Bifunctional aryl 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. 2021904198 filed on 22 December 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to 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 inhibiting necroptosis-associated diseases. Surprisingly, the inventors of the present invention have now discovered that other types of compounds are also suitable for inhibiting necroptosis-associated diseases. Furthermore, and 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. Additionally, the compounds described herein are potent inhibitors and degraders of different MLKL homologs, including human and mouse MLKL. Cross-homolog MLKL efficacy can provide useful preclinical safety and efficacy data.

[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, J is selected from the following moieties J1 and J2: [ka] A 1 and A 4 is independently selected from N and C; A 2 and A 3 are independently N and NR 1 , CH, O, and S; A 1 , A 2 , A 3 , and A 4 At least one of the following is N, NR 1, O, and S; A 5 is CH or N, A 6 is N or CR 2 and R 1 and R 3 are independently selected from H and optionally substituted C 1~6 -alkyl, R 2 teeth, (i) H, (ii) optionally substituted C 1~4 alkylamides, (iii) optionally substituted C 1~4 alkylaryl, (iv) optionally substituted C 2~4 Alkynyl, (v) optionally substituted aryl; (vi) optionally substituted 5- or 6-membered heterocyclyl, (vii) cyano; 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 , -NR 4 R 4 ', and halo; at least one of Y and Z is H; R 4 is an optionally substituted C 1~6 Alkyl, optionally substituted aryl, optionally substituted C 1~6alkylaryl, 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 4’ is H or optionally substituted C 1~6 is alkyl, R 5 is H, optionally substituted C 1~6 Alkyl, optionally substituted C 3~10 It is selected from cycloalkyl, and optionally substituted aryl.

[0011] In some embodiments, R 2 teeth, (i) H, (ii) optionally substituted C 1~4 alkylamides, (iii) optionally substituted C 1~4 alkylaryl, (iv) optionally substituted C 2~4 Alkynyl, (v) optionally substituted aryl; (vi) optionally substituted 5- or 6-membered heterocyclyl.

[0012] In some embodiments, MLKLi is a compound of formula (X) containing a radical at the following position: i)R2 and when J is J1, R is such that L is covalently bonded 2 , or ii)R 5 and when J is J2, R is such that L is covalently bonded 5 .

[0013] In some embodiments, the compound of formula (X) may be provided as a compound of formula (XX): [ka] In the formula, A 1 , A 2 , A 3 , A 4 ,n,R 1 , R 2 , R 3 , R 4 , R 4’ , X, Y, Z, L, and E3L are as defined herein.

[0014] In some embodiments, the compound of formula (X) can be provided as a compound of formula (XXa): [ka] In the formula, A 5 , A 6 , R 1 , R 2 , R 3 , R 4 , R 4’ , R 5 , X, Y, Z, L, and E3L are as defined herein.

[0015] 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.

[0016] The present inventors have discovered that compounds of formula (I) are selective degraders of MLKL. Degradation of MLKL may 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.

[0017] In some embodiments, the compound of the present invention is selected from any of compounds 1001-1031, 1037, and 1039-1145 described herein, preferably any of compounds 1001-1031, 1037, and 1039-1137.

[0018] In some embodiments, the compound of the present invention is selected from any of compounds 1001-1031, preferably any of compounds 1001-1023 and 1029-1031, and more preferably any of compounds 1003, 1005, 1006, 1008-1012, 1014, 1015, 1017, and 1022.

[0019] In some embodiments, the compound of the invention comprises a radical of any of compounds 1-173 described herein.

[0020] In some embodiments, the compound of the present invention comprises a radical of any of compounds 7, 9, 12, 13, 14, 15, 16, 18, 19, 20, and 72.

[0021] In some embodiments, the compound of the present invention comprises a radical of any of compounds 1, 7, 9, 12-16, 18-21, 23-32, 35-46, 48, 50-52, 55-62, 72-89, 92-109, 111, 113, 115-117, and 119-123, preferably a radical of any of compounds 19, 29-31, 36, 38, 40-41, 75-77, 81, 100-101, 103-104, 109, 120, and 123.

[0022] In some embodiments, the compound of the present invention comprises a radical of any of compounds 1, 5, 7-9, 11-16, 18-21, 23-32, 35-46, 48, 50-52, 55-62, 66, 69, 70, 72-89, 92-109, 111, 113, 115-117, and 119-123, preferably a radical of any of compounds 5, 7-9, 11-13, 15, 18-20, 60, 61, 66, 69, 70, and 72.

[0023] In some embodiments, the compound of the invention comprises a radical of any of compounds 3, 11, 13, 19, 29, 30, 46, 79, 80, 81, 97, 98, 99, 103, 104, 109, 113, 116, 120, 121, and 122.

[0024] 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.

[0025] In another aspect, there is provided a pharmaceutical composition comprising a compound of the invention and, optionally, a pharmaceutically acceptable excipient.

[0026] 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.

[0027] In another aspect, a method of degrading MLKL is provided, comprising contacting a cell with a compound of the invention.

[0028] In another aspect, there is provided a compound of the invention for use in treating necroptosis and for use in degrading MLKL.

[0029] Any embodiment herein shall be deemed to apply mutatis mutandis to any other embodiment unless otherwise stated.

[0030] 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.

[0031] 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.

[0032] definition Unless otherwise defined herein, the following terms shall be understood to have the following general meanings:

[0033] 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.

[0034] 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.

[0035] 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. 2~4 Alkynyl or C 2~3 Alkynyl is preferred.

[0036] 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. 3~6Cycloalkyl is preferred. Cycloalkyl groups also include polycyclic carbocycles, including fused, bridged, and spirocyclic systems.

[0037] The terms "hydroxy" and "hydroxyl" refer to the group --OH.

[0038] The term "oxo" refers to the group =O.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] The terms "carboxylate" or "carboxyl" refer to a -COO- or -COOH group.

[0043] The term "ester" refers to an ester in which the hydrogen is, for example, C 1~6 Alkyl group (carboxyl group) 1~6It 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).

[0044] The terms "cyano" and "nitrile" refer to the group --CN.

[0045] The term "nitro" refers to the group --NO.sub.2.

[0046] The term "amino" refers to the group --NH.sub.2.

[0047] 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 1~6 Also included are "disubstituted amino" (or "tertiary amino") groups, which refer to amino groups substituted with alkyl groups ("dialkylamino"), aryl and alkyl groups ("aryl(alkyl)amino"), and the like. Preferred tertiary amino groups include di(C) amino groups, such as dimethylamino (NMe), diethylamino (NEt), dipropylamino (NPr), and variations thereof (e.g., N(Me)(Et), etc.).1~3 alkyl)amino groups.

[0048] The term "aldehyde" refers to the group -C(=O)H.

[0049] The terms "acyl" and "acetyl" refer to the group -C(O)CH3.

[0050] The term "ketone" refers to a carbonyl group which may be represented by -C(O)-.

[0051] 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.

[0052] The terms "amido" or "amide" refer to the group -C(O)NH2.

[0053] 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 1~6 It refers to an amide group substituted with an aryl ("arylamide"), aralkyl ("aralkylamide"), or the like. For example, C groups such as methylamide (-C(O)NHMe), ethylamide (-C(O)NHEt), and propylamide (-C(O)NHPr) are used. 1~3 Alkyl amide groups are preferred, including their reverse amides (eg, -NHMeC(O)-, -NHEtC(O)-, and -NHPrC(O)-).

[0054] The term "disubstituted amido" or "disubstituted amide" refers to a disubstituted amide 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 a di(C(O)NMe2), an aralkyl group, and an alkyl group ("alkyl(aralkyl)amide"). For example, di(C(O)NMe2), diethylamide (-C(O)NEt2), dipropylamide (-C(O)NPr2), and variations thereof (e.g., -C(O)N(Me)Et, etc.) are examples of amide groups. 1~3 (Alkyl)amide groups are preferred, including their reverse amides.

[0055] The term "thiol" refers to the group --SH.

[0056] 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.

[0057] The term "thioxo" refers to the group ═S.

[0058] The term "sulfinyl" refers to the group -S(=O)H.

[0059] 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.

[0060] The term "sulfonyl" refers to the group -SO2H.

[0061] 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.

[0062] The term "sulfonyl" refers to the group -SO2NH2.

[0063] The term "substituted sulfonamido" or "substituted sulphonamide" refers to an amide in which 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 (eg, -NHSO2Me, -NHSO2Et, and -NHSO2Pr).

[0064] The term "disubstituted sulfonamido" or "disubstituted sulphonamide" refers to a sulfonamide in which the two hydrogens are, for example, the same or different, C 1~6 Alkyl group ("sulfonylamide di(C 1~6It 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.).

[0065] 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.

[0066] 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.

[0067] 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.

[0068] The term "alkoxyaryl" refers to C aryls such as benzyloxy. 1~6 It refers to alkyloxyaryl.

[0069] The term "heterocyclyl" refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has 3 to 10 ring atoms (unless otherwise specified), of which 1, 2, 3, or 4 are ring heteroatoms, each heteroatom being independently selected from O, S, and N. Heterocyclyl groups include monocyclic ring systems and polycyclic (e.g., bicyclic) ring systems, including fused, bridged, and spiro ring systems, provided that at least one of the rings in the ring system contains at least one heteroatom.

[0070] 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.

[0071] 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).

[0072] Heterocyclyl includes aromatic heterocyclyl and non-aromatic heterocyclyl. Such groups can be substituted or unsubstituted.

[0073] 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 may contain a heteroatom; not all rings must be aromatic.

[0074] 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.

[0075] 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.

[0076] An aromatic heterocyclyl group may be a 5- or 6-membered monocyclic aromatic ring system.

[0077] 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.

[0078] 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).

[0079] 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.

[0080] 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.

[0081] 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).

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] The non-aromatic heterocyclyl can be a 3- to 7-membered monocyclic ring.

[0088] 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.

[0089] 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.

[0090] Examples of 7-membered non-aromatic heterocyclyls include azepanyl, oxepanyl, thiepanyl, and the like.

[0091] 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.

[0092] The term "halo" refers to fluoro, chloro, bromo, or iodo.

[0093] 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.

[0094] 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.

[0095] It will be appreciated that suitable derivatives of nitrogen-containing aromatic heterocyclyls include their N-oxides.

[0096] 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 group ordering 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 a bond; for example, "-alkylaryl" or "arylalkyl-" indicates that the point of attachment of the radical to the rest of the compound is through the alkyl moiety, and "alkylaryl-" or "-arylalkyl" indicates that the point of attachment is through the aryl moiety.

[0097] [ka] It will be understood that represents a single or double bond, depending on the required valence. Unless otherwise specified, all bonds within a ring are [ka] When represented by, the ring is intended to be aromatic.

[0098] 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.

[0099] 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.

[0100] The term "and / or" can mean "and" or "or."

[0101] The term "(s)" following a noun contemplates either the singular or the plural, or both.

[0102] 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 with the term "about" to account, at least in part, for this variability. When used to describe a value, the term "about" can mean an amount within ±10%, ±5%, ±1%, or ±0.1% of that value.

[0103] 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:

[0104] Detailed Description of the Embodiments The present invention provides a compound of 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, J is selected from the following moieties J1 and J2: [ka] A 1 and A 4 is independently selected from N and C; A 2 and A 3 are independently N and NR 1 , CH, O, and S; A 1 , A 2 , A 3 , and A 4 At least one of the following is N, NR 1 , O, and S; A 5 is CH or N, A 6 is N or CR 2 and R 1 and R 3 are independently selected from H and optionally substituted C 1~6 -alkyl, R 2 teeth, (i) H, (ii) optionally substituted C 1~4 alkylamides, (iii) optionally substituted C 1~4 alkylaryl, (iv) optionally substituted C 2~4 Alkynyl, (v) optionally substituted aryl; (vi) optionally substituted 5- or 6-membered heterocyclyl, (vii) cyano; X is an optionally substituted C 1~6 alkyl, optionally substituted haloC 1~6 Alkyl, optionally substituted C 2~6Alkynyl, 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 4 ', and halo; at least one of Y and Z is H; R 4 is an optionally substituted C 1~6 Alkyl, optionally substituted aryl, optionally substituted C 1~6 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1~6 Alkylheterocyclyl, optionally substituted cycloalkyl, optionally substituted C 1~6 Alkyl C 3~10 Cycloalkyl, optionally substituted C 3~10 Cycloalkylaryl, optionally substituted C 3~10 Cycloalkylheterocyclyl, optionally substituted C 3~10 Cycloalkyl C 3~10 Cycloalkyl, optionally substituted 3- to 6-membered non-aromatic heterocyclyl-aryl, optionally substituted 3- to 6-membered non-aromatic heterocyclylC 3~10 cycloalkyl, and optionally substituted 3- to 6-membered non-aromatic heterocyclyl-3- to 10-membered heterocyclyl; R 4’ is H or optionally substituted C 1~6 is alkyl, R 5 is H, optionally substituted C 1~6 Alkyl, optionally substituted C 3~10 It is selected from cycloalkyl, and optionally substituted aryl.

[0105] MLKLi In the compounds of the present invention, MLKLi is a radical of the compound of formula (I).

[0106] 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.

[0107] In some embodiments, a compound of formula (I) is provided: [ka] During the ceremony, J is selected from the following moieties J1 and J2: [ka] A 1 and A 4 is independently selected from N and C; A 2 and A 3 are independently N and NR 1 , CH, O, and S; A 1 , A 2 , A 3 , and A 4 At least one of the following is N, NR 1 , O, and S; A 5 is CH or N, A 6 is N or CR 2 and R 1 and R 3 are independently selected from H and optionally substituted C 1~6 -alkyl, R 2 teeth, (i) H, (ii) optionally substituted C 1~4 alkylamides, (iii) optionally substituted C 1~4 alkylaryl, (iv) optionally substituted C 2~4 Alkynyl, (v) optionally substituted aryl; (vi) optionally substituted 5- or 6-membered heterocyclyl, (vii) cyano; 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 , -NR 4 R 4 ', and halo; at least one of Y and Z is H; R 4 is an optionally substituted C 1~6 Alkyl, optionally substituted aryl, optionally substituted C 1~6 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1~6 Alkylheterocyclyl, optionally substituted cycloalkyl, optionally substituted C 1~6 Alkyl C 3~10 Cycloalkyl, optionally substituted C 3~10 Cycloalkylaryl, optionally substituted C 3~10 Cycloalkylheterocyclyl, optionally substituted C 3~10 Cycloalkyl C 3~10 Cycloalkyl, optionally substituted 3- to 6-membered non-aromatic heterocyclyl-aryl, optionally substituted 3- to 6-membered non-aromatic heterocyclylC 3~10cycloalkyl, and optionally substituted 3- to 6-membered non-aromatic heterocyclyl-3- to 10-membered heterocyclyl; R 4’ is H or optionally substituted C 1~6 is alkyl, R 5 is H, optionally substituted C 1~6 Alkyl, optionally substituted C 3~10 It is selected from cycloalkyl, and optionally substituted aryl.

[0108] X In some embodiments, X is C 1~6 Alkyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, aryl, -(CH2) n Aryl, -(CH2) n Cycloalkyl, and -N(C 1~4 alkyl)2; 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.

[0109] In some embodiments, X is optionally substituted C 1~4 Alkyl, optionally substituted C 2~4Alkynyl, 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.

[0110] In some embodiments, X is optionally substituted C 1~4 alkyl, optionally substituted haloC 1~4 Alkyl, and C 3~6 cycloalkyl.

[0111] In some embodiments, X is optionally substituted C 1~2 alkyl, optionally substituted haloC 1~2 alkyl, and C3 cycloalkyl.

[0112] In some embodiments, X is an optionally substituted haloC selected from -CHF2, -CF3, -CH2CF3, -CH2CHF2, and -CH2CH2CF3. 1~4 It is alkyl.

[0113] In some embodiments, X is an optionally substituted haloC 1~2 It is alkyl.

[0114] In some embodiments, X is an optionally substituted amino, preferably —N(C 1~4In some embodiments, X is a disubstituted amino such as —N(CH 3 ) 2 .

[0115] 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] is selected from.

[0116] In some embodiments, X is selected from any one of the following groups: ethyl, difluoromethyl, trifluoroethyl, and cyclopropyl.

[0117] In some embodiments, X is difluoromethyl.

[0118] 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]

[0119] Y and Z In some embodiments, Y and Z are independently H, R 4 , -OR4 , and -NR 4 R 4’ is selected from At least one of Y and Z is H.

[0120] In some embodiments, Y and Z are independently H, R 4 , -OR 4 and halo; At least one of Y and Z is H.

[0121] In some embodiments, Y and Z are independently H, R 4 , -OR 4 , -NR 4 R 4’ and halo; At least one of Y and Z is H, and the remaining one of Y and Z is R 4 , -OR 4 , -NR 4 R 4’ and halo.

[0122] In some embodiments, Y and Z are independently H, R 4 , -OR 4 and halo; At least one of Y and Z is H, and the remaining one of Y and Z is R 4 , -OR 4 and halo.

[0123] In some embodiments, Y and Z are independently H, R 4 , -OR 4 is selected from At least one of Y and Z is H.

[0124] In some embodiments, Y and Z are independently H, —OR 4 and halo; At least one of Y and Z is H.

[0125] In some embodiments, Y and Z are independently H and —OR 4 is selected from At least one of Y and Z is H.

[0126] In some embodiments, Y is -OR 4 When Z is H. In these embodiments, the compound of formula (I) may be provided as a compound of formula (Ia): [ka] In the formula, J, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 ,n,R 1 , R 2 , R 3 , R 4 , R 5 and X is as defined for formula (I) or any embodiment thereof.

[0127] In some embodiments, Z is -OR 4 When Y is H. In these embodiments, the compound of formula (I) may be provided as a compound of formula (Ib): [ka] In the formula, J, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 ,n,R 1 , R 2 , R 3 , R 4 , R 5 and X is as defined for formula (I) or any embodiment thereof.

[0128] In some embodiments, Z is -R 4 Then Y is H.

[0129] In some embodiments, Y is -R 4 When

[0130] In some embodiments, when Z is halo, Y is H.

[0131] In some embodiments, when Y is halo, Z is H.

[0132] In some embodiments, both Y and Z are H.

[0133] In some embodiments, Y and Z are independently H, R 4 , -OR 4 and halo; At least one of Y and Z is H, and the remaining one of Y and Z is R 4 , -OR 4 and halo.

[0134] In some embodiments, Y and Z are independently H, R 4 , and -OR 4 is selected from At least one of Y and Z is H, and the remaining one of Y and Z is R 4 and -OR 4 is selected from.

[0135] In some embodiments, Y and Z are independently H, —OR 4 and halo; At least one of Y and Z is H, and the remaining one of Y and Z is -OR 4 and halo.

[0136] In some embodiments, the halo in Y and Z is fluoro.

[0137] R 4’ In some embodiments, R 4’ is H. In some embodiments, R4’ is C 1~6 It is alkyl.

[0138] R 4 In some embodiments, 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 1~4 optionally 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, and heterocyclyl.

[0139] 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 halo C 1~4 Optionally substituted with one or more groups selected from alkoxy.

[0140] In some embodiments, R 4 is C 1~6 Alkyl, aryl, cycloalkyl, heterocyclyl, and -(CH2) m R 9 is selected from R 9is 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.

[0141] In some embodiments, 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 1~2 Alkylaralkylhalo, -C 1~2 selected from alkylarylhaloalkoxy, cycloalkylaryl, cycloalkylheterocyclyl, cycloalkylcycloalkyl, 3- to 6-membered non-aromatic heterocyclyl-aryl, 3- to 6-membered non-aromatic heterocyclylcycloalkyl, and 3- to 6-membered non-aromatic heterocyclyl-3- to 10-membered heterocyclyl; Each alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, 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.

[0142] In some embodiments, R 4is an optionally substituted C1 alkylC6 aryl. In some embodiments, the C1 alkyl moiety is substituted. In some embodiments, the aryl moiety is substituted. In some embodiments, the C1 alkylC6 aryl moiety can be represented by the following 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.

[0143] In some embodiments, 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 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 C 1~4 When it is alkylamino, C 1~4 The alkyl or amino moieties may be optionally substituted.

[0144] 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.

[0145] 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.

[0146] In some embodiments, R 5 is H, C 1~6 Alkyl, C 3~8 In some embodiments, R is selected from cycloalkyl, cycloalkyl, and aryl. 5 is H and optionally substituted C 1~6 In some embodiments, R 5 is selected from H and optionally substituted aryl. In some embodiments, R 5 is selected from H, optionally substituted methyl, and optionally substituted phenyl. In some embodiments, R 5 is H.

[0147] In some embodiments, m is 0 or 1.

[0148] In some embodiments, m is 1 or 2.

[0149] In some embodiments, at least one R c is in the para position relative to the benzylic carbon atom.

[0150] In some embodiments, R c is selected from methyl, fluoro, and chloro.

[0151] In some embodiments, R a is selected from H and methyl; R b is H.

[0152] In some embodiments, R a and R b together with the carbon atom to which they are attached is cyclopropyl.

[0153] In some embodiments, R 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 1~5alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1~5 Alkylheterocyclyl, optionally substituted cycloalkyl, and optionally substituted C 1~5 Alkyl C 3~10 cycloalkyl.

[0154] In these embodiments, the compound of formula (I) may be provided as a compound of formula (IV): [ka] In the formula, X, R 3 , R d , R e , and J are as defined for any compound herein.

[0155] In some embodiments, R d is methyl.

[0156] 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.

[0157] In some embodiments, R e is selected from optionally substituted aryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl.

[0158] In some embodiments, R e is selected from optionally substituted aryl and optionally substituted heteroaryl.

[0159] In some embodiments, R dis an optionally substituted 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 The carbon to which R is attached may contain a chiral center. 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 e The carbon atom to which is attached is enriched as the (S) stereoisomer.

[0160] 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. dThe inventors have surprisingly found that compounds with this configuration at this position possess higher MLKL activity than compounds with other configurations. e is R in the Cahn-Ingold-Prelog rules for stereochemical assignment. d If it has a higher ranking, the MLKL activity may be more than 2-fold more active than the other corresponding stereoisomers, and in some embodiments may be at least about 5-fold or about 10-fold more active than the other corresponding stereoisomers for MLKL inhibition.

[0161] In some embodiments, the compound is provided as a compound of formula (S): [ka] wherein X, J, and R 3 is as defined for formula (I), and R e and R d is as defined for sub-formula (A).

[0162] In some embodiments, R 4 is selected from any one of the following groups: [ka] [ka]

[0163] In some embodiments, R 4 is selected from any one of the following groups: [ka] [ka]

[0164] In some embodiments, R 4is selected from any one of the following groups: [ka]

[0165] In some embodiments, R 4 is selected from any one of the following groups: [ka]

[0166] In some embodiments, R 4 teeth, [ka] is.

[0167] R 1 and R 3 In some embodiments, R 1 and R 3 is H.

[0168] In some embodiments, R 3 is H and R 1 is selected from H, methyl and isopropyl, preferably methyl.

[0169] In some embodiments, R 1 is selected from H, methyl, and isopropyl. In some embodiments, R 1 is methyl.

[0170] J1 In some embodiments, J is J. In these embodiments, the compound of formula (I) may be provided as a compound of formula (II): [ka] In the formula, X, R 2 , R 3 , R 4 , A1 , A 2 , A 3 , and A 4 is as defined for formula (I) or any embodiment thereof.

[0171] In embodiments where J is J1, the compound of formula (I) may also be provided as a compound of formula (IIe): [ka] In the formula, X, R 2 , R 3 , R 4 , A 1 , A 2 , A 3 , and A 4 is as defined for formula (I) or any embodiment thereof.

[0172] The J1 structure shown below (and equivalent structures in other formulas) depicts a conjugated fused aromatic ring system. [ka]

[0173] For example, in some embodiments, J1 may have the following substitution pattern: [ka]

[0174] Similarly, in other embodiments, J1 may have the following substitution pattern: [ka]

[0175] In compounds where J is J1, A 1 , A 2 , A 3 , and A 4 At least one of the following is N, NR 1 , O, and S. In some embodiments, A 3 is N, NR1 , O, and S.

[0176] In some embodiments, A 1 is C or N. In some embodiments, A 1 is C.

[0177] In some embodiments, A 2 is selected from N and CH.

[0178] In some embodiments, A 4 is selected from C and N.

[0179] In some embodiments, A 1 , A 2 , A 3 , and A 4 is selected from the following embodiments: [Table 1]

[0180] In some embodiments, any one of embodiment numbers 1 to 4 is preferred.

[0181] In some embodiments, embodiment number 2 is preferred.

[0182] R 2 In some embodiments, R 2 teeth, (i) H, (ii) optionally substituted C 1~4 alkylamides, (iii) optionally substituted C 1~4 alkylaryl, (iv) optionally substituted C 2~4 Alkynyl, (v) optionally substituted aryl; (vi) optionally substituted 5- or 6-membered heterocyclyl.

[0183] In some embodiments, R 2 teeth, (i) optionally substituted C 1~4 alkylamides, (ii) optionally substituted C 1~4 alkylaryl, (iii) optionally substituted C 2~4 Alkynyl, (iv) optionally substituted aryl; (v) optionally substituted 5- or 6-membered heterocyclyl.

[0184] In some embodiments, R 2 is an optionally substituted C 2~4 In some embodiments, R is selected from alkynyl and optionally substituted 5- or 6-membered heterocyclyl. 2 is an optionally substituted C 2~4 alkynyl and optionally substituted 5- or 6-membered aromatic heterocyclyl. In some embodiments, R 2 is an optionally substituted C 2~4 alkynyl and optionally substituted 5-membered aromatic heterocyclyl. In some embodiments, R 2 is an optionally substituted C 2~4 In some embodiments, R is selected from alkynyl and optionally substituted 5- or 6-membered heterocyclyl, wherein the ring heteroatom of the heterocyclyl is N. 2 is an optionally substituted C 2~4 It is selected from alkynyl and optionally substituted 5- or 6-membered aromatic heterocyclyl, the ring heteroatom of which is N.

[0185] In some embodiments, R 2 is halo, optionally substituted C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 1~6 Alkyl-N(R 11)2, -N(R 11 )2, optionally substituted (C 1~6 alkyl)2amino, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted haloheterocyclyl, optionally substituted C 1~6 alkylheterocyclyl, optionally substituted haloC 1~6 Alkylheterocyclyl, optionally substituted C 1~4 Alkoxyheterocyclyl, optionally substituted acylheterocyclyl, optionally substituted C 1~4 Alkoxy, optionally substituted C 1~4 Alkyl-OH, optionally substituted C 1~4 Alkylhalo, optionally substituted C 1~4 Alkylheterocyclyl, optionally substituted C 1~4 Alkyl C 3~8 Cycloalkyl, optionally substituted C 1~4 alkylaryl, and each R 11 are independently H, optionally substituted C 1~4 Alkyl and optionally substituted C 1~4 alkylhalo, or two R 11 together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclyl.

[0186] In some embodiments, R 2 is halo, optionally substituted C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 1~6 Alkyl-N(R 11 )2, -N(R 11 )2, optionally substituted (C 1~6 alkyl)2amino, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted haloheterocyclyl, optionally substituted C 1~6alkylheterocyclyl, optionally substituted haloC 1~6 Alkylheterocyclyl, optionally substituted C 1~4 Alkoxyheterocyclyl, optionally substituted acylheterocyclyl, optionally substituted C 1~4 Alkoxy, optionally substituted C 1~4 Alkyl-OH, optionally substituted C 1~4 Alkylhalo, optionally substituted C 1~4 Alkylheterocyclyl, optionally substituted C 1~4 Alkyl C 3~8 Cycloalkyl, optionally substituted C 1~4 alkylaryl; and each R 11 are independently H, optionally substituted C 1~4 Alkyl and optionally substituted C 1~4 alkylhalo, or two R 11 together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclyl.

[0187] In some embodiments, R 2 is halo, optionally substituted C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted C 1~4 Alkoxy, optionally substituted C 1~4 Alkyl-OH, optionally substituted C 1~4 Alkylhalo, optionally substituted C 1~4 Alkylheterocyclyl, optionally substituted C 1~4 Alkyl C 3~8 Cycloalkyl, optionally substituted C 1~4 and 5- or 6-membered heterocyclyl optionally substituted with one or more groups selected from alkylaryl. In some embodiments, R 2 is H.

[0188] In some embodiments, R 2 is cyano.

[0189] In some embodiments, R 2 is H or cyano.

[0190] In some embodiments, R 2 is an optionally substituted C 1~4 Alkylamide or optionally substituted C 2~4 It is alkynyl.

[0191] In some embodiments, R 2 is an optionally substituted C 1~4 It is selected from alkylaryl, optionally substituted aryl, and optionally substituted 5- or 6-membered heterocyclyl.

[0192] In some embodiments, R 2 teeth, (i) optionally substituted aryl; (ii) halo, optionally substituted C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted C 1~4 Alkoxy, optionally substituted C 1~4 Alkyl-OH, optionally substituted C 1~4 Alkylhalo, optionally substituted C 1~4 Alkylheterocyclyl, optionally substituted C 1~4 Alkyl C 3~8 Cycloalkyl, optionally substituted C 1~4 and 5- or 6-membered heterocyclyl optionally substituted with one or more groups selected from alkylaryl.

[0193] In some embodiments, R 2is a 5- or 6-membered heterocyclyl selected from pyrazolyl, pyridyl, tetrahydropyridyl, isozazolyl, pyrimidinyl, piperidinyl and tetrahydropyranyl; 5- or 6-membered heterosilyl includes halo, optionally substituted C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 1~6 Alkyl-N(R 11 )2, -N(R 11 )2, optionally substituted (C 1~6 alkyl)2amino, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted haloheterocyclyl, optionally substituted C 1~6 alkylheterocyclyl, optionally substituted haloC 1~6 Alkylheterocyclyl, optionally substituted C 1~4 Alkoxyheterocyclyl, optionally substituted acylheterocyclyl, optionally substituted C 1~4 Alkoxy, optionally substituted C 1~4 Alkyl-OH, optionally substituted C 1~4 Alkylhalo, optionally substituted C 1~4 Alkylheterocyclyl, optionally substituted C 1~4 Alkyl C 3~8 Cycloalkyl, optionally substituted C 1~4 alkylaryl, and each R 11 are independently H, optionally substituted C 1~4 Alkyl and optionally substituted C 1~4 alkylhalo, or two R 11 together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclyl. In some embodiments, R 2 is halo, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6Alkylamide, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 1~6 Alkyl C 3~8 cycloalkyl, optionally substituted haloC 1~6 Alkyl C 3~8 Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted C 1~6 Alkylheterocyclyl, optionally substituted C 1~6 Alkoxy, optionally substituted C 1~6 Alkyl-OH and optionally substituted C 1~6 In some embodiments, an optionally substituted C is a 5- or 6-membered heterocyclyl optionally substituted with one or more substituents selected from alkylhalo. 1~6 Alkylamides are -C 1~6 AlkylC(O)NR ’ R ’’ wherein R ’ and R ’’ are independently selected from H and optionally substituted C 1~6 In some embodiments, any heterocyclyl group of these optional substituents can be a 4- to 7-membered heterocyclyl (including non-aromatic heterocyclyl groups and heteroaryl groups).

[0194] In some embodiments, R 2 is R as described herein 2 is a 5- or 6-membered heterocyclyl optionally substituted with any one, two, or three of the optional substituents

[0195] In some embodiments, R 2is a 5- or 6-membered heterocyclyl optionally substituted with 1, 2, or 3 groups, preferably 1 or 2 groups, selected from methyl, methoxy, methoxyethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, isopropyl, tert-butyl, 2-hydroxyethyl, dimethylamino, cyclopentyl, oxetanyl, tetrahydrofuranyl, piperidinyl, N-methyl-piperidinyl, tetrahydropyranyl, and N-methyl-piperazinyl-2-ethyl.

[0196] In some embodiments, R 2 is an optionally substituted 5- or 6-membered heterocyclyl selected from 4-pyridyl, 3-pyridyl, 4-piperidinyl, 1,4-piperazinyl, 4-tetrahydropyranyl, 2H,4H,5H-3-piperidinyl, 3,4-pyrazolyl, 3H,5H,6H-4-tetrahydropyranyl, 2,4-pyrimidinyl, and 3,4-isoxazolyl.

[0197] In some embodiments, R 2 is an optionally substituted pyrazolyl, preferably a substituted pyrazolyl, more preferably a monosubstituted pyrazolyl. Preferably, the monosubstituted pyrazolyl is substituted at N.

[0198] In some embodiments, R 2 is an optionally substituted C 1~4 alkylhalo, optionally substituted heterocyclyl, optionally substituted C 1~6 alkylheterocyclyl and optionally substituted haloC 1~6 and alkylheterocyclyl, optionally substituted with one or more groups selected from: In these embodiments, the 5- or 6-membered heterocyclyl is preferably selected from pyrazolyl, pyridyl, tetrahydropyridyl, isozazolyl, pyrimidinyl, piperidinyl, and tetrahydropyranyl, more preferably pyrazolyl, and most preferably N-substituted pyrazolyl.

[0199] In some embodiments, R 2 is an optionally substituted C 1~4 alkylhalo, optionally substituted heterocyclyl, optionally substituted C 1~6 alkylheterocyclyl and optionally substituted haloC 1~6 alkylheterocyclyl; Optionally substituted C 1~4 alkylhalo, optionally substituted heterocyclyl, optionally substituted C 1~6 alkylheterocyclyl and optionally substituted haloC 1~6 Alkylheterocyclyl is C 1~4 Alkyl and C 3~4 cycloalkyl. In these embodiments, the 5- or 6-membered heterocyclyl is preferably selected from pyrazolyl, pyridyl, tetrahydropyridyl, isozazolyl, pyrimidinyl, piperidinyl, and tetrahydropyranyl, more preferably pyrazolyl, and most preferably N-substituted pyrazolyl.

[0200] In some embodiments, R 2 is an optionally substituted 6-membered non-aromatic heterocyclyl.

[0201] In some embodiments, R 2 is a 5- or 6-membered heterocyclyl containing at least one nitrogen heteroatom. In some embodiments, R 2 is a 5- or 6-membered heterocyclyl containing at least one oxygen heteroatom. In some embodiments, R 2 is a 5- or 6-membered heterocyclyl containing at least one nitrogen and at least one oxygen heteroatom. In some embodiments, R 2 is a 5- or 6-membered heterocyclyl containing two nitrogen heteroatoms.

[0202] In some embodiments, R 2is an optionally substituted fused heterocyclyl.

[0203] In some embodiments, R 2 is an optionally substituted 5- or 6-membered heteroaryl.

[0204] In some embodiments, R 2 is an optionally substituted pyridyl.

[0205] In some embodiments, R 2 is an optionally substituted isoxazolyl.

[0206] In some embodiments, R 2 is an optionally substituted morpholinyl.

[0207] In some embodiments, R 2 is an optionally substituted pyrimidinyl.

[0208] In some embodiments, R 2 is an optionally substituted pyrrolyl.

[0209] In some embodiments, R 2 is an optionally substituted 1,3-dihydro-2H-benzo[d]imidazol-2-one, preferably containing methyl substitutions.

[0210] In some embodiments, R 2 is an optionally substituted 1-methylindolinyl-2-one.

[0211] In some embodiments, R 2 is an optionally substituted 1-methyl-1H-indazolyl.

[0212] In some embodiments, R 2 is enriched with one or more of the following minor isotopes: 2 H, 3 H,13 C. 14 C. 15 N, and / or 17 O, preferably 2 H.

[0213] In some embodiments, R 2 is an optionally substituted C 2~4 Alkynyl. C 2~4 Alkynyl is an optionally substituted C 3~8 cycloalkyl, optionally substituted haloC 3~8 Cycloalkyl, optionally substituted (C 1~6 alkyl) 1~3 C 3~8 Cycloalkyl, optionally substituted heterocyclyl, optionally substituted haloheterocyclyl, optionally substituted (C 1~6 alkyl) 1~3 Heterocyclyl, and optionally substituted (C 1~6 alkyl halo) 1~3 It may be optionally substituted with one or more groups (preferably one group) selected from heterocyclyl.

[0214] In some embodiments, R 2 is an optionally substituted C 2~4 Alkynyl. C 2~4 Alkynyl is an optionally substituted C 3~8 cycloalkyl, optionally substituted haloC 3~8 Cycloalkyl, optionally substituted (C 1~6 alkyl) 1~3 C 3~8 Cycloalkyl, optionally substituted heterocyclyl, optionally substituted haloheterocyclyl, and optionally substituted (C 1~6 alkyl) 1~3 It may be optionally substituted with one or more groups (preferably one group) selected from heterocyclyl.

[0215] In some embodiments, R 2is H, cyano, methyl, 3-pyridyl, 4-pyridyl, benzyl, [ka] [ka] [ka] is selected from.

[0216] In some embodiments, R 2 is H, methyl, 3-pyridyl, 4-pyridyl, benzyl, [ka] [ka] is selected from.

[0217] In some embodiments, R 2 comprises a basic moiety (such as an optionally substituted amine, including an optionally substituted cyclic amine).

[0218] In some embodiments, R 2 includes nitrogen-containing heterocyclyls, the nitrogen atom of these cyclic amines is C 1~6 It may be optionally substituted with a group selected from alkyl and substituted ketones (such as acyl).

[0219] In some embodiments, R 2 is expressed by the following sub-formulas: -G-(R 10 ) w During the ceremony, G is (I C 1~4 alkylamides, (ii) C 1~4 alkylaryl, (iii)C 2~4 Alkynyl, (iv) aryl, (v) 5- or 6-membered heterocyclyl; Each R 10 are independently selected from halo, optionally substituted C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted C 1~4 Alkoxy, optionally substituted C 1~4 Alkyl-OH, optionally substituted C 1~4 Alkylhalo, optionally substituted C 1~4 Alkylheterocyclyl, optionally substituted C 1~4 Alkyl C 3~8 Cycloalkyl, optionally substituted C 1~4 alkylaryl; w is an integer of 0 to 3.

[0220] In some embodiments, the compound is provided as a compound of formula (IIA) or (IIB): [ka] In the formula, A 1 , A 2 , A 3 , A 4 , R 3 , R 4 , R d , R e , G, w, and R 10 is as defined herein.

[0221] In some embodiments, G is C 2~4 In some embodiments, G is ethynyl and w is 1.

[0222] In some embodiments, G is a 6-membered heterocyclyl. In these embodiments, G can be a 6-membered non-aromatic heterocyclyl or a 6-membered heteroaryl. In these embodiments, each R 10 are independently selected from halo, optionally substituted C1~6 Alkyl, optionally substituted C 1~4 Alkoxy, optionally substituted C 1~4 alkylhalo, and optionally substituted (C 1~6 Typically, in these embodiments, w is 1.

[0223] In some embodiments, G is a 6-membered non-aromatic heterocyclyl containing a heteroatom selected from N and O. When the heteroatom is N, R 10 is preferably attached to the N ring atom.

[0224] In some embodiments, G is a 5-membered heterocyclyl. In these embodiments, G can be a 5-membered non-aromatic heterocyclyl or a 5-membered heteroaryl. In some embodiments, the 5-membered heterocyclyl can contain a heteroatom selected from N and O.

[0225] In some embodiments, G is a 5- or 6-membered heterocyclyl containing at least one oxygen heteroatom. In some embodiments, G is a 5- or 6-membered heterocyclyl containing at least one nitrogen and at least one oxygen heteroatom. In some embodiments, G is a 5- or 6-membered heterocyclyl containing two nitrogen heteroatoms.

[0226] In some embodiments, G is an optionally substituted fused heterocyclyl.

[0227] In some embodiments, G is selected from morpholinyl, pyrimidinyl, pyrrolyl, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 1-methylindolinyl-2-one, 1-methyl-1H-indazolyl, pyrazolyl, and isoxazolyl.

[0228] In some embodiments, G is chosen from pyrazolyl and isoxazolyl.

[0229] In some embodiments, G is pyrazolyl. In these embodiments, R 10 may be attached to the nitrogen ring atom. In these embodiments, R 2 can be expressed by the following sub-formulas: [ka]

[0230] In these embodiments, the compound may be provided as a compound of formula (IIC) or (IID): [ka] In the formula, A 1 , A 2 , A 3 , A 4 , R 3 , R 4 , R d , R e , and R 10 is as defined herein.

[0231] In some embodiments, R 10 is C 1~6 Alkyl, heterocyclyl, C 1~6 Alkyl-OH, C 1~6 Alkyl-NH2, C 1~6 Alkoxy C 1~6 Alkyl, C 3~8 cycloalkyl, heterocyclyl and C 3~8 Cycloalkyl is C 1~6 Alkyl, HaloC 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-OH, C 1~6 Alkoxy C 1~6 Alkyl, Halo, C 1~6 Alkyl-NH2, C 1~6 It may be further substituted with one or more groups (preferably 1 to 3 groups, most preferably 1 group) selected from alkyl ketones (eg, acyl), and -NH2.

[0232] In some embodiments, R 10 is C 1~6 Alkyl, HaloC 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-OH, C 1~6 Alkoxy C 1~6 Alkyl, Halo, C 1~6 Alkyl-NH2, C 1~6 Heterocyclyl or alkylheterocyclyl optionally substituted with one or more groups (preferably 1 to 3 groups, most preferably 1 group) selected from alkyl ketone (e.g., acyl), and -NH2.

[0233] R 10 When is a group containing a heterocyclyl moiety, the heterocyclyl may be preferably a 4- to 8-membered heterocyclyl containing preferably one heteroatom selected from N and O, preferably N.

[0234] In some embodiments, R 10 is an optionally substituted heterocyclyl selected from an optionally substituted spirocyclic heterocyclyl, an optionally substituted fused heterocyclyl, or an optionally substituted bridged heterocyclyl. In some embodiments, R 10 is an optionally substituted heterocyclyl selected from optionally substituted spirocyclic heterocyclyl or optionally substituted bridged heterocyclyl. Preferred optional substituents for spirocyclic, fused, and bridged heterocyclyl groups include C 1~6 Alkyl and HaloC 1~6 Examples of alkyl include:

[0235] In some embodiments, R 10 is enriched with one or more of the following minor isotopes: 2 H, 3 H, 13 C. 14 C. 15 N, and / or 17 O, preferably 2 H.

[0236] In some embodiments, R 10 is methyl, difluoromethyl, trifluoromethyl, methoxy, tert-butyl, phenyl, acyl, dimethylamino, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, hydroxyethyl, methoxyethyl, isopropyl, cyclopentyl, difluorocyclopenyl, piperidinyl, N-methylpiperidinyl, N-acetylpiperidine, azetidinyl, [ka] is selected from.

[0237] In some embodiments, R 10 is methyl, difluoromethyl, trifluoromethyl, methoxy, tert-butyl, phenyl, acyl, dimethylamino, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, hydroxyethyl, methoxyethyl, isopropyl, cyclopentyl, difluorocyclopenyl, piperidinyl, N-methylpiperidinyl, N-acetylpiperidine, azetidinyl, [ka] is selected from.

[0238] In some embodiments, R 10 is C 3~8 cycloalkyl, aryl, and 4- to 8-membered heterocyclyl, each of which is selected from C 1~4 Alkyl, C 1~4 Alkyl-OH, C 1~4 alkyl-NR'R'', where R' and R'' are independently H and C 1~4 Alkyl, HaloC 1~4 Alkyl, Halo, C 1~4 Alkoxy and C 1~4 Alkoxy C 1~4 alkyl.

[0239] In some embodiments, w is 0 or 1.

[0240] In some embodiments, w is selected from 0, 1, and 3.

[0241] In these embodiments, the compound may be provided as a compound of formula (IIF) or (IIG): [ka] In the formula, A 1 , A 2 , A 3 , A 4 , R 3 , R 4 , R d , and R e is as defined herein; R 12 are independently H, 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 one or more groups selected from alkoxyhalo and amino; R 13 is H, C 1~6 Alkyl and haloC 1~6 alkyl.

[0242] In some embodiments, R 12 are independently H, C 1~6 Alkyl, and C 3~8 cycloalkyl. In some embodiments, R 12 are independently H, C 1~3 Alkyl, and C 3~4 Cycloalkyl, preferably one or more groups selected from C1 alkyl and C3 cycloalkyl.

[0243] In some embodiments, R 12 substitutes the carbon alpha to the piperidyl nitrogen.

[0244] In some embodiments, R 13 is H, C 1~3 Alkyl and haloC 1~3 Alkyl, preferably C 1~3 alkyl, more preferably C1 alkyl.

[0245] J2 In some embodiments, J is J. In these embodiments, the compound of formula (I) may be provided as a compound of formula (III): [ka] In the formula, X, R 3 , R 4 , R 5 , A 5 , and A 6 is as defined for formula (I) or any embodiment thereof described herein.

[0246] In some embodiments, A 5 is CH.

[0247] In some embodiments, A 5 is N.

[0248] In some embodiments, A 6 is N.

[0249] In some embodiments, A 6 is CR 2 is.

[0250] In some embodiments, A 5 is N and A 6 is N.

[0251] In some embodiments, A 5 is CH and A 6 is N.

[0252] In some embodiments, A 5 is N and A 6 is CR 2 is.

[0253] In some embodiments, A 5 and A 6 At least one of is N.

[0254] In some embodiments, R 5 is H.

[0255] In some embodiments, the compound of the present invention is selected from any of compounds 1001-1031, 1037, and 1039-1145 described herein, preferably any of compounds 1001-1031, 1037, and 1039-1137.

[0256] In some embodiments, the compound of the present invention is selected from any of compounds 1001-1031 described herein, preferably any of compounds 1001-1023 and 1029-1031, and more preferably any of compounds 1003, 1005, 1006, 1008-1012, 1014, 1015, 1017, and 1022.

[0257] In some embodiments, the compound comprises a radical of a compound selected from compounds 1-173 described herein.

[0258] In some embodiments, the compound of the invention comprises a radical of a compound selected from compounds 1-125 described herein.

[0259] In some embodiments, the compound of the invention comprises a radical of a compound selected from compounds 113, 116, 145, 154, 155, 170, and 171 described herein.

[0260] In some embodiments, MLKLi is a compound of formula (X) containing a radical at the following position: i)R 2 and when J is J1, R is such that L is covalently bonded 2 , or ii)R 5 and when J is J2, R is such that L is covalently bonded 5 .

[0261] In some embodiments, the compound of formula (X) may be provided as a compound of formula (XX): [ka] In the formula, A 1 , A 2 , A 3 , A 4 ,n,R 1 , R 2 , R 3 , R 4 , R 4’ , X, Y, Z, L, and E3L are as defined herein.

[0262] In some embodiments, the compound of formula (X) may be provided as a compound of formula (XXI): [ka] In the formula, A 1 , A 2 , A 3 , A 4 ,n,R 1 , R 3 , R 4 , R 4’ , X, Y, Z, L, and E3L are as defined herein; A 7 , A 8 , A 9 , and A 10 are independently C(R 12 ) q ,O,S,N,NR 13 , C(R 12 )-L-E3L, CL-E3L, and NL-E3L; A 7 , A 8 , A 9 , and A 10 One of them is C(R 12 )-L-E3L, CL-E3L, and NL-E3L; A 7 , A 8 , A 9 , and A 10 One of them is C(R 12 )2, O, S, NR 13 , C(R 12 )-L-E3L; Each R 12 are independently H and R 14 is selected from Each R 14 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 1~6 Alkylheterocyclyl, HaloC1~6 Alkoxyheterocyclyl, C 1~6 Alkyl C 1~6 alkoxy, and —COOH; Each R 13 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 7 , A 8 , A 9 , and A 10 two adjacent groups selected from CR 12 , C(R 12 )-L-E3L, and NR 13 When selected from 12 , 2 R 13 , or one R 12 and one R 13 together can form an optionally substituted 5- to 10-membered ring selected from cycloalkyl, aryl, and heterocyclyl; q is 1 or 2.

[0263] In some embodiments, A 9 is N and A 8 is NL-E3L, A 7 is CR 12 and A 10 is CR 12 is.

[0264] In some embodiments, the compound of formula (X) may be provided as a compound of formula (XXII): [ka] In the formula, A 1 , A 2 , A 3 , A 4 ,n,R 1 , R 3 , R 4 , R 4’ , X, Y, Z, L, and E3L are as defined herein.

[0265] In some embodiments, the compound of formula (X) may be provided as a compound of formula (XXIII): [ka] In the formula, A 1 , A 2 , A 3 , A 4 ,n,R 1 , R 3 , R 4 , R 4’ , X, Y, Z, L, and E3L are as defined herein.

[0266] In some embodiments, the compound of formula (X) may be provided as a compound of formula (XXIV): [ka] In the formula, A 1 , A 2 , A 3 , A 4 ,n,R 1 , R 3 , R 4 , R 4’ , X, Y, Z, L, and E3L are as defined herein; A 11 ~A 15 are independently N, CR 12 , and CL-E3L; A 11 ~A 15 One of them is the CL-E3L, A 11 , A 12 , A 13 , A 14 , and A 15 At most two of are N, Each R 12 are independently H and R 14 is selected from Each R 14 independently, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C3~6 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 1~6 Alkylheterocyclyl, HaloC 1~6 Alkoxyheterocyclyl, C 1~6 Alkyl C 1~6 alkoxy, and -COOH; or A 11 , A 12 , A 13 , A 14 , A 15 Two adjacent groups selected from CR 12 When two R 12 together can form an optionally substituted 5- to 10-membered ring selected from cycloalkyl, aryl, and heterocyclyl.

[0267] A 11 ~A 15 can be defined as any one of embodiments 1 to 4. [Table 2]

[0268] In some embodiments, the compound of formula (X) can be provided as a compound of formula (XXa): [ka] In the formula, A 5 , A 6 , R 1 , R 2 , R 3 , R 4 , R 4’ , R 5 , X, Y, Z, L, and E3L are as defined herein.

[0269] In some embodiments, the compound of Formula (X) may be provided as a compound of Formula (XXIa): [ka] In the formula, A 5 , A 6 , R 1 , R 2 , R 3 , R 4 , R 4’ , X, Y, Z, L, and E3L are as defined herein; A 7 , A 8 , A 9 , and A 10 are independently C(R 12 ) q ,O,S,N,NR 13 , C(R 12 )-L-E3L, CL-E3L, and NL-E3L; A 7 , A 8 , A 9 , and A 10 One of them is C(R 12 )-L-E3L, CL-E3L, and NL-E3L; A 7 , A 8 , A 9 , and A10 One of them is C(R 12 )2, O, S, NR 13 , C(R 12 )-L-E3L; Each R 12 are independently H and R 14 is selected from Each R 14 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 1~6 Alkylheterocyclyl, HaloC 1~6 Alkoxyheterocyclyl, C 1~6 Alkyl C 1~6 alkoxy, and —COOH; Each R 13 are independently H, C 1~6 Alkyl, HaloC 1~4 Alkyl, C 1~6 Alkyl acyl and halo C1~6 alkyl acyls; or A 7 , A 8 , A 9 , and A 10 two adjacent groups selected from CR 12 , C(R 12 )-L-E3L, and NR 13 When selected from 12 , 2 R 13 , or one R 12 and one R 13 together can form an optionally substituted 5- to 10-membered ring selected from cycloalkyl, aryl, and heterocyclyl; q is 1 or 2.

[0270] In some embodiments, A 9 is N and A 8 is NL-E3L, A 7 is CR 12 and A 10 is CR 12 is. In some embodiments, the compound of Formula (X) can be provided as a compound of Formula (XXIIa): [ka] In the formula, A 5 , A 6 , R 1 , R 2 , R 3 , R 4 , R 4’ , X, Y, Z, L, and E3L are as defined herein.

[0271] In some embodiments, the compound of Formula (X) may be provided as a compound of Formula (XXIIIa): [ka] In the formula, A 5 , A 6 , R 1 , R 2 , R 3, R 4 , R 4’ , X, Y, Z, L, and E3L are as defined herein.

[0272] In some embodiments, the compound of formula (X) may be provided as a compound of formula (XXIVa): [ka] In the formula, A 5 , A 6 , R 1 , R 2 , R 3 , R 4 , R 4’ , X, Y, Z, L, and E3L are as defined herein; A 11 ~A 15 are independently N, CR 12 , and CL-E3L; A 11 ~A 15 One of them is the CL-E3L. A 11 , A 12 , A 13 , A 14 , and A 15 At most two of are N, Each R 12 are independently H and R 14 is selected from Each R 14 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 1~6Alkyl 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 1~6 Alkylheterocyclyl, HaloC 1~6 Alkoxyheterocyclyl, C 1~6 Alkyl C 1~6 alkoxy, and -COOH; or A 11 , A 12 , A 13 , A 14 , A 15 Two adjacent groups selected from CR 12 When two R 12 together can form an optionally substituted 5- to 10-membered ring selected from cycloalkyl, aryl, and heterocyclyl.

[0273] A 11 ~A 15 can be defined as any one of embodiments 1 to 4. [Table 3]

[0274] E3L In the compound 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.

[0275] 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).

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] In some embodiments, the E3 ligase binding moiety is [ka] is selected from the radicals

[0283] 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-binding derivative is shown.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] In some embodiments, the E3 ligase binding derivative is an optionally substituted derivative of any of the E3 ligase binding moieties described herein.

[0300] 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.

[0301] In some embodiments, the linker has a minimum linear chain length of 1 to 50 atoms.

[0302] 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]

[0303] 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.

[0304] 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:

[0305] 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 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:

[0306] 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.

[0307] 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.

[0308] In some embodiments, the heteroaryl contains at least one N heteroatom, such as triazolyl or pyrazolyl, preferably pyrazolyl.

[0309] 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.

[0310] 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.

[0311] 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.

[0312] 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.

[0313] 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 successive positions along the alkyl chain.

[0314] Typically, the compounds of the present invention may be prepared by techniques known in the art.

[0315] In another aspect, there is also provided a process for preparing a compound of Formula (I), or a salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof. In some embodiments, the process comprises any of the following four steps: reacting a compound of formula (V) with a compound of formula (VI) [ka] In the formula, J and R 4 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 (VI) as an electrophile capable of reacting with the free aniline nitrogen of the compound of formula (V) under appropriate conditions. reacting a compound of formula (VII) with a compound of formula (VIII) [ka] In the formula, X, R 3 , R 4 and J is as defined for formula (I) or any embodiment thereof; E 1 and E 2 is a suitable electrophilic pair for inducing palladium-catalyzed cross-coupling reactions. In some embodiments, E 1 and E 2 is selected from halo, boronic acid, boronic ester, and triflate, or a group that can be converted to any of these moieties, such as hydroxyl, mixed anhydride, tetrafluorophenyl ether, etc. In some embodiments, E 1 is the halo, E 2 is selected from boronic acids, boronic esters, and triflates. 2 is the halo, E 1 is selected from boronic acids, boronic esters, and triflates. reacting a compound of formula (IX) with a compound of formula (X) [ka] In the formula, X, R 2 , R 3 , R 4 , A 1 , A 2 , A 3 , and A 4 is as defined for formula (I) or any embodiment thereof; E 3 and E 4is a suitable electrophilic pair for inducing palladium-catalyzed cross-coupling reactions. In some embodiments, E 3 and E 4 is selected from halo, boronic acid, boronic ester, and triflate, or a group that can be converted to any of these moieties, such as hydroxyl, mixed anhydride, tetrafluorophenyl ether, etc. In some embodiments, E 3 is the halo, E 4 is selected from boronic acids, boronic esters, and triflates. 4 is the halo, E 3 is selected from boronic acids, boronic esters, and triflates. - Converting the compound of formula (I) into one of its salts.

[0316] In some embodiments of the above process, reactive moieties in compounds of Formulae (V)-(X) are functionalized with suitable protecting groups.

[0317] An embodiment of these steps is shown in the general scheme below.

[0318] In some embodiments, the process comprises reacting with one or more of formula (XIII), formula (XIV), and formula (XV): LGV-L'-LGA LGV-L'-E3L' LGV-E3L' (XIII) (XIV) (XV) During the ceremony, L' is a linker moiety or a protected form of a linker moiety; E3L' is an E3 ligase binding moiety or a protected form of an E3 ligase binding moiety; LG V is a group cleavable upon reaction with its coupling partner, the coupling partner being selected from compounds of formula (I), formula (1A), formula (1B), formula (1A'), formula (1B'), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII); LGA is H or a group that is cleavable in a subsequent step by reacting the moiety L' with E3L'.

[0319] 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).

[0320] 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).

[0321] 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).

[0322] 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).

[0323] 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).

[0324] 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).

[0325] 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).

[0326] 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).

[0327] 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).

[0328] 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).

[0329] 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).

[0330] 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).

[0331] In some embodiments, L' can be deprotected before deprotection of E3L'. In some embodiments, L' can be deprotected after deprotection of E3L'.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] In some embodiments of the above process, the PG 1 When is an amino protecting group, the process further comprises a deprotection step.

[0340] An embodiment of these steps is shown in the general scheme below.

[0341] 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.

[0342] method In another aspect, there is provided a method for inhibiting necroptosis in a subject in need thereof, comprising administering a therapeutically effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

[0343] 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.

[0344] 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 refer to 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.

[0345] 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.

[0346] In one embodiment of the present disclosure, administration of a compound according to Formula (I) 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.

[0347] It is contemplated that some compounds of the present disclosure may bind to MLKL and inhibit necroptosis in various species.

[0348] 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.

[0349] 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.

[0350] As described herein, inhibition of 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.

[0351] 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.

[0352] 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.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] 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.

[0362] 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.

[0363] 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.

[0364] 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.

[0365] 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.

[0366] 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.

[0367] 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.

[0368] 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.

[0369] 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.

[0370] 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.

[0371] 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.

[0372] Nitrogen-containing groups can also be oxidized to form N-oxides.

[0373] 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.

[0374] 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]

[0375] Similar tautomerism may occur for any of the pyrazole-containing compounds described herein, including compounds of Formulas (II), (III), (IV), (VIII), (IX), (XX), (XXI), (XXII), (XXIII), and (XXIV), compounds 1-173, and compounds 1001-1145. 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.

[0376] 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.

[0377] 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, preferably 2 H. An isotope may be considered enriched when its abundance is higher than its natural abundance.

[0378] A "prodrug" is a compound that may not fully meet the structural requirements of the compounds described herein, but that is modified in vivo following administration to a subject or patient to produce a compound of formula (X) described herein. For example, a prodrug can be an acylated derivative of a compound described herein. Prodrugs include compounds in which a hydroxy, carboxy, amine, or sulfhydryl group is 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 described 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.

[0379] 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.

[0380] 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 injectable solution or suspension).

[0381] 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 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 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 or solvate thereof and a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0382] 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.

[0383] 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.

[0384] 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.

[0385] 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.

[0386] For in vitro analysis, necroptosis inhibition can be determined by assays used to measure TSQ-induced necroptosis, as described in the biological tests defined herein.

[0387] 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.

[0388] "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.

[0389] 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.

[0390] 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.

[0391] 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.

[0392] Because the compounds of the present invention contain both an MLKL binding moiety -MLKLi- based on the series of MLKL inhibitors described in AU2021904206 (hereby incorporated by reference in its entirety), the compounds of the present invention can both inhibit and degrade MLKL, which can enhance amelioration of necroptosis in a subject.

[0393] The compounds of the invention may be administered with a pharmaceutical carrier, diluent, and / or excipient as described above.

[0394] 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, such as 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).

[0395] 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.

[0396] 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.

[0397] In some embodiments, the compounds of the present invention may be administered in combination with another active pharmaceutical ingredient (API). The API may be any suitable 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.

[0398] 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.

[0399] 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.

[0400] 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).

[0401] 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 compound of formula (X), or a pharmaceutically acceptable salt or prodrug 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.

[0402] 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. [Example]

[0403] The compounds, compositions, kits and methods described herein are illustrated by the following illustrative and non-limiting examples.

[0404] 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.

[0405] 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.

[0406] 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.

[0407] 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.

[0408] The expressions "ambient temperature," "room temperature," 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.

[0409] 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.

[0410] general chemical methods Definition: [Table 4-1] [Table 4-2]

[0411] LCMS methodology Electrospray mass spectrometry (MS) was performed using the following method.

[0412] Method A (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.

[0413] Method B (3.5 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.

[0414] Method C: (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.

[0415] Method D: 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: 5-100% B over 3.8 minutes Acquisition Time: 4.1 minutes 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

[0416] Method E: Mass Detector: Agilent G6120B MSD Pump: 1260 Infinity G1312B Binary Pump Autosampler: 1260 Infinity G1367E HiPALS Detector: 1260 Infinity G4212B DAD Column: Atlantis T3, 3uM, 100A, 3.0 x 50mm Column Temperature: 30°C Injection Volume: 1µL Flow Rate: 1.0ml / min Solvent A: Water 0.1% Formic Acid Solvent B: Acetonitrile 0.1% Formic Acid Gradient: 5-50% B over 3.0 minutes Acquisition Time: 4.1 minutes Detection: 214 and 254nm 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

[0417] Method F: 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 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: 100-1000, step size: 0.1 sec

[0418] Method G: 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: 5-100% 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 sec

[0419] Method H: Waters: 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 sec, Acquisition time: 10 min, Gas flow rate: Desolvation L / h -650, Cone L / h -100

[0420] Preparative HPLC Method A: Instrument type: VARIAN 940 LC. Pump type: binary pump. Detector type: PDA. LC conditions: Column: Waters SunFire Preparative C18 OBD, 5 μm, 19 × 100 mm. Acquisition wavelengths: 214 nm, 254 nm. Mobile phase: A: 0.07% TFA in water (or 0.1% HCOOH in water), B: MeOH (or CH3CN).

[0421] 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: Column: Xbridge™ Preparative C18 OBD 5 μm 19 x 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 sec, Acquisition time: 20 min. Gas flow: Desolvation L / h -650, Cone L / h -100

[0422] Method C: Waters ZQ 3100-Mass Detector, Waters 2545-Pump, Waters SFO System Fluid Organizer, Waters 2996 Diode Array Detector, Waters 2767 Sample Manager. LC conditions: Column: Xbridge™ Prep C18 OBD 5 μm 19 x 100 mm, Solvent A: Water, Solvent B: Acetonitrile, 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 sec, Acquisition time: 20 min. Gas flow: Desolvation L / h - 650, Cone L / h - 100

[0423] NMR The nuclear magnetic resonance spectrum is designated 1 Spectroscopic data were recorded on a Bruker 400 MHz or 300 MHz spectrometer for H 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; bs, broad singlet; d, doublet; t, triplet; q, quartet; m, multiplet.

[0424] Synthesis of intermediate A Intermediate A1: 3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine [ka] Step 1: 4-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine To a solution of 4-chloro-1H-pyrazolo[4,3-c]pyridine (25 g, 162 mmol) in DMF (200 mL) was added NIS (43.6 g, 194 mmol), and the mixture was stirred at 85° C. overnight. The mixture was diluted with water (2,500 mL), and the solid was filtered to give the title product (43.0 g, 94%) as a yellow solid. LCMS (Method A): 2.99 min, m / z: 279.9 [M+H] + .

[0425] Step 2: 4-Chloro-3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridine To a pre-cooled solution of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (43 g, 153 mmol) in DMF (200 mL) at 0 °C was added NaH (60% in oil, 18.4 g, 765 mmol). The mixture was stirred under N2 at 0 °C for 10 min. Then, iodomethane (32.5 g, 229 mmol) was slowly added, and the mixture was stirred at room temperature for 1 h. Water (2,000 mL) was added, and the product was extracted with EtOAc (2 × 1000 mL). The combined organics were dried over MgSO4 and concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / PE = 4 / 1, v / v) to give the title product (23.5 g, 52%) as a white solid. LCMS (Method A): 3.42 min, m / z: 293.8 [M+H] + .

[0426] Step 3: 3-Iodo-N-(4-methoxybenzyl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine To a solution of 4-chloro-3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridine (23.5 g, 80.0 mmol) in 1-butanol (200 mL) was added (4-methoxyphenyl)methanamine (44.0 g, 320 mmol), and the mixture was stirred at 110° C. overnight. The mixture was concentrated under reduced pressure before the addition of water (2,000 mL). The precipitate was filtered off to give the title product (33.0 g) as a white solid. LCMS (Method A): 2.58 min, m / z: 395.0 [M+H] + .

[0427] Step 4: 3-Iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine A solution of 3-iodo-N-[(4-methoxyphenyl)methyl]-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (33 g, 83.7 mmol) in TFA (60 mL) was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between an aqueous solution of NaCO (250 mL) and DCM (250 mL). The organics were washed with water, dried over NaSO, and concentrated under reduced pressure to give the title product (16.4 g, 71% over two steps) as a white solid. LCMS (Method A): 0.91 min, m / z: 275.0 [M+H] + .

[0428] Intermediate A2: 3-iodo-1H-pyrazolo[4,3-c]pyridin-4-amine [ka] Step 1: 4-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine To a solution of 4-chloro-1H-pyrazolo[4,3-c]pyridine (25 g, 162 mmol) in DMF (200 mL) was added NIS (43.6 g, 194 mmol) and the reaction was stirred at 85° C. overnight. The mixture was diluted with water (2500 mL) and the precipitate was collected via filtration to give the title product (43.0 g, 95%) as a yellow solid. LCMS (Method A): 2.99 min, m / z: 279.9 [M+H] + .

[0429] Step 2: 3-Iodo-N-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridin-4-amine A mixture of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (5 g, 17.8 mmol) and 1-(4-methoxyphenyl)methanamine (12.2 g, 89.0 mmol) in DMSO (100 mL) was stirred at 150° C. for 6 hours. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL×2). The combined organic phases were dried (NaSO) and concentrated. The residue was purified by column chromatography (PE / EtOAc=3 / 1, v / v) to give the title product (2.2 g, 33%) as a yellow solid. LCMS (Method D): 0.70 min, m / z: 381.0 [M+H] + .

[0430] Step 3: 3-Iodo-1H-pyrazolo[4,3-c]pyridin-4-amine A solution of 3-iodo-N-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridin-4-amine (1.91 g, 5.02 mmol) in TFA (15 mL) was stirred at 75 °C overnight. The mixture was adjusted to pH 7-8 with saturated aqueous Na2CO3 and extracted with DCM (50 mL × 2). The organics were concentrated, and the residue was purified by preparative TLC (DCM / MeOH = 20 / 1, v / v) to give the title product (600 mg, 46%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):13.38(bs,1H),7.60(d,J=6.4Hz,1H),6.69(d,J=6.4Hz,1H),6.17(bs,2H).

[0431] Intermediate A3: 3-iodo-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-4-amine [ka] Step 1: 4-Chloro-3-iodo-1-isopropyl-1H-pyrazolo[4,3-c]pyridine To a mixture of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (6 g, 21.4 mmol) and CsCO (20.8 g, 64.1 mmol) in acetonitrile (200 mL) was added 2-bromopropane (5.26 g, 42.8 mmol), and the reaction mixture was stirred at 70 °C overnight. Water (200 mL) was added, and the product was extracted with EtOAc (2 × 100 mL). The combined organics were dried over NaSO and concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EtOAc = 4 / 1 to 1 / 4, v / v) to give the title product (4 g, 58%) as a yellow solid. LCMS (Method A): 2.60 min, m / z: 322.0 [M+H] + .

[0432] Step 2: 3-Iodo-1-isopropyl-N-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-4-amine To a solution of 4-chloro-3-iodo-1-isopropyl-1H-pyrazolo[4,3-c]pyridine (4 g, 12.4 mmol) in 1-butanol (40 mL) was added (4-methoxyphenyl)methanamine (8.50 g, 62.0 mmol), and the mixture was stirred at 110° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water (200 mL) and EtOAc (200 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (100 mL). The combined organics were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product (2 g, 38%) as a brown oil. LCMS (Method A): 2.95 min, m / z: 423.1 [M+H] + .

[0433] Step 3: 3-Iodo-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-4-amine A solution of 3-iodo-1-isopropyl-N-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-4-amine (3.7 g, 8.76 mmol) in TFA (20 mL) was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between an aqueous solution of NaCO (250 mL) and DCM (250 mL). The organics were washed with water, dried over NaSO, and concentrated under reduced pressure to give the title product (500 mg, 19%) as a yellow solid. LCMS (Method A): 1.83 min, m / z: 303.0 [M+H] + .

[0434] Intermediate A4: 3-Iodopyrazolo[1,5-a]pyrazin-4-amine [ka] Step 1: N-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide A mixture of 1H-pyrazole-5-carboxylic acid (10 g, 89.2 mmol) and carbonyldiimidazole (15.9 g, 98.1 mmol) in 1,4-dioxane (100 ml) was stirred at 50° C. under N for 1 h before the addition of 2,2-dimethoxyethan-1-amine (10.3 g, 98.1 mmol). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (500 mL). The aqueous solution was adjusted to pH=5 with 1 M HCl, and the organics were extracted with EtOAc (2×250 mL). The combined organics were dried over NaSO and concentrated under reduced pressure to give the title product (15 g, 84%) as a white solid. LCMS (Method A): 3.32 min, m / z: 222.1 [M+H] + .

[0435] Step 2: 7-Hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one A solution of N-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide (15 g, 75.2 mmol) in DCM (100 ml) and TFA (100 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the title product (12 g, 100%) as a brown oil.

[0436] Step 3: Pyrazolo[1,5-a]pyrazin-4(5H)-one A solution of 7-hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (12 g, 78.3 mmol) in polyphosphoric acid (50 mL) was stirred at 145° C. for 5 hours. The reaction mixture was adjusted to pH=10 with aqueous NaOH. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH=20 / 1) to give the title product (6.1 g, 58%) as a brown solid. 1 H NMR(400MHz,DMSO-d6):11.23(s,1H),7.89(s,1H),7.68(d,J=5.8Hz,1H),7.00(s,1H),6.86(d,J=11.5Hz,1H).

[0437] Step 4: 4-Chloropyrazolo[1,5-a]pyrazine A solution of pyrazolo[1,5-a]pyrazin-4(5H)-one (6.1 g, 45.1 mmol) in POCl (50 mL) and DMF (4 drops) was stirred at 130 °C overnight. The reaction mixture was slowly poured into ice water (300 mL) and then adjusted to pH = 10 with aqueous NaOH. The organics were extracted with EtOAc (2 × 100 mL), and the combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 10 / 1) to give the title product (3.6 g, 85%) as a white solid. 1 H NMR(400MHz,DMSO-d6):8.86(d,J=5.6Hz,1H),8.26(s,1H),7.75(d,J=4.7Hz,1H),7.05(d,J=0.9Hz,1H).

[0438] Step 5: 4-Chloro-3-iodopyrazolo[1,5-a]pyrazine To a solution of 4-chloropyrazolo[1,5-a]pyrazine (3.6 g, 23.4 mmol) in DMF (100 mL) was added NIS (10.5 g, 46.8 mmol) and the reaction was stirred overnight at 85° C. The reaction mixture was poured into water (100 mL) and the solid was filtered, washed with water and dried under reduced pressure to give the title product (4.9 g, 75%) as a white solid. 1 H NMR(400MHz,DMSO-d6):8.93(d,J=4.7Hz,1H),8.37(s,1H),7.75(d,J=4.7Hz,1H).

[0439] Step 6: 3-Iodopyrazolo[1,5-a]pyrazin-4-amine To a solution of 4-chloro-3-iodopyrazolo[1,5-a]pyrazine (4.9 g, 17.5 mmol) in MeOH (50 mL) was added a solution of ammonia in MeOH (7 M, 100 mL), and the mixture was stirred in a sealed tube overnight at 110° C. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH=50 / 1, v / v) to give the title product (3.00 g, 11.5 mmol) as a white solid. 1 H NMR(400MHz,DMSO-d6):8.08(d,J=4.7Hz,1H),8.02(d,J=11.8Hz,1H),7.26(t,J=4.7Hz,1H),6.68(d,J=37.2Hz,2H).

[0440] Synthesis of intermediate B Intermediate B1: (S)-1,1-difluoro-N-(2-(1-(4-fluorophenyl)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide [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 (60% in oil, 57.1 g, 1425 mmol), and the mixture was stirred at 0 °C under N for 30 min. 4-Bromo-2-fluoro-1-nitrobenzene (62.6 g, 285 mmol) was then added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3 × 500 mL). The combined organics were washed with water and brine, dried (NaSO), and concentrated under reduced pressure to give the crude product (70 g, 72%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6):δ 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).

[0441] 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 organics were washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 100 / 1, v / v) to give the title product (40 g, 63%) as a brown oil. LCMS (Method A): 4.13 min, m / z: 311.0, 312.0 [M+H] + .

[0442] 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 organics were washed with brine, dried (NaSO), and concentrated under reduced pressure. The residue was purified by 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).

[0443] 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 under reduced pressure. The residue was diluted with water (500 mL) and extracted with EtOAc (3 × 500 mL). The combined organics were washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 50 / 1) to give the desired 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).

[0444] The following Intermediate B was similarly prepared from the appropriate benzyl alcohol (Step 1) according to the preparation 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 B1). [Table 5-1] [Table 5-2]

[0445] Intermediate B17: N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamide [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 F): 1.44 min, m / z: 220.4 [M+H]+ .

[0446] 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 afford the title compound (1.88 g, 89%) as a white solid. LCMS (Method F): 1.98 min, m / z: 312.2 [M+H] + . 1 H 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).

[0447] Intermediate B18: 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 F): 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).

[0448] Intermediate B19: 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.

[0449] 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] + .

[0450] 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), pyridine (50 mL), and 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] + .

[0451] 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), AcOK (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).

[0452] Intermediate B20: 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] + .

[0453] 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).

[0454] 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), B2(pin)2 (987 mg, 3.89 mmol), AcOK (763 mg, 7.78 mmol), and Pd(dppf)Cl2 (317 mg, 389 μmol) in dioxane (10 mL) was stirred at 100 °C overnight under N2. 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 (Na2SO4), 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).

[0455] Intermediate B21: 1,1-difluoro-N-{2-[(4-fluorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methanesulfonamide [ka] Step 1: N-{4-bromo-2-[(4-fluorophenyl)methoxy]phenyl}-1,1-difluoromethanesulfonamide To a solution of 4-bromo-2-[(4-fluorophenyl)methoxy]aniline (8.2 g, 27.6 mmol) in DCM (10 mL) was added pyridine (6.54 g, 82.8 mmol) and difluoromethanesulfonyl chloride (4.98 g, 33.1 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EtOAc = 30 / 1) to give the title product (7.77 g, 69%) as a white solid.

[0456] Step 2: 1,1-Difluoro-N-{2-[(4-fluorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methanesulfonamide A mixture of N-{4-bromo-2-[(4-fluorophenyl)methoxy]phenyl}-1,1-difluoromethanesulfonamide (7.77 g, 18.9 mmol), B2(pin)2 (5.25 g, 20.7 mmol), AcOK (3.70 g, 37.8 mmol), and Pd(dppf)Cl2 (1.38 g, 1.89 mmol) in degassed 1,4-dioxane (100 mL) was stirred overnight at 100 °C under N2. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1) to give the title product (7.14 g, 82%) as a white solid.

[0457] Synthesis of intermediate AB Intermediate A1B1: N-(4-{4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: N-(4-{4-amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (compound 17) To a solution of 3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (8 g, 29.1 mmol) in degassed 1,4-dioxane and HO (4 / 1, 150 mL) was added 1,1-difluoro-N-{2-[(1S)-1-(4-fluorophenyl)ethoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methanesulfonamide (15.0 g, 32.0 mmol), NaCO (6.16 g, 58.2 mmol), and Pd(dppf)Cl (1.18 g, 1.45 mmol), and the mixture was stirred overnight at 100 °C. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=40 / 1) to give the title product (12.0 g, 84%) as a yellow solid. LCMS (Method A): 2.92 min, m / z: 492.2 [M+H] + .

[0458] Step 2: N-(4-{4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide To a solution of N-(4-{4-amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (12 g, 24.4 mmol) in DMF (150 mL) was added NIS (6.57 g, 29.2 mmol), and the mixture was stirred at 85° C. overnight. Water (1500 mL) was added, and the solid was filtered off, washed with water (200 mL), and dried under reduced pressure. The solid was further purified by column chromatography (PE / EA=1 / 1) to give the title product (8.00 g, 53%) as a yellow solid. LCMS (Method A): 3.35 min, m / z: 618.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6):8.00(s,1H),7.56(q,J=4.8Hz,2H),7.40(dd,J=8.8,2.0Hz,1H),7.18-7.10(m ,4H),7.02(t,J=52.4Hz,1H),5.85(s,2H),5.64(q,J=6.4Hz,1H),4.24(s,3H),1.58(d,J=6.4Hz,3H).

[0459] The following intermediates were similarly prepared from the appropriate intermediate A and the appropriate intermediate B according to the procedure for the synthesis of intermediate A1B1. [Table 6]

[0460] Intermediate A1B19: N-(4-(4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-((4-fluorobenzyl)oxy)phenyl)ethanesulfonamide [ka] Step 1: N-(4-{4-amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(4-fluorophenyl)methoxy]phenyl)ethane-1-sulfonamide A mixture of 3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (50 mg, 182 μmol), N-{2-[(4-fluorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}ethane-1-sulfonamide (94.8 mg, 218 μmol), Pd(dppf)Cl (14.8 mg, 18.2 μmol), and NaCO (57.8 mg, 546 μmol) in degassed 1,4-dioxane / HO (4 / 1, 10 mL) was stirred at 100 °C for 1 h under a 500 W. The mixture was poured into water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give the title product (20 mg, 24%) as a brown solid.

[0461] Step 2: N-(4-(4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-((4-fluorobenzyl)oxy)phenyl)ethanesulfonamide A mixture of N-(4-{4-amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(4-fluorophenyl)methoxy]phenyl)ethane-1-sulfonamide (3.5 g, 7.68 mmol) and NIS (3.44 g, 15.3 mmol) in DMF (100 mL) was stirred at 85 °C overnight. The mixture was poured into water (100 mL), and the organics were extracted with EtOAc (2 × 50 mL). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 4 / 1 to 1 / 4, v / v) to give the title product (1.5 g, 47%) as a yellow solid.

[0462] Intermediate A1B21: N-(4-(4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-((4-fluorobenzyl)oxy)phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: N-(4-{4-amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(4-fluorophenyl)methoxy]phenyl)-1,1-difluoromethanesulfonamide (compound 10) A mixture of methyl 3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (100 mg, 0.365 mmol), 1,1-difluoro-N-{2-[(4-fluorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methanesulfonamide (166 mg, 0.365 mmol), NaCO (77.3 mg, 0.7296 mmol), and Pd(dppf)Cl (29.7 mg, 0.03648 mmol) in 1,4-dioxane / HO (4 / 1, 7.5 mL) was stirred at 100 °C for 16 h under N. The mixture was poured into water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic phase was dried over NaSO and concentrated. The residue was purified by column chromatography (DCM / MeOH=20 / 1) to give the title product (130 mg, 75%) as a grey solid. LCMS (Method A): 3.04 min, m / z: 478.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6):7.81(d,J=8.0Hz,1H),7.64-7.60(m,2H),7.45-7.40(m,2) H),7.28-7.24(m,3H),7.03-6.76(m,2H),6.33(s,2H),5.23(s,2H),4.03(s,3H).

[0463] Step 2: N-(4-(4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-((4-fluorobenzyl)oxy)phenyl)-1,1-difluoromethanesulfonamide A mixture of N-(4-{4-amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(4-fluorophenyl)methoxy]phenyl)-1,1-difluoromethanesulfonamide (1.28 g, 2.68 mmol), NIS (661 mg, 2.94 mmol) in DMF (15 mL) was stirred at 85° C. under N for 16 hours. The mixture was poured into water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=20 / 1) to give the title product (550 mg, 34%) as a yellow solid. LCMS (Method A): 3.60 min, m / z: 604.2 [M+H] + .

[0464] Intermediate A3B1: (S)—N-(4-(4-amino-7-iodo-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: (S)—N-(4-(4-amino-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (compound 53) To a solution of 3-iodo-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine (500 mg, 1.65 mmol) in degassed 1,4-dioxane / water (4 / 1, 20 mL), 1,1-difluoro-N-{2-[(1S)-1-(4-fluorophenyl)ethoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methanesulfonamide (1.16 g, 1.82 mmol), NaCO (98.9 mg, 0.9334 mmol), and Pd(dppf)Cl (38.1 mg, 0.04667 mmol) were added, and the mixture was stirred overnight at 100° C. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=40 / 1) to give the title product (950 mg, >100%) as a yellow solid. LCMS (Method A): 3.17 min, m / z: 520.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6):11.32(s,1H),7.76(d,J=6.8Hz,1H),7.57(t,J=8.4Hz,2H),7.40(d,J=8.0Hz,1H),7.20-7.09(m,5H) ,7.00(t,J=52.4Hz,1H),6.55(s,2H),5.64(q,J=5.6Hz,1H),4.95-4.89(m,1H),1.58(d,J=6.0Hz,3H),1.45(q,J=4.8Hz,6H).

[0465] Step 2: (S)—N-(4-(4-amino-7-iodo-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide To a solution of N-{4-[4-amino-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl}-1,1-difluoromethanesulfonamide (980 mg, 1.88 mmol) in DMF (30 mL) was added NIS (1.05 g, 4.70 mmol), and the mixture was stirred at 85 °C overnight. Water (300 mL) was added, and the solid was filtered, washed with water (200 mL), and dried under reduced pressure. The solid was further purified by column chromatography (DCM / MeOH = 200 / 1) to give the title product (450 mg, 37%) as a brown solid. LCMS (Method A): 3.65 min, m / z: 646.1 [M+H] + .

[0466] Intermediate A4B1: (S)—N-(4-(4-amino-7-bromopyrazolo[1,5-a]pyrazin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: (S)—N-(4-(4-aminopyrazolo[1,5-a]pyrazin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (compound 22) A mixture of 3-iodopyrazolo[1,5-a]pyrazin-4-amine (2.3 g, 8.84 mmol), 1,1-difluoro-N-{2-[(1S)-1-(4-fluorophenyl)ethoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methanesulfonamide (4.16 g, 8.84 mmol), Pd(dppf)Cl (1.43 g, 1.76 mmol), and NaCO (1.86 g, 17.6 mmol) in degassed 1,4-dioxane / HO (4 / 1, 100 mL) was stirred overnight at 100 °C under N. The mixture was poured into water (100 mL) and extracted with EtOAc (2 × 70 mL). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=80 / 1) to give the title product (3 g, 71%) as a brown solid. LCMS (Method A): 4.62 min, m / z: 478.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6):10.45(s,1H),8.02(d,J=4.7Hz,1H),7.89(s,1H),7.58(dd,J=8.7,5.6Hz,2H),7.34(d,J=8.0Hz,1H) ,7.30(d,J=4.7Hz,1H),7.17(t,J=8.9Hz,2H),7.05-6.88(m,3H),5.99(s,2H),5.68(q,J=6.2Hz,1H),1.58(d,J=6.3Hz,3H).

[0467] Step 2: (S)—N-(4-(4-amino-7-bromopyrazolo[1,5-a]pyrazin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide To a solution of (S)—N-(4-(4-aminopyrazolo[1,5-a]pyrazin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (300 mg, 628 μmol) in DMF (10 mL) was added NBS (122 mg, 690 μmol) and the reaction was stirred at room temperature for 1 h. The mixture was poured into water (100 mL) and extracted with EtOAc (4×50 mL). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=50 / 1) to give the title product (100 mg, 28%) as a brown solid.

[0468] General Procedure A1 for Suzuki Reaction between Intermediate A1B1 and Boronic Esters [ka] A mixture of N-(4-{4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (1 equivalent), boronic ester (1.1 equivalents), NaCO (3 equivalents), and Pd(dppf)Cl (0.1 equivalents) in degassed 1,4-dioxane / HO (4 / 1, 0.2 M) was stirred at 100° C. overnight under N (or at 80° C. under μW irradiation for 2 hours). The mixture was diluted with water and extracted with EtOAc (3×). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH) to give the title compound.

[0469] The following compounds were prepared according to general procedure A1 using intermediate A1B1 and the corresponding boronic ester. [Table 7-1] [Table 7-2] [Table 7-3]

Table 7-4

Table 7-5

Table 7-6

Table 7-7

Table 7-8

Table 7-9

Table 7-10

Table 7-11

Table 7-12

Table 7-13

Table 7-14

Table 7-15

Table 7-16

Table 7-17

Table 7-18

Table 7-19

Table 7-20

[0470] General Procedure A2 for Suzuki Reaction followed by Acidic Deprotection between Intermediate A1B1 and Boc-Protected Boronic Ester [ka] A mixture of N-(4-{4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (1 equivalent), Boc-protected boronic ester (1.1 equivalents), NaCO (3 equivalents), and Pd(dppf)Cl (0.1 equivalents) in degassed 1,4-dioxane / HO (4 / 1, 0.2 M) was stirred at 100 °C overnight under N (or at 80 °C under μW irradiation for 2 hours). The mixture was diluted with water and extracted with EtOAc (3 times). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH) to give the Boc-protected product.

[0471] The solid was dissolved in pure HCOOH (2M) and the reaction mixture was stirred at room temperature for 30 minutes or until complete. The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH = 8 with saturated aqueous Na2CO3. The residue was further diluted with water, and the organics were extracted with EtOAc (3 times). The combined organics were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH), followed by preparative HPLC (neutral conditions, Method C) if necessary, to give the desired product.

[0472] The following compounds were prepared according to general procedure A2: [Table 8-1] [Table 8-2] [Table 8-3]

[0473] The following compounds were prepared according to general procedure A1 using 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and intermediates B2-B5: [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7]

[0474] Synthesis of Boronic Ester Intermediate C Intermediate C1: 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)piperidine [ka] Step 1: tert-Butyl 4-(benzyloxy)piperidine-1-carboxylate To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.96 mmol) in dry DMF (10 mL) at 0 °C was added NaH (60% in oil, 238 mg, 9.92 mmol). The mixture was stirred at 0 °C for 30 minutes, then (chloromethyl)benzene (755 mg, 5.95 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 × 30 mL), and the combined organics were washed with brine, dried over Na SO , and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 10 / 1) to give the title product (1.30 g, 92%) as a colorless oil.1 HNMR(400MHz,MeOD-d4):7.27-7.18(m,5H),4.48(s,2H),3.73-3.67(m,2H),3.51- 3.46(m,1H),3.06-3.00(m,2H),1.80-1.75(m,2H),1.55-1.48(m,2H),1.38(s,9H).

[0475] Step 2: 4-(Benzyloxy)piperidine Hydrochloride To a solution of tert-butyl 4-(benzyloxy)piperidine-1-carboxylate (1.3 g, 4.46 mmol) in dioxane (5 mL) was added HCl in dioxane (4 M, 10 mL), and the reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure to give the title product (2.10 g, 100%) as a white solid. 1 HNMR(400MHz,MeOD-d4):7.38-7.26(m,5H),4.58(s,2H),3.81-3.76(m,1H), 3.37-3.31(m,2H),3.16-3.10(m,2H),2.08-2.01(m,2H),1.97-1.91(m,2H).

[0476] Step 3: 4-(benzyloxy)-1-(2,2,2-trifluoroethyl)piperidine To a solution of 4-(benzyloxy)piperidine hydrochloride (2.1 g, 9.22 mmol) in DMF (15 mL) was added 1,1,1-trifluoro-2-iodoethane (5.79 g, 27.6 mmol) and K2CO3 (3.81 g, 27.6 mmol). The reaction mixture was stirred at 130 °C for 1.5 h using μW irradiation. The reaction mixture was partitioned between water (10 mL) and EtOAc (10 ml), and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organics were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 10 / 1) to give the title product (896 mg, 36%) as a yellow oil. 1HNMR(400MHz,MeOD-d4):7.36-7.24(m,5H),4.54(s,2H),3.50-3.43(m,1H),3.07-2.9 9(m,2H),2.92-2.87(m,2H),2.51-2.45(m,2H),1.95-1.89(m,2H),1.70-1.61(m,2H).

[0477] Step 4: 1-(2,2,2-trifluoroethyl)piperidin-4-ol To a solution of 4-(benzyloxy)-1-(2,2,2-trifluoroethyl)piperidine (890 mg, 3.25 mmol) in MeOH (10 mL) was added Pd(OH) (91.2 mg). The mixture was stirred under H at 55 °C overnight. The reaction mixture was filtered and the organics were concentrated under reduced pressure to give the title product (590 mg, 98%) as a colorless oil. 1 HNMR(400MHz, CDCl3):3.72-3.67(m,1H),3.00-2.91(m,2H),2.90-2.85(m,2H),2.51-2.44(m,2H),1.91-1.84(m,2H),1.64-1.55(m,2H).

[0478] Step 5: 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)piperidine To a solution of 1-(2,2,2-trifluoroethyl)piperidin-4-ol (590 mg, 3.22 mmol) in DCM (10 mL) was added EtN (1.45 g, 14.4 mmol) followed by MsCl (1.10 g, 9.66 mmol), and the mixture was stirred at room temperature overnight. The mixture was partitioned between water (10 mL) and DCM (10 mL), and the organic layer was washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude mesylate salt (880 mg, 100%) as a yellow oil. 1HNMR(400MHz,CDCl3):4.78-4.73(m,1H),3.13(s,1H),3.01-2.94(m,7H),2 .90-2.85(m,2H),2.64-2.60(m,2H),2.05-1.99(m,2H),1.94-1.88(m,2H).

[0479] The crude mesylate salt was dissolved in DMF (10 mL) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (465 mg, 2.40 mmol), CsCO (1.30 g, 4.00 mmol), and KI (44.3 mg, 267 μmol) were added. The reaction mixture was stirred in a sealed tube at 100° C. overnight. Water (10 mL) was added, and the mixture was extracted with EtOAc (2×40 mL). The combined organics were washed with water and brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc=70 / 30, v / v) to give the title product (70.0 mg, 7%) as a colorless oil. LCMS (Method A): 1.36 min, m / z: 360.2 [M+H] + .

[0480] Intermediate C2: 1-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)piperazine [ka] Step 1: 1-(2-bromoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.57 mmol) in DMSO (5 mL) was added KOH (1.43 g, 25.6 mmol). After stirring at room temperature for 1 hour, 1,2-dibromoethane (9.63 g, 51.3 mmol) was added. The mixture was stirred at room temperature overnight, then diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organics were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc=5 / 1) to give the title product (320 mg, 41%) as a colorless oil. LCMS (Method A): 2.03 min, m / z 301.1 / 303.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6):7.99(s,1H),7.62(s,1H),4.52(d,J=6.4Hz,2H),3.85(d,J=6.0Hz,2H),1.26(s,12H).

[0481] Step 2: 1-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)piperazine To a solution of 1-(2-bromoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 332 μmol) in MeCN (3 mL) was added 1-methylpiperazine (49.8 mg, 498 μmol) and CsCO (216 mg, 664 μmol). The mixture was stirred at 90 °C for 6 h. Water (10 mL) was added and the organics were extracted with EtOAc (3 × 15 mL). The combined organics were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the title product (60.0 mg, 56%) as a pale yellow oil, which was used directly without further purification. LCMS (Method B): 1.43 min, m / z: 321.3 [M+H] + .

[0482] Intermediate C3: 1-(2-(3,3-dimethylazetidin-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Step 1: 1-(2-(3,3-dimethylazetidin-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a solution of 1-(2-bromoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 332 μmol) in MeCN (3 mL) was added cesium carbonate (540 mg, 1.66 mmol) and 3,3-dimethylazetidine hydrochloride (60.5 mg, 498 μmol). The reaction mixture was refluxed for 4 h. The mixture was cooled to room temperature, filtered, and the residue was washed with MeCN (2×3 mL). The combined filtrates were concentrated under reduced pressure to give the title product (105 mg, >100%) as a pale yellow solid. This was used directly in the next step without further purification. LCMS (Method A): 0.32 min, m / z: 307.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6):7.88(s,1H),7.54(s,1H),4.04-4.01(m,2H),2.81-2.80(m,4H),2.72(t,J=6.4Hz,2H),1.26-1.24(m,12H),1.12(s,6H).

[0483] Intermediate C4: N-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-amine [ka] Step 1: N-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-amine To a solution of 1-(2-bromoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 332 μmol) in MeCN (3 mL) was added methylamine hydrochloride (44.1 mg, 664 μmol), CsCO (540 mg, 1.66 mmol), and KI (5.51 mg, 33.2 μmol) at room temperature. The reaction mixture was refluxed under a N atmosphere for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title product (118 mg, >100%) as a yellow oil. Used crude in the next step. LCMS (Method A): 0.30 min, m / z 169.9 [M+H] + .

[0484] Intermediate C5: N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-amine [ka] Step 1: N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-amine To a solution of 1-(2-bromoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.332 mmol) in MeCN (3 mL) was added methylamine hydrochloride (22.4 mg, 0.498 mmol), CsCO (540 mg, 1.66 mmol), and KI (5.51 mg, 0.033 mmol) at room temperature. The reaction mixture was stirred at 90 °C under N for 4 h. The solids were removed by filtration, washed with EtOAc (5 mL), and the combined organics were concentrated under reduced pressure to give the title product (120 mg, >100%) as a black oil. Used directly crude in the next step. LCMS (Method A): 0.45 min, m / z 266.1 [M+H] + .

[0485] Intermediate C6: 8-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-8-azabicyclo[3.2.1]octane [ka] Step 1: 8-methyl-8-azabicyclo[3.2.1]octan-3-yl methanesulfonate A mixture of 8-methyl-8-azabicyclo[3.2.1]octan-3-ol (3 g, 21.2 mmol) and EtN (5.57 g, 55.1 mmol) in DCM (30 mL) was stirred at 0 °C. MsCl (3.14 g, 27.5 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into water (40 mL) and extracted with EtOAc (40 mL × 2). The combined organics were dried over NaSO and concentrated under reduced pressure to give the crude title product (2.00 g, 9.11 mmol) as an orange solid. Used crude in the next step. LCMS (Method A): 0.72 min, m / z 219.9 [M+H] + .

[0486] Step 2: 8-Methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-8-azabicyclo[3.2.1]octane A mixture of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl methanesulfonate (500 mg, 2.27 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (440 mg, 2.27 mmol), and K2CO3 (941 mg, 6.81 mmol) in MeCN (10 mL) was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (40 mL) and extracted with EtOAc (40 mL × 2). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 4 / 1 to 1 / 4) to give the title product (200 mg, 28%) as a brown solid. LCMS (Method B): 2.58 min, m / z 318.2 [M+H] +

[0487] Intermediate C7: 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carbonitrile [ka] Step 1: 4-Bromo-1-methyl-1H-pyrrole-2-carbonitrile To a solution of 1-methyl-1H-pyrrole-2-carbonitrile (500 mg, 4.71 mmol) in DMF (5 mL) was added NBS (838 mg, 4.71 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EtOAc, 4:1) to give the title product (700 mg, 80%) as a white solid. 1 H NMR(400MHz, CDCl3):6.81(s,1H),6.76(s,1H),3.77(s,3H).

[0488] Step 2: 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carbonitrile To a solution of 4-bromo-1-methyl-1H-pyrrole-2-carbonitrile (300 mg, 1.62 mmol), B2pin2 (431 mg, 1.70 mmol), and AcOK (476 mg, 4.86 mmol) in degassed 1,4-dioxane (10 mL) was added Pd(dppf)Cl2 (74.1 mg, 81.0 μmol). The mixture was stirred overnight at 100 °C under N2. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE: EtOAc, 2:1) to give the title product (200 mg, 53%) as a white solid. No mass ion

[0489] Intermediate C8: 2-{3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]oxetan-3-yl}acetonitrile [ka] Step 1: 2-{3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]oxetan-3-yl}acetonitrile To a mixture of 2-(oxetan-3-ylidene)acetonitrile (200 mg, 2.10 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (520 mg, 2.68 mmol) in MeCN (15 mL) was added DBU (639 mg, 4.20 mmol), and the reaction mixture was stirred at 60° C. for 18 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organics were washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EtOAc, 4:1) to yield the title product (250 mg, 41%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6):8.30(s,1H),7.76(s,1H),5.01(d,J=7.2Hz,2H),4.74(d,J=7.2Hz,2H),3.61(s,2H),1.27(s,12H).

[0490] Intermediate C9: N-isopropyl-N-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-amine [ka] Step 1: 2-Chloro-N-isopropyl-N-methylpropanamide To a solution of methyl(propan-2-yl)amine (1 g, 13.6 mmol) in DCM (14 mL) was added EtN (2.28 g, 22.6 mmol) followed by 2-chloropropanoyl chloride (1.43 g, 11.3 mmol) at 0 °C. The solution was stirred under N at 0 °C for 1 h. The solution was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (3 mL), dried over NaSO, and concentrated under reduced pressure to give the title product (1.70 g, 76%) as a white oil. LCMS (Method C): 0.74 min, m / z: 163.9 [M+H] +

[0491] Step 2: 2-(4-bromo-1H-pyrazol-1-yl)-N-isopropyl-N-methylpropanamide To a solution of 2-chloro-N-methyl-N-(propan-2-yl)propanamide (1.56 g, 9.53 mmol) in DMF (25 mL) was added 4-bromo-1H-pyrazole (1.16 g, 7.94 mmol) and K2CO3 (3.28 g, 23.8 mmol) at room temperature. The solution was stirred overnight at 130 °C under N2. The solution was diluted with water (25 mL) and the organics were extracted with EtOAc (2 x 10 mL). The combined organics were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAC, 5:1) to give the title product (2.00 g, 76%) as a colorless oil. LCMS (Method C): 1.20 min, m / z: 275.9 [M+H] +

[0492] Step 3: 2-(4-bromo-1H-pyrazol-1-yl)-N-isopropyl-N-methylpropan-1-amine To a solution of 2-(4-bromo-1H-pyrazol-1-yl)-N-methyl-N-(propan-2-yl)propenamide (500 mg, 1.82 mmol) in THF (8 mL) was added LiAlH (138 mg, 3.64 mmol) at room temperature. The solution was stirred under N at room temperature for 1 h. The solution was diluted with water (25 mL) and the organics were extracted with EtOAc (2 × 10 mL). The combined organics were washed with water (10 mL) and brine (10 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 100 / 1) to give the title product (205 mg, 43%) as a white solid. LCMS (Method C): 0.29 min, m / z 259.9 [M+H] +

[0493] Step 4: Methyl(propan-2-yl){2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propyl}amine To a solution of 2-(4-bromo-1H-pyrazol-1-yl)-N-isopropyl-N-methylpropan-1-amine (100 mg, 384 μmol) in 1,4-dioxane (4 mL) was added B2pin2 (146 mg, 576 μmol), Pd(dppf)Cl2 (28.0 mg, 38.4 μmol), and AcOK (94.2 mg, 960 μmol). The solution was stirred at 100 °C under N2 for 8 hours. The solution was concentrated, and the crude product was purified by silica gel column chromatography (PE / EtOAc = 1 / 1) to yield the title compound (18.0 mg, 15%) as a white oil. LCMS (Method C): 0.36 min, m / z: 307.9 [M+H] +

[0494] Intermediate C10: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclopropane-1-carbonitrile [ka] Step 1: 2-(4-iodo-1H-pyrazol-1-yl)acetonitrile To a solution of 4-iodo-1H-pyrazole (1 g, 5.15 mmol) in DMF (10 mL) was added KCO (1.42 g, 10.3 mmol) and 2-bromoacetonitrile (678 mg, 5.66 mmol) at room temperature. The reaction mixture was stirred at 50 °C overnight. The reaction mixture was extracted with EtOAc (2 × 30 mL), and the combined organics were washed with water and brine, dried over NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc, 5:1) to yield the title product (1.10 g, 92%) as a white solid. 1 HNMR(400MHz,DMSO-d6):8.02(s,1H),7.68(s,1H),5.49(s,2H).

[0495] Step 2: 1-(4-iodo-1H-pyrazol-1-yl)cyclopropane-1-carbonitrile To a solution of 2-(4-iodo-1H-pyrazol-1-yl)acetonitrile (1.1 g, 4.72 mmol) in DMSO (8 mL) was added NaH (60% in oil, 451 mg, 18.8 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min. 1,2-Dibromoethane (2.64 g, 14.1 mmol) in DMSO (2 mL) was added dropwise, and the reaction was stirred at room temperature for 8 h. The mixture was quenched with water (10 mL), and the organics were extracted with EtOAc (30 mL × 2). The combined organics were washed with brine, dried over Na SO , and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc, 10 / 1) to give the title product (274 mg, 22%) as a yellow oil. LCMS (Method E): 0.95 min, m / z: 259.9 [M+H] +

[0496] Step 3: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclopropane-1-carbonitrile To a solution of 1-(4-iodo-1H-pyrazol-1-yl)cyclopropane-1-carbonitrile (255 mg, 984 μmol) in degassed DMSO (10 mL), B2(pin)2 (373 mg, 1.47 mmol), Pd(dppf)Cl2 (71.9 mg, 98.3 μmol), and AcOK (289 mg, 2.95 mmol) were added at room temperature, and the reaction mixture was stirred at 80 °C for 3 h. The mixture was partitioned between HO (10 mL) and EtOAc (10 mL), and the layers were separated. The aqueous fraction was extracted with EtOAc (30 mL × 2). The combined organics were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc, 20 / 1 to 5 / 1) to yield the title product (150 mg, 59%) as a white solid. LCMS (Method E): 1.03 min, m / z: 259.9 [M+H] +

[0497] Intermediate C11: 1-(methyl-d3)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine [ka] Step 1: 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine A solution of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (377 mg, 999 μmol) in HCOOH (2 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound as the formate salt (270 mg, 97%) as a colorless oil. LCMS (Method A): 2.17 min, m / z 278.1 [M+H] +

[0498] Step 2: 1-(methyl-d3)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine To a solution of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine (270 mg, 974 μmol) in MeCN (5 mL) was added KCO (134 mg, 974 μmol) and CDI (141 mg, 974 μmol). The reaction mixture was stirred at 80° C. for 2 h. The mixture was poured into water (5 mL) and extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the title product (290 mg, >100%) as a white solid. Used crude in the next step. LCMS (Method A): 2.09 min, m / z 295.1 [M+H] +

[0499] Intermediate C12: tert-butyl 3-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [ka] Step 1: tert-Butyl 3-methyl-5-(tosyloxy)piperidine-1-carboxylate To a solution of tert-butyl 3-hydroxy-5-methylpiperidine-1-carboxylate (575 mg, 2.67 mmol) in DCM (10 mL) and pyridine (10 mL) was added TsCl (610 mg, 3.20 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc, 25 / 1) to give the title product (800 mg, 81%) as a white solid. LCMS (Method A): 4.28 min, 392.2 [M+Na] +

[0500] Step 2: tert-butyl 3-(4-bromo-1H-pyrazol-1-yl)-5-methylpiperidine-1-carboxylate To a solution of tert-butyl 3-methyl-5-(tosyloxy)piperidine-1-carboxylate (500 mg, 1.35 mmol) in DMF (10 mL) were added 4-bromo-1H-pyrazole (257 mg, 1.75 mmol) and CsCO (1.31 g, 4.05 mmol). After stirring at 100 °C under N, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc, 5 / 1) to give the title product (230 mg, 50%) as a colorless oil. LCMS (Method A): 4.19 min, m / z: 288.0, 290.0 [M+H] +

[0501] Step 3: tert-butyl 3-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl 3-(4-bromo-1H-pyrazol-1-yl)-5-methylpiperidine-1-carboxylate (200 mg, 0.581 mmol) in DME (10 mL) was added AcOK (113 mg, 1.16 mmol), B2pin2 (221 mg, 871 μmol), and Pd(dppf)Cl2 (42.4 mg, 58.0 μmol). After stirring overnight at 100 °C under N2, the mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give the title product (400 mg, >100%) as a black oil. Used crude in the next step. LCMS (Method A): 3.50 min, m / z: 392.3 [M+H] +

[0502] Intermediate C13: tert-butyl 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate [ka] Step 1: tert-Butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate To a solution of (pyrrolidin-2-yl)methanol (500 mg, 4.94 mmol) in DCM (5 mL) was added EtN (2.49 g, 24.7 mmol) followed by BocO (1.29 g, 5.92 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 1:1) to give the title product (850 mg, 85%) as a yellow oil.

[0503] Step 2: tert-Butyl 2-{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate To a solution of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (850 mg, 4.22 mmol) in DCM (5 mL) was added TsCl (2.40 g, 12.6 mmol) and EtN (2.56 g, 25.3 mmol). The mixture was stirred at room temperature overnight. Water (10 mL) was added, and the organics were extracted with DCM (2 × 10 mL). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 4:1) to give the title product (1.40 g, 93%) as a yellow oil.

[0504] Step 3: tert-Butyl 2-[(4-bromo-1H-pyrazol-1-yl)methyl]pyrrolidine-1-carboxylate To a solution of tert-butyl 2-{[(4-methylbenzenesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (1.4 g, 3.93 mmol) in DMF (10 mL) was added CsCO (3.80 g, 11.7 mmol) and 4-bromo-1H-pyrazole (692 mg, 4.71 mmol). The reaction mixture was stirred at 100 °C for 16 h. Water (10 mL) was added, and the organics were extracted with EtOAc (2 × 20 mL). The combined organics were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 2:1) to give the title product (1.30 g, 100%) as a colorless oil.

[0505] Step 4: tert-butyl 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate To a solution of tert-butyl 2-[(4-bromo-1H-pyrazol-1-yl)methyl]pyrrolidine-1-carboxylate (1.3 g, 3.93 mmol) in DME (10 mL) was added AcOK (1.14 g, 11.7 mmol), B2(pin)2 (1.19 g, 4.71 mmol), and Pd(dppf)Cl2 (287 mg, 393 μmol). The reaction mixture was stirred at 100 °C under N2 for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EtOAc, 3:1) to yield the title compound (1.0 g, 67%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6):7.82(s,1H),7.58(s,1H),4.22-4.13(m,3H),3.20-3.10(m,2H),1.75-1.69(m,4H),1.41-1.37(m,9H),1.24(s,12H)

[0506] Intermediate C14: 6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] Step 1: tert-Butyl 6-[(4-methylbenzenesulfonyl)oxy]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (3.0 g, 14.0 mmol) in DCM / pyridine (4 / 1, 100 mL) was added TsCl (2.93 g, 15.4 mmol). The mixture was stirred at room temperature for 12 hours. Water (50 mL) was added, and the organics were extracted with EtOAc (3 × 50 mL). The combined organics were washed with brine (50 mL), dried over 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 (3.00 g, 58%) as a white solid.

[0507] Step 2: tert-Butyl 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4-methylbenzenesulfonyl)oxy]-2-azaspiro[3.3]heptane-2-carboxylate (1.2 g, 3.26 mmol) in DMF (40 mL) was added CsCO (2.12 g, 6.52 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (632 mg, 3.26 mmol), and the mixture was stirred overnight at 100° C. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 3:1) to give the title product (800 mg, 63%) as a yellow solid.

[0508] Intermediate C15: tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azepane-1-carboxylate [ka] Step 1: tert-Butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate To a solution of tert-butyl 4-hydroxyazepane-1-carboxylate (860 mg, 3.99 mmol) in DCM (10 mL) at 0 °C was added EtN (808 mg, 7.98 mmol) and MsCl (684 mg, 5.98 mol). The reaction was stirred at room temperature under N for 1 h. Water (10 mL) was added and the organics were extracted with DCM (3 × 15 mL). The combined organics were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the title compound (1.1 g, 94%) as a yellow oil. 1 HNMR:(400MHz,DMSO-d6):3.36-3.32(m,3H),3.22(brs,2H),3.16(s,3H),2.00-1.95(m,1H),1.84-1.77(m,4H),1.64-1.61(m,1H),1.40(s,9H).

[0509] Step 2: tert-Butyl 4-(4-bromo-1H-pyrazol-1-yl)azepane-1-carboxylate To a solution of tert-butyl 4-(methanesulfonyloxy)azepane-1-carboxylate (1.1 g, 3.74 mmol) in DMF (15 mL) was added CsCO (3.64 g, 11.2 mmol) and 4-bromo-1H-pyrazole (549 mg, 3.74 mmol) at room temperature. The reaction mixture was refluxed for 4 hours. The solvent was removed under reduced pressure and purified by silica gel column chromatography (PE: EtOAc, 5:1) to give the title product (1.0 g, 77%) as a yellow oil. LCMS (Method A): 1.20 min, m / z 287.7, 289.7 [M+H-tBu] + . 1 HNMR:(400MHz,DMSO-d6):8.03(s,1H),7.51(s,1H),4.32-4.26(m,1H),3.60-3.52(m,1H) ,3.38-3.36(m,2H),3.23-3.17(m,1H),2.03-1.81(m,5H),1.61-1.62(m,1H),1.41(s,9H).

[0510] Step 3: tert-Butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azepane-1-carboxylate A mixture of tert-butyl 4-(4-bromo-1H-pyrazol-1-yl)azepane-1-carboxylate (700 mg, 2.03 mmol), AcOK (595 mg, 6.08 mmol), B2(pin)2 (771 mg, 3.04 mmol), and Pd(dppf)Cl2 (147 mg, 202 μmol) in degassed 1,4-dioxane (15 mL) was stirred at 80 °C under N2 for 8 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc, 5:1) to give the title compound (700 mg, 1.78 mmol) as a yellow oil. LCMS (Method A): 1.80 min, m / z 391.9 [M+H] +

[0511] Intermediate C16: 1-(1-methylpyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Step 1: 1-(1-methylpyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole A mixture of 1-(pyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg, 760 μmol), formaldehyde (184 mg, 2.28 mmol), and NaBH(OAc) (1.28 g, 6.07 mmol) in DCM (10 mL) was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc (50 mL × 3). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA, 95:5) to give the title product (140 mg, 67%) as a yellow oil. LCMS (Method A): 3.04 min, m / z 278.2 [M+H]+

[0512] Intermediate C17: 1-(1-isopropylazetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Step 1: tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (5.0 g, 28.9 mmol) and EtN (8.75 g, 86.60 mmol) in DCM (50 mL) at 0 °C, MsCl (4.94 g, 43.30 mmol) was added and the reaction was stirred at 0 °C for 3 h. Water (20 mL) was added and the organics were extracted with DCM (2 × 20 mL). The combined organics were washed with brine, dried over Na SO and concentrated under reduced pressure to give the title compound (7.2 g, >100%) as a white solid. LCMS (Method C): 1.07 min, m / z 195.8 [M+H-tbu] +

[0513] Step 2: tert-Butyl 3-(4-bromo-1H-pyrazol-1-yl)azetidine-1-carboxylate To a solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (7.2 g, 28.65 mmol) in DMF (200 ml) was added CsCO (27.9 g, 85.95 mmol) and 4-bromo-1H-pyrazole (4.63 g, 31.51 mmol), and the reaction mixture was stirred at 80 °C for 3 h. Water (200 mL) was added, and the organics were extracted with EtOAc (2 × 100 mL). The combined organics were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc, 5 / 1) to give the title compound (7.7 g). LCMS (Method C): 0.79 min, m / z 245.0 [M+H-tbu] +

[0514] Step 3: tert-Butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate To a mixture of tert-butyl 3-(4-bromo-1H-pyrazol-1-yl)azetidine-1-carboxylate (7.7 g, 25.48 mmol), Pd(dppf)Cl (1.86 g, 2.55 mmol), and AcOK (7.49 g, 76.44 mmol) in degassed 1,4-dioxane (500 mL), B2(pin) (9.71 g, 38.22 mmol) was added, and the reaction was stirred at 100 °C under N for 6 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE: EtOAc, 3:1) to give the title compound (8.2 g) as a colorless oil. LCMS (Method C): 1.04 min, m / z 293.5 [M+H-tbu] +

[0515] Step 4: 1-(Azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole hydrochloride To a solution of tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (8.2 g, 23.47 mmol) in 1,4-dioxane (10 mL) was added HCl (4 M in 1,4-dioxane, 20 mL) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give the title product (6.7 g) as a yellow oil. LCMS (Method C): 0.76 min, m / z 250.2 [M+H] +

[0516] Step 5: 1-(1-isopropylazetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a solution of 1-(azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.00 mmol) in MeCN (10 mL) was added 2-iodopropane (1.01 g, 6.00 mmol) and K2CO3 (276 mg, 2.00 mmol), and the reaction was stirred at 45 °C overnight. Water (10 mL) was added, and the organics were extracted with EtOAc (2 x 40 mL). The combined organics were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 50 / 1) to give the title product (70 mg) as a colorless oil. LCMS (Method C): 0.44 min, m / z 292.1 [M+H] +

[0517] Intermediate C18: 1-(1-methylazetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Step 1: tert-Butyl 3-oxoazetidine-1-carboxylate A mixture of azetidin-3-one hydrochloride (1 g, 9.29 mmol), BocO (3.03 g, 13.9 mmol), and EtN (2.81 g, 27.8 mmol) in DCM (40 mL) was stirred at room temperature overnight. The mixture was washed with brine (2 × 20 mL) and concentrated under reduced pressure to give the title product (1.17 g, 73.5%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6):4.67(s,4H),1.42(s,9H).

[0518] Step 2: tert-Butyl 3-hydroxyazetidine-1-carboxylate A mixture of tert-butyl 3-oxoazetidine-1-carboxylate (6.77 g, 39.5 mmol) and NaBH (2.98 g, 79.0 mmol) in MeOH (80 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to give the title product (4.30 g, 63%) as a yellowish oil. 1 H NMR(400MHz,DMSO-d6):5.62(d,J=6.5Hz,1H),4.36(qt,J=6.7,4.5Hz,1H),4.03-3.92(m,2H),3.57(dd,J=9.2,4.5Hz,2H),1.36(s,9H).

[0519] Step 3: tert-Butyl 3-[(4-methylbenzenesulfonyl)oxy]azetidine-1-carboxylate A mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (2 g, 11.5 mmol), TsCl (2.28 g, 12.0 mmol), and EtN (2.32 g, 23.0 mmol) in DCM (5 mL) was stirred at room temperature overnight. The reaction mixture was washed with brine (50 mL × 2), dried over NaSO, and concentrated under reduced pressure to give the title product (1.25 g, 33%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6):7.81(d,J=8.4Hz,2H),7.50(d,J=8.2Hz,2H),5.08(tt,J= 6.6,3.9Hz,1H),4.13-4.00(m,2H),3.81-3.67(m,2H),2.43(s,3H),1.34(s,9H).

[0520] Step 4: tert-Butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate A mixture of tert-butyl 3-[(4-methylbenzenesulfonyl)oxy]azetidine-1-carboxylate (1.45 g, 4.42 mmol), CsCO (2.88 g, 8.84 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.28 g, 6.63 mmol) in DMF (40 mL) was stirred at 110 °C overnight. The mixture was poured into water (150 mL) and extracted with EtOAc (2 × 100 mL). The combined organics were washed with brine (2 × 100 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 10:1) to give the title product (750 mg, 49%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6):8.07(s,1H),7.70(s,1H),5.22(ddd,J=13.2,8.0,5.3Hz,1H),4.26(t,J=8.3Hz,2H),4.11(s,2H),1.40(s,9H),1.25(s,12H).

[0521] Step 5: 1-(Azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole A mixture of tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (500 mg, 1.43 mmol) in aqueous HCl (1 M, 2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title product (350 mg, 1.40 mmol, 98.3%) as a yellow oil. LCMS (Method A): 1.03 min, m / z 250.0 [M+H] + .

[0522] Step 6: 1-(1-methylazetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole A mixture of 1-(azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 1.40 mmol), paraformaldehyde (337 mg, 4.19 mmol), and NaBH(OAc) (2.37 g, 11.2 mmol) in DCM (30 mL) was stirred at room temperature for 45 minutes. The solution was diluted with DCM (30 mL) before adding saturated aqueous NaHCO (30 mL). The aqueous layer was extracted with a DCM / MeOH mixture (9:1, 3 × 10 mL). The combined organic layers were concentrated under reduced pressure to give the title product (70 mg, 19%) as a yellow solid. LCMS (Method A): 1.39 min, m / z 264.1 [M+H] + .

[0523] Intermediate C19: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-1H-pyrazole [ka] Step 1: tert-Butyl 3-(benzyloxy)azetidine-1-carboxylate To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (5 g, 28.9 mmol) in DMF (50 mL) at 0° C. was added NaH (60% in oil, 2.3 g, 57.8 mmol). The solution was stirred at 0° C. for 1 h. Benzyl chloride (4.4 g, 34.7 mmol) was added to the solution at 0° C., and the reaction mixture was stirred at room temperature for 2 h. Water (250 mL) was added, and the organics were extracted with EtOAc (2×300 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, and concentrated under reduced pressure to give the title product (7.1 g, 93%) as a white solid. LCMS (Method C): 1.53 min, m / z 208 [M+H-tBu] +

[0524] Step 2: 3-(benzyloxy)azetidine To a solution of tert-butyl 3-(benzyloxy)azetidine-1-carboxylate (4.8 g, 18.2 mmol) in DCM (30 mL) was added TFA (10 mL), and the solution was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, and the residue was dissolved in MeOH (3 mL). The pH was adjusted to pH = 8 by adding saturated aqueous NaHCO3. The organics were extracted with DCM (2 x 50 mL), and the combined organics were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to yield the title product (4.10 g, >100%) as a colorless oil. Used crude in the next step. 1 H NMR(400MHz,DMSO-d6):7.36-7.35(m,5H),4.46(s,2H),4.43-4.38(m,1H),4.03-3.98(m,2H),3.77-3.74(m,2H).

[0525] Step 3: 3-(benzyloxy)-1-(2,2,2-trifluoroethyl)azetidine To a solution of 3-(benzyloxy)azetidine (200 mg, 1.22 mmol) and 1,1,1-trifluoro-2-iodoethane (768 mg, 3.66 mmol) in DMF (3 mL) was added KCO (337 mg, 2.44 mmol), and the reaction was stirred at 130 °C for 90 min. Water (20 mL) was added, and the organics were extracted with EtOAc (3 × 20 mL). The combined organics were washed with water (50 mL) and brine (50 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc, 10:1) to give the title compound (80 mg, 27%) as a pale yellow oil. LCMS (Method A): 1.82 min, m / z: 246.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6):7.37-7.29(m,5H),4.39(s,2H),4.19-4.15(m,1H),3.60-3.57(m,2H),3.22-3.08(m,4H).

[0526] Step 4: 1-(2,2,2-trifluoroethyl)azetidin-3-ol To a solution of 3-(benzyloxy)-1-(2,2,2-trifluoroethyl)azetidine (130 mg, 530 μmol) in MeOH (10 mL) was added Pd(OH) (37.2 mg, 265 μmol), and the reaction mixture was stirred under H overnight. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title product (80.0 mg, 97%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6):5.37(s,1H),4.23-4.19(m,1H),3.61-3.58(m,2H),3.17-3.09(m,2H),3.00-2.96(m,2H).

[0527] Step 5: 1-(2,2,2-trifluoroethyl)azetidin-3-yl methanesulfonate To a solution of 1-(2,2,2-trifluoroethyl)azetidin-3-ol (80 mg, 515 μmol) in DCM (5 mL) at 0° C. was added EtN (103 mg, 1.02 mmol) and MsCl (70.7 mg, 618 μmol). The solution was stirred at room temperature for 1 h, then poured into water (10 mL) and extracted with DCM (2×20 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure to give the title product (100 mg, 83%) as a pale yellow oil. LCMS (Method C): 0.72 min, m / z: 233.8 [M+H] +

[0528] Step 6: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1H-pyrazole To a solution of 1-(2,2,2-trifluoroethyl)azetidin-3-yl methanesulfonate (500 mg, 2.14 mmol) in DMF (2 mL) was added CsCO (1.04 g, 3.21 mmol), KI (935 mg, 0.21 mmol), and 4-(4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (372 mg, 1.92 mmol), and the reaction was stirred at 80 °C for 2 h. Water (10 mL) was added, and the organics were extracted with EtOAc (2 × 10 mL). The combined organics were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 5:1 to 1:1) to give the title product (130 mg, 20%) as a colorless oil. LCMS (Method C): 1.25 min, m / z: 331.9 [M+H] +

[0529] Intermediate C20: N-methyl-N-(propan-2-yl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propenamide [ka] Step 1: Generate 2-chloro-N-methyl-N-(propan-2-yl)propanamide To a solution of methyl(propan-2-yl)amine (1 g, 13.6 mmol) in DCM (14 mL) was added EtN (2.28 g, 22.6 mmol) and 2-chloropropanoyl chloride (1.43 g, 11.3 mmol) at 0 °C. The solution was stirred under N at 0 °C for 1 h. The solution was partitioned between water (20 mL) and DCM (20 mL), then the organics were collected, washed with brine (10 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc, 5 / 1) to give the title product (1.46 g, 66%) as a white oil.

[0530] Step 2: N-methyl-N-(propan-2-yl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanamide To a solution of 2-chloro-N-methyl-N-(propan-2-yl)propanamide (1.45 g, 8.86 mmol) in DMF (25 mL) was added KCO (3.05 g, 22.1 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.43 g, 7.38 mmol). The solution was stirred overnight at 130 °C under N. Water (20 mL) was added, and the organics were extracted with EtOAc (2 × 10 mL). The combined organics were washed with brine (10 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAC, 5 / 1) to give the title product (1.46 g, 51%) as a white solid.

[0531] Intermediate C21: tert-butyl 2,2-dimethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [ka] Step 1: tert-Butyl 2,2-dimethyl-5-((methylsulfonyl)oxy)piperidine-1-carboxylate To a mixture of tert-butyl 5-hydroxy-2,2-dimethylpiperidine-1-carboxylate (50 mg, 218 μmol) in DCM (5 mL) was added EtN (51.7 mg, 654 μmol) and MsCl (29.8 mg, 261 μmol), and the mixture was stirred at room temperature overnight. The mixture was poured into water (10 mL), and the organics were extracted with EtOAc (3×10 mL). The combined organics were washed with brine (10 mL) and concentrated under reduced pressure to yield the title compound (60.0 mg, 89%) as a colorless oil.

[0532] Step 2: tert-butyl 2,2-dimethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate A mixture of tert-butyl 2,2-dimethyl-5-((methylsulfonyl)oxy)piperidine-1-carboxylate (370 mg, 1.20 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (242 mg, 1.25 mmol), and CsCO (779 mg, 2.40 mmol) in DMF (15 mL) was stirred at 90 °C overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were dried over NaSO and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 99 / 1) to give the title product as a yellow solid.

[0533] Intermediate C22: N,N-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclopentan-1-amine [ka] Step 1: 3-Hydroxycyclopentyl 4-methylbenzene-1-sulfonate A mixture of cyclopentane-1,3-diol (1 g, 9.79 mmol), EtN (3.95 g, 39.1 mmol), and TsCl (1.94 g, 10.2 mmol) in DCM (5 mL) was stirred at 0 °C for 2 h. The mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 2:1) to give the title product (1.20 g, 48%) as a yellow oil. LCMS (Method A): 2.93 min, m / z 279.0 [M+Na] +

[0534] Step 2: 3-(4-bromo-1H-pyrazol-1-yl)cyclopentan-1-ol A mixture of 3-hydroxycyclopentyl 4-methylbenzene-1-sulfonate (1.2 g, 4.68 mmol), CsCO (2.77 g, 4.68 mmol), and 4-bromo-1H-pyrazole (687 mg, 4.68 mmol) in DMF (30 mL) was stirred at 50 °C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give the title product (750 mg, 69%) as a yellow solid. LCMS (Method A): 4.25 min, m / z 231.0 [M+H] +

[0535] Step 3: 3-(4-bromo-1H-pyrazol-1-yl)cyclopentyl 4-methylbenzene-1-sulfonate A mixture of 3-(4-bromo-1H-pyrazol-1-yl)cyclopentan-1-ol (750 mg, 3.24 mmol), EtN (1.30 g, 12.9 mmol), and TsCl (739 mg, 3.88 mmol) in DCM (5 mL) was stirred at 0 °C for 2 h. The mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 2:1) to give the title product (100 mg, 8%) as a yellow oil. LCMS (Method A): 2.93 min, m / z 386.0 [M+H] + .

[0536] Step 4: 3-(4-bromo-1H-pyrazol-1-yl)-N,N-dimethylcyclopentan-1-amine To a mixture of 3-(4-bromo-1H-pyrazol-1-yl)cyclopentyl 4-methylbenzene-1-sulfonate (100 mg, 259 μmol) and K2CO3 (253 mg, 777 μmol) in DMF (3 mL) was added dimethylamine (1.2 equiv.), and the mixture was stirred at 80 °C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give the title product (110 mg, >100%) as a yellow solid. LCMS (Method B): 1.00 min, m / z 258.0 [M+H] + .

[0537] Step 5: N,N-Dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclopentan-1-amine A mixture of 3-(4-bromo-1H-pyrazol-1-yl)-N,N-dimethylcyclopentan-1-amine (110 mg, 426 μmol), B2(pin)2 (129 mg, 511 μmol), Pd(dppf)Cl2 (31.1 mg, 42.6 μmol), and AcOK (83.6 mg, 852 μmol) in degassed 1,4-dioxane (2 mL) was stirred at 100 °C overnight under N2. The mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give the title product (60 mg, 46%) as a yellow solid. LCMS (Method B): 3.5 min, m / z 306.0 [M+H] + .

[0538] General Procedure A3 for Suzuki Reaction between Intermediate A3B1 and Boronic Esters [ka] A mixture of (S)—N-(4-(4-amino-7-iodo-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (1 equiv.), boronic ester (1.1 equiv.), NaCO (3 equiv.), and Pd(dppf)Cl (0.1 equiv.) in degassed 1,4-dioxane / HO (4 / 1, 0.2 M) was stirred at 100° C. overnight under N. The mixture was diluted with water, and the organics were extracted with EtOAc (3×). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH) to give the title product as a yellow solid.

[0539] The following compounds were prepared according to general procedure A3 [Table 10]

[0540] General Procedure A4 for Suzuki Reaction between Intermediate A4B1 and Boronic Esters [ka] A mixture of (S)—N-(4-(4-amino-7-bromopyrazolo[1,5-a]pyrazin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (1 equiv.), boronic ester (1.1 equiv.), NaCO (3 equiv.), and Pd(dppf)Cl (0.1 equiv.) in degassed 1,4-dioxane / HO (4 / 1, 0.2 M) was stirred at 100° C. overnight under N. The mixture was diluted with water, and the organics were extracted with EtOAc (3×). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH or PE / EtOAc) to give the title product as a yellow solid.

[0541] The following compounds were prepared according to general procedure A4 [Table 11-1] [Table 11-2]

[0542] Synthesis of halogenopyrazole intermediate D Intermediate D1: (3aR,6aS)-5-(4-bromo-1H-pyrazol-1-yl)-octahydrocyclopenta[c]pyrrole-2-carboxylate tert-butyl [ka] Step 1: (3aR,6aS)-tert-butyl 5-hydroxy-octahydrocyclopenta[c]pyrrole-2-carboxylate To a solution of tert-butyl (3aR,6aS)-5-oxo-octahydrocyclopenta[c]pyrrole-2-carboxylate (2.3 g, 10.2 mmol) in MeOH (50 mL) was added NaBH (1.92 g, 50.9 mmol), and the mixture was stirred at 60 °C overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between DCM (10 mL) and HO (10 mL). The organic phase was removed, and the aqueous was extracted with DCM (2 × 25 ml). The combined organics were dried over NaSO and concentrated under reduced pressure to give the title product (2.20 g, 95%) as a yellow oil. LCMS: (Method A): 2.70 min, m / z: 228.1 [M+H] +

[0543] Step 2: (3aR,6aS)-tert-butyl 5-(methanesulfonyloxy)-octahydrocyclopenta[c]pyrrole-2-carboxylate To a solution of tert-butyl (3aR,6aS)-5-hydroxy-octahydrocyclopenta[c]pyrrole-2-carboxylate (2.2 g, 9.67 mmol) and EtN (2.93 g, 29.0 mmol) in DCM (50 mL) was added MsCl (1.65 g, 14.5 mmol). The mixture was stirred at room temperature for 1 h. The organics were extracted with DCM (2 × 100 mL), and the combined organics were dried over NaSO and concentrated under reduced pressure to give the title product (3.00 g, >100%) as a yellow oil. LCMS: (Method A), 3.22 min, m / z: 306.1 [M+H] + .

[0544] Step 3: (3aR,6aS)-tert-butyl 5-(4-bromo-1H-pyrazol-1-yl)-octahydrocyclopenta[c]pyrrole-2-carboxylate To a mixture of tert-butyl (3aR,6aS)-5-(methanesulfonyloxy)-octahydrocyclopenta[c]pyrrole-2-carboxylate (3 g, 9.82 mmol) and CsCO (6.38 g, 19.6 mmol) in MeCN (60 mL) was added 4-bromo-1H-pyrazole (2.16 g, 14.7 mmol), and the mixture was stirred at 80 °C overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between DCM (10 mL) and HO (10 mL). The organic phase was collected, and the aqueous was extracted with DCM (2 × 25 mL). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1) to give the title product (2.17 g, 62%) as a yellow solid. LCMS: (Method A), 2,19 min, m / z:378.1, 380.1[M+Na] +

[0545] The following intermediate D13 was prepared following the synthesis of intermediate D1 using 4-iodo-1H-pyrazole and tert-butyl 4-oxo-2-(trifluoromethyl)piperidine-1-carboxylate. [Table 12]

[0546] Intermediate D2: 7-(4-bromo-1H-pyrazol-1-yl)-4-methyl-4-azaspiro[2.5]octane [ka] Step 1: tert-Butyl 7-hydroxy-4-azaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-oxo-4-azaspiro[2.5]octane-4-carboxylate (25 g, 110 mmol) in MeOH (400 mL) was added NaBH (12.4 g, 330 mmol), and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (200 mL). The organics were washed with water (3 x 200 mL), dried over NaSO, and concentrated under reduced pressure to give the title product (26.0 g, >100%) as a colorless oil. Used crude in the next step. LCMS: (Method A): 1.29 min, m / z 250.2 [M+Na] +

[0547] Step 2: tert-Butyl 7-(methanesulfonyloxy)-4-azaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-hydroxy-4-azaspiro[2.5]octane-4-carboxylate (26 g, 114 mmol) and EtN (34.5 g, 342 mmol) in DCM (300 mL) was added MsCl (15.5 g, 136 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was washed with water (3 x 200 mL), dried over NaSO, and concentrated under reduced pressure to give the title product (34.0 g, 97%) as a yellow oil. LCMS: (Method A): 2.04 min, m / z 328.2 [M+Na] +

[0548] Step 3: tert-Butyl 7-(4-bromo-1H-pyrazol-1-yl)-4-azaspiro[2.5]octane-4-carboxylate A mixture of tert-butyl 7-(methanesulfonyloxy)-4-azaspiro[2.5]octane-4-carboxylate (34 g, 111 mmol), 4-bromo-1H-pyrazole (19.5 g, 133 mmol), and CsCO (72.3 g, 222 mmol) in MeCN (350 mL) was stirred at 80 °C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 20 / 1 to 1 / 1) to give the title product (28.0 g, 71%) as a colorless oil. LCMS: (Method A): 1.90 min, m / z 378.2, 380.2 [M+Na] +

[0549] Step 4: 7-(4-bromo-1H-pyrazol-1-yl)-4-azaspiro[2.5]octane A solution of tert-butyl 7-(4-bromo-1H-pyrazol-1-yl)-4-azaspiro[2.5]octane-4-carboxylate (28 g, 78.5 mmol) in HCl in dioxane (4 M, 60 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title product as the HCl salt (26.0 g) as a white solid. LCMS: (Method A) 0.93 min, m / z 256.1, 258.1 [M+H] +

[0550] Step 5: 7-(4-bromo-1H-pyrazol-1-yl)-4-methyl-4-azaspiro[2.5]octane 7-(4-bromo-1H-pyrazol-1-yl)-4-azaspiro[2.5]octane (26 g, 101 mmol) and (CHO) in DCM (300 mL) n To a solution of (15.2 g, 505 mmol) was added NaBH(OAc) (31.9 g, 151 mmol) and the mixture was stirred at room temperature for 1 h. H2O (100 mL) was added and the organics were separated. The organic layer was washed with water (2 x 100 mL), dried over Na2SO4 and concentrated under reduced pressure to give the title product (20.0 g, 73%) as a colorless oil. LCMS: (Method A): 0.64 min, m / z: 270.2, 272.2 [M+H] +

[0551] The following intermediates D3 to D10, D15 were prepared according to the synthesis of intermediate D2. [Table 13]

[0552] Intermediates D11 and D12: (R)-4-(4-bromo-1H-pyrazol-1-yl)-1,2,2-trimethylpiperidine and (S)-4-(4-bromo-1H-pyrazol-1-yl)-1,2,2-trimethylpiperidine [ka] (R)-4-(4-bromo-1H-pyrazol-1-yl)-1,2,2-trimethylpiperidine and (S)-4-(4-bromo-1H-pyrazol-1-yl)-1,2,2-trimethylpiperidine were obtained by chiral SFC purification of the racemic mixture (obtained from tert-butyl 4-(4-bromo-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate (according to steps 4 and 5 of the synthesis of intermediate D2, step 4, compound 13, 4-(4-(4-amino-3-((4-difluoromethyl)sulfonamido)-3-((S)-1-(4-fluorophenyl)ethoxy)phenyl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl)-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate). Instrument: SFC-150 mgm, Column: YMC Cellulose SC (20 × 250 mm, 5 μm), Temperature: 30 °C, Mobile phase: CO2 / IPA [0.5% NH3 (7 M in MeOH)] = 95 / 5, Flow rate: 40 ml / min, Back pressure: 100 bar. Peak 1 = 0.89 min, Peak 2 = 1.09 min

[0553] The enantiomeric excess was calculated using UPCC (Waters), column: YMC cellulose SC (4.6 × 100 mm, 3 μm), temperature: 40 °C, mobile phase: CO / IPA [1.0% NH (7 M in MeOH)] = 90 / 10, flow rate: 3 mL / min. Both enantiomers have an enantiomeric excess of >98% ee.

[0554] Intermediates D13 and D14: (R)-7-(4-bromo-1H-pyrazol-1-yl)-4-methyl-4-azaspiro[2.5]octane and (S)-7-(4-bromo-1H-pyrazol-1-yl)-4-methyl-4-azaspiro[2.5]octane [ka] (R)-7-(4-Bromo-1H-pyrazol-1-yl)-4-methyl-4-azaspiro[2.5]octane and (S)-7-(4-Bromo-1H-pyrazol-1-yl)-4-methyl-4-azaspiro[2.5]octane were obtained by chiral HPLC purification of racemic 7-(4-Bromo-1H-pyrazol-1-yl)-4-methyl-4-azaspiro[2.5]octane (Intermediate D2). Column: CHIRALCEL® AD-H, column size: 21.2 × 250 mm, 5 μm, mobile phase: n-hexane / ethanol / diethylamine = 70 / 30 / 0.1 (v / v / v), flow rate: 20 mL / min, temperature: 35 °C.

[0555] The enantiomeric excess was calculated using CHIRALCEL® AD-H column with dimensions of 0.46 cm i.d. × 25 cm length × 5 μm, injection volume of 5 μL, mobile phase of n-hexane / ethanol / diethylamine = 70 / 30 / 0.1 (v / v / v), flow rate of 1.0 mL min , and sample solution of 1.1 mg / mL in MeOH / EtOH = 1 / 1 (v / v). Peak 1 = 4.72 min, Peak 2 = 9.64 min. Both enantiomers have enantiomeric excesses of >99% ee.

[0556] General Procedure B for Sonogashira Reaction between Intermediate A1B1 and Alkynes [ka] To a solution of N-(4-{4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (1 equiv.), CuI (1 equiv.), EtN (3 equiv.), and alkyne (2 equiv.) in degassed DMF (0.2 M) was added Pd(dppf)Cl (0.1 equiv.), and the mixture was stirred at 130° C. with μW irradiation for 1 h or until reaction completion as checked by TLC. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH) or preparative TLC to give the title compound as a yellow solid.

[0557] The following compounds were prepared according to general procedure B: [Table 14-1] [Table 14-2]

[0558] Compounds 79 and 80 [ka] Step 1: tert-butyl 4-(2-{4-amino-3-[4-(difluoromethanesulfonamido)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl}ethynyl)piperidine-1-carboxylate Following general procedure B using tert-butyl 4-ethynylpiperidine-1-carboxylate gave the title compound (88%) as a yellow solid.

[0559] Step 2: (S)—N-(4-(4-amino-1-methyl-7-(piperidin-4-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (compound 79) A solution of tert-butyl 4-(2-{4-amino-3-[4-(difluoromethanesulfonamido)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl}ethynyl)piperidine-1-carboxylate (300 mg, 429 μmol) in HCOH (2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH = 8 with saturated aqueous NaCO. The residue was diluted with water (5 mL), and the organics were extracted with EtOAc (3 × 5 mL). The combined organics were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH: 95 / 5) to give the title product (140 mg, 54%) as a white solid. LCMS (Method A): 2.83 min, m / z599.1[M+H] + . 1 H NMR(400MHz,DMSO-d6):7.80(s,1H),7.64-7.53(m,1H),7.50(q,J=4Hz,2H),7 .34(d,J=8Hz,1H),7.12(t,J=8Hz,1H),6.90(d,J=8Hz,1H),7.18-7.10(m,1H) ,6.84(s,1H),6.33(t,J=52Hz,1H),6.00(s,2H),5.63(q,J=8Hz,1H),4.15(s, 3H),3.23(s,2H),3.00(s,3H),2.04(s,2H),1.76(s,2H),1.50(d,J=6.2Hz,3H)

[0560] Step 3: (S)—N-(4-(4-amino-1-methyl-7-((1-methylpiperidin-4-yl)ethynyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (compound 80) To a solution of N-(4-{4-amino-1-methyl-7-[2-(piperidin-4-yl)ethynyl]-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (120 mg, 0.2 mmol) in DCM (10 mL) was added paraformaldehyde (11.9 mg, 0.4 mmol) and NaBH(OAc) (127 mg, 0.6 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (MeOH / DCM: 1 / 20) to give the title compound (40 mg, 32%) as a yellow solid. LCMS (Method A): 2.80 min, m / z 613.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6):10.96(s,1H),7.88(s,1H),7.57(q,J=4Hz,2H),7.40(d,J=8Hz,1H),7.18-7.10(m,4H),7.13(t,J=52Hz,1H),6.1 1(s,2H),5.65(q,J=4Hz,1H),4.22(s,3H),3.16(s,2H),2.89(s,1H),2.70(s,3H),2.18-1.98(m,4H),1.57(d,J=6.2Hz,3H),1.23(s,2H).

[0561] Compound 91: (S)—N-(4-(4-amino-1-methyl-7-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: (S)—N-(4-(4-amino-1-methyl-7-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide To a solution of (S)—N-(4-(4-amino-1-methyl-7-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (compound 90, 34 mg, 55.4 μmol) in DCM (5 mL) was added paraformaldehyde (5.37 mg, 66.4 μmol) and NaBH(OAc) (58.7 mg, 277 μmol). The reaction mixture was stirred at room temperature for 45 min before saturated aqueous NaHCO (10 mL) was added and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organics were concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM:MeOH, 10:1) to give the title compound (10 mg, 29%) as a yellow solid. LCMS (Method B): 2.85 min, m / z: 627.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6):7.60(s,1H),7.53(d,J=8.1Hz,1H),7.48(dd,J=8.4,5.4Hz,3H),7.16(d,J=8.1Hz,1H),7.10-7.02(m,3H), 5.56(q,J=6.2Hz,1H),4.29(t,J=5.5Hz,2H),3.70(s,3H),3.57(s,2H),3.04(t,J=5.4Hz,2H),2.48(s,3H),1.69(d,J=6.3Hz,3H).

[0562] The following compounds were prepared similarly to compound 91: [Table 15-1] [Table 15-2]

[0563] Compound 54 and Compound 55 [ka] Step 1: (S)—N-(4-(4-amino-1-methyl-7-(1,2,5,6-tetrahydropyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (compound 54) To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.23 mmol) in 1,4-dioxane (15 mL) was added 2 M HCl in dioxane (10 mL) and the mixture was stirred at room temperature for 10 minutes. The solution was concentrated under reduced pressure to give a white solid. The solid was dissolved in degassed 1,4-dioxane / HO (4 / 1, 10 mL), and (S)—N-(4-(4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (700 mg, 1.13 mmol), NaCO (358 mg, 3.38 mmol), and Pd(dppf)Cl (92.2 mg, 113 μmol) were added. The solution was then stirred at 100° C. for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (20 mL) and extracted with EtOAc (2×20 mL). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give the title product (300 mg, 46%) as a brown solid. LCMS (Method A): 2.63 min, m / z: 573.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6):10.85(s,1H),7.54(dd,J=8.7,5.6Hz,2H),7.48(s,1H),7.37(d,J=8.1Hz,1H),7.15(t,J=8.9Hz,2H),7.06-6. 98(m,2H),5.87(s,1H),5.64(q,J=6.3Hz,1H),3.97(s,3H),3.52(s,2H),2.99(s,2H),2.61(s,3H),2.47(s,2H),1.55(d,J=6.3Hz,3H).

[0564] Step 2: (S)—N-(4-(4-amino-1-methyl-7-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (compound 55) A mixture of (S)—N-(4-(4-amino-1-methyl-7-(1,2,5,6-tetrahydropyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (20 mg, 34.9 μmol) and paraformaldehyde (20.8 mg, 348 μmol) in MeOH (3 mL) was stirred at room temperature for 12 h. NaBH(CN) (8.73 mg, 139 μmol) was added and the mixture was stirred at room temperature for 20 min. The reaction mixture was poured into water (40 mL) and the organics were extracted with EtOAc (2×40 mL). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=15 / 1) to give the title product (10.0 mg, 49%) as a brown solid. LCMS (Method A): 3.73 min, m / z: 611.2 [M+Na] + . 1 H NMR(400MHz,DMSO-d6):10.85(s,1H),7.54(dd,J=8.7,5.6Hz,2H),7.48(s,1H),7.37(d,J=8.1Hz,1H),7.15(t,J=8.9Hz,2H),7.06-6. 98(m,2H),5.87(s,1H),5.64(q,J=6.3Hz,1H),3.97(s,3H),3.52(s,2H),2.99(s,2H),2.61(s,3H),2.47(s,2H),1.55(d,J=6.3Hz,3H).

[0565] Compound 42: (S)—N-(4-(4-amino-1-methyl-7-(1-methylpiperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: (S)—N-(4-(4-amino-1-methyl-7-(1-methylpiperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide A mixture of (S)—N-(4-(4-amino-1-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (90 mg, 153 μmol), NaBH (11.5 mg, 306 μmol), and AcOH (27.5 mg, 459 μmol) in THF (10 mL) was stirred at 45° C. overnight. HCl (1 M, 5 mL) was added, and the reaction mixture was stirred for 5 min. The reaction mixture was adjusted to pH = 8 with saturated aqueous NaCO, and the organics were extracted with EtOAc (2 × 30 mL). The combined organic phases were dried over NaSO and concentrated. The residue was purified by preparative TLC (DCM / MeOH=15 / 1) to give the title product (7 mg, 7%) as a white solid. LCMS (Method A): 3.30 min, m / z 589.2 [M+H] + . 1 H NMR(400MHz,CDCl3):7.86(s,1H),7.69(d,J=8.2Hz,1H),7.34-7.29(m,2H),7.15( d,J=8.2Hz,1H),7.08(t,J=8.6Hz,2H),6.92(s,1H),6.35(t,J=53.6Hz,1H),5.72( s,2H),5.43(q,J=6.1Hz,1H),4.21(s,3H),3.26(d,J=8.1Hz,2H),2.99(s,2H),2.7 4(s,3H),2.22(d,J=15.3Hz,1H),2.00(s,2H),1.82(s,2H),1.70(d,J=6.4Hz,3H).

[0566] Compound 40: (S)—N-(4-(4-amino-1-methyl-7-(pyrimidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: (S)—N-(4-(4-amino-1-methyl-7-(pyrimidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide To a solution of (S)—N-(4-(4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide (70 mg, 113 μmol) in degassed MePh (2 mL), Pd(PPh3)4 (13.0 mg, 11.3 μmol), KF (32.8 mg, 565 μmol), and 4-(tributylstannyl)pyrimidine (41.7 mg, 113 μmol) were added, and the mixture was stirred at 130° C. for 2 h using μW irradiation. The mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM / MeOH=40 / 1) to give the title product (7.0 mg, 11%) as a yellow solid. LCMS (Method C): 3.30 min, m / z570.1[M+H] + . 1 H NMR(400MHz,CDCl3):9.30(s,1H),8.81(d,J=5.2Hz,1H),7.92(s,1H),7.68(d,J=8.4Hz,1H),7.59(d,J=4.4Hz,1H),7.32(q,J=4.4Hz,2H),7. 21(dd,J=8.4,1.6Hz,1H),7.07-7.02(m,3H),6.35(t,J=53.6Hz,1H),5.47(q,J=6.4Hz,1H),5.13(s,2H),3.95(s,3H),1.69(d,J=6.4Hz,3H).

[0567] Compound 109: (S)—N-(4-(7-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)-4-amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: (S)—N-(4-(7-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)-4-amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide To a solution of compound 59 (150 mg, 234 μmol) and EtN (70.9 mg, 702 μmol) in DCM (10 mL) was added AcCl (18.3 mg, 234 μmol). The reaction mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH, 20:1) to give the title product (80.0 mg, 50%) as a yellow solid. LCMS (Method A) 2.88 min, m / z 683.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6):7.99(s,1H),7.61(s,1H),7.59-7.55(m,3H),7.43-7.41(d,J=8Hz,1H),7.18-7.14(m,4H),6.99(t,J=52Hz,1H),5.82(s,2 H),5.66(q,J=4Hz,1H),4.55-4.44(m,2H),3.70(s,3H),2.80-2.74(m,1H) ),2.15-2.11(m,2H),2.05(s,3H),1.99-1.80(m,2H),1.60(d,J=8Hz,3H).

[0568] Compound 89: (S)—N-(4-(4-amino-7-(1-(1-(aminomethyl)cyclopropyl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: (S)—N-(4-(4-amino-7-(1-(1-(aminomethyl)cyclopropyl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide To a solution of N-(4-{4-amino-7-[1-(1-cyanocyclopropyl)-1H-pyrazol-4-yl]-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide 96 (30 mg, 48.1 μmol) in dry THF (2 mL) at 0° C. was added LiAlH (3.65 mg, 96.2 μmol). The reaction mixture was stirred at room temperature under N for 1 h and then concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 98:2) to give the title product (15.0 mg, 50%) as a yellow solid. LCMS (Method E): 0.34 min, m / z: 627.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6):7.99(s,1H),7.71(s,1H),7.53-7.49(m,3H),7.36-7.34(m,1H),7.13(t,J=8.4Hz,2 H),6.95-6.87(m,2H),6.40(t,J=14.4Hz,1H),5.65(brs,3H),3.72(s,3H),3.27(s,2H),1.52-1.23(m,7H).

[0569] Compound 141: N-{4-[4-amino-1-methyl-7-(morpholin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl}-1,1-difluoromethanesulfonamide [ka] Step 1: N-{4-[4-amino-1-methyl-7-(morpholin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl}-1,1-difluoromethanesulfonamide A mixture of N-(4-{4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (300 mg, 485 μmol), morpholine (422 mg, 4.85 mmol), and K2CO3 (200 mg, 1.45 mmol) in ethylene glycol (3 mL) was stirred at 130 °C overnight. The reaction mixture was concentrated under reduced pressure, and the crude mixture was purified by preparative TLC (DCM / MeOH: 99 / 1) to give the title compound (8 mg, 3%) as a yellow solid. LCMS (Method A): 3.04 min, m / z: 577.1 [M+H] + . 1 H NMR(400MHz,CDCl3):7.67(d,J=8.2Hz,1H),7.50(s,1H),7.35-7.29(m,2H),7.16(dd,J=8.2,1.8Hz,1H),7.07-6.99(m,3H),6.35(t,J=53.6Hz ,1H),5.83(s,2H),5.46(q,J=6.3Hz,1H),4.35(s,3H),3.97(d,J=9.4Hz ,2H),3.82-3.67(m,2H),3.00(d,J=16.7Hz,4H),1.68(d,J=6.4Hz,3H).

[0570] Compound 133: N-(4-{4-amino-7-cyano-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: N-(4-{4-amino-7-cyano-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide A mixture of N-(4-{4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (50 mg, 80.9 μmol), CuI (15.4 mg, 80.9 μmol), and Zn(CN) (9.49 mg, 80.9 μmol) in NMP (4 mL) was stirred at 130 °C under N overnight. The reaction was poured into EtOAc (20 mL), and the organics were then washed with water (20 mL × 3) and brine (10 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 15 / 1) to give the title product (7 mg, 17%) as a brown solid. LCMS (Method A): 3.69 min, m / z517.0[M+H] + . 1 H NMR(400MHz, CDCl3):8.21(s,1H),7.70(d,J=8.5Hz,1H),7.32(t,J=6.9Hz,2H),7.18(d,J=8.5Hz,1H),7.06(t,J=8. 4Hz,2H),7.01(s,1H),6.35(t,J=52Hz,1H),5.47(q,J=6.6Hz,1H),5.30(s,2H),4.27(s,3H),1.71(d,J=6.4Hz,3H).

[0571] Compound 44: (S)—N-(4-(4-amino-1-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-2,2,2-trifluoroethane-1-sulfonamide [ka] Step 1: (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-nitrophenyl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine A mixture of 3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (4 g, 14.5 mmol), (S)-2-(3-(1-(4-fluorophenyl)ethoxy)-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.61 g, 14.5 mmol), KCO (6.01 g, 43.5 mmol), and Pd(dppf)Cl (1.18 g, 1.45 mmol) in degassed 1,4-dioxane / HO (4 / 1, 125 mL) was stirred at 100 °C for 10 h under N. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EtOAc = 4:1 to 1:4) to give the title product (5.2 g, 88%) as a yellow solid. LCMS (Method A): 3.31 min, m / z: 408.4 [M+H] + .

[0572] Step 2: (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-nitrophenyl)-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine A mixture of (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-nitrophenyl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (2.5 g, 6.13 mmol) and NIS (2.74 g, 12.2 mmol) in DMF (50 mL) was stirred at 85 °C under N for 6 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EtOAc = 4:1 to 1:4) to give the title product (1.1 g, 33%) as a yellow solid. LCMS (Method A): 3.51 min, m / z: 534.3 [M+H] + .

[0573] Step 3: (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-nitrophenyl)-1-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine A mixture of (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-nitrophenyl)-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (1.1 g, 2.06 mmol), 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (573 mg, 2.06 mmol), KCO (854 mg, 6.18 mmol), and Pd(dppf)Cl (168 mg, 206 μmol) in 1,4-dioxane / HO (4 / 1, 25 mL) was stirred at 100 °C for 10 h under N. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EtOAc = 4: 1 to 1: 4) to give the title product (0.9 g, 76%) as a yellow solid. LCMS (Method A): 3.10 min, m / z: 558.6 [M+H] + .

[0574] Step 4: (S)-3-(4-amino-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine A mixture of (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-nitrophenyl)-1-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine (0.9 g, 1.61 mmol) and Zn powder (525 mg, 8.04 mmol) in MeOH (18 mL) and saturated aqueous NH4Cl (6 mL) was stirred at 60 °C for 8 h. The mixture was poured into water (20 mL), and the organics were extracted with DCM (2 × 10 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 1:4 to 1:10) to give the title product (330 mg, 39%) as a white solid. LCMS (Method A): 2.85 min, m / z: 528.6 [M+H] + .

[0575] Step 5: (S)—N-(4-(4-amino-1-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-2,2,2-trifluoroethane-1-sulfonamide A solution of (S)-3-(4-amino-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine (100 mg, 189 μmol) and 2,2,2-trifluoroethanesulfonyl chloride (51.6 mg, 283 μmol) in DCM (2.5 mL) and pyridine (0.5 mL) was stirred at 35° C. for 10 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH=20 / 1) to give the title product (7 mg, 6%) as a white solid. LCMS (Method A): 3.17 min, m / z: 674.7 [M+H] + . 1 H NMR(400MHz,CDCl3):7.71(d,J=8.2Hz,1H),7.62(s,1H),7.58(s,1H),7.54(s,1H) ,7.36-7.28(m,2H),7.25-7.20(m,1H),7.11-7.00(m,3H),5.47(q,J=6.4Hz,1H),4 .43(tt,J=10.4,4.8Hz,1H),4.15(dt,J=11.8,3.1Hz,2H),3.92(q,J=8.7Hz,2H),3 .77(s,3H),3.59(td,J=11.6,2.8Hz,2H),2.26-2.09(m,4H),1.69(d,J=6.4Hz,3H).

[0576] The following compounds were prepared similarly to the synthesis of (S)—N-(4-(4-amino-1-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-2,2,2-trifluoroethane-1-sulfonamide (compound 44) ​​using the indicated sulfonyl chloride in step 5. [Table 16-1] [Table 16-2]

[0577] General Procedure C1 for the Cross-Coupling Reaction between Intermediate A1B1 and Halogenopyrazole D [ka] A mixture of N-(4-{4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (1 equiv.), halogenopyrazole (1.0 equiv.), B2(pin)2 (2 equiv.), Pd(OAc)2 (0.2 equiv.), bis(adamantan-1-yl)(butyl)phosphane (0.4 equiv.), and K2CO3 (2 equiv.) was dissolved in degassed 1,4-dioxane / HO (4 / 1, 0.2 M), and the solution was stirred overnight at 100 °C under N2 (or 2 h at 80 °C under μW irradiation). The mixture was diluted with water and extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH or EtOAc / PE) or preparative TLC (DCM / MeOH).

[0578] The following compounds were prepared according to general procedure C1 [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5] [Table 17-6] [Table 17-7]

[0579] General Procedure C2 for the cross-coupling reaction followed by acidic deprotection between intermediate A1B1 and Boc-protected halogenopyrazole D [ka] A mixture of N-(4-{4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (1 equiv.), halogenopyrazole (1.0 equiv.), B2(pin)2 (2 equiv.), Pd(OAc)2 (0.2 equiv.), bis(adamantan-1-yl)(butyl)phosphane (0.4 equiv.), and K2CO3 (2 equiv.) was dissolved in degassed 1,4-dioxane / HO (4 / 1, 0.2 M), and the solution was stirred overnight at 100 °C under N2 (or 2 h at 80 °C under μW irradiation). The mixture was diluted with water and extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH or EtOAc / PE) or preparative TLC (DCM / MeOH).

[0580] The solid was dissolved in pure HCOOH (2M) and the reaction mixture was stirred at room temperature for 30 minutes or until complete. The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH = 8 with saturated aqueous Na2CO3. The residue was further diluted with water, and the organics were extracted with EtOAc (3 times). The combined organics were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH), followed by preparative HPLC (neutral conditions, Method C) if necessary, to give the desired product.

[0581] The following compounds were prepared according to general procedure C2 [Table 18]

[0582] Compound 120: N-(4-{4-amino-7-[1-(3,3-difluorocyclopentyl)-1H-pyrazol-4-yl]-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: 3-(4-iodo-1H-pyrazol-1-yl)cyclopentan-1-one To a mixture of 4-iodo-1H-pyrazole (500 mg, 2.57 mmol) and cyclopent-2-en-1-one (316 mg, 3.85 mmol) in DCM (10 mL) was added ScCl3 (77.7 mg, 514 μmol). The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc 95 / 5 to 20 / 80) to give the title product (657 mg, 93%) as a clear oil. LCMS (Method A): 3.21 min, m / z 277.0 [M+H] +

[0583] Step 2: 1-(3,3-Difluorocyclopentyl)-4-iodo-1H-pyrazole To a solution of 3-(4-iodo-1H-pyrazol-1-yl)cyclopentan-1-one (1.43 g, 5.17 mmol) in anhydrous DCM (10 mL) at 0 °C, DAST (2.49 g, 15.5 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred overnight under N. The reaction mixture was quenched with 1.5 M KHPO (10 mL), and the organics were extracted three times with EtOAc. The combined organics were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc 95 / 5 to 20 / 80) to give the title product (978 mg, 63%) as a clear oil.

[0584] Step 3: N-(4-{4-amino-7-[1-(3,3-difluorocyclopentyl)-1H-pyrazol-4-yl]-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide A mixture of 1-(3,3-difluorocyclopentyl)-4-iodo-1H-pyrazole (47.9 mg, 161 μmol), N-(4-{4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (1 equiv.), Pd(OAc) (3.61 mg, 16.1 μmol), KCO (22.2 mg, 161 μmol), butyldi-1-adamantylphosphine (11.5 mg, 32.3 μmol), and B2Pin2 (40.8 mg, 161 μmol) in degassed 1,4-dioxane (4 mL) and HO (1 mL) was heated at 100 °C for 12 h under N2. The solvent was evaporated and the residue was purified by silica gel column chromatography (PE / EtOAc 80 / 20 to 20 / 80) to give the title product (5.00 mg, 9%) as a yellow solid. LCMS (Method A): 3.86 min, m / z 662.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6):8.03(s,1H),7.66(s,1H),7.60-7.55(m,2H),7.54(d,J=1.7Hz ,1H),7.40(d,J=8.0Hz,1H),7.20-7.10(m,4H),7.10-6.85(m,1H),5.75(s,2H),5.65( q,J=6.3Hz,1H),5.00(p,J=7.4Hz,1H),2.80-2.70(m,1H),2.64(dd,J=15.7,7.5Hz,1H ),2.37(dddd,J=19.1,9.7,6.0,4.0Hz,2H),2.28-2.16(m,2H),1.58(d,J=6.3Hz,3H).

[0585] Compound 113: N-(4-(4-amino-1-methyl-7-(1-(1,2,2-trimethylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-((S)-1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: tert-Butyl 4-hydroxy-2,2-dimethylpiperidine-1-carboxylate To a solution of tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate (1 g, 4.39 mmol) in MeOH (20 mL) was added NaBH (495 mg, 13.1 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc: 90 / 10 to 10 / 90) to give the title product (740 mg) as a yellow oil.

[0586] Step 2: tert-Butyl 4-(methanesulfonyloxy)-2,2-dimethylpiperidine-1-carboxylate To a solution of tert-butyl 4-hydroxy-2,2-dimethylpiperidine-1-carboxylate (740 mg, 3.22 mmol) in DCM (5 mL) was added EtN (764 mg, 9.66 mmol) and MsCl (553 mg, 4.83 mmol). The mixture was stirred at room temperature for 16 h. The mixture was poured into water (20 mL) and the organics were extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure to give the title product (900 mg, 2.92 mmol) as a colorless oil. Used crude in the next step. LCMS (Method A): 3.96 min, m / z 674.4 [M+H] +

[0587] Step 3: tert-Butyl 4-(4-bromo-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate A mixture of tert-butyl 4-(methanesulfonyloxy)-2,2-dimethylpiperidine-1-carboxylate (900 mg, 2.92 mmol), 4-bromo-1H-pyrazole (557 mg, 3.79 mmol), and CsCO (2.84 g, 8.76 mmol) in DMF (20 mL) was stirred at 100 °C overnight. The mixture was poured into water (50 mL), and the organics were extracted with EtOAc (50 mL × 2). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc, 10 / 1) to give the title product (420 mg, 40%) as a white solid.

[0588] Step 4: tert-butyl 4-(4-(4-amino-3-(4-((difluoromethyl)sulfonamido)-3-((S)-1-(4-fluorophenyl)ethoxy)phenyl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl)-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate N-(4-{4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (344 mg, 558 μmol) and 4-(4-bromo-1H-pyrazole- To a mixture of tert-butyl (1-yl)-2,2-dimethylpiperidine-1-carboxylate (200 mg, 558 μmol), Pd(OAc) (24.9 mg, 111 μmol), KCO (153 mg, 1.11 mmol), butyldi-1-adamantylphosphine (79.9 mg, 223 μmol), and Bpin (281 mg, 1.11 mmol) was added. The mixture was stirred at 100 °C under N for 12 h. The mixture was poured into water (50 mL), and the organic matter was extracted with EtOAc (50 mL × 2). The combined organic matter was dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 95 / 5) to give the title product (170 mg, 39%) as a yellow solid. LCMS (Method A): 3.57 min, m / z769.1[M+H] +

[0589] Step 5: N-(4-(4-amino-7-(1-(2,2-dimethylpiperidin-4-yl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-((S)-1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide A solution of tert-butyl 4-(4-{4-amino-3-[4-(difluoromethanesulfonamido)-3-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl]-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl}-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate (150 mg, 195 μmol) in HCOOH (3 mL) was stirred at room temperature under N for 4 hours. The mixture was adjusted to pH=8 by addition of saturated aqueous NaCO and concentrated under reduced pressure. The solid was washed with EtOAc (2×5 mL) and dried under reduced pressure to give the title product (120 mg, 92%) as a white solid. LCMS (Method A): 2.73 min, m / z 670.1 [M+H] +

[0590] Step 6: N-(4-(4-amino-1-methyl-7-(1-(1,2,2-trimethylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-((S)-1-(4-fluorophenyl)ethoxy)phenyl)-1,1-difluoromethanesulfonamide A mixture of N-(4-{4-amino-7-[1-(2,2-dimethylpiperidin-4-yl)-1H-pyrazol-4-yl]-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (120 mg, 179.4 μmol), paraformaldehyde (72.7 mg, 897 μmol), and NaBH(OAc) (190 mg, 897 μmol) in MeOH (5 mL) was stirred at room temperature for 45 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH, 95 / 5) to give the title product (30 mg, 25%) as a yellow solid. LCMS (Method A): 2.88 min, m / z 683.1 [M+H] + . 1H NMR(400MHz,DMSO-d6):7.93(s,1H),7.62(s,1H),7.56-7.50(m,2H),7.50(d,J=1.5Hz,1H),7.36(d, J=8.1Hz,1H),7.18-7.12(m,2H),7.01(dd,J=8.1,1.9Hz,1H),6.96(d,J=1.9Hz,1H),6.65(s,1H),5. 66(s,2H),5.64(d,J=6.3Hz,1H),4.58(dd,J=10.9,5.4Hz,1H),3.67(s,3H),3.13-3.02(m,3H),2.19 -2.11(m,2H),2.10-2.07(m,1H),2.04-1.92(m,1H),1.54(d,J=6.3Hz,3H),1.29(s,3H),1.24(s,3H).

[0591] The following compounds were prepared similarly to compound 113: [Table 19]

[0592] Compound 104: N-(4-{4-amino-1-methyl-7-[1-(1,6,6-trimethylpiperidin-3-yl)-1H-pyrazol-4-yl]-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: N-(4-{4-amino-7-[1-(6,6-dimethylpiperidin-3-yl)-1H-pyrazol-4-yl]-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide General procedure A2 for Suzuki reaction followed by acidic deprotection between intermediate A1B1 and tert-butyl 2,2-dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (intermediate C21, 100 mg, 246 μmol) afforded the title compound (20 mg, 19%) as a colorless oil. LCMS (Method A): 2.71 min, m / z 335.2 [M+2H] 2+

[0593] Step 2: N-(4-{4-amino-1-methyl-7-[1-(1,6,6-trimethylpiperidin-3-yl)-1H-pyrazol-4-yl]-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide A mixture of N-(4-{4-amino-7-[1-(6,6-dimethylpiperidin-3-yl)-1H-pyrazol-4-yl]-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (30 mg, 44.8 μmol), paraformaldehyde (5.43 mg, 67.2 μmol), and NaBH(OAc) (47.4 mg, 224 μmol) in MeOH (5 mL) was stirred at room temperature for 45 min. The mixture was diluted with saturated aqueous NaHCO (30 mL) and DCM (30 mL). The aqueous layer was extracted with a DCM / MeOH mixture (9 / 1, 3 × 10 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH, 97 / 3) to give the title product (10.0 mg, 19%) as a yellow solid. LCMS (Method A): 2.64 min, m / z 683.1 [M+H] + . 1H NMR(400MHz,DMSO-d6):7.65(d,J=3.6Hz,2H),7.56(m,2H),7.34-7.26(m,2H),7.20(dd,J=2.0,8.0Hz,1H),7.06-7.01(m,3H),6.35(t,J=53.6Hz, 1H),5,47(q,J=2,4Hz,1H),3.75(s,3H),3,30-3,22(m,2H),2,56(s,3H), 2,30-2.12(m,4H),1,80-1,76(m,1H),1,69(d,J=6.4Hz,3H),1.29(s,6H).

[0594] Compound 111: (R)—N-(4-(4-amino-1-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-1,1-difluoromethanesulfonamide [ka] (R)—N-(4-(4-amino-1-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-1,1-difluoromethanesulfonamide was obtained by chiral HPLC purification of the racemic mixture (compound 102). Separation was performed on a UniChiral CND-5H (column dimensions 21.2 mm i.d. × 250 mm length) using n-hexane / ethanol / TFA = 50 / 50 / 0.1 as the mobile phase and a flow rate of 25 mL min at 25 °C. Product retention time = 5.38 min.

[0595] The residue was adjusted to pH=8 with saturated aqueous Na2CO3. The residue was further diluted with water and the organics were extracted with EtOAc (3x). The combined organics were washed with brine, dried over Na2SO4 and concentrated under reduced pressure.

[0596] The enantiomeric excess was calculated to be >98% ee on a UniChiral CND-5H, 4.6 × 250 mm column (50% n-hexane / 50% ethanol / 0.1% TFA, flow rate 1 mL / min, injection 10 μL, temperature 30 °C, retention time 5.38 min).

[0597] LCMS (Method A): 3.10 min, m / z672.1[M+H] + . 1 H NMR (400 MHz, CDCl 3 ):7.80(d,J=8.3Hz,1H),7.58(s,1H),7.56(s,1H),7.41(dd,J=8.5,5.2Hz,2H ),7.28-7.27(m,1H),7.12(t,J=8.6Hz,2H),6.86(d,J=1.5Hz,1H),6.40(t,J=5 3.5Hz,1H),4.96(dd,J=9.6,2.7Hz,1H),4.43(tt,J=10.2,4.8Hz,1H),4.19-4. 11(m,2H),3.76(s,3H),3.58(t,J=2.8Hz,4H),3.55(s,3H),2.17-2.09(m,4H).

[0598] Compound 112: (S)—N-(4-(4-amino-1-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-1,1-difluoromethanesulfonamide [ka] (S)—N-(4-(4-amino-1-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-1,1-difluoromethanesulfonamide was obtained by chiral HPLC purification of the racemic mixture (compound 102). Separation was performed on a UniChiral CND-5H (column dimensions 21.2 mm i.d. × 250 mm length) using n-hexane / ethanol / TFA = 50 / 50 / 0.1 as the mobile phase and a flow rate of 25 mL min at 25 °C. Product retention time = 7.14 min.

[0599] The residue was adjusted to pH=8 with saturated aqueous Na2CO3. The residue was further diluted with water and the organics were extracted with EtOAc (3x). The combined organics were washed with brine, dried over Na2SO4 and concentrated under reduced pressure.

[0600] The enantiomeric excess was calculated to be >98% ee on a UniChiral CND-5H, 4.6 × 250 mm column (50% n-hexane / 50% ethanol / 0.1% TFA, flow rate 1 mL / min, injection 10 μL, temperature 30 °C, retention time 5.38 min).

[0601] LCMS (Method A): 3.12 min, m / z672.1[M+H] + . 1 H NMR(400MHz,CDCl3):7.80(d,J=8.3Hz,1H),7.68(s,1H),7.60(s,1H),7.41(dd,J= 8.5,5.2Hz,2H),7.28-7.27(m,1H),7.10(t,J=8.6Hz,2H),6.86(d,J=1.5Hz,1H),6. 37(t,J=53.5Hz,1H),4.99(dd,J=9.6,2.7Hz,1H),4.43(tt,J=10.2,4.8Hz,1H),4.1 9-4.11(m,2H),3.76(s,3H),3.58(t,J=2.8Hz,4H),3.55(s,3H),2.17-2.09(m,4H).

[0602] Additional exemplary compounds prepared by methods similar to those described herein are detailed in Table 7 below. [Table 20-1] [Table 20-2]

[0603] General Procedure A5 for Suzuki Reaction between Intermediate A1B21 and Boronic Esters [ka] A mixture of N-(4-(4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-((4-fluorobenzyl)oxy)phenyl)-1,1-difluoromethanesulfonamide (1 equiv.), boronic ester (1.1 equiv.), NaCO (3 equiv.), and Pd(dppf)Cl (0.1 equiv.) in degassed 1,4-dioxane / HO (4 / 1, 0.2 M) was stirred at 100° C. overnight under N. The mixture was diluted with water, and the organics were extracted with EtOAc (3×). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH) to give the title product as a yellow solid.

[0604] The following compounds were prepared according to general procedure A5 [Table 21-1] [Table 21-2]

[0605] General Procedure A6 for Suzuki Reaction between Intermediate A1B19 and Boronates / Boronic Acids [ka] A mixture of N-(4-(4-amino-7-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-((4-fluorobenzyl)oxy)phenyl)ethanesulfonamide (1 equiv.), boronic ester / boronic acid (1.1 equiv.), NaCO (3 equiv.), and Pd(dppf)Cl (0.1 equiv.) in degassed 1,4-dioxane / HO (4 / 1, 0.2 M) was stirred at 100 °C overnight under N. The mixture was diluted with water, and the organics were extracted with EtOAc (3 x). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH) to give the desired product as a yellow solid.

[0606] The following compounds were prepared according to general procedure A6 [Table 22]

[0607] Compound 64: N-(4-(4-aminopyrazolo[1,5-a]pyrazin-3-yl)-2-((4-fluorophenyl)methoxy)phenyl)ethane-1-sulfonamide [ka] Step 1: N-(4-(4-aminopyrazolo[1,5-a]pyrazin-3-yl)-2-((4-fluorophenyl)methoxy)phenyl)ethane-1-sulfonamide To a mixture of 3-iodopyrazolo[1,5-a]pyrazin-4-amine (20 mg, 0.08 mmol), N-(2-((4-fluorophenyl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1-sulfonamide (36.8 mg, 0.08 mmol), and NaCO (16.3 mg, 0.15 mmol) in 1,4-dioxane / water (4 / 1, 2 mL), Pd(dppf)Cl (5.62 mg, 8 μmol) was added, and the reaction was heated at 120 °C for 1 h using μW irradiation. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (0–100% EtOAc:c-Hex) to give the title product (5.6 mg, 17%) as a brown solid. LCMS (Method D): 1.45 min, m / z442.2[M+H] + . 1 H NMR(300MHz,CDCl3):7.88(d,J=5.0Hz,1H),7.84(s,1H),7.66(d,J=8.2Hz,1H),7.37(dd,J=8.7,5.3Hz, 2H),7.31(d,J=5.0Hz,1H),7.13-7.07(m,4H),5.12(s,2H),3.15(q,J=7.4Hz,2H),1.36(t,J=7.4Hz,3H).

[0608] Compound 63: N-(4-(8-aminoimidazo[1,5-a]pyrazin-1-yl)-2-((4-fluorophenyl)methoxy)phenyl)ethane-1-sulfonamide [ka] Step 1: N-((3-chloropyrazin-2-yl)methyl)formamide A solution of 1-(3-chloropyrazin-2-yl)methanamine hydrochloride (1.0 g, 5.55 mmol) in HC(OMe) (6.06 mL, 55.5 mmol) was heated at 110° C. overnight under an atmosphere of N. The mixture was concentrated in vacuo and the residue was taken up in DCM. The organic phase was washed with water and brine, dried over MgSO, and concentrated in vacuo to give the title product (772 mg, 81%) as a yellow solid. LCMS (Method E): 0.33 min, m / z 172.0 [M+H] + . 1 H NMR (300MHz, CDCl3):8.46(d,J=2.6Hz,1H),8.38(d,J=1.0Hz,1H),8.35-8.33(m,1H),6.94(bs,1H),4.76-4.74(m,2H).

[0609] Step 2: 8-Chloroimidaz[1,5-a]pyrazine A solution of N-((3-chloropyrazin-2-yl)methyl)formamide (0.83 g, 4.83 mmol) in MeCN (20 mL) was cooled to 0 °C before POCl (1.34 mL, 14.4 mmol) was added dropwise. The reaction was stirred at 0 °C for 5 min before DMF (2 drops) was added. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was concentrated in vacuo and the residue was diluted with water. The pH was adjusted to approximately 8 with saturated aqueous NaHCO and the aqueous mixture was extracted with DCM. The combined organics were dried over MgSO and concentrated in vacuo to give the title product (631 mg, 85%) as a pink solid. LCMS (Method D): 0.62 min, m / z 154.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6):8.70(d,J=0.6Hz,1H),8.39(dd,J=4.9,1.0Hz,1H),7.88(d,J=1.0Hz,1H),7.41(d,J=4.9Hz,1H).

[0610] Step 3: 8-Chloro-1-iodoimidazo[1,5-a]pyrazine To a solution of 8-chloroimidazo[1,5-a]pyrazine (150 mg, 0.98 mmol) in DMF (20 mL) was added NIS (240 mg, 1.07 mmol), and the reaction was stirred at room temperature overnight. The mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (0-5% MeOH:DCM) to give the title product (51.9 mg, 19%) as a pale yellow solid. LCMS (Method D): 1.15 min, m / z 280.0 [M+H] + . 1 H NMR(300MHz,DMSO-d6):8.68(s,1H),8.43(d,J=4.9Hz,1H),7.40(d,J=4.9Hz,1H).

[0611] Step 4: 1-Iodoimidazo[1,5-a]pyrazin-8-amine To a solution of 8-chloro-1-iodoimidazo[1,5-a]pyrazine (50 mg, 0.18 mmol) in MeOH (1 mL) was added 7M NH3 in MeOH (3 mL) and the reaction was heated in a sealed tube at 100 °C overnight. Upon cooling, the mixture was concentrated in vacuo and the residue was purified by column chromatography (0-10% MeOH:DCM) to give the title product (24.9 mg, 54%) as a yellow solid. LCMS (Method D): 0.21 min, m / z 261.0 [M+H] + . 1 H NMR(300MHz,DMSO-d6):8.35(s,1H),7.23(d,J=4.9Hz,1H),6.98(d,J=4.9Hz,1H),6.58(bs,2H).

[0612] Step 5: N-(4-(8-aminoimidazo[1,5-a]pyrazin-1-yl)-2-((4-fluorophenyl)methoxy)phenyl)ethane-1-sulfonamide To a mixture of 1-iodoimidazo[1,5-a]pyrazin-8-amine (50 mg, 0.19 mmol), N-(2-((4-fluorophenyl)methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1-sulfonamide (92.0 mg, 0.21 mmol), and NaCO (40.7 mg, 0.38 mmol) in degassed 1,4-dioxane / water (4 / 1, 3 mL), Pd(dppf)Cl (14.0 mg, 19.2 μmol) was added, and the reaction was heated at 120 °C for 1 h using μW irradiation. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (0-5% MeOH:DCM) followed by preparative HPLC (Method B, gradient 30-60% MeCN) to give the title product (12.1 mg, 14%) as an orange solid (formate salt). LCMS (Method D): 1.26 min, m / z 442.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6):9.06(s,1H),8.43(s,1H),8.14(s,1H),7.70(d,J=4.8Hz,1H),7.64-7.59(m,2H),7.40(d,J=8.1Hz,1H) ,7.36(s,1H),7.27-7.16(m,3H),7.04(d,J=4.8Hz,1H),6.13(s,2H),5.19(s,2H),3.04(q,J=7.3Hz,2H),1.15(t,J=7.3Hz,3H).

[0613] Compound 2: N-(4-amino-3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl)acetamide [ka] Step 1: 3-Iodo-7-nitro-1H-pyrazolo[4,3-c]pyridin-4-amine To a solution of 3-iodo-1H-pyrazolo[4,3-c]pyridin-4-amine (500 mg, 1.92 mmol) in HSO (50 mL) was added HNO (238 μL, 5.76 mmol), and the solution was stirred at 25 °C overnight. The reaction mixture was poured into water (150 mL) and adjusted to pH = 8 with aqueous NaOH. The mixture was extracted with EtOAc (250 mL × 3), and the combined organics were washed with water and brine, dried over NaSO, and concentrated under reduced pressure to give the title product (270 mg, 46%) as a yellow solid. LCMS (Method A): 2.34 min, m / z: 305.9 [M+H] + .

[0614] Step 2: 3-Iodo-1-methyl-7-nitro-1H-pyrazolo[4,3-c]pyridin-4-amine A mixture of 3-iodo-7-nitro-1H-pyrazolo[4,3-c]pyridin-4-amine (160 mg, 0.52 mmol), K2CO3 (72.3 mg, 0.52 mmol), and iodomethane (74.4 mg, 0.52 mmol) in DMF (4 mL) was stirred at room temperature overnight. Water (20 mL) was added, and the solid was filtered. The filter cake was washed with water (5 mL) and dried under reduced pressure to give the title product (160 mg, 96%). LCMS (Method A): 3.14 min, m / z: 319.9 [M+H] + .

[0615] Step 3: N-(4-{4-amino-1-methyl-7-nitro-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(4-fluorophenyl)methoxy]phenyl)ethane-1-sulfonamide A mixture of 3-iodo-1-methyl-7-nitro-1H-pyrazolo[4,3-c]pyridin-4-amine (190 mg, 0.59 mmol), N-{2-[(4-fluorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}ethane-1-sulfonamide (259 mg, 0.60 mmol), Pd(dppf)Cl (24.3 mg, 0.03 mmol), and KCO (245 mg, 1.78 mmol) in degassed 1,4-dioxane / HO (4 / 1, 2.5 mL) was stirred at 100 °C overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (2 × 50 mL). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA=1 / 1) to give the title product (200 mg, 67%) as a yellow solid. LCMS (Method A): 3.78 min, m / z: 501.1 [M+H] + .

[0616] Step 4: N-(4-{4,7-diamino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(4-fluorophenyl)methoxy]phenyl)ethane-1-sulfonamide A mixture of N-(4-{4-amino-1-methyl-7-nitro-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(4-fluorophenyl)methoxy]phenyl)ethane-1-sulfonamide (125 mg, 0.25 mmol) and Zn powder (81.0 mg, 1.24 mmol) in MeOH (5 mL) and aqueous NH4Cl (5 mL) was stirred at 60°C for 2 h. The reaction mixture was poured into water (50 mL) and the organics were extracted with EtOAc (2 x 50 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the title product (27 mg, 23%) as a brown solid. LCMS (Method A): 2.97 min, m / z: 471.1 [M+H] + .

[0617] Step 5: N-(4-amino-3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl)acetamide To a solution of N-(4-{4,7-diamino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-[(4-fluorophenyl)methoxy]phenyl)ethane-1-sulfonamide (27 mg, 0.057 mmol), AcOH (3.44 mg, 57 μmol), and DIEA (22.2 mg, 0.17 mmol) in DMF (1 mL) was added HATU (30.5 mg, 0.12 mmol), and the reaction was stirred at room temperature for 6 h. The mixture was poured into water (10 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give the title product (8 mg, 27%) as a brown solid. LCMS (Method B): 2.80 min, m / z: 513.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6):9.60(s,1H),9.08(bs,1H),7.64-7.60(m,2H),7.46-7.44(m,2H),7.35(d,J=1.6Hz,1H),7. 26-7.19(m,3H),5.78(s,2H),5.20(s,2H),3.99(s,3H),3.05(q,J=7.6Hz,2H),2.09(s,3H),1.15(t,J=7.2Hz,3H).

[0618] Similarly, the intermediate B1 (S)-1,1-difluoro-N-(2-(1-(4-fluorophenyl)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide in step 3 of the synthesis of compound 2 was used to prepare the following compound: [Table 23]

[0619] Intermediate E1: N-(4-{4-amino-7-iodofuro[3,2-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: 3-Bromofuro[3,2-c]pyridin-4-amine A solution of 3-bromo-4-chlorofuro[3,2-c]pyridine (1 g, 4.30 mmol) in aqueous NH3 (200 mL) and 1,4-dioxane (20 mL) was stirred in a sealed tube at 150 °C for 36 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 5 / 1) to give the title product (400 mg, 44%) as a white solid. LCMS (Method A): 0.89 min, m / z: 212.9, 214.9 [M+H] + .

[0620] Step 2: N-(4-{4-aminofuro[3,2-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide To a solution of 3-bromofuro[3,2-c]pyridin-4-amine (350 mg, 1.64 mmol) in degassed 1,4-dioxane / HO (4 / 1, 20 mL) was added 1,1-difluoro-N-{2-[(1S)-1-(4-fluorophenyl)ethoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methanesulfonamide (772 mg, 0.542 mmol), NaCO (396 mg, 3.74 mmol), and Pd(dppf)Cl (152 mg, 0.187 mmol). The reaction was stirred overnight at 100 °C under N. The mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL). The organics were extracted with EtOAc (2 x 50 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 50 / 1) to give the title product (400 mg, 51%) as a black solid. LCMS (Method A): 3.02 min, m / z: 478.1 [M+H] + .

[0621] Step 3: N-(4-{4-amino-7-iodofuro[3,2-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide To a solution of N-(4-{4-aminofuro[3,2-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (400 mg, 0.838 mmol) in DMF (5 mL) was added NIS (375 mg, 1.67 mmol). After stirring at 85 °C under N for 4 h, the mixture was concentrated in vacuo. The residue was diluted with water (50 mL) and the organics were extracted with EtOAc (3 x 50 mL). The combined organics were washed with water and brine, dried over NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH = 25 / 1) to give the title product (90 mg, 18%) as a black solid. LCMS (Method A): 3.82 min, m / z: 604.0 [M+H] + .

[0622] General Procedure A7 for Suzuki Reaction between Intermediate E1 and Boronic Esters [ka] A mixture of N-(4-{4-amino-7-iodofuro[3,2-c]pyridin-3-yl}-2-[(1S)-1-(4-fluorophenyl)ethoxy]phenyl)-1,1-difluoromethanesulfonamide (1 equivalent), boronic ester (1.1 equivalents), NaCO (3 equivalents), and Pd(dppf)Cl (0.1 equivalents) in degassed 1,4-dioxane / HO (4 / 1, 0.2 M) was stirred at 100 °C overnight under N. The mixture was diluted with water, and the organics were extracted with EtOAc (3 times). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH) to give the title product as a yellow solid.

[0623] The following compounds were prepared according to general procedure A7 [Table 24]

[0624] Intermediate E2: N-(4-{4-amino-7-iodofuro[3,2-c]pyridin-3-yl}-2-[(4-fluorophenyl)methoxy]phenyl)-1,1-difluoromethanesulfonamide [ka] Step 1: 3-{4-amino-3-[(4-fluorophenyl)methoxy]phenyl}furo[3,2-c]pyridin-4-amine To a solution of 3-bromofuro[3,2-c]pyridin-4-amine (400 mg, 1.87 mmol) in degassed 1,4-dioxane / HO (4 / 1, 20 mL) was added 2-[(4-fluorophenyl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (641 mg, 0.5418 mmol), NaCO (396 mg, 3.74 mmol), and Pd(dppf)Cl (152 mg, 0.187 mmol). After stirring overnight at 100 °C under N, the mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=50 / 1) to give the title product (460 mg, 70%) as a brown oil. LCMS (Method A): 2.89 min, m / z: 350.1 [M+H] + .

[0625] Step 2: N-(4-{4-aminofuro[3,2-c]pyridin-3-yl}-2-[(4-fluorophenyl)methoxy]phenyl)-1,1-difluoromethanesulfonamide To a solution of 3-{4-amino-3-[(4-fluorophenyl)methoxy]phenyl}furo[3,2-c]pyridin-4-amine (480 mg, 1.37 mmol) in DCM (10 mL) and pyridine (541 mg, 6.85 mmol), difluoromethanesulfonyl chloride (550 μL, 2.05 mmol) was added. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=50 / 1) to give the title product (240 mg, 38%) as a yellow solid. ...

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, J is selected from the following moieties J1 and J2: 【Chemistry 2】 A １ and A ４ is independently selected from N and C; A ２ and A ３ However, independently, N, NR １ , CH, O, and S; A １ , A ２ , A ３ , and A ４ At least one of N, NR １ , O, and S; A ５ is CH or N, A ６ But N or CR ２ and R １ and R ３ are independently H and optionally substituted C １～６ - alkyl, R ２ but, (i) H, (ii) optionally substituted C １～４ alkylamides, (iii) optionally substituted C １～４ alkylaryl, (iv) optionally substituted C ２～４ Alkynyl, (v) optionally substituted aryl; (vi) optionally substituted 5- or 6-membered heterocyclyl; (vii) cyano; 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 ４ ', 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 ４’ is H or optionally substituted C １～６ is alkyl, R ５ is H, optionally substituted C １～６ Alkyl, optionally substituted C ３～１０ cycloalkyl, and optionally substituted aryl; The compound, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

2. 2. The compound of claim 1, wherein the compound of formula (X) is provided as a compound of formula (XX), or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof. 【Transformation 3】

3. R ２ but, (vi) C １～４ alkylamides, (vii) C １～４ alkylaryl, (viii) C ２～４ Alkynyl, (ix) aryl, (x) 5- or 6-membered heterocyclyl; Each of groups (i) to (v) is independently halo, optionally substituted C １～６ Alkyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted C １～４ Alkoxy, optionally substituted C １～４ Alkyl-OH, optionally substituted C １～４ Alkylhalo, optionally substituted C １～４ alkylheterocyclyl, optionally substituted C １～４ Alkyl C ３～８ Cycloalkyl, optionally substituted C １～４ 3. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, optionally substituted with 1 to 3 groups selected from alkylaryl.

4. the E3 ligase binding portion, 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 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.

5. 2. 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.

6. 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:

7. 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.

8. 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 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, wherein:

9. The compound of claim 1 selected from any of the following compounds: 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 【Chemistry 5-4】 【Transformation 5-5】 [Transformation 5-6] [Transformation 5-7] [Transformation 5-8] 【Chemistry 5-9】 【Chemistry 5-10】 【Chemistry 5-11】 【Chemistry 5-12】 【Chemistry 5-13】 【Chemistry 5-14】 【Chemistry 5-15】 【Chemistry 5-16】 【Chemistry 5-17】 【Chemistry 5-18】 【Chemistry 5-19】 【Chemistry 5-20】 【Chemistry 5-21】 【Chemistry 5-22】 【Chemistry 5-23】 [Chemistry 5-24] 【Chemistry 5-25】 [Chemistry 5-26] 【Chemistry 5-27】 [Chemistry 5-28] [Chemistry 5-29] 【Chemistry 5-30】 【Chemistry 5-31】 【Chemistry 5-32】 【Chemistry 5-33】 【Chemistry 5-34】 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

10. A pharmaceutical agent comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

11. 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof, and a pharmaceutically acceptable excipient.

12. 10. Use of a compound of any one of claims 1 to 9, 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 a disease, condition, and / or disorder selected from: - 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, such as 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).

13. 10. 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 9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

14. An agent for degrading MLKL, comprising the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug thereof.

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