (300 mg, 1.06 mmol), and THF (1.5 ml) was added to the solution consisting of potassium tert-butoxide (130 mg, 1.16 mmol) and THF (1 ml), at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was added to water (10 ml) and extracted using ethyl acetate (20 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (40-70% (v/v) CH3CN and H ₂ O with 0.05 % NH ₃ ) and lyophilized to obtain the title compound (117.60 mg, 26%). LCMS (ESI) m/z M+1: 433.9. 1H NMR (400 MHz, CDCl ₃ ) δ 8.75 (d, J=2.4 Hz, 1H), 8.49 (d, J=2.4 Hz, 1H), 8.31 (br.s, 1H), 8.07 (s, 1H), 7.94 (s, 2H), 7.58-7.51 (m, 3H), 7.49-7.42 (m, 2H).

Example 6.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 6

A. 3-Fluoro-4-hydrazinylpyridine, compound 6a

Οζ ^g , compound 6a

A mixture of 4-chloro-3-fluoropyridine (3.00 g, 22.8 mmol) and hydrazine hydrate (30 ml, 50 wt%) was stirred at 90°C for 2 hours. The mixture was cooled to room temperature and extracted using ethyl acetate (100 ml x3).

The combined organic extracts were dried over anhydrous Na2SO4 and the filtrate was concentrated to dryness under reduced pressure to give the title compound (3 g, crude), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d ₆ )

- 71 046082 δ 7.99 (d, J=4.0 Hz, 1H), 7.96 (d, J=5.2 Hz, 1H), 7.69 (br. s, 1H), 7.01 (dd, J=5.6, 7.6 Hz, 1H), 4.24 (br. s, 2H).

B. Ethyl 1-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 6b

Mixture consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (4.41 g, 18.3 mmol), 3-fluoro-4-hydrazinylpyridine, compound 6a (3.00 g, 18.3 mmol) and ethanol (40 ml), stirred at 80°C for 16 hours. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure to obtain a residue, which was purified by flash column chromatography (petroleum ether :ethyl acetate=10:1) to give the partially purified title compound (3 g, 54%), which was used in the next step without further purification.

C. 1-(3-Fluoropyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 6c

A mixture consisting of ethyl 1-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 6b (500 mg, 1.65 mmol), sodium hydroxide (5 ml, 4 .95 mmol, 1M) and ethanol (4 ml), stirred at room temperature for 4 hours. The mixture was neutralized with 1M HCl and extracted with ethyl acetate (40 ml x 3). The combined extracts were dried over anhydrous Na ₂ SO ₄ and the filtrate was concentrated to dryness under reduced pressure to give the title compound (423 mg, crude), which was used in the next step without further purification.

D. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)III -pyrazole-4-carboxamide, compound 6

POCl ₃ (268 mg, 1.74 mmol) was added to a mixture consisting of 1-(3-fluoropyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 6c (400 mg, 1 .45 mmol), 5-chloro-6-(2H

1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (310 mg, 1.45 mmol), and pyridine (5 ml), at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (34-44% (v/v) ACN and _H2O with 0.05 % NH3) and lyophilized to obtain the title compound (221.20 mg, 33%). LCMS (ESI) m/z M+1: 452.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.25 (br.s, 1H), 9.01 (d, J=1.6 Hz, 1H), 8.84 (d, J=2, 0 Hz, 1H), 8.77 (d, J=4.8 Hz, 1H), 8.66 (d, J=2.4 Hz, 1H), 8.63 (s, 1H), 8.20 (s, 2H), 7.97-7.91 (m, 1H).

Example 7.

No.(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-Spirazol- 4-carboxamide, compound 7

A. Ethyl 1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 7a

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (2.15 g, 8.97 mmol), 5-fluoro-2-hydrazinylpyridine (950 mg, 7.47 mmol) and ethanol (20 ml), stirred at 80°C for 16 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to give the crude product, which was purified using

- 72 046082 flash column chromatography (petroleum ether:ethyl acetate=5:1) to obtain the title compound (2.2 g, 97%) as a brown solid. LCMS (ESI) m/z M+1: 304.0. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (d, J=2.8 Hz, 1H), 8.34 (s, 1H), 8.13-8.08 (m, 1H) , 7.91 (dd, J=4.0, 8.8 Hz, 1H), 4.32 (k, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).

B. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide, compound 7

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (242 mg, 1.24 mmol), and THF (1 ml), and a solution consisting of ethyl 1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-Spirazole-4-carboxylate, compound 7a (250 mg, 0.825 mmol), and THF (1 ml) was added to the solution, consisting of potassium tert-butoxide (2.47 ml, 2.47 mmol, 1M in THF), at 0°C. The resulting mixture was stirred at room temperature for 16 hours. Water (5 ml) was added to the resulting mixture and the mixture was extracted using ethyl acetate (15 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (43-53% (v/v) CH3CN and H ₂ O with 0.05 % NH3) and lyophilized to dryness to obtain the title compound (151.10 mg, 40%). LCMS (ESI) m/z M+1: 453.0. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.71 (d, J=2.4 Hz, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.42 (d, J =2.8 Hz, 1H), 8.29 (br.s, 1H), 8.06 (s, 1H), 7.94 (s, 2H), 7.76-7.71 (m, 1H) , 7.707.64 (m, 1H).

Example 8.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol4- carboxamide, compound 8

A. Ethyl 1 -(pyridin-2-yl)-5-(trifluoromethyl)-1 ^pyrazole^-carboxylate, compound 8a

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (5.3 g, 22 mmol), 2-hydrazinylpyridine (2.0 g, 18 mmol) and ethanol (20 ml), stirred at 80°C for 16 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=5:1) to give the title compound (4.2 g, 80%) as a brown oil. LCMS (ESI) m/z M+1: 286.0. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.66-8.60 (m, 1H), 8.36 (s, 1H), 8.20-8.13 (m, 1H), 7. 82 (dd, J=0.8, 8.0 Hz, 1H), 7.70-7.62 (m, 1H), 4.39-4.30 (m, 2H), 1.32 (t, J=7.2 Hz, 3H)

B. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide, compound 8

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (309 mg, 1.58 mmol), and THF (1 ml), and a solution consisting of ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4carboxylate, compound 8a (300 mg, 1.05 mmol), and THF (1 ml) was added to the solution, consisting of potassium tert-butoxide (1.58 ml, 1.58 mmol, 1M in THF), at 0°C. The resulting mixture was stirred at room temperature for 16 hours. Water (5 ml) was added to the resulting mixture and the mixture was extracted using ethyl acetate (15 ml x 3). The combined organic extracts were dried over anhydrous

- 73 046082

Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC (30-60% (v/v) CH ₃ CN and H2O with 0.05% NH ₃ ) and lyophilized to dryness to obtain the title compound (97.20 mg, 21%) as a brown solid. LCMS (ESI) m/z M+1: 434.9. 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.29 (br.s, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.66-8.60 (m, 2H ), 8.45 (s, 1H), 8.21-8.12 (m, 3H), 7.85 (d, J=8.0 Hz, 1H), 7.67-7.62 (m, 1H).

Example 9.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide, compound 9

A. Ethyl 1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 9a

A mixture of 2-hydrazinopyrazine (500 mg, 2.73 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (849 mg, 3.01 mmol), and EtOH (5 ml), heated to 90°C and stirred for 20 hours, and then cooled to room temperature. The mixture was evaporated under reduced pressure to give a yellow oil, which was purified by flash column chromatography (ethyl acetate:petroleum ether=40:60). The title compound (610 mg, 78%) was obtained as a yellow solid. LCMS (ESI) m/z M+1: 287.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.14 (d, J=1.2 Hz, 1H), 8.93 (d, J=2.4 Hz, 1H), 8.75 (d , J=2.4 Hz, 1H), 8.43 (s, 1H), 4.34 (k, J=6.8 Hz, 2H), 1.31(t, 1=6.8 Hz, 3H) .

B. 1-(Pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 9b

F _a C ft

LAqh / ^N < J

N N connection 9b

A mixture of ethyl 1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 9a (200 mg, 0.699 mmol), lithium hydroxide (50.2 mg, 2.10 mmol), MeOH (1 ml), THF (1 ml) and H ₂ O (1 ml) were stirred for 20 hours at room temperature. The pH of the mixture was then adjusted to 2 using 6N aq. HCl. Organic solvents were removed under reduced pressure. The residue was diluted with water (30 ml) and extracted using ethyl acetate (30 ml x2). The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was evaporated to give the title compound (191 mg, 85%) as a yellow solid. LCMS (ESI) m/z M+1: 258.9.

C. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrazin-2-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide, compound 9

Phosphorus oxychloride (0.069 mL, 0.74 mmol) was added dropwise to a solution consisting of 1(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 9b (160 mg, 0.116 mmol), 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (121 mg, 0.620 mmol), and pyridine (2 ml). The mixture was stirred at 0°C for 1 hour and then concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative high performance liquid chromatography on a Phenomenex Gemini 150x25 mm x 10 µm (eluent: CH3CN in alkaline water (0. 05% CI ₃ -H ₂ O) from 37% to 67%, v/v). Pure fractions were collected and volatiles were removed under reduced pressure. The residue was resuspended in water (10 ml) and the resulting mixture was lyophilized to dryness to completely remove the remaining solvent to obtain the title compound (51.70 mg, 19%) as a yellow solid. LCMS (ESI) m/z M+1: 435.9. 1H NMR (400 MHz, DMSO-d6) δ 11.36 (br. s, 1H), 9.22 (d, J=1.2 Hz, 1H), 8.93 (d, J=2.4 Hz , 1H), 8.83 (d, J=2.4 Hz,

- 74 046082

1H), 8.77 (dd, J=1.2, 2.4 Hz, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.55 (s, 1H), 8, 19 (s, 2H).

Example 10.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1Hpyrazol-4- carboxamide, compound 10

A. Ethyl 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 10a g O

Oh, connection 10a

A mixture of 2-hydrazinopyrimidine (500 mg, 2.73 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3oxobutanoate, INT1 (849 mg, 3.01 mmol), and EtOH (5 mL), was heated to 90°C and stirred for 20 hours and then cooled to room temperature. The mixture was evaporated under reduced pressure to give a yellow oil, which was purified by flash column chromatography (ethyl acetate:petroleum ether=40:60) to give a yellow solid (620 mg, 79%). The crude product (250 mg) was further purified by flash column chromatography (ethyl acetate:petroleum ether=40:60) to obtain the title compound (217.30 mg, 84%) as a yellow solid. LCMS (ESI) m/z M+1: 287.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (d, J=4.4 Hz, 2H), 8.39 (s, 1H), 7.85-7.82 (m, 1H) , 4.34 (k, J=6.8 Hz, 2H), 1.31(t, J=6.8 Hz, 3H).

B. 1-(Pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 10b

OH, connection 10b

A mixture of ethyl 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 10a (200 mg, 0.699 mmol), lithium hydroxide (50.2 mg, 2.10 mmol), MeOH (1 ml), THF (1 ml) and H ₂ O (1 ml) were stirred for 20 hours at room temperature. The pH of the mixture was then adjusted to 2 using 6N aq. HCl. Organic solvents were removed under reduced pressure. The residue was diluted with water (30 ml) and extracted using ethyl acetate (30 ml x2). The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was evaporated to give the title compound (190 mg, 84%) as a yellow solid. LCMS (ESI) m/z M+1: 258.9.

C. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide, compound 10

Phosphorus oxychloride (0.069 mL, 0.74 mmol) was added dropwise to a solution consisting of 1(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 10b (160 mg, 0.620 mmol), 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (121 mg, 0.620 mmol) and pyridine (2 ml). The mixture was stirred at 0°C for 1 hour and then concentrated to dryness under reduced pressure to obtain the crude product, which was purified using preparative HPLC (CH ₃ CN in alkaline water (0.05% NH3-H2O) from 30% to 60 %, v/v) and lyophilized to dryness to obtain the title compound (75.00 mg, 28%) as a yellow solid. LCMS (ESI) m/z M+1: 435.9. 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.32 (br.s, 1H), 9.10 (d, J=5.2 Hz, 2H), 8.83 (d, J=2.4 Hz, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.50 (s, 1H), 8.20 (s, 2H), 7.84-7.82 (m, 1H ).

Example 11.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-cyanopyridin-2-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 11

- 75 046082

A. Ethyl 1-(5-cyanopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 11a

About CF"

N

, connection 11a

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (2.04 g, 8.50 mmol), 6-hydrazinylnicotinonitrile (950 mg, 7.08 mmol) and ethanol (20 ml), stirred at 80°C for 16 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=4:1) to give the title compound (1.9 g, 86%) as a brown solid colors. LCMS (ESI) m/z M+1: 311.0. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.17-9.07 (m, 1H), 8.68 (dd, J=2.4, 8.4 Hz, 1H), 8.44 (s , 1H), 8.10-8.05 (m, 1H), 4.34 (k, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).

B. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-cyanopyridin-2-yl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide, compound 11

Trimethylaluminum (0.725 ml, 1.45 mmol, 2M in toluene) was added to a solution consisting of ethyl 1-(5-cyanopyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 11a ( 300 mg, 0.967 mmol), 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (284 mg, 1.45 mmol), and toluene (5 ml ), under N2 atmosphere and the resulting solution was refluxed for 16 h. Water (10 ml) was added to the resulting mixture and extracted with ethyl acetate (15 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (35-55% (v/v) CH3CN and H2O with 10 mM NH4HCO3 ) and lyophilized to dryness to give the still crude product (160 mg). The product was purified by flash column chromatography (petroleum ether:ethyl acetate=1:1) to obtain the title compound (92.40 mg, 21%) as a white solid. LCMS (ESI) m/z M+1: 459.9. ¹ H NMR (400 MHz, DMSO-d6) δ 11.38 (br.s, 1H), 9.13 (d, J=1.6 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 8.67 (dd, J=2.4, 8.4 Hz, 1H), 8.63 (d, J=2.4 Hz, 1H), 8.53 (s, 1H), 8.19(s, 2H), 8.13(d, >8.4Hz, 1H).

Example 12.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide, compound 12

A. Ethyl 1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 12a O

, connection 12a

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1.32 g, 5.49 mmol), 3-hydrazinylpyridine (1.00 g, 5.49 mmol) , triethylamine (1.11 g, 11.0 mmol) and ethanol (5 ml), stirred at 80°C for 16 h and then cooled to room temperature and concentrated under reduced pressure to give the crude product, which was purified using a flash column -chromatography (petroleum ether:ethyl acetate=100:0-80:20) to obtain the title compound (550 mg, 35%). LCMS (ESI) m/z M+1: 286.0. 1H NMR (400 MHz, CDCl ₃ ) δ 8.81 (br s, 2H), 8.17 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.56-7 .45 (m, 1H), 4.39 (k, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).

IN.

N-(5-chloro-6-(2H-1,2,3 -triazol-2-yl)pyridin-3-yl)-1 -(pyridin-3-yl)-5-(trifluoromethyl)-1H- 76 046082 pyrazole-4-carboxamide, compound 12

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (137 mg, 0.701 mmol) and THF (1 ml) was added to 1M tert -potassium butoxide in THF (2.10 ml, 2.10 mmol) at 0°C, subsequently adding a solution consisting of ethyl 1-(pyridin-3-yl)-5-(trifluoromethyl)-III-pyrazole-4carboxylate, compound 12a (200 mg, 0.701 mmol), and THF (1 ml). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (30-60% (v/v) CH ₃ CN and H ₂ O with 0. 05% NH3) and lyophilized to dryness to obtain the title compound (154.30 mg, 51%). LCMS (ESI) m/z M+1: 434.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.84-8.83 (m, 3H), 8.65 (d, J=2.4 Hz, 1H), 8.50 (s, 1H) , 8.22-8.16 (m, 2 N), 8.14-8.09 (m, 1 N), 7.71 (dd, J=5.2, 8.4 Hz, 1 N).

Example 13.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide, compound 13

A. 5-Hydrazinyl-2-methoxypyridine, compound 13a

N.H.

NHz, connection 13a

A solution consisting of sodium nitrite (834 mg, 12.1 mmol) in water (1 ml) was added dropwise to a solution consisting of 6-methoxypyridin-3-amine (1.00 g, 8.06 mmol) and concentrated aq.

HCl (5 ml) at temperatures from -10°C to 0°C. The mixture was stirred at a temperature of -10 to 0°C for 1.5 hours. A solution consisting of SnCl ₂ -2 H ₂ O (3.64 g, 16.1 mmol) and concentrated aq. HCl (1 ml) was added dropwise at -10 to 0°C, then the mixture was stirred at room temperature for 16 hours. The reaction mixture was made alkaline to pH 10 with 4M aq. NaOH at 0°C, extracted with ethyl acetate (30 ml x3) and dried over anhydrous Na ₂ SO ₄ . The extracts were concentrated to dryness under reduced pressure to give the title compound (700 mg, crude), which was used in the next step without purification. LCMS (ESI) m/z M+1: 140.2.

B. Ethyl 1-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 13b

,connection 13b

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (793 mg, 3.30 mmol), 5-hydrazinyl-2-methoxypyridine, compound 13a (700 mg, 3. 30 mmol), triethylamine (668 mg, 6.60 mmol) and ethanol (5 ml), stirred at 80°C for 16 hours and then cooled to room temperature and concentrated under reduced pressure to give the crude product, which was purified at flash column chromatography (petroleum ether:ethyl acetate=100:070:30) to give the title compound (750 mg, 72%). LCMS (ESI) m/z M+1: 316.0.

C. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide, compound 13

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (124 mg, 0.634 mmol), and THF (1 ml) was added to 1M potassium tert-butoxide in THF (1.90 ml, 1.90 mmol) at 0°C, subsequently adding a solution consisting of ethyl 1-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole-4 -carboxylate, compound 13b (200 mg, 0.634 mmol), and THF (1 ml). The resulting mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure

- 77 046082 yielding the crude product, which was purified by preparative HPLC (4272% (v/v) CH3CN and H2O with 0.05% NH3) to give the title compound (148.50 mg, 50%) . LCMS (ESI) m/z M+1: 464.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.24 (br s, 1H), 8.83 (d, J=2.4 Hz, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.46-8.41 (m, 2H), 8.19 (s, 2H), 7.98 (dd, J=2.8, 8.8 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 3.96 (s, 3H).

Example 14.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxypyridin-3-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide, compound 14

A. di-tert-Butyl 1-(2-methoxypyridin-3-yl)hydrazine-1,2-dicarboxylate, compound 14a

, connection 14a

A mixture of 2-methoxypyridine-3-boronic acid (1.00 g, 6.54 mmol), di-tert-butyl azodicarboxylate (1.51 g, 6.54 mmol), copper acetate (39.2 mg, 0.216 mmol) and MeOH (10 ml) were heated to 60°C and stirred for 1 hour and then cooled to room temperature. The mixture was concentrated under reduced pressure to give a yellow solid, which was dissolved in MTBE (100 ml) and washed with sat. aq. NaHCO ₃ (100 ml) and saline solution (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the title compound (2.2 g, 99%) as a yellow solid, which was used directly in the next step. LCMS (ESI) m/z M+1: 340.1.

B. 3-Hydrazinyl-2-methoxypyridine dihydrochloride, compound 14b

HCI

N.H.

NH ₂ , connection 14b

Hydrogen chloride in 1,4-dioxane (6 mL, 4 M, 24 mmol) was added to a solution consisting of di-tert-butyl 1-(2-methoxypyridin-3-yl)hydrazin-1,2-dicarboxylate, compound 14a (1, 00 g, 2.95 mmol), and 1,4-dioxane (6 ml). The mixture was stirred for 2 days at room temperature and then concentrated under reduced pressure to give the crude product (510 mg, 82%) as a yellow solid, which was used directly in the next step. LCMS (ESI) m/z M+1: 140.1.

C. Ethyl 1-(2-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 14c

,connection 14c

Mixture of 3-hydrazinyl-2-methoxypyridine hydrochloride, compound 14b (510 mg, 2.41 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (747 mg, 2.65 mmol) , triethylamine (1.00 ml, 7.21 mmol) and EtOH (10 ml) were heated to 90°C and stirred for 20 hours and then cooled to room temperature. The mixture was evaporated under reduced pressure to give a yellow oil, which was purified by flash column chromatography (petroleum ether:ethyl acetate=50:50) to give the title compound (350 mg, 46%) as a yellow solid. LCMS (ESI) m/z M+1: 316.0.

D. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxypyridin-3-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide, compound 14

- 78 046082

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (93.1 mg, 0.476 mmol), and THF (1 ml) was added to 1M potassium tert-butoxide in THF (1.43 ml, 1.43 mmol) at 0°C, a solution consisting of ethyl 1-(2-methoxypyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole was subsequently added -4-carboxylate, compound 14c (150 mg, 0.476 mmol), and THF (1 ml). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified using preparative HPLC (40-70% (v/v) CH ₃ CN and H2O with 0. 05% NH ₃ ) and lyophilized to dryness to obtain the title compound (73.3 mg, 32%). LCMS (ESI) m/z M+1: 464.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.18 (br.s, 1H), 8.84 (d, J=2.4 Hz, 1H), 8.65 (d, J=2, 4 Hz, 1H), 8.49 (s, 1H), 8.43 (dd, J=2.0, 4.8 Hz, 1H), 8.19 (s, 2H), 8.06 (dd, J=2.0, 7.6 Hz, 1H), 7.26 (dd, J=5.2, 7.6 Hz, 1H), 3.90 (s, 3H).

Example 15.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrimidin-5-yl)-5-(trifluoromethyl)-1Hpyrazol-4- carboxamide, compound 15

A. di-tert-Butyl 1-(pyrimidin-5-yl)hydrazine-1,2-dicarboxylate, compound 15a

A mixture consisting of pyrimidin-5-ylboronic acid (1.00 g, 8.07 mmol), di-tert-butyl diazene-1,2-dicarboxylate (1.86 g, 8.07 mmol), copper acetate (P ) (147 mg, 0.807 mmol) and methanol (5 ml), stirred at 60°C for 1 hour and then cooled to room temperature, concentrated under reduced pressure, washed with water (10 ml) and extracted with ethyl acetate (10 ml x3 ). The extract was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain the title compound (1.8 g, crude), which was used in the next step without purification. LCMS (ESI) m/z M+1: 311.0.

B. 5-Hydrazinylpyrimidine dihydrochloride, compound 15b

HCI ^N =\ <4-nh

N NHj, compound 5b

A solution consisting of di-tert-butyl 1-(pyrimidin-5-yl)hydrazin-1,2-dicarboxylate, compound 15a (1.8 g, 5.8 mmol), 4 M HCl in 1,4-dioxane (12 ml) and 1,4-dioxane (12 ml), stirred at room temperature for 16 hours. The suspension was filtered and the residue was washed with ethyl acetate (10 ml x 2) and dried under reduced pressure to give the title compound (1.00 g , crude), which was used in the next step without purification.

C. Ethyl 1-(pyrimidin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 15c

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate,

INT1 (656 mg, 2.73 mmol), 5-hydrazinylpyrimidine dihydrochloride, compound 15b (500 mg, 2.73 mmol), triethylamine (553 mg, 5.46 mmol) and ethanol (5 ml), stirred at 80°C for 16 hours and then cooled to room temperature and concentrated under reduced pressure to give the crude product, which was purified using flash column chromatography (petroleum ether:ethyl acetate=100:0-70:30) to give the title compound ( 130 mg, 17%).

- 79 046082

LCMS (ESI) m/z M+1: 286.9.

D. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrimidin-5-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide, compound 15

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (75.2 mg, 0.384 mmol), and THF (0.5 ml) , was added to 1M potassium tert-butoxide in THF (1.15 ml, 1.15 mmol) at 0°C, subsequently added a solution consisting of ethyl 1-(pyrimidin-5-yl)-5-(trifluoromethyl)-1H -pyrazole-4carboxylate, compound 15c (110 mg, 0.384 mmol), and THF (0.5 ml). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (3242% (v/v) CH3CN and _H2O with 0.05% NH3) and lyophilized to dryness to obtain the title compound (82.10 mg, 48%). LCMS (ESI) m/z M+1: 435.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 9.21 (s, 2H), 8.84 (d, J=2.0 Hz, 1H), 8.66 (d, J=2.4 Hz, 1H), 8.58 (s, 1H), 8.19 (s, 2H).

Example 16.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-methylpyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide, compound 16

A. di-tert-Butyl 1-(5-methylpyridin-3-yl)hydrazine-1,2-dicarboxylate, compound 16a

, connection 16a

A mixture consisting of (5-methylpyridin-3-yl)boronic acid (1.5 g, 11 mmol), di-tert-butyl diazene-1,2-dicarboxylate (2.5 g, 11 mmol), copper(P )acetate (66 mg, 0.36 mmol) and MeOH (10 ml), were added to a 5~10 ml microwave tube and stirred at 60°C for 1 hour. The organic layer was concentrated under reduced pressure to dryness to obtain a residue , which was extracted using ethyl acetate (20 ml x3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=10:1) to give the title compound (2, 4 g, 34%) as a white solid. LC-MS (ESI) m/z M+1: 323.9. 1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (br.s, 1H), 8.22 (s, 1H), 7.72-7.53 (m, 1H), 6.99-6.87 (m, 1H), 2.33 (s, 3H), 1.50 (s, 18H).

B. 3-Hydrazinyl-5-methylpyridine dihydrochloride, compound 16b

2HCI

NH KH _g , compound 16b

HCl in 1,4-dioxane (15 ml, 4 M) was added to a solution consisting of di-tert-butyl 1-(5methylpyridin-3-yl)hydrazin-1,2-dicarboxylate, compound 16a (2.4 g, 7.4 mmol), and 1,4-dioxane (15 ml), and the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated to dryness under reduced pressure to give the compound (1.5 g, crude), which used in the next step without further purification. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (br.s, 1H), 8.38-8.30 (m, 2H), 7.94 (s, 1H), 2.41 (s , 3H).

C. Ethyl 1-(5-methylperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 16c

, connection 16c

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (2.1 g, 8.6

- 80 046082 mmol), 3-Hydrazinyl-5-methylperidine dihydrochloride, compound 16b (1.4 g, 7.1 mmol), triethylamine (2.0 ml, 14 mmol) and ethanol (20 ml), stirred at 80° C for 16 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product, which was added to water (10 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=5:1) to give the title compound (900 mg , 42%) in the form of a light yellow solid. LC-MS (ESI) m/z M+1: 300.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.37 (s, 1H), 7.93 (s, 1H), 4.33 (k, J=7.2 Hz, 2H), 2.42 (s, 3H), 1.31 (t, J=7.2 Hz, 3H).

D. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-methylpyridin-3-yl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide, compound 16

Cl

I A

A solution consisting of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (245 mg, 1.25 mmol), and THF (1 ml), and a solution consisting of ethyl 1-(5-methylpyridin-3-yl)-5-(trifluoromethyl)-Spirazole-4-carboxylate, compound 16c (250 mg, 0.835 mmol), and THF (1 ml) was added to the solution, consisting of potassium tert-butoxide (2.51 ml, 2.51 mmol, 1M in THF), at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was treated with water (5 ml) and extracted using ethyl acetate (15 ml x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (30-60% (v/v) CH3CN and H ₂ O with 0.05 % NH3) and lyophilized to dryness to obtain the title compound (203.90 mg, 54%) as a brown solid. LC-MS (ESI) m/z M+1: 448.9. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=2.0 Hz, 1H), 8.67 (d, J=1.2 Hz, 1H), 8.65 (d, J =2.4 Hz, 1H), 8.61 (d, J=2.4 Hz, 1H), 8.49 (s, 1H), 8.18 (s, 2H), 7.93 (s, 1H ), 2.43 (s, 3H).

Example 17.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-cyanopyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide, compound 17

N

A. di-tert-Butyl 1-(5-cyanopyridin-3-yl)hydrazine-1,2-dicarboxylate, compound 17a compound 17a

Mixture consisting of (5-cyanopyridin-3-yl)boronic acid (2.00 g, 13.5 mmol), di-tert-butyl diazene-1,2-dicarboxylate (3.11 g, 13.5 mmol) , copper(II) acetate (245 mg, 1.35 mmol) and methanol (10 ml), stirred at 60°C for 1 hour and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-70:30) to give the title compound (1.6 g, 35%). LCMS (ESI) m/z M+1: 335.0.

B. 5-Hydrazinylnicotinonitrile dihydrochloride, compound 17b

HCI

N—

_NH2 , compound 17b

A solution consisting of di-tert-butyl 1-(5-cyanopyridin-3-yl)hydrazin-1,2-dicarboxylate, compound 17a (1.6 g, 4.79 mmol), 4 M HCl in 1 ,4-dioxane (12 ml) and 1,4-dioxane (10 ml), were stirred at room temperature for 16 hours. The suspension was filtered and the residue was dried under reduced pressure to obtain the crude product (1.00 g, crude), which was used in the next step without purification. LCMS (ESI) m/z M+1: 135.1.

C. Ethyl 1-(5-cyanopyridin-3-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound

N, connection 17c

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (580 mg, 2.42 mmol), 5-hydrazinylnicotinonitrile dihydrochloride, compound 17b (500 mg, 2.42 mmol) , triethylamine (489 mg, 4.83 mmol) and ethanol (10 ml), stirred at 80°C for 16 hours and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-70:30) to give the title compound (420 mg, 56%). LCMS (ESI) m/z M+1: 310.9.

D. No(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-cyanopyridin-3-yl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide, compound 17

2M AlMe ₃ in toluene (0.363 ml, 0.725 mmol) was added to a solution consisting of 5-chloro-6-(2H1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (94.6 mg, 0.484 mmol), ethyl 1-(5-cyanopyridin-3-yl)-5(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 17c (150 mg, 0.484 mmol), and toluene (5 ml), under N2 atmosphere . The resulting mixture was refluxed for 16 hours and cooled to room temperature. The resulting mixture was quenched with water (10 ml), extracted with ethyl acetate (10 ml x 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain the crude product, which was purified using preparative HPLC (35-65% (v/v) .) CH3CN and H ₂ O with 0.05% NH ₃ ) and subsequently lyophilized to dryness to obtain the title compound (108.10 mg, 48%). LCMS (ESI) m/z M+1: 459.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (d, J=2.0 Hz, 1H), 9.17 (d, J=2.4 Hz, 1H), 8.86-8 .81 (m, 2H), 8.66 (d, J=2.4 Hz, 1H), 8.57 (s, 1H), 8.19 (s, 2H).

Example 18.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol4-carboxamide , connection 18

4-fluorophenylhydrazine hydrochloride (52 mg, 0.32 mmol), THF, and 1 M potassium tert-butoxide in THF (0.35 mL, 0.354 mmol) were placed in a 4 mL vial and stirred at room temperature for ~5 min. The reaction mixture was then treated with ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3oxobutanoate, INT1 (0.06 mL, 0.309 mmol) and anhydrous calcium sulfate (234 mg, 1.719 mmol) and stirred at 70°C for 10 min. The reaction mixture was then cooled to room temperature, treated with 1M potassium tert-butoxide in THF (0.48 ml, 0.485 mmol) and 5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine , INT2 (65.1 mg, 0.332 mmol), and then stirred at room temperature for 40 min. The reaction mixture was then partitioned between 5M NH ₄ Cl and EtOAc (1 ml each), and the amber organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was flash chromatographed on a 12 g Silicycle HP column (10-100% EtOAc at 25 column volumes) to give compound 18 (32.2 mg, 22% from arylhydrazine HCl). 1H NMR (400 MHz, CDCl ₃ ) δ 8.77 (d, J=2.02 Hz, 1H), 8.50 (d, J=2.02 Hz, 1H), 8.09 (s, 1H) , 7.93-7.97 (m, 3H), 7.44-7.50 (m, 2H), 7.21-7.26 (m, 2H); MS m/e 452.3 (M+H).

Example 19.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-cyanophenyl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide , connection 19

- 82 046082

A 4 ml vial was filled with 4-cyanophenylhydrazine hydrochloride (52.5 mg, 0.31 mmol), THF (0.62 ml, 0.5 M, 0.31 mmol) and 1 M potassium tert-butoxide in THF (0.34 ml, 0.343 mmol) and stirred at room temperature for 10 min. The reaction mixture was subsequently treated with ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (0.06 mL, 1.235 g/mL, 0.309 mmol), and stirred for 20 min. The reaction mixture was then treated with anhydrous calcium sulfate (white drayerite, 8 mesh) (204 mg, 1.498 mmol) and the mixture was stirred at room temperature for 10 min, then treated with 5-chloro-6-(2H-1,2,3-triazole -2-yl)pyridin-3-amine, INT2 (60.7 mg, 0.309 mmol) and 1 M potassium tert-butoxide in THF (0.46 ml, 0.464 mmol) and the resulting dark solution was stirred in air for 30 min . The reaction mixture was then partitioned between 5M NH4Cl and EtOAc (1 ml each), the organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give 133 mg of a clear dark amber oil. The oil was flash chromatographed on a 12 g Silicycle HP column (10-100% EtOAc/heptane at 25 column volumes) to give 19 as an off-white foam (41.4 mg, 29% from arylhydrazine HCl). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.76 (d, J=2.53 Hz, 1H), 8.50 (d, J=2.53 Hz, 1H), 8.14 (s, 1H ), 7.86-7.96 (m, 5H), 7.65 (d, J=8.59 Hz, 2H); MS m/e 459.1 (M+H).

Example 20.

N-(5-χλορ-6-(2Η- 1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(3-fluorophenyl)-5-(trifluoromethyl)-1 H-pyrazol4- carboxamide, compound 20

Prepared as described for Example 19 but using 3-fluorophenylhydrazine hydrochloride (51.4 mg, 0.316 mmol) instead of 4-cyanophenylhydrazine hydrochloride to give compound 20 as a white foam (44.8 mg, 31% arylhydrazine HCl) . 1H NMR (400 MHz, CDCl ₃ ) δ 8.78 (d, J=2.53 Hz, 1H), 8.51 (d, J=2.53 Hz, 1H), 8.10 (s, 1H) , 7.96 (s, 2H), 7.90 (s, 1H), 7.54 (dt, J=6.06, 8.08 Hz, 1H), 7.28-7.33 (m, 2H ), 7.23-7.26 (m, 1H); MS m/e 452.1 (M+H).

Example 21.

Ν-(5-χλορ-6-(2Η-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-cyanophenyl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide , connection 21

Prepared as described for Example 19, but using 3-cyanophenylhydrazine hydrochloride (72.3 mg, 0.426 mmol) instead of 4-cyanophenylhydrazine hydrochloride. Additional purification by preparative HPLC (10-90% CH3CN gradient using 0.1% TFA throughout) followed by lyophilization, neutralization at pH 8.5, DCM extraction and concentration of the dried organic layer provided compound 21 as a white solid color (15.8 mg, 11% from arylhydrazine HCl). 1H NMR (400 MHz, CDCl ₃ ) δ 8.76 (d, J=2.53 Hz, 1H), 8.51 (d, J=2.53 Hz, 1H), 8.13 (s, 1H) , 7.95 (s, 2H), 7.84-7.90 (m, 2H), 7.82 (s, 1H), 7.68-7.78 (m, 2H); MS m/e 459.1 (M+H).

Example 22.

N-(5-chloro-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(4-methylpyridin-2-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 22

A. 2-G idrasinyl-4-methylpyridine, compound 22a

- 83 046082

2-Fluoro-4methylpyridine (201.3 mg, 1.81 mmol) and hydrazine (0.57 mL, 18.2 mmol) were placed in a 2-5 mL Biotage microwave vial with a stirrer. The resulting clear, colorless solution was deaerated/rinsed with argon 4x and stirred at 150°C for 10 min and then concentrated at 150°C under a stream of argon to give an off-white translucent solution. The solution was cooled to room temperature, partitioned between toluene (2 ml) and water (0.1 ml) and the organic layer was dried (Na ₂ SO ₄ , filtered and concentrated to give the title compound as a beige solid (162 mg, 73%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J=6.06 Hz, 1H), 6.52 (m, 2H), 5.72 (br s, 1H), 3.80 (br s, 2H), 2.27 (s, 3H).

V. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-methylpyridin-2-yl)-5-(trifluoromethyl)III -pyrazole-4-carboxamide, compound 22

A 4 ml vial was filled with 2-hydrazinyl-4-methylpyridine, compound 22a (33.6 mg, 0.273 mmol), THF (0.39 ml) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3 -oxobutanoate, INT1 in THF (0.55 ml, 0.5 M, 0.275 mmol) and the reaction mixture was stirred at room temperature for 10 min and then at 70°C for 90 min. Calcium sulfate (white drayerite, 8 mesh) (196 mg, 1.44 mmol) was subsequently added to the reaction mixture and stirred at 70°C for 10 minutes. The reaction mixture was then cooled to room temperature, treated with 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3amine, INT2 (53.6 mg, 0.273 mmol) and potassium tert-butoxide ( 0.41 ml, 0.41 mmol, 1M in THF) and the resulting dark reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then partitioned between 5M NH4Cl and ethyl acetate (1 ml each) and the organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The 112 mg residue was purified by flash column chromatography on a 12 g Silicycle HP column (10-100% EtOAc in heptane at 25 column volumes) to give the title compound contaminated with 3 mol% 5-chloro-6-(2H-1,2, 3-triazol-2yl)pyridin-3-amine, INT2 (39.9 mg, 33%). The product was combined with a similarly contaminated previous 8 mg batch (48 mg total) and repurified by flash column chromatography as described above to obtain the title compound as an off-white solid (39.2 mg, 32%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (s, 1H), 8.67 (d, J=2.53 Hz, 1H), 8.44 (s, 1H), 8.39 (d , J=5.30 Hz, 1H), 8.00 (s, 1H), 7.92 (s, 2H), 7.47 (s, 1H), 7.24-7.26 (m, 1H) , 2.47 (s, 3H); MS m/e 449.1 (M+H).

Example 23.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-methylpyridin-2-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 23

A. 2-hydrazinyl-5-methylpyridine, compound 23 a

NH hill ^g , junction 23a

Prepared as described for 2-hydrazinyl-4-methylpyridine, compound 22a, using 2-fluoro-5 methylpyridine (206.1 mg, 1.855 mmol) instead of 2-fluoro-4-methylpyridine.

V. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-methylpyridin-2-yl)-5-(trifluoromethyl)III -pyrazole-4-carboxamide, compound 23

Prepared as described for N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-methylpyridin-2-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 22, but using 2-hydrazinyl-5methylpyridine, compound 23a (45 mg, 0.365 mmol) instead of 2-hydrazinyl-4-methylpyridine, compound

- 84 046082

22a, yielding the title compound contaminated with 2.5 mol% 5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-amine, INT2. Further purification by flash chromatography on two 12 g Silicycle columns (25-75% acetone in heptane at 25 column volumes and 1:1 isocratic acetone/heptane) gave the title compound as a white solid (46.9 mg , 29%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (d, J=2.02 Hz, 1H), 8.50 (d, J=2.53 Hz, 1H), 8.41 (d, J =1.52 Hz, 1H), 8.09 (s, 1H), 7.96 (s, 2H), 7.84 (s, 1H), 7.76 (dd, J=1.52, 8, 08 Hz, 1H), 7.59 (d, J=8.08 Hz, 1H), 2.47 (s, 3H); MS m/e 449.3 (M+H).

Example 24.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-methylpyridin-2-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 24

A. 2-Hydrazinyl-6-methylpyridine, compound 24a

NH, compound 24a

Prepared as described for 2-hydrazinyl-4-methylpyridine, compound 22a, using 2-fluoro

6-methylpyridine (201.1 mg, 1.81 mmol) instead of 2-fluoro-4-methylpyridine.

V. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-methylpyridin-2-yl)-5-(trifluoromethyl)III -pyrazole-4-carboxamide, compound 24b

Prepared as described for N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4 methylpyridin-2-yl)-5-( trifluoromethyl)-III-pyrazole-4-carboxamide, compound 22, but using 2-hydrazinyl-6-methylpyridine, compound 24a (47.1 mg, 0.382 mmol) instead of 2-hydrazinyl-4-methylpyridine, compound 22a, to obtain the title compound contaminated with a small amount of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2. Further purification by flash chromatography on two 12 g Silicycle columns (25-75% acetone in heptane at 25 column volumes and 1:1 isocratic acetone/heptane) gave the title compound as a white solid (35.7 mg , 21%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.75 (d, J=2.02 Hz, 1H), 8.49 (d, J=2.02 Hz, 1H), 8.08 (s, 1H ), 7.95 (s, 2H), 7.77-7.93 (m, 2H), 7.51 (d, J=7.82 Hz, 1H), 7.29-7.36 (m, 1H), 2.62 (s, 3H); MS m/e 449.3 (M+H).

Example 25.

N-(5 -chloro-6-(2H-1,2,3 -triazol-2-yl)pyridin-3-yl)-5 -(difluoromethyl)-1 -(pyridin-4-yl)-1 H- pyrazole4-carboxamide, compound 25

5-(difluoromethyl)-1-(pyridin-4-yl)-N-pyrazole-4-carboxylic acid (Enamine, Cat. No. EN300-185785) (55 mg, 0.23 mmol) was placed in an 8 ml vial. 5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-amine, INT2 (59.1 mg, 0.302 mmol), CH ₂ Cl ₂ (3 ml) and pyridine (0.11 ml, 1.37 mmol) and the resulting mixture was treated with phosphorus oxychloride (0.063 ml, 0.69 mmol) dropwise through a syringe over 15 s at room temperature. The reaction mixture was stirred at room temperature overnight (14 hours) and the resulting homogeneous yellow solution was quenched with portions of 5M K2CO3 (~1 ml total; pH of final composition > 8). The aqueous layer was extracted with DCM (1x3 ml) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give ~120 mg of oil. The oil was purified by flash chromatography on a 12 g Silicycle HP column (neat EtOAc; 10 column volumes) to give the title compound as a white solid (45.9 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 8.81-8.85 (m, 2H), 8.71 (d, J=2.53 Hz, 1H), 8.55 (d, J=2.53 Hz , 1H), 8.17 (s, 1H), 8.02-8.13 (m, 1H), 7.96 (s, 2H), 7.45-7.75 (m, 3H); MS m/e 417.1 (M+H).

Example 26.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-fluoro-1-phenyl-1 ^pyrazol^-carboxamide

- 85 046082

Prepared essentially as described for Na(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(difluoromethyl/^pyridin^-yl/III- pyrazolecarboxamide, compound 25, using 5-fluoro-1phenylpyrazole-4-carboxylic acid (Enamine, cat. no. EN300-211840) (101.7 mg, 0.493 mmol) instead of 5-(difluoromethyl)-1-(pyridin-4-yl) )-1H-pyrazole-4-carboxylic acid Purification by flash chromatography (30-80% EtOAc in heptane, 15 column volumes) afforded the title compound as a white solid (39.8 mg, 21%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (d, J=2.53 Hz, 1H), 8.51 (d, J=2.02 Hz, 1H), 8.09 (d, J =3.03 Hz, 1H), 7.86-7.98 (m, 3H), 7.63-7.70 (m, 2H), 7.517.59 (m, 2H), 7.44-7, 49 (m, 1H); MS m/e 384.1 (M+H).

Example 27.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(p-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide , connection 27

A 4-ml vial was filled with 4-tolylhydrazine hydrochloride (51.9 mg, 0.327 mmol), THF (0.65 ml), potassium tert-butoxide (0.33 ml, 0.33 mmol, 1M in THF) and the resulting suspension stirred at room temperature for 10 minutes. The reaction mixture was subsequently treated with ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 in THF (0.66 mL, 0.5 M, 0.33 mmol) and the mixture was stirred at room temperature for 10 min and at 70°C for 10 min. The suspension was then cooled to room temperature, treated with calcium sulfate (white drayerite, 8 mesh) (185 mg, 1.359 mmol) and stirred at 70°C for 10 minutes. The reaction mixture was then cooled to room temperature, treated with 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (64.7 mg, 0.329 mmol) and stirred for minutes, then treated with one portion of potassium tert-butoxide (0.49 ml, 0.495 mmol, 1 M in THF) at room temperature and the resulting dark reaction mixture was stirred for 1.5 hours. The reaction mixture was then partitioned between 5 M NH4Cl and EtOAc (1 each ml) and the organic layer was dried (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on a 12 g Silicycle HP column (30-100% EtOAc in heptane at 15 column volumes) to give the title compound as a white solid (27.9 mg, 19% of arylhydrazine HCl). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.78 (d, J=2.53 Hz, 1H), 8.50 (d, J=2.53 Hz, 1H), 8.07 (s, 1H ), 7.96 (s, 2H), 7.85-7.91 (m, 1H), 7.34 (s, 4H), 2.47 (s, 3H); MS m/e 448.1 (M+H).

Example 28.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(m-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide , connection 28

Prepared essentially as described for N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(ptolyl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide, compound 27, using 3-methylphenylhydrazine hydrochloride (51.6 mg, 0.325 mmol) instead of 4-tolylhydrazine hydrochloride to give, after purification by flash chromatography (30-90% EtOAc in heptane), the title compound in the form of an off-white powder (57.7 mg, 40%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (d, J=2.53 Hz, 1H), 8.48 (d, J=2.53 Hz, 1H), 8.03-8.11 (m, 2H), 7.94 (s, 2H), 7.34-7.44 (m, 2H), 7.23-7.26 (m, 2H), 2.45 (s, 3H); MS m/e 448.0 (M+H).

Example 29.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide , connection 29

- 86 046082

Prepared essentially as described for N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(ptolyl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide, compound 27, using 2-methylphenylhydrazine hydrochloride (51.6 mg, 0.325 mmol) instead of 4-tolylhydrazine hydrochloride to give, after purification by flash chromatography (40-90% EtOAc in heptane), the title compound in the form of an orange powder (46.1 mg, 32%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.79 (d, J=2.02 Hz, 1H), 8.51 (d, J=2.53 Hz, 1H), 8.14 (s, 1H ), 7.92-7.97 (m, 3H), 7.45-7.53 (m, 1H), 7.28-7.40 (m, 3H), 2.09 (s, 3H); MS m/e 448.0 (M+H).

Example 30.

1-(5-Bromo-3-chloropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 30

A. Ethyl 1-(5-bromo-3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound

30a, connection 30a

Solution of (5-bromo-3-chloropyridin-2-yl)hydrazine hydrochloride (1.0 g, 3.862 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (0.928 g, 3.862 mmol) and triethylamine (1.07 ml, 7.724 mmol) in ethanol (15 m) were stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 60% EA in heptane gradient) to give the title compound as a white solid (802 mg, 51%). ¹ H NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=7.1 Hz, 3H), 4.33 (k, J=7.1 Hz, 2H), 8.41 (s, 1H), 8.61 (d, J=2.3 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H). MS m/z 398 (MH ⁺ ).

B. 1-(5-Bromo-3-chloropyridin-2-yl)-5-trifluoromethyl-III-pyrazole-4-carboxylic acid, compound

30b, connection 30b

Lithium hydroxide (168 mg, 4.014 mmol) was added to a solution of ethyl 1-(5-bromo-3-chloropyridin-2-yl)5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 30a (800 mg, 2.007 mmol ) in THF (8 ml) and water (2 ml). The reaction was continued for 18 hours at room temperature, after which the pH was adjusted to 2-3 with 2N HCl. The mixture was concentrated to dryness. The residue was filtered through a short column of silica gel with a mixture of DCM/MeOH (9/1, v/v). After removal of the solvents, the carboxylic acid was obtained as a gum (790 mg, 105%). MS m/z 370 (MH ⁺ ).

C. 1-(5-Bromo-3-chloropyridin-2-yl)-N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5- (trifluoromethyl)-III-pyrazole-4-carboxamide, compound 30

1-(5-Bromo-3-chloropyridin-2-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound

- 87 046082

30b (790 mg, 2.232 mmol) was dissolved in DCM (15 ml). DMF (1 drop) was added followed by oxalyl chloride (0.366 mL, 4.264 mmol). The mixture was refluxed for 1 hour and subsequently concentrated to dryness to give the crude acid chloride. The mixture was dissolved in DCM (20 ml) and 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (595 mg, 3.197 mmol) was added, followed immediately by triethylamine (0.891 ml, 6.394 mmol). THF (10-15 ml) was added to increase solubility and the reaction was continued overnight at room temperature and then quenched with water (10 ml). After 15 minutes of stirring, 1M Na ₂ CO ₃ (25 ml) was added and the organic layers were extracted with DCM (2x50 ml). The combined extracts were dried over MgSO ₄ , filtered and the filtrate was concentrated to a solid. The crude product was suspended in DCM/MeOH (20 mL, 9/1, v/v) and most of the unreacted 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile was removed by filtration. The filtrate was concentrated and the residue was purified by silica gel chromatography (15 to 75% EA in heptane gradient) to give the title compound as an off-white solid (257 mg, 22%). ^1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 2H), 8.55 (s, 1H), 8.63 (d, J=2.3 Hz, 1H), 8.74 ( d, J=2.3 Hz, 1H), 8.86 (d, J=2.4 Hz, 1H), 9.07 (d, J=2.5 Hz, 1H), 11.30 (s, 1H). MS m/z 539 (MH+).

Example 31.

1-(3-Chloro-5-cyanopyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 31 n41

N'N

1-(5-Bromo-3-chloropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyln-pyrazole-carboxamide, compound 30 (150 mg, 0.278 mmol) was dissolved in DMF (3 ml) and the resulting solution was bubbled with nitrogen for approximately 15 minutes Copper cyanide (50 mg, 0.557 mmol) and copper iodide (5 mg) were added , 0.028 mmol) and tightly seal the reaction vessel with a screw cap. Subsequently, the mixture was heated at 140°C for 1.5 h and then allowed to cool to room temperature. The reaction mixture was diluted with EA (50 ml), washed twice with 10% NH4OH (2x30 ml), saline (20 ml), dried over MgSO ₄ , filtered and concentrated to a crude residue. Silica gel chromatography (0 to 3% MeOH gradient in DCM) gave a product of insufficient quality. Preparative LC ( gradient from 28 to 64% ACN/MeOH (1/1, v/v) in 25 mM aqueous ammonium acetate) followed by extraction to obtain the pure product as a sticky solid. Trituration in diethyl ether yielded a powder (32 mg, 23%). 1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 2H), 8.72 (s, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.92 (d , J=2.4 Hz, 1H), 9.05 (d, J=2.1 Hz, 1H), 9.16 (d, J=2.4 Hz, 1H). MC m/z 485(MH ⁺ ).

Example 32.

1-(3-Chloro-2-methoxypyridin-4-yl)-N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 32

A. 3-Chloro-4-fluoro-2-methoxypyridine, compound 32a

3-Chloro-2-methoxypyridin-4-ylamine (1.95 g, 12.296 mmol) was dissolved in pyridine hydrogen fluoride

- 88 046082 (15 ml) and cooled at -10°C. Sodium nitrite (1.273 g, 18.444 mmol) was added in portions over 30 minutes. The mixture was allowed to warm to room temperature and finally heated at 60°C for 1 hour. The mixture was poured onto crushed ice (approximately 50 g). The mixture was neutralized with 1M Na ₂ CO ₃ and the organic matter was extracted using EA (200 ml). The organic layer was washed with additional brine, dried over MgSO ₄ , filtered and concentrated to give crude 3-chloro-4-fluoro-2-methoxypyridine as a brownish oil (2.14 g, 75%).

B. (3-Chloro-2-methoxypyridin-4-yl)-hydrazine, compound 32b ^H2N NH

, connection 32b

Hydrazine monohydrate (2.1 ml, 27.816 mmol) was added to a solution of 3-chloro-4-fluoro-2-methoxypyridine, compound 32a (2.14 g, 9.272 mmol), in ethanol (15 ml) and stirred at 80°C during the night. The mixture was subsequently allowed to cool to room temperature and concentrated to a dark oil. Water (20 ml) and 1M Na ₂ CO ₃ (10 ml) were added. Organics were extracted with DCM (2x40 ml). The combined extracts were dried over MgSO ₄ , filtered and the filtrate was concentrated. Silica gel chromatography (0 to 5% MeOH gradient in DCM) provided the desired hydrazine as a reddish solid (762 mg, 33%). MS m/z 174 (MH ⁺ ).

C. Ethyl 1-(3-chloro-2-methoxypyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 32c

, connection 32c

(3-Chloro-2-methoxypyridin-4-yl)hydrazine solution, compound 32b (0.769 g, 4.43 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1.064 g , 4.43 mmol), and triethylamine (1.23 ml, 8.859 mmol) in ethanol (15 ml) were stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 60% EA in heptane gradient) to give the title compound as a white solid (349 mg, 21%). ¹ H NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=7.1 Hz, 3H), 4.04 (s, 3H), 4.33 (k, J=7.1 Hz, 2H), 7.49 (d, J=5.3 Hz, 1H), 8.40 (d, J=5.3 Hz, 1H), 8.46 (s, 1H). MS m/z 350 (MH ⁺ ).

C. 1-(3-Chloro-2-methoxypyridin-4-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 32d

OH, connection 32d

Lithium hydroxide (78 mg, 1.87 mmol) was added to a solution of ethyl 1-(3-chloro-2-methoxypyridin-4-yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 32c (327 mg, 0.935 mmol), in THF (4 ml) and water (1 ml). The reaction was continued for 18 hours at room temperature, after which the pH was adjusted to 2-3 with 2N HCl. The mixture was concentrated to dryness. The residue was filtered through a short column of silica gel with a mixture of DCM/MeOH (9/1, v/v). Removal of the solvents provided the carboxylic acid as a white crystalline solid (296 mg, 93%). MS m/z 322 (MH ⁺ ).

E. 1-(3-Chloro-2-methoxypyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 32

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Oxalyl chloride (0.158 ml, 1.841 mmol) was added to a solution of 1-(3-chloro-2-methoxypyridin-4-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 32d (296 mg, 0.92 mmol), in DCM (10 ml) and DMF (1 drop) at room temperature. Subsequently, the resulting solution was refluxed for 45 minutes and then concentrated to dryness. The crude acid chloride was dissolved in DCM (10 ml) and THF (10 ml) and 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (256 mg, 1.376 mmol) was added, followed immediately triethylamine (0.384 ml, 2.752 mmol) was added. The reaction was continued overnight at room temperature and finally quenched with water (10 ml). After 15 min of stirring, 1M Na ₂ CO ₃ (25 ml) was added and the organic matter was extracted with DCM (2x50 ml). The combined extracts were dried over MgSO ₄ , filtered and concentrated to give a crude solid. Silica gel chromatography (0 to 5% MeOH in DCM gradient) provided the impure title compound. Preparative LC (gradient 30 to 73% ACN/MeOH (1/1, v/v) in 25 mM aqueous ammonium bicarbonate) followed by extraction yielded the pure product as a sticky solid. Trituration in diethyl ether resulted in a powder (135 mg, 29%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.06 (s, 3H), 7.50 (d, J=5.3 Hz, 1H), 8.31 (s, 2H), 8.42 (d, J=5.3 Hz, 1H), 8.60 (s, 1H), 8.86 (d, J=2.5 Hz, 1H), 9.07 (d, J=2.5 Hz , 1H), 11.28 (s, 1H). MS m/z 490 (MH ⁺ ).

Example 33.

1-(3-Cyano-2-methylpyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 33

N ^Z 1 nn

A. 3-Bromo-4-fluoro-2-methylpyridine, compound 33a

F, connection 33a

3-Bromo-2-methylpyridin-4-ylamine (1.98 g, 10.586 mmol) was dissolved in pyridine hydrogen fluoride (15 ml) and cooled at -10°C. Sodium nitrite (1.096 g, 15.879 mmol) was added in portions over 30 minutes. The mixture was allowed to warm to room temperature and finally heated at 60°C for 1 hour. The mixture was poured onto crushed ice (approximately 50 g). The mixture was neutralized with 1M Na ₂ CO ₃ and the organic matter was extracted using EA (200 ml). The organic layer was further washed with brine, dried over MgSO ₄ , filtered, and the filtrate was concentrated to give crude 3-bromo-4-fluoro-2-methylpyridine as a brownish oil, compound 33a (1.48 g, 72%).

B. (3-Bromo-2-methylpyridin-4-yl)-hydrazine, compound 33b ^Нгш , compound 33b

Hydrazine monohydrate (1.76 ml, 23.367 mmol) was added to a solution of 3-bromo-4-fluoro-2-methylpyridine, compound 33a (1.48 g, 7.789 mmol), in ethanol (15 ml) and stirred at 80°C during

- 90 046082 nights. The mixture was then allowed to cool to room temperature and partially concentrated until the desired product crystallized. Water was added and the suspension was stirred for 30 minutes. The precipitate was filtered off and washed with water. Air drying resulted in pure hydrazine (737 mg, 46%). The filtrate was extracted with DCM (2x40 ml). The combined extracts were dried over MgSO ₄ , filtered and concentrated. Silica gel chromatography (0 to 5% MeOH gradient in DCM) provided the second portion of the desired hydrazine as an off-white solid (347 mg, 18%). MS m/z 202 (MH ⁺ ).

C. Ethyl 1-(3-bromo-2-methylpyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 33c

, connection 33c

(3-bromo-2-methylpyridin-4-yl)hydrazine solution, compound 33b (1.084 g, 5.365 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1.289 g, 5.365 mmol), and triethylamine (1.49 ml, 10.73 mmol) in ethanol (15 ml) were stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 60% EA in heptane gradient) to give the title compound as an oil (637 mg, 31%). ¹ H NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=7.1 Hz, 3H), 2.72 (s, 3H), 4.33 (k, J=7.1 Hz, 2H), 7.72 (d, J=5.1 Hz, 1H), 8.45 (s, 1H), 8.69 (d, J=5.1 Hz, 1H). MS m/z 378 (MH ⁺ ).

D. 1-(3-Bromo-2-methylpyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 33d

OH, connection 33d

Lithium hydroxide (78 mg, 1.87 mmol) was added to a solution of ethyl 1-(3-bromo-2-methylpyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 33c (310 mg, 0.820 mmol) in THF (4 ml) and water (1 ml). The reaction was continued for 18 hours at room temperature, after which the pH was adjusted to 2-3 with 2N HCl. The mixture was concentrated to dryness. The residue was filtered through a short column of silica gel with a mixture of DCM/MeOH (9/1, v/v). Removal of solvents provided the carboxylic acid as an amorphous solid (262 mg, 90%). MS m/z 349 (MH ⁺ ).

E. 1-(3-Bromo-2-methylpyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 33e

, connection ЗЗе

Oxalyl chloride (0.158 mL, 1.841 mmol) was added to a solution of 1-(3-bromo-2-methylpyridin-4-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 33d (262 mg, 0.748 mmol), in DCM (10 ml) and DMF (1 drop) at room temperature. Subsequently, the resulting solution was refluxed for 45 minutes and then concentrated to dryness. The crude acid chloride was dissolved in DCM (20 ml) and THF (20 ml) and 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile (208 mg, 1.119 mmol) was added, then immediately added triethylamine (0.312 ml, 2.239 mmol). The reaction was continued overnight at room temperature and finally quenched with water (10 ml). After 15 minutes of stirring, 1M Na ₂ CO ₃ (25 ml) was added and the organic layers were extracted with DCM (2x50 ml). The combined extracts were dried over MgSO ₄ , filtered and concentrated to give a crude solid. Silica gel chromatography (15 to 75% EA in heptane gradient) provided the title compound as a sticky solid (114 mg, 27%). MS m/z

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518(MH ⁺ ).

F. 1-(3-cyano-2-methylpyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 33

1-(3-Bromo-2-methylpyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 33e (114 mg, 0.220 mmol), was dissolved in DMF (2 ml) and the resulting solution was bubbled with nitrogen for approximately 15 minutes. Copper cyanide (39 mg, 0.440 mmol) and copper iodide (5 mg, 0.028 mmol) were added and the reaction vessel was tightly sealed with a screw cap. Subsequently, the mixture was heated at 140°C for 45 min and then allowed to cool to room temperature. The reaction mixture was diluted with EA (50 ml), washed twice with 10% NH4OH (2x30 ml), brine (20 ml), dried over MgSO ₄ , filtered and concentrated to a crude residue. Chromatography on silica gel (0 to 3% MeOH in DCM gradient) gave the product as a sticky solid. Recrystallization from ACN (3 mL) gave a white solid (43 mg, 38%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.84 (s, 3H), 7.88 (d, J=5.4 Hz, 1H), 8.31 (s, 2H), 8.65 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 9.04 (d, J=5.3 Hz, 1H), 9.07 (d, J=2.4 Hz , 1H), 11.38 (s, 1H). MS m/z 465 (MH ⁺ ).

Example 34.

1-(3-Bromo-5-fluoropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 34

A. 3-Bromo-2,5-difluoropyridine, compound 34a

Ε ΈΓ

N F, connection 34a

3-Bromo-5-fluoropyridin-2-ylamine (2.17 g, 11.361 mmol) was dissolved in pyridine hydrogen fluoride (15 ml) and cooled at -10°C. Sodium nitrite (1.176 g, 17.042 mmol) was added in portions over 30 minutes. The mixture was allowed to warm to room temperature and finally heated at 60°C for 1 hour. The mixture was poured onto crushed ice (approximately 50 g). The mixture was neutralized with 1M Na ₂ CO ₃ and the organic matter was extracted using EA (2 x 100 ml). The organic layers were washed with additional brine, dried over MgSO ₄ , filtered and concentrated to give crude 3-bromo-2,5-difluoropyridine as a brownish oil (1.48 g, 66%).

B. (3-Bromo-5-fluoropyridin-2-yl)-hydrazine, compound 34b

H, compound 34b

Hydrazine monohydrate (1.95 ml, 25.518 mmol) was added to a solution of 3-bromo-2,5-difluoropyridine, compound 34a (1.65 g, 8.506 mmol), in ethanol (15 ml) and stirred at 80°C for nights. The mixture was then allowed to cool to room temperature and partially concentrated until the desired product crystallized. Water was added and the suspension was stirred for 30 minutes. The precipitate was filtered off and washed with water. Air drying gave pure hydrazine (1.36 g, 72%). ^1H NMR (300 MHz, DMSO-d6) δ 4.18 (s, 2H), 7.36 (s, 1H), 7.93 (dd, J=7.8, 2.5 Hz, 1H), 8.14 (d, J=2.6

- 92 046082

Hz, 1H). MS m/z 206 (MH ⁺ ).

C. Ethyl 1-(3-bromo-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 34c

, connection 34c

(3-bromo-5-fluoropyridin-2-yl)hydrazine solution, compound 34b (1.36 g, 6.601 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1.586 g , 6.601 mmol), and triethylamine (1.83 ml, 13.203 mmol) in ethanol (15 ml) were stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 60% EA in heptane gradient) to give the title compound as an oil (1.86 mg, 73%). ¹ H NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=7.1 Hz, 3H), 4.34 (k, J=7.1 Hz, 2H), 8.46 (s, 1H), 8.67 (dd, J=7.7, 2.6 Hz, 1H), 8.75 (d, J=2.7 Hz, 1H). MS m/z 382 (MH ⁺ ).

D. 1-(3-Bromo-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 34d

OH, connection 34d

Lithium hydroxide (180 mg, 4.287 mmol) was added to a solution of ethyl 1-(3-bromo-5-fluoropyridin-2-yl)5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 34c (819 mg, 2.143 mmol ), in THF (8 ml) and water (2 ml). The reaction was continued for 18 hours at room temperature, after which the pH was adjusted to 2-3 with 2N HCl. The mixture was concentrated to dryness. The residue was filtered through a short column of silica gel with a mixture of DCM/MeOH (9/1, v/v). Removal of solvents provided the carboxylic acid as an amorphous solid (750 mg, 98%). MS m/z 354 (MH ⁺ ).

E. 1-(3-Bromo-5-fluoropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 34

Oxalyl chloride (0.364 ml, 4.237 mmol) was added to a solution of 1-(3-bromo-5-fluoropyridin-2-yl)-5-trifluoromethyl-N-pyrazole-carboxylic acid, compound 34d (750 mg, 2.118 mmol), in DCM ( 15 ml) and DMF (1 drop) at room temperature. Subsequently, the resulting solution was refluxed for 45 minutes and then concentrated to dryness. The crude acid chloride was dissolved in DCM (10 ml) and THF (30 ml) and 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (591 mg, 3.177 mmol) was added, followed immediately triethylamine (0.886 ml, 6.354 mmol) was added. The reaction was continued overnight at room temperature and finally quenched with water (10 ml). After 15 minutes of stirring, 1M Na ₂ CO ₃ (25 ml) was added and the organic layers were extracted with DCM (2x50 ml). The combined extracts were dried over MgSO ₄ , filtered and concentrated to give a crude solid. Chromatography on silica gel (0 to 5% MeOH gradient in DCM) gave the compound as a sticky solid. The pure title compound was obtained by chromatography on silica gel (15 to 100% EA gradient in heptane) as a white crystalline solid (252 mg, 23%). 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.31 (s, 2H), 8.59 (s, 1H), 8.70 (dd, J=7.6, 2.6 Hz, 1H), 8.78 (d, J=2.6 Hz, 1H), 8.86 (d, J=2.5 Hz, 1H), 9.07 (d, J=2.5 Hz, 1H), 11, 31 (s, 1H). MS m/z 522 (MH ⁺ ).

Example 35.

1-(3-Cyano-5-fluoropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-III-pyrazole-4-carboxamide, compound 35

- 93 046082

1-(3-Bromo-5-fluoropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 34 (198 mg, 0.379 mmol), was dissolved in DMF (5 ml) and the resulting solution was bubbled with nitrogen for approximately 15 minutes. Copper cyanide (68 mg, 0.758 mmol) and copper iodide (7 mg, 0.038 mmol) were added and the reaction vessel was tightly screw capped. Subsequently, the mixture was heated at 140°C for 90 min and then allowed to cool to room temperature. The reaction mixture was diluted with EA (50 ml), washed twice with 10% NH ₄ OH (2x30 ml), brine (20 ml), dried over MgSO ₄ , filtered and concentrated to a crude residue. Chromatography on silica gel (gradient of EA in heptane from 15 to 75%) gave the product as a white solid (138 mg, 77%). ^1H NMR (300 MHz, DMSOd6) δ 8.32 (s, 2H), 8.61 (s, 1H), 8.85 (d, J=2.5 Hz, 1H), 8.92 (dd, J=7.9, 2.9 Hz, 1H), 9.02-9.10 (m, 2H), 11.43 (s, 1H). MS m/z 369 (MH+).

Example 36.

N(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-dichloropyridin-2-yl)-5-(trifluoromethyl)III -pyrazole-4-carboxamide, compound 36

A. 3,4-Dichloro-2-fluoropyridine, compound 36a

CI a

F, connection 36a

3-Chloro-2-fluoropyridin-4-ylamine hydrochloride (2.25 g, 12.296 mmol) was dissolved in pyridine hydrogen fluoride (15 ml) and cooled at -10°C. Sodium nitrite (1.273 g, 18.444 mmol) was added in portions over 30 minutes. The mixture was left to warm to room temperature and finally heated at 60°C for 1 hour. The mixture was poured onto crushed ice (approximately 50 g). The mixture was neutralized with 1M Na ₂ CO ₃ and the organic matter was extracted using EA (200 ml). The organic layers were washed with additional brine, dried over MgSO ₄ , filtered and concentrated to give crude 3,4-dichloro-2-fluoropyridine as a brown solid (1.09 g, 50%). MS m/z 165 (MH+).

B. (3,4-Dichloropyridin-2-yl)-hydrazine, compound 36b

Cl

Cl

n* ²

Η, connection 36b

Hydrazine monohydrate (1.48 ml, 19.701 mmol) was added to a solution of 3,4-dichloro-2-fluoropyridine, compound 36a (1.09 g, 6.567 mmol), in ethanol (15 ml) and stirred at 60°C for nights. The mixture was then allowed to cool to room temperature and partially concentrated until the desired product crystallized. Water was added and the suspension was stirred for 30 minutes. The precipitate was filtered and washed with water to obtain crude hydrazine (487 mg, 50%). MS m/z 178 (MH ⁺ ).

C. Ethyl 1-(3,4-dichloropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 36c

- 94 046082

- ¹ , connection 36c

(3,4-Dichloropyridin-2-yl)hydrazine solution, compound 36b (487 mg, 2.736 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (657 mg, 2.736 mmol), and triethylamine (0.763 ml, 5.471 mmol) in ethanol (15 ml) were stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 25% EA in heptane gradient) to give the title compound as a clear oil (646 mg, 66%). 1H NMR (300 MHz, Chloroform-d) δ 1.39 (t, J=7.1 Hz, 3H), 4.39 (k, J=7.1 Hz, 2H), 7.63 (d, J =5.2 Hz, 1H), 8.22 (s, 1H), 8.41 (d, J=5.2 Hz, 1H). MS m/z 354 (MH ⁺ ).

D. 1-(3,4-Dichloropyridin-2-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 36d

Cl, compound 36d

Ethyl 1-(3,4-dichloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 36c (643 mg, 1.79 mmol) and lithium hydroxide (150 mg, 3.581 mmol) stirred at room temperature in THF (6 ml) and water (2 ml). The reaction was continued for 18 hours and then the pH was adjusted to 2-3 with 2N HCl. The mixture was concentrated to dryness. The residue was filtered through a short column of DCM/MeOH (9/1, v/v) silica gel to give the carboxylic acid as a white solid (645 mg, 109%). MS m/z 326 (MH ⁺ ).

E. X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-dichloropyridin-2-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 36

1-(3,4-Dichloropyridin-2-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 36e (645 mg, 1.978 mmol), was treated with oxalyl chloride (0.34 ml, 3.956 mmol) in DCM (15 ml) and DMF (1 drop) at room temperature. The mixture was then refluxed for 45 minutes and concentrated to dryness. The crude acid chloride was dissolved in DCM (10 ml) and THF (30 ml) and 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (552 mg, 2.967 mmol) was added, followed immediately triethylamine (0.827 ml, 5.934 mmol) was added. The reaction was continued overnight at room temperature and finally quenched with water (10 ml). After 15 minutes of stirring, 1M Na ₂ CO ₃ (25 ml) was added and the organic matter was extracted with DCM (2x50 ml). The combined extracts were dried over MgSO ₄ , filtered and the filtrate was concentrated to give a crude solid. Chromatography on silica gel (0 to 3% MeOH in DCM gradient) gave the compound as a sticky solid. Pure title compound was obtained after preparative LC (gradient 30 to 73% ACN/MeOH (1/1, v/v) in 25 mM aqueous ammonium bicarbonate) followed by extraction. As a result of trituration in diethyl ether, a white powder (233 mg, 24%) was obtained. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.17 (d, J=5.3 Hz, 1H), 8.31 (s, 2H), 8.59-8.73 (m, 2H), 8.88 (d, J=2.4 Hz, 1H), 9.11 (d, J=2.4 Hz, 1H), 11.43 (s, 1H). MS m/z 326 (MH ⁺ ).

Example 37.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-cyano-2-methylphenyl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 37

- 95 046082

A mixture of {Pc1(pinnamyl)C'1!2 (85.4 mg, 0.165 mmol) and Mor-DalPhos (152.9 mg, 0.33 mmol) in dioxane (5 ml) was deaerated using argon 4 times. The resulting clear yellow solution was stirred at room temperature under argon for 10 minutes. 4-chloro-3-methylbenzonitrile (500 mg, 3.30 mmol) and sodium tert-butoxide (633.3 mg, 6.60 mmol) were added to the mixture, and the mixture was deaerated using argon 4 times. The resulting yellow reaction mixture was stirred at room temperature for 5 min and subsequently treated with hydrazine monohydrate (337 mg, 6.60 mmol) using a syringe. The reaction mixture was deaerated using argon 4 times. The mixture was then stirred at 50°C under argon for 2 hours. The mixture was filtered and washed with ethyl acetate (50 ml x 3). The filtrate was collected and concentrated to give the product as a yellow solid directly for the next step.

B. Ethyl 1-(4-cyano-2-methylphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 37b

4-Hydrazinyl-3-methylbenzonitrile solution, compound 37a (560 mg, 3.80 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1.371 g, 5.71 mmol), and triethylamine (1.153 g, 11.42 mmol) in ethanol (10 ml) were stirred at 80°C for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 100:1 to 20 :1) to obtain the title compound as a brown oil (670 mg, 51%). MC m/z 323.9 (MH ⁺ ).

C. 1-(4-Cyano-2-methylphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 37c

Ethyl 1-(4-cyano-2-methylphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 37b (670 mg, 1.93 mmol), and lithium hydroxide (162 mg, 3.86 mmol ) was stirred at room temperature in THF (10 ml) and water (10 ml) for 3 hours. 5% KHSO4 was added to the mixture to adjust the pH to 3~4. Water (100 ml) and ethyl acetate (100 ml) were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO ₄ and concentrated under reduced pressure to obtain the product as a brown solid, which was directly used in the next step. Yield: 610 mg, 106.9%.

D. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-cyano-2-methylphenyl)-5-(trifluoromethyl)III -pyrazole-4-carboxamide, compound 37

1-(4-Cyano-2-methylphenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 37c (250 mg, 0.847 mmol), was treated with oxalyl chloride (260 mg, 1.694 mmol) in DCM (15 ml) and DMF (1 drop) at room temperature. The mixture was then stirred for 45 minutes and concentrated to

- 96 046082 dry. The crude acid chloride was dissolved in DCM (10 ml) and 5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-amine, INT2 (198.8 mg, 1.016 mmol) was added, followed immediately pyridine (167 mg, 2.12 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and finally quenched with water (50 ml) and extracted with DCM (2x50 ml). The combined extracts were dried over MgSO ₄ , filtered and concentrated to give a crude solid. The crude product was purified by HPLC to give N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-cyano-2-methylphenyl)-5( trifluoromethyl)-III-pyrazole-4-carboxamide, compound 37 (129.5 mg, 32%). ^1H NMR (400 MHz, DMSO d6) δ ppm 11.26 (s, 1H), 8.82 (d, J=2.21 Hz, 1H), 8.64 (d, J=2, 21 Hz, 1H), 8.54 (s, 1H), 8.16 (s, 2H), 8.04 (s, 1H), 7.91 (dd, J=8.16, 1.54 Hz , 1H), 7.72 (d, J=8.16 Hz, 1H), 2.04 (s, 3H). LC-MS: (ES, m/z): [M+1]+472.9.

Example 38.

N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-methoxy-3-methylpyridin-4-yl)-5 (trifluoromethyl) -III-pyrazole-4-carboxamide, compound 38

A. 3-Bromo-2-methoxypyridin-4-ylamine, compound 38a NH?

, connection 38a

A solution of bromosuccinimide (2.15 g, 12.083 mmol) in DCM (25 ml) was added dropwise to a solution of 2methoxypyridin-4-ylamine (1.5 g, 12.083 mmol) in DCM (85 ml), maintaining the temperature below 5°C. The reaction was continued for 30 minutes and subsequently concentrated to dryness. The residue was dissolved in EA (50 ml) and washed with water (40 ml) and saline (20 ml). Drying over MgSO ₄ , filtration and removal of solvent gave the crude product, which was further purified by silica gel chromatography (0 to 30% EA gradient in heptane) to give a pure oil (2.23 g, 90%). 1H NMR (300 MHz, Chloroform-d) δ 3.96 (s, 3H), 4.59 (s, 2H), 6.28 (d, J=5.6 Hz, 1H), 7.72 (d , J=5.6 Hz, 1H). MS m/z 203 (MH+).

B. 3-Bromo-4-fluoro-2-methoxypyridine, compound 38b

, connection 38b

3-Bromo-2-methoxypyridin-4-ylamine, compound 38a (2.2 g, 110.835 mmol), was dissolved in pyridine hydrogen fluoride (15 ml) and cooled at -10°C. Sodium nitrite (1.121 g, 16.253 mmol) was added in portions over 30 minutes. The mixture was left to warm to room temperature and finally heated at 60°C for 1 hour. The mixture was poured onto crushed ice (approximately 50 g). The mixture was neutralized with 1M Na ₂ CO ₃ and the organic matter was extracted using EA (2 x 100 ml). The organic layers were further washed with brine, dried over MgSO ₄ , filtered and concentrated to give pure 3-bromo-4-fluoro-2-methoxypyridine (1.78 g, 79%). 1H NMR (300 MHz, Chloroform-d) δ 4.02 (s, 3H), 6.72 (dd, J=7.3, 5.6 Hz, 1H), 8.03 (dd, J=7, 9, 5.5 Hz, 1H).

C. (3-Bromo-2-methoxypyridin-4-yl)-hydrazine, compound 38c

, connection 38c

A solution of 3-bromo-4-fluoro-2-methoxypyridine, compound 38b (1.75 g, 8.495 mmol), and hydrazine monohydrate (1.92 ml, 25.484 mmol) was heated at 80°C in dioxane (15 ml) for 16 hours. The mixture was subsequently allowed to cool to room temperature and concentrated to a dark oil. Water (20 ml) and 1M Na ₂ CO ₃ (10 ml) were added. Organics were extracted with DCM (2x40 ml). The combined extracts were dried over MgSO ₄ , filtered and concentrated. Silica gel chromatography (0 to 5% MeOH in DCM gradient) provided the desired hydrazine as a beige solid (1.51 g, 81%). 1H NMR (300 MHz, DMSO-d ₆ ) δ 3.82 (s, 3H), 4.35 (s, 2H), 6.76 (d, J=5.7 Hz, 1H), 7.19 ( s, 1H), 7.73 (d, J=5.7 Hz, 1H). MC m/z 218(MH ⁺ ).

- 97 046082

D. Ethyl 1-(3-bromo-2-methoxypyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 38d

, connection 38d

(3-bromo-2-methoxypyridin-4-yl)hydrazine solution, compound 38c (1.5 g, 6.879 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT 1 (1 .65 g, 6.879 mmol), and triethylamine (1.92 ml, 13.758 mmol) in ethanol (25 ml) were stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 25% EA in heptane gradient) to give the title compound as a yellow oil (1.02 g, 36%). ¹ H NMR (300 MHz, Chloroform-d) δ 1.39 (t, J=7.2 Hz, 3H), 4.09 (s, 3H), 4.39 (k, J=7.2 Hz, 2H), 6.95 (d, J=5.2 Hz, 1H), 8.20 (s, 1H), 8.24 (d, J=5.2 Hz, 1H). MS m/z 394 (MH ⁺ ).

E. Ethyl 1-(2-methoxy-3-methylpyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 38e (VILL_chrocaboy_2247_2)

, connection 38e

A solution of ethyl 1-(3-bromo-2-methoxypyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 38d (926 mg, 2.349 mmol), and trimethylboroxine (0.656 ml, 4.699 mmol ) in dioxane (15 ml) and water (2 ml) were bubbled with nitrogen. K ₂ CO ₃ (649 mg, 4.699 mmol) and Pd(dppf)Cl ₂ (211 mg, 0.235 mmol) were added. The resulting solution was heated at 100°C for 1 hour and subsequently allowed to cool to room temperature. The mixture was diluted with EA (50 ml) and washed with saline (20 ml). The aqueous layer was back-extracted with EA (25 ml) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated to a crude residue. As a result of chromatography on silica gel (gradient of EA in heptane from 0 to 30%), ethyl 1-(2-methoxy-3-methylpyridin-4-yl)-5(trifluoromethyl)-III-pyrazole-4-carboxylate was obtained in the form of a colorless oil . ¹ H NMR (300 MHz, Chloroform-d) δ 1.38 (t, J=7.1 Hz, 3H), 1.89 (s, 3H), 4.02 (s, 3H), 4.38 ( k, J=7.1 Hz, 2H), 6.80 (d, J=5.4 Hz, 1H), 8.12 (d, J=5.4 Hz, 1H), 8.16 (s, 1H). MS m/z 330 (MH ⁺ ).

F. 1-(2-Methoxy-3-methylpyridin-4-yl)-5-trifluoromethyl-III-pyrazole-4-carboxylic acid, compound 38f

OH, connection 38f

Ethyl 1-(2-methoxy-3-methylpyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 38e (642 mg, 1.95 mmol), and lithium hydroxide (164 mg, 3.899 mmol) was stirred at room temperature in THF (8 ml) and water (2 ml). The reaction was continued for 18 hours and then the pH was adjusted to 2-3 with 2 NHCl. The mixture was concentrated to dryness. The residue was filtered through a short column of DCM/MeOH (9/1, v/v) silica gel to give the carboxylic acid as a white solid (675 mg, 103%). MS m/z 302 (MH ⁺ ).

G. No.(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxy-3-methylpyridin-4-yl)-5- (trifluoromethyl)-III-pyrazole-4-carboxamide, compound 38

- 98 046082

Oxalyl chloride (0.385 ml, 4.482 mmol) was added to a solution of 1-(2-methoxy-3-methylpyridin-4-yl)5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 38e (675 mg, 2.241 mmol), in DCM (15 ml) and DMF (1 drop) and the mixture was refluxed for 45 min. After completion, the solution was concentrated to dryness. The crude acid chloride was dissolved in DCM (10 ml) and THF (30 ml) and 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile (626 mg, 3.362 mmol) was added, then immediately added triethylamine (0.937 ml, 6.723 mmol). The reaction was continued overnight at room temperature and finally quenched with water (10 ml). After 15 minutes of stirring, 1M Na ₂ CO ₃ (25 ml) was added and the organic layers were extracted with DCM (2x50 ml). The combined extracts were dried over MgSO ₄ , filtered and concentrated to give a crude solid. Filtration through a short silica gel column (0 to 5% MeOH in DCM gradient) afforded the title compound as a sticky solid. Final purification was performed using preparative LC (gradient 30 to 73% ACN/MeOH (1/1, v/v) in 25 mM aqueous ammonium bicarbonate) followed by extraction. Trituration with diethyl ether (2 ml) gave a white solid (137 mg, 13%). 1H NMR (300 MHz, DMSO-d ₆ ) δ 1.86 (s, 3H), 3.99 (s, 3H), 7.17 (d, J=5.4 Hz, 1H), 8.25 ( d, J=5.4 Hz, 1H), 8.31 (s, 2H), 8.53 (s, 1H), 8.85 (d, J=2.5 Hz, 1H), 9.07 ( d, J=2.5 Hz, 1H), 11.28 (s, 1H). MS m/z 470 (MH+).

Example 39.

1-(2-Chloropyridin-4-yl)-N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-Spirazol- 4-carboxamide, compound 39

A. Ethyl 1-(2-chloropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 39a

A solution of (2-chloropyridin-4-yl)hydrazine (1.0 g, 6.965 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro3-oxobutanoate, INT1 (1.67 g, 6.965 mmol), and triethylamine (1.92 ml, 13.758 mmol) in ethanol (25 ml) was stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 25% EA in heptane gradient) to give the title compound as a clear oil (765 mg, 34%). 1H NMR (300 MHz, Chloroform-d) δ 1.39 (t, J=7.2 Hz, 3H), 4.39 (k, J=7.2 Hz, 2H), 7.26 (s, 0H ), 7.36 (d, J=5.5 Hz, 1H), 7.51 (d, J=1.9 Hz, 1H), 8.16 (s, 1H), 8.57 (d, J =5.4 Hz, 1H). MS m/z 320 (MH+).

B. 1-(2-Chloropyridin-4-yl)-5-trifluoromethyl-III-pyrazole-4-carboxylic acid, compound 39b

- 99 046082

Ethyl 1-(2-chloropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 39a (758 mg, 2.371 mmol), and lithium hydroxide (199 mg, 4.742 mmol) were stirred at room temperature in THF (8 ml) and water (2 ml). The reaction was continued for 18 hours and then the pH was adjusted to 2-3 with 2 NHC1. The mixture was concentrated to dryness. The residue was filtered through a short column of DCM/MeOH (9/1, v/v) silica gel to give the carboxylic acid as a white solid (882 mg, 122%). MS m/z 292 (MH ⁺ ).

C. 1-(2-Chloropyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 39

1-(2-Chloropyridin-4-yl)-5-trifluoromethyl-III-pyrazole-4-carboxylic acid, compound 39b (691 mg, 2.371 mmol), was treated with oxalyl chloride (0.407 ml, 4.742 mmol) in DCM (15 ml) and DMF (1 drop) at room temperature. The mixture was then refluxed for 45 minutes and concentrated to dryness. The crude acid chloride was dissolved in DCM (10 ml) and THF (30 ml) and 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (662 mg, 3.557 mmol) was added, followed immediately triethylamine (0.991 ml, 7.113 mmol) was added. The reaction was continued overnight at room temperature and finally quenched with water (10 ml). After 15 minutes of stirring, 1M Na ₂ CO ₃ (25 ml) was added and the organic layers were extracted with DCM (2x50 ml). The combined extracts were dried over MgSO ₄ , filtered and concentrated to give a crude solid. Chromatography on silica gel (0 to 3% MeOH in DCM gradient) gave the compound as a sticky solid. Pure title compound was obtained after preparative LC (gradient 30 to 73% ACN/MeOH (1/1, v/v) in 25 mM aqueous ammonium bicarbonate) followed by extraction. As a result of trituration in diethyl ether, a white powder (225 mg, 20%) was obtained. ^1H NMR (300 MHz, DMSO-d6) δ 7.75 (dd, J=5.4, 1.8 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 8, 31 (s, 2H), 8.56 (s, 1H), 8.71 (d, J=5.4 Hz, 1H), 8.85 (d, J=2.5 Hz, 1H), 9, 07 (d, J=2.5 Hz, 1H), 11.34 (s, 1H). MS m/z 460 (MH ⁺ ).

Example 40.

N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-cyanopyridin-4-yl)-5-(trifluoromethyl)III-pyrazole -4-carboxamide, compound 40

^Nn

1-(2-Chloropyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 39 (174 mg, 0.378 mmol) was dissolved in DMA (5 ml). While bubbling with nitrogen, Pd(dppf)Cl ₂ (17 mg, 0.019 mmol) and Zn(0) (0.5 mg, 0.008 mmol) were added. Finally, zinc cyanide (27 mg, 0.227 mmol) was added and the mixture was heated at 140°C for 2 hours. The reaction mixture was allowed to cool to room temperature and diluted with EA (30 ml) and water (20 ml). The double phase was filtered through a small layer of diatomaceous earth, which was further washed with EA (2x10 ml). The organic layer was separated, washed with brine, dried over MgSO ₄ , filtered, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (0% to 5% MeOH in DCM gradient) to give a beige solid. Trituration with ACN and filtration provided the pure compound as a white solid (116 mg, 67%). 1H NMR (300 MHz, DMSO-d6) δ 8.07 (dd, J=5.3, 2.1 Hz, 1H), 8.32 (s, 2H), 8.49 (d, J=2, 0 Hz, 1H), 8.59 (s, 1H), 8.85 (d, J=2.5 Hz, 1H), 9.00-9.11 (m, 2H), 11.35 (s, 1H). MS m/z 451 (MH ⁺ ).

- 100 046082

Example 41.

N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxypyridin-4-yl)-5-(trifluoromethyl)III-pyrazole -4-carboxamide, compound 41

A. 1-(2-Methoxypyridin-4-yl)-5-trifluoromethyl-III-pyrazole-4-carboxylic acid, compound 41a

Ethyl 1-(2-chloropyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 39a (1.38 g, 4.137 mmol), and K ₂ CO ₃ (1.193 g, 8.634 mmol ) was dissolved in MeOH (30 ml) and refluxed overnight. The mixture was allowed to cool to room temperature and the pH was adjusted to 2-3 using 2N HCl. The reaction mixture was concentrated to dryness. The residue was filtered through a silica gel column of DCM/MeOH (9/1, v/v) to obtain the title compound as a white solid (1.0 g, 79%). MS m/z 288 (MH+).

B. No. (5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxypyridin-4-yl)-5-(trifluoromethyl)- Sh-pyrazole-4-carboxamide, compound 41

1-(2-Methoxypyridin-4-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 41a (0.5 g, 1.741 mmol), was treated with oxalyl chloride (0.299 ml, 3.482 mmol) in DCM (15 ml) and DMF (1 drop) under reflux. After 45 minutes, the reaction mixture was concentrated to dryness. The crude acid chloride was dissolved in DCM (10 ml) and THF (30 ml) and 5-amino-2[1,2,3]triazol-2-yl-nicotinonitrile (626 mg, 3.362 mmol) was added, followed immediately by triethylamine (0.937 ml, 6.723 mmol). The reaction was continued overnight at room temperature and finally quenched with water (10 ml). After 15 minutes of stirring, 1M Na ₂ CO ₃ (25 ml) was added and the organic layers were extracted with DCM (2x50 ml). The combined extracts were dried over MgSO ₄ , filtered and concentrated to give a crude solid. Chromatography on silica gel (0 to 5% MeOH gradient in DCM) gave the compound as a sticky solid. Pure title compound was obtained after preparative LC (30 to 73% ACN/MeOH (1/1, v/v) gradient in 0.1% aqueous formic acid) followed by DCM/1M Na ₂ CO ₃ extraction . N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxypyridin-4-yl)-5(trifluoromethyl)-1H-pyrazole -4-carboxamide was obtained as a white solid (140 mg, 34%). ^1H NMR (300 MHz, DMSO-d6) δ 3.96 (s, 3H), 7.11 (d, J=1.8 Hz, 1H), 7.19-7.33 (m, 1H), 8.31 (s, 2H), 8.43 (d, J=5.5 Hz, 1H), 8.49 (s, 1H), 8.84 (d, J=2.4 Hz, 1H), 9.05 (d, J=2.5 Hz, 1H), 11.31 (s, 1H). MS m/z 456 (MH+).

Example 42.

N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,3-dimethylpyridin-4-yl)-5-trifluoromethyl)III- pyrazole-4-carboxamide, compound 42

- 101 046082

A. (2,3-Dimethylpyridin-4-yl)-hydrazine, compound 42a

, connection 42a

Hydrazine monohydrate (5.74 ml, 76.143 mmol) was added to a solution of 4-chloro-2,3-dimethylpyridine 1oxide (4.0 g, 25.381 mmol) in dioxane (15 ml) and stirred at 140°C in a sealed tube in for 96 hours. The mixture was then left to cool to room temperature and concentrated to dryness. The residue was flash chromatographed on silica gel (9.0/0.9/0.1 v/v/v DCM gradient, 0 to 100%) to give a white solid (1. 72 g, 37%). MS m/z 138 (MH ⁺ ).

B. Ethyl 1-(2,3-dimethylpyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 42b

, connection 42b

(2,3-Dimethylpyridin-4-yl)hydrazine solution, compound 42a (1.72 g, 12.538 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (3.011 g, 12.538 mmol), and triethylamine (3.495 ml, 25.076 mmol) in ethanol (50 ml) were stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 25% EA in heptane gradient) to give the title compound as a white solid (285 mg, 7%). MS m/z 314 (MH+).

C. 1-(2,3-Dimethylpyridin-4-yl)-5-trifluoromethyl-III-pyrazole-4-carboxylic acid compound 42c

OH connection 42c

Ethyl 1-(2,3-dimethylpyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 42b (415 mg, 1.325 mmol), and lithium hydroxide (111 mg, 2.649 mmol) were stirred at room temperature in THF (8 ml) and water (2 ml). The reaction was continued for 18 hours and then the pH was adjusted to 2-3 with 2 NHCl. The mixture was concentrated to dryness. The residue was filtered through a short column of DCM/MeOH (9/1, v/v) silica gel to give the carboxylic acid as a white solid (472 mg, 123%). MS m/z 286 (MH ⁺ ).

D. No. (5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,3-dimethylpyridin-4-yl)-5-(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 42

1-(2,3-Dimethylpyridin-4-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 42c

- 102 046082 (0.472 g, 1.655 mmol), treated with oxalyl chloride (0.284 ml, 3.310 mmol) in DCM (15 ml) and DMF (1 drop) at reflux. After 45 minutes, the reaction mixture was concentrated to dryness. The crude acid chloride was dissolved in DCM (10 ml) and THF (30 ml) and 5-amino2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (462 mg, 2.483 mmol) was added, and then immediately added triethylamine (0.692 ml, 4.965 mmol). The reaction was continued overnight at room temperature and finally quenched with water (10 ml). After 15 minutes of stirring, 1M Na ₂ CO ₃ (25 ml) was added and the organic layers were extracted with DCM (2x50 ml). The combined extracts were dried over MgSO ₄ , filtered and the filtrate was concentrated to give a crude solid. Chromatography on silica gel (0 to 5% MeOH gradient in DCM) afforded the compound as a solid. Pure title compound was obtained after preparative LC (30 to 82% ACN/MeOH (1/1, v/v) gradient in 0.1% aqueous formic acid) followed by DCM/1M Na ₂ CO ₃ extraction . As a result of trituration in diethyl ether, N(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-1-(2,3-dimethylpyridin-4-yl)-5 was obtained -(trifluoromethyl)-1H-pyrazole-4-carboxamide as a white solid (97 mg, 13%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.95 (s, 3H), 2.59 (s, 3H), 7.40 (d, J=5.2 Hz, 1H), 8.31 (s, 2H), 8.46-8.60 (m, 2H), 8.85 (d, J=2.4 Hz, 1H), 9.07 (d, J=2.4 Hz, 1H) , 11.26 (s, 1H). MS m/z 454 (mH ⁺ ).

Example 43.

1-(3-Chloro-2-methylpyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-III-pyrazole-4-carboxamide, compound 43

A. (3-Chloro-2-methylpyridin-4-yl)-hydrazine, compound 43 a

, connection 43a

Hydrazine monohydrate (5.74 ml, 76.143 mmol) was added to a solution of 3,4-dichloro-2-methylpyridine (2.0 g, 12.344 mmol) in dioxane (15 ml) and stirred at 100°C overnight. The mixture was then allowed to cool to room temperature and concentrated to dryness. The residue was treated with 1M Na ₂ CO ₃ (10 ml) and water (20 ml). Organics were extracted with DCM (2x40 ml), dried over MgSO ₄ , filtered and the filtrate concentrated. The crude material was flash chromatographed on silica gel (0 to 7.5% MeOH gradient in DCM) to give a white solid (967 mg, 49%) 1H NMR (300 MHz, DMSO-d6) δ 2.37 (s , 3H), 4.30 (s, 2H), 6.91 (d, J=5.6 Hz, 1H), 7.39 (s, 1H), 7.94 (d, J=5.6 Hz , 1H). MS m/z 158 (MH ⁺ ).

B. Ethyl 1-(3-chloro-2-methylpyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 25b

, connection 43b

(3-Chloro-2-methylpyridin-4-yl)hydrazine solution, compound 43a (967 mg, 6.136 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (11.474 g, 6.136 mmol), and triethylamine (1.71 ml, 12.271 mmol) in ethanol (25 ml) were stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 25% EA in heptane gradient) to give the title compound as a colorless oil (678 mg, 33%). 1H NMR (300 MHz, Chloroform-d) δ 1.39 (t, J=7.1 Hz, 3H), 2.75 (s, 3H), 4.39 (k, J=7.1 Hz, 2H ), 7.23 (d, J=5.1 Hz, 1H), 8.21 (s, 1H), 8.58 (d, J=5.1 Hz, 1H). MS m/z 334 (MH+).

C. 1-(3-Chloro-2-methylpyridin-4-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 43c

- 103 046082

Ethyl 1-(3-chloro-2-methylpyridin-4-yl)-5-(trifluoromethyl)-1H-πyrazole-4-carboxylate, compound 43b (675 mg, 2.023 mmol), and lithium hydroxide (170 mg, 4.046 mmol) was stirred at room temperature in THF (8 ml) and water (2 ml). The reaction was continued for 18 hours, after which the pH was adjusted to 2-3 with 2N HCl. The mixture was concentrated to dryness. The residue was filtered through a short column of DCM/MeOH (9/1, v/v) silica gel to give the carboxylic acid as a white solid (774 mg, 125%). MS m/z 306 (MH+).

D. 1-(3-Chloro-2-methylpyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 43

-(3-Chloro-2-methylpyridin-4-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 43c (0.618 g, 2.023 mmol), was treated with oxalyl chloride (0.695 ml, 8.092 mmol) in DCM (15 ml) and DMF (1 drop) under reflux. After 45 minutes, the reaction mixture was concentrated to dryness. The crude acid chloride was dissolved in DCM (10 ml) and THF (30 ml) and 5-amino-2[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (565 mg, 3.055 mmol) was added, followed immediately triethylamine (0.846 mL, 6.069 mmol) was added. DMF (10 ml) was added to improve homogeneity. The reaction was continued overnight at room temperature and finally quenched with water (10 ml). After 15 minutes of stirring, 1M Na ₂ CO ₃ (25 ml) was added and the organic layers were extracted with DCM (2x50 ml). The combined extracts were dried over MgSO ₄ , filtered and concentrated to give a crude solid. Chromatography on silica gel (0 to 5% MeOH gradient in DCM) afforded the compound as an amorphous solid. Trituration with diethyl ether gave the desired product as a light yellow solid (430 mg, 44%). ¹ H NMR (300 MHz, Chloroform-d) δ 2.78 (s, 3H), 7.27 (d, J=5.0 Hz, 1H), 8.02 (s, 2H), 8.18 ( s, 1H), 8.22 (s, 1H), 8.62 (d, J=5.1 Hz, 1H), 8.83 (d, J=2.5 Hz, 1H), 8.97 ( d, J=2.6 Hz, 1H). MS m/z 474 (MH+)

Example 44.

1-(3-Chloropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-Spirazole -4-carboxamide, compound 44

A. Ethyl 1-(6-chloropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 44a

- Wow

Cl

, connection 44a

A solution of (3-chloropyridin-2-yl)hydrazine (0.80 g, 5.572 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1.338 g, 5.572 mmol), and triethylamine (1.545 ml, 11.144 mmol) in ethanol (15 ml) was stirred overnight at 80°C. The reaction mixture was concentrated at reduced

- 104 046082 pressure and the residue was purified by chromatography on silica gel (0 to 30% gradient of EA in heptane) to give the title compound as a white solid (1.48 g, 80%). 1H NMR (300 MHz, DMSO-d6) δ 1.32 (t, J=7.1 Hz, 2H), 4.34 (k, J=7.0 Hz, 1H), 7.81 (dd, J =8.2, 4.7 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.45 (s, 1H), 8.65 (d, J=5.3 Hz , 1H). MS m/z 320 (MH ⁺ ).

B. 1-(3-Chloropyridin-2-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 44b

Ethyl 1-(6-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 44a (801 mg, 2.506 mmol), and lithium hydroxide (315 mg, 7.517 mmol) were stirred at room temperature in THF (8 ml) and water (2 ml). The reaction was continued for 18 hours and then the pH was adjusted to 2-3 with 1N HCl. The mixture was concentrated to dryness to give the crude carboxylic acid (731 mg, 99%). MS m/z 292 (MH ⁺ )

C. 1-(3-Chloropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 44

N ^Z И n- ⁿ

(1-chloro-2-methylpropenyl)dimethylamine (1.375 ml, 9.979 mmol) was added portionwise to a solution of 1(3-chloropyridin-2-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 44b (0.750 g , 2.495 mmol), in dry THF (15 ml), monitored by LC-MS. To the crude solution of the resulting acid chloride were added 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (774 mg, 2.495 mmol), and triethylamine (0.696 ml, 4.990 mmol). The reaction was continued for 2 hours and then quenched with 1M Na ₂ CO ₃ . The aqueous phase was extracted with DCM, dried over MgSO ₄ , filtered and the filtrate concentrated to dryness. The residue was purified by silica gel flash column chromatography (0% to 2% MeOH in DCM gradient) to give pure product. As a result of trituration in diethyl ether, a white powder (466 mg, 58%) was obtained. 1H NMR (300 MHz, DMSO-d6) δ 7.82 (dd, J=8.1, 4.7 Hz, 1H), 8.31 (s, 2H), 8.41 (d, J=8, 2 Hz, 1H), 8.58 (s, 1H), 8.67 (d, J=4.7 Hz, 1H), 8.86 (d, J=2.5 Hz, 1H), 9.08 (d, J=2.5 Hz, 1H), 11.31 (s, 1H). MS m/z 460 (MH ⁺ ).

Example 45.

1-(3-Chloropyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 45

A. Ethyl 1-(3-chloropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 45a

A solution of (3-chloropyridin-4-yl)hydrazine (0.80 g, 5.572 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1.338 g, 5.572 mmol), and triethylamine ( 1.545 ml, 11.144 mmol) in ethano

- 105 046082 le (15 ml) was stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 50% EA in heptane gradient) to give the title compound as a clear oil (541 mg, 30%). 1H NMR (300 MHz, Chloroform-d) δ 1.39 (t, J=7.1 Hz, 3H), 4.39 (k, J=7.1 Hz, 2H), 7.39 (d, J =5.1 Hz, 1H), 8.23 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.83 (s, 1H). MS m/z 320 (MH+).

B. 1-(3-Chloropyridin-4-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 45b

OH, connection 45b

Ethyl 1-(3-chloropyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 45a (535 mg, 1.674 mmol), and lithium hydroxide (211 mg, 5.021 mmol) were stirred at room temperature in THF (8 ml) and water (2 ml). The reaction was continued for 18 hours, after which the pH was adjusted to 2-3 with 1N HCl. The mixture was concentrated to dryness to give the crude carboxylic acid (760 mg, 160%). MC m/z 291 (MH+).

C. 1-(3-Chloropyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 45

(1-Chloro-2-methylpropenyl)dimethylamine (0.898 ml, 6.520 mmol) was added portionwise to a solution of 1(3-chloropyridin-2-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 45b (0.490 g , 1.630 mmol), in dry THF (15 ml), monitored by LC-MS. To the crude solution of the resulting acid chloride were added 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (202 mg, 1.087 mmol), and triethylamine (0.454 mL, 3.260 mmol). The reaction was continued for 2 hours and then quenched with 1M Na ₂ CO ₃ . Organics were extracted with DCM, dried over MgSO ₄ , filtered and the filtrate concentrated to dryness. The residue was purified by silica gel chromatography (0% to 8% MeOH in DCM gradient) to give pure product. Trituration with diethyl ether gave a white solid (250 mg, 49%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.96 (d, J=5.2 Hz, 1H), 8.31 (s, 2H), 8.62 (s, 1H), 8.79 -8.96 (m, 2H), 9.00-9.11 (m, 2H), 11.29 (s, 1H). MS m/z 460 (MH+).

Example 46.

N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-cyanopyridin-4-yl)-5-(trifluoromethyl)III-pyrazole -4-carboxamide, compound 46 and

A. (3-Bromopyridin-4-yl)hydrazine, compound 46a

W

N NN ₂

N, connection 46a

A solution of 3-bromo-4-chloropyridine (1.295 g, 6729 mmol) and hydrazine monohydrate (1.01 mL, 13.459 mmol) was heated at 100°C in dioxane (15 mL) for 16 h.

The mixture was subsequently allowed to cool to room temperature and concentrated to a dark oil. Water (20 ml) and 1M Na ₂ CO ₃ (10 ml) were added. Organics were extracted with DCM (2x40 ml). The combined extracts were dried over MgSO ₄ , filtered, and the filter

- 106 046082 rats were concentrated. Silica gel chromatography (0 to 7% MeOH in DCM gradient) provided the desired hydrazine as a beige solid (492 mg, 35%). 1H NMR (300 MHz, DMSO-d ₆ ) δ 4.34 (s, 2H), 7.01 (d, J=5.6 Hz, 1H), 7.32 (s, 1H), 8.07 ( d, J=5.6 Hz, 1H), 8.18 (s, 1H). MS m/z 188 (MH ⁺ ).

B. Ethyl 1-(3-bromopyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 46b

, connection 46b

(3-bromopyridin-4-yl)hydrazine solution, compound 46a (0.492 g, 2.617 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (0.628 g, 2.617 mmol), and triethylamine (0.725 ml, 5.233 mmol) in ethanol (15 ml) were stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 30% EA in heptane gradient) to give the title compound as a white solid (300 mg, 31%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.31 (t, J=7.1 Hz, 3H), 4.34 (k, J=7.1 Hz, 2H), 7.93 (d , J=5.1 Hz, 1H), 8.47 (s, 1H), 8.84 (d, J=5.1 Hz, 1H), 9.08 (s, 1H). MS m/z 364 (MH ⁺ ).

C. Ethyl 1-(3-cyanopyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 46c

, connection 46c

Ethyl 1-(3-bromopyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 46b (300 mg, 0.824 mmol), was dissolved in DMF (5 ml) and the resulting solution was bubbled with nitrogen into for approximately 15 minutes. Copper cyanide (147 mg, 1.648 mmol) and copper iodide (15 mg, 0.082 mmol) were added and the reaction vessel was tightly screw capped. The mixture was then heated at 140°C for 2 hours and left to cool to room temperature. The reaction mixture was diluted with EA (30 ml), filtered through a pad of diatomaceous earth and concentrated to give a crude residue. As a result of chromatography on silica gel (gradient of EA in heptane from 0 to 30%), a product of sufficient quality was obtained in the form of a viscous oil (201 mg, 64%). MS m/z 311 (MH ⁺ ).

D. 1-(3-Cyanopyridin-4-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 46d

OH connection 46d

Ethyl D-cyanopyridinium-yl-trifluoromethylchloride-pyrazole-carboxylate, compound 46c (200 mg, 0.645 mmol), and lithium hydroxide (81 mg, 1.934 mmol) were stirred at room temperature in THF (2 ml) and water (1 ml). The reaction was continued for 18 hours and the mixture was concentrated to dryness to give the crude carboxylic acid (287 mg, 157%). MS m/z 283 (MH ⁺ ).

E. No. (5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-cyanopyridin-4-yl)-5-(trifluoromethyl)III -pyrazole-4-carboxamide, compound 46

(1-Chloro-2-methylpropenyl)dimethylamine (0.345 ml, 2.503 mmol) was added portionwise to a solution of 1(3-cyanopyridin-4-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 46d (0.182 g , 0.626 mmol), in dry THF (10 ml), monitored by LC-MS. To the crude solution of the resulting acid chloride was added 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (78 mg, 0.417

- 107 046082 mmol), and triethylamine (0.175 ml, 1.252 mmol). The reaction was continued for 2 h and then quenched with 1 M Na2CO3. Organics were extracted with DCM, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0 to 4% MeOH in DCM gradient) to give a mixture of the two products. Preparative LC (ACN/MeOH gradient (1/1, v/v) in 0.1% aqueous formic acid from 19 to 55%) separated the two compounds. Both fractions were treated with 1M Na2CO3, extracted with DCM, dried over MgSO ₄ and concentrated. As a result of trituration in diethyl ether, white solids were obtained: N(5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)-1-(3-cyanopyridin-4-yl) -5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 46 (35 mg, 18%); ^1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J=5.4 Hz, 1H), 8.32 (s, 2H), 8.67 (s, 1H), 8.86 ( d, J=2.5 Hz, 1H), 9.07 (d, J=2.5 Hz, 1H), 9.19 (d, J=5.4 Hz, 1H), 9.41 (s, 1H), 11.40 (s, 1H). MS m/z 451 (MH+)

Example 47.

1-(3-Chloro-4-methylpyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 47

A. (3-Chloro-4-methylpyridin-2-yl)-hydrazine, compound 47a

ΗΝ ¹ '

^Λα

IL 4, connection 47a

Hydrazine monohydrate (3.145 ml, 55.55 mmol) was added to a solution of 2,3-dichloro-4-methylpyridine (1.50 g, 9.258 mmol) in dioxane (30 ml) and stirred at 110°C overnight. The mixture was then allowed to cool to room temperature and concentrated to dryness. The residue was purified by silica gel chromatography (0 to 10% MeOH in DCM gradient) to give hydrazine as a foam (1.23 mg, 81%). 1H NMR (300 MHz, DMSO-d ₆ ) δ 2.25 (s, 3H), 4.18 (s, 2H), 6.60 (d, J=5.0 Hz, 1H), 7.48 ( s, 1H), 7.91 (d, J=5.0 Hz, 1H). MS m/z 158 (MH+).

B. Ethyl 1-(3-chloro-4-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 47b

, connection 47b

(3-Chloro-4-methylpyridin-2-yl)hydrazine solution, compound 47a (1.23 g, 7.805 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1.874 g , 7.805 mmol), and triethylamine (2.16 ml, 15.609 mmol) in ethanol (30 ml) were stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 30% EA in heptane gradient) to give the title compound as a white solid (300 mg, 31%). ¹ H NMR (300 MHz, DMSO-d6) δ 1.32 (t, J=7.1 Hz, 3H), 2.52 (s, 3H), 4.34 (k, J=7.1 Hz, 2H), 7.77 (d, J=4.9 Hz, 1H), 8.44 (s, 1H), 8.50 (d, J=4.9 Hz, 1H). MS m/z 334 (MH+).

C. 1-(3-Chloro-4-methylpyridin-2-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 47c

OH connection 47c

Ethyl 1-(3-chloro-4-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 47b (1.0 g, 2.997 mmol), and lithium hydroxide (377 mg, 8.99 mmol) stirred at room temperature

- 108 046082 ture in THF (8 ml) and water (2 ml). The reaction was continued for 18 hours and then the pH was adjusted to 2-3 with 2 NHCl. The mixture was concentrated to dryness to give the crude carboxylic acid (916 mg, 100%, theoretical yield). 1H NMR (300 MHz, DMSO-d ₆ ) δ 2.51 (s, 3H), 7.77 (d, J=4.9 Hz, 1H), 8.35 (s, 1H), 8.48 ( d, J=4.9 Hz, 1H). MS m/z 305 (MH ⁺ ).

D. 1-(3-Chloro-4-methylpyridin-2-yl)-M-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 47

(1-Chloro-2-methylpropenyl)dimethylamine (1.636 ml, 11.868 mmol) was added portionwise to a solution of 1(3-chloro-4-methylpyridin-2-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 47c (0.935 g, 2.967 mmol) in dry THF (15 ml) monitored by LC-MS. To the crude solution of the resulting acid chloride were added 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (368 mg, 1.978 mmol), and triethylamine (0.827 mL, 5.934 mmol). The reaction was continued for 2 hours and then quenched with 1M Na ₂ CO ₃ . Organics were extracted with DCM, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0 to 8% MeOH in DCM gradient) to give an improved product. Preparative LC (ACN/MeOH gradient (1/1, v/v) in 0.1% aqueous formic acid from 19 to 55%) provided the pure compound. Fractions were treated with 1M Na ₂ CO ₃ , extracted with DCM, dried over MgSO ₄ and concentrated to give a white solid (85 mg, 9%). 1H NMR (300 MHz, DMSO-d ₆ ) δ 2.54 (s, 3H), 7.78 (d, J=4.9 Hz, 1H), 8.31 (s, 2H), 8.51 ( d, J=4.9 Hz, 1H), 8.62 (s, 1H), 8.88 (d, J=2.5 Hz, 1H), 9.11 (d, J=2.5 Hz, 1H), 11.39 (s, 1H). MS m/z 305 (MH ⁺ ).

Example 48.

N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,5-dichloropyridin-4-yl)-5-(trifluoromethyl)III -pyrazole-4-carboxamide, compound 48

A. Ethyl 1-(3,5-dichloropyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 48a

- o G~ o

, connection 48a

A solution of (3,5-dichloropyridin-4-yl)hydrazine (1.0 g, 5.617 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1.349 g, 5.617 mmol), and triethylamine (1.55 ml, 11.235 mmol) in ethanol (15 ml) was stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 20% MeOH gradient in DCM) to give the title compound as an oil (558 mg, 27%). MS m/z 354 (MH ⁺ )

B. 1-(3,5-Dichloropyridin-4-yl)-5-trifluoromethyl-III-pyrazole-4-carboxylic acid, compound 48b

HE

, connection 48b

Ethyl 1-(3,5-dichloropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 48a

- 109 046082 (558 mg, 1.576 mmol), and lithium hydroxide (132 mg, 3.152 mmol) were stirred at room temperature in THF (60 ml) and water (15 ml). The reaction was continued for 18 hours and then the pH was adjusted to 2-3 with 2 NHCl. The mixture was concentrated to dryness to give the crude carboxylic acid (514 mg, 100%, theoretical yield). MS m/z 326 (MH ⁺ ).

S. No. (5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,5-dichloropyridin-4-yl)-5-(trifluorome til/N-pyrazole^-carboxamide, compound 48

N'N

(1-Chloro-2-methylpropenyl)dimethylamine (1.30 ml, 9.458 mmol) was added portionwise to a solution of 1(3,5-dichloropyridin-4-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid, compound 48b (0.514 g, 1.576 mmol), in dry THF (16 ml), monitored by LC-MS. To the crude solution of the resulting acid chloride were added 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (440 mg, 2.364 mmol), and triethylamine (0.659 mL, 4.728 mmol). The reaction was continued for 2 hours and then quenched with 1M Na ₂ CO ₃ . Organic substances were extracted with EA, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was purified by chromatography on silica gel (EA gradient in heptane from 0 to 100%). Final purification was performed using preparative LC (ACN/MeOH gradient (1/1, v/v) in 0.1% aqueous formic acid from 30 to 73%) to obtain the pure compound. Fractions were treated with 1M Na ₂ CO ₃ , extracted with DCM, dried over MgSO ₄ and the filtrate concentrated to an amorphous solid. As a result of trituration in diethyl ether, a white powder (215 mg, 27%) was obtained. ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.32 (s, 2H), 8.84 (s, 1H), 8.89 (s, 1H), 9.01-9.24 (m, 3H), 11.51 (s, 1H). MS m/z 494 (MH ⁺ ).

Example 49.

N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)-5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 49

A. (2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)hydrazine, compound 49a

To a stirred solution of 2,3-dihydrobenzo[b][1,4]dioxin-5-amine (300 mg, 1.958 mmol) in 5M

HCl (10 ml) at 0°C, a solution of NaNO ₂ (136.929 mg, 1.985 mmol) in water (2 ml) was added at a temperature below 0°C. The reaction mixture was stirred at 0°C for 30 min and a solution of SnCl ₂ (985.2 mg, 4.366 mmol) in conc. HCl (2 ml). The mixture was stirred at 60°C for 1.5 hours. The mixture was then adjusted to pH 13 with 20% aqueous sodium hydroxide solution. The mixture was extracted using ethyl acetate. The organic layer was dried (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate=0:100). The solvent was evaporated to give the product as a yellow solid (150 mg, 45.5%). LCMS (ESI) m/z M+1: 167.1.

B. Ethyl 1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 49b

- 110 046082

Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (263.04 mg, 1.095 mmol) was added to the solution of (2,3-dihydrobenzo[b][1,4]dioxin-5-yl )hydrazine, compound 49a (140 mg, 0.842 mmol), in EtOH (4 ml) and reacted at 80°C for 1 hour. The mixture was evaporated under reduced pressure and then purified with FFS (petroleum ether/ethyl acetate= 100:0 - petroleum ether/ethyl acetate = 70:30). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a brown oil. LCMS (ESI) m/z M+1: 342.9.

C. 1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 49c

, connection 49c

NaOH (41.53 mg, 1.038 mmol) was added to the ethyl 1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl) solution

5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 49b (120 mg, 0.346 mmol), in EtOH/H2O=1:1 (5 ml) and reacted at 28°C for 2 hours. Solvent evaporated under reduced pressure. A 1M HCl solution was added to the mixture to adjust the pH to ~5 and a solid formed. The solid was collected to give the product. (115 mg, 78.1%). LCMS (ESI) m/z M+1: 314.9.

D. N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin -5-yl)-5 (trifluoromethyl)-III-pyrazole-4-carboxamide, compound 49

1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 49c (95.20 mg, 0.224 mmol), 5-Amino-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, INT3 (50 mg, 0.269 mmol), POCl ₃ (41.18 mg, 0.269 mmol) was dissolved in DCM (2 ml) and added pyridine (53.101 mg,

0.671 mmol). The mixture was stirred at 25°C for 1 hour. Then saturated. NH ₄ Cl (20 ml) and extracted using CH ₂ Cl ₂ (20 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil, which was purified by preparative HPLC (3060% (v/v) CH ₃ CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (34 mg, 31.49%). LCMS (ESI) m/z M+1: 482.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.134.35 (m, 3H), 4.24-4.35 (m, 1H), 6.96-7.02 (m, 1H ), 7.03-7.07 (m, 1H), 7.09-7.13 (m, 1H), 8.29 (s, 2H), 8.41 (s, 1H), 8.83 (d, J=2.43 Hz, 1H), 9.05 (d, J=2.65 Hz, 1H), 11.21 (s, 1H).

Example 50.

1-(2-Bromo-4-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 50

A. (2-Bromo-4-fluorophenyl)hydrazine, compound 50a H ₂ N ^Br

HN

F, connection 50a

To a stirred solution of 2-bromo-4-fluoroaniline (2 g, 10.526 mmol) in 5 M HCl (15.18 ml) at

At 0°C, a solution of NaNO ₂ (1.089 g, 15.788 mmol) in H ₂ O (8 ml) was added at a temperature below 0°C. The reaction mixture was stirred at 0°C for 30 min and a solution of SnCl ₂ (5.94 mg, 15.788 mmol) in conc. HCl (2.82 ml). The mixture was stirred at room temperature for 3 hours. The mixture was then adjusted to pH 12-14 with 20% aqueous sodium hydroxide solution. The mixture was extracted using ethyl acetate. The organic layer was dried (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated under reduced pressure to give the crude product (2 g, 92.7%).

B. Ethyl 1-(2-bromo-4-fluorophenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 50b

- 111 046082

connection 50b

Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (3.162 g, 13.162 mmol), was added to a solution of (2-bromo-4-fluorophenyl)hydrazine, compound 50a (1.8 g, 8.779 mmol), in EtOH (10 ml) and reacted at 80°C for 1 hour. The mixture was evaporated under reduced pressure, then purified using FFS (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate= 80:20). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a brown oil. LCMS (ESI) m/z M+1: 382.8.

C. 1-(2-Bromo-4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 50c

Vg, connection 50s

LiOH (387.5 mg, 16.182 mmol) was added to a solution of 1-(2-bromo-4-fluorophenyl)-5-(trifluoromethyl)-1H pyrazole-4-carboxylic acid, compound 50b (387 mg, 16.182 mmol), in EtOH/H2O=2:1 (15 ml) and reacted at 23°C for 2 hours. The solvent was evaporated under reduced pressure. Solution

1M HCl was added to the mixture to adjust the pH to ~5 and a solid formed. The solid was collected by filtration to give the product (1 g, 83.4%). LCMS (ESI) m/z M+1: 352.6.

D. 1-(2-Bromo-4-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide, compound 50

Vg

1-(2-Bromo-4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 50c (200 mg, 0.540 mmol), 5-amino-2-(2H-1,2, 3-triazol-2-yl)nicotinonitrile, INT3 (102.5 mg, 0.551 mmol), POCl ₃ (99.359 mg, 0.648 mmol) were dissolved in DCM (5 ml) and pyridine (128.14 mg, 1.620 mmol) was added. The mixture was stirred at 25°C for 1 hour. Then saturated. NaHCO ₃ (10 ml) and the mixture was extracted using CH2C12 (15 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil, which was purified by preparative HPLC (46-66% (v/v) CH3CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (46 mg, 16.1%). LCMS (ESI) m/z M+1: 522.8. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.51 (td, J=8.49, 2.87 Hz, 1H), 7.85 (dd, J=8.82, 5, 29 Hz, 1H), 7.93 (dd, J=8.27, 2.76 Hz, 1H), 8.29 (s, 2H), 8.50 (s, 1H), 8.83 (d , J=2.21 Hz, 1H), 9.01-9.09 (m, 1H), 11.25 (br. s, 1H).

Example 51.

1-(2-Chloro-4-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 51

A. Ethyl 1-(2-chloro-4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 51a

A solution of 2-chloro-4-fluorophenylhydrazine hydrochloride (400 mg, 2.030 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (585.09 mg, 2.436 mmol), in EtOH ( 5 ml) was stirred at 55°C for 1 hour. The mixture was concentrated under reduced pressure. Unrefined ochi product

- 112 046082 was carried out by column chromatography on silica gel (petroleum ether/ethyl acetate from 100/0 to 50/50). The required fractions were collected and the solvent was concentrated under reduced pressure.

B. 1-(2-chloro-4-fluorophenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 51b

OH, compound 51b

A solution of compound 51a (585 mg, 1.668 mmol), LiOH (105 mg, 2.502 mmol) in EH/H ₂ O (2/1.5 ml) was stirred at room temperature for 2 hours. A solution of 1N HCl was added to neutralize the reaction solution . The mixture was extracted using ethyl acetate (10 ml x3). The separated organic layer was dried (MgSO ₄ ), filtered, and the solvent was evaporated under reduced pressure to give 51b (500 mg, 97.124% yield) as a white solid.

C. 1-(2-chloro-4-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 51

Phosphorus oxychloride (90.61 µl, 0.972 mmol) was added to a solution of 1-(2-chloro-4-fluorophenyl)-5(trifluoromethyl)-N-pyrazole-4-carboxylic acid, compound 51b (120 mg, 0.389 mmol), 5-amino-2(2H-1,2,3-triazol-2-yl)nicotinonitrile (94.11 mg, 0.505 mmol), pyridine (314.5 μl, 3.888 mmol) in CH ₂ Cl ₂ (2 ml) . The mixture was stirred at room temperature for 1 hour. Water (5 ml) was added to the mixture. Added sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 ml x 3). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC (45-75% (v/v) CH3CN and H ₂ O with 0 .05% HCl) and lyophilized to dryness to give the title compound (105 mg, 56.131%). LCMS (ESI) m/z M+1: 476.9. ¹ H NMR (400 MHz, METHANOL) δ ppm 7.35 (td, J=8.32, 2.76 Hz, 1H), 7.57 (dd, J=8.16, 2.87 Hz , 1H), 7.68 (dd, J=8.82, 5.29 Hz, 1H), 8.13 (s, 2H), 8.33 (s, 1H), 8.88 (d, J =2.65 Hz, 1H), 9.05 (d, J=2.43 Hz, 1H).

Example 52.

1-([1,3]Dioxolo[4,5-b]pyridin-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 52

A. 7-Hydrazinyl-[1,3]dioxolo[4,5-b]pyridine, compound 52a

ΗΝ-ΝΗ _ξ

, connection 52a

A mixture of palladium(II) chloride dimer (pi-cinnamyl) (19.24 mg, 0.037 mmol) and X-[2-(di-1adamantylphosphino)phenyl]morpholine (34.427 mg, 0.074 mmol) in dioxane (3 ml) was removed air using argon 4 times. The resulting clear yellow solution was stirred at room temperature under argon for 10 minutes. 7-Bromo[1,3]dioxolo[4,5-b]pyridine (150 mg, 0.74 mmol) and tBuONa (142.72 mg, 1.49 mmol) were added to the mixture and deaerated using argon 4 times. The resulting yellow reaction mixture was stirred at room temperature for 5 min and subsequently treated with hydrazine (75.86 mg, 1.49 mmol) using a syringe and deaerated using argon 4 times. The mixture was then stirred at 55°C under argon for 2 hours. The mixture was filtered and washed with ethyl acetate (5 ml x 3). The filtrate was concentrated under reduced pressure to give compound 52a (113.71 mg, crude) as a black solid.

B. Ethyl BO^dioxolo^A-EDpyridin^-yl^-StrifluoromethylfN-pyrazole^-carboxylate, compound 52b

- 113 046082

connection 52b

7-hydrazinyl-[1,3]dioxolo[4,5-b]pyridine solution, compound 52a (113 mg, 0.74 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (283.56 mg, 1.18 mmol) in MeCN (5 ml) was stirred at 60°C for 3 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 50/50). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 52b (200 mg, 82.3% yield) as a yellow solid. LCMS (ESI) m/z M+1: 330.1.

C. ^(P^Dioxolo^X-EDpyridin^-yl^Xtrifluoromethyl-pyrazoleM-carboxylic acid, compound 52c

A solution of compound 52b (200 mg, 0.607 mmol), LiOH (50.98 mg, 1.22 mmol) in THF/H2O (2/1, 2 ml) was stirred at room temperature overnight. A 1N HCl solution was added to neutralize the reaction solution. The mixture was extracted using ethyl acetate (10 ml x3). The separated organic layer was dried (MgSO ₄ ), filtered, and the solvent was evaporated under reduced pressure to give 1c (195 mg, 100% yield) as a yellow solid. LCMS (ESI) m/z M+1: 302.0.

D. No. (5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methoxyphenyl)-5-(trifluoromethyl)- Sh-pyrazole-4-carboxamide, compound 52

Phosphorus oxychloride (492.239 µl, 6.086 mmol) was added to a solution of 1-([1,3]dioxolo[4,5-pyridin-yl-Xtrifluoromethyl-pyrazole-carboxylic acid, compound 52c (195 mg, 0.61 mmol) , 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (154.77 mg, 0.79 mmol), pyridine (492.24 µl, 6, 09 mmol) in CH ₂ Cl ₂ (2 ml). The mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the mixture. Saturated NaHCO ₃ was added to adjust the pH of the reaction mixture to 7 ~

8. The mixture was extracted using CH ₂ Cl ₂ (5 ml x3). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (3262% (v/v) CH3CN and H ₂ O with 0.05 % HCl) and lyophilized to dryness to obtain the title compound (180 mg, 60.6%). LCMS (ESI) m/z M+1: 478.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.31 (s, 2 H), 7.16 (d, J=5.95 Hz, 1H), 7.80 (d, J =5.95 Hz, 1H), 8.19 (s, 2H), 8.55 (s, 1H), 8.64 (d, J=2.20 Hz, 1H), 8.82 (d, J=2.21 Hz, 1H), 11.27 (s, 1H).

Example 53.

1-([1,3]Dioxolo[4,5-b]pyridin-7-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 53

Phosphorus oxychloride (55.17 µl, 0.59 mmol) was added to a solution of 1-([1,3]dioxolo[4,5-b]pyridin7-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid acids, compound 52c (90 mg, 0.30 mmol), 5-amino

- 114 046082

2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, INT3 (71.62 mg, 0.39 mmol), pyridine (239.34 μl, 2.96 mmol) in CH ₂ Cl ₂ ( 2 ml). The mixture was stirred at room temperature for 1 hour. Water (5 ml) was added to the mixture. Added sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7~8. The mixture was extracted using CH ₂ Cl ₂ (5 ml x3). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (35-65% (v/v) CH3CN and H ₂ O with 0.05 % HCl) and lyophilized to dryness to obtain the title compound (180 mg, 60.6%). LCMS (ESI) m/z M+1: 470.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.31 (s, 2 H), 7.17 (d, J=5.95 Hz, 1H), 7.80 (d, J =5.95 Hz, 1H), 8.31 (s, 2H), 8.55 (s, 1H), 8.84 (d, J=2.43 Hz, 1H), 9.05 (d, J =2.43 Hz, 1H), 11.32 (br. s, 1H).

Example 54.

N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methoxyphenyl)-5-(trifluoromethyl)III-pyrazole -4-carboxamide, compound 54

A. (4-Fluoro-2-methoxyphenyl)hydrazine, compound 54a nA

, connection 54a

To a stirred solution of 4-fluoro-2-methoxyaniline (2000 mg, 14.17 mmol) in 5N HCl (19.84 mL, 99.19 mmol) was added a solution of NaNO ₂ (1466 mg, 21.26 mmol) in 20 mL water at 0°C. After stirring for 30 min, a solution of tin(II) chloride dihydrate (7994 mg, 35.43 mmol) in conc. HCl (3.543 ml, 42.51 mmol). The mixture was stirred at room temperature overnight. The pH of the mixture was adjusted to 10-12 using a 20% aqueous solution of sodium hydroxide. The mixture was extracted using CH ₂ Cl ₂ (5 ml x3). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to give 54a (2000 mg, 90.4%) as a brown solid. TLC: petroleum ether/ethyl acetate=2/1, 4-fluoro-2-methoxyaniline Rf=0.7.

B. Ethyl 1-(4-fluoro-2-methoxyphenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 54b

, connection 54b

(4-Fluoro-2-methoxyphenyl)hydrazine solution, compound 54a (800 mg, 5.12 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1477 mg, 6.15 mmol ), in MeCN (20 ml) was stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 50/50). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 54b (1100 mg, 64.6% yield) as a yellow solid.

C. 1-(4-Fluoro-2-methoxyphenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 54c

HE . , connection 54c

A solution of compound 54b (1100 mg, 3.31 mmol), NaOH (264.84 mg, 6.62 mmol) in THF/H2O (2/1, 10 ml) was stirred at room temperature overnight. 1N HCl solution was added to neutralize the reaction solution. The mixture was extracted using ethyl acetate (30 ml x3). The separated organic layer was dried (MgSO ₄ ), filtered, and the solvent was evaporated under reduced pressure to give compound 54c (950 mg, 87.6% yield) as a yellow solid. LCMS (ESI) m/z M+1: 304.8.

- 115 046082

D. No. (5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methoxyphenyl)-5-(methyl trifluoro) -1H-pyrazole-4-carboxamide, compound 54

Phosphorus oxychloride (106.70 µl, 1.15 mmol) was added to a solution of 1-(4-fluoro-2-methoxyphenyl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 54c (150 mg, 0. 46 mmol), 5-amino-2-(2H1,2,3-triazol-2-yl)nicotinonitrile, INT3 (102.29 mg, 0.55 mmol), pyridine (370.32 µl, 4.58 mmol) in CH ₂ Cl ₂ (5 ml). The mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the mixture. Added sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 ml x 3). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (35-65% (v/v) CH3CN and H ₂ O with 10 mM NH4HCO3 ) and lyophilized to dryness to obtain the title compound (140 mg, 64.1%). LCMS (ESI) m/z M+1: 472.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.81 (s, 3H), 6.99 (td, J=8.38, 2.65 Hz, 1H), 7.26 ( dd, J=10.91, 2.54 Hz, 1H), 7.59 (dd, J=8.71, 6.06 Hz, 1H), 8.32 (s, 2H), 8.43 ( s, 1H), 8.85 (d, J=2.65 Hz, 1H), 9.06 (d, J=2.65 Hz, 1H), 11.21 (s, 1H).

Example 55.

N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(o-tolyl)-5-(trifluoromethyl)-1I Ι-ιshrazo.ι -4 carboxamide, compound 55

A. Ethyl 1-(2,3-Dichloropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 55a

A solution of (2-methylphenyl)hydrazine (200 mg, 1.64 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (589.79 mg, 2.46 mmol), in EtOH (5 ml) was stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 50/50). The desired fractions were collected and the solvent was concentrated under reduced pressure to give compound 55a (300 mg, yield

61.4%) in the form of a yellow solid. LCMS (ESI) m/z M+1: 298.9.

B. 1-(2-Methylphenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 55b

A solution of compound 55a (300 mg, 1.0 mmol), NaOH (80.46 mg, 2.01 mmol) in THF/H2O (2/1, 1 ml) was stirred at room temperature overnight. IN HCl solution was added to neutralize the reaction solution. The mixture was extracted using ethyl acetate (10 ml x3). The separated organic layer was dried (MgSO ₄ ), filtered, and the solvent was evaporated under reduced pressure to give 55b (270 mg, 99.3% yield) as a white solid.

C. No(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(o-tolyl)-5-(trifluoromethyl)-III-pyrazol4- carboxamide, compound 55

- 116 046082

Phosphorus oxychloride (86.24 µl, 0.93 mmol) was added to a solution of 1-(2-methylphenyl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 55b (100 mg, 0.37 mmol), 5-amino-2-(2H1,2,3-triazol-2-yl)nicotinonitrile (82.68 mg, 0.44 mmol), pyridine (299.32 μl, 3.70 mmol) in CH ₂ Cl ₂ ( 5 ml). The mixture was stirred at room temperature for 1 hour. Water (5 ml) was added to the mixture. Added sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7~8. The mixture was extracted using CH ₂ Cl ₂ (5 ml x 3). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC (45-65% (v/v) CH3CN and H ₂ O with 0 .05% HCl) and lyophilized to dryness to give the title compound (38 mg, 23.1%). LCMS (ESI) m/z M+1: 438.9. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 2.01 (s, 3H), 7.39-7.46 (m, 2H), 7.477.51 (m, 1H), 7 .51-7.57 (m, 1H), 8.31 (s, 2H), 8.46 (s, 1H), 8.86 (d, J=2.21 Hz, 1H), 9.07 (d, J=2.20 Hz, 1H), 11.28 (s, 1H).

Example 56.

1-(2-Amino-3-chloropyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl )-III-pyrazole-4-carboxamide, compound 56

A. 2,3-Dichloro-4-hydrazinylpyridine, compound 56a

A solution of 2,3,4-trichloropyridine (2000 mg, 10.96 mmol), hydrazine hydrate (1120.0 mg, 21.93 mmol) in CH3CN (5 ml) was stirred at 100°C for 12 h. The mixture was concentrated at under reduced pressure to obtain compound 56a (2200 mg, >100% yield) as a white solid directly to the next step. TLC: petroleum ether/ethyl acetate=0/100, Rf=0.3 1H NMR (400

MHz, chloroform-d) δ ppm 7.96-8.01 (m, 1H), 6.83-6.88 (m, 1H), 6.30-6.40 (m, 1H), 4.00 (br. s, 2H).

B. Ethyl 1-(2,3-Dichloropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 56b

2,3-Dichloro-4-hydrazinylpyridine solution, compound 56a (2000 mg, 11.24 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT3 (4047.479 mg, 16, 85 mmol), triethylamine (3404.13 mg, 33.70 mmol) in EtOH (20 ml) was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 56b (1500 mg, 33.1% yield) as a yellow solid.

C. Ethyl 1-(2-amino-3-chloropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 56c

- 117 046082

, connection 56c

Ethyl 1-(2,3-dichloropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 57b (1100 mg, 2.73 mmol) was added to the NH2Boc mixture (1596.202 mg, 13.63 mmol). K ₂ CO ₃ (1128.21 mg, 8.18 mmol) in NMP (5 ml). The mixture was stirred at 130°C in a microwave oven for 1 hour. The mixture was diluted with water (200 ml) and extracted with EtOAc (50 ml x 3), washed with brine (100 ml), dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 50:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give compound 56c (1000 mg, 94.5% yield) as a yellow solid. TLC: petroleum ether/ethyl acetate=3/1, Rf=0.4 LCMS (ESI) m/z M+1: 334.9. ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.18-8.20 (m, 1H), 8.08 (d, J=5.51 Hz, 1H), 6.76-6 .79 (m, 1H), 4.92 (us s, 2H), 4.35-4.37 (m, 2H), 1.37-1.40 (m, 3H).

D. Ethyl 1-(2-((di-(tert-butoxycarbonyl))amino)-3-chloropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 56d

Solution of ethyl 1-(2-amino-3-chloropyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 56c (1000 mg 2.58 mmol), (Boc) ₂ O (1123 .79 mg, 5.15 mmol), Et3N (780.10 mg, 7.72 mmol), DMAP (31.41 mg, 0.26 mmol) in CH ₂ Cl ₂ (20 ml) stirred at RT for 12 h. The mixture was diluted with water (100 ml) and extracted using CH ₂ Cl ₂ (100 ml x3). The organic layer was dried (MgSO ₄ ) and concentrated. The residue was purified by column chromatography on silica gel (eluent: petroleum ether/ESAAc=100:0-70:30). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 56d (510 mg, 34.1%) as a white solid. LCMS (ESI) m/z M+1: 535.0.

E. 1-(2-((tert-Butoxycarbonyl)amino)-3-chloropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 56e

A solution of compound 56d (510 mg, 0.88 mmol), LiOH (73.652 mg, 1.755 mmol) in THF (10 ml), MeOH (10 ml) and H ₂ O (10 ml) was stirred at RT for 3 h. 5% KHSO4 was added to the mixture to adjust the pH to 3~4. Water (100 ml) and ethyl acetate (100 ml) were added to the mixture. The organic layer was washed with brine (50 mL), dried over MgSO ₄ and concentrated under reduced pressure to provide compound 56e (370 mg, 877% yield) as a yellow solid directly for the next step. LCMS (ESI) m/z M+H: 406.9.

F. tert-Butyl (3-chloro-4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-2-yl)carbamate, compound 56f

POCl ₃ (235.96 mg, 1.54 mmol) was added to a solution of 1-(2-((tert-butoxycarbonyl)amino)-3chloropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid acids, compound 56e (370 mg, 0.77 mmol), 5-amino-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, INT3 (171.9 mg, 0.92 mmol), pyridine (152.16 mg, 1.92 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at RT for 1 hour. Added to the mixture

- 118 046082 water (50 ml) and CH2C12 (50 ml). The organic layer was washed with saline (50 ml), dried over

MgSO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 56f (200 mg, 34.9% yield) as a white solid. TLC: petroleum ether/ethyl acetate=1/1), LCMS (ESI) m/z M+H: 575.0.

G. 1-(2-amino-3-chloropyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 56

tert-Butyl (3-chloro-4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl) -1H-pyrazol-1-yl)pyridin-2-yl)carbamate, compound 56f (200 mg, 0.27 mmol) was added to HCl/dioxane (20 ml, 4 mol/L). The mixture was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (32-52% (v/v) CH ₃ CN and H ₂ O with 0.05% HCl ) and lyophilized to dryness to obtain the title compound (61.1 mg, 440%) as a white solid. LCMS (ESI) m/z M+1: 474.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.27 (br.s, 1H), 9.07 (d, J=2.65 Hz, 1H), 8.85 (d, J=2.43 Hz, 1H), 8.51 (s, 1H) 8.28 (s, 2H) 7.96 (d, J=5.51 Hz, 1H) 6.96 (br. s, 2 N) 6.88 (d, J=5, 51 Hz, 1H).

Example 57.

1-(2-Amino-3-chloropyridin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl )-III-pyrazole-4-carboxamide, compound 57

A. tert-Butyl (3-chloro-4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)carbamate, compound 57a

POCl ₃ (110.51 mg, 0.72 mmol) was added to a solution of 1-(2-((tert-butoxycarbonyl)amino)-3chloropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid acid, compound 56c (180 mg, 0.36 mmol), 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (84.58 mg, 0. 43 mmol), pyridine (71.26 mg, 0.90 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at RT for 1 hour. Water (50 ml) and CH ₂ Cl ₂ (50 ml) were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 57a (160 mg, 75.5% yield) as a white solid. LCMS (ESI) m/z M-Voc: 483.9.

B. 1-(2-Amino-3-chloropyridin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 57

- 119 046082

tert-Butyl (3-chloro-4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl) -1H-pyrazol-1-yl)pyridin-2-yl)carbamate, compound 57a (150 mg, 0.26 mmol) was added to HCl/dioxane (15 ml, 4 mol/L). The mixture was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (30-60% (v/v) CH ₃ CN and H2O with 0.05% HCl) and lyophilized to dryness to obtain the title compound (30 mg, 22.6%) as a white solid. LCMS (ESI) m/z M+1: 483.9 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.46 (s, 1H), 8.87-8.94 (m, 1H), 8.66-8.73 (m, 2H), 8.16 (s, 2H), 8.10 (d, J=5.29 Hz, 1H), 6.86 (d, J =5.29 Hz, 1H).

Example 58.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,2-difluorobenzo^][1,3]dioxol-4-yl )-5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 58

A. (2,2-Difluorobenzo^][1,3]dioxol-4-yl)hydrazine, compound 58a hn- ^nh =

, connection 58a

A mixture of {Pd(cinnamyl)Cl} ₂ (65.58 mg, 0.13 mmol) and Mor-DalPhos (117.38 mg, 0.25 mmol) in dioxane (20 ml) was deaerated using argon 4 times. The resulting clear yellow solution was stirred at room temperature under argon for 10 minutes. 4-Bromo-2,2-difluorobenzo[1,3]dioxole (600 mg, 2.53 mmol) and t-BuONa (486.08 mg, 5.06 mmol) were added to the mixture and the mixture was deaerated. using argon 4 times. The resulting yellow reaction mixture was stirred at room temperature for 5 min and then treated with hydrazine hydrate (258.65 mg, 5.06 mmol) using a syringe. The reaction mixture was deaerated using argon 4 times. The mixture was then stirred at 50°C under argon for 2 hours. The mixture was filtered and washed with ethyl acetate (50 ml x 3). The filtrate was collected and concentrated to give crude compound 58a (500 mg, 75.3% yield) as a brown solid, which was used directly in the next step. LCMS (ESI) m/z M+Na: 212.9.

B. Ethyl 1-(2,2-difluorobenzo[1,3]dioxol-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 58b

(2,2-Difluorobenzo^][1,3]dioxol-4-yl)hydrazine solution, compound 58a (500 mg, 1.91 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3 -oxobutanoate, INT1 (686.59 mg, 2.86 mmol), triethylamine (577.5 mg, 5.72 mmol) in EtOH (30 ml) was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100:1 to 20:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 58b (410 mg, 49.8% yield) as a yellow oil. LCMS (ESI) m/z M+1: 364.8.

C. 1-(2,2-Difluorobenzo^][1,3]dioxol-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 58c

- 120 046082

OH, connection 58c

Solution of ethyl 1-(2,2-difluorobenzo[1,3]dioxol-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 58b (410 mg, 0.95 mmol), LiOH (79.71 mg, 1.9 mmol) in MeOH (10 ml), THF (10 ml) and H ₂ O (10 ml) was stirred at RT for 3 hours. 5% KHSO4 was added to the mixture to adjust the pH to 3~4. Water (100 ml) and ethyl acetate (100 ml) were added to the mixture. The organic layer was washed with brine (50 mL), dried over MgSO ₄ and concentrated under reduced pressure to give 58c (370 mg, 77.7% yield) as a yellow solid directly for the next step. LCMS (ESI) m/z M+H: 337.0.

D. No(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,2-difluorobenzo^][1,3]dioxol-4 -yl)-5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 58

POCl ₃ (226.2 mg, 1.475 mmol) was added to a solution of 1-(2,2-difluorobenzo[1,3]dioxol-4-yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 58c (370 mg, 0.74 mmol), 5-chloro-6-(2H1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (173.14 mg, 0.89 mmol), pyridine (145.86 mg, 1.844 mmol) in CH ₂ Cl ₂ (20 ml). The mixture was stirred at RT for 3 hours. Water (50 ml) and CH ₂ Cl ₂ (50 ml) were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO ₄ and concentrated under reduced pressure to obtain the crude product, which was purified using preparative HPLC (50-80 (v/v) CH3CN and H ₂ O with 0.05 % HCl) and lyophilized to dryness to obtain the title compound (160 mg, 42.1% yield) as a white solid. LCMS (ESI) m/z M+1: 513.8. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.36 (br.s, 1H), 8.84 (d, J=2.21 Hz, 1H), 8.65 (d, J=2.21 Hz, 1H), 8.59 (s, 1H), 8.16 (s, 2H), 7.71 (dd, J=8.16, 0.88 Hz, 1H), 7, 48-7.56 (m, 1H), 7.40-7.47 (m, 1H).

Example 59.

1-(Benzo^][1,3]dioxol-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 59

A. Benzo[1,3]dioxol-4-ylhydrazine, compound 59a

NH nh ₂ , connection 59a

To a stirred solution of benzo[1,3]dioxol-4-amine (250 mg, 1.44 mmol) in conc. HCl (4 ml) at -5°C, a solution of sodium nitrite (119.2 mg, 1.728 mmol) in water (0.5 ml) was slowly added at a temperature below 0°C. The reaction mixture was stirred at 0°C for 1 hour and a solution of tin(II) chloride dehydrate (649.9 mg, 2.88 mmol) dissolved in conc. HCl (1 ml). The mixture was then stirred at room temperature for 16 hours. The mixture was adjusted to pH 12-14 with 20% aqueous sodium hydroxide solution. The mixture was extracted using ethyl acetate (20 ml x3). The combined organic layers were washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give the crude product (250 mg, 114.1%) as a colorless oil, which was used in the next step without further purification .

B. Ethyl 1-(benzo^][1,3]dioxol-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 59b

- 121 046082

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (250 mg, 1.64 mmol), benzo[1,3]dioxol-4-ylhydrazine, compound 59a (473 mg, 1.97 mmol) and ethanol (20 ml) were stirred at 80°C for 16 h and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give the title compound (200 mg, 37.1%) in the form of a gray solid. LCMS (ESI) m/z M+1: 328.9.

C. 1-(Benzo^][1,3]dioxol-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound

59s

F with

Oh, connection 59c

Sodium hydroxide (48.7 mg, 1.22 mmol) was added to the solution of ethyl 1-(benzo^][1,3]dioxol-4-yl)-5(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 59b (0.2 g, 0.61 mmol) in THF/H2O (3:1, 8 ml).

The mixture was reacted at room temperature for 3 hours. The solvent was evaporated under reduced pressure to pH 5 and extracted using ethyl acetate (30 ml x3). The combined organic layers were washed with brine, dried with anhydrous MgSO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the product (167 mg, purity

95.1%, 86.8%) as a yellow solid. LCMS (ESI) m/z M+1: 300.9.

D. 1-(Benzo^][1,3]dioxol-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 59

1-(Benzo^][1,3]dioxol-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 59c (84.79 mg, 0.27 mmol), 5-amino -2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, INT 2 (50.0 mg, 0.27 mmol), pyridine (106.22 mg, 2.01 mmol), dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (82.36 mg, 0.537 mmol) was added. The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 ml x2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (45-75% (v/v) CH ₃ CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (55 mg, 43.4%). LCMS (ESI) m/z M+1: 468.9. ^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.30 (1H, s), 9.07 (1H, d, J=2.43 Hz), 8.85 (1H, d , J=2.43 Hz), 8.47 (1Н, s) 8.32 (2 Н, s), 7.15-7.23 (1Н, m), 6.99-7.10 (2 Н , m), 6.17 (2 N, s).

Example 60.

1-(2-Chloro-3,4-difluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)- Sh-pyrazole-4-carboxamide, compound 60

A. (2-Chloro-3,4-difluorophenyl)hydrazine, compound 60a

IF—6 /ΗΝΗ ΛΑ ^ΝΗ * F Cl compound 60a

To a stirred solution of 2-chloro-3,4-difluoroaniline (500 mg, 3.057 mmol) in 5 M HCl (4.4 ml) at 0° C., a solution of sodium nitrite (316.4 mg, 5 mmol) in H ₂ O was slowly added (2 ml) at temperatures below 0°C. The reaction mixture was stirred at 0°C for 30 min and a solution of tin(II) chloride dihydrate (1.725 g, 7.643 mmol) dissolved in conc. HCl (0.82 ml). The mixture was stirred at room temperature for 3 hours. The mixture was adjusted to pH 12-14 with 20% aqueous sodium hydroxide solution. The mixture was extracted using ethyl acetate (50 ml x3). Unite

- 122 046082 The raw organic layers were washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product (300 mg, 55.0%) as a yellow oil, which was used in the next step without further clean the eyes. LCMS (ESI) m/z M+1: 178.9.

B. Ethyl 1-(2-chloro-3,4-difluorophenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 60b

, connection 60b

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (0.605 g, 2.520 mmol), (2-chloro-3,4-difluorophenyl)hydrazine, compound 60a (300 mg , 1.680 mmol) and ethanol (20 ml), stirred at 80°C for 16 hours and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to give the title compound (0.77 g, purity 91, 6%, 118.4%) as brown oil. LCMS (ESI) m/z M+1: 354.9.

C. 1-(2-Chloro-3,4-difluorophenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound

60s

Sodium hydroxide (119.33 mg, 2.984 mmol) was added to a solution of ethyl 1-(2-chloro-3,4-difluorophenyl)5-(trifluoromethyl)-N-pyrazole-4-carboxylate, compound 60b (0.77 g, 1.989 mmol) in THF:H ₂ O (3:1, 8 ml). The mixture was reacted at room temperature for 3 hours. The solvent was evaporated under reduced pressure and water (10 ml) was added to the mixture. The mixture was acidified (pH 5) by adding 1 M hydrochloric acid and then extracted using ethyl acetate (30 ml x 3). The combined organic layers were washed with brine, dried with anhydrous MgSO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the product (600 mg, 82.1% purity, 75.9%) as a yellow solid. LCMS (ESI) m/z M+1: 326.9.

D. 1-(2-Chloro-3,4-difluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-III-pyrazole-4-carboxamide, compound 60

1-(2-Chloro-3,4-difluorophenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 60c (200 mg, 0.503 mmol), 5-amino-2-(2H-1, 2,3-triazol-2-yl)nicotinonitrile, INT 3 (93.63 mg, 0.503 mmol), pyridine (0.20 ml, 2.012 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (0 .18 ml, 2.514 mmol). The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 ml x2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC (45-75% (v/v) CH3CN and H ₂ O with 0 .05% HCl) and lyophilized to dryness to give the title compound (127 mg, 50.56%). LCMS (ESI) m/z M+1: 494.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.28 (1H, s), 9.04 (1H, d, J=2.65 Hz), 8.83 (1H, d, J=2.65 Hz), 8.54 (1H, s), 8.30 (2H, s), 7.71-7.84 (2H, m).

Example 61.

1-(2-Chloro-3-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-Spirazole -4-carboxamide, compound 61

A. (2-Chloro-3-phtophenyl)hydrazine, compound 61a

- 123 046082

To a stirred solution of 2-chloro-3-fluoroaniline (1 g, 6.870 mmol) in 5 M HCl (9.6 ml) at 0°C, a solution of sodium nitrite (711 mg, 10 mmol) in H2O (2 ml) was slowly added at below 0°C.

The reaction mixture was stirred at 0°C for 30 min and a solution of tin(II) chloride dehydrate (3.875 g, 17.175 mmol) dissolved in conc. HCl (1.7 ml). The mixture was then stirred at room temperature for 3 hours. The mixture was adjusted to pH 12-14 with 20% aqueous sodium hydroxide solution. The mixture was extracted using ethyl acetate (50 ml*3). The combined organic layers were washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give the crude product (900 mg, 81.6%) as a yellow oil, which was used in the next step without further purification . LCMS (ESI) m/z M+1: 161.0.

B. Ethyl 1-(2-chloro-3-fluorophenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 61b

Solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1.481 g, 6.165 mmol), (2-chloro-3-fluorophenyl)hydrazine, compound 61a (900 mg, 5.605 mmol), in ethanol (20 ml), stirred at 80°C for 16 h, and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate = 100/0-80/20) to give the title compound (1.3 g, 69%) in the form of brown butter. LCMS (ESI) m/z M+1: 337.0.

C. 1-(2-Chloro-3-fluorophenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 61c

OH connection 61c

Sodium hydroxide (231.67 mg, 5.792 mmol) was added to the solution of ethyl 1-(2-chloro-3-fluorophenyl)-5(trifluoromethyl)-N-pyrazole-4-carboxylate, compound 61b (1.3 g, 3.861 mmol ) in THF:H ₂ O=3:1 (12 ml). The mixture was reacted at room temperature for 3 hours. The solvent was evaporated under reduced pressure and water (10 ml) was added to the mixture. The mixture was acidified (pH 5) by adding 1M hydrochloric acid and then extracted using ethyl acetate (30 ml x3). The combined organic layers were washed with brine, dried with anhydrous MgSO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the product (660 mg, 95.9% purity, 53.1%) as a brown oil. LCMS (ESI) m/z M+1: 309.0.

D. 1-(2-Chloro-3-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 61

1-(2-Chloro-3-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 61c (100 mg, 0.311 mmol), 5-amino-2-(2H-1,2, 3-triazol-2-yl)nicotinonitrile, INT 3 (57.89 mg, 0.311 mmol), pyridine (0.13 ml, 1.555 mmol) was dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (0.11) was added ml, 1.244 mmol). The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 ml x2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC (44-74% (v/v) CH ₃ CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (52 mg, 35%). LCMS (ESI) m/z M+1: 476.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.28 (1H, s), 9.04 (1H, d, J=2.43 Hz), 8.82 (1H, d, J=2.43 Hz), 8.53 (1H, s), 8.28 (2H, s), 7.72-7.79 (1H, m), 7.60-7.69 (2H , m).

Example 62.

1-(6-Amino-5-fluoropyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 62

- 124 046082

A. 2-Bromo-3-fluoro-6-hydrazinylpyridine, compound 62a F

Vg

N, connection 62a

2-Bromo-3,6-difluoropyridine (900 mg, 4.64 mmol) was dissolved in MeCN (10 ml) and hydrazine hydrate (474 mg, .279 mmol) was added. The reaction mixture was stirred at 80°C for 16 h, after which it was cooled to room temperature. The reaction mixture was concentrated under reduced pressure to give the crude product (1 g, 38.9% purity, 40.6%) as a black solid, which was used in the next step without further purification. LCMS (ESI) m/z M+1: 208.0.

B. Ethyl 1-(6-bromo-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 62b

2-Bromo-3-fluoro-6-hydrazinylpyridine, compound 62a (1 g, 1.886 mmol) was dissolved in ethanol (20 ml), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT was added 1 (906 mg, 3.772 mmol) and stirred at 60°C for 2 hours and then cooled to room temperature. The combined mixture was concentrated under reduced pressure to give the crude product as a brown oil, which was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate 100/0 to 80/20) to give the title compound (500 mg, purity 68.7%, 47.7%) as a yellow solid. LCMS (ESI) m/z M+1: 384.1.

C. Ethyl 1-(6-((tert-butoxycarbonyl)amino)-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, compound 62c

Ethyl 1-(6-bromo-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 62b (450 mg, 0.809 mmol) and tert-butyl carbamate (189.53 mg , 1.168 mmol) was dissolved in dioxane (15 ml), tris(dibenzylideneacetone)dipalladium(0) (222.23 mg, 0.243 mmol), 4,5-bis(diphenylphosphino)9,9-dimethylxanthene (187.23 mg, 0.324 mmol) and cesium carbonate (527.15 mg, 1.618 mmol) and purged with N2 for 1 min. The reaction mixture was stirred at 80°C for 16 hours and then cooled to room temperature. The combined mixture was filtered through a pad of diatomaceous earth and the layer was washed with ethyl acetate (20 ml x 3). The filtrates were concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate 100/0 to 40/60) to give the title compound (350 mg, purity 73.0 %, 75.5%) in the form of a yellow solid. LCMS (ESI) m/z M+1: 440.9.

D. 1-(6-((tert-Butoxycarbonyl)amino)-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylic acid, compound 62d

- 125 046082

Ethyl 1-(6-((tert-butoxycarbonyl)amino)-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, compound 62d (350 mg, 0.611 mmol), was dissolved in THF ( 12 ml) and water (12 ml). Lithium hydroxide (43.89 mg, 1.833 mmol) was added. The reaction mixture was stirred at 30°C for 16 hours.

The reaction mixture was adjusted to pH 6 using HCl (2 N), extracted using

EtOAc/MeOH (10/1, 20 ml x5). The combined organic layers were dried with Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude title compound (300 mg, 69.3% purity, 87.2%) as a yellow solid. LCMS (ESI) m/z M+1: 413.2.

E. tert-Butyl (6-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)1H- pyrazol-1-yl)-3-fluoropyridin-2-yl)carbamate, compound 62e

1-(6-((tert-Butoxycarbonyl)amino)-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4carboxylic acid, compound 62d (150 mg, 0.266 mmol), 5-chloro- 6-(2H-1,2,3-triazol-2-yl)pyridin-3amine, INT 2 (52.1 mg, 0.266 mmol), pyridine (126.41 mg, 1.598 mmol) was dissolved in CH ₂ Cl ₂ ( 10 ml) and phosphorus oxychloride (122.52 mg, 0.799 mmol) was added. The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the title compound (200 mg, 67.2% purity, 88.8% yield) as a yellow solid. LCMS (ESI) m/z M+1: 467.9.

F. 1 -(6-Amino-5-fluoropyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 62

tert-Butyl (6-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1Hpyrazol-1 -yl)-3-fluoropyridin-2-yl)urea, compound 62e (200 mg, 0.237 mmol), was dissolved in CH ₂ Cl ₂ (5 ml) and trifluoroacetic acid (5 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (37-67% (v/v) CH3CN and _H2Oc 0.05% HCl) and lyophilized to dryness to give the title compound (57 mg, 50.441%). LCMS (ESI) m/z M+1: 467.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.23 (s, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.64 (d, J=2.2 Hz , 1H), 8.37 (s, 1H), 8.18 (s, 2H), 7.62 (dd, J=8.0, 10.5 Hz, 1H), 6.81 (dd, J= 2.5, 8.0 Hz, 1H), 6.76 (br. s, 2H).

Example 63.

1-(6-Amino-5-fluoropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 63

- 126 046082

_H2N

A. tert-Butyl (6-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1 H-pyrazol-1-yl)-3-fluoropyridin-2-yl)carbamate, compound 63 a

HN

B° ^c connection 63a

1-(6-((tert-Butoxycaronyl)amino)-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 62d (150 mg, 0.266 mmol), 5- amino-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, INT3 (52.1 mg, 0.266 mmol), pyridine (126.41 mg, 1.598 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (122.52 mg, 0.799 mmol) was added. The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the title compound (200 mg, 64.1% purity, 86.2% yield) as a yellow solid. LCMS (ESI) m/z M+1: 459.1.

B. 1-(6-Amino-5-fluoropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 63

tert-Butyl (6-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-Spirazol-1 -yl)-3-fluoropyridin-2-yl)urea, compound 63a (200 mg, 0.230 mmol), was dissolved in CH ₂ Cl ₂ (5 ml) and trifluoroacetic acid (5 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (23-53% (v/v) CH3CN and _H2Oc 0.05% HCl) and lyophilized to dryness to give the title compound (35 mg, 32.9%). LCMS (ESI) m/z M+1: 459.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.16 (br.s, 1H), 9.03 (d, J=2.6 Hz, 1H), 8.82 (d, J=2, 4 Hz, 1H), 8.34 (s, 1H), 8.29 (s, 2H), 7.61 (dd, J=8.2, 10.4 Hz, 1H), 6.80 (dd, J=2.5, 8.0 Hz, 1H), 6.74 (s, 2H).

Example 64.

N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)III-pyrazole -4-carboxamide, compound 64

A. 1-(4-Fluoro-2-methylphenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 64a

- 127 046082

Ethyl 1-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 1a (6.4 g, 20.237 mmol) was dissolved in THF (20 ml) and water (20 ml ). Lithium hydroxide (2.423 g, 101.185 mmol) was added. The reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was adjusted to pH 6 using HCl (2 N), extracted using CH ₂ Cl ₂ /MeOH (10/1, 80 ml x5). The combined organic layers were dried with Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude title compound (5.3 g, 96.8% purity, 87.9%) as a yellow solid. LCMS (ESI) m/z M+1: 289.0.

B. ^(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)III -pyrazole-4-carboxamide, compound 64

1-(4-Fluoro-2-methylphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 64a (170.28 mg, 0.591 mmol), 5-amino-2-(2H-1, 2,3-triazol-2-yl)nicotinonitrile, INT3 (100 mg, 0.537 mmol), pyridine (254.92 mg, 3.223 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (247.08 mg) was added , 1.611 mmol). The mixture was stirred at 25°C for 16 hours. Saturated. NaHCO ₃ (30 ml) and extracted using CH ₂ Cl ₂ (50 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (36-66% (v/v) CH3CN and H ₂ O with NH ₄ HCO ₃ ) and lyophilized to dryness to obtain the title compound (74 mg, 30.2%). LCMS (ESI) m/z M+1: 456.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.28 (s, 1H), 9.07 (d, J=2.2 Hz, 1H), 8.85 (d, J=2.2 Hz , 1H), 8.47 (s, 1H), 8.31 (s, 2H), 7.55 (dd, J=5.3, 8.6 Hz, 1H), 7.40 (dd, J= 2.4, 9.5 Hz, 1H), 7.27 (dt, J=2.8, 8.4 Hz, 1H), 2.01 (s, 3H).

Following the procedure described in Example 6 above, selecting and replacing appropriate reagents, starting materials and purification methods and adjusting reaction temperatures, times and other variables or parameters as necessary or desired, which should be understandable to those skilled in the art, the following compounds were prepared (examples 65-70).

Example 65.

1-(3-Chloro-4-methoxypyridin-2-yl)-N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 65

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.22 (br.s, 1H), 8.78-8.84 (m, 1H), 8.60-8.65 (m, 1H), 8.528.54 (m, 1H), 8.50 (d, J=5.73 Hz, 1H), 8.17 (s, 2H), 7.54 (d, J=5.95 Hz , 1H), 4.06 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 498.9.

Example 66.

1-(3-Chloro-4-methoxypyridin-2-yl)-N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 66

- 128 046082

1H NMR (400 MHz, DMSO-d6) δ ppm 11.29 (br.s, 1H), 9.05 (d, J=2.65 Hz, 1H), 8.84 (d, J= 2.65 Hz, 1H), 8.54 (s, 1H), 8.50 (d, J=5.73 Hz, 1H), 8.29 (s, 2H), 7.54 (d, J =5.95 Hz, 1H), 4.06 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 489.9.

Example 67.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,5-dichloropyridin-4-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 67

C.I.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (s, 2H), 8.21 (s, 1H), 8.28 (s, 1H), 8.49 (br.s , 1H), 8.73 (d, J=1.54 Hz, 1H), 8.75 (s, 2H). LC-MS: (ES, m/z): [M+1] ⁺ 502.8.

Example 68.

1-(5-Chloro-2-methylpyridin-4-yl)J-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 68

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.44 (s, 1H), 8.90-9.03 (m, 2 H), 8.77 (s, 2 H), 8 .28 (s, 2H), 7.90 (s, 1H), 2.69 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 482.9.

Example 69.

1-(3-Chloro-2-methylpyridin-4-yl)J-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 69

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.35 (1H, br.s), 8.86-8.93 (1H, m), 8.65-8.74 (3H, m), 8.19 (2H, s), 7.77 (1H, d, J=5.02 Hz), 2.71 (3H, s). LC-MS: (ES, m/z): [M+1] ⁺ 493.0.

Example 70.

1-(5-Chloro-2-methylpyridin-4-yl)J-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 70

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.36 (s, 1H), 9.04-9.11 (m, 1H), 8.80-8.88 (m, 2H ), 8.63 (s, 1H), 8.29 (s, 2H), 7.79 (s, 1H), 2.55-2.58 (m, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 473.9.

Following the procedure described in Example 50 above, selecting and replacing appropriate reagents, starting materials and purification methods and adjusting reaction temperatures, times and other variables or parameters as necessary or desired, which should be understandable to those skilled in the art, the following compounds were prepared (Example 71-104).

Example 71.

1-(2-Chloro-4-fluoro-3-methylphenyl)F-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 71

- 129 046082

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.16-11.26 (m, 1H), 11.21 (br. s, 1H), 8.82 (d, J=2, 21 Hz, 1H), 8.79-8.84 (m, 1H), 8.63 (d, J=2.21 Hz, 1H), 8.50 (s, 1H), 8.16 (s, 2 N), 7.70 (dd, J=8.82, 5.51 Hz, 1H), 7.45 (t, J=8.82 Hz, 1H), 2.34 (d, J=2, 21 Hz, 2H), 2.31-2.38 (m, 1H), 1.20 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 499.9.

Example 72.

1-(2-Chloro-4-fluoro-3-methylphenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 72

1H NMR (400 MHz, DMSO-d6) δ ppm 11.32 (br.s, 1H), 9.06 (d, J=2.43 Hz, 1H), 8.86 (d, J= 2.43 Hz, 1H), 8.53 (s, 1H), 8.29 (s, 2H), 7.71 (dd, J=8.71, 5.40 Hz, 1H), 7.46 (t, J=8.93 Hz, 1H), 2.35 (d, J=2.20 Hz, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 490.9.

Example 73.

1-(2-Chloro-3,4-difluorophenyl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 73

1H NMR (400 MHz, DMSO-d6) δ ppm 11.22 (1H, s), 8.81 (1H, d, J=2.20 Hz), 8.63 (1H, d, J= 2.21 Hz), 8.54 (1H, s), 8.17 (2H, s), 7.72-7.84 (2H, m). LC-MS: (ES, m/z): [M+1] ⁺ 503.8.

Example 74.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-(methylsulfonyl)phenyl)-5(trifluoromethyl)-III-pyrazole -4-carboxamide, compound 74

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.75 (d, J=2.4 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H), 8.18 -8.07 (m, 4H), 7.94 (s, 2H), 7.78 (d, J=5.7 Hz, 2H), 3.13 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 511.9.

Example 75.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methyl-4-(methylsulfonyl)phenyl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 75

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.76 (d, J=2.2 Hz, 1H), 8.51 (d, J=2.2 Hz, 1H), 8.18 (s, 1H), 8.03 (s, 1H), 7.99 (s, 1H), 7.98-7.91 (m, 3H), 7.50 (d, J=7.9 Hz, 1H), 3.13 (s, 3H), 2.19 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 525.9.

Example 76.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-isopropylphenyl)-5-(trifluoromethyl)-Spirazol-4-carboxamide , connection 76

- 130 046082

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 (t, J=6.39 Hz, 6H), 2.40 (q, J=6.84 Hz, 1H), 7.237, 26 (m, 1H), 7.31-7.36 (m, 1H), 7.48-7.52 (m, 1H), 7.53-7.59 (m, 1H), 7.88 ( s, 1H), 7.96 (s, 2H), 8.13 (s, 1H), 8.51 (d, J=2.43 Hz, 1H), 8.79 (d, J=2, 43 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 475.9.

Example 77.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2,3-dimethylphenyl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 77

1H NMR (400 MHz, DMSO-d6) δ ppm 11.20 (1H, s), 8.81 (1H, d, J=2.20 Hz), 8.63 (1H, d, J= 2.21 Hz), 8.43 (1H, s) 8.17 (2H, s), 7.36 (1H, dd, J=8.71, 4.96 Hz), 7.18-7, 25 (1H, m), 2.22 (3H, d, J=1.76 Hz), 1.86 (3H, s). LC-MS: (ES, m/z): [M+1] ⁺ 479.9.

Example 78.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-difluorophenyl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 78

1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (br. d, J=9.48 Hz, 1H), 7.64-7.73 (m, 1H), 7.89 ( ddd, J=10.42, 7.22, 2.65 Hz, 1H), 8.16 (s, 2H), 8.42 (s, 1H), 8.61 (d, J=2.21 Hz, 1H), 8.80 (d, J=2.21 Hz, 1H), 11.21 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 469.9.

Example 79.

1-(2-Chloro-5-fluorophenyl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 79

1H NMR (400 MHz, DMSO-d6) δ ppm 11.20 (s, 1H), 8.83 (d, J=2.21 Hz, 1H), 8.64 (d, J=2, 21 Hz, 1H), 8.54 (s, 1H), 8.17 (s, 1H), 8.13-8.21 (m, 1H), 7.93 (dd, J=8.38, 3 .09 Hz, 1H), 7.84 (dd, J=9.04, 5.29 Hz, 1H), 7.62 (td, J=8.60, 3.09 Hz, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 485.9.

Example 80.

1-(2-Chloro-5-fluorophenyl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-Spirazole -4-carboxamide, compound 80

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.36 (br.s, 1H), 11.22-11.51 (m, 1H), 9.08 (d, J=2, 43 Hz, 1H), 8.87 (d, J=2.43 Hz, 1H), 8.59 (s, 1H), 8.29 (s, 2H), 7.93 (dd, J=8 .49, 2.98 Hz, 1H), 7.83 (dd, J=8.93, 5.40 Hz, 1H), 7.61 (td, J=8.60, 3.09 Hz, 1H) , 2.05 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 476.9.

Example 81.

K-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methoxyphenyl)-5-(trifluoromethyl)- 131 046082

1H-pyrazole-4-carboxamide, compound 81

1H NMR (400 MHz, DMSO-d6) δ ppm 3.81 (s, 3H), 6.98 (td, J=8.49, 2.65 Hz, 1H), 7.25 (dd, J=10.91, 2.54 Hz, 1H), 7.59 (dd, J=8.71, 6.06 Hz, 1H), 8.19 (s, 2H) 8.43 (s, 1H ), 8.65 (d, J=2.21 Hz, 1H), 8.83 (d, J=2.21 Hz, 1H), 11.16 (br. s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 481.9.

Example 82.

-(2-Chloro-3-fluorophenyl)-X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide, compound 82

1H NMR (400 MHz, methanolM4) δ ppm 8.77 (1H, d, J=2.21 Hz), 8.68 (1H, d, J=2.43 Hz), 8.34 (1H , s), 8.02 (2 N, s), 7.54-7.62 (2 N, m), 7.43-7.51 (1 H, m). LC-MS: (ES, m/z): [M+1] ⁺ 485.9.

Example 83.

-(2-Bromo-4-fluorophenyl)-X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide, compound 83.

1H NMR (400 MHz, DMSO-d6) δ ppm 7.51 (td, J=8.49, 2.87 Hz, 1H), 7.84 (dd, J=8.82, 5.51 Hz, 1H), 7.93 (dd, J=8.27, 2.76 Hz, 1H), 8.16 (s, 2H), 8.50 (s, 1H), 8.63 (d, J=2.21 Hz, 1H), 8.81 (d, J=2.21 Hz, 1H), 11.19 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 531.8

Example 84.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2,3-dimethylphenyl)-5(trifluoromethyl)- Sh-pyrazole-4-carboxamide, compound 84

1H NMR (400 MHz, DMSO-d ₆ ) d ppm 11.25 (1H, s) 9.04 (1H, d, J=2.43 Hz) 8.83 (1H, d, J=2 ,43 Hz) 8.43 (1H, s) 8.29 (2H, s) 7.37 (1H, dd, J=8.82, 4.85 Hz) 7.22 (1H, t, J= 8.93 Hz) 2.22 (3H, d, J=1.76 Hz) 1.86 (3H, s). LC-MS: (ES, m/z): [M+1] ⁺ 471.0.

Example 85.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-cyano-4-fluorophenyl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 85

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.78 (t, J=8.93 Hz, 1H) 8.02-8.08 (m, 1H) 8.16 (s, 2 H) 8.36 (dd, J=5.51, 2.65 Hz, 1H) 8.46 (s, 1H) 8.62 (d, J=2.43 Hz, 1H) 8.80 (d, J=2.43 Hz, 1H) 11.21 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 476.9.

- 132 046082

Example 86.

1-(3-Cyano-4-fluorophenyl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide, compound 86

N

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.78 (t, J=8.93 Hz, 1H) 8.02-8.08 (m, 1H) 8.28 (s, 2H ) 8.37 (dd, J=5.62, 2.76 Hz, 1H) 8.45 (s, 1H) 8.82 (d, J=2.65 Hz, 1H) 9.03 (d, J =2.43 Hz, 1H) 11.25 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 467.9.

Example 87.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-fluoro-4-methylpyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 87

^1H NMR (400 MHz, DMSO-d6) δ ppm 11.20 (br.s, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.63 (d, J =2.2 Hz, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 8.16 (s, 2H), 7.43 (s, 1H), 2.10 (s , 3H). LC-MS: (ES, m/z): [M+1] ⁺ 467.0.

Example 88.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methylpyridin-3-yl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide, compound 88

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.20 (s, 3H) 7.47-7.56 (m, 1H) 7.52 (dd, J=7.72, 4, 85 Hz, 1H) 8.02 (br.d, J=7.72 Hz, 1H) 8.29 (s, 2H) 8.58 (s, 1H) 8.71 (d, J=3.97 Hz , 1H) 8.87 (d, J=2.21 Hz, 1H) 9.10 (d, J=2.20 Hz, 1H) 11.39-11.49 (m, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 439.9.

Example 89.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1-(2,3,4-trifluorophenyl)-1Hpyrazole -4-carboxamide, compound 89

J\

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.54-7.56 (m, 1H) 7.58-7.80 (m, 2H) 8.12-8.21 (m, 1H) 8.12-8.20 (m, 1H) 8.17 (s, 1H) 8.53 (s, 1H) 8.62 (d, J=2.21 Hz, 1H) 8.80 (d , J=2.20 Hz, 1H) 11.26 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 487.8.

Example 90.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-chloro-6-fluorophenyl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 90

Cl

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.58-7.71 (m, 2H) 7.74-7.84 (m, 1H) 8.17 (d, J=1, 10 Hz, 2H) 8.59 (s, 1H) 8.62 (s, 1H) 8.81 (s, 1H) 11.28 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 485.9.

Example 91.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-methylpyridin-3-yl)-5-(trifluoromethyl)- 133 046082

1H-pyrazole-4-carboxamide, compound 91

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.10 (s, 3H) 7.61 (d, J=5.07 Hz, 1H) 8.31 (s, 2H) 8.59 (s, 1H) 8.67-8.73 (m, 2H) 8.88 (d, J=2.43 Hz, 1H) 9.11 (d, J=2.65 Hz, 1H) 11.39 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 440.0.

Example 92.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-fluoro-6-methylphenyl)-5-(trifluoromethyl)-1H pyrazole-4-carboxamide, compound 92

^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.31 (br.s, 1H) 8.85 (d, J=1.54 Hz, 1H) 8.66 (d, J= 1.98 Hz, 1H) 8.59 (s, 1H) 8.18 (s, 2H) 7.60 (td, J=8.10, 5.84 Hz, 1H) 7.31-7.43 ( m, 2H) 2.03-2.08 (m, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 465.9.

Example 93.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-fluorophenyl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 93

1H NMR (400 MHz, DMSO-d6) δ ppm 11.27 (br.s, 1H) 8.84 (d, J=1.98 Hz, 1H) 8.67 (s, 1H) 8, 64 (d,

J=1.98 Hz, 1H) 8.15 (s, 2H) 7.94 (d, J=8.16 Hz, 2H). LC-MS: (ES, m/z): [M+1] ⁺ 521.8.

Example 94.

1-(2-Chloro-4,6-difluorophenyl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 94

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.43 (s, 1H) 8.85 (d, J=1.98 Hz, 1H) 8.62-8.71 (m, 2H ) 8.16 (s,

2H) 7.77-7.86 (m, 2H). LC-MS: (ES, m/z): [M+1] ⁺ 503.8.

Example 95.

1-(6-Chloro-2-methylpyridin-3-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 95

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.27 (s, 1H) 9.04 (d, J=2.43 Hz, 1H) 8.83 (d, J=2.43 Hz, 1H) 8.52 (s, 1H) 8.29 (s, 2H) 8.12 (d, J=8.38 Hz, 1H) 7.64 (d, J=8.38 Hz, 1H) 2.18 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 473.9.

Example 96.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)-Spirazole -4-carboxamide, compound 96

- 134 046082

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.95 (s, 3H) 7.39-7.46 (m, 1H) 7.48-7.54 (m, 2H) 8, 16 (s, 2H) 8.46 (s, 1H) 8.63 (d, J=2.43 Hz, 1H) 8.81 (d, J=2.43 Hz, 1H) 11.17 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 465.9.

Example 97.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1-(2,3,4-trifluorophenyl)-Spirazol -4-carboxamide, compound 97

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.54-7.82 (m, 2H) 8.29 (s, 2H) 8.53 (s, 1H) 8.82 (d, J=2.65 Hz, 1H) 9.04 (d, J=2.43 Hz, 1H) 11.32 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 478.9.

Example 98.

1-(2-Chloro-6-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-Spirazole -4-carboxamide, compound 98

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.57-7.70 (m, 2H) 7.74-7.81 (m, 1H) 8.29 (s, 2H) 8, 58 (s, 1H) 8.82 (d, J=2.65 Hz, 1H) 9.04 (d, J=2.43 Hz, 1H) 11.31 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 476.9.

Example 99.

1-(2-Chloro-4,6-difluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl)- Sh-pyrazole-4-carboxamide, compound 99

1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (br.s, 1H) 9.07 (d, J=2.65 Hz, 1H) 8.84 (d, J=2, 43 Hz, 1H) 8.65 (s, 1H) 8.28 (s, 2H) 7.77-7.86 (m, 2H). LC-MS: (ES, m/z): [M+1] ⁺ 494.9.

Example 100.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-cyclopropylphenyl)-5-(trifluoromethyl)-Spirazol-4-carboxamide , connection 100

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.24 (1H, s) 9.08 (1H, d, J=2.26 Hz) 8.86 (1H, d, J=2 ,26 Hz) 8.49 (1H, s) 8.32 (2H, s) 7.53 (1H, br. t, J=7.28 Hz) 7.40-7.47 (1H, m) 7.32-7.40 (1H, m) 7.12 (1H, br. d, J=7.78 Hz) 1.19-1.30 (1H, m) 0.85 (2 N, br. d, J=8.03 Hz) 0.77-0.84 (1H, m) 0.63 (1H, br. s). LC-MS: (ES, m/z): [M+1]+ 465.0.

Example 101.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-fluoro-6-methylphenyl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide, compound 101

- 135 046082

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.42 (br.s, 1H) 9.06-9.14 (m, 1H) 8.87 (s, 1H) 8.63 ( br. s, 1H) 8.28 (s, 2H) 7.58 (td, J=8.05, 5.73 Hz, 1H) 7.30-7.40 (m, 2H) 2.03 (s , 3H). LC-MS: (ES, m/z): [M+1]+ 456.9.

Example 102.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-fluorophenyl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 102

1H NMR (400 MHz, DMSO-d6) δ ppm 11.34 (br.s, 1H) 9.07 (s, 1H) 8.84 (d, J=2.21 Hz, 1H) 8, 67 (s, 1H) 8.28 (s, 2H) 7.94 (d, J=8.38 Hz, 2H). LC-MS: (ES, m/z): [M+1] ⁺ 510.8.

Example 103.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide, compound 103

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.95 (s, 3H) 7.43 (br.t, J=8.60 Hz, 1H) 7.47-7.57 (m , 2H) 8.28 (s, 2H) 8.46 (s, 1H) 8.83 (d, J=1.54 Hz, 1H) 9.04 (d, J=2.43 Hz, 1H) 11 .22 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 457.0.

Example 104.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-difluorophenyl)-5-(trifluoromethyl)-III pyrazol- 4-carboxamide, compound 104

1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (br. d, J=8.82 Hz, 1H), 7.64-7.74 (m, 1H), 7.90 ( ddd,

J=10.31, 7.33, 2.65 Hz, 1H), 8.28 (s, 2H), 8.42 (s, 1H), 8.82 (d, J=2.43 Hz, 1H ), 9.03 (d, J=2.43 Hz, 1H), 11.26 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 460.9.

Following the procedure described in Example 3 above, selecting and replacing appropriate reagents, starting materials and purification methods and adjusting reaction temperatures, times and other variables or parameters as necessary or desired, which should be understandable to those skilled in the art, the following compounds (105-117) were obtained.

Example 105.

1-(3-Chloro-5-fluoropyridin-2-yl)-X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl )-III-pyrazole-4-carboxamide, compound 105

C.I.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.17 (br. s, 2H), 8.60 (br. d, J=19.62 Hz, 3H), 8.68-8 .87 (m,

2H), 11.25 (br. s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 486.8.

- 136 046082

Example 106.

1-(3-Chloro-5-fluoropyridin-2-yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 106

^1H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (s, 2H), 8.57 (s, 1H), 8.61 (dd, J=7.83, 2.54 Hz , 1H), 8.76 (d, J=2.65 Hz, 1H), 8.83 (d, J=2.43 Hz, 1H), 9.05 (d, J=2.43 Hz, 1H ), 11.31 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 477.9.

Example 107.

-(2-Chloro-4-fluorophenyl)-N-(5-chloro-6-(2H-1,2,3 -triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-1Hpyrazol- 4-carboxamide, compound 107

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.52 (td, J=8.49, 2.87 Hz, 1H), 7.84-7.93 (m, 2H), 8.19 (s, 2H), 8.54 (s, 1H), 8.66 (d, J=2.21 Hz, 1H), 8.84 (d, J=2.20 Hz, 1H), 11.23 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 485.9.

Example 108.

1-(3-Chloro-4-fluorophenyl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 108

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.57-7.74 (m, 2H), 7.94-8.06 (m, 1H), 8.16 (s, 2H ), 8.43 (s, 1H), 8.62 (d, J=1.76 Hz, 1H), 8.81 (d, J=1.76 Hz, 1H), 11.21 (s, 1H ). LC-MS: (ES, m/z): [M+1] ⁺ 485.9.

Example 109.

1-(3-Chloro-4-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 109

^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.65-7.68 (m, 1H), 7.65-7.68 (m, 1H), 8.00 (br. d , J=6.17 Hz, 1H), 8.29 (s, 2H), 8.43 (s, 1H), 8.83 (d, J=2.43 Hz, 1H), 9.04 (d , J=2.65 Hz, 1H), 11.25 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 476.9.

Example 110.

1-(2-Chloro-4-cyanophenyl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 110

^1H NMR (400 MHz, DMSO-d6) δ ppm 11.23 (s, 1H), 8.84 (d, J=2.2 Hz, 1H), 8.65 (d, J=2 .2 Hz, 1H), 8.60 (s, 1H), 8.48 (d, J=1.8 Hz, 1H), 8.19 (s, 2H), 8.17-8.13 (m , 1H), 8.09-8.06 (m, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 492.9.

Example 111.

- 137 046082 \-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2,4-difluorophenyl)-5-(trifluoromethyl)- 1Hpyrazole-4-carboxamide, compound 111

^1H NMR (400 MHz, METHANOLM4) δ ppm 9.06 (1H, d, J=2.51 Hz), 8.90 (1H, d, J=2.51 Hz), 8.35 ( 1H, s), 8.16 (2H, s), 7.70 (1H, td, J=8.72, 5.65 Hz), 7.37 (1H, ddd, J=10.10, 8 .72, 2.76 Hz), 7.19-7.30 (1H, m). LCMS: (ES, m/z): [M+1]+ 531.8.

Example 112.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-3-methylpyridin-2-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 112

^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.24 (br.s, 1H), 8.82 (d, J=2.20 Hz, 1H), 8.64 (d, J=2.20 Hz, 1H), 8.46-8.54 (m, 2H), 8.17 (s, 2H), 8.06 (dd, J=8.93, 2.54 Hz, 1H ), 2.15 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 466.9.

Example 113.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-3-methylpyridin-2-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 113

1H NMR (400 MHz, DMSO-d6) δ ppm 11.28 (s, 1H), 9.05 (d, J=2.43 Hz, 1H), 8.84 (d, J=2, 43 Hz, 1H), 8.49-8.53 (m, 2H), 8.29 (s, 2H), 8.06 (dd, J=8.93, 2.32 Hz, 1H), 2, 15 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 458.0.

Example 114.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 114

1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (td, J=8.43, 2.54 Hz, 1H) 7.97 (dd, J=8.60, 4.85 Hz , 1H) 8.05 (dd, J=8.82, 2.65 Hz, 1H) 8.19 (s, 2H) 8.53 (s, 1H) 8.66 (d, J=2.21 Hz , 1H) 8.85 (d, J=2.21 Hz, 1H) 11.21 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 519.9.

Example 115.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 115

1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (td, J=8.38, 2.87 Hz, 1H) 7.99 (dd, J=8.82, 4.85 Hz , 1H) 8.05 (dd, J=8.49, 2.98 Hz, 1H) 8.32 (s, 2H) 8.53 (s, 1H) 8.86 (d, J=2.43 Hz , 1H) 9.07 (d, J=2.43 Hz, 1H) 11.25 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 510.9.

- 138 046082

Example 116.

1-(2-Chlorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-Spirazol-4-carboxamide , connection 116

^1H NMR (400 MHz, DMSO-d6) δ ppm 11.23 (1H, s) 9.04 (1H, d, J=2.43 Hz) 8.82 (1H, d, J=2 ,43 Hz) 8.49 (1H, s) 8.28 (2 H, s) 7.71-7.78 (2 N, m) 7.67 (1H, t, J=7.72 Hz) 7 .54-7.61 (1H, m). LC-MS: (ES, m/z): [M+1]+ 458.9.

Example 117.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,4-difluorophenyl)-5-(trifluoromethyl)-1Hpyrazol-4 -carboxamide, compound 117

^1H NMR (400 MHz, METHANOL) d ppm 8.80 (1H, d, J=2.51 Hz), 8.72 (1H, d, J=2.26 Hz) 8.34 (1H , s), 8.06 (2H, s), 7.70 (1H, td, J=8.66, 5.52 Hz), 7.37 (1H, ddd, J=10.04, 8, 66, 2.64 Hz), 7.19-7.30 (1H, m). LCMS: (ES, m/z): [M+1] ⁺ 469.9.

Example 118.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(1-methoxyethyl)phenyl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide, compound 118

A. 1-Bromo-2-(1-methoxyethyl)benzene, compound 118a

\, connection 118a

To a mixture of 1-(2-bromophenyl)ethanol (200 mg, 0.995 mmol) in THF (4 mL) cooled in an ice water bath, NaH (47.74 mg, 1.194 mmol) was added. The mixture was stirred at 0°C for 0.5 h. MeI (211.79 mg, 1.492 mmol) was then added to the mixture. The resulting mixture was stirred at room temperature for 1 hour. Water (20 ml) was added to the mixture. The mixture was extracted with ethyl acetate (30 ml). The combined organic layers were dried with Na ₂ SO ₄ then filtered. The filtrates were concentrated under reduced pressure to give a crude brown oil. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 80/20). The eluent was collected and the solvent was evaporated under reduced pressure to give 1-bromo-2-(1-methoxyethyl)benzene, compound 118a (200 mg, yield: 93.5%) as a light yellow oil.

B. (2-(1-methoxyethyl)phenyl)hydrazine, compound 118b

x, connection 118b

A mixture of {Pd(cinnamyl)Cl} ₂ (24.087 mg, 0.046 mmol) and Mor-DalPhos (43.11 mg, 0.093 mmol) in dioxane (10 ml) was deaerated using argon 4 times. The resulting clear yellow solution was stirred at room temperature under argon for 10 minutes. 1-Bromo-2-(1-methoxyethyl)benzene, compound 118a (200 mg, 0.930 mmol), and t-BuONa (178.73 mg, 1.860 mmol) were added to the mixture and the mixture was deaerated using argon 4 times. The resulting yellow reaction mixture was subsequently treated with NH ₂ NH ₂ .H ₂ O (95.0 mg, 1.860 mmol) using a syringe. The reaction mixture was deaerated using argon 4 times. Then the mixture

- 139 046082 was stirred at 50°C under argon for 2 hours. The mixture was filtered and washed with CH ₂ Cl ₂ /MeOH (20/1, 20 ml). The filtrate was collected and concentrated to give the crude product, compound 118b (154 mg, yield: 100%), which was directly used in the next step.

C. Ethyl 1-(2-(1-methoxyethyl)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 118c

, connection 118c

Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (356.03 mg, 1.482 mmol) was added to a solution of (2-(1-methoxyethyl)phenyl)hydrazine, compound 118b (154 mg, 0.926 mmol) in EtOH (5 ml). The mixture was stirred at 80°C overnight. The mixture was concentrated to obtain the crude product. The crude product was purified using a silica gel column (eluent: petroleum ether/ethyl acetate=3:1-1/1). The pure fractions were collected and evaporated to dryness to give ethyl 1-(2-(1methoxyethyl)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 118c, as a yellow oil (50 mg, yield: 15. 8%).

D. 1-(2-(1-Methoxyethyl)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 118d

'x, connection 118d

To a mixture of ethyl 1-(2-(1-methoxyethyl)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 118c (50 mg, 0.146 mmol), in MeOH (1 ml) and water (1 ml) LiOH (12.26 mg, 0.292 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was evaporated to dryness. Water/EtOAc (2 ml/2 ml) was added to the residue. The pH of the mixture was adjusted to 5 with HCl (1M injector). The organic layer was evaporated to dryness to give 1-(2-(1-methoxyethyl)phenyl)-5-(trifluoromethyl)-III-pyrazole-4carboxylic acid, compound 118d (35 mg , yield: 76.2%) as a yellow solid.

E. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(1-methoxyethyl)phenyl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide, compound 118

\

POCl ₃ (34.15 mg, 0.223 mmol) was added to a mixture of 1-(2-(1-methoxyethyl)phenyl)-5-(trifluoromethyl)-Spirazole-4-carboxylic acid, compound 118d (35 mg, 0.111 mmol), 5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin-3-amine, INT2 (21.79 mg, 0.111 mmol), and pyridine (44.05 mg, 0.557 mmol) in CH ₂ Cl ₂ (1 ml). The reaction mixture was stirred at 20°C for 1 hour. Saturated solution was added to the mixture. NaHCO ₃ solution (20 ml). The mixture was extracted with ethyl acetate (30 ml). The combined organic layers were dried with Na ₂ SO ₄ then filtered. The filtrates were concentrated under reduced pressure to give a crude brown oil. The residue was purified by preparative HPLC (50-80% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide) and lyophilized to dryness to give the title compound (19.5 mg, yield: 35. 5%). Ή NMR (400 MHz, chloroform-d) δ ppm 8.77 (d, J=2.2 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.11 (br. s, 2H), 7.94 (s, 2H), 7.72-7.57 (m, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.27 ( s, 1H), 4.09-3.72 (m, 1H), 3.10 (br. s, 3H), 1.48-1.24 (m, 3H). LC-MS: (ES, m/z): [M+1]+ 491.9.

Example 119.

1-(4-Amino-3-chloropyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 119

- 140 046082

A. 4,4-tert-Butylcarbamate-2,3-dichloropyridin-4-amine, compound 119a

C.I.

V° ^s , connection 119a

Solution of 2,3-dichloropyridin-4-amine (900 mg, 5.521 mmol), (Boc) ₂ O (3012.52 mg, 13.803 mmol), Et ₃ N (2230.61 mg, 22.085 mmol), DMAP (67, 36 mg, 0.552 mmol) in CH ₂ Cl ₂ was stirred at RT for 12

h. The mixture was diluted with water (100 ml) and extracted using CH ₂ Cl ₂ (100 ml x3). The organic layers were dried (MgSO ₄ ), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether/ESAAc = 100:070:30). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 4,4-tert-butylcarbamate-2,3-dichloropyridin-4-amine, compound 119a (1600 mg, 77.7% yield) as a white solid. LCMS (ESI) m/z M+1: 362.8.

B. tert-Butyl (3-chloro-2-hydrazinylpyridin-4-yl)carbamate, compound 119b

A solution of 4,4-tert-butylcarbamate-2,3-dichloropyridin-4-amine, compound 119a (1600 mg, 4.288 mmol), hydrazine hydrate (438.09 mg, 8.576 mmol) in CH3CN (10 ml) was stirred at 100° C in the microwave for 1 hour. The mixture was concentrated under reduced pressure to give tert-butyl (3-chloro-2-hydrazinylpyridin-4-yl)carbamate, compound 119b (1300 mg, >100% yield), as a white solid. directly to the next stage.

C. Ethyl 1-(4-((tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, compound 119c

F ₃ C ?

N .А,·'' 'сА· Qv

BocHN cl ₅ connection 119c

Tert-Butyl (3-chloro-2-hydrazinylpyridin-4-yl)carbamate solution, compound 119b (1300 mg, 5.025 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 ( 1810.3 mg, 7.538 mmol), Et ₃ N (1522.6 mg, 15.075 mmol) in EtOH (30 ml) was stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to obtain 450 mg of crude product as a yellow solid, which was purified by preparative HPLC (55-85% (v/v) CH3CN and _H2O with 0.05% ammonium hydroxide) and lyophilized to dryness to give ethyl 1-(4-((tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 119c (150 mg, yield 6.9%) as a yellow solid.

D. 1-(4-((tert-Butoxycarbonyl)amino)-3-chloropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 119d ^F X 1 CH?

BocHN Cl _s compound 119d

Solution of ethyl 1-(4-((tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 119c (150 mg, 0.345 mmol), LiOH .H ₂ O (28.95 mg, 0.690 mmol) in MeOH (10 ml), THF (10 ml) and water (10 ml) was stirred at RT for 3 hours. 5% KHSO4 was added to the mixture to adjust the mixture to pH 3-4. Water (100 ml) and ethyl acetate (100 ml) were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give 1-(4-((tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)5-( trifluoromethyl)-N-pyrazole-4-carboxylic acid, compound 119d (130 mg, 87.5% yield) as a yellow solid, which was directly used in the next step. LCMS (ESI) m/z M+H: 406.9.

- 141 046082

E. tert-Butyl (3-chloro-2-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-1H-pyrazol-1-yl)pyridin-4-yl)carbamate, compound 119e

BocHN, compound 119e

POCl ₃ (71.19 mg, 0.464 mmol) was added to a solution of 1-(4-((tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid acid, compound 119d (100 mg, 0.232 mmol), 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (54.49 mg, 0.279 mmol), pyridine (45.90 mg, 0.58 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at rt for 2 hours. Water (50 ml) and CH ₂ Cl ₂ (50 ml) were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give tert-butyl (3-chloro-2-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)carbamoyl)-5-(trifluoromethyl)1H-pyrazol-1-yl)pyridin-4-yl)carbamate, compound 119e (60 mg, 44.2% yield) as a white solid. LCMS (ESI) m/z M+Na: 606.0.

F. 1-(4-Amino-3-chloropyridin-2-yl)-A-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 119 tert-Butyl (3-chloro-2-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl )pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-III-pyrazol-1-yl)pyridin-4-yl)carbamate, compound 119e (60 mg 0.103 mmol), was added to HCl/dioxane (10 ml, 4 mol/l). The mixture was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (32-62 (v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to obtain the title compound 119 (23.4 mg, 43.8%) as a white solid. ^1H NMR (400 MHz, methanol^4) δ ppm 8.76-8.81 (m, 1H), 8.69 (d, J=2.21 Hz, 1H), 8.35 (s , 1H), 8.02 (s, 2H), 7.96 (d, J=5.95 Hz, 1H), 6.92 (d, J=5.95 Hz, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 483.9.

Example 120.

1-(4-Amino-3-chloropyridin-2-yl)-A-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-III-pyrazole-4-carboxamide, compound 120

A. tert-Butyl (3-chloro-2-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-III-pyrazol-1-yl)pyridin-4-yl)carbamate, compound 120a, compound 120a

POCl ₃ (21.356 mg, 0.139 mmol) was added to a solution of 1-(4-((tert-butoxycarbonyl)amino)-3-chloropy

- 142 046082 ridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 119d (30 mg, 0.070 mmol), 5-amino-2-(2H-1,2,3- triazol-2-yl)nicotinonitrile, INT3 (15.558 mg, 0.084 mmol), pyridine (13.771 mg, 0.174 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at RT for 2 hours. Water (50 ml) and CH ₂ Cl ₂ (50 ml) were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give tert-butyl (3-chloro-2-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)carbamoyl)-5-(trifluoromethyl)N-pyrazol-1-yl)pyridin-4-yl)carbamate, compound 120a (20 mg, 50.0% yield) as a white solid. TLC: petroleum ether/ethyl acetate=1/1, Rf=0.4; LCMS (ESI) m/z M+H: 575.1.

B. 1-(4-Amino-3-chloropyridin-2-yl)J-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5- (trifluoromethyl)-III-pyrazole-4-carboxamide, compound 120

tert-Butyl (3-chloro-2-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl) -1H-pyrazol-1-yl)pyridin-4-yl)carbamate, compound 120a (20 mg, 0.035 mmol), was added to HCl/dioxane (5 ml, 4 mol/L). The mixture was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (35-55% (v/v) CH ₃ CN and H2O with 0.05% HCl) and lyophilized to dryness to obtain the title compound (10.3 mg, 57.0%) as a white solid. ^1H NMR (400 MHz, methanolM4) δ ppm 9.05 (d, J=2.43 Hz, 1H), 8.87 (d, J=2.65 Hz, 1H), 8.34 ( s, 1H), 8.12 (s, 2H), 7.95 (d, J=5.73 Hz, 1H), 6.91 (d, J=5.73 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 474.9.

Example 121.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-fluoropyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 121

A. 2-Fluoro-5-hydrazinylpyridine, compound 121a

HN-NH?

F, connection 121a

To a stirred solution of 6-fluoropyridin-3-amine (3 g, 26.761 mmol) in HCl (6 N, 20 ml) at 10°C was added a solution of sodium nitrite (2.77 g, 40.141 mmol) in water (8 ml) at temperatures below -20°C. The reaction mixture was stirred at RT for 0.5 hour. Then cooled to -20°C, tin(II) chloride dihydrate (12.077 g, 53.521 mmol) was added to the mixture in portions and stirred for 1 hour. The reaction mixture was made basic with 3M NaOH, the residue was filtered and washed with EtOAc (100 ml x3). The organic layer was separated and the aqueous layer was extracted with EtOAc (50 ml x3). The combined organic layers were dried with Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude product (3 g, 52.1% purity, 45.9%) as a yellow solid, which was used in the next step. without additional cleaning. LCMS (ESI) m/z M+23: 150.1.

B. Ethyl 1-(6-fluoropyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 121b

- 143 046082

2-Fluoro-5-hydrazinylpyridine, compound 121a (3 g, 12.295 mmol), dissolved in ethanol (20 ml), added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (4.429 g , 18.442 mmol) and stirred at 70°C for 2 hours and then cooled to room temperature. The combined mixture was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate 100/0 to 85/15) to give the title compound (2 g, 50 .7%) in the form of a yellow solid. LCMS (ESI) m/z M+1: 304.0.

C. 1-(6-Fluoropyridin-3-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 121c

Ethyl 1-(6-fluoropyridin-3-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 121b (1 g, 3.298 mmol) was dissolved in THF (10 ml) and water (10 ml). Lithium hydroxide (157.96 mg, 6.596 mmol) was added. The reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was adjusted to pH

5 using HCl (2 N), then extracted using CHCl/McOH (10/1, 60 ml x5). The combined organic layers were dried with Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude title compound (630 mg, 85.7% purity, 59.5%) as a yellow solid. LCMS (ESI) m/z M+1: 276.0.

D. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-fluoropyridin-3-yl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide, compound 121

1-(6-Fluoropyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 121c (306.85 mg, 0.956 mmol), 5-chloro-6-(2H-1, 2,3-triazol-2-yl)pyridin-3-amine (170 mg, 0.869 mmol), pyridine (412.47 mg, 5.214 mmol) were dissolved in CH ₂ Cl ₂ (15 ml) and phosphorus oxychloride (399, 77 mg, 2.607 mmol). The mixture was stirred at 25°C for 16 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (50 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates were concentrated under reduced pressure to give the crude product as a yellow solid, which was then purified by flash column chromatography (eluent: petroleum ether/ethyl acetate 100/0 to 30/70) to obtain the title compound (370 mg, 93.1%) as a yellow solid. ^1H NMR (400

MHz, DMSO-d6) δ 8.82 (d, J=2.2 Hz, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.50 (s, 1H), 8.398.30 (m, 1H), 8.19 (s, 2H), 7.51 (dd, J=2.9, 8.8 Hz, 1H ). LCMS (ESI) m/z M+1: 452.9.

Example 122.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-(methylamino)pyridin-3-yl)-5-(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 122

- 144 046082 No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-fluoropyridin-3-yl)-5-(trifluoromethyl) β-Spirazole-4-carboxamide, compound 121 (100 mg, 0.219 mmol), and methylamine (5 ml, 2M) were stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a yellow solid color, which was purified by preparative HPLC (17-47% (v/v) CH ₃ CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compound (85 mg, 77.736%) . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.40 (s, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.69 (d, J= 2.2 Hz, 1H), 8.52 (s, 1H), 8.28 (d, J=2.2 Hz, 1H), 8.18 (s, 2H), 7.82 (br. d, J=9.3 Hz, 1H), 6.92 (d, J=9.5 Hz, 1H), 2.94 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 463.9.

Example 123.

N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-(fluoro)pyridin-3-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 123

VN

1-(6-Fluoropyridin-3-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 121c (303.44 mg, 0.945 mmol), 5-amino-2-(2H-1, 2,3-triazol-2-yl)nicotinonitrile, INT3 (160 mg, 0.859 mmol), pyridine (407.88 mg, 5.156 mmol) were dissolved in CH ₂ Cl ₂ (15 ml) and phosphorus oxychloride (395.33 mg) was added , 2.578 mmol). The mixture was stirred at 25°C for 16 hours. Saturated. NaHCO ₃ (20 ml) and the mixture was extracted with CH ₂ Cl ₂ (50 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow solid, which was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate 100/0 to 30/70) to obtain the title compound (230 mg, 59.1%) as a yellow solid. 1H

NMR (400 MHz, DMSO-d6) δ 11.29 (br.s, 1H), 9.06 (d, J=2.4 Hz, 1H), 8.85 (d, J=2.4 Hz, 1H), 8.59 (d, J=2.2 Hz, 1H), 8.51 (s, 1H), 8.35 (ddd, J=2.8, 6.7, 8.9 Hz, 1H ), 8.32 (s, 2H), 7.51 (dd, J=2.9, 8.6 Hz, 1H). LCMS (ESI) m/z M+1: 443.9.

Example 124.

N-(5 -cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(6-(methylamino)pyridin-3-yl)-5 (trifluoromethyl) -III-pyrazole-4-carboxamide, compound 124

N-(5 -cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(6-(methylamino)pyridin-3-yl)-5 -(trifluoro Methyl)-III-pyrazole-4-carboxamide, compound 123 (100 mg, 0.221 mmol), and methylamine (5 ml, 2 M) were stirred at 70°C for 3 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a yellow solid which was purified by preparative HPLC (13-43% (v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to give the title compound (65 mg, 60.0%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.43 (s, 1H), 9.12 (d, J=2.4 Hz, 1H), 8.89 (d, J=2 .4 Hz, 1H), 8.49 (s, 1H), 8.31 (s, 2H), 8.26 (d, J=2.2 Hz, 1H), 7.78 (br.d, J =7.7 Hz, 1H), 6.86 (br.d, J=9.3 Hz, 1H), 2.92 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 455.0.

Example 125.

1-(6-Aminopyridin-3-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 125

- 145 046082 No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-fluoropyridin-3-yl)-5-(trifluoromethyl) β-Spirazole-4-carboxamide, compound 121 (120 mg, 0.262 mmol), and NH ₃ /MeOH (6 ml, 7 M) were stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as yellow solid, which was purified by preparative HPLC (25-55% (v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to give the title compound (32 mg, 24. 7%). ^1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (s, 1H), 8.94 (s, 1H), 8.72 (s, 1H), 8.60 (s, 1H ), 8.40 (br.s, 1H), 8.18 (s, 2H), 8.01 (br.d, J=8.8 Hz, 1H), 7.05 (br.d, J= 9.5 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 449.9.

Example 126.

1-(4-Cyano-2-methylphenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide, compound 126

1-(4-Cyano-2-methylphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 37c (150 mg, 0.508 mmol), was treated with oxalyl chloride (100.5 mg, 1.27 mmol) in DCM (10 ml) and DMF (1 drop) at room temperature. The reaction mixture was then stirred for 45 minutes and then concentrated to dryness. The crude acid chloride was dissolved in DCM (10 ml) and 5-amino2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, INT3 (113.5 mg, 0.61 mmol) was added, and then immediately added pyridine (167 mg, 2.12 mmol). The reaction mixture was stirred at room temperature for 3 hours and finally quenched with water (50 ml) and extracted with DCM (2x50 ml). The combined extracts were dried over MgSO ₄ , filtered and the filtrate was concentrated to give a crude solid. The crude product was purified by HPLC to give 1-(4-cyano-2-methylphenyl)-X-(5-cyano6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 126 (53.6 mg, 23%). ^1H NMR (400 MHz, DMSO-d6) δ ppm 11.32 (br.s, 1H), 9.10 (d, J=2.43 Hz, 1H), 8.88 (d, J =2.43 Hz, 1H), 8.58 (s, 1H), 8.32 (s, 2H), 8.07 (s, 1H), 7.95 (dd, J=8.16, 1, 32 Hz, 1H), 7.76 (d, J=8.16 Hz, 1H), 2.07 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 472.9.

Example 127.

N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1,2,3,4-tetrahydroquinolin-5-yl )-5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 127

A. tert-Butyl 5-bromo-3,4-dihydroquinoline-1(2H)-carboxylate, compound 127a

Vg

, connection 127a

To a solution of 5-bromo-1,2,3,4-tetrahydroquinoline hydrochloride (0.90 g, 3.621 mmol) in dichloromethane (6 ml) was added N,N-dimethylaminopyridine (0.044 g, 0.362 mmol) and triethylamine (1.06 ml, 7.6 mmol). The mixture was stirred for 30 minutes at room temperature, then di-tert-butyl dicarbonate (0.873 mL, 3.802 mmol) was added portionwise. The solution was stirred at room temperature overnight. The mixture was diluted using ethyl acetate. The organic layer was washed with water and brine, filtered, and the filtrate was dried and concentrated. The mixture was purified by flash chromatography (SiO ₂ , heptane-ethyl acetate gradient). Pure fractions were combined and concentrated. The residue was dried under reduced pressure to give tert-butyl 5-bromo-3,4-dihydroquinoline-1(2H)-carboxylate, compound 127a (749 mg, 66% yield). MS m/z 213.9 (M+H-tBu)+.

B. tert-Butyl 5-(2-(diphenylmethylene)hydrazinyl)-3,4-dihydroquinoline-1(2H)-carboxylate, compound 127b

- 146 046082

, connection 127b

To a solution of tert-butyl 5-bromo-3,4-dihydroquinoline-1(2H)-carboxylate, compound 127a (0.749 g,

2.4 mmol), and benzophenone hydrazone (0.471 g, 2.4 mmol) in 1,4-dioxane (15 ml), BINAP (149 mg, 0.240 mmol), palladium (II) acetate ( 54 mg, 0.240 mmol) and sodium tert-butoxide (0.692 g, 7.2 mmol) and the mixture was heated at 100°C for 16 hours. The resulting mixture was cooled to room temperature, filtered through a filter paper, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by chromatography on silica gel (SiO ₂ , heptane-ethyl acetate gradient). Pure fractions were combined and concentrated. Dry under high vacuum to give tert-butyl 5-(2-(diphenylmethylene)hydrazinyl)-3,4dihydroquinoline-1(2H)-carboxylate, compound 127b (501 mg, 48.8% yield). MS m/z 328.1 (M+HBoc)+.

C. 5-Hydrazinyl-1,2,3,4-tetrahydroquinoline hydrochloride, compound 127с ⁿ %n

0Q

N, connection 127c

Concentrated hydrochloric acid ( 4 ml) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, then treated with diethyl ether (25 ml) and water (10 ml). The layers were separated. The aqueous phase was concentrated under reduced pressure to give (1,2,3,4-tetrahydroquinolin-5-yl)hydrazine hydrochloride, which was used in the next step without purification (1.172 mmol crude, 100% yield). MS m/z 164.1 (M+H)+.

E. Ethyl 1-(1,2,3,4-tetrahydroquinolin-5-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 127d

, connection127d

Ethyl 2-(ethoxymethylene)4,4 was added to a solution of 5-hydrazinyl-1,2,3,4-tetrahydroquinoline hydrochloride, compound 127c (1.172 mmol), and triethylamine (0.327 ml, 2.344 mmol) in ethanol (15 ml). 4-Trifluoro-3-oxobutanoate, INT1 (0.253 g, 1.055 mmol), and the mixture was stirred at 80°C for 16 hours. The mixture was diluted with ethyl acetate and washed with water/NaI ICX.% the organic layer was separated and dried with MgSO ₄ . filtered and the filtrate was then concentrated. The crude product was purified by chromatography on silica gel (heptane-ethyl acetate gradient). The pure fractions were combined and concentrated to give ethyl 1-(1,2,3,4-tetrahydroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 127d (265 mg, yield 66.6 %). 1H NMR (300 MHz, Chloroform-d) δ 1.37 (t, J=7.1 Hz, 3H), 1.77-1.89 (m, 2H), 2.10-2.43 (m, 2H), 3.27 (t, J=5.5 Hz, 3H), 4.36 (k, J=7.2 Hz, 2H), 6.50-6.60 (m, 2H), 7, 01 (t, J=8.0 Hz, 1H), 8.12 (s, 1H). MS m/z 340.0 (M+H)+.

E. Ethyl 1-(1 -methyl-1,2,3,4-tetrahydroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 127e

To a solution of ethyl 1-(1,2,3,4-tetrahydroquinolin-5-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate,

- 147 046082 compound 127d (598 mg, 1.76 mmol), paraformaldehyde (529 mg, 17.62 mmol) was added in acetic acid (9.6 ml) at RT. The mixture was stirred at room temperature for 15 minutes, then sodium cyanoborohydride (0.554 g, 8.812 mmol) was added and the mixture was stirred at RT for 4 hours. The reaction was quenched with saturated aqueous Na ₂ CO ₃ then extracted with dichloromethane. The organic layer was separated, dried over MgSO ₄ , filtered and the filtrate was concentrated to give ethyl 1(1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)-5-(trifluoromethyl)-III-pyrazol-4- carboxylate compound

127e (580 mg, 93%) as a sticky solid. MS m/z 354.0 (M+H)+.

F. 1-(1-Methyl-1,2,3,4-tetrahydroquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 127f

OH, connection 127f

To a solution of ethyl 1-(1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 127e (0.623 g, 1.762 mmol), in ethanol (22 ml), sodium hydroxide (141 mg, 3.52 mmol) was added and the mixture was heated at 60°C for 3 hours. The mixture was cooled to room temperature and poured into a stirred mixture of 1N HCl/ice/ethyl acetate. The organic layer was separated and washed with brine, then dried (MgSO ₄ ), and the filtrate was concentrated to give 1-(1-methyl-1,2,3,4tetrahydroquinolin-5-yl)-5-(trifluoromethyl)-III-pyrazol- 4-carboxylic acid, compound 127f (512 mg, 89% yield). MS m/z 326.0 (M+H)+.

G. 1-(1-Methyl-1,2,3,4-tetrahydroquinolin-5-yl)-5-(trifluoromethyl)-III-pyrazole-4-carbonyl chloride, compound 127g

To a solution of 1-(1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 127f (512 mg, 1.574 mmol), in dichloromethane (30 ml) and N,N-dimethylformamide (0.1 ml), oxalyl chloride (0.270 ml, 3.14 mmol) was added and the mixture was heated to reflux for 1 hour. The mixture was concentrated to dryness and the residue was dried at reduced pressure to constant weight to give crude 1-(1-methyl-1,2,3,4-tetrahydroquinolin5-yl)-5-(trifluoromethyl)-III-pyrazole-4-carbonyl chloride, compound 127g (1.574 mmol) as an oil , which was immediately used in this form.

N. No.(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1,2,3,4-tetrahydroquinolin-5yl )-5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 127

To a solution of 1-(1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)-5-(trifluoromethyl)-III-pyrazole-4-carbonyl chloride, compound 127g (1.574 mmol), in dichloromethane (20 ml ) and tetrahydrofuran (60 ml) at room temperature, 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (440 mg, 2.361 mmol) was added followed by triethylamine (0.878 ml, 6.296 mmol ) and the reaction mixture was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated. Purification by flash chromatography (SiO ₂ , ethyl acetate-heptane gradient) gave a mixture of product and starting material. The product was purified by reverse phase chromatography, eluting with an ammonium bicarbonate-water-acetonitrile gradient. The product fractions were combined and extracted with dichloromethane. The organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give pure N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1 -methyl-1,2,3,4-tetrahydroquinolin-5-yl)5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 127 (45 mg, 5.8%). 1H NMR (300 MHz, _DMSOd6 ) δ 1.73-1.89 (m, 2H), 1.98-2.18 (m, 1H), 2.21-2.36 (m, 1H), 2 .92 (s, 3H), 3.24 (t, J=5.7 Hz, 2H), 6.60 (d, J=7.7

- 148 046082

Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 7.10-7.25 (m, 1H), 8.31 (s, 2H), 8.45 (s, 1H ), 8.87 (d, J=2.4 Hz, 1H), 9.11 (d, >2.4 Hz, 1H), 11.33 (s, 1H). MS m/z 494.1 (M+H)+.

Example 128.

N(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methylindolin-4-yl)-5-(trifluoromethyl)III-pyrazole -4-carboxamide, compound 128

A. 4-Bromo-1-methylindoline, compound 128a

0g

\, connection 128a

Paraformaldehyde (3.293 g, 109.7 mmol) was added to a solution of 4-bromo-indole (2.15 g, 10.967 mmol) in acetic acid (59.6 mL) at RT. The mixture was stirred at room temperature for 15 minutes, then sodium cyanoborohydride (3.446 g, 54.83 mmol) was added and the mixture was stirred at RT for 4 hours. The reaction was quenched with saturated aqueous Na ₂ CO ₃ then extracted with dichloromethane. The organic layer was separated, dried over MgSO ₄ , filtered and concentrated to give the crude product. Purification by flash chromatography (SiO2, ethyl acetate-heptane gradient from 5% to 100%). The pure fractions were combined and concentrated to give pure 4-bromo-1-methylindoline (1.545 g, 66.4%) as a sticky solid. MS m/z 211.9(M+H)+.

B. 4-(2-(Diphenylmethylene)hydrazinyl)-1-methylindoline, compound 128b

BINAP (454 mg, 0.728 mmol), palladium(II) acetate (164 mg, 0.728 mmol) and sodium tert-butoxide (2.10 g, 21.85 mmol) and the mixture was heated at 100°C for 16 hours. The resulting mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (SiO ₂ , heptane-ethyl acetate gradient). Pure fractions were combined and concentrated. The solids were dried under reduced pressure to give 4-(2-(diphenylmethylene)hydrazinyl)-1-methylindoline, 128b (2.012 g, 84.3% yield). MS m/z 328.1 (M+H)+.

C. 4-Hydrazinyl-1-methylindoline hydrochloride, compound 128c (VILL_ltrabalon_2205_1)

To a solution of 4-(2-(diphenylmethylene)hydrazinyl)-1-methylindoline, compound 128b (2.012 g, 6.145 mmol), in ethanol (6 ml) was added concentrated hydrochloric acid (12 ml) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, then treated with diethyl ether (25 ml) and water (10 ml), and the layers were separated. The aqueous phase was concentrated under reduced pressure to give 4-hydrazinyl-1-methylindoline hydrochloride, compound 128c, which was used in the next step without purification (6.145 mmol crude product, 100% yield). MS m/z 164.1 (M+H)+.

D. Ethyl 1-(1-methylindolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 128d

- 149 046082

To a solution of 4-hydrazinyl-1-methylindoline hydrochloride, compound 128c (6.145 mmol), and triethylamine (4.282 ml, 30.72 mmol) in ethanol (60 ml) was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro -3oxobutanoate, INT1 (1.476 g, 6.145 mmol), and the mixture was stirred at 80°C for 16 hours. The mixture was diluted with ethyl acetate and washed with water/NuHCO3, the organic layer was separated and dried with MgSO ₄ , filtered, and the filtrate was then concentrated. The crude product was purified by chromatography on silica gel (SiO ₂ , heptane-ethyl acetate gradient). The pure fractions were combined and concentrated to give ethyl 1-(1-methylindolin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 128d (1.290 g, 61.8% yield). MS m/z 340.0 (M+H)+.

E. 1-(1-Methylindolin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 128e

OH, connection 128e

To a solution of ethyl 1-(1-methylindolin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 128d (1.29 g, 3.80 mmol), in ethanol (25 ml) was added sodium hydroxide (304 mg, 7.60 mmol) and the mixture was heated at 60°C for 3 hours. The mixture was cooled to room temperature and poured into a stirred 1N HCl/ice/ethyl acetate mixture. The organic layer was separated and washed with brine, then dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give 1-(1-methylindolin-4yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 128e ( 1.180 g, yield 99%). MS m/z 312.0 (M+H)+.

F. 1-(1-Methylindolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, compound 128f

, connection 128f

To a solution of 1-(1-methylindolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 128e (1.17 g, 3.759 mmol), in dichloromethane (30 ml) and N, N-dimethylformamide (0.1 ml) was added oxalyl chloride (0.645 ml, 7.52 mmol) and the mixture was heated to reflux for 1 hour. The mixture was concentrated to dryness and the residue was dried under reduced pressure to constant weight to obtain crude K N-methylindolin-yl-trifluoromethyl-pyrazole-carbonyl chloride, compound 128f (3.759 mmol), as an oil, which was immediately used as such.

G. N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methylindolin-4-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 128

To a solution of 1-(1-methylindolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, compound 128f (3.759 mmol), in dichloromethane (20 ml) and tetrahydrofuran (60 ml) at room temperature 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile (1.40 g, 7.52 mmol) INT3 was added followed by triethylamine (2.1 mL, 15 mmol) and the reaction mixture was stirred at room temperature for 25 hours. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated. Purification by flash chromatography (SiO ₂ , ethyl acetate-heptane gradient) gave a mixture of product and starting material. The product was purified by reverse phase chromatography, eluting with a formic acid-water-acetonitrile gradient. The product fractions were combined and extracted with dichloromethane. The organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give pure N(5-cyano-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)-1-(1-methylindoline -4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 128 (526 mg, 29.2% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.72 (t, J=8.4 Hz, 2H), 2.78 (s, 3H), 3.31-3.41 (m, 3H) , 6.63 (d, J=7.9 Hz, 1H), 6.69 (d, J=7.8 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 8 .30 (s, 2H), 8.40 (s,

- 150 046082

1H), 8.86 (d, J=2.5 Hz, 1H), 9.05 (d, J=2.5 Hz, 1H). MS m/z 480.1 (M+H)+.

Example 129.

No.(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5( trifluoromethyl)-III-pyrazole-4-carboxamide, compound 129

A. tert-Butyl 5-(2-(diphenylmethylene)hydrazinyl)-3,4-dihydroisoquinoline-2(III)carboxylate, compound 129a

To a solution of tert-butyl 5-bromo-3,4-dihydroisoquinoline-2(III)-carboxylate (1.0 g, 3.203 mmol) and benzophenone hydrazone (0.629 g, 3.203 mmol) in 1,4-dioxane (15 ml) At room temperature under a nitrogen atmosphere, BINAP (199 mg, 0.320 mmol), palladium(II) acetate (72 mg, 0.320 mmol) and sodium tert-butoxide (923 mg, 9.61 mmol) were added and the mixture was heated at 100°C for 16 h. The resulting mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (SiO ₂ , heptane-ethyl acetate gradient). Pure fractions were combined and concentrated. The solids were dried under reduced pressure to give tert-butyl 5-(2-(diphenylmethylene)hydrazinyl)-3,4dihydroisoquinoline-2(1H)-carboxylate, compound 129a (955 mg, 69.7% yield). MS m/z 372.0 (M+HtBu)+.

B. 5-Hydrazinyl-1,2,3,4-tetrahydroisoquinoline, compound 129b ⁿ =% n

XHCI, connection 129b

To a solution of tert-butyl 5-(2-(diphenylmethylene)hydrazinyl)-3,4-dihydroisoquinoline-2(III)-carboxylate, compound 129a (955 mg, 2.234 mmol), in ethanol (2.2 ml) was added concentrated hydrochloric acid acid (4.4 ml) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, then treated with diethyl ether (25 ml) and water (10 ml), and the layers were separated. The aqueous phase was concentrated under reduced pressure to 5hydrazinyl-1,2,3,4-tetrahydroisoquinoline, compound 129b, which was used in the next step without purification (2.234 mmol crude product, 100% yield). MS m/z 164.1 (M+H)+.

C. Ethyl 1-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 129c

Ethyl 2-(ethoxymethylene)-4,4 was added to a solution of 5-hydrazinyl-1,2,3,4-tetrahydroisoquinoline, compound 129b (2.234 mmol), and triethylamine (0.623 mL, 4.468 mmol) in ethanol (25 mL). 4-Trifluoro-3oxobutanoate, INT1 (0.483 g, 2.011 mmol) and the mixture was stirred at 80°C for 16 hours. The mixture was diluted with ethyl acetate and washed with water/NaHCO ₃ , the organic layer was separated and dried with MgSO ₄ , filtered and then the filtrate was concentrated. The crude product was purified by chromatography on silica gel (SiO ₂ , methanol-dichloromethane gradient). The pure fractions were combined and concentrated to give ethyl 1-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)-III-pyrazole-4carboxylate, compound 129c (423 mg, 55.8% yield) . MS m/z 340.1 (M+H)+.

D. tert-Butyl 5-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1 H-pyrazol-1 -yl)-3,4-dihydroisoquinoline2(III)-carboxylate, compound 129d

- 151 046082

To a solution of ethyl 1-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 129c (0.160 g, 0.472 mmol), in dichloromethane (5 ml ) N,Ndimethylaminopyridine (0.006 g, 0.047 mmol) and triethylamine (0.139 ml, 0.990 mmol) were added. The mixture was stirred for 30 minutes at room temperature, then di-tert-butyl dicarbonate (0.206 g, 0.943 mmol) was added in portions. The solution was stirred at room temperature overnight. The mixture was diluted using ethyl acetate. The organic layer was washed with water and brine, filtered, dried and concentrated. The mixture was purified by flash chromatography (SiO ₂ , heptane ethyl acetate gradient). The pure fractions were combined and concentrated, then dried under highly reduced pressure to give tert-butyl 5-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-3,4dihydroisoquinoline-2(1H)- carboxylate, compound 129d (127 mg, 61.3% yield). MS m/z 384.0 (M+HtBu)+.

E. 1-(2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)-III-pyrazole4-carboxylic acid, compound 129e

To a solution of tert-butyl 5-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-III-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(III)-carboxylate, compound 129d (0.127 g, 0.289 mmol ), in ethanol (5 ml) was added sodium hydroxide (23 mg, 0.578 mmol) and the mixture was heated at 60°C for 3 hours. The mixture was cooled to room temperature and poured into a stirred mixture of 1N HCl/ice/ethyl acetate. The organic layer was separated and washed with brine, then dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give 1-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5- (trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 129e (102 mg, 85.8% yield). MS m/z 356.0 (MtBu+H)+.

F. tert-Butyl 5-(4-(chlorocarbonyl)-5-(trifluoromethyl)-III-pyrazol-1-yl)-3,4-dihydroisoquinoline2(1H)-carboxylate, compound 129f

To a solution of 1 -(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxylic acid, compound 129e (36 mg, 0.088 mmol) 1-chloro-M^,2-trimethyl-1-propenylamine (0.046 mL, 0.350 mmol) was added in dichloromethane (2 mL) and the mixture was stirred at room temperature for 30 min to give tert-butyl 5-(4-( chlorocarbonyl)-5-(trifluoromethyl)-Spirazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, compound 129f (0.088 mmol), as a crude solution, which was used immediately as such.

G. tert-Butyl 5-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)1 H- pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1^-carboxylate, compound 129g

- 152 046082

To a solution of tert-butyl 5-(4-(chlorocarbonyl)-5-(trifluoromethyl)-III-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, compound 129f (0.088 mmol), in 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (25 mg, 0.132 mmol), in pyridine (1 ml) was added to pyridine (1 ml) at room temperature and the reaction mixture was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated. Purification by flash chromatography (SiO ₂ , ethyl acetate-heptane gradient) afforded pure tert-butyl 5-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin- 3yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, compound 129g (32 mg, 62.7%). MS m/z 524.0 (M-tBu+H)+.

N. No. (5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,2,3,4-tetrahydroisoquinolin-5-yl)- 5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 129

To a solution of tert-butyl 5-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-III- pyrazol-1-yl)-3,4-dihydroisoquinoline-2(III)-carboxylate, compound 129g (32 mg, 0.055 mmol), in dichloromethane (3 ml), trifluoroacetic acid (2 ml) was added and the mixture was stirred for 3 h at room temperature. The mixture was concentrated to dryness under reduced pressure and the residue was diluted with ethyl acetate and washed with NaHCO ₃ . The organic layer was dried over MgSO ₄ , filtered, and the filtrate was concentrated. The residue was purified by reverse phase chromatography (ammonium bicarbonate-water-acetonitrile gradient). The product fractions were combined and extracted with dichloromethane. The organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give pure N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1 ,2,3,4-tetrahydroisoquinolin-5-yl)-5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 129 (2 mg, 7.6%). ¹ H NMR (300 MHz, METHANOL-d4) δ 3.00-3.19 (m, 2H), 4.05-4.18 (m, 2H), 4.51-4.69 (m, 2H) , 7.22-7.42 (m, 3H), 8.14 (s, 2H), 8.29 (s, 1H), 8.89 (d, J=2.5 Hz, 1H), 9, 05 (d, J=2.5 Hz, 1H). MS m/z 480.1 (M+H)+.

Example 130.

No.(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(indolin-4-yl)-5-(trifluoromethyl)-Spirazol-4- carboxamide, compound 130

A. tert-Butyl 4-(2-(diphenylmethylene)hydrazinyl)indoline-1-carboxylate, compound 130a

BINAP ( 209 mg, 0.335 mmol), palladium(II) acetate (75 mg, 0.335 mmol) and sodium tert-butoxide (967 mg, 10.061 mmol) and the mixture was heated at 100°C for 16 hours. The resulting mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (SiO ₂ gradient heptane ethyl acetate). Pure fractions were combined and concentrated. The resulting solids were dried under reduced pressure to give tert-butyl 4-(2-(diphenylmethylene)hydrazinyl)indoline-1-carboxylate, compound 130a (912 mg, 65.8% yield). MS m/z 414.1 (M+H)+.

B. 4-Hydrazinilinindoline hydrochloride, compound 130b

- 153 046082

xHCI, connection 130b

To a solution of tert-butyl 4-(2-(diphenylmethylene)hydrazinyl)indoline-1-carboxylate, compound 130a (912 mg, 2.206 mmol), in ethanol (2.2 ml) was added concentrated hydrochloric acid (4.4 ml) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, then treated with diethyl ether (25 ml) and water (10 ml). The layers were separated. The aqueous phase was concentrated under reduced pressure to give 4-hydrazinyl indoline hydrochloride, compound 130b, which was used in the next step without purification (2.206 mmol, crude product, 100% yield). MS m/z 150.1 (M+H)+.

C. Ethyl 1-(indolin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 130c

To a solution of 4-hydrazinilindoline hydrochloride, compound 130b (2.206 mmol), and triethylamine (0.615 ml, 4.412 mmol) in ethanol (25 ml) was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (0.477 g, 1.985 mmol) and the mixture was stirred at 80°C for 16 hours. The mixture was diluted with ethyl acetate and washed with water/NHCO ₃ , the organic layer was separated and dried with MgSO ₄ , filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (SiO ₂ , methanol-dichloromethane gradient). The pure fractions were combined and concentrated to give ethyl 1-(indolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 130c (528 mg, 73.6% yield). MS m/z 326.0 (M+H)+.

D. tert-Butyl 4-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-III-pyrazol-1-yl)indoline-1-carboxylate, compound 130d

, connection 130d

N,N-dimethylaminopyridine ( 0.019 g, 0.153 mmol) and triethylamine (0.446 ml, 3.209 mmol). The mixture was stirred for 30 minutes at room temperature, then di-tert-butyl dicarbonate (0.369 mL, 1.604 mmol) was added portionwise. The solution was stirred at room temperature overnight. The mixture was diluted using ethyl acetate. The organic layer was washed with water and brine, filtered, dried, and the filtrate was concentrated. The mixture was purified by flash chromatography (SiO2, heptane-ethyl acetate gradient). Pure fractions were combined and concentrated. The resulting product was dried under reduced pressure to give tert-butyl 4-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)indoline-1-carboxylate, compound 1303d (366 mg, yield 56, 3%). MS m/z 426.0 (M+H-)+.

E. 1-(1 -(tert-Butoxycarbonyl)indolin-4-yl)-5-(trifluoromethyl)-1 ^pyrazole^-carboxylic acid, compound 103e

To a solution of tert-butyl 4-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)indoline-1-car

- 154 046082 boxylate, compound 130d (0.403 g, 0.947 mmol), sodium hydroxide (76 mg, 1.895 mmol) was added to ethanol (16 ml) and the mixture was heated at 60°C for 3 hours. The mixture was cooled to room temperature and poured into a stirred 1N HCl/ice/ethyl acetate mixture. The organic layer was separated and washed with brine, then dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give 1(1-(tert-butoxycarbonyl)indolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxylic acid, compound 130e (356 mg, yield 94.6%). ¹ H NMR (300 MHz, Chloroform-d) δ 1.58 (s, 9H), 2.92 (t, J=8.7 Hz, 2H), 4.02 (t, J=8.7 Hz, 2H), 6.89 (d, J=8.0 Hz, 1H), 7.22-7.34 (m, 2H), 8.20 (s, 1H). MS m/z 398.0 (M+H)+.

F. tert-Butyl 4-(4-(chlorocarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)indoline-1-carboxylate, compound 130f

To a solution of 1-(1 -(tert-butoxycarbonyl)indolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 130e (294 mg, 0.740 mmol), in dichloromethane (12 ml ) 1-χΛορ-Ν,Ν,2trimethyl-1-propenylamine (0.392 mL, 2.960 mmol) was added and the mixture was stirred at room temperature for 30 min to obtain a crude solution of tert-butyl 4-(4-(chlorocarbonyl)-5- (trifluoromethyl)N-pyrazol-1-yl)indoline-1-carboxylate, compound 130f (0.740 mmol), which was immediately used as such.

G. tert-Butyl 4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)III-pyrazole -1-yl)ivdolin-1-carboxylate, compound 130g

, connection 130g

To a solution of 4-tert-butyl 4-(4-(chlorocarbonyl)-5-(trifluoromethyl)-III-pyrazol-1-yl)indoline-1-carboxylate, compound 130f (0.740 mmol), in pyridine (6 ml) at room temperature 5-amino-2[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (207 mg, 1.11 mmol), in pyridine (6 ml) and the reaction mixture was stirred at room temperature for 20 h The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated. Purification by flash chromatography (SiO ₂ , ethyl acetate-heptane gradient) yielded tert-butyl 4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl )carbamoyl)-5-(trifluoromethyl)-III-pyrazol1-yl)indoline-1-carboxylate, compound 130g (300 mg, 71.7%). A portion (60 mg) of this product was further purified by reverse phase chromatography, eluting with a sodium bicarbonate water/methanol-acetonitrile gradient to obtain 33 mg of pure product. 1H NMR (300 MHz, Chloroform-d) δ 1.58 (s, 9H), 2.94 (t, J=8.7 Hz, 2H), 4.03 (t, J=8.7 Hz, 2H ), 6.91 (d, J=8.0 Hz, 1H), 7.31 (t, J=8.1 Hz, 1H), 8.02 (s, 2H), 8.14 (s, 1H ), 8.20 (s, 1H), 8.84 (d, J=2.6 Hz, 1H), 8.97 (d, J=2.5 Hz, 1H). MS m/z 566.1 (M +H)+.

N. No. (5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(indolin-4-yl)-5-(trifluoromethyl)-III- pyrazole-4-carboxamide, compound 130

A.

Ν Ν u, connection 130

To a solution of tert-butyl 4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-III- pyrazol-1-yl)indoline-1-carboxylate, compound 130g (300 mg, 0.530 mmol), trifluoroacetic acid (6 ml) was added in dichloromethane (9 ml) and the mixture was stirred for 3 hours at room temperature. The mixture was concentrated to dryness under reduced pressure and the residue was diluted

- 155 046082 with ethyl acetate and washed with NaHCO ₃ . The organic layer was dried with MgSO ₄ , filtered and the filtrate was concentrated. The residue was purified by reverse phase chromatography (ammonium bicarbonate-water-acetonitrile gradient). Fractions containing product were combined and extracted with dichloromethane. The organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated and the product was further purified by reverse phase chromatography, eluting with a sodium bicarbonate-water/methanol-acetonitrile gradient to give pure Na(5-cyano-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-1-(indolin-4-yl)-5-(trifluoromethyl)-III-pyrazol-4-carboxamide, compound 130 (113 mg 45.8 %). ¹ H NMR (300 MHz, Chloroform-d) δ 2.91 (t, J=8.5 Hz, 3H), 3.63 (t, J=8.5 Hz, 2H), 6.65 (d, J=7.9 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 7.12 (t, J=7.9 Hz, 1H), 8.02 (s, 3H) , 8.10 (s, 1H), 8.80 (d, J=2.5 Hz, 1H), 8.96 (d, J=2.5 Hz, 1H). MS m/z 466.0 (M+H)+.

Example 131.

N(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl )-5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 131

A. 8-Bromo-1-methyl-1,2,3,4-tetrahydroquinoline, compound 131a

Paraformaldehyde (1.208 g, 40.23 mmol) was added to a solution of 8-bromo-1,2,3,4-tetrahydroquinoline hydrochloride (1.0 g, 4.023 mmol) in acetic acid (21.8 mL) at RT. The mixture was stirred at room temperature for 15 minutes, then sodium cyanoborohydride (1.264 g, 20.12 mmol) was added and the mixture was stirred at RT for 4 hours. The reaction was quenched with saturated aqueous Na2CO3, then extracted with dichloromethane. The organic layer was separated, dried over MgSO ₄ , filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography (SiO ₂ , ethyl acetate-heptane gradient 5 to 100%). The pure fractions were combined and concentrated to give pure 8-bromo-1-methyl-1,2,3,4-tetrahydroquinoline, compound 131a (0.863 g, 95%). MS m/z 227.9 (M+H)+.

B. 8-(2-(Diphenylmethylene)hydrazinyl)-1-methyl-1,2,3,4-tetrahydroquinoline, compound 131b

To a solution of 8-bromo-1-methyl-1,2,3,4-tetrahydroquinoline, compound 131a (0.817 g, 3.613 mmol), and benzophenone hydrazone (0.709 g, 3.613 mmol) in 1,4-dioxane (17 ml) At room temperature under a nitrogen atmosphere, BINAP (225 mg, 0.361 mmol), palladium(II) acetate (81 mg, 0.361 mmol) and sodium tert-butoxide (1.042 mg, 10.84 mmol) were added and the mixture was heated at 100°C for 16 h. The resulting mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified using flash chromatography (SiO ₂ , heptane-ethyl acetate gradient). Pure fractions were combined and concentrated. The resulting solid was dried under reduced pressure to give 8-(2-(diphenylmethylene)hydrazinyl)-1methyl-1,2,3,4-tetrahydroquinoline, compound 131b (1.195 g, 96.9% yield). MS m/z 342.1 (M+H)+.

C. 8-Hydrazinyl-1-methyl-1,2,3,4-tetrahydroquinoline hydrochloride, compound 131c

To a solution of 8-(2-(diphenylmethylene)hydrazinyl)-1-methyl-1,2,3,4-tetrahydroquinoline, compound 131b (1.195 g, 3.5 mmol), in ethanol (3.5 ml) was added concentrated hydrochloric acid acid (7.0 ml) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, then treated with diethyl ether (25 ml) and water (10 ml). The layers were separated. The aqueous phase was concentrated under reduced pressure to give 8-hydrazinyl-1-methyl1,2,3,4-tetrahydroquinoline hydrochloride, compound 131c, which was used in the next step without purification (3.5 mmol crude product, 100% yield ). MS m/z 178.1 (M+H)+.

D. Ethyl 1-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 131d

Ethyl 2 -(ethoxymethylene)-4,4,4trifluoro-3-oxobutanoate, INT1 (0.672 g, 2.80 mmol), and the mixture was stirred at 80°C for 16 hours. The mixture was diluted with ethyl acetate and washed with water/NaI ICO3, organic layer separated and dried with MgSO ₄ , filtered and the filtrate was concentrated. The crude product was purified by flash chromatography (SiO ₂ , methanol-dichloromethane gradient). The pure fractions were combined and concentrated to give ethyl 1-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 131d (684 mg, yield 55.3%). 1H NMR (300 MHz, Chloroform-d) δ 1.38 (t, J=7.1 Hz, 3H), 1.69-2.06 (m, 2H), 2.18 (s, 3H), 2 .77 (t, J=6.4 Hz, 2H), 2.97-3.19 (m, 2H), 4.37 (k, J=7.2 Hz, 2H), 6.80 (t, J=7.6 Hz, 1H), 6.97-7.12 (m, 2H), 8.16 (s, 1H). MS m/z 354.0 (M+H)+.

E. 1-(1-Methyl-1,2,3,4-tetrahydroquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 131e

To ethyl 1-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-5-(trifluoromethyl)-1 N-pyrazoleY-carboxylate, compound 131d (0.684 g, 1.936 mmol), in ethanol (35 ml) sodium hydroxide (155 mg, 3.872 mmol) was added and the mixture was heated at 60°C for 3 hours. The mixture was cooled to room temperature and poured into a stirred 1N HCl/ice/ethyl acetate mixture. The organic layer was separated and washed with brine, then dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give 1-(1methyl-1,2,3,4-tetrahydroquinolin-8-yl)-5-(trifluoromethyl)-III- pyrazole-4-carboxylic acid, compound 131e (579 mg, 91.9% yield). MS m/z 326.0 (M +H)+.

F. 1-(1-Methyl-1,2,3,4-tetrahydroquinolin-8-yl)-5-(trifluoromethyl)-III-pyrazole-4-carbonyl chloride, compound 131f

To a solution of 1-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 131e (189 mg, 0.581 mmol), in dichloromethane (10 ml), 1-χλορ-Ν,Ν,2trimethyl-1-propenylamine (0.307 ml, 2.324 mmol) was added and the mixture was stirred at room temperature for 30 min to obtain a crude solution of 1-(1-methyl-1,2 ,3,4-tetrahydroquinolin-8-yl)-5(trifluoromethyl)-III-pyrazole-4-carbonyl chloride, compound 131f (0.581 mmol), which was immediately used as such.

G. No. (5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1,2,3,4-tetrahydroquinoline-8 -yl)5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 131

- 157 046082

1-(1-Methyl-1,2,3,4-tetrahydroquinolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, compound 131f (0.581 mmol), in pyridine (5 ml) at room temperature 5-amino-2-[1,2,3]triazol-2yl-nicotinonitrile, INT3 (162 mg, 0.872 mmol), in pyridine (5 ml) and the reaction mixture was stirred at room temperature for 20 hours. The mixture was diluted ethyl acetate and washed with water and saline. The organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated. Purification by flash chromatography (SiO ₂ , methanol-dichloromethane gradient) yielded N(5-cyano-6(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1 - methyl 1,2,3,4-tetrahydroquinolin-8-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxamide, compound 131, which was further purified by reverse phase chromatography, eluting with a sodium bicarbonate-water/methanol-acetonitrile gradient , yielding pure product (67 mg, 23.4%). ^1H NMR (300 MHz, Chloroform-d) δ 1.73-1.85 (m, 1H), 1.89-2.06 (m, 1H), 2.23 (s, 3H), 2.78 (t, J=6.4 Hz, 2H), 2.94-3.22 (m, 2H), 6.82 (t, J=7.7 Hz, 1H), 7.03 (d, J= 7.8 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 8.01 (s, 2H), 8.18 (s, 1H), 8.35 (s, 1H) , 8.84 (d, J=2.6 Hz, 1H), 8.95 (d, J=2.6 Hz, 1H). MS m/z 494.1 (M +H)+.

Example 132.

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-methyl-3,4-dihydro-2H-enzo[b] [1,4]oxazin8-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 132

A. tert-Butyl 8-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate, compound 132a

N,N-dimethylaminopyridine (0.057 g, 0.467 mmol) and triethylamine ( 1.36 ml, 9.8 mmol). The mixture was stirred for 30 minutes at room temperature, then di-tert-butyl dicarbonate (1.13 mL, 4.905 mmol) was added portionwise. The solution was stirred at room temperature overnight. The mixture was diluted using ethyl acetate. The organic layer was washed with water and brine, filtered, dried, and the filtrate was concentrated. The mixture was purified by flash chromatography (SiO ₂ , heptane-ethyl acetate gradient). Pure fractions were combined and concentrated. The resulting solids were dried under reduced pressure to give tert-butyl 8-bromo-2,3-dihydro-4Hbenzo^C^oxazine^-carboxylate, compound 135a (1.208 g, 82.3% yield). MS m/z 259.9 (M+H-tBu)+.

B. tert-Butyl 8-(2-(diphenylmethylene)hydrazinyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate, compound 132b

To a solution of tert-butyl 8-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate, compound 132a (1.156 g, 3.679 mmol), and benzophenone hydrazone (0.722 g, 3.679 mmol) in 1,4-dioxane (10 ml) at room temperature under nitrogen atmosphere, BINAP (229 mg, 0.368 mmol), palladium (II) acetate (83 mg, 0.368 mmol) and sodium tert-butoxide (1.061 g, 11.038) were added mmol) and the mixture was heated at 100°C for 16 hours. The resulting mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (SiO2, heptane-ethyl acetate gradient). Pure fractions were combined and concentrated. The resulting solids were dried under reduced pressure to give tert-butyl 8-(2-(diphenylmethylene)hydrazinyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate, compound 132b (0.820 g, yield 51.9%). MS m/z 430.1 (M+H)+.

C. 8-Hydrazinyl-3,4-dihydro-2H-benzo[b][1,4]oxazine hydrochloride, compound 132c

- 158 046082

To a solution of tert-butyl 8-(2-(diphenylmethylene)hydrazinyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4carboxylate, compound 132b (0.901 g, 2.098 mmol), in ethanol ( 2.2 ml) concentrated hydrochloric acid (4.4 ml) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, then treated with diethyl ether (25 ml) and water (10 ml). The layers were separated. The aqueous phase was concentrated under reduced pressure to give 8-hydrazinyl-3,4-dihydro-2H-benzo[b][1,4]oxazine hydrochloride, compound 132c, which was used in the next step without purification (2.098 mmol crude product, 100% yield %). MS m/z 166.1 (M+H)+.

D. Ethyl 1 -(3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 132d

To a solution of 8-hydrazinyl-3,4-dihydro-2H-benzo[b][1,4]oxazine hydrochloride, compound 132c (1.998 mmol), and triethylamine (0.557 ml, 4.0 mmol) in ethanol (15 ml) , ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (0.432 g, 1.80 mmol) was added and the mixture was stirred at 80°C for 16 hours. The mixture was diluted with ethyl acetate and washed with water/NaI ICO3, the organic layer was separated and dried with _MgSO4 , filtered and the filtrate was concentrated. The crude product was purified by flash chromatography (SiO ₂ , methanol-dichloromethane gradient). The pure fractions were combined and concentrated to give ethyl 1-(3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 132d (494 mg, 72.4% yield). 1H NMR (300 MHz, Chloroform-d) δ 1.37 (t, J=7.1 Hz, 3H), 3.33-3.50 (m, 2H), 4.10-4.28 (m, 2H), 4.36 (k, J=7.1 Hz, 2H), 6.66-6.75 (m, 2H), 6.82 (t, J=7.9 Hz, 1H), 8, 14 (s, 1H). MS m/z 342.0 (M+H)+.

E. Ethyl 1-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, compound 132e

, connection 132e

To a solution of ethyl 1-(3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylate, compound 132d (0.494 g, 1.447 mmol ), in acetic acid (7.9 ml) at RT, paraformaldehyde (0.435 g, 14.475 mmol) was added. The mixture was stirred at room temperature for 15 minutes, then sodium cyanoborohydride (0.455 g, 7.237 mmol) was added and the mixture was stirred at RT for 4 hours. The reaction was quenched with saturated aqueous Na ₂ CO ₃ then extracted with dichloromethane. The organic layer was separated, dried over MgSO ₄ , filtered, and the filtrate was concentrated to give ethyl 1-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5- (trifluoromethyl)-1H-pyrazole-4carboxylate, compound 132e (0.514 g, 99%). MS m/z 356.0 (M+H)+.

F. 1 -(4-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 13 2f

- 159 046082

To a solution of ethyl 1-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-(trifluoromethyl)-1Hpyrazole-4-carboxylate, compound 132e (0.514 g, 1.447 mmol), in ethanol (18 ml) was added sodium hydroxide (116 mg, 2.894 mmol) and the mixture was heated at 60°C for 3 hours. The mixture was cooled to room temperature and poured into a stirred mixture of 1N HCl/ice/ethyl acetate . The organic layer was separated and washed with brine, then dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give 1-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8- yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylic acid, compound 132f (473 mg, 99% yield). MC m/z 328.0 (M+H)+.

G. 1-(4-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, compound 132g

, 132g connection

To a solution of 1-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylic acid, compound 132f (474 mg, 1.447 mmol), in dichloromethane (12 ml) and N,Ndimethylformamide (0.1 ml) was added oxalyl chloride (0.248 ml, 2.894 mmol) and the mixture was heated to reflux for 1 hour. The mixture was concentrated to dryness and the residue dried under reduced pressure to constant weight to obtain crude 1-(4-methyl-3,4dihydro^H-benzo^C^oxazin^-yl^^trifluoromethyl^N-pyrazole^-carbonyl chloride, compound 132g (1.447 mmol), in the form of oil, which was immediately used in this form.

H. N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)niridin-3-yl)-1-(4-methyl-3,4-dihydro-2H-benzo[ b][1,4]oxazin-8-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 132

To a solution of 1-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-(trifluoromethyl)-1H-nirazol-4carbonyl chloride, compound 132g (1.447 mmol ), in dichloromethane (8 ml) and tetrahydrofuran (24 ml) at room temperature was added 5-amino-2-[1,2,3]triazol-2-yl-nicotinonitrile (539 mg, 2.894 mmol) followed by the addition of triethylamine ( 0.807 ml, 5.788 mmol) and the reaction mixture was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated. Purification by flash chromatography (SiO ₂ , ethyl acetate-heptane gradient) gave a mixture of product and starting material. The product was purified by reverse phase chromatography, eluting with an ammonium bicarbonate-water-acetonitrile gradient. The product fractions were combined and extracted with dichloromethane. The organic layer was dried (MgSO ₄ ) and concentrated to give pure N(5-cyano-6-(2H-1,2,3triazol-2-yl)niridin-3-yl)-1-(4-methyl-3,4 -dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-(trifluoromethyl)III-pyrazole-4-carboxamide, compound 132 (185 mg, 25.8%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.92 (s, 3H), 3.23-3.35 (m, 2H), 4.03-4.37 (m, 2H), 6, 67-6.77 (m, 1H), 6.84-6.99 (m, 2H), 8.31 (s, 2H), 8.49 (s, 1H), 8.90 (d, J= 2.5 Hz, 1H), 9.15 (d, J=2.4 Hz, 1H), 11.38 (s, 1H). MS m/z 496.1 (M+H)+.

Example 133.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxoisoindolin-4-yl)-5-(trifluoromethyl)III-pyrazole -4-carboxamide, compound 133

A. 4-(2-(Diphenylmethylene)hydrazinyl)isoindolin-1-one, compound 133a

- 160 046082

To a solution of 4-bromoisoindolin-1-one (1.0 g, 4.72 mmol) and benzophenone hydrazone (2.78 g, 14.15 mmol) in 1,4-dioxane (25 ml) at room temperature under nitrogen atmosphere BINAP (587 mg, 0.94 mmol), palladium(II) acetate (212 mg, 0.94 mmol) and sodium tert-butoxide (1.36 g, 11.15 mmol) were added and the mixture was heated at 100°C in for 16 hours. The resulting mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (SiO ₂ heptane-ethyl acetate gradient). Pure fractions were combined and concentrated. The product was dried under reduced pressure to give 4-(2(diphenylmethylene)hydrazinyl)isoindolin-1-one, compound 133a (1.544 g, 90.7% yield). MS m/z 328.0 (M+H)+.

B. 4-Hydrazinilisoindolin-1-one hydrochloride, compound 133b ⁿ %n

N.H.

Ό, compound 133b

To a solution of 4-(2-(diphenylmethylene)hydrazinyl)isoindolin-1-one, compound 133a (1.4 g, 4.28 mmol), in ethanol (4.3 ml) was added concentrated hydrochloric acid (8.6 ml) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, then treated with diethyl ether (25 ml) and water (10 ml). The layers were separated. The aqueous phase was concentrated under reduced pressure to give 4-hydrazinylisoindolin-1-one hydrochloride, compound 1336b, which was used in the next step without purification (3.20 mmol crude product, 75% yield). MS m/z 164.0 (M+H)+.

C. Ethyl 1-(1-oxoisoindolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 133 c

, connection 133c

Ethyl 2-(ethoxymethylene)- 4,4,4-trifluoro3-oxobutanoate, INT1 (768 mg, 3.20 mmol) and the mixture was stirred at 80°C for 16 hours. The mixture was diluted with ethyl acetate and washed with water/NaHCO3, the organic layer was separated and dried with MgSO ₄ , filtered, and then the filtrate was concentrated. The crude product was purified by flash chromatography (SiO ₂ , methanol-dichloromethane gradient). The pure fractions were combined and concentrated to give ethyl 1-(1-oxoisoindolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 133c (120 mg, 9.4% yield). ^1H NMR (300 MHz, Chloroform-d) δ 1.40 (t, J=7.1 Hz, 3H), 4.24-4.49 (m, 4H), 6.56 (s, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.65 (t, 1H), 8.04 (d, J=7.5 Hz, 1H), 8.18 (s, 1H). MS m/z 340.1 (M+H)+.

D. (1-Oxoisoindolin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 133d

To a solution of ethyl 1-(1-oxoisoindolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 133c (70 mg, 0.21 mmol), in THF-H2O (8 ml) was added sodium hydroxide (12.4 mg, 0.31 mmol) and the mixture was stirred at RT for 3 hours. The mixture was poured onto a stirred 1N HCl/ice/ethyl acetate mixture. The organic layer was separated and washed with brine, then dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give 1-(1-oxoisoindolin-4-yl)-5-161 046082 (trifluoromethyl)-1H-pyrazole-4-carboxylic acid , compound 133d (66 mg, 97% yield). MS m/z 311.9 (m+H)+.

E. 1-(2-(tert-Butoxycarbonyl)-1-oxoisoindolin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 133e

di-tert-Butyl decarbonate (56.8 mg, 0.26 mmol), DMAP (4.24 mg, 0.035 mmol) and triethylamine (52.7 mg, 0.52 mmol) were added to a solution of 1-(1-oxoisoindoline- 4-yl)-5-(trifluoromethyl)-1H-pyrazole-4carboxylic acid, compound 133d (54 mg, 0.17 mmol), in dichloromethane (5 ml). The mixture was stirred at 30°C for 48 hours. The crude product was purified by preparative high performance liquid chromatography to give 1-(2-(tert-butoxycarbonyl)-1-oxoisoindolin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4 -carboxylic acid, compound 133e, as a yellow solid (33 mg, 46.24%). [M+1] ⁺ 356.0.

F. tert-Butyl 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)III-pyrazole -1-yl)-1-oxoisoindoline-2-carboxylate, compound 133f

Phosphorus oxychloride (29.4 μL, 0.32 mmol) was added to a solution of 1-(2-(tert-butoxycarbonyl)-1oxoisoindolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 133e (33 mg, 0.08 mmol), 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (15.70 mg, 0.08 mmol) , pyridine (32.4 μl, 0.40 mmol) in CH ₂ Cl ₂ (5 ml). The mixture was stirred at room temperature for 2 hours and 5 ml of H ₂ O was added to the mixture. Added sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (5 ml*3). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give crude tert-butyl 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2- yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-III-pyrazol-1-yl)-1-oxoisoindoline-2-carboxylate, compound 133f (55.2 mg, 85%).

G. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-oxoisoindolin-4-yl)-5-(trifluoromethyl)III -pyrazole-4-carboxamide, compound 133

HCl in dioxane (1M) was added to the solution of tert-butyl 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5 -(trifluoromethyl)-1 H-pyrazol-1 -yl)-1-oxoisoindoline-2-carboxylate, compound 133f (50 mg, 0.073 mmol), in CH ₂ Cl ₂ (3 ml). The mixture was stirred at RT for 2 hours. The solvent was evaporated under reduced pressure. The reaction mixture was purified by preparative high-performance liquid chromatography to obtain N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1oxoisoindolin-4-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 133, as a pale white solid (13 mg, 36.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.26 (1H, s), 8.81 (2H, d, J=2.20 Hz), 8.63 (1H, d, J =2.43 Hz), 8.50 (1H, s) 8.16 (2H, s), 7.91 (1H, dd, J=7.06, 1.32 Hz), 7.69-7 .78 (2 N, m), 4.31 (2 N, s). LC-MS: (ES, m/z): [M+1] ⁺ 488.9.

Example 134.

1-(6-Aminopyridin-2-yl)^-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)III-pyrazole -4-carboxamide, compound 134

- 162 046082

A. Ethyl 1-(6-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 134a

A solution of 2-bromo-6-hydrazinylpyridine (3.0 g, 15.96 mmol) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro

3-Oxobutanoate, INT1 (5.75 g, 23.93 mmol), in ethanol (150 ml) was stirred at 80°C overnight and then cooled to RT. The solvent was removed under reduced pressure to give a yellow oil. The oil was purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 100/0 - petroleum ether/EtOAc 80/20). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the desired product as a yellow solid. LC-MS: (ES, m/z): [M+1]+ 365.6.

B. Ethyl 1-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 134b

, connection 134b

Palladium acetate (93.23 mg, 0.41 mmol) and Xantphos (238.36 mg, 0.41 mmol) in dioxane (75 ml) were stirred at RT for 10 min under nitrogen atmosphere. Ethyl 1-(6-bromopyridin-2-yl)-5(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 134a (3.0 g, 8.24 mmol), Cs ₂ CO ₃ (8.05 g, 24.72 mmol) and tert-butyl carbamate (1.16 g, 9.89 mmol) at room temperature. The reaction mixture was then left to warm at 90°C overnight and then cooled to RT. The reaction mixture was filtered through a layer of diatomaceous earth. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 100/0 - petroleum ether/EtOAc 80/20). The desired fractions were collected and the solvent was concentrated to dryness under reduced pressure to obtain the desired product as a white solid.

C. 1-(6-((tert-Butoxycarbonyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 134c

To a solution of ethyl 1-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxylate, compound 134b (100 mg, 0.25 mmol), in THF/ methanol/H ₂ O (1:1:1) (3 ml), lithium hydroxide (31.44 mg, 0.75 mmol) was added and the mixture was stirred at RT for 3 hours. The mixture was poured onto a stirred mixture of 1N HCl/ice/ ethyl acetate. The organic layer was separated and washed with brine, then dried (MgSO ₄ ), filtered, and the filtrate was concentrated and concentrated to give compound 134c (90 mg, 96.8% yield).

D. tert-Butyl (6-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H -pyrazol-1-yl)pyridin-2-yl)carbamate, compound 134d

- 163 046082

POCl ₃ (41.8 rL, 0.47 mmol) was added to a solution of 1-(6-((tert-butoxycarbonyl)amino)pyridin-2yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 134c (70 mg, 0.19 mmol), 5-amino2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, INT3 (45.51 mg, 0.24 mmol), pyridine (152 µl, 0.98 mmol) in CH ₂ Cl ₂ (3 ml). The mixture was stirred at RT for 1 hour. Water (5 ml) and CH ₂ Cl ₂ (10 ml) were added to the mixture. The organic layer was washed with brine (5 ml), dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give 134d (70 mg, 68.9% yield) as a white solid. LCMS (ESI) m/z M+H: 563.1.

E. 1-(6-Aminopyridin-2-yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 134

tert-Butyl (6-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)1H-pyrazol- 1-yl)pyridin-2-yl)carbamate 134d (70 mg, 0.13 mmol) was added to TFA/DCM (2 mL, 1:4). The mixture was stirred at RT for 4 hours. A solution of 1M NaOH was added to adjust the pH to 7~8. The aqueous portion was extracted using DCM (5 ml x3). The separated organic layer was dried (MgSO ₄ ), filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel flash column chromatography (eluent: 100/0 to 0/100 petroleum ether/ethyl acetate), evaporated and dried to give 134 (57.9 mg, 43.2%) as a white solid. . 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.37 (s, 2H) 6.58 (d, J=8.38 Hz, 1H) 6.74 (d, J=7.72 Hz, 1H) 7.60 (t, J=8.05 Hz, 1H) 8.28 (s, 2H) 8.33 (s, 1H) 8.82 (d, J=2.43 Hz, 1H) 9.03 (d, J=1.98 Hz, 1H) 11.25 (br. s, 1H). LC-MS: (ES, m/z): [M+1]+ 441.0.

Example 135.

1-(2-Cyano-4-fluorophenyl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide, compound 135

Pd(dba) ₂ (7.03 mg, 0.0077 mmol) and dppf (8.51 mg, 0.015 mmol) were added to a solution of 1-(2-bromo-4fluorophenyl)-N-(5-cyano-6-( 2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide, compound 50 (100 mg, 0.19 mmol), dicyanozinc (13 .52 mg, 0.12 mmol) and zinc (3.01 mg, 0.046 mmol) in DMA (2 ml) under N2 atmosphere. The reaction mixture was heated at 120°C for 4 hours. The mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography. The pure fractions were collected and the solvent was evaporated under reduced pressure to give compound 135 as a white solid (50 mg, 56%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.91 (td, J=8.54, 2.98 Hz, 1H) 8.04 (dd, J=8.93, 4, 74 Hz, 1H) 8.26 (dd, J=8.27, 2.98 Hz, 1H) 8.31 (s, 2H) 8.58 (s, 1H) 8.86 (d, J=2, 43 Hz, 1H) 9.08 (d, J=2.43 Hz, 1H) 11.36 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 467.9.

Example 136.

No.(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-cyano-4-fluorophenyl)-5-(trifluoromethyl)-Spirazol- 4-carboxamide, compound 136

- 164 046082

Pd(dba) ₂ (6.90 mg, 0.0075 mmol) and dppf (6.27 mg, 0.011 mmol) were added to a solution of 1-(2-bromo-4fluorophenyl)-N-(5-chloro-6-( 2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 84 (100 mg, 0.19 mmol), dicyanozinc (11 .51 mg, 0.10 mmol) and zinc (1.48 mg, 0.023 mmol) in DMA (2 ml) under N2 atmosphere. The reaction mixture was heated at 120°C for 4 hours. The mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography. The pure fractions were collected and the solvent was concentrated under reduced pressure to give compound 136 as a white solid (40 mg, 44%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.91 (td, J=8.49, 3.09 Hz, 1H), 8.03 (dd, J=8.93, 4 .74 Hz, 1H), 8.19 (s, 2H), 8.26 (dd, J=8.05, 2.76 Hz, 1H), 8.59 (s, 1H), 8.66 (d , J=2.21 Hz, 1H), 8.85 (d, J=1.98 Hz, 1H), 11.32 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 476.9.

Example 137.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(methylthio)phenyl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide, compound 137

A. (2-(Methylthio)phenyl)hydrazine, compound 137a

NH ₂

, connection 137a

To a stirred solution of 2-(methylthio)aniline (500 mg, 2.85 mmol) in conc. HCl (4.1 ml) at

At 5°C, a solution of sodium nitrite (295 mg, 4.27 mmol) in water (1.0 ml) was slowly added at a temperature below 0°C. The reaction mixture was stirred at 0°C for 1 hour and a solution of tin(II) chloride dihydrate (1.606 g, 7.12 mmol) dissolved in conc. HCl (1 ml). The mixture was then stirred at room temperature for 16 hours. The mixture was adjusted to pH 12-14 with 20% aqueous sodium hydroxide solution. The mixture was extracted using ethyl acetate (30 ml x3). The combined organic layers were washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give the crude product (400 mg, 91.1%) as a brown solid, which was used in the next step without additional cleaning.

B. Ethyl 1-(2-(methylthio)phenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound 137b

, connection 137b

A solution consisting of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (1246 mg, 5.19 mmol), (2-(methylthio)phenyl)hydrazine, compound 137a (400 mg, 2.59 mmol) and ethanol (20 ml), stirred at 80°C for 16 h, and then cooled to room temperature. The resulting solution was concentrated to dryness under reduced pressure to obtain the crude product, which was purified using flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to obtain the title compound (800 mg, 92.5%) in the form of a gray solid. LCMS (ESI) m/z M+1: 330.9.

C. 1-(2-(Methylthio)phenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 137с

- 165 046082

, connection 137c

Lithium hydroxide (100.7 mg, 2.40 mmol) was added to a solution of ethyl 1-(2-(methylthio)phenyl)-5(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 137b (400 mg, 1.2 mmol), in MeOH:H ₂ O = 1:1 (10 ml). The mixture was reacted at room temperature for 3 hours. The solvent was evaporated under reduced pressure and water (10 ml) was added to the mixture. The mixture was acidified (pH 5) by adding 1M hydrochloric acid and extracted using ethyl acetate (30 ml x3). The combined organic layers were washed with brine, dried with anhydrous MgSO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the product (350 mg, 96.5%) as a yellow solid. ^1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.20 (s, 1H), 7.48-7.42 (m, 1H), 7.32 (d, J=7.9 Hz , 1H), 7.23 (d, J=4.4 Hz, 2H), 2.36 (s, 3H).

D. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(methylthio)phenyl)-5-(trifluoromethyl)-Spirazole -4-carboxamide, compound 137

1-(2-(Methylthio)phenyl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 137c (350 mg, 1.16 mmol), 5-amino-2-(2H-1,2 ,3-triazol-2-yl)nicotinonitrile, INT 2 (226.5 mg, 1.16 mmol), pyridine (106.218 mg, 2.012 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (335, 1 mg, 2.32 mmol). The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and extracted using CH ₂ Cl ₂ (30 ml x2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated to dryness under reduced pressure to obtain the crude product, which was purified by preparative HPLC (50-80% (v/v) CH3CN and H ₂ O with 0 .05% HCl) and lyophilized to dryness to give the title compound (80 mg, 13.7%). ^1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.77 (d, J=2.2 Hz, 1H), 8.51 (d, J=2.2 Hz, 1H), 8, 16 (s, 1H), 8.04 (s, 1H), 7.95 (s, 2H), 7.60-7.52 (m, 1H), 7.42 (d, J=7.9 Hz , 1H), 7.36-7.31 (m, 2H), 2.45 (s, 3H). LC-MS: (ES, m/z): [M+1]+ 480.0.

Example 138.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(methylsulfonyl)phenyl)-5(trifluoromethyl)-III-pyrazol- 4-carboxamide, compound 138

To a solution of N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(methylthio)phenyl)-5-(trifluoromethyl)-III -pyrazole-4-carboxamide, compound 137 (100 mg, 0.20 mmol), mCPBA (93.1 mg, 0.46 mmol) was added to CH ₂ Cl ₂ (2 ml). The mixture was stirred at RT for 3 hours. Saturated Na ₂ SO ₃ (5 ml) and saturated NaHCO ₃ (5 ml) were added to the mixture. The resulting mixture was extracted using CH ₂ Cl ₂ (10 ml x2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography (petroleum ether: EtOAc=3:1-0:1). The desired fractions were evaporated to dryness to obtain compound 138 as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.73 (d, J=2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.31 (s, 1H), 8.27-8.22 (m, 1H), 8.12 (s, 1H), 7.94 (s, 2H), 7.88-7.82 (m, 2H), 7.54 (br. d, J=8.4 Hz, 1H), 3.21 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 512.0.

Example 139.

1-(6-Amino-5-cyanopyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 139

- 166 046082

A. tert-Butyl (6-chloro-3-cyanopyridin-2-yl)carbamate, compound 139a ° U~

HN

Νξ—'Jj—CI \=/ , connection 139a

To a solution of 2-amino-6-chloronicotinonitrile (118.9 mg, 6.5 mmol), DMAP (31.8 mg, 0.26 mmol) and TEA (988.4 mg, 9.8 mmol) in dichloromethane (15 ml) di-tert-butyl decarbonate (4263.5 mg, 19.5 mmol) was added at RT and the mixture was stirred at RT for 12 hours. Satur. NaHCO ₃ (15 ml) and the mixture was extracted using EtOAc (20 ml x2). The combined organic layers were dried with Na ₂ SO ₄ . After filtration, the solvent was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/EAAc=100:0-70:30). The desired fractions were collected and the solvent was removed to obtain a white solid (1500 mg, 90.8 mmol). LCMS (ESI) m/z M-55: 198.0.

B. tert-Butyl (3-cyano-6-hydrazinylpyridin-2-yl)carbamate, compound 139b ° U ^-

HN\-NH?

Νξ—ς ΝΗ \=/ , connection 139b

A mixture of palladium(P)(pi-cinnamyl) chloride dimer (153.2 mg, 0.27 mmol) and \-[2-(di-1adamantylphosphino)phenyl]morpholine (274.1 mg, 0.59 mmol) in dioxane (20 ml) was deaerated using argon 4 times. The resulting clear yellow solution was stirred at RT under an argon atmosphere for 10 min. Tert-butyl (6-chloro-3-cyanopyridin-2yl)carbamate, compound 139a (1500 mg, 5.9 mmol), and tBuONa (1136.5 mg, 11.8 mmol) were added to the mixture and deaerated using argon 4 times. The resulting yellow reaction mixture was stirred at RT for 5 min, then treated with hydrazine (592.0 mg, 11.8 mmol) using a syringe and then deaerated using argon 4 times. The mixture was stirred at 50° C. under argon for 2 hours. After filtering the reaction mixture, the solvent was concentrated under reduced pressure to obtain the crude product as a yellow solid. LCMS (ESI) m/z M-55: 194.1.

C. Ethyl 1-(6-((tert-butoxycarbonyl)amino)-5-cyanopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole4-carboxylate, compound 139c o U—

HN

Vn N.

N=—С N 1 \=/ ^F X %

I compound 139c tert-Butyl (3-cyano-6-hydrazinylpyridin-2-yl)carbamate (1100 mg, 1.45 mmol) was added to a solution of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate , INT1 (522.7 mg, 2.18 mmol), in EtOH (20 ml) and reacted at 80°C for 1 hour. The mixture was concentrated under reduced pressure, then purified using FFS (petroleum ether/ethyl acetate= 100:0 petroleum ether/ethyl acetate=80:20). The desired fractions were collected and the solvent was concentrated under reduced pressure to obtain the product as a white solid. LCMS (ESI) m/z M-55: 370.0.

D. 1-(6-((tert-Butoxycarbonyl)amino)-5-cyanopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 13 9d

LiOH (125.58 mg, 5.24 mmol) was added to the solution of ethyl 1-(6-((tert-butoxycarbonyl)amino)-5cyanopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (500 mg, 5.24 mmol) in THF/H2O (1:1,

- 167 046082 ml) and reacted at 23 °C for 2 hours. The solvent was concentrated under reduced pressure. A 1M HCl solution was added to the mixture to adjust the pH to 5 and the mixture was extracted using EtOAc (30 ml x 3). The combined organic layers were dried with Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude product as a brown oil (470 mg, 94.0%). LCMS (ESI) m/z M-55: 341.8.

E. tert-Butyl (3-cyano-6-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-2-yl)carbamate, compound 139e

N

, connection 139e

1-(6-((tert-Butoxycarbonyl)amino)-5-cyanopyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4carboxylic acid (230 mg, 0.43 mmol), 5-amino-2 -[1,2,3]triazol-2-yl-nicotinonitrile, INT3 (94.3 mg, 0.51 mmol), POCl ₃ (88.8 mg, 0.58 mmol) were dissolved in CH ₂ Cl ₂ (8 ml) and pyridine (114.5 mg, 1.45 mmol) was added. The mixture was stirred at 25°C for 1 hour. Saturated. NaHCO ₃ (10 ml) and the mixture was extracted using CH ₂ Cl ₂ (15 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil, which was purified with FFS (petroleum ether/ethyl acetate=50:50 - petroleum ether/ethyl acetate=0: 100). The desired fractions were collected and the solvent was concentrated under reduced pressure to obtain the desired product as a yellow solid. LCMS (ESI) m/z M-55: 466.1.

F. 1-(6-Amino-5-cyanopyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 139

Silica gel (214.4 mg, 3.57 mmol) was added to the solution of tert-butyl(3-cyano-6-(4-((5-cyano-6-(2H1,2,3-triazol-2-yl)pyridine -3-yl)carbamoyl)-5-(trifluoromethyl)-III-pyrazol-1-yl)pyridin-2yl)carbamate (150 mg, 0.24 mmol) in toluene (10 ml). The mixture was reacted at 110°C for 1 hour. The solution was concentrated to give a white solid, which was subsequently purified by preparative HPLC (63-33% (v/v) CH ₃ CN and H ₂ O with 0.05 % HCl) and the resulting residue was lyophilized to dryness to obtain the title compound (35.2 mg, 30.9%). LCMS (ESI) m/z M+1: 466.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.99 (d, J=8.16 Hz, 1H), 7.33 (s, 2H), 8.15 (d, J= 8.16 Hz, 1H), 8.27 (s, 2H), 8.40 (s, 1H), 8.80 (d, J=2.43 Hz, 1H), 9.03 (d, J= 2.43 Hz, 1H).

Example 140.

1-(6-Amino-5-cyanopyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 140

A. tert-Butyl (6-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)III- pyrazol-1-yl)-3-cyanopyridin-2-yl)carbamate, compound 140a

L.

N

Cl, compound 140a

1-(6-((tert-Butoxycarbonyl)amino)-5-cyanopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-168 046082 carboxylic acid (230 mg, 0.58 mmol), 5 -chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (118.9 mg, 0.61 mmol), POCl ₃ (88.8 mg, 0.58 mmol) was dissolved in CH ₂ Cl ₂ (8 ml) and pyridine (106.5 mg, 0.70 mmol) was added. The mixture was stirred at 25°C for 1 hour. Saturated. NaHCO ₃ (10 ml) and extracted using CH ₂ Cl ₂ (15 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give the crude product as a brown oil. The oil was purified using FFS (petroleum ether/ethyl acetate=50:50 - petroleum ether/ethyl acetate=0:100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid. LCMS (ESI) m/z M+23:597.3.

B. 1-(6-Amino-5-cyanopyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 140

Silica gel (344.890 mg, 5.740 mmol) was added to the solution of tert-butyl(6-(4-((5-chloro-6-(2H-1,2,3triazol-2-yl)pyridin-3-yl)carbamoyl)- 5-(trifluoromethyl)-1H-pyrazol-1-yl)-3-cyanopyridin-2-yl)carbamate (220 mg, 0.38 mmol) in toluene (10 ml). The mixture was reacted at 110°C for 1 hour. The solution was concentrated to give a white solid, which was purified by preparative HPLC (63-33% (v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to obtain the title compound (110 mg, 59.1%). LCMS (ESI) m/z M+1: 474.9. ¹ H NMR (400 MHz,

DMSO-d ₆ ) δ ppm 6.99 (d, J=8.16 Hz, 1H), 7.33 (s, 2H), 8.05-8.19 (m, 3H), 8, 38 (s, 1H), 8.59 (d, J=2.21 Hz, 1H), 8.76 (d, J=2.21 Hz, 1H), 11.11 (s, 1H).

Example 141.

1-(6-Amino-3-methylpyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 141

A. 2-Hydrazinyl-3-methylpyridine, 141a /HL <ζ y—ΝΗ ^— Ν ₅ compound 141a

A solution consisting of 2-fluoro-3-methylpyridine (4 g, 36.0 mmol) in hydrazine (1 ml) was stirred at 60°C for 3 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure with yielding crude title product 141a (4 g, 90.2% yield).

B. Ethyl 1-(3-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 141b

A solution consisting of 2-hydrazinyl-3-methylpyridine (4 g, 32.5 mmol) and ethyl 2-(ethoxymethylene)4,4,4-trifluoro-3-oxobutanoate (7.8 g, 32.5 mmol) in EtOH (5 ml), stirred at 60°C for 3 hours. The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain the crude title product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-70:30). The solvent was concentrated under reduced pressure to obtain the title compound (8 g, 82.3% yield) as a yellow solid. LCMS (ESI) m/z M+1: 299.9.

C. 2-(4-(Ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-3-methylpyridine 1-oxide, compound 141c

- 169 046082

, connection 141c

To a cooled solution (0°C) of ethyl 1-(3-methylpyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4carboxylate (8 g, 26.7 mmol) in CH ₂ Cl ₂ (50 ml) 3-chlorobenzoperoxoic acid (1.38 g, 80.2 mmol) was added over 10 min. The mixture was warmed to RT and left to stir overnight. The solution was washed twice with semi-saturated aqueous sodium bisulfite solution (50 ml) to destroy excess oxidizing agent. The mixture was then washed (2x) with semi-saturated aqueous potassium carbonate solution (50 ml) and brine (50 ml). The extracts were dried over magnesium sulfate, filtered and the filtrate was concentrated to give a crude oil. The residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 100/0 to 20/80). The desired fractions were collected and concentrated to dryness under reduced pressure to give compound 141c (3.8 g, 38.6% yield) as a yellow solid. LCMS (ESI) m/z M+1: 315.9.

D. Ethyl 1-(6-chloro-3-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 141d

, connection 141d

A solution consisting of phosphoryl trichloride (3.16 g, 20.6 mmol) and 2-(4-(ethoxycarbonyl)-5(trifluoromethyl)-1H-pyrazol-1-yl)-3-methylpyridine 1-oxide (3, 8 g, 10.3 mmol) in CHCl ₃ (20 ml), stirred at 60°C for 3 hours. Saturated. NaHCO ₃ solution (50 ml). The resulting solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain the crude title product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-70:30). The solvent was concentrated under reduced pressure to give the title compound (2.6 g, 75.5% yield) as a yellow solid. LCMS (ESI) m/z M+1: 333.9.

E. Ethyl 1-(6-((tert-butoxycarbonyl)amino)-3-methylpyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole 4-carboxylate, compound 141e

, connection 141e

2-(4-(Ethoxycarbonyl)-5-(trifluoromethyl)-III-pyrazol-1-yl)-3-methylpyridine 1-oxide (2.6 g, 7.79 mmol), tert-butyl carbamate (1.10 g, 9.35 mmol) and cesium carbonate (5.08 g, 15.58 mmol) were dissolved in dioxane, Pd ₂ (dba) ₃ (356.7 mg, 0.39 mmol) and Xantphos (450.8 mg) were added , 0.78 mmol) and purged with N2 for 1 min. The reaction mixture was stirred at 100°C for 16 hours. The mixture was filtered through a pad of celite and the layer was washed with ethyl acetate (50 ml x2). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-70:30). The solvent was evaporated to give the title compound (1.5 g, 46.5% yield) as a yellow solid. LCMS (ESI) m/z M+1: 359.0.

F. 1-(6-((tert-Butoxycarbonyl)amino)-3-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 141f

- 170 046082

Lithium hydroxide (433.4 mg, 18.10 mmol) was added to the solution of ethyl 1-(6-((tert-butoxycarbonyl)amino)-3-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxylate (1.5 g, 3.62 mmol) in

THF/H ₂ O=1:1 (10 ml). The mixture was reacted at 23°C for 2 hours. The solvent was concentrated under reduced pressure. A 1 M HCl solution was added to the mixture to adjust the pH of the mixture to 5 to form a solid. The solid was collected by filtration to give the title compound 141f (1.3 g, 71.1% yield). LCMS (ESI) m/z M+1: 330.9.

G. tert-Butyl (6-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1 H-pyrazol-1-yl)-5-methylpyridin-2-yl)carbamate, compound 141g

, connection 141g

POCl ₃ (0.29 ml) was added to a mixture of 5-amino-2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, INT3 (147.4 mg, 0.79 mmol), 1-( 6-((tert-butoxycarbonyl)amino)-3-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (400 mg, 0.792 mmol) and pyridine (0.32 ml, 3 .96 mmol) in CH2C12 (10 ml). The reaction mixture was stirred at 25°C for 2 hours. Saturated solution was added to the mixture. NaHCO ₃ solution (20 ml). The mixture was extracted using CH2C12 (30 ml x2). The combined organic layers were washed with brine, dried with anhydrous Na ₂ SO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the crude product as a brown oil,

141g (500 ml, yield 44.7%). LCMS (ffiP)m/z M+1: 555.2.

H. 1-(6-Amino-3-methylpyridin-2-yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 141

HCl/dioxane (0.663 ml) was added to the mixture of tert-butyl(6-(4-((5-cyano-6-(2H-1,2,3-triazol-2yl)pyridin-3-yl)carbamoyl)- 5-(trifluoromethyl)-1H-pyrazol-1-yl)-5-methylpyridin-2-yl)carbamate (500 mg, 0.35 mmol) and CH ₂ Cl ₂ (5 ml). The reaction mixture was stirred at 25°C for 2 hours. Saturated solution was added to the mixture. NaHCO ₃ solution (20 ml). The mixture was extracted using CH ₂ Cl ₂ (30 ml x2). The combined organic layers were washed with brine, dried with anhydrous Na ₂ SO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified by preparative high performance liquid chromatography.

Column: Phenomenex Gemini 150*25 mm* 10 µm; conditions: A: water (0.05% HCl); B. MeCN; at the beginning: A (90%) and B (10%), at the end: A (10%) and B (90%). The pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to give the product as a white solid (45 mg, 27.8% yield). LCMS (ESI) m/z M+1: 455.0. 1H

NMR (400 MHz, DMSO-d6) δ ppm 1.88 (s, 3H), 6.62 (d, J=8.28 Hz, 1H), 7.52 (d, J=8.53 Hz, 1H), 8.32 (s, 2H), 8.44 (s, 1H), 8.87 (d, J=2.51 Hz, 1H), 9.09 (d, J=2.26 Hz, 1H), 11.22 (s, 1H).

Example 142.

1-(2-Amino-5-methylpyridin-4-yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 142

A. 4-Chloro-3-methylpyridine 1-oxide, compound 142a

CI, connection 142a

A solution of 4-chloro-3-methylpyridine (6 g, 47.0 mmol) in CH ₂ Cl ₂ (30 ml) was stirred at room temperature overnight. Added sat. NaHCO ₃ to quench the reaction (pH 8-9). Extract mixture

- 171 046082 was performed using CH2C12 (50 ml x3). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates were concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (2.9 g, 42.9% yield) as a yellow solid. ¹ H NMR (400 MHz, chloroformd) δ ppm 2.33 (s, 3H), 7.25 (d, J=6.84 Hz, 1H), 8.01 (br.d, J=6 .61 Hz, 1H), 8.11 (s, 1H).

B. 4-Hydrazinyl-3-methylpyridine 1-oxide, compound 142b

A solution of 4-chloro-3-methylpyridine 1-oxide (2.9 g, 20.2 mmol) in hydrazine (5.16 g, 98%) was stirred at 80°C overnight. The mixture was concentrated to give the title compound (2.8 g, crude product) as a yellow solid.

C. 4-(4-(Ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-3-methylpyridine 1-oxide, compound 142c

Solution of 4-hydrazinyl-3-methylpyridine 1-oxide (2.8 g, 20.1 mmol), ethyl 2-(ethoxymethylene)-4,4,4trifluoro-3-oxobutanoate, INT1 (9.67 g, 40.2 mmol), in EtOH (30 ml) was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (3.13 g, 49.3% yield) as a yellow solid. LCMS (ESI) m/z M+1: 316.1.

D. Ethyl 1-(2-chloro-5-methylpyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate and ethyl 1-(2chloro-3-methylpyridin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 142d

Cl, compound 142d

A solution of 4-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-3-methylpyridine 1-oxide (2.3 g,

7.3 mmol) in POCl ₃ (15 ml) was stirred at 100°C for 2 hours. The mixture was diluted with CH ₂ Cl ₂ (30 ml). Saturated solution was added dropwise to the mixture. Na ₂ CO ₃ solution with stirring at 0°C to bring the pH of the solution to 8-9. The mixture was extracted using CH ₂ Cl ₂ (50 ml x3). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates were concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 50/50). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (1.57 g, 64% yield) as a yellow solid. LCMS (ESI) m/z M+1: 333.8, ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (t, J=7.06 Hz, 3H), 2.08 (s, 3H), 4.40 (k, J=7.06 Hz, 2H), 7.29 (s, 1H), 8.21 (s, 1H), 8.45 (s, 1H); ^1H NMR (400 MHz, chloroform-d) δ ppm 1.40 (t, J=7.06 Hz, 3H), 2.12 (s, 3H), 4.40 (k, J=7 .06 Hz, 2H), 7.19 (d, J=5.29 Hz, 1H), 8.21 (s, 1H), 8.43 (d, J=5.07 Hz, 1H).

E. Ethyl 1-(2-((tert-butoxycarbonyl)amino)-5-methylpyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole4-carboxylate, compound 142e

, connection 142e

To a solution of ethyl 1-(2-chloro-3-methylpyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1.7 g, 0.61 mmol), tert-butyl carbamate (1 .7 g, 2.55 mmol) and Cs ₂ CO ₃ (4.98 g, 15.3 mmol) in dioxane (20 ml) added Pd(OAc) ₂ (80.1 mg, 0.36 mmol) and Xantphos (206.3 mg, 0.36 mmol) with N2 bubbling.

- 172 046082

The mixture was stirred at 100°C overnight under N2 atmosphere. The reaction solution was filtered and washed with ethyl acetate (30 ml). The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (1.2 g, 57% yield) as a yellow solid. LCMS (ESI) m/z M+1: 315.1.

F. ^QuinolinA-yl^fluoromethylfN-pyrazole-carboxylic acid, compound 142f

Solution of ethyl 1 -(2-((tert-butoxycarbonyl)amino)-5-methylpyridin-4-yl)-5-(trifluoromethyl)-III pyrazole-4-carboxylate (1.2 g, 0.61 mmol), LiOHHiO (243.0 mg, 0.39 mmol) in THF/H2O (2/1, 10 ml) was stirred at room temperature for 3 hours. A solution of 1N HCl was added to neutralize the reaction solution. The mixture was extracted using ethyl acetate (5 ml x3). The organic layer was isolated, dried (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated under reduced pressure to give the title compound (119 mg, crude) as a yellow solid. LCMS (ESI) m/z M+1: 331.1.

G. tert-Butyl (4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1 H-pyrazol-1-yl)-5-methylpyridin-2-yl)carbamate, compound 142g

Phosphorus oxychloride (219.6 μl, 0.42 mmol) was added to a solution of 1-(quinolin-4-yl)-5-(trifluoromethyl)-N-pyrazole-4-carboxylic acid (500 mg, 1.18 mmol), 5-amino-2-[1,2,3]triazol-2-ylnicotinonitrile, INT3 (263.1 mg, 1.41 mmol), pyridine (952.6 μl, 11.78 mmol) in CH ₂ Cl ₂ ( 5 ml). The mixture was stirred at room temperature for 1 hour. Water (5 ml) was added to the mixture. Added sat.

NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (10 ml x3). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (600 mg, crude product). LCMS (ESI) m/z M+1: 555.2.

H. 1-(1-Aminoisoquinolin-4-yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 142

A mixture of tert-butyl (4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-III- pyrazol-1-yl)-5-methylpyridin-2-yl)carbamate (600 mg, 0.74 mmol) and silica gel (1334.9 mg,

22.22 mmol) in toluene (10 ml) was stirred at 120°C overnight. The mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and evaporated to give the product, which was further purified by preparative HPLC (10-40% (v/v) CH ₃ CN and H ₂ O with 0.05% HCl) and lyophilized to dryness to give the title compounds (80 mg, 23.2%). LCMS (ESI) m/z M+1: 454.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.88 (s, 3H), 6.99 (s, 1H), 8.10 (s, 1H), 8.30 (s, 2H), 8.61 (s, 1H), 8.86 (d, J=2.43 Hz, 1H), 9.10 (d, J=2.43 Hz, 1H), 11.42 (s, 1H).

Example 143.

1-(2-Amino-3-methylpyridin-4-yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 143

- 173 046082

A. Ethyl 1-(2-amino-3-methylpyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 143a

To a solution of ethyl 1-(2-chloro-5-methylpyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (750 mg, 1.12 mmol), tert-butyl carbamate (533.6 mg, 2.55 mmol) and Cs ₂ CO ₃ (2.23 g, 6.83 mmol) in dioxane (20 ml), Pd(OAc)2 (25.6 mg, 0.36 mmol) and Xantphos (65 .9 mg, 0.11 mmol) when bubbling N2. The mixture was stirred at 110°C overnight under N2 atmosphere. The reaction mixture was filtered and washed with ethyl acetate (20 ml). The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (150 mg, 21% yield) as a yellow solid. LCMS (ESI) m/z M+1: 315.1.

B. Ethyl 1-(2-((tert-butoxycarbonyl)amino)-3-methylpyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole4-carboxylate, compound 143b

A solution of ethyl 1-(2-amino-3-methylpyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate (150 mg, 0.24 mmol) and Boc ₂ O (416.7 mg, 1.91 mmol), DMAP (5.83 mg, 0.048 mmol) and TEA (200 μL, 1.43 mmol) in THF (5 ml) were stirred at room temperature overnight. The mixture was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/0 to 50/50). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (120 mg, yield

60%) in the form of a yellow solid. LCMS (ESI) m/z M+1: 359.1.

C. 1-(2-((tert-Butoxycarbonyl)amino)-3-methylpyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 143 c

Solution of ethyl 1-(2-((tert-butoxycarbonyl)amino)-3-methylpyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1.2 g, 0.61 mmol), LiOH.H ₂ O (243.0 mg, 0.39 mmol) in THF/H2O (2/1, 2 ml) was stirred at room temperature for 3 hours. A solution of 1N HCl was added to neutralize the reaction solution (pH 5~ 6). The mixture was extracted using ethyl acetate (10 ml x3). The separated organic layer was dried (Na ₂ SO ₄ ), filtered, and the solvent was concentrated under reduced pressure to give the title compound (110 mg, 98% yield) as a yellow solid.

D. tert-Butyl (4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1 H-pyrazol-1-yl)-3-methylpyridin-2-yl)carbamate, compound 143 d

- 174 046082

Phosphorus oxychloride (53 μL, 0.57 mmol) was added to a solution of 1-(2-((tert-butoxycarbonyl)amino)-3-methylpyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid acid (110 mg, 0.29 mmol), 5-amino-2-[1,2,3]triazol-2-ylnicotinonitrile, INT3 (79.5 mg, 0.43 mmol), pyridine (460 μl, 5, 7 mmol) in CH ₂ Cl ₂ (5 ml). The mixture was stirred at room temperature for 1 hour. Water (5 ml) was added to the mixture. Added sat. NaHCO ₃ to adjust the pH of the reaction mixture to 7 ~ 8. The mixture was extracted using CH ₂ Cl ₂ (10 ml x3). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (200 mg, crude product). LCMS (ESI) m/z M+1: 499.1.

E. 1-(2-Amino-3-methylpyridin-4-yl)-M-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 143

A mixture of tert-butyl (4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)-3-methylpyridin-2-yl)carbamate (200 mg, 0.213 mmol) and silica gel (510.7 mg, 8.5 mmol) in toluene (5 ml) were stirred at 120°C overnight . The mixture was filtered and concentrated to give the crude product, which was purified by preparative HPLC (35-65% (v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to give the title compound (25 mg, 25.0%). LCMS (ESI) m/z M+1: 455.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.82 (s, 3H), 6.99 (d, J=6.39 Hz, 1H), 8.06 (d, J= 6.62 Hz, 1H), 8.27 (s, 2H), 8.65 (s, 1H), 8.86 (d, J=2.43 Hz, 1H), 9.11 (d, J= 2.43 Hz, 1H), 11.46 (s, 1H).

Example 144.

-(6-Amino-5-chloropyridin-2-yl)-M-(5-cyano-6-(2H-1,2,3 -triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl) -III-pyrazole-4-carboxamide, compound 144

A. di-tert-Butyl (3,6-dichloropyridin-2-yl)carbamate, compound 144a

, connection 144a

Solution of 3,6-dichloropyridin-2-amine (1 g, 6.14 mmol), (Boc) ₂ O (2677.8 mg, 12.27 mmol), Et ₃ N (1858.8 mg, 18.40 mmol ), DMAP (74.84 mg, 0.61 mmol) in CH ₂ Cl ₂ (30 ml) was stirred at RT for 12 hours. The mixture was diluted with water (100 ml) and extracted with CH ₂ Cl ₂ (100 ml x3 ). The organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether/ESAAc = 100:0-10:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the title compound (2.2 g, 98.7% yield) as a colorless oil. LCMS (ESI) m/z M+1: 384.9.

B. tert-Butyl (3-chloro-6-hydrazinylpyridin-2-yl)carbamate, compound 144b

- 175 046082

Η N

NH ₂

c, connection 144b

A mixture of {^(cinnamyl)O} ₂ (78 mg, 0.15 mmol) and Mor-DalPhos (140.4 mg, 0.30 mmol) in dioxane (5 ml) was deaerated using argon 4 times. The resulting clear yellow solution was stirred at RT under an argon atmosphere for 10 min. Di-tert-butyl (3,6dichloropyridin-2-yl)carbamate (1.1 g, 3.0 mmol) and t-BuONa (581.4 mg, 6.06 mmol) were added to the mixture and the mixture was deaerated. using argon 4 times. The resulting yellow reaction mixture was stirred at RT for 5 min and then treated with N ₂ H4-H2O (309.4 mg, 6.06 mmol) using a syringe. The reaction mixture was deaerated using argon 4 times, then the mixture was stirred at 50°C under argon for 2 hours. The mixture was filtered and washed with ethyl acetate (50 ml x 3). The filtrate was collected and concentrated to give the title compound (1.3 g, 96.6% yield) as a yellow solid. LCMS (ESI) m/z M+1: 258.9.

C. Ethyl 1-(6-((tert-butoxycarbonyl)amino)-5-chloropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4carboxylate, compound 144c

Solution of tert-butyl (3-chloro-6-hydrazinylpyridin-2-yl)carbamate (1.3 g, 2.92 mmol), ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (1, 05 g, 4.4 mmol), Et ₃ N (0.89 g, 8.8 mmol) in EtOH (30 ml) was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 3:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the crude product as a yellow oil. The product was purified by preparative high-performance liquid chromatography on a column: Gemini 150*25 5u. Conditions: A: water (0.05% ammonium hydroxide v/v) B: CH ₃ CN. At the beginning: A (45%) and B (55%), at the end: A. (15%) and B (85%). Gradient elution time (min) 10; 100% B, hold time (min) 2; Flow rate (ml/min) 25. The pure fractions were collected and the solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the title compound (120 mg, 9.4% yield) as a yellow oil. LCMS (ESI) m/z M+1: 457.0.

D. 1-(6-((tert-Butoxycarbonyl)amino)-5-chloropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 144d

Cl

BocHN

Oh he, connection 144d

LiOH (3.2 mg, 0.55 mmol) was added to the solution of ethyl 1-(6-((tert-butoxycarbonyl)amino)-5chloropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate (120 mg, 0.28 mmol), THF (10 ml) in water (10 ml). The mixture was stirred at RT for 2 hours. 5% KHSO4 was added to the mixture to adjust the pH to 3~4. Water (100 ml) and ethyl acetate (100 ml) were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO ₄ and concentrated under reduced pressure to obtain the title compound (100 mg, 89.1% yield) as a yellow solid, which was directly used in the next step. LCMS (IER)i/2 M+1: 428.9.

E. tert-Butyl (3-chloro-6-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-III-pyrazol-1-yl)pyridin-2-yl)carbamate, compound 144e

POC13 (75.395 mg, 0.492 mmol) was added to a solution of 1-(6-((tert-butoxycarbonyl)amino)-5-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.25 mmol), 5-amino-2

- 176 046082

[1,2,3]triazol-2-ylnicotinonitrile, INT3 (54.9 mg, 0.30 mmol), pyridine (8.6 mg, 0.62 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at RT for 2 hours. 50 ml of H ₂ O and 50 ml of CH ₂ Cl ₂ were added to the mixture. The organic layer was washed with brine (50 ml), dried over MgSO ₄ and concentrated under reduced pressure to obtain the title compound (200 mg, 88.2% yield) as a brown solid directly for the next step. LCMS (ESI) m/z M+1: 597.0.

F. 1-(6-Amino-5-chloropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 144

tert-Butyl (3-chloro-6-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl) -1H-pyrazol-1-yl)pyridin-2-yl)carbamate (200 mg, 0.22 mmol) was added to HCl/dioxane (10 ml). The mixture was stirred at RT for 2 hours. The mixture was concentrated under reduced pressure. The crude material was purified by preparative high performance liquid chromatography. Column: Phenomenex Gemini 150*25 mm*10 µm. conditions: A: water (0.05% HCl). B. CH ₃ CN. At the beginning: A (60%) and B (40%), at the end: A. (40%) and B (60%). Gradient elution time (min) 10; 100% B, holding time (min) 3; Flow rate (ml/min) 25. The pure fractions were collected and the solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the title compound (21.1 mg, 19.0% yield) as a yellow solid. LCMS (ESI) m/z M+1: 474.9. ^1H NMR (400 MHz, DMSO-d6) δ ppm 6.77 (s, 2H), 6.84 (d, J=7.94 Hz, 1H), 7.83 (d, J=7 .94 Hz, 1H), 8.27 (s, 2H), 8.36 (s, 1H), 8.81 (d, J=2.43 Hz, 1H), 9.03 (d, J=2 .65 Hz, 1H), 11.29 (br. s, 1H).

Example 145.

1-(6-Amino-5-fluoro-3-methylpyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 145

A. 5-Fluoro-2-hydrazinyl-3-methylpyridine, compound 145a

A mixture of {Pd(cinnamyl)Cl} ₂ (711.8 mg, 1.37 mmol) and Mor-DalPhos (1274.1 mg, 2.75 mmol) in dioxane (80 ml) was deaerated using argon 4 times. The resulting clear yellow solution was stirred at RT under an argon atmosphere for 10 min. 2-chloro-5-fluoro-3methylpyridine (4 g, 27.48 mmol) and t-BuONa (5.28 g, 54.96 mmol) were added to the mixture and the mixture was deaerated using argon 4 times. The resulting yellow reaction mixture was stirred at RT for 5 min and then treated with hydrazine hydrate (2.81 g, 54.96 mmol) using a syringe. The reaction mixture was deaerated using argon 4 times. The mixture was then stirred at

50°C under argon for 2 hours. The mixture was filtered and washed with ethyl acetate (100 ml x3). The filtrate was collected and concentrated to give the title compound (5 g, 128.9% crude yield) as a brown solid which was used directly

B. Ethyl 145b in the next stage.

1-(5-fluoro-3-methylpyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate, compound

Solution of 5-fluoro-2-hydrazinyl-3-methylpyridine (5 g, 35.4 mmol), ethyl 2-(ethoxymethylene)-4,4,4 trifluoro-3-oxobutanoate, INT1 (12.77 g, 53.14 mmol), TEA (10.73 g, 106.27 mmol) in EtOH (100 ml) was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 5:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give product 145b (10 g, 81.8% yield) as a yellow oil. LCMS (ESI) m/z M+1: 317.9.

C. 2-(4-(Ethoxycarbonyl)-5-(trifluoromethyl)-III-pyrazol-1-yl)-5-fluoro-3-methylpyridine 1-oxide, compound 145c

b, connection 145c

A solution of ethyl 1-(5-fluoro-3-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (10 g, 28.96 mmol), 3-chlorobenzoperoxoic acid (18.74 g , 86.89 mmol) in 1,2-dichloroethane (100 ml) was stirred at 80°C for 16 hours. The reaction mixture was quenched with sat. NaHCO ₃ (1000 ml) and the mixture was extracted using ethyl acetate (500 ml x3). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product as a colorless oil. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 10/1 to 1/1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product (4.5 g, 45.8% yield) as a yellow oil. LCMS (ESI) m/z M+1: 334.3.

D. Ethyl 1-(6-chloro-5-fluoro-3-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 145d

, connection 145d

2-(4-(Ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluoro-3-methylpyridine 1-oxide (4.5 g, 13.26 mmol) was added to the POCl ₃ solution (122 g, 795.66 mmol) in CHCl ₃ (40 ml). The mixture was stirred at 90°C for 18 hours. The mixture was diluted with water (50 ml) and extracted using CH ₂ Cl ₂ (30 ml x3). The organic layer was dried (MgSO ₄ ) and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1 to 5:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give product 1d (4.3 g, 90.0% yield) as a yellow oil. LCMS (ESI) m/z M+1: 351.9. ^1H NMR (400 MHz, chloroform-d) δ ppm 1.37 (t, J=7.17 Hz, 3H), 2.15 (s, 3H), 4.36 (d, J=7 .06 Hz, 2H), 7.50-7.60 (m, 1H), 8.12-8.20 (m, 1H).

E. Ethyl 1-(6-((tert-butoxycarbonyl)amino)-5-fluoro-3-methylpyridin-2-yl)-5-(trifluoromethyl)-Spirazole-4-carboxylate, compound 145e

To a mixture of ethyl 1-(6-chloro-5-fluoro-3-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.0 g, 5.55 mmol), tert. butyl carbamate (2.60 g, 22.21 mmol) and Cs ₂ CO ₃ (3.62 g, 11.11 mmol) in dioxane (50 ml) was added Pd(OAc) ₂ (124.7 mg, 0.56 mmol) and Xantphos (642.6 mg, 1.11 mmol) under N2 and heated to 100°C for 10 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to give product 145e (2.1 g, 48.5% yield) as a yellow oil. LCMS (ESI) m/z M+1: 332.9 (-Voc).

F. 1-(6-((tert-Butoxycarbonyl)amino)-5-fluoro-3-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 145f

AM* / , connection 145f

LiOH (349.4 mg, 8.33 mmol) was added to the solution of ethyl 1-(6-((tert-butoxycarbonyl)amino)-5-fluoro3-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxylate, ethyl 1-(6-((tert-butoxycarbonyl)amino)-5-fluoro-3-methylpyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate (1,8 g, 4.16 mmol), THF (30 ml) in water (30 ml). The mixture was stirred at RT for 3 hours. 5% KHSO4 was added to the mixture to adjust the pH to 3~4. Water (100 ml) and ethyl acetate (100 ml) were added to the mixture. The organic layer was washed with brine (50 mL), dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give the product (1.6 g, 78.5% yield) as a solid.

- 178 046082 white, which was directly used in the next stage. LCMS (ESI) m/z M+1: 426.9 (+Na).

G. tert-Butyl (6-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-III -pyrazol-1-yl)-3-fluoro-5-methylpyridin-2-yl)carbamate, compound 145g

ΝΑ

Υ

Ν

CN, connection 145g

POC13 (187.97 mg, 1.23 mmol) was added to a solution of 1-(6-((tert-butoxycarbonyl)amino)-5-fluoro-3methylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxylic acid (300 mg, 0.61 mmol), 5-amino2-(2H-1,2,3-triazol-2-yl)nicotinonitrile, INT3 (136.9 mg, 0.74 mmol), and pyridine (121.2 mg, 1.53 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at rt for 2 hours. Water (50 ml) and CH ₂ Cl ₂ (50 ml) were added to the mixture. The organic layer was washed with brine (50 mL), dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give the product (400 mg, 70.4% yield) as a brown solid, which was directly used in the next step. LCMS (ESI) m/z M+1: 595.1 (+Na).

H. 1-(6-Amino-5-fluoro-3-methylpyridin-2-yl)-U-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3- yl)-5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 145

tert-Butyl (6-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)III-pyrazol- 1-yl)-3-fluoro-5-methylpyridin-2-yl)carbamate (400 mg, 0.43 mmol) was added to silica gel (214.4 mg, 3.57 mmol) in toluene (10 ml). The mixture was stirred at RT for 2 hours. The mixture was concentrated under reduced pressure. The crude material was purified by preparative high-performance liquid chromatography on a column: Phenomenex Gemini 150*25 mm* 10 µm. Conditions: A: water (0.05% HCl), B: CH3CN; at the beginning: A (68%) and B (32%), at the end: A. (38%) and B (62%); gradient elution time (min) 10; 100% B, holding time (min) 3; Flow rate (ml/min) 25. The pure fractions were collected and the solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the product (77.9 mg, 38.1% yield) as a white solid. LCMS (ESI) m/z M+1: 472.9. ^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.86 (s, 3H), 6.52 (s, 2H), 7.55 (d, J=11.03 Hz, 1H) , 8.28 (s, 2H), 8.43 (s, 1H), 8.83 (d, J=2.43 Hz, 1H), 9.05 (d, J=2.43 Hz, 1H) , 11.18 (br. s, 1H).

Example 146.

1-(6-Amino-5-fluoro-3-methylpyridin-2-yl)-U-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 146

A. tert-Butyl (6-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)III- pyrazol-1-yl)-3-fluoro-5-methylpyridin-2-yl)carbamate, compound 146a

N.A.

Cl, compound 146a

POCl ₃ (188.0 mg, 1.23 mmol) was added to a solution of 1-(6-((tert-butoxycarbonyl)amino)-5-fluoro-3methylpyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole -4-carboxylic acid (300 mg, 0.61 mmol), 5-chloro6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine, INT2 (136.9 mg, 0.74 mmol), and pyridine (121.2 mg, 1.53 mmol) in CH ₂ Cl ₂ (10 ml). The mixture was stirred at RT for 3 hours. Water (100 ml) was added to the mixture and

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CH2C12 (100 ml). The organic layer was washed with brine (100 ml), dried over MgSO ₄ and concentrated under reduced pressure to obtain the title compound (400 mg, 68.7% yield) as a brown solid, which was directly used in the next step. LCMS (ESI) m/z M+1: 604.0 (+Na).

B. 1-(6-Amino-5-fluoro-3-methylpyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3- yl)-5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 146

tert-Butyl (6-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1Hpyrazol-1 -yl)-3-fluoro-5-methylpyridin-2-yl)carbamate (400 mg, 0.42 mmol) was added to HCl/dioxane (20 ml). The mixture was stirred at RT for 2 hours. The mixture was concentrated under reduced pressure. The crude material was purified by preparative high-performance liquid chromatography on a column: Phenomenex Synergi C18 150*30 mm*4 µm; Conditions: A: water (0.05% HC1); B. CH ₃ CN at the beginning: A (60%) and B (40%), at the end: A. (50%) and B (50%). Gradient elution time (min) 12; 100% B; holding time (min) 2.2; flow rate (ml/min) 25. The pure fractions were collected and the solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the title product (60.5 mg, 29.6% yield) as a white solid. LCMS (ESI) m/z M+1: 481.9. ^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.86 (s, 3H), 6.52 (s, 2H), 7.55 (d, J=10.80 Hz, 1H) , 8.15 (s, 2H), 8.42 (s, 1H), 8.62 (d, J=2.21 Hz, 1H), 8.81 (d, J=2.21 Hz, 1H) , 11.14 (br. s, 1H).

Example 147.

No.(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(6-amino-5-fluoropyridin-2-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 147

A. 5-Nitro-2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridine, compound 147a

1-Chloro-4-nitro-2-(trifluoromethyl)pyridine (950 mg, 4.19 mmol), 1H-1,2,3-triazole (579.3 mg, 8.39 mmol) and potassium carbonate (1, 45 g, 10.48 mmol) was added to MeCN (20 ml) and stirred at room temperature for 16 hours. Water (200 ml) and ethyl acetate (200 ml) were added to the mixture. The organic layer was washed with brine (150 ml), dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified using FCC (petroleum ether/ethyl acetate 95:5 to 83:17) to give the above in the title compound (720 mg, 66.0%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 9.07 (d, J=2.43 Hz, 1H), 9.59 (d, J=2.43 Hz, 1H). 8.06 (s, 2H). LCMS (ESI) m/z M+1: 259.8.

B. 6-(2H-1,2,3-Triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine, compound 147b

N-, al/

Η ₂ Ν, connection 147b

5-Nitro-2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridine (720 mg, 2.77 mmol) was dissolved in methyl alcohol (30 ml) and zinc powder was added ( 1.799 g, 27.7 mmol), aq. NH ₄ Cl (30 ml). The reaction mixture was stirred at room temperature for 16 hours. Aqueous solution was added to the suspension. NaHCO ₃ to adjust the pH of the mixture to 9~10, the mixture was filtered through a layer of diatomaceous earth and the layer was washed using CH ₂ Cl ₂ (100 ml x3). The combined filtrates were washed with brine (200 ml), dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure to give the product (650 mg, 98.9%) as a yellow oil, which was used directly in the next step. LCMS (ESI) m/z M+1: 229.9.

C. tert-Butyl (6-(4-((6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)carbamoyl)-5(trifluoromethyl)- 1 H-pyrazol-1-yl)-3-fluoropyridin-2-yl)carbamate, compound 147c

- 180 046082

HN

Vos, connection 147c

1-(6-((tert-Butoxycarbonyl)amino)-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 62d (200 mg, 0.51 mmol), 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (146.0 mg, 0.62 mmol), pyridine (101.3 mg, 1.28 mmol) was dissolved in CH ₂ Cl ₂ (20 ml) and phosphorus oxychloride (157.1 mg, 1.03 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (50 ml) was added and the mixture was extracted using CH ₂ Cl ₂ (50 ml). The organic layer was washed with brine (50 mL), dried with Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the title product (350 mg, purity 57.193%, 65.0%) as a brown solid colors. LCMS (ESI) m/z M+23: 624.0.

D. No. (6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(6-amino-5-fluoropyridin-2-yl)5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 147

tert-Butyl (6-(4-((6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H α-pyrazol-1-yl)-3-fluoropyridin-2-yl)carbamate (300 mg, 0.29 mmol) was added to HCl/dioxane (15 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by preparative HPLC (40-70% (v/v) CH3CN and _H2O with 0.05% HCl) and lyophilized to dryness to give the title compound (96.5 mg, 67.5%). LCMS (ESI) m/z M+1: 501.9. ^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.71 (br.s, 1H), 6.79 (dd, J=8.05, 2.54 Hz, 1H), 7, 59 (dd, J=10.58, 8.16 Hz, 1H), 8.14-8.21 (m, 2H), 8.35 (s, 1H), 8.83 (d, J=2, 20 Hz, 1H), 9.10 (d, J=2.21 Hz, 1H), 11.31 (s, 1H).

Example 148.

-(2-Amino-5-chloropyridin-4-yl)-] 1 -(5 -cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 148

A. tert-Butyl (4-bromo-5-chloropyridin-2-yl)carbamate, compound 148a

Ν-Ύ

JL .JL HN'A' _Br , compound 148a

Solution of 4-bromo-5-chloropyridin-2-amine (2 g, 9.64 mmol), di-tert-butyl dicarbonate (4.21 g, 19.28 mmol), TEA (2.93 g, 28.92 mmol ), N,Ndimethylpyridin-4-amine (117.8 mg, 0.96 mmol) in CH ₂ Cl ₂ (20 ml) was stirred at RT for 2 hours. The mixture was diluted with water (40 ml) and extracted with CH ₂ Cl ₂ (40 ml x3). The combined organic layers were dried (MgSO ₄ ), filtered, and the filtrate was concentrated to give the crude product as a white solid. The crude product was purified using FCC (petroleum ether/ethyl acetate=100:0-70:30). The solvents were evaporated to give the title compound as a white solid (1.2 g).

- 181 046082

B. tert-Butyl (5-chloro-4-hydrazinylpyridin-2-yl)carbamate, compound 148b

NH ₂ , compound 148b {Pd(cinnamyl)Cl} ₂ (66.0 mg, 0.13 mmol) and Mor-DalPhos (118.1 mg, 0.26 mmol) were added to dioxane (10 ml) and air was immediately removed from the reaction vessel with N2. The resulting solution was stirred at RT in an N2 atmosphere for 10 min. The vessel was then filled with sodium tert-butoxide (489.5 mg, 5.09 mmol) and tert-butyl (4-bromo-5-chloropyridin-2-yl)carbamate (0.8 g, 2.55 mmol) and sealed closed and deaerated using N2. The resulting reaction mixture was stirred at RT for 5 min and then treated with hydrazine hydrate (382.4 mg, 7.64 mmol) using a syringe. The reaction mixture was stirred at 50°C under N2 atmosphere for 1.5 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow oil (1.0 g). LCMS (ESI) m/z M+1: 259.1.

C. Ethyl 1-(2-((tert-butoxycarbonyl)amino)-5-chloropyridin-4-yl)-5-(trifluoromethyl)-III-pyrazole-4carboxylate, compound 148c

, connection 148c

Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (136.9 mg, 0.57 mmol), was added to a solution of crude tert-butyl (5-chloro-4-hydrazinylpyridine-2- yl)carbamate (1 g) in EtOH (15 ml). The mixture was reacted at 80°C for 1 hour. The solvent was concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified using FCC (petroleum ether/ethyl acetate=100:0-90:10). The solvents were evaporated to give the product as a white solid (250 mg). LCMS (ESI) m/z M+1: 379.1.

D. IO-^tert-Butoxycarbonyl^mino^-chloropyridin^-yl^/trifluoromethyl/N-pyrazole^-carboxylic acid, compound 148d

OH, connection 148d

NaOH (11.5 mg, 0.29 mmol) was added to a solution of crude ethyl 1-(2-((tert-butoxycarbonyl)amino)-5-chloropyridin-4-yl)-5-(trifluoromethyl)-III-pyrazol- 4-carboxylate (250 mg) in THF/H ₂ O=1:1 (8 ml). The mixture was reacted at room temperature for 24 hours. The reaction mixture was extracted with ethyl acetate (20 ml x2). The aqueous layer was acidified using 1M hydrochloric acid to pH 5 and extracted with ethyl acetate (30 ml x 3). The combined organic layers were washed with brine, dried with anhydrous MgSO ₄ and filtered. The filtrates were concentrated under reduced pressure to give the product as a white solid (70 mg, purity 88.4%, 79.0%). LCMS (ESI) m/z M+1: 351.0.

E. tert-Butyl (5-chloro-4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-2-yl)carbamate, compound 148e

, connection 148e

IO-^tert-Butoxycarbonyl^mino^-chloropyridin^-yl^/trifluoromethyl/N-pyrazole^-carboxylic acid (70 mg, 0.15 mmol), 5-amino-2-(2H-1,2,3- triazol-2-yl)nicotinonitrile, INT3 (28.3 mg, 0.15 mmol), pyridine (0.061 ml, 0.76 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (0.056 ml, 0 .61 mmol). The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (20 ml) and the mixture was extracted using CH ₂ Cl ₂ (30 ml x2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated to dryness under reduced pressure to give the crude product as a brown oil (120 mg, 62.2% purity,

- 182 046082

85.3%). LCMS (ESI) m/z M+1: 475.1.

F. 1-(2-Amino-5-chloropyridin-4-yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 148

tert-Butyl (5-chloro-4-(4-((5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl) -1H-pyrazol-1-yl)pyridin-2-yl)carbamate (120 mg, 0.13 mmol) was added to HCl/dioxane (10 ml). The mixture was stirred at RT for 16 hours. The solvent was concentrated under reduced pressure to give the crude product as a yellow solid, which was purified by preparative HPLC (35-60% (v/v) CH ₃ CN and H2O with 0 .05% ammonium hydroxide), the pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the product as a pale yellow solid (22 mg, 99.1% purity, 35.4%). LCMS (ESI) m/z M+1: 474.9; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.70 (s, 1H), 8.18 (s, 1H), 8.28 (s, 2H), 8.54 (s, 1H), 8.83 (d, J=2.43 Hz, 1H), 9.06 (d, J=2.65 Hz, 1H), 11.31 (s, 1H).

Example 149.

1-(2-Amino-5-chloropyridin-4-yl)-X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-1H-pyrazole-4-carboxamide, compound 149

A. tert-Butyl (5-chloro-4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-( trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)carbamate, compound 149a

, compound 149a ^^-((tert-Butoxycarbonyl^mino^-chloropyridin^-yl^^trifluoromethyl^N-pyrazole^-carboxylic acid (110 mg, 0.27 mmol), 5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-amine, INT2 (58.19 mg, 0.30 mmol), pyridine (0.109 ml, 1.35 mmol) dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (0.099 ml, 1.08 mmol) was added. The mixture was stirred at 25°C for 2 hours. Saturated NaHCO ₃ (20 ml) was added and the mixture was extracted with CH ₂ Cl ₂ (30 ml x2). the organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness under reduced pressure to give the crude product as a brown oil (160 mg, purity 68.6%, 69.4%). LCMS (ESI) m/z M+1: 483.7

B. 1-(2-Amino-5-chloropyridin-4-yl)-X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 149

tert-Butyl (5-chloro-4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl) -III-pyrazol-1-yl)pyridin-2-yl)carbamate (140 mg, 0.16 mmol) was added to HCl/dioxane (5 ml) and CH ₂ Cl ₂ (5 ml). The mixture was stirred at RT for 16 hours. The solvent was concentrated under reduced pressure to give a crude yellow solid, which was purified by preparative HPLC (35-55% (v/v) CH3CN and _H2O with 0.05% HCl), the pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the product as a pale yellow solid (40 mg, 91.8% purity).

- 183 046082

The product was again purified by preparative HPLC (35-65% (v/v) CH ₃ CN and H2O with 0.05% ammonium hydroxide), the pure fractions were collected and the organic solvent was concentrated under reduced pressure. The aqueous layer was lyophilized to dryness to obtain the product as a pale yellow solid (25 mg, purity 99.80%, 31.4%). LCMS (ESI) m/z M+1: 483.9, 1H NMR (400 MHz, DMSO d ₆ ) δ ppm 6.71 (s, 1H), 6.73 (s, 2H), 8, 19 (s, 2H), 8.21 (s, 1H), 8.54 (s, 1H), 8.65 (d, J=2.26 Hz, 1H), 8.83 (s, 1H), 11.16 (s, 1H).

Example 150.

No.(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-6-(methylamino)pyridin-2-yl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 150

A. 6-Chloro-3-fluoro-N-methylpyridin-2-amine, compound 150a

2,6-Dichloro-3-fluoropyridine (1500 mg, 9.04 mmol) in methylamine in THF (2M) was reacted at

80°C for 16 hours. The solvent was concentrated under reduced pressure to obtain the crude compound, which was purified using FFS (petroleum ether/ethyl acetate=100:0 - petroleum ether/ethyl acetate=60:40). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a colorless oil (200 mg, 13.8%). LCMS (ESI) m/z M+1: 161.1. ^1H NMR (400 MHz, chloroform-d) δ ppm 3.00 (d, J=5.07 Hz, 3H), 4.68 (br s, 1H), 6.43 (dd, J= 8.05, 2.76 Hz, 1H), 7.02 (dd, J=10.25, 8.05 Hz, 1H).

B. 3-Fluoro-6-hydrazinyl-methylpyridin-2-amine, compound 150b

A mixture of palladium(P) chloride dimer (pi-cinnamyl) (25.8 mg, 0.05 mmol) and Na[2-(di-1-adamantylphosphino)phenyl]morpholine (46.2 mg, 0.10 mmol) in dioxane (5 ml) was deaerated using argon 4 times. The resulting clear yellow solution was stirred at RT under an argon atmosphere for 10 min. 6-Chloro-3-fluoro-N-methylpyridin-2-amine (160 mg, 1.0 mmol) and t-BuONa (191.5 mg, 1.99 mmol) were added to the mixture and the vessel was vented using argon. 4 times. The resulting yellow reaction mixture was stirred at room temperature for 5 min before being treated with hydrazine (99.8 mg, 1.99 mmol) using a syringe and the reaction vessel deaerated using argon 4 times. The mixture was stirred at 50°C under argon for 2 h. After filtration, the solvent was concentrated under reduced pressure to obtain the crude product as a brown solid, which was used directly in the next step.

C. Ethyl (5-fluoro-6-(methylamino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 150c

, connection 150s

3-Fluoro-6-hydrazinyl-N-methylpyridin-2-amine (160 mg, 1.03 mmol) was added to a solution of ethyl 2(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, INT1 (369.1 mg, 1.54 mmol) in EtOH (5 ml) and the mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure, then purified with FFS (petroleum ether/ethyl acetate = 100:0 - petroleum ether/ ethyl acetate=80:20). The desired fractions were collected and the solvent was concentrated under reduced pressure to give the product as a brown oil (180 mg, 49.0%). LCMS (ESI) m/z M-55: 331.0.

D. 1-(5-Fluoro-6-(methylamino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 150d

, connection 150d

LiOH (50.109 mg, 2.092 mmol) was added to a solution of ethyl (5-fluoro-6-(methylamino)pyridin-2-yl)-5-184 046082 (trifluoromethyl)-1H-pyrazole-4-carboxylate (150 mg, 0.418 mmol) in THF/H2O (2:1, 9 ml) and the mixture was reacted at 23°C for 2 hours. The solvent was concentrated under reduced pressure. A 1M HCl solution was added to the mixture to adjust the pH of the mixture to 5. A solid formed and was collected by filtration to give the product (130 mg, 88.1%). LCMS (ESI) m/z M+1: 305.0.

E. No. (5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-6-(methylamino)pyridin-2-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 150

1-(5-Fluoro-6-(methylamino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (130 mg, 0.37 mmol), 5-amino-2-[ 1,2,3]triazol-2-ylnicotinonitrile, INT3 (72.1 mg, 0.39 mmol), POCl ₃ (67.8 mg, 0.44 mmol) were dissolved in CH ₂ Cl ₂ (8 ml) and added pyridine (87.5 mg, 1.11 mmol). The mixture was stirred at 25°C for 1 hour. Saturated. NaHCO ₃ (10 ml) and the mixture was extracted using CH ₂ Cl ₂ (15 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates concentrated under reduced pressure to give a crude brown oil, which was purified by preparative HPLC (67-37% (v/v) CH3CN and H ₂ O with 0 .05% HCl) and lyophilized to dryness to give the title compound (39 mg, 21.8%). LCMS (ESI) m/z M+1: 473.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.81 (d, J=3.75 Hz, 3H), 6.83 (dd, J=8.16, 2.43 Hz, 1H), 7.18 (ush s, 1H), 7.58 (dd, J=10.58, 8.16 Hz, 1H), 8.28 (s, 2H), 8.32 (s, 1H) , 8.81 (d, J=2.43 Hz, 1H), 9.03 (d, J=2.43 Hz, 1H), 11.30 (s, 1H).

Example 151.

N-(5 -chloro-6-(2H-1,2,3 -triazol-2-yl)pyridin-3 -yl)-1 -(5-fluoro-6-(3 -hydroxyazetidin-1 -yl)pyridin2 -yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 151

A. 3,6-difluoro-2-hydrazinylpyridine, compound 151a

N

HjN-NH connection 151a

2,3,6-Trifluoropyridine (7 g, 52.60 mmol) was dissolved in hydrazine hydrate (5.374 g, 105.21 mmol) and EtOH (70 ml). The reaction mixture was stirred at reflux for 2 hours. The solvent was removed and the mixture was diluted with water (300 ml) and extracted with CH ₂ Cl ₂ (200 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to obtain the crude product. The residue was recrystallized from EtOH to give the product (7 g, 91.7%) as a light yellow solid.

B. 2-Bromo-3,6-difluoropyridine, compound 151b

^ig , connection 151b

3,6-Difluoro-2-hydrazinylpyridine (2.5 g, 17.23 mmol) was dissolved in CHCl ₃ (100 ml) and bromine was added dropwise. The reaction mixture was stirred at 60°C for 1 hour. Saturated solution was added dropwise. NaHCO ₃ (40 ml) and the mixture was extracted using CH ₂ Cl ₂ (100 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates were concentrated under reduced pressure to give the crude product, which was purified using FCC (eluent: petroleum ether/ethyl acetate 100/0 to 85/15) to give the title compound (1.8 g, 53.9%) as a yellow oil.

C. 2-Bromo-3-fluoro-6-hydrazinylpyridine, compound 151c f^Alnh )-N NH ₂

Вг, connection 151с

2-Bromo-3,6-difluoropyridine (1.8 g, 9.28 mmol) was dissolved in hydrazine hydrate (1.394 g, 27.84 mmol) and MeCN (50 ml). The reaction mixture was stirred at 80°C for 36 hours. The solvent was concentrated under reduced pressure to obtain a brown solid. The solid was co-evaporated with toluene three times to remove water to obtain the following:

- 185 046082 head of the compound (1.9 g, 99.4%) in the form of a brown solid.

D. Ethyl 1-(6-bromo-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate. connection 151d

, connection 151d

2-Bromo-3-fluoro-6-hydrazinylpyridine (1.9 g, 9.22 mmol) was dissolved in ethanol (15 ml), ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate was added, INT1 (3.323 g, 13.83 mmol). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a yellow oil, which was purified using FCC (eluent: petroleum ether/ethyl acetate 100/0 to 90/10) to give the title compound (2 g, 33.6%) as a yellow oil. LCMS (ESI) m/z M+1: 381.9.

E. 1-(6-Bromo-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid, compound 151e

Ethyl 1-(6-bromo-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylate (500 mg, 0.77 mmol) was dissolved in THF (5 ml) and water (5 ml). Lithium hydroxide (185.4 mg, 7.74 mmol) was added. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was adjusted to pH 5 using HCl (5~6 N), extracted using EtOAc (30 ml x3). The combined organic layers were dried with Na ₂ SO ₄ , filtered, and the filtrates were concentrated under reduced pressure to give the crude title compound (350 mg, 93.5%) as a yellow solid. LCMS (ESI) m/z M+1: 356.0.

F. 1-(6-Bromo-5-fluoropyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 151f νΛ

- Ν-ν

Cl ^Br , compound 151f

1-(6-Bromo-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxylic acid (350 mg, 0.72 mmol), 5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-amine, INT2 (141.6 mg, 0.72 mmol), pyridine (443.9 mg, 2.90 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (149.2 mg, 0.97 mmol) was added. The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (30 ml) and extracted using CH ₂ Cl ₂ (30 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates were concentrated under reduced pressure to give the crude product as a yellow oil, which was purified using FCC (eluent: petroleum ether/ethyl acetate 100/0 to 0/100) with obtaining the title compound (350 mg, 69.3%) as a yellow solid. LCMS (ESI) m/z M+1: 533.0.

G. No. (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-6-(3-hydroxyazetidin-1-yl) pyridin-2-yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 151

1-(6-Bromo-5-fluoropyridin-2-yl)-\-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide (300 mg, 0.56 mmol), azetidin-3-ol (123.64 mg, 1.13 mmol), cesium carbonate (551.6 mg, 1.69 mmol) dissolved in dioxane (10 ml) under N2 atmosphere. Tris(dibenzy) was added

- 186 046082 lideneacetone)dipalladium(O) (51.7 mg, 0.056 mmol) and 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine (65.3 mg, 0.11 mmol) and stirred at 100°C for 16 hours. The combined mixture was filtered and the filtrates were concentrated under reduced pressure to give the crude product as a yellow solid, which was purified by preparative HPLC (40-70% (v/v) CH ₃ CN and H2O with 0.05% ammonium hydroxide) and lyophilized to dryness to give the title compound (23 mg, 7.7%). LCMS (ESI) m/z M+1: 524.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.84 (US dd, J=8.56, 4.40 Hz, 2H), 4.29 (US t, J=7.21 Hz, 2H ), 4.50-4.65 (m, 1H), 5.72 (d, J=6.36 Hz, 1H), 6.99 (dd, J=8.07, 1.96 Hz, 1H) , 7.67 (dd, J=11.25, 8.31 Hz, 1H), 8.16 (s, 2H) 8.32 (s, 1H), 8.60 (d, J=1.96 Hz , 1H), 8.77 (d, J=1.96 Hz, 1H), 11.25 (br. s, 1H).

Example 152.

N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-6-(3-hydroxyazetidin-1yl)pyridin-2- yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 152

A. 1-(6-Bromo-5-fluoropyridin-2-yl)-N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5- (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 152a

1-(6-Bromo-5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (350 mg, 0.76 mmol), 5-amino-2-[1,2 ,3]triazol-2-ylnicotinonitrile, INT3 (141.7 mg, 0.76 mmol), pyridine (466.9 mg, 3.05 mmol) were dissolved in CH ₂ Cl ₂ (10 ml) and phosphorus oxychloride (361) was added .3 mg, 4.57 mmol). The mixture was stirred at 25°C for 2 hours. Saturated. NaHCO ₃ (30 ml) and the mixture was extracted using CH ₂ Cl ₂ (30 ml x2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and the filtrates were concentrated under reduced pressure to give the crude product as a yellow oil, which was purified using FCC (eluent: petroleum ether/ethyl acetate 100/0 to 0/100) with obtaining the title compound (250 mg, 62.9%) as a yellow solid. LCMS (ESI) m/z M+1: 524.0.

B. No.(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(5-fluoro-6-(3-hydroxyazetidin-1-yl) pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 152

1-(6-Bromo-5-fluoropyridin-2-yl)-X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide (250 mg, 0.48 mmol), azetidin-3-ol (104.9 mg, 0.96 mmol), cesium carbonate (467.9 mg, 1.44 mmol) dissolved in dioxane (10 ml) under N ₂ atmosphere. Tris(dibenzylideneacetone) dipalladium(0) (43.8 mg, 0.048 mmol) and 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (55.4 mg, 0.096 mmol) were added and the mixture was stirred at 100°C for 16 hours. The combined mixture was filtered and the filtrates concentrated under reduced pressure to give the crude product as a yellow solid, which was purified by preparative HPLC (35-65% (v/v) CH3CN and H ₂ O with 0.05% ammonium hydroxide) and lyophilized to dryness to give the title compound (38 mg, 14.7%). LCMS (ESI) m/z M+1: 515.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (br. dd, J=8.53, 4.77 Hz, 2H), 4.32 (br. t, J=7.28 Hz, 2H) , 4.56-4.67 (m, 1H), 5.75 (d, J=6.53 Hz, 1H), 7.03 (dd, J=8.03, 2.26 Hz, 1H), 7.71 (dd, J=11.29, 8.28 Hz, 1H), 8.27-8.39 (m, 3H), 8.83 (d, J=2.51 Hz, 1H), 9 .05 (d, J=2.51 Hz, 1H), 11.33 (br. s, 1H).

- 187 046082

Example 153.

4-(4-((5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1yl)- 3-methylpyridine 1-oxide, compound 153

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylpyridin-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide (898 mg, 2 mmol) was stirred in DCM (50 ml). mCPBA (518 mg, 3 mmol) was added in portions. The reaction mixture was stirred for 4 hours. Additional mCPBA (518 mg, 3 mmol) was added in portions. Stirring was continued for 4 hours. Additional mCPBA (518 mg, 3 mmol) was added in portions. Stirring was continued for 16 hours. The reaction mixture was poured into water (50 ml), treated with sodium sulfite solution (1260 mg, 10 mmol) and stirring was continued for 15 minutes. The reaction mixture was treated with NaHCO ₃ solution (840 mg, 10 mmol) and stirred for 5 min. The layers were separated and the aqueous layer was extracted with DCM-MeOH (90/10). The combined organic layers were concentrated under reduced pressure to give the title compound (992 mg, 101%). LCMS (ESI): mass calculated for C ₁₈ H ₁₂ ClF ₃ N ₈ O ₂ -464.1, obtained m/z - 465.1 [M+H]+.

Example 154 and 155.

1-(2-Chloro-5-methyl-4-pyridyl)-N-[5-chloro-6-(triazol-2-yl)-3-pyridyl]-5-(trifluoromethyl)pyrazole-4carboxamide, compound 154

1-(2-Chloro-3-methylpyridin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 155

N[5-chloro-6-(triazol-2-yl)-3-pyridyl]-1-(3-methyl-1-oxidopyridin-1-ium-4-yl)-5-(trifluoromethyl)pyrazol-4 α-carboxamide (930 mg, 2 mmol) was stirred in POCl ₃ (30 ml) at 80°C for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and slowly added to the aqueous Na ₂ CO ₃ solution.

The layers were separated and the organic layer was extracted twice using DCM. The combined organic layers were dried and concentrated. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN). Fractions containing the compound were collected and evaporated. The residue was purified by preparative SFC (stationary phase: Chiralpak Diacel AD 20x250 mm, mobile phase: CO ₂ , MeOH + 0.4 iPrNH2) to obtain the title compounds, compound 154 (117 mg, 12%): LCMS (ESI): wt , calculated for C18H11O2F3N8O - 482, the resulting m/z - 483 [M+H] ⁺ . 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.08 (s, 3H), 7.30 (s, 1H), 7.94 (s, 2H), 8.16 (s, 1H) , 8.47 (s, 1H), 8.49 (d, J=2.4 Hz, 1H), 8.52 (br. s, 1H), 8.70 (d, J=1.0 Hz, 1H) and compound 155 (123 mg, 13%): LCMS (ESI): mass calculated for C18H11O2F3N8O - 482, obtained m/z - 483 [M+H] ⁺ . 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.10 (s, 3H), 7.20 (d, J=5.3 Hz, 1H), 7.93 (s, 2H), 8 .19 (s, 1H), 8.44 (d, J=5.3 Hz, 1H), 8.52 (d, J=2.4 Hz, 1H), 8.67-8.76 (m, 2H).

Example 156.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(3-hydroxyazetidin-1-yl)-5-methylpyridin-4 -yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 156

- 188 046082

A mixture of 1-(2-chloro-5-methyl-4-pyridyl)-X-[5-chloro-6-(triazol-2-yl)-3-pyridyl]-5-(trifluoromethyl)pyrazole-4-carboxamide ( 50 mg, 0.1 mmol), 3-hydroxyazetidine (14 mg, 0.2 mmol) and Cs ₂ CO ₃ (63 mg, 0.2 mmol) in DMA (3 ml) were stirred at 100 ° C for 104 h The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative SFC (stationary phase: Chiralpak Diacel AD 20x250 mm, mobile phase: CO ₂ , EtOH+0.4 iPrNH ₂ ) to obtain the title compound (20 mg, 40%). LCMS (ESI): mass calculated for C ₂₁ H ₁₇ ClF ₃ N ₉ O ₂ -519, obtained m/z - 520 [M+H] ⁺ . 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.91 (s, 3H), 3.84-3.91 (m, 2H), 4.254.33 (m, 2H), 4.75- 4.84 (m, 1H), 6.21 (s, 1H), 7.93 (s, 2H), 8.11 (s, 1H), 8.14 (s, 1H), 8.50 (d , J=2.4 Hz, 1H), 8.62 (br. s, 1H), 8.73 (d, J=2.4 Hz, 1H).

Example 157.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(3-hydroxyazetidin-1-yl)-3-methylpyridin-4 -yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 157

1-(2-Chloro-3-methylpyridin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide (50 mg, 0.1 mmol), 3-hydroxyazetidine (14 mg, 0.2 mmol) and Cs ₂ CO ₃ (63 mg, 0.2 mmol) in DMA (3 ml) was stirred at 100°C for 32 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative SFC (stationary phase: Chiralpak Diacel AD 20x250 mm, mobile phase: CO2, EtOH+0.4 iPrNH2) to obtain the title compound (18 mg, 36%). LCMS (ESI): mass calculated for C ₂₁ H ₁₇ ClF ₃ N ₉ O ₂ 519, obtained m/z - 520 [M+H] ⁺ . ^1H NMR (400 MHz, chloroform-d) δ ppm 1.82 (s, 3H), 3.99-4.07 (m, 2H), 4.37-4.48 (m, 2H) , 4.71-4.80 (m, 1H), 6.65 (d, J=5.3 Hz, 1H), 7.93 (s, 2H), 8.12 (s, 1H), 8, 17 (d, J=5.3 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.53 (br. s, 1H), 8.73 (d, >1, 0Hz, 1H).

Following the procedure described in Example 156 above, selecting and replacing appropriate reagents, starting materials and purification methods and adjusting reaction temperatures, times and other variables or parameters as necessary or desired, which should be understandable to those skilled in the art, the following compounds were prepared (Examples 158-165).

Example 158.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-methylpyridin-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 158

1H NMR (400 MHz, DMSO-d6) δ ppm 2.06 (s, 3H), 7.57 (d, J=5.07 Hz, 1H), 8.17 (s, 2H), 8 .63 (d, J=2.20 Hz, 1H), 8.66 (d, J=5.07 Hz, 1H), 8.76 (s, 1H), 8.81 (d, J=2, 21 Hz, 1H), 11.21 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 449.0.

Example 159.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-methylpyridazin-3-yl)-5-(trifluoromethyl)III-pyrazole -4-carboxamide, compound 159

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.24 (s, 3H), 8.00 (d, J=4.63 Hz, 1H), 8.16 (s, 2H), 8.58 (s, 1H),

- 189 046082

8.63 (d, J=2.21 Hz, 1H), 8.81 (d, J=2.21 Hz, 1H), 9.35 (d, J=5.29 Hz, 1H). LC-MS: (ES, m/z): [M+1]+ 449.9.

Example 160.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-6-methylpyridin-2-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 160

^1H NMR (400 MHz, DMSO-d6) δ ppm 11.32 (s, 1H), 9.03 (d, J=2.43 Hz, 1H), 8.82 (d, J=2 .43 Hz, 1H), 8.41 (s, 1H), 8.29 (s, 2H), 7.99 (t, J=8.71 Hz, 1H), 7.74 (dd, J=8 .60, 2.87 Hz, 1H), 2.50 (br. d, J=1.76 Hz, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 458.0.

Example 161.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-6-methylpyridin-2-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 161

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.73 (d, J=2.43 Hz, 1H), 8.47 (d, J=2.21 Hz, 1H), 7.998.14 (m, 2H), 7.93 (s, 2H), 7.46-7.60 (m, 2H), 2.56 (d, J=3.09 Hz, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 466.9.

Example 162.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,6-dichloropyridin-2-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 162

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.27-11.34 (m, 1H), 8.99-9.07 (m, 1H), 8.78-8.86 ( m, 1H), 8.548.59 (m, 1H), 8.43-8.50 (m, 1H), 8.24-8.30 (m, 2H), 7.93-8.01 (m, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 494.0.

Example 163.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,6-dichloropyridin-2-yl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 163

1H NMR (400 MHz, DMSO-d6) δ ppm 11.32 (s, 1H), 8.83 (d, J=1.98 Hz, 1H), 8.58-8.66 (m, 2H), 8.46 (d, J=8.60 Hz, 1H), 8.12-8.18 (m, 2H), 7.97 (d, J=8.38 Hz, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 502.9.

Example 164.

1-(6-Chloro-3-(trifluoromethyl)pyridin-2-yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 164

1H NMR (400 MHz, DMSO-d6) δ ppm 11.34 (1H, s), 9.04 (1H, d, J=2.43 Hz), 8.83 (1H, d, J= 2.43 Hz), 8.70 (1H, d, J=8.38 Hz), 8.59 (1H, s), 8.28 (2H, s), 8.17 (1H, d, J =8.38 Hz). LC-MS: (ES, m/z): [M+1] ⁺ 527.9.

Example 165.

1-(6-Chloro-3-(trifluoromethyl)pyridin-2-yl)-X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5-190 046082 (trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 165

1H NMR (400 MHz, DMSO-d6) δ ppm 11.30 (1H, s), 8.82 (1H, d, J=2.21 Hz), 8.70 (1H, d, J= 8.38 Hz), 8.63 (1H, d, J=2.21 Hz), 8.60 (1H, s), 8.18 (1H, s), 8.16 (2H, s). LC-MS: (ES, m/z): [M+1] ⁺ 536.8.

Following the procedure described in Example 50 above, selecting and replacing appropriate reagents, starting materials and purification methods and adjusting reaction temperatures, times and other variables or parameters as necessary or desired, which should be understandable to those skilled in the art, the following compounds were prepared (Examples 166-174).

Example 166.

1-(4-Chloro-2-methylphenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide, compound 166

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.01 (s, 3H), 7.48-7.52 (m, 2H), 7.63 (s, 1H), 8.30 (s, 2H), 8.47 (s, 1H), 8.82-8.86 (m, 1H), 9.04-9.08 (m, 1H), 11.26 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 472.9.

Example 167.

K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide, compound 167

1H NMR (400 MHz, DMSO-d6) δ ppm 1.90 (d, J=1.76 Hz, 3H), 7.31-7.40 (m, 1H), 7.41-7, 54 (m, 2H), 8.29 (s, 2H), 8.47 (s, 1H), 8.83 (d, J=2.65 Hz, 1H), 9.05 (d, J=2 .43 Hz, 1H), 11.26 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 457.0.

Example 168.

K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-difluoro-2-methylphenyl)-5-(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 168

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.97 (d, J=1.98 Hz, 3H), 7.44-7.50 (m, 1H), 7.55 ( k, J=8.89 Hz, 1H), 8.31 (s, 2H), 8.49 (s, 1H), 8.85 (br. d, J=2.43 Hz, 1H), 9, 06 (d, J=2.43 Hz, 1H), 11.29 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 474.9.

Example 169.

K-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-cyanophenyl)-5-(trifluoromethyl)-Spirazol-4-carboxamide , connection 169

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.31 (1H, s), 9.07 (1H, d, J=2.51 Hz), 8.85 (1H, d, J=2.51 Hz), 8.51 (1H, s), 8.32 (2H, s), 8.15 (1H, s), 8.13 (1H, s), 7.85 (1H , s), 7.83 (1H, s). LC-MS: (ES, m/z): [M+1] ⁺ 450.0.

Example 170.

- 191 046082

X-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide, compound 170

1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3H), 2.65 (s, 3H), 7.27 (td, J=8.43, 2.76 Hz, 1H), 7.40 (dd, J=9.48, 2.87 Hz, 1H), 7.54 (dd, J=8.71, 5.18 Hz, 1H), 8.31 (s, 2H ), 8.46 (s, 1H), 8.66 (s, 1H), 10.62 (s, 1H), LC-MS: (ES, m/z): [M+1]+ 471.0 .

Example 171.

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 171

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.85-1.26 (m, 1H), 1.90 (d, J=1.76 Hz, 4H), 7.34- 7.38 (m, 1H), 7.44-7.51 (m, 2H), 8.17 (s, 2H), 8.47 (s, 1H), 8.63 (d, J=2, 21 Hz, 1H), 8.81 (d, J=2.43 Hz, 1H), 11.21 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 466.1.

Example 172.

X-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 172

¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.00 (s, 3H), 2.52 (s, 3H), 7.25 (td, J=8.54, 2.98 Hz , 1H), 7.38 (dd, J=9.59, 2.54 Hz, 1H), 7.51 (dd, J=8.49, 5.40 Hz, 1H), 8.16 (s, 2H) 8.41 (d, J=13.67 Hz, 2H), 10.55 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 479.9.

Example 173.

X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1-(2,4,6-trifluorophenyl)-1Hpyrazole -4-carboxamide, compound 173

1H NMR (400 MHz, DMSO-d6) δ ppm 11.40 (br s, 1H), 9.03 (d, J=2.43 Hz, 1H), 8.81 (d, J=2 ,43 Hz, 1H), 8.58 (s, 1H), 8.28 (s, 2H), 7.67 (t, J=8.93 Hz, 2H). LC-MS: (ES, m/z): [M+1] ⁺ 479.0.

Example 174.

X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-difluoro-2-methylphenyl)-5-(trifluoromethyl) Sh-pyrazole-4-carboxamide, compound 174

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.96 (d, J=2.21 Hz, 3H), 7.43-7.49 (m, 1H), 7.54 (k , J=9.11 Hz, 1H), 8.18 (s, 2H), 8.49 (s, 1H), 8.64 (d, J=2.21 Hz, 1H), 8.82 (d , J=2.43 Hz, 1H), 11.24 (br. s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 483.9.

Following the procedures described in Example 56, 139, or 141 above, selecting and substituting appropriate reagents, starting materials, and purification methods, and adjusting reaction temperatures,

- 192 046082 time and other variables or parameters as needed or desired, which should be understandable to those skilled in the art, the following compounds (175-201) were prepared.

Example 175.

1-(6-Amino-3-chloropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 175

1H NMR (400 MHz, DMSO-d6) δ ppm 11.25 (s, 1H), 9.06 (d, J=2.65 Hz, 1H), 8.84 (d, J=2, 65 Hz, 1H), 8.49 (s, 1H), 8.25-8.30 (m, 2H), 7.72 (d, J=8.82 Hz, 1H), 6.72 (br. s, 2H), 6.67-6.70 (m, 1H). LC-MS: (ES, m/z): [M+1]+ 474.9.

Example 176.

1-(6-Amino-4-methylpyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-III-pyrazole-4-carboxamide, compound 176

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.35 (s, 1H), 9.08-9.11 (m, 1H), 8.85-8.88 (m, 1H) , 8.38 (s, 1H), 8.31 (s, 2H), 6.64 (s, 1H), 6.42 (s, 1H), 2.26 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 455.0.

Example 177.

1-(6-Amino-5-cyanopyridin-2-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 177

1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 (s, 3H), 7.00 (d, J=8.16 Hz, 1H), 7.32 (s, 2H), 8 .15 (d, J=7.94 Hz, 1H), 8.27 (s, 2H), 8.36 (s, 1H), 8.65 (s, 1H), 10.65 (br. s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 480.0.

Example 178.

1-(6-Amino-5-cyanopyridin-2-yl)-N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 178

1H NMR (400 MHz, DMSO-d6) δ ppm 2.50 (s, 3H), 7.01 (d, J=8.16 Hz, 1H), 7.31 (s, 2H), 8 ,12-8.19 (m, 3H), 8.37 (s, 1H), 8.42 (s, 1H), 10.61 (br. s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 488.9.

Example 179.

1-(6-Amino-5-fluoropyridin-2-yl)-N-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 179

- 193 046082

1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H), 6.72 (s, 2H), 6.81 (dd, J=8.05, 2.54 Hz, 1H), 7.62 (dd, J=10.47, 8.27 Hz, 1H), 8.18 (s, 2H), 8.33 (s, 1H), 8.43 (s, 1H), 10.57 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 481.9.

Example 180.

1-(6-Aminopyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 180

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.682 (d, J=2.43 Hz, 1H), 8.421 (d, J=2.21 Hz, 1H), 7.977 (s, 1H), 7.874 (s, 2H), 7.807 (s, 1H), 7.572 (t, J=8.05 Hz, 1H), 6.904 (d, J=7.72 Hz, 1H), 6.540 (d, J=8, 16 Hz, 1H), 4.573 (br. s, 2H). LC-MS: (ES, m/z): [M+1]+ 449.9.

Example 181.

1-(6-Amino-5-fluoropyridin-2-yl)-X-(5-bromo-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 181

1H NMR (400 MHz, DMSO-d6) δ ppm 2.50 (br s, 3H), 6.71 (s, 2H), 6.79 (dd, J=8.05, 2.54 Hz , 1H), 7.60 (dd, J=10.36, 8.16 Hz, 1H), 8.15 (s, 2H), 8.33 (s, 1H), 8.52 (s, 1H) , 10.55 (br.s., 1H). LC-MS: (ES, m/z): [M+1] ⁺ 527.8.

Example 182.

1-(6-Amino-5-fluoropyridin-2-yl)-X-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 182

1H NMR (400 MHz, DMSO-d6) δ ppm 2.63 (s, 3H), 6.73 (s, 2H), 6.81 (dd, J=8.05, 2.54 Hz, 1H), 7.62 (dd, J=10.47, 8.05 Hz, 1H), 8.31 (s, 2H), 8.35 (s, 1H), 8.67 (s, 1H), 10.63 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 472.9.

Example 183.

1-(6-Amino-3-chloropyridin-2-yl)-X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-III-pyrazole-4-carboxamide, compound 183

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.84-11.22 (m, 1H), 8.78-8.85 (m, 1H), 8.59-8.66 ( m, 1H), 8.448.52 (m, 1H), 8.15 (s, 2H), 7.67-7.75 (m, 1H), 6.70-6.76 (m, 2H), 6 .66-6.70 (m, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 483.9.

Example 184.

1-(6-Amino-5-methylpyridin-2-yl)-X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-III-pyrazole-4-carboxamide, compound 184

- 194 046082

1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 3H), 6.15 (s, 2H), 6.71 (d, J=7.72 Hz, 1H), 7 .47 (d, J=7.72 Hz, 1H), 8.16 (s, 2H), 8.31 (s, 1H), 8.61 (d, J=2.21 Hz, 1H), 8 .79 (s, 1H), 11.17 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 463.9.

Example 185.

1-(6-Amino-3-methylpyridin-2-yl)-N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 185

1H NMR (400 MHz, DMSO-d6) δ ppm 1.88 (s, 3H), 6.63 (d, J=8.28 Hz, 1H), 7.52 (d, J=8, 53 Hz, 1H), 8.19 (s, 2H), 8.46 (s, 1H), 8.67 (d, J=2.01 Hz, 1H), 8.87 (d, J=2, 01 Hz, 1H), 11.21 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 463.9.

Example 186.

1-(6-Amino-5-fluoro-3-methylpyridin-2-yl)-N(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3yl )-5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 186

1H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (s, 1H), 8.40 (s, 1H), 8.28 (s, 2H), 7.55 (d, J= 11.03 Hz, 1H), 6.50 (s, 2H), 2.61 (s, 3H), 1.87 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 486.9.

Example 187.

1-(6-Amino-3-(trifluoromethyl)pyridin-2-yl)-N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 (trifluoromethyl)-III-pyrazole-4-carboxamide, compound 187

1H NMR (400 MHz, DMSO-d6) δ ppm 11.22 (1H, s), 9.06 (1H, d, J=2.43 Hz), 8.84 (1H, d, J= 2.43 Hz), 8.47 (1H, s), 8.29 (2H, s), 7.92 (1H, d, J=8.82 Hz), 7.31 (2H, br. s ), 6.75 (1H, d, J=8.60 Hz). LC-MS: (ES, m/z): [M+1] ⁺ 508.9.

Example 188.

1-(6-Amino-5-fluoro-3-methylpyridin-2-yl)-N(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3yl )-5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 188

1H NMR (400 MHz, DMSO-d6) δ ppm 10.71 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 8.15 (s, 2H) , 7.55 (d, J=11.03 Hz, 1H), 6.50 (s, 2H), 2.51 (s, 3H), 1.87 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 495.9.

Example 189.

N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(6-(methylamino)pyridin-2-yl)-5 -(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 189

- 195 046082

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.78 (s, 3H), 6.61 (d, J=8.25 Hz, 1H), 6.82 (d, J=7 .47 Hz, 1H), 7.62 (t, J=7.79 Hz, 1H), 8.31 (s, 2H), 8.34 (s, 1H), 8.84 (d, J=2 ,18 Hz, 1H), 9.06 (d, J=2.34 Hz, 1H), 11.33 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 455.0.

Example 190.

1-(6-Amino-4-methylpyridin-3-yl)-N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 190

1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (1H, s), 9.12 (1H, d, J=2.43 Hz), 8.88 (1H, d, J= 2.65 Hz), 8.58 (1H, s), 8.35 (1H, s), 8.26-8.30 (2H, m), 6.86 (1H, s), 1.97 (3H, s). LC-MS: (ES, m/z): [M+1]+ 455.0.

Example 191.

1-(6-Amino-4-methylpyridin-3-yl)-N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl) -III-pyrazole-4-carboxamide, compound 191

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.19 (br.s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.64 (d, J =2.0 Hz, 1H), 8.40 (s, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 6.44 (br.d, J=9.9 Hz , 1H), 1.87 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 464.0.

Example 192.

1-(6-Amino-3-(trifluoromethyl)pyridin-2-yl)-X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 192

1H NMR (400 MHz, DMSO-d6) δ ppm 11.15 (1H, s), 8.82 (1H, d, J=2.43 Hz), 8.63 (1H, d, J= 2.20 Hz), 8.46 (1Н, s), 8.16 (2 Н, s), 7.92 (1Н, d, J=8.82 Hz), 7.31 (2 Н, br. s), 6.74 (1H, d, J=8.38 Hz). LC-MS: (ES, m/z): [M+1]+ 517.9.

Example 193.

1-(6-Amino-5-fluoropyridin-2-yl)-X-(5-chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 193

1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H), 6.68 (s, 2H), 6.77 (dd, J=8.05, 2.54 Hz, 1H), 7.557.62 (m, 2H), 7.84 (s, 1H), 8.12 (s, 2H), 8.27 (s, 1H), 10.26 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 481.1.

Example 194.

1-(6-Aminopyridin-3-yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide, compound 194

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.79-6.90 (m, 1H), 7.83 (br. d, J=9.26 Hz, 1H), 8.25 (br. s, 1H),

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8.28 (s, 2H), 8.45 (s, 1H), 8.85 (d, J=2.65 Hz, 1H), 9.08 (d, J=2.43 Hz, 1H), 11.34 (s, 1H). LC-MS: (ES, m/z): [M+1]+ 441.0.

Example 195.

1-(6-Amino-5-fluoropyridin-2-yl)-X-(5-cyano-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-( trifluoromethyl)-III-pyrazole-4-carboxamide, compound 195

1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H), 6.68 (br. s, 2H), 6.78 (dd, J=8.05, 2.54 Hz, 1H), 7.59 (dd, J=10.58, 8.16 Hz, 1H), 8.01 (s, 1H), 8.13 (s, 1H), 8.24 (s, 2H ), 8.28 (s, 1H), 10.35 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 471.9.

Example 196.

1-(6-Amino-2-methylpyridin-3-yl)-X-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-III-pyrazole-4-carboxamide, compound 196

¹ H NMR (400 MHz, METHANOLM4) δ ppm 9.04 (br.s, 1H), 8.87 (br.s, 1H), 8.28 (s, 1H), 8.12 (s , 2H), 7.55 (br.d, J=9.04 Hz, 1H), 6.65 (br.d, J=8.60 Hz, 1H), 2.09 (s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 455.0.

Example 197.

1-(6-Amino-5-methylpyridin-2-yl)-X-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 197

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.10 (s, 3H), 2.61 (s, 3H), 6.12 (br. s, 2H), 6.72 (d , J=7.28 Hz, 1H), 7.47 (d, J=7.50 Hz, 1H), 8.29 (s, 3H), 8.65 (s, 1H), 10.56 (s , 1H). LC-MS: (ES, m/z): [M+1] ⁺ 469.0.

Example 198.

2-Amino-6-(4-((5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl) -1H-pyrazol-1-yl)nicotinamide, compound 198

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.51-2.52 (m, 3H), 6.92 (d, J=7.94 Hz, 1H), 7.49 (br .s, 3H), 8.07 (br. s, 1H), 8.16 (s, 2H), 8.19 (d, J=8.16 Hz, 1H), 8.35 (s, 1H) , 8.43 (s, 1H), 10.59 (s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 506.9.

Example 199.

1-(2-Amino-3-methylpyridin-4-yl)-X-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 199

1H NMR (400 MHz, DMSO-d6) δ ppm 1.70 (s, 3H), 6.31 (s, 2H), 6.61 (d, J=5.29 Hz, 1H), 7 .98 (d, J=5.29 Hz, 1H), 8.19 (s, 2H), 8.46 (s, 1H), 8.65 (d, J=2.43 Hz, 1H), 8 .82 (d, J=2.20 Hz, 1H), 11.20 (br. s, 1H). LC-MS: (ES, m/z): [M+1] ⁺ 463.9.

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Example 200.

1-(6-Amino-5-chloropyridin-2-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 200

^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.62 (br. s, 1H), 8.68 (s, 1H), 8.37 (s, 1H), 8.31 ( s, 2H), 7.87 (d, J=8.16 Hz, 1H), 6.88 (d, J=8.16 Hz, 1H), 6.79 (s, 2H), 2.64 ( s, 3H). LC-MS: (ES, m/z): [M+1] ⁺ 488.9.

Example 201.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-cyano-2-methylpyridin-3-yl)-5-(trifluoromethyl )-III-pyrazole-4-carboxamide, compound 201

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.27 (3H, s), 8.16 (2H, s), 8.19 (1H, d, J=8.07 Hz) , 8.36 (1H, d, J=8.07 Hz), 8.56 (1H, s), 8.63 (1H, d, J=1.96 Hz), 8.80 (1H, d, J=2.20 Hz), 11.21 (1H, br. s). LC-MS: (ES, m/z): [M+1]+ 474.1.

Example 202.

1-(6-Bromopyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide, compound 202

A. Ethyl 1-(6-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, compound 202a

A solution of 2-bromo-6-hydrazinopyridine (10 g, 53 mmol) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3oxobutanoate (16.6 g, 69 mmol) in ethanol (150 ml) was stirred at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate ratio 80/20 to 50/50). The solvent was evaporated under reduced pressure to give the title compound (21.6 g, 100%).

B. 1-(6-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, compound 202b ^F \ ^F

Вг fA/NO

Xiu°

N, connection 202b

Ethyl 1-(6-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (10 g, 27.5 mmol) and ethanol (20 ml) were stirred at room temperature. A solution of NaOH (3.3 g, 82.5 mmol) in water (10 ml) was slowly added. The reaction mixture was stirred for 3 hours. The reaction mixture was concentrated and adjusted to pH 3 with 1N HCl. The reaction mixture was extracted with DCM. The organic layer was washed with water, dried with MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give the title compound (9.1 g, 98.5%).

C. 1-(6-Bromopyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) III-pyrazole^-carboxamide, compound 202

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1-(6-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxylic acid (0.92 g, 2.75 mmol), 5-chloro-6-(triazol-2-yl )pyridin-3-amine (0.65 g, 3.3 mmol) and pyridine (1.2 g, 13.75 mmol) in DCM (4 ml) were stirred at room temperature. POCl ₃ (1 g, 8.25 mmol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was slowly poured into the NaHCO ₃ solution and extracted with DCM. The combined organic layers were washed with water, dried with MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN). The pure fractions were collected, evaporated and the residue was stirred in diisopropyl ether, collected by filtration and dried to give the title compound (443 mg, 31.5%). LCMS (ESI): mass calculated for C ₁₇ H ₉ BrClF ₃ N ₈ O - 512, obtained m/z - 515 [M+H]+. ^1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.617.67 (m, 1H), 7.70-7.75 (m, 1H), 7.77-7.84 (m, 1H) , 7.93 (s, 2H), 8.06 (s, 1H), 8.16 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H).

Example 203.

(*R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-methyl-2-(tetrahydrofuran-2- yl)pyridinU-ylChDtrifluoromethylfN-pyrazoleU-carboxamide, compound 203

(*S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-methyl-2-(tetrahydrofuran-2- yl)pyridinU-ylChDtrifluoromethylfN-pyrazoleU-carboxamide, compound 204

A mixture of THF (1422 mg, 20 mmol), CH3CN (10 ml), water (5 ml), 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2yl)pyridin- 3-yl)carbamoyl)-5-(trifluoromethyl)-III-pyrazol-1-yl)-3-methylpyridine 1-oxide (448 mg, 1 mmol), TFA (0.076 ml, 1 mmol) and ammonium persulfate (1140 mg , 5 mmol) was weighed into a 20 ml vial. (IR[DF(CF ₃ )PPY] ₂ (DTBPY))PF ₆ (56 mg, 0.05 mmol) was then added. The reaction mixture was degassed for 15 min and sealed. The reaction mixture was stirred under blue LED irradiation at room temperature for 3 hours. The reaction mixture was poured into water and extracted using DCM. The combined organic layers were dried with MgSO ₄ , filtered, and the filtrate was concentrated to dryness. Purification was carried out using preparative SFC (stationary phase: Chiralcel Diacel OJ 20x250 mm, mobile phase: CO ₂ , EtOH+0.4 iPrNH ₂ ) to obtain compound 203 (53 mg, 10.2%): LCMS (ESI): wt , calculated for C ₂₂ H ₁₈ ClF ₃ N ₈ O ₂ -518.1, the resulting m/z - 519 [M+H] ⁺ . 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.90-2.12 (m, 6 H), 2.47 (td, J=6.8, 4.3 Hz, 1H), 3 .94-4.01 (m, 1H), 4.03-4.11 (m, 1H), 5.08 (dd, J=7.3, 6.1 Hz, 1H), 7.39 (s , 1H), 7.94 (s, 2H), 8.14 (s, 1H), 8.49 (br. s, 1H), 8.53 (d, J=1.0 Hz, 1H), 8 .60 (s, 1H), 8.73 (d, J=2.4 Hz, 1H) and compound 204 (54 mg, 10.4%): LCMS (ESI): mass calculated for C ₂₂ H ₁₈ ClF ₃ N ₈ O ₂ -518.1, resulting m/z - 519 [M+H] ⁺ . 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.91-2.06 (m, 3H), 2.10 (s, 3H), 2.43-2.52 (m, 1H), 3.93-4.01 (m, 1H), 4.03-4.10 (m, 1H), 5.08 (dd, J=7.3, 5.7 Hz, 1H), 7.39 ( s, 1H), 7.94 (s, 2H), 8.13 (s, 1H), 8.48-8.51 (m, 2H), 8.60 (s, 1H), 8.73 (d , J=2.4 Hz, 1H).

Following the procedure described in Example 203 above, selecting and replacing appropriate reagents, starting materials and purification methods and adjusting reaction temperatures, times and other variables or parameters as necessary or desired, which should be understandable to those skilled in the art, the following compounds (205-206) were obtained.

Example 204.

(*S)-1-(2-(1,4-dioxan-2-yl)-5-methylpyridin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazole -2-yl)pyridin-3yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 205

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LCMS (ESI): mass calculated for C ₂₂ H ₁₈ ClF ₃ N ₈ O3-534.1, obtained m/z -535 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.10 (s, 3H), 3.48 (dd, J=11.6, 10.0 Hz, 1H), 3.64-3, 76 (m, 1H), 3.783.86 (m, 1H), 3.90-3.99 (m, 2H), 4.22 (dd, J=11.4, 2.8 Hz, 1H), 4 .80 (dd, J=10.0, 2.6 Hz, 1H), 7.43 (s, 1H), 7.94 (s, 2H), 8.15 (s, 1H), 8.48- 8.56 (m, 2H), 8.59 (s, 1H), 8.73 (d, J=2.0 Hz, 1H).

Example 205.

(*R)-1-(2-(1,4-dioxan-2-yl)-5-methylpyridin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazole -2-yl)pyridin-3yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 206

LCMS (ESI): mass calculated for C ₂₂ H ₁₈ ClF ₃ N ₈ O ₃ -534.1, obtained m/z -535 [M+H] ⁺ . 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.10 (s, 3H), 3.48 (dd, J=11.4, 10.2 Hz, 1H), 3.66-3, 75 (m, 1H), 3.783.86 (m, 1H), 3.91-3.99 (m, 2H), 4.22 (dd, J=11.4, 2.8 Hz, 1H), 4 .80 (dd, J=9.8, 2.8 Hz, 1H), 7.43 (s, 1H), 7.94 (s, 2H), 8.15 (s, 1H), 8.46- 8.53 (m, 2H), 8.59 (s, 1H), 8.73 (d, J=2.0 Hz, 1H).

Example 206.

No.(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-(furan-2-yl)pyridin-2-yl)-5 (trifluoromethyl)-III-pyrazole-4-carboxamide, compound 207

1-(6-Bromopyridin-2-yl)F-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-III pyrazole -4-carboxamide (103 mg, 0.2 mmol), 2-furanboronic acid pinacol ester (58 mg, 0.3 mmol) and K3PO4 (85 mg, 0.4 mmol) were suspended in dioxane (20 ml) and water ( 3 ml). Added

PdCl ₂ (dppf).CH ₂ Cl ₂ (16.5 mg, 0.02 mmol) and the mixture was heated at 100°C overnight. The solution was poured into 20 ml of water. The mixture was extracted with ethyl acetate (3x) and the organic layer was washed with water (10 ml), dried with MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN. The second purification was carried out by preparative SFC (stationary phase: Chiralpak Diacel AD 20x250 mm, mobile phase: CO ₂ , EtOH+0.4 iPrNH ₂ ) to obtain the title compound (52 mg, 52%).

LCMS (ESI): mass calculated for C ₂₁ H ₁₂ ClF ₃ N ₈ O ₂ -500, obtained m/z -501.2 [M+H] ⁺ . ^1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.55-6.60 (m, 1H), 7.12-7.17 (m, 1H), 7.56 (dd, J= 1.6, 0.8 Hz, 1H), 7.61 (dd, J=8.1, 0.8 Hz, 1H), 7.79 (dd, J=7.7, 0.8 Hz, 1H ), 7.91-7.99 (m, 3H), 8.04 (s, 1H), 8.18 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8 .72 (d, J=2.0 Hz, 1H).

Example 207.

N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-(5,6-dihydro-1,4-dioxin-2- yl)pyridin-2yl)-5-(trifluoromethyl)-III-pyrazole-4-carboxamide, compound 208

1-(6-Bromopyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide (103 mg, 0.2 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4- dioxin (63.5 mg, 0.3 mmol) and K ₃ PO ₄ (85 mg, 0.4 mmol) were suspended in dioxane (20 ml) and water (3 ml). PdCl ₂ (dppf).CH ₂ Cl ₂ (16.5 mg, 0.02 mmol) was added and the mixture was heated at 100° C. overnight. The solution was poured into 20 ml of water. The mixture was extracted with ethyl acetate (3x) and the organic layer was washed with water (10 ml), dried over MgSO ₄ , filtered and the filtrate concentrated to dryness. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 µm, 50x150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN) to give the title compound (52 mg, 50%). LCMS (ESI): mass calculated for C ₂₁ H ₁₄ ClF ₃ N ₈ O ₃

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518.1, obtained m/z -519.2 [M+H]+. ^1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.18-4.23 (m, 2H), 4.25-4.32 (m, 2H), 7.33 (s, 1H) , 7.48 (dd, J=10.8, 7.9 Hz, 2H), 7.85 (t, J=7.9 Hz, 1H), 7.92 (s, 2H), 8.01 ( s, 1H), 8.41 (s, 1H), 8.49 (d, J=2.4 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H).

Biological examples.

In vitro assays include assays that determine cell morphology, protein expression and/or cytotoxicity, enzyme inhibition activity and/or subsequent functional consequences of treating cells with compounds of the invention. Alternative or additional in vitro assays can be used to quantify the ability of an inhibitor to bind to protein or nucleic acid molecules within a cell.

Inhibitory binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/target molecule complex, and determining the amount of radiolabel bound. Alternatively or additionally, inhibitor binding can be determined by performing a competition experiment in which novel inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands. Detailed conditions of exemplary systems for assaying compounds of formula (I) of the present invention as MALT1 inhibitors are provided in the biological examples below.

Such analyzes are illustrative and are not intended to limit the scope of the invention. A practitioner of the art will appreciate that modifications can be made to traditional assays to develop equivalent or different assays that can be used for comparative assessment of the activity or other characteristics of compounds and/or compositions as described herein.

In vitro assays.

Biological example 1.

Biochemical analysis of MALT1 protease activity.

MALT1 protease activity was assessed in an in vitro assay using tetrapeptide as substrate and full-length MALT1 protein (Strep-MALT1(1-824)-His) purified from baculovirus-infected insect cells. The LRSR tetrapeptide was coupled to AMC (7-amino-4methylcoumarin) to produce a quenched fluorescent substrate for MALT1 protease (SM Biochemicals). Cleavage of AMC from the arginine residue resulted in an increase in coumarin fluorescence measured at 460 nm (excitation wavelength 355 nm). The final assay buffer consisted of 10 nM FL MALT1 protein, 200 μM Ac-LRSR-AMC, 50 mM Tris pH 7.5, 0.6 M citrate, 1 mM DTT, 1 mM EDTA, 0.05% BSA, and 1.5 %DMSO. Test compounds were applied 50 nL in 100% DMSO to a well of a black 384-Proxiplate (Perkin Elmer). Concentrations of test compounds were varied from 30 μM to 0.5 nM using 11 dilution steps (1:3). Background signal was measured in control wells containing assay buffer without enzyme, which served as minimal signal (MS) control. Maximum signal control (MS) values were obtained using the reaction with the enzyme but without the addition of compound. The compounds were preincubated with the MALT1 enzyme for 50 min at RT. Next, the substrate was added and fluorescence was measured on a Labsystems fluoroskan fluorescence scanner at an excitation wavelength of 355 nm and an emission wavelength of 460 nm, which corresponded to time point 0. The reaction mixture was then incubated for 4 h at RT and fluorescence was measured. To calculate _IC50 , the value at time point 0 was subtracted from the value at time point 4 h to account for possible autofluorescence of compounds. The enzymatic reaction was linear over an incubation period of 4 h. By characterizing the Ac-LRSR-AMC substrate, a Michaelis constant _K value of 200 µm was determined.

IC ₅₀ values were calculated using the following formula (Z initial must be > 0.5):

BC=median of minimum signal control values = minimum signal control: Reaction without enzyme HC=median of maximum signal control values = maximum signal control: Reaction with enzyme %Effect=100 - [(sample - LC) / (HC - LC) x 100] %Control = (sample/NS) x 100 %Controlmin = (sample - LC) / (NS - LC) x 100

The best fit curve was constructed using the least sum of squares method to plot the dependence of the %Controlmin value on the concentration of the compound. From this the IC ₅₀ value (the concentration of inhibitor causing 50% inhibition) can be obtained. In addition, an estimate of the slope of the graph was obtained in the form of the Hill coefficient.

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IC50 calculation:

y=i r+UB - LB ] ₊₁ Q(h(pCoiic-pIC50))

Where y=calculated answer

CV=upper limit

GL=lower limit

11=Hill

Used in Lexis Dose Response Curve Fitting version 1.0. The resulting data is presented in table. 2.

table 2

Conn. Activity MALTl_Biochemical (Ac-LRSR-amc) IC50 (µM) Conn. Activity MALTl_Biochemical (Ac-LRSR-amc) IC50 (µM) 1 0.117 105 0.537 2 0.132 106 0.251 3 0.282 107 0.141 4 0.282 108 0.776 5 0.295 109 0.427 6 0.832 110 0.123 7 0.912 111 0.112 8 1,230 112 0.457 9 2,570 FROM 0.158 10 4.365 114 1,000 eleven 4,571 115 0.363 12 1,349 116 0.117 13 1,698 117 0.288 14 0.148 118 2,951 15 3,467 119 0.209 16 1,698 120 0.126 17 2,089 121 1.175 18 0.151 122 1.318

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19 0.132 123 0.794 20 0.562 124 1,202 21 1.122 125 1,905 22 0.724 126 0.038 23 0.933 127 0.372 24 2,089 128 0.229 25 2,951 129 2,399 26 7,079 130 0.234 27 0.851 131 0.776 28 2.455 132 0.191 29 0.151 133 0.155 thirty 0.708 134 0.263 31 6,607 135 0.525 32 0.589 136 0.759 33 0.513 137 0.151 34 0.145 138 5.495 35 2.239 139 0.026 36 0.214 140 0.058 37 0.063 141 0.100 38 0.324 142 0.022 39 0.457 143 0.110 40 1,905 144 0.035 41 2,042 145 0.032 42 0.182 146 0.107 43 0.170 147 0.069 44 0.389 148 0.039 45 0.087 149 0.085 46 0.479 150 0.100 47 0.537 151 2,399 48 0.204 152 0.832 49 0.148 153 4,898 50 0.054 154 0.955 51 0.054 155 0.257 52 0.055 156 1,288

- 203 046082

53 0.074 157 8.128 54 0.089 158 0.209 55 0.062 159 3.162 56 0.078 160 0.288 57 0.107 161 0.741 58 0.145 162 0.302 59 0.041 163 0.794 60 0.071 164 1.413 61 0.078 165 2,291 62 0.045 166 0.050 63 0.024 167 0.069 64 0.054 168 0.074 65 5,754 169 0.091 66 3,981 170 0.102 67 0.525 171 0.145 68 0.427 172 0.151 69 0.257 173 0.151 70 0.204 174 0.170 71 0.832 175 0.141 72 0.603 176 0.170 73 0.234 177 0.195 74 2,884 178 0.200 75 1,072 179 0.204 76 0.676 180 0.219 77 0.891 181 0.234 78 0.646 182 0.234 79 0.380 183 0.282 80 0.209 184 0.331 81 0.162 185 0.331 82 0.162 186 0.339 83 0.129 187 0.380 84 0.309 188 0.380 85 2,630 189 0.437 86 1,549 190 0.447

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87 0.724 191 0.724 88 0.794 192 1.122 89 0.646 193 1.175 90 0.575 194 1.175 91 0.513 195 1,202 92 0.501 196 1.318 93 0.457 197 2,512 94 0.447 198 3.715 95 0.316 199 0.174 96 0.316 200 0.275 97 0.263 201 0.138 98 0.263 202 0.741 99 0.170 203 0.158 100 0.170 204 0.525 101 0.151 205 1,905 102 0.151 206 2,042 103 0.148 207 5.623 104 0.245 208 5.129

Biological example 2.

PMA-induced IL2 production in Jurkat cells.

Jurkat cells were grown in complete RPMI 1640 medium supplemented with 10% fetal bovine serum, 10 mM HEPES, 100 U/ml penicillin, and 100 μg/ml streptomycin. Before analysis, serial 2- to 4-fold dilutions in DMSO were made for the compounds. In each well, 10 μl of compound diluted in DMSO was further diluted with 240 μl of complete RPMI1640 medium. Jurkat cells were collected by centrifugation at 1200 rpm for 5 min, washed once with RPMI 1640 medium and suspended in fresh complete RPMI 1640 medium at a concentration of 1.25 x 10 ⁶ cells/ml. Jurkat cells (2x105 cells) in a volume of 160 μl were seeded into each well of 96-well flat-bottom plates. 20 μl of compound diluted in complete JAMPI 1640 medium was added to each well and incubated with Jurkat cells for 30 min at 37°C in a 5% CO ₂ incubator. 20 μl of diluted PMA/Ionomycin solution (81 nM/1.3 μM, respectively, ebioscience, cat. no. 00-4970-93) in complete JAMPI 1640 medium was added to each well. After incubation at 37°C in a 5 % CO ₂ for 20 h, supernatants were collected. IL-2 concentration was determined by ELISA (IL2 Duoset, R&D Systems, cat. no. DY202). Colorimetric intensity at 450 nm was read by a Spectramax plate scanner and analyzed by Softmax Pro software. Cell viability was determined using a Cell Titer Glo kit (Promega, cat. no. G7571) using a Victor Luminescence scanner (Victor 3V 4202938 from Perkin Elmer).

The resulting data is presented in table. 3.

Biological example 3.

Mesoscale analysis of human IL6/IL10.

NFkB signaling regulates the secretion of several cytokines, including IL6 and IL10. The secretion of IL6 and IL10 cytokines by TMD8 or OCI-LY3 ABC-DLBCL cells was measured using a Mesoscale assay. Inhibition of NFkB signaling using MALT1 or BTK inhibitors results in decreased IL6/10 secretion.

TMD8 or OCI-LY3 cells were grown in RPMI-1640 medium (Sigma Aldrich) supplemented with 10% fetal bovine serum (HyClone), 1 mM sodium pyruvate (Invitrogen), 2 mM L-glutamine (Sigma Aldrich), and 1% PenStrep (Sigma Aldrich). The number of cell passages should not exceed 30. The cell concentration during cultivation should be maintained at 0.5-2.5 million per ml, and 50 µM of fresh beta-mercaptoethanol should be added every 2-3 days. Betamercaptoethanol was not used in the Mesoscale assay.

For the Mesoscale assay, 100,000 TMD8 or OCI-LY3 cells were seeded per well of black clear-bottom 96-well plates (Corning #3904) and test compounds were added in 9 serial dilutions (1:2) ranging from 15 µM to 58.6 nM (final DMSO concentration - 0.3%). To determine the maximum signal (maximum signal control (MS)), control wells with DMSO were used. Treatment with the BTK inhibitor RN486 at doses ranging from 30 nM to 131 pM (9 dilutions 1:2) served as a positive control for NFkB pathway inhibition and was used to determine

- 205 046082 maximum inhibition (minimum signal control (LC)). Compounds and cells were incubated for 24 hours at 37°C and 5% _CO2 (assay volume was 150 µl). After 24 h of incubation, 50 μl of the supernatant was transferred to an MSD plate (V-Plex Proinflammation Panel 1 (human), Mesoscale (MSD)) and incubated for 2 h with vigorous shaking (600 rpm) at room temperature. After incubation, the plates were washed 3 times with PBS+0.05% Tween-20 and 25 μl of detection antibody solution (IL6 & IL10 antibodies in diluent 3 (MSD)) was added per well and incubated for 2 hours with vigorous shaking (600 rpm). min) at room temperature. After washing 3 times with PBS+0.05% Tween-20, the plates were incubated with 150 μl of 2x Read Buffer T and read with a SECTOR imaging device. The resulting data is presented in table. 3.

Table 3

Conn. Mesoscale analysis of human IL10 Mesoscale analysis of human IL6 Mesoscale analysis of human IL6 Mesoscale analysis of human IL10 (OCI-LY3) (OCI-LY3) (TMD-8) (TMD-8) 1 0.058 0.083 0.079 0.085 2 0.148 0.065 3 0.832 4 0.933 5 0.263 0.741 7 0.407 0.417 14 0.316 0.282 18 0.115 19 0.117 20 1,000 21 0.912 1.259 22 0.437 0.724 23 0.891 1,072 27 1,202 1,380 29 0.135 0.132 32 1.122 0.646 34 0.407 0.631 36 1,549 1.148 37 0.063 0.095 43 4,786 2.239 44 0.490 1,230 45 0.162 0.339 48 1.622 0.513 49 0.145 0.151 50 51 0.071 0.098 52 0.056 0.120 53 0.145 0.166 0.089 0.209 56 0.363 0.389 57 0.117 0.162 58 0.195 0.407 59 0.035 0.048

- 206 046082

60 0.151 0.178 62 0.427 0.380 63 0.049 0.069 68 5,495 7,079 69 2,291 3.236 70 4,467 3,548 73 0.110 0.138 81 0.138 0.138 97 0.095 0.151 98 0.166 0.191 99 0.174 0.148 100 0.093 0.129 101 0.120 0.166 102 0.158 0.158 103 0.141 0.129 106 2,291 2,042 107 0.112 0.158 111 0.063 0.071 FROM 0.324 0.372 116 0.105 0.107 119 0.148 0.282 120 0.794 0.741 1,096 1,349 126 0.068 0.076 128 1.023 2.239 130 0.437 0.245 132 0.550 1,349 137 0.100 0.123 139 0.076 0.074 140 0.123 0.132 141 0.407 0.427 142 0.355 0.676 143 0.617 1.047 144 0.026 0.046 145 0.018 0.017

- 207 046082

146 0.158 0.195 147 0.040 0.052 148 0.263 0.398 149 0.155 0.166 150 0.204 0.269 158 0.302 0.275 160 0.457 0.646 162 0.182 0.251 166 0.078 0.066 167 0.041 0.054 168 0.046 0.078 169 0.076 0.105 170 0.380 0.417 171 0.076 0.098 172 0.178 0.200 173 0.095 0.129 174 0.083 175 0.229 0.331 176 0.813 0.813 177 2,754 7,413 179 0.324 0.676 180 0.170 0.257 181 0.240 0.363 182 0.389 0.490 183 0.195 0.269 185 0.355 0.490 193 0.741 0.871 195 1.862 5,370 200 0.245 0.794

Biological example 4.

Proliferation assays.

To analyze antiproliferative effects, MALT1 inhibitory compounds were tested in 4-day proliferation assays using three different DLBCL cell lines. Two ABC-DLBCL cell lines with activating mutations in the classical NFkB pathway (OCI-Ly3 (CARD11, MYD88 & A20 mutations), TMD8 (CD79B & MYD88 mutations), which are intrinsically sensitive to NFkB pathway inhibition, were evaluated. GCB-DLBCL cell line ( OCI-Ly7), which was found to lack active NFkB signaling, served as a negative control to exclude compounds with common cytotoxic effects.

OCI-Ly3 cells were grown in RPMI-1640 medium (Sigma Aldrich) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich), and 1% PenStrep (Sigma Aldrich). TMD8 cells were grown in RPMI-1640 medium (Sigma Aldrich) supplemented with 10% fetal bovine serum (HyClone), 1 mM sodium pyruvate (Invitrogen), 2 mM L-glutamine (Sigma Aldrich), and 1% PenStrep (Sigma Aldrich). The cell concentration during culture should be maintained at 0.52.5 million per ml, and 50 µM of fresh beta-mercaptoethanol should be added every 2-3 days. Beta-mercaptoethanol was not used in the proliferation assay. OCI-Ly7 cells were grown in IMDM medium (ThermoFisher) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich), and 50 μg/ml gentamicin. The number of cell passages should not exceed 30.

To evaluate antiproliferative effects, 400 nl of the test compounds were applied to a well of 96-well plates (Costar, cat. no. 3904). Seed 10,000 TMD8 cells, 10,000 OCILy3 cells or 2000 OCI-Ly7 cells in 100 μl of medium per well and incubated for 4 days at 37°C and 5%

- 208 046082

CO2. The number of cells to be seeded was chosen based on growth curves to ensure linear cell growth. After 4 days of incubation, 50 μl of CellTiterGLO reagent (Promega) was added to each well, and luminescence was measured with an Envision instrument after 10 min of incubation at room temperature.

IC50 values were calculated using the following formula (Z initial should be

> 0.5): bC=median of minimum signal control values = minimum signal control: reaction without cells HC=median of maximum signal control values = kMaximum signal control: reaction with cells without connection %Effect=100 - (sample - LC) / (HC - LC) x 100 %Control = (sample/NS) x 100 %Controlmin = (sample - LC) / (NS - LC) x 100

The best fit curve was constructed using the least sum of squares method to plot the dependence of the %Control value on the concentration of the compound. From this the IC50 value (the concentration of inhibitor that causes 50% cytotoxicity) can be obtained. In addition, an estimate of the slope of the graph was obtained in the form of the Hill coefficient.

The resulting data is presented in table. 4.

- 209 046082

Table 4

Conn. Antiproliferative effect: OCI-LY-3 IC50 (µM) 1 1,349 2 0.741 3 2.455 4 1.047 5 0.380 7 1,549 14 2.138 18 6,457 19 7,943 20 12,589 21 0.741 22 0.490 23 0.479 27 3,890 29 1,230 32 0.575 34 0.457 36 4,266 43 6,310 44 10,965 45 4,786 48 3.631 49 0.437 50 1,072 51 0.851 52 2,399 53 1.862 54 1.622 55 3,388 56 5,012 57 1,202 58 7,244

- 210 046082

Biological example 5.

Tumor efficacy study.

OCI-Ly3 tumor cells (DSMZ, cat. no. ACC 761) of human diffuse large B-cell lymphoma can be cultured in vitro in RPMI medium supplemented with heat-inactivated fetal bovine serum (10% v/v) and 2 mM L-glutamine 200 mM at 37°C in an air atmosphere with 5% CO ₂ . Cells can be subcultured regularly twice a week. Cells in the exponential growth phase can be collected and counted, diluted 1:1 in Matrigel (Corning Matrigel Matrix Basement Membrane Growth Factor Reduced) for tumor cell engraftment.

Male NSG mice (NOD.Cg-Prkdc ^scld I12rg ^tm1Wj1 /SzJ) can be inoculated subcutaneously with OCI-Ly3 cells (10 x 10 ⁶ cells in a 1:1 mixture of medium:Matrigel™ in a volume of 200 μl) in the groin region of each animal. The day of tumor inoculation can be referred to as day 0. Tumor size monitoring can be done twice weekly starting on the seventh day after implantation until the average tumor volume reaches 169 ± 42 mm ³ , at which time mice can be randomized into treatment groups based on tumor volume . The compound or vehicle may be administered orally based on body weight (5 ml/kg) once or twice daily until completion of the study. Tumor size and body weight can be recorded twice a week.

Study endpoints are tumor growth inhibition, maximum tumor burden (individual tumor size equal to 10 wt.% of the body) and weight loss greater than 20% of body weight at the start of treatment. The percentage change in body weight can be calculated using the formula Change in body weight = [(CI)/I]*1OO, where C is the current body weight and I is the body weight at the start of treatment. The size of the tumor can be measured twice a week in two directions using a caliper and the volume can be expressed in ^mm3 using the formula:

V=0.5 axb ² where a and b represent the major and minor diameters of the tumor, respectively. Complete tumor regression (CR) was defined as tumors shrinking to the extent that they are undetectable.

- 211 046082 palpation (20 mm ³ ). Partial tumor regression (PR) was defined as tumors shrinking to at least half the original tumor volume. For CR or PR to be considered sustained, CR or PR was required to be detectable for at least three or more consecutive tumor measurements.

The corresponding study tables provide summary statistics, including the mean and standard error of the mean (SEM) by tumor volume and differences in tumor volume within each group for each time point. Statistical analysis of differences in tumor volume between groups can be performed using two-way analysis of variance (ANOVA) for repeated measures followed by Tukey's test using GraphPad Prism version 6 software.

While the foregoing description sets forth the principles of the present invention with examples given for illustrative purposes, it is to be understood that the practice of the invention is intended to embrace all normal variations, adaptations and/or modifications included within the scope of the following claims and their equivalents.

Claims (4)

1. A connection selected from the group consisting of N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(4-chloro-2-methylphenyl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(3-methylpyridin-2-yl)-5 -(trifluoromethyl)-Spirazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazole4 -carboxamide; N-(5-chloro-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(5-cyanopyridin-2-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1 -(pyridin-3-yl)-5 -(trifluoromethyl)-III-pyrazole4 -carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxypyridin-3-yl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(pyrimidin-5-yl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-methylpyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-cyanopyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol4-carboxamide ; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazol-4 -carboxamide; N-(5-chloro-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(3-fluorophenyl)-5-(trifluoromethyl)-III-pyrazol4-carboxamide ; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-cyanophenyl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide ; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-methylpyridin-2-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; - 212 046082 H-(5-chloro-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1-(5-methylpyridin-2-yl)-5-(tri(|)tormethyl) -1Hpyrazole-4-carboxamide; H-(5-chloro-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1-(6-methylpyridin-2-yl)-5-(tri(|)tormethyl) -1Hpyrazole-4-carboxamide; H-(5-chloro-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-5-(di(|)tormethyl)-1-(pyridin-4-yl)-1H -pyrazole4-carboxamide; H-(5-chloro-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-5-(|)tor-1-(|)enyl-1H-pyrazol-4-carboxamide ; H-(5-chloro-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1-(p-tolyl)-5-(tri(|)tormethyl)-1H-pyrazole -4carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(m-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide ; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide ; 1-(5-bromo-3-chloropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-Ίriazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(3-chloro-5-cyanopyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-Ίriazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(3-chloro-2-methoxypyridin-4-yl)-H-(5-cyano-6-(2H- 1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(3-cyano-2-methylpyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(3-bromo-5-fluoropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(3-cyano-5-fluoropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-dichloropyridin-2-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-cyano-2-methylphenyl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxy-3-methylpyridin-4-yl)-5-(trifluoromethyl )-1H-pyrazole-4-carboxamide; 1-(2-chloropyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-cyanopyridin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methoxypyridin-4-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,3-dimethylpyridin-4-yl)-5-(trifluoromethyl) - 1H-pyrazole-4-carboxamide; 1 -(3-chloro-2-methylpyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(3-chloropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(3-chloropyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; H-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1 -(3-cyanopyridin-4-yl)-5 -(tri(tormethyl)1H- pyrazole-4-carboxamide; 1 -(3-chloro-4-methylpyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl) - 1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,5-dichloropyridin-4-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; H-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1-(2.3-dihydrobenzo|b||1.4|dioxin-5-yl)-5( Ίrifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(2-bromo-4-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(2-chloro-4-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-([1,3]dioxolo[4,5-b]pyridin-7-yl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-5-(tri(tormethyl)-1H-pyrazol-4-carboxamide; 1-([1,3]dioxolo[4,5-b]pyridin-7-yl)-H-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-5-(tri(tormethyl)-1H-pyrazol-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methoxyphenyl)-5-(trifluoromethyl)- 213 046082 1H-pyrazole-4-carboxamide; H-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4carboxamide; 1 -(2-amino-3-chloropyridin-4-yl)-H-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(2-amino-3-chloropyridin-4-yl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; H-(5-chloro-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1-(2.2-difluorobenzoI||1.3|dioxol-4-yl)-5(trifluoromethyl) -1H-pyrazole-4-carboxamide; 1-(oenzo||1.3|dioxol-4-yl)-H-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide; 1 -(2-chloro-3.4-difluorophenyl)-H-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)1H- pyrazole-4-carboxamide; 1 -(2-chloro-3-fluorophenyl)-H-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(6-amino-5-fluoropyridin-2-yl)-H-(5-chloro-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide; 1-(6-amino-5-fluoropyridin-2-yl)-H-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide; H-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)1H-pyrazol- 4-carboxamide; 1 -(3-chloro-4-methoxypyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(3-chloro-4-methoxypyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,5-dichloropyridin-4-yl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide; 1 -(5-chloro-2-methylpyridin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(3-chloro-2-methylpyridin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(5-chloro-2-methylpyridin-4-yl)-H-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(2-chloro-4-fluoro-3-methylphenyl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(2-chloro-4-fluoro-3-methylphenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(2-chloro-3,4-difluorophenyl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl) 1H-pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-(methylsulfonyl)phenyl)-5-(trifluoromethyl)-1H-pyrazole -4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-methyl-4-(methylsulfonyl)phenyl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide; No.(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-isopropylphenyl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2,3-dimethylphenyl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-difluorophenyl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide; 1-(2-chloro-5-fluorophenyl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1 -(2-chloro-5-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methoxyphenyl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide; 1-(2-chloro-3-fluorophenyl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(2-bromo-4-fluorophenyl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; No.(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2,3-dimethylphenyl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-cyano-4-fluorophenyl)-5-(trifluoromethyl)-1H - 214 046082 pyrazole-4-carboxamide; 1-(3-cyano-4-fluorophenyl)-H-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; H-(5-chloro-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1-(6-(|)tor-4-methylpyridin-3-yl)-5- (tri(|)tormethyl)-1H-pyrazole-4-carboxamide; H-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1-(2-methylpyridin-3-yl)-5-(tri(|)tormethyl) 1H-pyrazole-4-carboxamide; H-(5-chloro-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-5-(tri(|)tormethyl)-1-(2.3.4-tri(|) tor(|)enyl)-1Hpyrazol-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-chloro-6-fluorophenyl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-methylpyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-fluoro-6-methylphenyl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-fluorophenyl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; 1 -(2-chloro-4,6-difluorophenyl)-N-(5-chloro-6-(2H-1.2.3-triazol-2-yl)pyridin-3 -yl)-5 -(tri(tormethyl) 1H-pyrazole-4-carboxamide; 1 -(6-chloro-2-methylpyridin-3 -yl)-K-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3 -yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-2-methylphenyl)-5-(Ίrifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1-(2,3,4-trifluorophenyl)-1Hpyrazole -4-carboxamide; 1-(2-chloro-6-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(2-chloro-4,6-difluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-cyclopropylphenyl)-5-(trifluoromethyl)-1Hpyrazol-4-carboxamide ; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-fluoro-6-methylphenyl)-5-(Ίriforomethyl)1H- pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-fluorophenyl)-5-(Ίfluoromethyl) 1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-2-methylphenyl)-5-(Ίriforomethyl)1H- pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-difluorophenyl)-5-(Ίrifluoromethyl)-1Hpyrazol-4 -carboxamide; 1-(3-chloro-5-fluoropyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl) - 1H-pyrazole-4-carboxamide; 1-(3-chloro-5-fluoropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl) - 1H-pyrazole-4-carboxamide; 1-(2-chloro-4-fluorophenyl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(3-chloro-4-fluorophenyl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(3-chloro-4-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(2-chloro-4-cyanophenyl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2,4-difluorophenyl)-5-(Ίrifluoromethyl)-1Hpyrazol-4 -carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-3-methylpyridin-2-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-3-methylpyridin-2-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-5-(Ίfluoromethyl )-1H-pyrazole-4-carboxamide; N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-5-(Ίfluoromethyl )-1H-pyrazole-4-carboxamide; 1 -(2-chlorophenyl)-N-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-5 -(tri(tormethyl)-1H-pyra - 215 046082 zol-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyrvdin-3-yl)-1-(2,4-difluorophenyl)-5-(trifluoromethyl)-III-pyrazol- 4-carboxamide; H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-(1-methoxyethyl)phenyl)-5 -(trifluoromethyl)1H -pyrazole-4-carboxamide; 1 -(4-amino-3-chloropyridin-2-yl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(4-amino-3-chloropyridin-2-yl)-H-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -( trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyrvdin-3-yl)-1-(6-fluoropyrvdin-3-yl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyrvdin-3-yl)-1-(6-(methylamino)pyrvdin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide; N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyrvdin-3-yl)-1-(6-(fluoro)pyridin-3-yl)-5-(trifluoromethyl) 1H-pyrazole-4-carboxamide; N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyrvdin-3-yl)-1-(6-(methylamino)pyrvdin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide; 1 -(6-aminopyridin-3 -yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl)-1Hpyrazole -4-carboxamide; 1-(4-cyano-2-methylphenyl)-H-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyrvdin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; No.(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1,2,3,4-tetrags,droquinoline-5 -yl)-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(1-methylindolin-4-yl)-5-(trifluoromethyl)1H-pyrazole -4-carboxamide; No.(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(indolin-4-yl)-5-(trifluoromethyl)-1H-pyrazol- 4-carboxamide; N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl )-5(trifluoromethyl)-1H-pyrazole-4-carboxamide; Na(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-methyl-3,4-dihydro-2H-benzo[b][ 1,4]oxazin-8-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1 -(1-oxoisoindolin-4-yl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide; 1-(6-aminopyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide; 1-(2-cyano-4-fluorophenyl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)III- pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(2-cyano-4-fluorophenyl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl)-1-(2-(methylthio)phenyl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(2-(methylsulfonyl)phenyl)-5-(trifluoromethyl)-III- pyrazole-4-carboxamide; 1-(6-amino-5-cyanopyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-III-pyrazole-4-carboxamide; 1-(6-amino-5-cyanopyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-III-pyrazole-4-carboxamide; 1 -(6-amino-3-methylpyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -( trifluoromethyl)-III-pyrazole-4-carboxamide; 1 -(2-amino-5-methylpyridin-4-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -( trifluoromethyl)-III-pyrazole-4-carboxamide; 1 -(2-amino-3-methylpyridin-4-yl)-N-(5-cyano-6-(2H- 1,2,3-triazol-2-yl)pyridin-3-yl)-5 -( trifluoromethyl)-III-pyrazole-4-carboxamide; 1 -(6-amino-5-chloropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -( trifluoromethyl)-III-pyrazole-4-carboxamide; 1 -(6-amino-5-fluoro-3-methylpyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triαzol-2-yl)pyridin-3-yl) -5 (trifluoromethyl)-III-pyrazole-4-carboxamide; 1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-III-pyrazole-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(6-amino-5-fluoropyridin-2-yl)-5 - 216 046082 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(2-amino-5-chloropyridin-4-yl)-H-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(2-amino-5-chloropyridin-4-yl)-H-(5-chloro-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide; H-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-6-(methylamino)pyridin-2-yl)-5( trifluoromethyl)-1H-pyrazole-4-carboxamide; H-(5-chloro-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1 -(5-fluoro-6-(3-hydroxyazetidin-1-yl)pyridin2-yl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; H-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1 -(5-fluoro-6-(3-hydroxyazetidin-1-yl)pyridin-2 -yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; 4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5 -(trifluoromethyl)-1H-pyrazol-1yl)- 3-methylpyridine 1-oxide; 1-(2-chloro-5-methyl-4-pyridyl)-H-[5-chloro-6-(triazol-2-yl)-3-pyridyl]-5-(trifluoromethyl)pyrazole-4carboxamide; 1 -(2-chloro-3-methylpyridin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-(3-hydroxyazetidin-1-yl)-5-methylpyridin-4 -yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(2-(3-hydroxyazetidin-1-yl)-3-methylpyridin-4 -yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(3-methylpyridin-4-yl)-5 -(trifluoromethyl)-1Hpyrazol- 4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1 -(4-methylpyridazin-3-yl)-5 -(trifluoromethyl)1H-pyrazole -4-carboxamide; N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-6-methylpyridin-2-yl)-5-(trifluoromethyl )-1H-pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(5-fluoro-b-methylpyridin-2-yl)-5-(trifluoromethyl )-1H-pyrazole-4-carboxamide; N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,6-dichloropyridin-2-yl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,6-dichloropyridin-2-yl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide; 1 -(6-chloro-3 -(trifluoromethyl)pyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(6-chloro-3 -(trifluoromethyl)pyridin-2-yl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(4-chloro-2-methylphenyl)-H-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; H-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-1 -(3-fluoro-2-methylphenyl)-5 -(trifluoromethyl)1H-pyrazol- 4-carboxamide; No.(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-difluoro-2-methylphenyl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide; N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazol-4- carboxamide; N(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl ) -1H-pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)-1Hpyrazol- 4-carboxamide; No.(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl )-1H-pyrazole-4-carboxamide; H-(5-cyano-6-(2H-1.2.3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1-(2.4.6-trifluorophenyl)-1Hpyrazole-4-carboxamide ; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(3,4-difluoro-2-methylphenyl)-5-(trifluoromethyl)1H -pyrazole-4-carboxamide; 1 -(6-amino-3-chloropyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(6-amino-4-methylpyridin-2-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(6-amino-5-cyanopyridin-2-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(6-amino-5-cyanopyridin-2-yl)-K-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5- 217 046082 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(6-amino-5-fluoropyrvdin-2-yl)-H-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(6-aminopyridin-2-yl)-H-(5-x.tor-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -(trifluoromethyl) -Spirazol-4-carboxamide; 1-(6-amino-5-fluoropyrvdin-2-yl)-H-(5-bromo-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(6-amino-5-fluoropyrvdin-2-yl)-H-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(6-amino-3-chloropyridin-2-yl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(6-amino-5-methylpyridin-2-yl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(6-amino-3-methylpyridin-2-yl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(6-amino-5-fluoro-3-methylpyrvdin-2-yl)-H-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin- 3yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(6-amino-3 -(trifluoromethyl)pyridin-2-yl)-H-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(6-amino-5-fluoro-3-methylpyrvdin-2-yl)-H-(5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin- 3yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyrvdin-3-yl)-1-(6-(methylamino)pyrvdin-2-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide; 1 -(6-amino-4-methylpyridin-3-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(6-amino-4-methylpyridin-3-yl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(6-amino-3 -(trifluoromethyl)pyridin-2-yl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 5 (trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(6-amino-5-fluoropyrvdin-2-yl)-H-(5-chloro-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(6-aminopyridin-3-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)1H- pyrazole-4-carboxamide; 1-(6-amino-5-fluoropyrvdin-2-yl)-N-(5-cyano-2-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1 -(6-amino-2-methylpyridin-3-yl)-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5 -( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(6-amino-5-methylpyridin-2-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyrvdin-3-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; 2-amino-6-(4-((5-chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl) -1H-pyrazol-1-yl)nicotinamide; 1 -(2-amino-3-methylpyridin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-( trifluoromethyl)-1H-pyrazole-4-carboxamide; 1-(6-amino-5-chloropyridin-2-yl)-N-(5-cyano-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyrvdin-3-yl) -5(trifluoromethyl)-1H-pyrazole-4-carboxamide; N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyrvdin-3-yl)-1-(6-cyano-2-methylpyridin-3-yl)-5-(trifluoromethyl )-1H-pyrazole-4-carboxamide; 1-(6-bromopyrvdin-2-yl)-H-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyrvdin-3-yl)-5-(trifluoromethyl)-1Hpyrazole -4-carboxamide; (*R)-N-(5 -chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3 -yl)-1 -(5-methyl-2-(tetrahydrofuran-2- yl)pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; ^)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyrvdin-3-yl)-1-(5-methyl-2-(tetrahydrofuran-2-yl) pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide; (*S)-1-(2-(1,4-dioxan-2-yl)-5-methylpyridin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triαzole -2-yl)pyridin-3yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; (*R)-1-(2-(1,4-dioxan-2-yl)-5-methylpyridin-4-yl)-N-(5-chloro-6-(2H-1,2,3-triazole -2-yl)pyridin-3yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; No.(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-(furan-2-yl)pyridin-2-yl)-5 -(trifluoromethyl)-1H-pyrazole-4-carboxamide; and N(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(6-(5,6-dihydro-1,4-dioxin-2 -yl)pyridin-2yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; or a pharmaceutically acceptable salt form thereof. - 218 046082 2. A pharmaceutical composition having the ability to inhibit MALT1 activity, comprising a therapeutically effective amount of a compound according to claim 1 and at least one of: a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and a pharmaceutically acceptable diluent. 3. Pharmaceutical composition according to claim 2, presented in solid dosage form for oral administration. 4. Pharmaceutical composition according to claim 2, presented in the form of a syrup, elixir or suspension.