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

Abstract

The present invention relates to a compound represented by chemical formula 1 below, or a pharmaceutically acceptable salt thereof. The compound according to the present invention can be effectively used for preventing or treating cancer or autoimmune disease. [Chemical formula 1] In chemical formula 1, X, L, R1, and R2 are as defined in the specification.

Description

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

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

[0002]

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

[0004] 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.

[0005] 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.

[0006] 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.

[0007]

[0008] The present invention provides a novel structural compound that can be usefully used for the prevention or treatment of cancer or autoimmune diseases.

[0009] In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer or autoimmune disease comprising the compound.

[0010]

[0011] To solve the above problem, the present invention provides a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof:

[0012] [Chemical Formula 1]

[0013]

[0014] In the above chemical formula 1,

[0015] X is S or NR,

[0016] The above R is hydrogen or C 1-4 It is alkyl,

[0017] L is a single bond; or -O-,

[0018] R1 is C 3-6 Cycloalkyl; or C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 It is heterocycloalkyl,

[0019] The above R1 is unsubstituted; or halogen, amino, amino(C 1-4 alkyl), -NHCO-(C 1-4 alkyl), -NHCO-(C 2-4 alkenyl), -CH2-NHCO-(C 1-4 alkyl), -CH2-NHCO-(C 2-4 alkenyl), hydroxy, hydroxy(C 1-4 alkyl), -CH2-O-(C 1-4 C containing 1 to 3 heteroatoms each independently selected from the group consisting of alkyl), and N, O and S 3-10Substituted with one or two substituents selected from the group consisting of heterocycloalkyl,

[0020] R2 is hydrogen; or C 1-4 It's alkyl.

[0021]

[0022] In this specification, "heterocycloalkyl" means C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S. 3-10 C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, including a heterocycloalkyl single ring 3-10 Heterocycloalkyl and C 3-6 A condensed ring of cycloalkyl; and C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S. 3-10 C containing 1 to 3 heteroatoms each independently selected from the group consisting of heterocycloalkyl and N, O and S 3-10 It also includes condensed rings such as condensed rings of heterocycloalkyl, and there is no particular limitation on the number of rings included in the condensed rings.

[0023]

[0024] Preferably, R is hydrogen or methyl. More preferably, R is hydrogen.

[0025]

[0026] Preferably, R1 is cyclopentyl, piperidinyl, or octahydro-1H-pyrrolo[3,4-c]pyridinyl,

[0027] wherein R1 is unsubstituted or substituted with one or two substituents selected from the group consisting of fluoro, amino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, -NHCO-(methyl), -NHCO-(ethyl), -NHCO-(propyl), -NHCO-(isopropyl), -NHCO-(ethenyl), -CH2-NHCO-(methyl), -CH2-NHCO-(ethyl), -CH2-NHCO-(propyl), -CH2-NHCO-(isopropyl), -CH2-NHCO-(ethenyl), hydroxy, hydroxymethyl, hydroxypropyl, -CH2-O-(methyl), and piperidinyl.

[0028]

[0029] Preferably,

[0030] L is a single bond,

[0031] R1 is C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S. 3-10 It is heterocycloalkyl,

[0032] The above R1 is unsubstituted; or halogen, amino, amino(C 1-4 alkyl), -NHCO-(C 1-4 alkyl), -NHCO-(C 2-4 alkenyl), -CH2-NHCO-(C 1-4 alkyl), -CH2-NHCO-(C 2-4 alkenyl), hydroxy, hydroxy(C 1-4 alkyl), -CH2-O-(C 1-4 C containing 1 to 3 heteroatoms each independently selected from the group consisting of alkyl), and N, O and S 3-10 Selected from the group consisting of heterocycloalkyl.

[0033]

[0034] Preferably,

[0035] L is a single bond,

[0036] R1 is piperidinyl or octahydro-1H-pyrrolo[3,4-c]pyridinyl,

[0037] wherein R1 is unsubstituted or substituted with one or two substituents selected from the group consisting of fluoro, amino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, -NHCO-(methyl), -NHCO-(ethyl), -NHCO-(propyl), -NHCO-(isopropyl), -NHCO-(ethenyl), -CH2-NHCO-(methyl), -CH2-NHCO-(ethyl), -CH2-NHCO-(propyl), -CH2-NHCO-(isopropyl), -CH2-NHCO-(ethenyl), hydroxy, hydroxymethyl, hydroxypropyl, -CH2-O-(methyl), and piperidinyl.

[0038]

[0039] Preferably,

[0040] L is -O-,

[0041] R1 is C 3-6 It is cycloalkyl,

[0042] The above R1 is unsubstituted.

[0043]

[0044] Preferably,

[0045] L is -O-,

[0046] R1 is cyclopentyl,

[0047] The above R1 is unsubstituted.

[0048]

[0049] Preferably, R2 is hydrogen, methyl, or isopropyl.

[0050]

[0051] Preferably, the above chemical formula 1 is represented by the following chemical formula 2:

[0052] [Chemical Formula 2]

[0053]

[0054] In the above chemical formula 2,

[0055] X is S or NH,

[0056] R'1 and R'2 are each independently hydrogen, halogen, amino, amino(C 1-4 alkyl), -NHCO-(C 1-4 alkyl), -NHCO-(C 2-4 alkenyl), -CH2-NHCO-(C 1-4 alkyl), -CH2-NHCO-(C 2-4 alkenyl), hydroxy, hydroxy(C 1-4 alkyl), -CH2-O-(C 1-4 C containing 1 to 3 heteroatoms each independently selected from the group consisting of alkyl), or N, O and S 3-10 It is heterocycloalkyl,

[0057] R2 is C 1-4 It's alkyl.

[0058]

[0059] Representative examples of compounds represented by the above chemical formula 1 are as follows:

[0060] 1) N-(2-(cyclopentyloxy)-5-(1-methylpiperidin-4-ylamino)phenyl)-2-(pyridin-3-yl)thiazole-4-carboxamide,

[0061] 2) N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-methylpiperidin-4-ylamino)phenyl)-2-(pyridin-3-yl)thiazole-4-carboxamide,

[0062] 3) N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-3-yl)thiazole-4-carboxamide,

[0063] 4) N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide,

[0064] 5) N-(2-(4-aminopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide,

[0065] 6) N-(2-(4-acrylamidopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide,

[0066] 7) N-(2-(4-acetamidopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide,

[0067] 8) N-(2-(4-isobutyramidopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide,

[0068] 9) N-(2-(4-(3-hydroxypropyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide,

[0069] 10) N-(2-(4,4'-bipiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide,

[0070] 11) N-(2-(4-(aminomethyl)-4-hydroxypiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide,

[0071] 12) N-(5-((1-isopropylpiperidin-4-yl)amino)-2-(octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide,

[0072] 13) N-(2-(4-(aminomethyl)-3-fluoropiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide,

[0073] 14) N-(2-(4-(acetamidomethyl)-3-fluoropiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide,

[0074] 15) N-(2-(3-aminopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide,

[0075] 16) N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)-1H-imidazole-4-carboxamide, and

[0076] 17) N-(5-((1-Isopropylpiperidin-4-yl)amino)-2-(4-(methoxymethyl)piperidin-1-yl)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide.

[0077]

[0078] 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.

[0079]

[0080] 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.

[0081]

[0082] Additionally, a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base. For example, the compound represented by the above chemical formula 1 is dissolved in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, the undissolved compound salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. In this case, it is particularly preferable to prepare a sodium salt, a potassium salt, or a calcium salt as the metal salt.

[0083]

[0084] 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.

[0085]

[0086] Meanwhile, in the present invention, for example, when L is -O-, a compound represented by the chemical formula 1 can be prepared through the following reaction scheme 1.

[0087] [Reaction Formula 1]

[0088]

[0089] In the above reaction formula 1, R1 and R2 are as defined in the above chemical formula 1, and L is -O-.

[0090]

[0091] 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 under DIAD (diisopropyl azodicarboxylate).

[0092] 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.

[0093] The above step 1-3 is a step for producing a compound represented by the above chemical formula 1-6 by reducing NO2 in the compound represented by the above chemical formula 1-5. The above reaction is preferably performed under a palladium catalyst.

[0094] The above step 1-4 is a step for producing a compound represented by the above chemical formula 1 by reacting a compound represented by the above chemical formula 1-6 with a compound represented by the above chemical formula 1-7. The above reaction is an amidation reaction and is preferably performed under DCC.

[0095] Additionally, in the above reaction scheme 1, a reaction of protecting with a protecting group and a reaction of removing the protecting group may be added depending on each substituent.

[0096]

[0097] In addition, the present invention can produce a compound represented by the chemical formula 1 through the following reaction scheme 2, for example, when R1 is a substituent containing amide. In the following reaction scheme 2, R1, which is a substituent containing amide, can be expressed as -Ra-NHCO-Rb.

[0098] [Reaction Formula 2]

[0099]

[0100] In the above reaction formula 2, L, R1 and R2 are as defined in the above chemical formula 1, R1 is expressed as -Ra-NHCO-Rb, and Ra and Rb are determined according to the specific type of R1, R1' is -Ra-NH2, and R1" is a substituent to which a protecting group is attached to -Ra-NH2.

[0101]

[0102] The above step 2-1 is a step of producing a compound represented by the above chemical formula 2-3 by reacting a compound represented by the above chemical formula 2-1 with a compound represented by the above chemical formula 2-2, and it is preferable that the reaction be performed in the presence of a base.

[0103] 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.

[0104] The above step 2-3 is a step for producing a compound represented by the above chemical formula 2-6 by reducing NO2 in the compound represented by the above chemical formula 2-5. The above reaction is preferably performed under a palladium catalyst.

[0105] The above step 2-4 is a step for producing a compound represented by the above chemical formula 2-8 by reacting a compound represented by the above chemical formula 2-6 with a compound represented by the above chemical formula 2-7. The above reaction is an amidation reaction, and is preferably performed under HATU and HOAt.

[0106] The above step 2-5 is a step for preparing a compound represented by the above chemical formula 2-9 by removing a protecting group (e.g., BOC; tert-butyloxycarbonyl protecting group) from the compound represented by the above chemical formula 2-8. The above reaction is preferably performed under acid conditions capable of removing the protecting group.

[0107] The above step 2-6 is a step for producing a compound represented by the above chemical formula 1 by reacting a compound represented by the above chemical formula 2-9 with a compound represented by the above chemical formula 2-10. The above reaction is an amidation reaction and is preferably performed in the presence of a base.

[0108] In addition, in the above reaction scheme 2, if a protecting group is not required, a reactant in which R1' is connected instead of R1" can be used, and in this case, the protecting group removal step can be omitted. That is, depending on the type of R1, the reaction for protecting with a protecting group and the reaction for removing the protecting group may or may not be included.

[0109] In addition, when R1 does not contain an amide, steps 2-6 in the above reaction scheme 2 can be omitted to prepare a compound represented by the above chemical formula 1.

[0110] 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.

[0111]

[0112] 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.

[0113]

[0114] 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.

[0115]

[0116] 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.

[0117]

[0118] 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.

[0119]

[0120] 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.

[0121]

[0122] 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.

[0123]

[0124] 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.

[0125]

[0126] 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.

[0127]

[0128] 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.

[0129]

[0130] 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.

[0131]

[0132] 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.

[0133]

[0134] Example 1: Preparation of N-(2-(cyclopentyloxy)-5-(1-methylpiperidin-4-ylamino)phenyl)-2-(pyridin-3-yl)thiazole-4-carboxamide

[0135] (Step 1-1) Preparation of 4-chloro-1-(cyclopentyloxy)-2-nitrobenzene

[0136]

[0137] 4-Chloro-2-nitrophenol (1000.0 mg, 1.0 eq), cyclopentanol (595.0 mg, 1.2 eq), and triphenylphosphine (3000.0 mg, 2.0 eq) were added to tetrahydrofuran (10.0 mL) and cooled to 0 °C. 1.9 M diisopropyl acadicarboxylate toluene solution (6.0 mL, 2.0 eq) was added dropwise. The mixture was stirred at 0 °C for 1 hour, then heated to 25 °C and stirred for 16 hours. After layer separation with ethyl acetate and purified water, the organic layer was washed with purified water. The obtained organic layer was dried using sodium sulfate, concentrated, and purified by column chromatography (volume ratio = ethyl acetate:hexane = 1:10) to obtain the title compound (1.1 g, yield 80.5%).

[0138]

[0139] (Step 1-2) Preparation of N-(4-(cyclopentyloxy)-3-nitrophenyl)-1-methylpiperidin-4-amine

[0140]

[0141] 4-Chloro-1-(cyclopentyloxy)-2-nitrobenzene (245.0 mg, 1.0 eq), 1-methylpiperidin-4-amine (230.6 mg, 2.0 eq), palladium acetate (22.4 mg, 0.1 eq), zonphos (59.7 mg, 0.2 eq), and potassium phosphate (297.2 mg, 1.4 eq) were placed in a reactor and degassed under vacuum. Dimethoxyethane (5.0 mL) was added to the reactor, filled with nitrogen, and stirred at 100 °C for 20 hours. After layer separation with ethyl acetate and purified water, the organic layer was washed with purified water. The obtained organic layer was concentrated, dehydrated using sodium sulfate, and purified by column chromatography (volume ratio = dichloromethane: methanol = 3:1) to obtain the title compound (amount obtained 190.7 mg, yield 59.1%).

[0142]

[0143] (Step 1-3) Preparation of 4-(cyclopentyloxy)-N1-(1-methylpiperidin-4-yl)benzene-1,3-diamine

[0144]

[0145] N-(4-(cyclopentyloxy)-3-nitrophenyl)-1-methylpiperidin-4-amine (89.0 mg, 1.0 eq) and 10% palladium carbon (8.9 mg, 0.1 wt%) were placed in a flask and vacuum degassed. Methanol (3.0 mL) was added, replaced with H2 gas, and the mixture was stirred at 25 °C for 2 hours. The reaction was confirmed to be complete using TLC. The mixture was filtered through Celite and concentrated to obtain the title compound (74.2 mg, yield 92.1%).

[0146]

[0147] (Step 1-4) Preparation of N-(2-(cyclopentyloxy)-5-(1-methylpiperidin-4-ylamino)phenyl)-2-(pyridin-3-yl)thiazole-4-carboxamide

[0148]

[0149] 4-(Cyclopentyloxy)-N1-(1-methylpiperidin-4-yl)benzene-1,3-diamine (35.0 mg, 1.0 eq), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (25.0 mg, 1.0 eq), N,N′-dicyclohexylcarbodiimide (25.0 mg, 1.0 eq), and chloroform (2.0 mL) were stirred at 60 °C for 6 hours and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (volume ratio = dichloromethane: methanol = 1:10) to obtain the title compound (2.9 mg, yield 5.0%).

[0150] 1H NMR (500 MHz, MeOD): 9.22(d, 1H), 8.68(s, 1H), 8.41(d, 2H), 7.94(s, 1H), 7.61(s, 1H), 6.90(d, 1H), 6.48(t, 1H), 2.25-2.12(m, 3H), 2.23-1.89(m, 13H), 1.71-1.58(m, 5H)

[0151]

[0152] Example 2: Preparation of N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-methylpiperidin-4-ylamino)phenyl)-2-(pyridin-3-yl)thiazole-4-carboxamide

[0153] (Step 2-1) Preparation of tert-butyl ((1-(4-bromo-2-nitrophenyl)piperidin-4-yl)methyl)carbamate

[0154]

[0155] 4-Bromo-1-fluoro-2-nitrobenzene (660.0 mg, 1.0 eq) was dissolved in ethanol (5.0 mL). tert-Butyl(piperidin-4-ylmethyl)carbamate (642.9 mg, 1.0 eq) and diisopropylamine (775.4 mg, 2.0 eq) were added and stirred at 60 ℃ for 24 hours. After completion of the reaction, the layers were separated with ethyl acetate and purified water, and the organic layer was washed with purified water. The obtained organic layer was dried using sodium sulfate, concentrated, and purified by column chromatography (volume ratio = ethyl acetate:hexane = 2:3) to obtain the title compound (1100.0 mg, yield 87.1%).

[0156]

[0157] (Step 2-2) Preparation of tert-butyl ((1-(4-((1-methylpiperidin-4-yl)amino)-2-nitrophenyl)piperidin-4-yl)methyl)carbamate

[0158]

[0159] tert-Butyl ((1-(4-bromo-2-nitrophenyl)piperidin-4-yl)methyl)carbamate (597.0 mg, 1.0 eq), 4-aminomethylpiperidine (493.6 mg, 3.0 eq), palladium acetate (32.4 mg, 0.1 eq), zonphos (85.9 mg, 0.2 eq), and potassium phosphate (917.0 mg, 3.0 eq) were placed in a reactor and degassed under vacuum. Dimethoxyethane (5.0 mL) was added to the reactor, filled with nitrogen, and stirred at 100 °C for 20 hours. After layer separation with ethyl acetate and purified water, the organic layer was washed with purified water. The obtained organic layer was concentrated, dehydrated using sodium sulfate, and purified by column chromatography (volume ratio = ethyl acetate: methanol = 4:1) to obtain the title compound (amount obtained 360.2 mg, yield 55.9%).

[0160]

[0161] (Step 2-3) Preparation of tert-butyl ((1-(2-amino-4-((1-methylpiperidin-4-yl)amino)phenyl)piperidin-4-yl)methyl)carbamate

[0162]

[0163] tert-Butyl ((1-(4-((1-methylpiperidin-4-yl)amino)-2-nitrophenyl)piperidin-4-yl)methyl) carbamate (200.0 mg, 1.0 eq) and 10% palladium carbon (20.0 mg, 0.1 wt%) were placed in a flask and degassed under vacuum. Methanol (10.0 mL) was added and hydrogen gas was replaced. After stirring at 25 °C for 3 hours, the completion of the reaction was confirmed by TLC. After filtration through Celite, the mixture was concentrated to obtain the title compound (197.0 mg).

[0164]

[0165] (Step 2-4) Preparation of tert-butyl ((1-(4-((1-methylpiperidin-4-yl)amino)-2-(2-(pyridin-3-yl)thiazole-4-carboxamido)phenyl)piperidin-4-yl)methyl)carbamate

[0166]

[0167] To tert-butyl ((1-(2-amino-4-((1-methylpiperidin-4-yl)amino)phenyl)piperidin-4-yl)methyl) carbamate (50.0 mg, 1.0 eq), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (24.7 mg, 1.0 eq), HATU (91.3 mg, 2.0 eq), HOAt (32.7 mg, 2.0 eq), and diisopropylethylamine (46.5 mg, 3.0 eq) was added N,N-dimethylformamide (2.0 mL), stirred at 25 °C for 24 hours, and the completion of the reaction was confirmed by TLC. The reaction solution was concentrated under reduced pressure, and the layers were separated with ethyl acetate and purified water, and the organic layer was washed with purified water. The obtained organic layer was concentrated after removing water using sodium sulfate, and separated and purified by column chromatography (volume ratio = ethyl acetate: methanol = 4:1) to obtain the title compound (10.5 mg, yield 14.4%).

[0168]

[0169] (Step 2-5) Preparation of N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-methylpiperidin-4-ylamino)phenyl)-2-(pyridin-3-yl)thiazole-4-carboxamide

[0170]

[0171] Tert-Butyl ((1-(4-((1-methylpiperidin-4-yl)amino)-2-(2-(pyridin-3-yl)thiazole-4-carboxamido)phenyl)piperidin-4-yl)methyl)carbamate (9.3 mg, 1.0 eq) was added to methanol (1.0 mL). A 4 M hydrochloric acid 1,4-dioxane solution (0.5 mL) was added, and the mixture was stirred at 25 °C for 4 hours and concentrated to obtain the title compound (yield: 11.2 mg).

[0172] 1H NMR (500 MHz, MeOD): 9.92(s, 1H), 9.36(s, 1H), 9.00(d, 1H), 8.16(s, 1H), 8.28(t, 1H), 7.62(d, 1H), 7.07-6.78(m, 2H), 3.79-3.65(m, 3H), 3.47-3.35(m, 4H), 3.28-3.16(m, 2H), 2.95(s, 2H), 2.89(s, 3H), 2.35-2.05(m, 6H), 1.90-1.75(m, 3H)

[0173]

[0174] Example 3: Preparation of N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-3-yl)thiazole-4-carboxamide

[0175] (Step 3-1) Preparation of tert-butyl ((1-(4-((1-isopropylpiperidin-4-yl)amino)-2-nitrophenyl)piperidin-4-yl)methyl)carbamate

[0176]

[0177] tert-Butyl ((1-(4-bromo-2-nitrophenyl)piperidin-4-yl)methyl)carbamate (1,000.0 mg, 1.0 eq), 1-isopropylpiperidin-4-amine (697.2 mg, 2.0 eq), palladium acetate (53.9 mg, 0.1 eq), zonphos (143.2 mg, 0.2 eq), and potassium phosphate (1,500.0 mg, 3.0 eq) were placed in a reactor and degassed under vacuum. Dimethoxyethane (10.0 mL) was added to the reactor, filled with nitrogen, and stirred at 100°C for 48 hours. After layer separation with ethyl acetate and purified water, the organic layer was washed with purified water. The obtained organic layer was concentrated, dehydrated using sodium sulfate, and purified by column chromatography (volume ratio = dichloromethane: methanol = 9:1) to obtain the title compound (824.4 mg, yield 72.3%).

[0178]

[0179] (Step 3-2) Preparation of tert-butyl ((1-(2-amino-4-((1-isopropylpiperidin-4-yl)amino)phenyl)piperidin-4-yl)methyl)carbamate

[0180]

[0181] tert-Butyl ((1-(4-((1-isopropylpiperidin-4-yl)amino)-2-nitrophenyl)piperidin-4-yl)methyl) carbamate (824.0 mg, 1.0 eq) and 10% palladium carbon (82.4 mg, 0.1 wt%) were placed in a flask and vacuum degassing was performed. Methanol (30.0 mL) was added and hydrogen gas was replaced. After stirring at 25 °C for 18 hours, the completion of the reaction was confirmed by TLC. After filtration through Celite and concentration, the title compound (751.2 mg, yield 97.4%) was obtained.

[0182]

[0183] (Step 3-3) Preparation of tert-butyl ((1-(4-((1-isopropylpiperidin-4-yl)amino)-2-(2-(pyridin-3-yl)thiazole-4-carboxamido)phenyl)piperidin-4-yl)methyl)carbamate

[0184]

[0185] To tert-butyl ((1-(2-amino-4-((1-isopropylpiperidin-4-yl)amino)phenyl)piperidin-4-yl)methyl) carbamate (150.0 mg, 1.0 eq), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (104.1 mg, 1.5 eq), HATU (190.1 mg, 1.5 eq), HOAt (68.1 mg, 1.5 eq), and diisopropylethylamine (131.8 mg, 3.0 eq) was added N,N-dimethylformamide (3.0 mL), stirred at 25 °C for 3 hours, and the completion of the reaction was confirmed by TLC. The reaction solution was concentrated under reduced pressure, and the layers were separated with ethyl acetate and purified water, and the organic layer was washed with purified water. The obtained organic layer was concentrated, dehydrated using sodium sulfate, and purified by column chromatography (volume ratio = dichloromethane: methanol = 9:1) to obtain the title compound (98.1 mg, yield 45.5%).

[0186]

[0187] (Step 3-4) Preparation of N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-3-yl)thiazole-4-carboxamide

[0188]

[0189] tert-Butyl ((1-(4-((1-isopropylpiperidin-4-yl)amino)-2-(2-(pyridin-3-yl)thiazole-4-carboxamido) phenyl)piperidin-4-yl)methyl)carbamate (98.1 mg, 1.0 eq) was added to methanol (1.0 mL). A 4 M hydrochloric acid 1,4-dioxane solution (0.5 mL) was added, and the mixture was stirred at 25 °C for 2 hours and concentrated to obtain the title compound (47.7 mg, yield 57.7%).

[0190] 1H NMR (500 MHz, MeOD): 9.31(s, 1H), 8.70(t, 1H), 8.46(d, 1H), 8.41(s, 1H), 7.89(s, 1H), 7.61(t, 1H), 7.10(d, 1H), 6.45(d, 1H), 2.98(t, 4H), 2.77(t, 3H), 2.60(s, 2H), 2.39(t, 2H), 2.09(d, 2H), 1.93(t, 2H), 1.91(s, 1H), 1.59-1.43(m, 5H), 1.11(d, 6H)

[0191]

[0192] Example 4: Preparation of N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0193]

[0194] The title compound (80.8 mg, yield 79.7%) was obtained by the same method as in Example 3, except that 2-(pyridin-4-yl)thiazole-4-carboxylic acid was used instead of 2-(pyridin-3-yl)thiazole-4-carboxylic acid.

[0195] 1H NMR (500 MHz, MeOD): 8.74(d, 2H), 8.48(s, 1H), 8.07(d, 2H), 7.88(s, 1H), 7.10(d, 1H), 6.45(d, 1H), 2.97(t, 4H), 2.85-2.73(m, 3H), 2.70-2.65(m, 2H), 2.40(t, 2H), 2.15-1.90(m, 4H), 1.62-1.49(m, 5H), 1.22(d, 6H)

[0196]

[0197] Example 5: Preparation of N-(2-(4-aminopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0198] (Step 5-1) Preparation of tert-butyl (1-(4-((1-isopropylpiperidin-4-yl)amino)-2-nitrophenyl)piperidin-4-yl)carbamate

[0199]

[0200] tert-Butyl (1-(4-bromo-2-nitrophenyl)piperidin-4-yl)carbamate (500.0 mg, 1.0 eq), 1-isopropylpiperidin-4-amine (356.0 mg, 2.0 eq), palladium acetate (28.1 mg, 0.1 eq), zonphos (74.6 mg, 0.2 eq), and potassium phosphate (796.0 mg, 3.0 eq) were placed in a reactor and degassed under vacuum. Dimethoxyethane (10.0 mL) was added to the reactor, filled with nitrogen, and stirred at 100 °C for 48 hours. After layer separation with ethyl acetate and purified water, the organic layer was washed with purified water. The obtained organic layer was concentrated after removing water using sodium sulfate and purified by column chromatography (volume ratio = dichloromethane: methanol = 9:1) to obtain the title compound (amount obtained 312.2 mg, yield 54.1%).

[0201]

[0202] (Step 5-2) Preparation of tert-butyl (1-(2-amino-4-((1-isopropylpiperidin-4-yl)amino)phenyl)piperidin-4-yl)carbamate

[0203]

[0204] tert-Butyl (1-(4-((1-isopropylpiperidin-4-yl)amino)-2-nitrophenyl)piperidin-4-yl)carbamate (312.0 mg, 1.0 eq) and 10% palladium carbon (31.2 mg, 0.1 wt%) were placed in a flask and vacuum degassing was performed. Methanol (30.0 mL) was added and hydrogen gas was replaced. After stirring at 25 °C for 18 hours, the completion of the reaction was confirmed by TLC. After filtration through Celite and concentration, the title compound (yield 276.8 mg, yield 94.3%) was obtained.

[0205]

[0206] (Step 5-3) Preparation of tert-butyl (1-(4-((1-isopropylpiperidin-4-yl)amino)-2-(2-(pyridin-4-yl)thiazole-4-carboxamido)phenyl)piperidin-4-yl)carbamate

[0207]

[0208] To a mixture of tert-butyl (1-(2-amino-4-((1-isopropylpiperidin-4-yl)amino)phenyl)piperidin-4-yl)carbamate (100.0 mg, 1.0 eq), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (71.1 mg, 1.5 eq), HATU (131.2 mg, 1.5 eq), HOAt (46.9 mg, 1.5 eq), and diisopropylethylamine (87.1 mg, 3.0 eq) was added N,N-dimethylformamide (3.0 mL), stirred at 25 °C for 3 hours, and the completion of the reaction was confirmed by TLC. The reaction solution was concentrated under reduced pressure, and the layers were separated with ethyl acetate and purified water, and the organic layer was washed with purified water. The obtained organic layer was concentrated, dehydrated using sodium sulfate, and purified by column chromatography (volume ratio = dichloromethane: methanol = 9:1) to obtain the title compound (97.0 mg, yield 68.0%).

[0209]

[0210] (Step 5-4) Preparation of N-(2-(4-aminopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0211]

[0212] tert-Butyl (1-(4-((1-isopropylpiperidin-4-yl)amino)-2-(2-(pyridin-4-yl)thiazole-4-carboxamido)phenyl)piperidin-4-yl)carbamate (97.0 mg, 1.0 eq) was added to methanol (1.0 mL). A 4 M hydrochloric acid solution in 1,4-dioxane (0.5 mL) was added, and the mixture was stirred at 25 °C for 2 hours to obtain the title compound (96.6 mg).

[0213] 1H NMR (500 MHz, MeOD): 8.77(d, 2H), 8.49(s, 1H), 8.09(d, 2H), 7.88(s, 1H), 7.11(d, 1H), 6.45(t, 1H), 2.97-2.68(m, 8H), 2.37(t, 2H), 2.11-1.97(m, 4H), 2.79-2.66(m, 2H), 2.57-2.40(m, 2H), 1.09(d, 6H)

[0214]

[0215] Example 6: Preparation of N-(2-(4-acrylamidopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0216]

[0217] N-(2-(4-aminopiperidin-1-yl)-5-((1-isopropylpiperidin-4-yl)amino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide (90.0 mg, 1.0 eq), trimethylamine (86.0 mg, 5.0 eq), and 1-methyl-2-pyrrolidone (2.0 mL) were added and cooled to 0 °C. After cooling, acryloyl chloride (18.4 mg, 1.2 eq) was added, the temperature was raised to 25 °C, and the mixture was stirred for 0.5 h. After layer separation with ethyl acetate and purified water, the organic layer was washed with purified water, and the water was removed with sodium sulfate. The obtained organic layer was concentrated and purified by column chromatography (volume ratio = dichloromethane: methanol = 9:1) to obtain the title compound (5.7 mg, yield 5.8%).

[0218] 1H NMR (500 MHz, MeOD): 9.72(d, 2H), 9.45(s, 1H), 8.08(d, 2H), 7.90(s, 1H), 7.15(d, 1H), 6.49(d, 1H), 6.31-6.23(m, 2H), 5.70(d, 1H), 3.84(t, 1H), 3.54(t, 1H), 3.05-2.95(m, 4H), 2.87(t, 2H), 2.26-1.80(m, 11H), 1.30(d, 6H)

[0219]

[0220] Example 7: Preparation of N-(2-(4-acetamidopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0221]

[0222] N-(2-(4-aminopiperidin-1-yl)-5-((1-isopropylpiperidin-4-yl)amino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide (45.0 mg, 1.0 eq), trimethylamine (38.5 mg, 5.0 eq), and 1-methyl-2-pyrrolidone (2.0 mL) were added and cooled to 5 °C. After cooling, acetyl chloride (8.9 mg, 1.5 eq) was added and stirred at 5 °C for 1 hour. After layer separation with ethyl acetate and purified water, the organic layer was washed with purified water, and the water was removed with sodium sulfate. The obtained organic layer was concentrated and purified by column chromatography (volume ratio = dichloromethane: methanol = 9:1) to obtain the title compound (10.3 mg, yield 24.2%).

[0223] 1H NMR (500 MHz, MeOD): 8.76(d, 2H), 8.48(s, 1H), 8.07(d, 2H), 7.88(s, 1H), 7.12(d, 1H), 6.45(d, 1H), 3.75(t, 1H), 3.00-2.92(m, 4H), 2.89-2.71(m, 3H), 2.42(t, 2H), 2.09(t, 4H), 1.97(s, 3H), 1.81(q, 2H), 1.49(d 2H), 1.52(d, 6H)

[0224]

[0225] Example 8: Preparation of N-(2-(4-isobutyramidopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0226]

[0227] N-(2-(4-aminopiperidin-1-yl)-5-((1-isopropylpiperidin-4-yl)amino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide (45.0 mg, 1.0 eq), trimethylamine (38.5 mg, 5.0 eq), and 1-methyl-2-pyrrolidone (2.0 mL) were added and cooled to 5 °C. After cooling, isobutyryl chloride (12.1 mg, 1.5 eq) was added and stirred at 5 °C for 1 hour. After layer separation with ethyl acetate and purified water, the organic layer was washed with purified water, and the water was removed with sodium sulfate. The obtained organic layer was concentrated and purified by column chromatography (volume ratio = dichloromethane: methanol = 9:1) to obtain the title compound (21.2 mg, yield 47.3%).

[0228] 1H NMR (500 MHz, MeOD): 8.75(d, 2H), 8.47(s, 1H), 8.05(d, 2H), 7.86(s, 1H), 7.08(d, 1H), 6.44(d, 1H), 3.72(t, 1H), 3.29-3.19(m, 1H), 2.95(t, 5H), 2.82(t, 2H), 2.78(t, 1H), 2.46(t, 1H), 2.38(t, 2H), 2.08(t 4H), 1.78(q, 2H), 1.52(q, 2H), 1.10(d, 12H)

[0229]

[0230] Example 9: Preparation of N-(2-(4-(3-hydroxypropyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0231] (Step 9-1) Preparation of 3-(1-(4-bromo-2-nitrophenyl)piperidin-4-yl)propan-1-ol

[0232]

[0233] 4-Bromo-1-fluoro-2-nitrobenzene (462.0 mg, 1.0 eq) was dissolved in ethanol (10.0 mL). 3-(piperidin-4-yl)propan-1-ol (302.0 mg, 1.0 eq) and diisopropylethylamine (542.8 mg, 2.0 eq) were added and stirred at 60 ℃ for 4 hours. After completion of the reaction, the layers were separated with ethyl acetate and purified water, and the organic layer was washed with purified water and the water was removed with sodium sulfate. The obtained organic layer was concentrated and purified by column chromatography (volume ratio = ethyl acetate:hexane = 2:3) to obtain the title compound (581.4 mg, yield 80.7%).

[0234]

[0235] (Step 9-2) Preparation of 3-(1-(4-((1-isopropylpiperidin-4-yl)amino)-2-nitrophenyl)piperidin-4-yl)propan-1-ol

[0236]

[0237] 3-(1-(4-Bromo-2-nitrophenyl)piperidin-4-yl)propan-1-ol (578.0 mg, 1.0 eq), 1-isopropylpiperidin-4-amine (479.9 mg, 2.0 eq), palladium acetate (37.8 mg, 0.1 eq), zonphos (100.7 mg, 0.2 eq), and potassium phosphate (1,070.0 mg, 3.0 eq) were placed in a reactor and degassed under vacuum. Dimethoxyethane (5.0 mL) was added to the reactor, filled with nitrogen, and stirred at 100 °C for 18 hours. After layer separation with ethyl acetate and purified water, the organic layer was washed with purified water. The obtained organic layer was concentrated, dehydrated using sodium sulfate, and purified by column chromatography (volume ratio = dichloromethane: methanol = 1:9) to obtain the title compound (342.0 mg, yield 50.1%).

[0238]

[0239] (Step 9-3) Preparation of 3-(1-(2-amino-4-((1-isopropylpiperidin-4-yl)amino)phenyl)piperidin-4-yl)propan-1-ol

[0240]

[0241] 3-(1-(4-((1-Isopropylpiperidin-4-yl)amino)-2-nitrophenyl)piperidin-4-yl)propan-1-ol (342.0 mg, 1.0 eq) and 10% palladium carbon (34.2 mg, 0.1 wt%) were placed in a flask and vacuum degassing was performed. Methanol (15.0 mL) was added and hydrogen gas was replaced. After stirring at 25 °C for 48 hours, the completion of the reaction was confirmed by TLC. After filtration through Celite and concentration, the title compound (244.7 mg, yield 77.3%) was obtained.

[0242]

[0243] (Step 9-4) Preparation of N-(2-(4-(3-hydroxypropyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0244]

[0245] 3-(1-(2-amino-4-((1-isopropylpiperidin-4-yl)amino)phenyl)piperidin-4-yl)propan-1-ol (74.9 mg, 1.0 eq), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (61.9 mg, 1.5 eq), HATU (114.1 mg, 1.5 eq), HOAt (40.8 mg, 1.5 eq), diisopropylethylamine (129.3 mg, 3.0 eq) was added N,N-dimethylformamide (1.5 mL), stirred at 25 ℃ for 1.5 hours, and the completion of the reaction was confirmed by TLC. The reaction solution was concentrated under reduced pressure, and the layers were separated with ethyl acetate and purified water, and the organic layer was washed with purified water. The obtained organic layer was concentrated, dehydrated using sodium sulfate, and purified by column chromatography (volume ratio = dichloromethane: methanol = 2:8) to obtain the title compound (yield 3.2 mg, yield 2.8%).

[0246] 1H NMR (500 MHz, MeOD): 8.74(d, 2H), 8.49(s, 1H), 8.08(d, 2H), 7.90(s, 1H), 7.12(d, 1H), 6.47(d, 1H), 3.69-3.58(m, 3H), 3.50-3.41(m, 3H), 3.17(t, 2H), 2.94(d, 2H), 2.76(t, 2H), 3.35-3.21(m, 2H), 1.92-1.23(m, 16H)

[0247]

[0248] Example 10: Preparation of N-(2-(4,4'-bipiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0249]

[0250] The title compound (118.3 mg) was obtained in the same manner as in Example 3, except that tert-butyl 1'-(4-bromo-2-nitrophenyl)-[4,4'-bipiperidine]-1-carboxylate was used instead of tert-butyl ((1-(4-bromo-2-nitrophenyl)piperidin-4-yl)methyl)carbamate and 2-(pyridin-4-yl)thiazole-4-carboxylic acid was used instead of 2-(pyridin-3-yl)thiazole-4-carboxylic acid.

[0251] 1H NMR (500 MHz, MeOD): 8.74(d, 2H), 8.49(s, 1H), 8.08(d, 2H), 7.87(s, 1H), 7.08(d, 1H), 6.45(d, 1H), 3.10-2.88(m, 7H), 2.72-2.31(m, 6H), 2.11-1.98(m, 3H), 1.91-1.81(m, 2H), 2.79-1.69(m, 2H), 1.62-1.43(m, 5H), 1.11(d, 6H)

[0252]

[0253] Example 11: Preparation of N-(2-(4-(aminomethyl)-4-hydroxypiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0254]

[0255] The title compound (71.0 mg) was obtained in the same manner as in Example 3, except that tert-butyl ((1-(4-bromo-2-nitrophenyl)-4-hydroxypiperidin-4-yl)methyl)carbamate was used instead of tert-butyl ((1-(4-bromo-2-nitrophenyl)piperidin-4-yl)methyl)carbamate and 2-(pyridin-4-yl)thiazole-4-carboxylic acid was used instead of 2-(pyridin-3-yl)thiazole-4-carboxylic acid.

[0256] 1H NMR (500 MHz, MeOD): 8.74(d, 2H), 8.49(s, 1H), 8.08(d, 2H), 7.89(s, 1H), 7.14(d, 1H), 6.45(d, 1H), 3.11-2.91(m, 4H), 2.88-2.83(m, 3H), 2.69(s, 2H), 2.44(t, 2H), 2.16-2.08(m, 2H), 1.88(s, 3H), 1.87-1.80(m, 3H), 1.51(1, 2H), 1.12(d, 6H)

[0257]

[0258] Example 12: Preparation of N-(5-((1-isopropylpiperidin-4-yl)amino)-2-(octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0259]

[0260] The title compound (72.0 mg) was obtained in the same manner as in Example 3, except that tert-butyl 5-(4-bromo-2-nitrophenyl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate was used instead of tert-butyl ((1-(4-bromo-2-nitrophenyl)piperidin-4-yl)methyl)carbamate and 2-(pyridin-4-yl)thiazole-4-carboxylic acid was used instead of 2-(pyridin-3-yl)thiazole-4-carboxylic acid.

[0261] 1H NMR (500 MHz, MeOD): 8.76(d, 2H), 8.50(s, 1H), 8.06(d, 2H), 7.81(s, 1H), 7.11(d, 1H), 6.46(d, 1H), 3.21-2.92(m, 7H), 2.90-2.60(m, 6H), 2.52-2.40(m, 3H), 2.27-2.03(m, 3H), 1.91-1.82(m, 1H), 1.51(q, 1H), 1.12(d, 6H)

[0262]

[0263] Example 13: Preparation of N-(2-(4-(aminomethyl)-3-fluoropiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0264]

[0265] The same method as in Example 3 was followed, except that tert-butyl ((1-(4-bromo-2-nitrophenyl)-3-fluoropiperidin-4-yl)methyl)carbamate was used instead of tert-butyl ((1-(4-bromo-2-nitrophenyl)piperidin-4-yl)methyl)carbamate and 2-(pyridin-4-yl)thiazole-4-carboxylic acid was used instead of 2-(pyridin-3-yl)thiazole-4-carboxylic acid, thereby obtaining the title compound (yield 72.0 mg).

[0266] 1H NMR (500 MHz, MeOD): 8.74(d, 2H), 8.69(s, 1H), 8.17(d, 2H), 7.93(s, 1H), 7.11(d, 1H), 6.45(d, 1H), 2.97-2.89(m, 4H), 2.82-2.70(m, 3H), 2.38(t, 2H), 2.11-1.90(m, 3H), 1.80-1.65(m, 2H), 1.50-1.41(m, 2H), 1.09(d, 6H)

[0267]

[0268] Example 14: Preparation of N-(2-(4-(acetamidomethyl)-3-fluoropiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0269]

[0270] N-(2-(4-(aminomethyl)-3-fluoropiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide (35.0 mg, 1.0 eq), triethylamine (26.8 mg, 5.0 eq), and 1-methyl-2-pyrrolidone (2.0 mL) were added, and the pH was confirmed to be 10 or higher. After cooling to 5 ℃ or lower, acetyl chloride (464.6 mg, 1.0 eq) was added, and the mixture was stirred for 1 hour. After completion of the reaction, the layers were separated with ethyl acetate and a saturated aqueous solution of sodium bicarbonate, and the organic layer was washed with purified water. The obtained organic layer was concentrated, dehydrated using sodium sulfate, and purified by column chromatography (volume ratio = dichloromethane: methanol = 4:1) to obtain the title compound (11.0 mg, yield 35.0%).

[0271] 1H NMR (500 MHz, MeOD): 8.76(d, 2H), 8.46(s, 1H), 8.17(d, 2H), 7.93(s, 1H), 7.11(d, 1H), 6.43(d, 1H), 3.41-3.15(m, 4H), 3.09-2.81(m, 5H), 2.71(t, 1H), 2.49(t, 2H), 2.78-2.08(m, 2H), 1.95(s, 3H), 1.71-1.49(m, 3H), 1.30-1.21(m, 1H), 1.11(d, 6H)

[0272]

[0273] Example 15: Preparation of N-(2-(3-aminopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0274]

[0275] The title compound (168.1 mg) was obtained in the same manner as in Example 3, except that tert-butyl (1-(4-bromo-2-nitrophenyl)piperidin-3-yl)carbamate was used instead of tert-butyl ((1-(4-bromo-2-nitrophenyl)piperidin-4-yl)methyl)carbamate and 2-(pyridin-4-yl)thiazole-4-carboxylic acid was used instead of 2-(pyridin-3-yl)thiazole-4-carboxylic acid.

[0276] 1H NMR (500 MHz, MeOD): 8.76(d, 2H), 8.48(s, 1H), 8.06(d, 2H), 7.87(s, 1H), 7.09(d, 1H), 6.44(d, 1H), 3.18-2.61(m, 6H), 2.51(m, 1H), 2.31(t, 2H), 2.11-1.83(m, 5H), 1.51(q, 2H), 1.38-1.22(m, 2H), 1.10(d, 6H)

[0277]

[0278] Example 16: Preparation of N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)-1H-imidazole-4-carboxamide

[0279]

[0280] The title compound (amount 10.3 mg, yield 24.2%) was obtained by the same method as in Example 2, except that 4-amino isopropylpiperidine was used instead of 4-amino methylpiperidine and 2-(pyridin-4-yl)-1H-imidazole-4-carboxylic acid was used instead of 2-(pyridin-3-yl)thiazole-4-carboxylic acid. 1H NMR (500 MHz, MeOD): 8.46(d, 2H), 8.43(s, 1H), 8.05(s, 1H), 7.78(s, 1H), 7.02(d, 1H), 6.38(d, 1H), 3.00(d, 2H), 2.93(d, 2H), 2.81-2.67(m, 4H), 2.32(t, 2H), 2.10-2.02(m, 1H), 1.92-1.84(m, 1H), 1.72-1.60(m, 3H), 1.57-1.42(m, 3H), 1.32-1.22(m, 2H) 1.08(d, 6H)

[0281]

[0282] Example 17: Preparation of N-(5-((1-isopropylpiperidin-4-yl)amino)-2-(4-(methoxymethyl)piperidin-1-yl)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[0283]

[0284] The title compound (32.0 mg) was obtained by the same method as in Step 2-1 of Example 2, except that 4-(methoxymethyl)piperidine was used instead of tert-butyl(piperidin-4-ylmethyl)carbamate, 1-(4-bromo-2-nitrophenyl)-4-(methoxymethyl)piperidine was used instead of 4-chloro-1-(cyclopentyloxy)-2-nitrobenzene, 1-isopropylpiperidin-4-amine was used instead of methylpiperidin-4-amine, and 2-(pyridin-3-yl)thiazole-4-carboxylic acid was used instead of 2-(pyridin-4-yl)thiazole-4-carboxylic acid. 1H NMR (500 MHz, MeOD): 8.75(d, 2H), 8.50(s, 1H), 8.09(d, 2H), 7.90(s, 1H), 7.13(d, 1H), 6.48(d, 1H), 4.58(s, 1H), 3.05-2.71(m, 8H), 2.24(m, 2H), 1.97-1.51(m, 13H), 1.45-1.23(m, 8H)

[0285]

[0286] Experimental example: Inhibitory activity against IRAK4

[0287] 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.

[0288] 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.

[0289]

[0290] IRAK4 IC 50 (nM)IRAK4 IC 50 (nM)IRAK4 IC 50 (nM) Example 1120.1 Example 76.0 Example 134.8 Example 216.4 Example 864.1 Example 1425.6 Example 38.5 Example 911.6 Example 15166.2 Example 43.7 Example 1020.6 Example 16337.7 Example 526.9 Example 112.5 Example 17277.0 Example 67.4 Example 1233.2

Claims

1. A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, X is S or NR, The above R is hydrogen or C 1-4 It is alkyl, L is a single bond; or -O-, R1 is C 3-6 Cycloalkyl; or C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S 3-10 It is heterocycloalkyl, The above R1 is unsubstituted; or halogen, amino, amino(C 1-4 alkyl), -NHCO-(C 1-4 alkyl), -NHCO-(C 2-4 alkenyl), -CH2-NHCO-(C 1-4 alkyl), -CH2-NHCO-(C 2-4 alkenyl), hydroxy, hydroxy(C 1-4 alkyl), -CH2-O-(C 1-4 C containing 1 to 3 heteroatoms each independently selected from the group consisting of alkyl), and N, O and S 3-10 Substituted with one or two substituents selected from the group consisting of heterocycloalkyl, R2 is hydrogen; or C 1-4 It's alkyl.

2. In paragraph 1, R is hydrogen, A compound, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, R1 is cyclopentyl, piperidinyl, or octahydro-1H-pyrrolo[3,4-c]pyridinyl, wherein R1 is unsubstituted or substituted with one or two substituents selected from the group consisting of fluoro, amino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, -NHCO-(methyl), -NHCO-(ethyl), -NHCO-(propyl), -NHCO-(isopropyl), -NHCO-(ethenyl), -CH2-NHCO-(methyl), -CH2-NHCO-(ethyl), -CH2-NHCO-(propyl), -CH2-NHCO-(isopropyl), -CH2-NHCO-(ethenyl), hydroxy, hydroxymethyl, hydroxypropyl, -CH2-O-(methyl), and piperidinyl. A compound, or a pharmaceutically acceptable salt thereof.

4. In paragraph 1, L is a single bond, R1 is C containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S. 3-10 It is heterocycloalkyl, The above R1 is unsubstituted; or halogen, amino, amino(C 1-4 alkyl), -NHCO-(C 1-4 alkyl), -NHCO-(C 2-4 alkenyl), -CH2-NHCO-(C 1-4 alkyl), -CH2-NHCO-(C 2-4 alkenyl), hydroxy, hydroxy(C 1-4 alkyl), -CH2-O-(C 1-4 C containing 1 to 3 heteroatoms each independently selected from the group consisting of alkyl), and N, O and S 3-10 A compound substituted with one or two substituents selected from the group consisting of heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, L is -O-, R1 is C 3-6 It is cycloalkyl, The above R1 is unsubstituted, A compound, or a pharmaceutically acceptable salt thereof.

6. In paragraph 1, R2 is hydrogen, methyl, or isopropyl, A compound, or a pharmaceutically acceptable salt thereof.

7. In paragraph 1, The above chemical formula 1 is represented by the following chemical formula 2, A compound, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] In the above chemical formula 2, X is S or NH, R'1 and R'2 are each independently hydrogen, halogen, amino, amino(C 1-4 alkyl), -NHCO-(C 1-4 alkyl), -NHCO-(C 2-4 alkenyl), -CH2-NHCO-(C 1-4 alkyl), -CH2-NHCO-(C 2-4 alkenyl), hydroxy, hydroxy(C 1-4 alkyl), -CH2-O-(C 1-4 C containing 1 to 3 heteroatoms each independently selected from the group consisting of alkyl), or N, O and S 3-10 It is heterocycloalkyl, R2 is C 1-4 It's alkyl.

8. In paragraph 1, The compound represented by the above chemical formula 1 is 1) N-(2-(cyclopentyloxy)-5-(1-methylpiperidin-4-ylamino)phenyl)-2-(pyridin-3-yl)thiazole-4-carboxamide, 2) N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-methylpiperidin-4-ylamino)phenyl)-2-(pyridin-3-yl)thiazole-4-carboxamide, 3) N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-3-yl)thiazole-4-carboxamide, 4) N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide, 5) N-(2-(4-aminopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide, 6) N-(2-(4-acrylamidopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide, 7) N-(2-(4-acetamidopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide, 8) N-(2-(4-isobutyramidopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide, 9) N-(2-(4-(3-hydroxypropyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide, 10) N-(2-(4,4'-bipiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide, 11) N-(2-(4-(aminomethyl)-4-hydroxypiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide, 12) N-(5-((1-isopropylpiperidin-4-yl)amino)-2-(octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide, 13) N-(2-(4-(aminomethyl)-3-fluoropiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide, 14) N-(2-(4-(acetamidomethyl)-3-fluoropiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide, 15) N-(2-(3-aminopiperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide, 16) N-(2-(4-(aminomethyl)piperidin-1-yl)-5-(1-isopropylpiperidin-4-ylamino)phenyl)-2-(pyridin-4-yl)-1H-imidazole-4-carboxamide, and 17) N-(5-((1-isopropylpiperidin-4-yl)amino)-2-(4-(methoxymethyl)piperidin-1-yl)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide Any one compound selected from the group consisting of, A compound, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition for preventing or treating cancer or autoimmune disease, comprising a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

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