Novel compound, and pharmaceutical composition for preventing or treating 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 preventing or treating cancer or autoimmune diseases. [Chemical formula 1] In chemical formula 1, X1, Y1 to Y4, and R1 to R3 are as defined in the specification.

Description

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

[0001] The present invention relates to a novel compound having a structure useful as an IRAK4 (interleukin-1 receptor-associated kinase 4) inhibitor, a pharmaceutical composition comprising the same, a method for producing the same, and the production of a drug for treating and / or preventing autoimmune diseases, inflammatory diseases, and cancer 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] X1 is CH or N,

[0019] Two of Y1 to Y4 are N, one is CH, and one is CH, C-NH-R4, or C-(morpholino),

[0020] The above R4 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; C 6-10 Aryl; or C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 Heteroaryl; and,

[0021] Here, R4 is unsubstituted or is amino, acrylamide, hydroxy, C 1-4 Hydroxyalkyl, C 1-4 Substituted with at least one selected from the group consisting of aminoalkyl and halogen,

[0022] R1 is hydrogen, cyano, or -CONH2,

[0023] R2 is hydrogen, or -NH-R5,

[0024] The above R5 is C substituted with at least one selected from the group consisting of amino and hydroxy. 3-10 Cycloalkyl; or C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 Heterocycloalkyl; and,

[0025] R3 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 containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 Heteroaryl; and,

[0026] Here, R3 is unsubstituted or C 1-4 Alkyl, morpholino, N(C 1-4 Alkyl)2, C 1-4 Alkoxy, pyrrolidinyl, pyridinyl, -CO(C 2-4 alkenyl), and -CO(C 1-4 is substituted with at least one selected from the group consisting of alkyl.

[0027]

[0028] Preferably, the above chemical formula 1 can be represented by the following chemical formula 1-1:

[0029] [Chemical Formula 1-1]

[0030]

[0031] In the above chemical formula 1-1,

[0032] Descriptions of X1, Y1 to Y4 and R1 to R3 are as defined in the above chemical formula 1.

[0033]

[0034] Preferably, X1 can be CH.

[0035]

[0036] Preferably, Y1 and Y4 are N, Y2 is CH, and Y3 is CH, C-NH-R4, or C-(morpholino);

[0037] Y2 and Y3 are N, Y1 is CH, and Y4 can be CH, C-NH-R4, or C-(morpholino).

[0038]

[0039] Preferably, R4 is C 1-4 Alkyl, wherein R4 may be substituted with one or more of amino and acrylamide.

[0040] More preferably, R4 is ethyl or propyl, wherein R4 may be substituted with -NH2 or -NHCO-CH=CH2.

[0041] Most preferably, R4 can be 2-aminoethyl, 3-aminopropyl, or ethylacrylamide.

[0042]

[0043] Preferably, R4 is C 5-10 Cycloalkyl, wherein R4 is unsubstituted or is amino, hydroxy, and C 1-4 It may be substituted with one or more selected from the group consisting of hydroxyalkyl.

[0044] More preferably, R4 is cyclopentyl or cyclohexyl, wherein R4 is unsubstituted or is amino, hydroxy, and C 1-4 It may be substituted with one or more selected from the group consisting of hydroxyalkyl.

[0045] More preferably, R4 can be cyclopentyl, cyclopentyl substituted with two hydroxy and one hydroxymethyl, cyclohexyl, or cyclohexyl substituted with one amino.

[0046] Most preferably, R4 can be cyclopentyl, 2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl, cyclohexyl, 3-aminocyclohexyl, or 4-aminocyclohexyl.

[0047]

[0048] Preferably, R4 is C 6-10 Aryl, where R4 is unsubstituted or is amino, hydroxy, C 1-4 It may be substituted with one or more selected from the group consisting of aminoalkyl, and halogen.

[0049] More preferably, R4 is phenyl, wherein R4 is unsubstituted or is amino, hydroxy, C 1-4 It may be substituted with one or more selected from the group consisting of aminoalkyl, and halogen.

[0050] More preferably, R4 is phenyl, wherein R4 may be unsubstituted or substituted with one or more selected from the group consisting of amino, hydroxy, aminomethyl, and fluoro.

[0051] More preferably, R4 can be phenyl, phenyl substituted with one amino, phenyl substituted with one amino and one fluoro, phenyl substituted with one aminomethyl, or phenyl substituted with two hydroxyl.

[0052] Most preferably, R4 can be phenyl, 3-aminophenyl, 4-aminophenyl, 3-amino-4-fluorophenyl, (4-aminomethyl)phenyl, or 3,4-dihydroxyphenyl.

[0053]

[0054] Preferably, R4 can be piperidinyl or indolyl.

[0055]

[0056] Preferably, R4 can be 2-aminoethyl, 3-aminopropyl, ethylacrylamide, cyclopentyl, 2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl, cyclohexyl, 3-aminocyclohexyl, 4-aminocyclohexyl, phenyl, 3-aminophenyl, 4-aminophenyl, 3-amino-4-fluorophenyl, (4-aminomethyl)phenyl, 3,4-dihydroxyphenyl, piperidinyl, or indolyl.

[0057]

[0058] Preferably, R5 is C substituted with at least one selected from the group consisting of amino and hydroxy. 5-10 Cycloalkyl; or C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-5 It may be heterocycloalkyl.

[0059] More preferably, R5 can be cyclohexyl substituted with one amino, cyclohexyl substituted with one hydroxy, piperidinyl, or pyrrolidinyl.

[0060] Most preferably, R5 can be 2-aminocyclohexyl, 4-hydroxycyclohexyl, piperidinyl, or pyrrolidinyl.

[0061]

[0062] Preferably, R3 is piperidinyl, wherein R3 is unsubstituted, or C 1-4 Alkyl, -CO(C 2-4 alkenyl), or -CO(C 1-4 It can be substituted with alkyl.

[0063] More preferably, R3 is piperidinyl, wherein R3 may be unsubstituted or substituted with ethyl, acryloyl, or acetyl.

[0064] Most preferably, R3 can be piperidinyl, 1-ethylpiperidin-4-yl, 1-acryloylpiperidin-4-yl, or 1-acetylpiperidin-4-yl.

[0065]

[0066] Preferably, R3 may be tetrahydrofuranyl or tetrahydropyranyl.

[0067]

[0068] Preferably, R3 is methyl substituted with pyridinyl; morpholino, N(C 1-4 Alkyl)2, C 1-4 It may be ethyl substituted with alkoxy, or pyrrolidinyl; cyclohexyl; or pyridinyl.

[0069] More preferably, R3 can be pyridin-3-ylmethyl, 2-morpholinoethyl, (dimethylamino)ethyl, 2-methoxyethyl, (pyrrolidin-1-yl)ethyl, cyclohexyl, or pyridinyl.

[0070]

[0071] Representative examples of compounds represented by the above chemical formula 1 are as follows:

[0072] 1) 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0073] 2) 1-(5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0074] 3) N-(piperidin-3-yl)-1-(2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-5-yl)-1H-indol-6-amine,

[0075] 4) 1-(4-((2-aminoethyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0076] 5) N-(piperidin-3-yl)-1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indol-6-amine,

[0077] 6) N-(2-((5-(1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-(5-cyano-1H-indol-1-yl)pyrimidin-4-yl)amino)ethyl)acrylamide,

[0078] 7) 1-(4-(piperidin-3-ylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0079] 8) 1-(4-((3-aminopropyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0080] 9) 1-(4-morpholino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0081] 10) 1-(4-(cyclopentylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0082] 11) 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-N-(pyrrolidin-3-yl)-1H-indol-6-amine,

[0083] 12) 1-(4-(cyclopentylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carboxamide,

[0084] 13) 1-(4-((4-aminocyclohexyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0085] 14) 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-N-(pyrrolidin-3-yl)-1H-indol-6-amine,

[0086] 15) N1-(1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indol-6-yl)cyclohexane-1,2-diamine,

[0087] 16) 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-6-(pyrrolidin-3-ylamino)-1H-indole-5-carbonitrile,

[0088] 17) 1-(4-(cyclopentylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0089] 18) 1-(4-(piperidin-3-ylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0090] 19) 1-(4-(phenylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0091] 20) 1-(4-(cyclohexylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0092] 21) 1-(4-((3-aminocyclohexyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0093] 22) N-(2-((5-(1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-(5-cyano-1H-indazol-1-yl)pyrimidin-4-yl)amino)ethyl)acrylamide,

[0094] 23) (R)-1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-6-(pyrrolidin-3-ylamino)-1H-indole-5-carbonitrile,

[0095] 24) 1-(4-((4-aminophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0096] 25) 1-(4-((4-aminophenyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0097] 26) 1-(4-((3-aminophenyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0098] 27) 1-(4-((3-amino-4-fluorophenyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0099] 28) 1-(4-((1H-indol-5-yl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0100] 29) 1-(4-(((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0101] 30) (R)-6-(pyrrolidin-3-ylamino)-1-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0102] 31) 1-(4-((4-(aminomethyl)phenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0103] 32) 1-(4-((4-aminophenyl)amino)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0104] 33) 1-(4-((4-aminophenyl)amino)-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0105] 34) 1-(5-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0106] 35) 1-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0107] 36) 1-(5-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0108] 37) 1-(5-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0109] 38) 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole,

[0110] 39) 1-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0111] 40) 1-(5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0112] 41) 1-(5-(1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile,

[0113] 42) 1-(4-((2-aminoethyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indazole-5-carbonitrile,

[0114] 43) 1-(5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-6-((4-hydroxycyclohexyl)amino)-1H-indole-5-carbonitrile, and

[0115] 44) 1-(4-((3,4-dihydroxyphenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile.

[0116]

[0117] 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.

[0118]

[0119] 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.

[0120]

[0121] 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 can be dissolved in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, the undissolved compound salt can be filtered, and the filtrate can be 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.

[0122]

[0123] In addition, a salt or solvate of a compound represented by the chemical formula 1 that is not pharmaceutically acceptable can be used as an intermediate in the production of a compound represented by the chemical formula 1, a pharmaceutically acceptable salt, or a solvate thereof.

[0124]

[0125] Meanwhile, the present invention can produce a compound represented by the chemical formula 1 through the following reaction scheme 1, for example, when R2 is -N-R5 within the range defined in the chemical formula 1.

[0126] [Reaction Formula 1]

[0127]

[0128] In the above reaction formula 1, X1, Y1 to Y4, R1 to R3 are as defined in the above chemical formula 1, R2' is a substituent having a protecting group attached to R2, -NH-R5', R2" is chloro, bromo, or iodo, R3' is a substituent having a protecting group attached to R3, and R5' is a substituent having a protecting group attached to R5.

[0129]

[0130] 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 palladium catalyst and a base.

[0131] 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.

[0132] The above step 1-3 is a step of 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, and the reaction is preferably performed in the presence of a palladium catalyst and a base.

[0133] The above step 1-4 is a step for preparing a compound represented by the above chemical formula 1 by removing a protecting group (for example, BOC) 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.

[0134] In addition, in the above reaction scheme 1, if a protecting group is not required, a reactant in which R2 is connected instead of R2' and R3 is connected instead of R3' may be used, and in this case, the protecting group removal step may be omitted. That is, depending on the type of R2 or R3, the reaction for protecting with a protecting group and the reaction for removing the protecting group may or may not be included.

[0135] 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.

[0136]

[0137] In addition, the present invention is characterized in that, for example, R3 is -CO(C 2-4 C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S substituted with alkenyl 3-10 C heterocycloalkyl, or Y4 is C-NH-R4, and R4 is substituted with acrylamide 1-4In the case of alkyl, a compound represented by the chemical formula 1 can be prepared through the following reaction scheme 2.

[0138] [Reaction Formula 2]

[0139]

[0140] In the above reaction formula 2, X1, Y1 to Y3, R1 to R3 are as defined in the above chemical formula 1, Y4 is C-NH-R4, and R3' is C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S. 3-10 Heterocycloalkyl, R3" is a substituent with a protecting group attached to R3', and R4' is C 1-4 is an amine, R4" is a substituent with a protecting group attached to R4', and R4'" is ethylenyl.

[0141]

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

[0143] 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.

[0144] 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, and the reaction is preferably performed in the presence of a palladium catalyst and a base.

[0145] 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; tert-butyloxycarbonyl protecting group) 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.

[0146] 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.

[0147] In addition, in the above reaction scheme 2, if a protecting group is not required, a reactant in which R3 is connected instead of R3' and R4 is connected instead of R4' can be used, and in this case, the protecting group removal step can 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.

[0148] 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.

[0149]

[0150] 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.

[0151]

[0152] 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.

[0153]

[0154] 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.

[0155]

[0156] 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.

[0157]

[0158] 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.

[0159]

[0160] 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.

[0161]

[0162] 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.

[0163]

[0164] 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.

[0165]

[0166] 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.

[0167]

[0168] 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.

[0169]

[0170] 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.

[0171]

[0172] Example 1: Preparation of 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0173] (Step 1-1) Preparation of 1-(5-bromopyrimidin-2-yl)-1H-indole-5-carbonitrile

[0174]

[0175] 5-Cyanoindole (500 mg, 1.0 eq) was dissolved in anhydrous dimethylformamide (10.0 mL), 60% sodium hydride (281.4 mg, 2.0 eq) was added at 0 °C, and the mixture was stirred for 10 minutes. 5-Bromo-2-chloropyrimidine (1.02 g, 1.5 eq) was added to the reaction mixture and stirred for 6 hours at 60 °C. After confirming that the starting material had disappeared on TLC, water was added and the mixture was extracted with ethyl acetate. The separated organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 2:1) to obtain the title compound (500.8 mg, yield 47.6%).

[0176]

[0177] (Step 1-2) Preparation of tert-butyl 4-(4-(2-(5-cyano-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0178]

[0179] 1-(5-Bromopyrimidin-2-yl)-1H-indole-5-carbonitrile (100.0 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous dimethylformamide (4.0 mL, 1:1), then potassium carbonate (92.4 mg, 2.0 eq), tetrakis(triphenylphosphine)palladium(0) (38.6 mg, 0.1 eq), and 1-(1-Boc-4-piperidinyl)pyrazole-4-boronic acid pinacol ester (189.2 mg, 1.5 eq) were added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was reacted at 150 °C for 15 minutes using a microwave reactor, and the reaction was terminated when the starting material disappeared on TLC. The reaction mixture was washed with water, extracted with ethyl acetate, and the separated organic layer was dried over magnesium sulfate, filtered, 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 (110.0 mg, yield 70.1%).

[0180]

[0181] (Step 1-3) Preparation of 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0182]

[0183] tert-Butyl 4-(4-(2-(5-cyano-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)-piperidine-1-carboxylate (100.0 mg, 1.0 eq) was dissolved in a 4N hydrochloric acid 1,4-dioxane solution (2.0 mL), stirred at room temperature for 4 hours, and concentrated under reduced pressure to remove all solvent in the reaction vessel. Chloroform was added, and the resulting precipitate was crystallized at room temperature for 1 hour. The resulting precipitate was filtered and dried to obtain the title compound (59.1 mg, yield 68.4%).

[0184] 1H NMR (500 MHz, DMSO): 9.17 (s, 2H), 9.05 (s, 1H), 8.86 (d, 1H), 8.85 (s, 1H), 8.48 (d, 2H), 8.17 (d, 2H), 7.72 (d, 1H), 6.92 (d, 1H), 4.57-4.52 (m, 1H), 4.45-4.38 (d, 2H), 3.18-3.02 (m, 2H), 2.29-2.08 (m, 4H)

[0185]

[0186] Example 2: Preparation of 1-(5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0187]

[0188] The title compound (45.0 mg, yield 52.1%) was obtained by the same method as in Example 1, except that 1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolain-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one was used instead of 1-(1-Boc-4-piperidinyl)pyrazole-4-boronic acid pinacol ester.

[0189] 1 H NMR (500 MHz, CDCl3): 8.88(d, 1H), 8.80(s, 2H), 8.37(s, 1H), 7.94(s, 1H), 7.84(s, 1H), 7.76(s, 1H), 7.55(d, 1H), 6.75(s, 1H), 4.79(d, 1H), 4.50-4.38(m, 1H), 3.99(d, 1H), 3.25(t, 1H), 2.78(t, 1H), 2.31(d, 1H), 2.28(d, 1H), 2.21(s, 3H), 1.96-2.10(m, 2H)

[0190]

[0191] Example 3: Preparation of N-(piperidin-3-yl)-1-(2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-5-yl)-1H-indol-6-amine

[0192] (Step 3-1) Preparation of tert-butyl 3-((1-(2-(1-(1-(tert-butylcarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-5-yl)-1H-indol-6-yl)amino)piperidine-1-carboxylate

[0193]

[0194] tert-Butyl 4-(4-(5-(6-bromo-1H-indol-1-yl)pyrimidin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (50.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (2.0 mL), then tris(dibenzylideneacetone)dipalladium(0) (17.5 mg, 0.2 eq), Expos (18.2 mg, 0.4 eq), cesium carbonate (62.2 mg, 2.0 eq), and 3-amino-1-tert-butylcarbonylpiperidine (18.8 ml, 1.0 eq) were added, stirred at 100 °C for 16 hours, and the reaction was terminated when the starting material disappeared on TLC. The reaction mixture was washed with water, extracted with ethyl acetate, and the separated organic layer was dried over magnesium sulfate, filtered, 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 32.6%).

[0195]

[0196] (Step 3-2) Preparation of N-(piperidin-3-yl)-1-(2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-5-yl)-1H-indol-6-amine

[0197]

[0198] tert-Butyl 3-((1-(2-(1-(1-(tert-butylcarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-5yl)-1H-indol-6-yl)amino)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 4 hours, and then concentrated under reduced pressure to remove all solvent. Dichloromethane was added, and the resulting precipitate was crystallized at room temperature for 2 hours, filtered, and the title compound (13.0 mg) was obtained.

[0199] 1 H NMR (500 MHz, MeOD): 9.05(d, 2H), 8.42(s, 1H), 8.34(s, 1H), 8.06(s, 1H), 7.78(d, 1H), 7.27(d, 1H), 6.82(s, 1H), 4.80-4.65(m, 1H), 4.1-3.90(m, 1H), 3.76-3.56(m, 3H), 3.12-2.95(m, 1H), 2.49-1.80(m, 7H)

[0200]

[0201] Example 4: Preparation of 1-(4-((2-aminoethyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0202] (Step 4-1) Preparation of tert-butyl (2-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)carbamate

[0203]

[0204] 2,4-Dichloro-5-iodopyrimidine (5.5 g, 1.0 eq) was added to a solution of tert-butyl(2-aminoethyl)carbamate (3.4 g, 1.1 eq), 36.0 mL of acetonitrile, and 3.6 mL of triethylamine, and stirred at room temperature. After reacting for 24 hours, purified water was added to the reaction mixture, and the mixture was stirred for 30 minutes to precipitate a precipitate. The precipitate was filtered and washed with purified water to obtain the title compound (6.2 g, yield 77.9%).

[0205]

[0206] (Step 4-2) Preparation of tert-butyl 4-(4-(4-((2-((tert-butylcarbonyl)amino)ethyl)amino)-2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0207]

[0208] Tert-Butyl(2-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)carbamate (398.6 mg, 1.0 eq), 1-(1-boc-4-piperidinyl)pyrazole-4-boronic acid pinacol ester (452.8 mg, 1.2 eq), tetrakis(triphenylphosphine)palladium (231.1 mg, 0.2 eq), cesium carbonate (1,954.9 mg, 6.0 eq), and 8.4 mL of 1,2-dimethoxyethane were placed in a microwave reaction vessel, stirred, degassed, and filled with nitrogen. Then, 2.8 mL of purified water was added, degassed for 10 minutes, and filled with nitrogen, and stirred at 100 °C for 18 hours. After confirming by TLC that the starting material had disappeared, purified water was added and extracted with ethyl acetate. Then, sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:1) to obtain the title compound (470.0 mg, yield 90.0%).

[0209]

[0210] (Step 4-3) Preparation of tert-butyl 4-(4-(4-((2-((tert-butylcarbonyl)amino)ethyl)amino)-2-(5-cyano-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0211]

[0212] tert-Butyl 4-(4-(4-((2-((tert-butylcarbonyl)amino)ethyl)amino)-2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (261.0 mg, 1.0 eq), indole-5-carbonitrile (74.6 mg, 1.1 eq), palladium acetate (11.2 mg, 0.1 eq), xantphos (28.9 mg, 0.1 eq), cesium carbonate (342.1 mg, 2.1 eq), and 3.9 mL of 1,4-dioxane were placed in a microwave reactor, stirred for 10 minutes, degassed, and filled with nitrogen, and stirred in the microwave reactor at 120 °C for 45 minutes. After that, purified water was added, extraction was performed with ethyl acetate, sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: hexane = 2:3) to obtain the title compound (184.9 mg, yield 58.9%).

[0213]

[0214] (Step 4-4) Preparation of 1-(4-((2-aminoethyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0215]

[0216] To tert-butyl 4-(4-(4-((2-((tert-butylcarbonyl)amino)ethyl)amino)-2-(5-cyano-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (100.0 mg, 1.0 eq) was added 2.0 mL of 1,4-dioxane and 0.5 mL of methanol, followed by 2.0 mL of a 4.0 N hydrochloric acid solution in 1,4-dioxane, and stirred at room temperature for 4 hours. Afterwards, the solvent was removed by concentration under reduced pressure, and the addition of methanol and concentration under reduced pressure were repeated three times to obtain the title compound (67.4 mg).

[0217] 1 H NMR (500 MHz, MeOD): 8.87(s, 1H), 8.31(s, 1H), 8.23(s, 1H), 8.18(s, 1H), 8.09(d, 1H), 7.85(d, 1H), 7.68(d, 1H), 6.94(d, 1H), 4.71-4.68(m, 1H), 4.01(t, 2H), 3.65-3.59(m, 2H), 3.36-3.10(m, 5H), 2.45-2.37(m, 4H)

[0218]

[0219] Example 5: Preparation of N-(piperidin-3-yl)-1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indol-6-amine

[0220]

[0221] The title compound (10.0 mg, yield 89.3%) was obtained by the same method as in Example 3, except that tert-butyl 4-(4-(5-(6-bromo-1H-indol-1-yl)pyrimidin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate was used instead of tert-butyl 4-(4-(2-(6-chloro-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.

[0222] 1H NMR (500 MHz, MeOD): 9.03(s, 2H), 8.32(s, 1H), 8.29(s, 1H), 8.05(s, 1H), 7.63(d, 1H), 7.05(d, 1H), 6.72(s, 1H), 4.71-4.58(m, 1H), 3.99-3.89(m, 1H), 3.75-3.55(m, 3H), 3.19-2.98(m, 2H), 2.41-2.09(m, 5H), 1.95-1.78(m, 2H)

[0223]

[0224] Example 6: Preparation of N-(2-((5-(1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-(5-cyano-1H-indol-1-yl)pyrimidin-4-yl)amino)ethyl)acrylamide

[0225]

[0226] 1.5 mL of tetrahydrofuran and 76.7 μL of triethylamine were added to tert-butyl 1-(4-((2-aminoethyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile (50.0 mg, 1.0 eq), cooled to 0 °C, and 17.9 μL of acryloyl chloride was added. After stirring at room temperature for 2 hours, 5 mL of dichloromethane was additionally added, and after stirring for 3 hours, 3.0 mL of 1-methyl-2-pyrrolidinone was additionally added. The reaction mixture was stirred for 24 hours, and the disappearance of the starting material was confirmed by TLC. Then, purified water was added, extracted with ethyl acetate, and filtered without sodium sulfate treatment. The mixture was concentrated under reduced pressure and methanol was added. The process of adding methanol and concentrating under reduced pressure was repeated three times. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: methanol = 8:2) to obtain the title compound (yield 25.6%).

[0227] 1H NMR (500 MHz, MeOD): 8.81(s, 1H), 8.35(s, 1H), 8.01(s, 1H), 7.93(s, 1H), 7.70(s, 1H), 7.48(d, 1H), 6.85-6.81(m, 1H), 6.79(s, 1H), 6.24-6.18(m, 3H), 5.76(d, 1H), 5.61(d, 1H), 4.72(d, 1H), 4.53(t, 1H), 4.29(d, 1H), 3.68(t, 2H), 3.57(t, 2H), 3.33(t, 1H), 2.28-1.95(m, 4H)

[0228]

[0229] Example 7: Preparation of 1-(4-(piperidin-3-ylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0230] (Step 7-1) Preparation of tert-butyl 3-((5-(1-(1-(tert-butylcarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2-(5-cyano-1H-indol-1-yl)pyrimidin-4-yl)amino)-piperidine-1-carboxylate

[0231]

[0232] tert-Butyl 3-((5-(1-(1-(tert-butylcarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2-chloropyrimidin-4-yl)amino)-piperidine-1-carboxylate (100.0 mg, 1.0 eq), indole-5-carbonitrile (26.6 mg, 1.1 eq), palladium acetate (4.0 mg, 0.1 eq), xantphos (10.3 mg, 0.1 eq), cesium carbonate (121.7 mg, 2.1 eq), and 1.5 mL of 1,4-dioxane were placed in a microwave reactor, stirred for 10 minutes, degassed, and filled with nitrogen, and stirred in the microwave reactor at 120 °C for 45 minutes. After that, purified water was added, extraction was performed with ethyl acetate, sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: hexane = 2:3) to obtain the title compound (96.5 mg, yield 81.2%).

[0233]

[0234] (Step 7-2) Preparation of 1-(4-(piperidin-3-ylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0235]

[0236] tert-Butyl 3-((5-(1-(1-(tert-butylcarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2-(5-cyano-1H-indol-1-yl)pyrimidin-4-yl)amino)-3l3-piperidine-1-carboxylate (91.0 mg, 1.0 eq) was mixed with 0.5 mL of 1,4-dioxane and 1.7 mL of a 4.0 N hydrochloric acid solution of 1,4-dioxane, and stirred at room temperature for 4 hours. Then, 1.7 mL of methanol was additionally added and stirred for 12 hours. Afterwards, the mixture was concentrated under reduced pressure to remove 1,4-dioxane, and the addition of methanol and concentration under reduced pressure were repeated three times to obtain the title compound (82.1 mg).

[0237] 1H NMR (500 MHz, MeOD): 8.80 (d, 1H), 8.37 (d, 1H), 8.17 (d, 2H), 8.06 (s, 1H), 7.81 (s, 1H), 7.69 (d, 1H), 6.90 (s, 1H), 4.69-4.62(m, 2H), 4.68-2.88(m, 8H), 2.45-1.65(m, 8H)

[0238]

[0239] Example 8: Preparation of 1-(4-((3-aminopropyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0240] (Step 8-1) Preparation of tert-butyl 4-(4-(4-((3-((tert-butylcarbonyl)amino)propyl)amino)-2-(5-cyano-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0241]

[0242] tert-Butyl 4-(4-(4-((3-((tert-butylcarbonyl)amino)propyl)amino)-2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (268.0 mg, 1.0 eq), indole-5-carbonitrile (74.6 mg, 1.1 eq), palladium acetate (11.2 mg, 0.1 eq), xantphos (28.9 mg, 0.1 eq), cesium carbonate (342.1 mg, 2.1 eq), and 4.0 mL of 1,4-dioxane were placed in a microwave reactor, stirred for 10 minutes, degassed, and filled with nitrogen, and stirred in the microwave reactor at 120 °C for 45 minutes. After that, purified water was added, extraction was performed with ethyl acetate, sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: hexane = 3:2) to obtain the title compound (235.0 mg, yield 73.2%).

[0243]

[0244] (Step 8-2) Preparation of 1-(4-((3-aminopropyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0245]

[0246] 1.0 mL of 1,4-dioxane was added to tert-butyl 4-(4-(4-((3-((tert-butylcarbonyl)amino)propyl)amino)-2-(5-cyano-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (232.0 mg, 1.0 eq), 4.5 mL of a 4.0 N hydrochloric acid solution of 1,4-dioxane was added, and the mixture was stirred at room temperature for 4 hours. Then, 4.5 mL of methanol was additionally added, and the mixture was stirred for 24 hours. Afterwards, the mixture was concentrated under reduced pressure to remove 1,4-dioxane, and the addition of methanol and concentration under reduced pressure were repeated three times to obtain the title compound (111.0 mg, 70%).

[0247] 1 H NMR (500 MHz, MeOD): 8.80(d, 1H), 8.36(s, 1H), 8.12(s, 1H), 8.07(s, 1H), 7.78(s, 1H), 7.63(d, 1H), 6.86(s, 1H), 4.69-4.64(m, 1H), 3.75(t, 2H), 3.65(d, 2H), 3.30-3.03(m, 4H), 2.45-2.30 (m, 4H), 2.11(t, 2H)

[0248]

[0249] Example 9: Preparation of 1-(4-morpholino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0250] (Step 9-1) Preparation of tert-butyl 4-(4-(2-(5-cyano-1H-indol-1-yl)-4-morpholinopyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0251]

[0252] tert-Butyl 4-(4-(2-chloro-4-morpholinopyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (112.2 mg, 1.0 eq), indole-5-carbonitrile (37.3 mg, 1.1 eq), palladium acetate (5.6 mg, 0.1 eq), xantphos (14.5 mg, 0.1 eq), cesium carbonate (171.0 mg, 2.1 eq), and 1.7 mL of 1,4-dioxane were placed in a microwave reactor and stirred for 10 minutes, degassed, and filled with nitrogen. The mixture was stirred in a microwave reactor at 120 ℃ for 45 minutes. Afterwards, purified water was added, extracted with ethyl acetate, and sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate:hexane = 3:2) to obtain the title compound (122.0 mg, yield 88.0%).

[0253]

[0254] (Step 9-2) Preparation of 1-(4-morpholino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0255]

[0256] tert-Butyl 4-(4-(2-(5-cyano-1H-indol-1-yl)-4-morpholinopyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (119.5 mg, 1.0 eq) was mixed with 0.5 mL of 1,4-dioxane and 2.7 mL of a 4.0 N hydrochloric acid solution in 1,4-dioxane, followed by stirring at room temperature for 4 hours. 2.7 mL of methanol was additionally added and stirred for 24 hours. The mixture was concentrated under reduced pressure to remove the solvent, and the addition of methanol and concentration under reduced pressure were repeated three times to obtain the title compound (95.6 mg).

[0257] 1H NMR (500 MHz, MeOD): 8.88 (d, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 8.03 (s, 2H), 7.84 (s, 1H), 7.59 (d, 1H), 6.81 (d, 1H), 4.66-4.60(m, 1H), 3.77(t, 4H), 3.61(d, 2H), 3.51(t, 4H), 3.30-3.15(m, 2H), 2.39-2.30(m, 4H)

[0258]

[0259] Example 10: Preparation of 1-(4-(cyclopentylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0260] (Step 10-1) Preparation of tert-butyl 4-(4-(2-(5-cyano-1H-indol-1-yl)-4-(cyclopentylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0261]

[0262] tert-Butyl 4-(4-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (111.8 mg, 1.0 eq), indole-5-carbonitrile (37.3 mg, 1.1 eq), palladium acetate (5.6 mg, 0.1 eq), xantphos (14.5 mg, 0.1 eq), cesium carbonate (171.1 mg, 2.1 eq), and 1.7 mL of 1,4-dioxane were placed in a microwave reactor and stirred for 10 minutes, degassed, and filled with nitrogen. The mixture was stirred in a microwave reactor at 120 ℃ for 45 minutes. Afterwards, purified water was added, extracted with ethyl acetate, and sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate:hexane = 2:3) to obtain the title compound (123.0 mg, yield 88.0%).

[0263]

[0264] (Step 10-2) Preparation of 1-(4-(cyclopentylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0265]

[0266] 0.5 mL of 1,4-dioxane was added to tert-butyl 4-(4-(2-(5-cyano-1H-indol-1-yl)-4-(cyclopentylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (120.0 mg, 1.0 eq), 2.7 mL of a 4.0 N hydrochloric acid solution in 1,4-dioxane, and stirred at room temperature for 4 hours. Then, 2.7 mL of methanol was additionally added, and stirred for 24 hours. Thereafter, the solvent was removed by concentration under reduced pressure, and the addition of methanol and concentration under reduced pressure were repeated three times to obtain the title compound (72.0 mg).

[0267] 1 H NMR (500 MHz, MeOD): 8.76 (d, 1H), 8.15 (dd, 3H), 8.02 (s, 1H), 7.80 (s, 1H), 7.69 (d, 1H), 7.00 (s, 1H), 4.71-4.66 (m, 1H), 3.62-3.59(m, 2H), 2.28-2.18(m, 2H), 2.39-2.19(m, 6H), 1.82-1.69(m, 6H)

[0268]

[0269] Example 11: Preparation of 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-N-(pyrrolidin-3-yl)-1H-indol-6-amine

[0270] (Step 11-1) Preparation of 1-(5-bromopyrimidin-2-yl)-6-chloro-1H-indole

[0271]

[0272] 6-Chloroindole (300 mg, 1.0 eq) was dissolved in anhydrous dimethylformamide (12.0 mL), and 60% sodium hydride (158.3 mg, 2.0 eq) was added at 0 °C and stirred for 10 minutes. 5-Bromo-2-chloropyrimidine (574.1 mg, 1.5 eq) was added to the reaction mixture and stirred at room temperature for 1 hour and 30 minutes. After confirming that the starting material had disappeared on TLC, water was added and extracted with ethyl acetate. The separated organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 4:1) to obtain the title compound (430.0 mg, yield 70.4%).

[0273]

[0274] (Step 11-2) Preparation of tert-butyl 4-(4-(2-(6-chloro-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0275]

[0276] 1-(5-Bromopyrimidin-2-yl)-6-chloro-1H-indole (100.0 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous dimethylformamide (3.0 mL, 1:1), then potassium carbonate (37.4 mg, 2.0 eq), tetrakis(triphenylphosphine)palladium(0) (37.4 mg, 0.1 eq), and 1-(1-Boc-4-piperidinyl)pyrazole-4-boronic acid pinacol ester (183.4 mg, 1.5 eq) were added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was reacted at 150 °C for 20 minutes using a microwave reactor, and the reaction was terminated when the starting material disappeared on TLC. The reaction mixture was washed with water, extracted with ethyl acetate, and the separated organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = ethyl acetate:hexane = 1:2) to obtain the title compound (95.0 mg, yield 61.3%).

[0277]

[0278] (Step 11-3) Preparation of tert-butyl 4-(4-(2-(6-((1-(tert-butylcarbonyl)pyrrolidin-3-yl)amino)-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0279]

[0280] tert-Butyl 4-(4-(2-(6-chloro-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (70.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (2.5 mL), then tris(dibenzylideneacetone)dipalladium(0) (26.8 mg, 0.2 eq), Expos (27.9 mg, 0.4 eq), cesium carbonate (95.2 mg, 2.0 eq), and tert-butyl 3-aminopyrrolidine-1-carboxylate (40.8 mg, 1.5 eq) were added, stirred at 100 °C for 16 hours, and the reaction was terminated when the starting material disappeared on TLC. The reaction mixture was washed with water, extracted with ethyl acetate, and the separated organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (volume ratio = ethyl acetate:hexane = 1:1) to obtain the title compound (25.0 mg, yield 27.2%).

[0281]

[0282] (Step 11-4) Preparation of 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-N-(pyrrolidin-3-yl)-1H-indol-6-amine

[0283]

[0284] tert-Butyl 4-(4-(2-(6-((1-(tert-butylcarbonyl)pyrrolidin-3-yl)amino)-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (24.1 mg, 1.0 eq) was dissolved in a 1.25 N hydrochloric acid methanol solution (2.5 mL), stirred at 40 °C for 6 hours, and concentrated under reduced pressure to remove all solvent in the reaction vessel. Dichloromethane was added, and the resulting precipitate was crystallized at room temperature for 1 hour, filtered, and dried to obtain the title compound (15.0 mg, yield 84.3%).

[0285] 1H NMR (500 MHz, MeOD): 9.18 (s, 1H), 9.05 (s, 2H), 8.45 (s, 1H), 8.34 (s, 1H), 7.82 (d, 1H), 7.40 (d, 1H), 6.83 (s, 1H), 4.70-4.65(m, 2H), 3.82-3.71(m, 3H), 3.65(d, 2H), 3.42-3.30(m, 1H), 2.60-2.25(m, 6H)

[0286]

[0287] Example 12: Preparation of 1-(4-(cyclopentylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carboxamide

[0288] (Step 12-1) Preparation of tert-butyl 4-(4-(2-(5-cyano-1H-indol-1-yl)-4-(cyclopentylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0289]

[0290] tert-Butyl-4-(4-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (111.8 mg, 1.0 eq), indole-5-carbonitrile (37.3 mg, 1.1 eq), palladium acetate (5.6 mg, 0.1 eq), xantphos (14.5 mg, 0.1 eq), cesium carbonate (171.1 mg, 2.1 eq), and 1.7 mL of 1,4-dioxane were placed in a microwave reactor, stirred for 10 minutes, degassed, and filled with nitrogen, and reacted in a microwave reactor at 120 ℃ for 45 minutes. Purified water was added to the reaction mixture, extracted with ethyl acetate, and sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate:hexane = 4:6) to obtain the title compound (123.0 mg, yield 88.0%).

[0291]

[0292] (Step 12-2) Preparation of 1-(4-(cyclopentylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0293]

[0294] tert-Butyl-4-(4-(2-(5-cyano-1H-indol-1-yl)-4-(cyclopentylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (120.0 mg, 1.0 eq) was mixed with 0.5 mL of 1,4-dioxane and 2.7 mL of a 4.0 N hydrochloric acid solution in 1,4-dioxane, followed by stirring at room temperature for 4 hours. Then, 2.7 mL of methanol was additionally added and stirred for 4 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 three times to obtain the title compound (123.0 mg).

[0295]

[0296] (Step 12-3) Preparation of 1-(4-(cyclopentylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carboxamide

[0297]

[0298] 1-(4-(cyclopentylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile hydrochloride (48.9 mg, 1.0 eq) was added 1.0 mL of ethanol, 250.0 μL of 4.0 N aqueous sodium hydroxide solution and 1.0 mL of 30% hydrogen peroxide were added, and the mixture was stirred at room temperature for 18 hours. 10.0 mL of purified water was added to the suspended reaction mixture, filtered, and the filtrate was extracted with ethyl acetate. Sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure to obtain the title compound (8.0 mg, yield 17.0%).

[0299] 1H NMR (500 MHz, MeOD): 8.84(d, 1H), 8.258(s, 1H), 8.16(s, 1H), 8.01(s, 1H), 7.93(s, 1H), 7.81(d, 1H), 7.79-7.71(m, 1H), 6.74(s, 1H), 4.62-4.45(m, 2H), 3.60-3.05(m, 4H), 2.25-2.25(m, 12H)

[0300]

[0301] Example 13: Preparation of 1-(4-((4-aminocyclohexyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0302] (Step 13-1) Preparation of tert-butyl 4-(4-(4-((4-((tert-butylcarbonyl)amino)cyclohexyl)amino)-2-(5-cyano-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0303]

[0304] tert-Butyl-4-(4-(4-((4-((tert-butylcarbonyl)amino)cyclohexyl)amino)-2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (203.0 mg, 1.0 eq), 1H-indazole-5-carbonitrile (52.6 mg, 1.1 eq), palladium acetate (7.9 mg, 0.1 eq), xantphos (20.3 mg, 0.1 eq), cesium carbonate (241.1 mg, 2.1 eq), and 3.0 mL of 1,4-dioxane were placed in a microwave reactor, stirred for 10 minutes, degassed, and filled with nitrogen, and reacted in the microwave reactor at 120 °C for 45 minutes. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified twice by column chromatography (volume ratio = ethyl acetate:hexane = 2:3) to obtain the title compound (78.5 mg, yield 32.9%).

[0305]

[0306] (Step 13-2) Preparation of 1-(4-((4-aminocyclohexyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0307]

[0308] 0.5 mL of 1,4-dioxane was added to tert-butyl-4-(4-((4-((tert-butylcarbonyl)amino)cyclohexyl)amino)-2-(5-cyano-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (75.0 mg, 1.0 eq), 1.4 mL of 4.0 N hydrochloric acid solution of 1,4-dioxane was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane, and the addition of methanol and concentration under reduced pressure were repeated twice to obtain the title compound (96.1 mg).

[0309] 1 H NMR (500 MHz, MeOD): 8.89(d, 1H), 8.36(s, 3H), 8.20(s, 1H), 8.16(s, 1H), 8.04(s, 1H),7.84(s, 1H), 7.60(d, 1H), 4.95-4.80(m, 2H), 4.386(m, 1H), 3.70-3.25(m, 5H), 2.41-2.30(m, 4H), 2.25-21.78(m, 8H)

[0310]

[0311] Example 14: Preparation of 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-N-(pyrrolidin-3-yl)-1H-indol-6-amine

[0312] (Step 14-1) Preparation of tert-butyl 4-(4-(2-bromopyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0313]

[0314] 2-Bromo-5-chloropyrimidine (100.0 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous dimethylformamide (4.0 mL, 1:1), and then potassium carbonate (142.9 mg, 2.0 eq), tetrakis(triphenylphosphine)palladium(0) (59.7 mg, 0.1 eq), and 1-(1-Boc-4-piperidinyl)pyrazole-4-boronic acid pinacol ester (292.6 mg, 1.5 eq) were added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was reacted in a microwave reactor at 150 °C for 15 minutes, and the reaction was terminated when the starting material disappeared on TLC. The reaction mixture was washed with water, extracted with ethyl acetate, and the separated organic layer was dried over magnesium sulfate, filtered, 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 (110.0 mg, yield 52.1%).

[0315]

[0316] (Step 14-2) Preparation of tert-butyl 4-(4-(2-(6-bromo-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0317]

[0318] 6-Bromoindole (15.0 mg, 1.0 eq) was dissolved in anhydrous dimethylformamide (10.0 mL), and 60% sodium hydride (6.1 mg, 2.0 eq) was added at 0 °C and stirred for 10 minutes. tert-Butyl 4-(4-(5-bromopyrimidin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (46.9 mg, 1.5 eq) obtained above was added to the reaction mixture and stirred at room temperature for 3 hours. After confirming that the starting material had disappeared on TLC, water was added and extracted with ethyl acetate. The separated organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (volume ratio = hexane:ethyl acetate = 2:1) to obtain the title compound (25.0 mg, yield 62.5%).

[0319]

[0320] (Step 14-3) Preparation of tert-butyl 4-(4-(5-(6-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-1H-indol-1-yl)pyrimidin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0321]

[0322] tert-Butyl 4-(4-(5-(6-bromo-1H-indol-1-yl)pyrimidin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (80.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (2.5 mL), then tris(dibenzylideneacetone)dipalladium(0) (28.0 mg, 0.2 eq), Expos (29.1 mg, 0.4 eq), cesium carbonate (99.6 mg, 2.0 eq), and tert-butyl 3-aminopyrrolidine-1-carboxylate (42.7 mg, 1.5 eq) were added, stirred at 100 °C for 16 hours, and the reaction was terminated when the starting material disappeared on TLC. The reaction mixture was washed with water, extracted with ethyl acetate, and the separated organic layer was dried over magnesium sulfate, filtered, 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 (35.0 mg, yield 36.4%).

[0323]

[0324] Step 14-4: Preparation of 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-N-(pyrrolidin-3-yl)-1H-indol-6-amine

[0325]

[0326] tert-Butyl 4-(4-(5-(6-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-1H-indol-1-yl)pyrimidin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (35.0 mg, 1.0 eq) was dissolved in a 1.25 N hydrochloric acid methanol solution (3.5 mL), stirred at 50 °C for 5 hours, and concentrated under reduced pressure to remove all solvent in the reaction vessel. Dichloromethane was added, and the resulting precipitate was crystallized at room temperature for 1 hour, filtered, and dried to obtain the title compound (20.0 mg, yield 77.2%).

[0327] 1H NMR (500 MHz, MeOD): 9.01(d, 3H), 8.43(s, 1H), 8.33(s, 1H), 8.06(s, 1H), 7.81(d, 1H), 7.35(d, 1H), 6.82(s, 1H), 4.71-4.67(m, 2H), 3.78-3.49(m, 5H), 2.56-2.28(m, 5H)

[0328]

[0329] Example 15: Preparation of N1-(1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indol-6-yl)cyclohexane-1,2-diamine

[0330]

[0331] The title compound (25.0 mg, yield 74.0%) was obtained by the same method as in Example 14, except that tert-butyl N-(2-aminocyclohexyl)carbamate was used instead of tert-butyl 4-(4-(5-bromopyrimidin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.

[0332] 1 H NMR (500 MHz, MeOD): 8.99 (s, 2H), 8.30 (m, 2H), 8.03 (s, 1H), 7.62 (d, 1H), 7.21-7.08 (m, 2H), 6.72 (s, 1H), 4.70-4.69 (m, 1H), 3.74-3.40(m, 6H), 3.48-3.3.05(m, 7H), 1.95-1.22(m, 7H)

[0333]

[0334] Example 16: Preparation of 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-6-(pyrrolidin-3-ylamino)-1H-indole-5-carbonitrile

[0335]

[0336] The title compound (30.0 mg, yield 80.2%) was obtained by the same method as in Example 11, except that 6-chloroindole-5-carbonitrile was used instead of 6-chloroindole.

[0337] 1 H NMR (500 MHz, MeOD): 9.05(s, 2H), 8.40(s, 1H), 8.34(s, 1H), 8.23(s, 1H), 8.05(s, 1H), 7.82(s, 1H), 6.68(s, 1H), 4.71-4.60(m, 1H), 4.51-4.41(m, 1H), 3.72(d, 1H), 3.63-3.11(m, 7H), 2.61-2.19(m, 7H)

[0338]

[0339] Example 17: Preparation of 1-(4-(cyclopentylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0340] (Step 17-1) Preparation of 2-chloro-N-cyclopentyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-amine

[0341]

[0342] 2-Chloro-N-cyclopentyl-5-iodopyrimidin-4-amine (276.6 mg, 1.0 eq), 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (333.8 mg, 1.2 eq), tetrakis(triphenylphosphine)palladium (231.1 mg, 0.2 eq), cesium carbonate (1,954.9 mg, 6.0 eq), and 8.3 mL of 1,2-dimethoxyethane were placed in a microwave reaction vessel, stirred, degassed, and filled with nitrogen. Then, 3.9 mL of purified water was added, degassed for 10 minutes, and filled with nitrogen, 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 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 (256.0 mg, yield 73.6%).

[0343]

[0344] (Step 17-2) Preparation of 1-(4-(cyclopentylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0345]

[0346] 2-Chloro-N-cyclopentyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-amine (256.0 mg, 1.0 eq), 1H-indazole-5-carbonitrile (109.9 mg, 1.1 eq), palladium acetate (16.5 mg, 0.1 eq), xantphos (42.6 mg, 0.1 eq), cesium carbonate (503.6 mg, 2.1 eq), and 3.8 mL of 1,4-dioxane were placed in a microwave reactor, stirred for 10 minutes, degassed, and filled with nitrogen, and reacted in the microwave reactor at 120 °C for 45 minutes. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate:hexane = 3:2) to obtain the title compound (206.5 mg, yield 61.9%).

[0347] 1 H NMR (500 MHz, CDCl3): 8.91(s, 1H), 8.41(s, 1H), 8.03(s, 1H), 7.95(s, 1H), 7.66(s, 1H), 7.82(s, 1H), 7.55(s, 1H), 7.53(d, 1H), 6.71(s, 1H), 5.21(s, 1H), 4.68-4.35(m, 2H), 4.17(d, 2H), 3.60(t, 2H), 2.25-1.18(m, 6H), 1.81-1.45(m, 6H)

[0348]

[0349] Example 18: Preparation of 1-(4-(piperidin-3-ylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0350] (Step 18-1) Preparation of tert-butyl 3-((2-(5-cyano-1H-indol-1-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylate

[0351]

[0352] 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), 1H-indazole-5-carbonitrile (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, and reacted at 120 °C for 45 minutes in the microwave reactor. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the 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%).

[0353]

[0354] (Step 18-2) Preparation of 1-(4-(piperidin-3-ylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0355]

[0356] 2.0 mL of 1,4-dioxane was added to tert-butyl-3-((2-(5-cyano-1H-indol-1-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) pyrimidin-4-yl)amino)piperidine-1-carboxylate (284.3 mg, 1.0 eq), and 6.3 mL of a 4.0 N hydrochloric acid solution of 1,4-dioxane was added, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane, and then the addition of methanol and concentration under reduced pressure were repeated five times to obtain the title compound (281.0 mg).

[0357] 1 H NMR (500 MHz, MeOD): 8.81(s, 1H), 8.40(s, 1H), 8.18(s, 1H), 8.08(s, 2H), 7.81(s, 1H), 7.70-7.61(m, 1H), 6.88(m, 1H), 4.78-4.50(m, 2H), 4.08(d, 2H), 3.70-3.55(m, 4H), 3.45-3.33(m, 3H), 3.11-3.02(m, 1H), 3.01-3.98(m, 1H), 2.28-1.70(m, 7H)

[0358]

[0359] Example 19: Preparation of 1-(4-(phenylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0360]

[0361] The title compound (116.8 mg) was obtained by the same method as in Example 4, except that aniline was used instead of tert-butyl(2-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)carbamate.

[0362] 1 H NMR (500 MHz, MeOD): 8.32(s, 1H), 8.20(s, 2H), 8.13(s, 1H), 7.98(s, 1H), 7.89(s, 1H), 7.54-7.42(m, 1H), 7.33(t, 1H), 7.28(d, 1H), 6.81(s, 1H), 4.70-4.61(m, 1H), 3.71-3.55(m, 3H), 3.32-3.25(m, 2H), 2.48-2.30(m, 4H)

[0363]

[0364] Example 20: Preparation of 1-(4-(cyclohexylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0365]

[0366] The title compound (199.9 mg) was obtained by the same method as in Example 4, except that cyclohexylamine was used instead of tert-butyl(2-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)carbamate.

[0367] 1 H NMR (500 MHz, MeOD): 8.72(d, 1H), 8.14(s, 1H), 8.10(s, 2H), 8.01(s, 1H), 7.80(s, 1H), 7.72(d, 1H), 7.04(s, 1H), 4.72-4.63(m, 1H), 4.31-4.22(m, 1H), 3.69-3.54(m, 3H), 3.28-3.21(m, 2H), 2.41-2.30(m, 4H), 2.16-1.71(m, 5H), 1.58-1.44(m, 4H)

[0368]

[0369] Example 21: Preparation of 1-(4-((3-aminocyclohexyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0370]

[0371] The title compound (260.0 mg) was obtained by the same method as in Example 4, except that tert-butyl(2-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)carbamate was used instead of tert-butyl(3-aminocyclohexyl)carbamate.

[0372] 1H NMR (500 MHz, MeOD): 8.88(d, 1H), 8.41(d, 1H), 8.34(s, 1H), 8.17(s, 1H), 8.06(d, 1H), 7.79(d, 1H), 7.60(d, 1H), 6.86(d, 1H), 4.80-4.58(m, 3H), 4.34(t, 1H), 3.77-3.47(m, 5H), 2.51-2.30(m, 7H), 2.19(t, 1H), 2.02-1.56(m, 6H)

[0373]

[0374] Example 22: Preparation of N-(2-((5-(1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-(5-cyano-1H-indazol-1-yl)pyrimidin-4-yl)amino)ethyl)acrylamide

[0375] (Step 22-1) Preparation of tert-butyl 4-(4-(4-((2-((tert-butylcarbonyl)amino)ethyl)amino)-2-(5-cyano-1H-indazol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0376]

[0377] tert-Butyl 4-(4-(4-((2-((tert-butylcarbonyl)amino)ethyl)amino)-2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (170.0 mg, 1.0 eq), 1H-indazole-5-carbonitrile (48.9 mg, 1.1 eq), palladium acetate (7.3 mg, 0.1 eq), xantphos (18.9 mg, 0.1 eq), cesium carbonate (222.8 mg, 2.1 eq), and 2.5 mL of 1,4-dioxane were placed in a microwave reactor, stirred for 10 minutes, degassed, and filled with nitrogen, and stirred in the microwave reactor at 120 °C for 45 minutes. After that, purified water was added, extraction was performed with ethyl acetate, sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: hexane = 3:2) to obtain the title compound (59.5 mg, yield 29.0%).

[0378]

[0379] (Step 22-2) Preparation of 1-(4-((2-aminoethyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indazole-5-carbonitrile

[0380]

[0381] 1.0 mL of 1,4-dioxane was added to tert-butyl 4-(4-(4-((2-((tert-butylcarbonyl)amino)ethyl)amino)-2-(5-cyano-1H-indazol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (50.3 mg, 1.0 eq), 1.0 mL of a 4.0 N hydrochloric acid solution of 1,4-dioxane and 0.5 mL of methanol were added, and the mixture was stirred at room temperature for 3 hours. Afterwards, the mixture was concentrated under reduced pressure to remove 1,4-dioxane, and the addition of methanol and concentration under reduced pressure were repeated three times to obtain the title compound (48.0 mg).

[0382]

[0383] (Step 22-3) Preparation of N-(2-((5-(1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-(5-cyano-1H-indazol-1-yl)pyrimidin-4-yl)amino)ethyl)acrylamide

[0384]

[0385] 1-(4-((2-aminoethyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indazole-5-carbonitrile (25.1 mg, 1.0 eq) was added 1.5 mL of 1-methyl-2-pyrrolidinone and 55.8 μL of triethylamine, cooled to 0 °C, and then 10.6 μL of acryloyl chloride was added. After stirring at room temperature for 23 hours, the starting material was confirmed to have almost disappeared by TLC. Purified water was added, extracted with ethyl acetate, then sodium sulfate was added, water was removed, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: methanol = 8:2) to obtain the title compound (17.0 mg).

[0386] 1 H NMR (500 MHz, DMSO): 8.79(d, 1H), 8.55(s, 1H), 8.50(s, 1H), 8.36(t, 1H), 8.22(s, 1H), 8.13(s, 1H), 7.89(s, 1H), 7.12(t, 1H), 6.89-6.81(m, 1H), 6.25-6.00(m, 3H), 5.70(d, 1H), 5.56(d, 1H), 4.60-4.44(m, 2H), 4.18(d, 1H), 4.68-4.40(m, 4H), 2.21-2.09(m, 2H), 1.91-1.81(m, 2H), 1.21(s, 2H)

[0387]

[0388] Example 23: Preparation of (R)-1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-6-(pyrrolidin-3-ylamino)-1H-indole-5-carbonitrile

[0389] (Step 23-1) Preparation of tert-butyl (R)-4-(4-(2-(6-((1-(tert-butylcarbonyl)pyrrolidin-3-yl)amino)-5-cyano-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0390]

[0391] tert-Butyl 4-(4-(2-(6-chloro-5-cyano-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (100.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (2.0 mL), then tris(dibenzylideneacetone)dipalladium(0) (36.3 mg, 0.2 eq), xantphos (45.9 mg, 0.4 eq), cesium carbonate (129.3 mg, 2.0 eq), and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (50.5 mL, 1.5 eq) were added, and the mixture was stirred at room temperature for 5 minutes. The reaction product was reacted using a microwave reactor at 150°C for 45 minutes, and the disappearance of the starting material was confirmed on TLC, and the reaction was terminated. The reaction product was washed with water, extracted with ethyl acetate, and the separated organic layer was dried over magnesium sulfate, filtered, 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 (55.0 mg, yield 42.4%).

[0392]

[0393] (Step 23-2) Preparation of (R)-1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-6-(pyrrolidin-3-ylamino)-1H-indole-5-carbonitrile

[0394]

[0395] tert-Butyl(R)-4-(4-(2-(6-((1-(tert-butylcarbonyl)pyrrolidin-3-yl)amino)-5-cyano-1H-indol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (50.0 mg, 1.0 eq) was dissolved in a 1.25 N hydrochloric acid methanol solution (5.0 mL), stirred at room temperature for 16 hours, and concentrated under reduced pressure to remove all solvent in the reaction vessel. Dichloromethane was added, and the resulting precipitate was crystallized at room temperature for 1 hour, filtered, and dried to obtain the title compound (20.0 mg, yield 53.3%).

[0396] 1 H NMR (500 MHz, MeOD): 9.04(s, 1H), 8.37(s, 1H), 8.30(s, 1H), 8.24(s, 1H), 8.04(s, 1H), 7.83(s, 1H), 6.67(s, 1H), 4.95-4.80(m, 2H), 4.68-4.59(m, 2H), 4.47(t, 1H), 3.71-3.68(m, 1H), 3.61-3.14(m, 10H), 2.58-2.48(m, 1H), 2.40-2.25(m, 5H), 1.26(s, 3H)

[0397]

[0398] Example 24: Preparation of 1-(4-((4-aminophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0399]

[0400] The same procedure as in Example 18 was followed, except that tert-butyl-3-((2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylate was replaced with tert-butyl (4-((2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)carbamate, to obtain the title compound (64.2 mg, yield 90.2%).

[0401] 1 H NMR (500 MHz, DMSO): 8.92 (s, 1H), 8.40 (d, 2H), 8.27 (s, 2H), 8.14 (s, 1H), 7.86 (s, 1H), 7.65 (d, 1H), 7.51 (d, 1H), 7.44 (d, 2H), 6.82(s, 1H), 4.48(t, 1H), 4.10-3.90(m, 1H), 3.69(m, 1H), 3.48(t, 1H), 2.10-1.89(m, 4H)

[0402]

[0403] Example 25: Preparation of 1-(4-((4-aminophenyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0404]

[0405] The title compound (34.0 mg) was obtained in the same manner as in Example 7, except that tert-butyl 3-((5-(1-(1-(tert-butylcarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2-chloropyrimidin-4-yl)amino)-piperidine-1-carboxylate was used instead of tert-butyl 4-(4-(4-((4-((tert-butylcarbonyl)amino)phenyl)amino)-2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.

[0406] 1H NMR (500 MHz, DMSO): 9.02-8.81 (m, 4H), 8.41 (d, 2H), 8.29 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.65-7.25 (m, 5H), 6.81(s, 1H), 4.56(t, 1H), 3.42-3.35(m, 2H), 3.14.-3.03(m, 2H), 2.31-2.12(m, 4H)

[0407]

[0408] Example 26: Preparation of 1-(4-((3-aminophenyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0409] (Step 26-1) Preparation of tert-butyl(3-((2-chloro-5-iodopyrimidin-4-yl)amino)phenyl)carbamate

[0410]

[0411] 2,4-Dichloro-5-iodopyrimidine (1.4 g, 1.0 eq) was added to a solution of tert-butyl(3-aminophenyl)carbamate (1.1 g, 1.05 eq), 16.5 mL of acetonitrile, and 906.5 μL of triethylamine, and the mixture was stirred at room temperature for 18 hours. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (volume ratio = ethyl acetate:hexane = 1:4) to obtain the title compound (1.6 g, yield 68.6%).

[0412]

[0413] (Step 26-2) Preparation of tert-butyl (3-((2-chloro-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)carbamate

[0414]

[0415] Tert-Butyl(3-((2-chloro-5-iodopyrimidin-4-yl)amino)phenyl)carbamate (223.3 mg, 1.0 eq), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)piperidine (226.4 mg, 1.2 eq), tetrakis(triphenylphosphine)palladium (115.6 mg, 0.2 eq), cesium carbonate (977.5 mg, 6.0 eq), and 4.7 mL of 1,2-dimethoxyethane were placed in a microwave reactor, stirred, degassed, and filled with nitrogen. Then, 1.6 mL of purified water was added, degassed and filled with nitrogen for 10 minutes, 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 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 (81.8 mg, yield 28.7%).

[0416]

[0417] (Step 26-3) Preparation of tert-butyl (3-((2-(5-cyano-1H-indol-1-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)carbamate

[0418]

[0419] Tert-butyl (3-((2-chloro-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl) pyrimidin-4-yl)amino)phenyl)carbamate (80.0 mg, 1.0 eq), indole-5-carbonitrile (20.9 mg, 1.1 eq), palladium acetate (3.2 mg, 0.1 eq), xantphos (8.1 mg, 0.1 eq), cesium carbonate (96.0 mg, 2.1 eq), and 1.2 mL of 1,4-dioxane were placed in a microwave reactor, stirred for 10 minutes, degassed, and filled with nitrogen, and reacted in a microwave reactor at 120 °C for 45 minutes. Purified water was added to the reaction mixture, extracted with ethyl acetate, and sodium sulfate was added to the 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 (76.0 mg, yield 80.1%).

[0420]

[0421] (Step 26-4) Preparation of 1-(4-((3-aminophenyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0422]

[0423] Tert-butyl (3-((2-(5-cyano-1H-indol-1-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl) amino)phenyl)carbamate (70.9 mg, 1.0 eq) was added 1.0 mL of 1,4-dioxane, 1.3 mL of 4.0 N hydrochloric acid solution of 1,4-dioxane, and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane, and the addition of methanol and concentration under reduced pressure were repeated twice to obtain the title compound (66.3 mg).

[0424] 1H NMR (500 MHz, DMSO): 8.50 (t, 1H), 8.38 (d, 1H), 8.27 (t, 1H), 8.17 (d, 1H), 8.12 (d, 1H), 7.87 (d, 1H), 7.64-7.33 (m, 4H), 7.09-7.10(m, 1H), 6.84(s, 1H), 4.53(t, 1H), 3.40(q, 2H), 3.07(t, 2H), 2.27-2.07(m, 4H)

[0425]

[0426] Example 27: Preparation of 1-(4-((3-amino-4-fluorophenyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0427]

[0428] The title compound (100.2 mg) was obtained by the same method as in Example 26, except that (5-amino-2-fluorophenyl)carbamic acid tert-butyl ester was used instead of tert-butyl (3-aminophenyl)carbamate.

[0429] 1 H NMR (500 MHz, DMSO): 8.48 (d, 1H), 8.30 (d, 1H), 8.28 (d, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.40 (d, 1H), 7.20-7.01(m, 2H), 6.82(s, 1H), 6.78(s, 1H), 4.53(t, 1H), 3.40(q, 2H), 3.07(t, 2H), 2.27-2.07(m, 4H)

[0430]

[0431] Example 28: Preparation of 1-(4-((1H-indol-5-yl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0432]

[0433] The title compound (188.0 mg) was obtained in the same manner as in Example 26, using tert-butyl 5-amino-1H-indole-1-carboxylate instead of tert-butyl(3-aminophenyl)carbamate and 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole instead of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole.

[0434] 1 H NMR (500 MHz, DMSO): 8.95-8.65 (m, 3H), 8.32 (d, 2H), 8.29-8.01 (d, 2H), 7.88 (d, 1H), 7.70-7.45 (d, 2H), 7.15-6.86 (m, 3H), 4.53(t, 1H), 3.72-3.60(m, 2H), 3.15-3.02(m, 2H), 2.29-2.04(m, 4H)

[0435]

[0436] Example 29: Preparation of 1-(4-(((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0437] (Step 29-1) Preparation of (1R,2S,3R,5R)-3-((2-chloro-5-iodopyrimidin-4-yl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol

[0438]

[0439] 2,4-Dichloro-5-iodopyrimidine (274.9 mg, 1.0 eq) was added to a solution of (1R, 2S, 3R, 5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (183.6 mg, 1.0 eq), 8.0 mL ethanol, and triethylamine (557.9 μL, 4.0 eq), and stirred at 80 °C for 18 hours. The mixture was immediately concentrated to obtain the title compound without purification, which was used in the reaction in Step 29-2.

[0440]

[0441] (Step 29-2) Preparation of ((3aR,4R,6R,6aS)-6-((2-chloro-5-iodopyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol

[0442]

[0443] (1R,2S,3R,5R)-3-((2-chloro-5-iodopyrimidin-4-yl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol was placed in a microwave reaction vessel, 2,2-dimekoxypropane (61.3 μL, 0.5 eq) and 8.0 mL of acetone were added, cooled to 0 °C, methanesulfonic acid was added, and the mixture was stirred at room temperature for 3 days. Purified water was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was added with sodium sulfate to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: hexane = 1:3) to obtain the title compound (200.5 mg, yield 47.1%).

[0444]

[0445] (Step 29-3) Preparation of ((3aR,4R,6R,6aS)-6-((2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol

[0446]

[0447] ((3aR, 4R, 6R, 6aS)-6-((2-chloro-5-iodopyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol (200.5 mg, 1.0 eq), (1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester (157.2 mg, 1.2 eq), tetrakis(triphenylphosphine)palladium (108.9 mg, 0.2 eq), cesium carbonate (920.9 mg, 6.0 eq), and 4.2 mL of 1,2-dimethoxyethane were placed in a microwave reaction vessel, stirred, degassed, and filled with nitrogen. Then, 1.4 mL of purified water was added, degassed and nitrogen was filled for 10 minutes, 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 organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: methanol = 10:1) to obtain the title compound (125.1 mg, yield 59.0%).

[0448]

[0449] (Step 29-4) Preparation of 1-(4-(((3aS,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0450]

[0451] ((3aR, 4R, 6R, 6aS)-6-((2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol (125.1 mg 1.0 eq), indole-5-carbonitrile (41.5 mg, 1.1 eq), palladium acetate (6.2 mg, 0.1 eq), xantphos (16.1 mg, 0.1 eq), cesium carbonate (190.1 mg, 2.1 eq), and 1.9 mL of 1,4-dioxane were placed in a microwave reaction vessel, stirred for 10 minutes, degassed, and filled with nitrogen, and microwave The reaction was carried out at 120°C for 45 minutes in a reactor. Purified water was added to the reaction mixture, extracted with ethyl acetate, and then sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = ethyl acetate: methanol = 10:1) to obtain the title compound (109.2 mg, yield 70.8%).

[0452]

[0453] (Step 29-5) Preparation of 1-(4-(((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0454]

[0455] 1-(4-(((3aS,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile (109.0 mg, 1.0 eq) was added 7.9 mL of 1.25 N hydrochloric acid methanol solution and stirred at 40 °C for 4 hours. The reaction mixture was depressurized to obtain the title compound (102.3 mg).

[0456] 1 H NMR (500 MHz, DMSO): 8.94(d, 1H), 8.42(d, 1H), 8.18(d, 2H), 8.11(s, 1H), 7.77(s, 1H), 7.61(d, 1H), 6.85(d, 1H), 6.67(d, 1H), 4.48-4.39(m, 2H), 3.99-3.77(m, 4H), 3.57(t, 2H), 3.38(d, 2H), 2.38-2.27(m, 1H), 2.10-1.94(m, 5H)

[0457]

[0458] Example 30: Preparation of (R)-6-(pyrrolidin-3-ylamino)-1-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0459] (Step 30-1) Preparation of 6-chloro-1-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0460]

[0461] 6-Chloro-1H-indole-5-carbonitrile (150.0 mg, 1.0 eq) was dissolved in anhydrous dimethylformamide (8.0 mL), 60% sodium hydride (68.0 mg, 2.0 eq) and 2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidine (269.8 mg, 1.2 eq) were added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was reacted at 40 °C for 5 hours, and the disappearance of the starting material was confirmed on TLC, and the reaction was terminated. The reaction mixture was washed with water, extracted with ethyl acetate, and the separated organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. After removing all the solvent, ethyl acetate was added, and the resulting precipitate was crystallized at room temperature for 30 minutes, filtered, and dried to obtain the title compound (100.0 mg, yield 29.1%).

[0462]

[0463] (Step 30-2) Preparation of tert-butyl (R)-3-((5-cyano-1-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indol-6-yl)amino)pyrrolidine-1-carboxylate

[0464]

[0465] 6-Chloro-1-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile (90.0 mg, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (2.5 mL), then tris(dibenzylideneacetone)dipalladium(0) (407 mg, 0.2 eq), xantphos (51.4 mg, 0.4 eq), cesium carbonate (144.8 mg, 2.0 eq), and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (56.6 μL, 1.5 eq) were added, and the mixture was stirred at room temperature for 5 minutes. The reaction product was reacted using a microwave reactor at 150°C for 45 minutes, and the disappearance of the starting material was confirmed on TLC, and the reaction was terminated. The reaction product was washed with water, extracted with ethyl acetate, and the separated organic layer was dried over magnesium sulfate, filtered, 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 (65.0 mg, yield 52.7%).

[0466]

[0467] (Step 30-3) Preparation of (R)-6-(pyrrolidin-3-ylamino)-1-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0468]

[0469] tert-Butyl (R)-3-((5-cyano-1-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indol-6-yl)amino)pyrrolidine-1-carboxylate (62.6 mg, 1.0 eq) was dissolved in a 1.25 N hydrochloric acid methanol solution (5.0 mL), stirred at room temperature for 16 hours, and concentrated under reduced pressure to remove all solvent in the reaction vessel. Dichloromethane was added, and the resulting precipitate was crystallized at room temperature for 1 hour, filtered, and dried to obtain the title compound (30.0 mg, yield 54.2%).

[0470] 1 H NMR (500 MHz, MeOD): 8.99 (s, 1H), 8.30 (d, 1H), 8.20 (s, 1H), 8.01 (s, 1H), 7.77 (s, 1H), 6.64 (s, 1H), 5.59-5.43 (m, 2H), 4.10(d, 2H), 3.75(t, 1H), 3.67-3.40(m, 6H), 2.60-2.48(m, 1H), 2.32-1.07(m, 5H)

[0471]

[0472] Example 31: Preparation of 1-(4-((4-(aminomethyl)phenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0473]

[0474] The title compound (154.6 mg) was obtained in the same manner as in Example 26, except that 4-(N-boc-aminomethyl)aniline was used instead of tert-butyl (3-aminophenyl)carbamate and (1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester was used instead of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolein-2-yl)-1H-pyrazol-1-yl)piperidine.

[0475] 1H NMR (500 MHz, MeOD): 8.51(s, 1H), 8.29(s, 1H), 8.23(s, 1H), 8.16(s, 1H), 8.03(s, 1H), 7.88(s, 1H), 7.69-7.57(m, 5H), 7.44 (d, 1H), 6.68(s, 1H), 4.54(s, 1H), 4.2(s 2H), 4.09(d, 2H), 4.65-4.53(m, 2H), 2.19-2.10(m, 4H)

[0476]

[0477] Example 32: Preparation of 1-(4-((4-aminophenyl)amino)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0478]

[0479] The title compound (175.0 mg) was obtained in the same manner as in Example 26, except that 4-(tert-butylcarbonylamino)acetonitrile was used instead of tert-butyl (3-aminophenyl)carbamate and 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1h-pyrazole was used instead of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1h-pyrazole.

[0480] 1 H NMR (500 MHz, MeOD): 8.43(t, 1H), 8.32(s, 1H), 8.26(s, 1H), 8.17(d, 1H), 8.02(s, 1H), 7.93(d, 1H), 7.76(d, 2H), 7.61-7.48(m, 2H), 7.40(d, 1H), 6.85(s, 1H), 4.30(t, 2H), 2.23(d, 2H), 1.98(d, 2H), 1.87(d, 2H), 1.57-1.22(m, 3H)

[0481]

[0482] Example 33: Preparation of 1-(4-((4-aminophenyl)amino)-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0483]

[0484] The title compound (93.2 mg) was obtained in the same manner as in Example 26, except that 4-(tert-butoxycarbonylamino)acetonitrile was used instead of tert-butyl (3-aminophenyl)carbamate and 1-(4-pyridinyl)-1H-pyrazole-4-boronic acid pinacol ester was used instead of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolein-2-yl)-1H-pyrazol-1-yl)piperidine.

[0485] 1 H NMR (500 MHz, DMSO): 9.06 (s, 1H), 8.88 (s 1H), 8.79 (s, 2H), 8.49 (s, 1H), 8.43 (d, 1H), 8.31 (s, 2H), 8.17-8.10 (m, 5H), 7.70-7.45(m, 7H), 6.84(s, 1H)

[0486]

[0487] Example 34: Preparation of 1-(5-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0488]

[0489] 1-(5-Bromopyrimidin-2-yl)-1H-indole-5-carbonitrile (31.6 mg, 1.0 eq) was dissolved in anhydrous toluene and anhydrous dimethylformamide (2.0 mL, 1:1), and then potassium carbonate (29.2 mg, 2.0 eq), tetrakis(triphenylphosphine)palladium(0) (12.2 mg, 0.1 eq), and 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolein-2-yl)-1H-pyrazole (40.0 mg, 1.5 eq) obtained above were added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was reacted in a microwave reactor at 150°C for 15 minutes, and the disappearance of the starting material was confirmed on TLC, thereby completing the reaction. The reaction mixture was washed with water, extracted with ethyl acetate, and the separated organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was crystallized under ethyl acetate / methanol conditions, and the resulting precipitate was filtered and dried to obtain the title compound (yield 41.2%).

[0490] 1 H NMR (500 MHz, DMSO): 9.13(s, 2H), 8.87(d, 1H), 8.43(d, 1H), 8.34(s, 1H), 8.20(s, 1H), 8.09(s, 1H), 7.71(d, 1H), 6.91(s, 1H), 4.31(t, 2H), 3.71(t, 2H), 3.27(s, 3H), 3.38(d, 2H), 2.38-2.27(m, 1H), 2.10-1.94(m, 5H)

[0491]

[0492] Example 35: Preparation of 1-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0493]

[0494] The title compound (25.0 mg, yield 37.4%) was obtained by the same method as in Example 1, except that 1-(2-morpholinoethyl)-1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-(1-Boc-4-piperidinyl)pyrazole-4-boronic acid pinacol ester.

[0495] 1 H NMR (500 MHz, CDCl3): 9.00(d, 1H), 8.91(s, 1H), 8.85(s, 1H), 7.96(s, 1H),7.84(d, 1H), 7.68(d, 1H), 6.76(s, 1H), 4.31(t, 2H), 3.86(t, 4H), 2.87(t, 2H), 2.65(t, 4H)

[0496]

[0497] Example 36: Preparation of 1-(5-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0498]

[0499] 1-(1-Boc-4-piperidinyl)pyrazole-4-boronic acid pinacol ester The title compound (20.0 mg, yield 31.7%) was obtained in the same manner as in Example 1, except that 1-(pyridin-3-ylmethyl)-1H-pyrazole-4-boronic acid pinacol ester was used instead.

[0500] 1 H NMR (500 MHz, CDCl3): 8.98(d, 1H), 8.88(s, 2H), 8.75(s, 2H), 8.63(s, 1H),7.96(s, 1H), 7.86(s, 1H), 7.77(s, 1H), 7.68(d, 1H), 7.57(d, 1H), 7.31(t, 1H), 6.75(t, 1H), 5.56(s, 2H)

[0501]

[0502] Example 37: Preparation of 1-(5-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0503]

[0504] The title compound (30.0 mg, yield 46.8%) was obtained by the same method as in Example 1, except that 1-(2-(pyrrolidin-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolein-2-yl)-1H-pyrazole was used instead of 1-(1-Boc-4-piperidinyl)pyrazole-4-boronic acid pinacol ester.

[0505] 1 H NMR (500 MHz, CDCl3): 8.99 (d, 1H), 8.90 (s, 2H), 8.82 (s, 1H), 7.96 (s, 1H), 7.85 (d, 2H), 7.57 (d, 1H), 7.28-7.20 (m, 3H), 7.19-7.10(m, 1H), 6.76(s, 1H), 4.37(t, 2H), 3.02(t, 2H), 2.59(t, 4H), 3.35(s, 1H), 1.81(t, 4H)

[0506]

[0507] Example 38: Preparation of 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole

[0508]

[0509] The title compound (70.0 mg, yield 57.5%) was obtained by the same method as in Example 1, except that indole was used instead of 5-cyanoindole.

[0510] 1H NMR (500 MHz, MeOD): 8.98(s, 2H), 8.78(s, 1H), 8.28(d, 2H), 8.04(s, 1H), 7.59(d, 1H), 7.29(t, 1H), 7.19(t, 1H), 6.70(s, 1H), 4.68-4.60(m, 1H), 3.57(d, 2H), 3.25(t, 2H), 2.41-2.24(m, 4H)

[0511]

[0512] Example 39: Preparation of 1-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0513]

[0514] The title compound (30.0 mg, yield 50.2%) was obtained by the same method as in Example 1, except that N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3-2-dioxaborolein-2-yl)-1H-pyrazol-1-yl)ethanamine was used instead of 1-(1-Boc-4-piperidinyl)pyrazole-4-boronic acid pinacol ester.

[0515] 1 H NMR (500 MHz, CDCl3): 9.00(d, 1H), 8.94(s, 2H), 8.76(d, 1H), 8.39(s, 1H), 7.96(s, 2H), 7.86(d, 2H), 7.59(d, 1H), 6.76(d, 1H), 4.34(t, 2H), 2.92(t, 2H), 2.34(s, 6H)

[0516]

[0517] Example 40: Preparation of 1-(5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0518]

[0519] The title compound (35.0 mg, yield 58.7%) was obtained by the same method as in Example 1, except that 1-(3-tetrahydrofuryl)-1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-(1-Boc-4-piperidinyl)pyrazole-4-boronic acid pinacol ester.

[0520] 1 H NMR (500 MHz, CDCl3): 8.91(d, 1H), 8.89(s, 2H), 8.40(s, 1H), 7.96(s, 1H), 7.84(s, 2H), 7.65(d, 1H), 6.75(s, 1H), 5.07(t, 1H), 4.28-4.05(m, 4H), 2.60-2.34(m, 2H)

[0521]

[0522] Example 41: Preparation of 1-(5-(1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0523]

[0524] 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile (35.0 mg, 1.0 eq) was dissolved in anhydrous dimethylformamide (1.3 mL), triethylamine (60.0 ml, 5.0 eq) was added, and the mixture was stirred at 0 °C for 5 minutes. Acryloyl chloride (12.3 ml, 2.0 eq) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours while injecting nitrogen gas. After confirming that the starting material had disappeared on TLC, water was added, and the mixture was extracted with ethyl acetate. The separated organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (volume ratio = ethyl acetate: methanol = 9:1) to obtain the title compound (15.0 mg, yield 45.3%).

[0525] 1H NMR (500 MHz, CDCl3): 8.92(d, 1H), 8.82(s, 2H), 8.39(s, 1H), 7.97(s, 1H), 7.83(s, 1H), 7.79(s, 1H), 6.59(d, 1H), 6.77(t, 1H), 6.68-6.58(m, 1H), 6.31(d, 1H), 5.73(d, 1H), 4.82(t, 1H), 4.18(t, 1H), 3.29(t, 1H), 2.89(t, 1H)

[0526]

[0527] Example 42: Preparation of 1-(4-((2-aminoethyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indazole-5-carbonitrile

[0528] (Step 42-1) Preparation of tert-butyl 4-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-(5-cyano-1H-indazol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0529]

[0530] tert-Butyl 4-(4-(4-((2-((tert-butylcarbonyl)amino)ethyl)amino)-2-chloropyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (170.0 mg, 1.0 eq), 1H-indazole-5-carbonitrile (48.9 mg, 1.1 eq), palladium acetate (7.3 mg, 0.1 eq), xantphos (18.9 mg, 0.1 eq), cesium carbonate (222.8 mg, 2.1 eq), and 2.5 mL of 1,4-dioxane were placed in a 2-5 mL microwave reactor, stirred for 10 minutes, degassed, and filled with nitrogen, and stirred in the microwave reactor at 120 °C for 45 minutes. After that, purified water was added, extraction was performed with ethyl acetate, sodium sulfate was added to the organic layer to remove water, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = hexane:ethyl acetate = 1:2) to obtain the title compound (59.5 mg, yield 29.0%).

[0531]

[0532] (Step 42-2) Preparation of 1-(4-((2-aminoethyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indazole-5-carbonitrile

[0533]

[0534] 1.0 mL of 1,4-dioxane was added to tert-butyl 4-(4-(4-((2-((tert-butylcarbonyl)amino)ethyl)amino)-2-(5-cyano-1H-indazol-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (50.3 mg, 1.0 eq), 1.0 mL of 4.0 N hydrochloric acid solution of 1,4-dioxane was added, and the mixture was stirred at room temperature for 4 hours. Then, 0.5 mL of methanol was additionally added, and the mixture was stirred for 3 hours. Afterwards, the mixture was concentrated under reduced pressure to remove 1,4-dioxane, and the addition of methanol and concentration under reduced pressure were repeated three times to obtain the title compound.

[0535] 1 H NMR (500 MHz, MeOD): 8.91(d, 1H), 8.59(s, 1H), 8.42(s, 1H), 8.23(s, 1H), 8.12(s, 1H), 7.90(d, 1H), 7.83(s, 1H), 4.85-4.60(m, 2H), 3.87(t, 2H), 3.59(t, 2H), 3.30-3.18(m, 2H), 2.40-2.25(m, 4H)

[0536]

[0537] Example 43: Preparation of 1-(5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-6-((4-hydroxycyclohexyl)amino)-1H-indole-5-carbonitrile

[0538]

[0539] The title compound (25.0 mg) was obtained in the same manner as in Example 30, except that 4-((trimethylsilyl)oxy)cyclohexan-1-amine was used instead of tert-butyl (R)-3-aminopyrrolidine-1-carboxylate and 2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidine was used instead of 2-chloro-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine.

[0540] 1 H NMR (500 MHz, MeOD): 8.78(s, 2H), 8.24(s, 1H), 8.13(s, 1H), 7.85(s, 1H), 7.78(s, 1H), 7.65(s, 1H), 6.65(s, 1H),4.43-4.20(m, 4H), 3.78(t, 1H), 3.50(t, 1H), 2.93(m, 1H), 2.31-2.10(m, 6H), 1.95(q, 2H), 1.58(s, 6H), 1.51(s, 9H), 1.37(q, 3H), 1.24(t, 2H)

[0541]

[0542] Example 44: Preparation of 1-(4-((3,4-dihydroxyphenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile

[0543]

[0544] The title compound (77.8 mg, yield 50.1%) was obtained by the same method as in Example 29, except that 4-aminobenzene-1,2-diol was used instead of (1R, 2S, 3R, 5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride.

[0545] 1 H NMR (500 MHz, DMSO): 9.01 (s, 1H), 8.91 (s, 1H), 8.45-8.40 (m, 2H), 8.30 (s, 2H), 8.21 (s, 1H), 8.11 (s, 1H), 7.78 (s, 1H), 7.32(d, 1H), 6.89(s, 1H), 6.79(d, 2H), 6.69(d, 1H), 4.48-4.35(m, 1H), 4.02-3.90(m, 2H), 3.45(t, 2H), 2.19-1.96(m, 4H)

[0546]

[0547] Experimental example: Inhibitory activity against IRAK4

[0548] 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.

[0549] 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.

[0550]

[0551] IRAK4 IC 50 (nM)IRAK4 IC 50 (nM)IRAK4 IC 50(nM) Example 146 Example 162.1 Example 313.6 Example 255 Example 1776.8 Example 3210.6 Example 310.8 Example 1833.7 Example 3313.5 Example 466.4 Example 1915.7 Example 34530 Example 520 Example 2020.7 Example 35133 Example 670.8 Example 2112.8 Example 36314 Example 716.8 Example 2295.8 Example 37298 Example 828.8 Example 231.2 Example 38974 Example 914.5 Example 2413.4 Embodiment 39683 Embodiment 107.2 Embodiment 252.3 Embodiment 401000 Embodiment 114.2 Embodiment 266.1 Embodiment 41213 Embodiment 1227.7 Embodiment 279.8 Embodiment 42128 Embodiment 137.9 Embodiment 2831.1 Embodiment 43440.9 Embodiment 145.5 Embodiment 2950.6 Embodiment 44108.6 Embodiment 1554.6 Embodiment 301.8

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, X1 is CH or N, Two of Y1 to Y4 are N, one is CH, and one is CH, C-NH-R4, or C-(morpholino), The above R4 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; C 6-10 Aryl; or C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 Heteroaryl; and, Here, R4 is unsubstituted or is amino, acrylamide, hydroxy, C 1-4 Hydroxyalkyl, C 1-4 Substituted with at least one selected from the group consisting of aminoalkyl and halogen, R1 is hydrogen, cyano, or -CONH2, R2 is hydrogen, or -NH-R5, The above R5 is C substituted with at least one selected from the group consisting of amino and hydroxy. 3-10 Cycloalkyl; or C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 Heterocycloalkyl; and, R3 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 containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 Heteroaryl; and, Here, R3 is unsubstituted or C 1-4 Alkyl, morpholino, N(C 1-4 Alkyl)2, C 1-4 Alkoxy, pyrrolidinyl, pyridinyl, -CO(C 2-4 alkenyl), and -CO(C 1-4 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 X1, Y1 to Y4 and R1 to R3 are as defined in paragraph 1.

3. In paragraph 1, X1 is CH, A compound, or a pharmaceutically acceptable salt thereof.

4. In paragraph 1, Y1 and Y4 are N, Y2 is CH, and Y3 is CH, C-NH-R4, or C-(morpholino); Y2 and Y3 are N, Y1 is CH, and Y4 is CH, C-NH-R4, or C-(morpholino), A compound, or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, R4 is ethyl or propyl, Here, R4 is substituted with -NH2 or -NHCO-CH=CH2, A compound, or a pharmaceutically acceptable salt thereof.

6. In paragraph 1, R4 is cyclopentyl or cyclohexyl, Here, R4 is unsubstituted or is amino, hydroxy, and C 1-4 Substituted with at least one selected from the group consisting of hydroxyalkyl, A compound, or a pharmaceutically acceptable salt thereof.

7. In paragraph 1, R4 is phenyl, Here, R4 is unsubstituted or is amino, hydroxy, C 1-4 substituted with at least one selected from the group consisting of aminoalkyl, and halogen, A compound, or a pharmaceutically acceptable salt thereof.

8. In paragraph 1, R4 is piperidinyl or indolyl, A compound, or a pharmaceutically acceptable salt thereof.

9. In paragraph 1, R5 is amino-substituted cyclohexyl, hydroxy-substituted cyclohexyl, piperidinyl, or pyrrolidinyl, A compound, or a pharmaceutically acceptable salt thereof.

10. In paragraph 1, R3 is piperidinyl, Here, R3 is unsubstituted or C 1-4 Alkyl, -CO(C 2-4 alkenyl), or -CO(C 1-4 Substituted with alkyl), A compound, or a pharmaceutically acceptable salt thereof.

11. In paragraph 1, R3 is tetrahydrofuranyl or tetrahydropyranyl, A compound, or a pharmaceutically acceptable salt thereof.

12. In paragraph 1, R3 is methyl substituted with pyridinyl; Morpholino, N(C 1-4 Alkyl)2, C 1-4 Ethyl substituted with alkoxy or pyrrolidinyl; Cyclohexyl; or Pyridinyl, A compound, or a pharmaceutically acceptable salt thereof.

13. In paragraph 1, The compound represented by the above chemical formula 1 is 1) 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 2) 1-(5-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 3) N-(piperidin-3-yl)-1-(2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-5-yl)-1H-indol-6-amine, 4) 1-(4-((2-aminoethyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 5) N-(piperidin-3-yl)-1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indol-6-amine, 6) N-(2-((5-(1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-(5-cyano-1H-indol-1-yl)pyrimidin-4-yl)amino)ethyl)acrylamide, 7) 1-(4-(piperidin-3-ylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 8) 1-(4-((3-aminopropyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 9) 1-(4-morpholino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 10) 1-(4-(cyclopentylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 11) 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-N-(pyrrolidin-3-yl)-1H-indol-6-amine, 12) 1-(4-(cyclopentylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carboxamide, 13) 1-(4-((4-aminocyclohexyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 14) 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-N-(pyrrolidin-3-yl)-1H-indol-6-amine, 15) N1-(1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indol-6-yl)cyclohexane-1,2-diamine, 16) 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-6-(pyrrolidin-3-ylamino)-1H-indole-5-carbonitrile, 17) 1-(4-(cyclopentylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 18) 1-(4-(piperidin-3-ylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 19) 1-(4-(phenylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 20) 1-(4-(cyclohexylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 21) 1-(4-((3-aminocyclohexyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 22) N-(2-((5-(1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-(5-cyano-1H-indazol-1-yl)pyrimidin-4-yl)amino)ethyl)acrylamide, 23) (R)-1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-6-(pyrrolidin-3-ylamino)-1H-indole-5-carbonitrile, 24) 1-(4-((4-aminophenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 25) 1-(4-((4-aminophenyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 26) 1-(4-((3-aminophenyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 27) 1-(4-((3-amino-4-fluorophenyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 28) 1-(4-((1H-indol-5-yl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 29) 1-(4-(((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 30) (R)-6-(pyrrolidin-3-ylamino)-1-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 31) 1-(4-((4-(aminomethyl)phenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 32) 1-(4-((4-aminophenyl)amino)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 33) 1-(4-((4-aminophenyl)amino)-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 34) 1-(5-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 35) 1-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 36) 1-(5-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 37) 1-(5-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 38) 1-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole, 39) 1-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 40) 1-(5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 41) 1-(5-(1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile, 42) 1-(4-((2-aminoethyl)amino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indazole-5-carbonitrile, 43) 1-(5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-6-((4-hydroxycyclohexyl)amino)-1H-indole-5-carbonitrile, and 44) 1-(4-((3,4-dihydroxyphenyl)amino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1H-indole-5-carbonitrile Any one selected from the group consisting of, A compound, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition for preventing or treating cancer or autoimmune disease, comprising a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

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