Novel compound, and pharmaceutical composition for prevention or treatment of cancer or autoimmune disease comprising same

Abstract

The present invention relates to a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof. The compound according to the present invention can be effectively used for the prevention or treatment of cancer or autoimmune diseases. [Chemical formula 1] wherein, in chemical formula 1, X and R1 to R4 are as defined herein.

Description

Novel compound and pharmaceutical composition comprising the same for preventing or treating cancer or autoimmune disease

[0001] The present invention relates to a novel structural compound useful as an IRAK4 (interleukin-1 receptor-associated kinase 4) inhibitor and a method for preparing a pharmaceutical composition comprising the same, and to the preparation of a drug for treating and / or preventing autoimmune diseases, inflammatory diseases and cancers mediated by IRAK4 and its application.

[0002]

[0003] IRAK4 is a type of serine / threonine kinase expressed in macrophages, T cells, and B cells, and plays a key role in antigen recognition and immune system activation by Toll-like receptors (TLRs) and IL-1R, and is involved in the expression of inflammatory cytokines IL-1 and TNF-α. IRAK4 is a key protein in the signaling pathway of IL-1β family receptors and TLRs, and it was shown that IRAK4 deficiency does not respond to stimulation by TLR and IL-1β.

[0004]

[0005] IRAK exists as IRAK1, 2, M (3), and 4 depending on the subtype, and IRAK4 is known to have the most potent signal transduction regulation function. TLR / IL-1β exists in macrophages, T cells, and B cells, and when it recognizes antigens such as LPS and is activated, it recruits MYD88 molecules, and MYD88 additionally recruits IRAK4 to the TLR / IL-1β complex, and activates NF-κB and MAPK signaling pathways through the activation of TAK1 in the lower signaling pathway, causing the release of various inflammatory cytokines (Toll-Like Receptor Signaling Pathways―Therapeutic Opportunities, Mediators of InammationVolume 2010, Article ID 781235, 7 pages). In this way, IRAK4 can function as a powerful regulator of major immune cells, and inhibition of IRAK4 can be applied to various autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis, Sjögren's syndrome, etc. as well as inflammatory diseases (IRAK family in inflammatory autoimmune diseases, Autoimmunity Reviews, Volume 19, Issue 3, March 2020, 102461). Some cancers including lymphoma can promote tumor cell survival through active signaling through IRAK4 (Kelly et al. IRAK4 inhibitors for autoimmunity and lymphoma, J. Exp. Med. 2015 Vol. 212 No. 13 2189-2201), so inhibitors of IRAK4 can be applied to the treatment of cancers including lymphoma.

[0006]

[0007] IRAK4 inhibitors are expected to exhibit powerful therapeutic effects through the suppression of multiple activations of macrophages, T cells, and B cells, key players in autoimmune diseases. While there are currently no approved IRAK4 inhibitors, several substances targeting IRAK4 are being developed. There are a number of reported IRAK4 inhibitors, including BMS-986126 and PF-06650833, which selectively inhibit the kinase activity of IRAK4 and can be used to treat autoimmune diseases, inflammatory diseases, and cancer (WO2016210034, WO2016210036, WO2015150995, WO2016127024 WO2016210037, US2019 / 0151295, US2019 / 0192688, WO2019 / 160915, and WO2020 / 113233). Recently, in order to further enhance the protein inhibition effect of small molecule drugs, development of PROTAC (Proteolysis Targeting Chimeria), a protein decomposition mechanism that goes beyond the IRAK4 protein inhibition mechanism, is also actively underway (PROTAC Targeted Degradation of IRAK4 as Potential Treatment in Cancer, ACS Med. Chem. Lett. 2023, 14, 5, 539-540), and it is expected that more therapeutic drugs will be developed.

[0008]

[0009] Accordingly, the inventors of the present invention studied a medicine that can be usefully used for the prevention or treatment of cancer or autoimmune diseases, and as a result, they confirmed that the compound according to the present invention, which will be described later, has inhibitory activity against IRAK4, or that it has the potential to exhibit a pharmacological action as an agonist due to a special internal environment or a product of a metabolic process after being absorbed into the body, and through this, it can be usefully used for the prevention or treatment of cancer or autoimmune diseases, thereby completing the present invention.

[0010]

[0011] The present invention provides a novel structural compound that can be usefully used for the prevention or treatment of cancer or autoimmune diseases.

[0012] In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer or autoimmune disease comprising the compound.

[0013]

[0014] To solve the above problem, the present invention provides a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof:

[0015] [Chemical Formula 1]

[0016]

[0017] In the above chemical formula 1,

[0018] X is CH or N,

[0019] R1 is hydrogen or halogen,

[0020] R2 is hydrogen, halogen or NHR5,

[0021] The above R5 is C 1-4 Alkyl; C 3-10 Cycloalkyl; C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 Heterocycloalkyl; or C 6-10 Aryl; and,

[0022] Here, R5 is unsubstituted or amino; acrylamide; hydroxy; C 1-4 Alkyl; C 1-4 Alkenyl; C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 Heterocycloalkyl; -CO(C 2-4 alkenyl); and -CO(C 1-4 is substituted with at least one selected from the group consisting of alkyl);

[0023] R3 is hydrogen, piperazinyl, (acryloyl)piperazinyl, or NHR6,

[0024] The above R6 is C 1-4 Alkyl; C 3-10 Cycloalkyl; C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 Heterocycloalkyl; or C 6-10 Aryl; and,

[0025] Here R6 is amino, C 1-4 Aminoalkyl, acrylamide, C 1-4 Alkyl acrylamide, and -CO(C 1-4 substituted with at least one selected from the group consisting of alkenyl),

[0026] R4 is hydrogen, phenyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl,

[0027] Here, R4 is unsubstituted or C 1-3 Alkyl; -CO(C 1-4 C substituted with alkyl); phenyl 1-3 alkyl; and C 3-10 C substituted with cycloalkyl 1-3 is substituted with at least one selected from the group consisting of alkyl;

[0028]

[0029] Preferably, the above chemical formula 1 can be represented by the following chemical formula 1-1:

[0030] [Chemical Formula 1-1]

[0031]

[0032] In the above chemical formula 1-1,

[0033] Descriptions of X and R1 to R4 are as defined in paragraph 1.

[0034]

[0035] Preferably, X can be CH.

[0036]

[0037] Preferably, R1 can be hydrogen or fluoro.

[0038]

[0039] Preferably, R2 can be hydrogen, chloro, or NHR5.

[0040]

[0041] Preferably, R5 is C 1-4 Alkyl, wherein R5 is amino; acrylamide; or C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S. 3-10 Heterocycloalkyl; may be substituted with.

[0042] More preferably, R5 is methyl or ethyl, wherein R5 is amino; acrylamide; or C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S. 3-10 Heterocycloalkyl; may be substituted with.

[0043] More preferably, R5 is methyl or ethyl, wherein R5 may be substituted with amino, acrylamide, or azetidinyl.

[0044] Most preferably, R5 can be azetidin-3-ylmethyl, 2-aminoethyl, or ethylacrylamide.

[0045]

[0046] Preferably, R5 is C 3-6 Cycloalkyl, wherein R5 is unsubstituted or substituted with amino, acrylamide, or hydroxy.

[0047] More preferably, R5 is cyclobutyl, cyclopentyl, or cyclohexyl, wherein R5 is unsubstituted or substituted with amino, acrylamide, or hydroxy.

[0048] More preferably, R5 can be cyclobutyl substituted with one amino, cyclobutyl substituted with one acrylamide, cyclopentyl, cyclopentyl substituted with one hydroxy, cyclohexyl substituted with one amino, or cyclohexyl substituted with one hydroxy.

[0049] Most preferably, R5 can be a 3-aminocyclobutyl, N-cyclobutylacrylamide substituent, cyclopentyl, 3-hydroxycyclopentyl, 3-aminocyclohexyl, 4-aminocyclohexyl, or 4-hydroxycyclohexyl.

[0050]

[0051] Preferably, R5 is C containing one heteroatom each independently selected from the group consisting of N, O and S. 3-6 Heterocycloalkyl, wherein R5 is unsubstituted or C 1-4 Alkyl, C 1-4 Alkenyl, -CO(C 2-4 alkenyl), or -CO(C 1-4 It can be substituted with alkyl.

[0052] More preferably, R5 is azetidinyl, pyrrolidinyl, or piperidinyl, wherein R5 is unsubstituted, or C 1-4 Alkyl, C 1-4 Alkenyl, -CO(C 2-4 alkenyl), or -CO(C 1-4 It can be substituted with alkyl.

[0053] More preferably, R5 can be azetidinyl, azetidinyl substituted with one acryloyl, pyrrolidinyl, pyrrolidinyl substituted with one ethyl, pyrrolidinyl substituted with one allyl, pyrrolidinyl substituted with one acryloyl, pyrrolidinyl substituted with one acetyl, or piperidinyl.

[0054] Most preferably, R5 can be azetidin-3-yl, 1-acryloylazetidin-3-yl, pyrrolidin-3-yl, 1-ethylpyrrolidin-3-yl, 1-allylpyrrolidin-3-yl, 1-acryloylpyrrolidin-3-yl, 1-acetylpyrrolidin-3-yl, or piperidin-4-yl.

[0055]

[0056] Preferably, R5 may be hydroxyphenyl or aminophenyl.

[0057] More preferably, R5 can be 4-hydroxyphenyl, 3-aminophenyl, or 4-aminophenyl.

[0058]

[0059] Preferably, R6 is C 3-6 Cycloalkyl, where R6 is amino, C 1-4 Aminoalkyl, acrylamide, or C 1-4 It can be substituted with alkyl acrylamide.

[0060] More preferably, R6 is cyclopentyl, or cyclohexyl, wherein R6 is amino, C 1-4 Aminoalkyl, acrylamide, or C 1-4 It can be substituted with alkyl acrylamide.

[0061] More preferably, R6 can be cyclopentyl substituted with one amino, cyclopentyl substituted with one aminomethyl, cyclopentyl substituted with one acrylamide, cyclopentyl substituted with one methyl acrylamide, cyclohexyl substituted with one amino, or cyclohexyl substituted with one acrylamide.

[0062] Most preferably, R6 can be a 3-aminocyclopentyl, a 3-(aminomethyl)cyclopentyl, an N-cyclopentylacrylamide substituent, a cyclopentylmethylacrylamide substituent, a 3-aminocyclohexyl, or an N-cyclohexylacrylamide substituent.

[0063]

[0064] Preferably, R6 can be aminopropyl, aminophenyl, phenyl substituted with acrylamide, unsubstituted piperidinyl, or (acryloyl)piperidinyl.

[0065] More preferably, R6 can be 3-aminopropyl, 3-aminophenyl, 4-aminophenyl, N-phenylacrylamide substituent, piperidin-3-yl, or 1-acryloylpiperidin-3-yl.

[0066]

[0067] Preferably, R4 can be hydrogen, phenyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0068]

[0069] Preferably, R4 is piperidinyl, wherein R4 is unsubstituted, or C 1-3 Alkyl; -CO(C 1-4 C substituted with alkyl); phenyl 1-3 alkyl; and C 3-10 C substituted with cycloalkyl 1-3 is substituted with at least one selected from the group consisting of alkyl;

[0070] More preferably, R4 is piperidinyl, wherein R4 may be unsubstituted or substituted with methyl, ethyl, (cyclopropyl)methyl, benzyl, or -COCH3.

[0071] More preferably, R4 can be piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-(cyclopropylmethyl)piperidin-4-yl, 1-benzylpiperidin-4-yl, or 1-acetylpiperidin-4-yl.

[0072]

[0073] Representative examples of compounds represented by the above chemical formula 1 are as follows:

[0074] 1) 4-((4-((3-aminocyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0075] 2) 4-((4-((3-(aminomethyl)cyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0076] 3) N-(3-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide,

[0077] 4) N-((3-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentyl)methyl)acrylamide,

[0078] 5) 4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile,

[0079] 6) 2-(piperidin-3-ylamino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0080] 7) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile,

[0081] 8) 4-((5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile,

[0082] 9) 2-((4-aminocyclohexyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0083] 10) 4-((4-((3-aminocyclohexyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0084] 11) 2-(azetidin-3-ylamino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0085] 12) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(azetidin-3-ylamino)benzonitrile,

[0086] 13) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((4-aminocyclohexyl)amino)benzonitrile,

[0087] 14) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((1-acryloylazetidin-3-yl)amino)benzonitrile,

[0088] 15) 2-((4-aminophenyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0089] 16) 2-(cyclopentylamino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0090] 17) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((2-aminoethyl)amino)benzonitrile,

[0091] 18) N-(2-((5-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-cyanophenyl)amino)ethyl)acrylamide,

[0092] 19) (R)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile,

[0093] 20) (S)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile,

[0094] 21) 2-(azetidin-3-ylamino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0095] 22) 4-((4-((3-aminophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0096] 23) 4-((4-((4-aminophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0097] 24) (R)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile,

[0098] 25) 4-((5-(1-((S)-pyrrolidin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(((R)-pyrrolidin-3-yl)amino)benzonitrile,

[0099] 26) 2-((3-aminocyclobutyl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0100] 27) (R)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((1-ethylpyrrolidin-3-yl)amino)benzonitrile,

[0101] 28) (R)-2-((1-allylpyrrolidin-3-yl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0102] 29) N-(4-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide,

[0103] 30) N-(4-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide,

[0104] 31) (R)-4-((5-(1-(1-(cyclopropylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile,

[0105] 32) (R)-4-((5-(1-(1-Benzylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile,

[0106] 33) 2-((azetidin-3-ylmethyl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0107] 34) (R)-5-fluoro-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile,

[0108] 35) (R)-4-((5-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile,

[0109] 36) (R)-2-(pyrrolidin-3-ylamino)-4-((5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0110] 37) 4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0111] 38) 4-((4-(piperidin-3-ylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0112] 39) 4-((4-((1-acryloylpiperidin-3-yl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0113] 40) 2-chloro-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0114] 41) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((1-acryloylpyrrolidin-3-yl)amino)benzonitrile,

[0115] 42) 2-((3-aminophenyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0116] 43) 6-((4-((3-aminocyclohexyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)nicotinonitrile,

[0117] 44) 4-((5-(1-phenyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile,

[0118] 45) 2-((3-aminocyclohexyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0119] 46) 4-((4-((3-aminopropyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0120] 47) 4-((4-(piperazin-1-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0121] 48) 4-((4-(4-acryloylpiperazin-1-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0122] 49) N-(3-((2-cyano-5-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)amino)cyclobutyl)acrylamide,

[0123] 50) (R)-2-((1-acetylpyrrolidin-3-yl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile,

[0124] 51) 4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((4-hydroxyphenyl)amino)benzonitrile,

[0125] 52) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((4-hydroxycyclohexyl)amino)benzonitrile,

[0126] 53) 2-((3-hydroxycyclopentyl)amino)-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, and

[0127] 54) 2-((3-hydroxycyclopentyl)amino)-4-((5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile.

[0128]

[0129] Furthermore, the compounds of the present invention may exist in the form of salts, particularly pharmaceutically acceptable salts. As salts, any salt commonly used in the art, such as acid addition salts formed with pharmaceutically acceptable free acids, may be used without limitation. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, which has a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and wherein the side effects caused by the salt do not diminish the beneficial effects of the compound represented by Chemical Formula 1.

[0130]

[0131] As the above-mentioned acid, organic acids and inorganic acids can be used. As the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used. As the organic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used, but are not limited thereto. Preferably, the salt may be hydrochloride.

[0132]

[0133] Additionally, a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base. For example, the compound represented by the above chemical formula 1 is dissolved in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, the undissolved compound salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. In this case, it is particularly preferable to prepare a sodium salt, a potassium salt, or a calcium salt as the metal salt.

[0134]

[0135] In addition, a pharmaceutically unacceptable salt or solvate of the compound represented by the chemical formula 1 can be used as an intermediate in the production of the compound represented by the chemical formula 1, a pharmaceutically acceptable salt, or a solvate thereof.

[0136]

[0137] Meanwhile, the present invention can produce a compound represented by the chemical formula 1 through, for example, the following reaction schemes 1 to 4.

[0138] [Reaction Formula 1]

[0139]

[0140] In the above reaction formula 1, X, R1 to R4 are as defined in the above chemical formula 1, R3' is a substituent having a protecting group attached to R3, and R4' is a substituent having a protecting group attached to R4.

[0141]

[0142] The above step 1-1 is a step of producing a compound represented by the above chemical formula 1-3 by reacting a compound represented by the above chemical formula 1-1 with a compound represented by the above chemical formula 1-2, and the reaction is preferably performed in the presence of a base.

[0143] The above step 1-2 is a step of producing a compound represented by the above chemical formula 1-5 by reacting a compound represented by the above chemical formula 1-3 with a compound represented by the above chemical formula 1-4, and the reaction is preferably performed in the presence of a palladium catalyst and a base.

[0144] The above step 1-3 is a step for producing a compound represented by the above chemical formula 1-7 by reacting a compound represented by the above chemical formula 1-5 with a compound represented by the above chemical formula 1-6. The above reaction is preferably performed in the presence of a palladium catalyst and a base.

[0145] The above step 1-4 is a step for preparing a compound represented by the above chemical formula 1 by removing a protecting group (e.g., BOC; tert-butyloxycarbonyl protecting group) from a compound represented by the above chemical formula 1-7. It is preferable that the above reaction be performed under acid conditions capable of removing the protecting group.

[0146] In addition, in the above reaction scheme 1, if a protecting group is not required, a reactant in which R3 is connected instead of R3' and R4 is connected instead of R4' may be used, and in this case, the protecting group removal step may be omitted. That is, depending on the type of R3 or R4, the reaction for protecting with a protecting group and the reaction for removing the protecting group may or may not be included.

[0147] The attachment and removal of the reactor and protecting group for each reaction step can be changed as known in the art, and the manufacturing method can be further specified in the manufacturing example described below.

[0148]

[0149] In addition, the present invention can produce a compound represented by the chemical formula 1 through the following reaction scheme 2, for example, when R2 is a substituent including amide within the range defined in the chemical formula 1. The substituent R2 including amide can be expressed as -Ra-NHCO-Rb in the following reaction scheme 2.

[0150] [Reaction Formula 2]

[0151]

[0152] In the above reaction formula 2, X, R1, R3 and R4 are as defined in the above chemical formula 1, R2 is expressed as -Ra-NHCO-Rb, where Ra and Rb are determined according to the specific type of R2, R2' is -Ra-NH2, R2" is a substituent having a protecting group attached to -Ra-NH2, and R4' is a substituent having a protecting group attached to R4.

[0153]

[0154] The above step 2-1 is a step of producing a compound represented by the above chemical formula 2-3 by reacting a compound represented by the above chemical formula 2-1 with a compound represented by the above chemical formula 2-2, and the reaction is preferably performed in the presence of a palladium catalyst and a base.

[0155] The above step 2-2 is a step of producing a compound represented by the above chemical formula 2-5 by reacting a compound represented by the above chemical formula 2-3 with a compound represented by the above chemical formula 2-4, and the reaction is preferably performed in the presence of a palladium catalyst and a base.

[0156] The above step 2-3 is a step of producing a compound represented by the above chemical formula 2-7 by reacting a compound represented by the above chemical formula 2-5 with a compound represented by the above chemical formula 2-6. The above reaction is preferably performed in the presence of a palladium catalyst and a base.

[0157] The above step 2-4 is a step for preparing a compound represented by the above chemical formula 2-8 by removing a protecting group (e.g., BOC) from the compound represented by the above chemical formula 2-7. The above reaction is preferably performed under acid conditions capable of removing the protecting group.

[0158] The above step 2-5 is a step of producing a compound represented by the above chemical formula 1 by reacting a compound represented by the above chemical formula 2-8 with a compound represented by the above chemical formula 2-9. The above reaction is an amidation reaction and is preferably performed in the presence of a base.

[0159] In addition, in the above reaction scheme 2, if a protecting group is not required, a reactant in which R4 is connected may be used instead of R4', in which case the protecting group removal step may be omitted. That is, depending on the type of R4, the reaction for protecting with a protecting group and the reaction for removing the protecting group may or may not be included.

[0160] The attachment and removal of the reactor and protecting group for each reaction step can be changed as known in the art, and the manufacturing method can be further specified in the manufacturing example described below.

[0161]

[0162] In addition, the present invention can produce a compound represented by the chemical formula 1 through the following reaction scheme 3, for example, when R3 is a substituent including amide within the range defined in the chemical formula 1. The substituent R3 including amide can be expressed as -Ra-NHCO-Rb in the following reaction scheme 3.

[0163] [Reaction Formula 3]

[0164]

[0165] In the above reaction formula 3, X, R1, R2 and R4 are as defined in the above chemical formula 1, R3 is expressed as -Ra-NHCO-Rb, where Ra and Rb are determined according to the specific type of R3, R3' is Ra-NH2, R3" is a substituent to which a protecting group is attached to Ra-NH2, and R4' is a substituent to which a protecting group is attached to R4.

[0166]

[0167] The above step 3-1 is a step of producing a compound represented by the above chemical formula 3-3 by reacting a compound represented by the above chemical formula 3-1 with a compound represented by the above chemical formula 3-2, and it is preferable that the reaction be performed in the presence of a base.

[0168] The above step 3-2 is a step of producing a compound represented by the above chemical formula 3-5 by reacting a compound represented by the above chemical formula 3-3 with a compound represented by the above chemical formula 3-4, and the reaction is preferably performed in the presence of a palladium catalyst and a base.

[0169] The above step 3-3 is a step of producing a compound represented by the above chemical formula 3-7 by reacting a compound represented by the above chemical formula 3-5 with a compound represented by the above chemical formula 3-6. The above reaction is preferably performed in the presence of a palladium catalyst and a base.

[0170] The above step 3-4 is a step for preparing a compound represented by the above chemical formula 3-8 by removing a protecting group (e.g., BOC; tert-butyloxycarbonyl protecting group) from the compound represented by the above chemical formula 3-7. The above reaction is preferably performed under acid conditions capable of removing the protecting group.

[0171] The above step 3-5 is a step of producing a compound represented by the above chemical formula 1 by reacting a compound represented by the above chemical formula 3-8 with a compound represented by the above chemical formula 3-9. The above reaction is an amidation reaction and is preferably performed in the presence of a base.

[0172] Additionally, in the above reaction scheme 3, if a protecting group is not required, a reactant in which R4 is connected may be used instead of R4', in which case the protecting group removal step may be omitted. That is, depending on the type of R4, the reaction for protecting with a protecting group and the reaction for removing the protecting group may or may not be included.

[0173] The attachment and removal of the reactor and protecting group for each reaction step can be changed as known in the art, and the manufacturing method can be further specified in the manufacturing example described below.

[0174]

[0175] In addition, the present invention can produce a compound represented by the chemical formula 1 through the following reaction scheme 4, for example, when R2 and R4 are substituents including amide within the range defined in the chemical formula 1. In the following reaction scheme 4, the substituent R2 including the amide can be expressed as -Ra-NHCO-Rb, and the substituent R4 including the amide can be expressed as -Rc-NHCO-Rd.

[0176] [Reaction Formula 4]

[0177]

[0178] In the above reaction formula 4, X, R1 and R3 are as defined in the above chemical formula 1, R2 is expressed as -Ra-NHCO-Rb, where Ra and Rb are determined according to the specific type of R2, R2' is Ra-NH2, and R2" is a substituent to which a protecting group is attached to Ra-NH2, and R4 is expressed as -Rc-NHCO-Rd, where Rc and Rd are determined according to the specific type of R4, R4' is Rc-NH2, and R4" is a substituent to which a protecting group is attached to Rc-NH2.

[0179]

[0180] The above step 4-1 is a step of producing a compound represented by the above chemical formula 4-3 by reacting a compound represented by the above chemical formula 4-1 with a compound represented by the above chemical formula 4-2, and the reaction is preferably performed in the presence of a palladium catalyst and a base.

[0181] The above step 4-2 is a step of producing a compound represented by the above chemical formula 4-5 by reacting a compound represented by the above chemical formula 4-3 with a compound represented by the above chemical formula 4-4, and the reaction is preferably performed in the presence of a palladium catalyst and a base.

[0182] The above step 4-3 is a step for preparing a compound represented by the above chemical formula 4-6 by removing a protecting group (e.g., BOC) from the compound represented by the above chemical formula 4-5. The above reaction is preferably performed under acid conditions capable of removing the protecting group.

[0183] The above step 4-4 is a step of producing a compound represented by the above chemical formula 4-8 by reacting a compound represented by the above chemical formula 4-6 with a compound represented by the above chemical formula 4-7. The above reaction is an amidation reaction and is preferably performed in the presence of a base.

[0184] The above step 4-5 is a step of producing a compound represented by the above chemical formula 4-10 by reacting a compound represented by the above chemical formula 4-8 with a compound represented by the above chemical formula 4-9, and the reaction is preferably performed in the presence of a palladium catalyst and a base.

[0185] The above step 4-6 is a step for removing a protecting group (e.g., BOC) from a compound represented by the above chemical formula 4-10 to prepare a compound represented by the above chemical formula 4-11. The above reaction is preferably performed under acid conditions capable of removing the protecting group.

[0186] The above step 4-7 is a step for producing a compound represented by the above chemical formula 1 by reacting a compound represented by the above chemical formula 4-11 with a compound represented by the above chemical formula 4-12. The above reaction is an amidation reaction and is preferably performed in the presence of a base.

[0187] Additionally, in the above reaction scheme 4, a reaction of protecting with a protecting group and a reaction of removing the protecting group may be added depending on each substituent.

[0188] The attachment and removal of the reactor and protecting group for each reaction step can be changed as known in the art, and the manufacturing method can be further specified in the manufacturing example described below.

[0189]

[0190] In addition, the present invention provides a pharmaceutical composition comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof. Specifically, the present invention provides a pharmaceutical composition for preventing or treating cancer or an autoimmune disease, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0191]

[0192] The term "cancer" includes hematological cancer, extranodal marginal zone B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myeloid leukemia, macroglobulinemia, B-cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, hairy cell leukemia, mantle cell lymphoma, glioblastoma, bladder cancer, pancreatic cancer, ovarian cancer, colon cancer, kidney cancer, stomach cancer, transitional cell carcinoma, carcinoid tumor, breast cancer, non-small cell lung cancer, or multiple myeloma.

[0193]

[0194] Additionally, the term "autoimmune disease" includes rheumatoid arthritis, systemic lupus erythematosus, juvenile diabetes, psoriasis, aphthous stomatitis, chronic thyroiditis, some acquired aplastic anemias, primary cirrhosis, ulcerative colitis, Behcet's disease, Crohn's disease, silicosis, asbestosis, Sjogren's syndrome, Guillain-Barré syndrome, dermatomyositis, polymyositis, multiple sclerosis, autoimmune hemolytic anemia, autoimmune encephalomyelitis, myasthenia gravis, Grave's hyperthyroidism, polyarteritis nodosa, ankylosing spondylitis, fibromyalgia, temporal arteritis, Wilson's disease, asthma, hidradenitis suppurativa, or Fanconi syndrome.

[0195]

[0196] The term "prevention" of the present invention means any act of inhibiting or delaying the occurrence, spread, and recurrence of the disease by administering the composition of the present invention, and "treatment" means any act of improving or beneficially changing the symptoms of the disease by administering the composition of the present invention.

[0197]

[0198] The pharmaceutical composition of the present invention can be formulated into oral or parenteral dosage forms according to standard pharmaceutical practices. These dosage forms may contain, in addition to the active ingredient, pharmaceutically acceptable additives such as carriers, adjuvants, or diluents.

[0199]

[0200] Suitable carriers include, but are not limited to, saline, polyethylene glycol, ethanol, vegetable oils, and isopropyl myristate, and diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine. In addition, the compounds of the present invention can be dissolved in oils, propylene glycol, or other solvents commonly used in the preparation of injectable solutions. In addition, the compounds of the present invention can be formulated as ointments or creams for topical action.

[0201]

[0202] The preferred dosage of the compound of the present invention varies depending on the patient's condition and body weight, the severity of the disease, the form of the drug, the route of administration, and the duration of administration, but can be appropriately selected by those skilled in the art. However, for desirable effects, the compound of the present invention is preferably administered at a daily dose of 0.0001 to 100 mg / kg (body weight), preferably 0.001 to 100 mg / kg (body weight). Administration may be administered orally or parenterally once daily or in divided doses.

[0203]

[0204] Depending on the administration method, the pharmaceutical composition may contain 0.001 to 99 wt%, preferably 0.01 to 60 wt%, of the compound of the present invention.

[0205]

[0206] The pharmaceutical composition according to the present invention can be administered to mammals, including rats, mice, livestock, and humans, via various routes. Any route of administration is conceivable, including oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine, or intracerebroventricular injection.

[0207]

[0208] The compound represented by chemical formula 1 according to the present invention or a pharmaceutically acceptable salt thereof can be usefully used for the prevention or treatment of cancer or autoimmune diseases.

[0209]

[0210] Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only to illustrate the present invention and the scope of the present invention is not limited to the following examples.

[0211]

[0212] Example 1: Preparation of 4-((4-((3-aminocyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0213] (Step 1-1) Preparation of tert-butyl (3-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclopentyl)carbamate

[0214]

[0215] 2,4-Dichloro-5-iodopyrimidine (2.7 g, 1.0 eq) was added to tert-butyl 3-aminopiperidine-1-carboxylate (2.1 g, 1.1 eq), 33.0 mL of acetonitrile, and triethylamine (1.8 mL, 1.2 eq), and the mixture was stirred at room temperature for 22 hours. After completion of the reaction, purified water was added to the reaction mixture to precipitate a precipitate, which was then filtered and washed with purified water to obtain the title compound (3.9 g, yield 88.2%).

[0216]

[0217] (Step 1-2) Preparation of tert-butyl (3-((2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentyl)carbamate

[0218]

[0219] Tert-Butyl (3-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclopentyl)carbamate (658.0 mg, 1.0 eq), 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500.7 mg, 1.2 eq), tetrakis(triphenylphosphine)palladium(0) (346.7 mg, 0.2 eq), cesium carbonate (2,932.4 mg, 6.0 eq), and 13.8 mL of 1,2-dimethoxyethane were added, and the mixture was degassed and filled with nitrogen gas. Then, 4.6 mL of purified water was added, degassed for 10 minutes and nitrogen gas was filled, and stirred at 100°C for 18 hours. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the separated organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: hexane = 1:1) to obtain the title compound (488.2 mg, yield 70.3%).

[0220]

[0221] (Step 1-3) Preparation of tert-butyl (3-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentyl)carbamate

[0222]

[0223] Tert-butyl (3-((2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentyl)carbamate (488.0 mg, 1.0 eq), 4-aminobenzonitrile (157.3 mg, 1.1 eq), palladium acetate (23.7 mg, 0.1 eq), xantphos (61.0 mg, 0.1 eq), cesium carbonate (721.2 mg, 2.1 eq), and 7.3 mL of 1,4-dioxane were added and stirred for 10 minutes, degassed, and nitrogen gas was filled, and the mixture was reacted at 120°C for 45 minutes using a microwave reactor. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the separated organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate:hexane = 1:1) to obtain the title compound (70.5 mg, yield 78.5%).

[0224]

[0225] (Step 1-4) Preparation of 4-((4-((3-aminocyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0226]

[0227] 2.0 mL of 1,4-dioxane was added to tert-butyl (3-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentyl)carbamate (284.3 mg, 1.0 eq), and 6.3 mL of a 4.0 N hydrochloric acid solution in 1,4-dioxane was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then the addition of methanol and concentration under reduced pressure were repeated five times to obtain the title compound (281.0 mg).

[0228] 1H NMR (500 MHz, MeOD): 8.01 (s, 1H), 7.82-7.75 (m, 4H), 7.72 (s, 1H), 7.69 (s, 1H), 4.60 (t, 1H), 4.49 (t, 1H), 4.19 (dd, 2H), 3.71(t, 1H), 2.68-2.53(m, 5H), 2.61(q, 1H), 2.21-2.04(m, 5H), 1.94-1.79(m, 2H), 1.70(q, 1H)

[0229]

[0230] Example 2: Preparation of 4-((4-((3-(aminomethyl)cyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0231]

[0232] The title compound (104.5 mg) was obtained as a solid by the same method as in Example 1, except that tert-butyl ((3-aminocyclopentyl)methyl)carbamate was used instead of tert-butyl 3-aminopiperidine-1-carboxylate.

[0233] 1 H NMR (500 MHz, MeOD): 7.98 (s, 1H), 7.89 (d, 4H), 7.70 (s, 1H), 7.67 (s, 1H), 4.67-4.57 (m, 1H), 4.52-4.43 (m, 1H), 4.11-4.03 (m, 2H), 3.67-3.55(t, 4H), 2.99-2.84(m, 3H), 2.42-2.31(m, 1H), 2.26-2.19(m, 1H), 2.12-2.04(m, 4H), 1.97-1.68(m, 3H), 1.41-1.31(m, 2H)

[0234]

[0235] Example 3: Preparation of N-(3-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide

[0236]

[0237] 1.5 mL of 1-methyl-2-pyrrolidone and triethylamine (41.8 μL, 3 eq) were added to 4-((4-((3-aminocyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile (50.5 mg, 1.0 eq), cooled to 0 °C, and then acryloyl chloride (9.8 μL, 1.2) was added. After stirring at room temperature for 18 hours, purified water was added to the reaction mixture, and extracted with ethyl acetate. Sodium sulfate was added to the separated organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: methanol = 9:1) to obtain the title compound (38.0 mg, yield 72.7%).

[0238] 1 H NMR (500 MHz, MeOD): 7.97-7.87(m, 3H), 7.81(s, 1H), 7.70-7.60(m, 3H), 6.19(s, 2H), 5.62(d, 1H), 4.51(t, 1H), 4.50-4.42(m, 1H), 4.19(t, 1H), 4.09(d, 1H), 3.58(t, 2H), 2.61-2.51(m, 1H), 2.20-2.01(m, 6H), 1.75-1.67(m, 2H), 1.54-1.46(m, 1H)

[0239]

[0240] Example 4: Preparation of N-((3-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentyl)methyl)acrylamide

[0241]

[0242] 1.5 mL of 1-methyl-2-pyrrolidone and triethylamine (41.8 μL, 3.0 eq) were added to 4-((4-((3-(aminomethyl)cyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile (50.5 mg, 1.0 eq), cooled to 0 °C, and then acryloyl chloride (9.8 μL, 1.2 eq) was added. After stirring at room temperature for 18 hours, purified water was added to the reaction mixture, and extracted with ethyl acetate. Sodium sulfate was added to the separated organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: methanol = 9:1) to obtain the title compound (38.0 mg, yield 72.7%).

[0243] 1 H NMR (500 MHz, MeOD): 7.97-7.83 (m, 3H), 7.81 (s, 1H), 7.63-7.54 (m, 3H), 6.27-6.19 (m, 2H), 6.63 (t, 1H), 4.69-4.31 (m, 2H), 4.11-4.03(m, 2H), 3.58(t, 2H), 3.28(d, 2H), 2.38-2.76(m, 9H), 1.64-1.31(m, 4H)

[0244]

[0245] Example 5: Preparation of 4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0246] (Step 5-1) Preparation of tert-butyl 4-(4-(2-((3-chloro-4-cyanophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0247]

[0248] tert-Butyl 4-(4-(2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (80.0 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous N,N-dimethylformamide (2.0 mL, 3:1), then palladium acetate (4.9 mg, 0.1 eq), xantphos (12.7 mg, 0.1 eq), cesium carbonate (150.4 mg, 2.1 eq), and 4-amino-2-chlorobenzonitrile (40.3 mg, 1.2 eq) were placed in a microwave reactor, and the reaction mixture was reacted using a microwave reactor at 120 °C for 30 min. After confirming the disappearance of the starting material on TLC, the mixture was extracted with water and ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:1) to obtain the title compound (80.0 mg, yield 75.8%).

[0249]

[0250] (Step 5-2) Preparation of tert-butyl 4-(4-(2-((3-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-4-cyanophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0251]

[0252] tert-Butyl 4-(4-(2-((3-chloro-4-cyanophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (80.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (3.0 mL), then tris(dibenzylideneacetone)palladium(0) (30.5 mg, 0.2 eq), xantphos (38.6 mg, 0.4 eq), cesium carbonate (108.6 mg, 2.0 eq), and 3-(tert-butoxycarbonylamino)pyrrolidine (45.2 μL, 1.5 eq) were placed in a microwave reactor, and the mixture was reacted at 150 °C for 45 minutes using a microwave reactor. The reaction was terminated after confirming the disappearance of the starting material on TLC. The reaction product was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:1) to obtain the title compound (33.0 mg, yield 31.4%).

[0253]

[0254] (Step 5-3) Preparation of 4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0255]

[0256] tert-Butyl 4-(4-(2-((3-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-4-cyanophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (40.0 mg, 1.0 eq) was dissolved in a 1.25 N methanol solution of hydrochloric acid (4.0 mL), stirred at room temperature for 5 hours, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, crystallized at room temperature for 1 hour, and the resulting precipitate was filtered and dried to obtain the title compound (20.0 mg, yield 67.6%).

[0257] 1 H NMR (500 MHz, MeOD): 8.78 (s, 2H), 8.20 (s, 1H), 7.94 (s, 1H), 7.57 (s, 1H), 7.39 (d, 1H), 7.10 (d, 1H), 4.71-4.55 (m, 1H), 4.72-4.62(m, 1H), 3.62-3.14(m, 8H), 2.58-2.43(m, 1H), 2.41-2.19(m, 5H)

[0258]

[0259] Example 6: Preparation of 2-(piperidin-3-ylamino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0260]

[0261] The title compound (40.0 mg, yield 89.5%) was obtained by the same method as in Example 5, except that 3-amino-1-tert-butoxycarbonylpiperidine was used instead of 3-(tert-butoxycarbonylamino)pyrrolidine.

[0262] 1 H NMR (500 MHz, MeOD): 8.81 (s, 2H), 8.24 (s, 1H), 7.95 (s, 1H), 7.59 (s, 1H), 7.37 (d, 1H), 7.04 (d, 1H), 4.68-4.58 (m, 1H), 4.99-4.90(m, 1H), 3.61-3.51(m, 3H), 3.42-3.29(m, 5H), 3.09-2.95(m, 2H), 2.41-1.69(m, 5H)

[0263]

[0264] Example 7: Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0265] (Step 7-1) Preparation of 2-chloro-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine hydrochloride

[0266]

[0267] tert-Butyl 4-(4-(2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2.0 g, 1.0 eq) was dissolved in a 1.25 N hydrochloric acid methanol solution (40.0 mL), stirred at room temperature for 5 hours, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, crystallized at room temperature for 1 hour, and the resulting precipitate was filtered and dried to obtain the title compound (1.0 g, yield 60.0%).

[0268]

[0269] (Step 7-2) 1-(4-(4-(2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one

[0270]

[0271]

[0272] 2-Chloro-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine hydrochloride (100.0 mg, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (2.0 mL), triethylamine (83.7 μL, 2.5 eq) and acetyl chloride (34.3 μL, 2.0 eq) were added, and the mixture was reacted at room temperature for 16 h. The reaction was terminated when the starting material disappeared on TLC. The reactant was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (80.0 mg, yield 80.0%).

[0273]

[0274] (Step 7-3) Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-chlorobenzonitrile

[0275]

[0276] 1-(4-(4-(2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one (80.0 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous N,N-dimethylformamide (10.0 mL, 4:1), and then palladium acetate (19.3 mg, 0.1 eq), xantphos (50.0 mg, 0.1 eq), cesium carbonate (591.2 mg, 2.1 eq), and 4-amino-2-chlorobenzonitrile (158.2 mg, 1.2 eq) were placed in a microwave reactor, and the reaction was performed at 120 °C for 30 minutes using a microwave reactor. The reaction was terminated when the starting material disappeared on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = methanol:dichloromethane = 1:4) to obtain the title compound (21.0 mg, yield 23.5%).

[0277]

[0278] (Step 7-4) Preparation of tert-butyl 3-((5-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-cyanophenyl)amino)pyrrolidine-1-carboxylate

[0279]

[0280] 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-chlorobenzonitrile (21.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (2.0 mL), then tris(dibenzylideneacetone)palladium(0) (9.7 mg, 0.2 eq), xantphos (12.8 mg, 0.4 eq), cesium carbonate (34.8 mg, 2.0 eq), and 3-(tert-butoxycarbonylamino)pyrrolidine (14.4 μL, 1.5 eq) were placed in a microwave reactor, and the mixture was reacted at 150 °C for 45 minutes using a microwave reactor. The reaction was terminated after confirming the disappearance of the starting material on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = methanol:dichloromethane = 1:4) to obtain the title compound (12.9 mg, yield 44.0%).

[0281]

[0282] (Step 7-5) Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0283]

[0284] tert-Butyl 3-((5-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-cyanophenyl)amino)pyrrolidine-1-carboxylate (10.0 mg, 1.0 eq) was dissolved in a 1.25 N hydrochloric acid methanol solution (4.0 mL), stirred at room temperature for 5 hours, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, crystallized at room temperature for 1 hour, and the resulting precipitate was filtered and dried to obtain the title compound (5.0 mg, yield 70.8%).

[0285] 1H NMR (500 MHz, MeOD): 8.86(s, 2H), 8.26(s, 1H), 7.96(s, 1H), 7.50(s, 1H), 7.42(d, 1H), 7.07(d, 1H), 4.66(d, 1H), 4.54(t, 1H), 4.40(t, 1H), 4.10 (d, 1H), 3.71(t, 1H), 3.59-3.31(m, 4H), 2.87(t, 1H), 2.57-2.42(m, 1H), 2.29-2.15(m, 3H), 2.11-2.01(m, 1H). 2.00-1.89(m, 1H)

[0286]

[0287] Example 8: Preparation of 4-((5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0288] (Step 8-1) Preparation of 2-chloro-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine

[0289]

[0290] tert-Butyl 4-(4-(2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2.0 g, 1.0 eq) was dissolved in a 1.25 N hydrochloric acid methanol solution (40.0 mL), stirred at room temperature for 5 hours, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, crystallized at room temperature for 1 hour, and the resulting precipitate was filtered and dried to obtain the title compound (1.0 g, yield 60.0%).

[0291]

[0292] (Step 8-2) Preparation of 2-chloro-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine

[0293]

[0294] 2-Chloro-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine hydrochloride (500.0 mg, 1.0 eq) was dissolved in anhydrous dichloroethane (20.0 mL), and then 36% formaldehyde (230 μL, 1.8 eq), diisopropylethylamine (348.1 μL, 1.2 eq), and sodium triacetoxyborohydride (706.0 mg, 2.0 eq) were added, and the mixture was stirred at 50 °C for 2 h. After confirming the disappearance of the starting material on TLC, water was added, and extraction was performed with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the title compound (300.0 mg, yield 64.8%) was obtained.

[0295]

[0296] (Step 8-3) Preparation of 2-chloro-4-((5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0297]

[0298] 2-Chloro-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine (300.0 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous N,N-dimethylformamide (10.0 mL, 4:1), and then palladium acetate (24.2 mg, 0.1 eq), xantphos (62.5 mg, 0.1 eq), cesium carbonate (739.0 mg, 2.1 eq), and 4-amino-2-chlorobenzonitrile (197.8 mg, 1.2 eq) were placed in a microwave reactor, and the reaction was conducted at 120 °C for 30 minutes using a microwave reactor. The reaction was terminated when the starting material disappeared on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = methanol:dichloromethane = 1:4) to obtain the title compound (100.0 mg, yield 23.5%).

[0299]

[0300] (Step 8-4) Preparation of tert-butyl 3-((2-cyano-5-((5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)amino)pyrrolidine-1-carboxylate

[0301]

[0302] 2-Chloro-4-((5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile (65.8 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (2.0 mL), then tris(dibenzylideneacetone)palladium(0) (30.6 mg, 0.2 eq), xantphos (38.7 mg, 0.4 eq), cesium carbonate (108.9 mg, 2.0 eq), and 3-(tert-butoxycarbonylamino)pyrrolidine (45.3 μL, 1.5 eq) were placed in a microwave reactor, and the mixture was reacted at 150 °C for 45 minutes using a microwave reactor. The reaction was terminated after confirming the disappearance of the starting material on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = methanol:dichloromethane = 1:4) to obtain the title compound (40.0 mg, yield 44.0%).

[0303]

[0304] (Step 8-5) Preparation of 4-((5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0305]

[0306] tert-Butyl 3-((2-cyano-5-((5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)amino)pyrrolidine-1-carboxylate (40.0 mg, 1.0 eq) was dissolved in a 1.25 N methanol solution of hydrochloric acid (4.0 mL), stirred at room temperature for 5 hours, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, crystallized at room temperature for 1 hour, and the resulting precipitate was filtered and dried to obtain the title compound (20.0 mg, yield 70.8%).

[0307] 1 H NMR (500 MHz, MeOD): 8.87(s, 2H), 8.20(s, 1H), 7.93(s, 1H), 7.55(s, 1H), 7.45(d, 1H), 7.10(d, 1H), 4.78-4.55(m, 1H), 4.45-4.35(m, 1H), 4.08(t, 1H), 3.78-3.38(m, 8H), 2.97(s, 3H), 2.58-2.12(m, 8H)

[0308]

[0309] Example 9: Preparation of 2-((4-aminocyclohexyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0310] (Step 9-1) Preparation of tert-butyl 4-(4-(2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0311]

[0312] 5-Bromo-2-chloropyrimidine (100.0 mg, 1.0 eq) was dissolved in anhydrous toluene (4.0 mL) and anhydrous N,N-dimethylformamide (4.0 mL), potassium carbonate (142.9 mg, 2.0 eq), tetrakis(triphenylphosphine)palladium(0) (59.7 mg, 0.1 eq), and 1-(1-Boc-4-piperidyl)pyrazole-4-boronic acid pinacol ester (292.6 mg, 1.5 eq) were placed in a microwave-safe reaction vessel, and the mixture was reacted at 150 °C for 15 minutes using a microwave reactor. The reaction was terminated when the starting material disappeared on TLC. The reactant was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:1) to obtain the title compound (110.0 mg, yield 52.1%).

[0313]

[0314] (Step 9-2) Preparation of tert-butyl 4-(4-(2-((3-chloro-4-cyanophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0315]

[0316] tert-Butyl 4-(4-(2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (80.0 mg, 1.0 eq) was dissolved in anhydrous toluene (6.0 mL) and anhydrous N,N-dimethylformamide (2.0 mL), and then palladium acetate (4.9 mg, 0.1 eq), xantphos (12.7 mg, 0.1 eq), cesium carbonate (150.4 mg, 2.1 eq), and 4-amino-2-chlorobenzonitrile (40.3 mg, 1.2 eq) were placed in a microwave reactor, and the mixture was reacted at 120 °C for 30 minutes using a microwave reactor. The reaction was terminated when the starting material disappeared on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:1) to obtain the title compound (80.0 mg, yield 75.8%).

[0317]

[0318] (Step 9-3) Preparation of tert-butyl 4-(4-(2-((3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-cyanophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0319]

[0320] tert-Butyl 4-(4-(2-((3-chloro-4-cyanophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (100.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (3.0 mL), then tris(dibenzylideneacetone)palladium(0) (38.2 mg, 0.2 eq), xantphos (48.2 mg, 0.4 eq), cesium carbonate (135.8 mg, 2.0 eq), and tert-butyl (4-aminocyclohexyl)carbamate (67.0 mg, 1.5 eq) were placed in a microwave reactor, and the mixture was reacted at 150°C for 45 minutes using a microwave reactor. The reaction was terminated after confirming the disappearance of the starting material on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:1) to obtain the title compound (95.0 mg, yield 69.3%).

[0321]

[0322] (Step 9-4) Preparation of 2-((4-aminocyclohexyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0323]

[0324] tert-Butyl 4-(4-(2-((3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-cyanophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (90.0 mg, 1.0 eq) was dissolved in a 1.25 N methanol solution of hydrochloric acid (9.0 mL), stirred at room temperature for 16 h, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, crystallized at room temperature for 1 h, and the resulting precipitate was filtered and dried to obtain the title compound (55.0 mg, yield 81.4%).

[0325] 1 H NMR (500 MHz, MeOD): 8.87(s, 2H), 8.20(s, 1H), 7.93(s, 1H), 7.55(s, 1H), 7.45(d, 1H), 7.10(d, 1H), 4.75-4.53(m, 1H), 4.42-4.32(m, 1H), 4.05(t, 1H), 3.75-3.33(m, 8H), 2.57-2.15(m, 8H)

[0326]

[0327] Example 10: Preparation of 4-((4-((3-aminocyclohexyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0328] (Step 10-1) Preparation of tert-butyl (3-((2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate

[0329]

[0330] Tert-Butyl (3-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexyl)carbamate (425.0 mg, 1.0 eq), (1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester (313.4 mg, 1.2 eq), tetrakis(triphenylphosphine)palladium (217.0 mg, 0.2 eq), cesium carbonate (1,835.2 mg, 6.0 eq), and 8.9 mL of 1,2-dimethoxyethane were placed in a flask, stirred, degassed, and filled with nitrogen gas. 3.0 mL of purified water was added to the reaction mixture, degassed for 10 minutes, and filled with nitrogen gas, and stirred at 100 °C for 18 hours. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the separated organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate:hexane = 9:1) to obtain the title compound (yield 64.8%).

[0331]

[0332] (Step 10-2) Preparation of tert-butyl (3-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate

[0333]

[0334] Tert-Butyl (3-((2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate (71.6 mg, 1.0 eq), 4-aminobenzonitrile (18.6 mg, 1.1 eq), palladium acetate (3.4 mg, 0.1 eq), xantphos (8.7 mg, 0.1 eq), cesium carbonate (103.6 mg, 2.1 eq), and 1.1 mL of 1,4-dioxane were placed in a microwave reactor, stirred for 10 minutes, degassed, and filled with nitrogen gas, and reacted at 120 °C for 45 minutes in a microwave reactor. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the separated organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (ethyl acetate: hexane = 9:1) to obtain the title compound (62.3 mg, yield 74.3%).

[0335]

[0336] (Step 10-3) Preparation of 4-((4-((3-aminocyclohexyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0337]

[0338] Tert-butyl (3-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) pyrimidin-4-yl)amino)cyclohexyl)carbamate (60.0 mg, 1.0 eq) was added 0.5 mL of 1,4-dioxane, 4.0 N hydrochloric acid solution in 1,4-dioxane (1.3 mL), methanol (1.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the addition of methanol and concentration under reduced pressure were repeated twice to obtain the title compound (80.5 mg).

[0339] 1H NMR (500 MHz, MeOD): 8.08 (s, 1H), 8.01 (s, 1H), 7.85-7.78 (m, 2H), 7.75 (s, 2H), 7.69 (s, 1H), 4.58-4.41 (m, 3H), 4.22 (t, 2H), 4.11-4.04(m, 4H), 4.62-4.57(m, 4H), 2.358-2.26(m, 2H), 1.90-1.78(m, 2H), 1.68-1.58(m, 2H)

[0340]

[0341] Example 11: Preparation of 2-(azetidin-3-ylamino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0342]

[0343] The title compound (40.0 mg, yield 44.0%) was obtained by the same method as in Example 9, except that tert-butyl 3-aminoazetidine-1-carboxylate was used instead of tert-butyl (4-aminocyclohexyl)carbamate.

[0344] 1 H NMR (500 MHz, MeOD): 8.81 (d, 2H), 8.24 (d, 1H), 7.96 (d, 1H), 7.53 (s, 1H), 7.45-7.35 (m, 1H), 7.21-7.08 (m, 1H), 4.69-4.60 (m, 1H), 4.58-4.50(m, 1H), 4.22-4.18(m, 2H), 4.01-3.90(m, 1H), 3.69-3.47(m, 3H), 3.32-3.20(m, 2H), 2.40-2.31(m, 4H)

[0345]

[0346] Example 12: Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(azetidin-3-ylamino)benzonitrile

[0347] (Step 12-1) Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-chlorobenzonitrile

[0348]

[0349] 2-Chloro-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile hydrochloride (100.0 mg, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (2.0 mL), then triethylamine (83.7 μL, 2.5 eq) and acetyl chloride (34.3 μL, 2.0 eq) were added and reacted at room temperature for 16 h. The reaction was terminated when the starting material disappeared on TLC. The reactant was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (80.0 mg, yield 80.0%).

[0350]

[0351] (Step 12-2) Preparation of tert-butyl 3-((5-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-cyanophenyl)amino)azetidine-1-carboxylate

[0352]

[0353] 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-chlorobenzonitrile (100.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (3.0 mL), and then tris(dibenzylideneacetone)palladium(0) (43.4 mg, 0.2 eq), xantphos (54.8 mg, 0.4 eq), cesium carbonate (154.4 mg, 2.0 eq), and tert-butyl 3-aminoazetidine-1-carboxylate (61.2 mg, 1.5 eq) were placed in a microwave reactor, and the mixture was reacted at 150°C for 45 minutes using a microwave reactor. The reaction was terminated after confirming the disappearance of the starting material on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = methanol:ethyl acetate = 1:4) to obtain the title compound (117.4 mg, yield 88.8%).

[0354]

[0355] (Step 12-3) Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(azetidin-3-ylamino)benzonitrile

[0356]

[0357] tert-Butyl 3-((5-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-cyanophenyl)amino)azetidine-1-carboxylate (110.0 mg, 1.0 eq) was dissolved in a 1.25 N methanol solution of hydrochloric acid (10.0 mL), stirred at room temperature for 16 hours, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, crystallized at room temperature for 1 hour, and the resulting precipitate was filtered and dried to obtain the title compound (90.0 mg, yield 92.4%).

[0358] 1H NMR (500 MHz, MeOD): 8.88 (d, 2H), 8.27 (d, 1H), 7.99 (d, 1H), 7.53 (s, 1H), 7.50-7.35 (m, 3H), 7.06 (d, 1H), 4.67 (d, 1H), 4.56(t, 1H), 4.15-3.91(m, 3H), 3.70-3.45(m, 3H), 2.85(t, 1H), 2.30-1.91(m, 8H)

[0359]

[0360] Example 13: Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((4-aminocyclohexyl)amino)benzonitrile

[0361]

[0362] The title compound (8.0 mg, yield 99.5%) was obtained by the same method as in Example 12, except that tert-butyl(4-aminocyclohexyl)carbamate was used instead of tert-butyl3-aminoazetidine-1-carboxylate.

[0363] 1 H NMR (500 MHz, MeOD): 8.89 (d, 2H), 8.32 (d, 1H), 8.00 (s, 1H), 7.50-7.31 (m, 3H), 7.18-7.02 (m, 1H), 4.67 (d, 1H), 4.55 (t, 1H), 4.11(d, 1H), 3.78(s, 1H), 3.40-3.32(m, 2H), 2.88(t, 1H), 2.28-1.75(m, 12H), 1.75-1.60(m, 1H), 1.60-1.45(m, 1H)

[0364]

[0365] Example 14: Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((1-acryloylazetidin-3-yl)amino)benzonitrile

[0366]

[0367] 4-((5-(1-(1-Acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(azetidin-3-ylamino)benzonitrile (50.0 mg, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (1.5 mL), triethylamine (35.3 μL, 2.5 eq) and acryloyl chloride (12.8 μL, 2.0 eq) were added, and the mixture was reacted at room temperature for 16 h. The reaction was terminated when the starting material disappeared on TLC. The reactant was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (25.0 mg, yield 48.3%).

[0368] 1 H NMR (500 MHz, MeOD): 8.69(d, 2H), 8.13(s, 1H), 7.87(s, 1H), 7.63(s, 1H), 7.30(d, 1H), 6.98(d, 1H), 6.32-6.18(q, 2H), 5.69(d, 1H), 4.80-46(m, 5H), 4.11(t, 3H), 3.80(q, 2H), 3.68-3.40(m, 2H), 2.84(t, 1H), 2.25-2.10(m, 4H)

[0369]

[0370] Example 15: Preparation of 2-((4-aminophenyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0371]

[0372] The title compound (70.0 mg, yield 93.4%) was obtained by the same method as in Example 9, except that tert-butyl (4-aminocyclohexyl) carbamate was used instead of tert-butyl (4-aminophenyl) carbamate.

[0373] 1H NMR (500 MHz, MeOD): 8.75 (d, 2H), 8.25 (s, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 7.52 (d, 1H), 7.36 (d, 2H), 7.33-7.28 (m, 3H), 4.68-4.58(m, 1H), 3.59(d, 2H), 3.34-3.16(m, 2H), 2.37-2.24(m, 4H)

[0374]

[0375] Example 16: Preparation of 2-(cyclopentylamino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0376]

[0377] The title compound (25.0 mg, yield 63.1%) was obtained by the same method as in Example 9, except that cyclopentanamine was used instead of tert-butyl (4-aminocyclohexyl)carbamate.

[0378] 1 H NMR (500 MHz, MeOD): 8.77(s, 2H), 8.20(s, 1H), 7.95(s, 1H), 7.60 (s, 1H), 7.40(s, 1H), 7.08(d, 1H), 4.65-4.56(m, 1H), 3.94(t, 1H), 3.59(d, 2H), 3.39-3.19(m, 2H), 2.40-2.38(m, 4H), 2.19-2.09(m, 2H), 1.89-1.59(m, 6H)

[0379]

[0380] Example 17: Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((2-aminoethyl)amino)benzonitrile

[0381]

[0382] The title compound (55.0 mg, yield 65.6%) was synthesized using the same method as in Example 12, except that tert-butyl (2-aminoethyl)carbamate was used instead of tert-butyl 3-aminoazetidine-1-carboxylate.

[0383] 1 H NMR (500 MHz, MeOD): 8.86 (s, 2H), 8.24 (s, 1H), 7.98 (s, 1H), 7.44 (d, 2H), 7.05 (d, 1H), 4.66 (d, 1H), 4.55-4.47 (m, 1H), 4.13(t, 1H), 3.59(t, 2H), 4.39-3.25(m, 3H), 2.89(t, 1H), 2.29-2.10(m, 4H), 2.09-2.00(m, 1H), 2.01-1.89(m, 1H)

[0384]

[0385] Example 18: Preparation of N-(2-((5-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-cyanophenyl)amino)ethyl)acrylamide

[0386]

[0387] The title compound (15.0 mg, yield 32.2%) was obtained in the same manner as in Example 14, except that 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(azetidin-3-ylamino)benzonitrile was used instead of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((2-aminoethyl)amino)benzonitrile.

[0388] 1H NMR (500 MHz, MeOD): 8.84(s, 2H), 8.25(s, 1H), 7.96(s, 1H), 7.43 (d, 2H), 7.06(d, 1H), 6.97(d, 1H), 6.20(d, 1H), 5.68(d, 1H), 4.66(d, 1H), 4.56-4.49(m, 1H), 4.10(t, 1H), 3.61(t, 2H), 4.38-3.22(m, 3H), 2.88(t, 1H), 2.28-2.13(m, 4H), 2.12-2.03(m, 1H), 2.03-1.91(m, 1H)

[0389]

[0390] Example 19: Preparation of (R)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0391]

[0392] The title compound (30.0 mg, yield 67.6%) was obtained by the same method as in Example 9, except that tert-butyl (R)-3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl (4-aminocyclohexyl)carbamate.

[0393] 1 H NMR (500 MHz, MeOD): 8.76 (s, 2H), 8.19 (s, 1H), 7.93 (s, 1H), 7.59 (s, 1H), 7.38 (d, 1H), 7.12 (d, 1H), 4.67-4.58 (m, 1H), 4.41-4.38(m, 1H), 3.70-3.65(m, 1H), 3.61-3.15(m, 8H), 2.55-2.45(m, 1H), 2.42-2.18(m, 4H)

[0394]

[0395] Example 20: Preparation of (S)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0396]

[0397] The title compound (40.0 mg, yield 90.1%) was obtained by the same method as in Example 9, except that tert-butyl (S)-3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl (4-aminocyclohexyl)carbamate.

[0398] 1 H NMR (500 MHz, MeOD): 8.79 (s, 2H), 8.21 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 7.40 (d, 1H), 7.09 (d, 1H), 4.67-4.57 (m, 1H), 4.39(t, 1H), 3.73-3.68(m, 1H), 3.65-3.20(m, 7H), 2.58-2.48(m, 1H), 2.38-2.18(m, 5H)

[0399]

[0400] Example 21: Preparation of 2-(azetidin-3-ylamino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0401] (Step 21-1) Preparation of 2-chloro-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine

[0402]

[0403] 2-Chloro-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine hydrochloride (100.0 mg, 1.0 eq) was dissolved in anhydrous dimethylformamide (20.0 mL), then iodoethane (53.5 uL, 2.0 eq) and triethylamine (117.4 uL, 2.5 eq) were added, and the mixture was stirred at room temperature for 12 hours. After confirming that the starting material had disappeared on TLC, water was added, and extraction was performed with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the title compound (82.1 mg, yield 84.6%) was obtained.

[0404]

[0405] (Step 21-2) Preparation of 2-(azetidin-3-ylamino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0406]

[0407] The same method as steps 8-3 to 8-5 of Example 8 was followed, except that 2-chloro-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine was used instead of 2-chloro-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine and tert-butyl 3-aminoazetidine-1-carboxylate was used instead of 3-(tert-butoxycarbonylamino)pyrrolidine, to obtain the title compound (5.0 mg, yield 95.8%).

[0408] 1 H NMR (500 MHz, MeOD): 8.79(s, 2H), 8.28(s, 1H), 7.95(s, 1H), 7.55 (s, 1H), 7.41(d, 1H), 7.07(d, 1H), 4.65(t, 1H), 4.10-91(m, 3H), 3.76(d, 1H), 3.38-3.19(m, 14H)

[0409]

[0410] Example 22: Preparation of 4-((4-((3-aminophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0411]

[0412] The title compound (89.3 mg) was obtained by the same method as in Example 10, except that tert-butyl (3-((2-chloro-5-iodopyrimidin-4-yl)amino)phenyl)carbamate was used instead of tert-butyl (3-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexyl)carbamate.

[0413] 1 H NMR (500 MHz, MeOD): 8.11(s, 1H), 7.93(s, 1H), 7.80(s, 1H), 7.67 (s, 1H), 7.58(q, 4H), 7.50(s, 1H), 7.41(s, 1H), 4.59-4.49(m, 1H), 4.10(d, 2H), 3.68-3.57(m, 2H), 2.19-2.09(m, 4H)

[0414]

[0415] Example 23: Preparation of 4-((4-((4-aminophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0416]

[0417] The title compound (106.5 mg) was obtained by the same method as in Example 10, except that tert-butyl (4-((2-chloro-5-iodopyrimidin-4-yl)amino)phenyl)carbamate was used instead of tert-butyl (3-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexyl)carbamate.

[0418] 1 H NMR (500 MHz, MeOD): 8.09 (s, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.66-59 (m, 5H), 7.46 (d, 2H), 4.56-4.48 (m, 1H), 4.10(d, 2H), 3.65-3.55(m, 2H), 2.16-2.08(m, 4H)

[0419]

[0420] Example 24: Preparation of (R)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0421]

[0422] The title compound (60.0 mg, yield 61.6%) was obtained by the same method as in Example 12, except that iodoethane was used instead of acetyl chloride and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl 3-aminoazetidine-1-carboxylate.

[0423] 1 H NMR (500 MHz, MeOD): 8.81 (s, 2H), 8.24 (s, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 7.40 (d, 1H), 7.08 (d, 1H), 4.68-4.60 (m, 1H), 4.37(t, 1H), 3.74(d, 2H), 3.67(q, 1H), 3.56-3.39(m, 2H), 3.38-3.19(m, 3H), 2.58-2.46(m, 1H), 2.45-2.30(m, 3H), 2.25-2.18(m, 1H), 1.42(t, 3H)

[0424]

[0425] Example 25: Preparation of 4-((5-(1-((S)-pyrrolidin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(((R)-pyrrolidin-3-yl)amino)benzonitrile

[0426]

[0427] The same method as Example 9 was followed, except that tert-butyl (S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate was used instead of 1-(1-Boc-4-piperidyl)pyrazole-4-boronic acid pinacol ester, and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl (4-aminocyclohexyl)carbamate, to obtain the title compound (45.0 mg, yield 88.9%).

[0428] 1H NMR (500 MHz, MeOD): 8.80 (s, 2H), 8.23 ​​(s, 1H), 7.97 (s, 1H), 7.59 (s, 1H), 7.40 (d, 1H), 7.08 (d, 1H), 5.32-5.28 (m, 1H), 4.43-4.37(m, 1H), 3.80-3.61(m, 4H), 3.53-3.30(m, 4H), 2.65-2.48(m, 2H), 2.49-2.38(m, 1H), 2.27-2.18(m, 1H)

[0429]

[0430] Example 26: Preparation of 2-((3-aminocyclobutyl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0431]

[0432] The title compound (30.0 mg, yield 60.2%) was obtained by the same method as in Example 8-3, 8-4, and 8-5, except that 2-chloro-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine was used instead of 2-chloro-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine and tert-butyl (3-aminocyclobutyl)carboxylate was used instead of 3-(tert-butoxycarbonylamino)pyrrolidine.

[0433] 1 H NMR (500 MHz, MeOD): 8.80 (s, 2H), 8.25 (s, 1H), 7.94 (s, 1H), 7.45-7.29 (m, 2H), 7.02 (d, 1H), 4.69-4.60 (m, 1H), 4.35-4.28 (m, 1H), 4.01-3.88(m, 1H),3.75(d, 2H), 3.44-3.17(m, 3H), 2.78-2.68(m, 1H), 2.58-2.52(m, 1H), 2.45-2.31(m, 3H), 2.19-2.12(m, 1H), 1.42(t, 3H)

[0434]

[0435] Example 27: Preparation of (R)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((1-ethylpyrrolidin-3-yl)amino)benzonitrile

[0436]

[0437] (R)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile (28.0 mg, 1 eq) was dissolved in anhydrous N,N-dimethylformamide (10.0 mL), then triethylamine (36.1 μL, 2.5 eq) and iodoethane (16.5 μL, 2.0 eq) were added and reacted at room temperature for 12 h. The reaction was terminated when the starting material disappeared on TLC. The reactant was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (15.0 mg, yield 50.8%).

[0438] 1 H NMR (500 MHz, MeOD): 8.81 (s, 2H), 8.21 (s, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 7.38 (d, 1H), 7.06 (d, 1H), 5.30-5.27 (m, 1H), 4.45-4.36(m, 1H), 3.79-3.57(m, 4H), 3.56-2.95(m, 8H), 2.63-2.45(m, 2H), 2.45-2.38(m, 1H), 2.26-2.16(m, 1H), 1.45-1.39(m, 6H)

[0439]

[0440] Example 28: Preparation of (R)-2-((1-allylpyrrolidin-3-yl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0441]

[0442] The same method as Step 12-1 and Step 12-2 of Example 12 was followed, except that iodoethane was used instead of acetyl chloride and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl 3-aminoazetidine-1-carboxylate, and then the same method as Example 14 was followed, except that aryl bromide was used instead of acryloyl chloride, to obtain the title compound (10.0 mg, yield 33.1%).

[0443] 1 H NMR (500 MHz, MeOD): 8.82 (s, 2H), 8.23 ​​(s, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.42 (d, 1H), 7.10 (d, 1H), 6.99 (d, 1H), 6.35-6.18(d, 1H), 5.68(d, 1H), 5.30-5.28(m, 1H), 4.41-4.36(m, 1H), 3.81-3.61(m, 4H), 3.63-3.10(m, 6H), 2.66-2.50(m, 2H), 2.41-2.36(m, 1H), 2.26-2.19(m, 1H), 1.40(t, 3H)

[0444]

[0445] Example 29: Preparation of N-(4-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide

[0446] (Step 29-1) Preparation of tert-butyl (4-((2-chloro-5-iodopyrimidin-4-yl)amino)phenyl)carbamate

[0447]

[0448] 2,4-Dichloro-5-iodopyrimidine (321.3 mg, 1.0 eq) was added to a solution of tert-butyl (4-aminophenyl)carbamate (263.0 mg, 1.05 eq), 3.9 mL of acetonitrile, and triethylamine (211.9 μL, 1.2 eq), and stirred at room temperature for 18 hours. Purified water was added to the reaction mixture, extracted with ethyl acetate, and the separated organic layer was removed with sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: hexane = 2:8) to obtain 436 mg (yield 82.4%) of the title compound as a solid.

[0449]

[0450] (Step 29-2) Preparation of tert-butyl (4-((2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)carbamate

[0451]

[0452] Tert-Butyl (4-((2-chloro-5-iodopyrimidin-4-yl)amino)phenyl)carbamate (425.0 mg, 1.0 eq), (1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester (313.4 mg, 1.2 eq), tetrakis(triphenylphosphine)palladium (217.0 mg, 0.2 eq), cesium carbonate (1,835.2 mg, 6.0 eq), and 8.9 mL of 1,2-dimethoxyethane were placed in a flask, stirred, degassed, and filled with nitrogen gas. 3.0 mL of purified water was added, degassed for 10 minutes, and filled with nitrogen gas, and stirred at 100 °C for 18 hours. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the separated organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate:hexane = 1:9) to obtain the title compound (290.0 mg, yield 64.8%).

[0453]

[0454] (Step 29-3) Preparation of tert-butyl (4-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)carbamate

[0455]

[0456] Tert-Butyl (4-((2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)carbamate (71.6 mg, 1.0 eq), 4-aminobenzonitrile (18.6 mg, 1.1 eq), palladium acetate (3.4 mg, 0.1 eq), xantphos (8.7 mg, 0.1 eq), cesium carbonate (103.6 mg, 2.1 eq), and 1.1 mL of 1,4-dioxane were placed in a microwave reactor, stirred for 10 minutes, degassed, and filled with nitrogen gas, and reacted at 120 °C for 45 minutes using a microwave reactor. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the separated organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate:hexane = 9:1) to obtain the title compound (62.3 mg, yield 74.3%).

[0457]

[0458] (Step 29-4) 4-((4-((4-aminophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile hydrochloride

[0459]

[0460] To tert-butyl (4-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)carbamate (60.0 mg, 1.0 eq) was added 0.5 mL of 1,4-dioxane, 1.3 mL of a 4.0 N hydrochloric acid solution in 1,4-dioxane, 1.0 mL of methanol was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then the addition of methanol and concentration under reduced pressure were repeated twice to obtain the title compound (80.5 mg).

[0461]

[0462] (Step 29-5) Preparation of N-(4-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide

[0463]

[0464]

[0465] 4-((4-((4-aminocyclohexyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile hydrochloride (67.0 mg, 1.0 eq) was added 2.0 mL of 1-methyl-2-pyrrolidone and 56.6 μL of triethylamine, cooled to 0 °C, and then acryloyl chloride (13.0 μL, 1.2 eq) was added. After stirring at room temperature for 18 hours, purified water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with sodium sulfate to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: methanol = 9:1) to obtain the title compound (5.1 mg, yield 10.1%).

[0466] 1 H NMR (500 MHz, DMSO): 10.14 (s, 1H), 9.74 (s, 1H), 8.22 (s, 1H), 8.12 (d, 1H), 7.84 (d, 1H), 7.73 (s, 1H), 7.64 (d, 1H), 7.56-7.44(m, 2H), 6.45(q, 1H), 6.27(d, 1H), 5.75(d, 1H), 4.44(t, 1H), 3.97(d, 2H), 3.49(t, 2H), 2.05-1.95(m, 4H)

[0467]

[0468] Example 30: Preparation of N-(4-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide

[0469]

[0470] The title compound (21.2 mg, yield 41.4%) was obtained by the same method as in Example 29, except that tert-butyl (4-aminocyclohexyl) carbamate was used instead of tert-butyl (4-aminophenyl) carbamate.

[0471] 1 H NMR (500 MHz, DMSO): 9.70 (s, 1H), 8.05 (s, 1H), 8.99-7.88 (m, 3H), 7.69 (d, 2H), 6.27 (q, 1H), 6.08 (d, 1H), 5.71 (d, 1H), 5.54 (d, 1H), 4.48-4.40(m, 1H), 4.09-3.99(m, 1H), 3.97(d, 2H), 3.91-3.82(m, 1H), 3.44(t, 2H), 2.67(s, 1H), 2.05-1.57(m, 9H)

[0472]

[0473] Example 31: Preparation of (R)-4-((5-(1-(1-(cyclopropylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0474]

[0475] The title compound (25.0 mg, yield 50.3%) was obtained in the same manner as in Example 12, except that (bromomethyl)cyclopropane was used instead of acetyl chloride and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl 3-aminoazetidine-1-carboxylate.

[0476] 1H NMR (500 MHz, MeOD): 8.80 (s, 2H), 8.24 (s, 1H), 7.94 (s, 1H), 7.62 (s, 1H), 7.39 (d, 1H), 7.06 (d, 1H), 4.70-4.64 (m, 1H), 4.42-4.36(m, 1H), 3.85(d, 2H), 3.72-3.30(m, 5H), 3.12(d, 1H), 2.67-2.35(m, 4H), 2.27-2.18(m, 1H), 0.85-0.74(m, 2H), 0.45(d, 2H)

[0477]

[0478] Example 32: Preparation of (R)-4-((5-(1-(1-benzylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0479]

[0480] The title compound (25.0 mg, yield 49.7%) was obtained in the same manner as in Example 12, except that benzyl bromide was used instead of acetyl chloride and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl 3-aminoazetidine-1-carboxylate.

[0481] 1 H NMR (500 MHz, MeOD): 8.82 (s, 2H), 8.21 (s, 1H), 7.93 (s, 1H), 7.61-48 (m, 7H), 7.40 (d, 1H), 7.08 (d, 1H), 4.67-4.60 (m, 1H), 4.40(s, 1H), 3.70-3.67(m, 3H), 3.68-3.30(m, 5H), 2.71-2.68(m, 3H), 3.58-2.35(m, 5H), 2.55-2.45(m, 1H), 2.43-2.33(m, 4H), 2.28-2.17(m, 1H)

[0482]

[0483] Example 33: Preparation of 2-((azetidin-3-ylmethyl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0484] (Step 33-1) Preparation of tert-butyl 3-(((2-cyano-5-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)azetidine-1-carboxylate

[0485]

[0486] 2-Chloro-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile (100.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (2.5 mL), and then tris(dibenzylideneacetone)palladium(0) (44.8 mg, 0.2 eq), xantphos (56.8 mg, 0.4 eq), cesium carbonate (159.8 mg, 2.0 eq), and tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (66.9 μL, 1.5 eq) were placed in a microwave reactor, and the mixture was reacted at 150 °C for 45 minutes using a microwave reactor. The reaction was terminated after confirming the disappearance of the starting material on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = ethyl acetate: methanol = 4:1) to obtain the title compound (95.0 mg, yield 69.5%).

[0487]

[0488] (Step 33-2) Preparation of 2-((azetidin-3-ylmethyl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0489]

[0490] tert-Butyl 3-(((2-cyano-5-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-pyrimidin-2-yl)amino)phenyl)amino)methyl)azetidine-1-carboxylate (90.0 mg, 1.0 eq) was dissolved in a 1.25 N methanol solution of hydrochloric acid (8.0 mL), stirred at room temperature for 16 h, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, crystallized at room temperature for 1 h, and the resulting precipitate was filtered and dried to obtain the title compound (60.0 mg, yield 75.3%).

[0491] 1 H NMR (500 MHz, MeOD): 8.87(s, 2H), 8.27(s, 1H), 7.97(d, 1H), 7.97(s, 1H), 7.35(d, 1H), 4.68-4.57(m, 1H), 4.39(t, 1H), 3.72(q, 1H), 3.65-3.25(m, 7H), 2.57-2.47(m, 1H), 2.38-2.25(m, 4H), 2.27-2.18(m, 1H)

[0492]

[0493] Example 34: Preparation of (R)-5-fluoro-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0494] (Step 34-1) Preparation of tert-butyl 4-(4-(2-((5-chloro-4-cyano-2-fluorophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0495]

[0496] tert-Butyl 4-(4-(2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (150.0 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous N,N-dimethylformamide (4.0 mL, 3:1), and then palladium acetate (9.2 mg, 0.1 eq), xantphos (23.8 mg, 0.1 eq), cesium carbonate (282.1 mg, 2.1 eq), and 4-amino-2-chloro-5-fluorobenzonitrile (63.6 mg, 1.2 eq) were placed in a microwave reactor, and the mixture was reacted at 120 °C for 30 minutes using a microwave reactor. The reaction was terminated when the starting material disappeared on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:1) to obtain the title compound (80.0 mg, yield 42.6%).

[0497]

[0498] (Step 34-2) Preparation of tert-butyl (R)-4-(4-(2-((5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-4-cyano-2-fluorophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0499]

[0500] tert-Butyl 4-(4-(2-((5-chloro-4-cyano-2-fluorophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (80.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (2.0 mL), then tris(dibenzylideneacetone)palladium(0) (32.1 mg, 0.2 eq), xantphos (40.6 mg, 0.4 eq), cesium carbonate (114.3 mg, 2.0 eq), and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (33.8 mg, 1.5 eq) were placed in a microwave reactor, and the mixture was reacted at 150°C for 45 minutes using a microwave reactor. The reaction was terminated after confirming the disappearance of the starting material on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (100% ethyl acetate) to obtain the title compound (20.0 mg, yield 18.8%).

[0501]

[0502] (Step 34-3) Preparation of (R)-5-fluoro-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0503]

[0504] tert-Butyl (R)-4-(4-(2-((5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-4-cyano-2-fluorophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (20.0 mg, 1.0 eq) was dissolved in a 1.25 N hydrochloric acid methanol solution (2.0 mL), stirred at room temperature for 16 h, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, crystallized at room temperature for 1 h, and the resulting precipitate was filtered and dried to obtain the title compound (75.0 mg, yield 91.2%).

[0505] 1 H NMR (500 MHz, MeOD): 8.87(s, 2H), 8.27(s, 1H), 7.97(d, 1H), 7.97(s, 1H), 7.35(d, 1H), 4.68-4.57(m, 1H), 4.39(t, 1H), 3.72(q, 1H), 3.65-3.25(m, 7H), 2.57-2.47(m, 1H), 2.38-2.25(m, 4H), 2.27-2.18(m, 1H)

[0506]

[0507] Example 35: Preparation of (R)-4-((5-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0508]

[0509] The title compound (40.0 mg, yield 62.7%) was obtained in the same manner as in Example 36, except that 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0510] 1 H NMR (500 MHz, MeOD): 8.85 (s, 2H), 8.36 (s, 2H), 7.56 (s, 1H), 7.40 (d, 1H), 7.11 (d, 1H), 4.43-4.38 (m, 1H), 3.69 (q, 1H), 5.59-3.39(m, 3H), 2.58-2.48(m, 1H), 2.28-2.17(m, 1H)

[0511]

[0512] Example 36: Preparation of (R)-2-(pyrrolidin-3-ylamino)-4-((5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0513] (Step 36-1) Preparation of 2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidine

[0514]

[0515] 5-Bromo-2-chloropyrimidine (500.0 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous N,N-dimethylformamide (16.0 mL, volume ratio = 1:1), potassium carbonate (714.6 mg, 2.0 eq), tetrakis(triphenylphosphine)palladium(0) (298.7 mg, 0.1 eq), and 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 1.4 eq) in a microwave-safe reaction vessel, and the mixture was reacted at 150 °C for 15 minutes using a microwave reactor. The reaction was terminated when the starting material disappeared on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:2) to obtain the title compound (380.0 mg, yield 55.5%).

[0516]

[0517] (Step 36-2) Preparation of 2-chloro-4-((5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0518]

[0519] 2-Chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidine (300.0 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous N,N-dimethylformamide (10.0 mL, 3:1), and then palladium acetate (25.4 mg, 0.1 eq), xantphos (65.6 mg, 0.1 eq), cesium carbonate (775.4 mg, 2.1 eq), and 4-amino-2-chlorobenzonitrile (207.5 mg, 1.2 eq) were placed in a microwave reactor, and the reaction was performed at 120 °C for 30 minutes using a microwave reactor. The reaction was terminated when the starting material disappeared on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:2) to obtain the title compound (250.0 mg, yield 57.9%).

[0520]

[0521] (Step 36-3) Preparation of tert-butyl (R)-3-((2-cyano-5-((5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)amino)pyrrolidine-1-carboxylate

[0522]

[0523] 2-Chloro-4-((5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile (80.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (2.0 mL), then tris(dibenzylideneacetone)palladium(0) (38.5 mg, 0.2 eq), xantphos (48.6 mg, 0.4 eq), cesium carbonate (136.9 mg, 2.0 eq), and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (53.4 μL, 1.5 eq) were placed in a microwave reactor, and the mixture was reacted at 150 °C for 45 minutes using a microwave reactor. The reaction was terminated by confirming the disappearance of the starting material on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:2) to obtain the title compound (100.0 mg, yield 89.7%).

[0524]

[0525] (Step 36-4) Preparation of (R)-2-(pyrrolidin-3-ylamino)-4-((5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0526]

[0527] tert-Butyl (R)-3-((2-cyano-5-((5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)amino)pyrrolidine-1-carboxylate (98.7 mg, 1.0 eq) was dissolved in a 1.25 N methanol solution of hydrochloric acid (7.0 mL), stirred at room temperature for 16 h, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, crystallized at room temperature for 1 h, and the resulting precipitate was filtered and dried to obtain the title compound (40.0 mg, yield 46.1%).

[0528] 1 H NMR (500 MHz, MeOD): 8.81 (s, 2H), 8.23 ​​(s, 1H), 7.95 (s, 1H), 7.54 (s, 1H), 7.42 (d, 1H), 7.08 (d, 1H), 4.55-4.45 (m, 1H), 4.41(t, 1H), 4.09(d, 1H), 3.69(m, 1H), 3.65-3.35(m, 5H), 2.56-2.40(m, 1H), 2.28-2.09(m, 5H)

[0529]

[0530] Example 37: Preparation of 4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0531] (Step 37-1) Preparation of tert-butyl 4-(4-(2-((4-cyanophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0532]

[0533] tert-Butyl 4-(4-(2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (100.0 mg, 1.0 eq) was dissolved in anhydrous toluene (2.0 mL), then tris(dibenzylideneacetone)palladium(0) (5.0 mg, 0.02 eq), xantphos (3.9 mg, 0.03 eq), sodium tert-butoxide (52.8 mg, 2.0 eq), and 4-aminobenzonitrile (64.9 mg, 1.5 eq) were added, and the mixture was stirred at 90 °C for 16 h while injecting nitrogen using a balloon. The reaction was terminated when the disappearance of the starting material was confirmed on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:2) to obtain the title compound (80.0 mg, yield 65.4%).

[0534]

[0535] (Step 37-2) Preparation of 4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0536]

[0537] tert-Butyl 4-(4-(2-((4-cyanophenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (75.0 mg, 1.0 eq) was dissolved in a 1.25 N methanol solution of hydrochloric acid (5.0 mL), stirred at room temperature for 3 hours and 30 minutes, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, crystallized at room temperature for 1 hour, and the resulting precipitate was filtered and dried to obtain the title compound (55.0 mg, yield 85.5%). 1 H NMR (500 MHz, MeOD): 8.91 (s, 2H), 8.30 (s, 1H), 8.00 (s, 1H), 7.89 (d, 1H), 7.73 (d, 1H), 4.70-4.65 (m, 1H), 3.59 (d, 2H), 3.40-3.20(m, 2H), 2.40-2.28(m, 4H)

[0538]

[0539] Example 38: Preparation of 4-((4-(piperidin-3-ylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0540] (Step 38-1) Preparation of tert-butyl 3-((2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylate

[0541]

[0542] tert-Butyl 3-((2-chloro-5-iodopyrimidin-4-yl)amino)piperidine-1-carboxylate (658.0 mg, 1.0 eq), 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500.7 mg, 1.2 eq), tetrakis(triphenylphosphine)palladium (346.7 mg, 0.2 eq), cesium carbonate (2,932.4 mg, 6.0 eq), and 13.8 mL of 1,2-dimethoxyethane were placed in a flask, stirred, degassed, and filled with nitrogen gas. Then, 4.6 mL of purified water was added, degassed for 10 minutes and nitrogen gas was filled, and stirred at 100°C for 18 hours. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the separated organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: hexane = 1:1) to obtain the title compound (488.2 mg, yield 70.3%).

[0543]

[0544] (Step 38-2) Preparation of tert-butyl 3-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylate

[0545]

[0546] tert-Butyl-3-((2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylate (488.0 mg, 1.0 eq), 4-aminobenzonitrile (157.3 mg, 1.1 eq), palladium acetate (23.7 mg, 0.1 eq), xantphos (61.0 mg, 0.1 eq), cesium carbonate (721.2 mg, 2.1 eq), and 7.3 mL of 1,4-dioxane were placed in a microwave reactor, stirred for 10 minutes, degassed, and filled with nitrogen gas, and reacted at 120°C for 45 minutes using a microwave reactor. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the separated organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: hexane = 1:1) to obtain the title compound (470.5 mg, yield 78.5%).

[0547]

[0548] (Step 38-3) Preparation of 4-((4-(piperidin-3-ylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0549]

[0550]

[0551] 2.0 mL of 1,4-dioxane was added to tert-butyl 3-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylate (284.3 mg, 1.0 eq), followed by 4.0 N hydrochloric acid solution in 1,4-dioxane (6.3 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then the addition of methanol and concentration under reduced pressure were repeated five times to obtain the title compound (281.0 mg).

[0552] 1H NMR (500 MHz, MeOD): 8.01(s, 1H), 7.87(d, 2H), 7.81-7.70(m, 3H), 7.60(s, 1H), 4.56-4.48(m, 1H), 4.09(d, 2H), 3.63-3.09(m, 6H), 3.11(t, 1H), 2.91(t, 1H), 2.19-2.00(m, 6H), 1.89-1.78(m, 1H), 1.71-1.62(m, 1H)

[0553]

[0554] Example 39: Preparation of 4-((4-((1-acryloylpiperidin-3-yl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0555]

[0556] The title compound (29.5 mg, yield 59.2%) was obtained in the same manner as in Example 3, except that 4-((4-((3-aminocyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile was used instead of 4-((4-(piperidin-3-ylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile.

[0557] 1 H NMR (500 MHz, MeOD): 7.98-7.10 (m, 4H), 7.69-7.63 (m, 3H), 7.82 (q, 1H), 6.52 (q, 1H), 6.26 (d, 1H), 6.19 (d, 1H), 5.80 (d, 1H), 5.49(d, 1H), 4.50-4.41(m, 1H), 4.35(d, 1H), 4.28-4.21(m, 1H), 4.18(d, 2H), 3.96-3.78(m, 2H), 3.59(t, 2H), 3.48-3.40(m, 1H), 2.13-2.02(m, 4H), 2.85-2.71(m, 2H), 2.70-2.59(m, 1H)

[0558]

[0559] Example 40: Preparation of 2-chloro-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0560]

[0561] The title compound (25.0 mg, yield 72.0%) was obtained by the same method as in Example 37, except that 4-amino-2-chlorobenzonitrile was used instead of 4-aminobenzonitrile.

[0562] 1 H NMR (500 MHz, MeOD): 8.78 (s, 2H), 8.30 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.73 (d, 1H), 7.65 (d, 1H), 4.67-4.56 (m, 1H), 3.59(d, 2H), 3.29-3.19(m, 3H), 2.41-2.25(m, 5H)

[0563]

[0564] Example 41: Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((1-acryloylpyrrolidin-3-yl)amino)benzonitrile

[0565] (Step 41-1) Preparation of 1-(4-(4-(2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one

[0566]

[0567] 2-Chloro-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine hydrochloride (500.0 mg, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (13.0 mL), triethylamine (580.3 μL, 2.5 eq) and acetyl chloride (237.7 μL, 2.0 eq) were added, and the mixture was reacted at room temperature for 3 hours. The reaction was terminated when the starting material disappeared on TLC. The reactant was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (400.0 mg, yield 78.5%).

[0568]

[0569] (Step 41-2) Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-chlorobenzonitrile

[0570]

[0571] 4-(4-(4-(2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one (300.0 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous N,N-dimethylformamide (8.0 mL, 3:1), and then palladium acetate (22.0 mg, 0.1 eq), xantphos (56.8 mg, 0.1 eq), cesium carbonate (671.3 mg, 2.1 eq), and 4-amino-2-chlorobenzonitrile (179.7 mg, 1.2 eq) were placed in a microwave reactor, and the reaction was performed at 120 °C for 30 minutes using a microwave reactor. The reaction was terminated when the starting material disappeared on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = methanol:ethyl acetate = 1:4) to obtain the title compound (180.0 mg, yield 43.5%).

[0572]

[0573] (Step 41-3) Preparation of tert-butyl 3-((5-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-cyanophenyl)amino)pyrrolidine-1-carboxylate

[0574]

[0575] 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-chlorobenzonitrile (100.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (2.5 mL), and then tris(dibenzylideneacetone)palladium(0) (43.5 mg, 0.2 eq), xantphos (55.0 mg, 0.4 eq), cesium carbonate (154.7 mg, 2.0 eq), and 3-(tert-butoxycarbonylamino)pyrrolidine (64.4 μL, 1.5 eq) were placed in a microwave reactor, and the mixture was reacted at 150 °C for 45 minutes using a microwave reactor. The reaction was terminated after confirming the disappearance of the starting material on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = methanol:ethyl acetate = 1:4) to obtain the title compound (100.0 mg, yield 73.7%).

[0576]

[0577] (Step 41-4) Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0578]

[0579] tert-Butyl 3-((5-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-cyanophenyl)amino)pyrrolidine-1-carboxylate (100.0 mg, 1.0 eq) was dissolved in a 1.25 N hydrochloric acid methanol solution (10.0 mL), stirred at room temperature for 5 hours, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, crystallized at room temperature for 1 hour, and the resulting precipitate was filtered and dried to obtain the title compound (80.0 mg, yield 90.0%).

[0580]

[0581] (Step 41-5) Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((1-acryloylpyrrolidin-3-yl)amino)benzonitrile

[0582]

[0583] 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile (40.0 mg, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (1.0 mL), triethylamine (27.4 μL, 2.5 eq) and acryloyl chloride (10.0 μL, 2.0 eq) were added, and the mixture was reacted at room temperature for 3 hours. The reaction was terminated when the starting material disappeared on TLC. The reactant was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (25.0 mg, yield 60.4%).

[0584] 1H NMR (500 MHz, MeOD): 8.59 (d, 2H), 7.75 (s, 1H), 7.71-7.56 (m, 3H), 7.36 (s, 1H), 6.78-6.73 (m, 1H), 6.51-6.39 (m, 2H), 5.79-5.68(m, 1H), 4.78(d, 1H), 4.59(d, 1H), 4.41(t, 1H), 4.30-3.95(m, 3H), 3.87-3.55(m, 2H), 3.38-3.20(m, 1H), 2.78(t, 1H), 2.49-1.90(m, 6H)

[0585]

[0586] Example 42: Preparation of 2-((3-aminophenyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0587]

[0588] The title compound (60.0 mg, yield 80.1%) was obtained by the same method as in Example 9, except that tert-butyl (3-aminophenyl) carbamate was used instead of tert-butyl (4-aminocyclohexyl) carbamate.

[0589] 1 H NMR (500 MHz, MeOD): 8.78(s, 1H), 8.57(d, 2H), 8.13(s, 1H), 7.80(s, 1H), 7.55(s, 1H), 7.35(d, 2H), 7.10(d, 3H), 6.40(d, 2H), 3.70-3.65(m, 1H), 3.20-3.11(m, 4H), 2.40-2.35(m, 4H), 1.56-1.20(m, 3H),

[0590]

[0591] Example 43: Preparation of 6-((4-((3-aminocyclohexyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)nicotinonitrile

[0592]

[0593] The title compound (72.0 mg) was obtained by the same method as in Example 10, except that 2-amino-5-cyanopyridine was used instead of 4-aminobenzonitrile.

[0594] 1 H NMR (500 MHz, MeOD): 8.78(s, 1H), 8.08(s, 1H), 8.01(s, 1H), 8.91-7.78(m, 2H), 7.48-7.19(m, 1H), 4.60-4.31(m, 3H), 4.08(d, 2H), 3.67-3.51(m, 3H), 2.41-1.50(m, 11H)

[0595]

[0596] Example 44: Preparation of 4-((5-(1-phenyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile

[0597]

[0598] The same method as Example 9 was followed, except that 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-(1-Boc-4-piperidyl)pyrazole-4-boronic acid pinacol ester and tert-butyl 3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl (4-aminocyclohexyl)carbamate, to obtain the title compound (50.0 mg, yield 56.9%).

[0599] 1 H NMR (500 MHz, MeOD): 8.85 (s, 2H), 8.71 (s, 1H), 8.12 (s, 1H), 7.82 (d, 2H), 7.61 (s, 1H), 7.53 (t, 2H), 7.43-7.35 (m, 2H), 7.09(d, 1H), 4.44-4.37(m, 1H), 3.68(q, 1H), 3.57-3.40(m, 3H), 2.57-2.45(m, 1H), 2.28-2.20(m, 1H), 1.48(s, 2H)

[0600]

[0601] Example 45: Preparation of 2-((3-aminocyclohexyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0602]

[0603] The title compound (30.0 mg, yield 52.5%) was obtained by the same method as in Example 9, except that tert-butyl (3-aminocyclohexyl) carbamate was used instead of tert-butyl (4-aminocyclohexyl) carbamate.

[0604] 1 H NMR (500 MHz, MeOD): 8.08 (s, 2H), 8.24 (s, 1H), 7.95 (s, 1H), 7.47 (d, 1H), 7.38 (d, 1H), 7.06 (t, 1H), 4.68-4.58 (m, 1H), 4.04(s, 1H), 3.60(s, 3H), 3.48-3.40(m, 1H), 3.32-3.21(m, 3H), 2.39-2.30(m, 7H), 2.05(s, 1H), 1.91-1.70(m, 6H), 1.16(q, 1H)

[0605]

[0606] Example 46: Preparation of 4-((4-((3-aminopropyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0607]

[0608] The title compound (126.0 mg) was obtained by the same method as in Example 10, except that tert-butyl (3-((2-chloro-5-iodopyrimidin-4-yl)amino)propyl)carbamate was used instead of tert-butyl (3-aminocyclohexyl)carbamate.

[0609] 1H NMR (500 MHz, MeOD): 8.01 (s, 1H), 8.86-8.51 (m, 6H), 5.95-4.90 (m, 1H), 4.51-4.47 (m, 2H), 4.18 (d, 2H), 3.68-3.54 (m, 6H), 3.05-2.99(m, 2H), 2.15-1.95(m, 6H)

[0610]

[0611] Example 47: Preparation of 4-((4-(piperazin-1-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0612]

[0613] The title compound (114.5 mg) was obtained by the same method as in Example 10, except that tert-butyl 4-(2-chloro-5-iodopyrimidin-4-yl)piperazine-1-carboxylate was used instead of tert-butyl(3-aminocyclohexyl)carbamate.

[0614] 1 H NMR (500 MHz, MeOD): 8.02 (s, 1H), 7.97 (s, 1H), 7.80-7.59 (m, 5H), 4.92-4.78 (m, 4H), 4.52-4.42 (m, 1H), 4.18 (d, 2H), 4.88-4.79(m, 4H), 3.61-3.52(m, 2H), 2.12-1.02(m, 4H)

[0615]

[0616] Example 48: Preparation of 4-((4-(4-acryloylpiperazin-1-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0617]

[0618] The title compound (62.0 mg, yield 60.9%) was obtained in the same manner as in Example 3, except that 4-((4-((3-aminocyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile was used instead of 4-((4-(piperazin-1-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile.

[0619] 1 H NMR (500 MHz, CDCl3): 8.07(s, 1H), 7.74(d, 2H), 7.65(s, 1H), 7.61-7.58(m, 2H), 7.19(s, 1H), 6.58(q, 1H), 6.34(d, 1H), 5.75(d, 1H), 4.42(t, 1H), 4.20-4.08(m, 2H), 3.71-3.50(m, 6H), 4.42-4.31(m, 4H), 2.20-2.15(m, 4H)

[0620]

[0621] Example 49: Preparation of N-(3-((2-cyano-5-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)amino)cyclobutyl)acrylamide

[0622]

[0623] 2-((3-Aminocyclobutyl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile (40.0 mg, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (10.0 mL), then triethylamine (30.7 μL, 2.5 eq) and acryloyl chloride (14.1 μL, 2.0 eq) were added and reacted at room temperature for 3 h. The reaction was terminated when the starting material disappeared on TLC. The reactant was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (20.0 mg, yield 42.9%).

[0624] 1 H NMR (500 MHz, CDCl3): 8.59(s, 1H), 8.01(s, 1H), 7.73(d, 2H), 7.50-7.30(m, 3H), 6.30(q, 1H), 6.12(d, 1H), 5.95-5.87(m, 1H), 5.69(d, 1H), 4.75-4.60(m, 4H), 4.48-4.28(m, 2H), 3.80-3.70(m, 1H),3.50(s, 3H) 3.20-3.11(m, 1H), 2.80(d, 4H) 2.60-2.49(m, 3H)

[0625]

[0626] Example 50: Preparation of (R)-2-((1-acetylpyrrolidin-3-yl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0627]

[0628] (R)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile (28.0 mg, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (10.0 mL), triethylamine (14.7 μL, 2.5 eq) and acetyl chloride (8.7 μL, 2.0 eq) were added, and the mixture was reacted at room temperature for 3 hours. The reaction was terminated when the starting material disappeared on TLC. The reactant was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (20.0 mg, yield 66.0%).

[0629] 1 H NMR (500 MHz, MeOD): 8.60 (d, 2H), 7.73 (s, 1H), 7.72-7.56 (m, 3H), 7.39 (s, 1H), 4.80 (d, 1H), 4.61 (d, 1H), 4.43 (t, 1H), 4.28-3.94(m, 3H), 3.88-3.56(m, 2H), 3.39-3.14(m, 3H), 2.80(t, 1H), 2.50-1.91(m, 6H), 1.60-1.47(t, 3H)

[0630]

[0631] Example 51: Preparation of 4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((4-hydroxyphenyl)amino)benzonitrile

[0632]

[0633] The title compound (10.0 mg, yield 17.0%) was obtained by the same method as in Example 12, except that iodoethane was used instead of acetyl chloride and 4-aminophenol was used instead of tert-butyl 3-aminoazetidine-1-carboxylate.

[0634] 1H NMR (500 MHz, MeOD): 8.75(s, 1H), 8.60(d, 2H), 8.10(s, 1H), 7.83(s, 1H), 7.58(s, 1H), 7.36(d, 2H), 7.12(d, 3H), 6.38(d, 2H), 4.31-4.23(m, 1H), 3.22(d, 2H), 2.61(q, 2H), 2.41-2.37(m, 2H), 2.28-2.12(m, 5H), 1.55-1.20(m, 8H), 0.99-0.85(m, 5H)

[0635]

[0636] Example 52: Preparation of 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((4-hydroxycyclohexyl)amino)benzonitrile

[0637]

[0638] The same method as Example 33 was followed, except that 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-chlorobenzonitrile was used instead of 2-chloro-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile and 4-aminocyclohexan-1-ol was used instead of tert-butyl 3-(aminomethyl)azetidine-1-carboxylate, to obtain the title compound (12.0 mg, yield 12.6%).

[0639] 1 H NMR (500 MHz, CDCl3): 8.63 (s, 2H), 8.26 (s, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.55 (s, 1H), 7.11 (d, 1H), 4.48-4.25 (m, 4H), 3.40-3.82(m, 1H), 3.69-3.20(m, 3H), 3.0-2.85(m, 2H), 2.32(s, 1H), 2.16(d, 2H), 2.05-1.90(m, 3H) 1.65-1.45(m, 6H)

[0640]

[0641] Example 53: Preparation of 2-((3-hydroxycyclopentyl)amino)-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0642] (Step 53-1) Preparation of 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidine

[0643]

[0644] 5-Bromo-2-chloropyrimidine (400.0 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous N,N-dimethylformamide (18.0 mL, 1:1), potassium carbonate (571.7 mg, 2.0 eq), tetrakis(triphenylphosphine)palladium(0) (239.0 mg, 0.1 eq), and 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (757.1 mg, 1.5 eq) in a microwave-safe reaction vessel, and the mixture was reacted at 150 °C for 15 minutes using a microwave reactor. The reaction was terminated when the starting material disappeared on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 2:1) to obtain the title compound (320.0 mg, yield 67.1%).

[0645]

[0646] (Step 53-2) Preparation of 2-chloro-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0647]

[0648] 2-Chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidine (100.0 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous N,N-dimethylformamide (4.0 mL, volume ratio = 3:1), and then palladium acetate (9.7 mg, 0.1 eq), xantphos (25.1 mg, 0.1 eq), cesium carbonate (296.7 mg, 2.1 eq), and 4-(l2-azanyl)-2-chlorobenzonitrile (79.4 mg, 1.5 eq) were placed in a microwave reactor, and the reaction was performed at 120 °C for 30 minutes using a microwave reactor. The reaction was terminated when the starting material disappeared on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:1) to obtain the title compound (55.0 mg, yield 36.6%).

[0649]

[0650] (Step 53-3) Preparation of 2-((3-hydroxycyclopentyl)amino)-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0651]

[0652] 2-Chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidine (50.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (2.0 mL), then tris(dibenzylideneacetone)palladium(0) (26.4 mg, 0.2 eq), xantphos (33.4 mg, 0.4 eq), cesium carbonate (94.0 mg, 2.0 eq), and 3-aminocyclopentan-1-ol (18.7 μL, 1.5 eq) were placed in a microwave-safe reaction vessel, and the mixture was reacted at 150 °C for 45 min using a microwave reactor. The reaction was terminated when the starting material disappeared on TLC. The reaction mixture was extracted with water and ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:1) to obtain the title compound (20.0 mg, yield 36.0%).

[0653] 1 H NMR (500 MHz, MeOD): 8.72(s, 2H), 8.23(s, 1H), 7.91(s, 1H), 7.59(s, 1H), 7.26(d, 1H), 6.95(d, 1H), 5.42(d, 1H), 4.43-4.33(m, 1H), 4.18-4.03(m, 1H), 3.74(t, 1H), 2.44-22.32(m, 1H), 2.28-1.98(m, 5H), 1.83-1.56(m, 7H)

[0654]

[0655] Example 54: Preparation of 2-((3-hydroxycyclopentyl)amino)-4-((5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile

[0656]

[0657] In the same manner as in Example 53, using 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the title compound (15.0 mg, yield 21.2%) as a yellow solid was obtained.

[0658] 1 H NMR (500 MHz, MeOD): 8.73 (s, 2H), 8.10 (s, 1H), 7.85 (s, 1H), 7.56 (s, 1H), 7.25 (d, 1H), 6.96 (d, 1H), 4.43-4.37 (m, 1H), 4.20-4.00(m, 2H), 3.98-3.89(m, 1H), 2.55-2.44(m, 1H), 2.43-2.28(m, 2H), 2.26-2.18(m, 1H), 2.16-2.08(m, 1H), 1.82-1.78(m, 1H), 1.75-1.43(m, 2H), 1.43-1.34(m, 1H), 0.98-0.88(m, 1H)

[0659]

[0660] Experimental example: Inhibitory activity against IRAK4

[0661] The inhibitory activity of the compound prepared in the above example against IRAK4 was measured as follows, and the results of the IRAK4 activity evaluation are shown in Table 1 below.

[0662] The inhibitory activity against IRAk4 was evaluated using the ADP-Glo™ Kinase Assay + IRAK4 Kinase Enzyme System kit from Promega. IC 50For evaluation, 10 μL of compounds at concentrations of 3,000, 1,000, 300, 100, 30, 10, and 0 nM were mixed with IRAK4 enzyme prepared to be 10 ng / uL in a white 96-well plate, and then 25 μM ATP and 0.1 μg / uL substrate were added, and the 96-well plate mixture was used for reaction at room temperature for 60 minutes. Next, 25 μL of ADP-Glo™ Reagent was treated to all wells, and the reaction was performed at room temperature for 40 minutes. Next, 50 μL of Kinase Detection Reagent was treated to all wells, and the reaction was performed at room temperature for 30 minutes. After the reaction, the luminescence of the plate was measured to calculate the results. The evaluation was performed in duplicate, and negative and positive controls were calculated depending on whether the enzyme was added without compound treatment, and the IC was calculated based on the value. 50 was calculated.

[0663]

[0664] IRAK4 IC 50 (nM)IRAK4 IC 50 (nM)IRAK4 IC 50(nM) Example 144.3 Example 192.5 Example 37580 Example 210.1 Example 2016.0 Example 38120 Example 3113.7 Example 219.3 Example 39331.2 Example 493.9 Example 2217.9 Example 40394.4 Example 54.5 Example 2310.7 Example 41401.4 Example 633 Example 242.0 Example 42317.2 Example 73.4 Example 2511.7 Example 43198.9 Example 811.4 Example 2617.5 Example 44119.2 Example 924.7 Embodiment 2712.9 Embodiment 45376.4 Embodiment 1030.7 Embodiment 2810.6 Embodiment 46582.9 Embodiment 1110.0 Embodiment 2983.6 Embodiment 47247.1 Embodiment 123.0 Embodiment 3058.3 Embodiment 48494.8 Embodiment 1318.1 Embodiment 317.3 Embodiment 49975.9 Embodiment 14277.0 Embodiment 3210.4 Embodiment 50396.5 Embodiment 15218.9 Embodiment 3350.5 Embodiment 51338.4 Embodiment 16373.4 Embodiment 342.8 Embodiment 52166.7 Embodiment 177.7 Embodiment 3511.1 Embodiment 53253.3 Embodiment 181000.0 Embodiment 362.3 Embodiment 54> 250

Claims

1. A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, X is CH or N, R1 is hydrogen or halogen, R2 is hydrogen, halogen or NHR5, The above R5 is C 1-4 Alkyl; C 3-10 Cycloalkyl; C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 Heterocycloalkyl; or C 6-10 Aryl; and, Here, R5 is unsubstituted or amino; acrylamide; hydroxy; C 1-4 Alkyl; C 1-4 Alkenyl; C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 Heterocycloalkyl; -CO(C 2-4 alkenyl); and -CO(C 1-4 is substituted with at least one selected from the group consisting of alkyl); R3 is hydrogen, piperazinyl, (acryloyl)piperazinyl, or NHR6, The above R6 is C 1-4 Alkyl; C 3-10 Cycloalkyl; C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 Heterocycloalkyl; or C 6-10 Aryl; and, Here R6 is amino, C 1-4 Aminoalkyl, acrylamide, C 1-4 Alkyl acrylamide, and -CO(C 1-4 substituted with at least one selected from the group consisting of alkenyl), R4 is hydrogen, phenyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl, Here, R4 is unsubstituted or C 1-3 Alkyl; -CO(C 1-4 C substituted with alkyl); phenyl 1-3 alkyl; and C 3-10 C substituted with cycloalkyl 1-3 is substituted with at least one selected from the group consisting of alkyl; 2. In paragraph 1, The above chemical formula 1 is represented by the following chemical formula 1-1, A compound, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1-1] In the above chemical formula 1-1, Descriptions of X and R1 to R4 are as defined in paragraph 1.

3. In paragraph 1, X is CH, A compound, or a pharmaceutically acceptable salt thereof.

4. In paragraph 1, R1 is hydrogen or fluoro, A compound, or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, R2 is hydrogen, chloro, or NHR5, A compound, or a pharmaceutically acceptable salt thereof.

6. In paragraph 1, R5 is methyl or ethyl, Here, R5 is amino; acrylamide; or C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S. 3-10 substituted with heterocycloalkyl; A compound, or a pharmaceutically acceptable salt thereof.

7. In paragraph 1, R5 is cyclobutyl, cyclopentyl, or cyclohexyl, Here, R5 is unsubstituted or substituted with amino, acrylamide, or hydroxy, A compound, or a pharmaceutically acceptable salt thereof.

8. In paragraph 1, R5 is azetidinyl, pyrrolidinyl, or piperidinyl, Here, R5 is unsubstituted, or C 1-4 Alkyl, C 1-4 Alkenyl, -CO(C 2-4 alkenyl), or -CO(C 1-4 substituted with alkyl), A compound, or a pharmaceutically acceptable salt thereof.

9. In paragraph 1, R5 is hydroxyphenyl or aminophenyl, A compound, or a pharmaceutically acceptable salt thereof.

10. In paragraph 1, R6 is cyclopentyl or cyclohexyl, Here R6 is amino, C 1-4 Aminoalkyl, acrylamide, or C 1-4 Substituted with alkyl acrylamide, A compound, or a pharmaceutically acceptable salt thereof.

11. In paragraph 1, R6 is aminopropyl, aminophenyl, phenyl substituted with acrylamide, unsubstituted piperidinyl, or (acryloyl)piperidinyl, A compound, or a pharmaceutically acceptable salt thereof.

12. In paragraph 1, R4 is hydrogen, phenyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, A compound, or a pharmaceutically acceptable salt thereof.

13. In paragraph 1, R4 is piperidinyl, Here, R4 is unsubstituted or substituted with methyl, ethyl, (cyclopropyl)methyl, benzyl, or -COCH3. A compound, or a pharmaceutically acceptable salt thereof.

14. In paragraph 1, The compound represented by the above chemical formula 1 is 1) 4-((4-((3-aminocyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 2) 4-((4-((3-(aminomethyl)cyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 3) N-(3-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide, 4) N-((3-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclopentyl)methyl)acrylamide, 5) 4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile, 6) 2-(piperidin-3-ylamino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 7) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile, 8) 4-((5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile, 9) 2-((4-aminocyclohexyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 10) 4-((4-((3-aminocyclohexyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 11) 2-(azetidin-3-ylamino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 12) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(azetidin-3-ylamino)benzonitrile, 13) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((4-aminocyclohexyl)amino)benzonitrile, 14) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((1-acryloylazetidin-3-yl)amino)benzonitrile, 15) 2-((4-aminophenyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 16) 2-(cyclopentylamino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 17) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((2-aminoethyl)amino)benzonitrile, 18) N-(2-((5-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-cyanophenyl)amino)ethyl)acrylamide, 19) (R)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile, 20) (S)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile, 21) 2-(azetidin-3-ylamino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 22) 4-((4-((3-aminophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 23) 4-((4-((4-aminophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 24) (R)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile, 25) 4-((5-(1-((S)-pyrrolidin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(((R)-pyrrolidin-3-yl)amino)benzonitrile, 26) 2-((3-aminocyclobutyl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 27) (R)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((1-ethylpyrrolidin-3-yl)amino)benzonitrile, 28) (R)-2-((1-allylpyrrolidin-3-yl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 29) N-(4-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, 30) N-(4-((2-((4-cyanophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide, 31) (R)-4-((5-(1-(1-(cyclopropylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile, 32) (R)-4-((5-(1-(1-Benzylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile, 33) 2-((azetidin-3-ylmethyl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 34) (R)-5-fluoro-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile, 35) (R)-4-((5-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile, 36) (R)-2-(pyrrolidin-3-ylamino)-4-((5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 37) 4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 38) 4-((4-(piperidin-3-ylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 39) 4-((4-((1-acryloylpiperidin-3-yl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 40) 2-chloro-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 41) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((1-acryloylpyrrolidin-3-yl)amino)benzonitrile, 42) 2-((3-aminophenyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 43) 6-((4-((3-aminocyclohexyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)nicotinonitrile, 44) 4-((5-(1-phenyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-(pyrrolidin-3-ylamino)benzonitrile, 45) 2-((3-aminocyclohexyl)amino)-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 46) 4-((4-((3-aminopropyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 47) 4-((4-(piperazin-1-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 48) 4-((4-(4-acryloylpiperazin-1-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 49) N-(3-((2-cyano-5-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenyl)amino)cyclobutyl)acrylamide, 50) (R)-2-((1-acetylpyrrolidin-3-yl)amino)-4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, 51) 4-((5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((4-hydroxyphenyl)amino)benzonitrile, 52) 4-((5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-((4-hydroxycyclohexyl)amino)benzonitrile, 53) 2-((3-hydroxycyclopentyl)amino)-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile, and 54) 2-((3-hydroxycyclopentyl)amino)-4-((5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzonitrile Any one selected from the group consisting of, A compound, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition for preventing or treating cancer or autoimmune disease, comprising a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

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