MALT1 Modulators and Uses Thereof

Abstract

Provided herein are compounds, compositions, and methods useful for modulating MALT1 and for treating related diseases, disorders, and conditions.

Description

Detailed Description of the Invention

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 325,852, filed March 31, 2022, the entire disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] background Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular signaling protein known from innate immune cells (e.g., natural killer cells NK, dendritic cells DC, and mast cells) and adaptive immune cells (e.g., T cells and B cells). MALT1 plays an important role in influencing immune responses. For example, in T cell receptor signaling, MALT1 mediates nuclear factor kappa-beta (NFKB) signaling, activating and proliferating T cells. Thus, MALT1 is of interest in the mechanisms of autoimmune and inflammatory pathologies. Furthermore, constitutive (dysregulated) MALT1 activity is associated with cancer, e.g., MALT lymphoma and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Modulators of MALT1 activity may be useful as potential therapeutic agents.

[0003] summary Provided herein is a compound designed to act as MALT1 modulator.In some embodiments, it is assumed that such compound is useful as a therapeutic agent for treating autoimmune and inflammatory diseases, disorders or conditions or cancer.

[0004] In one embodiment, a compound represented by formula (I): [ka] or stereoisomers and / or pharma- ceutically acceptable salts thereof are provided herein, wherein: R 1 is C1~6 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, and aryl; R 1 is R 1a may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 2 is C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, aryl, and 5- to 10-membered heteroaryl; R 2 is R 2a may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 3 is hydrogen or C 1~3 is alkyl; R 1a is independently, for each occurrence, hydroxyl or -OC 1~3 is alkyl; R 2a is independently, for each occurrence, hydroxyl, cyano, C 1~6 Alkyl, and -OC 1~3 selected from the group consisting of alkyl; Z is -C(H)(R A )-, -SO2-, or -NR A - and; R A is -C(O)C 1~6 alkyl, -C(O)OH, or 5-6 membered heteroaryl; m is 0 or 1; where n is 0 or 1).

[0005] In another embodiment, the compound represented by formula (Ia) [ka] or stereoisomers and / or pharma- ceutically acceptable salts thereof are provided herein, wherein: R 1 is C 1~6 Alkyl, C 1~3 haloalkyl, or aryl; C 1~6 Alkyl is R 1a may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 2 is C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, aryl, and 5- to 10-membered heteroaryl; R 2 is R 2a may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 1a is independently, for each occurrence, hydroxyl or -OC 1~3 is alkyl; R 2a is independently, for each occurrence, hydroxyl, cyano, C 1~6 Alkyl, and -OC 1~3 alkyl).

[0006] In another embodiment, the compound represented by formula (Ib) [ka] or stereoisomers and / or pharma- ceutically acceptable salts thereof are provided herein, wherein: R 1 is C 1~6 Alkyl, C 1~3 Haloalkyl, or C 3~6 Cycloalkyl, C 1~6 Alkyl is -OC 1~3 optionally substituted with alkyl; R2 is aryl or 5-6 membered heteroaryl, the aryl being optionally substituted with cyano; m is 0 or 1; where n is 0 or 1).

[0007] In another embodiment, the compound represented by formula (Ic) [ka] or stereoisomers and / or pharma- ceutically acceptable salts thereof are provided herein, wherein: R 1 is C 1~6 Alkyl or C 1~3 haloalkyl, C 1~6 Alkyl is -OC 1~3 optionally substituted with alkyl; R 2 is aryl or 5-6 membered heteroaryl, the aryl being optionally substituted with cyano; R 4 is -C(O)OH or 5-6 membered heteroaryl; m is 0 or 1; where n is 0 or 1).

[0008] In some embodiments, the compounds provided herein are selected from the compounds shown in Table 1 or a pharma- ceutically acceptable salt thereof.

[0009] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein and a pharma- ceutically acceptable carrier.

[0010] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or stereoisomer and / or pharmaceutical composition disclosed herein.

[0011] In another aspect, provided herein is a method of treating an autoimmune or inflammatory disorder or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.

[0012] Detailed Description As generally described herein, the present invention provides compounds designed to act, for example, as MALT1 modulators. In certain embodiments, such compounds are expected to be useful as therapeutic agents for treating autoimmune and inflammatory diseases, disorders, or conditions, or cancer.

[0013] definition chemical definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0014] It is understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers" and those that are non-superimposable mirror images of one another are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers may be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or the way in which the molecule rotates the plane of polarized light and are designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds may exist as either individual enantiomers or mixtures of these. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0015] The compounds described herein may contain one or more asymmetric centers, and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers.Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0016] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of a compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound, and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" indicates that a compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of an enantiomer. In certain embodiments, the weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0017] In the compositions provided herein, the enantiomerically pure compound may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may comprise, for example, about 90% of excipients and about 10% of enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition may comprise, for example, at least about 95% by weight of the R-compound and up to about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may comprise, for example, about 90% of excipients and about 10% of enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition may comprise, for example, at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0018] The compounds described herein may also contain one or more isotopic substitutions. For example, H is: 1 H, 2 H (D or deuterium), and 3 H may be of any isotopic form, including T or tritium; 12 C. 13 C, and 14 C may be in any isotopic form; O may be 16 O and 18 O may be in any isotopic form; F is 18 F and 19 It may be of any isotopic form, including F; and the like.

[0019] The following terms are intended to have the meanings presented therewith below and are useful in describing and understanding the intended scope of the present invention. In describing the present invention, which may include compounds and pharma- ceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. It should also be understood that any of the moieties defined below, as described herein, may be substituted with various substituents, and the individual definitions are intended to include such substituted moieties within their scope as set forth below. Unless otherwise indicated, the term "substituted" will be defined as set forth below. It should further be understood that the terms "group" and "radical" may be considered interchangeable as used herein. The articles "a" and "an" may be used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0020] When various values ​​are listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6Alkyl" is C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Alkyl is intended to be included.

[0021] As used herein, "alkyl" refers to the radical of a straight chain or branched saturated hydrocarbon group having, for example, 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, an alkyl group has one carbon atom ("C alkyl"). 1~6Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0022] As used herein, "alkenyl" refers to the radical of a straight chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 In certain embodiments, the alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., as in 2-butenyl) or terminal (e.g., as in 1-butenyl). C 2~4Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc.

[0023] As used herein, "alkynyl" refers to the radical of a straight chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2~20 In certain embodiments, the alkynyl does not contain any double bonds. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., as in 2-butynyl) or terminal (e.g., as in 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), etc.

[0024] As used herein, "alkylene," "alkenylene," "alkynylene," "cycloalkylene," "heterocyclylene," "heteroarylene," and "phenylene" refer to divalent radicals of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl (e.g., saturated and partially saturated), heteroaryl, and phenyl groups, respectively.

[0025] When a range or number of carbons is applied to a particular "alkylene", "alkenylene", or "alkynylene" group, it is understood that the range or number refers to the range or number of carbons in a linear divalent carbon chain. "Alkylene", "alkenylene", and "alkynylene" groups can be unsubstituted or substituted with one or more substituents described herein.

[0026] As used herein, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms in the aromatic ring system (see "C 6~14In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "aryl"; e.g., anthracyl). Exemplary aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, and indenyl.

[0027] As used herein, "heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in the cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or at a nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, with the point of attachment being on either the aryl or heteroaryl ring, in such cases the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups, one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), and the point of attachment may be in either ring, i.e., either the ring containing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0028] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0029] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0030] Representative examples of heteroaryls include: [ka] (wherein each Z is carbonyl, N, NR65 , O, and S; R 65 are independently hydrogen, C 1~8 Alkyl, C 3~10 Carbocyclyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl).

[0031] As used herein, "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 Carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3~8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~6 Carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~8Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As illustrated in the examples above, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic carbocyclyl"), which may be saturated or partially unsaturated.

[0032] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, and is used herein to refer to, for example, the "C" radical derived from a cycloalkane. 4~8 Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0033] As used herein, "C 3~6 Monocyclic cycloalkyl" or "monocyclic C 3~6 "Cycloalkyl" refers to a saturated 3- to 7-membered monocyclic hydrocarbon ring system. 3- to 7-membered monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When optionally substituted or specified as substituted, the substituents on a cycloalkyl (e.g., in the case of an optionally substituted cycloalkyl) may be present at any substitutable position, including, for example, the position at which the cycloalkyl group is attached.

[0034] As used herein, "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and one to four ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or at a nitrogen atom, as valence permits. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in either or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, with the point of attachment being on either the carbocyclyl or the heterocyclyl ring, or a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, in such cases the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" may be used interchangeably.

[0035] In some embodiments, a heterocyclyl group is a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("4- to 7-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0036] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0037] Examples of saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl, and tetrahydropyrimidinyl. When optionally substituted or specified as substituted, substituents on a heterocyclyl (e.g., in the case of an optionally substituted heterocyclyl) may be present at any substitutable position, including, for example, the position at which the heterocyclyl group is attached.

[0038] "Hetero", when used to describe a compound or a group present in a compound, means that one or more carbon atoms in the compound or group are replaced with a nitrogen, oxygen, or sulfur heteroatom. Hetero may apply to any of the above mentioned hydrocarbyl groups, such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and the like having 1 to 5 heteroatoms, especially 1 to 3 heteroatoms.

[0039] As used herein, "cyano" refers to --CN.

[0040] The terms "halo" and "halogen," as used herein, refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In certain embodiments, a halo group is either fluoro or chloro.

[0041] The term "alkoxy," as used herein, refers to an alkyl group that is attached to another moiety via an oxygen atom (-O(alkyl)). Non-limiting examples include, for example, methoxy, ethoxy, propoxy, and butoxy.

[0042] "Haloalkoxy" is a haloalkyl group that is attached to another moiety via an oxygen atom, such as, but not limited to, -OCHF2 or -OCF3.

[0043] The term "haloalkyl" includes mono-, poly-, and perhaloalkyl groups, where the halogen is replaced with one or more halogen atoms independently selected from fluorine, chlorine, bromine, and iodine. 1~4 Haloalkyl-OC 1~4 For alkyl groups, the point of attachment occurs on the halogenated alkyl portion.

[0044] As used herein, "oxo" refers to -C=O.

[0045] In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present in the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that upon substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent at each position is the same or different.

[0046] Nitrogen atoms may be substituted or unsubstituted where valence permits, including primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR. aa , -N(R cc )2, -CN, -C(=O)Raa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 Aryl, and 5- to 14-membered heteroaryl or two R attached to the nitrogen atom cc groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is 0, 1, 2, 3, 4, or 5R dd is independently substituted with R aa , R bb , R cc and R dd is as defined above.

[0047] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The invention is not intended to be limited in any way by the above list of exemplary substituents.

[0048] Other definitions As used herein, " pharmaceutically acceptable carrier " refers to non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound that is formulated.The pharmaceutically acceptable carrier, adjuvant or vehicle that may be used in the compositions described herein includes, but is not limited to, ion exchanger, alumina, aluminum stearate, lecithin, serum protein, such as human serum albumin, buffer substances, such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and wool fat.

[0049] As used herein, "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., J. Pharmaceutical Sciences (1977) 66:1-19, describe pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfonate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. + (C 1~4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0050] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) and / or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and / or a dog. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0051] Disease, disorder, and condition are used interchangeably herein.

[0052] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with a specified disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject begins to suffer from a specified disease, disorder, or condition ("prophylactic treatment").

[0053] As used herein, the "effective amount" of a compound refers to an amount sufficient to induce desired biological response.As will be understood by those skilled in the art, the effective amount of the compound of the present invention may vary depending on factors such as the desired biological end point, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health and condition of the subject.The effective amount includes therapeutic and prophylactic treatment.

[0054] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with a disease, disorder or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may include an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0055] compound In one embodiment, a compound represented by formula (I): [ka] or stereoisomers and / or pharma- ceutically acceptable salts thereof are provided herein, wherein: R 1 is C 1~6 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, and aryl; R 1 is R 1a may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 2 is C 1~6 Alkyl, C 3~6is selected from the group consisting of cycloalkyl, aryl, and 5- to 10-membered heteroaryl; R 2 is R 2a may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 3 is hydrogen or C 1~3 is alkyl; R 1a is independently, for each occurrence, hydroxyl or -OC 1~3 is alkyl; R 2a is independently, for each occurrence, hydroxyl, cyano, C 1~6 Alkyl, and -OC 1~3 selected from the group consisting of alkyl; Z is -C(H)(R A )-, -SO2-, or -NR A - and; R A is -C(O)C 1~6 alkyl, -C(O)OH, or 5-6 membered heteroaryl; m is 0 or 1; where n is 0 or 1).

[0056] In some embodiments, the compound has formula (I'): [ka] or a stereoisomer and / or a pharma- ceutically acceptable salt thereof, wherein: R 1 is C 1~6 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, and aryl; R 1 is R 1a may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R2 is C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, aryl, and 5- to 10-membered heteroaryl; R 2 is R 2a may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 3 is hydrogen or C 1~3 is alkyl; R 1a is independently, for each occurrence, hydroxyl or -OC 1~3 is alkyl; R 2a is independently, for each occurrence, hydroxyl, cyano, C 1~6 Alkyl, and -OC 1~3 selected from the group consisting of alkyl; Z is -C(H)(R A )-, -SO2-, or -NR A - and; R A is -C(O)C 1~6 alkyl, -C(O)OH, or 5-6 membered heteroaryl; m is 0 or 1; where n is 0 or 1).

[0057] In some embodiments, R 1 is C 1~6 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, and aryl; 1~6 Alkyl is hydroxyl or -OC 1~3 It may be optionally substituted with alkyl.

[0058] In some embodiments, R 1 is C 1~6 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, and aryl;1~6 The alkyl may be optionally substituted with hydroxyl or -O-CH3.

[0059] In some embodiments, R 1 is -CH(CH3)2, CF3, cyclopropyl, phenyl, [ka] is selected from the group consisting of:

[0060] In some embodiments, R 2 is C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, aryl, and 5-10 membered heteroaryl; 1~6 Alkyl and aryl are hydroxyl, cyano, C 1~6 Alkyl, or -OC 1~3 It may be optionally substituted with alkyl.

[0061] In some embodiments, R 2 is C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, aryl, and 5-10 membered heteroaryl; 1~6 The alkyl and aryl may be optionally substituted with hydroxyl, cyano, CH3, or -O-CH3.

[0062] In some embodiments, R 2 is CH3, cyclopropyl, -C(H)(CH3)2, -CH2C(CH3)3, phenyl, [ka] is selected from the group consisting of:

[0063] In some embodiments, R 2is CH3, cyclopropyl, -C(H)(CH3)2, -CH2C(CH3)3, phenyl, [ka] is selected from the group consisting of:

[0064] In some embodiments, R 2 is C 1~6 Alkyl or aryl, C 1~6 The alkyl and aryl are substituted with hydroxyl, cyano, CH3, or -O-CH3.

[0065] In some embodiments, R 2 is C 1~6 Alkyl or phenyl, C 1~6 The alkyl or phenyl is substituted with hydroxyl, cyano, CH3, or -O-CH3.

[0066] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0067] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0068] In some embodiments, R 2 is CH3, cyclopropyl, -C(H)(CH3)2, -CH2C(CH3)3, phenyl, [ka] is selected from the group consisting of:

[0069] In some embodiments, R 3 is hydrogen or CH. In some embodiments, R 3 is CH3.

[0070] In some embodiments, Z is -SO2-.

[0071] In some embodiments, m is 1 and n is 1.

[0072] In some embodiments, Z is -NR A -It is.

[0073] In some embodiments, m is 0 and n is 0. In some embodiments, m is 1 and n is 1.

[0074] In some embodiments, R A -C(O)C 1~6 In some embodiments, R A is -C(O)CH3.

[0075] In some embodiments, Z is -C(H)(R A )-.

[0076] In some embodiments, m is 0 and n is 0.

[0077] In some embodiments, R A is -C(O)OH.

[0078] In some embodiments, m is 1 and n is 1.

[0079] In some embodiments, R A is -C(O)OH or 5-6 membered heteroaryl. In some embodiments, R A is -C(O)OH or [ka] It is.

[0080] In another embodiment, the compound represented by formula (Ia): [ka] or stereoisomers and / or pharma- ceutically acceptable salts thereof are provided herein, wherein: R 1 is C 1~6 Alkyl, C 1~3 haloalkyl, or aryl; C 1~6 Alkyl is R 1a may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 2 is C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, aryl, and 5- to 10-membered heteroaryl; R 2 is R 2a may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 1a is independently, for each occurrence, hydroxyl or -OC 1~3 is alkyl; R 2a is independently, for each occurrence, hydroxyl, cyano, C 1~6 Alkyl, and -OC 1~3 alkyl).

[0081] In some embodiments, the compound has formula (Ia'): [ka] or a stereoisomer and / or a pharma- ceutically acceptable salt thereof, wherein: R 1 is C 1~6 Alkyl, C 1~3 haloalkyl, or aryl; C 1~6 Alkyl is R 1a may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 2 is C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, aryl, and 5- to 10-membered heteroaryl; R 2 is R 2a may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 1a is independently, for each occurrence, hydroxyl or -OC 1~3 is alkyl; R 2a is independently, for each occurrence, hydroxyl, cyano, C 1~6 Alkyl, and -OC 1~3 alkyl).

[0082] In some embodiments, R 1 is C 1~6 Alkyl, C 1~3 haloalkyl, or aryl, C 1~6 Alkyl is hydroxyl or -OC 1~3 It may be optionally substituted with alkyl.

[0083] In some embodiments, R 1 is C 1~6 Alkyl, C 1~3 haloalkyl, or aryl, C 1~6 The alkyl may be optionally substituted with hydroxyl or -O-CH3.

[0084] In some embodiments, R 1 is -CH(CH3)2, CF3, phenyl, [ka] is selected from the group consisting of:

[0085] In some embodiments, R 2 is C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, aryl, and 5-10 membered heteroaryl; 1~6 Alkyl and aryl are hydroxyl, cyano, C 1~6 Alkyl, or -OC 1~3 It may be optionally substituted with alkyl.

[0086] In some embodiments, R 2 is C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, aryl, and 5-10 membered heteroaryl; 1~6 The alkyl and aryl may be optionally substituted with hydroxyl, cyano, CH3, or -O-CH3.

[0087] In some embodiments, R 2 is CH3, cyclopropyl, -C(H)(CH3)2, -CH2C(CH3)3, phenyl, [ka] is selected from the group consisting of:

[0088] In some embodiments, R 2 is CH3, cyclopropyl, -C(H)(CH3)2, -CH2C(CH3)3, phenyl, [ka] is selected from the group consisting of:

[0089] In some embodiments, R 2 is C 1~6 Alkyl or aryl, C 1~6 The alkyl and aryl are substituted with hydroxyl, cyano, CH3, or -O-CH3.

[0090] In some embodiments, R 2 is C 1~6 Alkyl or phenyl, C 1~6 The alkyl or phenyl is substituted with hydroxyl, cyano, CH3, or -O-CH3.

[0091] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0092] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0093] In some embodiments, R 2 is CH3, cyclopropyl, -C(H)(CH3)2, -CH2C(CH3)3, phenyl, [ka] is selected from the group consisting of:

[0094] In another embodiment, the compound represented by formula (Ib): [ka] or stereoisomers and / or pharma- ceutically acceptable salts thereof are provided herein, wherein: R 1 is C 1~6 Alkyl, C 1~3 Haloalkyl, or C 3~6 Cycloalkyl, C 1~6 Alkyl is -OC 1~3 optionally substituted with alkyl; R 2 is aryl or 5-6 membered heteroaryl, the aryl being optionally substituted with cyano; m is 0 or 1; where n is 0 or 1).

[0095] In some embodiments, the compound has formula (Ib'): [ka] or a stereoisomer and / or a pharma- ceutically acceptable salt thereof, wherein: R 1 is C 1~6 Alkyl, C 1~3 Haloalkyl, or C 3~6 Cycloalkyl, C 1~6 Alkyl is -OC 1~3 optionally substituted with alkyl; R 2 is aryl or 5-6 membered heteroaryl, the aryl being optionally substituted with cyano; m is 0 or 1; where n is 0 or 1).

[0096] In some embodiments, R 1 is C 1~6 Alkyl, C 1~3 Haloalkyl, or C 3~6 Cycloalkyl, C 1~6 The alkyl may be optionally substituted with -O-CH3.

[0097] In some embodiments, R 1 are -CH(CH3)2, CF3, cyclopropyl, and [ka] is selected from the group consisting of:

[0098] In some embodiments, R 2 is phenyl or [ka] wherein the phenyl is optionally substituted with cyano.

[0099] In some embodiments, R 2 is phenyl, [ka] is selected from the group consisting of:

[0100] In some embodiments, R 2 teeth [ka] In some embodiments, R 2 teeth [ka] In some embodiments, R 2 is phenyl, [ka] is selected from the group consisting of:

[0101] In some embodiments, m is 0 and n is 0. In some embodiments, m is 1 and n is 1.

[0102] In another embodiment, the compound represented by formula (Ic): [ka] or stereoisomers and / or pharma- ceutically acceptable salts thereof are provided herein, wherein: R 1 is C 1~6 Alkyl or C 1~3 haloalkyl, C 1~6 Alkyl is -OC 1~3 optionally substituted with alkyl; R 2 is aryl or 5-6 membered heteroaryl, the aryl being optionally substituted with cyano; R 4 is -C(O)OH or 5-6 membered heteroaryl; m is 0 or 1; where n is 0 or 1).

[0103] In some embodiments, the compound has formula (Ic'): [ka] or a stereoisomer and / or a pharma- ceutically acceptable salt thereof, wherein: R 1 is C 1~6 Alkyl or C 1~3 haloalkyl, C 1~6 Alkyl is -OC 1~3 optionally substituted with alkyl; R 2 is aryl or 5-6 membered heteroaryl, the aryl being optionally substituted with cyano; R 4is -C(O)OH or 5-6 membered heteroaryl; m is 0 or 1; where n is 0 or 1).

[0104] In some embodiments, R 1 is C 1~6 Alkyl or C 1~3 haloalkyl, C 1~6 The alkyl may be optionally substituted with -O-CH3.

[0105] In some embodiments, R 1 CF3 or [ka] It is.

[0106] In some embodiments, R 2 is phenyl, [ka] wherein the phenyl is optionally substituted with cyano.

[0107] In some embodiments, R 2 is phenyl, [ka] is selected from the group consisting of:

[0108] In some embodiments, R 2 teeth [ka] In some embodiments, R 2 teeth [ka] In some embodiments, R 2 is phenyl, [ka] is selected from the group consisting of:

[0109] In some embodiments, m is 0 and n is 0.

[0110] In some embodiments, R 4 is -C(O)OH.

[0111] In some embodiments, the compound is selected from any compound shown in Table 1 or a pharma- ceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0112] Pharmaceutical Compositions and Routes of Administration The compound provided according to the present invention is usually administered in the form of pharmaceutical composition.Therefore, the present invention provides pharmaceutical composition comprising one or more of the compounds described as active ingredient or their pharmaceutically acceptable salt or ester, and one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants.Pharmaceutical composition can be administered alone or in combination with other therapeutic agents.Such composition is prepared in a manner well known in the pharmaceutical field (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Edition (edited by GS Banker & C. t. Rhodes)).

[0113] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities as described in the patents and patent applications incorporated by reference, including, for example, rectal, buccal, intranasal and transdermal routes, by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or via an impregnated or coated device, e.g., a stent or cylindrical polymer for arterial insertion.

[0114] One mode of administration is parenterally, particularly by injection. Forms in which the novel composition of the present invention can be incorporated for administration by injection include aqueous or oily suspensions or emulsions using sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol solutions, dextrose solutions, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but are less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0115] Sterile injectable solution is prepared by incorporating the compound according to the present invention in the required amount in a suitable solvent with various other ingredients as listed above as necessary, followed by filtering and sterilization.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains basic dispersion medium and other ingredients as listed above.For sterile powder for preparing sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains a powder of active ingredient and any additional desired ingredient from the previously sterile-filtered solution of the powder.

[0116] Oral administration is another route for administering the compounds according to the present invention. Administration may be via capsules or enteric coated tablets, etc. In preparing pharmaceutical compositions containing at least one compound described herein, the active ingredient is usually diluted with an excipient and / or enclosed in a carrier, which may be in the form of a capsule, sachet, paper or other container. When an excipient serves as a diluent, it may be in the form of a solid, semi-solid, or liquid material (as described above), and acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0117] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose.The formulation may further include lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[0118] The compositions of the present invention may be formulated to provide rapid, sustained or delayed release of active ingredient after administration to a patient by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems that contain polymer-coated reservoirs, or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the method of the present invention uses a transdermal delivery device ("patch"). Such transdermal patches may be used to provide a controlled amount of continuous or discontinuous infusion of the compounds of the present invention. The construction and use of transdermal patches to deliver pharmaceuticals is well known in the art. See, for example, U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0119] The composition is preferably formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compound is generally administered in a pharmacologic effective amount. However, it will be understood that the amount of the compound actually administered will usually be determined by the physician in view of the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0120] For the preparation of solid compositions, such as tablets, the principal active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogenous mixture of the compound of the present invention. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient is evenly dispersed throughout the composition, such that the composition can be readily subdivided into uniformly effective unit dosage forms, such as tablets, pills, and capsules.

[0121] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablet or pill may comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or to delay its release.Various materials may be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0122] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal route for localized or systemic effect. Compositions, preferably in pharma- ceutically acceptable solvents, may be nebulized by the use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be preferably administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0123] In some embodiments, the pharmaceutical composition comprises a disclosed compound or a stereoisomer and / or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

[0124] Usage The compounds and compositions described herein are generally useful for modulating MALT1 and are useful for treating diseases or disorders, particularly those that are sensitive to the modulation of MALT1 proteolytic and / or autoproteolytic activity.In some embodiments, the compounds and compositions described herein are useful for inhibiting MALT1.In some embodiments, it is believed that the compounds and compositions of the present invention may be useful in treating diseases, disorders, or conditions characterized by dysregulated NF-kB activation, such as autoimmune or immunological disorders and inflammatory, allergic, respiratory, and oncological disorders.

[0125] In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, as well as pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomers, polymorphs, and prodrugs of such compounds.In some embodiments, the present invention includes pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, solvates (e.g., hydrates) of addition salts, tautomers, polymorphs, enantiomers, mixtures of enantiomers, stereoisomers, or mixtures of stereoisomers (either pure or as racemic or non-racemic mixtures) of the compounds described herein, such as compounds of formula I, Ia, Ib, or Ic.

[0126] In some embodiments, the autoimmune and inflammatory disorder is selected from arthritis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, gastritis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, rheumatic fever, gout, organ or transplant rejection, acute or chronic graft-versus-host disease, chronic allograft rejection, Behcet's disease, uveitis, psoriasis, psoriatic arthritis, BENTA disease, polymyositis, dermatitis, atopic dermatitis, dermatomyositis, acne vulgaris, myasthenia gravis, hidradenitis suppurativa, Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome, and antibody-mediated vasculitis syndromes (primary or secondary to an infection or cancer), including blistering disorders (e.g., pemphigus vulgaris), ANCA-associated vasculitis, Henoch-Schönlein purpura, and immune-complex vasculitis.

[0127] In some embodiments, the autoimmune or inflammatory disorder or disease is selected from the group consisting of acute graft-versus-host disease, chronic graft-versus-host disease, lupus, scleroderma, psoriatic arthritis, primary sclerosing cholangitis, rheumatoid arthritis, and inflammatory bowel disease.

[0128] In some embodiments, the oncological disorder is selected from the group consisting of carcinoma, sarcoma, lymphoma, leukemia and germ cell tumors, adenocarcinoma, bladder cancer, clear cell carcinoma, skin cancer, brain cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, brain tumor, breast cancer, gastric cancer, germ cell tumor, glioblastoma, hepatic adenoma, Hodgkin's lymphoma, liver cancer, kidney cancer, lung cancer, pancreatic cancer, head / neck / throat cancer, ovarian cancer, skin tumor, prostate cancer, renal cell carcinoma, gastric cancer, hematological cancer, medulloblastoma, non-Hodgkin's lymphoma, diffuse large B cell lymphoma (DLBCL), activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), mantle cell lymphoma, marginal zone lymphoma, T cell lymphoma, particularly Sézary syndrome, mycosis fungoides, cutaneous T cell lymphoma, T cell acute lymphoblastic leukemia, melanoma, mucosal Lymphoma of associated lymphoid tissue (MALT), multiple myeloma, plasma cell neoplasm, lentigo maligna melanoma, acral lentiginous melanoma, squamous cell carcinoma, chronic myeloid leukemia, myeloid leukemia, superficial spreading melanoma, acral lentiginous melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, desmoplastic melanoma, amelanotic melanoma, soft tissue melanoma, melanoma with small nevus-like cells, melanoma with features of Spitz nevus Selected from melanoma, uveal melanoma, precursor T-cell, leukemia / lymphoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, follicular lymphoma, chronic lymphocytic leukemia / lymphoma, Burkitt's lymphoma, mycosis fungoides, peripheral T-cell lymphoma, nodular sclerosis from Hodgkin's lymphoma, mixed cellularity variant of Hodgkin's lymphoma, non-small cell lung cancer, large cell carcinoma, and small cell lung carcinoma.

[0129] In some embodiments, the oncological disorder is cancer in the form of a tumor or a congenital hematological cancer. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is malignant and / or metastatic. In some embodiments, the tumor is selected from adenoma, adenocarcinoma, blastoma (e.g., hepatoblastoma, glioblastoma, neuroblastoma, and retinoblastoma), carcinoma (e.g., colorectal carcinoma or hepatocellular carcinoma, pancreatic, prostate, gastric, esophageal, cervical, and head and neck carcinomas, and adenocarcinoma), desmoid tumor, desmoplastic small round cell tumor, endocrine tumor, germ cell tumor, lymphoma, leukemia, sarcoma (e.g., Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, or other soft tissue sarcomas), Wilms' tumor, lung tumor, colon tumor, lymphatic tumor, breast tumor, or melanoma.

[0130] In some embodiments, the allergic disorder is selected from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, and beryllium disease.

[0131] In some embodiments, the respiratory disorder is selected from asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, primary pulmonary hypertension, and emphysema.

[0132] In some embodiments, the compounds and compositions of the invention may be useful in the treatment of rheumatoid arthritis, systemic lupus erythematosus, vasculitic conditions, allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), acute or chronic transplant rejection, graft-versus-host disease, cancers or solid tumors of hematopoietic origin, chronic myeloid leukemia, myeloid leukemia, non-Hodgkin's lymphoma or other B-cell lymphomas.

[0133] Combination Therapy The compounds of the compositions described herein may be administered in combination with another drug or therapy. The subject to whom the compounds disclosed herein are to be administered may have a disease, disorder, or condition, or symptoms thereof, that would benefit from treatment with another drug or therapy.

[0134] In some embodiments, the compounds of the compositions described herein may be administered simultaneously with, before, or after one or more other therapeutic agents.In some embodiments, the compounds of the compositions described herein may be administered separately by the same or different administration route as the other agent, or together in the same pharmaceutical composition.

[0135] In some embodiments, the compound described herein can be administered as the sole active ingredient, or can be administered with other drugs, such as immunosuppressants or immunomodulators or other anti-inflammatory drugs, such as those for treating or preventing acute or chronic rejection of allografts or inflammatory or autoimmune disorders, or chemotherapeutic drugs, such as malignant cell anti-proliferative drugs, for example, as adjuvants thereto.For example, the compound of the present invention can be used in combination with calcineurin inhibitors, such as cyclosporine A or FK506; mTOR inhibitors, such as rapamycin, 40-0-(2-hydroxyethyl)-rapamycin, biolimus-7 or biolimus-9; ascomycins with immunosuppressive properties, such as ABT-281, ASM981; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid or salt; mycophenolate mofetil; or IL-1 beta inhibitors.

[0136] In some embodiments, the compounds described herein are used in combination with a co-agent that is a PI3K inhibitor.

[0137] In some embodiments, the compounds described herein are used in combination with an ancillary agent that affects BTK (Bruton's tyrosine kinase).

[0138] For the treatment of oncological diseases, the compounds described herein may be used in combination with B cell modulating agents, such as rituximab, ofatumumab, inhibitors of BTK or SYK, inhibitors of PKC, PI3K, PDK, PIM, JAK and mTOR, and BH3 mimetics. EXAMPLES

[0139] Working Example The following representative examples are intended to help illustrate the invention and are not intended, nor should they be construed, to limit the scope of the invention.

[0140] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary with the particular reactants or solvents used, but such conditions may be determined by one skilled in the art through routine optimization.

[0141] Moreover, as will be understood by those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.Selection of suitable protecting groups for specific functional groups and suitable conditions for protection and deprotection are well known in the art.For example, many protecting groups and their introduction and removal are described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991 and the references cited therein.

[0142] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high performance liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). It should be noted that flash chromatography may be performed manually or through an automated system. The compounds provided herein may be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in parts per million (ppm) and are generated using methods well known to those skilled in the art. List of abbreviations: EtOAc, EA ethyl acetate THF Tetrahydrofuran PE Petroleum Ether MeOH Methanol EtOH Ethanol DMF N,N-Dimethylformamide FA Formic Acid DCM Dichloromethane MeCN, ACN, CH3CN Acetonitrile Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene h, hr, hrs time Calcd Calculated value UV ultraviolet light rt room temperature DIEA, DIPEA N,N-Diisopropylethylamine Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) Et3N, TEA triethylamine Cs2CO3 Cesium carbonate INT intermediate t-BuOH tert-butyl alcohol Boc tert-Butyloxycarbonyl LiOH.H2O Lithium hydroxide monohydrate NH4Cl Ammonium chloride DPPA Diphenylphosphoryl azide NaOH Sodium hydroxide (COCl)2Oxalyl chloride NaN3 Sodium Azide CDI 1,1'-Carbonyldiimidazole BnOH Benzyl alcohol Cbz benzyloxycarbonyl SnCl2 Tin chloride HCl Hydrochloric acid NaNO2 Sodium nitrite KOH Potassium hydroxide BH3.DMS Borane dimethyl sulfide complex H2O2 Hydrogen Peroxide RuCl3 Ruthenium trichloride NaIO4 Sodium Periodate NaH Sodium hydride KNO3 Potassium nitrate H2SO4 Sulfuric acid Pd / C Palladium on Carbon DMF-DMA, (CH3)2NCH(OCH3)2N,N-Dimethylformamide dimethyl acetal CF3CH2OH 2,2,2-trifluoroethanol N2H4Hydrazine CH3(NH)NH2Methylhydrazine MeI Methyl iodide LiHMDS Lithium bis(trimethylsilyl)amide (n-Bu)4NOAc Tetrabutylammonium acetate TMSCF3 Trimethyl(trifluoromethyl)silane AcOH Acetic acid PtO2 Platinum Oxide NaBH3CN Sodium cyanoborohydride CuCN Cuprous cyanide MgCl2 Magnesium chloride K2CO3 Potassium Carbonate CuI Cuprous iodide CH2I2 Diiodomethane Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride NaBH4 Sodium borohydride

[0143] Example 1. Preparation of Compounds Methods for preparing the compounds described herein are shown in the following synthetic schemes. These schemes are provided for the purpose of illustrating the present invention and should not be considered as limiting the scope or spirit of the present invention in any manner. Starting materials shown in the schemes may be obtained from commercially available sources or may be prepared from commercially available sources based on procedures described in the literature.

[0144] 1. Compounds prepared using Scheme 1 Scheme 1: [ka] G-1a to R 1’ Reaction with a containing carboxamide G-1b gives the compound of formula (A).

[0145] Exemplary Procedure for Compounds Prepared Using Scheme 1: Synthesis of (S)-N-methyl-N-(2,2,2-trifluoro-1-(4-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (compound 1.1) [ka] To a mixture of 1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-amine [free base of INT1.1] (50 mg, 302 μmol) and (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT5.1] (155 mg, 362 μmol) in dioxane (2 mL) was added Pd2(dba)3 (27.6 mg, 30.2 μmol), Xantphos (34.9 mg, 60.4 μmol) and Cs2CO3 (295 mg, 906 μmol). The mixture was stirred at 100 °C under N2 atmosphere for 2 h, then quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: YMC-Actus Triart C18 150*30mm*5μm, condition: 42%-62% CH3CN (0.05v / v% ammonia hydroxide)-ACN in water, flow rate: 35mL / min) to give (S)-N-methyl-N-(2,2,2-trifluoro-1-(4-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [Compound 1.1] (20.6mg, 40.1μmol, yield 13.3%) as a white dry powder. m / z: calculated for [M+H]+C20H23F6N4O3S 513.1; found 513.2. 1 H NMR (400 MHz,CD3OD) δ = 7.55 (s,1H),7.19 (d,J = 8.4 Hz,2H),6.82 (d,J = 8.4 Hz,2H),6.57 - 5.95 (m,1H),4.00 (s,3H),3.30 - 3.09 (m,5H),2.98 (s,3H),2.39 - 2.10 (m,4H).

[0146] 2. Compounds prepared using Scheme 2 Scheme 2: [ka] Starting material G-2a is treated with base (LiOH.HO or NaOH) to give the compound of formula (B). 2 is phenyl, pyridyl, or pyridazine; R 1 is CF3 or (S)-methoxyethane; m and n are each independently 0 or 1. R 3’ is methyl or benzyl.

[0147] Exemplary procedure for compounds prepared using Scheme 2: Synthesis of (1S,4r)-4-(methyl((S)-2,2,2-trifluoro-1-(4-((1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)phenyl)ethyl)carbamoyl)cyclohexane-1-carboxylic acid (compound 2.1) [ka] To a mixture of methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclohexane-1-carboxylate [INT6.1] (280 mg, 480 μmol) in THF (3 mL) and HO (1 mL) was added LiOH.HO (60.4 mg, 1.44 mmol) and the mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by Prep-HPLC (Column: YMC Actus Triart C18 150*30mm*5μm, Table: 50-70%B (A=water (0.225% formic acid)-ACN), B=acetonitrile), Flow rate: 35mL / min, UV detector 220nm) to give (1S,4r)-4-(methyl((S)-2,2,2-trifluoro-1-(4-((1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)phenyl)ethyl)carbamoyl)cyclohexane-1-carboxylic acid [Compound 2.1] (30.5mg, 53.6μmol, 11.2% yield) as a white dry powder. m / z: [M+H]+Calculated for C27H27F6N4O3 569.2 Found 569.1. 1 H NMR (400 MHz,CDCl3) δ = 7.80 (s,1H),7.54 - 7.44 (m,5H),7.26 - 7.24 (m,2H),6.94 (d,J = 8.8 Hz,2H),6.60 (q,J = 9.2 Hz,1H),5.51 (s,1H),2.90 (s,3H),2.62 - 2.53 (m,1H),2.42 (tt,J = 3.6,12.0 Hz,1H),2.15 (br t,J = 8.8 Hz,2H),2.01 - 1.82 (m,2H),1.67 (q,J = 12.8 Hz,2H),1.56 - 1.42 (m,2H).

[0148] Synthesis of (1r,3r)-3-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclobutane-1-carboxylate amine (compound 2.11) and (1s,3s)-3-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclobutane-1-carboxylate amine (compound 2.12) [ka] A mixture of benzyl 3-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclobutane-1-carboxylate [INT6.12] (390 mg, 617 μmol) and sodium hydroxide (98.3 mg, 2.46 mmol) in THF (5 mL) and water (5 mL) was stirred at 25° C. for 2 h. The reaction mixture was combined with another of the same type. The mixture was diluted with water (10 mL), adjusted to pH=4 with 1N HCl, and extracted with EtOAc (50 mL×2). The combined organic phase was concentrated under reduced pressure to give the crude product, which was purified by Prep-HPLC (column: YMC-Triart Prep C18 150*40mm*7μm, column: 9-49%B (A=water (0.1% NH3.H2O and 10mM NH4HCO3), B=acetonitrile), flow rate: 60mL / min, UV detector 220nm) to give 120mg of off-white solid. The material was purified by SFC (column: DAICEL CHIRALPAK Purify with AS (250mm*30mm, 10μm, Table: 25%B (A=CO2(0.1%NH3H2OEtOH), B=EtOH), flow rate: 60mL / min, UV detector 220nm) to obtain (1r,3r)-3-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclobutane-1-carboxylate amine [Compound 2.11] (41.0 mg, 73.4 μmol, 11.9% yield) and (1s,3s)-3-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclobutane-1-carboxylate amine [Compound 2.12] (55.1 mg, 98.6 μmol, 16.0% yield) were obtained as white solids. Compound 2.11: m / z: [M+H]+ calculated for C24H22F6N5O3 542.2; found 542.2. 1H NMR (400 MHz,CDCl3) δ = 8.58 - 8.48 (m,1H),7.89 (dt,J = 2.0,8.0 Hz,1H),7.84 (s,1H),7.75 (d,J = 8.8 Hz,1H),7.34 (dd,J = 4.0,6.8 Hz,1H),7.31-7.27 (m,2H),6.97 (d,J = 8.4 Hz,2H),6.57 (q,J = 8.4 Hz,1H),5.67 (s,1H),3.51 (br t,J = 8.3 Hz,1H),3.23 (td,J = 4.4,9.5 Hz,1H),2.78 (s,3H),2.74 - 2.65 (m,2H), 2.64 - 2.49 (m,2H). Compound 2.12: m / z: [M+H]+ calculated for C24H22F6N5O3 542.2; found 542.2. 1 H NMR (400 MHz,CDCl3) δ = 8.58 - 8.49 (m,1H),7.88 (dt,J = 1.6,8.0 Hz,1H),7.85 (s,1H),7.75 (d,J = 8.8 Hz,1H),7.34 (dd,J = 4.8,7.2 Hz,1H),7.31-7.27 (m,2H),6.97 (d,J = 8.4 Hz,2H),6.55 (q,J = 8.8 Hz,1H),5.68 (s,1H),3.29 (quintet,J = 8.8 Hz,1H),3.17 (quintet,J = 8.8 Hz,1H),2.80 (s,3H),2.75 - 2.62 (m,2H),2.61 - 2.46 (m,2H).

[0149] 3. Compounds prepared using Scheme 3 Scheme 3: [ka] Synthesis of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(1H-tetrazol-5-yl)cyclohexane-1-carboxamide (compound 3.1) To a solution of (1r,4r)-4-cyano-N-methyl-N-[(1S)-2,2,2-trifluoro-1-(4-{[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]cyclohexane-1-carboxamide [INT6.11] (100 mg, 181 μmol) and ammonium chloride (14.4 mg, 271 μmol) in DMF (5 mL) was added sodium azide (40 mg, 615 μmol). The reaction mixture was stirred at 105° C. under nitrogen for 12 h. H2O (10 mL) was added and the mixture was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude (1r,4S)—N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(1H-tetrazol-5-yl)cyclohexane-1-carboxamide [compound 3.1] (100 mg, 168 μmol, 93.4% yield). The material was purified by prep-HPLC (column: YMC-Triart Prep C18 150*40mm*7μm, table: 16-56%B (A=water (ammonia hydroxide), B=acetonitrile), flow rate: 60mL / min, UV detector 220nm) to give (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(1H-tetrazol-5-yl)cyclohexane-1-carboxamide [compound 3.1] (3.90mg, 6.58μmol, 3.9% yield) as an off-white solid. m / z: calculated for [M+H]+C27H27F6N8O 593.2; found 593.2. 1H NMR (400 MHz,CDCl3) δ = 7.81 (s,1H),7.49 (br s,5H),7.27 (s,2H),6.96 (d,J = 8.8 Hz,2H),6.67 - 6.51 (m,1H),5.60 (s,1H),3.22 - 3.15 (m,1H),3.03 - 2.85 (m,3H),2.79 (br s,1H),2.28 (br s,2H),2.13 - 1.95 (m,2H),1.82 (br s,4H).

[0150] Synthesis of Exemplary Intermediates The following exemplary intermediates were synthesized and used to synthesize one or more exemplary compounds of the present disclosure. Synthesis of 1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.1]: [ka]

[0151] Synthesis of tert-butyl N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-b]: To a solution of 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-a] (500 mg, 2.57 mmol), 2-methylpropan-2-ol (285 mg, 3.85 mmol), and triethylamine (780 mg, 7.71 mmol) in toluene (5 mL) was added DPPA (1.05 g, 3.85 mmol). The reaction mixture was stirred at 100 °C under N2 for 1 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAC / PE = 0 / 1 to 1 / 1) to give tert-butyl N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-b] (540 mg, 2.03 mmol, 79% yield) as a white solid. m / z: calculated for [M+H]+C10H15F3N3O2 266.1; found 266.1.

[0152] 1-Methyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.1]: A solution of tert-butyl N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-b] (540 mg, 2.03 mmol) in 4M HCl / dioxane (10 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure to give 1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.1] (350 mg, 1.73 mmol, 86% yield) as a brown solid. m / z: calculated for [M+H]+C5H7F3N3 166.1; found 166.1.

[0153] Synthesis of 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [Intermediate 1.2]: [ka] Synthesis of 5-hydrazinylquinoline [INT1-d]: To a solution of quinolin-5-amine [INT1-c] (1 g, 6.93 mmol) in HCl (6 mL) was added dropwise a solution of NaNO2 (525 mg, 7.62 mmol) in H2O (1.5 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min and warmed to 21 °C over 30 min until an orange solution formed. The mixture was cooled to 0 °C and a solution of tin(II) chloride (3.11 g, 13.8 mmol) dissolved in HCl (3 mL) was added dropwise. A yellow precipitate formed immediately upon addition of the tin salt. The mixture was stirred at 0 °C for 30 min and then warmed to 21 °C over 12 h with vigorous stirring. The reaction mixture was filtered. The filter cake was washed with chilled EtOH (10 mL×3) and dried under reduced pressure to give crude 5-hydrazinylquinoline [INT1-d] (1.10 g, 6.90 mmol) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ = 10.05 (br s,1H),9.28 - 9.18 (m,2H),8.05 - 7.96 (m,2H),7.92 (d,J = 8.4 Hz,1H),7.29 (d,J = 7.6 Hz,1H).

[0154] Synthesis of ethyl 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-e]: To a solution of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (668 mg, 2.78 mmol) in EtOH (5 mL) was added 5-hydrazinylquinoline [INT1-d] (367 mg, 2.31 mmol). The mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (CH2Cl2 / MeOH=100 / 0 to 95 / 5) to give ethyl 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-e] (185 mg, 551 μmol, 23.9% yield) as a brown semi-solid. m / z: [M+H]+calculated for C16H13F3N3O2 336.1; found 336.2.

[0155] Synthesis of 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-f]: To a solution of ethyl 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-e] (419 mg, 1.24 mmol) in HO (0.5 mL) and THF (3 mL) was added lithium hydroxide monohydrate (104 mg, 2.48 mmol). The mixture was stirred at 21 °C for 2 h, after which it was concentrated under reduced pressure to give a brown solid. HO (3 mL) was then added and the reaction mixture was adjusted to pH 5 with 1 M HCl. The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous NaSO and concentrated under reduced pressure to give crude 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-f] (120 mg, 390 μmol, 31.5% yield) as a brown solid. m / z: calculated for [M+H]+C14H9F3N3O2 308.1; found 308.0.

[0156] Synthesis of benzyl (1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)carbamate [INT1-g]: A solution of 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-f] (180 mg, 585 μmol), benzyl alcohol (75.9 mg, 702 μmol), Et3N (59.1 mg, 585 μmol) and DPPA (241 mg, 877 μmol) in toluene (2 mL) was stirred at 90° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=0 / 1 to 1 / 3) to give benzyl (1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)carbamate [INT1-g] (100 mg, 242 μmol, 41.4% yield) as a yellow solid. m / z: [M+H]+calculated for C21H16F3N4O2 413.1; found 413.1.

[0157] Synthesis of 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.2]: To a solution of benzyl (1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)carbamate [INT1-g] (100 mg, 242 μmol) in THF (2 mL) was added NaOH (96.8 mg, 2.42 mmol) and HO (2 mL). The resulting mixture was stirred at 60° C. for 12 h. Water (10 mL) was added and the mixture was extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine (20 mL), dried over NaSO and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / Hexane=0 / 1 to 1 / 1) to give 1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.2] (45.0 mg, 161 μmol, 66.8% yield) as a white solid. m / z: calculated for [M+H]+C13H10F3N4 279.1; found 279.1.

[0158] Synthesis of 1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [Intermediate 1.3]: [ka] Synthesis of ethyl 1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-i]: To a solution of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (3 g, 12.4 mmol) in EtOH (30 mL), (2-methylphenyl)hydrazine hydrochloride [INT1-h] (1.96 g, 12.4 mmol) was added at 25° C., and the reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EA=1 / 0 to 3 / 1) to give ethyl 1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-i] (3.10 g, 10.3 mmol, 84.0% yield) as a yellow oil. m / z: [M+H]+calculated for C14H14F3N2O2 299.1; found 298.9.

[0159] Synthesis of 1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-j]: To a mixture of ethyl 1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-i] (3.1 g, 10.3 mmol) in HO (10 mL) and THF (20 mL) was added lithium hydroxide monohydrate (1.07 g, 25.7 mmol). The reaction mixture was stirred at 15° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The mixture was then acidified to pH=4 with 1M HCl and concentrated under reduced pressure to give crude 1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-j] (2.6 g, 9.62 mmol, 93.5% yield). m / z: [M+H]+calculated for C12H10F3N2O2 271.1; found 270.8.

[0160] Synthesis of tert-butyl (1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)carbamate [INT1-k]: To a mixture of 1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-j] (2 g, 7.40 mmol) in t-BuOH (20 mL) was added DPPA (3.05 g, 11.1 mmol) and triethylamine (1.49 g, 14.8 mmol). The reaction mixture was stirred at 100° C. under nitrogen for 3 h. The reaction mixture was concentrated under reduced pressure to give a solid, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give tert-butyl (1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)carbamate [INT1-k] (400 mg, 1.17 mmol, 15.8% yield) as a white solid. m / z: calculated for [M+H]+C16H19F3N3O2 342.1; found 342.0.

[0161] Synthesis of 1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.3]: A mixture of tert-butyl (1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)carbamate [INT1-k] (220 mg, 644 μmol) in 4M HCl / dioxane (6 mL) was stirred at 20° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give crude 1-(o-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.3] (100 mg, 414 μmol, 70.9% yield). m / z: [M+H]+calculated for C11H11F3N3 242.1; found 241.9.

[0162] Synthesis of 1-methyl-5-phenyl-1H-pyrazol-4-amine [Intermediate 1.4]: [ka] Synthesis of 2-(2-oxo-2-phenylethyl)isoindoline-1,3-dione [INT1-m]: To a solution of potassium 1,3-dioxo-2,3-dihydro-1H-isoindol-2-ide [INT1-l] (3 g, 16.1 mmol) in DMF (10 mL) was added 2-bromo-1-phenylethan-1-one (3.20 g, 16.1 mmol). The reaction mixture was stirred at 25° C. for 20 h. Water (20 mL) was added and the mixture was extracted with DCM (30 mL×2). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 5 / 1) to give 2-(2-oxo-2-phenylethyl)isoindoline-1,3-dione [INT1-m] (4.16 g, 15.6 mmol, 97.4% yield) as a white solid. m / z: calculated for [M+H]+C16H12NO3 266.1; found 266.1. 1 H NMR (400 MHz,CDCl3) δ = 8.05 - 8.00 (m,2H),7.96 - 7.86 (m,2H),7.79 - 7.74 (m,2H),7.67 - 7.62 (m,1H),7.56 - 7.50 (m,2H),5.15 (s,2H).

[0163] Synthesis of 2-[1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl]-2,3-dihydro-1H-isoindole-1,3-dione [INT1-n]: A suspension of 2-(2-oxo-2-phenylethyl)-2,3-dihydro-1H-isoindole-1,3-dione [INT1-m] (1.0 g, 3.76 mmol) in (dimethoxymethyl)dimethylamine (3 mL, 15.0 mmol) was heated at 105° C. for 18 h and concentrated under reduced pressure. The resulting amber oil was crystallized from isopropanol (10 mL) and washed with isopropanol (2×5 mL) to give 2-[1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl]-2,3-dihydro-1H-isoindole-1,3-dione [INT1-n] (930 mg, 2.90 mmol, 77.5% yield) as a yellow solid. m / z: Calculated for [M+H]+C19H17N2O3 321.1; found 321.1. 1 H NMR (400 MHz,CDCl3) δ = 7.94 - 7.89 (m,2H),7.78 - 7.73 (m,2H),7.59 (d,J=6.8 Hz,2H),7.45 (s,1H),7.43 - 7.35 (m,3H),2.99 (s,6H).

[0164] Synthesis of 1-methyl-5-phenyl-1H-pyrazol-4-amine [INT1.4]: To a solution of 2-[1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl]-2,3-dihydro-1H-isoindole-1,3-dione [INT1-n] (930 mg, 2.90 mmol) in EtOH (6 mL) was added methylhydrazine (723 mg, 15.7 mmol). The reaction was stirred at 25° C. under N2 for 1 h. The reaction was then heated to 80° C. for 1 h. The reaction was cooled to 25° C. and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 1) to give a mixture of 1-methyl-5-phenyl-1H-pyrazol-4-amine [INT1.4] (152 mg, 877 μmol, 30.2% yield) and 1-methyl-3-phenyl-1H-pyrazol-4-amine (190 mg, 1.09 mmol, 37.8% yield) as a brown solid. The mixture was purified by Prep-HPLC (Column: Phenomenex Gemini C18 250*50mm*10μm, Table: 1-41%B (A=water (0.05%NH3H2O+10mM NH4HCO3), B=acetonitrile), Flow rate: 25mL / min, UV detector 220nm) to give 1-Methyl-5-phenyl-1H-pyrazol-4-amine [INT1.4] (40.0mg, 230μmol) as a white solid. m / z: Calculated for [M+H]+C10H12N3 174.1; Found 174.1.

[0165] Synthesis of 5-isopropyl-1-methyl-1H-pyrazol-4-amine [Intermediate 1.5]: [ka] Synthesis of 1-methyl-5-(propan-2-yl)-1H-pyrazole [INT1-p] and 1-methyl-3-(propan-2-yl)-1H-pyrazole [INT1-q]: To a solution of 5-(propan-2-yl)-1H-pyrazole [INT1-o] (3 g, 27.2 mmol) in DMF (20 mL) was added sodium hydride (1.63 g, 40.8 mmol) at 0° C. and the reaction mixture was stirred at 0° C. under nitrogen for 0.5 h. Iodomethane (11.5 g, 81.6 mmol) was then added and the reaction was warmed to 25° C. over 2 h. The reaction was quenched by the addition of NH4Cl(aq) (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc=1 / 0 to 1 / 2) to give a mixture of 1-methyl-5-(propan-2-yl)-1H-pyrazole [INT1-p] and 1-methyl-3-(propan-2-yl)-1H-pyrazole [INT1-q] (1.30 g, 5.23 mmol, 19.2% yield) as colorless oil. m / z: calculated for [M+H]+C7H13N2 125.1; found 125.3.

[0166] Synthesis of 1-methyl-4-nitro-5-(propan-2-yl)-1H-pyrazole [INT1-r] and 1-methyl-4-nitro-3-(propan-2-yl)-1H-pyrazole [INT1-s]: To a mixture of 1-methyl-5-(propan-2-yl)-1H-pyrazole [INT1-p] and 1-methyl-3-(propan-2-yl)-1H-pyrazole [INT1-q] in H2SO4 (1 mL) was added KNO3 (203 mg, 2.01 mmol) and the reaction mixture was stirred under nitrogen at 60° C. for 16 h. The reaction was quenched by adding 1N NaOH(aq) (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1-methyl-4-nitro-5-(propan-2-yl)-1H-pyrazole [INT1-r] and 1-methyl-4-nitro-3-(propan-2-yl)-1H-pyrazole [INT1-s] (100 mg, 295 μmol, 73.5% yield) as yellow solids. m / z: calculated for [M+H]+C7H12N3O2 170.1; found 170.1.

[0167] Synthesis of 1-methyl-5-(propan-2-yl)-1H-pyrazol-4-amine [INT1.5]: To a solution of 1-methyl-4-nitro-5-(propan-2-yl)-1H-pyrazole [INT1-r] and 1-methyl-4-nitro-3-(propan-2-yl)-1H-pyrazole [INT1-s] (1 g, 2.95 mmol) in MeOH (10 mL) was added Pd / C (313 mg, 295 μmol) and the suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 1-methyl-5-(propan-2-yl)-1H-pyrazol-4-amine [INT1.5] and 1-methyl-3-(propan-2-yl)-1H-pyrazol-4-amine. The mixture was purified by SFC (column: REGIS(S,S)WHELK-O1 (250mm*25mm, 10μm), condition: 15%-15% 0.1% NH3H2O ​​ETOH, flow rate: 60mL / min) to give 1-methyl-5-(propan-2-yl)-1H-pyrazol-4-amine [INT1.5] (100mg, 718μmol) as a blue oil (m / z: [M+H]+calculated for C7H14N3 140.1; found 140.3) and 1-methyl-3-(propan-2-yl)-1H-pyrazol-4-amine (200mg, 1.43mmol) as a blue oil ([M+H]+calculated for C7H14N3 140.1; found 140.3).

[0168] Synthesis of 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.6]: [ka] Synthesis of ethyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-u]: A mixture of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (3 g, 12.4 mmol) and phenylhydrazine [INT1-t] (1.47 g, 13.6 mmol) in EtOH (35 mL) was stirred at 80° C. for 4 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=1 / 1 to 1 / 0) to give ethyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-u] (2.44 g, 8.58 mmol, 69.3% yield) as a yellow oil. m / z: [M+H]+calculated for C13H12F3N2O2 285.1; found 285.1. 1 H NMR (400 MHz,CDCl3) δ = 8.13 (s,1H),7.56 - 7.49 (m,3H),7.47 - 7.41 (m,2H),4.44 - 4.35 (m,2H),1.40 (t,J = 7.2Hz,3H)

[0169] Synthesis of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-v]: To a mixture of ethyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-u] (2.34 g, 8.23 ​​mmol) in THF (15 mL) and H2O (5 mL) was added LiOH.H2O (1.03 g, 24.6 mmol) and the mixture was stirred at 15 °C for 16 h. The mixture was concentrated under reduced pressure to give the crude product. H2O (30 mL) and EtOAc (30 mL) were added and the precipitate was collected by filtration. The aqueous phase was washed with EtOAc (30 mL x 2), acidified to pH = 3 with 1M HCl and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated to give a yellow solid, which was combined with the precipitate to give 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-v] (1.88 g, 7.33 mmol, 89.5% yield) as a yellow solid. m / z: calculated for [M+H]+C11H8F3N2O2 257.0; found 256.9. 1H NMR (400 MHz,CDCl3) δ = 8.22 (s,1H),7.59 - 7.50 (m,3H),7.49 - 7.43 (m,2H).

[0170] Synthesis of tert-butyl (1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)carbamate [INT1-w]: A mixture of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-v] (400 mg, 1.56 mmol), 2-methylpropan-2-ol (1.73 g, 23.4 mmol), diphenylphosphoryl azide (569 mg, 2.34 mmol) and triethylamine (473 mg, 4.68 mmol) in toluene (4 mL) was stirred for 2 h at 100° C. NaHCO3 (30 mL) was added and the mixture was extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=1 / 20 to 1 / 0) to give tert-butyl (1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)carbamate [INT1-w] (335 mg, 1.02 mmol, 65.6% yield) as a yellow oil. m / z: [M+H]+calculated for C15H17F3N3O2 328.1; found 328.2. 1 H NMR (CDCl3) δ = 8.27 (br s,1H),7.52 - 7.46 (m,3H),7.46 - 7.39 (m,2H),6.54 (br s,1H),1.56 - 1.54 (m,9H).

[0171] Synthesis of 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.6]: A mixture of tert-butyl N-[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-w] (235 mg, 717 μmol) in 4M HCl / dioxane (10 mL, 40.0 mmol) was stirred at 25° C. for 4 h. The mixture was concentrated under reduced pressure to give 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.6] (160 mg, 606 μmol, 84.6% yield) as a yellow solid. m / z: calculated for [M+H]+C10H9F3N3 228.1; found 228.0.

[0172] Synthesis of 1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.7]: [ka] Synthesis of ethyl 1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-y]: A mixture of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (5 g, 20.8 mmol) and cyclopropylhydrazine hydrochloride [INT1-x] (2.47 g, 22.8 mmol) in EtOH (50 mL) was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=1 / 10 to 1 / 0) to give ethyl 1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-y] (608 mg, 2.44 mmol, 11.7% yield) as a yellow oil. m / z: [M+H]+calculated for C10H12F3N2O2 249.1; found 249.1. 1 H NMR (400MHz,CDCl3) δ = 7.85 (s,1H),4.36 - 4.30 (m,2H),3.73 (dtt,J = 1.2,3.6,7.2 Hz,1H),1.39 - 1.34 (m,3H),1.33 - 1.29 (m,2H),1.17 - 1.10 (m,2H).

[0173] Synthesis of 1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-z]: To a mixture of ethyl 1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-y] (608 mg, 2.44 mmol) in THF (3 mL) and HO (1 mL), LiOH.HO (307 mg, 7.32 mmol) was added and the mixture was stirred at 15 °C for 16 h. The mixture was concentrated under reduced pressure to give the crude product. 1N HCl was added to adjust the pH to 3-4, and the mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-z] (436 mg, 1.98 mmol, 81.1% yield) as a yellow solid. m / z: calculated for [M+H]+C8H8F3N2O2 221.0; found 221.0. 1 H NMR (400 MHz,CDCl3) δ = 7.95 (s,1H),2.17 - 2.11 (m,1H),1.38 - 1.32 (m,2H),1.20 - 1.14 (m,2H).

[0174] Synthesis of tert-butyl N-[1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-aa]: A mixture of 1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-z] (336 mg, 1.52 mmol), 2-methylpropan-2-ol (1.69 g, 22.8 mmol), diphenylphosphoryl azide (554 mg, 2.28 mmol), and triethylamine (461 mg, 4.56 mmol) in toluene (4 mL) was stirred for 2 h at 100° C. NaHCO3 (30 mL) was added and the mixture was extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=1 / 10 to 1 / 0) to give tert-butyl N-[1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-aa] (287 mg, 985 μmol, 64.9% yield) as a colorless oil. m / z: [M+H]+calculated for C12H17F3N3O2 292.1; found 292.1. 1 H NMR (400 MHz,CDCl3) δ = 7.94 (br s,1H),7.43 - 7.36 (m,1H),3.55 (tt,J = 3.6,7.2 Hz,1H),1.51 (s,9H),1.30 - 1.23 (m,2H),1.09 - 1.02 (m,2H).

[0175] Synthesis of 1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.7]: A mixture of tert-butyl N-[1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-aa] (187 mg, 642 μmol) in 4M HCl / dioxane (10 mL, 40.0 mmol) was stirred at 25° C. for 4 h. The mixture was concentrated under reduced pressure to give 1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.7] (100 mg, 439 μmol, 68.4% yield) as a brown solid. m / z: calculated for [M+H]+C7H9F3N3 192.1; found 192.0.

[0176] Synthesis of 1-phenyl-5-(propan-2-yl)-1H-pyrazol-4-amine hydrochloride [intermediate 1.8]: [ka] Synthesis of methyl 1-phenyl-5-(propan-2-yl)-1H-pyrazole-4-carboxylate [INT1-bb]: To a mixture of methyl 4-methyl-3-oxopentanoate (1 g, 6.93 mmol) and (dimethoxymethyl)dimethylamine (990 mg, 8.31 mmol) in 2,2,2-trifluoroethanol (5 mL) was added phenylhydrazine [INT1-t] (898 mg, 8.31 mmol) in 2,2,2-trifluoroethanol (5 mL). The reaction mixture was stirred at 15 °C for 1 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (0-6% EtOAc in petroleum ether) to give methyl 1-phenyl-5-(propan-2-yl)-1H-pyrazole-4-carboxylate [INT1-bb] (620 mg, 2.53 mmol, 36.6% yield) as an orange solid. m / z: calculated for [M+H]+C14H17N2O2 245.1; found 245.0. 1 H NMR (400 MHz,CDCl3) δ = 8.03 (s,1H),7.55 - 7.48 (m,3H),7.40 - 7.34 (m,2H),3.87 (s,3H),3.34 - 3.21 (m,1H),1.36 (d,J = 7.2 Hz,6H).

[0177] Synthesis of 1-phenyl-5-(propan-2-yl)-1H-pyrazole-4-carboxylic acid [INT1-cc]: To a mixture of methyl 1-phenyl-5-(propan-2-yl)-1H-pyrazole-4-carboxylate [INT1-bb] (620 mg, 2.53 mmol) in THF (6 mL) and H2O (2 mL) was added lithium hydroxide monohydrate (318 mg, 7.58 mmol). The reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was concentrated, diluted with water (20 mL), and washed with EtOAc (10 mL×2). The aqueous phase was acidified to pH=3 with 1M HCl and extracted with EtOAc (10 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give 1-phenyl-5-(propan-2-yl)-1H-pyrazole-4-carboxylic acid [INT1-cc] (460 mg, 1.99 mmol, 79.0%) as a yellow solid. 1 H NMR (400 MHz,CDCl3) δ = 8.13 (s,1H),7.57 - 7.48 (m,3H),7.43 - 7.36 (m,2H),3.37 - 3.24 (m,1H),1.39 (d,J=6.8 Hz,6H).

[0178] Synthesis of tert-butyl N-[1-phenyl-5-(propan-2-yl)-1H-pyrazol-4-yl]carbamate [INT1-dd]: To a mixture of 1-phenyl-5-(propan-2-yl)-1H-pyrazole-4-carboxylic acid [INT1-cc] (410 mg, 1.78 mmol), 2-methylpropan-2-ol (1.97 g, 26.7 mmol) and triethylamine (540 mg, 5.34 mmol) in toluene (5 mL) was added diphenylphosphoryl azide (734 mg, 2.67 mmol). The reaction mixture was stirred at 100° C. under nitrogen for 3 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (0-20% EtOAc in petroleum ether) to give tert-butyl N-[1-phenyl-5-(propan-2-yl)-1H-pyrazol-4-yl]carbamate [INT1-dd] (270 mg, 895 μmol, 50.3% yield) as a colorless oil. m / z: [M+H]+calculated for C17H24N3O2 302.2; found 302.1. 1 H NMR (400 MHz,CDCl3) δ = 7.82 (br s,1H),7.55 - 7.44 (m,3H),7.41 - 7.36 (m,2H),5.81 (br s,1H),3.07 (Septet,J = 7.2 Hz,1H),1.53 (s,9H),1.29 (d,J = 7.2 Hz,6H).

[0179] Synthesis of 1-phenyl-5-(propan-2-yl)-1H-pyrazol-4-amine hydrochloride [INT1.8]: A mixture of tert-butyl N-[1-phenyl-5-(propan-2-yl)-1H-pyrazol-4-yl]carbamate [INT1-dd] (270 mg, 895 μmol) in 4M HCl / dioxane (5 mL, 20 mmol) was stirred for 1 h at 15° C. The reaction mixture was concentrated to give 1-phenyl-5-(propan-2-yl)-1H-pyrazol-4-amine hydrochloride [INT1.8] (210 mg, 883 μmol, 99.0% yield) as a yellow solid. 1H NMR (400 MHz,MeOD) δ = 7.71 (s,1H),7.63 - 7.55 (m,3H),7.46 - 7.39 (m,2H),3.23 - 3.09 (m,1H),1.27 (d,J=7.2 Hz,6H).

[0180] Synthesis of 1-(propan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [intermediate 1.9]: [ka] Synthesis of ethyl 1-(propan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-ff]: A mixture of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (2 g, 8.32 mmol) and (propan-2-yl)hydrazine hydrochloride [INT1-ee] (920 mg, 8.32 mmol) in EtOH (20 mL) was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=0 / 1 to 1 / 10) to give ethyl 1-(propan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-ff] (1.40 g, 5.59 mmol, 67.3% yield) as a colorless oil. m / z: [M+H]+calculated for C10H14F3N2O2 251.1; found 251.1. 1 H NMR (400 MHz,DMSO-d6) δ = 8.08 (s,1H),4.80 (septet,J = 6.4 Hz,1H),4.25 (q,J = 7.2 Hz,2H),1.45 (d,J = 6.4 Hz,6H),1.26 (t,J = 7.2 Hz,3H).

[0181] Synthesis of 1-(propan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-gg]: To a solution of ethyl 1-(propan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-ff] (900 mg, 3.59 mmol) in THF (9 mL) and H2O (3 mL) was added lithium hydroxide monohydrate (448 mg, 10.7 mmol). The reaction mixture was stirred at 20° C. for 12 h, after which it was concentrated under reduced pressure. The crude product was quenched with water (20 mL) and washed with EtOAc (30 mL×2). The aqueous phase was then acidified to pH=4 with 1 M HCl and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1-(propan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-gg] (250 mg, 1.12 mmol, 31.3% yield) as a colorless oil. m / z: [M+H]+calculated for C8H10F3N2O2 223.1; found 223.0.

[0182] Synthesis of tert-butyl N-[1-(propan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-hh]: A mixture of 1-(propan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-gg] (250 mg, 1.12 mmol), 2-methylpropan-2-ol (1.24 g, 16.8 mmol), diphenylphosphoryl azide (408 mg, 1.68 mmol) and triethylamine (340 mg, 3.36 mmol) in toluene (4 mL) was stirred for 2 h at 100° C. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=0 / 1 to 1 / 20) to give tert-butyl N-[1-(propan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-hh] (150 mg, 511 μmol, 45.7% yield) as a yellow oil. m / z: calculated for [M+H]+C12H19F3N3O2 294.1; found 294.1.

[0183] Synthesis of 1-(propan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.9]: A solution of tert-butyl N-[1-(propan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-hh] (150 mg, 511 μmol) in 4M HCl in dioxane (3 mL) was stirred for 2 h at 20° C. The reaction mixture was concentrated under reduced pressure to give 1-(propan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.9] (110 mg, 479 μmol, 94.0% yield). m / z: calculated for [M+H]+C7H11F3N3 194.1; found 193.9.

[0184] Synthesis of 1-[4-amino-5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylpropan-2-ol hydrochloride [Intermediate 1.10]: [ka] Synthesis of 1-hydrazinyl-2-methylpropan-2-ol [INT1-jj]: To a suspension of 2,2-dimethyloxirane [INT1-ii] (1.0 g, 13.8 mmol) in EtOH (5 mL) was added hydrazine (884 mg, 27.6 mmol). The reaction mixture was stirred at 60° C. for 4 h, after which it was concentrated under reduced pressure to give 1-hydrazinyl-2-methylpropan-2-ol [INT1-jj] (1.24 g, 11.9 mmol, 86.7% yield) as a colorless oil. 1 H NMR (400 MHz,CDCl3) δ = 3.52 (s,4H),2.71 (s,2H),1.21 - 1.18 (m,6H).

[0185] Synthesis of ethyl 1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-kk]: To a solution of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (2.0 g, 8.32 mmol) in EtOH (8 mL) was added 1-hydrazinyl-2-methylpropan-2-ol [INT1-jj] (1.03 g, 9.98 mmol). The reaction was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give ethyl 1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-kk] (1 g, 3.56 mmol, 42.9% yield) as a yellow oil. m / z: [M+H]+calculated for C11H16F3N2O3 281.1; found 280.9. 1 H NMR (400 MHz,CDCl3) δ = 8.01 (s,1H),4.40 - 4.30 (m,4H),3.85 (s,1H),1.37 (t,J=7.2 Hz,3H),1.19 (s,6H).

[0186] Synthesis of 1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ll]: To a solution of ethyl 1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-kk] (1.0 g, 3.56 mmol) in THF (5 mL) was added lithium hydroxide monohydrate (298 mg, 7.12 mmol) in HO (5 mL). The reaction was stirred at 20 °C for 3 h. The reaction mixture was poured into water (10 mL), acidified to pH = 5-6 with 1N HCl, and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give 1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ll] (710 mg, 2.81 mmol, 79.1% yield) as a yellow solid. m / z: calculated for [M+H]+C9H12F3N2O3 253.1; found 252.9.

[0187] Synthesis of tert-butyl N-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-mm]: A mixture of 1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ll] (710 mg, 2.81 mmol), diphenylphosphoryl azide (1.54 g, 5.62 mmol) and triethylamine (1.41 g, 14.0 mmol) in t-BuOH (8 mL) was stirred under N2 at 100° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give tert-butyl N-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-mm] (600 mg, 1.85 mmol, 66.0% yield) as a yellow oil. m / z: Calculated for [M+H]+C13H21F3N3O3 324.1; found 323.9. 1 H NMR (400 MHz,CDCl3) δ = 8.11 (s,1H),6.47 (s,1H),4.42 (s,1H),4.08 (s,2H),1.52 (s,9H),1.17 (s,6H).

[0188] Synthesis of 1-[4-amino-5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylpropan-2-ol hydrochloride [INT1.10]: A solution of tert-butyl N-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-mm] (600 mg, 1.85 mmol) in HCl / dioxane (5 mL) was stirred for 3 h at 20° C. The reaction mixture was concentrated under reduced pressure to give 1-[4-amino-5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylpropan-2-ol hydrochloride [INT1.10] (480 mg, 1.84 mmol) as a yellow oil. m / z: calculated for [M+H]+C8H13F3N3O 224.1; found 223.9.

[0189] Synthesis of 1-(1-methoxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.11]: [ka] Synthesis of N'-[(2Z)-1-methoxypropan-2-ylidene](tert-butoxy)carbohydrazide [INT1-oo]: To a mixture of 1-methoxypropan-2-one [INT1-nn] (10 g, 113 mmol) in heptane (400 mL) at 50° C. was added (tert-butoxy)carbohydrazide (19.2 g, 146 mmol) in toluene (30 ml). The mixture was stirred at 70° C. for 2 h. Then the mixture was stirred at 15° C. for 12 h. The precipitate formed was collected, washed with heptane, and dried to give N′-[(2Z)-1-methoxypropan-2-ylidene](tert-butoxy)carbohydrazide [INT1-oo] (19.6 g, 96.9 mmol, 85.9% yield) as a white solid. 1 H NMR (400 MHz,CDCl3) δ = 7.59 (br d,J = 6.8 Hz,1H),4.02 (d,J = 2.4 Hz,2H),3.32 - 3.28 (m,3H),1.84 (s,3H),1.50 (d,J = 2.4 Hz,9H).

[0190] Synthesis of N'-(1-methoxypropan-2-yl)(tert-butoxy)carbohydrazide [INT1-pp]: A mixture of N'-[(2Z)-1-methoxypropan-2-ylidene](tert-butoxy)carbohydrazide [INT1-oo] (5 g, 24.7 mmol) and PtO2 (0.05 g, 220 μmol) in AcOH (50 ml) under H2 (15 psi) was stirred at 15 °C for 12 h. After the mixture was filtered through Celite, a solution of NaHCO3 was added to adjust the pH to 8-9. The mixture was extracted with EtOAc (100 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (CH2Cl2 / MeOH=1 / 20 to 1 / 0) to give N'-(1-methoxypropan-2-yl)(tert-butoxy)carbohydrazide [INT1-pp] (3.25 g, 15.9 mmol, 64.4% yield) as a yellow oil. m / z: calculated for [M-56+H]+C9H21N2O3 149.0; found 148.9. 1 H NMR (400 MHz,CDCl3) δ = 6.45 - 5.99 (m,1H),4.25 (br s,1H),3.34 (s,3H),3.31 (t,J=4.4 Hz,1H),3.27 - 3.17 (m,2H),1.44 (s,9H),0.99 (br s,3H).

[0191] Synthesis of (1-methoxypropan-2-yl)hydrazine hydrochloride [INT1-qq]: A mixture of N'-(1-methoxypropan-2-yl)(tert-butoxy)carbohydrazide [INT1-pp] (3.25 g, 15.9 mmol) in 4M HCl / dioxane (30 mL, 120 mmol) was stirred at 25° C. for 4 h. The mixture was concentrated under reduced pressure to give (1-methoxypropan-2-yl)hydrazine hydrochloride [INT1-qq] (2.00 g, 14.2 mmol, 89.6% yield) as a yellow oil. m / z: calculated for [M+H]+C4H13N2O 105.1; found 104.8.

[0192] Synthesis of ethyl 1-(1-methoxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-rr]: A mixture of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (2 g, 8.32 mmol), (1-methoxypropan-2-yl)hydrazine hydrochloride [INT1-qq] (1.28 g, 9.10 mmol), and triethylamine (841 mg, 8.32 mmol) in EtOH (20 mL) was stirred at 80° C. for 12 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=1 / 10 to 1 / 0) to give ethyl 1-(1-methoxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-rr] (990 mg, 3.55 mmol, 42.8% yield) as a yellow oil. m / z: calculated for [M+H]+C11H16F3N2O3 281.1; found 281.1. 1 H NMR (400 MHz,DMSO-d6) δ = 8.11 (s,1H),4.88 - 4.77 (m,1H),4.25 (q,J=6.8 Hz,2H),3.74 - 3.66 (m,1H),3.62 - 3.55 (m,1H),3.19 - 3.12 (m,3H),1.40 (d,J = 6.8 Hz,3H),1.27 (t,J = 7.2 Hz,3H).

[0193] Synthesis of 1-(1-methoxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ss]: To a mixture of ethyl 1-(1-methoxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-rr] (890 mg, 3.17 mmol) in THF (6 mL) and HO (2 mL), LiOH.HO (1.06 g, 25.3 mmol) was added and the mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure to give the crude product. 1N HCl was added to adjust the pH to 3-4, and the mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 1-(1-methoxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ss] (395 mg, 1.56 mmol, 49.4% yield) as a yellow oil. m / z: calculated for [M+H]+C9H12F3N2O3 253.1; found 253.0. 1 H NMR (400 MHz,CDCl3) δ = 8.07 (s,1H),4.88 (qd,J = 6.8,13.2 Hz,1H),3.85 (t,J = 9.2 Hz,1H),3.63 (dd,J = 5.2,10.0 Hz,1H),3.30 (s,3H),1.52 (d,J = 6.8 Hz,3H).

[0194] Synthesis of tert-butyl N-[1-(1-methoxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-tt]: A mixture of 1-(1-methoxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ss] (295 mg, 1.16 mmol), 2-methylpropan-2-ol (1.28 g, 17.4 mmol), diphenylphosphoryl azide (423 mg, 1.74 mmol) and triethylamine (352 mg, 3.48 mmol) in toluene (3 mL) was stirred for 2 h at 100° C. NaHCO3 (30 mL) was added and the mixture was extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=1 / 10 to 1 / 0) to give tert-butyl N-[1-(1-methoxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-tt] (208 mg, 643 μmol, 55.4% yield) as a yellow oil. m / z: [M+H]+calculated for C13H21F3N3O3 324.1; found 324.1. 1 H NMR (400 MHz,CDCl3) δ = 8.07 (br s,1H),6.44 (br s,1H),4.55 (sextet,J = 6.8 Hz,1H),3.84 (dd,J = 7.6,9.6 Hz,1H),3.60 (dd,J = 5.6,10.0 Hz,1H),3.30 (s,3H),1.51 (s,9H),1.45 (d,J = 6.8 Hz,3H).

[0195] 1-(1-Methoxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.11]: A mixture of tert-butyl N-[1-(1-methoxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-tt] (158 mg, 488 μmol) in 4M HCl / dioxane (15 mL, 60.0 mmol) was stirred at 15° C. for 4 hours. The mixture was concentrated under reduced pressure to give 1-(1-methoxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.11] (150 mg, 577 μmol) as a yellow oil. m / z: calculated for [M+H]+C8H13F3N3O 224.1; found 223.9.

[0196] Synthesis of 1-neopentyl-5-(trifluoromethyl)-1H-pyrazol-4-amine [Intermediate 1.12]: [ka] Synthesis of N'-(2,2-dimethylpropyl)(tertbutoxy)carbohydrazide [INT1-vv]: A mixture of 2,2-dimethylpropanal [INT1-uu] (5 g, 58.0 mmol) and (tert-butoxy)carbohydrazide (7.66 g, 58.0 mmol) in MeOH (80 mL) was stirred at 20° C. for 2 h. Then 10% Pd / C (1 g) was added. The flask was evacuated and refilled with N2 three times, then evacuated and refilled with H2 three more times. The reaction mixture was stirred at 20° C. for 12 h under H2 (15 psi). The reaction was filtered and the filter cake was washed with MeOH (20 mL×3). The filtrate was cooled to 0° C., then sodium cyanoborohydride (3.64 g, 58.0 mmol) was added. The mixture was stirred at 20° C. for 1 h. The reaction was quenched by adding water (80 mL). The mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (2×80 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give N′-(2,2-dimethylpropyl)(tertbutoxy)carbohydrazide [INT1-vv] (11.0 g, 54.3 mmol, 94% yield) as a grey solid. m / z: calculated for [Mt-Bu+H]+C6H15N2O2 147.2; found 147.1. 1 H NMR (400 MHz,CDCl3) δ = 2.59 (s,2H),1.39 (s,9H),0.88 (s,9H).

[0197] Synthesis of (2,2-dimethylpropyl)hydrazine [INT1-ww]: N'-(2,2-dimethylpropyl)(tert-butoxy)carbohydrazide [INT1-vv] (6 g, 29.6 mmol) was added to HCl / dioxane (40 mL) at 15° C., and the mixture was stirred for 2 h. The mixture was concentrated under reduced pressure to give (2,2-dimethylpropyl)hydrazine [INT1-ww] (3.02 g, 29.5 mmol). 1 H NMR (400 MHz,DMSO-d6) δ = 2.67 (s,2H),0.91 (s,9H).

[0198] Synthesis of ethyl 1-(2,2-dimethylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-xx]: To a solution of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (8.50 g, 35.4 mmol) in EtOH (100 mL) at 10° C. was added (2,2-dimethylpropyl)hydrazine [INT1-ww] (3.02 g, 29.5 mmol) and Et3N (5.97 g, 59.0 mmol). The mixture was stirred at 80° C. for 3 h. The reaction was concentrated under reduced pressure, quenched by adding water (50 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc = 1 / 0 to 20 / 1) to give ethyl 1-(2,2-dimethylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-xx] (1.81 g, 6.50 mmol, 22.0% yield) as a colorless oil. m / z: [M+H]+calculated for C12H18F3N2O2 279.1; found 278.9. (400 MHz,CDCl3) δ = 7.97 (s,1H), 4.34 (q,J = 8.0 Hz,2H), 4.19 (s,2H), 1.37 (t,J = 8.0 Hz,3H), 0.99 (s,9H).

[0199] 1-(2,2-Dimethylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-yy]: To a solution of ethyl 1-(2,2-dimethylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-xx] (1.81 g, 6.50 mmol) in THF (10 mL) and HO (3 mL) at 10° C., lithium hydroxide monohydrate (1.36 g, 32.5 mmol) was added, and the mixture was then stirred for 12 h. The aqueous phase was acidified to pH=4 with 1M HCl and extracted with EtOAc (30 mL×2). The combined organic layers were concentrated under reduced pressure to give 1-(2,2-dimethylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-yy] (1.16 g, 4.63 mmol, 71.6% yield) as a white solid. 1 H NMR (400 MHz,DMSO) δ = 8.04 (s,1H),4.16 (s,2H),0.91 (s,9H).

[0200] Synthesis of tert-butyl N-[1-(2,2-dimethylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-zz]: A mixture of 1-(2,2-dimethylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-yy] (1.06 g, 4.23 mmol), 2-methylpropan-2-ol (4.69 g, 63.4 mmol), diphenylphosphoryl azide (1.54 g, 6.34 mmol) and triethylamine (2.13 g, 21.1 mmol) in toluene (10 mL) was stirred at 100° C. for 2 h. The mixture was worked up with material from two of the same reactions. Water (40 mL) was added and the mixture was extracted with EtOAc (40 mL×2). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (petroleum ether / EtOAc = 1 / 10 to 20 / 1) to give tert-butyl N-[1-(2,2-dimethylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-zz] (1.27 g, 3.95 mmol) as a white solid. 1H NMR (400 MHz,CDCl3) δ = 8.02 (s,1H),6.43 (s,1H),3.94 (s,2H),1.52 (s,9H),0.99 (s,9H).

[0201] 1-Neopentyl-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT 1.12]: A solution of tert-butyl N-[1-(2,2-dimethylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-zz] (500 mg, 1.55 mmol) in HCl / dioxane (10 mL) was stirred at 10° C. for 1 h. TLC showed complete consumption of starting material and formation of a new spot. The mixture was concentrated under reduced pressure to give 1-neopentyl-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.12] (342 mg, 1.54 mmol).

[0202] Synthesis of 1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.13]: [ka] Synthesis of ethyl 1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-bbb]: A solution of ethyl 2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (9.39 g, 39.1 mmol), 3-hydrazinylpyridine hydrochloride [INT1-aaa] (5.7 g, 39.1 mmol), Et3N (7.91 g, 78.2 mmol) and EtOH (50 mL) was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0 to 80:20) to give ethyl 1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-bbb] (3.45 g, 12.0 mmol, 31.0% yield). m / z: calculated for [M+H]+C12H11F3N3O2 286.1; found 285.9. 1 H NMR (400 MHz,CDCl3) δ = 8.78 (dd,J = 1.2,4.8 Hz,1H),8.74 (d,J = 2.4 Hz,1H),8.18 (s,1H),7.84 - 7.76 (m,1H),7.50 (dd,J = 4.8,8.0 Hz,1H),4.40 (q,J = 7.2 Hz,2H),1.41 (t,J = 7.2 Hz,3H).

[0203] 1-(Pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride [INT1-ccc]: To a solution of ethyl 1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-bbb] (3.45 g, 12.0 mmol) in THF (1 mL) was added lithium hydroxide monohydrate (12.0 mL, 24.0 mmol). The mixture was stirred at 25° C. for 16 h. The resulting solution was concentrated to dryness under reduced pressure to give the crude product, which was poured into water (20 mL) and acidified to pH=5 with 1M HCl. The resulting solution was filtered, the cake was washed with water (20 mL), and then dried under reduced pressure to give 1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate hydrochloride [INT1-ccc] (2.30 g, 7.83 mmol, 65.3% yield) as a white solid. m / z: calculated for [M+H]+C10H7F3N3O2 258.0; found 257.9.

[0204] Synthesis of tert-butyl N-[1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-ddd]: A solution of 1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride [INT1-ccc] (500 mg, 1.70 mmol), triethylamine (472 μL, 3.40 mmol) and diphenylphosphoryl azide (701 mg, 2.55 mmol) in tert-butanol (2 mL, 21.1 mmol) was stirred at 90° C. for 2 h under N2. The reaction was quenched by adding water (15 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=0 / 1 to 1 / 4) to give tert-butyl N-[1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-ddd] (443 mg, 1.34 mmol, 79.3% yield) as a white solid. m / z: [M+H]+calculated for C14H16F3N4O2 329.1; found 328.9. 1H NMR (400 MHz,CDCl3) δ = 8.80 - 8.69 (m,2H),8.35 (br s,1H),7.81 (br d,J = 8.0 Hz,1H),7.47 (dd,J = 4.8,8.0 Hz,1H),6.60 (br s,1H),1.56 (s,9H).

[0205] 1-(Pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.13]: A solution of tert-butyl N-[1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-ddd] (443 mg, 1.34 mmol) in HCl (4M in dioxane, 5 mL, 20.0 mmol) was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give 1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.13] (343 mg, 1.29 mmol, 96.8% yield) as a yellow solid. m / z: calculated for [M+H]+C9H8F3N4 229.1; found 228.9. 1 H NMR (400 MHz,DMSO-d6) δ = 8.81 (d,J = 2.4 Hz,1H),8.79 (dd,J = 1.2,4.8 Hz,1H),8.12 (br d,J = 8.4 Hz,1H),7.83 (s,1H),7.75 (dd,J = 4.8,8.4 Hz,1H).

[0206] Synthesis of 1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [Intermediate 1.14]: [ka] Synthesis of ethyl 1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-fff]: To a solution of ethyl 2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (7.20 g, 30.0 mmol) in EtOH (50 mL) at 10° C., 4-hydrazinylpyridine hydrochloride [INT1-eee] (4.37 g, 30.0 mmol) and Et3N (3.03 g, 30.0 mmol) were added, and the mixture was then stirred at 80° C. for 3 h. The reaction was concentrated under reduced pressure, quenched by adding water (50 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc=1 / 0 to 3 / 1) to give ethyl 1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-fff] (3.00 g, 10.5 mmol, 35.0% yield) as a yellow solid. m / z: [M+H]+calculated for C12H11F3N3O2 286.0; found 285.9.

[0207] Synthesis of 1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ggg]: To a solution of ethyl 1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-fff] (2.5 g, 8.76 mmol) in THF (15 mL) and H2O (3 mL) at 10°C, lithium hydroxide monohydrate (1.83 g, 43.8 mmol) was added, and the mixture was then stirred at 50°C for 2 h. The aqueous phase was acidified to pH = 4 with 1M HCl and extracted with EtOAc (30 mL x 2). The combined organic layers were concentrated under reduced pressure to give 1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ggg] (1.45 g, 5.63 mmol, 64.4% yield) as a white solid. m / z: calculated for [M+H]+C10H7F3N3O2 258.0; found 257.8.

[0208] Synthesis of tert-butyl N-[1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-hhh]: To a mixture of 1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ggg] (1 g, 3.88 mmol) in t-BuOH (3 mL) and dioxane (5 mL), triethylamine (1.96 g, 19.4 mmol) and diphenylphosphoryl azide (1.88 g, 7.76 mmol) were added at 10° C., and the mixture was then stirred for 2 h at 100° C. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (petroleum ether / EtOAc=1 / 10 to 3 / 1) to give tert-butyl N-[1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-hhh] (360 mg, 1.09 mmol, 28.3% yield) as a white solid. 1 H NMR (400 MHz,DMSO) δ = 8.78 (d,J = 4.0 Hz,2H),8.58 (s,1H),8.00 (s,1H),7.56 (d,J = 4.0 Hz,2H),1.46 (s,9H).

[0209] Synthesis of 1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.14]: A solution of tert-butyl N-[1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-hhh] (360 mg, 1.09 mmol) in HCl / dioxane (10 mL) was stirred at 50° C. for 12 hours. The mixture was concentrated under reduced pressure to give 1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.14] (248 mg, 1.08 mmol). m / z: calculated for [M+H]+C9H8F3N4 229.1; found 229.1.

[0210] Synthesis of 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [Intermediate 1.15]: [ka] Synthesis of ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-jjj]: To a solution of ethyl 2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (5 g, 20.8 mmol) and 2-hydrazinylpyridine [INT1-iii] (2.26 g, 20.8 mmol) in EtOH (30 mL) was added triethylamine (2.10 g, 20.8 mmol). The mixture was stirred at 80° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 10 / 1) to give ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-jjj] (5.00 g, 17.5 mmol, 84.3% yield) as a yellow oil. m / z: calculated for [M+H]+C12H11F3N3O2 286.1; found 285.9. 1 H NMR (400 MHz,DMSO-d6) δ = 8.64 - 8.59 (m,1H),8.34 (s,1H),8.19 - 8.12 (m,1H),7.80 (dd,J = 0.8,8.0 Hz,1H),7.68 - 7.63 (m,1H),4.33 (q,J = 7.2 Hz,2H),1.31 (t,J = 7.2 Hz,3H).

[0211] Synthesis of 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-kkk]: To a mixture of ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-jjj] (1 g, 3.50 mmol) in THF (6 mL) and H2O (2 mL) was added lithium hydroxide monohydrate (440 mg, 10.5 mmol). The reaction mixture was stirred at 15° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was acidified to pH=4 with 1M HCl. The reaction mixture was quenched by adding H2O (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-kkk] (800 mg, 3.11 mmol, 88.8% yield) as a yellow solid. 1 H NMR (400 MHz,DMSO-d6) δ = 13.43 (br s,1H),8.60 (td,J = 0.8,4.8 Hz,1H),8.28 (s,1H),8.14 (dt,J = 2.0,7.6 Hz,1H),7.79 (d,J = 8.0 Hz,1H),7.64 (ddd,J = 0.8,4.8,7.6 Hz,1H).

[0212] Synthesis of tert-butyl N-[1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-lll]: A mixture of 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-kkk] (400 mg, 1.55 mmol), triethylamine (784 mg, 7.75 mmol), and diphenylphosphoryl azide (564 mg, 2.32 mmol) in t-BuOH (3 mL) and dioxane (3 mL) was stirred at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (petroleum ether / EtOAc = 1 / 0 to 1 / 1) to give tert-butyl N-[1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-lll] (470 mg, 1.43 mmol, 92.5% yield) as a white solid. m / z: Calculated for [M+H]+C14H16F3N4O2 329.1; found 328.9. 1 H NMR (400 MHz,DMSO-d6) δ = 9.14 (br s,1H),8.56 - 8.51 (m,1H),8.06 (dt,J = 1.8,7.6 Hz,1H),7.95 (s,1H),7.77 (d,J = 8.0 Hz,1H),7.55 - 7.46 (m,1H),1.46 (s,9H).

[0213] Synthesis of 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.15]: A solution of tert-butyl N-[1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-lll] (470 mg, 1.43 mmol) in 4M HCl / dioxane (4 mL) was stirred for 2 h at 15° C. The reaction mixture was concentrated under reduced pressure to give 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.15] (260 mg, 1.13 mmol, 79.7% yield) as a white solid. m / z: calculated for [M+H]+C9H8F3N4 229.1; found 228.9. 1H NMR (400 MHz,DMSO-d6) δ = 8.48 (dd,J = 1.2,4.8 Hz,1H),8.01 (dt,J = 1.6,7.6 Hz,1H),7.76 - 7.72 (m,2H),7.65 (br s,2H),7.43 (dd,J = 4.8,6.8 Hz,1H).

[0214] Synthesis of 2-[4-amino-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile [Intermediate 1.16]: [ka] Synthesis of ethyl 1-(2-bromophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-nnn]: To a solution of (2-bromophenyl)hydrazine hydrochloride [INT1-mmm] (5 g, 22.3 mmol) and ethyl 2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (4.44 g, 18.5 mmol) in EtOH (6 mL) was added triethylamine (2.81 g, 27.8 mmol). The mixture was stirred at 80° C. for 12 h. The reaction was quenched by adding water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc=1 / 0 to 1 / 10) to give ethyl 1-(2-bromophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-nnn] (3.00 g, 8.26 mmol, 44.7% yield) as a red oil. m / z: [M+H]+calculated for C13H11BrF3N2O2 363.0; found 362.9.

[0215] Synthesis of 1-(2-bromophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ooo]: To a solution of ethyl 1-(2-bromophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-nnn] (2 g, 3.30 mmol) in THF (3 mL) and HO (1 mL) was added lithium hydroxide monohydrate (276 mg, 6.60 mmol). The mixture was stirred at 25° C. for 16 h. The reaction was quenched by adding 1N HCl (10 mL) and HO (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 1-(2-bromophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ooo] (800 mg, 2.38 mmol, 72.7% yield) as a red solid. 1 H NMR (400 MHz,DMSO-d6) δ = 13.43 (br s,1H),8.31 (s,1H),7.88 (dd,J = 1.6,7.6 Hz,1H),7.74 (dd,J = 2.0,7.6 Hz,1H),7.59 (double quintet,J = 1.6,7.6 Hz,2H).

[0216] Synthesis of tert-butyl N-[1-(2-bromophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-ppp]: To a solution of 1-(2-bromophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ooo] (1.2 g, 3.58 mmol) in toluene (1 mL) was added diphenylphosphoryl azide (1.47 g, 5.37 mmol), triethylamine (1.08 g, 10.7 mmol) and 2-methyl-2-propanol (2.65 g, 35.8 mmol). The reaction mixture was stirred at 100° C. under N2 for 16 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (100 mL×2). The combined organic layer was washed with brine (50 mL×2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 5) to give tert-butyl N-[1-(2-bromophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-ppp] (400 mg, 984 μmol, 27.5% yield) as a yellow oil. m / z: [M+H]+calculated for C15H16BrF3N3O2 406.0; found 406.1. 1 H NMR (400 MHz,DMSO-d6) δ = 9.04 (br s,1H),7.92 (br s,1H),7.88 - 7.85 (m,1H),7.65 - 7.52 (m,3H),1.46 (s,9H).

[0217] Synthesis of 1-(2-bromophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1-qqq]: A mixture of tert-butyl N-[1-(2-bromophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-ppp] (400 mg, 1.13 mmol) in HCl / dioxane (4 mL) was stirred at 25° C. under N for 12 h. The reaction was quenched by adding saturated NaHCO3(aq) (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1-(2-bromophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1-qqq] (290 mg, 947 μmol, 96.6% yield) as a yellow oil. m / z: calculated for [M+H]+C10H8BrF3N3 306.0; found 305.8. 1 H NMR (400 MHz,DMSO-d6) δ = 7.81 (d,J = 7.6 Hz,1H),7.56 - 7.35 (m,4H),4.81 (s,2H).

[0218] Synthesis of 2-[4-amino-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile [INT1.16]: A mixture of 1-(2-bromophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1-qqq] (240 mg, 784 μmol) and cupric cyanide (351 mg, 3.92 mmol) in DMF (3 mL) was stirred under N2 at 140° C. for 2 h. The reaction was combined with another similar one and quenched by the addition of NH3.H2O (5 mL) and H2O (20 mL), then the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (petroleum ether / EtOAc=1 / 0 to 1 / 1) to give 2-[4-amino-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile [INT1.16] (160 mg, 634 μmol, 81.2% yield) as a yellow oil. m / z: [M+H]+calculated for C11H8F3N4 253.1; found 252.9. 1 H NMR (400 MHz,DMSO-d6) δ = 8.06 (d,J = 7.6 Hz,1H),7.91 - 7.84 (m,1H),7.77 - 7.70 (m,1H),7.65 (d,J = 8.0 Hz,1H),7.47 (s,1H),5.01 (s,2H).

[0219] Synthesis of 3-[4-amino-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile hydrochloride [Intermediate 1.17]: [ka] Synthesis of ethyl 1-(3-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-sss]: To a solution of ethyl 2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (3.0 g, 12.4 mmol) in EtOH (5 mL) was added 3-hydrazinylbenzonitrile hydrochloride [INT1-rrr] (2.10 g, 12.4 mmol) and triethylamine (1.37 g, 13.6 mmol). The reaction was stirred at 20° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 5) to give ethyl 1-(3-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-sss] (350 mg, 1.13 mmol, 9.1% yield) as a red solid. m / z: Calculated for [M+H]+C14H11F3N3O2 310.1; found 310.0. 1 H NMR (400 MHz,CDCl3) δ = 8.17 (s,1H),7.87 - 7.81 (m,1H),7.79 (s,1H),7.75 - 7.62 (m,2H),4.41 (q,J = 7.2 Hz,2H),1.41 (t,J = 7.2 Hz,3H).

[0220] Synthesis of 1-(3-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ttt]: To a solution of ethyl 1-(3-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-sss] (2.35 g, 5.30 mmol) in THF (15 mL) was added lithium hydroxide monohydrate (444 mg, 10.6 mmol) in HO (5 mL). The reaction was stirred at 20 °C for 12 h. The reaction mixture was poured into 10 mL of water, acidified to pH = 3-4 with 1N HCl, and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (MeOH / DCM=0 / 1 to 1 / 20) to give 1-(3-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ttt] (1.50 g, 5.33 mmol, 100% yield) as a brown solid. 1 H NMR (400 MHz,DMSO-d6) δ = 13.41 (br s,1H),8.29 (s,1H),8.20 (t,J = 1.6 Hz,1H),8.12 - 8.07 (m,1H),7.94 (br d,J = 8.8 Hz,1H),7.83 - 7.78 (m,1H).

[0221] Synthesis of tert-butyl N-[1-(3-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-uuu]: A solution of 1-(3-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ttt] (1.45 g, 5.15 mmol), triethylamine (781 mg, 7.72 mmol) and diphenylphosphoryl azide (2.83 g, 10.3 mmol) in t-BuOH (6 mL) was stirred under N2 at 100° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 5) to give tert-butyl N-[1-(3-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-uuu] (1 g, 2.83 mmol, 55.2% yield) as a white solid. m / z: Calculated for [M+H]+C16H16F3N4O2 353.1; found 353.1. 1 H NMR (400 MHz,CDCl3) δ = 8.32 (br s,1H),7.79 - 7.73 (m,2H),7.71 (br d,J = 8.0 Hz,1H),7.65 - 7.59 (m,1H),6.55 (br s,1H),1.55 (s,9H).

[0222] Synthesis of 3-[4-amino-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile hydrochloride [INT1.17]: A solution of tert-butyl N-[1-(3-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-uuu] (100 mg, 283 μmol) in HCl / dioxane (1.5 mL) was stirred at 20° C. for 2 h. The reaction was concentrated under reduced pressure to give 3-[4-amino-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile hydrochloride [INT1.17] (82.0 mg, 284 μmol, 100% yield) as an off-white solid. m / z: calculated for [M+H]+C11H8F3N4 253.1; found 253.0. 1 H NMR (400 MHz,DMSO-d6) δ = 8.04 - 7.94 (m,2H),7.85 - 7.71 (m,2H),7.61 (s,1H).

[0223] Synthesis of 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [Intermediate 1.18]: [ka] Synthesis of ethyl 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-www]: To a solution of ethyl 2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (5.45 g, 22.7 mmol) in EtOH (10 mL) at 10° C., 2-hydrazinylpyrimidine [INT1-vvv] (2.5 g, 22.7 mmol) and Et3N (2.29 g, 22.7 mmol) were added. The mixture was stirred at 80° C. for 3 h. The reaction was concentrated under reduced pressure, quenched by adding water (100 mL), and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine (80 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc=1 / 0 to 5 / 1) to give ethyl 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-www] (4.72 g, 16.5 mmol, 72.7% yield) as a yellow oil. 1 H NMR (400 MHz,DMSO) δ = 9.08 (d,J = 4.0 Hz,2H),8.38 (s,1H),7.83 (t,J = 4.0 Hz,1H),4.33 (q,J = 8.0 Hz,2H),1.31 (t,J = 8.0 Hz,3H).

[0224] Synthesis of 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-xxx]: To a solution of ethyl 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-www] (4 g, 13.9 mmol) in THF (6 mL) and H2O (2 mL) at 10°C, lithium hydroxide monohydrate (2.91 g, 69.5 mmol) was added. The mixture was then stirred at 50°C for 2 h. The mixture was worked up with another of the same reaction. The mixture was acidified to pH = 5 with 1M HCl and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-xxx] (3.80 g, 14.7 mmol) as a pale yellow solid. 1 H NMR (400 MHz,DMSO) δ = 9.07 (d,J = 4.0 Hz,2H),8.30 (s,1H),7.82 (t,J = 6.0 Hz,1H)

[0225] Synthesis of tert-butyl N-[1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-yyy]: To a mixture of 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-xxx] (500 mg, 1.93 mmol) in t-BuOH (2 mL) and dioxane (6 mL) was added triethylamine (781 mg, 7.72 mmol) and diphenylphosphoryl azide (1.40 g, 5.79 mmol) at 10° C. Then the mixture was stirred at 100° C. for 2 h. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (petroleum ether / EtOAc=1 / 0 to 3 / 1) to give tert-butyl N-[1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-yyy] (340 mg, 1.03 mmol, 53.5% yield) as a white solid. 1 H NMR (400 MHz,DMSO) δ = 9.23 (s,1H),8.98 (d,J = 4.0 Hz,2H),7.99 (s,1H),7.65 (t,J = 4.0 Hz,1H),1.47 (s,9H).

[0226] Synthesis of 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.18]: A solution of tert-butyl N-[1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-yyy] (340 mg, 1.03 mmol) in HCl / dioxane (10 mL) was stirred for 1 h at 15° C. The mixture was concentrated under reduced pressure to give 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.18] (236 mg, 1.02 mmol, 100% yield) as a brown solid. 1 H NMR (400 MHz,DMSO) δ = 8.86 (d,J = 4.0 Hz,2H),7.56 (s,1H),7.49 (t,J = 4.0 Hz,1H).

[0227] Synthesis of 1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.19]: [ka] Synthesis of ethyl 1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-aaaa]: To a solution of 2-hydrazinylpyrazine [INT1-zzz] (2.0 g, 18.1 mmol) in EtOH (15 mL) was added ethyl 2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (4.34 g, 18.1 mmol) and triethylamine (2.01 g, 19.9 mmol). The reaction was stirred at 20° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 5) to give ethyl 1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-aaaa] (3.00 g, 10.4 mmol, 57.9% yield) as an oil. m / z: calculated for [M+H]+C11H10F3N4O2 287.1; found 287.1. 1 H NMR (400 MHz,CDCl3) δ = 9.01 (d,J = 1.2 Hz,1H),8.73 (d,J = 2.8 Hz,1H),8.59 - 8.54 (m,1H),8.18 (s,1H),4.40 (q,J = 6.8 Hz,2H),1.40 (t,J = 7.2Hz,3H).

[0228] Synthesis of 1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-bbbb]: To a solution of ethyl 1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-aaaa] (2.8 g, 9.78 mmol) in THF (12 mL) was added lithium hydroxide monohydrate (818 mg, 19.5 mmol) in HO (4 mL). The reaction was stirred at 20 °C for 4 h. The reaction mixture was poured into 20 mL of water, acidified to pH = 3-4 with 1N HCl, and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give 1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-bbbb] (2.25 g, 8.71 mmol, 89.2% yield) as a white solid. 1 H NMR (400 MHz,CDCl3) δ = 13.57 (br s,1H),9.14 (s,1H),8.92 (d,J = 2.4 Hz,1H),8.75 (d,J = 1.2 Hz,1H),8.37 (s,1H).

[0229] Synthesis of tert-butyl N-[1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-cccc]: A solution of 1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-bbbb] (2.25 g, 8.71 mmol), triethylamine (1.31 g, 13.0 mmol) and diphenylphosphoryl azide (4.78 g, 17.4 mmol) in t-BuOH (20 mL) was stirred under N2 at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 5) to give tert-butyl N-[1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-cccc] (2.33 g, 7.07 mmol, 81.4% yield) as a white solid. m / z: Calculated for [M+H]+C13H15F3N5O2 330.1; found 330.0. 1H NMR (400 MHz,CDCl3) δ = 9.15 (d,J = 0.8 Hz,1H),8.56 (d,J = 2.4 Hz,1H),8.51 - 8.36 (m,2H),6.76 (br s,1H),1.54 (s,9H).

[0230] Synthesis of 1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.19]: A mixture of tert-butyl N-[1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-cccc] (100 mg, 303 μmol) in HCl / dioxane (5 mL) was stirred at 20° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give 1-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.19] (81.0 mg, 304 μmol) as a brown solid. m / z: [M+H]+calculated for C8H7F3N5 230.1; found 229.9. 1 H NMR (400 MHz,DMSO-d6) δ = 9.04 (d,J = 1.6 Hz,1H),8.59 (d,J = 2.4 Hz,1H),8.53 - 8.49 (m,1H),7.64 (s,1H).

[0231] Synthesis of 1-(pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.20]: [ka] Synthesis of ethyl 1-(pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-eeee]: A mixture of ethyl 2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (5 g, 20.8 mmol) and 4-hydrazinylpyrimidine [INT1-dddd] (2.74 g, 24.9 mmol) in EtOH (50 mL) was stirred at 80° C. for 4 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (0-15% EtOAc in petroleum ether) to give ethyl 1-(pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-eeee] (3.90 g, 13.6 mmol, 65.5% yield) as a white solid. m / z: [M+H]+calculated for C11H10F3N4O2 287.1; found 287.0. 1 H NMR (400 MHz,CDCl3) δ = 9.21 (s,1H),8.96 (dd,J = 2.0,5.6 Hz,1H),8.14 (s,1H),7.80 (td,J = 1.2,5.6 Hz,1H),4.40 (tq,J = 1.6,7.2 Hz,2H),1.44 - 1.36 (m,3H).

[0232] Synthesis of 1-(pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ffff]: To a mixture of ethyl 1-(pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-eeee] (2.9 g, 10.1 mmol) in THF (15 mL) and H2O (5 mL), LiOH.H2O (1.27 g, 30.3 mmol) was added and the mixture was stirred at 50 °C for 6 h. The mixture was concentrated under reduced pressure to give the crude product. H2O (200 mL) and EtOAc (200 mL) were added and the precipitate was collected by filtration. The aqueous phase was washed with EtOAc (200 mL x 2), acidified to pH = 3 with 1M HCl and extracted with EtOAc (200 mL x 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated to give a yellow solid which was combined with the precipitate to give 1-(pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ffff] (2.10 g, 8.13 mmol, 80.7% yield) as a white solid. 1 H NMR (400 MHz,CDCl3) δ = 9.23 (s,1H),8.99 (d,J = 5.6 Hz,1H),8.22 (s,1H),7.81 (d,J=4.4 Hz,1H).

[0233] Synthesis of tert-butyl N-[1-(pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-gggg]: A mixture of 1-(pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-ffff] (1.6 g, 6.19 mmol), 2-methylpropan-2-ol (6.87 g, 92.8 mmol), diphenylphosphoryl azide (2.25 g, 9.28 mmol) and triethylamine (1.87 g, 18.5 mmol) in toluene (20 mL) was stirred for 3 h at 100° C. NaHCO3 (100 mL) was added and the mixture was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (0-10% EtOAc in petroleum ether) to give tert-butyl N-[1-(pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-gggg] (1.80 g, 5.46 mmol, 88.6% yield) as a white solid. m / z: [M+H]+calculated for C13H15F3N5O2 330.1; found: 330.1. 1 H NMR (400 MHz,CDCl3) δ = 9.06 (s,1H),8.79 (d,J = 5.6 Hz,1H),8.49 (br s,1H),7.88 (d,J = 5.6 Hz,1H),6.82 (br s,1H),1.54 (s,9H).

[0234] Synthesis of 1-(pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.20]: A mixture of tert-butyl N-[1-(pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-gggg] (150 mg, 455 μmol) in 4M HCl / dioxane (10 mL, 40.0 mmol) was stirred at 25° C. for 6 h. The mixture was concentrated under reduced pressure to give 1-(pyrimidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.20] (120 mg, 451 μmol) as a brown solid. m / z: [M+H]+calculated for C8H7F3N5 230.1; found 230.0.

[0235] Synthesis of 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.21]: [ka] Synthesis of ethyl 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-iiii]: A solution of 3-hydrazinylpyridazine [INT1-hhhh] (800 mg, 7.26 mmol), Et3N (1.46 g, 14.5 mmol), ethyl 2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (1.74 g, 7.26 mmol) and EtOH (50 mL) was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure to give a brown oil, which was purified by flash column chromatography (petroleum ether:ethyl acetate=0:1 to 85:15) to give ethyl 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-iiii] (1 g, 3.49 mmol, 48.3% yield) as a white solid. m / z: calculated for [M+H]+C11H10F3N4O2 287.1; found 286.9. 1H NMR (400 MHz,CDCl3) δ = 9.36 (dd,J = 1.2,4.8 Hz,1H),8.23 (s,1H),7.95 (dd,J = 1.6,8.8 Hz,1H),7.80 (dd,J = 4.8,8.8 Hz,1H),4.46 - 4.41 (m,2H),1.45 - 1.41 (m,3H).

[0236] Synthesis of 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-jjjj]: A mixture of ethyl 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-iiii] (800 mg, 2.79 mmol) in THF (9 mL) and HO (3 mL) was stirred at 20° C. for 12 h. The reaction was concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (column: Boston Prime C18 150*30 mm*5 μm, table: 2-42% B (A=water (0.05% HCl), B=acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to give 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-jjjj] (240 mg, 929 μmol, 33.3% yield) as a yellow solid. m / z: calculated for [M+H]+C9H6F3N4O2 259.0; found 258.9. 1 H NMR (400 MHz,DMSO-d6) δ = 9.46 (dd,J = 1.2,4.8 Hz,1H),8.41 (s,1H),8.21 (dd,J = 1.2,8.8 Hz,1H),8.10 (dd,J = 4.8,8.8 Hz,1H).

[0237] Synthesis of tert-butyl N-[1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-kkkk]: To a solution of 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-jjjj] (200 mg, 774 μmol) in t-BuOH (3 mL) was added diphenylphosphoryl azide (319 mg, 1.16 mmol) and Et3N (234 mg, 2.32 mmol). The reaction mixture was stirred at 100° C. under N2 for 2 h, after which it was quenched by adding water (15 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=0 / 1 to 1 / 4) to give tert-butyl N-[1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-kkkk] (142 mg, 431 μmol, 55.9% yield) as a colorless oil. m / z: [M+H]+calculated for C13H15F3N5O2 330.1; found 330.0. 1 H NMR (400 MHz,CDCl3) δ = 9.20 (d,J = 4.4 Hz,1H),8.51 (br s,1H),8.07 (br d,J = 8.8 Hz,1H),7.68 (dd,J = 4.8,8.8 Hz,1H),6.79 (br s,1H),1.57 (s,9H).

[0238] Synthesis of 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.21]: tert-Butyl N-[1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-kkkk] (142 mg, 431 μmol) in HCl (4M in dioxane, 5 mL, 20.0 mmol) was stirred at 20° C. for 12 h. The mixture was concentrated under reduced pressure to give 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.21] (114 mg, 429 μmol) as a yellow solid. m / z: [M+H]+calculated for C8H7F3N5 230.1; found 230.0.

[0239] Synthesis of 1-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.22]: [ka] Synthesis of 4-hydrazinylpyridazine [INT1-mmmm]: To a mixture of 4-chloropyridazine hydrochloride [INT1-llll] (900 mg, 5.96 mmol) in EtOH (10 mL) was added NH2NH2·H2O (3.50 g, 59.6 mmol). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated to give 4-hydrazinylpyridazine [INT1-mmmm] (656 mg, 5.95 mmol) as a brown oil. 1 H NMR (400 MHz,DMSO-d6) δ = 8.59 (d,J = 2.4 Hz,1H),8.47 (dd,J = 0.8,6.0 Hz,1H),6.73 (dd,J = 2.8,6.0 Hz,1H).

[0240] Synthesis of ethyl 1-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-nnnn]: To a mixture of 4-hydrazinylpyridazine [INT1-mmmm] (656 mg, 5.95 mmol) and ethyl 2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (7.13 g, 29.7 mmol) in EtOH (10 mL) was added triethylamine (6.02 g, 59.5 mmol). The reaction mixture was stirred at 80° C. for 3 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (20-25% EtOAc in petroleum ether) to give ethyl 1-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-nnnn] (1 g, 3.49 mmol, 58.8% yield) as a brown oil. m / z: [M+H]+calculated for C11H10F3N4O2 287.1; found 287.0. 1 H NMR (400 MHz,CDCl3) δ = 9.55 - 9.42 (m,2H),8.25 (s,1H),7.71 (br s,1H),4.42 (q,J = 7.2 Hz,2H),1.41 (t,J = 7.2 Hz,3H).

[0241] Synthesis of 1-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-oooo]: To a mixture of ethyl 1-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [INT1-nnnn] (950 mg, 3.31 mmol) in THF (10 mL) and H2O (3 mL) was added lithium hydroxide monohydrate (416 mg, 9.93 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated, diluted with water (50 mL), and washed with EtOAc (50 mL x 2). The aqueous phase was acidified to pH = 3 with 1 M HCl and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give 1-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-oooo] (530 mg, 2.05 mmol, 62.0% yield) as a yellow solid. m / z: calculated for [M+H]+C9H6F3N4O2 259.0; found 258.9. 1 H NMR (400 MHz,DMSO-d6) δ = 9.58 (d,J = 2.4 Hz,1H),9.56 (dd,J = 1.2,5.6 Hz,1H),8.42 (s,1H),8.06 (dd,J = 2.4,5.6 Hz,1H).

[0242] Synthesis of tert-butyl N-[1-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-pppp]: To a mixture of 1-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [INT1-oooo] (500 mg, 1.93 mmol) and 2-methylpropan-2-ol (2.14 g, 28.9 mmol) in toluene (5 mL) was added diphenylphosphoryl azide (795 mg, 2.89 mmol) and triethylamine (585 mg, 5.79 mmol). The reaction mixture was stirred under nitrogen at 100° C. for 2 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give tert-butyl N-[1-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-pppp] (250 mg, 759 μmol, 39.3% yield) as a white solid. m / z: calculated for [M+H]+C13H15F3N5O2 330.1; found 330.1. 1 H NMR (400 MHz,CDCl3) δ = 9.51 (d,J = 2.4 Hz,1H),9.32 (dd,J = 0.8,5.6 Hz,1H),8.48 (br s,1H),7.66 - 7.59 (m,1H),6.69 (br s,1H),1.58 - 1.51 (m,9H).

[0243] Synthesis of 1-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.22]: A solution of tert-butyl N-[1-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbamate [INT1-pppp] (230 mg, 698 μmol) in HCl / dioxane (5 mL) was stirred for 12 h at 25° C. The reaction mixture was concentrated under reduced pressure to give 1-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.22] (185 mg, 696 μmol) as a white solid. 1H NMR (400 MHz,DMSO-d6) δ = 9.47 (d,J = 2.4 Hz,1H),9.35 (dd,J = 0.8,6.0 Hz,1H),7.76 - 7.71 (m,1H),7.68 (s,1H).

[0244] Synthesis of 5-(1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine [Intermediate 1.23]: [ka] Synthesis of ethyl 4-methoxy-3-oxopentanoate [INT1-rrrr]: To a solution of 2-methoxypropanoic acid [INT1-qqqq] (5 g, 48.0 mmol) in THF (50 mL) was added CDI (9.32 g, 57.5 mmol) at 0° C., and the mixture was stirred at 20° C. for 2 h. Magnesium chloride (4.57 g, 48.0 mmol) and potassium ethyl malonate (12.2 g, 72.0 mmol) were added to the reaction solution, and the mixture was stirred at 20° C. for 6 h. 1N HCl (200 mL) was then added, and the mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product ethyl 4-methoxy-3-oxopentanoate [INT1-rrrr] (6.15 g, 35.3 mmol, 73.5% yield) as a yellow oil. 1 H NMR (400 MHz,CDCl3) δ = 4.24 - 4.10 (m,2H),3.79 (q,J = 6.8 Hz,1H),3.60 - 3.47 (m,2H),3.40 - 3.29 (m,3H),1.37 - 1.17 (m,6H).

[0245] Synthesis of ethyl 2-((dimethylamino)methylene)-4-methoxy-3-oxopentanoate [INT1-ssss]: A mixture of ethyl 4-methoxy-3-oxopentanoate [INT1-rrrr] (6.15 g, 35.3 mmol) and (dimethoxymethyl)dimethylamine (8.41 g, 70.6 mmol) in 2,2,2-trifluoroethanol (60 mL) was stirred for 4 hours at 50° C. The mixture was concentrated under reduced pressure to give the crude product, ethyl 2-((dimethylamino)methylene)-4-methoxy-3-oxopentanoate [INT1-ssss].

[0246] Synthesis of ethyl 5-(1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-tttt]: To a mixture of ethyl 2-((dimethylamino)methylene)-4-methoxy-3-oxopentanoate [INT1-ssss] (5.38 g, 23.4 mmol) and triethylamine (11.8 g, 117 mmol) in 2,2,2-trifluoroethanol (50 mL) was added 3-hydrazinylpyridine hydrochloride (11.9 g, 81.9 mmol). The reaction mixture was stirred at 80° C. for 12 h. The mixture was concentrated under reduced pressure to give the crude product. Brine (200 mL) was added and the mixture was extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (200 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (0-40% EtOAc in petroleum ether) to give ethyl 5-(1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-tttt] (4.40 g, 15.9 mmol, 68.3% yield) as a yellow oil. m / z: [M+H]+calculated for C14H18N3O3 276.1; found 276.1. 1H NMR (400 MHz,CDCl3) δ = 8.80 (d,J = 2.4 Hz,1H),8.70 (d,J = 4.4 Hz,1H),8.08 (s,1H),7.91 - 7.87 (m,1H),7.43 (dd,J = 4.8,8.4 Hz,1H),5.44 (q,J = 6.8 Hz,1H),4.39 - 4.31 (m,2H),3.27 - 3.21 (m,3H),1.39 (t,J = 7.2 Hz,3H),1.34 (d,J = 6.8 Hz,3H).

[0247] Synthesis of 5-(1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid [INT1-uuuu]: To a mixture of ethyl 5-(1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-tttt] (4.4 g, 15.9 mmol) in THF (30 mL) and H2O (10 mL), LiOH·H2O (2.00 g, 47.7 mmol) was added and the mixture was stirred at 50 °C for 8 h. The mixture was concentrated under reduced pressure to give the crude product. H2O (200 mL) and EtOAc (200 mL) were added and the precipitate was collected by filtration. The aqueous phase was washed with EtOAc (100 mL x 2), acidified to pH = 3 with 1M HCl and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated and combined with the precipitate to give 5-(1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid [INT1-uuuu] (2.80 g, 11.3 mmol, 71.2% yield) as a white solid. m / z: [M+H]+calculated for C12H14N3O3 248.1; found 248.1. 1 H NMR (400 MHz,DMSO-d6) δ = 8.80 - 8.66 (m,2H),8.06 (s,1H),8.02 - 7.96 (m,1H),7.59 (dd,J = 4.8,8.0 Hz,1H),5.30 (q,J = 6.8 Hz,1H),3.08 (s,3H),1.28 (d,J = 6.8 Hz,3H).

[0248] Synthesis of tert-butyl N-[5-(1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-yl]carbamate [INT1-vvvv]: A mixture of 5-(1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid [INT1-uuuu] (2.8 g, 11.3 mmol), 2-methylpropan-2-ol (12.5 g, 169 mmol), diphenylphosphoryl azide (4.11 g, 16.9 mmol) and triethylamine (3.43 g, 33.9 mmol) in toluene (20 mL) was stirred for 2 h at 100° C. Saturated aqueous NaHCO3 (200 mL) was added and the mixture was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (0-10% EtOAc in petroleum ether) to give tert-butyl N-[5-(1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-yl]carbamate [INT1-vvvv] (2.50 g, 7.85 mmol, 69.6% yield) as a white solid. m / z: [M+H]+calculated for C16H23N4O3 319.2; found 319.2. 1 H NMR (400 MHz,CDCl3) δ = 8.66 (br s,2H),8.20 (br s,1H),7.82 - 7.74 (m,1H),7.45 (dd,J = 5.2,8.0 Hz,1H),6.88 (br s,1H),4.48 (q,J = 6.8 Hz,1H),3.28 (s,3H),1.54 (s,9H),1.50 (d,J = 6.8 Hz,3H).

[0249] Synthesis of 5-(1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine [INT1.23]: A mixture of tert-butyl N-[5-(1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-yl]carbamate [INT1-vvvv] (500 mg, 1.57 mmol) in 4M HCl / dioxane (10 mL, 40.0 mmol) was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure to give a yellow solid, which was purified by Prep-HPLC (column: Boston Prime C18 150*30mm*5μm, table: 0~30%B (A=water (ammonia hydroxide v / v)~ACN), B=acetonitrile), flow rate: 20mL / min, UV detector 220nm) to give 5-(1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine [INT1.23] (185mg, 847μmol, 53.9% yield) as a white solid. Calculated for [M+H]+C11H15N4O 219.1; Found: 219.0. 1 H NMR (400 MHz,CDCl3) δ = 8.68 (d,J = 2.3 Hz,1H),8.63 (d,J = 4.8 Hz,1H),7.78 (dd,J = 1.5,8.0 Hz,1H),7.47 - 7.42 (m,1H),7.42 - 7.39 (m,1H),4.49 (q,J = 6.5 Hz,1H),3.27 (d,J = 1.3 Hz,3H),3.13 - 2.80 (m,2H),1.53 (d,J = 6.5 Hz,3H).

[0250] Synthesis of 1-[4-amino-1-(pyridin-3-yl)-1H-pyrazol-5-yl]ethan-1-ol [Intermediate 1.24]: [ka] Synthesis of ethyl 5-amino-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-xxxx]: A suspension of ethyl 5-amino-1H-pyrazole-4-carboxylate [INT1-wwww] (18.5 g, 119 mmol), 3-bromopyridine (15.6 g, 99.1 mmol), CuI (942 mg, 4.95 mmol), K2CO3 (27.3 g, 198 mmol) and trans-1,2-diaminocyclohexane (1.13 g, 9.91 mmol) in DMF (100 mL) was stirred at 120 °C under N2 for 12 h. The reaction mixture was filtered. The filtrate was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=1 / 4 to 1 / 1) to give a mixture of ethyl 5-amino-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-xxxx] (10.1 g, 43.4 mmol, 43.9% yield) and ethyl 3-amino-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate (5.20 g, 22.3 mmol, 22.6% yield) as yellow oil. m / z: calculated for [M+H]+C11H13N4O2 233.1; found 233.2.

[0251] Synthesis of ethyl 5-iodo-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-yyyy]: Ethyl 5-amino-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-xxxx] (6.78 g, 29.2 mmol) was suspended in acetonitrile (100 mL) at room temperature. Diiodomethane (46.8 g, 175 mmol) was added followed by isopentyl nitrite (10.2 g, 87.6 mmol). The reaction was heated at 50 °C for 12 h, after which it was combined with another of the same type and partitioned between water (500 mL) and ethyl acetate (300 mL). The aqueous layer was extracted with ethyl acetate (300 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude material was purified using silica gel column chromatography (10-25% ethyl acetate in petroleum ether). Compound ethyl 5-iodo-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-yyyy] (2.25 g, 6.55 mmol) was obtained as a yellow solid. m / z: calculated for [M+H]+C11H11IN3O2 344.0; found 343.9. 1 H NMR (400 MHz,CDCl3) δ = 8.76 (d,J = 2.4 Hz,1H),8.68 (d,J = 4.8 Hz,1H),8.14 (s,1H),7.86 - 7.78 (m,1H),7.43 (dd,J = 4.8,8.0 Hz,1H),4.35 - 4.29 (m,2H),1.33 (t,J = 7.2 Hz,3H).

[0252] Synthesis of 5-iodo-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid [INT1-zzzz]: A solution of ethyl 5-iodo-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-yyyy] (156 mg, 454 μmol) and lithium hydroxide monohydrate (28.5 mg, 681 μmol) in a mixture of THF (3 mL) and HO (1 mL) was stirred at 20° C. for 12 h. The mixture was adjusted to pH=4 with 1N HCl. The resulting suspension was filtered and washed with water (5 mL×2). The cake was dried to give 5-iodo-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid [INT1-zzzz] (56.0 mg, 177 μmol, 39.1% yield) as a yellow solid. m / z: calculated for [M+H]+C9H7IN3O2 316.0; found 315.9. 1 H NMR (400 MHz,DMSO-d6) δ = 12.81 (br s,1H),8.83 - 8.70 (m,2H),8.20 (s,1H),8.11 - 8.01 (m,1H),7.66 (dd,J = 4.8,8.0 Hz,1H).

[0253] Synthesis of tert-butyl N-[5-iodo-1-(pyridin-3-yl)-1H-pyrazol-4-yl]carbamate [INT1-aaaaa]: To a solution of 5-iodo-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid [INT1-zzzz] (2.2 g, 6.98 mmol) in t-BuOH (20 mL) was added diphenylphosphoryl azide (2.86 g, 10.4 mmol) and Et3N (2.11 g, 20.9 mmol). The reaction mixture was stirred at 100° C. under N2 for 2 h. The reaction was quenched by adding water (100 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=0 / 1 to 1 / 1) to give tert-butyl N-[5-iodo-1-(pyridin-3-yl)-1H-pyrazol-4-yl]carbamate [INT1-aaaaa] (1.80 g, 4.66 mmol, 66.9% yield) as a white solid. m / z: [M+H]+calculated for C13H16IN4O2 387.0; found 387.0. 1 H NMR (400 MHz,CDCl3) δ = 8.89 (d,J = 1.6 Hz,1H),8.68 (br d,J = 4.4 Hz,1H),8.20 (br s,1H),7.96 (br d,J = 8.0 Hz,1H),7.49 (dd,J = 4.8,8.0 Hz,1H),6.15 (br s,1H),1.56 (s,9H).

[0254] Synthesis of tert-butyl N-[5-(1-ethoxyethenyl)-1-(pyridin-3-yl)-1H-pyrazol-4-yl]carbamate [INT1-bbbbb]: A mixture of tert-butyl N-[5-iodo-1-(pyridin-3-yl)-1H-pyrazol-4-yl]carbamate [INT1-aaaaa] (500 mg, 1.29 mmol), Pd(PPh3)2Cl2 (90.5 mg, 129 μmol), tributyl(1-ethoxyethenyl)stannane (1 g, 2.76 mmol) and dioxane (10 mL) under N2 was stirred at 60 °C for 12 h. The mixture was quenched with saturated KF solution (100 mL) and stirred at 25 °C for 1 h. The aqueous layer was extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash column chromatography (30% ethyl acetate in PE) to give tert-butyl N-[5-(1-ethoxyethenyl)-1-(pyridin-3-yl)-1H-pyrazol-4-yl]carbamate [INT1-bbbbb] (400 mg, 1.21 mmol, 93.8% yield) as a brown gum. m / z: [M+H]+calculated for C17H23N4O3 331.2; found 331.1. 1 H NMR (400 MHz,DMSO-d6) δ = 8.64 (d,J = 2.4 Hz,1H),8.57 (dd,J = 1.3,4.7 Hz,1H),8.49 (br s,1H),7.88 - 7.84 (m,1H),7.81 (br s,1H),7.54 (dd,J = 4.8,8.2 Hz,1H),4.66 (d,J = 2.6 Hz,1H),4.62 (d,J = 2.6 Hz,1H),3.68 (q,J = 7.1 Hz,2H),1.45 (s,9H),0.86 (t,J = 7.0 Hz,3H).

[0255] Synthesis of 1-[4-amino-1-(pyridin-3-yl)-1H-pyrazol-5-yl]ethan-1-one hydrochloride [INT1-ccccc]: tert-Butyl N-[5-(1-ethoxyethenyl)-1-(pyridin-3-yl)-1H-pyrazol-4-yl]carbamate [INT1-bbbbb] (400 mg, 1.21 mmol) was dissolved in 1M HCl (10 mL) and the mixture was stirred at 25° C. for 3 h. The mixture was adjusted to pH 8 with saturated aqueous NaHCO3 and extracted with ethyl acetate (20 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was diluted with 4N HCl in dioxane (5 mL) and stirred at 30° C. for 12 h. The mixture was concentrated to give 1-[4-amino-1-(pyridin-3-yl)-1H-pyrazol-5-yl]ethan-1-one hydrochloride [INT1-ccccc] (280 mg, 1.17 mmol, 97.2% yield) as a brown solid. m / z: calculated for [M+H]+C10H11N4O 203.1; found 203.0.

[0256] Synthesis of 1-[4-amino-1-(pyridin-3-yl)-1H-pyrazol-5-yl]ethan-1-ol [INT1.24]: A solution of 1-[4-amino-1-(pyridin-3-yl)-1H-pyrazol-5-yl]ethan-1-one [free base of INT1-ccccc] (180 mg, 0.8901 mmol) in methanol (5 mL) was cooled to 0 °C. Sodium borohydride (101 mg, 2.67 mmol) was added and the reaction mixture was stirred at 0-25 °C for 12 h. MeOH was removed and the residue was diluted with water (10 mL). The pH of the reaction mixture was adjusted to 8-9 with saturated aqueous NaHCO3 solution and the resulting mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give crude 1-[4-amino-1-(pyridin-3-yl)-1H-pyrazol-5-yl]ethan-1-ol [INT1.24] (180 mg, 0.8813 mmol, 99.4% yield) as a brown gum. m / z: calculated for [M+H]+C10H13N4O 205.1; found 204.8. 1H NMR (400 MHz,DMSO-d6) δ = 8.78 (d,J = 2.4 Hz,1H),8.61 (dd,J = 1.3,4.7 Hz,1H),8.01 - 7.97 (m,1H),7.58 (dd,J = 4.7,7.8 Hz,1H),7.30 (s,1H),5.47 (br s,1H),4.94 - 4.80 (m,1H),4.45 - 4.02 (m,2H),1.41 (d,J = 6.8 Hz,3H).

[0257] Synthesis of (S)-3-(4-amino-5-(1-methoxyethyl)-1H-pyrazol-1-yl)benzonitrile [Intermediate 1.25]: [ka] Synthesis of ethyl (4S)-4-methoxy-3-oxopentanoate [INT1-eeeee]: To a solution of (2S)-2-methoxypropanoic acid [INT1-ddddd] (5 g, 48.0 mmol) in THF (50 mL) was added 1,1'-carbonyldiimidazole (9.32 g, 57.5 mmol) at 0° C. and the mixture was stirred at 20° C. for 2 h. Magnesium chloride (4.57 g, 48.0 mmol) and 1-ethyl 3-potassium propanedioate (12.2 g, 72.0 mmol) were added to the reaction solution and the mixture was stirred at 20° C. for 6 h. The reaction was quenched by adding 1N aqueous HCl (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous NaSO and concentrated under reduced pressure to give ethyl (4S)-4-methoxy-3-oxopentanoate [INT1-eeeee] (8.00 g, 45.9 mmol, 95.6% yield) as a yellow oil. 1 H NMR (400 MHz,CDCl3) δ = 4.24 - 4.06 (m,2H),3.86 - 3.70 (m,1H),3.62 - 3.47 (m,2H),3.39 - 3.32 (m,3H),1.32 - 1.23 (m,6H).

[0258] Synthesis of ethyl 1-(3-cyanophenyl)-5-[(1S)-1-methoxyethyl]-1H-pyrazole-4-carboxylate [INT1-fffff]: To a mixture of ethyl (4S)-4-methoxy-3-oxopentanoate [INT1-eeeee] (1.5 g, 8.61 mmol) in 2,2,2-trifluoroethanol (15 mL) was added N,N-dimethylformamide dimethyl acetal (1.22 g, 10.3 mmol). The mixture was stirred at 20° C. for 30 min. 3-hydrazinylbenzonitrile hydrochloride [INT1-rrr] (1.74 g, 10.3 mmol) was added and the mixture was stirred at 20° C. for 12 h. The mixture was concentrated to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give ethyl 1-(3-cyanophenyl)-5-[(1S)-1-methoxyethyl]-1H-pyrazole-4-carboxylate [INT1-fffff] (1.95 g, 6.51 mmol, 75.8% yield) as an orange solid. m / z: [M+H]+calculated for C16H18N3O3 300.1; found 300.0. 1 H NMR (400 MHz,CDCl3) δ = 8.06 (s,1H),7.90 (t,J = 1.6 Hz,1H),7.87 - 7.82 (m,1H),7.74 (td,J = 1.6,8.0 Hz,1H),7.62 - 7.57 (m,1H),5.47 (q,J = 6.8 Hz,1H),4.40 - 4.29 (m,2H),3.27 (s,3H),1.39 (t,J = 7.2 Hz,3H),1.33 - 1.30 (m,3H).

[0259] Synthesis of 1-(3-cyanophenyl)-5-[(1S)-1-methoxyethyl]-1H-pyrazole-4-carboxylic acid [INT1-ggggg]: To a solution of ethyl 1-(3-cyanophenyl)-5-[(1S)-1-methoxyethyl]-1H-pyrazole-4-carboxylate [INT1-fffff] (1.8 g, 6.01 mmol) in THF (15 mL) was added lithium hydroxide monohydrate (302 mg, 7.21 mmol) in HO (5 mL). The reaction was stirred at 20 °C for 12 h. The reaction mixture was poured into 10 mL of water, acidified to pH = 5-6 with 1N HCl, and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (MeOH / DCM=0 / 1 to 1 / 20) to give 1-(3-cyanophenyl)-5-[(1S)-1-methoxyethyl]-1H-pyrazole-4-carboxylic acid [INT1-ggggg] (1.20 g, 4.42 mmol, 73.6% yield) as a yellow solid. 1 H NMR (400 MHz,DMSO-d6) δ = 12.76 (br s,1H),8.07 - 8.03 (m,2H),8.00 (d,J = 8.0 Hz,1H),7.90 - 7.86 (m,1H),7.77 - 7.71 (m,1H),5.29 (q,J = 6.8 Hz,1H),3.08 (s,3H),1.28 (d,J = 6.8 Hz,3H).

[0260] Synthesis of tert-butyl N-[1-(3-cyanophenyl)-5-[(1S)-1-methoxyethyl]-1H-pyrazol-4-yl]carbamate [INT1-hhhhh]: A solution of 1-(3-cyanophenyl)-5-[(1S)-1-methoxyethyl]-1H-pyrazole-4-carboxylic acid [INT1-ggggg] (1.2 g, 4.42 mmol), triethylamine (670 mg, 6.63 mmol) and diphenylphosphoryl azide (2.43 g, 8.84 mmol) in t-BuOH (15 mL) was stirred under N2 at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give tert-butyl N-[1-(3-cyanophenyl)-5-[(1S)-1-methoxyethyl]-1H-pyrazol-4-yl]carbamate [INT1-hhhhh] (1 g, 2.92 mmol, 66.2% yield) as a yellow oil. m / z: calculated for [M+H]+C18H23N4O3 343.2; found 343.2. 1 H NMR (400 MHz,CDCl3) δ = 8.18 (br s,1H),7.73 - 7.67 (m,2H),7.67 - 7.57 (m,2H),6.86 (br s,1H),4.49 (q,J = 6.8 Hz,1H),3.28 (s,3H),1.54 (s,9H),1.50 (d,J = 6.8 Hz,3H).

[0261] Synthesis of (S)-3-(4-amino-5-(1-methoxyethyl)-1H-pyrazol-1-yl)benzonitrile [INT1.25]: A mixture of tert-butyl N-[1-(3-cyanophenyl)-5-[(1S)-1-methoxyethyl]-1H-pyrazol-4-yl]carbamate [INT1-hhhhh] (500 mg, 1.46 mmol) in 4M HCl / dioxane (8 mL) was stirred for 12 h at 20° C. The reaction mixture was poured into 10 mL of water, basified with NH3·H2O to pH=9-10, and extracted with EtOAc (30 mL×2). The combined organic layer was washed with brine (30 mL×2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give (S)-3-(4-amino-5-(1-methoxyethyl)-1H-pyrazol-1-yl)benzonitrile [INT1.25] (100 mg, 412 μmol, 28.3% yield) as a yellow solid. m / z: calculated for [M-OCH3]+C12H11N4 211.1; found 210.9. 1 H NMR (400 MHz,CDCl3) δ = 7.76 - 7.73 (m,1H),7.69 - 7.64 (m,2H),7.62 - 7.55 (m,1H),7.39 (s,1H),4.50 (q,J = 6.8 Hz,1H),3.28 (s,3H),1.53 (d,J = 6.4 Hz,3H).

[0262] Synthesis of 5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazol-4-amine hydrochloride [Intermediate 1.26]: [ka] Synthesis of ethyl 5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazole-4-carboxylate [INT1-iiiii]: To a mixture of phenylhydrazine [INT1-t] (1.5 g, 13.8 mmol) and N,N-dimethylformamide dimethyl acetal (1.96 g, 16.5 mmol) in 2,2,2-trifluoroethanol (20 mL) was added ethyl (4S)-4-methoxy-3-oxopentanoate [INT1-eeeee] (2.87 g, 16.5 mmol) in 2,2,2-trifluoroethanol (10 mL). The reaction mixture was stirred at 25° C. for 12 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (0-15% EtOAc in petroleum ether) to give ethyl 5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazole-4-carboxylate [INT1-iiiii] (2.00 g, 7.29 mmol, 52.9% yield) as a brown oil. m / z: [M+H]+calculated for C15H19N2O3 275.1; found 275.1. 1 H NMR (400 MHz,CDCl3) δ = 8.05 (s,1H),7.53 - 7.43 (m,5H),5.34 (q,J = 6.8 Hz,1H),4.40 - 4.29 (m,2H),3.25 (s,3H),1.39 (t,J = 7.2 Hz,3H),1.35 (d,J = 6.8 Hz,3H).

[0263] Synthesis of 5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazole-4-carboxylic acid [INT1-jjjjj]: To a mixture of ethyl 5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazole-4-carboxylate [INT1-iiiii] (1.8 g, 6.56 mmol) in THF (5 mL), MeOH (5 mL) and HO (5 mL) was added lithium hydroxide monohydrate (822 mg, 19.6 mmol). The reaction mixture was stirred at 50° C. for 2 h, after which it was concentrated, diluted with water (50 mL) and washed with EtOAc (100 mL×2). The aqueous phase was acidified to pH=3 with 1M aqueous HCl and extracted with EtOAc (100 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give 5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazole-4-carboxylic acid [INT1-jjjjj] (950 mg, 3.85 mmol, 59.0% yield) as an orange solid. Calculated for [M+H]+C13H15N2O3 247.1; Found: 247.2. 1 H NMR (400 MHz,CDCl3) δ = 8.18 (d,J = 1.2 Hz,1H),7.51 (br d,J = 2.0 Hz,3H),7.48 - 7.42 (m,2H),5.13 - 5.00 (m,1H),3.32 (d,J = 3.6 Hz,3H),1.46 (t,J = 5.6 Hz,3H).

[0264] Synthesis of tert-butyl N-{5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazol-4-yl}carbamate [INT1-kkkkk]: To a mixture of 5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazole-4-carboxylic acid [INT1-jjjjj] (850 mg, 3.45 mmol), 2-methylpropan-2-ol (3.83 g, 51.7 mmol) and triethylamine (1.04 g, 10.3 mmol) in toluene (10 mL) was added diphenylphosphoryl azide (1.42 g, 5.17 mmol). The reaction mixture was stirred at 100° C. under nitrogen for 2 h. The reaction mixture was diluted with EtOAc (100 mL×3) and washed with aqueous saturated NaHCO3 (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (0-13% EtOAc in petroleum ether) to give tert-butyl N-{5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazol-4-yl}carbamate [INT1-kkkkk] (770 mg, 2.42 mmol, 70.6% yield) as a yellow solid. m / z: [M+H]+calculated for C17H24N3O3 318.2; found 318.1. 1 H NMR (400 MHz,CDCl3) δ = 8.15 (br s,1H),7.52 - 7.33 (m,5H),6.90 (br s,1H),4.48 (q,J = 6.4 Hz,1H),3.27 (s,3H),1.54 (br s,9H),1.48 (d,J = 6.4Hz,3H).

[0265] Synthesis of 5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazol-4-amine hydrochloride [INT1.26]: A mixture of tert-butyl N-{5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazol-4-yl}carbamate [INT1-kkkkk] (150 mg, 472 μmol) in 4M HCl / dioxane (10 mL, 40.0 mmol) was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure to give 5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazol-4-amine hydrochloride [INT1.26] (119 mg, 469 μmol) as a brown oil. m / z: calculated for [M+H]+C12H16N3O 218.1; found 217.9.

[0266] Synthesis of 5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.27]: [ka] Synthesis of ethyl 5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate [INT1-llll]: To a mixture of ethyl (4S)-4-methoxy-3-oxopentanoate [INT1-eeeee] (3 g, 17.2 mmol) and triethylamine (2.08 g, 20.6 mmol) in 2,2,2-trifluoroethanol (50 mL) was added N,N-dimethylformamide dimethyl acetal (10.2 g, 85.9 mmol) and 2-hydrazinylpyridine [INT1-iii] (2.24 g, 20.6 mmol) at 15° C. The reaction mixture was stirred at 80° C. for 12 h. The mixture was concentrated and the resulting residue was quenched with water (60 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give ethyl 5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate [INT1-lllll] (1.30 g, 4.72 mmol, 27.4% yield) as a yellow oil.1 H NMR (400 MHz,DMSO) δ = 8.59 - 8.53 (m,1H),8.10 - 8.01 (m,2H),7.67 - 7.61 (m,1H),7.58 - 7.52 (m,1H),5.19 (q,J = 8.0 Hz,1H),4.26 (q,J = 8.0 Hz,2H),2.91 (s,3H),1.61 (d,J = 8.0 Hz,3H),1.30 (t,J = 8.0 Hz,3H).

[0267] Synthesis of 5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylic acid [INT1-mmmmm]: A solution of ethyl 5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate [INT1-llll] (1.3 g, 4.72 mmol) and lithium hydroxide monohydrate (990 mg, 23.6 mmol) in EtOH (10 mL) and HO (3 mL) was stirred at 50° C. for 3 h. The reaction was acidified to pH=4 with 1M aqueous HCl and extracted with EtOAc (25 mL×2). The combined organic layers were concentrated under reduced pressure to give 5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylic acid [INT1-mmmmm] (946 mg, 3.82 mmol, 81.5% yield) as a pale yellow solid. 1 H NMR (400 MHz,DMSO) δ = 8.59 - 8.50 (m,1H),8.10 - 7.96 (m,2H),7.65 - 7.58 (m,1H),7.57 - 7.51 (m,1H),5.22 (q,J = 8.0 Hz,1H),2.90 (s,3H),1.59 (d,J = 8.0 Hz,3H).

[0268] Synthesis of tert-butyl N-{5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazol-4-yl}carbamate [INT1-nnnnn]: To a mixture of 5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylic acid [INT1-mmmmm] (946 mg, 3.82 mmol) in t-BuOH (3 mL) and dioxane (9 mL) was added triethylamine (1.92 g, 19.0 mmol) and diphenylphosphoryl azide (2.77 g, 11.4 mmol) at 10° C. Then the mixture was stirred at 100° C. for 2 h. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (petroleum ether / EtOAc=1 / 0 to 17 / 3) to give tert-butyl N-{5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazol-4-yl}carbamate [INT1-nnnnn] (265 mg, 832 μmol, 21.9% yield) as a white solid. m / z: [M+H]+calculated for C16H23N4O3 319.2; found 319.3. 1 H NMR (400 MHz,DMSO) δ = 8.49 - 8.45 (m,1H),7.99 - 7.81 (m,4H),7.40 - 7.35 (m,1H),5.35 (q,J = 8.0 Hz,1H),3.15 (s,3H),1.52 (d,J = 8.0 Hz,3H),1.46 (s,9H).

[0269] Synthesis of 5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazol-4-amine hydrochloride [INT1.27]: A solution of tert-butyl N-{5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazol-4-yl}carbamate [INT1-nnnnn] (265 mg, 832 μmol) in HCl / dioxane (10 mL) was stirred for 1 h at 20° C. The mixture was concentrated under reduced pressure to give 5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazol-4-amine hydrochloride [INT1.27] (211 mg, 828 μmol) as a black solid.1 H NMR (400 MHz,CDCl3) δ = 8.41 - 8.32 (m,1H),7.86 (d,J = 8.0 Hz,1H),7.80 - 7.71 (m,1H),7.35 (s,1H),7.15 - 7.08 (m,1H),5.62 (q,J = 8.0 Hz,1H),3.35 (s,3H),1.62 (s,3H).

[0270] Synthesis of 5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazol-4-amine [Intermediate 1.28]: [ka] Synthesis of ethyl 5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazole-4-carboxylate [INT1-ooooo]: To a mixture of ethyl (4S)-4-methoxy-3-oxopentanoate [INT1-eeeee] (1.7 g, 9.75 mmol) and N,N-dimethylformamide dimethyl acetal (1.39 g, 11.7 mmol) in 2,2,2-trifluoroethanol (30 mL) was added 4-hydrazinylpyridine hydrochloride [INT1-eee] (1.70 g, 11.7 mmol) and triethylamine (1.18 g, 11.7 mmol). The reaction mixture was stirred at 15° C. for 12 h. The mixture was concentrated to give the crude product. The mixture was worked up with another of the same type. The residue was quenched with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give ethyl 5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazole-4-carboxylate [INT1-ooooo] (1.80 g, 6.53 mmol, 67.1% yield) as a yellow oil. 1H NMR (400 MHz,DMSO) δ = 8.80 - 8.71 (m,2H),8.14 (s,1H),7.67 - 7.64 (m,2H),5.29 (q,J = 8.0 Hz,1H),4.28 (q,J = 8.0 Hz,2H),3.10 (s,3H),1.36 (d,J = 8.0 Hz,3H),1.31 (t,J = 8.0 Hz,3H).

[0271] Synthesis of 5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazole-4-carboxylic acid [INT1-ppppp]: To a solution of ethyl 5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazole-4-carboxylate [INT1-ooooo] (1.76 g, 6.39 mmol) in THF (20 mL) and H2O (4 mL) at 10°C, lithium hydroxide monohydrate (1.33 g, 31.9 mmol) was added. The mixture was stirred at 40°C for 2 h. The mixture was acidified to pH = 5 with 1M aqueous HCl and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazole-4-carboxylic acid [INT1-ppppp] (1.57 g, 6.34 mmol) as a pale yellow solid. 1 H NMR (400 MHz,DMSO) δ = 8.66 (d,J = 4.0 Hz,2H),7.89 (s,1H),7.74 (d,J = 4.0 Hz,2H),6.04 (q,J = 4.0 Hz,1H),3.19 (s,3H),1.21 (d,J = 8.0 Hz,3H).

[0272] Synthesis of benzyl N-{5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazol-4-yl}carbamate [INT1-qqqqq]: To a mixture of 5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazole-4-carboxylic acid [INT1-ppppp] (1.25 g, 5.05 mmol) in BnOH (3 mL) and dioxane (12 mL), diphenylphosphoryl azide (3.67 g, 15.1 mmol) and triethylamine (2.55 g, 25.2 mmol) were added at 20° C. The mixture was then stirred at 100° C. under N2 for 3 h. The reaction was quenched by adding water (40 mL) and extracted with EtOAc (30 mL×2). The combined organic layer was washed with brine (40 mL×2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc=1 / 0 to 5 / 1) to give benzyl N-{5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazol-4-yl}carbamate [INT1-qqqqq] (390 mg, 1.10 mmol, 22.0% yield) as a pale yellow oil. m / z: [M+H]+calculated for C19H21N4O3 353.2; found 353.2.

[0273] Synthesis of 5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazol-4-amine [INT1.28]: To a mixture of 10% Pd / C (40 mg) in EtOH (40 mL) at 20° C., benzyl N-{5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazol-4-yl}carbamate [INT1-qqqqq] (390 mg, 1.10 mmol) was added. The mixture was then stirred under H2 (15 psi) for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazol-4-amine [INT1.28] (200 mg, 916 μmol, 83.3% yield) as a white solid. 1H NMR (400 MHz,DMSO) δ = 8.60 (d,J = 8.0 Hz,2H),7.60 (d,J = 8.0 Hz,2H),7.36 (s,1H),4.71 (q,J = 8.0 Hz,1H),4.24 (s,2H),3.18 (s,3H),1.37 (d,J = 8.0 Hz,3H).

[0274] Synthesis of 5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.29]: [ka] Synthesis of ethyl 5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-rrrrr]: A mixture of ethyl (4S)-4-methoxy-3-oxopentanoate [INT1-eeeee] (3 g, 17.2 mmol) and N,N-dimethylformamide dimethyl acetal (3.07 g, 25.8 mmol) in 2,2,2-trifluoroethanol (20 mL) was stirred for 12 h at 25° C. The mixture was concentrated under reduced pressure to give crude ethyl (2Z,4S)-2-[(dimethylamino)methylidene]-4-methoxy-3-oxopentanoate, which was used directly in the next step.

[0275] To a mixture of ethyl (2Z,4S)-2-[(dimethylamino)methylidene]-4-methoxy-3-oxopentanoate (3.94 g, 17.1 mmol) and triethylamine (8.65 g, 85.5 mmol) in 2,2,2-trifluoroethanol (20 mL) was added 3-hydrazinylpyridine hydrochloride [INT1-aaa] (7.46 g, 51.3 mmol). The reaction mixture was stirred at 80° C. for 2 h. The mixture was concentrated under reduced pressure to give the crude product. Brine (200 mL) was added and the mixture was extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (200 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (0-40% EtOAc in petroleum ether) to give ethyl 5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-rrrrr] (2.20 g, 7.99 mmol, 46.8% yield) as a yellow oil. m / z: [M+H]+calculated for C14H18N3O3 276.1; found 276.1. 1 H NMR (400 MHz,CDCl3) δ = 8.80 (br s,1H),8.70 (br d,J = 3.6 Hz,1H),8.11 - 8.05 (m,1H),7.94 - 7.86 (m,1H),7.44 (dd,J = 4.8,8.0 Hz,1H),5.49 - 5.39 (m,1H),4.42 - 4.29 (m,2H),3.30 - 3.20 (m,3H),1.42 - 1.36 (m,3H),1.36 - 1.31 (m,3H).

[0276] Synthesis of 5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid [INT1-sssss]: To a mixture of ethyl 5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-rrrrr] (2.2 g, 7.99 mmol) in THF (15 mL) and H2O (5 mL) was added lithium hydroxide monohydrate (1 g, 23.9 mmol). The reaction mixture was stirred at 50° C. for 12 h, after which it was concentrated, diluted with water (100 mL) and washed with EtOAc (200 mL×2). The aqueous phase was acidified to pH=3 with 1M aqueous HCl and extracted with EtOAc (200 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give 5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid [INT1-sssss] (1.30 g, 5.25 mmol, 65.9% yield) as a white solid. [M+H]+Calculated for C12H14N3O3 248.1; found 248.2. 1 H NMR (400 MHz,CDCl3) δ = 8.83 (d,J = 1.6 Hz,1H),8.76 (br d,J = 4.0 Hz,1H),8.20 (s,1H),7.94 (td,J = 1.6,8.0 Hz,1H),7.51 (dd,J = 4.8,8.0 Hz,1H),5.30 (q,J = 6.8 Hz,1H), 3.30 (s,3H),1.43 (d,J = 6.8 Hz,3H).

[0277] Synthesis of tert-butyl N-{5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazol-4-yl}carbamate [INT1-ttttt]: To a mixture of 5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid [INT1-sssss] (1.2 g, 4.85 mmol), 2-methylpropan-2-ol (5.38 g, 72.7 mmol) and diphenylphosphoryl azide (2.00 g, 7.27 mmol) in toluene (10 mL) was added triethylamine (1.46 g, 14.5 mmol). The reaction mixture was stirred at 100° C. under nitrogen for 2 h. The reaction mixture was diluted with EtOAc (100 mL×3) and washed with saturated NaHCO3 (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (0-40% EtOAc in petroleum ether) to give tert-butyl N-{5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazol-4-yl}carbamate [INT1-ttttt] (490 mg, 1.53 mmol, 31.8% yield) as a white solid. m / z: [M+H]+calculated for C16H23N4O3 319.2; found 319.1. 1 H NMR (400 MHz,CDCl3) δ = 8.76 - 8.65 (m,2H),8.21 (br s,1H),7.99 - 7.78 (m,1H),7.59 - 7.43 (m,1H),6.86 (br d,J = 12.8 Hz,1H),4.56 - 4.45 (m,1H),3.29 (d,J = 6.8 Hz,3H),1.55 (s,9H),1.52 - 1.48 (m,3H).

[0278] Synthesis of 5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazol-4-amine hydrochloride [INT1.29]: A mixture of tert-butyl N-{5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazol-4-yl}carbamate [INT1-ttttt] (490 mg, 1.53 mmol) in 4M HCl / dioxane (10 mL, 40.0 mmol) was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure to give 5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazol-4-amine hydrochloride [INT1.29] (389 mg, 1.52 mmol) as a yellow solid. m / z: calculated for [M+H]+C11H15N4O 219.1; found: 219.1.

[0279] Synthesis of 3-(4-amino-5-cyclopropyl-1H-pyrazol-1-yl)benzonitrile hydrochloride [Intermediate 1.30]: [ka] Synthesis of ethyl 1-(3-cyanophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate [INT1-uuuuu]: To a mixture of ethyl 3-cyclopropyl-3-oxopropanoate (2.0 g, 12.8 mmol) in 2,2,2-trifluoroethanol (15 mL) was added N,N-dimethylformamide dimethyl acetal (1.82 g, 15.3 mmol). The mixture was stirred at 20° C. for 30 min. 3-Hydrazinylbenzonitrile hydrochloride [INT1-rrr] (2.59 g, 15.3 mmol) was added and the mixture was stirred at 20° C. for 12 h. The mixture was concentrated to give the crude product. The residue was quenched with water (40 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 5) to give ethyl 1-(3-cyanophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate [INT1-uuuuu] (2.00 g, 7.10 mmol, 55.5% yield) as an orange solid. m / z: calculated for [M+H]+C16H16N3O2 282.1; found 282.0. 1 H NMR (400 MHz,CDCl3) δ = 8.04 (s,1H),7.90 (s,1H),7.85 (d,J = 8.0 Hz,1H),7.75 - 7.70 (m,1H),7.67 - 7.59 (m,1H),4.34 (q,J = 7.2 Hz,2H),1.66 (br s,1H),1.39 (t,J = 7.2 Hz,3H),1.05 - 0.98 (m,2H),0.59 (q,J = 5.6 Hz,2H).

[0280] Synthesis of 1-(3-cyanophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid [INT1-vvvvv]: To a solution of ethyl 1-(3-cyanophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate [INT1-uuuuu] (1.5 g, 5.33 mmol) in MeOH (6 mL) was added lithium hydroxide monohydrate (335 mg, 7.99 mmol) in H2O (2 mL). The reaction was stirred at 80 °C for 2 h. The reaction mixture was poured into 10 mL of water, acidified to pH = 3-4 with 1N HCl aqueous solution, and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (MeOH / DCM = 0 / 1 to 1 / 10) to give 1-(3-cyanophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid [INT1-vvvvv] (740 mg, 2.92 mmol, 55.2% yield) as an off-white solid. 1 H NMR (400 MHz,DMSO-d6) δ = 12.38 (s,1H),8.18 - 8.15 (m,1H),7.99 (s,1H),7.98 - 7.92 (m,2H),7.79 - 7.73 (m,1H),2.22 - 2.12 (m,1H),0.86 - 0.81 (m,2H),0.47 - 0.41 (m,2H).

[0281] Synthesis of tert-butyl N-[1-(3-cyanophenyl)-5-cyclopropyl-1H-pyrazol-4-yl]carbamate [INT1-wwwww]: A solution of 1-(3-cyanophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid [INT1-vvvvv] (640 mg, 2.52 mmol), triethylamine (382 mg, 3.78 mmol) and diphenylphosphoryl azide (1.38 g, 5.04 mmol) in t-BuOH (8 mL) was stirred at 100 °C under N for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 5) and preparative HPLC (column: YMC Triart30*150mm*7μm, table: 30-70%B (A=water (ammonia hydroxide v / v)-(ACN-THF 50 / 50), B=acetonitrile), flow rate: 50mL / min, UV detector 220nm) to give tert-butyl N-[1-(3-cyanophenyl)-5-cyclopropyl-1H-pyrazol-4-yl]carbamate [INT1-wwwww] (110mg, 339μmol, 13.4% yield) as a white solid. m / z: [M+H]+calculated for CHNO2 325.2; found 325.1. 1 H NMR (400 MHz,CDCl3) δ = 8.00 - 7.91 (m,2H),7.91 - 7.86 (m,1H),7.66 - 7.60 (m,1H),7.60 - 7.54 (m,1H),6.19 (s,1H),1.88 - 1.76 (m,1H),1.54 (s,9H),1.00 - 0.93 (m,2H),0.52 - 0.46 (m,2H).

[0282] Synthesis of 3-(4-amino-5-cyclopropyl-1H-pyrazol-1-yl)benzonitrile hydrochloride [INT1.30]: A solution of tert-butyl N-[1-(3-cyanophenyl)-5-cyclopropyl-1H-pyrazol-4-yl]carbamate [INT1-wwwww] (110 mg, 339 μmol) in HCl / dioxane (3 mL) was stirred at 20° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give 3-(4-amino-5-cyclopropyl-1H-pyrazol-1-yl)benzonitrile hydrochloride [INT1.30] (89.0 mg, 341 μmol) as an off-white solid. m / z: calculated for [M+H]+C13H13N4 225.1; found 225.0. 1 H NMR (400 MHz,DMSO-d6) δ = 10.22 (br s,2H),8.18 (s,1H),8.02 (br d,J = 8.0 Hz,1H),7.94 (br d,J = 7.6 Hz,1H),7.79 (s,1H),7.78 - 7.72 (m,1H),2.15 - 2.03 (m,1H),0.91 - 0.80 (m,2H),0.61 - 0.47 (m,2H).

[0283] Synthesis of 5-cyclopropyl-1-(pyridin-2-yl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.31]: [ka] Synthesis of ethyl (2Z)-2-[(Z)-cyclopropanecarbonyl]-3-(dimethylamino)prop-2-enoate [INT1-xxxxx]: A mixture of ethyl 3-cyclopropyl-3-oxopropanoate (20 g, 128 mmol) and N,N-dimethylformamide dimethyl acetal (30.5 g, 256 mmol) was stirred at 100° C. for 4 h. The mixture was concentrated under reduced pressure to give ethyl (2Z)-2-[(Z)-cyclopropanecarbonyl]-3-(dimethylamino)prop-2-enoate [INT1-xxxxx] (27.0 g, 127 mmol). m / z: [M+H]+calculated for C11H18NO3 212.1; found 212.1.

[0284] Synthesis of ethyl 5-cyclopropyl-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate [INT1-yyyyy]: A solution of ethyl (2Z)-2-[(Z)-cyclopropanecarbonyl]-3-(dimethylamino)prop-2-enoate [INT1-xxxxx] (5 g, 21.3 mmol), 2-hydrazinylpyridine hydrochloride [HCl salt of INT1-iii] (3.71 g, 25.5 mmol), and Et3N (4.30 g, 42.6 mmol) in EtOH (50 mL) was stirred for 16 h at 25° C. The reaction was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give ethyl 5-cyclopropyl-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate [INT1-yyyyy] (2.80 g, 10.8 mmol, 51.0% yield) as a yellow oil. m / z: calculated for [M+H]+C14H16N3O2 258.1; found 258.0. 1 H NMR (400 MHz,CDCl3) δ = 8.57 (dd,J = 1.0,4.8 Hz,1H),8.02 (s,1H),7.87 (dt,J = 1.8,7.8 Hz,1H),7.64 (d,J = 8.1 Hz,1H),7.41 - 7.30 (m,1H),4.32 (q,J = 7.1 Hz,2H),2.29 (tt,J = 5.6,8.6 Hz,1H),1.37 (t,J = 7.1 Hz,3H),1.02 - 0.85 (m,2H),0.68 - 0.50 (m,2H).

[0285] Synthesis of 5-cyclopropyl-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylic acid [INT1-zzzzz]: A solution of ethyl 5-cyclopropyl-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate [INT1-yyyyy] (2.5 g, 9.71 mmol) and lithium hydroxide monohydrate (1.01 g, 24.2 mmol) in THF (10 mL), HO (10 mL) and CHOH (10 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the resulting solution was acidified to pH=6 with 1M aqueous HCl. The resulting suspension was filtered and the cake was concentrated under reduced pressure to give 5-cyclopropyl-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylic acid [INT1-zzzz] (1.90 g, 8.28 mmol, 85.5% yield) as a white solid. m / z: calculated for [M+H]+C12H12N3O2 230.1; found 230.0. 1 H NMR (400 MHz,DMSO-d6) δ = 12.41 (br s,1H),8.67 - 8.52 (m,1H),8.06 (dt,J = 2.0,7.8 Hz,1H),7.96 (s,1H),7.69 (d,J = 8.1 Hz,1H),7.53 (ddd,J = 1.0,4.9,7.5 Hz,1H),2.25 (tt,J = 5.6,8.7 Hz,1H),0.86 - 0.78 (m,2H),0.60 - 0.53 (m,2H).

[0286] Synthesis of tert-butyl N-[5-cyclopropyl-1-(pyridin-2-yl)-1H-pyrazol-4-yl]carbamate [INT1-aaaaaa]: A solution of 5-cyclopropyl-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylic acid [INT1-zzzzz] (1.8 g, 7.85 mmol), DPPA (3.21 g, 11.7 mmol), and Et3N (2.37 g, 23.5 mmol) in toluene (20 mL) was stirred at 25° C. for 15 min. 2-Methylpropan-2-ol (581 mg, 7.84 mmol) was added and the reaction mixture was stirred at 100° C. for 1 h. The reaction was quenched by adding water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give tert-butyl N-[5-cyclopropyl-1-(pyridin-2-yl)-1H-pyrazol-4-yl]carbamate [INT1-aaaaaa] (800 mg, 2.66 mmol, 34.0% yield) as a colorless oil. m / z: [M+H]+calculated for C16H21N4O2 301.2; found 301.2. 1 H NMR (400 MHz,CDCl3) δ = 8.47 (dd,J = 1.0,4.8 Hz,1H),7.97 (br s,1H),7.84 - 7.76 (m,1H),7.75 - 7.66 (m,1H),7.21 (ddd,J = 1.0,4.9,7.2 Hz,1H),6.28 (br s,1H),2.14 (ddd,J = 2.7,5.5,8.2 Hz,1H),1.53 (s,9H),0.96 - 0.81 (m,2H),0.54 - 0.39 (m,2H).

[0287] Synthesis of 5-cyclopropyl-1-(pyridin-2-yl)-1H-pyrazol-4-amine hydrochloride [INT1.31]: A solution of tert-butyl N-[5-cyclopropyl-1-(pyridin-2-yl)-1H-pyrazol-4-yl]carbamate [INT1-aaaaaa] (700 mg, 2.33 mmol) in 4M HCl in dioxane (10 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure to give 5-cyclopropyl-1-(pyridin-2-yl)-1H-pyrazol-4-amine hydrochloride [INT1.31] (550 mg, 2.32 mmol, 99.8% yield) as a yellow solid. m / z: calculated for [M+H]+C11H13N4 201.1; found 201.1.

[0288] Synthesis of 5-cyclopropyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine hydrochloride [Intermediate 1.32]: [ka] Synthesis of ethyl 5-cyclopropyl-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-bbbbbb]: A solution of ethyl (2Z)-2-[(Z)-cyclopropanecarbonyl]-3-(dimethylamino)prop-2-enoate [INT1-xxxxx] (5 g, 23.6 mmol), 3-hydrazinylpyridine hydrochloride [INT1-aaa] (4.12 g, 28.3 mmol), and Et3N (4.76 g, 47.2 mmol) in EtOH (50 mL) was stirred for 16 h at 25° C. The reaction was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 1) to give ethyl 5-cyclopropyl-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-bbbbbb] (1.70 g, 6.60 mmol, 28.0% yield) as a yellow oil. m / z: calculated for [M+H]+C14H16N3O2 258.1; found 258.1. 1H NMR (400 MHz,CDCl3) δ = 8.85 (d,J = 2.2 Hz,1H),8.65 (dd,J = 1.2,4.7 Hz,1H),8.04 (s,1H),7.94 - 7.83 (m,1H),7.45 (dd,J = 4.8,8.2 Hz,1H),4.32 (q,J = 7.2 Hz,2H),2.01 - 1.88 (m,1H),1.37 (t,J = 7.2 Hz,3H),1.05 - 0.90 (m,2H),0.66 - 0.48 (m,2H).

[0289] Synthesis of 5-cyclopropyl-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid [INT1-cccccc]: To a mixture of ethyl 5-cyclopropyl-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylate [INT1-bbbbbb] (1.7 g, 6.60 mmol) in THF (6 mL) and H2O (2 mL) was added lithium hydroxide monohydrate (826 mg, 19.7 mmol). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was acidified to pH = 4 with 1 M aqueous HCl. The reaction mixture was quenched by adding H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-cyclopropyl-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid [INT1-cccccc] (1 g, 4.36 mmol, 66.2% yield) as a yellow solid. m / z: calculated for [M+H]+C12H12N3O2 230.1; found 230.1.

[0290] Synthesis of tert-butyl (5-cyclopropyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate [INT1-dddddd]: To a mixture of 5-cyclopropyl-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid [INT1-cccccc] (500 mg, 2.18 mmol) in toluene (3 mL) and t-BuOH (2 mL) was added diphenylphosphoryl azide (899 mg, 3.27 mmol) and triethylamine (661 mg, 6.54 mmol). The reaction mixture was stirred at 100 °C under nitrogen for 3 h. The reaction mixture was concentrated to give a residue which was purified by silica gel flash chromatography (0-50% EtOAc in petroleum ether) to give tert-butyl (5-cyclopropyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate [INT1-dddddd] (500 mg, 1.66 mmol, 76.4% yield) as a yellow oil. m / z: calculated for [M+H]+C16H21N4O2 301.2; found 301.2.

[0291] Synthesis of 5-cyclopropyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine hydrochloride [INT1.32]: A solution of tert-butyl N-[5-cyclopropyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl]carbamate [INT1-dddddd] (500 mg, 1.66 mmol) in 4M HCI / dioxane (5 mL) was stirred at 20° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give 5-cyclopropyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine hydrochloride [INT1.32] (250 mg, 1.24 mmol, 75.3% yield) as a yellow solid. m / z: calculated for [M+H]+C11H13N4 201.1; found 201.0.

[0292] Synthesis of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [Intermediate 2.1]: [ka] Synthesis of (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide [INT2-b]: To a solution of 4-bromobenzaldehyde [INT2-a] (100 g, 541 mmol, 1.0 eq) in toluene (500 mL) was added (R)-2-methylpropane-2-sulfinamide (72.1 g, 595 mmol, 1.1 eq) at 25° C. The mixture was stirred at 25° C. for 15 min. Then NaOH (21.6 g, 541 mmol, 1.0 eq) was added to the above reaction and the mixture was stirred at 25° C. for 12 h. Na2SO4 (50 g) was added to the mixture and stirred for 20 min. The four reaction mixtures were combined and filtered through Celite to obtain the filtrate, which was concentrated in vacuo to obtain the crude product as an oil. The crude product was dissolved in petroleum ether (1.0 L), stirred at -50°C for 1.0 h, and filtered to give (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide [INT2-b] (620 g, 2.15 mol, 99.5% yield) as a solid.

[0293] Synthesis of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT2.1]: To a solution of (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide [INT2-b] (206 g, 715 mmol, 1.0 eq) and tetrabutylammonium acetate (216 g, 715 mmol, 218 mL, 1.0 eq) in DMF (1.4 L) was added TMSCF3 (259 g, 1.82 mol, 2.5 eq) at 0 °C. The mixture was stirred at 5 °C for 1.5 h. This process was repeated twice and the three reaction mixtures were combined for workup. The mixture was poured into a saturated NH4Cl solution (13.0 L) and stirred for 10 min to give a suspension. The suspension was filtered and the cake was washed with water (5.0 L). The filter cake was triturated with MTBE / petroleum ether (v / v=1:4, 2.0 L) to give the product as a solid, and the mother liquor was concentrated in vacuo to give the crude product as an oil, which was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1 to 1 / 1) to give (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT2.1] (389 g, 1.09 mol, 50.6% yield) as a solid. 1 H NMR (400 MHz,CDCl3) δ = 1.25 (s,9H),3.64 (d,J = 6.40 Hz,1H),4.79-4.83 (m,1H),7.32 (d,J = 8.40 Hz,2H),7.56 (d,J = 6.40 Hz,2H).

[0294] Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine [Intermediate 3.1]: [ka] Synthesis of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT3-b]: To a solution of LiHMDS (1.0 M, 838 mL, 3.0 eq) was added (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT2.1] (100 g, 279 mmol, 1.0 eq) at 0-10 °C, and the resulting mixture was stirred at 0-10 °C for 0.5 h. To the above mixture was added MeI (119 g, 838 mmol, 52.1 mL, 3.0 eq) at 0-10 °C, and the reaction was stirred at 25 °C for 1 h. The process was repeated twice and the three combined reaction mixtures were poured into saturated aqueous NH4Cl (3.0 L) and diluted with EtOAc (1.0 L). The mixture was separated to obtain the organic layer and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with saturated NaCl (1.0 L), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product as an oil. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (15 / 1 to 1 / 1) to give (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT3-b] (161 g, 432.5 mmol, 51.6% yield) as an oil.

[0295] Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT3.1]: To a mixture of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT3-b] (202 g, 543 mmol, 1.0 eq) in EtOAc (600 mL) was slowly added HCl / EtOAc (4.0 M, 2.02 L, 14.9 eq). The mixture was stirred at 20° C. for 1 h. The reaction mixture was filtered to give a solid, which was eluted with EtOAc (200 mL) and the mother liquor was concentrated in vacuo to give a solid. The solid was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1 to 1 / 0), combined with the filter cake, and concentrated on an oil pump at 45 °C for 1 h to remove the solvent residues to give (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT3.1] (115 g, 378 mmol, 69.6% yield, 100% purity, HCl) as a solid. 1 H NMR (400 MHz,DMSO-d6) δ = 2.45 (s,3H),5.51 (s,1H),7.62 (d,J = 8.4 Hz,2H),7.78 (d,J = 8.40 Hz,2H),10.59 (s,2H).

[0296] SFC: Rt=0.776 min, 99.98%ee; Column: Chiralpak AD-3, 100 x 4.6 mm, ID, 3 μm; Mobile phase: A: CO2, B: MeOH (0.05% IPAm); Gradient: A: B = 97:3; Flow rate: 3 mL / min; Column temperature: 35 °C.

[0297] LCMS: Rt=1.755 min, purity 100.0%, m / z=268.0, 270.0 (M+1)+. The gradient was 5% B at 0.40 min and 5-95% B at 0.4-3.0 min, held at 95% B for 1.00 min, then 95-5% B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50*2.1 mm column (5 μm particles). The detection method was diode array (DAD) as well as positive electrospray ionization. The MS range was 100-1000.

[0298] Synthesis of tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide [intermediate 4.1]: [ka] To a solution of tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide [INT4-a] (41.0 g, 230 mmol, 1.0 eq) in DCM (410 mL) was added (COCl)2 (58.4 g, 460 mmol, 40.3 mL, 2.0 eq) and DMF (168 mg, 2.30 mmol, 177 μL, 0.01 eq) at 0 °C under N2. The mixture was warmed to 20 °C and stirred at 20 °C for 2 h. The reaction mixture was concentrated in vacuo to give the crude product tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide [INT4.1] (46.5 g, crude) as a solid.

[0299] Synthesis of 1-acetylpiperidine-4-carbonyl chloride [intermediate 4.2]: [ka] To a mixture of 1-acetylpiperidine-4-carboxylic acid [INT4-b] (1 g, 5.84 mmol) in dichloromethane (10 mL), oxalyl dichloride (2.20 g, 17.5 mmol) and DMF (42.6 mg, 584 μmol) were slowly added and the mixture was stirred for 2 h at 40° C. The mixture was concentrated under reduced pressure to give crude 1-acetylpiperidine-4-carbonyl chloride [INT4.2] (1.10 g, 5.80 mmol) as a green oil.

[0300] Synthesis of 1-acetylazetidine-3-carbonyl chloride (intermediate 4.3): [ka] To a solution of 1-acetylazetidine-3-carboxylic acid [INT4-c] (300 mg, 2.09 mmol) in DCM (4 mL) was added oxalyl chloride (397 mg, 3.13 mmol) at 0° C. The mixture was stirred at 20° C. for 1.5 h. The reaction was concentrated under reduced pressure to give 1-acetylazetidine-3-carbonyl chloride [INT4.3] (337 mg, 2.08 mmol).

[0301] Synthesis of methyl (1r,4r)-4-(chlorocarbonyl)cyclohexane-1-carboxylate (intermediate 4.4): [ka] To a mixture of (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid [INT4-d] (1.45 g, 7.78 mmol) in dichloromethane (10 mL), oxalyl dichloride (2.93 g, 23.3 mmol) and DMF (56.8 mg, 778 μmol) were slowly added and the mixture was stirred for 2 h at 40° C. The mixture was concentrated under reduced pressure to give crude methyl (1r,4r)-4-(chlorocarbonyl)cyclohexane-1-carboxylate [INT4.4] (1.59 g, 7.76 mmol) as a yellow gum.

[0302] Synthesis of methyl (1r,3r)-3-(carbonochloridoyl)cyclobutane-1-carboxylate (intermediate 4.5): [ka] To a mixture of (1r,3r)-3-(methoxycarbonyl)cyclobutane-1-carboxylic acid [INT4-e] (100 mg, 632 μmol) in CHCl (2 mL) was added DMF (1 drop) and oxalic dichloride (239 mg, 1.89 mmol) at 20° C. The mixture was stirred at 20° C. for 1 h. The reaction was concentrated under reduced pressure to give crude methyl (1r,3r)-3-(carbonochloridoyl)cyclobutane-1-carboxylate [INT4.5] (111 mg, 628 μmol) as a pale yellow oil.

[0303] Synthesis of benzyl 3-(chlorocarbonyl)cyclobutane-1-carboxylate (intermediate 4.6): [ka] Synthesis of 3-methylidenecyclobutane-1-carboxylic acid [INT4-g]: To a mixture of 3-methylidenecyclobutane-1-carbonitrile [INT4-f] (20 g, 214 mmol) in EtOH (100 mL) and water (100 mL) was added potassium hydroxide (48.0 g, 856 mmol). The mixture was stirred at 100° C. for 2 h. Ethanol was removed under reduced pressure, then the solution was cooled to below 10° C. and acidified to pH=1 with concentrated HCl. The mixture was extracted with EtOAc (300 mL×2) and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-methylidenecyclobutane-1-carboxylic acid [INT4-g] (23.0 g, 205 mmol, 96.2% yield) as a yellow oil. 1 H NMR (400 MHz,CDCl3) δ = 9.51 (br s,1H),4.82 (quintet,J = 2.4 Hz,2H),3.25 - 3.12 (m,1H),3.08 - 2.89 (m,4H).

[0304] Synthesis of benzyl 3-methylidenecyclobutane-1-carboxylate [INT4-h]: To a mixture of 3-methylidenecyclobutane-1-carboxylic acid [INT4-g] (13 g, 115 mmol) in DMF (120 mL) was added potassium carbonate (23.7 g, 172 mmol) and (bromomethyl)benzene (21.5 g, 126 mmol). The mixture was stirred at 25 °C for 12 h, after which it was combined with another of the same type. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (250 mL x 2). The combined organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE = 0 / 1 to 10 / 1) to give benzyl 3-methylidenecyclobutane-1-carboxylate [INT4-h] (33.0 g, 163 mmol) as a pale yellow oil. 1 H NMR (400 MHz,CDCl3) δ = 7.43 - 7.31 (m,5H),5.16 (s,2H),4.83 (quintet,J = 2.4 Hz,2H),3.26 - 3.13 (m,1H),3.10 - 2.86 (m,4H).

[0305] Synthesis of benzyl 3-(hydroxymethyl)cyclobutane-1-carboxylate [INT4-i]: To a mixture of benzyl 3-methylidenecyclobutane-1-carboxylate [INT4-h] (20 g, 98.8 mmol) in THF (200 mL) was added borane dimethyl sulfide (29.5 mL, 296 mmol) dropwise under ice-salt bath. The mixture was stirred at 25° C. for 1 h. Sodium hydroxide (20 mL, 60.0 mmol) and hydrogen peroxide (18 mL, 98.8 mmol) were then added under ice-salt bath. The mixture was stirred at 25° C. for another 2 h. The reaction was quenched with saturated sodium sulfite solution (100 mL), diluted with water (50 mL) and extracted with ethyl acetate (2×200 mL). The organic phase was washed with saturated brine (2×100 mL), dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc=1:0 to 1 / 3) to give benzyl 3-(hydroxymethyl)cyclobutane-1-carboxylate [INT4-i] (6.50 g, 29.5 mmol, 29.9% yield) as a pale yellow oil. 1 H NMR (400 MHz,CDCl3) δ = 7.41 - 7.30 (m,5H),5.14 (d,J = 9.2 Hz,2H),3.67 (d,J = 6.4 Hz,1H),3.60 (d,J = 6.0 Hz,1H),3.22 - 3.05 (m,1H),2.64 - 2.28 (m,3H),2.14 - 2.01 (m,2H).

[0306] Synthesis of 3-[(benzyloxy)carbonyl]cyclobutane-1-carboxylic acid [INT4-j]]: To a mixture of benzyl 3-(hydroxymethyl)cyclobutane-1-carboxylate [INT4-i] (4.5 g, 20.4 mmol) in CH3CN (30 mL), water (30 mL) and CHCl2 (30 mL), sodium periodate (13.0 g, 61.1 mmol) and ruthenium(III) chloride (421 mg, 2.03 mmol) were added at 0°C. The temperature of the mixture was raised to 25°C and reacted for 12 h. The reaction was poured into 1N HCl (100 mL). The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give 3-[(benzyloxy)carbonyl]cyclobutane-1-carboxylic acid [INT4-j] (3.36 g, 14.3 mmol, 70.4% yield) as a brown oil. m / z: [M+H]+calculated for C13H15O4 235.1; found 235.1. 1 H NMR (400 MHz,CDCl3) δ = 7.44 - 7.30 (m,5H),5.15 (d,J = 8.0 Hz,2H),3.37 - 3.04 (m,2H),2.69 - 2.44 (m,4H).

[0307] Synthesis of benzyl 3-(chlorocarbonyl)cyclobutane-1-carboxylate [INT4.6]: To a mixture of 3-[(benzyloxy)carbonyl]cyclobutane-1-carboxylic acid [INT4-j] (3.36 g, 14.3 mmol) in CHCl (80 mL) was added DMF (1 drop) and oxalyl chloride (3.62 g, 28.6 mmol) at 25° C. The mixture was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure to give crude benzyl 3-(chlorocarbonyl)cyclobutane-1-carboxylate [INT4.6] (3.61 g, 14.2 mmol) as a black oil.

[0308] Synthesis of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [Intermediate 5.1]: [ka] To a solution of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT3.1] (39.0 g, 128 mmol, 1.0 eq, HCl) and TEA (45.7 g, 451 mmol, 62.8 mL, 3.5 eq) in DCM (200 mL) was added tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide [INT4.1] (45.3 g, 231 mmol, 1.8 eq) at 0-10 °C. The mixture was stirred at 20 °C for 12 h. The mixture was separated to obtain the organic layer and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were concentrated in vacuo to obtain the crude product as an oil. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (15 / 1 to 3 / 1) to give (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT5.1] (26.0 g, 60.7 mmol, 47.4% yield, 100% purity) as a solid. 1 H NMR (400 MHz,CDCl3) δ = 2.25-2.37 (m,1H),2.38-2.40 (m,3H),2.88-3.00 (m,6H),3.30-3.31 (m,1H),3.22-3.45 (m,1H),6.56-6.63 (m,1H),7.23 (d,J = 8.00 Hz,2H),7.55 (d,J = 8.40 Hz,2H).

[0309] SFC: Rt=1.21 min, 100.0%ee; Column: Chiralpak AD-3, 50 × 4.6 mm I.D., 3 μm; Mobile phase: A: CO2, B: MeOH (0.05% IPAm, v / v); Flow rate: 3.4 mL / min; Column temperature: 35 °C.

[0310] LCMS: Rt=2.431 min, purity 100%, m / z=428.0, 430.0 (M+1)+. The gradient was 5% B at 0.40 min and 5-95% B at 0.4-3.0 min, held at 95% B for 1.00 min, then 95-5% B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50*2.1 mm column (5 μm particles). The detection method was diode array (DAD) as well as positive electrospray ionization. The MS range was 100-1000.

[0311] Synthesis of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide [Intermediate 5.2]: [ka] To a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (500 mg, 1.64 mmol) and Et3N (829 mg, 8.20 mmol) in dichloromethane (10 mL), 1-acetylpiperidine-4-carbonyl chloride [INT4.2] (550 mg, 2.90 mmol) was added, and the mixture was stirred for 3 hours at 25° C. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (methanol / dichloromethane=0 / 1 to 1 / 20) to give 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide [INT5.2] (680 mg, 1.61 mmol, 98.5% yield) as a yellow solid. m / z: calculated for [M+H]+C17H21BrF3N2O2 421.1, 423.1; found 423.1. 1H NMR (400 MHz,CDCl3) δ = 7.55 (d,J = 8.4 Hz,2H),7.24 (d,J = 8.4 Hz,2H),6.62 (q,J = 8.8 Hz,1H),4.05 - 3.82 (m,1H),3.23 - 3.04 (m,1H),2.90 (s,3H),2.87 - 2.71 (m,2H),2.70 - 2.43 (m,1H),2.13 (s,3H),1.92 - 1.63 (m,4H).

[0312] Synthesis of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylazetidine-3-carboxamide (Intermediate 5.3): [ka] To a solution of 1-acetylazetidine-3-carbonyl chloride [INT4.3] (300 mg, 1.85 mmol) and [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (563 mg, 1.85 mmol) in CHCl (3 mL) was added triethylamine (561 mg, 5.55 mmol). The mixture was stirred at 20° C. for 4 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 5) to give 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylazetidine-3-carboxamide [INT5.3] (250 mg, 635 μmol, 34.3% yield) as a yellow oil. m / z: calculated for [M+H]+C15H17BrF3N2O2 393.0, 395.0; found 394.8.

[0313] Synthesis of methyl (1S,4r)-4-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate (Intermediate 5.4): [ka] To a mixture of methyl (1r,4r)-4-(carbonochloridoyl)cyclohexane-1-carboxylate [INT4.4] (1.59 g, 7.76 mmol) and Et3N (2.65 g, 26.2 mmol) in dichloromethane (6 mL) was added a solution of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (1.6 g, 5.25 mmol) in dichloromethane (6 mL) and the mixture was stirred for 16 h at 25° C. Water (30 mL) was added and the mixture was extracted with dichloromethane (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether=1 / 10 to 1 / 5) to give methyl (1S,4r)-4-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [INT5.4] (1.10 g, 2.52 mmol, 32.5% yield) as a yellow oil. m / z: [M+H]+calculated for C18H22BrF3NO3 436.1, 438.1; found 438.0.

[0314] Synthesis of methyl (1S,3r)-3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate (Intermediate 5.5): [ka] To a mixture of methyl (1r,3r)-3-(carbonochloridoyl)cyclobutane-1-carboxylate [INT4.5] (111 mg, 628 μmol) and [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (120 mg, 394 μmol) in CHCl (2 mL) was added N,N-diisopropylethylamine (254 mg, 1.97 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and then at 20° C. for 12 h. The reaction was diluted with CHCl (50 mL) and 1N HCl (20 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give methyl (1S,3r)-3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate [INT5.5] (84.8 mg, 207 μmol, 53.0% yield (53% purity)) as a yellow oil. m / z: [M+H]+calculated for C16H18BrF3NO3 408.0; found 408.0.

[0315] Synthesis of benzyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclobutane-1-carboxylate (Intermediate 5.6): [ka] To a mixture of benzyl 3-(carbonochloridoyl)cyclobutane-1-carboxylate [INT4.6] (3.61 g, 14.2 mmol) and [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (2.5 g, 8.20 mmol) in CHCl (100 mL) was added N,N-diisopropylethylamine (5.28 g, 40.9 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and at 20° C. for 12 h. The reaction was diluted with CHCl (100 mL) and 1N HCl (50 mL). The organic phase was separated, washed with brine (50 mL), dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3). The obtained product was further purified by Prep-HPLC (Column: YMC-Triart Prep C18 150*40mm*7μm, Table: 48-68%B (A=water (0.025% FA), B=acetonitrile), Flow rate: 60mL / min, UV detector 220nm) to give benzyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclobutane-1-carboxylate [INT5.6] (760mg, 1.56mmol, Yield 19.1%) as a yellow oil. m / z: Calculated for [M+H]+C22H22BrF3NO3 484.1; Found 484.0. 1 H NMR (400 MHz,CDCl3) δ = 7.60 - 7.51 (m,2H),7.41 - 7.31 (m,5H),7.29 - 7.19 (m,2H),6.66 - 6.34 (m,1H),5.18 - 5.11 (m,2H),3.57 - 3.07 (m,2H),2.77 - 2.73 (m,3H),2.70 - 2.43 (m,4H).

[0316] Synthesis of (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-cyano-N-methylcyclohexane-1-carboxamide (Intermediate 5.7): [ka] A mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (350 mg, 1.14 mmol) and triethylamine (576 mg, 5.70 mmol) in CHCl (5 mL) was stirred for 20 min at 25° C. A solution of (1r,4r)-4-cyanocyclohexane-1-carbonyl chloride [INT4.7] (391 mg, 2.28 mmol) in CHCl (5 mL) was added and the reaction was stirred at 25° C. for 3 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (0-30% EtOAc in petroleum ether) to give (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-cyano-N-methylcyclohexane-1-carboxamide [INT5.7] (300 mg, 743 μmol, 65.3% yield) as a white solid. 1 H NMR (400 MHz,CDCl3) δ = 7.57 - 7.51 (m,2H),7.23 (d,J = 8.4 Hz,2H),6.60 (q,J = 8.8 Hz,1H),2.87 (s,3H),2.68 - 2.59 (m,1H),2.58 - 2.48 (m,1H),2.32 - 2.19 (m,2H),2.01 - 1.93 (m,1H),1.92 - 1.84 (m,1H),1.72 - 1.62 (m,4H).

[0317] Synthesis of methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclohexane-1-carboxylate [Intermediate 6.1]: [ka] A mixture of 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.6] (140 mg, 531 μmol), methyl (1r,4r)-4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT5.4] (231 mg, 531 μmol), Xantphos (30.7 mg, 53.1 μmol), Pd2(dba)3 (48.6 mg, 53.1 μmol) and Cs2CO3 (518 mg, 1.59 mmol) in dioxane (3 mL) was heated at 100° C. for 1 h under N2 atmosphere. o C for 3 h. Brine (50 mL) was added and the mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (0-8% EtOAc in petroleum ether) to give methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclohexane-1-carboxylate [INT6.1] (152 mg, 260 μmol, 49.1% yield) as a brown solid. m / z: [M+H]+calculated for C28H29F6N4O3 583.2; found 583.2.

[0318] Synthesis of methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclohexane-1-carboxylate [Intermediate 6.2]: [ka] A mixture of 1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.14] (80 mg, 350 μmol), methyl (1r,4r)-4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT5.4] (152 mg, 350 μmol), Pd2(dba)3 (32.0 mg, 35.0 μmol), Xantphos (40.5 mg, 70.0 μmol) and Cs2CO3 (228 mg, 700 μmol) in dioxane (3 mL) was stirred at 100° C. for 12 h under N2. The mixture was worked up in another reaction of the same type. The reaction was quenched by adding water (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc=1 / 0 to 1 / 1) to give methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclohexane-1-carboxylate [INT6.2] (115 mg, 197 μmol) as a pale yellow oil. m / z: [M+H]+calculated for C27H28F6N5O3 584.2; found 584.1.

[0319] Synthesis of methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclohexane-1-carboxylate [Intermediate 6.3]: [ka] A suspension of 1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.13] (150 mg, 566 μmol), methyl (1r,4r)-4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT5.4] (246 mg, 566 μmol), Cs2CO3 (550 mg, 1.69 mmol), Pd2(dba)3 (25.9 mg, 28.3 μmol) and Xantphos (32.7 mg, 56.6 μmol) in dioxane (2 mL) was stirred at 100 °C under N2 for 1.5 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (MeOH / dichloromethane=0 / 1 to 1 / 99) to give methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclohexane-1-carboxylate [INT6.3] (231 mg, 396 μmol, 70.0% yield) as a yellow oil. m / z: [M+H]+calculated for C27H28F6N5O3 584.2; found 584.1. 1 H NMR (400 MHz,CDCl3) δ = 8.80 (d,J = 2.8 Hz,1H),8.74 (dd,J = 1.2,4.8 Hz,1H),7.91 - 7.81 (m,2H),7.49 (dd,J = 4.8,8.0 Hz,1H),7.30 (s,1H),6.97 (d,J = 8.8 Hz,2H),6.61 (q,J = 8.8 Hz,1H),5.59 (s,1H),3.71 (s,3H),2.91 (s,3H),2.63 - 2.51 (m,1H),2.39 (tt,J = 3.6,12.0 Hz,1H),2.11 (br t,J = 8.8 Hz,2H),1.96 - 1.83 (m,2H),1.70 - 1.61 (m,2H),1.56 - 1.45 (m,2H).

[0320] Synthesis of methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclohexane-1-carboxylate [Intermediate 6.4]: [ka] To a solution of 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine [INT1.15] (100 mg, 438 μmol), methyl (1r,4r)-4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT5.4] (191 mg, 438 μmol), CsCO (426 mg, 1.31 mmol) and Xantphos (50.6 mg, 87.6 μmol) in dioxane (3 mL) was added Pd(dba) (40.1 mg, 43.8 μmol) and the reaction mixture was stirred at 100 °C under N for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclohexane-1-carboxylate [INT6.4] (170 mg, 291 μmol, 66.6% yield) as a yellow oil. m / z: [M+H]+calculated for C27H28F6N5O3 584.2; found 584.1.

[0321] Synthesis of methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-[4-({5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazol-4-yl}amino)phenyl]ethyl]carbamoyl}cyclohexane-1-carboxylate [Intermediate 6.5]: [ka] A mixture of 5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazol-4-amine [free base of INT1.27] (75 mg, 343 μmol), methyl (1r,4r)-4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT5.4] (149 mg, 343 μmol), Pd2(dba)3 (31.3 mg, 34.3 μmol), Xantphos (39.6 mg, 68.6 μmol) and Cs2CO3 (223 mg, 686 μmol) in dioxane (3 mL) was stirred at 100° C. for 3 h under N2. The reaction was quenched by adding water (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc=1 / 0 to 5 / 1) to give methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-[4-({5-[(1S)-1-methoxyethyl]-1-(pyridin-2-yl)-1H-pyrazol-4-yl}amino)phenyl]ethyl]carbamoyl}cyclohexane-1-carboxylate [INT6.5] (85.0 mg, 148 μmol, 43.3% yield) as a pale yellow oil. 1 H NMR (400 MHz,DMSO) δ = 8.50 (d,J = 4.0 Hz,1H),8.05 - 7.97 (m,1H),7.84 - 7.77 (m,1H),7.45 - 7.36 (m,1H),7.20 (s,1H),7.10 (d,J = 8.0 Hz,2H),6.86 (d,J = 8.0 Hz,2H),6.41 (q,J = 8.0 Hz,1H),5.29 (q,J = 8.0 Hz,1H),3.58 (s,3H),3.06 (s,3H),2.87 (s,3H),2.73 - 2.65 (m,1H),1.96 - 1.64 (m,5H),1.52 (d,J = 6.0 Hz,3H),1.48 - 1.37 (m,4H).

[0322] Synthesis of methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-[4-({5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazol-4-yl}amino)phenyl]ethyl]carbamoyl}cyclohexane-1-carboxylate [Intermediate 6.6]: [ka] A mixture of 5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazol-4-amine [free base of INT1.26] (100 mg, 460 μmol), methyl (1r,4r)-4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT5.4] (200 mg, 460 μmol), Xantphos (26.6 mg, 46.0 μmol), Pd2(dba)3 (42.1 mg, 46.0 μmol) and Cs2CO3 (449 mg, 1.38 mmol) in dioxane (1 mL) was stirred at 100° C. for 3 h under N2 atmosphere. Brine (20 mL) was added and the mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (0-20% EtOAc in petroleum ether) to give methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-[4-({5-[(1S)-1-methoxyethyl]-1-phenyl-1H-pyrazol-4-yl}amino)phenyl]ethyl]carbamoyl}cyclohexane-1-carboxylate [INT6.6] (230 mg, 401 μmol, 87.4% yield) as a white solid. m / z: [M+H]+calculated for C30H36F3N4O4 573.3; found 573.3.

[0323] Synthesis of methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-[4-({5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazol-4-yl}amino)phenyl]ethyl]carbamoyl}cyclohexane-1-carboxylate [Intermediate 6.7]: [ka] A mixture of 5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazol-4-amine [INT1.28] (100 mg, 458 μmol), methyl (1r,4r)-4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT5.4] (199 mg, 458 μmol), Pd2(dba)3 (41.9 mg, 45.8 μmol), Xantphos (53.0 mg, 91.6 μmol) and Cs2CO3 (298 mg, 916 μmol) in dioxane (3 mL) was stirred at 100° C. for 3 h under N2. The reaction was quenched by adding water (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc=1 / 0 to 1 / 1) to give methyl (1r,4r)-4-{methyl[(1S)-2,2,2-trifluoro-1-[4-({5-[(1S)-1-methoxyethyl]-1-(pyridin-4-yl)-1H-pyrazol-4-yl}amino)phenyl]ethyl]carbamoyl}cyclohexane-1-carboxylate [INT6.7] (230 mg, 400 μmol, 87.7% yield) as a pale yellow oil. m / z: [M+H]+calculated for C29H35F3N5O4 574.3; found 574.3. 1H NMR (400 MHz,DMSO) δ = 8.71 (d,J = 8.0 Hz,2H),7.85 (s,1H),7.78 - 7.73 (m,2H),7.55 (s,1H),7.11 (d,J = 8.0 Hz,2H),6.78 (d,J = 8.0 Hz,2H),6.41 (q,J = 8.0 Hz,1H),4.65 (q,J = 8.0 Hz,1H),3.59 (s,3H),3.17 (s,3H),2.86 (s,2.5H),2.74 - 2.67 (m,1H),2.62 (s,0.5H),2.33 - 2.29 (m,1H),1.96 - 1.87 (m,2H),1.83 - 1.69 (m,2H),1.47 - 1.36 (m,4H),1.33 (d,J = 4.0 Hz,3H).

[0324] Synthesis of methyl (1S,4r)-4-(methyl((S)-2,2,2-trifluoro-1-(4-((5-((S)-1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amino)phenyl)ethyl)carbamoyl)cyclohexane-1-carboxylate [Intermediate 6.8]: [ka] A mixture of 5-[(1S)-1-methoxyethyl]-1-(pyridin-3-yl)-1H-pyrazol-4-amine [the free base of INT1.29] (20 mg, 91.6 μmol), methyl (1r,4r)-4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT5.4] (39.9 mg, 91.6 μmol), Xantphos (5.30 mg, 9.16 μmol), Pd2(dba)3 (8.38 mg, 9.16 μmol) and Cs2CO3 (89.2 mg, 274 μmol) in dioxane (1 mL) was stirred at 100 °C under N2 atmosphere for 3 h. The mixture was concentrated under reduced pressure to give methyl (1S,4r)-4-(methyl((S)-2,2,2-trifluoro-1-(4-((5-((S)-1-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amino)phenyl)ethyl)carbamoyl)cyclohexane-1-carboxylate [INT6.8] (50.0 mg, 87.1 μmol, 95.2% yield). m / z: [M+H]+calculated for C29H35F3N5O4 574.3; found 574.2.

[0325] Synthesis of methyl (1S,4r)-4-(methyl((S)-2,2,2-trifluoro-1-(4-((1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)phenyl)ethyl)carbamoyl)cyclohexane-1-carboxylate [Intermediate 6.9]: [ka] A suspension of 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.21] (500 mg, 1.88 mmol), methyl (1r,4r)-4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT5.4] (820 mg, 1.88 mmol), Cs2CO3 (1.83 g, 5.64 mmol), Pd2(dba)3 (86.0 mg, 94.0 μmol) and Xantphos (108 mg, 188 μmol) in dioxane (10 mL) was stirred at 100 °C under N2 for 2 h. The reaction mixture was concentrated to give methyl (1S,4r)-4-(methyl((S)-2,2,2-trifluoro-1-(4-((1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)phenyl)ethyl)carbamoyl)cyclohexane-1-carboxylate [INT 6.9]. m / z: [M+H]+calculated for C26H27F6N6O3 585.2; found 585.1.

[0326] Synthesis of methyl (1r,4r)-4-{[(1S)-1-(4-{[1-(3-cyanophenyl)-5-[(1S)-1-methoxyethyl]-1H-pyrazol-4-yl]amino}phenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [Intermediate 6.10]: [ka] To a mixture of 3-{4-amino-5-[(1S)-1-methoxyethyl]-1H-pyrazol-1-yl}benzonitrile [INT1.25] (160 mg, 660 μmol) in dioxane (5 mL) was added methyl (1r,4r)-4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT5.4] (316 mg, 726 μmol), Xantphos (114 mg, 198 μmol), Cs2CO3 (645 mg, 1.98 mmol) and Pd2(dba)3 (60.4 mg, 66.0 μmol). The reaction was stirred at 100 °C under N2 for 2 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 1) to give methyl (1r,4r)-4-{[(1S)-1-(4-{[1-(3-cyanophenyl)-5-[(1S)-1-methoxyethyl]-1H-pyrazol-4-yl]amino}phenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT6.10] (250 mg, 418 μmol, 63.4% yield) as a yellow solid. m / z: [M+H]+calculated for C31H35F3N5O4 598.3; found 598.1.

[0327] Synthesis of (1r,4r)-4-cyano-N-methyl-N-[(1S)-2,2,2-trifluoro-1-(4-{[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]cyclohexane-1-carboxamide [Intermediate 6.11]: [ka] To a mixture of 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-amine [free base of INT1.6] (100 mg, 440 μmol) in dioxane (5 mL) was added (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-cyano-N-methylcyclohexane-1-carboxamide [INT5.6] (195 mg, 484 μmol), Xantphos (76.3 mg, 132 μmol), Cs2CO3 (430 mg, 1.32 mmol) and Pd2(dba)3 (40.2 mg, 44.0 μmol). The reaction was stirred at 100 °C under N2 for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE=0 / 1 to 1 / 3) to give (1r,4r)-4-cyano-N-methyl-N-[(1S)-2,2,2-trifluoro-1-(4-{[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]cyclohexane-1-carboxamide [INT6.11] (100 mg, 181 μmol, 41.4% yield) as a yellow solid. m / z: calculated for [M+H]+C27H26F6N5O 550.2; found 550.4.

[0328] Synthesis of benzyl 3-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclobutane-1-carboxylate [Intermediate 6.12]: [ka] A mixture of benzyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclobutane-1-carboxylate [INT5.6] (300 mg, 619 μmol), 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [HCl salt of INT1.15] (163 mg, 619 μmol), Pd2(dba)3 (56.6 mg, 61.9 μmol), Xantphos (71.1 mg, 123 μmol) and Cs2CO3 (602 mg, 1.85 mmol) in dioxane (10 mL) was stirred at 100° C. for 2 h under N2 atmosphere. The reaction was quenched by adding water (40 mL) and extracted with EtOAc (2×80 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous NaSO and concentrated under reduced pressure to give benzyl 3-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclobutane-1-carboxylate [INT6.12] (390 mg, 617 μmol) as a black oil. m / z: [M+H]+calculated for C31H28F6N5O3 632.2; found 632.3.

[0329] Synthesis of benzyl 3-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclobutane-1-carboxylate [Intermediate 6.13]: [ka] A mixture of benzyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclobutane-1-carboxylate [INT5.6] (650 mg, 805 μmol), 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride [INT1.6] (150 mg, 568 μmol), Pd2(dba)3 (52.0 mg, 56.8 μmol), Xantphos (65.3 mg, 113 μmol) and Cs2CO3 (553 mg, 1.70 mmol) in dioxane (10 mL) was stirred at 100° C. for 2 h under N2 atmosphere. The reaction was quenched by adding water (50 mL) and extracted with EtOAc (2×80 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give benzyl 3-{methyl[(1S)-2,2,2-trifluoro-1-(4-{[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}phenyl)ethyl]carbamoyl}cyclobutane-1-carboxylate [INT6.13] (330 mg, 523 μmol, 92.1% yield) as a brown oil. m / z: [M+H]+calculated for C32H29F6N4O3 631.2; found 631.2.

[0330] Exemplary Compounds of Formula (I) The following compounds in Table 2 were synthesized according to Schemes 1-3 above using the intermediates identified. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

[0331] Example 2. MALT1 biochemical assay The potency of the inhibitors was evaluated by measuring the enzymatic activity of full-length MALT1 at different concentrations of compounds. The enzymatic assay consists of a single substrate reaction, monitoring the release of a fluorescent dye upon cleavage of the peptide substrate. The peptide substrate has the following sequence: Ac-Leu-Arg-Ser-Arg-Rh110-dPro (custom synthesized from WuXi AppTec, Shanghai, China). The assay buffer consisted of 50 mM Hepes, pH 7.5, 0.8 M sodium citrate, 1 mM DTT, 0.004% tween-20, and 0.005% bovine serum albumin (BSA). Steady-state kinetic analysis of peptide substrate binding revealed a Michaelis-Menten constant (K) of 150 μM.M ) was obtained. Assays were performed in 384-well F-bottom polypropylene black microplates (Greiner Bio_One, Cat. No. 781209) with 15 nM enzyme and 30 μM peptide substrate. Reactions were quenched after 60 min by the addition of iodoacetic acid to a final concentration of 10 mM. Total fluorescence was measured using an Envision (PerkinElmer) with fluorescence excitation at 485 nm and emission at 520 nm.

[0332] For potency determination, 1 μL of serially diluted compound (in 100% DMSO) was pre-incubated with 40 μL of enzyme for 30 min. The reaction was initiated by adding 10 μL of peptide substrate. Relative fluorescence units were converted to percent inhibition by using 0% and 100% inhibition controls as references. The 100% inhibition control was (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)urea (IC) at a final concentration of 1 μM. 50 = 15 nM), while the 0% inhibition control consisted of 2% DMSO. 50 Values ​​were calculated by fitting concentration-response curves to a 4-parameter logistic equation in GraphPad Prism.

[0333] The results from this assay are summarized in Table 3 below, where "A" denotes an IC less than 0.1 μM. 50 "B" indicates IC from 0.1 μM to 1 μM 50 "C" indicates IC > 1 μM 50 "N / A" indicates not tested. For compounds tested more than once, the results shown represent the average. [Table 3-1] [Table 3-2]

[0334] Example 3. Jurkat IL-2 Assay Inhibition in cell-based assays using immortalized T cell line Jurkat (ATCC, clone E6.1) was exposed to compound dose response and assessed for viability and determined, and IL-2 inhibition was assessed by ELISA. Cells were cultured in RPMI / 10%FBS (Invitrogen 11875093, Atlanta Biologicals S12450H), maintained at less than 3E6 / mL, and used in assays only for less than 25 passages. Compounds were stamped onto 384w plates (PerkinElmer Culturplate, 6007680) by ECHO. Cells were plated on top of compounds in fresh medium and incubated for 30 minutes before stimulation with soluble anti-CD3 / 28 / 2 (Stemcell, 10970) for 24 hours. Supernatants were collected and assessed for IL-2 (MSD, 384w, L21SA-1). To assess the viability of cells treated with compounds, cells were lysed with CTG reagent (Promega, G7570) and measured in a luminometer. IL-2 curves were calculated as a percentage of DMSO (100%) and signal inhibition (0%, (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)urea) controls. IC 50 was calculated using a four parameter fit in GraphPad Prism.

[0335] The results from this assay are summarized in Table 4 below, where "A" denotes an IC less than 0.1 μM. 50 "B" indicates IC from 0.1 μM to 1 μM 50 "C" indicates IC > 1 μM 50 "N / A" indicates not tested. For compounds tested more than once, the results shown represent the average. [Table 4-1] [Table 4-2]

[0336] Equivalence and Scope In the claims, articles such as "a," "an," and "the" can mean one or more than one, unless indicated to the contrary or clear from the context. A claim or description containing "or" between one or more members of a group is considered to be satisfied if one, more than one, or all of the group members are present in, employed in, or associated with a given product or process, unless indicated to the contrary or clear from the context. The invention includes embodiments in which exactly one member of a group is present in, employed in, or associated with a given product or process. The invention includes embodiments in which more than one or all of the group members are present in, employed in, or associated with a given product or process.

[0337] Moreover, the present invention encompasses all variations, combinations, and arrangements in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations permitted in any other claim that is dependent on the same base claim. Where elements are presented as enumerations, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element may be deleted from the group. In general, where the invention or aspects of the invention are deemed to include certain elements and / or features, it should be understood that certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For simplicity, those embodiments are not specifically set forth herein in their original form. It should also be noted that the terms "comprising" and "containing" are intended to be open, allowing for the inclusion of additional elements or steps. Where ranges are given, both ends are included. Furthermore, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​given as ranges may assume any specific value or subrange within the ranges defined in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0338] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any inconsistency between the incorporated references and this specification, this specification shall prevail. Furthermore, any particular embodiment of the present invention that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein, since they are deemed known to those skilled in the art. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether related to the existence of prior art or not.

[0339] Those skilled in the art will recognize or be able to ascertain, without more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. Compounds represented by formula (I) 【Chemistry 1】 or a stereoisomer and / or a pharma- ceutically acceptable salt thereof, wherein: R １ is C １～６ Alkyl, C １～３ Haloalkyl, C ３～６ cycloalkyl, and aryl; R １ is R １ａ may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R ２ is C １～６ Alkyl, C ３～６ is selected from the group consisting of cycloalkyl, aryl, and 5- to 10-membered heteroaryl; R ２ is R ２ａ may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R ３ is hydrogen or C １～３ is alkyl; R １ａ is independently at each occurrence hydroxyl or -O-C １～３ is alkyl; R ２ａ is independently, at each occurrence, hydroxyl, cyano, C １～６ Alkyl, and —O—C １～３ selected from the group consisting of alkyl; Z is -C(H)(R Ａ ) -, -SO ２ - or -NR Ａ - and R Ａ is -C(O)C １～６ alkyl, —C(O)OH, or 5-6 membered heteroaryl; m is 0 or 1; (n is 0 or 1).

2. R １ But, C １～６ Alkyl, C １～３ Haloalkyl, C ３～６ cycloalkyl, and aryl, １～６ The alkyl is hydroxyl or -O-C １～３ 2. The compound of claim 1, optionally substituted with alkyl.

3. R １ But, C １～６ Alkyl, C １～３ Haloalkyl, C ３～６ cycloalkyl, and aryl, １～６ The alkyl is hydroxyl or -O-CH ３ 3. The compound of claim 1 or 2, optionally substituted with

4. R １ is -CH(CH ３ ) ２ , C.F. ３ , cyclopropyl, phenyl, 【Chemistry 2】 4. The compound according to any one of claims 1 to 3, selected from the group consisting of:

5. R ２ But, C １～６ Alkyl, C ３～６ is selected from the group consisting of cycloalkyl, aryl, and 5- to 10-membered heteroaryl; １～６ The alkyl and the aryl are each independently selected from hydroxyl, cyano, C １～６ Alkyl, or -O-C １～３ 5. The compound of claim 1, optionally substituted with alkyl.

6. R ２ But, C １～６ Alkyl, C ３～６ is selected from the group consisting of cycloalkyl, aryl, and 5- to 10-membered heteroaryl; １～６ The alkyl and the aryl are each independently selected from hydroxyl, cyano, CH ３ or —O—CH ３ 6. The compound according to claim 1 , optionally substituted with

7. R ２ But, CH ３ , cyclopropyl, -C(H)(CH ３ ) ２ , -CH ２ C (CH ３ ) ３ , phenyl, 【Chemistry 3】 7. The compound according to any one of claims 1 to 6, selected from the group consisting of:

8. R ２ But, CH ３ , cyclopropyl, -C(H)(CH ３ ) ２ , -CH ２ C (CH ３ ) ３ , phenyl, 【Chemistry 4】 8. The compound according to any one of claims 1 to 7, selected from the group consisting of:

9. R ２ But, C １～６ alkyl or aryl, １～６ The alkyl and the aryl are each independently selected from hydroxyl, cyano, CH ３ or —O—CH ３ 7. The compound of claim 1 , substituted with:

10. R ２ But, C １～６ alkyl or phenyl, １～６ The alkyl or phenyl may be hydroxyl, cyano, CH ３ or —O—CH ３ 10. The compound of claim 1 , 2 or 3, substituted with

11. R ２ but, 【Chemistry 5】 11. The compound according to any one of claims 1 to 6, 9, and 10, selected from the group consisting of:

12. R ２ but, 【Chemistry 6】 12. The compound according to any one of claims 1 to 6 and 9 to 11, selected from the group consisting of:

13. R ２ But, CH ３ , cyclopropyl, -C(H)(CH ３ ) ２ , -CH ２ C (CH ３ ) ３ , phenyl, 【Chemistry 7】 7. The compound according to any one of claims 1 to 6, selected from the group consisting of:

14. R ３ is hydrogen or CH ３ 14. The compound according to any one of claims 1 to 13, wherein

15. R ３ CH ３ 15. The compound according to any one of claims 1 to 14, wherein

16. Z is -SO ２ The compound according to any one of claims 1 to 15, wherein

17. 17. The compound of claim 16, wherein m is 1 and n is 1.

18. Z is -NR Ａ The compound according to any one of claims 1 to 15, wherein

19. 20. The compound of claim 18, wherein m is 0 and n is 0.

20. 20. The compound of claim 18, wherein m is 1 and n is 1.

21. R Ａ -C(O)C １～６ 21. The compound of any one of claims 18 to 20, which is alkyl.

22. R Ａ -C(O)CH ３ 22. The compound according to any one of claims 18 to 21, wherein

23. Z is -C(H)(R Ａ 16. The compound according to any one of claims 1 to 15, wherein

24. 24. The compound of claim 23, wherein m is 0 and n is 0.

25. R Ａ The compound of claim 24, wherein is -C(O)OH.

26. 24. The compound of claim 23, wherein m is 1 and n is 1.

27. R Ａ is -C(O)OH or 5-6 membered heteroaryl.

28. R Ａ is -C(O)OH or 【Chemistry 8】 28. The compound of claim 26 or 27,

29. Compounds represented by formula (Ia): 【Chemistry 9】 or a stereoisomer and / or a pharma- ceutically acceptable salt thereof, wherein: R １ is C １～６ Alkyl, C １～３ haloalkyl, or aryl; １～６ Alkyl is R １ａ may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R ２ is C １～６ Alkyl, C ３～６ is selected from the group consisting of cycloalkyl, aryl, and 5- to 10-membered heteroaryl; R ２ is R ２ａ may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R １ａ is independently at each occurrence hydroxyl or -O-C １～３ is alkyl; R ２ａ is independently, at each occurrence, hydroxyl, cyano, C １～６ Alkyl, and —O—C １～３ (selected from the group consisting of alkyl).

30. R １ But, C １～６ Alkyl, C １～３ haloalkyl, or aryl, １～６ The alkyl is hydroxyl or -O-C １～３ 30. The compound of claim 29, optionally substituted with alkyl.

31. R １ But, C １～６ Alkyl, C １～３ haloalkyl, or aryl, １～６ The alkyl is hydroxyl or -O-CH ３ 31. The compound of claim 29 or 30, optionally substituted with

32. R １ is -CH(CH ３ ) ２ , C.F. ３ , phenyl, 【Chemistry 10】 32. The compound according to any one of claims 29 to 31, selected from the group consisting of:

33. R ２ But, C １～６ Alkyl, C ３～６ is selected from the group consisting of cycloalkyl, aryl, and 5- to 10-membered heteroaryl; １～６ The alkyl and the aryl are each independently selected from hydroxyl, cyano, C １～６ Alkyl, or -O-C １～３ 33. The compound of any one of claims 29 to 32, optionally substituted with alkyl.

34. R ２ But, C １～６ Alkyl, C ３～６ is selected from the group consisting of cycloalkyl, aryl, and 5- to 10-membered heteroaryl; １～６ The alkyl and the aryl are each independently selected from hydroxyl, cyano, CH ３ or —O—CH ３ 34. The compound of any one of claims 29 to 33, optionally substituted with:

35. R ２ But, CH ３ , cyclopropyl, -C(H)(CH ３ ) ２ , -CH ２ C (CH ３ ) ３ , phenyl, 【Chemistry 11】 35. The compound according to any one of claims 29 to 34, selected from the group consisting of:

36. R ２ But, CH ３ , cyclopropyl, -C(H)(CH ３ ) ２ , -CH ２ C (CH ３ ) ３ , phenyl, 【Chemistry 12】 36. The compound according to any one of claims 29 to 35, selected from the group consisting of:

37. R ２ But, C １～６ alkyl or aryl, １～６ The alkyl and the aryl are each independently selected from hydroxyl, cyano, CH ３ or —O—CH ３ 35. The compound of any one of claims 29 to 34, substituted with:

38. R ２ But, C １～６ alkyl or phenyl, １～６ The alkyl or phenyl may be hydroxyl, cyano, CH ３ or —O—CH ３ 40. The compound of any one of claims 29 to 34 and 37, substituted with:

39. R ２ but, 【Chemistry 13】 40. The compound of any one of claims 29 to 34, 37, and 38, selected from the group consisting of:

40. R ２ but, 【Chemistry 14】 40. The compound according to any one of claims 29 to 34 and 37 to 39, selected from the group consisting of:

41. R ２ But, CH ３ , cyclopropyl, -C(H)(CH ３ ) ２ , -CH ２ C (CH ３ ) ３ , phenyl, 【Chemistry 15】 35. The compound according to any one of claims 29 to 34, selected from the group consisting of:

42. Compounds represented by formula (Ib): 【Chemistry 16】 or a stereoisomer and / or a pharma- ceutically acceptable salt thereof, wherein: R １ is C １～６ Alkyl, C １～３ Haloalkyl, or C ３～６ cycloalkyl, １～６ Alkyl is —O—C １～３ optionally substituted with alkyl; R ２ is aryl or 5-6 membered heteroaryl, said aryl being optionally substituted with cyano; m is 0 or 1; (n is 0 or 1).

43. R １ C １～６ Alkyl, C １～３ Haloalkyl, or C ３～６ cycloalkyl, １～６ Alkyl is -O-CH ３ 43. The compound of claim 42, optionally substituted with:

44. R １ is -CH(CH ３ ) ２ , C.F. ３ , cyclopropyl, and 【Chemistry 17】 44. The compound according to claim 42 or 43, selected from the group consisting of:

45. R ２ is phenyl or 【Chemistry 18】 45. The compound of any one of claims 42 to 44, wherein said phenyl is optionally substituted with cyano.

46. R ２ But phenyl, 【Chemistry 19】 46. ​​The compound according to any one of claims 42 to 45, selected from the group consisting of:

47. R ２ but 【Chemistry 20】 46. ​​The compound according to any one of claims 42 to 45, wherein

48. R ２ but 【Chemistry 21】 48. The compound of any one of claims 42 to 45 and 47, wherein

49. R ２ But phenyl, 【Chemistry 22】 46. ​​The compound according to any one of claims 42 to 45, selected from the group consisting of:

50. 50. The compound according to any one of claims 42 to 49, wherein m is 0 and n is 0.

51. 50. The compound of any one of claims 42 to 49, wherein m is 1 and n is 1.

52. Compounds represented by formula (Ic): 【Chemistry 23】 or a stereoisomer and / or a pharma- ceutically acceptable salt thereof, wherein: R １ is C １～６ Alkyl or C １～３ haloalkyl, １～６ Alkyl is —O—C １～３ optionally substituted with alkyl; R ２ is aryl or 5-6 membered heteroaryl, said aryl being optionally substituted with cyano; R ４ is —C(O)OH or 5-6 membered heteroaryl; m is 0 or 1; (n is 0 or 1).

53. R １ But, C １～６ Alkyl or C １～３ haloalkyl, １～６ Alkyl is -O-CH ３ 53. The compound of claim 52, optionally substituted with:

54. R １ But, CF ３ or 【Chemistry 24】 54. The compound of claim 52 or 53,

55. R ２ But phenyl, 【Chemistry 25】 55. The compound of any one of claims 52 to 54, wherein said phenyl is optionally substituted with cyano.

56. R ２ But phenyl, 【Chemistry 26】 56. The compound according to any one of claims 52 to 55, selected from the group consisting of:

57. R ２ but 【Chemical 27】 56. The compound according to any one of claims 52 to 55, wherein

58. R ２ but 【Chemistry 28】 58. The compound of any one of claims 52 to 55 and 57, wherein

59. R ２ But phenyl, 【Chemical Formula 29】 56. The compound according to any one of claims 52 to 55, selected from the group consisting of:

60. 60. The compound of any one of claims 52 to 59, wherein m is 0 and n is 0.

61. R ４ The compound of claim 60, wherein is -C(O)OH.

62. 60. The compound of any one of claims 52 to 59, wherein m is 1 and n is 1.

63. R ４ is -C(O)OH or 【Chemistry 30】 63. The compound of claim 62, wherein:

64. A compound selected from any of the compounds shown in Table 1 or a pharma- ceutically acceptable salt thereof.

65. 65. A pharmaceutical composition comprising a compound according to any one of claims 1 to 64 and a pharma- ceutically acceptable carrier.

66. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of claims 1 to 64 or a pharmaceutical composition described in claim 65.

67. A method for treating an autoimmune or inflammatory disorder or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of claims 1 to 64 or a pharmaceutical composition described in claim 65.

68. 68. The method of claim 67, wherein the autoimmune or inflammatory disorder or disease is selected from the group consisting of acute graft-versus-host disease, chronic graft-versus-host disease, lupus, scleroderma, psoriatic arthritis, primary sclerosing cholangitis, rheumatoid arthritis, and inflammatory bowel disease.

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