Bifunctional Sulfonamide Compounds

Abstract

The present invention relates to compounds of formula (X), as well as their salts, solvates, tautomers, N-oxides, stereoisomers, polymorphs and / or prodrugs. Use of compounds of formula (X) for treating necroptosis and / or inhibiting and / or degrading MLKL is also disclosed.

Description

[Technical Field]

[0001] cross reference This application claims priority to Australian Provisional Patent Application No. 2021904204 (filed on 22 December 2021), the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to bifunctional sulfonamide compounds that treat necroptosis and / or inhibit and / or degrade mixed lineage kinase domain-like protein (MLKL), and methods of their use. [Background technology]

[0003] In many diseases, cell death is mediated through apoptotic and / or necrotic pathways. While the mechanisms that control apoptosis are well known, the regulation of necrosis is less well understood. Understanding the mechanisms of both necrosis and apoptosis in cells is necessary to be able to treat conditions such as neurodegenerative diseases, stroke, coronary heart disease, kidney disease, liver disease, AIDS, and AIDS-related conditions.

[0004] Cell death has traditionally been classified as either 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 demonstrated that the underlying cell death mechanisms leading to these two phenotypes are much more complex and, under certain circumstances, are 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 by various stimuli (e.g., TNF-alpha and Fas ligand) in a range of cell types (e.g., monocytes, fibroblasts, lymphocytes, macrophages, epithelial cells, and neurons). Necroptosis may 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 present inventors reported that certain compounds described in US2005 / 0085637 were found to be suitable for inhibiting necroptosis. The present inventors also discussed particularly suitable compounds for inhibiting necroptosis in WO2016 / 127213.

[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 that matter forms part of the prior art document or was common general knowledge in the art relevant to the present disclosure as it existed before the priority date of each claim of this application. Summary of the Invention

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

[0010] In one aspect, there is provided a compound according to formula (X): MLKLi-L-E3L (X) During the ceremony, E3L is the E3 ligase binding moiety; L is a linker that covalently connects MLKLi to E3L; MLKLi is a radical of formula (I) [ka] During the ceremony, 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 are independently selected from H and optionally substituted C 1~6 -alkyl, R 2 is an optionally substituted C1-C6-alkyl, an optionally substituted aryl, or an optionally substituted heterocyclyl, X is an optionally substituted C 1~6alkyl, 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 alkylcycloalkyl, and optionally substituted amino; Y and Z are independently H, R 4 , -OR 4 , and -NR 4 R 5 , and halo; at least one of Y and Z is H; R 4 independently represents 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, 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 It is alkyl.

[0011] In some embodiments, the compound of Formula (X) is provided as a compound of Formula (XI): [ka] E3L is the E3 ligase binding moiety; L is a linker that covalently connects MLKLi to E3L; 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 are independently selected from H and optionally substituted C 1~6 -alkyl, R 2 is an optionally substituted C1-C6-alkyl, an optionally substituted aryl, or an 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 alkylcycloalkyl, and optionally substituted amino; Y and Z are independently H, R 4 , -OR 4 , and -NR 4 R 5 , and halo; at least one of Y and Z is H; R 4 independently represents an optionally substituted C 1~6 Alkyl, optionally substituted aryl, optionally substituted C 1~6 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1~6Alkylheterocyclyl, 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 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 It is alkyl.

[0012] In any aspect or embodiment described herein, the compound of the invention may be provided in the form of a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

[0013] The present inventors have discovered that compounds of formula (I) are selective degraders of MLKL. Degradation of MLKL may in some cases be preferable to inhibition of MLKL, because degradation results in loss of function of the degraded protein, while the effect of inhibition only lasts as long as the inhibitor interacts with the protein.

[0014] In some embodiments, the compound of the present invention is selected from any of compounds 1001-1014, 1016-1037, 1039-1053, and 1055-1060.

[0015] In some embodiments, the compound of the present invention is selected from any one of compounds 1001-1014 and 1016-1036 described herein, preferably any one of compounds 1001-1014, 1016-1030, 1032-1033, and 1036, and more preferably any one of compounds 1001, 1005, 1007, 1013, 1016, 1019-1021, and 1023-1030.

[0016] In some embodiments, the compounds of the present invention may be prepared by the radical 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 Contains any of the radicals of ~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.

[0017] In another aspect, there is provided a medicament comprising a compound of the invention, and the use of a compound of the invention in the preparation of a medicament, which can be for treating necroptosis, and which can also be for degrading MLKL.

[0018] In another aspect, there is provided a pharmaceutical composition comprising a compound of the invention and, optionally, a pharmaceutically acceptable excipient.

[0019] 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 invention.

[0020] In another aspect, a method of degrading MLKL is provided, comprising contacting a cell with a compound of the invention.

[0021] In another aspect, there is provided a compound of the invention for use in treating necroptosis and for use in degrading MLKL.

[0022] Any embodiment herein shall be deemed to apply mutatis mutandis to any other embodiment unless otherwise stated.

[0023] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention as described herein.

[0024] Throughout this specification, unless otherwise indicated or the context requires a different interpretation, references 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.

[0025] definition Unless otherwise defined herein, the following terms shall be understood to have the following general meanings:

[0026] 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 encompasses alkyl groups containing one less hydrogen atom, such that the group is attached through two positions, i.e., 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.

[0027] The term “C 2~6 "Alkenyl" refers to an optionally substituted straight or branched chain hydrocarbon group having at least one double bond of E or Z stereochemistry, where applicable, and 2 to 6 carbon atoms. Examples include vinyl, 1-propenyl, 1- and 2-butenyl, and 2-methyl-2-propenyl. Unless the context requires otherwise, the term "C 2~6 "Alkenyl" also encompasses alkenyl groups containing one less hydrogen atom, such that the group is attached through two positions, i.e., is divalent. "C" includes ethenyl, propenyl, and butenyl. 2~4 alkenyl" and "C 2~3 Alkenyl is preferred, with ethenyl being particularly preferred.

[0028] 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. Unless the context indicates otherwise, the term "C 2~6 "Alkynyl" also encompasses alkynyl groups that contain one less hydrogen atom, such that the group is attached through two positions, i.e., is divalent. 2~3 Alkynyl is preferred.

[0029] 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 will be understood that the cycloalkyl group can be saturated, such as cyclohexyl, or unsaturated, such as cyclohexenyl. C 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.

[0030] The terms "hydroxy" and "hydroxyl" refer to the group --OH.

[0031] The term "oxo" refers to the group =O.

[0032] The term “C 1~6 "Alkoxy" refers to an alkyl group as defined above covalently bonded through an O bond, containing 1 to 6 carbon atoms, 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.

[0033] 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 For example, haloC such as -CH2CF3 and -CF3 1~3 Alkyl groups are preferred.

[0034] 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.

[0035] The terms "carboxylate" or "carboxyl" refer to a -COO- or -COOH group.

[0036] The term "ester" refers to an ester in which the hydrogen is, for example, C 1~6 Alkyl group (carboxyl group) 1~6 It refers to a carboxyl group substituted with an alkyl group ("alkyl" or "alkyl ester"), an aryl group, or an aralkyl group ("aryl ester" or "aralkyl ester"). For example, CO2C esters such as methyl ester (CO2Me), ethyl ester (CO2Et), and propyl ester (CO2Pr) 1~3 Alkyl groups are preferred, including their reverse esters (e.g., -OC(O)Me, -OC(O)Et, and -OC(O)Pr).

[0037] The terms "cyano" and "nitrile" refer to the group --CN.

[0038] The term "nitro" refers to the group --NO.sub.2.

[0039] The term "amino" refers to the group --NH.sub.2.

[0040] 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 "amino group" refers to an amino group in which a single hydrogen has been replaced by, for example, a 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 Substituted amino groups include alkylamino groups, where both hydrogens are, for example, C 1~6Also 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.

[0041] The term "aldehyde" refers to the group -C(=O)H.

[0042] The terms "acyl" and "acetyl" refer to the group -C(O)CH3.

[0043] The term "ketone" refers to a carbonyl group which may be represented by -C(O)-.

[0044] The term "substituted ketone" refers to a ketone having at least one additional group, such as C 1~6 Alkyl group ("C 1~6 C 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.

[0045] The terms "amido" or "amide" refer to the group -C(O)NH2.

[0046] The term "substituted amido" or "substituted amide" refers to an amide where the hydrogen is replaced by, for example, C 1~6 Alkyl group ("C 1~6 Alkylamide" or "C 1~6It 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) are used. 1~3 Alkyl amide groups are preferred, including their reverse amides (eg, -NHMeC(O)-, -NHEtC(O)-, and -NHPrC(O)-).

[0047] The term "disubstituted amido" or "disubstituted amide" refers to a group in which two hydrogens are replaced by, for example, C 1~6 Alkyl group (di(C 1~6 alkyl)amide" or "di(C 1~6 This refers to an amide group substituted with an aryl group, such as an aryl group ("alkyl(aralkyl)amide"), an aralkyl group, and an alkyl group ("alkyl(aralkyl)amide"). For example, di(C(O)amide such as dimethylamide (-C(O)NMe2), diethylamide (-C(O)NEt2), and dipropylamide (-C(O)NPr2), and variations thereof (e.g., -C(O)N(Me)Et, etc.). 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).

[0048] The term "thiol" refers to the group --SH.

[0049] The term “C 1~6 "Alkylthio" is a group where hydrogen is C 1~6 Refers to a thiol group substituted with an alkyl group. For example, C groups such as thiolmethyl, thiolethyl, and thiolpropyl. 1~3 Alkylthio groups are preferred.

[0050] The term "thioxo" refers to the group ═S.

[0051] The term "sulfinyl" refers to the group -S(=O)H.

[0052] The term "substituted sulfinyl" or "sulfoxide" refers to a group in which the hydrogen is replaced with, 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.

[0053] The term "sulfonyl" refers to the group -SO2H.

[0054] 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 a sulfonyl group substituted with an aryl ("arylsulfonyl"), an aralkyl ("aralkylsulfonyl"), or the like. For example, sulfonyl C groups such as -SOMe, -SOEt, and -SOPr 1~3 Alkyl groups are preferred.

[0055] The terms "sulfonylamido," "sulfonamido," "sulfonamide," "sulfonylamido," "sulphonamido," "sulphonylamide," or "sulphonamide" refer to the group -SO2NH2.

[0056] The terms "substituted sulfonamido", "substituted sulfonamide", "substituted sulphonamido" or "substituted sulphonamide" refer to amides where hydrogen is replaced with, for example, C 1~6 Alkyl groups (e.g., sulfonyl amide C 1~6 "Sulfonyl amide" refers to a sulfonyl amide group substituted with an alkyl group ("aryl sulfonamide"), an aryl group ("aryl sulfonamide"), an aralkyl group ("aralkyl sulfonamide"), or the like. For example, sulfonyl amide C groups such as -SO2NHMe, -SO2NHEt, and -SO2NHPr are also included. 1~3 Alkyl groups are preferred, including their reverse sulfonamides (e.g., -NHSOMe, -NHSOEt, and -NHSOPr). In some embodiments, alkylsulfonamides can be optionally substituted, for example, with halo groups.

[0057] The terms "disubstituted sulfonamido," "disubstituted sulfonamide," "disubstituted sulphonamido," or "disubstituted sulphonamide" refer to a disubstituted sulfonamide in which the two hydrogens are, for example, the same or different, C 1~6 Alkyl group ("sulfonylamide di(C 1~6 It refers to sulfonylamido groups substituted with an alkyl group ("sulfonamido(aralkyl)alkyl"), an aralkyl group, and an alkyl group ("sulfonamido(aralkyl)alkyl"). For example, sulfonylamido di(C) groups such as -SONMe, -SONNEt, -SONPr, and variations thereof (e.g., -SON(Me)Et, etc.) are included. 1~3 Alkyl) groups are preferred, including their reserve sulfonamide (e.g., -N(Me)SO2Me, etc.).

[0058] The term "sulfate" refers to the group OS(O)OH, where the hydrogen is, for example, C 1~6 These include 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.

[0059] The term "sulfonate" refers to a SO3H group, where the hydrogen is, for example, C 1~6 These include groups substituted with alkyl groups ("alkyl sulfonates"), aryl groups ("aryl sulfonates"), aralkyl groups ("aralkyl sulfonates"), etc. For example, C groups such as SO3Me, SO3Et, and SO3Pr. 1~3 Sulfonates are preferred.

[0060] The term "aryl" refers to a carbocyclic (non-heterocyclic) aromatic ring system, or a monocyclic, bicyclic, or tricyclic ring system. Polycyclic ring systems may be referred to as "aryl" provided that at least one of the rings in the system is aromatic. Aromatic rings or ring systems generally consist 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.

[0061] The term "alkoxyaryl" refers to C aryls such as benzyloxy. 1~6 It refers to alkyloxyaryl.

[0062] The term "heterocyclyl" refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has (unless otherwise specified) 3 to 10 ring atoms, 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 spiro ring systems, provided that at least one of the rings in the ring system contains at least one heteroatom.

[0063] 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, the term "3- to 10-membered heterocyclyl" as used herein pertains 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.

[0064] 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, for example, 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, for example, 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); 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).

[0065] Heterocyclyl includes aromatic and non-aromatic heterocyclyl. Such groups can be substituted or unsubstituted.

[0066] 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.

[0067] 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 of the 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, the group may be attached to another moiety by either the aromatic ring or the non-aromatic ring.

[0068] Examples of heteroaryl groups are 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 typically contain up to about four heteroatoms 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., a single heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in a heteroaryl ring can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogens. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, will be less than five.

[0069] An aromatic heterocyclyl group can be a 5- or 6-membered monocyclic aromatic ring system.

[0070] 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.

[0071] 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).

[0072] 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 a nitrogen atom fused to a phenyl ring, or 5-membered aromatic heterocyclyls containing one or two nitrogen atoms fused to a phenyl ring.

[0073] 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 1- or 2-membered ring fused to a 5- or 6-membered ring containing one or 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; l) 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.

[0074] Particular examples of bicyclic heteroaryl groups containing a 5-membered ring fused to another 5-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).

[0075] Specific examples of bicyclic heteroaryl groups containing a 6-membered ring 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. A further 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.

[0076] Specific 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.

[0077] 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.

[0078] Thus, examples of aromatic heterocyclyls fused to a carbocyclic aromatic ring can 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.

[0079] 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 may contain 1, 2, or 3 heteroatoms. The ring may 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.

[0080] The non-aromatic heterocyclyl can be a 3- to 7-membered monocyclic ring.

[0081] 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.

[0082] Examples of 6-membered non-aromatic heterocyclyls include piperidinyl, piperidinoyl, pyranyl, dihyrdopyranyl, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, thianyl, thianyloxide, thianyldioxide, 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.

[0083] Examples of 7-membered non-aromatic heterocyclyls include azepanyl, oxepanyl, thiepanyl, and the like.

[0084] 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.

[0085] The term "halo" refers to fluoro, chloro, bromo, or iodo.

[0086] Unless otherwise defined, the term "optionally substituted" or "optional substituent" as used herein means any of the groups defined in 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 one, two, three, four or more groups, preferably one, two or three, more preferably one or two groups, selected from the group consisting of alkyl, heterocyclyl, and heteroaryl, and each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, and groups containing them, may be further optionally substituted. 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.

[0087] Optionally substituted "C 1~6 Alkyl," "C 2~6 alkenyl," and "C 2~6 For "alkynyl," the one or more optional substituents 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 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, HaloC1~6 Alkoxy, halo, hydroxyl, and carboxyl are preferred.

[0088] It will be appreciated that suitable derivatives of nitrogen-containing aromatic heterocyclyls include their N-oxides.

[0089] 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 moiety (or both, in the case of diradical species). The direction of attachment of such hybrid radicals can be indicated by the inclusion of the 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 moiety, and "alkylaryl-" or "-arylalkyl" indicates that the point of attachment is through the aryl moiety.

[0090] As used herein, 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.

[0091] 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" may include plural salts, reference to "at least one heteroatom" may include one or more heteroatoms, etc.

[0092] The term "and / or" can mean "and" or "or."

[0093] The term "(s)" following a noun contemplates either the singular or the plural, or both.

[0094] 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, therefore, should 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.

[0095] Further aspects of the invention, and further embodiments of the aspects described in the preceding paragraphs, will become apparent from the following description, given by way of example, and with reference to the accompanying drawings, in which: DETAILED DESCRIPTION OF THE INVENTION

[0096] The present invention relates to a compound of formula (X): MLKLi-L-E3L (X) During the ceremony, E3L is an E3 ligase binding moiety; L is a linker that covalently attaches MLKLi to E3L; MLKLi is a radical of formula (I), [ka] During the ceremony, Q 1 and Q 2 However, N and NR 1 Selected from Q 1 When N, Q 2 NR 1 and Q 2 When N, Q 1 NR 1 and R 1 and R 3 independently H and optionally substituted C 1~6 -alkyl, R 2 optionally substituted C 1~6 -alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; X is 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 alkylcycloalkyl, and optionally substituted amino; Y and Z are independently H, R 4 , -OR 4 , -NR 4 R 5 and halo; at least one of Y and Z is H; R 4 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 heterocyclylC3~10 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 is alkyl, Provided are compounds, or pharmaceutically acceptable salts, solvates, tautomers, N-oxides, stereoisomers, and / or prodrugs thereof.

[0097] MLKLi In the compounds of the present invention, MLKLi is a radical of the compound of formula (I).

[0098] Various embodiments of compounds of formula (I) are described below. It will be understood that in compounds of formula (X) of the present invention, any of the compounds described herein capable of MLKL binding can be included as the MLKLi moiety.

[0099] In some embodiments, a compound of formula (I) is provided: [ka] During the ceremony, 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 are independently selected from H and optionally substituted C 1~6 -alkyl, R 2 is an optionally substituted C1-C6-alkyl, an optionally substituted aryl, or an optionally substituted heterocyclyl, X is an optionally substituted C 1~6 alkyl, optionally substituted haloC1~6 Alkyl, optionally substituted C 2~6 Alkynyl, optionally substituted cycloalkyl, optionally substituted halocycloalkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted C 1~6 alkylcycloalkyl, and optionally substituted amino; Y and Z are independently H, R 4 , -OR 4 , -NR 4 R 5 and halo; at least one of Y and Z is H; R 4 independently represents 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 It is alkyl.

[0100] In some embodiments, X is C 1~6 Alkyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, aryl, -(CH2) n Aryl, -(CH2) n Cycloalkyl, and -N(C 1~4 alkyl)2; During the ceremony, n is 1 or 2, Each alkyl and alkynyl is 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 are independently H, C 1~6 Alkyl and haloC 1~6 alkyl, Each aryl and cycloalkyl may independently be selected from halo, nitrile, C 1~4 Alkyl, C 1~4 Alkoxy, HaloC 1~4 Alkyl and haloC 1~4 Optionally substituted with one or more groups selected from alkoxy.

[0101] [ka] It will be understood that denotes a single or double bond. For example, [ka] The 5-membered heterocyclyl depicted in formula (I) having the formula: is a pyrazole which can adopt one of two isomeric forms.

[0102] 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]

[0103] In some embodiments, Q 2 is NR 1 and Q 1 is N. In these embodiments, the compound of formula (I) may be a compound of formula (1B). [ka]

[0104] 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.

[0105] 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 C alkylaryl, optionally substituted haloC alkylaryl, optionally substituted haloC alkoxyaryl, optionally substituted benzyl, optionally substituted halobenzyl, optionally substituted C alkylbenzyl, optionally substituted C alkoxybenzyl, and optionally substituted haloC alkoxybenzyl.

[0106] In some embodiments, X is optionally substituted C 1~4 alkyl, optionally substituted haloC 1~4 Alkyl, and C 3~6 cycloalkyl.

[0107] In some embodiments, X is optionally substituted C 1~2 alkyl, optionally substituted haloC 1~2 alkyl, and C3 cycloalkyl.

[0108] In some embodiments, X is an optionally substituted haloC selected from -CHF2, -CF3, -CH2CF3, -CH2CHF2, and -CH2CH2CF3. 1~4 It is alkyl.

[0109] In some embodiments, X is an optionally substituted amino, preferably —N(C 1~4 In some embodiments, X is a disubstituted amino such as —N(CH 3 ) 2 .

[0110] In some embodiments, X is selected from any one of the following groups: Methyl, ethyl, isopropyl, tert-butyl, -CHF2, -CF3, -CH2CF3, -CH2CHF2, -CH2CH2CF3, -CH2CH2OCH3, -CH2CH2NH2, -CH2CH2N(CH3)2, cyclohexyl, cyclopropyl, -N(CH3)2, [ka]

[0111] In some embodiments, X is selected from any one of the following groups: ethyl, difluoromethyl, trifluoroethyl, and cyclopropyl.

[0112] In some embodiments, X is C 1~4 Alkyl and C 1~4 Fluoroalkyl, preferably selected from -CHF2, -CH2CF3, and -CH2CH3.

[0113] In some embodiments, X is difluoromethyl.

[0114] In some embodiments, X is a group having a longest linear 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 linear 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 linear 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 linear chain is 3. The longest linear chains for each of these exemplary X-substituents are numbered in the subformulas shown below. [ka]

[0115] In some embodiments, Y and Z are independently H, R 4 , -OR 4 , -NR 4 R 5 and halo, and at least one of Y and Z is H; and 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.

[0116] In some embodiments, the halo in Y and Z is fluoro.

[0117] In some embodiments, Y and Z are independently H, R 4 , -OR 4 , -NR 4 R 5 and fluoro, and at least one of Y and Z is H.

[0118] In some embodiments, Y and Z are independently H, R 4 , -OR 4 , -NR 4 R 5 and at least one of Y and Z is H;

[0119] R 4 is C 1~6 Alkyl, 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) independently represents halo, C 1~4 Alkoxy, hydroxy, nitrile, amino, C 1~4 Alkylamino, (C 1~4 alkyl)2 optionally substituted with one or more groups selected from amino, aryl, cycloalkyl, and heterocyclyl; Each aryl (including when present as an optional substituent) independently represents 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 selected from alkoxy, aryl, cycloalkyl, and heterocyclyl; Each cycloalkyl (including when present as an optional substituent) independently represents 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 1~4optionally substituted with one or more groups selected from alkoxy, aryl, cycloalkyl, and heterocyclyl; Each heterocyclyl (including when present as an optional substituent) independently represents 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 It is optionally substituted with one or more groups selected from alkoxy, cycloalkyl, heterocyclyl, heterocyclyl, and aryl.

[0120] 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 each cycloalkyl, aryl, and heterocyclyl is independently 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 haloC 1~4 Optionally substituted with one or more groups selected from alkoxy.

[0121] In some embodiments, Y and Z are independently H, R 4 , -OR 4 , -NR4 R 5 and at least one of Y and Z is H; R 4 is C 1~6 Alkyl, aryl, cycloalkyl, heterocyclyl, and -(CH2) m R 9 is selected from R 9 is C 3~10 selected from cycloalkyl, aryl, heterocyclyl; m is an integer selected from 1 to 6; Each cycloalkyl, aryl, and heterocyclyl independently is selected from halo, C 1~4 Alkyl, C 1~4 Alkoxy, HaloC 1~4 Alkyl and haloC 1~4 Optionally substituted with one or more groups selected from alkoxy.

[0122] In some embodiments, Y and Z are independently H, R 4 , -OR 4 , -NR 4 R 5 and at least one of Y and Z is H; R 4 is 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 1~2Alkylarylhaloalkoxy, 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; Each alkyl, cycloalkyl, aryl, aralkyl, non-aromatic heterocyclyl, heteroaryl, and alkoxy is optionally substituted with 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 It is optionally substituted with a group selected from alkoxy, and acyl.

[0123] In some embodiments, Y and Z are independently H and —OR 4 is selected from.

[0124] In some embodiments, Z is H.

[0125] In some embodiments, Y is H, R 4 , -OR 4 , -NR 4 R 5 is selected from.

[0126] In some embodiments, Z is H and Y is R 4 , -OR 4 , -NR 4 R 5 is selected from.

[0127] In some embodiments, Z is H and Y is -OR4 is.

[0128] 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.

[0129] In some embodiments, R 4 is an optionally substituted C1 alkylC6 aryl moiety represented by the subformula: [ka] During the ceremony, R a and R b are independently 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, 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.

[0130] In some embodiments, R a and R b are independently H, optionally substituted C 1~4Alkyl, 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 selected from the group consisting of alkyl, 2-amino, a and / or R b is optionally substituted with C 1~4 When it is alkylamino, C 1~4 The alkyl or amino moieties may be optionally substituted.

[0131] In some embodiments, R a and R b together with the carbon atoms to which they are attached, optionally substituted C 3~6 cycloalkyl, or a 3- to 6-membered non-aromatic heterocyclyl selected from optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted oxetane, and optionally substituted azetidine.

[0132] In some embodiments, R a and R b together with the carbon atom to which they are attached form a 3- to 6-membered non-aromatic heterocyclyl containing 1 or 2, preferably 1, heteroatom, preferably selected from O and N.

[0133] In some embodiments, m is 0 or 1.

[0134] In some embodiments, m is 1 or 2.

[0135] In some embodiments, at least one R cis in the para position relative to the benzylic carbon atom.

[0136] In some embodiments, R c is selected from methyl, fluoro, and chloro.

[0137] In some embodiments, R a is selected from H and methyl; R b is H.

[0138] In some embodiments, R a and R b together with the carbon atom to which they are attached is cyclopropyl.

[0139] In some embodiments, R 4 -CR a R b heteroaryl, and 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 or optionally substituted thiazolyl.

[0140] In some embodiments, Y is -OR 4 , -NR 4 R 5 is selected from.

[0141] In some embodiments, Y is -OR 4 , -NR 4 R 5 R when selected from 4 has a partial structure (A), [ka] During the ceremony, 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, 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.

[0142] In some embodiments, R d is methyl.

[0143] In some embodiments, R e is an optionally substituted aryl, 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.

[0144] In some embodiments, Re is selected from optionally substituted aryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl.

[0145] In some embodiments, R e is selected from optionally substituted aryl and optionally substituted heteroaryl.

[0146] In some embodiments, R d is an optionally 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, then substructure (A) is d and R e may 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 optionally substituted C 1~4 alkyl, and R d and R eis enriched as the (S) stereoisomer. The inventors have surprisingly found that compounds having the (S) configuration at this position possess 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 can be at least about five-fold or about ten-fold more active for MLKL inhibition than the corresponding R-stereoisomer.

[0147] 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.

[0148] In some embodiments, the compound of formula (I) is provided as a compound of formula (SI): [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 is selected from.

[0149] In some embodiments, R 4 is selected from any one of the following groups: [ka] [ka]

[0150] In some embodiments, R 4 teeth, [ka] is.

[0151] In some embodiments, R 5 is selected from H and methyl.

[0152] In some embodiments, R 5 is H.

[0153] In some embodiments, Y is H.

[0154] In some embodiments, Z is H.

[0155] In some embodiments, Y and Z are both H.

[0156] In some embodiments, R 1 and R 3 is H.

[0157] 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.

[0158] 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.

[0159] In some embodiments, R 2is represented by any one of the sub-formulas Ar1 to Ar3, [ka] During the ceremony, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 is independently 11 and N, A 9 , A 10 , A 11 , and A 12 are independently C(R 11 ) q , O, S, N, and NR 12 is selected from A 1 , A 2 , A 3 , A 4 , and A 5 At most two of are N, A 6 , A 7 , and A 8 At most two 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 Each R 11 are independently H and R 10 is selected from Each R 10 independently, halo, C 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 1~6Alkylamides, (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, 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, HaloC 1~6 Alkylheterocyclyl, HaloC 1~6 Alkoxyheterocyclyl, C 1~6 Alkyl C 1~6 alkoxy, and —COOH; Each R 12 are independently H, C 1~6 Alkyl, HaloC 1~4 Alkyl, C 1~6 Alkyl acyl and halo C 1~6 alkyl acyls; 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 (e.g., A 1 and A 2 , A 2 and A 3 , A 3 and A 4 , A 4 and A5 , A 8 and A 7 , A 9 and A 10 , A 10 and A 11 , A 11 and A 12 ) but CR 11 and NR 12 When selected from 11 , 2 R 12 , or one R 11 and one R 12 together can 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.

[0160] In some embodiments, A 1 , A 2 , A 3 , A 4 , and A 5 0, 1, or 2 of are N.

[0161] In some embodiments, A 6 , A 7 , and A 8 0, 1, or 2 of are N.

[0162] 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.

[0163] In some embodiments, the compound is R 10 This includes no more than one, two, three, or four instances of:

[0164] In some embodiments, R 2 is represented by the sub-formula Ar1.

[0165] In some embodiments, R 2 is represented by the sub-formula Ar3.

[0166] In some embodiments, A 10 is NR 12 and A 12 is CR 11 is.

[0167] In some embodiments, A 9 and A 11 is independently 11 , N, O, and S. In some embodiments, A 9 is CR 11 When A 11 is N, O, or S, and A 9 is N, O, or S, then A 11 is CR 11 is.

[0168] In some embodiments, A 9 and A 11 are CR 11 is.

[0169] In some embodiments, A 10 and A 12 are CR 11 is.

[0170] In some embodiments, A 9 , A 10 , A 11 , and A 12 At least one of is O, S, N, and NR 12 is selected from.

[0171] In some embodiments, A 9 , A 10 , A 11 , and A 12 One of the groups is O, S, and NR. 12 is selected from.

[0172] In some embodiments, the subformula Ar3 is provided by any one of the subformulas Ar3-I, Ar3-II, Ar3-III, and Ar3-IV: [ka] During the ceremony, 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 NR 12 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 is selected from.

[0173] In some embodiments, A 10 and A 11 is two R 11 , 2 R 12 , or R 11 and R 12 independently, CR, so that together form a 5- to 10-membered cycloalkyl, aryl, or heterocyclyl ring; 11 and NR 12 is selected from.

[0174] In some embodiments, A 10 is CR 11 and A 11 is NR 12 and R 11 and R 12together form a 5-10 membered cycloalkyl, aryl, or heterocyclyl ring. In these embodiments, A 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 together form a 5- to 10-membered heterocyclyl ring, preferably a non-aromatic heterocyclyl ring. 10 is CR 11 and A 11 NR 12 When R 11 and R 12 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.

[0175] Two R on adjacent ring atoms 11 , 2 R 12 , or one R 11 and R 12 When R forms a condensed ring, the condensed ring is 10 Any R group described herein may be optionally substituted. 10 groups may be suitable.

[0176] In some embodiments, R 12 is methyl.

[0177] 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.

[0178] In some embodiments, A 1 is N.

[0179] In some embodiments, A 4 is N.

[0180] In some embodiments, A 1 and A 4 is N.

[0181] In some embodiments, A 2 is N.

[0182] In some embodiments, A 1 and A 3 is N.

[0183] In some embodiments, A 2 is CR 10 is.

[0184] In some embodiments, A 6 is N.

[0185] In some embodiments, A 7 is N.

[0186] In some embodiments, A 6 and A 7 is N.

[0187] 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 2When is a 10-membered heteroaryl, it is a fused bicyclic ring system.

[0188] 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.

[0189] In some embodiments, 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. Typically, when a substituent is present, it is selected from R 2 is attached to the nitrogen atom at the meta or para position (e.g., A in subformula Ar1) 2 or A 3 (corresponding to the position shown for

[0190] In some embodiments, R 2 is selected from any one of the following radicals: Methyl, [ka] [ka] [ka]

[0191] In some embodiments, R 2 is selected from any one of the following radicals: [ka]

[0192] In some embodiments of the compounds of Formula (I), X is optionally substituted C 1~4 alkyl, optionally substituted haloC 1~4Alkyl 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.

[0193] In some embodiments of the compounds of Formula (I), X is an optionally substituted haloC 1~4 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.

[0194] In some embodiments, the compound of the present invention is selected from any of compounds 1001-1014, 1016-1037, 1039-1053, and 1055-1060 described herein.

[0195] In some embodiments, the compound of the present invention is selected from any one of compounds 1001-1014 and 1016-1036 described herein, preferably any one of compounds 1001-1014, 1016-1030, 1032-1033, and 1036, and more preferably any one of compounds 1001, 1005, 1007, 1013, 1016, 1019-1021, and 1023-1030.

[0196] 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, 173-174, 175-176, 177-178, 179-180, 181-182, 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, 200-2011, 201-202, 202-203, 203-204, 205-206, 207-208, 208-209, 210-211, 211-212, 212-213, 213-214, 214-215, 215-216 71, 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 radicals.

[0197] In some embodiments, MLKLi is R 2 and L are covalently bonded to R 2 is a compound of the formula containing a radical

[0198] In some embodiments, the compound of formula (X) may be provided as a compound of formula (XI): [ka] In the formula, X, R 2 , R 3 , Y, Z, Q 1 , Q 2 , L, and E3L are as defined herein.

[0199] In some embodiments of compounds of Formula (X) or (XI), R 2 is optionally substituted aryl or optionally substituted heterocyclyl.

[0200] In some embodiments, the compound of formula (X) may be provided by the following formula (XII): [ka] In the formula, A 1 ~A 5 are independently N, CR 11 , and CL-E3L; A 1 ~A 5 One of them is the CL-E3L, A 1 , A 2 , A 3 , A 4 , and A 5 At most two of are N, Each R 11 are independently H and R 10 is selected from Each R 10 independently, halo, C 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 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, cycloalkyl acyl, heterocyclyl, halo C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 1~6 Alkyl C 3~10 Cycloalkyl, C 1~6Alkoxy 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, HaloC 1~6 Alkylheterocyclyl, HaloC 1~6 Alkoxyheterocyclyl, C 1~6 Alkyl C 1~6 alkoxy, and -COOH; or A 1 , A 2 , A 3 , A 4 , A 5 Two adjacent groups selected from CR 11 When two R 11 together can form an optionally substituted 5- to 10-membered ring selected from cycloalkyl, aryl, and heterocyclyl.

[0201] A 1 ~A 5 can be defined as any one of embodiments 1 to 4. [Table 1] Embodiments 1 to 3 are preferred.

[0202] In some embodiments, the compound of formula (X) may be provided by the following formula (XIII): [ka] During the ceremony, A 9 , A 10 , A 11 , and A 12 are independently C(R 11 ) q ,O,S,N,NR 12 , C(R 11 )-L-E3L, CL-E3L, and NL-E3L; A 9 , A 10 , A 11 , and A 12 One of them is C(R 11 )-L-E3L, CL-E3L, and NL-E3L; A 9 , A 10 , A 11 , and A 12 At least one of C(R 11 )2, O, S, NR 12 , C(R 11 )-L-E3L; Each R 11 are independently H and R 10 is selected from Each R 10 independently, halo, C 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 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, 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, C 1~6 Alkylheterocyclyl, C 1~6 Alkoxyheterocyclyl, HaloC 1~6Alkylheterocyclyl, HaloC 1~6 Alkoxyheterocyclyl, C 1~6 Alkyl C 1~6 alkoxy, and —COOH; Each R 12 are independently H, C 1~6 Alkyl, HaloC 1~4 Alkyl, C 1~6 Alkyl acyl and halo C 1~6 alkyl acyls; or A 9 , A 10 , A 11 , and A 12 two adjacent groups selected from CR 11 , C(R 11 )-L-E3L, and NR 12 When selected from 11 , 2 R 12 , or one R 11 and one R 12 together can form an optionally substituted 5- to 10-membered ring selected from cycloalkyl, aryl, and heterocyclyl; q is 1 or 2.

[0203] In some embodiments, A 12 is N and A 11 is NL-E3L, A 10 is CR 11 and A 9 is CR 11 is.

[0204] E3L In compounds of formula (X), E3L represents an E3 ligase binding moiety. Any suitable E3 ligase binding moiety can be included in the compounds of the present invention. Suitable E3 ligase binding moieties include different suitable linker attachment points and / or different suitable stereochemistries of the E3 ligase binding moiety. E3 ligase binding moieties are reviewed in Bricelj et al., Front. Chem., 2021, 9, 707317; Schapira et al., Nat Rev Drug Discovery, 2019, 18, 949; Bricelj, A. et al., Front. Chem. 2021, 9, 707317; Maple, HJ et al., Med. Chem. Commun., 2019, 10, 1755; and Ishida, T. and Ciulli, A., SLAS Discovery, 2021, 26(4), 484, the entire contents of each of which are incorporated by reference. Those skilled in the art will appreciate that suitable E3 ligase binding moieties include the E3 ligase binding structures depicted in Bricelj et al, Front. Chem., 2021, 9, 707317; Schapira et al, Nat Rev Drug Discovery, 2019, 18, 949; Bricelj, A. et al., Front. Chem. 2021, 9, 707317; Maple, HJ et al., Med. Chem. Commun., 2019, 10, 1755; and Ishida, T. and Ciulli, A. SLAS Discovery, 2021, 26(4), 484, as well as E3 ligase binding structures characterized by different suitable linker attachment points and / or different suitable stereochemistries.

[0205] The human genome contains over 600 E3 ligases (or E3 ubiquitin ligases). E3 ligases participate in the protein ubiquitination cascade, whereby one or more molecules of ubiquitin are attached to substrate proteins, marking them for degradation via the ubiquitin-proteasome pathway. E3 ligases are classified into three broad classes: Really Interesting New Gene (RING), E6AP C-terminal homolog (HECT), and RING-RING (RBR). Of these, RING E3 ligases are the most common. Thus, an E3 ligase-binding moiety can bind to a RING, HECT, or RBR E3 ligase, with E3L typically representing the RING E3 ligase-binding moiety. Examples include, but are not limited to, MDM2 (mouse double minute 2 homolog) and cellular IAPs (inhibitors of apoptosis).

[0206] E3L can also be a moiety capable of binding to any of these E3 ligases. Binders of the following E3 ligases have been described: RING-type zinc finger protein 114 (RNF114), damage-specific DNA-binding protein 1 (DDB1)-CUL4-associated factor 16 (DCAF16), Kelch-like ECH-associated protein 1 (KEAP1), cereblon (CRBL or CRBN), and von Hippel-Lindau (VHL) tumor suppressor protein. Preferably, when E3L is a moiety capable of binding to any of these E3 ligases, it is a moiety capable of binding to CRBL and / or VHL.

[0207] In some embodiments, the E3 ligase binding moiety is [ka] [ka] is selected from where the arrow represents a covalent bond to L, or an E3 ligase-binding derivative thereof.

[0208] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, or an E3 ligase-binding derivative thereof.

[0209] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, or an E3 ligase-binding derivative thereof.

[0210] In some embodiments, the E3 ligase binding moiety is: [ka] where the arrow represents a covalent bond to L, or an E3 ligase-binding derivative thereof.

[0211] In some embodiments, the E3 ligase binding moiety is: [ka] where the arrow represents a covalent bond to L, or an E3 ligase-binding derivative thereof.

[0212] In some embodiments, the E3 ligase binding moiety is [ka] is selected from the radicals

[0213] In some embodiments, the E3 ligase binding moiety is [ka] [ka] [ka] [ka] is selected from where the arrow represents a covalent bond to L, Any portion of L not depicted in the structure, or Its E3 ligase-bound derivative is shown.

[0214] In some embodiments, the E3 ligase binding moiety is [ka] [ka] [ka] is selected from where the arrow represents a covalent bond to L, Any portion of L not depicted in the structure, or Its E3 ligase-binding derivative is shown.

[0215] In some embodiments, the E3 ligase binding moiety is [ka] [ka] is selected from where the arrow represents a covalent bond to L, Any portion of L not depicted in the structure, or Its E3 ligase-binding derivative is shown.

[0216] In some embodiments, the E3 ligase binding moiety is [ka] [ka] [ka] is selected from where the arrow represents a covalent bond to L, Any portion of L not depicted in the structure, or Its E3 ligase-binding derivative is shown.

[0217] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, Any portion of L not depicted in the structure, or Its E3 ligase-binding derivative is shown.

[0218] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, Any portion of L not depicted in the structure, or Its E3 ligase-binding derivative is shown.

[0219] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, Any portion of L not depicted in the structure, or Its E3 ligase-binding derivative is shown.

[0220] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, Any portion of L not depicted in the structure, or Its E3 ligase-binding derivative is shown.

[0221] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, Any portion of L not depicted in the structure, or Its E3 ligase-binding derivative is shown.

[0222] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, Any portion of L not depicted in the structure, or Its E3 ligase-binding derivative is shown.

[0223] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, or an E3 ligase-binding derivative thereof.

[0224] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, or an E3 ligase-binding derivative thereof.

[0225] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, or an E3 ligase-binding derivative thereof.

[0226] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, or an E3 ligase-binding derivative thereof.

[0227] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, or an E3 ligase-binding derivative thereof.

[0228] In some embodiments, the E3 ligase binding moiety is [ka] is selected from where the arrow represents a covalent bond to L, or an E3 ligase-binding derivative thereof.

[0229] In some embodiments, the E3 ligase binding derivative is an optionally substituted derivative of any of the E3 ligase binding moieties described herein.

[0230] L In compounds of formula (X), L represents a linker that covalently links MLKLi and E3L. Any suitable linking group may be used that is compatible with MLKLi and E3L, does not interfere with the binding of MLKLi and E3L to their respective protein targets, and allows ubiquitin transfer from the E3 ligase to MLKL.

[0231] In some embodiments, the linker has a minimum linear chain length of 1 to 50 atoms.

[0232] As used herein, "shortest linear chain length" defines the number of atoms in the chain that defines the shortest path from MLKLi to E3L in the compounds of the invention. For example, the shortest linear chain length in each of the following structures is 7 atoms (the shortest chain length is numbered in each structure): [ka]

[0233] In some embodiments, a linker has a minimum shortest linear chain length of at least 1, 2, 3, 4, 5, 6, or 7 atoms. A linker may have a maximum shortest linear chain length of 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, or 7 atoms or less. A linker may be characterized by a shortest linear chain length from any of these minimum lengths to any of these maximum lengths, provided that the minimum is less than the maximum. For example, a linker may be characterized by a shortest linear chain length of 1 to 35 atoms, 1 to 25 atoms, 1 to 20 atoms, 1 to 10 atoms, 2 to 10 atoms, 3 to 10 atoms, or 5 to 9 atoms.

[0234] In some embodiments, the linker is a C optionally interrupted by one or more groups selected from the following: 1~50 is alkyl, a.-O-, b.-NR z -, cC 3~8 cycloalkyl, d.aryl, eC 1~4Al-Khalil, f. heteroaryl, g.(C 1~4 alkoxy) 1~4 aryl, h. haloaryl, i. 4- to 8-membered non-aromatic heterocyclyl, j.-C(O)NR z -, k. alkenyl, l. alkynyl, In the formula, each R z are independently H and C 1~4 alkyl, Each of the one or more groups a to l. is C 3~6 Cycloalkyl, halo, -OH, -CN, -NR z 2. C 1~4 Alkyl, C 1~4 Alkoxy, oxo, C 1~4 Alkyl ketone, -COOH, -C(O)N(R z )2, and -NR z C(O)R z In some embodiments, one or more groups a-l can be further optionally substituted with a group selected from oxo, —C(O)N(R z )2, and -NR z C(O)R z It may be optionally substituted with one or more groups selected from:

[0235] In some embodiments, each of one or more groups a-l. is halo, —OH, —CN, —NR z 2. C 1~4 Alkyl, C 1~4 Alkoxy, oxo, C 1~4 Alkyl ketone, -COOH, -C(O)N(R z )2, and -NR z C(O)R z In some embodiments, one or more of groups a-l. may be further optionally substituted with a group selected from oxo, —C(O)N(R z )2, and -NR z C(O)R z It may be optionally substituted with one or more groups selected from:

[0236] C 1~50 The alkyl may be optionally interrupted by any number of groups a-l, provided that the stability of the linker is sufficient to maintain the covalent bond between MLKLi and E3L under physiological conditions. Typically, no more than two optional interrupting groups are present in C 1~50 In some embodiments, C 1~50 The alkyl linker can be optionally interrupted and optionally substituted by any number of a-l groups.

[0237] In some embodiments, C 1~50 The alkyl linker can include 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 of one or more a-l groups. 1~50 The alkyl linker can include any number of a-l groups from any of these numbers to any other of these numbers, for example, 1-20 or 4-12 groups.

[0238] In some embodiments, the heteroaryl contains at least one N heteroatom, such as triazolyl or pyrazolyl, preferably pyrazolyl.

[0239] The linker is the moiety -(OCH2CH2) v -, where v is an integer from 1 to 15. The inclusion of repeating ethylene oxide moieties can assist in controlling the hydrophilicity (and therefore solubility) of the compounds of the invention. In some embodiments, the linker can include 1 to 6 ethylene glycol units, preferably 2 to 5 ethylene glycol units.

[0240] The linker is -C(O)O-, -C(O)NR z -, -OC(O)O-, -NR z C(O)NR z -, -OC(O)NR zand each R may comprise at least one coupling moiety selected from -, triazolyl, aryl, α,β-unsubstituted ketone, β-hydroxy-ketone, 4- to 8-membered heteroaryl, unsaturated C6-cycloalkyl, and optionally substituted C2 alkenyl; z are independently H and C 1~4 The coupling moiety is typically the product of the reaction used to couple MLKLi with E3L. In some embodiments, the coupling moiety is -C(O)O, C(O)NR z -, triazolyl, aryl, 4- to 8-membered heteroaryl (such as pyrazolyl), and aryl.

[0241] In some embodiments, the linker is 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, C 1~6 Alkoxyhalo, 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 C optionally substituted with one or more groups selected from alkyl, heterocyclyl, and heteroaryl 1~50 Alkyl, and each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, as well as groups comprising them, can be further optionally substituted.

[0242] In some embodiments, the linker is C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C3~4 Cycloalkyl, hydroxyl, oxo, C 1~4 Alkoxy, C 1~4 Alkoxyaryl, halo, C 1~4 Alkyl halo, C 1~4 C optionally substituted with one or more groups selected from alkoxyhalo, carboxyl, ester, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketone, substituted ketone, amide, thiol, alkylthio, thioxo, sulfate, sulfonate, sulfinyl, heterocyclyl, and heteroaryl. 1~50 Alkyl, and each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, as well as groups comprising them, can be further optionally substituted.

[0243] C 1~50 The alkyl may be optionally substituted with any number of groups, provided that the stability of the linker is sufficient to maintain the covalent bond between MLKLi and E3L under physiological conditions. Typically, no more than two optional substituents are present in C. 1~50 It is included at consecutive positions along the alkyl chain.Typically, the compounds of the present invention can be prepared by techniques known in the art.

[0244] In another aspect, there is provided a process for preparing a compound of formula (I), or a salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

[0245] In some embodiments, the process includes any of the following four steps: reacting a compound of formula (III) with a compound of formula (IV) [ka] In the formula, X and R 2 is as defined for formula (I), Q 3 and Q 4 N and N-PG 1 Selected from Q3 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 can be any leaving group capable of activating the sulfonyl moiety of the compound of formula (IV) as an electrophile capable of reacting with the free aniline nitrogen of the compound of formula (III) under appropriate conditions. E 6 is selected from —CN and —C(O)NH2. 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, wherein 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 2is selected from NH2 or halo, provided that one of is NH2 and the other is halo. 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, with the proviso that one of is halo and the other is a boronic acid or boronic ester; E 7 are halo, -NH2, and -NHR 2 Selected from R 2 is as defined for formula (I). - Converting the compound of formula (I) into one of its salts.

[0246] In some embodiments, Q 3 is N and Q 4 is N-PG 1 is.

[0247] In some embodiments, Q 3 is N-PG 1 and Q 4 is N.

[0248] In some embodiments of the above process, the PG 1 When is an amino protecting group, the process further comprises a deprotection step.

[0249] In some embodiments, when Y' is halo, the process further comprises reacting a compound of formula (III), (V), or (VII) with Y-LG2 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).

[0250] In some embodiments, when Z' is halo, the process further comprises reacting a compound of formula (III), (V), or (VII) with Z-LG 3 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).

[0251] In some embodiments, E 6 When is -CN, the process further comprises converting -CN to -C(O)NH2.

[0252] An embodiment of these steps is R 2 is shown below in Schemes 1-7 for compounds represented by subformula Ar1.

[0253] In another aspect, processes for preparing compounds of formula (X), or salts, solvates, tautomers, N-oxides, stereoisomers, and / or prodrugs thereof, are also provided.

[0254] In some embodiments, the process comprises reacting with one or more of formula (XIII), formula (XIV), and formula (XV):

number

[0255] In some embodiments, the process comprises reacting a compound of Formula (I) with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0256] In some embodiments, the process comprises reacting a compound of Formula (1A) with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0257] In some embodiments, the process comprises reacting a compound of Formula (1B) with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0258] In some embodiments, the process comprises reacting a compound of Formula (1A') with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0259] In some embodiments, the process comprises reacting a compound of Formula (1B') with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0260] In some embodiments, the process comprises reacting a compound of Formula (SI) with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0261] In some embodiments, the process comprises reacting a compound of Formula (II) with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0262] In some embodiments, the process comprises reacting a compound of Formula (III) with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0263] In some embodiments, the process comprises reacting a compound of Formula (IV) with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0264] In some embodiments, the process comprises reacting a compound of Formula (V) with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0265] In some embodiments, the process comprises reacting a compound of Formula (VI) with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0266] In some embodiments, the process comprises reacting a compound of Formula (VII) with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0267] In some embodiments, the process comprises reacting a compound of Formula (VIII) with a compound selected from the group consisting of Formula (XIII), Formula (XIV), and Formula (XV).

[0268] In some embodiments, L' can be deprotected before deprotection of E3L'. In some embodiments, L' can be deprotected after deprotection of E3L'.

[0269] In some embodiments, L' can be deprotected before coupling with a coupling partner. In some embodiments, L' can be deprotected after coupling with a coupling partner.

[0270] In some embodiments, L' is LG A In some embodiments, L' can be deprotected prior to cleavage of LG. A After cleavage of the formula (I), the compound can be deprotected.

[0271] In some embodiments, E3L' can be deprotected before coupling with a coupling partner. In some embodiments, E3L' can be deprotected after coupling with a coupling partner.

[0272] In some embodiments, E3L' is LG A In some embodiments, E3L' may be deprotected prior to cleavage of LG. A After cleavage of the formula (I), the compound can be deprotected.

[0273] In some embodiments, LG A is cleaved before coupling with the coupling partner. A is cleaved before coupling with the coupling partner, in preferred embodiments, the process comprises reacting a compound of formula (XIII) with a compound of formula (XIV), thereby forming a compound of formula (XV). A is cleaved after coupling with the coupling partner.

[0274] In some embodiments, the process involving reaction with one or more of Formula (XIII), Formula (XIV), and Formula (XV) comprises a palladium-mediated cross-coupling reaction.

[0275] In some embodiments, the process involving reaction with one or more of Formula (XIII), Formula (XIV), and Formula (XV) includes deprotection of amino protein groups.

[0276] In some embodiments of the above process, the PG 1 When is an amino protecting group, the process further comprises a deprotection step.

[0277] An embodiment of these steps is shown in the synthesis below.

[0278] The specific reagents and conditions for effecting each of these steps will depend on the specific substituents selected for each reaction partner. Those skilled in the art will 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 will be able to design and carry out its preparation based on previously described techniques and reactions. Embodiments of these steps are described in the Examples for specific compounds described herein.

[0279] method In another aspect, provided is a method for inhibiting necroptosis in a subject in need thereof, comprising administering a therapeutically effective amount of a compound according to Formula (X), or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

[0280] Without wishing to be bound by any particular theory, it is believed that the compounds of the present invention treat necroptosis by binding to the ATP-binding site of the pseudokinase domain of the mixed lineage kinase domain-like (MLKL) protein, inducing its ubiquitination and proteolysis via the ubiquitin-proteasome pathway.

[0281] Thus, in another aspect, there is a method for degrading mixed lineage kinase domain-like protein (MLKL). As used herein in the context of the present invention, the terms "degrade" and "degradation" will be understood by those skilled in the art to mean partial or complete proteolysis of a protein via the ubiquitin-proteasome pathway. An E3 ubiquitin ligase facilitates the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme, leading to ubiquitination of the target protein and degradation by the proteasome.

[0282] As used herein, the term "effective amount" refers to an amount of a drug or agent that elicits the biological or medical response in 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 amelioration of a disease, disorder, or side effects, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject who has not received such amount. This term also includes within its scope amounts effective to enhance normal physiological function.

[0283] In one embodiment of the present disclosure, administration of a compound according to formula (X) inhibits a conformational change in MLKL. In another embodiment, the conformational change in 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 translocation of MLKL to the cell membrane. In another embodiment, administration of the compound inhibits the conformational change in MLKL, inhibits the oligomerization of MLKL, and inhibits the translocation of MLKL to the cell membrane.

[0284] It is contemplated that some compounds of the present disclosure may bind to MLKL and inhibit necroptosis in various species.

[0285] As used herein, the term "pseudo-kinase domain" refers to a protein comprising a catalytically inactive or catalytically defective kinase domain, as understood by those of skill in the art. "Pseudo-kinase domains" are often referred to as "protein kinase-like domains" because these domains lack conserved residues known to catalyze phosphoryl transfer. While pseudo-kinase domains are predicted to function primarily as catalysis-independent protein interaction modules, it will be understood by those of skill in the art that some pseudo-kinase domains have been ascribed unexpected catalytic functions. Thus, in the present disclosure, the term "pseudo-kinase domain" includes "pseudo-kinase domains" that lack kinase activity and "pseudo-kinase domains" that possess weak kinase activity.

[0286] 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 is utilized by the protein 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" can also be referred to as the "nucleotide-binding site" because binding at this site includes binding of nucleotides other than ATP. It will be understood by those skilled in the art that the term "nucleotide" includes any nucleotide. Exemplary nucleotides include, but are not limited to, AMP, ADP, ATP, AMPPNP, GTP, CTP, and UTP.

[0287] 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.

[0288] Binding of a compound to the ATP-binding site of the pseudokinase domain of MLKL may inhibit phosphorylation of MLKL by effector kinases, or binding of a compound to the ATP-binding site of the pseudokinase domain of MLKL may not inhibit phosphorylation of MLKL by effector kinases. The present disclosure demonstrates 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.

[0289] RIP1, RIP3, and MLKL are three proteins involved in the necroptosis pathway. Upon stimulation of necroptosis (e.g., using a combination of TNF, SMAC mimetics, and QVD-OPh in a suitable cell line), RIP1 is autophosphorylated and associates with RIP3, which in turn autophosphorylates itself. Activated RIP3 phosphorylates MLKL, leading to a predicted conformational change that triggers its necroptotic activity (Murphy, Immunity, 39, pp. 443-453, 2013). MLKL acts downstream of RIP1 and RIP3 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.

[0290] The compounds of the invention can be selective for MLKL. In some embodiments, the compounds of the invention are selective for MLKL over RIP1. In some embodiments, the compounds of the invention are selective for MLKL over RIP3. In some embodiments, the compounds of the invention are selective for MLKL over RIP1 and RIP3. A selective compound 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 activity of MLKL can be assessed 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.

[0291] In another aspect, there is provided a compound of formula (X), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, N-oxide, and / or prodrug thereof, for use as a medicament.

[0292] In another aspect, there is provided the use of a compound of formula (X), a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, in the preparation of a medicament for inhibiting necroptosis in a subject.

[0293] In another aspect, there is provided a use of a composition comprising a compound of Formula (X), or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, for inhibiting necroptosis in a subject.

[0294] In another aspect, there is provided a use of a compound of formula (X), or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, for inhibiting necroptosis.

[0295] In another aspect, there is provided a use of a composition comprising a compound of Formula (X), or a salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, for inhibiting necroptosis.

[0296] In yet another aspect, there is provided a compound according to Formula (X), or a salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, for use in inhibiting necroptosis.

[0297] In yet another aspect, there is provided a composition comprising a compound according to Formula (X), 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.

[0298] In yet another aspect, there is provided a compound according to Formula (X), or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, when used to inhibit necroptosis.

[0299] In yet another aspect, there is provided a composition comprising a compound according to Formula (X), or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, when used to inhibit necroptosis.

[0300] In another aspect, a method of inhibiting MLKL is provided, comprising contacting a cell with an effective amount of a compound of formula (X), or a salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

[0301] Salts of compounds of formula (X) are preferably pharmaceutically acceptable salts, although it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure, since, for example, these salts may be useful as intermediates in processes that do not require the preparation of a pharmaceutically acceptable salt or administration to a subject.

[0302] 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, is capable of providing (directly or indirectly) a compound of formula (X) or an active metabolite or residue thereof and that is typically not deleterious to the subject.

[0303] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of 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.

[0304] Base salts include, but are not limited to, salts formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium salts such as salts formed with triethylamine, alkoxyammonium salts 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" by P.H. Stahl and C.G. Wermuth, 1st edition, 2002, Wiley-VCH.

[0305] It will be understood by those skilled in the art that, for compounds that are solids, the compounds, agents, and salts of the invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the invention and the specified formula.

[0306] The present invention includes all crystalline forms of the compound of formula (X), including anhydrous crystalline forms, hydrates, solvates, and mixed solvates. If any of these crystalline forms exhibit polymorphism, all polymorphs are within the scope of the present invention.

[0307] Formula (X) is intended to include solvated and unsolvated forms of the compounds, where applicable. Thus, Formula (X) includes compounds having the depicted structure, including hydrated or solvated forms, as well as unhydrated and unsolvated forms.

[0308] The compound of formula (X), or its salt, tautomer, N-oxide, polymorph, or prodrug, may be provided in the form of a solvate. Solvates contain either stoichiometric or non-stoichiometric amounts of a 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. The solvate forms part of the crystalline lattice either by non-covalent bonding or by occupying holes in the crystalline lattice. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. 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 for the purposes of the present invention.

[0309] Basic nitrogen-containing groups include C groups such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides. 1~6 It may be quaternized with agents such as alkyl halides, alkyl sulfates such as dimethyl and diethyl sulfate, and others.

[0310] Nitrogen-containing groups can also be oxidized to form N-oxides.

[0311] Compounds of formula (X), or salts, tautomers, N-oxides, solvates, and / or prodrugs thereof, that form crystalline solids may exhibit polymorphism. All polymorphic forms of the compounds, salts, tautomers, N-oxides, solvates, and / or prodrugs are within the scope of the invention.

[0312] Compounds of formula (I) (and therefore compounds of formula (X)) may exhibit tautomerism. Tautomers are two interchangeable forms of a molecule that typically exist in equilibrium. Any tautomer of a compound of formula (I) is understood to be within the scope of the present invention when included in the compound of the present invention as the moiety MLKLi. For example, R 1 When R is H, the compounds of formula (1A) and (1B) may exist as tautomers, for example, in equilibrium with each other. 1 Compounds of formula (1A) and (1B) where is H are depicted below as compounds of formula (1A') and (1B'). The ratio of compounds of formula (1A') to (1B') at equilibrium may depend on the specific compounds and conditions, such as solvent, temperature, concentration, etc. This equilibrium may be described as follows: [ka]

[0313] Similar tautomerism can occur for any of the pyrazole-containing compounds described herein, including compounds of Formulas (II), (III), (V), (VIII), and (SI), compounds 1-320, and compounds 1001-1014, 1016-1037, 1039-1053, and 1055-1060. All tautomers of these compounds are contemplated and considered within the scope of the invention. In addition, different tautomeric forms may exist for the compounds described herein, depending, for example, on the various substituents selected.

[0314] The compound of formula (X) may contain one or more stereocenters. All stereoisomers of the compound of formula (X) are within the scope of the present invention. Stereoisomers include enantiomers, diastereomers, geometric isomers (E and Z olefin forms and cis and trans substitution patterns), and atropisomers. In some embodiments, the compound is a stereoisomerically enriched form of the compound of formula (X) at any stereocenter. The compound may be enriched in one stereoisomer by at least about 60, 70, 80, 90, 95, 98, or 99% over another stereoisomer.

[0315] The compounds of formula (X), or salts, tautomers, solvates, N-oxides, and / or stereoisomers thereof, may be isotopically enriched with one or more of the isotopes of atoms present in the compounds. For example, the compounds may be enriched with one or more of the following minor isotopes: 2 H, 3 H, 13 C. 14 C. 15 N, and / or 17 O. An isotope may be considered enriched when its abundance is higher than its natural abundance.

[0316] A "prodrug" is a compound that may not fully meet the structural requirements of the compounds provided herein, but that is modified in vivo following administration to a subject or patient to produce a compound of formula (X) provided herein. For example, a prodrug can be an acylated derivative of a compound provided herein. Prodrugs include compounds in which a hydroxy, carboxy, amine, or sulfhydryl group is bonded to any group that, upon administration to a mammalian subject, cleaves to form the 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 provided herein. Prodrugs of the compounds provided herein can be prepared by modifying functional groups present in the compound such that the modifications are cleaved in vivo to produce the parent compound.

[0317] 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 (X). Amino acid residues include the 20 naturally occurring amino acids, commonly designated by their three-letter codes, 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 (X) through the carbonyl carbon prodrug side chain.

[0318] Pharmaceutical compositions may be formulated from the compounds according to formula (X) 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 injection solution or suspension).

[0319] 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, 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. The formulations may be presented in unit or multi-dose containers, such as sealed ampoules or vials. Examples of ingredients are described in Martindale-The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Remington: The Science and Practice of Pharmacy, 21st Ed., 2005, Lippincott Williams & Wilkins. All methods include the step of bringing the active ingredient, e.g., a compound defined by formula (X), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, N-oxide, and / or prodrug thereof, into association 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 (X), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, N-oxide, and / or prodrug thereof, 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 medicament comprising a compound of Formula (X), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, N-oxide, and / or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0320] In the context of this specification, the term "administering" and variations thereof, including "administer" and "administration," includes contacting, applying, delivering, or providing a compound or composition of the invention to an organism or surface by any suitable means.

[0321] For inhibiting necroptosis, the dosage of biologically active compound according to the present invention can vary within a wide range and can be adjusted to individual requirements.The active compound according to 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 subject being treated and specific mode of administration.

[0322] However, it is understood that the specific dosage level for any particular subject will depend on a variety of factors, including the activity of the specific compound employed, the subject's age, weight, general health, sex, and diet, the timing, route of administration, and excretion rate, drug combinations (i.e., other drugs being used to treat the subject), and the severity of the particular disorder being treated. Such treatment may be administered as often as necessary and for as long as deemed necessary by the treating physician. Those skilled in the art will understand that the dosage regimen or therapeutically effective amount of the compound of formula (X) administered may need to be optimized for each individual.

[0323] It is also recognized that different dosages may be required to treat different disorders. An effective amount of an agent is an amount that causes a statistically significant reduction in necroptosis.

[0324] For in vitro analysis, necroptosis inhibition can be determined by the assays used to measure TSQ-induced necroptosis, as described in the biological tests defined herein.

[0325] The terms "treating," "treatment," and "therapy" are used herein to refer to curative, prophylactic, and preventative therapies. Thus, in the context of this disclosure, the term "treating" encompasses curing, ameliorating, or lessening the severity of necroptosis and / or related diseases or symptoms thereof.

[0326] "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.

[0327] 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.

[0328] The term "inhibit" is used to describe any form of inhibition that results in the prevention, reduction, or otherwise amelioration of necroptosis and / or MLKL function, including complete and partial inhibition.

[0329] The term "degrade" is used to describe any degree of degradation of a target protein that results in reduced function of MLKL and otherwise amelioration of necroptosis. In some embodiments, compounds of the invention induce substantially complete degradation of the target MLKL protein to which they bind. Accordingly, methods of degrading MLKL in a subject are also described herein, comprising administering a compound of the invention to the subject.

[0330] Because the compounds of the present invention contain both an MLKL binding moiety -MLKLi- based on the series of MLKL inhibitors described in WO2021 / 253,095A1 (which is incorporated by reference in its entirety herein), the compounds of the present invention can both inhibit and degrade MLKL, which can enhance the amelioration of necroptosis in a subject.

[0331] The compounds of the invention may be administered with a pharmaceutical carrier, diluent, and / or excipient as described above.

[0332] 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, and Cushing's syndrome; Muscular dystrophies, e.g., muscle diseases such as Duchenne muscular dystrophy, myotonic dystrophy, myopathy, and myasthenia; skin disorders such as dermatitis, eczema, psoriasis, age-related or even scar changes, Cardiovascular diseases 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, and 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 blood cell fragmentation syndrome, neutropenia, leukopenia, medullary hypoplasia, pancytopenia, thrombocytopenia, and hemophilia. Pulmonary diseases, including pneumonia and asthma, and chronic obstructive pulmonary diseases such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, and emphysema Gastrointestinal disorders such as ulcers, Crohn's disease, and inflammatory bowel disease (IBD), including ulcerative colitis; - diseases of the liver such as, for example, hepatitis, in particular hepatitis of viral origin or with other infectious pathogens as the etiological agent, autoimmune hepatitis, fulminant hepatitis, inflammatory hepatitis, certain 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 caused by toxins and drugs such as drug-induced liver injury, ethanol (or alcohol)-induced liver disease, - diseases of the pancreas, for example acute or chronic pancreatitis, metabolic diseases such as diabetes mellitus, thyroiditis, including diabetes mellitus, prediabetes and diabetes insipidus; kidney disease such as acute kidney injury (e.g., acute kidney injury (AKI) including ischemia-reperfusion injury (IRI)) or glomerulonephritis, Viral and bacterial infections such as sepsis, severe poisoning from chemicals, toxins, or drugs; - Degenerative diseases related to acquired immune deficiency syndrome (AIDS), Age-related disorders such as accelerated ageing syndromes, Inflammatory diseases such as Crohn's disease, rheumatoid polyarthritis, and terminal ileitis, including TNF-induced systemic inflammatory syndrome; Autoimmune diseases such as lupus erythematosus (including systemic lupus erythematosus) and amputation-resistant RIPK1-induced autoinflammation (CRIA) syndrome, • Dental disorders, such as those resulting in tissue breakdown, e.g., periodontitis; 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-operative 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); Mitochondrial-related diseases (mitochondrial diseases) such as Friedreich's ataxia, congenital muscular dystrophies with structural mitochondrial abnormalities, certain muscle disorders (MELAS syndrome, MERFF syndrome, Pearson syndrome), MIDD (mitochondrial diabetes and deafness) syndrome, Wolfram syndrome, and dystonia. Cancer of the lung and bronchus, including non-small cell lung cancer (NSCLC), squamous cell lung cancer, brochioloalveolar 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 carcinoma; multiple myeloma; esophageal cancer, including squamous cell carcinoma and adenocarcinoma of the esophagus; acute myeloid leukemia (AML); accelerated Chronic myeloid leukemia (CML), including phase CML and blastic phase CML (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; cancers of the brain, including glioma / glioblastoma, anaplastic oligodendroglioma, and adult anaplastic astrocytoma; neuroendocrine carcinomas, including metastatic neuroendocrine tumors; cancers of the head and neck, including squamous cell carcinoma of the head and neck and nasopharyngeal carcinoma; cancers of the oral cavity, pharynx, and small intestine; bone cancer; soft tissue sarcoma; and colon villous adenoma, including, but not limited to, cancers and metastases; and • Central nervous system (CNS) diseases such as multiple sclerosis (MS).

[0333] In some embodiments, the disclosed method may be 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 is provided 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, comprising administering to a subject in need of such treatment and / or prevention an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

[0334] The method can also be used to protect cells, tissues, and / or transplanted organs, whether before, during (removal, transfer and / or re-implantation), or after transplantation.

[0335] In some embodiments, the compounds of the present invention may be administered in combination with an additional active pharmaceutical ingredient (API). The API may be any suitable 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 the additional API in any of the pharmaceutical compositions described herein, or the compounds of the present invention may be administered simultaneously, sequentially, or separately. Simultaneous administration includes administering the compounds of the present invention simultaneously with the other API, whether co-formulated or in separate dosage forms administered via the same or different route. Sequential administration includes administering the compounds of the present invention and the other API according to a determined dosing schedule, 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. Separate administration includes administering the compounds of the present invention and the other API according to regimens independent of each other, which may be the same or different, by any route suitable for either active.

[0336] The method may include administering a compound of formula (X) in any pharmaceutically acceptable form. In some embodiments, the compound of formula (X) is provided in the form of a pharmaceutically acceptable salt, solvate, N-oxide, polymorph, tautomer, or prodrug thereof, or a combination of these forms in any ratio.

[0337] The method may also include administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formula (X), or a pharmaceutically acceptable salt, solvate, N-oxide, polymorph, tautomer, or prodrug thereof. The pharmaceutical composition may include any pharmaceutically acceptable carrier, diluent, and / or excipient described herein.

[0338] The compounds of formula (X), or pharmaceutically acceptable salts or prodrugs thereof, as defined herein, may be administered by any suitable means, for example, orally, rectally, nasally, vaginally, topically (including buccal and sublingually), parenterally, such as by subcutaneous, intraperitoneal, intravenous, intramuscular, or intracisternal injection, inhalation, insufflation, infusion, or implantation techniques (e.g., as sterile aqueous or non-aqueous injectable solutions or suspensions).

[0339] 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 (X), or pharmaceutically acceptable salts or prodrugs thereof, together with a conventional adjuvant, carrier, or diluent, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as a solid, such as a tablet or filled capsule, or as a liquid, such as a solution, suspension, emulsion, elixir, or filled capsule therewith, all for oral use, or in the form of a sterile injectable solution for oral (including subcutaneous) use.

[0340] Also, separate parts, a compound of formula (X) or a pharmaceutically acceptable salt, solvate, N-oxide, polymorph, tautomer, or prodrug thereof; Also provided is a kit of parts comprising: - instructions for its use in any of the methods of the invention.

[0341] The compounds, compositions, kits and methods described herein are illustrated by the following illustrative and non-limiting examples. [Example]

[0342] 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.

[0343] 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 material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, a temperature that can range 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 more than one solvent. Depending on the specific reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0344] The preparation of the compounds of the present invention can 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 one 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 Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0345] 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., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0346] The expressions "ambient temperature," "room temperature," "RT," and "rt," as used herein, 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.

[0347] The compounds of the invention can be prepared according to a number of preparative routes known in the literature. Exemplary synthetic methods for preparing the compounds of the invention are provided in the following schemes.

[0348] Overview of Chemistry Scheme 1 illustrates a general synthesis of aminopyrazolocarboxamide compounds of the present invention. Aminopyrazolonitriles (F1), which can be prepared via routes known to those skilled in the art, can be 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 under microwave conditions, such as 150°C (Step 1). The nitrile group can be converted to a primary amide 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 using 30% hydrogen peroxide in water with aqueous sodium hydroxide in a polar solvent, such as dimethyl sulfoxide, and 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 powder at room temperature (Step 3). The aniline can then be converted to the sulfonamide with the appropriate sulfonyl chloride in the presence of an amine base such as pyridine or triethylamine in a chlorinated solvent such as dichloromethane or chloroform, or without solvent at room temperature (Step 4). Compounds 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. Scheme 1 [ka]

[0349] Alternatively, compound F2 can be prepared from iodoheteroarenes (examples 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 in a solvent such as 1,4-dioxane at elevated temperatures such as 65°C. Scheme 2 [ka]

[0350] 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. Scheme 3 [ka]

[0351] 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 carried out in the presence of a reagent such as a Ghaffar-Parkins catalyst in a solvent such as 1,4-dioxane and water at elevated temperatures such as 100°C, or using 30% hydrogen peroxide in water with aqueous sodium hydroxide in a polar solvent such as dimethyl sulfoxide and a protic solvent such as ethanol at elevated temperatures such as 100°C (Step 2). The subsequent coupling reaction 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 1,4-dioxane and water or a mixture of acetonitrile and water at an elevated temperature such as 100°C or under microwave irradiation at an elevated temperature such as 100°C to provide F5 (Step 3). The SEM protecting group can be removed under acidic conditions such as trifluoroacetic acid in a solvent such as dichloromethane or using aqueous hydrogen chloride at room temperature to provide compounds of the invention. Scheme 4 [ka]

[0352] Alternatively (Scheme 5), Steps 2 and 3 from Scheme 4 can be interconverted to provide F4 to F5 following the same instructions depicted in Scheme 4. Scheme 5 [ka]

[0353] Alternatively, Suzuki cross-coupling reactions can be carried out with boronic esters F8, F9, or F11 following the previous reaction (Scheme 6). Scheme 6 [ka]

[0354] Scheme 7 outlines the preparation of bromoaryl F6 and the boronic esters F7, F8, F9, and F11 which can be obtained from F6 or F10.

[0355] F7 can be obtained following the nitro reduction and sulfonylation reactions previously described above, and the boronation reaction 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 elevated temperatures such as 100° C. F8 can be obtained from F6 via the previously described boronation reaction, and F9 can be obtained from F8 via the previously described nitro reduction.

[0356] F11 can be obtained from F10 via the previously described 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 at elevated temperatures such as 70 °C.

[0357] F6 can be obtained via alkylation of substituted phenols F8 with the corresponding halogenoalkyl or halogenomethyl(hetero)aryl in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, or via nucleophilic substitution of fluoronitroarenes F9 with the corresponding alcohol / (hetero)aryl alcohol in the presence of a strong base such as sodium hydride in a polar solvent such as N,N-dimethylformamide or tetrahydrofuran. Scheme 7 [ka]

[0358] Scheme 8 summarizes the synthesis of F10 and F11. F10 can be obtained via 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 previously described boronation reaction of F10. Scheme 8 [ka]

[0359] 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 in the presence of an alcohol / (hetero)aryl alcohol with a strong base such as sodium hydride in a polar solvent such as N,N-dimethylformamide or tetrahydrofuran can provide F15, which can then be substituted into compounds of the invention according to the routes described below (Steps 3-6). Scheme 9 [ka]

[0360] general chemical methods Definition: [Table 2-1] [Table 2-2] [Table 2-3]

[0361] 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 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.

[0362] 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.

[0363] 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 to 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 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.

[0364] 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 in water, 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 / h, Cone: 50 L / h. Desolvation Temperature: 500 °C. Source Temperature: 120 °C.

[0365] Method E (5 min): LC model: Method A 1200 (pump type: binary pump, detector type: DAD) MS model: Method A 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.

[0366] Method F: Mass Detector: Agilent G6120B MSD Pump: 1260 Infinity G1312B Binary Pump Autosampler: 1260 Infinity G1367E HiPALS Detector: 1260 Infinity G4212B DAD Column: Poroshell 120 EC-C18, 2.1 x 30 mm 2.7 micron column Temperature: 30°C Injection Volume: 2 μL Flow Rate: 1.0 ml / min Solvent A: Water 0.1% formic acid Solvent B: Acetonitrile 0.1% formic acid Gradient: 5 to 100% B over 3.8 min Acquisition Time: 4.1 min Detection: 254 nm and 254 nm Ion Source: Single Quadrupole Ion Mode: API-ES Drying Gas Temperature: 350°C Capillary Voltage (V): 4000 (Positive) Capillary Voltage (V): 4000 (Negative) Scan range: 100~1000 Step size: 0.1 seconds

[0367] Method G: Agilent, Mass Detector: Agilent G6120B MSD, Pump: 1260 Infinity G1312B Binary Pump, Autosampler: 1260 Infinity G1367E HiPALS, Detector: 1260 Infinity G4212B DAD. LC Conditions: Column: Poroshell 120 EC-C18, 2.1 x 30 mm 2.7 micron, Column Temperature: 30 °C, Injection Volume: 1 uL, Flow Rate: 1.0 ml / min, Solvent A: Water 0.1% formic acid, Solvent B: Acetonitrile 0.1% formic acid, Gradient: 5-100% B over 3.8 min, Acquisition Time: 4.1 min, Detection: 214 and 254 nm. MS conditions: ion source: single quadrupole, ion mode: API-ES, drying gas temperature: 350 °C, capillary voltage (V): 4000 (positive), capillary voltage (V): 4000 (negative), scan range: 100–1000, step size: 0.1 s.

[0368] Method H: Agilent High MW, Mass Detector: Agilent G6120B MSD, Pump: 1260 Infinity G1312B Binary Pump, Autosampler: 1260 Infinity G1367E HiPALS, Detector: 1260 Infinity G4212B DAD. LC Conditions: Column: Poroshell 120 EC-C18, 2.1 x 30 mm 2.7 micron, Column Temperature: 30 °C, Injection Volume: 1 uL, Flow Rate: 1.0 ml / min, Solvent A: Water 0.1% formic acid, Solvent B: Acetonitrile 0.1% formic acid, Gradient: 5 to 100% B over 3.8 min, Acquisition Time: 4.1 min, Detection: 214 and 254 nm. MS conditions: ion source: single quadrupole, ion mode: API-ES, drying gas temperature: 350 °C, capillary voltage (V): 4000 (positive), capillary voltage (V): 4000 (negative), scan range: 100–2000, step size: 0.1 s.

[0369] Method I: Waters, ZQ 3100 Mass Detector, Waters 2545 Pump, Waters SFO System Fluid Organizer, Waters 2996 Diode Array Detector, Waters 2767 Sample Manager. LC conditions: Reverse-phase HPLC analytical, Column: Xbridge™ C18 5 μm 4.6 × 100 mm, Injection volume 10 μL, Solvent A: Water 0.1% formic acid, Solvent B: Acetonitrile 0.1% formic acid, Gradient: 10–100% B over 8 min, Flow rate: 1.5 ml / min, Detection: 100–600 nm. MS conditions: Ion source: single quadrupole, Ion mode: ES positive, Source temperature: 150 °C, Desolvation temperature: 350 °C, Detection: Ion counting, Capillary (KV) - 3.00, Cone (V): 30, Extractor (V): 3, RF lens (V): 0.1, Scan range: 100-1000 Amu, Scan time: 0.5 s, Acquisition time: 10 min, Gas flow rate: Desolvation L / h - 650, Cone L / h - 100.

[0370] Preparative HPLC Method A: 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.

[0371] Preparative HPLC was carried out according to Method A unless otherwise indicated.

[0372] Method B: Waters ZQ 3100 Mass Detector, Waters 2545 Pump, Waters SFO System Fluid Organizer, Waters 2996 Diode Array Detector, Waters 2767 Sample Manager. LC conditions: Reverse-phase HPLC analytical, Column: Xbridge™ Preparative C18 OBD 5 μm 19 × 100 mm, Solvent A: Water 0.1% formic acid, Solvent B: Acetonitrile 0.1% formic acid, Gradient: Variable, Flow rate: 20 ml / min, Detection: 100-600 nm. MS conditions: Ion source: single quadrupole, Ion mode: ES positive, Source temperature: 150 °C, Desolvation temperature: 350 °C, Detection: Ion counting, Capillary (KV) - 3.00, Cone (V): 30, Extractor (V): 3, RF lens (V): 0.1, Scan range: 100-1000 Amu, Scan time: 0.5 s, Acquisition time: 20 min, Gas flow rate: Desolvation L / h - 650, Cone L / h - 100.

[0373] NMR Nuclear magnetic resonance spectra were recorded on a Bruker Avance DRX 300 instrument at 300.13 MHz or a Bruker 400 MHz for the designated 1H nuclei. Samples were recorded in the designated deuterated solvents and data were acquired at 25°C. Chemical shifts are reported in ppm on the δ scale and are 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; m, multiplet.

[0374] Synthesis of common intermediates Intermediate A1: 3-(4-aminophenyl)-1-(tert-butyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide [ka] Step 1: Intermediate A1': 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, and then a solution of malononitrile (52.5 g, 0.79 mol) and NaOEt (112.7 g, 1.66 mol) in EtOH (300 mL) was slowly added at 0 °C over a period of 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 Intermediate A1' (58 g, 31%) as a yellow solid. LCMS (Method A): 1.93 min, m / z: 286.1 [M+H] + .

[0375] Step 2: 1-(tert-butyl)-3-(4-nitrophenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carbonitrile To a solution of 5-amino-1-(tert-butyl)-3-(4-nitrophenyl)-1H-pyrazole-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] + .

[0376] 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] + .

[0377] 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 powder (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] + .

[0378] The following intermediates (Table 1) were prepared similarly from 5-amino-1-(tert-butyl)-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile 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). [Table 3]

[0379] Intermediate B1: 3-bromo-5-((2-methoxypyridin-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile [ka] 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] + .

[0380] Step 2: Intermediate B1': 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 Intermediate B1' (16.0 g, 42%) as a clear oil. LCMS (Method B): 0.43 min, m / z: 380.0, 382.0 [M+H] + .

[0381] 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 for 12 h under N. 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] + .

[0382] Intermediate B2: 3-bromo-5-(pyridin-2-ylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide [ka] 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] + .

[0383] 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 give 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] + . 1H NMR(400MHz,MeOD-d4):8.84(s,1H),8.24(s,1H),9.01(d,J=4.0Hz,1H),7.79(t,J=7.6Hz,1H),7.29(s,1H),6.7 9(t,J=6.0Hz,1H),6.74(d,J=8.4Hz,1H),5.27(s,2H),3.44(t,J=8.4Hz,2H),0.74(t,J=8.0Hz,2H),0.11(s,9H).

[0384] 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] Step 1: 3-Bromo-5-(pyrazin-2-ylamino)-1-((2-(trimethylsilyl)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 rinsed 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] + .

[0385] 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] + . 1 H NMR(400MHz,DMSO-d6):9.34(s,1H),8.19(d,J=1.2Hz,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=8.4Hz,2H),0.75(t,J=7.6Hz,2H),-0.11(s,9H).

[0386] 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] 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 (1.03 g, 48%) as a yellow solid. LCMS (Method A): 4.10 min, m / z: 409.1, 411.1 [M+H] + .

[0387] 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] + .

[0388] 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. [Table 4]

[0389] Intermediate C1: N-(2-((4-fluorobenzyl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide [ka] 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 then concentrated under reduced pressure to give the title product (15.0 g, 100%) as a white solid.

[0390] 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) in MeOH (300 mL) and saturated aqueous NH4Cl (100 mL) was added Zn powder (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 then 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] + .

[0391] 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] + .

[0392] 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(400MHz,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=14.8,7.2Hz,2H),1.29(s,12H),1.11(t,J=7.2Hz,3H).

[0393] 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). [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0394] Intermediate C1a: [ka] Intermediate C1a was prepared according to the procedure of Intermediate C1 using difluoromethanesulfonyl chloride at the appropriate steps. 1 H NMR (300MHz, CDCl3):7.55(d,J=7.9Hz,1 H),7.45-7.37(m,4 H),7.13-7.08(m,3 H),6.22(t,J=53.5Hz,1 H),5.11(s,2 H),1.34(s,12 H).

[0395] Intermediate C11 [ka] 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 minutes. Then, 4-bromo-2-fluoro-1-nitrobenzene (62.6 g, 285 mmol) was added to the mixture 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 phases were washed with water and brine, dried (Na SO ), and concentrated under reduced pressure to give the crude product (70 g, 72%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6):7.80(d,J=8.4Hz,1H),7.54(d,J=2.0Hz,1H),7.48(q,J=4.8Hz,2H),7. 26(dd,J=8.8,2.0Hz,1H),7.20(t,J=8.8Hz,1H),5.89(q,J=6.4Hz,1H),1.54(d,J=6.0Hz,3H).

[0396] 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 powder (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 × 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] + .

[0397] 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 at room temperature overnight, 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(400MHz,DMSO-d6):10.43(s,1H),7.57(q,J=4.8Hz,2H),7.21-7.15(m,3H),7.0 7-7.04(m,2H),6.98(t,J=52.4Hz,1H),5.65(q,J=6.4Hz,1H),1.54(d,J=6.0Hz,3H).

[0398] 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), B2pin2 (34.7 g, 137 mmol), and Pd(dppf)Cl2 (2.01 g, 2.75 mmol). The mixture was stirred under N2 at 100 °C overnight and then 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 (Na2SO4), 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. 1H NMR(400MHz,DMSO-d6):10.41(s,1H),7.58(q,J=4.8Hz,2H),7.27(d,J=7.6Hz,1H),7.20-7.16(m,3H),7 .12(s,1H),6.98(t,J=52.4Hz,1H),5.63(q,J=6.4Hz,1H),1.54(d,J=6.4Hz,3H),1.25(d,J=4.8Hz,12H).

[0399] 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). [Table 6-1] [Table 6-2]

[0400] Intermediate C11a: N-{2-[(1S)-1-(4-fluorophenyl)ethoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}ethane-1-sulfonamide [ka] Intermediate C11a was prepared according to the procedure of Intermediate C11, using methanesulfonyl chloride at the appropriate steps. 1 H NMR(400MHz,DMSO-d6):9.08(s,1H),7.61-7.58(m,2H),7.35(d,J=7.6Hz,1H),7.19-7.17(m,3H),7 .14(s,1H),5.64(q,J=6.0Hz,1H),3.09(q,J=7.6Hz,2H),1.56(d,J=6.0Hz,3H),1.29-1.13(m,15H).

[0401] Intermediate C16: N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide [ka] Step 1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline A mixture of (4-aminophenyl)boronic acid hydrochloride (2 g, 11.5 mmol), pinacol (1.48 g, 12.6 mmol), MgSO (4.15 g, 34.5 mmol), and NaHCO (1.93 g, 23.0 mmol) in anhydrous THF (11.5 mL) was stirred overnight at room temperature under N. The mixture was diluted with EtOAc, filtered through Celite, and concentrated to give an off-white solid. The solid was triturated with EtO, collected via filtration, washed with EtO, and air-dried to give the title compound (1.49 g, 59%) as a white solid. LCMS (Method C): 1.44 min, m / z: 220.4 [M+H] + .

[0402] Step 2: N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamide To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.49 g, 6.80 mmol) in anhydrous DCM (13.6 mL) was added pyridine (2.74 mL, 33.9 mmol) and EtSO2Cl (1.28 mL, 13.6 mmol), and the reaction was stirred at room temperature under N2 for 4 h. The mixture was concentrated, and the residue was diluted with HO (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (0-50% EtOAc:c-Hex) to give the title compound (1.88 g, 89%) as a white solid. LCMS (Method C): 1.98 min, m / z: 312.2 [M+H] + . 1H NMR(CDCl3):7.77(d,J=8.5Hz,2H),7.19(d,J=8.5Hz,2H),6.72(s,1H),3.15(q,J=7.4Hz,2H),1.33(t,J=7.4Hz,3H).

[0403] Intermediate C17: 1,1-difluoro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide [ka] Step 1: 1,1-Difluoro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.28 mmol) in DCM (8 mL) was added pyridine (921 μL, 11.4 mmol) and difluoromethanesulfonyl chloride (241 μL, 2.73 mmol), and the reaction was stirred at room temperature under N. After 1 h, the mixture was concentrated and then azeotroped with PhMe (10 mL). The residue was purified by flash chromatography (0-25% EtOAc / heptane) to give the title compound (555 mg, 73%) as a white solid. LCMS (Method G): 2.47 min, m / z: 334.2 [M+H] + . 1 H NMR (300MHz, CDCl3):7.81-7.79(m,2H),7.27-7.24(m,2H),6.71(br. s,1H),6.25(t,J=53.5Hz,1H),1.33(s,12H).

[0404] Intermediate C18: N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamide [ka] Step 1: 4-Bromo-2-fluoroaniline To a solution of 4-bromo-2-fluoro-1-nitrobenzene (5 g, 22.7 mmol) in MeOH (12 mL) and saturated aqueous NH4Cl (4 mL) was added Zn (7.39 g, 113 mmol), and the reaction was stirred at 60 °C for 6 h. The mixture was concentrated, and the residue was diluted with water (150 mL) and extracted with EtOAc (150 mL x 3). The combined organic phases were washed with water and brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography to give the title product (2.5 g, 58%) as a brown oil. LCMS (Method A): 3.39 min, m / z: 189.9, 191.9 [M+H] + .

[0405] Step 2: N-(4-bromo-2-fluorophenyl)ethane-1-sulfonamide To a solution of 4-bromo-2-fluoroaniline (5 g, 26.3 mmol) in pyridine (20 mL) and DCM (80 mL) was added EtSO2Cl (3.38 g, 26.3 mmol), and the reaction was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc (3 times). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by column chromatography (DCM / MeOH = 20 / 1, v / v) to give the title product (6.67 g, 90%) as a white solid. 1 H NMR(400MHz,DMSO-d6):9.77(s,1H),9.63(dd,J=10.0,2.0Hz,1H),7.39-7.35(m,2H),3.11(q,J=7.6Hz,2H),1.24,(t,J=7.6Hz,3H).

[0406] Step 3: N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamide A mixture of N-(4-bromo-2-fluorophenyl)ethane-1-sulfonamide (1.1 g, 3.89 mmol), bis(pinacolato)diboron (987 mg, 3.89 mmol), AcOK (763 mg, 7.78 mmol), and Pd(dppf)Cl (317 mg, 389 μmol) in dioxane (10 mL) was stirred at 100° C. overnight under N. The mixture was concentrated, and the residue was diluted with water (200 mL) and extracted with DCM (150 mL × 3). The combined organic layers were washed with brine (200 mL), dried (NaSO), and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1, v / v) to give the title compound (1 g, 78%) as a black oil. 1 H NMR(400MHz,DMSO-d6):9.87(bs,1H),7.45-7.35(m,3H),3.11(q,J=7.6Hz,2H),1.28(s,12H),1.22,(t,J=7.6Hz,3H).

[0407] Intermediate D1: 5-((6-(difluoromethyl)pyridin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide. [ka] 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 then 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 HO, dried (NaSO), 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] + .

[0408] Intermediate E1: 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine [ka] 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 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 afford the title compound (4.60 g, 95%) as a yellow oil. 1 H NMR(400MHz, CDCl3):3.95(s,2H),1.60(dtd,J=5.4,3.8,1.5Hz,2H),1.49(t,J=3.6Hz,2H).

[0409] 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] + .

[0410] Intermediate E2: 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine [ka] 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 (400MHz, DMSO-d6): 3.59 (s, 3H), 3.32 (s, 2H), 3.22 (s, 3H), 1.10 (s, 6H).

[0411] Step 2: 5-Methoxy-4,4-dimethyl-3-oxopentanenitrile Acetonitrile (1.68 g, 41.0 mmol) was added dropwise to a solution of LDA (4.39 g, 41.0 mmol) in THF (60 mL), and the solution was stirred at −78° C. for 30 minutes. Then, 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×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(400MHz,DMSO-d6):4.18(s,2H),3.36(s,3H),3.34(s,2H),1.06(s,6H).

[0412] 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] + .

[0413] Intermediate E3: 5-(4-methyltetrahydro-2H-pyran-4-yl)isoxazol-3-amine [ka] Step 1: Methyl 4-methyltetrahydro-2H-pyran-4-carboxylate 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 minutes. Then, 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 column chromatography on silica gel (PE / EtOAc = 100 / 1, V / V) to give the title product (5.40 g, 34.1 mmol, 98.7%) as a yellow oil.

[0414] 1 H NMR (400MHz, CDCl3):3.78(dt,J=11.8,4.1Hz,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).

[0415] 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, followed by the addition of methyl 4-methyloxane-4-carboxylate (5.4 g, 34.1 mmol) in dry THF (40 mL) 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 HCl (2 M). 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(400MHz, CDCl3):3.74(ddd,J=12.0,6.4,3.7Hz,2H),3.55(ddd,J=11.7,8.1,3. 3Hz,2H),2.02-1.95(m,2H),1.90(d,J=0.7Hz,2H),1.59-1.51(m,2H),1.24(s,3H).

[0416] 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 column chromatography on silica gel (PE:EtOAc, 9:1 to 1:9) to give the title product (1.20 g, 16%) as a red oil. 1H NMR(400MHz,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=13.6,9.5,4.0Hz,2H),1.26(s,3H).

[0417] Intermediate E4: 5-(2-fluoropropan-2-yl)isoxazol-3-amine [ka] 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), followed by dropwise addition of acetonitrile (1.66 g, 40.5 mmol). The resulting mixture was heated at 70° C. for 3 hours. 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.

[0418] 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 SO ) and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (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] + .

[0419] Intermediate E5: 5-(3-methyloxetan-3-yl)isoxazol-3-amine [ka] 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 column chromatography on silica gel (PE:EtOAc, 10:1) to give the title product (6.9 g, 97%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6):7.41-7.31(m,5H),5.18(s,2H),4.77(d,J=5.9Hz,2H),4.34(d,J=5.9Hz,2H),1.53(s,3H).

[0420] Step 2: 3-(3-methyloxetan-3-yl)-3-oxopropanenitrile Acetonitrile (2.04 g, 49.7 mmol) was added to a solution of LDA (2 M in THF, 25 mL, 49.7 mmol) in dry THF (100 mL), and the solution was stirred at −78° C. for 1 h under N 2 . Then, 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(400MHz,DMSO-d6):4.74(d,J=6.2Hz,2H),4.28(t,J=3.1Hz,4H),1.49(s,3H).

[0421] 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 at 80 °C overnight 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] + .

[0422] Intermediate E6: 5-(adamantan-1-yl)isoxazol-3-amine [ka] Step 1: 3-(adamantan-1-yl)-3-oxopropanenitrile A solution of LDA (2 M in THF, 23.1 mL, 46.2 mmol) was slowly added to a precooled solution of acetonitrile (1.26 g, 30.8 mmol) in dry THF (25 mL) at −78 °C, and the mixture was stirred at −78 °C for 1 h. Then, 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.

[0423] 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) was stirred overnight at 65 °C under N. 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 column chromatography on silica gel (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] + .

[0424] Intermediate E7: 5-(tetrahydrofuran-3-yl)isoxazol-3-amine [ka] Step 1: 3-Oxo-3-(tetrahydrofuran-3-yl)propanenitrile Acetonitrile (4.14 mL) was added to a solution of LDA (2 M in THF, 12.5 mL, 24.9 mmol) in dry THF (50 mL), and the mixture was stirred at −78° C. for 1 hour under N2. Then, 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 phases were dried (Na2SO4) and concentrated under reduced pressure to give the title product (2 g, 75%) as a yellow oil.

[0425] 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) was 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] + .

[0426] Intermediate E8: 5-(difluoromethyl)isoxazol-3-amine [ka] 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 N 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 then 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 then added, and the reaction mixture was stirred at room temperature overnight. Water (100 mL) was then added, and the mixture was concentrated under reduced pressure. The aqueous residue was extracted with EtOAc (200 mL × 3), and the combined organics were washed with brine, dried (Na SO ), and concentrated under reduced pressure to yield the title product (5 g, >100%) as a brown oil.

[0427] 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 column chromatography on silica gel (PE:EA, 10:1) to give the title product (876 mg, 16%) as a yellow oil.

[0428] Intermediate E9: 5-cyclopropyl-1,2-oxazol-3-amine [ka] 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 column chromatography on silica gel (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] + .

[0429] Intermediate F1: 5-(tert-butyl)pyrazin-2-amine [ka] 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), followed by 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 then 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] + .

[0430] 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 column chromatography on silica gel (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] + .

[0431] 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 column chromatography on silica gel (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] + .

[0432] 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 column chromatography on silica gel (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] + .

[0433] 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 at room temperature overnight. 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] + .

[0434] Intermediate F2: 5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine [ka] Step 1: 5-(3,6-Dihydro-2H-pyran-4-yl)pyrazin-2-amine To a mixture of 5-bromopyrazin-2-amine (828 mg, 4.76 mmol), 2-(3,6-dihydro-2H-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) in degassed 1,4-dioxane (30 mL) and HO (7.5 mL) was added Pd(dppf)Cl (217 mg, 238 μmol), and the reaction mixture was stirred under N at 100 °C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE:EtOAc, 1:1 to 0:1) to give the title product (700 mg, 83%) as a brown solid.

[0435] 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 H at 50° C. overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (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] + .

[0436] Intermediate F3: 5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine [ka] 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 column chromatography on silica gel (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] + .

[0437] 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 H at room temperature for 6 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (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] + .

[0438] Intermediate F4: 5-Cyclopropylpyrazine-2-amine [ka] 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 KCO (5.80 g, 42.0 mmol) in water (20 mL), followed by cyclopropylboronic acid (1.72 g, 20.1 mmol), Pd(OAc) (188 mg, 840 μmol), and Pd(dppf)Cl (685 mg, 840 μmol). The reaction mixture was stirred at 120 °C for 16 h before filtering 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 (NaSO), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (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] + .

[0439] 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 at 100 °C overnight 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 column chromatography on silica gel (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] + .

[0440] 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 column chromatography on silica gel (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] + .

[0441] Intermediate G1: 5-methyl-2-nitro-4H,5H,6H,7H,8H-pyrazolo[1,5-a][1,4]diazepine [ka] Step 1: Methyl 1-(3-bromopropyl)-3-nitro-1H-pyrazole-5-carboxylate To a solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (1.0 g, 5.84 mmol) in acetone (30 mL) was added KCO (4.02 g, 29.1 mmol) and 1,3-dibromopropane (2.10 mL, 17.5 mmol), and the reaction was then heated at reflux for 2 h. The mixture was then 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] + .

[0442] 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, then quenched with saturated NH Cl (20 mL) and extracted with EtOAc (3×30 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] + .

[0443] 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] + .

[0444] 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 MeNH (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 NaHCO (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 (MgSO), and concentrated. The residue was purified by flash chromatography (0-20% MeOH:DCM) to give the title compound (468 mg, 72%) as a yellow oil. LCMS (Method D): 0.14 min, m / z 197.0 [M+H] + .

[0445] 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] + .

[0446] Compound 131 [ka] 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 then 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] + .

[0447] 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(400MHz,DMSO-d6):12.83(s,1H),10.26(br s,1H),9.48(s,1H),8.17(d,J=2.4Hz,1H),7.99(d,J=8.0Hz,1H),7.80-7.60 (m,1H),7.56(d,J=8.0Hz,2H),7.13-7.12(m,3H),6.85-6.84(m,1H),6.05(br s,1H),3.17(q,J=7.2Hz,2H),1.23(t,J=7.2Hz,3H).

[0448] 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. [Table 7-1] [Table 7-2] [Table 7-3]

[0449] compound 81 [ka] 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), cyclobutylmethanesulfonyl chloride (286 mg, 1.7 mmol), and pyridine (202 mg, 2.56 mmol) in CHCl (10 mL) was stirred at room temperature for 16 h. 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 mg, 29%) as a white solid. LCMS (Method A): 3.53 min, m / z: 484.2 [M+H] + .

[0450] 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, then 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] + . 1H NMR(400MHz,MeOD-d4):12.94(s,1H),10.10(s,1H),9.64(s,1H),9.26(s,1H),8.22(t,J=4.0Hz,1H),8.11( d,J=8.4Hz,1H),7.55(d,J=8.4Hz,2H),7.32(d,J=8.0Hz,2H),3.30(s,2H),2.08(s,1H),1.83-1.73(m,4H).

[0451] 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. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7]

[0452] compound 60 [ka] 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) at 0° C., (4-chlorophenyl)methanesulfonyl chloride (115 mg, 510 μmol) was added, 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] + .

[0453] 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 then neutralized to pH 7-8 with saturated aqueous NaCO. The mixture was diluted with HO (10 mL), and the precipitate was collected via filtration and purified by preparative TLC (DCM:MeOH, 15:1) to afford the title product (18 mg, 28%) as a yellow solid.

[0454] 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. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5]

[0455] Compound 119 [ka] 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 H2O (20 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried (Na2SO4) and then 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] + .

[0456] 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 then heated to 80 °C for 16 hours. The mixture was concentrated under reduced pressure and then diluted with HO (20 mL). The precipitate was collected via 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] + .

[0457] Step 3: 3-(4-aminophenyl)-1-tert-butyl-5-(methylamino)-1H-pyrazole-4-carboxamide A mixture of 1-tert-butyl-5-(methylamino)-3-(4-nitrophenyl)-1H-pyrazole-4-carboxamide (185 mg, 0.58 mmol), saturated aqueous NH4Cl (5 mL), Zn powder (190 mg, 2.91 mmol), and MeOH (10 mL) was heated to 60°C for 16 h. The reaction mixture was filtered, concentrated under reduced pressure, and then 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] + .

[0458] 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: 380.0 [M+H] + .

[0459] 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(400MHz,MeOD-d4):7.51(d,J=8.4Hz,2H),7.38(d,J=8.4Hz,2H),3.19-3.14(q,J=7.2Hz,2H),2.94(s,3H),1.34(t,J=7.2Hz,3H).

[0460] compound 64 [ka] 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 mg, 18%) as a yellow solid. LCMS (Method A): 3.15 min, m / z: 395.0, 397.1 [M+H] + .

[0461] 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 for 20 min under microwave irradiation. 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] + .

[0462] 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 the mixture was heated to 100° C. under N for 16 h. The reaction mixture was then concentrated under reduced pressure, and the crude residue was purified by preparative TLC (PE: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] + .

[0463] 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(400MHz,MeOD-d4):7.67(d,J=8.4Hz,2H),7.44(d,J=8.4Hz,2H),7.41- 7.37(m,1H),7.30-7.26(m,1H),3.35(s,1H),3.20(q,J=7.2Hz,2H),1.35(t,J=7.6Hz,3H).

[0464] 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 with the described intermediates used as described in Step 1. [Table 10]

[0465] compound 89 [ka] 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] + .

[0466] 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 then 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] + .

[0467] 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 H 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] + .

[0468] 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: 493.1 [M+H] + .

[0469] 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 reduced pressure 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(400MHz,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=8.0Hz,1H),7.81(d,J=8.0Hz,1H),7.33-7.66(m,8H),6.17(br s,1H),3.18(t,J=7.2Hz,2H),1.24(t,J=7.2Hz,3H).

[0470] compound 84 [ka] 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] + .

[0471] 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, then 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] + .

[0472] Step 3: 3-(4-aminophenyl)-1-tert-butyl-5-[(6-methylpyrazin-2-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 overnight at room temperature under H. 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] + .

[0473] 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] + .

[0474] 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 then 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(400MHz,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 .4Hz,2H),7.35(d,J=8.8Hz,2H),6.09(s,1H),3.19(q,J=7.2Hz,2H),2.38(s,3H),1.23(t,J=7.2Hz,3H).

[0475] Following the complete synthesis of compound 84, the following compounds (Table 9) were prepared starting from 5-amino-1-tert-butyl-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile with the indicated starting materials used as described in Step 1. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7]

[0476] compound 98 [ka] 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 for 16 h under N. 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] + .

[0477] 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] + .

[0478] 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 (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] + .

[0479] 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 powder (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 H2O and EtOAc. The organic layer was separated, 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] + .

[0480] 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 then 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 give the title product (110 mg, 19%) as a yellow solid. LCMS (Method A): 3.12 min, m / z: 488.2 [M+H] + .

[0481] 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) followed by 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(400MHz,DMSO-d6):13.04(s,1H),10.11(s,1H),9.75(s,1H),8.26(s,1H),7.57(d,J=8.4Hz,2H),7.45(s,1H), 7.35(d,J=8.4Hz,2H),4.31(q,J=6.8Hz,2H),3.19(q,J=7.2Hz,2H),1.31(t,J=14.0Hz,3H),1.23(t,J=7.2Hz,3H).

[0482] compound 66 [ka] 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), KCO (7.93 g, 57.4 mmol), and Pd(dppf)Cl (2.34 g, 2.87 mmol) in degassed 80% aqueous 1,4-dioxane (300 mL) was heated to 100 °C overnight under N. The mixture was diluted with HO (300 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 (2.9 g, 75%) as a yellow solid. LCMS (Method A): 1.38 min, m / z: 136.1 [M+H] + .

[0483] 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] + .

[0484] 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] + .

[0485] 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] + .

[0486] 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 at 100 °C overnight 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] + .

[0487] 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 to pH 7-8 with NH4OH and then 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] + . 1 H NMR(400MHz,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=8.4Hz,2H),7.36(d,J=8.0Hz,2H),6.10(br s,1H),3.19(q,J=6.8Hz,2H),3.08-2.99(m,1H),1.24(t,J=8.0Hz,9H).

[0488] compound 121 [ka] 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 then concentrated under reduced pressure to give the title compound (868 mg, 82%) as a yellow oil. 1H NMR (300MHz, CDCl3):7.83(dd,J=5.4,0.5Hz,1H),7.20(dd,J=5.4,1.4Hz,1H),7.17(dd,J=1.4,0.5Hz,1H),3.90(s,3H).

[0489] 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(300MHz,CDCl3):8.33-8.28(m,2H),8.19-8.16(m,2H),7.96(d,J=6.1Hz,1H),6.46(dd,J=6.0,2.0Hz,1H),6.19(br s,1H),3.92(s,3H),1.70(s,9H).

[0490] 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] + . 1 H NMR(300MHz,DMSO-d6):8.51(s,1H),8.30-8.27(m,2H),8.03-8.00(m,2H),7.79(d,J=5.7Hz,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).

[0491] 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(300MHz,MeOD-d4):7.76(d,J=5.9Hz,1H),7.46-7.43(m,2H),6.78-6.73(m,2H),6.29(d,J=4.9Hz,1H),5.93(s,1H),3.80(s,3H),1.63(m,9H).

[0492] 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), 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(300MHz,MeOD-d4):7.77(d,J=5.9Hz,1H),7.71-7.67(m,2H),7.30-7.26(m,2H),6.31(d,J=4.8Hz,1H),5.94(br s,1H),3.80(s,3H),3.11(q,J=7.3Hz,2H),1.65(s,9H),1.30(t,J=7.3Hz,3H).

[0493] 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 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 (24.2 mg, 98%) as a white solid. LCMS (Method C): 1.58 min, m / z: 417.0 [M+H] + . 1 H NMR(300MHz,MeOD-d4):7.84(d,J=6.1Hz,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,3H),3.19(q,J=7.4Hz,2H),1.33(t,J=7.4Hz,3H).

[0494] Following the complete synthesis of compound 121 with the corresponding alcohol in step 1, the following compounds (Table 10) were prepared. [Table 12]

[0495] compound 118 [ka] 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 (300MHz, CDCl3):7.91(s,1H),7.26(s,1H),3.87(s,3H),2.30(s,3H).

[0496] 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] + . 1H NMR(300MHz,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).

[0497] 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 hours. 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(300MHz,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).

[0498] 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] + . 1 H NMR(300MHz,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).

[0499] 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 by 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] + . 1H NMR(300MHz,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=7.3Hz,2H),2.16(s,3H),1.56(s,9H),1.21(t,J=7.3Hz,3H).

[0500] 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 h. 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(300MHz,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=7.3Hz,3H).

[0501] 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 along with the intermediates described in Step 2. [Table 13]

[0502] Compound 102 [ka] 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. for 3 hours under microwave irradiation. The mixture was diluted with HO (20 mL) and then 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] + .

[0503] 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 powder (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] + .

[0504] 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 give the title product (27 mg, 14%) as a yellow solid. LCMS (Method A): 2.57 min, m / z: 467.3 [M+H] + .

[0505] Step 4: 5-((4-cyanophenyl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide (Compound 102) A solution of 1-tert-butyl-5-[(4-cyanophenyl)amino]-3-(4-ethanesulfonamidophenyl)-1H-pyrazole-4-carboxamide (27 mg, 0.0578 mmol) in TFA (1 mL) 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 then dried under reduced pressure 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(400MHz,MeOD-d4):7.69(d,J=8.4Hz,2H),7.62-7.57(m,4H),7.43(d,J=8.4Hz,2H),3.21(q,J=7.2Hz,2H),1.34(t,J=7.2Hz,3H).

[0506] compound 237 [ka] 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] + .

[0507] 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 at 100 °C under N. 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] + .

[0508] 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 column chromatography on silica gel (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] + This gave 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] + .

[0509] Step 4: 3-(4-aminophenyl)-1-tert-butyl-5-[(6-cyanopyridin-2-yl)amino]-1H-pyrazole-4-carboxamide A mixture of 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) was stirred at 60°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated and then 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] + .

[0510] 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] + .

[0511] 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 hours. 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(400MHz,DMSO-d6):12.99(br s,1H),10.75(br s,1H),9.88(br s,1H),8.21(d,J=8.4Hz,1H),7.93(t,J=7.6Hz,1H),7.58(d,J=8.4Hz,2H),7.45(d,J=7.2Hz,1H),7.36(d,J=7.6Hz,2H),4.60(q,J=10.0Hz,2H).

[0512] compound 258 [ka] 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] + .

[0513] 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 to pH 7-8 with saturated Na2CO3. The resulting precipitate was collected by filtration and then purified by preparative TLC (DCM:MeOH, 15:1) to give 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(400MHz,DMSO-d6):13.00(brs,1H),9.76(br s,1H),8.19(d,J=8.4Hz,1H),9.25(t,J=8.0Hz,1H),7.54(d,J=8.0Hz,2H),7.44(d,J=7.2Hz,1H),7.34(d,J=8.0Hz,2H),7.09(t,J=12.4Hz,1H).

[0514] compound 257 [ka] Step 1: 6-((3-(4-aminophenyl)-1-(tert-butyl)-4-carbamoyl-1H-pyrazol-5-yl)amino)picolinamide A mixture of 6-{[1-tert-butyl-4-carbamoyl-3-(4-nitrophenyl)-1H-pyrazol-5-yl]amino}pyridine-2-carboxamide (from compound 237, 390 mg, 0.9210 mmol) and Zn powder (300 mg, 4.60 mmol) in MeOH (10 mL) and saturated aqueous NH4Cl (2 mL) was stirred at 45°C overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (MeOH:DCM, 1:35) to give the title product (320 mg, 88%) as a yellow solid. LCMS (Method A): 2.33 min, m / z: 394.2 [M+H] + .

[0515] 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] + .

[0516] 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 then 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(400MHz,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=7.6Hz,1H),7.52-7.47(m,2H),7.28 s,1H),7.22(d,J=8.8Hz,2H),7.08(d,J=8.8Hz,2H),6.24(t,J=54.8Hz,1H),5.82(br s,1H).

[0517] compound 115 [ka] 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 then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 1:0 to 3:2) to give 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(300MHz,DMSO-d6):9.23(br s,1H),8.04(dd,J=2.8,0.6Hz,1H),7.58(dd,J=8.8,2.8Hz,1H),6.84(dd,J=8.8,0.6H z,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).

[0518] 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 compound (191 mg, 76%) as a colorless glass. LCMS (Method A): 2.72 min, m / z: 529.2 [M+H] + . 1 H NMR(300MHz,CDCl3):10.04(brs,1H),8.97(br s,1H),8.02(dd,J=2.8,0.6Hz,1H),7.76-7.71(m,2H),7.54(dd,J=8.8,2.8Hz,1H),7.32-7.27(m,2H),6.83(dd,J=8.8,0.6Hz,1 H),5.45(s,2H),3.83(s,3H),3.66-3.61(m,2H),3.14(q,J=7.3Hz,2H),1.19(t,J=7.4Hz,3H),0.90-0.84(m,2H),-0.061(s,9H).

[0519] 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 colorless glass. LCMS (Method A): 2.47 min, m / z: 547.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6):9.93(br s,1H),7.84(s,1H),7.69-7.64(m,2H),7.63(dd,J=2.9,0.5Hz,1H),7.25-7.21(m,2H),7.18(br s,1H),7.14(br s,1H),7.12(dd,J=8.8,2.9Hz,1H),6.66(dd,J=8.8,0.5Hz,1H),5.33(s,2H),3.74(s,3H),3.5 2-3.46(m,2H),3.12(q,J=7.4Hz,2H),1.21(t,J=7.4Hz,3H),0.79-0.74(m,2H),-0.10(s,9H).

[0520] Step 4: 3-(4-(ethylsulfonamido)phenyl)-5-((6-methoxypyridin-3-yl)amino)-1H-pyrazole-4-carboxamide (Compound 115) A solution of 3-(4-(ethylsulfonamido)phenyl)-5-((6-methoxypyridin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (30 mg, 54.8 μmol) in TFA (0.5 mL) and DCM (0.5 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by preparative HPLC to give the title compound as a white solid (6.7 mg, 29%). LCMS (Method A): 1.83 min, m / z: 417.0 [M+H] + . 1H NMR(300MHz,DMSO-d6):12.59(s,1H),10.10(br s,1H),8.74(s,1H),8.37(s,1H),7.94(d,J=6.7Hz,2H),7.52(d,J=8.2Hz,2H),7.33(d,J=8.2Hz ,2H),6.75(d,J=8.6Hz,1H),5.75(s,1H),3.79(s,3H),3.21-3.14(m,2H),1.22(t,J=7.1Hz,3H).

[0521] compound 127 [ka] 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 (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] + .

[0522] 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 afford the title product (25 mg, 23%) as a yellow oil. LCMS (Method A): 2.00 min, m / z: 455.2 [M+H] + .

[0523] 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] + .

[0524] 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 give the title product (12 mg, 47%) as an off-white solid. LCMS (Method A): 1.82 min, m / z: 517.2 [M+H] + .

[0525] 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 product (10 mg, 93%) as a cream-colored solid. LCMS (Method A): 1.64 min, m / z: 461.2 [M+H] + . 1 H NMR(400MHz,MeOD-d4):7.85(d,J=5.7Hz,1H),7.59(d,J=8.7Hz,2H),7.43(d,J=8.7Hz,2H),7.22(br s,1H),6.92(dd,J=5.9,1.9Hz,1H),4.35(m,2H),3.76(m,2H),3.43(s,3H),3.21(q,J=7.3Hz,2H),1.35(t,J=7.5Hz,2H).

[0526] 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 with the corresponding sulfonyl chloride as described in Step 4. [Table 14-1] [Table 14-2]

[0527] compound 116 [ka] 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-carboxamine (100 mg, 19%) as a yellow solid. LCMS (Method B): 0.43 min, m / z: 551.0 [M+H] + .

[0528] 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 the mixture was 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] + .

[0529] 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 then triturated with EtO (2 × 5 mL) to give the title product as the mono-TFA salt (28 mg, 38%) as a white solid. LCMS (Method B): 0.33 min, m / z: 505.0 [M+H] + . 1H NMR (400 MHz, MeOD-d): 7.93 (d, J = 5.6 Hz, 1H), 7.63-7.61 (d, 3H), 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 absent.

[0530] compound 117 [ka] 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 then 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 compound (45 mg, 44%) as a yellow solid. LCMS (Method B): 0.48 min, m / z: 439.2 [M+H] + .

[0531] 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] + .

[0532] 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 then concentrated under reduced pressure to give the title product as the mono-TFA salt (10 mg, 86%) as a brown solid. LCMS (Method B): 2.37 min, m / z: 475.0 [M+H] + . 1 H NMR(400MHz,MeOD-d4):7.94(d,J=5.6Hz,1H),7.67-7.62(m,5H),7.36(s,1H),4.50(t,J=4.0Hz,2 H),3.83(t,J=4.0Hz,2H),3.42(s,3H),3.39(s,3H),3.22(q,J=7.6Hz,2H),1.35(t,J=7.6Hz,3H).

[0533] compound 86 [ka] 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(400MHz,DMSO-d6):8.41(d,J=8.8Hz,2H),8.11(d,J=9.2Hz,2H),1.77(s,1H).

[0534] 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] + .

[0535] 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 reaction mixture was concentrated under reduced pressure and diluted with HO. 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] + .

[0536] 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) and 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] + .

[0537] 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] + .

[0538] 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(400MHz,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=8.0Hz,1H),7.56(d,J=8.0Hz,2H),7.47-7.35(m,4H),7.27(t,J=7.2Hz,1H),6.07(br s,1H),3.18(q,J=6.8Hz,2H),1.23(t,J=3.2Hz,3H).

[0539] compound 100 [ka] Step 1: 3-Bromo-5-[(1-methyl-1H-pyrazol-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 (500 mg, 1.31 mmol), 1-methyl-1H-pyrazol-4-amine (127 mg, 1.31 mmol), Pd(dba) (119 mg, 0.131 mmol), Xantphos (151 mg, 0.262 mmol), and 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(400MHz,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=8.4Hz,2H),0.85(t,J=8.4Hz,2H),0.00(s,9H).

[0540] 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 under microwave irradiation for 1 h. 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] + . 1 H NMR(400MHz,DMSO-d6):10.00(s,1H),8.55(s,1H),7.76(s,1H),7.69(d,J=8.4Hz,2H),7.39(s,1H),7.26(d,J=8.4Hz,2H),5.4 1(s,2H),3.81(s,3H),3.64(t,J=7.6Hz,2H),3.13(q,J=7.2Hz,2H),1.19(t,J=7.6Hz,2H),0.87(t,J=8.0Hz,2H),-0.04(s,9H).

[0541] 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 H2SO4 (1 mL) and HO (1 mL) was stirred at 60 °C for 2 days. The reaction mixture was basified to pH 9-10 with NH4OH and then extracted with DCM (3 × 10 mL). The combined organic layers were dried (Na2SO4), concentrated under reduced pressure, and the crude residue was purified by preparative TLC (DCM:MeOH:NH4OH, 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] + . 1 H NMR(400MHz,DMSO-d6):12.39(br s,1H),8.26(s,1H),7.76(s,1H),7.50(d,J=8.4Hz,2H),7.45(s,1H),7.33(d,J=8.4Hz,2H),7.20(br s,1H),6.64(br s,1H),3.77(s,3H),3.16(q,J=7.2Hz,2H),1.22(m,3H).

[0542] Following the synthesis of compound 100, the following compounds (Table 13) were prepared starting from 3,5-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile along with the intermediates described in Step 1: [Table 15]

[0543] compound 22 [ka] 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] + .

[0544] 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] + .

[0545] 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 mixture was adjusted to pH 7-8 with saturated aqueous Na2CO3 and then concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 10:1) to give 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(400MHz,DMSO-d6):13.05(s,1H),9.51(s,1H),9.17(s,1H),8.11(s,1H),7.62(dd,J=4.8Hz,2H),7.44(d,J=9.6Hz,2H),7.24( t,J=8.8Hz,2H),7.19(dd,J=1.2Hz,8Hz,1H),6.18(s,1H),5.19(s,2H),3.05(q,J=7.2Hz,2H),2.40(s,3H),1.16(t,J=7.2Hz,3H).

[0546] 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. [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4]

[0547] compound 37 [ka] 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 give the title product (110 mg, 86%) as a yellow solid. LCMS (Method A): 4.18 min, m / z: 589.2 [M+H] + .

[0548] 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(400MHz,MeOD-d4):12.84(s,1H),9.57(s,1H),9.01(s,1H),8.20(s,1H),7.72(t,J=8.4Hz,1H),7.43(d,J=8.0Hz,1H),7.24(s,1H),7.14(d,J= 8.0Hz,1H),6.87(s,1H),6.14(s,1H),3.83(d,J=6.4Hz,2H),3.11(q,J=7. 2Hz,2H),2.18-2.08(m,1H),1.27(t,J=7.2Hz,3H),1.02(d,J=6.8Hz,6H).

[0549] 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. [Table 17-1] [Table 17-2] [Table 17-3]

[0550] compound 223 [ka] 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 compound (23 g, 77%) as a yellow solid. LCMS (Method A): 3.99 min, m / z: 678.2 [M+H] + .

[0551] 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(400MHz,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=4.8Hz,2H),7.14(dd,J=8. 0,1.6Hz,1H),7.04(t,J=8.4Hz,2H),6.99(d,J=1.6Hz,1H),6.35(t,J=53.6Hz,1H),5.40(q,J=6.4Hz,1H),5.21(s,2H),1.67(d,J=6.4Hz,3H).

[0552] The following compounds (Table 16) were similarly prepared from the appropriate Intermediate C and Intermediate 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. [Table 18-1] [Table 18-2] [Table 18-3]

[0553] Compounds 279 and 280 [ka] Racemic compound 293 (500 mg) was purified by chiral HPLC on a UniChiral CND-5H column (column dimensions: 50 mm i.d. × 250 mm length, 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 × 50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 1:0–20:1) to give the title product. The enantiomeric excess was calculated on a UniChiral CND-5H, (4.6 x 250 mm, 50% n-hexane / 50% ethanol, flow rate 1 mL / min, injection 5 μL, temperature 30°C).

[0554] 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(400MHz,CDCl3):12.41(s,1H),10.32(s,1H),8.39(s,1H),8.21(dd,J=2.9,1.4Hz,1H),8.17(d,J=2.8Hz,1H),7.66(dd,J=4.5,3.7Hz,2H),7.35( d,J=1.8Hz,1H),7.30(dd,J=8.2,1.9Hz,1H),7.12(d,J=0.8Hz,1H),6.33(t ,J=53.6Hz,1H),5.50(q,J=6.7Hz,1H),5.44(s,2H),1.84(d,J=6.7Hz,3H).

[0555] 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] + . 1 H NMR(400MHz,CDCl3):12.41(s,1H),10.32(s,1H),8.39(s,1H),8.21(dd,J=2.9,1.4Hz,1H),8.17(d,J=2.8Hz,1H),7.66(dd,J=4.5,3.7Hz,2H),7.35( d,J=1.8Hz,1H),7.30(dd,J=8.2,1.9Hz,1H),7.12(d,J=0.8Hz,1H),6.33(t ,J=53.6Hz,1H),5.50(q,J=6.7Hz,1H),5.44(s,2H),1.84(d,J=6.7Hz,3H).

[0556] compound 252 [ka] 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) at 0 °C was added NaH (60% in oil, 763 mg, 19.1 mmol). 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. 1H NMR(400MHz,DMSO-d6):7.82(d,J=8.4Hz,1H),7.54(d,J=2.0Hz,1H),7.46(s, 4H),7.29(dd,J=8.4,1.6Hz,1H),5.91(q,J=6.4Hz,1H),1.54(d,J=6.4Hz,3H).

[0557] 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(400MHz,DMSO-d6):7.48-7.39(m,4H),6.81(d,J=2Hz,1H),6.75(dd,J=8.4,2.4Hz ,1H),6.55(d,J=8.4Hz,1H),5.52(q,J=6.4Hz,1H),4.99(s,2H),1.52(d,J=6.4Hz,3H).

[0558] 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(400MHz,DMSO-d6):7.49-7.38(m,4H),7.00(dd,J=7.6,0.8Hz,1H),6.94(m,1H),6.60 (d,J=8.0Hz,1H),5.47(q,J=6.4Hz,1H),5.24(s,2H),1.50(d,J=6.4Hz,3H),1.21(s,12H).

[0559] 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 A mixture of 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)Cl.DCM (102 mg, 126 μmol), NaCO (534 mg, 5.04 mmol), 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 × 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] + .

[0560] 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] + .

[0561] 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 then concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM:MeOH, 15:1) to give the title compound (10.6 mg, 33%) as a white solid. LCMS (Method A): 1.80 min, m / z: 564.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6):10.54(s,1H),9.64(s,1H),9.04(s,1H),8.21-8.20(m,1H),8.10(d,J=2.8Hz,1H),7.57(d,J=8.4Hz, 2H),7.42(d,J=8.4Hz,2H),7.39(d,J=8.0Hz,1H),7.20(m,1H),7.15(dd,J=8.0,1.6Hz,1H),7.04(t,J=52.8Hz,1H),6.20(br s,1H),5.63(q,J=6.0Hz,1H),1.59(d,J=6.4Hz,3H).

[0562] compound 12 [ka] 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 another 5 h. The reaction mixture was then 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 HO (20 mL). The precipitated solid was collected by filtration, washed with HO (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] + .

[0563] 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), 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]+ .

[0564] Step 3: 1-tert-butyl-3-[3-(2-methylpropoxy)-4-nitrophenyl]-5-{[6-trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carbonitrile A mixture of 2-methylpropan-1-ol (131 mg, 1.78 mmol), 1-tert-butyl-3-(3-fluoro-4-nitrophenyl)-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carbonitrile (800 mg, 1.78 mmol), and NaH (876 mg, 7.12 mmol) in THF (12 mL) 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 (NaSO), 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] + .

[0565] 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] + .

[0566] 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 NH 4 Cl (3 mL), and Zn powder (288 mg, 4.41 mmol) in MeOH (12 mL) was stirred at 60° C. overnight. The reaction mixture was concentrated, diluted with saturated NaHCO 3 (10 mL), and then extracted with EtOAc (3×10 mL). The combined organic phases were dried (Na 2 SO 4 ) 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] + .

[0567] 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 then 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] + .

[0568] Step 7: 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide (compound 12) A solution of 1-tert-butyl-3-[4-ethanesulfonamido-3-(2-methylpropoxy)phenyl]-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carboxamide (100 mg, 171 μmol) in DCM (4 mL) and TFA (4 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, neutralized to pH 7-8 with NHOH, diluted with HO (20 mL), and extracted with DCM (3 × 30 mL). The combined organics were washed with brine, dried (NaSO), 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] + . 1H NMR(400MHz,DMSO-d6):12.97(s,1H) 12.97(s,1H),9.77(s,1H),9.02(s,1H),8.22(d,J=7.6Hz,1H),7.98(t,J=7.6Hz,1H),7.45(d,J=8.0Hz,1H),7.23(t,J=7.6Hz,2H), 7.16(q,J=1.2Hz,1H),3.85(d,J=6.8Hz,2H),3.14(q,J=7.5Hz,2H),2.17-2.10(m,1H),1.26(q,J=7.2Hz,3H),1.03(d,J=6.4Hz,6H).

[0569] The following compounds (Table 17) were similarly prepared 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. [Table 19-1] [Table 19-2] [Table 19-3]

[0570] compound 5 [ka] 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, NaH (133 mg, 3.33 mmol) was added. 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] + .

[0571] 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] + .

[0572] 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) in MeOH (10 mL), saturated aqueous NH4Cl (2 mL), and Zn powder (285 mg, 4.36 mmol) was stirred at 60°C for 5 h. The reaction mixture was filtered, concentrated under reduced pressure, and diluted with HO. The precipitated solid was collected by filtration and then 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] + .

[0573] The compounds shown in Table 18 were prepared by a similar synthetic route as described for compound 46 (steps 6 and 7). [Table 20]

[0574] compound 46 [ka] 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 KCO (16.4 g, 119 mmol) in MeCN (200 mL) was stirred at 70 °C overnight under N. The 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, 15:1) to give the title product (3 g, 20%) as a yellow solid. 1H NMR(400MHz,DMSO-d6):10.70(s,1H),8.10(d,J=8.0Hz,1H),7.93(d,J=1.2Hz,1H),7.69(dd,J=8.0,1.2Hz,1H),7.48-7.34(m,5H),5.42(s,2H).

[0575] 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 reduced pressure to provide 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), 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] + .

[0576] Step 3: 3-[3-(benzyloxy)-4-nitrophenyl]-1-tert-butyl-5-{[6-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-4-carbonitrile A mixture of 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), Pd(dba) (350 mg, 383 μmol), Xantphos (221 mg, 383 μmol), and CsCO (2.49 g, 7.66 mmol) in degassed 1,4-dioxane (75 mL) was stirred at 100 °C for 16 h under N. The reaction 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, 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] + .

[0577] 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), forming 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] + .

[0578] 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 NH 4 Cl (2 mL), and Zn powder (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 (Na 2 SO 4 ) 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] + .

[0579] 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] + .

[0580] 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 NaCO, and diluted with H0 (10 mL). The precipitated solid was collected by filtration and dried under reduced pressure 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(400MHz,DMSO-d6):13.01(s,1H),9.78(s,1H),9.19(s,1H),8.23(d,J=8.0Hz,1H),7.99(t,J=7.6Hz,1H),7.63-7.15(m,10H),6.21(br s,1H),5.21(s,2H),3.06(q,J=6.8Hz,2H),1.17(t,J=6.8Hz,3H).

[0581] compound 229 [ka] 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 HO (50 mL) and then extracted with EtOAc (3 x 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, 30:1) to give the title product (190 mg, 61%) as a yellow solid. LCMS (Method A): 4.35 min, m / z: 725.2 [M+H] + .

[0582] 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 then 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] + .

[0583] Step 3: 3-[4-(Difluoromethanesulfonamido)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-5-{[6-(trifluoromethyl)pyridin-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 minutes. The reaction mixture was neutralized to pH 7-8 with NH4OH and then 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 compound (19.2 mg, 52%) as a white solid. LCMS (Method A): 4.03 min, m / z: 615.1 [M+H] + . 1H NMR:(400MHz,DMSO-d6):13.01(s,1H),10.55(s,1H),9.67(s,1H),8.16(d,J=8.4Hz,1H),7.99-7.95(m,1H),7.6 0-7.57(m,1H),7.40(d,J=8.0Hz,1H),7.30(d,J=7.2Hz,1H),7.21-7.14(m,5H),7.02(t,J=52.8Hz,1H),6.12(br s 1H),5.65(m,1H),1.58(d,J=6.0Hz,3H).

[0584] compound 45 [ka] 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-[(py...

Claims

1. A compound of formula (X): MLKLi-L-E3L (X) During the ceremony, E3L is an E3 ligase binding moiety; L is a linker covalently linking MLKLi to E3L; MLKLi is a radical of formula (I), 【Chemistry 1】 During the ceremony, Q １ and Q ２ However, N and NR １ is selected from １ When is N, Q ２ NR １ and Q ２ When is N, Q １ NR １ and R １ and R ３ are independently H and optionally substituted C １～６ - alkyl, R ２ is optionally substituted C １～６ - alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; X is 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 alkylcycloalkyl, and optionally substituted amino; Y and Z are independently H, R ４ , -OR ４ , -NR ４ R ５ and halo; at least one of Y and Z is H; R ４ is 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 is alkyl, The compound, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

2. R ２ is optionally substituted aryl or optionally substituted heterocyclyl, and / or R2 is optionally substituted 5- or 6-membered heterocyclyl, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, and / or prodrug thereof.

3. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, and / or prodrug thereof, provided by the following formula (XI): 【Chemistry 2】

4. provided by the following formula (XII): 【Transformation 3】 In the formula, A １ ~A ５ However, independently, N, CR １１ and CL-E3L; A １ ~A ５ One of them is CL-E3L, A １ , A ２ , A ３ , A ４ , and A ５ at most two of are N, Each R １１ independently H and R １０ is selected from Each R １０ But independently, Halo, C 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 acyl, arylacyl, heterocyclyl acyl, 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, C １～６ Alkylheterocyclyl, C １～６ Alkoxyheterocyclyl, halo C １～６ Alkylheterocyclyl, haloC １～６ Alkoxyheterocyclyl, C １～６ Alkyl C １～６ alkoxy, and —COOH; or A １ , A ２ , A ３ , A ４ , A ５ two adjacent groups selected from CR １１ When two R １１ can together form an optionally substituted 5- to 10-membered ring selected from cycloalkyl, aryl, and heterocyclyl, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, and / or prodrug thereof.

5. A １ ~A ５ is as defined for any one of embodiments 1-4, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, and / or prodrug thereof. Table 1

6. It is provided by the following formula (XIII): 【Chemistry 4】 During the ceremony, A ９ , A １０ , A １１ , and A １２ But independently, C(R １１ ) ｑ ,O,S,N,NR １２ , C(R １１ )-L-E3L, CL-E3L, and NL-E3L; A ９ , A １０ , A １１ , and A １２ One of them is C(R １１ )-L-E3L, CL-E3L, and NL-E3L; A ９ , A １０ , A １１ , and A １２ At least one of C(R １１ ) ２ ,O,S,NR １２ , C(R １１ )-L-E3L; Each R １１ independently H and R １０ is selected from Each R １０ But independently, Halo, C 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 acyl, arylacyl, heterocyclyl acyl, 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, C １～６ Alkylheterocyclyl, C １～６ Alkoxyheterocyclyl, halo C １～６ Alkylheterocyclyl, haloC １～６ Alkoxyheterocyclyl, C １～６ Alkyl C １～６ alkoxy, and —COOH; Each R １２ However, independently, H, C １～６ Alkyl, haloC １～４ Alkyl, C １～６ Alkyl acyl and halo C １～６ alkyl acyls; or A ９ , A １０ , A １１ , and A １２ two adjacent groups selected from CR １１ , C(R １１ )-L-E3L, and NR １２ When selected from １１ , two R １２ , or one R １１ and one R １２ together can form an optionally substituted 5-10 membered ring selected from cycloalkyl, aryl, and heterocyclyl; 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, and / or prodrug thereof, wherein q is 1 or 2.

7. A １２ is N and A １１ is N-L-E3L, and A １０ But, CR １１ and A ９ But, CR １１ 7. The compound of claim 6, wherein:

8. the E3 ligase binding portion, 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 【Chemistry 5-4】 is selected from where the arrow indicates a covalent bond to L, any portion of L not depicted in the structure, or 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, representing an E3 ligase binding derivative thereof.

9. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, wherein the linker has a minimum linear chain length of 1 to 50 atoms.

10. The linker is optionally interrupted by one or more groups selected from １～５０ is alkyl, a. -O-, b.-NR ｚ -、 c.C ３～８ cycloalkyl, d. aryl, e.C １～４ Al-Khalil, f. heteroaryl, g. (C １～４ alkoxy) １～４ aryl, h. haloaryl, i. 4- to 8-membered non-aromatic heterocyclyl, j. Each R ｚ independently H and C １～４ alkyl, —C(O)NR ｚ -, k. alkenyl, l. alkynyl, Each of said one or more groups a through l is C ３～６ Cycloalkyl, halo, —OH, —CN, —NR ｚ ２ , C １～４ Alkyl, C １～４ Alkoxy, oxo, C １～４ Alkyl ketone, —COOH, —C(O)N(R ｚ ) ２ , and -NR ｚ C(O)R ｚ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, optionally further substituted with a group selected from:

11. The linker is a moiety -(OCH ２ CH ２ ) ｖ -, wherein v is an integer from 1 to 15, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

12. The linker is —C(O)O—, —C(O)NR ｚ -, -OC(O)O-, -NR ｚ C(O)NR ｚ -, -OC(O)NR ｚ -, triazolyl, aryl, α,β-unsubstituted ketone, β-hydroxy-ketone, 4-8 membered heteroaryl, unsaturated C ６ -cycloalkyl, and optionally substituted C ２ alkenyl; and each R ｚ independently H and C １～４ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, wherein:

13. The compound is 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 【Chemistry 6-4】 【Transformation 6-5】 【Transformation 6-6】 [Transformation 6-7] [Transformation 6-8] 【Transformation 6-9】 【Chemistry 6-10】 【Chemistry 6-11】 【Chemistry 6-12】 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, selected from:

14. A medicament comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

15. 14. A pharmaceutical composition comprising the compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, and a pharmaceutically acceptable excipient.

16. 14. Use of a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, in the manufacture of a medicament for treating necroptosis and / or for preventing or treating one or more diseases, conditions, and / or disorders selected from the following: - 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, Muscular dystrophies, for example Duchenne muscular dystrophy, myotonic dystrophy, myopathies and myasthenia, skin disorders such as dermatitis, eczema, psoriasis, age-related or even scar changes, cardiovascular diseases such as cardiac and / or vascular ischemia, myocardial infarction, ischemic heart disease, chronic or acute congestive heart failure, cardiac dysrhythmia, atrial fibrillation, ventricular fibrillation, paroxysmal tachycardia, congestive heart failure, hypertrophic heart disease, anoxia, hypoxia, secondary effects of anti-cancer drug therapy, - cardiovascular diseases such as atherosclerosis, arteriosclerosis and peripheral vascular disease, stroke including cerebrovascular accident, aneurysm, - hematological and vascular diseases such as anemia, aplastic anemia, vascular amyloidosis, bleeding, sickle cell disease, red cell fragmentation syndrome, neutropenia, leukopenia, medullary hypoplasia, pancytopenia, thrombocytopenia, hemophilia, Pulmonary diseases, including pneumonia, asthma, chronic obstructive pulmonary diseases such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, and emphysema, - gastrointestinal diseases 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 pathogens as etiological agents, autoimmune hepatitis, fulminant hepatitis, inflammatory hepatitis, certain inherited metabolic disorders, Wilson's disease, cirrhosis, non-alcoholic fatty liver disease (NAFLD), including non-alcoholic fatty liver and / or non-alcoholic steatohepatitis (NASH), liver diseases caused by toxins and drugs, such as drug-induced liver injury, ethanol (or alcohol)-induced liver disease, diseases of the pancreas, such as acute or chronic pancreatitis, metabolic diseases such as diabetes, thyroiditis, including diabetes mellitus, pre-diabetes and diabetes insipidus, kidney diseases such as acute kidney injury (such as acute kidney injury (AKI) including ischemia-reperfusion injury (IRI)) or glomerulonephritis, - viral and bacterial infections such as sepsis, - severe poisoning by chemicals, toxins or drugs; - degenerative diseases associated with acquired immune deficiency syndrome (AIDS), - age-related disorders such as the syndrome of accelerated ageing, - inflammatory diseases such as Crohn's disease, rheumatoid polyarthritis, terminal ileitis, including TNF-induced systemic inflammatory syndrome; autoimmune diseases such as lupus erythematosus (including systemic lupus erythematosus), amputation-resistant RIPK1-induced autoinflammation (CRIA) syndrome, - dental disorders, such as those resulting in tissue degradation, for example periodontitis, - ocular 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-operative complications, drug-induced retinopathy, cataracts, cone cell degeneration; - disorders of the Eustachian tube, 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 related to mitochondria (mitochondrial diseases), such as Friedreich's ataxia, congenital muscular dystrophies with structural mitochondrial abnormalities, certain 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 carcinoma; multiple myeloma; esophageal cancer, including squamous cell carcinoma and adenocarcinoma of the esophagus; acute myeloid leukemia (AML); accelerated Chronic myeloid leukemia (CML), including primary 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; cancers of the brain, including glioma / glioblastoma, anaplastic oligodendroglioma, and adult anaplastic astrocytoma; neuroendocrine cancers, including metastatic neuroendocrine tumors; cancers of the head and neck, including squamous cell carcinoma of the head and neck and nasopharyngeal carcinoma; cancers of the oral cavity, pharynx, and small intestine; bone cancer; soft tissue sarcoma; and colon villous adenoma, including, but not limited to, cancers and metastases; and - Diseases of the central nervous system (CNS), such as multiple sclerosis (MS).

17. 14. An in vitro or ex vivo method of inhibiting and / or degrading mixed lineage kinase domain-like protein (MLKL), comprising contacting a cell in vitro or ex vivo with a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

18. An agent for degrading MLKL, comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

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