Sulfonamide compound

Abstract

To provide use of a compound having necroptosis and / or mixed lineage kinase domain-like protein (MLKL) inhibitory action in the manufacture of a medicament.SOLUTION: Use of a compound of formula (I), or pharmaceutically acceptable salts, solvates, tautomers, N-oxides, and / or stereoisomers thereof, in the manufacture of a medicament for treating and / or preventing one or more diseases, conditions and / or disorders: A compound of formula (I) is in particular e.g. 3 - (3 - ((3, 4-difluorobenzyl) oxy) - 4 - (ethylsulfonamido) phenyl) - 5 - (pyrazin-2-ylamino) - 1H - pyrazole-4-carboxamide.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority to Australian Provisional Patent Application No. 2020902035 (filed June 19, 2020), the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to sulfonamide compounds that treat necroptosis and / or inhibit MLKL, and methods of their use. [Background technology]

[0003] In many diseases, cell death is mediated through apoptosis and / or necrosis pathways. The mechanisms of action that control apoptosis are well known, but the control of necrosis is less well understood. To be able to treat conditions such as neurodegenerative diseases, stroke, coronary heart disease, kidney disease, liver disease, AIDS, and conditions associated with AIDS, it is necessary to understand the mechanisms of both necrosis and apoptosis in cells.

[0004] Cell death has traditionally been classified as apoptosis or necrosis based on morphological characteristics (Wyllie et al., Int. Rev. Cytol., 68:251, 1980). These two modes of cell death were initially thought to occur through regulated (caspase-dependent) and unregulated processes, respectively. However, more recent studies have revealed that the underlying cell death mechanisms leading to these two phenotypes are much more complex and, under certain circumstances, may be interrelated. Furthermore, conditions leading to necrosis can occur through regulated, caspase-independent processes or unregulated processes.

[0005] A regulated, caspase-independent cell death pathway called necroptosis, whose morphological characteristics resemble those of necrosis, has been described (Degterev et al., Nat. Chem. Biol., 1:112, 2005). This cell death modality can be initiated in a range of cell types (e.g., monocytes, fibroblasts, lymphocytes, macrophages, epithelial cells, and neurons) by various stimuli (e.g., TNF-α and Fas ligand). Necroptosis can represent a significant contributor to, and in some cases the primary mode of, cellular death under pathological conditions involving excessive cellular stress, rapid energy loss, and massive oxygen species generation, in which the highly energy-dependent apoptotic process is not viable.

[0006] In WO2015 / 172203, the inventors reported that certain compounds described in US2005 / 0085637 have been found to be suitable for inhibiting necroptosis. In WO2016 / 127213, the inventors also discussed compounds that are particularly suitable for inhibiting necroptosis.

[0007] All publications, patents, and patent applications that may be cited herein are hereby incorporated by reference in their entirety.

[0008] Any discussion of documents, acts, materials, devices, articles or the like contained in this specification should not be construed as an admission that any or all of such matters form part of the prior art document or were common general knowledge in the art relevant to this disclosure as they existed prior to the priority date of each claim of this application. Summary of the Invention

[0009] As discussed above, some compounds described in WO2016 / 127213, US2005 / 0085637, and WO2015 / 172203 have been found to be suitable for treating necroptosis. Surprisingly, the inventors of the present invention have now discovered that other types of compounds are also suitable for treating necroptosis. Furthermore, and equally surprisingly, the compounds described in the present invention target a key effector of the necroptosis pathway, namely, mixed lineage kinase domain-like protein (MLKL). The inventors have also found that the compounds described in the present invention target human MLKL.

[0010] In one embodiment, a compound according to formula (I) is provided [ka] [In the formula, Q 1 and Q 2 are N and NR 1 Selected from Q 1 When N, Q 2 is NR 1 and Q 2 When N, Q 1 is NR 1 and R 1 and R 3 is H and optionally substituted C 1~6 -alkyl; R 2 is optionally substituted C1-C6-alkyl, optionally substituted aryl or optionally substituted heterocyclyl, X is an optionally substituted C 1~6 Alkyl, optionally substituted haloC 1~6 Alkyl, optionally substituted C 2~6 Alkynyl, optionally substituted cycloalkyl, optionally substituted halocycloalkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted C 1~6selected from alkylcycloalkyl and optionally substituted amino; Y and Z are H, R 4 , -OR 4 and -NR 4 R 5 and at least one of Y and Z is H; R 4 is an arbitrarily substituted C 1~6 Alkyl, optionally substituted aryl, optionally substituted C 1~6 alkylaryl, optionally substituted heterocyclyl, C 1~6 Alkylheterocyclyl, optionally substituted cycloalkyl, optionally substituted C 1~6 Alkyl C 3~10 Cycloalkyl, optionally substituted C 3~10 Cycloalkylaryl, optionally substituted C 3~10 Cycloalkylheterocyclyl, optionally substituted C 3~10 Cycloalkyl, optionally substituted 3- to 6-membered non-aromatic heterocyclyl-aryl, optionally substituted 3- to 6-membered non-aromatic heterocyclylC 3~10 independently selected from cycloalkyl and optionally substituted 3- to 6-membered non-aromatic heterocyclyl-3- to 10-membered heterocyclyl; R 5 is H or optionally substituted C 1~6 alkyl].

[0011] In any aspect or embodiment described herein, the compounds of the invention may be provided in the form of a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof.

[0012] The present inventors have found that the compounds of formula (I) are selective inhibitors of MLKL.

[0013] In some embodiments, the compound of the present invention is selected from any of compounds 1-320 described herein, preferably compounds 9, 14, 21-22, 24-25, 34, 39, 41-43, 53, 62-63, 66, 68, 71, 84, 88, 90, 92-93, 101-102, 108, 113, 115, 123-124, 127-128, 139-140, 143-144, 146, 150, 152-158, 160-166 , 169-171, 175-176, 181, 188, 190-191, 194, 196, 198-199, 202, 208, 222-223, 229, 233-235, 238, 242, 245-246, 248-249, 251-253, 256, 259-260, 262, 264-266, 271, 273-279, 281-286, 288-299, 301-312, 314, and 316-320.

[0014] In another aspect, a medicament comprising a compound of the invention is provided.

[0015] In another aspect, there is provided a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.

[0016] In another aspect, there is provided a method of treating necroptosis, comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0017] In another embodiment, a method of inhibiting MLKL is provided, comprising contacting a cell with a compound of the invention.

[0018] Any embodiment herein shall be deemed to apply mutatis mutandis to any other embodiment unless otherwise stated.

[0019] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended to be exemplary only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention as described herein.

[0020] Throughout this specification, unless otherwise stated or the context requires a different interpretation, a reference to a single step, composition, group of steps or group of compositions shall be deemed to encompass one and more (i.e., one or more) of that step, composition, group of steps or group of compositions.

[0021] definition Unless otherwise defined herein, the following terms shall be understood to have the following general meanings:

[0022] The term “C 1~6 "Alkyl" refers to an optionally substituted straight or branched chain hydrocarbon group having from 1 to 6 carbon atoms. Examples include methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (Bu), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), pentyl, neopentyl, hexyl, and the like. Unless the context requires otherwise, the term "C 1~6 "Alkyl" also includes alkyl groups that contain one less hydrogen atom so that there are two points of attachment, i.e., the group is divalent. "C" includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. 1~4 Alkyl" and "C 1~3 Alkyl is preferred, with methyl being particularly preferred.

[0023] The term “C 2~6 "Alkenyl" refers to an optionally substituted straight or branched chain hydrocarbon group having at least one double bond and 2 to 6 carbon atoms, of E or Z stereochemistry, where applicable. Examples include vinyl, 1-propenyl, 1- and 2-butenyl, and 2-methyl-2-propenyl. Unless the context requires a different interpretation, the term "C 2~6"Alkenyl" also includes alkenyl groups that contain one less hydrogen atom so that there are two points of attachment, i.e., the group is divalent. "C" includes ethenyl, propenyl, and butenyl. 2~4 alkenyl" and "C 2~3 Alkenyl is preferred, with ethenyl being particularly preferred.

[0024] The term “C 2~6 "Alkynyl" refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and 2 to 6 carbon atoms. Examples include ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl, and the like. Unless the context indicates otherwise, the term "C 2~6 "Alkynyl" also encompasses alkynyl groups that contain one less hydrogen atom so that there are two points of attachment, i.e., the group is divalent. 2~3 Alkynyl is preferred.

[0025] The term “C 3~10 "Cycloalkyl" refers to a non-aromatic cyclic group having 3 to 10 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. It is understood that a cycloalkyl group can be a saturated cycloalkyl group, such as cyclohexyl, or an unsaturated cycloalkyl group, such as cyclohexenyl. C cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are also included. 3~6 Cycloalkyl is preferred. Cycloalkyl groups also include polycyclic carbocycles, including fused, bridged, and spirocyclic systems.

[0026] The terms "hydroxy" and "hydroxyl" refer to the --OH group.

[0027] The term "oxo" refers to the group =O.

[0028] The term “C 1~6"Alkoxy" refers to an alkyl group as defined above containing from 1 to 6 carbon atoms covalently bonded through an O bond, such as methoxy, ethoxy, propoxy, isoproxy, butoxy, tert-butoxy, and pentoxy. "C" includes methoxy, ethoxy, propoxy, and butoxy. 1~4 Alkoxy" and "C 1~3 Alkoxy is preferred, with methoxy being particularly preferred.

[0029] The term "Halo C 1~6 Alkyl" and "C 1~6 "Alkylhalo" refers to a C alkyl group substituted with one or more halogens. 1~6 Refers to alkyl. For example, haloC such as -CH2CF3 and -CF3 1~3 Alkyl groups are preferred.

[0030] The term "Halo C 1~6 Alkoxy" and "C 1~6 "Alkoxyhalo" refers to a C substituted with one or more halogens. 1~6 Refers to alkoxy. For example, C such as -OCF3 1~3 Alkoxyhalo groups are preferred.

[0031] The term "carboxylate" or "carboxyl" refers to a -COO- or -COOH group.

[0032] The term "ester" refers to an ester in which the hydrogen is, for example, C 1~6 Alkyl group (carboxyl group) 1~6 refers to a carboxyl group substituted with an alkyl group or an aralkyl group ("aryl ester" or "aralkyl ester"), etc. For example, CO2C such as methyl ester (CO2Me), ethyl ester (CO2Et), and propyl ester (CO2Pr) 1~3 Alkyl groups are preferred, including their reverse esters (eg, -OC(O)Me, -OC(O)Et and -OC(O)Pr).

[0033] The terms "cyano" and "nitrile" refer to the group --CN.

[0034] The term "nitro" refers to the group --NO.sub.2.

[0035] The term "amino" refers to the group --NH.sub.2.

[0036] The term "substituted amino" refers to an amino group in which at least one hydrogen has been replaced with, for example, C 1~6 Alkyl group ("C 1~6 The term "substituted amino group" refers to an amino group in which only one hydrogen atom has been replaced by a group such as C 1~6 "Monosubstituted amino" (or "secondary amino") groups refer to amino groups substituted with alkyl, aryl, or aralkyl groups, etc. Preferred secondary amino groups include C methylamino (NHMe), ethylamino (NHEt), and propylamino (NHPr), etc. 1~3 The substituted amino group includes alkylamino groups, in which both hydrogen atoms may be the same or different, such as C 1~6 Also included are "disubstituted amino" (or "tertiary amino") groups, which refer to amino groups substituted with alkyl groups ("dialkylamino"), aryl and alkyl groups ("aryl(alkyl)amino"), and the like. Preferred tertiary amino groups include di(C) amino groups, such as dimethylamino (NMe), diethylamino (NEt), dipropylamino (NPr), and variations thereof (e.g., N(Me)(Et), etc.). 1~3 alkyl)amino groups.

[0037] The term "aldehyde" refers to the group -C(=O)H.

[0038] The terms "acyl" and "acetyl" refer to the group -C(O)CH3.

[0039] The term "ketone" refers to a carbonyl group which can be represented by -C(O)-.

[0040] The term "substituted ketone" refers to a ketone that is substituted with at least one other group, e.g., C 1~6 Alkyl group ("C 1~6 It refers to a ketone group covalently bonded to an aryl group ("aryl ketone"), an aralkyl group ("aralkyl ketone"), or the like. 1~3 Alkylacyl groups are preferred.

[0041] The terms "amido" or "amide" refer to the group -C(O)NH2.

[0042] The term "substituted amido" or "substituted amide" refers to an amide in which hydrogen is replaced by, for example, C 1~6 Alkyl group ("C 1~6 Alkylamide" or "C 1~6 It refers to an amide group substituted with an aryl ("arylamide"), aralkyl ("aralkylamide"), or the like. For example, C groups such as methylamide (-C(O)NHMe), ethylamide (-C(O)NHEt), and propylamide (-C(O)NHPr). 1~3 Alkyl amide groups are preferred, including their reverse amides (eg, -NHMeC(O)-, -NHEtC(O)-, and -NHPrC(O)-).

[0043] The term "disubstituted amido" or "disubstituted amide" refers to "Disubstituted amide" refers to a group in which two hydrogens are replaced with, for example, C 1~6 Alkyl group (di(C 1~6 alkyl)amide" or "di(C 1~6 This refers to amide groups substituted with alkyl groups ("alkyl(aralkyl)amides"), aralkyl groups, and alkyl groups ("alkyl(aralkyl)amides"). For example, di(C(O)amides such as dimethylamide (-C(O)NMe2), diethylamide (-C(O)NEt2), dipropylamide (-C(O)NPr2) and variations thereof (e.g., -C(O)N(Me)Et, etc.) are also included.1~3 (Alkyl)amide groups are preferred, including their reverse amides (e.g., —N(Me)C(O)Me, —N(Et)C(O)Et, —N(Pr)C(O)Pr, and —N(Me)C(O)Et).

[0044] The term "thiol" refers to the group --SH.

[0045] The term “C 1~6 "Alkylthio" is a group where hydrogen is C 1~6 Refers to thiol groups substituted with alkyl groups. For example, C groups such as thiolmethyl, thiolethyl, and thiolpropyl. 1~3 Alkylthio groups are preferred.

[0046] The term "thioxo" refers to the group ═S.

[0047] The term "sulfinyl" refers to the group -S(=O)H.

[0048] The term "substituted sulfinyl" or "sulfoxide" refers to a group in which the hydrogen is replaced by, for example, C 1~6 Alkyl group ("C 1~6 alkylsulfinyl" or "C 1~6 It refers to sulfinyl groups substituted with aryl ("arylsulfoxide"), aralkyl ("aralkylsulfinyl"), etc. For example, C groups such as -SOmethyl, -SOethyl, and -SOpropyl. 1~3 Alkylsulfinyl groups are preferred.

[0049] The term "sulfonyl" refers to the group -SO2H.

[0050] The term "substituted sulfonyl" refers to a group in which the hydrogen is replaced by, for example, C 1~6 Alkyl group (sulfonyl C 1~6 It refers to sulfonyl groups substituted with alkyl ("arylsulfonyl"), aralkyl ("aralkylsulfonyl"), etc. For example, sulfonyl C groups such as -SOMe, -SOEt, and -SOPr. 1~3 Alkyl groups are preferred.

[0051] The terms "sulfonylamido", "sulfonamido", "sulfonamide", "sulfonylamide", "sulfonamide", "sulfonylamide" or "sulphonamide" refer to the group -SO2NH2.

[0052] The terms "substituted sulfonamido", "substituted sulfonamide", "substituted sulphonamido" or "substituted sulphonamide" refer to amides in which hydrogen is replaced by, for example, C 1~6 Alkyl groups (e.g., sulfonyl amide C 1~6 Sulfonyl amide groups substituted with alkyl ("aryl sulfonamide"), aralkyl ("aralkyl sulfonamide"), etc. For example, sulfonyl amide C groups such as -SO2NHMe, -SO2NHEt, and -SO2NHPr. 1~3 Alkyl groups are preferred, including their reverse sulfonamides (e.g., -NHSOMe, -NHSOEt, and -NHSOPr). In some embodiments, alkylsulfonamides may be optionally substituted, for example, with halo groups.

[0053] The term "disubstituted sulfonamido", "disubstituted sulfonamide", "disubstituted sulphonamido" or "disubstituted sulphonamide" refers to a disubstituted sulfonamide in which the two hydrogen atoms may be the same or different, e.g., C 1~6 Alkyl group ("sulfonylamide di(C 1~6It refers to sulfonylamido groups substituted with aryl groups such as -SO2NMe2, -SO2NEt2, -SO2NPr2, and variations thereof (e.g., -SO2N(Me)Et, etc.). 1~3 Alkyl) groups are preferred, including their reserve sulfonamide (e.g., -N(Me)SO2Me, etc.).

[0054] The term "sulfate" refers to the OS(O)OH group, where the hydrogen is, e.g., C 1~6 This includes groups substituted with alkyl groups ("alkyl sulfates"), aryl groups ("aryl sulfates"), aralkyl groups ("aralkyl sulfates"), etc. For example, C groups such as OS(O)2OMe, OS(O)2OEt, and OS(O)2OPr. 1~3 Sulfates are preferred.

[0055] The term "sulfonate" refers to the group SO3H, where the hydrogen is, for example, C 1~6 This includes groups substituted with alkyl groups ("alkylsulfonates"), aryl groups ("arylsulfonates"), aralkyl groups ("aralkylsulfonates"), etc. For example, C groups such as SO3Me, SO3Et, and SO3Pr. 1~3 Sulfonates are preferred.

[0056] The term "aryl" refers to a carbocyclic (non-heterocyclic) aromatic ring system or a monocyclic, bicyclic, or tricyclic ring system. Polycyclic ring systems can be called "aryl" provided that at least one of the rings in the system is aromatic. The aromatic ring or ring system as a whole is composed of 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and tetrahydronaphthyl. 6-membered aryls such as phenyl are preferred. The term "alkylaryl" refers to C alkyl groups such as benzyl. 1~6 Refers to alkylaryl.

[0057] The term "alkoxyaryl" refers to C aryls such as benzyloxy. 1~6 It refers to alkyloxyaryl.

[0058] The term "heterocyclyl" refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has 3 to 10 ring atoms (unless otherwise specified), of which 1, 2, 3, or 4 are ring heteroatoms, each heteroatom being independently selected from O, S, and N. Heterocyclyl groups include monocyclic ring systems and polycyclic (e.g., bicyclic) ring systems, including fused, bridged, and spirocyclic systems, provided that at least one of the rings in the ring system contains at least one heteroatom.

[0059] In this context, the prefixes 3, 4, 5, 6, 7, 8, 9, and 10-membered refer to the number or range of ring atoms, whether carbon atoms or heteroatoms. For example, as used herein, the term "3-10-membered heterocyclyl" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms. Examples of heterocyclyl groups include 5- to 6-membered monocyclic heterocyclyl and 9- to 10-membered fused bicyclic heterocyclyl.

[0060] Examples of monocyclic heterocyclyl groups include those containing one nitrogen atom, such as aziridine (3-membered ring), azetidine (4-membered ring), pyrrolidine (tetrahydropyrrole), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) or pyrrolidinone (5-membered ring), piperidine, dihydropyridine, tetrahydropyridine (6-membered ring), and azepine (7-membered ring); those containing two nitrogen atoms, such as imidazoline, pyrazolidine (diazoline, zolidine), imidazoline, pyrazoline (dihydropyrazole) (5-membered ring), piperazine (6-membered ring); those containing one oxygen atom, such as oxirane (3-membered ring), oxetane (4-membered ring), oxolane (tetrahydrofuran), oxole (dihydrofuran) (5-membered ring), oxane (tetrahydropyran), dihydropyran, pyran (6-membered ring), oxepin (7-membered ring); those containing two oxygen atoms, such as dioxolane (5-membered ring), dioxane (6-membered ring), and dioxepane (7-membered ring); those containing one sulfur atom, such as thiirane (3-membered ring), thietane (4-membered ring), thiolane (tetrahydrothiophene) (5-membered ring), thiane (tetrahydrothiopyran) (6-membered ring), thiepane (7-membered ring); those containing one nitrogen atom and one oxygen atom, such as tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole (5-membered ring), morpholine, tetrahydrooxazine, dihydrooxazine, oxazine (6-membered ring). membered ring); those containing one nitrogen atom and one sulfur atom, such as thiazoline, thiazolidine (5-membered ring), thiomorpholine (6-membered ring); those containing two nitrogen atoms and one oxygen atom, such as oxadiazine (6-membered ring); those containing one oxygen atom and one sulfur atom, such as oxathiol (5-membered ring) and oxathiane (thioxane) (6-membered ring); and those containing one nitrogen atom, one oxygen atom, and one sulfur atom, such as oxathiazine (6-membered ring).

[0061] Heterocyclyl includes aromatic and non-aromatic heterocyclyl. Such groups may be substituted or unsubstituted.

[0062] The term "aromatic heterocyclyl" may be used interchangeably with the term "heteroaromatic" or the terms "heteroaryl" or "hetaryl." The heteroatoms in an aromatic heterocyclyl group may be independently selected from N, S, and O. An aromatic heterocyclyl group may contain 1, 2, 3, 4, or more ring heteroatoms. In the case of fused aromatic heterocyclyl groups, only one of the rings must contain a heteroatom; not all rings must be aromatic.

[0063] The term "heteroaryl" is used herein to refer to heterocyclic groups having aromatic character and includes aromatic monocyclic and polycyclic (e.g., bicyclic) ring systems containing one or more aromatic rings. The term aromatic heterocyclyl also includes pseudoaromatic heterocyclyl. The term "pseudoaromatic" refers to a ring system that is not strictly aromatic but is stabilized by electron delocalization and behaves similarly to an aromatic ring. Thus, the term aromatic heterocyclyl includes polycyclic ring systems in which all fused rings are aromatic, and ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In polycyclic systems in which both aromatic and non-aromatic rings are fused, groups may be attached to another moiety by either the aromatic ring or the non-aromatic ring.

[0064] Examples of heteroaryl groups include monocyclic and bicyclic groups containing 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings, or bicyclic structures formed from fused 5- and 6-membered rings, or two fused 6-membered rings, or two fused 5-membered rings. Each ring can contain up to about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Heteroaryl rings contain up to four heteroatoms, more typically up to three heteroatoms, and more usually up to two, e.g., only one heteroatom. In embodiments, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of an imidazole or pyridine, or essentially non-basic, as in the case of an indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents on the ring, is less than five.

[0065] An aromatic heterocyclyl group can be a 5- or 6-membered monocyclic aromatic ring system.

[0066] Examples of 5-membered monocyclic heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4-oxadiazolyl and furazanyl, i.e., 1,2,5-oxadiazolyl), thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1,2,3, 1,2,4 and 1,3,4-triazolyl), oxatriazolyl, tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4-thiadiazolyl), and the like.

[0067] Examples of 6-membered monocyclic heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl, etc. Examples of 6-membered aromatic heterocyclyls containing nitrogen include pyridyl (one nitrogen), pyrazinyl, pyrimidinyl, and pyridazinyl (two nitrogens).

[0068] Aromatic heterocyclyl groups can also be bicyclic or polycyclic heteroaromatic ring systems, such as fused ring systems (including purine, pteridinyl, napthyridinyl, 1H-thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, etc.) or linked ring systems (oligothiophenes, polypyrroles, etc.). Fused ring systems can also include 5- or 6-membered aromatic heterocyclyls fused to carbocyclic aromatic rings such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, etc., such as 5-membered aromatic heterocyclyls containing nitrogen fused to a phenyl ring, and 5-membered aromatic heterocyclyls containing one or two nitrogen atoms fused to a phenyl ring.

[0069] Bicyclic heteroaryl groups include, for example, a) a benzene ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; g) an oxazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; h) a 5- or 6-membered ring containing one or two ring heteroatoms; may be a group selected from an isoxazole ring fused to a 5- or 6-membered ring containing two ring heteroatoms; i) a thiazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; j) an isothiazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms; I) a furan ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms.

[0070] Particular examples of bicyclic heteroaryl groups in which one five-membered ring is fused to another five-membered ring include, but are not limited to, imidazothiazoles (e.g., imidazo[2,1-b]thiazole) and imidazoimidazoles (e.g., imidazo[1,2-a]imidazole). It will not be done.

[0071] Specific examples of bicyclic heteroaryl groups in which a 6-membered ring is fused to a 5-membered ring include, but are not limited to, benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine), benzodioxole, and pyrazolopyridine (e.g., pyrazolo[1,5-a]pyridine) groups. Another example of a 6-membered ring fused to a 5-membered ring is a pyrrolopyridine group, such as a pyrrolo[2,3-b]pyridine group.

[0072] Particular examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxane, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, and pteridine groups.

[0073] Examples of heteroaryl groups containing aromatic and non-aromatic rings include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoline, isoindoline, and indane groups.

[0074] Thus, examples of aromatic heterocyclyls fused to a carbocyclic aromatic ring include, but are not limited to, benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, isobenzoxazoyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl, and the like.

[0075] The term "non-aromatic heterocyclyl" encompasses optionally substituted saturated and unsaturated rings containing at least one heteroatom selected from the group consisting of N, S, and O. The ring can contain 1, 2, or 3 heteroatoms. The ring can be a monocyclic ring or part of a polycyclic ring system. Polycyclic ring systems include fused rings and spiro rings. In non-aromatic heterocyclic polycyclic ring systems, not all rings must contain heteroatoms, provided that at least one ring contains one or more heteroatoms.

[0076] The non-aromatic heterocyclyl can be a 3- to 7-membered monocyclic ring.

[0077] Examples of 5-membered non-aromatic heterocyclyl rings include 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl, 3-dioxalanyl, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl, and the like.

[0078] Examples of 6-membered non-aromatic heterocyclyls include piperidinyl, piperidinoyl, and pyranyl. , dihydropyranyl, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, thianyl, thianyl oxide, thianyl dioxide, piperazinyl, diozanyl, 1,4-dioxinyl, 1,4-dithianyl, 1,3,5-triozalanyl, 1,3,5-trithianyl, 1,4-morpholinyl, thiomorpholinyl, 1,4-oxathianyl, triazinyl, 1,4-thiazinyl, and the like.

[0079] Examples of 7-membered non-aromatic heterocyclyls include azepanyl, oxepanyl, thiepanyl, and the like.

[0080] Non-aromatic heterocyclyl rings can also be bicyclic heterocyclyl rings, such as linked ring systems (e.g., uridinyl, etc.) or fused ring systems. Fused ring systems include 5-, 6-, or 7-membered non-aromatic heterocyclyls fused to a carbocyclic aromatic ring, such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, etc. Examples of 5-, 6-, or 7-membered non-aromatic heterocyclyls fused to a carbocyclic aromatic ring include indolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl, etc.

[0081] The term "halo" refers to fluoro, chloro, bromo or iodo.

[0082] Unless otherwise defined herein, the term "optionally substituted" or "optional substituent" refers to any group selected from the group consisting of C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, hydroxyl, oxo, C 1~6 Alkoxy, aryloxy, C 1~6 Alkoxyaryl, halo, C 1~6 Alkyl halo (CF3, etc.), C 1~6Alkoxyhalo (OCF3, etc.), carboxyl, ester, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketone, substituted ketone, amide, aminoacyl, substituted amide, disubstituted amide, thiol, alkylthio, thioxo, sulfate, sulfonate, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamide, substituted sulfonamide, disubstituted sulfonamide, aryl, arC 1~6 It refers to a group that may or may not be further substituted with 1, 2, 3, 4 or more groups, preferably 1, 2 or 3, more preferably 1 or 2 groups, selected from the group consisting of alkyl, heterocyclyl, and heteroaryl (each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, and groups containing them, may be further substituted optionally). Optional substituents in the case of N-containing heterocycles include C 1~6 Alkyl, i.e., NC 1~3 Included may also be, but is not limited to, alkyl, more preferably methyl, especially N-methyl.

[0083] Optionally substituted "C 1~6 Alkyl," "C 2~6 alkenyl" and "C 2~6 In "alkynyl", the optional substituent(s) are preferably halo, aryl, heterocyclyl, C 3~8 Cycloalkyl, C 1~6 Alkoxy, hydroxyl, oxo, aryloxy, haloC 1~6 Alkyl, HaloC 1~6 Each of these optional substituents may also be optionally substituted with any of the optional substituents mentioned above, including nitro, amino, substituted amino, cyano, heterocyclyl (including non-aromatic heterocyclyl and heteroaryl), C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, HaloC 1~6 Alkyl, HaloC 1~6Alkoxy, halo, hydroxyl and carboxyl are preferred.

[0084] It will be appreciated that suitable derivatives of nitrogen-containing aromatic heterocyclyls include their N-oxides.

[0085] In the case of hybrid nomenclature of substituent radicals, such as alkylamino and alkylaryl, which describe two moieties that can both form a bond connecting the radical to the rest of the compound, no direction of ordering of the groups is intended; therefore, the point of attachment can be to either of the moieties included in the hybrid radical. For example, the terms "alkylaryl" and "arylalkyl" are intended to refer to the same group, and the point of attachment can be through either the alkyl or aryl portion (or both, in the case of diradical species). The direction of attachment of such hybrid radicals can be indicated by the inclusion of a bond; for example, "-alkylaryl" or "arylalkyl-" indicates that the point of attachment of the radical to the rest of the compound is through the alkyl portion, and "alkylaryl-" or "-arylalkyl" indicates that the point of attachment is through the aryl portion.

[0086] In this specification, unless the context requires otherwise, the term "comprise" and variations of that term, such as "comprising", "comprises" and "comprised", are not intended to exclude other additives, ingredients, integers or steps.

[0087] It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "salt" can include plural salts, reference to "at least one heteroatom" can include one or more heteroatoms, etc.

[0088] The term "and / or" can mean "and" or "or."

[0089] The term "(s)" following a noun contemplates either the singular or the plural, or both.

[0090] Various features of the present invention are described with reference to certain values ​​or ranges of values. These values ​​are intended to relate to the results of various appropriate measurement techniques and should therefore be interpreted as including the range of error inherent in any particular measurement technique. Some of the values ​​referred to herein are expressed by the term "about" to account for at least some of this variation. When used to describe a value, the term "about" can mean an amount within ±25%, ±10%, ±5%, ±1%, or ±0.1% of that value.

[0091] Further aspects of the invention and further embodiments of the aspects described in the above paragraphs will become apparent from the following description, given by way of example only, and with reference to the accompanying drawings, in which: DETAILED DESCRIPTION OF THE INVENTION

[0092] The present invention provides compounds of formula (I) [ka] [In the formula, Q 1 and Q 2 are N and NR 1 Selected from Q 1 When N, Q 2 is NR 1 and Q 2 When N, Q 1 is NR 1 and R 1 and R 3 is H and optionally substituted C 1~6 -alkyl; R 2is optionally substituted C1-C6-alkyl, optionally substituted aryl or optionally substituted heterocyclyl, X is an optionally substituted C 1~6 Alkyl, optionally substituted haloC 1~6 Alkyl, optionally substituted C 2~6 Alkynyl, optionally substituted cycloalkyl, optionally substituted halocycloalkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted C 1~6 selected from alkylcycloalkyl and optionally substituted amino; Y and Z are H, R 4 , -OR 4 , -NR 4 R 5 and at least one of Y and Z is H; R 4 is an arbitrarily substituted C 1~6 Alkyl, optionally substituted aryl, optionally substituted C 1~6 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1~6 Alkylheterocyclyl, optionally substituted cycloalkyl, optionally substituted C 1~6 Alkyl C 3~10 Cycloalkyl, optionally substituted C 3~10 Cycloalkylaryl, optionally substituted C 3~10 Cycloalkylheterocyclyl, optionally substituted C 3~10 Cycloalkyl C 3~10 Cycloalkyl, optionally substituted 3- to 6-membered non-aromatic heterocyclyl-aryl, optionally substituted 3- to 6-membered non-aromatic heterocyclylC 3~10 independently selected from cycloalkyl and optionally substituted 3- to 6-membered non-aromatic heterocyclyl-3- to 10-membered heterocyclyl; R 5 is H or optionally substituted C 1~6 alkyl].

[0093] In some embodiments, X is C 1~6 Alkyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, aryl, -(CH2) n Aryl, -(CH2) n Cycloalkyl, and -N(C 1~4 alkyl)2; where: n is 1 or 2, Alkyl and alkynyl are each independently selected from halo, nitrile, -OR 6 , -N(R 7 )R 8 and optionally substituted with one or more groups selected from R 6 , R 7 and R 8 is H, C 1~6 Alkyl and HaloC 1~6 alkyl; Aryl and cycloalkyl are each independently halo, nitrile, C 1~4 Alkyl, C 1~4 Alkoxy, HaloC 1~4 Alkyl and HaloC 1~4 and optionally substituted with one or more groups independently selected from alkoxy. [ka] It is understood that represents a single or double bond. For example, [ka] The 5-membered heterocyclyl depicted in formula (I) is a pyrazole which can exist in one of two isomeric forms.

[0094] In some embodiments, Q 2 is N and Q 1 is NR 1 In these embodiments, the compound of formula (I) can be a compound of formula (1A): [ka]

[0095] In some embodiments, Q 2 is NR 1 and Q 1 is N. In these embodiments, the compound of formula (I) can be a compound of formula (1B). [ka]

[0096] In the compounds of formula (1A) and / or (1B), R 1 , R 2 , R 3 , X, Y and Z are as defined in formula (I) or any embodiment thereof described herein.

[0097] In some embodiments, X is optionally substituted C 1~4 Alkyl, optionally substituted C 2~4 Alkynyl, optionally substituted C 1~4 Alkylnitrile, optionally substituted haloC 1~4 Alkyl, optionally substituted C 3~6 Cycloalkyl, optionally substituted C alkyl 3~6 Selected from cycloalkyl, optionally substituted aryl, optionally substituted haloaryl, optionally substituted C1 alkylaryl, optionally substituted haloC1 alkylaryl, optionally substituted haloC1 alkoxyaryl, optionally substituted benzyl, optionally substituted halobenzyl, optionally substituted C1 alkylbenzyl, optionally substituted C1 alkoxybenzyl and optionally substituted haloC1 alkoxybenzyl.

[0098] In some embodiments, X is optionally substituted C 1~4 Alkyl, optionally substituted haloC1~4 Alkyl and C 3~6 cycloalkyl.

[0099] In some embodiments, X is optionally substituted C 1~2 Alkyl, optionally substituted haloC 1~2 is selected from alkyl and C3 cycloalkyl.

[0100] In some embodiments, X is an optionally substituted haloC selected from -CHF2, -CF3, -CH2CF3, -CH2CHF2, and -CH2CH2CF3. 1~4 It is alkyl.

[0101] In some embodiments, X is an optionally substituted amino, preferably a disubstituted amino, such as —N(C 1~4 In some embodiments, X is —N(CH 3 ) 2 .

[0102] In some embodiments, X is one of the following groups: methyl, ethyl, isopropyl, tert-butyl, -CHF, -CF, -CHCF, -CHCHF, -CHCHCF, -CHCHOCH, -CHCHNH, -CHCHN(CH), cyclohexyl, cyclopropyl, -N(CH). [ka] is selected from one of the following.

[0103] In some embodiments, X is selected from any one of the following groups: ethyl, difluoromethyl, trifluoroethyl, and cyclopropyl.

[0104] In some embodiments, X is C 1~4 Alkyl and C 1~4 Fluoroalkyl, preferably selected from -CHF2, -CH2CF3 and -CH2CH3.

[0105] In some embodiments, X is difluoromethyl.

[0106] In some embodiments, X is a group having a longest straight chain extending from the sulfur atom depicted in Formula (I) by 6, 5, 4, 3, or 2 atoms or less, preferably 3 to 6 atoms. "Longest straight chain" refers to the number of atoms from the point of attachment, not including any branches or rings. For example, when X is benzyl, the longest straight chain is 6 atoms, including the methylene carbon atom, the four ring atoms, and the hydrogen atom attached to the 4-carbon of the benzyl; when X is -CHCF, the longest straight chain is 3 atoms. The longest straight chains for each of these exemplary X-substituents are numbered in the subformulas shown below. [ka]

[0107] In some embodiments, Y and Z are H, R 4 , -OR 4 , -NR 4 R 5 wherein at least one of Y and Z is H, and R 4 is arbitrarily substituted C 1~6 Alkyl, optionally substituted aryl, optionally substituted C 1~6 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1~6 Alkylheterocyclyl, optionally substituted cycloalkyl, optionally substituted C 1~6 Alkyl C 3~10 cycloalkyl.

[0108] In some embodiments, Y and Z are H, R 4 , -OR 4 , -NR 4 R 5 and at least one of Y and Z is H; R 4 But C 1~6Alkyl, aryl, cycloalkyl, heterocyclyl, C 1~6 Alkylcycloalkyl, C 1~6 Alkylaryl and C 1~6 alkylheterocyclyl; Each alkyl (including when present as an optional substituent) is selected from the group consisting of halo, C 1~4 Alkoxy, hydroxy, nitrile, amino, C 1~4 Alkylamino, (C 1~4 alkyl)2 optionally substituted with one or more groups independently selected from amino, aryl, cycloalkyl, and heterocyclyl; Aryl (including when present as an optional substituent) is selected from halo, hydroxy, nitrile, amino, C 1~4 Alkylamino and (C 1~4 Alkyl)2amino, C 1~4 Alkyl, C 1~4 Alkoxy, HaloC 1~4 Alkyl, HaloC 1~4 optionally substituted with one or more groups independently selected from alkoxy, aryl, cycloalkyl, and heterocyclyl; Cycloalkyl (including when present as an optional substituent) is selected from halo, hydroxy, nitrile, amino, C 1~4 Alkylamino and (C 1~4 Alkyl)2amino, C 1~4 Alkyl, C 1~4 Alkoxy, HaloC 1~4 Alkyl, HaloC 1~4 optionally substituted with one or more groups independently selected from alkoxy, aryl, cycloalkyl, and heterocyclyl; Heterocyclyl (including when present as an optional substituent) is selected from halo, hydroxy, nitrile, amino, C 1~4 Alkylamino and (C 1~4 Alkyl)2amino, C 1~4 Alkyl, C 1~4 Alkoxy, HaloC 1~4 Alkyl, HaloC 1~4It is optionally substituted with one or more groups independently selected from alkoxy, cycloalkyl, heterocyclyl and aryl.

[0109] In some embodiments, R 4 is C 1~6 Alkyl, aryl, cycloalkyl, heterocyclyl, C 1~6 Alkylcycloalkyl, C 1~6 Alkylaryl, C 1~6 Alkylheterocyclyl, C 3~10 Cycloalkylaryl, C 3~10 Cycloalkylheterocyclyl, C 3~10 Cycloalkyl C 3~10 Cycloalkyl, 3- to 6-membered non-aromatic heterocyclyl-aryl, 3- to 6-membered non-aromatic heterocyclyl-C 3~10 cycloalkyl and 3- to 6-membered non-aromatic heterocyclyl-3- to 10-membered heterocyclyl, wherein cycloalkyl, aryl, and heterocyclyl are each selected from halo, hydroxy, nitrile, amino, C 1~4 Alkylamino and (C 1~4 Alkyl)2amino, C 1~4 Alkyl, C 1~4 Alkoxy, HaloC 1~4 Alkyl and halo C 1~4 and optionally substituted with one or more groups independently selected from alkoxy.

[0110] In some embodiments, Y and Z are H, R 4 , -OR 4 , -NR 4 R 5 and at least one of Y and Z is H; R 4 But C 1~6 Alkyl, aryl, cycloalkyl, heterocyclyl and -(CH2) m R 9 is selected from R 9 But C 3~10 selected from cycloalkyl, aryl, heterocyclyl; m is an integer selected from 1 to 6; Cycloalkyl, aryl and heterocyclyl are each independently selected from halo, C 1~4 Alkyl, C 1~4 Alkoxy, HaloC 1~4 Alkyl and HaloC 1~4 and optionally substituted with one or more groups independently selected from alkoxy.

[0111] In some embodiments, Y and Z are H, R 4 , -OR 4 , -NR 4 R 5 and at least one of Y and Z is H; R 4 But C 1~4 Alkyl, cycloalkyl, haloaryl, -C 1~2 Alkylaryl, -C 1~2 Alkylarylhalo, -C 1~2 Alkyl C 3~6 Cycloalkyl, -C 1~2 Alkylheterocyclyl, -C 1~2 AlkylarylC1 alkylhalo, -C 1~2 AlkylarylhaloC1 alkyl, -C 1~2 Alkylarylhaloalkoxy, cycloalkylaryl, cycloalkylheterocyclyl, cycloalkylcycloalkyl, 3- to 6-membered non-aromatic heterocyclyl-aryl, 3- to 6-membered non-aromatic heterocyclylcycloalkyl, 3- to 6-membered non-aromatic heterocyclyl-3- to 10-membered heterocyclyl, 3- to 6-membered heteroaryl-aryl, 3- to 6-membered heteroarylcycloalkyl, 3- to 6-membered heteroaryl-3- to 10-membered heteroaryl, C 1~2 Alkyl-3 to 6-membered non-aromatic heterocyclyl and C 1~2 alkyl-3- to 6-membered heteroaryl; Alkyl, cycloalkyl, aryl, aralkyl, non-aromatic heterocyclyl, heteroaryl and alkoxy are each selected from halo, hydroxy, nitrile, amino, C 1~4 Alkylamino and (C 1~4Alkyl)2amino, C 1~4 Alkyl, C 1~4 Alkoxy, HaloC 1~4 Alkyl, HaloC 1~4 It is optionally substituted with a group selected from alkoxy and acyl.

[0112] In some embodiments, Y and Z are H and -OR 4 are independently selected from

[0113] In some embodiments, Z is H.

[0114] In some embodiments, Y is H, R 4 , -OR 4 , -NR 4 R 5 is selected from.

[0115] In some embodiments, Z is H and Y is R 4 , -OR 4 , -NR 4 R 5 is selected from.

[0116] In some embodiments, Z is H and Y is -OR 4 is.

[0117] In some embodiments, R 4 is an optionally substituted C alkyl C aryl or an optionally substituted C alkyl heteroaryl. In some embodiments, the C alkyl moiety is substituted. In some embodiments, the aryl or heteroaryl moiety is substituted.

[0118] In some embodiments, R 4 is an optionally substituted C1 alkylC6 aryl moiety represented by the subformula [ka] [In the formula, Ra and R b is H, optionally substituted C 1~4 Alkyl, optionally substituted C 1~4 Alkoxy, optionally substituted C 1~4 Alkylhydroxy, optionally substituted C 1~4 Alkylnitrile, optionally substituted amino, optionally substituted C 1~4 Alkylamino and optionally substituted (C 1~4 alkyl)2amino, or R a and R b together with the carbon atoms to which they are attached, form an optionally substituted C 3~6 forming a cycloalkyl or a 3- to 6-membered non-aromatic heterocyclyl; R c is halo and optionally substituted C 1~4 alkyl, m is 0, 1 or 2].

[0119] In some embodiments, R a and R b is H, optionally substituted C 1~4 Alkyl, optionally substituted C 1~4 Alkoxy, optionally substituted C 1~4 Alkoxy C 1~2 Alkyl, optionally substituted C 1~4 Alkylhydroxy, optionally substituted C 1~4 Alkylnitriles, optionally substituted C 1~4 Alkylamino and optionally substituted (C 1~4 R is independently selected from the group consisting of alkyl, 2-amino, a and / or R b is arbitrarily substituted C 1~4 When it is alkylamino, C 1~4 The alkyl or amino moiety may be optionally substituted.

[0120] In some embodiments, R a and Rb together with the carbon atom to which they are attached, form an optionally substituted C selected from optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted oxetane, and optionally substituted azetidine. 3~6 It forms a cycloalkyl or a 3- to 6-membered non-aromatic heterocyclyl.

[0121] In some embodiments, R a and R b together with the carbon atoms to which they are attached form a 3- to 6-membered non-aromatic heterocyclyl containing 1 or 2, preferably 1, heteroatom, preferably a heteroatom selected from O and N.

[0122] In some embodiments, m is 0 or 1.

[0123] In some embodiments, m is 1 or 2.

[0124] In some embodiments, at least one R c is in the para position relative to the benzylic carbon atom.

[0125] In some embodiments, R c is selected from methyl, fluoro and chloro.

[0126] In some embodiments, R a is selected from H and methyl, and R b is H.

[0127] In some embodiments, R a and R b together with the carbon atom to which they are attached is cyclopropyl.

[0128] In some embodiments, R 4 Ha-CR a Rb heteroaryl, wherein the heteroaryl moiety is one or two R c Optionally substituted by a group R a , R b and R c may be as defined for any embodiment described herein. In some embodiments, -CR a R b The heteroaryl portion of the heteroaryl group is a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, S, and O. In some embodiments, the heteroaryl portion is selected from optionally substituted oxazolyl and optionally substituted thiazolyl.

[0129] In some embodiments, Y is -OR 4 , -NR 4 R 5 is selected from.

[0130] In some embodiments, Y is -OR 4 , -NR 4 R 5 R when selected from 4 has a partial structure (A) [ka] [In the formula, R d is H, optionally substituted C 1~4 Alkyl, optionally substituted C 1~4 Alkoxy, optionally substituted C 1~4 Alkoxy C 1~4 Alkyl, optionally substituted C 1~4 Alkylhydroxy, optionally substituted C 1~4 Alkylnitriles, optionally substituted C 1~4 Alkylamino and optionally substituted (C 1~4 alkyl)2amino, optionally substituted cycloalkyl and optionally substituted C 1~4 alkylcycloalkyl; R e is an optionally substituted aryl, an optionally substituted C 1~5 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1~5 Alkylheterocyclyl, optionally substituted cycloalkyl, and optionally substituted C 1~5 Alkyl C 3~10 cycloalkyl.

[0131] In some embodiments, R d is methyl.

[0132] In some embodiments, R e is an optionally substituted aryl, an optionally substituted C 1~5 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1~4 Alkylheterocyclyl, optionally substituted cycloalkyl, and optionally substituted C 1~4 Alkyl C 3~10 cycloalkyl.

[0133] In some embodiments, R e is selected from optionally substituted aryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl.

[0134] In some embodiments, R e is selected from optionally substituted aryl and optionally substituted heteroaryl.

[0135] In some embodiments, R d is an arbitrarily substituted C 1~4 Alkyl, optionally substituted C 1~4 Alkoxy, optionally substituted C 1~4 Alkoxy C 1~4 Alkyl, optionally substituted cycloalkyl and optionally substituted C 1~4 In these embodiments, R d and R e are not the same group, the substructure (A) is d and R e can contain a chiral center at the carbon to which R is attached. d and R e The carbon atom to which R is attached may be enantiomerically enriched. d and R e The carbon atom to which is bonded is, for example, R e However, in the Cahn-Ingold-Prelog rules for stereochemical assignment, R d When it has a higher ranking, it is enriched as the (S) stereoisomer. d and R e The carbon atom to which is bonded is, for example, R e However, in the Cahn-Ingold-Prelog rules for stereochemical assignment, R d When it has a lower ranking, it is enriched as the (R) stereoisomer. d is an arbitrarily substituted C 1~4 alkyl, and R d and R e is enriched as the (S) stereoisomer. The inventors have surprisingly found that compounds having the (S) configuration at this position have higher MLKL activity than compounds having the (R) configuration at the same position. In some cases, the S-stereoisomer is more than two-fold more active than the corresponding R-stereoisomer, and in some embodiments, the S-stereoisomer is at least about five-fold or about ten-fold more active for MLKL inhibition than the corresponding R-stereoisomer.

[0136] In some embodiments, substructure (A) can have the stereochemical configuration shown by substructure (A1): [ka] [In the formula, R e is R in the Cahn-Ingold-Prelog rules for stereochemical assignment. d have a higher ranking].

[0137] In some embodiments, the compound is provided as a compound of formula (S) [ka] [In the formula, X, Q 1 , Q 2 , R 2 and R 3 is as defined for formula (I), and R e and R d is as defined for sub-formula (A), and Y 1 O and NR 5 Select from].

[0138] In some embodiments, R 4 is selected from any one of the following groups: [ka] [ka]

[0139] In some embodiments, R 4 teeth, [ka] is.

[0140] In some embodiments, R 5 is selected from H and methyl.

[0141] In some embodiments, R 5 is H.

[0142] In some embodiments, Y is H.

[0143] In some embodiments, Z is H.

[0144] In some embodiments, Y and Z are both H.

[0145] In some embodiments, R 1 and R 3 is H.

[0146] In some embodiments, R 2 is selected from optionally substituted phenyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, optionally substituted 8-membered heteroaryl, optionally substituted 9-membered heteroaryl, and optionally substituted 10-membered heteroaryl.

[0147] In some embodiments, R 2 is selected from optionally substituted phenyl, optionally substituted 5-membered monocyclic heteroaryl, optionally substituted 6-membered monocyclic heteroaryl, and optionally substituted 10-membered bicyclic heteroaryl.

[0148] In some embodiments, R 2 is represented by any one of the sub-formulas Ar1 to Ar3 [ka] [In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 is CR 11 and N are independently selected from A 9 , A 10 , A 11 and A 12 is C(R 11 ) q , O, S, N and NR12 are independently selected from A 1 , A 2 , A 3 , A 4 and A 5 Two or less of are N, A 6 , A 7 and A 8 Two or less of are N, A 9 , A 10 , A 11 and A 12 At least one of C(R 11 ) q , O, S and NR 12 is selected from R 11 are H and R, respectively. 10 are independently selected from R 10 are halo and C, respectively. 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, -OC 1~6 Alkyl C 1~4 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, nitrile, amide, C 1~6 Alkylamides, (C 1~6 Alkyl)2 amide, halo C 1~6 Alkylamides, (HaloC 1~6 Alkyl)2 Amide, Acyl, C 1~6 Alkyl acyl, halo C 1~6 Alkyl acyl, arylacyl, heterocyclyl acyl, C 3~10 Cycloalkyl acyl, heterocyclyl, halo C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 1~6 Alkyl C 3~10 Cycloalkyl, C 1~6 Alkoxy C 3~10 Cycloalkyl, HaloC 1~6 Alkyl C 3~10 Cycloalkyl, HaloC 1~6 Alkoxy C 3~10 Cycloalkyl, C1~6 Alkylheterocyclyl, C 1~6 Alkoxyheterocyclyl, HaloC 1~6 Alkylheterocyclyl, HaloC 1~6 Alkoxyheterocyclyl, C 1~6 Alkyl C 1~6 independently selected from alkoxy, and —COOH; R 12 are H and C, respectively. 1~6 Alkyl, HaloC 1~4 Alkyl, C 1~6 Alkyl acyl and halo C 1~6 independently selected from alkyl acyl; Or, A 1 , A 2 , A 3 , A 4 , A 5 , A 7 , A 8 , A 9 , A 10 , A 11 and A 12 Two adjacent groups (e.g., A 1 and A 2 , A 2 and A 3 , A 3 and A 4 , A 4 and A 5 , A 8 and A 7 , A 9 and A 10 , A 10 and A 11 , A 11 and A 12 ) is CR 11 and N.R. 12 When selected from two R 11 , two R 12 or one R 11 and one R 12 can be taken together to form an optionally substituted 5- to 10-membered ring selected from cycloalkyl, aryl, and heterocyclyl; p is an integer from 0 to 4, q is 1 or 2].

[0149] In some embodiments, A 1 , A 2 , A 3 , A 4 and A 5 0, 1 or 2 of the are N.

[0150] In some embodiments, A 6 , A 7 and A 8 0, 1 or 2 of the are N.

[0151] In some embodiments, R 10 is selected from fluoro, chloro, methyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoroethoxy, nitrile, amido, trifluoromethoxy, —OCH 2 CH 2 OCH 3 , cyclopropyl, and morpholino.

[0152] In some embodiments, the compound is R 10 In the case of , it includes 1, 2, 3 or 4 or less.

[0153] In some embodiments, R 2 is represented by the sub-formula Ar1.

[0154] In some embodiments, R 2 is represented by the sub-formula Ar3.

[0155] In some embodiments, A 10 is NR 12 and A 12 is CR 11 is.

[0156] In some embodiments, A 9 and A 11 is CR 11 , N, O and S. In some embodiments, A 9 is CR 11 When A11 is N, O or S, and A 9 is N, O or S, then A 11 is CR 11 is.

[0157] In some embodiments, A 9 and A 11 are CR 11 is.

[0158] In some embodiments, A 10 and A 12 are CR 11 is.

[0159] In some embodiments, A 9 , A 10 , A 11 and A 12 At least one of the groups is O, S, N, and NR 12 is selected from.

[0160] In some embodiments, A 9 , A 10 , A 11 and A 12 One of the is O, S and NR 12 is selected from.

[0161] In some embodiments, the subformula Ar3 is provided by any one of the subformulas Ar3-I, Ar3-II, Ar3-III, and Ar3-IV. [ka] [In the formula, In Ar3-I, A 9 is C(R 11 )2, O, S and NR 12 , preferably O, S and NR 12 is selected from In Ar3-II, A 10 is C(R 11 )2, O, S and NR 12 , preferably O, S and NR12 is selected from In Ar3-III, A 11 is C(R 11 )2, O, S and NR 12 , preferably O, S and NR 12 is selected from In Ar3-IV, A 12 is C(R 11 )2, O, S and NR 12 , preferably O, S and NR 12 Select from].

[0162] In some embodiments, A 10 and A 11 are two R 11 , two R 12 or R 11 and R 12 are taken together to form a 5- to 10-membered cycloalkyl, aryl, or heterocyclyl ring. 11 and N.R. 12 are independently selected from

[0163] In some embodiments, A 10 is CR 11 and A 11 is NR 12 and R 11 and R 12 taken together form a 5-10 membered cycloalkyl, aryl or heterocyclyl ring. 12 can be N and / or A 9 is CR 11 In some embodiments, A 10 is CR 11 and A 11 NR 12 When R 11 and R 12 taken together form a 5- to 10-membered heterocyclyl ring, preferably a non-aromatic heterocyclyl ring. 10 is CR 11 and A 11 NR12 When R 11 and R 12 taken together form a 5- to 8-membered cycloalkyl, aryl or heterocyclyl ring, preferably a 6- or 7-membered ring, more preferably a 6- or 7-membered heterocyclyl ring.

[0164] Two R on adjacent ring atoms 11 , two R 12 or one R 11 and R 12 When R forms a condensed ring, the condensed ring is 10 The R groups described herein may be optionally substituted. 10 Any group may be suitable.

[0165] In some embodiments, R 12 is methyl.

[0166] In some embodiments, the compound of formula (I) is a compound of formula (II) [ka] [In the formula, Q 1 , Q 2 , X, Y, Z and R 3 is as defined in formula (I), and A 1 ~A 5 is as defined for the sub-formula Ar1].

[0167] In some embodiments, A 1 is N.

[0168] In some embodiments, A 4 is N.

[0169] In some embodiments, A 1 and A 4 is N.

[0170] In some embodiments, A 2 is N.

[0171] In some embodiments, A 1 and A 3 is N.

[0172] In some embodiments, A 2 is CR 10 is.

[0173] In some embodiments, A 6 is N.

[0174] In some embodiments, A 7 is N.

[0175] In some embodiments, A 6 and A 7 is N.

[0176] In some embodiments, R 2 is a 5-, 6-, or 10-membered heteroaryl containing 0, 1, or 2 substituents selected from fluoro, chloro, methyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoroethoxy, trifluoromethoxy, -OCH2CH2OCH3, cyclopropyl, nitrile, amido, and morpholino. Preferably, the substituents are selected from methyl, trifluoromethyl, and methoxy. Preferably, R 2 When is a 10-membered heteroaryl, it is a fused bicyclic ring system.

[0177] In some embodiments, R 2 is a 5-, 6-, or 10-membered heteroaryl containing 1 or 2 nitrogen atoms substituted by 0, 1, or 2 substituents.

[0178] In some embodiments, R 2 is one or two nitrogen atoms substituted by zero or one substituent selected from methyl, trifluoromethyl and methoxy; Typically, the substituents, if present, are R 2 is attached to the nitrogen atom in the meta or para position (e.g., A in the subformula Ar1) 2 or A 3 (corresponding to the position shown for

[0179] In some embodiments, R 2 is the following radical: methyl, [ka] [ka] is selected from one of the following.

[0180] In some embodiments, R 2 is the following radical: [ka] is selected from one of the following.

[0181] In some embodiments of the compounds of Formula (I), X is an optionally substituted C 1~4 Alkyl, optionally substituted haloC 1~4 Alkyl and optionally substituted C 3~6 cycloalkyl; Y and Z are independently selected from H and —OC1 alkylaryl; R 1 and R 3 is H, R 2 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms substituted by 0 or 1 substituent selected from methyl, trifluoromethyl and methoxy.

[0182] In some embodiments of the compounds of Formula (I), X is an optionally substituted haloC1~4 alkyl, preferably optionally substituted haloC 1~2 alkyl, more preferably difluoromethyl; Y is -OR 4 , preferably optionally substituted -OC 1~4 alkylaryl, more preferably S)-1-(4-fluorophenyl)-1-methyl-methoxy; Z is H, R 1 and R 3 is H, R 2 is a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O, substituted by 0 or 1 substituents selected from methyl, trifluoromethyl and methoxy, preferably substituted by 0 or 1 methyl substituents.

[0183] In some embodiments, the compound is any of compounds 1-320 described herein, preferably 9, 14, 21-22, 24-25, 34, 39, 41-43, 53, 62-63, 66, 68, 71, 84, 88, 90, 92-93, 101-102, 108, 113, 115, 123-124, 127-128, 139-140, 143-144, 146, 150, 152-158, 160-166, 169-170, 171-172, 172-174, 173-175, 174-175, 175-176, 177-178, 178-179, 180-181, 182-183, 183-184, 185-186, 187-188, 189-200, 189-201, 189-202, 190-192, 191-203, 192-204, 193-205, 194-206, 195-207, 196-208, 197-209, 198-209, 199-2010, 199-2011, 199-2012, 200-2013, 2010-2014, 2010-2020, 2010-2021, 2010-2022, 2010-2023, 2010 171, 175-176, 181, 188, 190-191, 194, 196, 198-199, 202, 208, 222-223, 229, 233-235, 238, 242, 245-246, 248-249, 251-253, 256, 259-260, 262, 264-266, 271, 273-279, 281-286, 288-299, 301-312, 314 and 316-320.

[0184] Typically, the compounds of the present invention may be prepared by techniques known in the art.

[0185] In another aspect, methods for preparing a compound of Formula (I) or a salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof are also provided. In some embodiments, the method comprises any of the following four steps:

[0186] reacting a compound of formula (III) with a compound of formula (IV) [ka] [Wherein X and R 2 is as defined for formula (I), Q 3 and Q 4 N and N-PG 1 Selected from Q 3 When N, Q 4 is N-PG 1 and Q 4 When N, Q 3 is N-PG 1 and Y' is selected from halo and Y, where Y is as defined for formula (I); Z' is selected from halo and Z, where Z is as defined for formula (I); PG 1 is R 1 or an amino protecting group, such as tert-butyl, benzyl, BOC, etc., and R 1 is as defined for formula (I), LG is a leaving group such as halo. The leaving group may be any leaving group capable of activating the sulfonyl moiety of the compound of formula (IV) as an electrophile that can react with the free aniline nitrogen of the compound of formula (III) under appropriate conditions; E 6 is selected from -CN and -C(O)NH2;

[0187] reacting a compound of formula (V) with a compound of formula (VI) [ka] [In the formula, Q 3 , Q 4 , E 6 , Y′ and Z′ are as defined for formula (III), and R 2 is as defined for formula (I), E 3 -NO2, -NHR 3 , -NR 3 PG 2 and -NHSOX, where X and R are selected from 3 is as defined in formula (I), and PG 2 is an amino protecting group, E 1 is selected from NH2 or halo; E 2 is E 1 and E 2 selected from NH2 or halo, provided that one of is NH2 and the other is halo;

[0188] reacting a compound of formula (VII) with a compound of formula (VIII) [ka] [In the formula, E 3 is as defined for formula (V), and Q 3 , Q 4 , E 6 , Y' and Z' are as defined for formula (III); E 4 is selected from halo, boronic acid and boronic ester; E 5 is E 4 and E 5 is selected from halo, boronic acid, and boronic ester, provided that one of is halo and the other is a boronic acid or boronic ester; E 7 Halo, -NH2 and -NHR 2 Selected from R 2 is as defined for formula (I)],

[0189] converting the compound of formula (I) into one of its salts.

[0190] In some embodiments, Q 3 is N and Q 4 is N-PG 1 is.

[0191] In some embodiments, Q 3 is N-PG 1 and Q 4 is N.

[0192] In some embodiments of the above method, PG 1 is an amino protecting group, the method , further comprising a deprotection step.

[0193] In some embodiments, when Y' is halo, the method comprises reacting a compound of formula (III), (V) or (VII) with Y-LG 2 (Here, LG 2 is a leaving group and Y is as defined in formula (I). Typically, this reaction is a palladium-mediated crosslinking reaction. In some embodiments, this reaction occurs with the reaction product of compounds of formulas (III) and (IV), (V) and (VI), or (VII) and (VIII).

[0194] In some embodiments, when Z' is halo, the method comprises reacting a compound of formula (III), (V) or (VII) with Z-LG 3 (Here, LG 3 is a leaving group and Z is as defined in Formula (I). Typically, this reaction is a palladium-mediated crosslinking reaction. In some embodiments, this reaction occurs with the reaction product of compounds of Formulas (III) and (IV), (V) and (VI), or (VII) and (VIII).

[0195] In some embodiments, E 6When is -CN, the method further comprises converting -CN to -C(O)NH2.

[0196] An embodiment of these steps is R 2 is the subexpression AR 1 For compounds represented by the formula:

[0197] The specific reagents and conditions for effecting each of these steps depend on the specific substituents selected for each reaction partner. Those skilled in the art will readily understand how to determine and / or optimize these reagents and conditions. Similarly, if the starting material is not commercially available, those skilled in the art can design and carry out its preparation based on the techniques and reactions previously described. Embodiments of these steps are described in the Examples for the specific compounds described herein.

[0198] method In another aspect, there is provided a method of inhibiting necroptosis in a subject in need thereof, comprising administering a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof.

[0199] Without wishing to be bound by any particular theory, the compounds of the present invention are believed to treat necroptosis by binding to the ATP-binding site of the pseudokinase domain of the mixed lineage kinase domain-like (MLKL) protein.

[0200] As used herein, the term "effective amount" refers to an amount of a drug or agent that elicits the biological or medical response of a tissue, system, animal, or human that is being sought, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" refers to any amount that results in improved treatment, cure, prevention, or reversal of a disease, disorder, or side effect, or a slower rate of progression of a disease or disorder, compared to a corresponding subject that has not received such amount. This term also includes within its scope an amount effective to improve normal physiological function.

[0201] In one embodiment of the present disclosure, administration of a compound according to formula (I) inhibits a conformational change of MLKL. In another embodiment, the conformational change of MLKL is accompanied by the release of the four-helix bundle (4HB) domain of MLKL. In another embodiment, administration of the compound inhibits the oligomerization of MLKL. In yet another embodiment, administration of the compound inhibits the oligomerization of MLKL. Inhibiting translocation of MLKL to the cell membrane In another embodiment, administration of the compound inhibits conformational changes in MLKL, inhibits oligomerization of MLKL, and inhibits translocation of MLKL to the cell membrane.

[0202] It is contemplated that some compounds of the present disclosure can bind to MLKL and inhibit necroptosis in various species.

[0203] As used herein, the term "pseudokinase domain," as understood by those skilled in the art, refers to a protein containing a catalytically inactive or catalytically defective kinase domain. "Pseudokinase domains" are often referred to as "protein kinase-like domains" because these domains lack conserved residues known to catalyze phosphoryl transfer. Those skilled in the art will appreciate that while pseudokinase domains are expected to function primarily as catalysis-independent protein interaction modules, some pseudokinase domains have been implicated in unexpected catalytic functions. Thus, in the present disclosure, the term "pseudokinase domain" includes "pseudokinase domains" that lack kinase activity and "pseudokinase domains" that have weak kinase activity.

[0204] As used herein, the term "ATP-binding site" refers to a specific sequence of a protein subunit that facilitates the binding of ATP to a target protein, as understood by those skilled in the art. The ATP-binding site is a protein microenvironment where ATP is captured and hydrolyzed to ADP, thereby releasing energy that the protein utilizes to work by changing the shape of the protein and / or making the enzyme catalytically active. In pseudokinase domains, the "ATP-binding site" is often referred to as the "pseudoactive site." The term "ATP-binding site" may also be referred to as the "nucleotide-binding site," since binding at this site includes binding of nucleotides other than ATP. Those skilled in the art will understand that the term "nucleotide" includes any nucleotide. Exemplary nucleotides include, but are not limited to, AMP, ADP, ATP, AMPPNP, GTP, CTP, and UTP.

[0205] As described herein, treating and / or inhibiting necroptosis includes both complete and partial inhibition of necroptosis. In one embodiment, the inhibition of necroptosis is complete. In another embodiment, the inhibition of necroptosis is partial.

[0206] Binding of a compound to the ATP-binding site of the pseudokinase domain of MLKL can inhibit phosphorylation of MLKL by effector kinases, or binding of a compound to the ATP-binding site of the pseudokinase domain of MLKL can inhibit phosphorylation of MLKL by effector kinases. The present disclosure reveals that compounds that bind to the ATP-binding site of the pseudokinase domain of the MLKL protein described herein can inhibit necroptosis without inhibiting phosphorylation of MLKL by effector kinases. In one embodiment, binding of a compound to the ATP-binding site of the pseudokinase domain of MLKL does not inhibit phosphorylation of MLKL by effector kinases. In another embodiment, binding of a compound to the ATP-binding site of the pseudokinase domain of MLKL inhibits phosphorylation of MLKL by effector kinases.

[0207] RIP1, RIP3, and MLKL are three proteins implicated in the necroptosis pathway. Upon stimulation of necroptosis (e.g., using a combination of TNF, SMAC mimetics, and QVD-OPh on a suitable cell line), RIP1 is autophosphorylated and binds to RIP3, which itself autophosphorylates. Activated RIP3 phosphorylates MLKL, leading to a predicted conformational change that triggers its necroptotic activity (Murphy, Immunity, 39, 443-453, 2013). MLKL is a RIP3-dependent phosphoprotein. MLKL acts downstream of RIP3 and RIP4, and is therefore understood to be a key effector of necroptosis. Compounds of the present invention can bind to MLKL and block this conformational change or any other key event in its activation.

[0208] Compounds of the invention can be selective for MLKL. In some embodiments, compounds of the invention are selective for MLKL over RIP1. In some embodiments, compounds of the invention are selective for MLKL over RIP3. In some embodiments, compounds of the invention are selective for MLKL over RIP1 and RIP3. Selective compounds can have 5-fold, 10-fold, 50-fold, 100-fold, 500-fold, 1000-fold or more greater selectivity for MLKL compared to RIP1 and / or RIP3. Typically, relative selectivity is measured by the K D The assay can be evaluated by comparing the values. Suitable assay conditions are described in the Examples below. Compounds selective for MLKL can avoid the undesirable side effects associated with loss of RIP1 and / or RIP3 function.

[0209] In another aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, N-oxide and / or prodrug thereof for use as a pharmaceutical.

[0210] In another aspect, there is provided the use of a compound of formula (I), a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof in the preparation of a medicament for the inhibition of necroptosis in a subject.

[0211] In another aspect, there is provided a use of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof for inhibiting necroptosis in a subject.

[0212] In another aspect, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof for inhibiting necroptosis.

[0213] In another aspect, there is provided a use of a composition comprising a compound of formula (I) or a salt, solvate, N-oxide, stereoisomer and / or prodrug thereof for inhibiting necroptosis.

[0214] In yet another aspect, there is provided a compound according to formula (I) or a salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof for use in inhibiting necroptosis.

[0215] In yet another aspect, there is provided a composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof for use in inhibiting necroptosis. In some embodiments, the composition is a pharmaceutical composition.

[0216] In yet another embodiment, there is provided a compound according to formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof when used to inhibit necroptosis.

[0217] In yet another embodiment, there is provided a composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof when used to inhibit necroptosis.

[0218] In another aspect, a method of inhibiting MLKL is provided, comprising contacting a cell with an effective amount of a compound of formula (I) or a salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof.

[0219] Salts of compounds of formula (I) are preferably pharmaceutically acceptable salts, although it is recognized that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure as, for example, they may be useful as intermediates in processes that do not require the preparation of a pharmaceutically acceptable salt or administration to a subject.

[0220] The term "pharmaceutically acceptable" may be used to describe any salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug, or any other compound that, when administered to a subject, can yield (directly or indirectly) a compound of Formula (I) or an active metabolite or residue thereof and that is typically not deleterious to the subject.

[0221] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or salts of pharmaceutically acceptable organic acids, such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, mucic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid.

[0222] Base salts include, but are not limited to, salts formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium (such as salts formed with triethylamine), alkoxyammonium (such as salts formed with ethanolamine), and salts formed with ethylenediamine, choline, or amino acids such as arginine, lysine, or histidine. General information regarding the types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and can be found in comprehensive textbooks such as "Handbook of Pharmaceutical Salts," PH Stahl, CG Wermuth, 1st Edition, 2002, Wiley-VCH.

[0223] For compounds that are solids, one of skill in the art will recognize that the compounds, agents, and salts of the present invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specified formulas.

[0224] The present invention includes all crystalline forms of the compound of formula (I), including anhydrous crystalline forms, hydrates, solvates and mixed solvates. If any of these crystalline forms exhibit crystalline polymorphism, all polymorphs are within the scope of the present invention.

[0225] Formula (I) is intended to include, where applicable, solvated and unsolvated forms of the compounds. Thus, Formula (I) includes compounds having the indicated structure, including hydrated or solvated forms as well as unhydrated and unsolvated forms.

[0226] Compounds of formula (I) or their salts, tautomers, N-oxides, polymorphs or prodrugs The compound may be provided in the form of a solvate. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and may be formed with pharmaceutically acceptable solvents such as water, alcohols such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethylformamide (DMF), acetic acid, etc. during the crystallization process, and solvates form part of the crystal lattice by non-covalent bonding or by occupying holes in the crystal lattice. When the solvent is water, a hydrate is formed, and when the solvent is alcohol, an alcoholate is formed. Solvates of the compounds of the present invention can be conveniently prepared or formed during the processes described herein. In general, solvated forms are considered equivalent to unsolvated forms in the present invention.

[0227] Basic nitrogen-containing groups include C groups such as methyl, ethyl, propyl, and butyl chloride, bromide, and iodide. 1~6 They may be quaternized with agents such as alkyl halides; dialkyl sulfates such as dimethyl and diethyl sulfate; and the like.

[0228] Nitrogen-containing groups can also be oxidized to form N-oxides.

[0229] Compounds of formula (I) or their salts, tautomers, N-oxides, solvates and / or prodrugs that form crystalline solids may exhibit crystalline polymorphism. All crystalline polymorphs of the compounds, salts, tautomers, N-oxides, solvates and / or prodrugs are within the scope of the present invention.

[0230] Compounds of formula (I) may exhibit tautomerism. Tautomers are two interchangeable forms of a molecule that typically exist in equilibrium. It should be understood that all tautomers of compounds of formula (I) are within the scope of the present invention. For example, R 1 When R is H, the compounds of formula (1A) and (1B) may exist as tautomers, e.g., in equilibrium with each other. 1is H) are depicted below as compounds of formula (1A') and (1B'). The proportion of compounds of formula (1A') and (1B') at equilibrium may depend on the particular compound and conditions, such as solvent, temperature, concentration, etc. This equilibrium may be described as follows: [ka]

[0231] Similar tautomerism may occur for any of the pyrazole-containing compounds described herein, including compounds of Formulas (II), (III), (V), (VIII), and (SI), as well as compounds 1-320. All tautomers of these compounds are contemplated and considered within the scope of the present invention. Additionally, for the compounds described herein, alternative tautomeric forms may exist, depending, for example, on the selection of various substituents.

[0232] The compounds of formula (I) may contain one or more stereocenters. All stereoisomers of the compounds of formula (I) are within the scope of the present invention. Stereoisomers include enantiomers, diastereomers, geometric isomers (E and Z olefin forms and cis and tra forms). n-substitution patterns) and atropisomers. In some embodiments, the compound is a stereoisomerically enriched form at any stereocenter of the compound of Formula (I). The compound may be at least about 60, 70, 80, 90, 95, 98, or 99% enriched in one stereoisomer over another.

[0233] The compounds of formula (I) or their salts, tautomers, solvates, N-oxides, and / or stereoisomers may be isotopically enriched with one or more of the isotopes of atoms present in the compounds. For example, the compounds may contain the following minor isotopes: 2 H, 3 H, 13 C. 14 C. 15 N and / or 17It may be enriched with one or more of O. An isotope may be considered enriched when its abundance is above its natural abundance.

[0234] A "prodrug" is a compound that may not fully meet the structural requirements of the compounds described herein, but that is modified in vivo following administration to a subject or patient to produce a compound of Formula (I) described herein. For example, a prodrug can be an acylated derivative of a compound described herein. Prodrugs include compounds in which a hydroxy, carboxy, amine, or sulfhydryl group is attached to either group, which, upon administration to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate, and benzoate derivatives of alcohol and amine functional groups within the compounds described herein. Prodrugs of the compounds described herein can be prepared by modifying functional groups present in the compound such that the modified group is cleaved in vivo to yield the parent compound.

[0235] Prodrugs include compounds in which an amino acid residue or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues is covalently bonded to free amino and amide groups of a compound of Formula (I). The amino acid residues include the 20 naturally occurring amino acids, usually designated by their three-letter code, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norbrine, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs also include compounds in which carbonates, carbamates, amides, and alkyl esters are covalently bonded to the above substituents of Formula (I) through the carbonyl carbon prodrug side chain.

[0236] Pharmaceutical compositions may be formulated from the compounds according to formula (I) for any suitable route of administration, including, for example, oral, rectal, nasal, intravaginal, topical (including transdermal, buccal, ocular and sublingual), parenteral (including subcutaneous, intraperitoneal, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, intracisternal injection, and any other similar injection or infusion technique), inhalation, insufflation, infusion or implantation techniques (e.g., as a sterile aqueous or non-aqueous injectable solution or suspension).

[0237] In some embodiments, compositions in a form suitable for oral or parenteral use are preferred. Suitable oral forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. For intravenous, intramuscular, subcutaneous, or intraperitoneal administration, one or more compounds may be combined with a sterile aqueous solution that is preferably isotonic with the recipient's blood. Such formulations may be prepared by dissolving the solid active ingredient in water containing physiologically compatible substances such as sodium chloride or glycine and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering the solution sterile. Formulations may be presented in unit or multi-dose containers such as sealed ampoules or vials. See M for examples of ingredients. Artindale - The Extra Pharmacopoeia (Pharmaceutical Press, London, 1993), and Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, Lippincott Williams & Wilkins. All methods include the step of bringing into association the active ingredient, e.g., a compound defined by Formula (I) or its pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, N-oxide and / or prodrug, with the carrier, which constitutes one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing into association the active ingredient, e.g., a compound defined by Formula (I) or its pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, N-oxide and / or prodrug, with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active object compound is present in an amount sufficient to produce the desired effect. In some embodiments, the methods of the present invention include administering a pharmaceutical preparation comprising a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, N-oxide, and / or prodrug thereof and a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0238] Within the context of this specification, the terms "administering" and variations thereof, including "administer" and "administration," include contacting, applying, delivering, or providing a compound or composition of the invention to an organism or surface by any suitable means.

[0239] For inhibiting necroptosis, the dosage of the bioactive compound of the present invention can vary within a wide range and can be adjusted to individual requirements.The active compound of the present invention is generally administered in a therapeutically effective amount.The daily dosage can be administered as a single dose or multiple doses.The amount of active ingredient that can be combined with carrier material to produce a single dosage form varies depending on the treatment subject and specific administration mode.

[0240] However, it is understood that the specific dose level for any particular subject will depend on various factors, including the activity of the specific compound used, the subject's age, body weight, general health, sex and diet, administration time, administration route and excretion rate, drug combinations (i.e., other drugs used to treat the subject), and the severity of the specific disorder being treated. Such treatment can be administered as often as necessary and for as long as the treating physician deems necessary. Those skilled in the art will understand that the dosing regimen or therapeutically effective amount of the compound of formula (I) administered may need to be optimized for each individual.

[0241] It is also recognized that different dosages may be required to treat different disorders. An effective amount of an agent is an amount that results in a statistically significant reduction in necroptosis.

[0242] For in vitro analysis, necroptosis inhibition may be determined by the assay used to measure TSQ-induced necroptosis, as described in the biological test defined herein.

[0243] The terms "treating," "treatment," and "therapy" are used herein to refer to curative, prophylactic, and preventative therapies. Thus, within the context of this disclosure, the term "treating" encompasses curing, ameliorating, or lessening the severity of necroptosis and / or related diseases or symptoms thereof.

[0244] "Preventing" or "prevention" means preventing necroptosis from occurring or reducing its severity if necroptosis occurs following administration of a compound or pharmaceutical composition of the present invention.

[0245] A "subject" includes any human or non-human animal. Thus, in addition to being useful for human treatment, the compounds of the invention may also be useful for veterinary treatment of mammals, including companion animals and livestock, such as, but not limited to, dogs, cats, horses, cattle, sheep, and pigs.

[0246] The term "inhibit" is used to describe any form of inhibition, including complete and partial inhibition, that results in the prevention, reduction, or otherwise amelioration of necroptosis and / or MLKL function.

[0247] The compounds of the invention may be administered together with pharmaceutical carriers, diluents and / or excipients as described above.

[0248] The methods of the present disclosure can be used to prevent or treat the following diseases, conditions and / or disorders in a subject: Diseases of the bones, joints, connective tissue and cartilage, such as osteoporosis, osteomyelitis including chronic relapsing multiple osteomyelitis, arthritis including osteoarthritis, rheumatoid arthritis and psoriatic arthritis, avascular necrosis, fibrodysplasia ossificans progressiva, rickets, Cushing's syndrome; · Muscle diseases such as muscular dystrophies, for example Duchenne muscular dystrophy, myotonic dystrophy, myasthenia and myasthenia; · Skin disorders such as dermatitis, eczema, psoriasis, age-related or even scarring changes; Cardiovascular disease, such as cardiac and / or vascular ischemia, myocardial infarction, ischemic heart disease, chronic or acute congestive heart failure, cardiac dysrythmia, atrial fibrillation, ventricular fibrillation, paroxysmal tachycardia, congestive heart failure, hypertrophic heart disease, anoxia, hypoxia, or secondary effects of anti-cancer drug therapy; · Cardiovascular diseases such as atherosclerosis, arteriosclerosis and peripheral vascular disease, stroke, including cerebrovascular accident, and aneurysms; Hematological and vascular diseases such as anemia, aplastic anemia, vascular amyloidosis, bleeding, sickle cell disease, red cell fragmentation syndrome, neutropenia, leukopenia, medullary hypoplasia, pancytopenia (pantocytopenia), thrombocytopenia, and hemophilia; · Pulmonary diseases, including pneumonia and asthma, and chronic obstructive lung diseases such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, and emphysema; Gastrointestinal disorders such as ulcers; inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis; diseases of the liver, such as, for example, hepatitis, in particular hepatitis of viral origin or with other infectious agents as the etiological agent, autoimmune hepatitis, fulminant hepatitis, inflammatory hepatitis, some inherited metabolic disorders, Wilson's disease, cirrhosis, non-alcoholic fatty liver disease (NAFLD) including non-alcoholic fatty liver disease and / or non-alcoholic steatohepatitis (NASH), liver diseases due to toxins and drugs, such as drug-induced liver injury and ethanol (or alcohol)-induced liver disease; · Diseases of the pancreas, for example acute or chronic pancreatitis; Metabolic diseases such as diabetes mellitus, prediabetes, and diabetes insipidus; thyroiditis; kidney disease, such as acute kidney injury (ischemia-reperfusion injury (IRI) or acute kidney injury (AKI), including glomerulonephritis); · Viral and bacterial infections such as sepsis; · Severe poisoning from chemicals, toxins or drugs; · Degenerative diseases associated with acquired immune deficiency syndrome (AIDS); · Age-related disorders such as the syndrome of accelerated aging; Crohn's disease, rheumatoid polyarthritis, and TNF-induced systemic inflammatory syndrome, inflammatory diseases such as terminal ileitis; · Autoimmune diseases such as lupus erythematosus (including systemic lupus erythematosus) and amputation-resistant RIPK1-induced autoinflammation (CRIA) syndrome; Dental disorders, such as periodontitis, which result in tissue degradation; · Eye diseases or disorders, including diabetic retinopathy, glaucoma, macular degeneration, degenerative retinal degeneration, retinitis pigmentosa, retinal holes or tears, retinal detachment, retinal ischemia, acute retinopathy associated with trauma, inflammatory degeneration, post-surgical complications, drug-induced retinopathy, cataracts, and cone cell degeneration; · Eustachian tube disorders such as antibiotic-induced otosclerosis and hearing loss; · Ischemia-reperfusion injury, including retinal ischemia-reperfusion injury; Neuronal loss, including neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS; also known as motor neuron disease (MND) and Charcot's disease); Diseases that are related to mitochondria (mitochondrial diseases), such as Friedreich's ataxia, congenital muscular dystrophies with structural mitochondrial abnormalities, some muscle disorders (MELAS syndrome, MERFF syndrome, Pearson syndrome), MIDD (Mitochondrial Diabetes and Deafness) syndrome, Wolfram syndrome, dystonia; Cancer of the lung and bronchus, including non-small cell lung cancer (NSCLC), squamous cell lung cancer, bronchioloalveolar carcinoma (BAC), lung adenocarcinoma, and small cell lung cancer (SCLC); prostate cancer, including androgen-dependent and androgen-independent prostate cancer; breast cancer, including metastatic breast cancer; pancreatic cancer; cancer of the colon and rectum; thyroid cancer; cancer of the liver and intrahepatic bile duct; hepatocellular carcinoma; gastric cancer; endometrial cancer; melanoma; cancer of the kidney, renal pelvis, bladder, uterine corpus, and cervix; ovarian cancer, including advanced epithelial or primary peritoneal cancer; multiple myeloma; esophageal cancer, including squamous cell carcinoma and adenocarcinoma of the esophagus; acute myeloid leukemia (AM) L); chronic myeloid leukemia (CML), including accelerated-phase CML and CML blastic phase (CML-BP); lymphocytic leukemia; myeloid leukemia; acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL); T-cell lymphoma; multiple myeloma (MM); amyloidosis; Waldenstrom's macroglobulinemia; refractory anemia (RA), ringed sideroblasts myelodysplastic syndromes (MDS), including refractory anemia with excess blasts (RARS), refractory anemia with excess blasts (RAEB), and RAEB with excess blasts in transition (RAEB-T); and myeloproliferative syndromes; brain cancer, including glioma / glioblastoma, anaplastic oligodendroglioma, and adult anaplastic astrocytoma; neuroendocrine carcinoma, including metastatic neuroendocrine tumors; head and neck cancer, including squamous cell carcinoma of the head and neck and nasopharyngeal carcinoma; cancer of the oral cavity, pharynx, and small intestine; bone cancer; soft tissue sarcoma; and colon villous adenoma; and · Central nervous system (CNS) diseases such as multiple sclerosis (MS).

[0249] In some embodiments, the method of the present disclosure may be a method for treating and / or preventing any one or more of the diseases, conditions, and / or disorders disclosed herein. For example, in some embodiments, a method for treating and / or preventing any one or more of retinal ischemia-reperfusion injury, chronic recurrent multifocal osteomyelitis, aplastic anemia, CRIA, ethanol-induced liver disease, NASH, inflammatory hepatitis, acute kidney injury, IRI, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, stroke, systemic lupus erythematosus, myocardial infarction, diabetes, Crohn's disease, inflammatory bowel disease, and COPD is provided, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

[0250] The method may be performed before, during (removal, transfer and / or re-implantation), or after implantation. They may also be used to protect cells, tissues and / or transplanted organs.

[0251] In some embodiments, the compounds of the present invention may be administered in combination with another active pharmaceutical ingredient (API). The API may be any suitable API for treating any of the diseases, conditions, and / or disorders associated with necroptosis, such as those described herein. The compounds of the present invention may be co-formulated with another API in any of the pharmaceutical compositions described herein, or the compounds of the present invention may be administered simultaneously, sequentially, or synchronously. Simultaneous administration includes administering the compounds of the present invention simultaneously with the other API, whether co-formulated or in separate dosage forms administered by the same or different routes. Sequential administration includes administering the compounds of the present invention and the other API according to a determined dosing regimen, such as within about 0.5, 1, 2, 3, 4, 5, or 6 hours of the other, by the same or different routes. When administered sequentially, the compounds of the present invention may be administered before or after the administration of the other API. Non-synchronous administration includes administering the compounds of the present invention and the other API according to independent regimens by any route appropriate for either active, which may be the same or different.

[0252] The method can include administering a compound of formula (I) in any pharmaceutically acceptable form. In some embodiments, the compound of formula (I) is provided in the form of a pharmaceutically acceptable salt, solvate, N-oxide, polymorph, tautomer, or prodrug thereof, or as a combination of any ratio of these forms.

[0253] The method can also include administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, N-oxide, polymorph, tautomer, or prodrug thereof. The pharmaceutical composition can include any pharmaceutically acceptable carrier, diluent, and / or excipient described herein.

[0254] The compounds of formula (I) or pharmaceutically acceptable salts or prodrugs thereof, as defined herein, may be administered by any suitable means, for example, oral, rectal, nasal, vaginal, topical (including buccal and sublingual), parenteral administration, for example subcutaneous, intraperitoneal, intravenous, intramuscular, or intracisternal injection, inhalation, insufflation, infusion, or implantation techniques (e.g., as sterile aqueous or non-aqueous injection solutions or suspensions).

[0255] The compounds of the present invention may be provided as pharmaceutical compositions, including those for oral, rectal, nasal, topical (including buccal and sublingual), parenteral (including intramuscular, intraperitoneal, subcutaneous, and intravenous) administration, or in a form suitable for administration by inhalation or insufflation. Thus, the compounds of formula (I) or pharmaceutically acceptable salts or prodrugs thereof, together with conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or as liquids, such as solutions, suspensions, emulsions, elixirs, or filled capsules thereof, all for oral use, or in the form of sterile injectable solutions for oral (including subcutaneous) use.

[0256] Kit of parts, separate parts a compound of formula (I) or a pharmaceutically acceptable salt, solvate, N-oxide, polymorph, tautomer or prodrug thereof; instructions for its use in any of the methods of the invention; Also provided is a kit comprising:

[0257] The compounds, compositions, kits and methods described herein are illustrated by the following illustrative and non-limiting examples. [Example]

[0258] chemistry synthesis The compounds of the present invention, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0259] The reaction for preparing the compounds of the present invention can be carried out in a suitable solvent, which can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, for example, at a temperature ranging from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the specific reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0260] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), the entire contents of which are incorporated herein by reference.

[0261] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., H or C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or chromatography, such as high performance liquid chromatography (HPLC) or thin-layer chromatography.

[0262] As used herein, the expressions "ambient temperature," "room temperature," "RT," and "rt" are art-recognized and generally refer to a temperature, e.g., a reaction temperature, i.e., the temperature of the room in which a reaction is carried out, e.g., a temperature of about 20°C to about 30°C.

[0263] The compounds of the present invention can be prepared according to a number of preparative routes known in the literature. Examples of synthetic methods for preparing compounds of the present invention are provided in the following schemes.

[0264] Overview of Chemistry Scheme 1 illustrates a general synthesis of the aminopyrazolocarboxamide compounds of the present invention. Aminopyrazolonitriles (F1) can be prepared via routes known to those skilled in the art and converted to N-heteroarylaminopyrazolonitriles F2 by treatment with a haloheteroarene in the presence of a ligand such as Xantphos with palladium, such as tris(dibenzylideneacetone)dipalladium(0) or palladium(II) acetate, and a base, such as cesium carbonate, in a solvent such as 1,4-dioxane or diglyme at elevated temperatures, such as 65°C, or in a microwave environment, such as 150°C (Step 1). The nitrile group can be converted to a primary amide using 30% aqueous hydrogen peroxide in a solvent such as 1,4-dioxane and water at elevated temperatures, such as 100°C, in the presence of a reagent such as Ghaffar-Parkins catalyst, or in a polar solvent, such as dimethyl sulfoxide, in aqueous sodium hydroxide, and in a protic solvent, such as ethanol, at elevated temperatures, such as 100°C (Step 2). The nitro substituent can be reduced to the aniline in the presence of aqueous ammonium chloride in a protic solvent such as methanol in the presence of zinc dust at room temperature (Step 3). The aniline can then be reduced to the aniline in the presence of an amine base such as pyridine or triethylamine in a chlorinated solvent such as dichloromethane or chloroform. The compound can be converted to a sulfonamide with an appropriate sulfonyl chloride in the presence of an acid, or can be converted without a solvent at room temperature (Step 4). The compound of the present invention can be obtained via acidic deprotection with an acid such as trifluoroacetic acid in a solvent such as dichloromethane at room temperature. [ka]

[0265] Alternatively, compound F2 can be prepared from an iodoheteroarene (example where A1 and A5 are CH) by treatment with a palladium species such as palladium acetate in the presence of a ligand such as Xantphos with a base such as cesium carbonate at an elevated temperature such as 65°C in a solvent such as 1,4-dioxane. [ka]

[0266] Alternatively, compound F2 can be prepared from F1 by treatment with a reagent such as isoamyl nitrite in the presence of a copper species such as copper(II) bromide in a polar solvent such as acetonitrile at room temperature (Step 1). The bromopyrazole can be converted to F2 bearing an aryl amine by treatment with a palladium species such as tris(dibenzylideneacetone)dipalladium(0) in the presence of a ligand such as Xantphos with a base such as cesium carbonate in a solvent such as 1,4-dioxane at an elevated temperature such as 65°C. [ka]

[0267] Scheme 4 illustrates an alternative general synthesis of the aminopyrazolocarboxamide compounds of the present invention. Dibromopyrazoles (F3) can be prepared via routes known to those skilled in the art and converted to N-heteroarylbromopyrazolonitriles F4 (Step 1) in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0), a phosphine ligand such as xantphos, and a base such as cesium carbonate in a nonpolar solvent such as 1,4-dioxane at elevated temperatures such as 65°C. Conversion of the nitrile group to a primary amide can be achieved in the presence of a reagent such as Ghaffar-Parkins catalyst in a solvent such as 1,4-dioxane and water at elevated temperatures such as 100°C, or with aqueous sodium hydroxide in a polar solvent such as dimethyl sulfoxide and 30% aqueous hydrogen peroxide in a protic solvent such as ethanol at elevated temperatures such as 100°C (Step 2). Subsequent coupling reactions can be carried out in the presence of a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) or palladium(II) acetate, with a ligand such as SPhos and a base such as sodium carbonate or potassium carbonate, in a solvent such as a mixture of 1,4-dioxane and water or acetonitrile and water, at elevated temperatures such as 100°C, or under microwave irradiation at elevated temperatures such as 100°C, to provide F5 (Step 3). Removal of the SEM protecting group can provide compounds of the invention under acidic conditions such as trifluoroacetic acid, in a solvent such as dichloromethane, or using aqueous hydrogen chloride at room temperature. [ka]

[0268] Alternatively (Scheme 5), steps 2 and 3 from Scheme 4 can be interconverted to provide F5 from F4 following the same instructions depicted in Scheme 4. [ka]

[0269] Alternatively, a Suzuki cross-coupling reaction can be carried out with boronic esters F8, F9, or F11, followed by the reaction described above (Scheme 6). [ka]

[0270] Scheme 7 outlines the preparation of bromoaryl F6 and boronic esters F7, F8, F9 and F11, which can be obtained from F6 or F10.

[0271] F7 can be obtained after the aforementioned nitro reduction, sulfonylation, and boronation reactions in the presence of palladium species such as bis(pinacolato)diboron and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) and a base such as potassium acetate in a solvent such as 1,4-dioxane at an elevated temperature such as 100° C. F8 can be obtained from F6 via the aforementioned boronation reaction, and F9 can be prepared from F8 via the aforementioned nitro reduction reaction.

[0272] F11 can be obtained from F10 via the aforementioned boronation reaction, which in turn can be obtained from phenols and the desired alcohol via a Mitsunobu reaction with PPh3, DIAD, or DEAD in solvents such as THF or toluene at room temperature or elevated temperatures such as 70 °C.

[0273] F6 can be obtained by alkylation of substituted phenols F8 with the corresponding haloalkyl or halomethyl(hetero)aryl in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, or by nucleophilic substitution of fluoronitroarenes F9 with the corresponding alcohols / (hetero)arylalcohols in the presence of a strong base such as sodium hydride in a polar solvent such as N,N-dimethylformamide or tetrahydrofuran. [ka]

[0274] Scheme 8 summarizes the synthesis of F10 and F11. F10 can be obtained by alkylation of substituted phenol F12 with the corresponding halogenoalkyl or halogenomethyl(hetero)aryl in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, and F11 can be obtained via the boronation reaction of F10 as previously described. [ka]

[0275] Scheme 9 illustrates an alternative route for the synthesis of trisubstituted phenyl derivatives. Compound F13 can be prepared via routes known to those skilled in the art and converted to N-(hetero)arylpyrazolonitrile F14 as previously described (Step 1). Displacement of fluoroaryl F14 with a strong base such as sodium hydride in the presence of an alcohol / (hetero)aryl alcohol in a polar solvent such as N,N-dimethylformamide or tetrahydrofuran can provide F15, which can then be transformed into compounds of the invention according to the routes described below (Steps 3-6). [ka]

[0276] general chemical methods Definition: AcCl (acetyl chloride); Ac2O (acetic anhydride); AcOH (acetic acid); atm(atmosphere); B2pin2(bis(pinacolato)diboron); BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); BnBr (benzyl bromide); Boc2O(di-tert-butyl dicarbonate); c-Hex (cyclohexane); C6H 19O3P3Pt (dimethylphosphinite; dimethylphosphinic acid; platinum(2+)-Ghaffar-Parkins catalyst); CDCl3 (deuterated chloroform); CD3OD (deuterated methanol); CHCl3 (chloroform); Cs2CO3 (cesium carbonate); CsF (cesium fluoride); conc.(concentration); d(day); DAST (diethylaminosulfur trifluoride); dba (dibenzylideneacetone); DCM (dichloromethane); DEAD (diethyl azodicarboxylate); DIAD (diisopropyl azodicarboxylate); DIPEA (N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DME (1,2-dimethoxyethane); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); eq(equivalent); ES-API (electrospray atmospheric pressure ionization); Et3N (triethylamine); Et2O (diethyl ether); EtOAc (ethyl acetate); EtOH (ethanol); EtSO2Cl (ethanesulfonyl chloride); g(grams); h(time); H2 (hydrogen) H2O2 (hydrogen peroxide) HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); HCl (hydrochloric acid / hydrogen chloride); HOBt (hydroxybenzotriazole); 1 H NMR (proton nuclear magnetic resonance); Hz (Hertz); i-PrOH (isopropanol); KI (potassium iodide) L (liters); LCMS (liquid chromatography-mass spectrometry); LiHMDS (lithium bis(trimethylsilyl)amide); M (molar); MeCN (acetonitrile); Me2NH(dimethylamine); MeOH (methanol); MeOD-d4 (deuterated methanol); mg (milligrams); MHz (megahertz); min(minutes); mL (milliliters); mmol (millimol); MsCl (methanesulfonyl chloride); n-BuLi (n-butyllithium); NaH (sodium hydride); NaHCO3 (sodium bicarbonate); NaOEt (sodium ethoxide); NaOH (sodium hydroxide); NaOMe (sodium methoxide); Na2SO4 (sodium sulfate); NBS (N-bromosuccinimide); NH4Cl (ammonium chloride); NMP (N-methyl-2-pyrrolidone); Pd / C (palladium on activated carbon); Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0)); Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM); Pd(OH)2 (palladium(II) hydroxide carbon-Pearlman catalyst); PE (petroleum ether); prep-HPLC (preparative high-performance liquid chromatography); prep-TLC (preparative thin layer chromatography); ppm (parts per million); psi (pounds per square inch); p-TSA (p-toluenesulfonic acid); quant.(quantitative yield); RT (room temperature); SEMCl (2-(trimethylsilyl)ethoxymethyl chloride); SPhos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl); TBAF (tetra-n-butylammonium fluoride); t-BuNHNH2.HCl (tert-butylhydrazine hydrochloride); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin layer chromatography); v / v(capacity / capacity); Xantphos (9,9-dimethyl-4,5-bis(di-tert-butylphosphino)xanthene);

[0277] LCMS methodology Electrospray mass spectrometry (MS) was performed using the following method. Method A (5 min): LC model: Agilent 1200 (Pump type: Binary pump, Detector type: DAD). MS model: Agilent G6110A Quadrupole. Column: Xbridge-C18, 2.5 μm, 2.1 × 30 mm. Column temperature: 30 °C. Acquisition wavelengths: 214 nm, 254 nm. Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH. Run time: 5 min. MS: Ion source: ES+ (or ES-). MS range: 50-900 m / z. Fragmenter: 60. Drying gas flow: 10 L / min. Nebulizer pressure: 35 psi. Drying gas temperature: 350 °C. Vcap: 3.5 kV.

[0278] Method B (3.5 min): LC model: Agilent 1200 (Pump type: Binary pump, Detector type: DAD). MS model: Agilent G6110A Quadrupole. Column: Xbridge-C18, 2.5 μm, 2.1 × 30 mm. Column temperature: 30 °C. Acquisition wavelengths: 214 nm, 254 nm. Mobile phase: A: 0.07% HCOOH in water, B: MeOH. Run time: 5 min. MS: Ion source: ES+ (or ES-). MS range: 50–900 m / z. Fragmenter: 60. Drying gas flow: 10 L / min. Nebulizer pressure: 35 psi. Drying gas temperature: 350 °C. Vcap: 3.5 kV.

[0279] Method C (4 min): Agilent LCMS system consisting of an Agilent G6120B mass detector, a 1260 Infinity G1312B binary pump, a 1260 Infinity G1367E HiPALS autosampler, and a 1260 Infinity G4212B diode array detector. The LCMS conditions were as follows: column, Poroshell 120 EC-C18, 2.1 × 50 mm, 2.7 μm at 30 °C; injection volume, 2 μL; gradient, 5–100% B over 3 min (solvent A: water / 0.1% formic acid; solvent B: AcCN / 0.1% formic acid); flow rate, 1.0 mL / min; detection, 214 nm and 254 nm; acquisition time, 4.1 min; ion source: single quadrupole; ion mode: API-ES; drying gas temperature: 350 °C; capillary voltage: 4.0 kV; scan range, 100–1000; step size, 0.1.

[0280] Method D: (8 min) LC model: Waters 2695 alliance, pump: quaternary pump, detector: 2996 photodiode array detector, MS model: Micromass ZQ, LC column: Xbridge-C18, 3.5 μm, 2.1 × 50 mm, column temperature: 20 °C. Acquisition wavelengths: 214 nm, 254 nm. Mobile phase: A: 0.05% HCOOH aqueous solution, B: CAN. Run time: 8 min. MS: Ion source: ES+ (or ES-)MS range: 100-1000 m / z Capillary: 3 kV Cone: 40 V Extractor: 3 V Drying gas flow: 800 L / hr Cone: 50 L / hr Desolvation temperature: 500 °C Source temperature: 120 °C

[0281] Preparative HPLC Instrument type: VARIAN 940 LC. Pump type: binary pump. Detector type: PDA. LC conditions: Column: Waters SunFire Prep C18 OBD, 5 μm, 19 × 100 mm. Acquisition wavelengths: 214 nm, 254 nm. Mobile phase: A: 0.07% TFA in water, B: MeOH.

[0282] NMR Nuclear magnetic resonance spectra were recorded on a Bruker Avance DRx 300 instrument at 300.13 MHz or a Bruker 400 MHz instrument at the indicated 1H nuclei. Samples were recorded in the indicated deuterated solvents, and data were acquired at 25 °C. Chemical shifts are reported in ppm on the δ scale and referenced to the appropriate solvent peak. In reporting spectral data, the following abbreviations are used: s, singlet; br, s, broad singlet; d, doublet; t, triplet; q, quartet; and m, multiplet.

[0283] Synthesis of common intermediates Intermediate A1: 3-(4-aminophenyl)-1-(tert-butyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide [ka]

[0284] Step 1: 5-amino-1-(tert-butyl)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile A mixture of 4-nitrobenzaldehyde (100 g, 0.66 mol) and t-BuNHNH2.HCl (90.7 g, 0.73 mol) in DMF (500 mL) was stirred at room temperature overnight. The reaction mixture was cooled to 0 °C, and NBS (129.6 g, 0.73 mol) was slowly added. The resulting mixture was stirred at 0 °C for 5 h, followed by the slow addition of a solution of malononitrile (52.5 g, 0.79 mol) and NaOEt (112.7 g, 1.66 mol) in EtOH (300 mL) at 0 °C over 30 min. The mixture was stirred at room temperature for 16 h and then partitioned between H2O (3 L) and EtOAc (3 L). The aqueous layer was extracted with EtOAc (2 × 3 L), and the combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE: EtOAc, 5:1) to give the title product (58 g, 31%) as a yellow solid. LCMS (Method A): 1.93 min; m / z: 286.1 [M+H] + .

[0285] Step 2: 1-(tert-butyl)-3-(4-nitrophenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carbonitrile 5-amino-1-(tert-butyl)-3-(4-nitrophenyl)-1H-pyrazo To a solution of benzoyl-4-carbonitrile (13 g, 45.6 mmol) in diglyme (200 mL) were added 2-bromopyridine (7.6 g, 47.8 mmol), Pd(OAc) (614 mg, 2.73 mmol), Xantphos (1.6 g, 2.73 mmol), and CsCO (37.1 g, 114 mmol), and the mixture was stirred at 150 °C under N for 8 h. The reaction mixture was filtered through Celite, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 5:1) to give the title product (7.0 g, 42%) as a yellow solid. LCMS (Method A): 2.91 min; m / z: 363.2 [M+H] + .

[0286] Step 3: 1-(tert-butyl)-3-(4-nitrophenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide To a solution of 1-(tert-butyl)-3-(4-nitrophenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carbonitrile (11 g, 30.3 mmol) in DMSO (35 mL) and EtOH (130 mL) was added 30% aqueous HO (35 mL) and 5% aqueous NaOH (0.3 mL), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water to form a yellow suspension. The solid was collected by filtration and dried under reduced pressure to give the title product (10.5 g, 90%) as a yellow solid. LCMS (Method A): 2.65 min; m / z: 381.1 [M+H] + .

[0287] Step 4: 3-(4-aminophenyl)-1-(tert-butyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide To a solution of 1-(tert-butyl)-3-(4-nitrophenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide (10 g, 26.3 mmol) in MeOH (200 mL) was added saturated aqueous NH4Cl (100 mL) and Zn dust (8.6 g, 131.5 mmol), and the mixture was stirred at 40 °C for 2 h. The reaction mixture was filtered through Celite, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure, diluted with HO, and then basified to pH 10 with saturated aqueous Na2CO3. The mixture was extracted with DCM (3 × 100 mL), and the combined organics were washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give the title product (8.0 g, 75%) as a yellow solid. LCMS (Method A): 0.53 min; m / z: 351.1 [M+H] + .

[0288] The following intermediates (Table 1) were prepared similarly according to the method described for the synthesis of 3-(4-aminophenyl)-1-(tert-butyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide (Intermediate A1) from 5-amino-1-(tert-butyl)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile.

[0289] [Table 1]

[0290] Intermediate B1: 3-bromo-5-((2-methoxypyridin-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonite Lil [ka]

[0291] Step 1: 3,5-Dibromo-1H-pyrazole-4-carbonitrile To a stirred solution of 1H-pyrazole-4-carbonitrile (15.0 g, 161 mmol) and NaOAc (89.3 g, 1.09 mol) in 40% aqueous EtOH (550 mL) was added Br (24 mL, 644 mmol) slowly at room temperature. The mixture was stirred at 30 °C for 3.5 h, then diluted with H O (600 mL) and extracted with DCM (3 × 300 mL). The combined organic layers were washed with brine, dried (Na SO ), and concentrated under reduced pressure to give the title product (25 g, 62%) as a yellow solid. LCMS (Method B): 0.87 min; m / z: 249.7 [M+H] + .

[0292] Step 2: 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile To a solution of 3,5-dibromo-1H-pyrazole-4-carbonitrile (25 g, 99.6 mmol) in DMF (150 mL) was added NaH (60% in oil, 2.85 g, 119 mmol) at room temperature, and the mixture was stirred for 0.5 h. SEM-Cl (24.8 g, 149 mmol) was added, and the mixture was stirred at room temperature for 4 h, then diluted with HO (200 mL) and extracted with EtO (3 × 150 mL). The combined organics were washed with brine, dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 20:1) to give the title product (16.0 g, 42%) as a clear oil. LCMS (Method B): 0.43 min; m / z: 380.0, 382.0 [M+H] + .

[0293] Step 3: 3-Bromo-5-[(2-methoxypyridin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile A mixture of 3,5-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (13.8 g, 36.2 mmol), 2-methoxypyridin-4-amine (4.9 g, 39.8 mmol), Pd(OAc) (812 mg, 3.62 mmol), Xantphos (4.18 g, 7.24 mmol), and CsCO (17.6 g, 54.3 mmol) in degassed 1,4-dioxane (200 mL) was heated to 110 °C under N for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EtOAc, 12:1) to give the title product (7.5 g, 49%) as a white solid. LCMS (Method B): 2.56 min; m / z: 424.1, 426.1 [M+H] + .

[0294] Intermediate B2: 3-bromo-5-(pyridin-2-ylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide [ka]

[0295] Step 1: 3-Bromo-5-[(pyridin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile A mixture of 3,5-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (10 g, 26.2 mmol), pyridin-2-amine (2.46 g, 26.2 mmol), Pd(dba) (2.39 g, 2.62 mmol), Xantphos (3.03 g, 5.24 mmol), and CsCO (25.6 g, 78.6 mmol) in degassed 1,4-dioxane (150 mL) was stirred at 100 °C for 16 h under N. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EtOAc, 5:1) to give the title product (5.0 g, 49%) as a yellow solid. LCMS (Method A: 3.79 min; m / z: 394.0, 396.0 [M+H] +.

[0296] Step 2: 3-Bromo-5-(pyridin-2-ylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Intermediate B2) A mixture of 3-bromo-5-[(pyridin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (4.3 g, 10.9 mmol) and Ghaffar-Parkins catalyst (50.0 mg, 0.1170 mmol) in 50% aqueous 1,4-dioxane (200 mL) was stirred at 100 °C for 16 h. The reaction mixture was extracted with EtOAc (2 × 200 mL), and the combined organics were washed with water and brine, dried (Na SO ), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE: EtOAc, 3:1) to afford the title product (2.5 g, 56%) as a yellow solid. LCMS (Method A): 3.77 min; m / z: 412.1, 414.1 [M+H] + . 1 H NMR (400 MHz, MeOD-d4): 8.84 (s, 1H), 8.24 (s, 1H), 9.01 (d, J = 4.0 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.29 (s, 1H), 6.79 (t, J = 6.0 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.27 (s, 2H), 3.44 (t, J = 8.4 Hz, 2H), 0.74 (t, J = 8.0 Hz, 2H), 0.11 (s, 9H).

[0297] Intermediate B3 (3-bromo-5-(pyrazin-2-ylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile) and Intermediate B4 (3-bromo-5-(pyrazin-2-ylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide) [ka]

[0298] Step 1: 3-Bromo-5-(pyrazin-2-ylamino)-1-((2-(trimethyl Silyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (Intermediate B3) A mixture of 3,5-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (4 g, 10.4 mmol), pyrazin-2-amine (989 mg, 10.4 mmol), Pd(dba) (952 mg, 1.04 mmol), Xantphos (1.20 g, 2.08 mmol), and CsCO (10.1 g, 31.2 mmol) in degassed 1,4-dioxane (50 mL) was stirred at 100 °C for 16 h under N. The reaction mixture was filtered, and the filter cake was washed with EtOAc (3 × 20 mL). The combined filtrate was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 10:1 to 8:1) to give the title compound (2.5 g, 61%) as a yellow solid. LCMS (Method A): 4.14 min; m / z: 395.0, 397.0 [M+H] + .

[0299] Step 2: 3-Bromo-5-(pyrazin-2-ylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Intermediate B4) A mixture of 3-bromo-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (6 g, 15.1 mmol), Ghaffar-Parkins catalyst (100 mg, 0.2340 mmol), and 50% aqueous 1,4-dioxane (120 mL) was stirred at 100 °C under N for 16 h. The mixture was concentrated, and the crude residue was purified by silica gel column chromatography (DCM:MeOH, 200:1 to 10:1) to give the title product (2.1 g, 34%) as a brown solid. LCMS (Method A): 3.59 min; m / z: 415.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6): 9.34 (s, 1H), 8.19 (d, J = 1.2 Hz, 1H), 8.05-8.03 (m, 1H), 8.02-8.00 (m, 1H), 7.31 (s, 1H), 7.04 (s, 1H). 5.31 (s, 2H), 8.46 (t, J = 8.4 Hz, 2H), 0.75 (t, J = 7.6 Hz, 2H), -0.11 (s, 9H).

[0300] Intermediate B5 3-bromo-5-[(5-methylpyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile and Intermediate B6 3-bromo-5-[(5-methylpyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide [ka]

[0301] Step 1: 3-Bromo-5-[(5-methylpyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (Intermediate B5) To a solution of 3,5-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (2 g, 5.24 mmol) in 1,4-dioxane (100 mL) was added 5-methylpyrazin-2-amine (571 mg, 5.24 mmol), Xantphos (302 mg, 0.524 mmol), CsCO (3.38 g, 10.4 mmol), and Pd(dba) (239 mg, 0.262 mmol). The mixture was evacuated and backfilled with N three times, then stirred at 100 °C overnight. The mixture was concentrated, and the residue was purified by preparative TLC (PE:EtOAc, 20:1) to give the title product (1. 03g, 48%) as a yellow solid. LCMS (Method A): 4.10 min; m / z: 409.1, 411.1 [M+H] + .

[0302] Step 2: 3-Bromo-5-[(5-methylpyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (Intermediate B6) A mixture of 3-bromo-5-[(5-methylpyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (1.05 g, 2.56 mmol), Ghaffar-Parkin's catalyst (150 mg, 0.35 mmol), and 75% aqueous 1,4-dioxane (55 mL) was stirred at 100 °C under N. After 16 h, the reaction mixture was concentrated and the crude residue was purified by preparative TLC (DCM:MeOH, 60:1) to give the title product (490 mg, 45%) as a yellow solid. LCMS (Method A): 3.58 min; m / z: 427.1, 429.1 [M+H] + .

[0303] The following Intermediate B (see Table 2 below) were similarly prepared from the appropriate aminoaryl / alkyl (Step 1) following the method described for the synthesis of Intermediate B5.

[0304] [Table 2]

[0305] Intermediate C1: N-(2-((4-fluorobenzyl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide [ka]

[0306] Step 1: 4-Bromo-2-((4-fluorobenzyl)oxy)-1-nitrobenzene A mixture of 5-bromo-2-nitrophenol (10 g, 45.8 mmol), K2CO3 (12.6 g, 91.6 mmol), and 1-(bromomethyl)-4-fluorobenzene (8.65 g, 45.8 mmol) in MeCN (100 mL) was stirred at 70 °C under N2 for 16 h. The mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the title product (15.0 g, 100%) as a white solid.

[0307] Step 2: 4-Bromo-2-((4-fluorobenzyl)oxy)aniline To a solution of 4-bromo-2-((4-fluorobenzyl)oxy)-1-nitrobenzene (15 g, 45.9 mmol) and saturated aqueous NH₄Cl (100 mL) in MeOH (300 mL) was added Zn dust (14.9 g, 229 mmol), and the reaction mixture was stirred at 60°C for 4 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned between HO (250 mL) and EtOAc (300 mL), and the organic layer was separated, dried (Na₂SO₄), and concentrated under reduced pressure to give the title product (13.0 g, 96%) as a black oil. LCMS (Method A): 4.24 min; m / z: 296.0 [M+H] + .

[0308] Step 3: N-(4-bromo-2-((4-fluorobenzyl)oxy)phenyl)ethanesulfonamide A mixture of 4-bromo-2-((4-fluorobenzyl)oxy)aniline (13 g, 43.8 mmol), EtSO2Cl (8.43 g, 65.6 mmol), and pyridine (50 mL) in CHCl3 (50 mL) was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 1:1) to give the title product (12.5 g, 73%) as a yellow solid. LCMS (Method A): 4.24 min; m / z: 410.0 [M+H] + .

[0309] Step 4: N-(2-((4-fluorobenzyl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide A mixture of N-(4-bromo-2-((4-fluorobenzyl)oxy)phenyl)ethanesulfonamide (12.5 g, 32.1 mmol), Pd(dppf)Cl (1.46 g, 1.60 mmol), KOAc (6.29 g, 64.2 mmol), and B2pin2 (8.96 g, 35.2 mmol) in degassed 1,4-dioxane (200 mL) was stirred at 100 °C under N2 for 16 h. The mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 2:1) to give the title product (14.8 g, >100%) as a brown solid. LCMS (Method A): 4.51 min; m / z: 453.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 8.99 (s, 1H), 7.63-7.60 (m, 2H), 7.38-7.32 (m, 2H), 7.28-7.21 (m, 3H), 5.15 (s, 2H), 3.03 (q, J = 14.8, 7 .2 Hz, 2H), 1.29 (s, 12H), 1.11 (t, J = 7.2 Hz, 3H).

[0310] The following Intermediate C (Table 3) was similarly prepared from the appropriate bromoaryl / alkyl (Step 1) according to the method described for the synthesis of N-(2-((4-fluorobenzyl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide (Intermediate C1).

[0311] [Table 3-1]

[0312] [Table 3-2]

[0313] [Table 3-3]

[0314] Intermediate C11 [ka]

[0315] Step 1: (S)-4-Bromo-2-(1-(4-fluorophenyl)ethoxy)-1-nitrobenzene To a solution of (1S)-1-(4-fluorophenyl)ethan-1-ol (40 g, 285 mmol) in THF (600 mL) was added NaH (57.1 g, 1425 mmol). The mixture was stirred under N at 0 °C for 30 min. 4-Bromo-2-fluoro-1-nitrobenzene (62.6 g, 285 mmol) was added and stirred at room temperature overnight. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic phase was washed with water and brine, dried (NaSO), and concentrated under reduced pressure to give the crude product (70 g, 72%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6): 7.80 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.48 (q, J = 4.8 Hz, 2H), 7.26 (dd, J = 8.8, 2.0 Hz, 1H), 7.20 (t, J = 8.8 Hz, 1H), 5.89 (q, J = 6.4 Hz, 1H), 1.54 (d, J = 6.0 Hz, 3H).

[0316] Step 2: 4-Bromo-2-[(1S)-1-(4-fluorophenyl)ethoxy]aniline To a solution of 4-bromo-2-[(1S)-1-(4-fluorophenyl)ethoxy]-1-nitrobenzene (70 g, 205 mmol) in MeOH (500 mL) was added Zn dust (67.0 g, 1025 mmol), followed by saturated aqueous NH4Cl (170 mL). The mixture was stirred at 60 °C for 6 h, then diluted with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic phases were washed with water and brine, dried (Na2SO4), and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (PE: EtOAc, 100:1) to give the title product (40 g, 63%) as a brown oil. LCMS (Method A): 4.13 min; m / z: 311.0, 311.9 [M+H] + .

[0317] Step 3: N-{4-bromo-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl}-1,1-difluoromethanesulfonamide To a solution of 4-bromo-2-[(1S)-1-(4-fluorophenyl)ethoxy]aniline (40 g, 128 mmol) in DCM (200 mL) and pyridine (40.5 g, 512 mmol) was added difluoromethanesulfonyl chloride (24.9 g, 166 mmol). After stirring overnight at room temperature, the residue was diluted with water (500 mL) and extracted with DCM (3 × 500 mL). The combined organic layers were washed (brine), dried (NaSO), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 100:1) to give the title product (39 g, 72%) as a brown oil. 1 H NMR (400 MHz, DMSO-d6): 10.43 (s, 1H), 7.57 (q, J = 4.8 Hz, 2H), 7.21-7.15 (m, 3H), 7.07-7.04 (m, 2H), 6.98 (t, J = 52.4 Hz, 1H), 5.65 (q, J = 6.4 Hz, 1H), 1.54 (d, J = 6.0 Hz, 3H).

[0318] Step 4: (S)-1,1-difluoro-N-(2-(1-(4-fluorophenyl)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide To a solution of N-{4-bromo-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl}-1,1-difluoromethanesulfonamide (39 g, 91.9 mmol) in dioxane (300 mL) was added KOAc (26.9 g, 275 mmol), B2pin 2 (34.7 g, 137 mmol) and Pd(dppf)Cl (2.01 g, 2.75 mmol) were added. The mixture was stirred under N at 100 °C overnight and concentrated in vacuo. The residue was diluted with water (500 mL) and extracted with EtOAc (3 × 500 mL). The combined organic phases were washed with water and brine, dried (Na SO ), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc, 50:1) to give the title product (41 g, 94%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6): 10.41 (s, 1H), 7.58 (q, J = 4.8 Hz, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.20-7.16 (m, 3H), 7.12 (s, 1H), 6.98 (t, J = 52.4 Hz, 1H), 5.63 (q, J = 6.4 Hz, 1H), 1.54 (d, J = 6.4 Hz, 3H), 1.25 (d, J = 4.8 Hz, 12H).

[0319] The following intermediates C12-C15 (Table 4) were prepared similarly according to the method described for the synthesis of (S)-1,1-difluoro-N-(2-(1-(4-fluorophenyl)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate C11).

[0320] [Table 4-1]

[0321] [Table 4-2]

[0322] Intermediate C16: N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide [ka]

[0323] Step 1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline A mixture of (4-aminophenyl)boronic acid hydrochloride (4.0 g, 23.0 mmol), NaHCO3 (3.86 g, 46.0 mmol), MgSO4 (8.30 g, 69.0 mmol), and pinacol (2.98 g, 25.3 mmol) in THF (23 mL) was stirred at room temperature for 22 hours. The reaction mixture was diluted with EtOAc (50 mL), filtered through Celite, and concentrated under reduced pressure. The residue was triturated (Et2O) to give the title compound (1.33 g, 26%) as an off-white solid. LCMS (Method C): 1.40 min; m / z: 220.2 [M+H] + . 1 H NMR (300 MHz, CDCl3): 7.65-7.61 (m, 2H), 6.70-6.66 (m, 2H), 1.32 (s, 12H).

[0324] Step 2: N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.6 g, 7.30 mmol), EtSOCl (1.37 mL, 14.6 mmol), pyridine (2.94 mL, 36.5 mmol), and DCM (15 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, diluted with HO (50 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried (MgSO) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 1:0 to 1:1) to afford the title compound (1.37 g, 60%) as a beige solid. LCMS (Method A): 1.92 min; m / z: 312.2 [M+H] + . 1 H NMR (300 MHz, CDCl3): 7.80-7.76 (m, 2H), 7.21-7.17 (m, 2H), 6.63 (br s, 1H), 3.15 (q, J = 7.4 Hz, 2H), 1.34 (t, J = 7.4 Hz, 3H), 1.33 (s, 9H).

[0325] Intermediate D1: 5-((6-(difluoromethyl)pyridin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide [ka]

[0326] Step 1: 5-((6-(difluoromethyl)pyridin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide A solution of 6-chloropyridine-2-carbaldehyde (5 g, 35.3 mmol) in DCM (50 mL) was stirred at -20 °C for 1 h. DAST (9.65 ml, 60.0 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was neutralized to pH 7-8 with saturated aqueous NaHCO and extracted with DCM (3 x 20 mL). The combined organic layers were washed with H2O, dried (Na2SO4), and concentrated under reduced pressure to give the title product (1.65 g, 29%) as a black liquid. LCMS (Method A): 0.92 min; m / z: 164.0 [M+H] + .

[0327] Intermediate E1: 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine [ka]

[0328] Step 1: 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile To a solution of NaH (60% in oil, 2.18 g, 54.8 mmol) in THF (70 mL) was added ethyl 1-(trifluoromethyl)cyclopropane-1-carboxylate (5 g, 27.4 mmol), followed by the dropwise addition of acetonitrile (1.68 g, 41.0 mmol) over 45 min. The suspension was heated at 70 °C overnight. Once cooled, the reaction mixture was poured into water (150 mL) and the organics were extracted with EtOAc (2 × 100 mL). The combined organics were dried (NaSO) and concentrated under reduced pressure to give the title product (4.60 g, 95%) as a yellow oil. 1 H NMR (400 MHz, CDCl3): 3.95 (s, 2H), 1.60 (dtd, J = 5.4, 3.8, 1.5 Hz, 2H), 1.49 (t, J = 3.6 Hz, 2H).

[0329] Step 2: 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine A mixture of 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile (460 mg, 2.59 mmol), NHOH.HCl (0.215 mg, 3.10 mmol), and NaHCO (435 mg, 5.2 mmol) in MeOH (1 mL) and water (9 mL) was heated at 140 °C for 5 min under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (10 mL) and extracted with EtOAc (5 mL x 2). The combined organics were dried (NaSO) and concentrated under reduced pressure to give the title product (330 mg, 66%) as a pale yellow solid. LCMS (Method A): 3.00 min; m / z: 193.1 [M+H] + .

[0330] Intermediate E2: 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine [ka]

[0331] Step 1: Methyl 3-methoxy-2,2-dimethylpropanoate A mixture of methyl 3-hydroxy-2,2-dimethylpropanoate (5 g, 37.8 mmol), KOH (8.47 g, 151 mmol), and MeI (21.4 g, 151 mmol) in DMSO (150 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (500 mL) and extracted with EtOAc (300 mL × 5). The combined organic phases were dried (NaSO) and concentrated under reduced pressure to give the title product (3 g, 54%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6): 3.59 (s, 3H), 3.32 (s, 2H), 3.22 (s, 3H), 1.10 (s, 6H).

[0332] Step 2: 5-Methoxy-4,4-dimethyl-3-oxopentanenitrile Acetonitrile (1.68 g, 41.0 mmol) was dissolved in THF (60 mL) and LDA ( The resulting solution was stirred at -78°C for 30 minutes. Methyl 3-methoxy-2,2-dimethylpropanoate (3 g, 20.5 mmol) was added dropwise at -78°C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (100 mL) and extracted with EtOAc (50 mL x 2). The combined organics were dried (NaSO) and concentrated under reduced pressure to give the title product (2.3 g, 72%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6): 4.18 (s, 2H), 3.36 (s, 3H), 3.34 (s, 2H), 1.06 (s, 6H).

[0333] Step 3: 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine A mixture of 5-methoxy-4,4-dimethyl-3-oxopentanenitrile (2.3 g, 14.8 mmol), NHOH.HCl (1.12 g, 16.2 mmol), and NaOH (647 mg, 16.2 mmol) in water (20 mL) and EtOH (20 mL) was stirred at 80 °C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (100 mL) and extracted with EtOAc (50 mL × 2). The combined organics were dried (NaSO) and concentrated under reduced pressure to give the title product (960 mg, 38%) as a yellow oil. LCMS (Method A): 0.9 min; m / z: 171.1 [M+H] + .

[0334] Intermediate E3: 5-(4-methyltetrahydro-2H-pyran-4-yl)isoxazol-3-amine [ka]

[0335] Step 1: 4-methyltetrahydro-2H-pyran-4-carboxylate methyl To a solution of methyl oxane-4-carboxylate (5 g, 34.6 mmol) in dry THF (15 mL) was added LDA (2 M in THF, 34.6 mL, 69.2 mmol), and the mixture was stirred at −78° C. for 30 min. MeI (5.89 g, 41.5 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was adjusted to pH 3 with aqueous HCl (0.5 M), and the organic matter was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 100 / 1, V / V) to give the title product (5.40 g, 34.1 mmol, 98.7%) as a yellow oil. 1 H NMR (400 MHz, CDCl3): 3.78 (dt, J = 11.8, 4.1 Hz, 2H), 3.70 (s, 3H), 3.50-3.42 (m, 2H), 2.10-2.01 (m, 2H), 1.53-1.43 (m, 2H), 1.21 (s, 3H).

[0336] Step 2: 3-(4-methyltetrahydro-2H-pyran-4-yl)-3-oxopropanenitrile Acetonitrile (4.31 g, 105 mmol) was slowly added to a solution of lithium diisopropylamide (2 M / THF, 10.9 g, 102 mmol) in dry THF (50 mL) and stirred at −78° C. for 1 h. After that, methyl 4-methyloxane-4-carboxylate (5.4 g, 34.1 mmol) in dry THF (40 mL) was added over 10 min. The mixture was stirred at −78° C. for 1 h and at room temperature overnight. The mixture was diluted with water (100 mL) and the pH was adjusted to pH = 3 with 2 M HCl. The organics were extracted with EtOAc (3 × 50 mL), and the combined organics were dried (NaSO) and concentrated under reduced pressure to give the title product (4.20 g, 74%) as a yellow oil. 1 H NMR (400 MHz, CDCl3): 3.74 (ddd, J = 12.0, 6.4, 3.7 Hz, 2H), 3.55 (ddd, J = 11.7, 8.1, 3.3 Hz, 2H), 2.02-1.95 (m, 2H), 1.90 (d, J = 0.7 Hz, 2H), 1.59-1.51 (m, 2H), 1.24 (s, 3H).

[0337] Step 3: 5-(4-methyltetrahydro-2H-pyran-4-yl)isoxazol-3-amine A mixture of 3-(4-methyltetrahydro-2H-pyran-4-yl)-3-oxopropanenitrile (7 g, 41.8 mmol), NHOH.HCl (3.30 g, 50.1 mmol), and NaHCO (8.73 g, 104 mmol) in water (63 mL) and MeOH (7 mL) was stirred overnight at 65 °C under N. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (40 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were dried (NaSO) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 9:1 to 1:9) to give the title product (1.20 g, 16%) as a red oil. 1 H NMR (400 MHz, CDCl3): 4.96 (s, 1H), 4.52 (br s, 2H), 3.82-3.71 (m, 2H), 3.64-3.57 (m, 2H), 2.03-1.97 (m, 2H), 1.63 (ddd, J = 13.6, 9.5, 4.0 Hz, 2H), 1.26 (s, 3H).

[0338] Intermediate E4: 5-(2-fluoropropan-2-yl)isoxazol-3-amine [ka]

[0339] Step 1: 4-Fluoro-4-methyl-3-oxopentanenitrile To a suspension of NaH (60% in oil, 2.49 g, 104 mmol) in THF (30 mL) was added ethyl 2-fluoro-2-methylpropanoate (3.5 g, 26.0 mmol) and acetonitrile (1.66 g, 40.5 mmol) was added dropwise. The resulting mixture was heated at 70 °C for 3 h. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were dried (NaSO) and concentrated under reduced pressure to give the title product (3.10 g, 92%) as a yellow oil.

[0340] Step 2: 5-(2-fluoropropan-2-yl)isoxazol-3-amine A mixture of 4-fluoro-4-methyl-3-oxopentanenitrile (2.3 g, 17.8 mmol), NaHCO (3.73 g, 44.5 mmol), and NH OH.HCl (703 mg, 21.3 mmol) in HO (27 mL) and MeOH (3 mL) was stirred at 65° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic phases were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 5:1) to give the title product (450 mg, 18%) as a yellow oil. LCMS (Method A): 2.496 min; m / z: 145.1 [M+H] + .

[0341] Intermediate E5: 5-(3-methyloxetan-3-yl)isoxazol-3-amine [ka]

[0342] Step 1: Benzyl 3-methyloxetane-3-carboxylate A mixture of 3-methyloxetane-3-carboxylic acid (4 g, 34.4 mmol), K2CO3 (14.2 g, 103 mmol), and benzyl bromide (5.88 g, 34.4 mmol) in acetonitrile (50 mL) was stirred at 70 °C overnight under N2. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 10:1) to give the title product (6.9 g, 97%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6): 7.41-7.31 (m, 5H), 5.18 (s, 2H), 4.77 (d, J = 5.9 Hz, 2H), 4.34 (d, J = 5.9 Hz, 2H), 1.53 (s, 3H).

[0343] Step 2: 3-(3-methyloxetan-3-yl)-3-oxopropanenitrile To a solution of LDA (2 M in THF, 25 mL, 49.7 mmol) in dry THF (100 mL) was added acetonitrile (2.04 g, 49.7 mmol), and the solution was stirred at −78° C. for 1 h under N 2 . Benzyl 3-methyloxetane-3-carboxylate (7.9 g, 38.3 mmol) was added at −78° C., and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic phases were dried (Na 2 SO 4 ) and concentrated under reduced pressure to give the title product (3 g, 56%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6): 4.74 (d, J = 6.2 Hz, 2H), 4.28 (t, J = 3.1 Hz, 4H), 1.49 (s, 3H).

[0344] Step 3: 5-(3-methyloxetan-3-yl)isoxazol-3-amine A mixture of 3-(3-methyloxetan-3-yl)-3-oxopropanenitrile (3 g, 21.5 mmol), NHOH.HCl (1.63 g, 23.6 mmol), and NaOH (943 mg, 23.6 mmol) in water (40 mL) and EtOH (40 mL) was stirred overnight at 80 °C under N. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (100 mL). The mixture was extracted with EtOAc (50 mL × 2), and the combined organics were dried (NaSO) and concentrated under reduced pressure to give the title product (1.9 g, 57%) as a yellow oil. LCMS (Method A): 3.22 min; m / z: 155.1 [M+H] + .

[0345] Intermediate E6: 5-(adamantan-1-yl)isoxazol-3-amine [ka]

[0346] Step 1: 3-(adamantan-1-yl)-3-oxopropanenitrile To a precooled solution of acetonitrile (1.26 g, 30.8 mmol) in dry THF (25 mL) was slowly added a solution of LDA (2 M in THF, 23.1 mL, 46.2 mmol) at −78 °C, and the mixture was stirred at −78 °C for 1 h. A solution of methyl adamantane-1-carboxylate (3 g, 15.4 mmol) in dry THF (15 mL) was added dropwise at −78 °C, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of NH₄Cl (50 mL) was added, and the organics were extracted with EtOAc (3 × 50 mL). The combined organics were dried (Na₂SO₄) and concentrated under reduced pressure to give the title product (3.5 g, 99%) as a yellow liquid.

[0347] Step 2: 5-(adamantan-1-yl)isoxazol-3-amine A mixture of 3-(adamantan-1-yl)-3-oxopropanenitrile (3.5 g, 17.2 mmol), NHOH.HCl (1.36 g, 20.6 mmol) and NaHCO (3.60 g, 42.9 mmol) in water (54 mL) and MeOH (6 mL) The mixture was stirred overnight at 65° C. under N2. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 5:1) to give the title product (0.8 g, 21%) as a yellow solid. LCMS (Method A): 4.74 min, m / z: 292.2 [M+H] + .

[0348] Intermediate E7: 5-(tetrahydrofuran-3-yl)isoxazol-3-amine [ka]

[0349] Step 1: 3-oxo-3-(tetrahydrofuran-3-yl)propanenitrile To a solution of LDA (2 M in THF, 12.5 mL, 24.9 mmol) in dry THF (50 mL) was added acetonitrile (4.14 mL), and the mixture was stirred at −78° C. for 1 h under N 2 . Methyl tetrahydrofuran-3-carboxylate (2.5 g, 19.2 mmol) was added at −78° C., and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic phase was dried (Na 2 SO 4 ) and concentrated under reduced pressure to give the title product (2 g, 75%) as a yellow oil.

[0350] Step 2: 5-(tetrahydrofuran-3-yl)isoxazol-3-amine To a solution of 3-oxo-3-(tetrahydrofuran-3-yl)propanenitrile (2 g, 14.3 mmol) in HO (10 mL) and EtOH (10 mL) were added NHOH.HCl (1.09 g, 15.7 mmol) and NaOH (627 mg, 15.7 mmol), and the reaction mixture was stirred at 80 °C overnight. The mixture was diluted with water (50 mL), and the organics were extracted with EtOAc (50 mL × 3). The combined organic phases were washed with water and brine, dried (NaSO), and concentrated under reduced pressure to give the title product (1.9 g, 86%) as a yellow solid. LCMS (Method A): 1.08 min; m / z: 155.1 [M+H] + .

[0351] Intermediate E8: 5-(difluoromethyl)isoxazol-3-amine [ka]

[0352] Step 1: 4,4-Difluoro-3-oxobutanenitrile A solution of diisopropylamine (5.28 g, 52.2 mmol) in dry THF (100 mL) was cooled to -78 °C under N2, and a solution of n-BuLi (1.6 M in hexane, 52.2 mmol) was added dropwise and stirred at -78 °C for 1 h. A solution of MeCN (2.14 g, 52.2 mmol) in dry THF (20 mL) was added dropwise, and the resulting mixture was stirred at -78 °C for 30 min. A solution of 2,2-difluoroethyl acetate (5 g, 40.2 mmol) in dry THF (10 mL) was added, and the reaction mixture was stirred at room temperature overnight. Water (100 mL) was added, and the mixture was concentrated under reduced pressure. The aqueous residue was extracted with EtOAc (200 mL × 3). The combined organics were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give the title product (5 g, >100%) as a brown oil.

[0353] Step 2: 5-(Difluoromethyl)isoxazol-3-amine To a mixture of 4,4-difluoro-3-oxobutanenitrile (5 g, 41.9 mmol) and NaOH (1.83 g, 46.0 mmol) in EtOH (100 mL) and HO (100 mL), NHOH.HCl (3.19 g, 46.0 mmol) was added, and the mixture was stirred at 80 °C overnight. Water (30 mL) was added, and the organics were extracted with EtOAc (300 mL × 3). The combined organics were washed with brine, dried (NaSO), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 10:1) to give the title product (876 mg, 16%) as a yellow oil.

[0354] Intermediate E9: 5-cyclopropyl-1,2-oxazol-3-amine [ka]

[0355] Step 1: 5-Cyclopropyl-1,2-oxazol-3-amine A mixture of 3-cyclopropyl-3-oxopropanenitrile (1 g, 9.16 mmol), NHOH.HCl (359 mg, 10.9 mmol), and NaHCO (1.92 g, 22.9 mmol) in MeOH (2 mL) and HO (18 mL) was stirred at 65 °C under N for 15 h. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were dried (NaSO) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 5:1) to give the title product (320 mg, 28%) as a brown oil. LCMS (Method A): 0.78 min; m / z: 145.1 [M+H] + .

[0356] Intermediate F1: 5-(tert-butyl)pyrazin-2-amine [ka]

[0357] Step 1: 2-Bromo-N-(3,3-dimethyl-2-oxobutyl)acetamide To a solution of 2-bromoacetyl bromide (17.5 g, 86.8 mmol) in DCM (120 mL) was added saturated aqueous Na2CO3 (60 mL) and 1-amino-3,3-dimethylbutan-2-one (10 g, 86.8 mmol) at 0 °C. The solution was stirred at room temperature for 4 h. Water (100 mL) was added and the organics were extracted with DCM (200 mL x 3). The combined organics were washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure to give the title product (6.76 g, 33%) as a white solid. LCMS (Method A): 2.80 min; m / z: 236.1 [M+H] + .

[0358] Step 2: 5-(tert-butyl)pyrazin-2-ol To a solution of 2-bromo-N-(3,3-dimethyl-2-oxobutyl)acetamide (6.76 g, 28.6 mmol) in EtOH.NH3 (20 mL) was added KI (949 mg, 5.72 mmol), and the reaction was stirred at 60 °C overnight. The mixture was poured into water (200 mL), and the organics were extracted with DCM (120 mL × 4). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 30:1) to give the title product (2.6 g, 50%) as a yellow oil. LCMS (Method B): 1.90 min; m / z: 152.9 [M+H] + .

[0359] Step 3: 5-(tert-butyl)pyrazin-2-yl trifluoromethanesulfonate To a mixture of 5-tert-butylpyrazin-2-ol (2.6 g, 17.0 mmol) and EtN (3.44 g, 34.0 mmol) in DCM (70 mL) at 0 °C, TfO (7.19 g, 25.5 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was poured into water (60 mL), and the organic phase was extracted with EtOAc (150 mL × 2). The combined organics were washed with brine, dried (NaSO), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 20:1) to give the title product (2.72 g, 56%) as a yellow oil. LCMS (Method B): 5.30 min; m / z: 284.9 [M+H] + .

[0360] Step 4: N-(5-(tert-butyl)pyrazin-2-yl)-1,1-diphenylmethanimine A mixture of 5-tert-butylpyrazin-2-yl trifluoromethanesulfonate (2.72 g, 9.56 mmol), Xantphos (1.10 g, 1.91 mmol), Pd(dba) (875 mg, 956 μmol), CsCO (6.22 g, 19.1 mmol), and diphenylmethanimine (2.06 g, 11.4 mmol) in degassed 1,4-dioxane (80 mL) was stirred at 100 °C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE: EtOAc, 10:1) to give the title product (2 g, 66%) as a white solid. LCMS (Method B): 5.42 min; m / z: 316.1 [M+H] + .

[0361] Step 5: 5-(tert-butyl)pyrazin-2-amine A mixture of N-(5-tert-butylpyrazin-2-yl)-1,1-diphenylmethanimine (150 mg, 475 μmol) in aqueous HCl (2 M, 6 mL) and MeOH (6 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (PE: EtOAc, 2:1) to give the title product (47 mg, 65%) as a white solid. LCMS (Method B): 4.33 min; m / z 152.1 [M+H] + .

[0362] Intermediate F2: 5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine [ka]

[0363] Step 1: 5-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-amine 5-Bromopyrazin-2-amine (828 mg, 4.76 mmol), 2-(3,6-dihydro-2-pyrazine-2-amine) (30 mL) and HO (7.5 mL) were dissolved in degassed 1,4-dioxane (30 mL). To a mixture of (H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 4.76 mmol) and NaCO (1.50 g, 14.2 mmol), Pd(dppf)Cl (217 mg, 238 μmol) was added, and the reaction mixture was stirred overnight at 100 °C under N. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EtOAc, 1:1 to 0:1) to give the title product (700 mg, 83%) as a brown solid.

[0364] Step 2: 5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine A mixture of 5-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-amine (700 mg, 3.95 mmol) and 10% Pd / C (70 mg, 0.658 mmol) in MeOH (30 mL) was stirred under H2 at 50 °C overnight. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc, 4:1 to 1:4) to give the title product (520 mg, 74%) as a brown oil. LCMS (Method A): 0.85 min, m / z: 180.0 [M+H] + .

[0365] Intermediate F3: 5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine [ka]

[0366] Step 1: 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine A mixture of 5-bromopyridin-2-amine (2 g, 11.5 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.41 g, 11.5 mmol), NaCO (4.87 g, 46.0 mmol), and Pd(dppf)Cl (516 mg, 2.30 mmol) in degassed 1,4-dioxane (100 mL) and HO (20 mL) was heated at 100 °C for 12 h under N. The mixture was cooled to room temperature, and the organics were extracted with EtOAc (2 × 10 mL). The combined organics were washed with brine, dried (NaSO), and concentrated. The residue was purified by silica gel column chromatography (PE: EtOAc, 10:1) to give the title product (800 mg, 4.53 mmol) as a yellow oil. LCMS (Method A): 3.02 min; m / z: 177.1 [M+H] + .

[0367] Step 2: 5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine A mixture of 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine (3 g, 17 mmol) and 10% Pd / C (361 mg, 3.40 mmol) in MeOH (20 mL) was stirred under H2 at room temperature for 6 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EtOAc, 5:1 to 1:5) to give the title product (2.0 g, 11.2 mmol) as a yellow oil. LCMS (Method A): 0.72 min, m / z: 179.2 [M+H] + .

[0368] Intermediate F4: 5-Cyclopropylpyrazine-2-amine [ka]

[0369] Step 1: 2-Bromo-5-cyclopropylpyrazine To a solution of 2,5-dibromopyrazine (4.0 g, 16.8 mmol) in degassed 1,4-dioxane (80 mL) was added a solution of K2CO3 (5.80 g, 42.0 mmol) in water (20 mL), and cyclopropylboronic acid (1.72 g, 20.1 mmol), Pd(OAc)2 (188 mg, 840 μmol), and Pd(dppf)Cl2 (685 mg, 840 μmol) were added. The reaction mixture was stirred at 120 °C for 16 h and filtered through Celite. The filtrate was diluted with EtOAc (200 mL), and the organics were separated, washed with water (100 mL) and brine (100 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 100:1) to give the title product (1.6 g, 43%) as a yellow solid. LCMS (Method A): 3.83 min, m / z: 200.9 [M+H] + .

[0370] Step 2: N-(5-cyclopropylpyrazin-2-yl)-1,1-diphenylmethanimine A mixture of 2-bromo-5-cyclopropylpyrazine (700 mg, 3.51 mmol), Pd(dba) (160 mg, 175 μmol), Xantphos (203 mg, 351 μmol), CsCO (2.28 g, 7.02 mmol), and diphenylmethanimine (699 mg, 3.86 mmol) in degassed 1,4-dioxane (5 mL) was stirred overnight at 100 °C under N. The mixture was poured into water (10 mL), and the organics were extracted with EtOAc (50 mL × 2). The combined organics were dried (NaSO) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 5:1) to give the title product (1.3 g, 62%) as a yellow solid. LCMS (Method A): 4.27 min, m / z 300.2 [M+H] + .

[0371] Step 3: 5-Cyclopropylpyrazin-2-amine To a solution of N-(5-cyclopropylpyrazin-2-yl)-1,1-diphenylmethanimine (1.3 g, 4.34 mmol) in MeOH (40 mL) was added aqueous HCl (2 M, 10 mL), and the mixture was stirred at 30 °C overnight. Most of the MeOH was removed under reduced pressure, and the remaining mixture was adjusted to pH = 8 with saturated aqueous Na2CO3. The aqueous mixture was extracted with EtOAc (50 mL x 2), and the combined organics were washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 1:1) to give the title product (100 mg, 17%) as a brown solid. LCMS (Method A): 4.45 min, m / z: 136.0 [M+H] + .

[0372] Intermediate G1: 5-methyl-2-nitro-4H,5H,6H,7H,8H-pyrazolo[1,5-a][1,4]diazepine [ka]

[0373] Step 1: 1-(3-bromopropyl)-3-nitro-1H-pyrazole-5-carboxylate methyl To a solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (1.0 g, 5.84 mmol) in acetone (30 mL) was added K2CO3 (4.02 g, 29.1 mmol) and 1,3-dibromopropane (2.10 mL, 17.5 mmol), and the reaction was refluxed for 2 h. The mixture was heated at RT. The mixture was cooled to 0° C., filtered, and concentrated. The residue was purified by flash chromatography (EtOAc:n-Hep 0-50%) to give the title compound (1.22 g, 72%) as a colorless oil. LCMS (Method D): 1.90 min, m / z 291.8 / 293.8 [M+H] + .

[0374] Step 2: [1-(3-bromopropyl)-3-nitro-1H-pyrazol-5-yl]methanol To a solution of methyl 1-(3-bromopropyl)-3-nitro-1H-pyrazole-5-carboxylate (1.22 g, 4.17 mmol) in THF (40 mL) at 0 °C was added LiBH (2.08 mL, 4.17 mmol) in portions. The reaction was stirred at 0 °C for 4 h, quenched with saturated NH Cl (20 mL), and extracted with EtOAc (3 x 30 mL). The combined organics were dried (MgSO) and concentrated to give the title compound (882 mg, 80%) as a colorless oil. LCMS (Method D): 1.17 min, m / z 263.8 / 265.8 [M+H] + .

[0375] Step 3: 5-(Bromomethyl)-1-(3-bromopropyl)-3-nitro-1H-pyrazole To a suspension of [1-(3-bromopropyl)-3-nitro-1H-pyrazol-5-yl]methanol (880 mg, 3.33 mmol) in CHCl (30 mL) was added PBr (468 μL, 4.99 mmol) and the reaction was heated at reflux for 2 h. Once cooled, the mixture was basified to pH 9 with saturated NaHCO. The mixture was extracted with CHCl (3×25 mL) and the combined organics were washed with water (25 mL), dried (MgSO), and concentrated to give the title compound (1.09 g, quantitative) as a white solid. LCMS (Method D): 1.98 min, m / z 327.8 [M+H] + .

[0376] Step 4: 5-Methyl-2-nitro-4H,5H,6H,7H,8H-pyrazolo[1,5-a][1,4]diazepine To a solution of 5-(bromomethyl)-1-(3-bromopropyl)-3-nitro-1H-pyrazole (1.09 g, 3.33 mmol) in THF (33.3 mL) was added MeNH2 (2.0 M in THF, 9.95 mL, 19.9 mmol), and the reaction was stirred at room temperature overnight. The mixture was concentrated, and the residue was diluted with saturated NaHCO3 (15 mL). The aqueous mixture was extracted with DCM (2 x 20 mL), and the combined organics were washed with water (15 mL) and brine (10 mL), dried (MgSO4), and concentrated. The residue was purified by flash chromatography (0-20% MeOH:DCM) to afford the title compound (468 mg, 72%) as a yellow oil. LCMS (Method D): 0.14 min, m / z 197.0 [M+H] + .

[0377] Step 5: 5-Methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-a][1,4]diazepin-2-amine A mixture of 5-methyl-2-nitro-4H,5H,6H,7H,8H-pyrazolo[1,5-a][1,4]diazepine (465 mg, 2.36 mmol) and 10% Pd / C (251 mg, 236 μmol) in MeOH (11.7 mL) was stirred under H overnight. The reaction was filtered through Celite and concentrated to give the title compound (387 mg, 99%) as a yellow oil. LCMS (Method D): RT 0.10 min, m / z 167.0 [M+H].

[0378] compound 131 [ka]

[0379] Step 1: 1-(tert-butyl)-3-(4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide A mixture of 3-(4-aminophenyl)-1-(tert-butyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide (Intermediate A, 200 mg, 0.57 mmol), EtSOCl (88 mg, 0.69 mmol), and pyridine (90 mg, 1.14 mmol) in CHCl (5 mL) was stirred at room temperature for 16 h. The mixture was diluted with HO (5 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were dried (NaSO) and concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title product (100 mg, 40%) as a yellow solid. LCMS (Method A): 2.12 min; m / z: 443.2 [M+H] + .

[0380] Step 2: 3-(4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide (Compound 131) A solution of 1-(tert-butyl)-3-(4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide (50 mg, 0.11 mmol) in TFA (4 mL) was stirred at 60° C. for 2 h. The mixture was concentrated under reduced pressure, basified with NHOH (1 mL), and extracted with DCM (3×5 mL). The combined organic layers were dried (NaSO), concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH:NHOH, 10:1:0.1) to give the title product (40 mg, 94%) as a yellow solid. LCMS (Method A): 0.29 min; m / z: 387.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 12.83 (s, 1H), 10.26 (br s, 1H), 9.48 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.80-7.60 (m, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.13-7.12 (m, 3H), 6.85-6.84 (m, 1H), 6.05 (br s, 1H), 3.17 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H).

[0381] The following compounds (Table 5) were similarly prepared from the appropriate sulfonyl chloride and intermediate A1 according to the method described for the synthesis of 3-(4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide.

[0382] [Table 5-1]

[0383] [Table 5-2]

[0384] [Table 5-3]

[0385] compound 81 [ka]

[0386] Step 1: 1-(tert-butyl)-3-(4-((cyclobutylmethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide A mixture of 3-(4-aminophenyl)-1-(tert-butyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide (Intermediate A3, 300 mg, 853 μmol), cyclobutyl methanesulfonyl chloride (286 mg, 1.7 mmol), and pyridine (202 mg, 2.56 mmol) in CHCl (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH, 12:1) to give the title product (120 g, 29%) as a white solid. LCMS (Method A): 3.53 min; m / z: 484.2 [M+H] + .

[0387] Step 2: 3-(4-((cyclobutylmethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (Compound 81) A mixture of 1-(tert-butyl)-3-(4-((cyclobutylmethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (60 mg, 124 μmol) in DCM (4 mL) and TFA (4 mL) was stirred at 30° C. for 16 h. The mixture was concentrated under reduced pressure, and the residue was neutralized to pH 7-8 with NH4OH and extracted with DCM (3×40 mL). The combined organic layers were dried (Na2SO4), concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH, 12:1) to give the title product (20 mg, 37%) as a white solid. LCMS (Method A): 3.20 min; m / z: 428.1 [M+H] + . 1 H NMR (400 MHz, MeOD-d4): 12.94 (s, 1H), 10.10 (s, 1H), 9.64 (s, 1H), 9.26 (s, 1H), 8.22 (t, J = 4.0 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 3.30 (s, 2H), 2.08 (s, 1H), 1.83-1.73 (m, 4H).

[0388] The following compounds (Table 6) were similarly prepared from the appropriate sulfonyl chloride and intermediate A3 according to the method described for the synthesis of 3-(4-((cyclobutylmethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide.

[0389] [Table 6-1]

[0390] [Table 6-2]

[0391] [Table 6-3]

[0392] [Table 6-4]

[0393] [Table 6-5]

[0394] [Table 6-6]

[0395] compound 60 [ka]

[0396] Step 1: 1-tert-butyl-3-{4-[(4-chlorophenyl)methanesulfonamido]phenyl}-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide To a solution of 3-(4-aminophenyl)-1-tert-butyl-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide (Intermediate A2, 124 mg, 296 μmol) in pyridine (5 mL) was added (4-chlorophenyl)methanesulfonyl chloride (115 mg, 510 μmol) at 0° C., and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH, 15:1) to give the title product (70 mg, 39%) as a yellow solid. LCMS (Method A): 4.32 min; m / z: 607.1 [M+H] + .

[0397] Step 2: 3-(4-(((4-chlorophenyl)methyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide (Compound 60) A solution of 1-tert-butyl-3-{4-[(4-chlorophenyl)methanesulfonamido]phenyl}-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide (70 mg, 115 μmol) in DCM (4 mL) and TFA (4 mL) was stirred at 35° C. for 2 h. The reaction mixture was concentrated under reduced pressure and neutralized to pH 7-8 with saturated aqueous Na2CO3. The mixture was diluted with HO (10 mL), and the precipitate was collected by filtration and purified by preparative TLC (DCM:MeOH, 15:1) to give the title product (18 mg, 28%) as a yellow solid.

[0398] The following compounds (Table 7) were similarly prepared from the appropriate sulfonyl chloride starting material (SM) and intermediate A2 according to the method described for the synthesis of 3-(4-(((4-chlorophenyl)methyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide.

[0399] [Table 7-1]

[0400] [Table 7-2]

[0401] [Table 7-3]

[0402] [Table 7-4]

[0403] [Table 7-5]

[0404] Compound 119 [ka]

[0405] Step 1: 1-(tert-butyl)-5-(methylamino)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile A mixture of 5-amino-1-(tert-butyl)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (300 mg, 1.05 mmol), paraformaldehyde (315 mg, 10.5 mmol), NaOMe (228 mg, 4.2 mmol), and MeOH (20 mL) was stirred at room temperature for 16 hours. NaBH (160 mg, 4.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, diluted with H O (20 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried (Na SO ) and concentrated under reduced pressure to give the crude product (300 mg, 76%) as a yellow solid. LCMS (Method B): 2.45 min; m / z: 300.0 [M+H] + .

[0406] Step 2: 1-tert-butyl-5-(methylamino)-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide To a solution of 1-tert-butyl-5-(methylamino)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (270 mg, 0.9 mmol) in DMSO (20 mL) and EtOH (20 mL) was added 30% aqueous HO (20 mL) and 5% aqueous NaOH (1 mL). The mixture was stirred at room temperature for 20 minutes and heated to 80 °C for 16 hours. The mixture was concentrated under reduced pressure and diluted with HO (20 mL). The precipitate was collected by filtration, washed with HO, and dried under reduced pressure to give the title product (250 mg, 87%) as a yellow solid. LCMS (Method B): 1.92 min; m / z: 318.0 [M+H] + .

[0407] Step 3: 3-(4-aminophenyl)-1-tert-butyl-5-(methylamino)-1H-pyrazole-4-carboxamide 1-tert-Butyl-5-(methylamino)-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (185 mg, 0.58 mmol), saturated aqueous NH4Cl (5 mL), Zn dust (190 mg, 2.91 mmol), and MeOH (10 mL) were heated to 60 °C for 16 h. The reaction mixture was filtered, concentrated under reduced pressure, and diluted with HO. The precipitate was collected by filtration and dried under reduced pressure to give the title product (150 mg, 90%) as a yellow solid. LCMS (Method B): 0.35 min; m / z: 288.1 [M+H] + .

[0408] Step 4: 1-tert-butyl-3-(4-ethanesulfonamidophenyl)-5-(methylamino)-1H-pyrazole-4-carboxamide To a solution of 3-(4-aminophenyl)-1-tert-butyl-5-(methylamino)-1H-pyrazole-4-carboxamide (100 mg, 0.35 mmol) and pyridine (55.0 mg, 0.7 mmol) in CHCl (5 mL) was added EtSOCl (53.6 mg, 0.42 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the crude residue was purified by preparative TLC (DCM:MeOH, 15:1) to give the title product (35 mg, 27%) as a yellow solid. LCMS (Method B): 0.87 min; m / z: 38 0.0[M+H] + .

[0409] Step 5: 3-(4-(ethylsulfonamido)phenyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 119) A solution of 1-tert-butyl-3-(4-ethanesulfonamidophenyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (35 mg, 0.09 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH:NH4OH, 10:1:0.1) to give the title product (12 mg, 40%) as a gray solid. LCMS (Method B): 3.50 min; m / z: 324.0 [M+H] + . 1 H NMR (400 MHz, MeOD-d4): 7.51 (d, J = 8.4 Hz, 2H),7.38 (d, J = 8.4 Hz, 2H), 3.19-3.14 (q, J = 7.2 Hz, 2H), 2.94 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H).

[0410] compound 64 [ka]

[0411] Step 1: 3-Bromo-5-[(pyridazin-3-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile A mixture of 3,5-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (2 g, 5.24 mmol), pyrazin-3-amine (498 mg, 5.24 mmol), Pd(dba) (479 mg, 524 μmol), Xantphos (599 mg, 1.04 mmol), and CsCO (5.11 g, 15.7 mmol) in degassed 1,4-dioxane (150 mL) was stirred at 80 °C under N for 16 h. The mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 1:1) to give the title product (380 g, 18%) as a yellow solid. LCMS (Method A): 3.15 min; m / z: 395.0, 397.1 [M+H] + .

[0412] Step 2: N-(4-{4-cyano-5-[(pyridazin-3-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl}phenyl)ethane-1-sulfonamide A mixture of 3-bromo-5-[(pyridazin-3-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (300 mg, 758 μmol), N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamide (235 mg, 758 μmol), Pd(dppf)Cl (69.4 mg, 75.8 μmol), and NaCO (3.79 mmol) in degassed 1,4-dioxane (10 mL) was stirred at 100 °C under microwave irradiation for 20 min. The mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 1:0 to 0:1) to give the title product (230 mg, 87%) as a yellow solid. LCMS (Method A): 3.31 min; m / z: 500.0 [M+H] + .

[0413] Step 3: 3-(4-ethanesulfonamidophenyl)-5-[(pyridazin-3-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide To a solution of N-(4-{4-cyano-5-[(pyridazin-3-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl}phenyl)ethane-1-sulfonamide (200 mg, 400 μmol) in 50% aqueous 1,4-dioxane (20 mL) was added Ghaffar-Parkins catalyst (10 mg, 23.4 μmol) and heated to 100° C. under N for 16 h. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by preparative TLCPE:EtOAc (10:1) to give the title product (80 mg, 38%) as a yellow solid. LCMS (Method A): 3.53 min; m / z: 518.2 [M+H] + .

[0414] Step 4: 3-(4-ethanesulfonamidophenyl)-5-[(pyridazin-3-yl)amino]-1H-pyrazole-4-carboxamide (Compound 64) A mixture of 3-(4-ethanesulfonamidophenyl)-5-[(pyridazin-3-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (80 mg, 154 μmol), 12.0 M HCl (0.5 mL), and THF (5 mL) was stirred overnight at 30° C. under N. The mixture was concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH:NHOH, 10:1:0.1) to give the title product (10 mg, 25%) as a yellow solid. LCMS (Method A): 2.44 min; m / z: 388.0 [M+H] + . 1 H NMR (400 MHz, MeOD-d4): 7.67 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.41- 7.37 (m, 1H), 7.30-7.26 (m, 1H), 3.35 (s, 1H), 3.20 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H).

[0415] Following the complete synthesis of compound 64, the following compounds (Table 8) were prepared starting from 3,5-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile and using the indicated intermediates used as described in Step 1.

[0416] [Table 8]

[0417] compound 89 [ka]

[0418] Step 1: 1-tert-butyl-3-(4-nitrophenyl)-5-[(quinolin-2-yl)amino]-1H-pyrazole-4-carbonitrile A mixture of 5-amino-1-tert-butyl-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (2 g, 7.00 mmol), 2-chloroquinoline (1.03 g, 6.30 mmol), Pd(dba) (641 mg, 0.7 mmol), Xantphos (810 mg, 1.40 mmol), and CsCO (6.84 g, 21.0 mmol) in degassed 1,4-dioxane (5 mL) was stirred at 100 °C for 16 h. The mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 2:1) to give the title product (520 mg, 18% yield) as a yellow oil. LCMS (Method A): 3.54 min; m / z: 413.0 [M+H] + .

[0419] Step 2: 1-tert-butyl-3-(4-nitrophenyl)-5-[(quinolin-2-yl)amino]-1H-pyrazole-4-carboxamide To a mixture of 1-tert-butyl-3-(4-nitrophenyl)-5-[(quinolin-2-yl)amino]-1H-pyrazole-4-carbonitrile (520 mg, 1.26 mmol) in EtOH (20 mL) and DMSO (10 mL) was added 30% aqueous HO (10 mL) and 5% aqueous NaOH (1.5 mL), and the reaction was stirred at 80 °C overnight. The mixture was concentrated under reduced pressure, and the residue was diluted with HO (150 mL) and extracted with EtOAc (3 × 70 mL). The combined organic layers were dried (NaSO) and concentrated under reduced pressure to give the title product (1 g, >100%) as a brown solid. LCMS (Method A): 3.80 Min; m / z: 431.1 [M+H] + .

[0420] Step 3: 3-(4-aminophenyl)-1-tert-butyl-5-[(quinolin-2-yl)amino]-1H-pyrazole-4-carboxamide A mixture of 1-tert-butyl-3-(4-nitrophenyl)-5-[(quinolin-2-yl)amino]-1H-pyrazole-4-carboxamide (500 mg, 1.16 mmol) and 10% Pd / C (50 mg) in MeOH (10 mL) was stirred under H2 at room temperature overnight. The suspension was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title product (460 mg, 99%) as a yellow solid. LCMS (Method A): 2.60 min; m / z: 401.2 [M+H] + .

[0421] Step 4: 1-tert-butyl-3-(4-ethanesulfonamidophenyl)-5-[(quinolin-2-yl)amino]-1H-pyrazole-4-carboxamide A mixture of 3-(4-aminophenyl)-1-tert-butyl-5-[(quinolin-2-yl)amino]-1H-pyrazole-4-carboxamide (460 mg, 1.14 mmol), EtSOCl (174 mg, 1.36 mmol), and pyridine (270 mg, 3.42 mmol) in CHCl (5 mL) was stirred at room temperature overnight. The mixture was concentrated, and the crude residue was purified by preparative TLC (DCM:MeOH, 12:1) to give the title product (120 mg, 21%) as a yellow solid. LCMS (Method A): 2.12 min; m / z: 49 3.1[M+H] + .

[0422] Step 5: 3-(4-(ethylsulfonamido)phenyl)-5-(quinolin-2-ylamino)-1H-pyrazole-4-carboxamide (Compound 89) A solution of 1-tert-butyl-3-(4-ethanesulfonamidophenyl)-5-[(quinolin-2-yl)amino]-1H-pyrazole-4-carboxamide (120 mg, 0.2436 mmol) in TFA (5 mL) and DCM (5 mL) was stirred at room temperature overnight. The mixture was concentrated, and the residue was basified with 1.0 M NH4Cl to pH 9-10. The precipitate was triturated with PE (3 x 5 mL), collected by filtration, and then dried under vacuum to give the title product (80 mg, 75%) as a yellow solid. LCMS (Method A): 2.80 min; m / z: 437.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 13.52 (br s, 1H), 12.93 (br s, 1H), 10.31 (br s, 1H), 10.04 (s, 1H), 8.23 ​​(d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.33-7.66 (m, 8H), 6.17 (br s, 1H), 3.18 (t, J = 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H).

[0423] compound 84 [ka]

[0424] Step 1: 1-tert-butyl-5-[(6-methylpyrazin-2-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile A mixture of 5-amino-1-tert-butyl-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (2 g, 7.00 mmol), 2-chloro-6-methylpyrazine (899 mg, 7.00 mmol), Pd(dba) (641 mg, 700 μmol), Xantphos (810 mg, 1.40 mmol), and CsCO (6.84 g, 21.0 mmol) in degassed 1,4-dioxane (60 mL) was stirred at 100 °C overnight. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 2:1) to give the title product (2.22 g, 84%) as a yellow solid. LCMS (Method A): 3.20 min; m / z: 378.2 [M+H] + .

[0425] Step 2: 1-tert-butyl-5-[(6-methylpyrazin-2-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide To a solution of 1-tert-butyl-5-[(6-methylpyrazin-2-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (1 g, 2.64 mmol) in DMSO (15 mL) and EtOH (30 mL) was added 30% aqueous HO (15 mL) and 5% aqueous NaOH (0.8 mL). The mixture was heated to 80 °C overnight, concentrated under reduced pressure, and diluted with HO (50 mL). The precipitate was collected by filtration and dried under reduced pressure to give the title product (750 mg, 72%) as a yellow solid. LCMS (Method A): 2.65 min; m / z: 396.2 [M+H] + .

[0426] Step 3: 3-(4-aminophenyl)-1-tert-butyl-5-[(6-methylphenyl)- (2-pyrazine-4-yl)amino]-1H-pyrazole-4-carboxamide A mixture of 1-tert-butyl-5-[(6-methylpyrazin-2-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (200 mg, 505 μmol) and 10% Pd / C (20 mg) in MeOH (10 mL) was stirred under H at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title product (210 mg, >100%) as a yellow solid. LCMS (Method A): 1.02 min; m / z: 366.2 [M+H] + .

[0427] Step 4: 1-tert-butyl-3-(4-ethanesulfonamidophenyl)-5-[(6-methylpyrazin-2-yl)amino]-1H-pyrazole-4-carboxamide A mixture of 3-(4-aminophenyl)-1-tert-butyl-5-[(6-methylpyrazin-2-yl)amino]-1H-pyrazole-4-carboxamide (200 mg, 547 μmol), EtSOCl (84.3 mg, 656 μmol), and pyridine (86.2 mg, 1.09 mmol) in CHCl (7 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (DCM:MeOH, 10:1) to give the title product (140 mg, 56%) as a yellow solid. LCMS (Method A): 1.49 min; m / z: 458.2 [M+H] + .

[0428] Step 5: 3-(4-(ethylsulfonamido)phenyl)-5-((6-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide (Compound 84) A solution of 1-tert-butyl-3-(4-ethanesulfonamidophenyl)-5-[(6-methylpyrazin-2-yl)amino]-1H-pyrazole-4-carboxamide (130 mg, 284 μmol) in DCM (4 mL) and TFA (4 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and neutralized with NH4OH to pH = 7-8. The precipitate was collected by filtration, triturated with PE (2 × 5 mL), and dried under reduced pressure to give the title product (80 mg, 70%) as a yellow solid. LCMS (Method A): 2.97 min; m / z: 402.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 12.91 (s, 1H), 10.13 (s, 1H), 9.55 (s, 1H), 9.09 (s, 1H), 8.01 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 6.09 (s, 1H), 3.19 (q, J = 7.2 Hz, 2H), 2.38 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H).

[0429] Following the complete synthesis of compound 84, starting from 5-amino-1-tert-butyl-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile, the following compounds (Table 9) were prepared using the indicated starting materials used as described in Step 1.

[0430] [Table 9-1]

[0431] [Table 9-2]

[0432] [Table 9-3]

[0433] [Table 9-4]

[0434] [Table 9-5]

[0435] [Table 9-6]

[0436] [Table 9-7]

[0437] compound 98 [ka]

[0438] Step 1: 1-tert-butyl-5-[(2-chloropyrimidin-4-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile A mixture of 5-amino-1-(tert-butyl)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (3 g, 10.5 mmol), 2,4-dichloropyrimidine (1.6 g, 11 mmol), Pd(dba) (960 mg, 1.05 mmol), CsCO (10.27 g, 31.5 mmol), and Xantphos (1.2 g, 2.1 mmol) in degassed 1,4-dioxane (100 mL) was stirred at 100 °C under N for 16 h. The mixture was concentrated under reduced pressure, diluted with HO (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic phases were dried (NaSO) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 1:1) to give the title product (1.2 g, 28%) as a yellow solid. LCMS (Method A): 2.46 min; m / z: 398.0 [M+H] + .

[0439] Step 2: 1-tert-butyl-5-[(2-ethoxypyrimidin-4-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile A mixture of 1-tert-butyl-5-[(2-chloropyrimidin-4-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (700 mg, 1.75 mmol) and NaOEt (595 mg, 8.75 mmol) in THF (30 mL) was stirred overnight at 65° C. under N. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 15:1) to give the title product (735 mg, 96%) as a yellow solid. LCMS (Method A): 3.38 min; m / z: 409.1 [M+H] + .

[0440] Step 3: 1-tert-butyl-5-[(2-ethoxypyrimidin-4-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide To a mixture of 1-tert-butyl-5-[(2-ethoxypyrimidin-4-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (635 mg, 1.55 mmol) in DMSO (44.5 mL) and EtOH (200 mL) was added 30% aqueous HO (44.5 mL) and aqueous NaOH solution (2 M, 5 drops), and the resulting mixture was stirred overnight at 100 °C under N. The mixture was concentrated under reduced pressure, and the residue was diluted with HO and EtOAc. The organic phase was separated, dried (NaSO), and concentrated under reduced pressure to give the title product (675 mg, 88%) as a yellow solid. LCMS (Method A): 2.61 min; m / z: 426.0 [M+H] + .

[0441] Step 4: 3-(4-aminophenyl)-1-tert-butyl-5-[(2-ethoxypyrimidin-4-yl)amino]-1H-pyrazole-4-carboxamide A mixture of 1-tert-butyl-5-[(2-ethoxypyrimidin-4-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (625 mg, 1.46 mmol), saturated NH4Cl (12 mL), and Zn dust (476 mg, 7.29 mmol) in MeOH (50 mL) was stirred overnight at 60 °C under N2. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was diluted with HO and EtOAc. The organic layer was separated. The mixture was filtered, dried (Na2SO4), and concentrated under reduced pressure to give the title product (475 mg, 82%) as a white solid. LCMS (Method A): 3.14 min; m / z: 396.2 [M+H] + .

[0442] Step 5: 1-tert-butyl-3-(4-ethanesulfonamidophenyl)-5-[(2-ethoxypyrimidin-4-yl)amino]-1H-pyrazole-4-carboxamide A mixture of 3-(4-aminophenyl)-1-tert-butyl-5-[(2-ethoxypyrimidin-4-yl)amino]-1H-pyrazole-4-carboxamide (271 mg, 0.685 mmol), EtSOCl (131 mg, 1.02 mmol), and pyridine (107 mg, 1.36 mmol) in CHCl (25 mL) was stirred at room temperature overnight and diluted with HO and EtOAc. The organic layer was separated, washed with water, dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 50:1) to afford the title product (110 mg, 19%) as a yellow solid. LCMS (Method A): 3.12 min; m / z: 488.2 [M+H] + .

[0443] Step 6: 5-((2-ethoxypyrimidin-4-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide (Compound 98) A solution of 1-tert-butyl-3-(4-ethanesulfonamidophenyl)-5-[(2-ethoxypyrimidin-4-yl)amino]-1H-pyrazole-4-carboxamide (110 mg, 225 μmol) in TFA (2 mL) was stirred at 60° C. under N for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was basified with saturated NH4Cl (2 mL). The precipitate was filtered, and the filter cake was washed with Et2O (2×2 mL) and n-hexane (2 mL) to give the title product (71 mg, 73%) as a white solid. LCMS (Method A): 0.96 min; m / z: 433.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 13.04 (s, 1H), 10.11 (s, 1H), 9.75 (s, 1H), 8.26 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.45 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 4.31 (q, J = 6.8 Hz, 2H), 3.19 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 14.0 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H).

[0444] compound 66 [ka]

[0445] Step 1: 5-(prop-1-en-2-yl)pyrazin-2-amine A mixture of 5-bromopyrazin-2-amine (5 g, 28.7 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.78 g, 34.4 mmol), K2CO3 (7.93 g, 57.4 mmol), and Pd(dppf)Cl2 (2.34 g, 2.87 mmol) in degassed 80% aqueous 1,4-dioxane (300 mL) was heated to 100 °C overnight under N2. The mixture was diluted with HO (300 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 4:1) to give the title product (2.9 g, 75%) as a yellow solid. LCMS (Method A): 1.38 min; m / z: 136.1 [M+H] + .

[0446] Step 2: 5-(propan-2-yl)pyrazin-2-amine A mixture of 5-(prop-1-en-2-yl)pyrazin-2-amine (1 g, 7.39 mmol), Pd(OH) (24 mg, 167 μmol), and MeOH (8 mL) was stirred under H at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title product (850 mg, 84%) as a brown solid. LCMS (Method A): 0.94 min; m / z: 138.0 [M+H] + .

[0447] Step 3: 3-Bromo-5-{[5-(propan-2-yl)pyrazin-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile A mixture of 3,5-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (2.08 g, 5.46 mmol), 5-(propan-2-yl)pyrazin-2-amine (750 mg, 5.46 mmol), Pd(dba) (499 mg, 546 μmol), Xantphos (630 mg, 1.09 mmol), and CsCO (5.31 g, 16.3 mmol) in degassed 1,4-dioxane (70 mL) was stirred overnight at 100 °C under N. The mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 8:1) to give the title product (1.48 g, 62%) as a yellow solid. LCMS (Method A): 4.64 min; m / z: 438.1 [M+H] + .

[0448] Step 4: N-[4-(4-cyano-5-{[5-(propan-2-yl)pyrazin-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)phenyl]ethane-1-sulfonamide A mixture of 3-bromo-5-{[5-(propan-2-yl)pyrazin-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (1.38 g, 3.15 mmol), N[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamide (980 mg, 3.15 mmol), Pd(dppf)Cl (257 mg, 315 μmol), and KCO (870 mg, 6.30 mmol) in degassed 80% aqueous 1,4-dioxane (50 mL) was stirred overnight at 100 °C under N. The mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 4:1) to give the title product (1.2 g, 71%) as a yellow solid. LCMS (Method A): 4.39 min; m / z: 542.2 [M+H]+ .

[0449] Step 5: 3-(4-ethanesulfonamidophenyl)-5-{[5-(propan-2-yl)pyrazin-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A mixture of N-[4-(4-cyano-5-{[5-(propan-2-yl)pyrazin-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)phenyl]ethane-1-sulfonamide (540 mg, 996 μmol), 30% aqueous HO (60 mL), and 5% aqueous NaOH (60 drops) in EtOH (120 mL) and DMSO (60 mL) was stirred overnight at 100 °C under N. The mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (NaSO) and concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH, 15:1) to give the title product (90 mg, 16%) as a yellow solid. LCMS (Method A): 3.99 min; m / z: 560.2 [M+H] + .

[0450] Step 6: 3-(4-(ethylsulfonamido)phenyl)-5-((5-isopropylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide (Compound 66) A mixture of 3-(4-ethanesulfonamidophenyl)-5-{[5-(propan-2-yl)pyrazin-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (90 mg, 0.16 mmol) and 2.0 M HCl (0.5 mL) in THF (5 mL) was stirred at room temperature for 2 h. The reaction mixture was neutralized with NH4OH to pH = 7-8 and concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 10:1) to afford the title product (12 mg, 17%) as a white solid. LCMS (Method A): 3.34 min; m / z: 430.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6): 12.90 (s, 1H), 10.07 (s, 1H), 9.52 (s, 1H), 9.20 (s, 1H), 8.14 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.10 (br s, 1H), 3.19 (q, J = 6.8 Hz, 2H), 3.08-2.99 (m, 1H), 1.24 (t, J = 8.0 Hz, 9H).

[0451] compound 121 [ka]

[0452] Step 1: 4-Iodo-2-methoxypyridine A mixture of 2-fluoro-4-iodopyridine (1.00 g, 4.48 mmol), CsCO (4.41 g, 13.5 mmol), DMF (20 mL), and MeOH (0.5 mL) was stirred at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with HO (50 mL), and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried (MgSO), and concentrated under reduced pressure to give the title compound (868 mg, 82%) as a yellow oil. 1 H NMR (300 MHz, CDCl3): 7.83 (dd, J = 5.4, 0.5 Hz, 1H), 7.20 (dd, J = 5.4, 1.4 Hz, 1H), 7.17 (dd, J = 1.4, 0.5 Hz, 1H), 3.90 (s, 3H).

[0453] Step 2: 1-(tert-butyl)-5-((2-methoxypyridin-4-yl)amino)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile A mixture of 5-amino-1-(tert-butyl)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (1.05 g, 3.68 mmol), 4-iodo-2-methoxypyridine (804 mg, 3.42 mmol), Pd(OAc) (83.4 mg, 0.368 mmol), Xantphos (426 mg, 0.736 mmol), and CsCO (1.81 g, 5.52 mmol) in 1,4-dioxane (22 mL) was stirred at 110 °C for 3 h. The reaction mixture was diluted with EtOAc (40 mL), filtered through Celite, and concentrated under reduced pressure. The residue was diluted with HO (50 mL), and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic fractions were dried (MgSO4) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 1:0 to 0:1) to give the title compound (1.04 g, 77%) as an orange foam. LCMS (Method C): 2.31 min; m / z: 393.2 [M+H] + . 1 H NMR (300 MHz, CDCl3): 8.33-8.28 (m, 2H), 8.19-8.16 (m, 2H), 7.96 (d, J = 6.1 Hz, 1H), 6.46 (dd, J = 6.0, 2.0 Hz, 1H), 6.19 (br s, 1H), 3.92 (s, 3H), 1.70 (s, 9H).

[0454] Step 3: 1-(tert-butyl)-5-((2-methoxypyridin-4-yl)amino)-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide A mixture of 1-tert-butyl-5-((2-ethoxypyrimidin-4-yl)amino)-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (500 mg, 1.20 mmol) and Ghaffar-Parkins catalyst (25.7 mg, 59.9 μmol) in 90% aqueous EtOH (50 mL) was stirred at 120° C. for 16 h. The mixture was filtered through Celite and concentrated under reduced pressure to give the title compound (530 mg, quantitative) as a yellow solid. LCMS (Method C): 1.98 min; m / z: 411.2 [M+H] + . 1H NMR (300 MHz, DMSO-d6): 8.51 (s, 1H), 8.30-8.27 (m, 2H), 8.03-8.00 (m, 2H), 7.79 (d, J = 5.7 Hz, 1H), 7.41 (br s, 1H), 7.39 (br s, 1H), 6.32 (br s, 1H), 5.82 (br s, 1H), 3.74 (s, 3H), 1.59 (s, 9H).

[0455] Step 4: 3-(4-aminophenyl)-1-(tert-butyl)-5-((2-methoxypyridin-4-yl)amino)-1H-pyrazole-4-carboxamide A mixture of 1-(tert-butyl)-5-((2-methoxypyridin-4-yl)amino)-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (280 mg, 0.68 mmol) and 5% Pd / C (14 mg) in MeOH (30 mL) was stirred under H at room temperature for 3 days. The reaction mixture was filtered through Celite and concentrated to give the title compound (257 mg, 99%) as a yellow solid. LCMS (Method C): 1.36 min; m / z: 381.2 [M+H] + . 1 H NMR (300 MHz, MeOD-d4): 7.76 (d, J = 5.9 Hz, 1H), 7.46-7.43 (m, 2H), 6.78-6.73 (m, 2H), 6.29 (d, J = 4.9 Hz, 1H), 5.93 (s, 1H), 3.80 (s, 3H), 1.63 (m, 9H).

[0456] Step 5: 1-(tert-butyl)-3-(4-(ethylsulfonamido)phenyl)-5-((2-methoxypyridin-4-yl)amino)-1H-pyrazole-4-carboxamide A mixture of 3-(4-aminophenyl)-1-(tert-butyl)-5-((2-methoxypyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (50.0 mg, 0.13 mmol) and pyridine (106 μL, 1.31 mmol) in DCM (1 mL) was cooled to 0 °C, and EtSO2Cl (25 μL, 0.26 mmol) was added dropwise. After 1 h, the reaction mixture was diluted with HO (10 mL) and extracted with DCM:MeOH (9:1, 5 × 2 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (DCM:MeOH, 1:0 to 9:1) to give the title compound (28.0 mg, 45%) as a white solid. LCMS (Method C): 1.81 min; m / z: 473.2 [M+H] + . 1 H NMR (300 MHz, MeOD-d4): 7.77 (d, J = 5.9 Hz, 1H), 7.71-7.67 (m, 2H), 7.30-7.26 (m, 2H), 6.31 (d, J = 4.8 Hz, 1H), 5.94 (br s, 1H), 3.80 (s, 3H), 3.11 (q, J = 7.3 Hz, 2H), 1.65 (s, 9H), 1.30 (t, J = 7.3 Hz, 3H).

[0457] Step 6: 3-(4-(ethylsulfonamido)phenyl)-5-((2-methoxypyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (Compound 121) A solution of 1-(tert-butyl)-3-(4-(ethylsulfonamido)phenyl)-5-((2-methoxypyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (28.0 mg, 0.059 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by SCX cartridge (MeOH, then 2.0 M NH in MeOH) to give the title compound (24.2 mg, 98%) as a white solid. LCMS (Method C): 1.58 min; m / z: 417.0 [M+H] + . 1H NMR (300 MHz, MeOD-d4): 7.84 (d, J = 6.1 Hz, 1H), 7.59-7.55 (m, 2H), 7.45-7.40 (m, 2H), 7.18 (s, 1H), 6.93-6.90 (m, 1H), 3.87 (s, 3 H), 3.19 (q, J = 7.4 Hz, 2H), 1.33 (t, J = 7.4 Hz, 3H).

[0458] Following the complete synthesis of compound 121 in step 1 with the corresponding alcohol, the following compounds (Table 10) were prepared.

[0459] [Table 10]

[0460] compound 118 [ka]

[0461] Step 1: 4-iodo-2-methoxy-5-methylpyridine A mixture of 2-fluoro-4-iodo-5-methylpyridine (1.06 g, 4.47 mmol), CsCO (4.36 g, 13.4 mmol), MeOH (542 μL, 13.4 mmol), and DMF (10 mL) was stirred at 90 °C for 3 h. The reaction mixture was diluted with HO (100 mL) and extracted with EtO (5 × 50 mL). The combined organic fractions were washed with brine, dried (MgSO), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 1:0 to 9:1) to afford the title compound (746 mg, 67%) as a white solid. LCMS (Method C): 2.44 min; m / z: 250.0 [M+H] + . 1 H NMR (300 MHz, CDCl3): 7.91 (s, 1H), 7.26 (s, 1H), 3.87 (s, 3H), 2.30 (s, 3H).

[0462] Step 2: 1-(tert-butyl)-5-((2-methoxy-5-methylpyridin-4-yl)amino)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile A mixture of 5-amino-1-(tert-butyl)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (696 mg, 2.43 mmol), 4-iodo-2-methoxy-5-methylpyridine (724 mg, 2.91 mmol), Pd(OAc) (54.5 mg, 0.24 mmol), Xantphos (281 mg, 0.486 mmol), and CsCO (1.18 g, 3.64 mmol) in 1,4-dioxane (35 mL) was stirred at 110 °C for 21 h. The reaction mixture was diluted with EtOAc (40 mL), filtered through Celite, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 1:0 to 2:3) to afford the title compound (992 mg, 83%) as an orange oil. LCMS (Method C): 2.31 min; m / z: 407.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6): 8.43-8.38 (m, 2H), 8.18-8.13 (m, 3H), 7.80 (s, 1H), 5.62 (s, 2H), 3.71 (s, 3H), 2.18 (s, 3H), 1.62 (s, 9H).

[0463] Step 3: 1-(tert-butyl)-5-((2-methoxy-5-methylpyridin-4-yl)amino)-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide A mixture of 1-(tert-butyl)-5-((2-methoxy-5-methylpyridin-4-yl)amino)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (443 mg, 1.08 mmol), Ghaffar-Parkins catalyst (23.1 mg, 54.0 μmol) and 90% aqueous EtOH (50 mL) was stirred at 110° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by recrystallization (EtOH) to give the title compound (346 mg, 72%) as an off-white solid. LCMS (Method C): 1.95 min; m / z: 425.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6): 8.30-8.25 (m, 2H), 8.06-8.01 (m, 2H), 7.73 (s, 1H), 7.56 (s, 1H), 7.34 (br s, 1H), 7.27 (br s, 1H), 5.43 (s, 1H), 3.67 (s, 3H), 2.17 (s, 3H), 1.59 (s, 9H).

[0464] Step 4: 3-(4-aminophenyl)-1-(tert-butyl)-5-((2-methoxy-5-methylpyridin-4-yl)amino)-1H-pyrazole-4-carboxamide A mixture of 1-(tert-butyl)-5-((2-methoxy-5-methylpyridin-4-yl)amino)-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (246 mg, 0.553 mmol) and 10% Pd / C (25 mg) in MeOH (30 mL) was stirred under H at room temperature for 16 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give the title compound (215 mg, 96%) as a white solid. LCMS (Method C): 1.44 min; m / z: 395.2 [M+H] + . 1H NMR (300 MHz, DMSO-d6): 7.69 (s, 1H), 7.46 (s, 1H), 7.45-7.41 (m, 2H), 7.07 (br s, 1H), 7.00 (br s, 1H), 6.58-6.51 (m, 2H), 5.41 (s, 1H), 5.16 (br s, 2H), 3.66 (s, 3H), 2.14 (s, 3H), 1.54 (s, 9H).

[0465] Step 5: 1-(tert-butyl)-3-(4-(ethylsulfonamido)phenyl)-5-((2-methoxy-5-methylpyridin-4-yl)amino)-1H-pyrazole-4-carboxamide A mixture of 3-(4-aminophenyl)-1-(tert-butyl)-5-((2-methoxy-5-methylpyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (115 mg, 0.291 mmol), EtSOCl (55 μL, 0.583 mmol), pyridine (235 μL, 2.91 mmol), and DCM (5 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (DCM:MeOH, 1:0 to 4:1) to give a yellow residue (75.7 mg). Further purification on an SCX cartridge (MeOH, followed by 2 M NH in MeOH) afforded the title compound (32.7 mg, 22%) as a white solid. LCMS (Method C): 1.82 min; m / z: 487.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6): 9.84 (br s, 1H), 7.72-7.68 (m, 3H), 7.48 (s, 1H), 7.26-7.21 (m, 2H), 7.18 (br s, 1H), 7.10 (br s, 1H), 5.41 (s, 1H), 3.68 (s, 3H), 3.11 (q, J = 7.3 Hz, 2H), 2.16 (s, 3H), 1.56 (s, 9H), 1.21 (t, J = 7.3 Hz, 3H).

[0466] Step 6: 3-(4-(ethylsulfonamido)phenyl)-5-((2-methoxy-5-methylpyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (Compound 118) A solution of 1-(tert-butyl)-3-(4-(ethylsulfonamido)phenyl)-5-((2-methoxy-5-methylpyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (29.6 mg, 0.0569 mmol) in TFA (0.5 mL) and DCM (0.5 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by SCX cartridge (MeOH, then 2M NH in MeOH) to give the title compound (22.0 mg, 90%) as a white solid. LCMS (Method C): 1.66 min; m / z: 431.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6): 12.88 (br, s, 1H), 9.59 (s, 1H), 7.77 (s, 1H), 7.55-7.53 (m, 3H), 7.38-7.34 (m 2H), 3.77 (s, 3H), 3.22-3.14 (m, 2H), 2.14 (s, 3H), 1.22 (t, J = 7.3 Hz, 3H).

[0467] Following the complete synthesis of compound 118, the following compounds (Table 11) were prepared starting from 5-amino-1-(tert-butyl)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile and using the indicated intermediates used as described in Step 2.

[0468] [Table 11]

[0469] Compound 102 [ka]

[0470] Step 1: 1-(tert-butyl)-5-((4-cyanophenyl)amino)-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide A mixture of 5-amino-1-tert-butyl-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (455 mg, 1.50 mmol), CsF (683 mg, 4.50 mmol), and 4-fluorobenzonitrile (236 mg, 1.95 mmol) in DMSO (10 mL) was stirred at 150 °C under microwave irradiation for 3 h. The mixture was diluted with HO (20 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine, dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 20:1) to give the title product (304 mg, 23%) as a yellow solid. LCMS (Method B): 2.40 min; m / z: 405.0 [M+H] + .

[0471] Step 2: 3-(4-aminophenyl)-1-(tert-butyl)-5-((4-cyanophenyl)amino)-1H-pyrazole-4-carboxamide A mixture of 1-tert-butyl-5-[(4-cyanophenyl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (304 mg, 0.751 mmol), saturated aqueous NH4Cl (6 mL), and Zn dust (245 mg, 3.75 mmol) in MeOH (18 mL) was stirred at 60 °C overnight. The mixture was filtered, concentrated under reduced pressure, and the residue was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give the title product (255 mg, 90%) as a yellow solid. LCMS (Method B): 0.82 min; m / z: 375.1 [M+H] + .

[0472] Step 3: 1-(tert-butyl)-5-((4-cyanophenyl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide To a stirred solution of 3-(4-aminophenyl)-1-tert-butyl-5-[(4-cyanophenyl)amino]-1H-pyrazole-4-carboxamide (150 mg, 400 mmol) and pyridine (126 mg, 1.60 mmol) in CHCl (10 mL) was added EtSOCl (102 mg, 800 mmol). The mixture was stirred at room temperature overnight, then diluted with HO (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM:MeOH, 20:1) to afford the title product (27 mg, 14%) as a yellow solid. LCMS (Method A): 2.57 min; m / z: 467.3 [M+H] + .

[0473] Step 4: 5-((4-cyanophenyl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide (Compound 102) 1-tert-butyl-5-[(4-cyanophenyl)amino] in TFA (1 mL) A solution of 1H-3-(4-ethanesulfonamidophenyl)-1H-pyrazole-4-carboxamide (27 mg, 0.0578 mmol) was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with EtO (3×3 mL) and dried under vacuum to give the title product as a TFA salt (10 mg, 40%) as a yellow solid. LCMS (Method A): 1.28 min; m / z: 411.2 [M+H] + . 1 H NMR (400 MHz, MeOD-d4): 7.69 (d, J = 8.4 Hz, 2H), 7.62-7.57 (m, 4H), 7.43 (d, J = 8.4 Hz, 2H), 3.21 (q, J = 7.2 Hz, 2H), 1.34(t, J = 7.2 Hz, 3H).

[0474] compound 237 [ka]

[0475] Step 1: 5-[(6-bromopyridin-2-yl)amino]-1-tert-butyl-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile A mixture of 5-amino-1-tert-butyl-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (3.0 g, 10.5 mmol), 2,6-dibromopyridine (2.48 g, 10.5 mmol), Pd(dba) (961 mg, 1.05 mmol), Xantphos (1.21 g, 2.10 mmol), and CsCO (6.84 g, 21.0 mmol) in 1,4-dioxane (60 mL) was stirred at 100 °C under N for 16 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH, 30:1) to give the title product (3.6 g, 77%) as a yellow solid. LCMS (Method A): 4.37 min; m / z: 441.1, 443.1 [M+H] + .

[0476] Step 2: 5-((6-bromopyridin-2-yl)amino)-1-(tert-butyl)-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide A mixture of 5-[(6-bromopyridin-2-yl)amino]-1-tert-butyl-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (2.0 g, 4.53 mmol), Ghaffar-Parkin's catalyst (194 mg, 0.45 mmol), and 90% aqueous 1,4-dioxane (110 mL) was stirred under N at 100 °C. After 16 h, the reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (DCM:MeOH, 40:1) to give the title product (630 mg, 30%) as a yellow solid. LCMS (Method A): 3.92 min; m / z: 459.0, 461.0 [M+H] + .

[0477] Step 3: 1-tert-butyl-5-[(6-cyanopyridin-2-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide and 6-((1 -(tert-butyl)-4-carbamoyl-3-(4-nitrophenyl)-1H-pyrazol-5-yl)amino)picolinamide A mixture of 5-[(6-bromopyridin-2-yl)amino]-1-tert-butyl-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (10 g, 21.7 mmol), CuI (4.13 g, 21.7 mmol), and CuCN (3.88 g, 43.4 mmol) in NMP (100 mL) was stirred at 150 °C under N overnight. The reaction was poured into EtOAc (100 mL) and washed with water (100 mL × 3). The organic layer was collected, washed with brine, dried (NaSO), and concentrated. The residue was purified by silica gel column chromatography (EtOAc:PE, 1:4) to give 1-tert-butyl-5-[(6-cyanopyridin-2-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (2.2 g, 25%) as a yellow solid LCMS (Method A): 3.65 min, m / z: 406.1 [M+H]+, and 6-((1-(tert-butyl)-4-carbamoyl-3-(4-nitrophenyl)-1H-pyrazol-5-yl)amino)picolinamide (390 mg) as a brown solid. LCMS (Method A): 3.25 min, m / z: 424.1 [M+H] + .

[0478] Step 4: 3-(4-aminophenyl)-1-tert-butyl-5-[(6-cyanopyridin-2-yl)amino]-1H-pyrazole-4-carboxamide 1-tert-Butyl-5-[(6-cyanopyridin-2-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (90 mg, 0.22 mmol), Zn powder (71.9 mg, 1.10 mmol), saturated NH4Cl (2 mL), and MeOH (10 mL) were stirred at 60 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated and purified by preparative TLC (DCM:MeOH, 20:1) to give the title product (50 mg, 60%) as a yellow solid. LCMS (Method A): 2.80 min; m / z: 376.2 [M+H] + .

[0479] Step 5: 1-tert-butyl-5-[(6-cyanopyridin-2-yl)amino]-3-[4-(2,2,2-trifluoroethanesulfonamido)phenyl]-1H-pyrazole-4-carboxamide A mixture of 3-(4-aminophenyl)-1-tert-butyl-5-[(6-cyanopyridin-2-yl)amino]-1H-pyrazole-4-carboxamide (50 mg, 0.13 mmol), 2,2,2-trifluoroethane-1-sulfonyl chloride (31.5 mg, 0.17 mmol), pyridine (31.5 mg, 0.39 mmol), and DCM (4 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was purified by preparative TLC (DCM:MeOH, 20:1) to give the title product (20 mg, 29%) as a yellow solid. LCMS (Method A): 3.53 min; m / z: 522.2 [M+H] + .

[0480] Step 6: 5-[(6-cyanopyridin-2-yl)amino]-3-[4-(2,2,2-trifluoroethanesulfonamido)phenyl]-1H-pyrazole-4-carboxamide (Compound 237) A solution of 1-tert-butyl-5-[(6-cyanopyridin-2-yl)amino]-3-[4-(2,2,2-trifluoroethanesulfonamido)phenyl]-1H-pyrazole-4-carboxamide (20 mg, 0.03 mmol) in DCM (3 mL) and TFA (2 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the residue was neutralized to pH 7-8 with saturated Na2CO3. The resulting precipitate was collected by filtration and air-dried to give the title compound (10 mg, 56%) as a white solid. LCMS (Method A): 3.32 min; m / z: 466.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 12.99 (br s, 1H), 10.75 (br s, 1H), 9.88 (br s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.93 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 7.6 Hz, 2H), 4.60 (q, J = 10.0 Hz, 2H).

[0481] compound 258 [ka]

[0482] Step 1: 1-tert-butyl-5-[(6-cyanopyridin-2-yl)amino]-3-[4-(difluoromethanesulfonamido)phenyl]-1H-pyrazole-4-carboxamide A mixture of 3-(4-aminophenyl)-1-tert-butyl-5-[(6-cyanopyridin-2-yl)amino]-1H-pyrazole-4-carboxamide (200 mg, 0.53 mmol), FCHSOCl (120 mg, 0.79 mmol), pyridine (210 mg, 2.66 mmol), and DCM (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was purified by preparative TLC (DCM:MeOH, 20:1) to give the title product (100 mg, 38%) as a yellow solid. LCMS (Method A): 3.48 min; m / z: 490.2 [M+H] + .

[0483] Step 2: 5-[(6-cyanopyridin-2-yl)amino]-3-[4-(difluoromethanesulfonamido)phenyl]-1H-pyrazole-4-carboxamide (Compound 258) A mixture of 1-tert-butyl-5-[(6-cyanopyridin-2-yl)amino]-3-[4-(difluoromethanesulfonamido)phenyl]-1H-pyrazole-4-carboxamide (50 mg, 0.1021 mmol) and 1:1 DCM:TFA (8 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was neutralized with saturated Na2CO3 to pH 7-8. The resulting precipitate was collected by filtration and purified by preparative TLC (DCM:MeOH, 15:1) to afford the title product (20 mg, 45%) as a yellow solid. LCMS (Method A): 3.18 min; m / z: 434.1 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6): 13.00 (br s, 1H), 9.76 (br s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 9.25 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 7.2 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.09 (t, J = 12.4 Hz, 1H).

[0484] compound 257 [ka]

[0485] Step 1: 6-((3-(4-aminophenyl)-1-(tert-butyl)-4-carbamoyl-1H-pyrazol-5-yl)amino)picolinamide 6-{[1-tert A mixture of 390 mg (0.9210 mmol) of 4-butyl-4-carbamoyl-3-(4-nitrophenyl)-1H-pyrazol-5-yl]amino}pyridine-2-carboxamide (from compound 237) and Zn dust (300 mg, 4.60 mmol) was stirred at 45° C. overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM, 1:35) to give the title product (320 g, 88%) as a yellow solid. LCMS (Method A): 2.33 min, m / z: 394.2 [M+H] + .

[0486] Step 2: 6-({1-tert-butyl-4-carbamoyl-3-[4-(difluoromethanesulfonamido)phenyl]-1H-pyrazol-5-yl}amino)pyridine-2-carboxamide A mixture of 6-{[3-(4-aminophenyl)-1-tert-butyl-4-carbamoyl-1H-pyrazol-5-yl]amino}pyridine-2-carboxamide (150 mg, 0.38 mmol), FCHSOCl (86.0 mg, 0.57 mmol), pyridine (150 mg, 1.90 mmol), and DCM (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH, 20:1) to give the title product (75 mg, 39%) as a yellow solid. LCMS (Method A): 3.12 min; m / z: 508.2 [M+H] + .

[0487] Step 3: 6-({4-carbamoyl-3-[4-(difluoromethanesulfonamido)phenyl]-1H-pyrazol-5-yl}amino)pyridine-2-carboxamide (Compound 257) A solution of 6-({1-tert-butyl-4-carbamoyl-3-[4-(difluoromethanesulfonamido)phenyl]-1H-pyrazol-5-yl}amino)pyridine-2-carboxamide (50 mg, 0.09 mmol) in 1:1 DCM:TFA (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated and the residue was neutralized to pH 7-8 with saturated Na2CO3. The resulting precipitate was collected by filtration and dried to give the title product (30 mg, 68%) as a yellow solid. LCMS (Method A): 2.71 min; m / z: 452.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 12.62 (br s, 1H), 9.69 (br s, 1H), 8.16 (br s, 1H), 7.95 (br s, 1H), 7.86 (t, J = 7.6 Hz, 1H), 7.52-7.47 (m, 2H), 7.28 s, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 6.24 (t, J = 54.8 Hz, 1H), 5.82 (br s, 1H).

[0488] compound 115 [ka]

[0489] Step 1: 3-Bromo-5-((6-methoxypyridin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile A mixture of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (400 mg, 1.04 mmol), 5-amino-2-methoxypyridine (153 mg, 1.24 mmol), Pd(OAc) (23.3 mg, 0.104 mmol), Xantphos (120 mg, 0.208 mmol), and CsCO (508 mg, 1.56 mmol) in 1,4-dioxane (20 mL) was stirred at 110 °C for 3 h. The reaction mixture was diluted with EtOAc (25 mL), filtered through Celite, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 1:0 to 3:2) to afford the title compound (257 mg, 58%) as a white solid. LCMS (Method A): 2.80 min; m / z: 426.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6): 9.23 (br s, 1H), 8.04 (dd, J = 2.8, 0.6 Hz, 1H), 7.58 (dd, J = 8.8, 2.8 Hz, 1H), 6.84 (dd, J = 8.8, 0.6 Hz, 1H), 5.38 (s, 2H), 3.84 (s, 3H), 3.64-3.58 (m, 2H), 0.89-0.84 (m, 2H), -0.04 (s, 9H).

[0490] Step 2: N-(4-(4-cyano-5-((6-methoxypyridin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)phenyl)ethanesulfonamide A mixture of 3-bromo-5-((6-methoxypyridin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (200 mg, 0.471 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide (Intermediate C16, 219 mg, 0.706 mmol), Pd(OAc) (5.28 mg, 23.5 μmol), SPhos (19.3 mg, 47.1 μmol), and KCO (194 mg, 1.41 mmol) in 60% aqueous MeCN (10 mL) was stirred at 100° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE: EtOAc, 1:0 to 1:1) to give the title product (191 mg, 76%) as a colorless glass. LCMS (Method A): 2.72 min; m / z: 529.2 [M+H] + . 1 H NMR (300 MHz, CDCl3): 10.04 (br s, 1H), 8.97 (br s, 1H), 8.02 (dd, J = 2.8, 0.6 Hz, 1H), 7.76-7.71 (m, 2H), 7.54 (dd, J = 8.8, 2.8 Hz, 1H), 7.32-7.27 (m, 2H), 6.83 (dd, J = 8.8, 0.6 Hz, 1H), 5.45 (s, 2H), 3.83 (s, 3H), 3.66-3.61 (m, 2H), 3.14 (q, J = 7.3 Hz, 2H), 1.19 (t, J = 7.4 Hz, 3H), 0.90-0.84 (m, 2H), -0.061 (s, 9H).

[0491] Step 3: 3-(4-(ethylsulfonamido)phenyl)-5-((6-methoxypyridin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide A mixture of N-(4-(4-cyano-5-((6-methoxypyridin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)phenyl)ethanesulfonamide (180 mg, 0.340 mmol) and Ghaffar-Parkins catalyst (7.30 mg, 17.0 μmol) in 80% aqueous EtOH (10 mL) was stirred at 110° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound (181 mg, 97%) as a white glass. LCMS (Method A): 2.47 min; m / z: 547.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6): 9.93 (br s, 1H), 7.84 (s, 1H), 7.69-7.64 (m, 2H), 7.63 (dd, J = 2.9, 0.5 Hz, 1H), 7.25-7.21 (m, 2H), 7.18 (br s, 1H), 7.14 (br s, 1H), 7.12 (dd, J = 8.8, 2.9 Hz, 1H), 6.66 (dd, J = 8.8, 0.5 Hz, 1H), 5.33 (s, 2H), 3.74 (s, 3H), 3.52-3.46 (m, 2H), 3.12 (q, J = 7.4 Hz, 2H), 1.21 (t, J = 7.4 Hz, 3H), 0.79-0.74 (m, 2H), -0.10 (s, 9H).

[0492] Step 4: 3-(4-(ethylsulfonamido)phenyl)-5-((6-methoxypyridin-3-yl)amino)-1H-pyrazole-4-carboxamide (Compound 115) 3-(4-(ethylsulfonyl)-2-methyl-2-methylpropional)-2-methylpropional in TFA (0.5 mL) and DCM (0.5 mL) A solution of (6-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (20 mg, 54.8 mol) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by preparative HPLC to give the title product (6.7 mg, 29%) as a white solid. LCMS (Method A): 1.83 min; m / z: 417.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6): 12.59 (s, 1H), 10.10 (br s, 1H), 8.74 (s, 1H), 8.37 (s, 1H), 7.94 (d, J = 6.7 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 8.6 Hz, 1H), 5.75 (s, 1H), 3.79 (s, 3H), 3.21-3.14 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0493] compound 127 [ka]

[0494] Step 1: 1-(tert-butyl)-3-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-5-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile A mixture of 3-amino-1-(tert-butyl)-5-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (Intermediate A, 103 mg, 0.360 mmol), 4-bromo-2-(2-methoxyethoxy)pyridine (0.1 g, 0.43 mmol), Pd(OAc) (8.11 mg, 0.0400 mmol), Xantphos (36 mg, 0.070 mmol), and CsCO (0.18 g, 0.54 mmol) in 1,4-dioxane (3 mL) was stirred at 80 °C for 0.5 h under N. The reaction mixture was heated to 100 °C for an additional 1.5 h, then diluted with HO (50 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE: EtOAc, 1:0 to 1:1) to give the title compound (105 mg, 67%) as a yellow oil. LCMS (Method A): 2.37 min; m / z: 437.2 [M+H] + .

[0495] Step 2: 1-(tert-butyl)-3-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-5-(4-nitrophenyl)-1H-pyrazole-4-carboxamide A mixture of 1-(tert-butyl)-3-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-5-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (105 mg, 0.240 mmol), K2CO3 (0.10 g, 0.72 mmol), and 30% aqueous HO2 (2 mL) in DMSO (5 mL) was stirred at 60 °C for 1 h. An additional charge of HO2 was added, and the mixture was stirred for an additional 2 h. The mixture was diluted with HO (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE: EtOAc, 1:0 to 1:1) to give the title product ( 25 mg, 23%) was obtained as a yellow oil. LCMS (Method A): 2.00 min; m / z: 455.2 [M+H] + .

[0496] Step 3: 5-(4-aminophenyl)-1-(tert-butyl)-3-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide A mixture of 1-(tert-butyl)-3-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-5-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (25 mg, 0.05 mmol), 10% Pd / C (5 mg) and MeOH (5 mL) was stirred under H at room temperature overnight. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give the title product (21 mg, 90%) as a yellow oil that solidified upon standing. LCMS (Method A): 1.52 min; m / z: 425.2 [M+H] + .

[0497] Step 4: 1-(tert-butyl)-5-(4-(ethylsulfonamido)phenyl)-3-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide A mixture of 5-(4-aminophenyl)-1-(tert-butyl)-3-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (21 mg, 0.050 mmol), EtSOCl (0.01 mL, 0.10 mmol), and pyridine (0.04 mL, 0.49 mmol) in DCM (2 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM:MeOH, 1:0 to 9:1) to afford the title product (12 mg, 47%) as an off-white solid. LCMS (Method A): 1.82 min; m / z: 517.2 [M+H] + .

[0498] Step 5: 5-(4-(ethylsulfonamido)phenyl)-3-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (Compound 127) A solution of 1-(tert-butyl)-5-(4-(ethylsulfonamido)phenyl)-3-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (12 mg, 0.020 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by SCX cartridge (MeOH, then 2.0 M NH in MeOH) to give the title compound (10 mg, 93%) as a cream solid. LCMS (Method A): 1.64 min; m / z: 461.2 [M+H] + . 1 H NMR (400 MHz, MeOD-d4): 7.85 (d, J = 5.7 Hz, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.22 (br s, 1H), 6.92 (dd, J = 5.9, 1.9 Hz, 1H), 4.35 (m, 2H), 3.76 (m, 2H), 3.43 (s, 3H), 3.21 (q, J = 7.3 Hz, 2H), 1.35 (t, J = 7.5 Hz, 2H).

[0499] Following the complete synthesis of compound 127, the following compounds (Table 12) were prepared starting from 5-(4-aminophenyl)-1-(tert-butyl)-3-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide using the corresponding sulfonyl chloride as described in step 4.

[0500] [Table 12-1]

[0501] [Table 12-2]

[0502] compound 116 [ka]

[0503] Step 1: 1-(tert-butyl)-3-(4-((2-chloroethyl)sulfonamido)phenyl)-5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide A mixture of 3-(4-aminophenyl)-1-tert-butyl-5-{[2-(2-methoxyethoxy)pyridin-4-yl]amino}-1H-pyrazole-4-carboxamide (400 mg, 0.9422 mmol), 2-chloroethane-1-sulfonyl chloride (306 mg, 1.88 mmol), and pyridine (297 mg, 3.76 mmol) in DMF (10 mL) was stirred at room temperature overnight. The mixture was diluted with HO (20 mL) and extracted with DCM (30 mL). The organic layer was dried (NaSO), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM:MeOH, 10:1) to give a mixture of the title product and the elimination product 1-(tert-butyl)-5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-(vinylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide (100 mg, 19%) as a yellow solid. LCMS (Method B): 0.43 min; m / z: 551.0 [M+H] + .

[0504] Step 2: 1-tert-butyl-3-{4-[2-(dimethylamino)ethanesulfonamido]phenyl}-5-{[2-(2-methoxyethoxy)pyridin-4-yl]amino}-1H-pyrazole-4-carboxamide To a solution of 1-tert-butyl-3-[4-(2-chloroethanesulfonamido)phenyl]-5-{[2-(2-methoxyethoxy)pyridin-4-yl]amino}-1H-pyrazole-4-carboxamide (100 mg, 0.18 mmol) in THF (5 mL) was added MeNH (905 μL, 1.81 mmol) and stirred at 40° C. overnight. Additional MeNH (136 μL, 0.27 mmol) was added and the solution was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was used directly in the next step without further purification. LCMS (Method B): 0.34 min; m / z: 560.1 [M+H] + .

[0505] Step 3: 3-(4-((2-(dimethylamino)ethyl)sulfonamido)phenyl)-5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide A solution of 1-tert-butyl-3-{4-[2-(dimethylamino)ethanesulfonamido]phenyl}-5-{[2-(2-methoxyethoxy)pyridin-4-yl]amino}-1H-pyrazole-4-carboxamide (80 mg, 0.036 mmol) in TFA (1.5 mL) and DCM (1.5 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and triturated with EtO (2 × 5 mL) to give the title product as a white solid as the mono-TFA salt (28 mg, 38%). LCMS (Method B): 0.33 min; m / z: 505.0 [M+H] + . 1 H NMR (400 MHz, MeOD-d4): 7.93 (d, J = 5.6 Hz, 1H), 7.63-7.61 (d, 3 H), 7.48 (d, J = 8.4 Hz, 2H), 7.32 (br s,1H), 4.49 (t, J = 3.6 Hz, 2H), 3.82 (t, J = 4.0 Hz, 2H), 3.76 (t, J = 7.6 Hz, 2H), 3.63 (t, J = 7.6 Hz, 2H), 3.43 (s, 3H), 2.95 (s, 6H). Five active protons are missing.

[0506] Compound 117 [ka]

[0507] Step 1: 1-(tert-butyl)-5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-(methylamino)phenyl)-1H-pyrazole-4-carboxamide A mixture of 3-(4-aminophenyl)-1-tert-butyl-5-{[2-(2-methoxyethoxy)pyridin-4-yl]amino}-1H-pyrazole-4-carboxamide (100 mg, 0.1177 mmol), NaOMe (25.4 mg, 0.4708 mmol), and paraformaldehyde (35.1 mg, 1.17 mmol) in MeOH (5 mL) was heated to 60 °C under N for 3 h. NaBH (44.2 mg, 1.17 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with HO (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 12:1) to give the title product (45 mg, 44%) as a yellow solid. LCMS (Method B): 0.48 min; m / z: 439.2 [M+H] + .

[0508] Step 2: 1-tert-butyl-5-{[2-(2-methoxyethoxy)pyridin-4-yl]amino}-3-[4-(N-methylethanesulfonamido)phenyl]-1H-pyrazole-4-carboxamide To a solution of 1-tert-butyl-5-{[2-(2-methoxyethoxy)pyridin-4-yl]amino}-3-[4-(methylamino)phenyl]-1H-pyrazole-4-carboxamide (40 mg, 0.09121 mmol) in CHCl (5 mL) was added EtSOCl (23.4 mg, 0.1824 mmol) and pyridine (28.8 mg, 0.3648 mmol). The mixture was stirred at room temperature overnight and then diluted with HO (10 mL) and DCM (20 mL). The organic layer was dried (NaSO), and the crude residue was purified by preparative TLC (DCM:MeOH, 12:1) to give the title product (13 mg, 27%) as a yellow solid. LCMS (Method B): 1.13 min; m / z: 531.2 [M+H] + .

[0509] Step 3: 5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-((2-methoxyethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide (Compound 117) A solution of 1-tert-butyl-5-{[2-(2-methoxyethoxy)pyridin-4-yl]amino}-3-[4-(N-methylethanesulfonamido)phenyl]-1H-pyrazole-4-carboxamide (13 mg, 0.024 mmol) in TFA (1.5 mL) and DCM (1.5 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give the title product as the mono-TFA salt (10 mg, 86%) as a brown solid. LCMS (method B):2.37min;m / z:475.0[M+H] + . 1 H NMR (400 MHz, MeOD-d4): 7.94 (d, J = 5.6 Hz, 1H), 7.67-7.62 (m, 5H), 7.36 (s, 1H), 4.50 (t, J = 4.0 Hz, 2H), 3.83 (t, J = 4.0 Hz, 2H), 3.42 (s, 3H), 3.39 (s, 3H), 3.22 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H).

[0510] compound 86 [ka]

[0511] Step 1: 5-Bromo-1-(tert-butyl)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile A mixture of 5-amino-1-tert-butyl-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (500 mg, 1.75 mmol), CuBr (448 mg, 2.01 mmol), and isobutyl nitrite (215 mg, 2.09 mmol) in MeCN (60 mL) was stirred overnight at room temperature under N. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (100 mL) and saturated aqueous NH.sub.4Cl (100 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 15:1) to give the title product (310 mg, 50%) as a yellow solid. LCMS (Method B): 2.13 min; m / z: 349.0, 351.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 8.41 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 9.2 Hz, 2H), 1.77 (s, 1H).

[0512] Step 2: 1-tert-butyl-5-[(naphthalen-2-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile A mixture of 5-bromo-1-tert-butyl-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (2 g, 5.72 mmol), naphthalen-2-amine (819 mg, 5.72 mmol), Pd(dba) (523 mg, 0.5720 mmol), Xantphos (659 mg, 1.14 mmol), and CsCO (5.57 g, 17.1 mmol) in degassed 1,4-dioxane (50 mL) was stirred at 100 °C overnight. The reaction mixture was diluted with DCM (150 mL), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 5:1) to give the title product (970 mg, 41%) as a yellow solid. LCMS (Method A): 3.92 min; m / z: 412.1 [M+H] + .

[0513] Step 3: 1-tert-butyl-5-[(naphthalen-2-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide A mixture of 1-tert-butyl-5-[(naphthalen-2-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (970 mg, 2.35 mmol), 30% aqueous HO (15 mL), 5% aqueous NaOH (1.5 mL), and DMSO (15 mL) in EtOH (30 mL) was stirred at 80 °C overnight. The residue was concentrated under reduced pressure and diluted with H2O. The precipitated solid was collected by filtration and dried under reduced pressure to give the title product (1.0 g, 100%) as a yellow solid. LCMS (Method A): 2.12 min; m / z: 430.2 [M+H] + .

[0514] Step 4: 3-(4-aminophenyl)-1-tert-butyl-5-[(naphthalen-2-yl)amino]-1H-pyrazole-4-carboxamide A mixture of 1-tert-butyl-5-[(naphthalen-2-yl)amino]-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (500 mg, 1.16 mmol) on 10% Pd / C (100 mg) in i-PrOH (15 mL) was stirred under H at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (DCM:MeOH, 15:1) to give the title product (160 mg, 34%) as a yellow solid. LCMS (Method A): 2.97 min; m / z: 399.9 [M+H] + .

[0515] Step 5: 1-tert-butyl-3-(4-ethanesulfonamidophenyl)-5-[(naphthalen-2-yl)amino]-1H-pyrazole-4-carboxamide A mixture of 3-(4-aminophenyl)-1-tert-butyl-5-[(naphthalen-2-yl)amino]-1H-pyrazole-4-carboxamide (160 mg, 0.401 mmol), EtSOCl (61.7 mg, 0.48 mmol), and pyridine (76.0 mg, 0.9612 mmol) in CHCl (7 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH, 12:1) to give the title product (80 mg, 41%) as a yellow solid. LCMS (Method A): 4.02 min; m / z: 492.2 [M+H] + .

[0516] Step 6: 3-(4-(ethylsulfonamido)phenyl)-5-(naphthalen-2-ylamino)-1H-pyrazole-4-carboxamide (Compound 86) A solution of 1-tert-butyl-3-(4-ethanesulfonamidophenyl)-5-[(naphthalen-2-yl)amino]-1H-pyrazole-4-carboxamide (75 mg, 0.1525 mmol) in TFA (3 mL) and DCM (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was basified to pH 9-10 with NH4OH. The precipitated solid was collected by filtration, washed (H2O), and dried under reduced pressure to give the title product (20 mg, 30%) as a yellow solid. LCMS (Method A): 3.70 min; m / z: 436.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 12.73 (s, 1H), 10.11 (br s, 1H), 9.23 (s, 1H), 8.23 ​​(s, 1H), 7.78 (m, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.47-7.35 (m, 4H), 7.27 (t, J = 7.2 Hz, 1H), 6.07 (br s, 1H), 3.18 (q, J = 6.8 Hz, 2H), 1.23 (t, J = 3.2 Hz, 3H).

[0517] compound 100 [ka]

[0518] Step 1: 3-Bromo-5-[(1-methyl-1H-pyrazol-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile 3,5-Dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (500 mg, 1.31 mmol), 1-methyl-1H-pyrazol-4-amine (127 mg, 1.31 mmol), Pd2(dba)3(11 A mixture of Xantphos (151 mg, 0.262 mmol), CsCO (1.28 g, 3.93 mmol) in 1,4-dioxane (30 mL) was stirred at 100° C. overnight. The mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 1:1) to give the title product (220 mg, 42%) as a brown oil. LCMS (Method A): 3.05 min; m / z: 396.9, 398.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 8.81 (s, 1H), 7.78 (s, 1H), 7.38 (s, 1H), 5.33 (s, 2H), 3.80 (s, 3H), 3.60 (t, J = 8.4 Hz, 2H), 0.85 (t, J = 8.4 Hz, 2H), 0.00 (s, 9H).

[0519] Step 2: N-(4-{4-cyano-5-[(1-methyl-1H-pyrazol-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl}phenyl)ethane-1-sulfonamide A mixture of 3-bromo-5-[(1-methyl-1H-pyrazol-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (210 mg, 0.5284 mmol) and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamide (164 mg, 0.5284 mmol), Pd(dppf)Cl (38.6 mg, 0.05 mmol), and NaCO (111 mg, 1.05 mmol) in 80% aqueous 1,4-dioxane (5 mL) was stirred at 120 °C for 1 h under microwave irradiation. The reaction mixture was diluted with EtOAc (5 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE: EtOAc, 1:1) to give the title product (170 mg, 64%) as a brown solid. LCMS (Method A): 2.91 min; m / z: 502.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6): 10.00 (s, 1H), 8.55 (s, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 7.26 (d, J = 8.4 Hz, 2H), 5.41 (s, 2H), 3.81 (s, 3H), 3.64 (t, J = 7.6 Hz, 2H), 3.13 (q, J = 7.2 Hz, 2H), 1.19 (t, J = 7.6 Hz, 2H), 0.87 (t, J = 8.0 Hz, 2H), -0.04 (s, 9H).

[0520] Step 3: 3-(4-(ethylsulfonamido)phenyl)-5-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazole-4-carboxamide (Compound 100) A mixture of N-(4-{4-cyano-5-[(1-methyl-1H-pyrazol-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl}phenyl)ethane-1-sulfonamide (20 mg, 0.039 mmol) in concentrated HSO (1 mL) and HO (1 mL) was stirred at 60 °C for 2 days. The reaction mixture was basified to pH 9-10 with NHOH and extracted with DCM (3 × 10 mL). The combined organic layers were dried (NaSO) and concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH:NHOH, 8:1:0.1) to give the title product (4 mg, 25%) as a white solid. LCMS (Method A): 2.57 min; m / z: 390.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6): 12.39 (br s, 1H), 8.26 (s, 1H), 7.76 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.45 (s, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.20 (br s, 1H), 6.64 (br s,1H), 3.77 (s, 3H), 3.16 (q, J = 7.2 Hz, 2H), 1.22 (m, 3H).

[0521] Following the complete synthesis of compound 100, starting from 3,5-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile, the following compounds (Table 13) were prepared as described in Step 1 using the intermediates listed:

[0522] [Table 13]

[0523] compound 22 [ka]

[0524] Step 1: N-(4-(4-cyano-5-((5-methylpyrazin-2-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-2-((4-fluorobenzyl)oxy)phenyl)ethanesulfonamide A mixture of 3-bromo-5-[(5-methylpyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (Intermediate B5, 200 mg, 488 μmol), N-{2-[(4-fluorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}ethane-1-sulfonamide (Intermediate C1, 212 mg, 488 μmol), Pd(dppf)Cl (39.8 mg, 48.8 μmol) and NaCO (103 mg, 976 μmol) in degassed 80% aqueous 1,4-dioxane (12.5 mL) was stirred at 100 °C for 1 h under microwave irradiation. The mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (PE: EtOAc, 1:1) to give the title product (200 mg, 64%) as a yellow solid. LCMS (Method A): 4.49 min; m / z: 638.2 [M+Na] + .

[0525] Step 2: 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide A mixture of N-(4-(4-cyano-5-((5-methylpyrazin-2-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-2-((4-fluorobenzyl)oxy)phenyl)ethanesulfonamide (200 mg, 313 μmol) and Ghaffar-Parkins catalyst in 50% aqueous EtOH (20 mL) was stirred at 100° C. overnight. The mixture was concentrated under reduced pressure and the crude residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title product (100 mg, 48%) as a yellow solid. LCMS (Method A): 4.14 min; m / z: 656.2 [M+H] + .

[0526] Step 3: 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide A solution of 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (100 mg, 152 μmol) in TFA (2 mL) and DCM (2 mL) was stirred at room temperature for 1 h. The reaction mixture was neutralized to pH 7-8 with saturated aqueous Na2CO3 and concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 10:1) to afford the title product (40.0 mg, 50%) as a white solid. LCMS (Method A): 3.50 min; m / z: 526 .1[M+H] + . 1 H NMR (400 MHz, DMSO-d6): 13.05 (s, 1H), 9.51 (s, 1H), 9.17 (s, 1H),8.11 (s, 1H), 7.62 (dd, J = 4.8 Hz, 2H), 7.44 (d, J = 9.6 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.19 (dd, J = 1.2 Hz, 8Hz, 1H), 6.18 (s, 1H), 5.19 (s, 2H), 3.05 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H).

[0527] The following compounds (Table 14) were similarly prepared from the appropriate arylamine starting material according to the method described for the synthesis of 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide.

[0528] [Table 14-1]

[0529] [Table 14-2]

[0530] [Table 14-3]

[0531] compound 37 [ka]

[0532] Step 1: 3-[4-ethanesulfonamido-3-(2-methylpropoxy)phenyl]-5-[(pyridin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A mixture of 3-bromo-5-[(pyridin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (Intermediate B2, 90 mg, 0.2182 mmol), N-[2-(2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamide (Intermediate C9, 83.6 mg, 0.218 mmol), Pd(dppf)Cl (16.0 mg, 0.022 mmol) and NaCO (69.3 mg, 0.65 mmol) in 80% aqueous 1,4-dioxane (2.5 mL) was stirred at 100 °C under microwave irradiation for 2 h. The mixture was concentrated under reduced pressure, diluted with H2O (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 18:1) to afford the title product (110 mg, 86%) as a yellow solid. LCMS (Method A): 4.18 min; m / z: 589.2 [M+H] + .

[0533] Step 2: 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide (Compound 37) A solution of 3-[4-ethanesulfonamido-3-(2-methylpropoxy)phenyl]-5-[(pyridin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (100 mg, 0.1698 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was neutralized to pH 7-8 with saturated aqueous Na2CO3. The mixture was diluted with H2O (30 mL), and the precipitated solid was collected by filtration. The crude residue was purified by preparative TLC (DCM:MeOH, 15:1) to afford the title product (20 mg, 25%) as a white solid. LCMS (Method A): 3.06 min; m / z: 459.1 [M+H] + . 1 H NMR (400 MHz, MeOD-d4): 12.84 (s, 1H), 9.57 (s, 1H), 9.01 (s, 1H), 8.20 (s, 1H), 7.72 (t, J =8.4 Hz, 1H), 7.43 (d, J =8.0 Hz, 1H), 7.24 (s, 1H), 7.14 (d, J =8.0 Hz, 1H), 6.87 (s, 1H), 6.14 (s, 1H), 3.83 (d, J =6.4 Hz, 2H), 3.11 (q, J =7.2 Hz, 2H), 2.18-2.08 (m, 1H), 1.27 (t, J =7.2 Hz, 3H), 1.02 (d, J = 6.8 Hz, 6H).

[0534] The following compounds (Table 15) were similarly prepared from Intermediate B1 and the appropriate Intermediate C according to the method described for the synthesis of 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide.

[0535] [Table 15-1]

[0536] [Table 15-2]

[0537] [Table 15-3]

[0538] compound 223 [ka]

[0539] Step 1: 3-[4-(difluoromethanesulfonamido)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A mixture of 1,1-difluoro-N-{2-[(1S)-1-(4-fluorophenyl)ethoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methanesulfonamide (Intermediate C11, 23.5 g, 50 mmol), 3-bromo-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (Intermediate B4, 18.2 g, 44 mmol), NaCO (10.6 g, 100 mmol), and Pd(dppf)Cl (2.5 g, 3 mmol) in degassed 80% aqueous 1,4-dioxane (250 mL) was stirred at 100 °C overnight. The mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (PE: EtOAc, 1:1) to give the title product (23 g, 77%) as a yellow solid. LCMS (Method A): 3.99 min; m / z: 678.2 [M+H] + .

[0540] Step 2: 3-[4-(difluoromethanesulfonamido)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-5-[(pyrazin-2-yl)amino]-1H-pyrazole-4-carboxamide (Compound 223) A mixture of 3-[4-(difluoromethanesulfonamido)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (23 g, 33.9 mmol), DCM (400 mL), and TFA (20 mL) was stirred at room temperature for 16 h. The mixture was neutralized to pH 7-8 with saturated Na2CO3, and the organic phase was washed with water (3 × 50 mL) and dried (Na2SO4). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 1:0 to 20:1) to give the title product (5.8 g, 31%) as a white solid. LCMS (Method A): 3.45 min; m / z: 548.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): 12.40 (s, 1H), 10.28 (s, 1H), 8.35 (s, 1H), 8.20-8.15 (m, 2H), 7.61 (d, J = 8.0Hz, 1H), 7.31 (q, J = 4.8 Hz, 2H), 7.14 (dd, J = 8.0, 1.6 Hz, 1H), 7.04 (t, J = 8.4 Hz, 2H), 6.99 (d, J = 1.6 Hz, 1H), 6.35 (t, J = 53.6 Hz, 1H), 5.40 (q, J = 6.4 Hz, 1H), 5.21 (s, 2H), 1.67 (d, J = 6.4 Hz, 3H).

[0541] The following compounds (Table 16) were similarly prepared from the appropriate intermediates C and B according to the method described for the synthesis of 3-[4-(difluoromethanesulfonamido)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-5-[(pyrazin-2-yl)amino]-1H-pyrazole-4-carboxamide.

[0542] [Table 16-1]

[0543] [Table 16-2]

[0544] [Table 16-3]

[0545] Compounds 279 and 280 [ka]

[0546] Racemic compound 293 (500 mg) was purified by chiral HPLC on a UniChiral CND-5H column (column size 50 mm ID x 250 mm L. Mobile phase 60% n-hexane / 40% ethanol / 0.1% TFA (v / v / v), flow rate 90 mL / min, temperature 25 °C). Fractions corresponding to the appropriate peak were combined and concentrated under reduced pressure. The residue was dissolved in DCM (50 mL), and the mixture was neutralized to pH 7-8 with saturated aqueous Na2CO3. The organic phase was washed with water (3 x 50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 1:0 to 20:1) to give the title product. The enantiomeric excess was calculated using a UniChiral CND-5H column (4.6 x 250 mm, 50% n-hexane / 50% ethanol, flow rate 1 mL / min, injection 5 μL, temperature 30 °C).

[0547] Peak 1: (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(oxazol-2-yl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (143 mg, retention time 7.49 min, ee>99%). LCMS (Method A): 3.00 min; m / z: 521.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): 12.41 (s, 1H), 10.32 (s, 1H), 8.39 (s, 1H), 8.21 (dd, J = 2.9, 1.4 Hz, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.66 (dd, J = 4.5, 3.7 Hz, 2H), 7.35 (d, J = 1.8 Hz, 1H), 7.30 (dd, J = 8.2, 1.9 Hz, 1H), 7.12 (d, J = 0.8 Hz, 1H), 6.33 (t, J = 53.6 Hz, 1H), 5.50 (q, J = 6.7 Hz, 1H), 5.44 (s, 2H), 1.84 (d, J = 6.7 Hz, 3H).

[0548] Peak 2: (R)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(oxazol-2-yl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (147 mg, retention time 9.06 min, ee>99%). LCMS (Method A): 3.00 min; m / z: 521.1 [M+H] + . 1H NMR (400 MHz, CDCl3): 12.41 (s, 1H), 10.32 (s, 1H), 8.39 (s, 1H), 8.21 (dd, J = 2.9, 1.4 Hz, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.66 (dd, J = 4.5, 3.7 Hz, 2H), 7.35 (d, J = 1.8 Hz, 1H), 7.30 (dd, J = 8.2, 1.9 Hz, 1H), 7.12 (d, J = 0.8 Hz, 1H), 6.33 (t, J = 53.6 Hz, 1H), 5.50 (q, J = 6.7 Hz, 1H), 5.44 (s, 2H), 1.84 (d, J = 6.7 Hz, 3H).

[0549] compound 252 [ka]

[0550] Step 1: 4-Bromo-2-[(1S)-1-(4-chlorophenyl)ethoxy]-1-nitrobenzene To a solution of (1S)-1-(4-chlorophenyl)ethan-1-ol (1.00 g, 6.38 mmol) in THF (20 mL) was added NaH (60% in oil, 763 mg, 19.1 mmol) at 0 °C. After 1 h, 4-bromo-2-fluoro-1-nitrobenzene (1.40 g, 6.38 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, diluted with HO (50 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed (brine), dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 10:1) to afford the title product (1.78 g, 78%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): 7.82 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.46 (s, 4H), 7.29 (dd, J = 8.4, 1.6 Hz, 1H), 5.91 (q, J = 6.4 Hz, 1H), 1.54 (d, J = 6.4 Hz, 3H).

[0551] Step 2: 4-Bromo-2-[(1S)-1-(4-chlorophenyl)ethoxy]aniline A mixture of 4-bromo-2-[(1S)-1-(4-chlorophenyl)ethoxy]-1-nitrobenzene (1.78 g, 4.99 mmol), Zn powder (1.62 g, 24.9 mmol), saturated NH4Cl (3 mL), and MeOH (12 mL) was stirred at 60 °C for 30 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 5:1) to give the title product (1.40 g, 86%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): 7.48-7.39 (m, 4H), 6.81 (d, J = 2Hz, 1H), 6.75 (dd, J = 8.4, 2.4 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 5.52 (q, J = 6.4 Hz, 1H), 4.99 (s, 2H), 1.52 (d, J = 6.4 Hz, 3H).

[0552] Step 3: 2-[(1S)-1-(4-chlorophenyl)ethoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline A mixture of 4-bromo-2-[(1S)-1-(4-chlorophenyl)ethoxy]aniline (1.4 g, 4.28 mmol), B2pin2 (1.19 g, 4.70 mmol), Pd(dppf)Cl2 (174 mg, 214 μmol), KOAc (840 mg, 8.56 mmol), and 1,4-dioxane (20 mL) was stirred at 100 °C for 16 h. The reaction mixture was concentrated, and the residue was diluted with HO (200 mL) and extracted with DCM (3 × 150 mL). The combined organic layers were washed (brine), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 1:1) to afford the title product (1.08 g, 68%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6): 7.49-7.38 (m, 4H), 7.00 (dd, J = 7.6, 0.8 Hz, 1H), 6.94 (m, 1H), 6.60 (d, J = 8.0 Hz, 1H), 5.47 (q, J = 6.4 Hz, 1H), 5.24 (s, 2H), 1.50 (d, J = 6.4 Hz, 3H), 1.21 (s, 12H).

[0553] Step 4: 3-{4-amino-3-[(1S)-1-(4-chlorophenyl)ethoxy] {phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide 2-[(1S)-1-(4-chlorophenyl)ethoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (945 mg, 2.52 mmol), 3-bromo-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (Intermediate B4, 987 mg, 2.39 mmol), Pd(dppf)Cl2, DCM (102 mg, 126 μmol), Na2CO3 (534 mg, 5.04 mmol), A mixture of 1,4-dioxane (2.5 mL) and 80% aqueous 1,4-dioxane (2.5 mL) was irradiated in a microwave reactor at 100 °C. After 1 h, the reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed (brine), dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM:MeOH, 30:1) to give the title product (561 mg, 38%) as a grey solid. LCMS (Method A): 4.07 min; m / z: 580.2 [M+H] + .

[0554] Step 5: 3-{3-[(1S)-1-(4-chlorophenyl)ethoxy]-4-(difluoromethanesulfonamido)phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A mixture of 3-{4-amino-3-[(1S)-1-(4-chlorophenyl)ethoxy]phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (70 mg, 120 μmol) and FCHSOCl (27.0 mg, 180 μmol) in 1:1 DCM:pyridine (4 mL) was stirred at room temperature. After 16 h, the reaction mixture was concentrated and the crude residue was purified by preparative TLC (DCM:MeOH, 15:1) to give the title product (30 mg, 36%) as a white solid. LCMS (Method D): 5.06 min; m / z: 715.9 [M+Na] + .

[0555] Step 6: 3-{3-[(1S)-1-(4-chlorophenyl)ethoxy]-4-(difluoromethanesulfonamido)phenyl}-5-[(pyrazin-2-yl)amino]-1H-pyrazole-4-carboxamide (Compound 252) A solution of 3-{3-[(1S)-1-(4-chlorophenyl)ethoxy]-4-(difluoromethanesulfonamido)phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (40 mg, 57.6 μmol) in 10:1 DCM:TFA (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was neutralized with saturated Na2CO3 and concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 15:1) to afford the title product (10.6 mg, 33%) as a white solid. LCMS (Method A): 1.80 min; m / z: 564.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 10.54 (s, 1H), 9.64 (s, 1H), 9.04 (s, 1H), 8.21-8.20 (m, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.20 (m, 1H), 7.15 (dd, J = 8.0, 1.6 Hz, 1H), 7.04 (t, J = 52.8 Hz, 1H), 6.20 (br s, 1H), 5.63 (q, J = 6.0 Hz, 1H), 1.59 (d, J = 6.4 Hz, 3H).

[0556] compound 12 [ka]

[0557] Step 1: 5-amino-1-(tert-butyl)-3-(3-fluoro-4-nitrophenyl)-1H-pyrazole-4-carbonitrile A mixture of 3-fluoro-4-nitrobenzaldehyde (10 g, 59.1 mmol) and t-BuNHNH2.HCl (8.09 g, 65.0 mmol) in DMF (50 mL) was stirred at room temperature overnight to give a solution of the hydrazone intermediate. LCMS (Method A): 4.38 min; m / z: 240.2 [M+H] + To this mixture, NBS (11.4 g, 64.3 mmol) was added slowly over 5 h at 0 °C, and the mixture was stirred at room temperature for an additional 5 h. The reaction mixture was cooled to 0 °C, and a premixed solution of malonitrile (8.39 g, 127 mmol) and NaOEt (14.4 g, 212 mmol) in EtOH (20 mL) was added. After 2 h at 0 °C, the reaction mixture was concentrated under reduced pressure and diluted with H2O (20 mL). The precipitated solid was collected by filtration, washed with H2O (2 × 10 mL), and dried under reduced pressure to give the title product (15 g, 60%) as a yellow solid. LCMS (Method A): 4.18 min; m / z: 304.1 [M+H] + .

[0558] Step 2: 1-tert-butyl-3-(3-fluoro-4-nitrophenyl)-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carbonitrile A mixture of 5-amino-1-tert-butyl-3-(3-fluoro-4-nitrophenyl)-1H-pyrazole-4-carbonitrile (5 g, 16.4 mmol), 2-chloro-6-(trifluoromethyl)pyridine (3.55 g, 19.6 mmol), Pd(dba) (1.50 g, 1.64 mmol), Xantphos (1.89 g, 3.28 mmol), and CsCO (15.9 g, 49.1 mmol) in degassed 1,4-dioxane (30 mL) was heated overnight at 110° C. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCO (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 30:1) to give the title product (2.5 g, 34%) as a yellow solid. LCMS (Method A): 4.60 min; m / z: 449.1 [M+H] + .

[0559] Step 3: 1-tert-butyl-3-[3-(2-methylpropoxy)-4-nitrophenyl]-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carbonitrile In THF (12 mL), 2-methylpropan-1-ol (131 mg, 1.78 mmol), 1-tert-butyl-3-(3-fluoro-4-nitrophenyl)-5-{[6 A mixture of {-(trifluoromethyl)pyridin-2-yl}amino-1H-pyrazole-4-carbonitrile (800 mg, 1.78 mmol) and NaH (876 mg, 7.12 mmol) was stirred at 0 °C overnight. The mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCO (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (Na SO ), concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE: EtOAc, 10:1) to give the title product (740 mg, 82%) as a yellow solid. LCMS (Method A): 3.55 min; m / z: 503.2 [M+H] + .

[0560] Step 4: 1-tert-butyl-3-[3-(2-methylpropoxy)-4-nitrophenyl]-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide A mixture of 1-tert-butyl-3-[3-(2-methylpropoxy)-4-nitrophenyl]-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carbonitrile (680 mg, 1.35 mmol) and Ghaffar-Parkins catalyst (106 mg, 270 μmol) in 50% aqueous 1,4-dioxane (22 mL) was stirred at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCO (20 mL), and extracted with EtOAc (3×20 mL). The combined organics were dried (NaSO) and concentrated under reduced pressure to give the title product (610 mg, 87%) as a yellow solid. LCMS (Method A): 2.67 min; m / z: 521.2 [M+H] + .

[0561] Step 5: 3-[4-amino-3-(2-methylpropoxy)phenyl]-1-tert-butyl-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide A mixture of 1-tert-butyl-3-[3-(2-methylpropoxy)-4-nitrophenyl]-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide (460 mg, 883 μmol), saturated NH4Cl (3 mL), and Zn dust (288 mg, 4.41 mmol) in MeOH (12 mL) was stirred at 60 °C overnight. The reaction mixture was concentrated, diluted with saturated NaHCO3 (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to give the title product (270 mg, 61%) as a yellow solid. LCMS (Method A): 4.08 min; m / z: 491.2 [M+H] + .

[0562] Step 6: 1-tert-butyl-3-[4-ethanesulfonamido-3-(2-methylpropoxy)phenyl]-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide A mixture of 3-[4-amino-3-(2-methylpropoxy)phenyl]-1-tert-butyl-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide (136 mg, 277 μmol), EtSOCl (42.6 mg, 332 μmol), and pyridine:CHCl (1:1, 6 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with saturated NaHCO (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried (NaSO) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (DCM:MeOH, 20:1) to give the title product (79 mg, 49%) as a yellow solid. LCMS (Method A): 4.27 min; m / z: 583.2 [M+H] + .

[0563] Step 7: 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide (Compound 12) 1-tert-Butyl-3-[4-ethoxybenzoate] in DCM (4 mL) and TFA (4 mL) A solution of phenylsulfonamido-3-(2-methylpropoxy)phenyl]-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide (100 mg, 171 μmol) was stirred at room temperature overnight. The reaction mixture was concentrated, neutralized to pH 7-8 with NH4OH, diluted with HO (20 mL), and extracted with DCM (3 × 30 mL). The combined organics were washed with brine, dried (Na2SO4), and concentrated to give the title product (30 mg, 33%) as a yellow solid. LCMS (Method A): 4.21 min; m / z: 527.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 12.97 (s, 1H) 12.97 (s, 1H), 9.77 (s, 1H), 9.02 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.98 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 7.6 Hz, 2H), 7.16 (q, J = 1.2 Hz, 1H), 3.85 (d, J = 6.8 Hz, 2H), 3.14 (q, J = 7.5 Hz, 2H), 2.17-2.10 (m, 1H), 1.26 (q, J = 7.2 Hz, 3H), 1.03 (d, J = 6.4 Hz, 6H).

[0564] The following compounds (Table 17) were prepared similarly according to the method described for the synthesis of 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, using the appropriate aryl / alkylmethanol in step 3.

[0565] [Table 17-1]

[0566] [Table 17-2]

[0567] [Table 17-3]

[0568] compound 5 [ka]

[0569] Step 1: 1-(tert-butyl)-3-(3-((4-fluorobenzyl)oxy)-4-nitrophenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carbonitrile To a solution of (4-fluorophenyl)methanol (209 mg, 1.66 mmol) in THF (20 mL) at 0° C. was added NaH (133 mg, 3.33 mmol). After 10 min, 1-tert-butyl-3-(3-fluoro-4-nitrophenyl)-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carbonitrile (500 mg, 1.11 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (DCM:MeOH, 50:1) to give the title product (500 mg, 81%) as a yellow solid. LCMS (Method A): 4.87 min; m / z: 555.2 [M+H] + .

[0570] Step 2: 1-(tert-butyl)-3-(3-((4-fluorobenzyl)oxy)-4-nitrophenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide A mixture of 1-(tert-butyl)-3-(3-((4-fluorobenzyl)oxy)-4-nitrophenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carbonitrile (500 mg, 0.90 mmol) and Ghaffar-Parkins catalyst (100 mg) in 70% aqueous 1,4-dioxane (7 mL) was stirred at 100° C. overnight. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (DCM) to give the title product (400 mg, 78%) as a yellow solid. LCMS (Method A): 2.66 min; m / z: 573.1 [M+H] + .

[0571] Step 3: 3-(4-amino-3-((4-fluorobenzyl)oxy)phenyl)-1-(tert-butyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide (Compound 5) A mixture of 1-(tert-butyl)-3-(3-((4-fluorobenzyl)oxy)-4-nitrophenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide (500 mg, 0.87 mmol), saturated aqueous NH4Cl (2 mL), and Zn dust (285 mg, 4.36 mmol) in MeOH (10 mL) was stirred at 60°C for 5 hours. The reaction mixture was filtered, concentrated under reduced pressure, and diluted with HO. The precipitated solid was collected by filtration and purified by silica gel column chromatography (DCM:MeOH, 50:1) to give the title product (230 mg, 49%) as a yellow solid. LCMS (Method A): 4.17 min; m / z: 543.2 [M+H] + .

[0572] The compounds shown in Table 18 were prepared by a similar synthetic route as described for compound 46 (steps 6 and 7).

[0573] [Table 18]

[0574] compound 46 [ka]

[0575] Step 1: 3-(benzyloxy)-4-nitrobenzaldehyde A mixture of 3-hydroxy-4-nitrobenzaldehyde (10 g, 59.8 mmol), benzyl bromide (10.2 g, 59.8 mmol), and K2CO3 (16.4 g, 119 mmol) in MeCN (200 mL) was stirred at 70 °C overnight under N2. The mixture was diluted with HO (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 15:1) to give the title product (3 g, 20%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): 10.70 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.69 (dd, J = 8.0, 1.2 Hz, 1H), 7.48-7.34 (m, 5H), 5.42 (s, 2H).

[0576] Step 2: 5-amino-3-[3-(benzyloxy)-4-nitrophenyl]-1-tert-butyl-1H-pyrazole-4-carbonitrile A solution of 3-(benzyloxy)-4-nitrobenzaldehyde (3 g, 11.6 mmol) and t-BuNHNH2.HCl (1.44 g, 11.6 mmol) in DMF (60 mL) was stirred at room temperature overnight. The mixture was neutralized to pH 7-8 with saturated aqueous Na2CO3 and diluted with H2O (100 mL). The precipitated solid was collected by filtration and dried under vacuum to give the hydrazine intermediate (3.5 g, 92%). LCMS (Method A): 4.61 min; m / z: 328.1 [M+H] + The crude material was dissolved in DMF (60 mL) and NBS (2.06 g, 11.6 mmol) was added at room temperature. After 2 h, a premixed solution of malononitrile (1.04 g, 15.7 mmol) and NaOEt (1.06 g, 15.7 mmol) in EtOH (40 mL) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with H2O (70 mL), and extracted with DCM (3 x 60 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 4:1) to give the title product (1.6 g, 39%) as a yellow solid. LCMS (Method A): 4.49 min; m / z: 392.2 [M+H] + .

[0577] Step 3: 3-[3-(benzyloxy)-4-nitrophenyl]-1-tert-butyl-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carbonitrile 5-amino-3-[3-(benzyloxy)-4-nitrophenyl]-1-tert-butyl-1H-pyrazole-4-carbonitrile (1.5 g, 3.83 mmol), 2-chloro-6-(trifluoromethyl)pyridine (764 mg, 4.21 mmol), Pd2(dba)3 (350 mg, 383 μmol), Xantphos (221 mg, 383 μmol), A mixture of CsCO (2.49 g, 7.66 mmol) and CsCO (2.49 g, 7.66 mmol) in degassed 1,4-dioxane (75 mL) was stirred under N at 100 °C for 16 h. The reaction mixture was diluted with HO (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried (NaSO) and concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 4:1) to give the title product (2 g, 98%) as a yellow solid. LCMS (Method A): 4.78 min; m / z: 537.3 [M+H] + .

[0578] Step 4: 3-[3-(benzyloxy)-4-nitrophenyl]-1-tert-butyl-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide A mixture of 3-[3-(benzyloxy)-4-nitrophenyl]-1-tert-butyl-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carbonitrile (1.9 g, 3.54 mmol), 30% aqueous HO (100 mL), 5% aqueous NaOH (10 mL), and DMSO (100 mL) in EtOH (200 mL) was stirred at 100° C. overnight. The reaction mixture was concentrated under reduced pressure and diluted with water (60 mL), resulting in the formation of a precipitate. The precipitated solid was collected by filtration and dried under reduced pressure to give the title product (1.8 g, 92%) as a white solid. LCMS (Method A): 4.45 min; m / z: 555.2 [M+H] + .

[0579] Step 5: 3-[4-amino-3-(benzyloxy)phenyl]-1-tert-butyl-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide A mixture of 3-[3-(benzyloxy)-4-nitrophenyl]-1-tert-butyl-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide (500 mg, 901 μmol), saturated aqueous NH₄Cl (2 mL), and Zn dust (294 mg, 4.50 mmol) in MeOH (8 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with HO (30 mL) and extracted with DCM (3×50 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure to give the title product (300 mg, 63%) as a yellow solid. LCMS (Method A): 3.27 min; m / z: 525.3 [M+H] + .

[0580] Step 6: 3-[3-(benzyloxy)-4-ethanesulfonamidophenyl]-1-tert-butyl-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide A mixture of 3-[4-amino-3-(benzyloxy)phenyl]-1-tert-butyl-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide (200 mg, 0.38 mmol) and EtSO2Cl (73.4 mg, 0.57 mmol) in pyridine (5 mL) was stirred at 35 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH, 15:1) to give the title product (140 mg, 60%) as a yellow solid. LCMS (Method A): 4.28 min; m / z: 617.2 [M+H] + .

[0581] Step 7: 3-(3-(benzyloxy)-4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide (Compound 46) A solution of 3-[3-(benzyloxy)-4-ethanesulfonamidophenyl]-1-tert-butyl-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide (120 mg, 194 μmol) in TFA (2 mL) and DCM (2 mL) was stirred at 30° C. for 1 h. The reaction mixture was concentrated under reduced pressure, neutralized to pH 7-8 with saturated aqueous Na2CO3, and diluted with HO (10 mL). The resulting solid was collected by filtration and dried under vacuum to give the title product (50 mg, 46%) as a white solid. LCMS (Method A): 4.13 min; m / z: 561.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 13.01 (s, 1H), 9.78 (s, 1H), 9.19 (s, 1H), 8.23 ​​(d, J = 8.0 Hz, 1H), 7.99 (t, J = 7.6 Hz, 1H), 7.63-7.15 (m, 10H), 6.21 (br s, 1H), 5.21 (s, 2H), 3.06 (q, J = 6.8 Hz, 2H), 1.17 (t, J = 6.8 Hz, 3H).

[0582] compound 229 [ka]

[0583] Step 1: N-[4-(4-cyano-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide A mixture of 1,1-difluoro-N-{2-[(1S)-1-(4-fluorophenyl)ethoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methanesulfonamide (Intermediate C11, 200 mg, 424 μmol), 3-bromo-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (196 mg, 424 μmol), Pd(dppf)Cl.DCM (34.6 mg, 42.4 μmol), NaCO (89.8 mg, 848 μmol), and 80% aqueous 1,4-dioxane (15 mL) was stirred at 100 °C under N. After 1 h, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed (brine), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 30:1) to afford the title product (190 mg, 61%) as a yellow solid. LCMS (Method A): 4.35 min; m / z: 725.2 [M+H] + .

[0584] Step 2: 3-[4-(difluoromethanesulfonamido)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A solution of N-[4-(4-cyano-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1,1-difluoromethanesulfonamide (160 mg, 220 μmol) and Ghaffar-Parkins catalyst (16 mg, 37.4 μmol) in 50% aqueous 1,4-dioxane (4 mL) was stirred at 100° C. under N. After 16 h, the reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed (brine), dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 30:1) to give the title product (70.0 mg, 43%) as a yellow solid. LCMS (Method D): 6.41 min; m / z: 745.0 [M+H] + .

[0585] Step 3: 3-[4-(difluoromethanesulfonamido)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-5-{[6-(trifluoromethyl)pyridine Zin-2-yl]amino}-1H-pyrazole-4-carboxamide (Compound 229) A solution of 3-[4-(difluoromethanesulfonamido)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (45 mg, 60.4 μmol) in DCM:TFA (4:1, 2.5 mL) was stirred at room temperature for 5 min. The reaction mixture was neutralized to pH 7-8 with NH4OH and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (Na2SO4), concentrated, and the crude residue was purified four times consecutively by preparative TLC (DCM:MeOH, 60:1) to afford the title product (19.2 mg, 52%) as a white solid. LCMS (Method A): 4.03 min; m / z: 615.1 [M+H] + . 1H NMR: (400 MHz, DMSO-d6): 13.01 (s, 1H), 10.55 (s, 1H), 9.67 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.99-7.95 (m, 1H), 7.60-7.57 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.21-7.14 (m, 5H), 7.02 (t, J = 52.8 Hz, 1H), 6.12 (br s 1H), 5.65 (m, 1H), 1.58 (d, J = 6.0 Hz, 3H).

[0586] compound 45 [ka]

[0587] Step 1: 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-(pyrazin-2-ylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide A mixture of 3-bromo-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (Intermediate B4, 100 mg, 0.2419 mmol), N-(2-isobutoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide (Intermediate C9, 120 mg, 0.3130 mmol), Pd(dppf)Cl (17.7 mg, 24.1 μmol) and NaCO (76.9 mg, 0.7257 mmol) in degassed 70% aqueous 1,4-dioxane (6.5 mL) was stirred at 100 °C under microwave irradiation for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with HO (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (NaSO) and concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH, 18:1) to give the title product (90 mg, 63%) as a yellow solid. LCMS (Method A): 4.16 min; m / z: 590.2 [M+H] + .

[0588] Step 2: 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (Compound 45) A solution of 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-(pyrazin-2-ylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (90 mg, 0.1525 mmol) in DCM (3 mL) and TFA (3 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, neutralized to pH 7-8 with saturated aqueous Na2CO3, and diluted with H2O (30 mL). The precipitated solid was collected by filtration and purified by preparative TLC (DCM:MeOH, 15:1) to give the title product (25 mg, 36%) as a white solid. LCMS (Method A): 3.45 min; m / z: 460.1 [M+H] + . 1 H NMR (400 MHz, MeOD-d4): 8.27 (s, 1H), 13.00 (s, 1H) , 9.63 (s, 1H), 9.26 (s, 1H), 9.05 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.29 (s, 1H), 3.84 (d, J = 6.4 Hz, 2H), 3.13 (q, J = 7.2 Hz, 2H), 2.14 (s, 1H), 1.27 (t, J = 7.6 Hz, 3H), 1.03 (d, J = 6.4 Hz, 6H).

[0589] Following the method described for the synthesis of 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, the following compounds (Table 19) were similarly prepared using the appropriate intermediate C in step 1.

[0590] [Table 19]

[0591] compound 1 [ka]

[0592] Step 1: 4-Bromo-2-[(3,4-difluorophenyl)methoxy]-1-nitrobenzene To a solution of (3,4-difluorophenyl)methanol (981 mg, 6.81 mmol) in THF (15 mL) at 0 °C was added NaH (489 mg, 20.4 mmol). After 10 min, 4-bromo-2-fluoro-1-nitrobenzene (1.5 g, 6.81 mmol) was added, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 30:1) to afford the title product (1.8 g, 77%) as a white solid.

[0593] Step 2: 4-Bromo-2-[(3,4-difluorophenyl)methoxy]aniline A mixture of 4-bromo-2-[(3,4-difluorophenyl)methoxy]-1-nitrobenzene (1 g, 2.90 mmol), saturated aqueous NH4Cl (5 mL), and Zn dust (941 mg, 14.4 mmol) in MeOH (10 mL) was stirred at 60 °C for 3 h. The reaction mixture was diluted with HO (200 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 3:1) to give the title product (810 mg, 89%) as a white solid. LCMS (Method A): 4.18 min; m / z: 314.0, 316.0 [M+H] + .

[0594] Step 3: N-{4-bromo-2-[(3,4-difluorophenyl)methoxy]phenyl}ethane-1-sulfonamide A mixture of 4-bromo-2-[(3,4-difluorophenyl)methoxy]aniline (800 mg, 2.54 mmol), EtSO2Cl (489 mg, 3.81 mmol), and pyridine (8 mL) in CHCl3 (8 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with HO (200 mL) and extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 3:1) to give the title product (720 mg, 70%) as a white solid. LCMS (Method A): 4.26 min; m / z: 427.9, 429.9 [M+H] + .

[0595] Step 4: N-{2-[(3,4-difluorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}ethane-1-sulfonamide N-{4-bromo-2-[(3,4-difluorophenyl)methoxy]phenyl}ethane-1-sulfonamide (600 mg, 1.47 m A mixture of B2pin2 (558 mg, 2.20 mmol), Pd(dppf)Cl2 (1.07 g, 1.47 mmol), KOAc (432 mg, 4.41 mmol), and B2pin2 (558 mg, 2.20 mmol) was stirred at 110 °C for 16 h. The reaction mixture was diluted with HO (200 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 2:1) to give the title product (480 mg, 72%) as a white solid. LCMS (Method A): 4.46 min; m / z: 476.4 [M+H] + .

[0596] Step 5: 3-{3-[(3,4-difluorophenyl)methoxy]-4-ethanesulfonamidophenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A mixture of N-{2-[(3,4-difluorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}ethane-1-sulfonamide (200 mg, 441 μmol), 3-bromo-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (Intermediate B4, 182 mg, 441 μmol), Pd(dppf)Cl (32.2 mg, 44.1 μmol), and NaCO (139 mg, 1.32 mmol) in 70% aqueous 1,4-dioxane (15 mL) was stirred at 110° C. for 16 hours. The reaction mixture was diluted with HO (200 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine, dried (NaSO) and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM:MeOH, 30:1) to give the title product (180 mg, 62%) as a yellow oil. LCMS (Method A): 4.15 min; m / z: 660.2 [M+H] + .

[0597] Step 6: 3-(3-((3,4-difluorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (Compound 1) A solution of 3-{3-[(3,4-difluorophenyl)methoxy]-4-ethanesulfonamidophenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (150 mg, 227 μmol) in DCM (5 mL) and TFA (5 mL) was stirred at 25 °C for 3 h. The reaction mixture was neutralized to pH 7-8 with saturated aqueous NaHCO and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine, dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 30:1) to afford the title product (50 mg, 41%) as a white solid. LCMS (Method A): 3.59 min; m / z: 530.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6): 13.01 (s, 1H), 9.64 (s, 1H), 9.26 (s, 2H), 8.23 ​​(s, 1H), 8.12 (s, 1H), 7.78-7.74 (m, 1H), 7.52-7.41 (m, 3H), 7.20 (d, J = 8.4 Hz, 1H), 6.22 (s, 1H), 5.21 (s, 2H), 3.11-3.05 (m, 2H), 1.19 (t, J =7.2 Hz, 3H).

[0598] Following the method described for the synthesis of 3-(3-((3,4-difluorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, the following compounds (Table 20) were similarly prepared using the appropriate alcohol in step 1.

[0599] [Table 20-1]

[0600] [Table 20-2]

[0601] [Table 20-3]

[0602] [Table 20-4]

[0603] compound 248 [ka]

[0604] Step 1: 1-(4-fluorophenyl)cyclopropan-1-ol To a solution of methyl 4-fluorobenzoate (9.0 g, 58.3 mmol) and Ti(Oi-Pr) (29.5 g, 104 mmol) in THF (180 mL) at 0 °C, EtMgBr (23.1 g, 174 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NH Cl (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were dried (Na SO ) and concentrated, and the crude residue was purified by silica gel column chromatography (PE: EtOAc, 20:1) to give the title product (7.5 g, 85%) as a yellow oil.

[0605] Step 2: 4-Bromo-2-[1-(4-fluorophenyl)cyclopropoxy]-1-nitrobenzene To a solution of 1-(4-fluorophenyl)cyclopropan-1-ol (4.5 g, 29.5 mmol) in THF (90 mL) at 0 °C was added NaH (3.20 g, 80.4 mmol). After 15 min, 4-bromo-2-fluoro-1-nitrobenzene (5.89 g, 26.8 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was quenched with HO (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed (brine), dried (NaSO), and concentrated under reduced pressure to give the crude product (10.0 g, >100%) as a brown oil.

[0606] Step 3: 4-Bromo-2-[1-(4-fluorophenyl)cyclopropoxy]aniline A mixture of 4-bromo-2-[1-(4-fluorophenyl)cyclopropoxy]-1-nitrobenzene (13.0 g, 36.9 mmol), Zn powder (12.0 g, 184 mmol), saturated NH4Cl (35 mL), and MeOH (105 mL) was stirred at 60 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was diluted with HO (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed (brine), dried (Na2SO4), and concentrated to give the crude product (10.0 g, 42%) as a brown oil. LCMS (Method D): 5.20 min; m / z: 322.0, 324.0 [M+H] + .

[0607] Step 4: N-{4-bromo-2-[1-(4-fluorophenyl)cyclopropoxy]phenyl}ethane-1-sulfonamide A mixture of 4-bromo-2-[1-(4-fluorophenyl)cyclopropoxy]aniline (2.0 g, 6.20 mmol) and EtSOCl (956 mg, 7.44 mmol) in CHCl:pyridine (4:1, 25 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 30:1) to give the title product (1.0 g, 39%) as a yellow solid. LCMS (Method D): 4.05 min; m / z: 322.0, 324.0 [M+H] + .

[0608] Step 5: N-{2-[1-(4-fluorophenyl)cyclopropoxy]-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}ethane-1-sulfonamide A mixture of N-{4-bromo-2-[1-(4-fluorophenyl)cyclopropoxy]phenyl}ethane-1-sulfonamide (500 mg, 1.20 mmol), B2pin2 (454 mg, 1.79 mmol), Pd(dppf)Cl2 (87.7 mg, 0.12 mmol), KOAc (235 mg, 2.40 mmol), and 1,4-dioxane (10 mL) was stirred at 100 °C under N2 for 16 h. The mixture was concentrated, and the residue was diluted with HO (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed (brine), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by preparative TLC (PE:EtOAc, 20:1) to afford the title product (240 mg, 43%) as a yellow solid. LCMS (Method D): 5.48 min; 462.2[M+H] + .

[0609] Step 6: N-(4-{4-cyano-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl}-2-[1-(4-fluorophenyl)cyclopropoxy]phenyl)ethane-1-sulfonamide A mixture of N-{2-[1-(4-fluorophenyl)cyclopropoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}ethane-1-sulfonamide (250 mg, 0.54 mmol), 3-bromo-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (Intermediate B3, 214 mg, 0.54 mmol), Pd(dppf)Cl.DCM (44.2 mg, 0.05 mmol), NaCO (114 mg, 1.08 mmol) and 80% aqueous 1,4-dioxane (10 mL) was stirred at 100 °C under microwave irradiation for 2 h. The reaction mixture was concentrated, diluted with H2O (100 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 20:1) to give the title product (50 mg, 14%) as a yellow solid. LCMS (Method D): 5.48 min; 650.2 [M+H]+ .

[0610] Step 7: 3-{4-ethanesulfonamido-3-[1-(4-fluorophenyl)cyclopropoxy]phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A mixture of N-(4-{4-cyano-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl}-2-[1-(4-fluorophenyl)cyclopropoxy]phenyl)ethane-1-sulfonamide (50 mg, 76.9 μmol), Ghaffar-Parkins catalyst (20 mg, 46.8 μmol), and 65% aqueous 1,4-dioxane (4.5 mL) was stirred at 100° C. for 16 h. The mixture was concentrated, and the residue was diluted with HO (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed (brine), dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 20:1) to afford the title product (30 mg, 59%) as a yellow solid. LCMS (Method D): 4.82 min; m / z: 668.2 [M+H] + .

[0611] Step 8: 3-{4-ethanesulfonamido-3-[1-(4-fluorophenyl)cyclopropoxy]phenyl}-5-[(pyrazin-2-yl)amino]-1H-pyrazole-4-carboxamide (Compound 248) A mixture of 3-{4-ethanesulfonamido-3-[1-(4-fluorophenyl)cyclopropoxy]phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (30 mg, 44.9 μmol) in DCM:TFA (1:1, 3 mL) was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was neutralized with saturated Na2CO3 to pH 7-8. The resulting precipitate was collected by filtration and washed with MeOH to give the title product (10 mg, 41%) as a yellow solid. LCMS (Method A): 3.87 min; m / z: 538.2 [M+H]+ . 1 H NMR (400 MHz, MeOD-d4): 12.93 (s, 1H), 9.59 (s, 1H), 9.22 (s, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 8.8 Hz, 2H), 7.13 (t, J = 8.8 Hz, 3H), 7.05 (s, 1H), 6.21 (s, 1H), 3.16 (q, J = 6.8 Hz, 2H), 1.47 (s, 2H), 1.41 (s, 2H), 1.31 (t, J = 7.2 Hz, 3H).

[0612] The following compounds (Table 21) were prepared similarly following the synthesis of compound 248 using the appropriate sulfonyl chloride in step 4 and the appropriate intermediate B in step 6.

[0613] [Table 21]

[0614] compound 269 [ka]

[0615] Step 1: 3-{4-amino-3-[(4-chlorophenyl)methoxy]phenyl}-5-[(pyridin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A mixture of 3-bromo-5-[(pyridin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (Intermediate B2, 500 mg, 1.21 mmol), 2-[(4-chlorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (435 mg, 1.21 mmol), Pd(dppf)Cl (98.8 mg, 121 μmol) and NaCO (256 mg, 2.42 mmol) in 80% aqueous 1,4-dioxane (12.5 mL) was irradiated in a microwave reactor at 100 °C. After 1 h, the reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (PE: EtOAc, 20:1) to give the title product (680 mg, 95%) as a yellow solid. LCMS (Method A): 4.43 min; m / z: 595.1 [M+H] + .

[0616] Step 2: 3-{3-[(4-chlorophenyl)methoxy]-4-(2,2,2-trifluoroethanesulfonamido)phenyl}-5-[(pyridin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide To a solution of 3-{4-amino-3-[(4-chlorophenyl)methoxy]phenyl}-5-[(pyridin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (300 mg, 530 μmol) in CHCl3:pyridine (1:1, 6 mL) was added 2,2,2-trifluoroethane-1-sulfonyl chloride (145 mg, 795 μmol). The mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was diluted with HO (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed (brine), dried (Na2SO4), and concentrated. The crude residue was purified by preparative TLC (DCM:MeOH, 15:1) to afford the title product (100 mg, 33%) as a yellow solid. LCMS (Method A): 3.56 min; m / z: 710.5 [M+H] + .

[0617] Step 3: 3-{3-[(4-chlorophenyl)methoxy]-4-(2,2,2-trifluoroethanesulfonamido)phenyl}-5-[(pyridin-2-yl)amino]-1H-pyrazole-4-carboxamide (Compound 269) A solution of 3-{3-[(4-chlorophenyl)methoxy]-4-(2,2,2-trifluoroethanesulfonamido)phenyl}-5-[(pyridin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (100 mg, 28.1 μmol) in DCM:TFA (1:1, 6 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the residue was neutralized with saturated Na2CO3 to pH 7-8. The resulting precipitate was collected by filtration and purified by preparative TLC (DCM:MeOH, 15:1) to afford the title product (30 mg, 26%) as a yellow solid. LCMS (Method A): 3.41 min; m / z: 580.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 12.56 (s, 1H), 9.67 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.69 (t, J = 6.8 Hz, 1H), 7.52-7.32 (m, 8H), 6.96 (d, J = 11.2 Hz, 2H), 6.84 (d, J = 6.4 Hz, 1H), 5.07 (s, 1H), 3.67-3.58 (m, 2H).

[0618] compound 266 [ka]

[0619] Step 1: Cyclobutyl(4-fluorophenyl)methanol To a solution of 4-fluorobenzaldehyde (3.10 g, 25.0 mmol) in THF (10 mL) at 0 °C, c-BuMgBr (21.40 g, 161 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed (brine), dried (Na2SO4), and concentrated. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 20:1 to 5:1) to afford the title product (4.30 g, 95%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6): 7.38-7.29 (m, 2H), 7.15-7.05 (m, 2H), 5.17 (d, J = 4.4 Hz, 2H), 4.48 (d, J = 5.6 Hz, 1H), 2.46-2.38 (m, 1H), 1.94-1.61 (m, 5H).

[0620] Step 2: 4-Bromo-2-[cyclobutyl(4-fluorophenyl)methoxy]-1-nitrobenzene To a mixture of cyclobutyl(4-fluorophenyl)methanol (4.30 g, 23.8 mmol) in THF (100 mL) at 0 °C was added NaH (2.85 g, 71.4 mmol). After 30 min, 4-bromo-2-fluoro-1-nitrobenzene (5.23 g, 23.8 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the residue was diluted with HO (200 mL) and extracted with EtOAc (2 × 80 mL). The combined organic layers were washed (brine), dried (NaSO), and concentrated to give the title product (6.50 g, 72%) as a brown oil. 1 H NMR (400 MHz, DMSO-d6): 7.80 (d, J = 8.8 Hz, 1H), 7.43-7.42 (m, 3H), 7.26-7.24 (m, 1H), 7.22-7.17 (m, 2H), 5.70 (d, J = 7.2 Hz, 1H), 2.73-2.68 (m, 1H), 2.05-1.74 (m, 6H).

[0621] Step 3: 4-Bromo-2-[cyclobutyl(4-fluorophenyl)methoxy]aniline A mixture of 4-bromo-2-[cyclobutyl(4-fluorophenyl)methoxy]-1-nitrobenzene (6.50 g, 17.0 mmol), Zn powder (5.55 g, 85.0 mmol), saturated NH4Cl (30 mL), and MeOH (100 mL) was stirred at 60 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated, diluted with HO (50 mL), and extracted with DCM (3 × 50 mL). The combined organic layers were washed (brine), dried (Na2SO4), and concentrated to give the title product (6.00 g, 17.1 mmol) as a brown oil.

[0622] Step 4: 2-[cyclobutyl(4-fluorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 4-Bromo-2-[cyclobutyl(4-fluorophenyl)methoxy]aniline (1.0 g, 2.85 mmol), B2pin2 (723 mg, 2.85 mmol), Pd(dppf)Cl2 (260 mg, 285 μmol), KOAc (559 mg, 5.70 mmol), A mixture of 1,4-dioxane (150 mL) and 1,4-dioxane (150 mL) was stirred at 100° C. for 16 h. The reaction mixture was concentrated, and the residue was diluted with HO (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed (brine), dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 10:1) to give the title product (660 mg, 58%) as a black oil. LCMS (Method A): 4.67 min; m / z: 398.2 [M+H] + .

[0623] Step 5: 3-{4-amino-3-[cyclobutyl(4-fluorophenyl)methoxy]phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A mixture of 2-[cyclobutyl(4-fluorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (600 mg, 1.51 mmol), 3-bromo-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (624 mg, 1.51 mmol), Pd(dppf)Cl.DCM (123 mg, 151 μmol), NaCO (320 mg, 3.02 mmol), and 80% aqueous 1,4-dioxane (100 mL) was stirred under N at 100 °C. After 16 h, the reaction mixture was concentrated, and the residue was diluted with HO (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed (brine), dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM:MeOH, 60:1) to give the title product (400 mg, 43%) as a brown solid. LCMS (Method A): 4.18 min; m / z: 604.3 [M+H] + .

[0624] Step 6: 3-{3-[cyclobutyl(4-fluorophenyl)methoxy]-4-(2,2,2-trifluoroethanesulfonamido)phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A mixture of 3-{4-amino-3-[cyclobutyl(4-fluorophenyl)methoxy]phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (400 mg, 662 μmol), 2,2,2-trifluoroethanesulfonyl chloride (181 mg, 993 μmol), and DCM:pyridine (1:1, 30 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the residue was diluted with HO (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed (brine), dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM:MeOH, 50:1) to afford the title product (350 mg, 70%) as a brown solid. LCMS (Method A): 4.32 min; m / z: 750.3 [M+H] + .

[0625] Step 7: 3-{3-[cyclobutyl(4-fluorophenyl)methoxy]-4-(2,2,2-trifluoroethanesulfonamido)phenyl}-5-[(pyrazin-2-yl)amino]-1H-pyrazole-4-carboxamide (Compound 266) A solution of 3-{3-[cyclobutyl(4-fluorophenyl)methoxy]-4-(2,2,2-trifluoroethanesulfonamido)phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (200 mg, 266 μmol) in DCM:TFA (10:1, 11 mL) was stirred at room temperature for 5 minutes. The reaction mixture was concentrated, and the residue was neutralized with saturated Na2CO3 to pH 7-8. The resulting precipitate was collected by filtration and purified by preparative TLC (DCM:MeOH, 20:1) to afford the title product (20.0 mg, 12%) as a white solid. LCMS (Method A): 3.85 min; m / z: 620.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 13.01 (s, 1H), 9.94 (s, 1H), 9.58 (s, 1H), 9.21 (s, 1H), 8.21-8.20 (m, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.59-7.56 (m, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.22 (s, 1H), 7.15-7.09 (m, 3H), 5.46-5.44 (m, 1H), 4.55-4.42 (m, 2H), 2.85-2.78 (m, 1H), 2.07-1.99 (m, 2H), 1.83 (s, 3H), 1.73-1.68 (m, 1H).

[0626] compound 236 [ka]

[0627] Step 1: 3-{3-[cyclobutyl(4-fluorophenyl)methoxy]-4-(difluoromethanesulfonamido)phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A solution of 3-{4-amino-3-[cyclobutyl(4-fluorophenyl)methoxy]phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (700 mg, 1.15 mmol) and FCHSOCl (258 mg, 1.72 mmol) in DCM:pyridine (1:1, 10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the residue was diluted with HO (80 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed (brine), dried (NaSO), and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM:MeOH, 55:1) to afford the title product (400 mg, 48%) as a yellow solid. LCMS (Method A): 4.37 min; 718.3 [M+H] + .

[0628] Step 2: 3-{3-[cyclobutyl(4-fluorophenyl)methoxy]-4-(difluoromethanesulfonamido)phenyl}-5-[(pyrazin-2-yl)amino]-1H-pyrazole-4-carboxamide (Compound 236) A solution of 3-{3-[cyclobutyl(4-fluorophenyl)methoxy]-4-(difluoromethanesulfonamido)phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (180 mg, 250 μmol) in DCM:TFA (8:1, 9 mL) was stirred at room temperature for 5 minutes. The reaction mixture was concentrated, and the residue was neutralized with saturated Na2CO3 to pH 7-8. The resulting precipitate was collected by filtration and purified by preparative HPLC to give the title product (20.0 mg, 13%) as a white solid. LCMS (Method A): 3.74 min; m / z: 588.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 12.92 (s, 1H), 10.51 (s, 1H), 9.56 (s, 1H), 9.20 (s, 1H), 8.20 (s, 1H), 8.10-8.09 (m, 1H), 7.54-7.51 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.15-7.07 (m, 5H), 6.05 (s, 1H), 5.39 (d, J = 6.4 Hz, 1H), 2.80-2.74 (m, 1H), 2.17-2.09 (m, 1H), 2.03-1.90 (m, 2H), 1.84-1.72 (m, 3H).

[0629] The following compounds (Table 22) were similarly prepared from the appropriate benzyl alcohol 1-(4-fluorophenyl)-2-methoxyethan-1-ol, following the method described for the synthesis of compound 23, step 2 of compound 266.

[0630] [Table 22]

[0631] The following compound was prepared by the reaction of 3-{3-[cyclobutyl(4-fluorophenyl)methoxy]-4-(2,2,2-trifluoroethanesulfonamido)phenyl}-5-[(pyrazine- Prepared similarly from the appropriate benzyl alcohol following step 1 according to the method described for the synthesis of [2-yl)amino]-1H-pyrazole-4-carboxamide.

[0632] compound 263 [ka]

[0633] 3-(3-(1-(4-fluorophenyl)propoxy)-4-(2,2,2-trifluoroethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide A solution of 3-{3-[1-(4-fluorophenyl)propoxy]-4-(2,2,2-trifluoroethanesulfonamido)phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (90 mg, 124 μmol) in CHCl3:TFA (1:1, 5 mL) was stirred at room temperature for 2 minutes. The reaction mixture was neutralized to pH 7-8 with NH4OH and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to afford the title product (22.0 mg, 29%) as a white solid. LCMS (Method A): 3.67 min; m / z: 594.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 13.06 (s, 1H), 9.77 (s, 1H), 9.31 (br s, 1H), 8.36-8.29 (m, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.68-7.62 (m, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.30-7.24 (m, 3H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 6.17 (br s, 1H), 5.54-5.44 (m, 1H), 4.50 (t, J = 7.2 Hz, 2H), 2.21-2.09 (m, 1H), 2.08-1.86 (m, 1H), 1.00 (t, J = 7.6 Hz, 3H).

[0634] Compounds 250 and 251 [ka]

[0635] Racemic 3-(3-(1-(4-fluorophenyl)propoxy)-4-(2,2,2-trifluoroethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide was purified by chiral HPLC on an AD-H column using heptane:EtOH, 60:40 with 0.1% EtNH as the mobile phase.

[0636] Peak 1: (S)-3-(3-(1-(4-fluorophenyl)propoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazine-2 -ylamino)-1H-pyrazole-4-carboxamide. Retention time of product = 2.72 min. LCMS (Method A): 2.13 min; m / z: 594.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 12.95 (s, 1H), 9.93 (s, 1H), 9.60 (s, 1H), 9.22 (s, 1H), 8.21 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.56 (q, J = 4.8 Hz, 3H), 7.43 (d, J = 7.2 Hz, 1H), 7.18-7.10 (m, 5H), 5.40 (s, 1H), 4.48 (q, J = 6.4 Hz, 2H), 2.08-2.02 (m, 1H), 1.88-1.81 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H).

[0637] Peak 2: (R)-3-(3-(1-(4-fluorophenyl)propoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide. Retention time of product = 7.29 min. LCMS (Method A): 2.13 min; m / z: 594.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 12.93 (s, 1H), 9.91 (s, 1H), 9.60 (s, 1H), 9.22 (s, 1H), 8.21 (s, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.57 (q, J = 4.8 Hz, 3H), 7.41 (d, J = 8.0 Hz, 1H), 7.18-7.09 (m, 5H), 5.38 (s, 1H), 4.46 (q, J = 5.6 Hz, 2H), 2.07-2.02 (m, 1H), 1.87-1.80 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H).

[0638] compound 233 [ka]

[0639] Step 1: 3-[4-(Difluoromethanesulfonamido)-3-[1-(4-fluorophenyl)propoxy]phenyl]-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A solution of 3-{4-amino-3-[1-(4-fluorophenyl)propoxy]phenyl}-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (420 mg, 726 μmol) and FCHSOCl (141 mg, 943 μmol) in CHCl:pyridine (2:1, 15 mL) was stirred at room temperature for 5 minutes. The reaction mixture was concentrated, and the crude residue was purified by silica gel column chromatography (PE:EtOAc, 5:1 to 0:1) to give the title product (190 mg, 37%) as a brown solid. LCMS (Method A): 4.10 min; m / z: 692.2 [M+H] + .

[0640] Step 2: 3-[4-(difluoromethanesulfonamido)-3-[1-(4-fluorophenyl)propoxy]phenyl]-5-[(pyrazin-2-yl)amino]-1H-pyrazole-4-carboxamide A solution of 3-[4-(difluoromethanesulfonamido)-3-[1-(4-fluorophenyl)propoxy]phenyl]-5-[(pyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (190 mg, 274 μmol) in DCM:TFA (1:1, 6 mL) was stirred at room temperature for 5 minutes. The reaction mixture was neutralized to pH 7-8 with NH4OH and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to give the title product (7.9 mg, 5%) as a white solid. LCMS (Method A): 3.57 min; m / z: 562.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6): 12.96 (s, 1H), 10.52 (br s, 1H), 9.53 (s, 1H), 9.19 (s, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.58-7.46 (m, 2H), 7.38 (d, J = 7.2 Hz, 1H), 7.22-7.06 (m, 4H), 6.10 (br s, 1H), 5.39 (s, 1H), 2.10-1.94 (m, 1H), 1.93-1.76 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H).

[0641] Compounds 272 and 273 [ka]

[0642] Racemic compound 233 (232 mg) was purified by chiral HPLC. Separation was performed on a UniChiral CMD-5H column (column dimensions: 21.2 mm ID x 250 mm length, mobile phase: 100% ethanol, flow rate: 12 mL / min, temperature: 25 °C). The enantiomeric excess was calculated using a UniChiral CMD-5H, 4.6*250 mm (100% MeOH, flow rate: 1 mL / min, injection: 10 μL, temperature: 25 °C).

[0643] Peak 1: (R)-3-(4-((difluoromethyl)sulfonamido)-3-(2-(4-fluorophenyl)-3-methoxypropyl)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (91 mg, retention time 5.89 min, ee>99%).

[0644] Peak 2: (S)-3-(4-((difluoromethyl)sulfonamido)-3-(2-(4-fluorophenyl)-3-methoxypropyl)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (114 mg, retention time 11.92 min, ee>99%).

[0645] Compounds 299 and 300 [ka]

[0646] Racemic compound 298 was purified by chiral SFC separation (Chiralpak IG 4.6*100mm 3 μm, CO2:methanol 55:45, 130 bar, flow rate 2.5 mL / min).

[0647] Peak 1: (R)-3-(4-((difluoromethyl)sulfonamido)-3-(1- (4-Fluorophenyl)-2-methoxyethoxy)phenyl)-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide.

[0648] Peak 2: (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide.

[0649] compound 264 [ka]

[0650] Step 1: 3-{4-amino-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl}-5-[(5-methylpyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A mixture of 3-bromo-5-[(5-methylpyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (Intermediate B6, 300 mg, 0.70 mmol), 2-[(1S)-1-(4-fluorophenyl)ethoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (250 mg, 0.70 mmol), Pd(dppf)Cl (57.3 mg, 0.07 mmol), NaCO (222 mg, 2.10 mmol), and 80% aqueous 1,4-dioxane (25 mL) was stirred under N at 100 °C for 16 h. The reaction mixture was concentrated, and the residue was diluted with HO (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed (brine), dried (NaSO), and concentrated. The crude residue was purified by preparative TLC (DCM:MeOH, 20:1) to give the title product (220 mg, 54%) as a yellow solid. LCMS (Method A): 2.86 min; m / z: 578.3 [M+H] + .

[0651] Step 2: 3-{3-[(1S)-1-(4-fluorophenyl)ethoxy]-4-(2,2,2-trifluoroethanesulfonamido)phenyl}-5-[(5-methylpyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide A solution of 3-{4-amino-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl}-5-[(5-methylpyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole 4-carboxamide (210 mg, 0.36 mmol) and 2,2,2-trifluoroethane-1-sulfonyl chloride (99 mg, 0.54 mmol) in DCM:pyridine (3:1, 20 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was purified by preparative TLC (DCM:MeOH, 20:1) to give the title product (150 mg, 57%) as a yellow solid. LCMS (Method A): 3.37 min; m / z: 724.2 [M+H] + .

[0652] Step 3: 3-{3-[(1S)-1-(4-fluorophenyl)ethoxy]-4-(2,2,2-trifluoroethanesulfonamido)phenyl}-5-[(5-methylpyrazin-2-yl)amino]-1H-pyrazole-4-carboxamide (Compound 264) A solution of 3-{3-[(1S)-1-(4-fluorophenyl)ethoxy]-4-(2,2,2-trifluoroethanesulfonamido)phenyl}-5-[(5-methylpyrazin-2-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbo...

Claims

1. Compounds of formula (I) or pharmaceutically acceptable salts, solvates, tautomers, N-oxides, stereoisomers and / or prodrugs thereof 【Chemistry 1】 [In the formula, Q １ and Q ２ is N and NR １ is selected from １ When is N, Q ２ is NR １ and Q ２ When is N, Q １ is NR １ and R １ and R ３ is H and optionally substituted C １～６ -alkyl; R ２ is an optionally substituted C １～６ - alkyl, optionally substituted aryl or optionally substituted heterocyclyl; X is an optionally substituted C １～６ alkyl, optionally substituted haloC １～６ Alkyl, optionally substituted C ２～６ Alkynyl, optionally substituted cycloalkyl, optionally substituted halocycloalkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted C １～６ selected from alkylcycloalkyl and optionally substituted amino; Y and Z are H, R ４ , -OR ４ , -NR ４ R ５ and at least one of Y and Z is H; R ４ is an optionally substituted C １～６ alkyl, optionally substituted aryl, optionally substituted C １～６ alkylaryl, optionally substituted heterocyclyl, optionally substituted C １～６ alkylheterocyclyl, optionally substituted cycloalkyl, optionally substituted C １～６ Alkyl C ３～１０ Cycloalkyl, optionally substituted C ３～１０ Cycloalkylaryl, optionally substituted C ３～１０ Cycloalkylheterocyclyl, optionally substituted C ３～１０ Cycloalkyl C ３～１０ Cycloalkyl, optionally substituted 3- to 6-membered non-aromatic heterocyclyl-aryl, optionally substituted 3- to 6-membered non-aromatic heterocyclylC ３～１０ cycloalkyl and optionally substituted 3- to 6-membered non-aromatic heterocyclyl-3- to 10-membered heterocyclyl; R ５ is H or optionally substituted C １～６ alkyl].

2. X is C １～６ Alkyl, C ２～６ Alkynyl, C ３～６ Cycloalkyl, aryl, -(CH ２ ) ｎ Aryl, -(CH ２ ) ｎ cycloalkyl, and —N(R ７ ) R ８ is selected from n is 1 or 2; Alkyl and alkynyl are each independently selected from halo, nitrile, -OR ６ , -N(R ７ ) R ８ and optionally substituted with one or more groups selected from R ６ , R ７ and R ８ is H, C １～６ Alkyl and HaloC １～６ alkyl; Aryl and cycloalkyl are each independently selected from halo, nitrile, C １～４ Alkyl, C １～４ Alkoxy, HaloC １～４ Alkyl and HaloC １～４ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer and / or prodrug thereof, optionally substituted with one or more groups independently selected from alkoxy.

3. R ４ But C １～６ Alkyl, aryl, cycloalkyl, heterocyclyl, C １～６ Alkyl C ３～１０ Cycloalkyl, C １～６ Alkylaryl and C １～６ alkylheterocyclyl; Each alkyl is a halo, C １～４ Alkoxy, hydroxy, nitrile, amino, C １～４ alkylamino, (C １～４ alkyl) ２ optionally substituted with one or more groups independently selected from amino, aryl, cycloalkyl, and heterocyclyl; Aryl is halo, hydroxy, nitrile, amino, C １～４ alkylamino, (C １～４ alkyl) ２ Amino, C １～４ Alkyl, C １～４ Alkoxy, HaloC １～４ Alkyl, haloC １～４ optionally substituted with one or more groups independently selected from alkoxy, aryl, cycloalkyl, and heterocyclyl; Cycloalkyl is selected from halo, hydroxy, nitrile, amino, C １～４ alkylamino, (C １～４ alkyl) ２ Amino, C １～４ Alkyl, C １～４ Alkoxy, HaloC １～４ Alkyl, haloC １～４ optionally substituted with one or more groups independently selected from alkoxy, aryl, cycloalkyl, and heterocyclyl; Heterocyclyl is selected from halo, hydroxy, nitrile, amino, C １～４ alkylamino, (C １～４ alkyl) ２ Amino, C １～４ Alkyl, C １～４ Alkoxy, HaloC １～４ Alkyl, haloC １～４ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, optionally substituted with one or more groups independently selected from alkoxy, cycloalkyl, heterocyclyl and aryl.

4. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, wherein Z is H.

5. Y is -OR ４ , -NR ４ R ５ 5. The compound of claim 4, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, selected from:

6. R ４ or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, wherein 【Chemistry 2】 [In the formula, R ｄ is H, optionally substituted C １～４ Alkyl, optionally substituted C １～４ Alkoxy, optionally substituted C １～４ Alkoxy C １～４ Alkyl, optionally substituted C １～４ alkylhydroxy, optionally substituted C １～４ Alkylnitriles, optionally substituted C １～４ alkylamino, optionally substituted (C １～４ Archi L) ２ Amino, optionally substituted cycloalkyl and optionally substituted C １～４ alkylcycloalkyl; R ｅ is an optionally substituted aryl, an optionally substituted C １～５ alkylaryl, optionally substituted heterocyclyl, optionally substituted C １～５ Alkylheterocyclyl, optionally substituted cycloalkyl and optionally substituted C １～５ Alkyl C ３～１０ cycloalkyl].

7. R ｄ is optionally substituted C １～４ alkyl, and R ｄ and R ｅ is enriched in the (S) stereoisomer, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof.

8. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, wherein Y and Z are H.

9. R ２ is selected from optionally substituted phenyl, optionally substituted 5-membered monocyclic heteroaryl, optionally substituted 6-membered monocyclic heteroaryl, or optionally substituted 10-membered bicyclic heteroaryl, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof.

10. R ２ or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof. 【Transformation 3】 [In the formula, A １ , A ２ , A ３ , A ４ , A ５ , A ６ , A ７ , and A ８ is CR １１ and N, A ９ , A １０ , A １１ and A １２ is C(R １１ ) ｑ , O, S, N and NR １２ are independently selected from A １ , A ２ , A ３ , A ４ and A ５ Two or less of these are N, A ６ , A ７ and A ８ Two or less of these are N, A ９ , A １０ , A １１ and A １２ At least one of C(R １１ ) ｑ , O, S and NR １２ is selected from R １１ are H and R, respectively. １０ are independently selected from R １０ are halo and C, respectively. １～６ Alkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, —OC １～６ Alkyl C １～６ Alkoxy, HaloC １～６ Alkyl, haloC １～６ Alkoxy, nitrile, amide, C １～６ Alkylamide, (C １～６ alkyl) ２ Amide, Halo C １～６ Alkylamide, (halo C １～６ alkyl) ２ Amide, Acyl, C １～６ Alkyl acyl, halo C １～６ Alkyl acyls, arylacyls, heterocyclyl acyls aryl, cycloalkylacyl, heterocyclyl, haloC １～６ Alkoxy, C ３～１０ Cycloalkyl, C １～６ Alkyl C ３～１０ Cycloalkyl, C １～６ Alkoxy C ３～１０ Cycloalkyl, haloC １～６ Alkyl C ３～１０ Cycloalkyl, haloC １～６ Alkoxy C ３～１０ Cycloalkyl, C １～６ Alkylheterocyclyl, C １～６ Alkoxyheterocyclyl, halo C １～６ Alkylheterocyclyl, haloC １～６ Alkoxyheterocyclyl, C １～６ Alkyl C １～６ independently selected from alkoxy, and —COOH; R １２ are H and C, respectively. １～６ Alkyl, haloC １～４ Alkyl, C １～６ Alkyl acyl and halo C １～６ independently selected from alkyl acyl; Or, A １ , A ２ , A ３ , A ４ , A ５ , A ７ , A ８ , A ９ , A １０ , A １１ and A １２ two adjacent groups selected from CR １１ and N.R. １２ When selected from １１ , two R １２ or one R １１ and one R １２ can be taken together to form an optionally substituted 5- to 10-membered ring selected from cycloalkyl, aryl, and heterocyclyl; p is an integer from 0 to 4, q is 1 or 2.

11. R ２ 11. The compound of claim 10, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, represented by the sub-formula Ar1:

12. A １ is N, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof.

13. A ４ is N, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof.

14. A ２ is CR １０ 14. The compound of any one of claims 10 to 13, wherein: or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof.

15. R １ and R ３ is H, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof.

16. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, wherein the compound of formula (I) is a compound of formula (1A): 【Chemistry 4】

17. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, wherein the compound of formula (I) is a compound of formula (1B): 【Transformation 5】

18. The compound is 3-(3-((3,4-difluorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((2-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((3-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((4-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((1-acetylpiperidin-4-yl)methoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-(cyclopentylmethoxy)-4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-methoxypyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)(methyl)amino)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(pyridin-4-ylmethoxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((2-methoxypyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(4-fluorophenoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(benzyloxy)-4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-2-((4-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((3,3-difluoropropyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(4-fluorophenethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(benzyloxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((3-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(pyridin-4-ylmethoxy)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(pyridin-4-ylmethoxy)phenyl) -5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((cyanomethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(pyridin-3-ylmethoxy)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(pyridin-3-ylmethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(pyridin-3-ylmethoxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-isopropylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-(cyclohexylmethoxy)-4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(cyclopentylmethoxy)-4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((3-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((4-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(cyclopentylmethoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((3-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((4-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(benzyloxy)-4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-(cyclohexylmethoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((2,2-difluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((2-methoxyethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide Do, 3-(4-((2-(dimethylamino)ethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(cyclopropanesulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((1-methylethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(((4-fluorophenyl)methyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(((3,4-dichlorophenyl)methyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((p-tolylmethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(((2-chlorophenyl)methyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(((3-chlorophenyl)methyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(((4-chlorophenyl)methyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-methoxyphenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-(pyridazin-3-ylamino)-1H-pyrazole-4-carboxamide, 5-((6-chloroquinoxalin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((5-isopropylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-(quinoxalin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(cyclopropanesulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((1,1-dimethylethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(((4-chlorophenyl)methyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((1-methylethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-(pyrazin-2-ylamino)-3-(4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 5-(pyrazin-2-ylamino)-3-(4-((3-(trifluoromethyl)phenyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(cyclohexanesulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 5-(pyrazin-2-ylamino)-3-(4-(((4-(trifluoromethyl)phenyl)methyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-((phenylmethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-(pyrazin-2-ylamino)-3-(4-((4-(trifluoromethoxy)phenyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 5-(pyrazin-2-ylamino)-3-(4-((4-(trifluoromethyl)phenyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 5-(pyrazin-2-ylamino)-3-(4-(((4-(trifluoromethoxy)phenyl)methyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-((cyclobutylmethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((4-methoxyphenyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-(pyrazin-2-ylamino)-3-(4-(((3-(trifluoromethyl)phenyl)methyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((6-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((4-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-(naphthalen-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-(isoquinolin-3-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((5-methoxypyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-(quinolin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((5-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazole-4-carboxamide, 5-((6-(difluoromethyl)pyridin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((6-methylpyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((4-methoxypyridine-2- yl)amino)-1H-pyrazole-4-carboxamide, 5-((6-ethoxypyridin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(propylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-((2-ethoxypyrimidin-4-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((6-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 5-((4-cyanophenyl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethoxy)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((2-(trifluoromethyl)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, 5-((2-ethoxypyridin-4-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 5-((2-(2,2-difluoroethoxy)pyridin-4-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((6-methoxypyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-(prop-2-yn-1-ylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-((cyanomethyl)sulfonamido)phenyl)-5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((5-fluoro-2-methylpyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, 5-((2,6-dimethylpyridin-4-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((2-methylpyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, 5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-((trifluoromethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((6-methoxypyridin-3-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((2-(dimethylamino)ethyl)sulfonamido)phenyl)-5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, 5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-(N-methylethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((2-methoxy-5-methylpyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, 5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-((2-methoxyethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((2-methoxypyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, 5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((2-methoxypyrimidin-4-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-(phenylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((2-methylpyrimidin-4-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((6-(2-methoxyethoxy)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(((3-chlorophenyl)methyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-((5-(2-methoxyethoxy)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((2-phenylethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-(pyridin-2-ylamino)-3-(4-((p-tolylmethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(phenylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((cyclobutylmethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-(pyridin-2-ylamino)-3-(4-(((4-(trifluoromethoxy)phenyl)methyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-((phenylmethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-(pyrazin-2-ylamino)-3-(4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 5-((7-chloroquinolin-2-yl)amino)-3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-1H-pyrazole-4-carboxamide, 3-(2-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(2-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridine-2 -yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-2-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluoro-2,6-dimethylbenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-(1-(4-fluorophenyl)cyclopropoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)phenyl)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((4-chloro-3-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-(4-fluorophenoxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-(4-fluorophenoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(4-fluorophenoxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((3-chloro-4-fluorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((3,4-difluorobenzyl)oxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(1-phenylcyclopropoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((3-chloro-4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((5-fluoropyridin-2-yl)methoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((4-chlorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methoxypyrazin-2-yl)amino) -1H-pyrazole-4-carboxamide, 5-((5-cyclopropylpyrazin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-methoxypyridin-3-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((3,4-difluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(1-phenylcyclopropoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((4-chlorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((4-chloro-3-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((4-chloro-3-fluorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(3-fluorophenoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(4-chlorophenoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(cyclopropanesulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluoro-2-methylbenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethoxy)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 5-((6-(difluoromethyl)pyridin-2-yl)amino)-3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(2-methoxyethoxy)pyridin-2-yl)amino)-1H-pyridin-2-yl azol-4-carboxamide, 3-(3-((3,4-difluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-(4-fluorophenoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((2,2-difluoroethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 5-((6-(difluoromethyl)pyridin-2-yl)amino)-3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-((2,2-difluoroethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-((5-(tert-butyl)pyrazin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(3-((4-fluorobenzyl)oxy)-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((4-fluorobenzyl)oxy)-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((4-fluorobenzyl)oxy)-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(4-chlorophenoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((2-(trifluoromethyl)pyrimidin-4-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((1-methylpiperidin-3-yl)methoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide, 5-((6-(trifluoromethyl)pyridin-2-yl)amino)-3-(4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(3-((4-chlorobenzyl)oxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-((5-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((2-(trifluoromethyl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide, (R)-3-(4-(ethylsulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((2-(trifluoromethyl)pyrimidin-4-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-methoxypyridin-3-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-methoxypyridin-3-yl)amino)-1H-pyrazole-4-carboxamide, 3-(2-((4-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-(ethylsulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(cyclohexylmethoxy)-4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-2-((4-fluorobenzyl)oxy)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((1-methylpiperidin-4-yl)methoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(3-fluorophenoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-((6-(trifluoromethyl)pyridin-2-yl)amino)-3-(4-((trifluoromethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(3-(2-chlorophenethoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-2-((3-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-2-methoxyphenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-phenethoxyphenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(2-fluorophenethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(3-chlorophenethoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((4-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((3-(trifluoromethoxy)benzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-(trifluoromethoxy)benzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((4-(trifluoromethyl)benzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(3-fluorophenethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-((6-chloroquinolin-2-yl)amino)-3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-((N,N-dimethylsulfamoyl)amino)phenyl)-5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, 5-(4-(ethylsulfonamido)phenyl)-1-methyl-3-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((3-chloro-4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((3,4-difluorobenzyl)oxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-(pyrazin-2-ylamino)-3-(3-(pyridin-2-ylmethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((2-(4-fluorophenyl)propan-2-yl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-(ethylsulfonamido)-3-(1-(pyridin-2-yl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((5-fluoropyridin-2-yl)methoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((1,2,3,4-tetrahydronaphthalen-1-yl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)propoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((4-chlorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((4-chlorobenzyl)oxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-(cyclobutyl(4-fluorophenyl)methoxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 5-((6-cyanopyridin-2-yl)amino)-3-(4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((5-fluoropyridin-2-yl)methoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-((5-fluoropyridin-2-yl)methoxy)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((5-chloropyridin-2-yl)methoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(2-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((4-chlorobenzyl)oxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(1-(4-fluorophenyl)cyclopropoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(3-(1-(4-fluorophenyl)propoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (R)-3-(3-(1-(4-fluorophenyl)propoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(3-(1-(4-chlorophenyl)ethoxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-5-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1-methyl-3-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (R)-3-(2-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (R)-3-(4-((difluoromethyl)sulfonamido)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(3-(1-(3-chlorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 6-((4-carbamoyl-3-(4-((difluoromethyl)sulfonamido)phenyl)-1H-pyrazol-5-yl)amino)picolinamide, 5-((6-cyanopyridin-2-yl)amino)-3-(4-((difluoromethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, (S)-3-(3-(1-(4-chlorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(4-(ethylsulfonamido)-3-(pyridin-2-ylmethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-((5-chloropyridin-2-yl)methoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(1-(4-fluorophenyl)propoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H -pyrazole-4-carboxamide, (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(3-(1-(3-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, 3-(3-(cyclobutyl(4-fluorophenyl)methoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-5-(pyrazin-2-ylamino)-3-(3-(1-(pyridin-2-yl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 5-(pyridin-2-ylamino)-3-(4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 3-(3-((4-chlorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-1H-pyrazole-4-carboxamide, (R)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (R)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-ethylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-(thiazol-2-ylmethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(1-methylcyclopropyl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(oxazol-2-yl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (R)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(oxazol-2-yl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazin zole-4-carboxamide, (S)-5-((5-cyclobutylisoxazol-3-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide, (S)-5-((5-(tert-butyl)isoxazol-3-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((1-methyl-1H-1,2,4-triazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((4,5-dimethylthiazol-2-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)cyclopropoxy)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(3-((3,4-difluorobenzyl)oxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(3-methyloxetan-3-yl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-(1-(oxazol-2-yl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-methoxy-1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-5-((3-(tert-butyl)isoxazol-5-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(tetrahydro-2H-pyran-4- yl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(2-fluoropropan-2-yl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (R)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(4-methyltetrahydro-2H-pyran-4-yl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((3-methylisoxazol-5-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(tetrahydro-2H-pyran-4-yl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-5-((5-(adamantan-1-yl)isoxazol-3-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-((S)-1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(tetrahydrofuran-3-yl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)cyclopropoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((2-methylpyrimidin-4-yl)amino)-1H-pyrazole-4-carboxamide, (S)-5-((5-cyclopropylisoxazol-3-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide, (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, (S)-5-((5-(tert-butyl)pyrazin-2-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-(oxazol-2-ylmethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-5-((5-(difluoromethyl)isoxazol-3-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide, (S)-6-((4-carbamoyl-3-(4-(ethylsulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazol-5-yl)amino)nicotinic acid, (S)-5-((5-cyclopropylpyrazin-2-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide, (S)-3-(4-(ethylsulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-(difluoromethanesulfonamido)-3-((1S)-1-(4-fluorophenyl)ethoxy)phenyl]-5-((5-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)-1H-pyrazole-4-carboxamide, 3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide, (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1-methyl-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide, 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, selected from:

19. A medicament comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof.

20. 19. A pharmaceutical composition comprising a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, and a pharmaceutically acceptable excipient.

21. A method of treating necroptosis, comprising the step of administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, a medicament according to claim 19, or a pharmaceutical composition according to claim 20.

22. The subject is diagnosed with a disease selected from the group consisting of bone, joint, connective tissue and cartilage diseases, muscle diseases, skin diseases, cardiovascular diseases, circulatory diseases, blood and vascular diseases, lung diseases, gastrointestinal tract diseases, liver diseases, pancreatic diseases, metabolic diseases, kidney diseases, viral and bacterial infections, severe intoxication, degenerative diseases associated with acquired immune deficiency syndrome (AIDS), age-related disorders, inflammatory diseases, autoimmune diseases, dental disorders, eye diseases or disorders, Eustachian tube diseases, mitochondria-related diseases, neuronal loss, ischemia-reperfusion injury, diseases of the central nervous system, cancer, and metastatic cancer.

22. The method of claim 21, comprising:

23. 20. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, in the manufacture of a medicament for treating necroptosis.

24. 20. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, for use in the treatment of necroptosis.

25. 20. A method of inhibiting mixed lineage kinase domain-like protein (MLKL), comprising contacting a cell with a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof.

26. 19. An MLKL inhibitor comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof.

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