Use of heterocyclic compound

Abstract

[式中，各記號係如說明書所記載。]。;

Description

Technical Field

[0001] This invention relates to heterocyclic compounds that may have MALT1 (mucosa-associated lymphoid tissue protein 1) blocking effects and are expected to be used as preventive or therapeutic agents for cancer, etc. Prior Technology

[0002] T-cell and B-cell receptor signaling play crucial roles in the function of T-cell and B-cell receptor signaling, which are the main cells responsible for cellular immunity. Abnormalities in this signaling transmission are a cause of various diseases, including cancer and inflammatory disorders. In fact, in the case of cancer, gene analysis of patients with T-cell-derived leukemia-lymphomas such as ATL (adult T-cell leukemia-lymphoma), which is one of the refractory lymphomas, has confirmed gene abnormalities in the T-cell receptor signaling / NF-κB pathway. In addition, the B-cell receptor signaling / NF-κB pathway has been reported to be persistently activated in other B-cell lymphomas such as ABC type DLBCL (diffuse large cell B-cell lymphoma) and MCL (mantle cell lymphoma).

[0003] The CBM protein complex, which facilitates the convergence of T-cell and B-cell receptor signals, consists of the scaffold protein CARD11, the transfer protein BCL10, and MALT1, which possesses paracaspase activity. The formation of the CBM protein complex is promoted by both T-cell and B-cell receptor signals, inducing an increase in the paracaspase activity of MALT1 and activating the transcription factor NF-κB.

[0004] Therefore, inhibitors that block MALT1 activity are expected to correct the hyperactivity of MALT1 caused by abnormal T-cell receptor or B-cell receptor signals, and are considered to be used as preventive or therapeutic drugs for cancers or inflammatory diseases caused by MALT1 activity.

[0005] The compounds of this invention are intended for the prevention or treatment of diseases potentially affected by MALT1 (sometimes referred to herein as "MALT1-related diseases"). This is not limited to the following diseases, but is intended for the prevention or treatment of cancers such as colorectal cancer (e.g., colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors, etc.), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer, pancreatic endocrine tumors, etc.), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary gland cancer, mucinous adenocarcinoma, adenosquamous carcinoma, etc.), and dodecandibular joint cancer. Diuretic cancer, small bowel cancer, breast cancer (e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer, etc.), ovarian cancer (e.g., epithelial ovarian cancer, gonadal ectodermal tumors, ovarian germ cell tumors, low-grade ovarian tumors, etc.), testicular tumors, prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer, castration-resistant prostate cancer, etc.), liver cancer (e.g., hepatocellular carcinoma, primary liver cancer, extrahepatic bile duct cancer, etc.), thyroid cancer (e.g., medullary thyroid carcinoma). (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), uterine cancer (e.g., cervical cancer, uterine body cancer, uterine sarcoma), gestational choriocarcinoma, brain tumors (e.g., medulloblastoma, glioma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, degenerative astrocytoma, pituitary adenoma), retinoid blastoma, skin cancer (e.g., basal cell carcinoma, malignant melanoma). [This includes various cancers such as melanoma, sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft sarcoma, spindle cell sarcoma, osteosarcoma), malignant bone tumors, bladder cancer, hematologic malignancies (e.g., multiple myeloma, leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia), malignant lymphomas (e.g., diffuse large cell B-cell lymphoma, mantle cell lymphoma, adult T-cell leukemia lymphoma, chronic myeloproliferative disorders), Hodgkin's disease, and cancers of unknown primary origin]. These cancers can inhibit cancer proliferation, suppress metastasis, promote apoptosis, or prevent or treat precancerous lesions (e.g., myelodysplastic syndrome). Furthermore, the compounds of the present invention are expected to be used for the prevention or treatment of autoimmune diseases and / or inflammatory diseases (e.g., encephalomyelitis, colitis, atopic diseases, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, etc.), bone diseases, metabolic diseases, neurological diseases and neurodegenerative diseases, cancer, circulatory organ diseases, allergies and asthma, Alzheimer's disease and hormone-related inflammatory diseases, viral infections (e.g., human immunodeficiency virus infections, etc.), and bacterial infections (e.g., sepsis, etc.).

[0006] In Patent Document 1, the following compound has been disclosed as having MALT1 blocking activity and is used to treat autoimmune disorders and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and vasculitis, as well as cancers or solid tumors of the hematopoietic system, including chronic myeloid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.

[0007]

[0008]

[0009] [In the formula, each notation is as defined in the relevant document.]

[0010] In Patent Document 2, a compound with MALT1 blocking activity has been disclosed for the treatment of autoimmune disorders and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, Sjogren's syndrome, systemic lupus erythematosus, and vasculitis, as well as cancers or solid tumors originating from the hematopoietic system, including chronic myeloid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.

[0011]

[0012]

[0013] [In the formula, each notation is as defined in the relevant document.]

[0014] In Patent Document 3, the following compound has been disclosed as a compound that has MALT1 blocking effect and is used to treat autoimmune disorders, inflammatory diseases, cancer, etc.

[0015]

[0016]

[0017] [In the formula, each symbol is defined as in the literature.]

[0018] In Patent Document 4, as a compound having two functions of inhibiting MALT1 and promoting the degradation of MALT1 protein by supplementing an E3 ubiquitin ligase, and being useful for treating cancers such as blood cancer, lymphoid malignancies, leukemia, lymphoma, multiple myeloma, etc., the following compounds have been disclosed.

[0019]

[0020]

[0021] [In the formula, each symbol is defined as in the literature.]

[0022] [Prior Art Documents]

[0023] [Patent Documents]

[0024]

[0025] [Patent Document 1] WO2015 / 181747

[0026] [Patent Document 2] WO2017 / 081641

[0027] [Patent Document 3] WO2018 / 020474

[0028] [Patent Document 4] WO2018 / 085247 Summary of the Invention Problems to be Solved by the Invention

[0029] An object of the present invention is to provide a novel compound having an MALT1 inhibitory effect and expected to be useful as a preventive or therapeutic drug for cancers, etc., and a medicine containing the same. Means for Solving the Problems

[0030] As a result of the inventors' intensive studies to solve the above problems, it was found that the compound represented by the following formula (I) can have an excellent MALT1 inhibitory effect, and thus the present invention was completed.

[0031] That is, the present invention is as follows.

[0032] [1] A compound of formula (I) or a salt thereof, or a co-crystallization, hydrate or solvent compound thereof (in this specification, it is sometimes abbreviated as "compound (I)"):

[0033]

[0034]

[0035] (in the formula,

[0036] A represents

[0037]

[0038]

[0039] R1 represents 1) a hydrogen atom, 2) a halogen atom, 3) a cyano group, 4) a C1-3 alkyl group that can be substituted with 1 to 3 halogen atoms, 5) a C1-3 alkoxy group, 6) a C3-6 cycloalkyl group, or 7) a phenyl group;

[0040] R2 represents either 1) a hydrogen atom or 2) a halogen atom;

[0041] R3 represents: 1) a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from C1-3 alkoxy, hydroxyl, and halogen atoms; 2) a pyrazolyl group that can be substituted with 1 to 3 substituents selected from C1-3 alkyl and halogen atoms; 3) a C3-6 cycloalkyl group; 4) an amino group disubstituted with a C1-3 alkyl group; or 5) a phenyl group that can be substituted with 1 to 3 halogen atoms.

[0042] R4 and R6 represent 1) a hydrogen atom, 2) a halogen atom, 3) a C1-3 alkyl group that can be substituted by 1 to 3 substituents selected from: a) a hydroxyl group, b) a C1-3 alkoxy group that can be substituted by 4-methoxyphenyl group, and c) a halogen atom, or 4) a C1-3 alkoxy group that can be substituted by 1 to 3 halogen atoms;

[0043] R5, R7, and R9 represent 1) C1-6 alkyl groups that can be substituted with 1 to 3 C1-3 alkoxy groups, or 2) phenyl groups that can be substituted with 1 to 3 halogen atoms;

[0044] R8 indicates a C1-3 alkyl group;

[0045] B indicates

[0046] 1) A phenyl group that can be substituted with 1 to 3 substituents selected from the following: a) halogen atom, b) cyano group, c) C1-3 alkoxy group that can be substituted with 1 to 3 halogen atoms, and d) triazolyl group.

[0047] 2) C3-6 cycloalkyl groups that can be substituted with 1 to 3 substituents selected from the following: a) C1-3 alkyl groups that can be substituted with 1 to 3 halogen atoms and b) halogen atoms,

[0048] 3) Pyridyl groups that can be substituted with 1 to 3 substituents selected from the following: a) halogen atom, b) cyano, c) C1-3 alkyl groups that can be substituted with 1 to 3 halogen atoms, d) C1-3 alkoxy groups that can be substituted with 1 to 3 substituents selected from halogen atoms and C1-3 alkoxy groups, e) pyrazolyl groups that can be substituted with 1 to 3 C1-3 alkyl groups, f) imidazolyl groups that can be substituted with 1 to 3 C1-3 alkyl groups, g) triazolyl groups that can be substituted with 1 to 3 C1-3 alkyl groups, wherein the 1 to 3 C1-3 alkyl groups can be substituted with 1 to 3 substituents selected from C1-3 alkoxy groups and halogen atoms, h) aziridine, i) pyrrolidonyl, j) tetrazolyl groups that can be substituted with 1 to 3 C1-3 alkyl groups, k) pyrimidinyl and l) azole group,

[0049] 4) A pyrazolyl group that can be substituted with 1 to 3 substituents selected from the following: a) a C1-3 alkyl group that can be substituted with 1 to 3 halogen atoms, b) a C1-3 alkoxy group that can be substituted with 1 to 3 halogen atoms, c) a cyano group, and d) a halogen atom, or

[0050] 5) Imidazolyl groups that can be substituted with 1 to 3 halogen atoms.

[0051] [2] As described in [1], in which A is

[0052]

[0053]

[0054] [3] As described in [1], in which A is

[0055]

[0056]

[0057] [4] As described in [1], in which A is

[0058]

[0059]

[0060] R1 is either a halogen atom or a C1-3 alkyl atom;

[0061] R2 is a hydrogen atom;

[0062] R3 is a C1-6 alkyl group that can be substituted with 1 to 3 C1-3 alkoxy groups;

[0063] R4 is either a halogen atom or a C1-3 alkyl atom;

[0064] R5 is a C1-6 alkyl group that can be substituted with 1 to 3 C1-3 alkoxy groups;

[0065] B is a pyridinyl group that can be substituted by 1 to 3 substituents selected from the following: a) halogen atom, b) cyano group, c) C1-3 alkyl group that can be substituted by 1 to 3 halogen atoms, d) C1-3 alkoxy group that can be substituted by 1 to 3 halogen atoms, and e) triazolyl group.

[0066] [5] As described in [1], it is a compound

[0067] (S)-N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil) -7-base)urea,

[0068] (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5- (Pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea,

[0069] (S)-N-(4-(1-methoxyethyl)-6-methyl-1,5- (Pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea,

[0070] (S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil) -7-base)urea,

[0071] (S)-N-(5-cyano-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil) -7-base)urea,

[0072] (S)-N-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil -7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea,

[0073] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(2-methoxypropyl-2-yl)-2-methylimidazo[1,2-b]tadalafil -7-base)urea,

[0074] N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-chloro-8-(prop-2-yl)imidazo[1,2-b]tadalafil -7-based urea, or

[0075] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(2-methyl-8-(prop-2-yl)imidazo[1,2-b]tadalafil -7-based) urea.

[0076] [6] The compound as described in [1], which is (S)-N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)urea. -7-yl)urea.

[0077] [7] The compound as described in [1], which is (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5-pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea. -3-yl)urea.

[0078] [8] A medicament, which contains the compound as described in [1] or its salt, or its co-crystal, hydrate or solvate.

[0079] [9] The medicament as described in [8], which is a MALT1 inhibitor.

[0080]

[10] The medicament as described in [8], which is a prophylactic or therapeutic agent for cancer. [[ID=​​​​​​​​​​​​​​​​​​​​​​In this specification, examples of "C3-6 cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0086] In this specification, examples of "C1-3 alkoxy" include methoxy, ethoxy, propoxy, and isopropoxy.

[0087] In this specification, examples of "amino groups disubstituted with C1-3 alkyl groups" include dimethylamino, ethylmethylamino, diethylamino, ethylpropylamino, and dipropylamino.

[0088] In this specification, "C1-3 alkyl" can be used to list those "C1-6 alkyl" with 1 to 3 carbon atoms.

[0089] The definitions of each symbol in equation (I) will be described in detail below.

[0090] A represents

[0091]

[0092]

[0093] A is better.

[0094]

[0095]

[0096] In one suitable embodiment of the present invention, A is

[0097]

[0098]

[0099] In another suitable embodiment of the present invention, A is...

[0100]

[0101]

[0102] .

[0103] R1 represents 1) a hydrogen atom, 2) a halogen atom (e.g., chlorine atom, bromine atom), 3) a cyano group, 4) a C1-3 alkyl group (e.g., methyl group) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atom), 5) a C1-3 alkoxy group (e.g., methoxy group), 6) a C3-6 cycloalkyl group (e.g., cyclopropyl group), or 7) a phenyl group.

[0104] R1 is preferably 1) a halogen atom (e.g., a chlorine atom) or 2) a C1-3 alkyl group (e.g., a methyl group).

[0105] R2 represents 1) a hydrogen atom, or 2) a halogen atom (e.g., a fluorine atom, a chlorine atom).

[0106] R2 is preferably a hydrogen atom.

[0107] R3 represents 1) a C1-6 alkyl group (e.g., ethyl, isopropyl, dibutyl) that can be substituted with 1 to 3 substituents selected from C1-3 alkoxy (e.g., methoxy), hydroxyl, and halogen atom (e.g., fluorine), 2) a pyrazolyl group (e.g., 4-pyrazolyl) that can be substituted with 1 to 3 substituents selected from C1-3 alkyl (e.g., methyl) and halogen atom (e.g., chlorine), 3) a C3-6 cycloalkyl group (e.g., cyclopropyl), 4) an amino group disubstituted with a C1-3 alkyl group (e.g., methyl), or 5) a phenyl group that can be substituted with 1 to 3 halogen atom (e.g., chlorine).

[0108] R3 is preferably a C1-6 alkyl group (e.g., ethyl, isopropyl) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy groups).

[0109] R4 and R6 represent 1) a hydrogen atom, 2) a halogen atom (e.g., a chlorine atom), 3) a C1-3 alkyl group (e.g., methyl, ethyl) that can be substituted with 1 to 3 substituents selected from the following: a) hydroxyl group, b) a C1-3 alkoxy group (e.g., methoxy) that can be substituted with 4-methoxyphenyl group, and c) a halogen atom (e.g., a fluorine atom), or 4) a C1-3 alkoxy group (e.g., methoxy, ethoxy) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms).

[0110] R4 is preferably 1) a halogen atom (e.g., a chlorine atom) or 2) a C1-3 alkyl group (e.g., a methyl group).

[0111] R6 is preferably 1) a hydrogen atom, 2) a halogen atom (e.g., a chlorine atom), 3) a C1-3 alkyl group (e.g., a methyl group), or 4) a C1-3 alkoxy group (e.g., a methoxy group).

[0112] R5, R7 and R9 represent 1) C1-6 alkyl groups (e.g., ethyl, isopropyl) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy, ethoxy) or 2) phenyl groups that can be substituted with 1 to 3 halogen atoms (e.g., chlorine atoms).

[0113] R5 is preferably a C1-6 alkyl group (e.g., ethyl group) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy groups).

[0114] R7 is preferably 1) a C1-6 alkyl group (e.g., ethyl, isopropyl) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy groups), or 2) a phenyl group that can be substituted with 1 to 3 halogen atoms (e.g., chlorine atoms).

[0115] R9 is preferably a C1-3 alkyl group (e.g., ethyl group) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy groups).

[0116] R8 represents a C1-3 alkyl group (e.g., methyl).

[0117] B indicates

[0118] 1) A phenyl group that can be substituted with 1 to 3 substituents selected from the following: a) a halogen atom (e.g., fluorine atom, chlorine atom), b) a cyano group, c) a C1-3 alkoxy group (e.g., methoxy group) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atom), and d) a triazolyl group.

[0119] 2) C3-6 cycloalkyl groups (e.g., cyclohexyl) that can be substituted with 1 to 3 substituents selected from the following: a) C1-3 alkyl groups (e.g., methyl) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) and b) halogen atoms (e.g., fluorine atoms).

[0120] 3) A pyridyl group that can be substituted with 1 to 3 substituents selected from the following: a) a halogen atom (e.g., fluorine, chlorine, bromine), b) a cyano group, c) a C1-3 alkyl group (e.g., methyl) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine), d) a C1-3 alkoxy group (e.g., methoxy, ethoxy) that can be substituted with 1 to 3 substituents selected from a halogen atom (e.g., fluorine) and a C1-3 alkoxy group (e.g., methoxy), e) a C1-3 alkoxy group (e.g., methoxy, ethoxy) that can be substituted with 1 to 3 C1-3 alkyl groups. f) pyrazolyl group substituted with alkyl (e.g., methyl), g) imidazolyl group substituted with 1 to 3 C1-3 alkyl (e.g., methyl), i) triazolyl group substituted with 1 to 3 C1-3 alkyl (e.g., methyl), wherein the 1 to 3 C1-3 alkyl group may be substituted with 1 to 3 substituents selected from C1-3 alkoxy (e.g., methoxy) and halogen atoms (e.g., fluorine), h) aziridine, i) pyrrolidone group, j) tetrazolyl group substituted with 1 to 3 C1-3 alkyl (e.g., methyl), k) pyrimidinyl group and l) azole group,

[0121] 4) A pyrazolyl group that can be substituted with 1 to 3 substituents selected from the following: a) a C1-3 alkyl group (e.g., methyl, ethyl, isopropyl) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); b) a C1-3 alkoxy group (e.g., methoxy) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); c) a cyano group; and d) a halogen atom (e.g., chlorine atom).

[0122] 5) Imidazolyl groups that can be substituted with 1 to 3 halogen atoms (e.g., chlorine atoms).

[0123] B is preferably a pyridyl group that can be substituted with 1 to 3 substituents selected from the following: a) a halogen atom (e.g., chlorine atom), b) a cyano group, c) a C1-3 alkyl group (e.g., methyl group) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atom), d) a C1-3 alkoxy group (e.g., methoxy group) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atom), and e) a triazolyl group.

[0124] As suitable examples of compound (I), the following compounds can be listed.

[0125] [Compound I-1]

[0126] Compound (I), in which,

[0127] A is

[0128]

[0129]

[0130] ;

[0131] R1 can be 1) a hydrogen atom, 2) a halogen atom (e.g., chlorine atom, bromine atom), 3) a cyano group, 4) a C1-3 alkyl group (e.g., methyl group) that can be substituted with 1-3 halogen atoms (e.g., fluorine atom), 5) a C1-3 alkoxy group (e.g., methoxy group), 6) a C3-6 cycloalkyl group (e.g., cyclopropyl group), or 7) a phenyl group;

[0132] R2 can be either 1) a hydrogen atom or 2) a halogen atom (e.g., a fluorine atom or a chlorine atom);

[0133] R3 can be: 1) a C1-6 alkyl group (e.g., ethyl, isopropyl, dibutyl) that can be substituted with 1 to 3 substituents selected from C1-3 alkoxy groups (e.g., methoxy), hydroxyl groups, and halogen atoms (e.g., fluorine atoms); 2) a pyrazolyl group (e.g., 4-pyrazolyl) that can be substituted with 1 to 3 substituents selected from C1-3 alkyl groups (e.g., methyl) and halogen atoms (e.g., chlorine atoms); 3) a C3-6 cycloalkyl group (e.g., cyclopropyl); 4) an amino group disubstituted with a C1-3 alkyl group (e.g., methyl); or 5) a phenyl group that can be substituted with 1 to 3 halogen atoms (e.g., chlorine atoms).

[0134] R4 is 1) a hydrogen atom, 2) a halogen atom (e.g., a chlorine atom), 3) a C1-3 alkyl group (e.g., methyl, ethyl) that may be substituted with 1 to 3 substituents selected from the following: a) hydroxyl group, b) a C1-3 alkoxy group (e.g., methoxy) that may be substituted with 4-methoxyphenyl, and c) a halogen atom (e.g., a fluorine atom), or 4) a C1-3 alkoxy group (e.g., methoxy, ethoxy) that may be substituted with 1 to 3 halogen atoms (e.g., fluorine).

[0135] R5 is 1) a C1-6 alkyl group (e.g., ethyl, isopropyl) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy, ethoxy), or 2) a phenyl group that can be substituted with 1 to 3 halogen atoms (e.g., chlorine atoms);

[0136] R6 can be 1) a hydrogen atom, 2) a halogen atom (e.g., a chlorine atom), 3) a C1-3 alkyl group (e.g., a methyl group), or 4) a C1-3 alkoxy group (e.g., an ethoxy group);

[0137] R7 is 1) a C1-6 alkyl group (ethyl, isopropyl) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy groups), or 2) a phenyl group that can be substituted with 1 to 3 halogen atoms (e.g., chlorine atoms);

[0138] R8 is a C1-3 alkyl group (e.g., methyl);

[0139] R9 is a C1-3 alkyl group (e.g., ethyl group) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy groups);

[0140] B is

[0141] 1) A phenyl group that can be substituted with 1 to 3 substituents selected from the following: a) a halogen atom (e.g., fluorine atom, chlorine atom), b) a cyano group, c) a C1-3 alkoxy group (e.g., methoxy group) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atom), and d) a triazolyl group.

[0142] 2) C3-6 cycloalkyl groups (e.g., cyclohexyl) that can be substituted with 1 to 3 substituents selected from the following: a) C1-3 alkyl groups (e.g., methyl) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) and b) halogen atoms (e.g., fluorine atoms).

[0143] 3) A pyridyl group that can be substituted with 1 to 3 substituents selected from the following: a) a halogen atom (e.g., fluorine, chlorine, bromine); b) a cyano group; c) a C1-3 alkyl group (e.g., methyl) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine); d) a C1-3 alkoxy group (e.g., methoxy, ethoxy) that can be substituted with 1 to 3 substituents selected from a halogen atom (e.g., fluorine) and a C1-3 alkoxy group (e.g., methoxy); e) a C1-3 alkyl group (e.g., methyl... (f) pyrazolyl group substituted with 1 to 3 C1-3 alkyl groups (e.g., methyl), (g) triazolyl group substituted with 1 to 3 C1-3 alkyl groups (e.g., methyl), wherein the 1 to 3 C1-3 alkyl groups may be substituted with 1 to 3 substituents selected from C1-3 alkoxy groups (e.g., methoxy groups) and halogen atoms (e.g., fluorine atoms), (h) aziridineyl group, (i) pyrrolidone group, (j) tetrazolyl group substituted with 1 to 3 C1-3 alkyl groups (e.g., methyl groups), (k) pyrimidinyl group and (l) pyrimidinyl group. azole group,

[0144] 4) A pyrazolyl group that can be substituted with 1 to 3 substituents selected from the following: a) a C1-3 alkyl group (e.g., methyl, ethyl, isopropyl) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); b) a C1-3 alkoxy group (e.g., methoxy) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); c) a cyano group; and d) a halogen atom (e.g., chlorine atom).

[0145] 5) Imidazolyl groups that can be substituted with 1 to 3 halogen atoms (e.g., chlorine atoms).

[0146] [Compound I-2]

[0147] Compound (I), in which,

[0148] A is

[0149]

[0150]

[0151] ;

[0152] R1 is either a halogen atom (e.g., a chlorine atom) or a C1-3 alkyl group (e.g., a methyl group);

[0153] R2 is a hydrogen atom;

[0154] R3 is a C1-6 alkyl group (e.g., ethyl, isopropyl) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy groups);

[0155] R4 is either 1) a halogen atom (e.g., a chlorine atom) or 2) a C1-3 alkyl group (e.g., a methyl group);

[0156] R5 is a C1-6 alkyl group (e.g., ethyl group) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy groups);

[0157] B is a pyridinyl group that can be substituted by 1 to 3 substituents selected from the following: a) halogen atom (e.g., chlorine atom), b) cyano, c) C1-3 alkyl group (e.g., methyl) that can be substituted by 1 to 3 halogen atom (e.g., fluorine atom), d) C1-3 alkoxy group (e.g., methoxy) that can be substituted by 1 to 3 halogen atom (e.g., fluorine atom), and e) triazolyl group.

[0158] [Compound I-3]

[0159] Compound (I), in which,

[0160] A is

[0161]

[0162]

[0163] ;

[0164] R1 is a C1-3 alkyl group (e.g., methyl);

[0165] R2 is a hydrogen atom;

[0166] R3 is a C1-6 alkyl group (e.g., ethyl, isopropyl) substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy groups);

[0167] R4 is either 1) a halogen atom (e.g., a chlorine atom) or 2) a C1-3 alkyl group (e.g., a methyl group);

[0168] R5 is a C1-6 alkyl group (e.g., ethyl group) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy groups);

[0169] B is a pyridyl group that can be substituted by 1 to 3 substituents selected from the following: a) a halogen atom (e.g., chlorine atom), b) a C1-3 alkyl group (e.g., methyl) that can be substituted by 1 to 3 halogen atoms (e.g., fluorine atom), c) a C1-3 alkoxy group (e.g., methoxy) that can be substituted by 1 to 3 halogen atoms (e.g., fluorine atom), and d) a triazolyl group.

[0170] [Compound I-4]

[0171] Compound (I), in which,

[0172] A is

[0173]

[0174]

[0175] ;

[0176] R1 can be 1) a hydrogen atom, 2) a halogen atom (e.g., chlorine atom, bromine atom), 3) a cyano group, 4) a C1-3 alkyl group (e.g., methyl group) that can be substituted with 1-3 halogen atoms (e.g., fluorine atom), 5) a C1-3 alkoxy group (e.g., methoxy group), 6) a C3-6 cycloalkyl group (e.g., cyclopropyl group), or 7) a phenyl group;

[0177] R2 can be either 1) a hydrogen atom or 2) a halogen atom (e.g., a fluorine atom or a chlorine atom);

[0178] R3 can be: 1) a C1-6 alkyl group (e.g., ethyl, isopropyl, dibutyl) that can be substituted with 1 to 3 substituents selected from C1-3 alkoxy groups (e.g., methoxy), hydroxyl groups, and halogen atoms (e.g., fluorine atoms); 2) a pyrazolyl group (e.g., 4-pyrazolyl) that can be substituted with 1 to 3 substituents selected from C1-3 alkyl groups (e.g., methyl) and halogen atoms (e.g., chlorine atoms); 3) a C3-6 cycloalkyl group (e.g., cyclopropyl); 4) an amino group disubstituted with a C1-3 alkyl group (e.g., methyl); or 5) a phenyl group that can be substituted with 1 to 3 halogen atoms (e.g., chlorine atoms).

[0179] B is

[0180] 1) A phenyl group that can be substituted with 1 to 3 substituents selected from the following: a) a halogen atom (e.g., fluorine atom, chlorine atom), b) a cyano group, c) a C1-3 alkoxy group (e.g., methoxy group) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atom), and d) a triazolyl group.

[0181] 2) A pyridyl group that can be substituted with 1 to 3 substituents selected from the following: a) a halogen atom (e.g., chlorine atom, bromine atom), b) a cyano group, c) a C1-3 alkyl group (e.g., methyl group) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atom), d) a C1-3 alkoxy group (e.g., methoxy group) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atom), e) a pyrazolyl group that can be substituted with 1 to 3 C1-3 alkyl groups (e.g., methyl group), f) an imidazolyl group that can be substituted with 1 to 3 C1-3 alkyl groups (e.g., methyl group), g) a triazolyl group that can be substituted with 1 to 3 C1-3 alkyl groups (e.g., methyl group), wherein the 1 to 3 C1-3 alkyl groups can be substituted with 1 to 3 substituents selected from C1-3 alkoxy groups (e.g., methoxy group) and halogen atoms (e.g., fluorine atom), and h) azole group,

[0182] 3) A pyrazolyl group that can be substituted with 1 to 3 substituents selected from the following: a) a C1-3 alkyl group (e.g., methyl) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); b) a C1-3 alkoxy group (e.g., methoxy) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); c) a cyano group; and d) a halogen atom (e.g., chlorine atom).

[0183] 4) Imidazolyl groups that can be substituted with 1 to 3 halogen atoms (e.g., chlorine atoms).

[0184] [Compound I-5]

[0185] Compound (I), in which,

[0186] A is

[0187]

[0188]

[0189] ;

[0190] R4 is 1) a hydrogen atom, 2) a halogen atom (e.g., a chlorine atom), 3) a C1-3 alkyl group (e.g., methyl, ethyl) that may be substituted with 1 to 3 substituents selected from the following: a) hydroxyl group, b) a C1-3 alkoxy group (e.g., methoxy) that may be substituted with 4-methoxyphenyl, and c) a halogen atom (e.g., a fluorine atom), or 4) a C1-3 alkoxy group (e.g., methoxy, ethoxy) that may be substituted with 1 to 3 halogen atoms (e.g., fluorine).

[0191] R5 is 1) a C1-6 alkyl group (e.g., ethyl, isopropyl) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy, ethoxy), or 2) a phenyl group that can be substituted with 1 to 3 halogen atoms (e.g., chlorine atoms);

[0192] B is

[0193] 1) Phenyl groups that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms),

[0194] 2) C3-6 cycloalkyl groups (e.g., cyclohexyl) that can be substituted with 1 to 3 substituents selected from the following: a) C1-3 alkyl groups (e.g., methyl) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) and b) halogen atoms (e.g., fluorine atoms).

[0195] 3) A pyridyl group that can be substituted with 1 to 3 substituents selected from the following: a) a halogen atom (e.g., fluorine, chlorine, bromine), b) a cyano group, c) a C1-3 alkyl group (e.g., methyl) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine), d) a C1-3 alkoxy group (e.g., methoxy, ethoxy) that can be substituted with 1 to 3 substituents selected from a halogen atom (e.g., fluorine) and a C1-3 alkoxy group (e.g., methoxy), e) a triazolyl group that can be substituted with 1 to 3 C1-3 alkyl groups (e.g., methyl), wherein the 1 to 3 C1-3 alkyl groups can be substituted with 1 to 3 substituents selected from a C1-3 alkoxy group (e.g., methoxy) and a halogen atom (e.g., fluorine), f) an azacyclobutyl group, g) a pyrrolidone group, h) a tetrazolyl group that can be substituted with 1 to 3 substituents selected from a C1-3 alkyl group (e.g., methyl), i) a pyrimidinyl group, and j) a pyrimidinyl group. azole group, or

[0196] 4) A pyrazolyl group that can be substituted with 1 to 3 C1-3 alkyl groups (e.g., methyl, ethyl, isopropyl), wherein the 1 to 3 C1-3 alkyl groups can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms).

[0197] [Compound I-6]

[0198] Compound (I), in which,

[0199] A is

[0200]

[0201]

[0202] ;

[0203] R6 can be 1) a hydrogen atom, 2) a halogen atom (e.g., a chlorine atom), 3) a C1-3 alkyl group (e.g., a methyl group), or 4) a C1-3 alkoxy group (e.g., an ethoxy group);

[0204] R7 is 1) a C1-6 alkyl group (ethyl, isopropyl) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy groups), or 2) a phenyl group that can be substituted with 1 to 3 halogen atoms (e.g., chlorine atoms);

[0205] B is

[0206] 1) Phenyl groups that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), or

[0207] 2) A pyridyl group that can be substituted with 1 to 3 substituents selected from the following: a) a halogen atom (e.g., chlorine atom), b) a cyano group, c) a C1-3 alkyl group (e.g., methyl group) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atom), d) a C1-3 alkoxy group (e.g., methoxy group) that can be substituted with 1 to 3 halogen atoms (e.g., fluorine atom), and e) a triazolyl group.

[0208] [Compound I-7]

[0209] Compound (I), in which,

[0210] A is

[0211]

[0212]

[0213] R8 is a C1-3 alkyl group (e.g., methyl);

[0214] R9 is a C1-3 alkyl group (e.g., ethyl group) that can be substituted with 1 to 3 C1-3 alkoxy groups (e.g., methoxy groups);

[0215] B is a pyridinyl group that can be substituted by 1 to 3 substituents selected from the following: a) a halogen atom (e.g., chlorine atom), b) a C1-3 alkyl group (e.g., methyl) that can be substituted by 1 to 3 halogen atoms (e.g., fluorine atom), c) a C1-3 alkoxy group (e.g., methoxy) and d) a triazolyl group.

[0216] [Compound I-8]

[0217] (S)-N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil) -7-base)urea,

[0218] (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5- (Pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea,

[0219] (S)-N-(4-(1-methoxyethyl)-6-methyl-1,5- (Pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea,

[0220] (S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil) -7-base)urea,

[0221] (S)-N-(5-cyano-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil) -7-base)urea,

[0222] (S)-N-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil -7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea,

[0223] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(2-methoxypropyl-2-yl)-2-methylimidazo[1,2-b]tadalafil -7-base)urea,

[0224] N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-chloro-8-(prop-2-yl)imidazo[1,2-b]tadalafil -7-based urea, or

[0225] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(2-methyl-8-(prop-2-yl)imidazo[1,2-b]tadalafil -7-based) urea.

[0226] [Compound I-9]

[0227] (S)-N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil) -7-based urea, or

[0228] (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5- (Pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea.

[0229] The salt of the compound shown in formula (I) is preferably a pharmacologically permissible salt. Examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.

[0230] Examples of suitable salts that are compatible with inorganic bases include sodium salts, potassium salts, and other alkaline metal salts; calcium salts, magnesium salts, and other alkaline earth metal salts; aluminum salts; and ammonium salts.

[0231] Examples of suitable salts with organic bases include salts with trimethylamine, triethylamine, pyridine, methylpyridine, ethanolamine, diethanolamine, triethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane [sans(hydroxymethyl)methylamine], tributylamine, cyclohexylamine, benzylamine, dicyclohexylamine, and N,N-dibenzylethylenediamine.

[0232] Suitable examples of salts that react with inorganic acids include those reacting with hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, and phosphate.

[0233] Suitable examples of salts of organic acids include salts of formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0234] Suitable examples of salts of basic amino acids include salts of arginine, lysine, and ornithine.

[0235] Suitable examples of salts of acidic amino acids include salts of aspartic acid and glutamic acid.

[0236] The following describes the method for manufacturing the compound of the present invention.

[0237] The raw materials or reagents used in each step of the following manufacturing method, as well as the resulting compounds, can each form a salt. Examples of such salts include those similar to the salts of the compounds of the present invention described above.

[0238] If the compound obtained in each step is a free compound, it can be converted into the target salt using known methods. Conversely, if the compound obtained in each step is a salt, it can be converted into a free substance or another type of salt of the target using known methods.

[0239] The compounds obtained in each step can be used in the next reaction as is, or as crude products. Alternatively, they can be separated and / or purified from the reaction mixture by conventional methods such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, and chromatography.

[0240] If the compounds used as raw materials or reagents in each step are commercially available, the commercially available products can be used as is.

[0241] In each step of the reaction, the reaction time may vary depending on the reagents or solvents used. Unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 24 hours.

[0242] In each step of the reaction, the reaction temperature may vary depending on the reagents or solvents used. Unless otherwise specified, it is usually -78℃ to 300℃, and preferably -78℃ to 150℃.

[0243] In each step of the reaction, the pressure may vary depending on the reagents or solvents used. Unless otherwise specified, it is usually 1 to 20 atmospheres, preferably 1 to 3 atmospheres.

[0244] In each step of the reaction, a microwave synthesis apparatus, such as the Biotage Initiator, is sometimes used. The reaction temperature can vary depending on the reagents or solvents used; unless otherwise specified, it is typically room temperature to 300°C, preferably 50°C to 250°C. The reaction time can also vary depending on the reagents or solvents used; unless otherwise specified, it is typically 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0245] In each reaction step, unless otherwise specified, the reagent is used in amounts of 0.5 to 20 equivalents relative to the matrix, preferably 0.8 to 5 equivalents. When the reagent is used as a catalyst, it is used in amounts of 0.001 to 1 equivalent relative to the matrix, preferably 0.01 to 0.2 equivalents. When the reagent also functions as a reaction solvent, the amount of reagent used is the solvent amount.

[0246] In each step of the reaction, unless otherwise specified, the reaction is carried out without a solvent, or dissolved or suspended in a suitable solvent. Specific examples of solvents may be listed below, as described in the examples. Alcohols: methanol, ethanol, tributyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Acetamides: N,N-dimethylmethoxylamine, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Acid ions: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; Water.

[0247] The above-mentioned solvents can also be used in appropriate proportions by mixing two or more.

[0248] In each step of the reaction, if a base is used, it is either the base shown below or the base described in the examples. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc.; Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, potassium tributyloxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amines: sodium amination, lithium diisopropylamine, lithium hexamethyldisilamine, etc.; Organolithium compounds: n-butyllithium, etc.

[0249] In each step of the reaction, if an acid or acidic catalyst is used, it is the acid or acidic catalyst shown below, or the acid or acidic catalyst described in the examples. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, etc.

[0250] Unless otherwise specified, the reactions in each step are performed according to well-known methods, such as those described in: 5th Edition of Lectures on Experimental Chemistry, Volumes 13-19 (edited by the Chemical Society of Japan); New Lectures on Experimental Chemistry, Volumes 14-15 (edited by the Chemical Society of Japan); Revision of the 2nd Edition of Precision Organic Chemistry (LF Tietze, Th. Eicher, Nan'e-do); Revision of the Structure and Key Points of Named Organic Reactions (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volumes I-VII (John Wiley & Sons Inc); Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental Procedures (by Jie Jack Li, published by Oxford University); Comprehensive Heterocyclic Chemistry III, Vol. 1-Vol. 14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies for Learning from Named Reactions (translated by Kiyoshi Tomioka, published by Chemical Writers); Comprehensive Organic Transformations (VCH Publishers). The method described in the 1989 issue of Inc., or the method described in the examples, shall be performed.

[0251] In each step, the protection or deprotection reaction of the functional groups is carried out according to methods known in themselves, such as those described in Wiley-Interscience 2007 "Protective Groups in Organic Synthesis, 4th Ed." (by Theodora W. Greene and Peter GMWuts); Thieme 2004 "Protecting Groups 3rd Ed." (by PJ Kocienski), or the methods described in the examples.

[0252] Examples of protecting groups for the hydroxyl or phenolic hydroxyl groups of alcohols include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tributyldimethylsilyl ether, and tetrahydropiperanyl ether; carboxylic acid ester-type protecting groups such as acetate; sulfonate-type protecting groups such as methanesulfonate; and carbonate-type protecting groups such as tributyl carbonate.

[0253] Examples of acetal protecting groups that protect the carbonyl group of aldehydes include dimethyl acetal and other acetal-type protecting groups; 1,3-dimethyl acetal... Protecting groups such as cyclic acetals, etc.

[0254] Examples of ketal protecting groups, such as dimethyl ketal, include ketal-type protecting groups; 1,3-dimethyl ketal, etc. Cyclic ketal protecting groups such as alkyl groups; oxime protecting groups such as O-methyloxime groups; hydrazone protecting groups such as N,N-dimethylhydrazone groups, etc.

[0255] Examples of carboxyl protecting groups include ester-type protecting groups such as methyl ester and amide-type protecting groups such as N,N-dimethylamide.

[0256] Examples of protecting groups for thiol groups include ether-type protecting groups such as benzyl thioether; and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate.

[0257] As protecting groups for amine groups, or aromatic heterocycles such as imidazole, pyrrole, and indole, examples include carbamate-type protecting groups such as benzyl carbamate; acetamide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide.

[0258] The removal of the protecting group can be carried out using methods known to the public, such as using acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or reduction methods.

[0259] In each step, when a reduction reaction is carried out, the reducing agents used can include metal hydrides such as lithium aluminum hydride, sodium triethoxyborohydride, sodium cyanoboronide, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triethoxyborohydride; boranes such as borane tetrahydrofuran complexes; Reinhold nickel; Reinhold cobalt; hydrogen; formic acid; and triethylsilane. When reducing carbon-carbon double or triple bonds, methods using catalysts such as palladium-carbon or Lindlar catalysts are employed.

[0260] In each step, when performing an oxidation reaction, the oxidizing agents used can include peracids such as m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodophenyl iodide; reagents containing manganese such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; reagents containing chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide / pyridine complexes; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0261] In each step, when performing a free radical cyclization reaction, examples of free radical initiators used include azo compounds such as azobisisobutyronitrile (AIBN); water-soluble free radical initiators such as 4,4'-azobis-4-cyanopentanoic acid (ACPA); triethylboron in the presence of air or oxygen; and benzoyl peroxide. Furthermore, examples of free radical reaction reagents used include tributyltinane, trimethylsilyl silane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.

[0262] In each step of the Wittig reaction, alkylphosphines and similar reagents can be used as Wittig reagents. Alkylphosphines can be prepared by methods known to them, such as reacting phosphonium salts with strong bases.

[0263] In each step, when performing the Horner-Emmons reaction, the reagents used can include phosphonoacetates such as dimethylphosphonoacetate and diethylphosphonoacetate; alkali metal hydrides; organolithium compounds; and other bases.

[0264] In each step, when performing the Friedel-Crafts reaction, the reagents used can include combinations of Lewis acid and acetic acid, or combinations of Lewis acid and alkylating agents (such as halogenated alkyl groups, alcohols, alkenes, etc.). Alternatively, organic or inorganic acids can be used instead of Lewis acid, and acid anhydrides such as acetic anhydride can be used instead of acetic acid.

[0265] In each step, when carrying out an aromatic nucleophilic substitution reaction, the reagents used are nucleophiles (such as amines, imidazoles, etc.) and bases (such as organic bases, etc.).

[0266] In each step, when performing a nucleophilic addition reaction of a carboanion, a nucleophilic 1,4-addition reaction of a carboanion (Michael addition reaction), or a nucleophilic substitution reaction of a carboanion, the bases used to generate carboanions can include organolithium compounds, metal alkoxides, inorganic bases, and organic bases.

[0267] In each step, when performing the Grignard reaction, Grignard reagents include aryl magnesium halides such as phenyl magnesium bromide and alkyl magnesium halides such as methyl magnesium bromide. Grignard reagents can be prepared by methods known to them, such as using ethers or tetrahydrofurans as solvents, to react alkyl or aryl halides with metallic magnesium.

[0268] In each step, when performing the Knoevenagel condensation reaction, the reagents used are an active methylene compound sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases).

[0269] In each step, when performing the Vilsmeier-Haack reaction, phosphatidyl chloride and amide derivatives (such as N,N-dimethylmethamide) are used as reagents.

[0270] In each step, when performing azidation reactions of alcohols, alkyl halides, or sulfonates, the azidating agents used include diphenyl phosphate azide (DPPA), trimethylsilyl azide, and sodium azide. For example, when azidation of alcohols, methods using diphenyl phosphate azide (DPPA) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or methods using trimethylsilyl azide and Lewis acid are used.

[0271] In each step, when a reductive amination reaction is performed, reducing agents used include sodium triethoxyborohydride, sodium cyanoboronide, hydrogen, and formic acid. When the matrix is ​​an amine compound, carbonyl compounds used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the matrix is ​​a carbonyl compound, amines used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0272] In each step, when performing the photoelongation reaction, azodicarboxylic acid esters (such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0273] In each step, when performing esterification, amination, or ureation reactions, the reagents used include halogenated amide groups such as amide chloride and amide bromide; and activated carboxylic acids such as acid anhydrides, active esters, and sulfate esters. Activators of carboxylic acids include carbodiimide condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); and 4-(4,6-dimethoxy-1,3,5-trimethylammonium chloride). -2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM) and other three Carbonate condensing agents include: 1,1-carbonyldiimidazole (CDI) and other carbonate condensing agents; diphenyl phosphate azide (DPPA); benzotriazole-1-yloxy-trimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Xiangshan reagent); thionyl chloride; lower alkyl alkyl halogenates such as ethyl chloroformate; O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate (HATU); sulfuric acid; or combinations thereof. When using carbodiimide condensing agents, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinic acid pyrimidine (HOSu), and 4-dimethylaminopyridine (DMAP) can also be added to the reaction.

[0274] In each step, when a coupling reaction is performed, the metal catalysts used can include palladium compounds such as palladium(II) acetate, tetra(triphenylphosphine)palladium(O), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), triphenylacetone dipalladium(O), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride; nickel compounds such as tetra(triphenylphosphine)nickel(O); rhodium compounds such as triphenylphosphine rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide(I); and platinum compounds. A base can also be added to the reaction; such bases can be inorganic bases.

[0275] In each step, when performing the thiocarbonylation reaction, phosphorus pentasulfide is typically used as the thiocarbonylating agent. In addition to phosphorus pentasulfide, reagents with the 1,3,2,4-dithiaphosphazene-2,4-disulfide structure, such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphazene-2,4-disulfide (Lawesson reagent), can also be used.

[0276] In each step of the Wohl-Ziegler reaction, halogenating agents used include N-iodosuccinate imine, N-bromosuccinate imine (NBS), N-chlorosuccinate imine (NCS), bromine, and thiocyanate chloride. Furthermore, the reaction can be accelerated by adding thermal, light-induced, benzoyl peroxide, or azobisisobutyronitrile (APBS) radical initiators to the reaction.

[0277] In each step, when performing the halogenation reaction of the hydroxyl group, the halogenating agents used can include hydrohalic acids and acehalides of inorganic acids. Specifically, for chlorination, hydrochloric acid, thionyl chloride, and phosphorus oxychloride can be used; for bromination, 48% hydrobromic acid can be used. Alternatively, a method can be used to obtain alkyl halides from alcohols through the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide. Or, a two-stage reaction can be used to synthesize alkyl halides by converting the alcohol to a sulfonate ester and then reacting it with lithium bromide, lithium chloride, or sodium iodide.

[0278] In each step, when performing the Arbuzov reaction, the reagents used may include alkyl halides such as ethyl bromoacetate; and phosphites such as triethyl phosphite or tri(isopropyl) phosphite.

[0279] In each step, when performing a sulfonation reaction, the sulfonating agents used may include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, etc.

[0280] In each step, when hydrolysis is performed, an acid or base is used as the reagent. Furthermore, in the acid hydrolysis of tributyl ester, formic acid or triethylsilane is sometimes added to capture the byproduct tributyl cation in a reducing manner.

[0281] In each step, when a dehydration reaction is carried out, the dehydrating agents used may include sulfuric acid, phosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, etc.

[0282] If the compounds obtained in each step have amine, imidazole, pyrrole, indole, or other aromatic heterocycles, or carboxyl, hydroxyl, or other substituents, these groups can also be protected by the protecting groups listed above. In this case, the target compound can be obtained by removing the protecting groups at the desired stage. The introduction or removal of these protecting groups is carried out by the same methods described above.

[0283] Furthermore, the reactions listed above can be combined in various steps as desired.

[0284] The method for manufacturing compound (I) will be described below.

[0285] Unless otherwise specified, all symbols in the following reaction formulas have the same meaning as those described above. The raw material compounds, unless otherwise specified, are readily available commercially, or can be manufactured using methods known to them or methods based thereon.

[0286] Compound (I) can be produced from compound (II) by the following methods.

[0287]

[0288]

[0289] Compound (II) can be manufactured using commercially available products or by methods known to them.

[0290] Compound (IV) can be produced in the presence of a base or acid of compound (III) by an amination reaction of a hydroxylamine derivative. Examples of hydroxylamine derivatives include O-(4-nitrobenzoyl)hydroxylamine, hydroxylamine-O-sulfonic acid, and O-diphenylphosphine hydroxylamine.

[0291] Compound (V) can be manufactured by reacting compound (IV) with an acrylate in an oxygen-rich environment in the presence of an inorganic salt such as a palladium catalyst or lithium bromide. Examples of palladium catalysts include palladium acetate (II), and examples of acrylates include methyl acrylate and ethyl acrylate. Alternatively, compound (V) can also be manufactured by reacting compound (IV) with methyl 3,3-dimethoxypropionate in the presence of an acid, followed by intramolecular cyclization in the presence of a base.

[0292] Compound (VIII) may be used as is, or manufactured by methods known to them or methods that are based thereon.

[0293] Compound (I) can be prepared by reacting compound (VII) with compound (VIII), wherein compound (VII) is obtained by reacting compound (VI) with diphenylphosphide azide (DPPA) in the presence of a desired base using Curtius transposition. In addition to the above, 2-methyltetrahydrofuran can also be used as a solvent.

[0294] Compound (IX) can be prepared by reacting compound (VI) with diphenylphosphine azide (DPPA) in the presence of a desired base using Curtius transposition. In addition to the above-mentioned solvents, 2-methyltetrahydrofuran and other solvents can also be used.

[0295] Compound (I) can be prepared by ureation of compounds (IX) and (VIII) in the presence of an activator and a desired base. Examples of activators include chloroformate derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, or p-nitrobenzene chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole, or N,N'-disuccinimidyl carbonate, with triphosgene and 2,2,2-trichloroethyl chloroformate being preferred.

[0296] In the above steps, substituents R1 and R2 can be converted into other types of substituents by performing electrophilic substitution reactions, coupling reactions, or methods known to the public at the desired stage. For example, a compound (IV) with a hydrogen atom as R1 can be converted into a compound (IV) with a halogen atom as R1 by performing an electrophilic substitution reaction. Examples of electrophilic agents used in this reaction include N-iodosuccinic anhydride, N-bromosuccinic anhydride (NBS), N-chlorosuccinic anhydride (NCS), bromine, and thiosuccinic chloride. Furthermore, a compound (V) with a C1-3 alkyl group (e.g., a halogen atom) as R1 can be converted into a compound (V) with a C1-3 alkyl group (e.g., methyl) by reacting a compound (V) with an organoboronic acid or organoboronic ester reagent (e.g., 2,4,6-trimethyltriboranetrioxane). This reaction can be carried out in the presence of a base or inorganic salt (e.g., tripotassium phosphate), the aforementioned palladium metal complexes, or a phosphine ligand. Examples of such phosphine ligands include 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos).

[0297] In addition, compound (V) can also be manufactured by the following methods.

[0298]

[0299]

[0300] Compound (X) can be manufactured using commercially available products or by methods known to them.

[0301] Compound (XI) can be produced by the amination reaction of compound (X). As a method of amination, the same method as the method for producing compound (IV) from compound (III) can be listed.

[0302] Compound (XIII) can be prepared by reacting compound (XII) in the presence of N,N-dimethylformamide dimethyl acetal.

[0303] In compound (XIV), X1 represents a halogen atom. In addition to those mentioned above, halogenating agents used in the halogenation reaction during the manufacture of compound (XIV) may include phosphorus oxybromide, etc.

[0304] Compound (V) can be produced from compound (XIV) by means of a combination coupling reaction or substitution reaction, or by methods known to the public.

[0305] In the above steps, substituents R1 and R2 can be converted into other types of substituents by performing an electrophilic substitution reaction at the desired stage or by methods known to the public.

[0306] In addition, compound (I) can also be manufactured by the following methods.

[0307]

[0308]

[0309] The compound (XV) can be manufactured using commercially available products or by methods known to them. X1 represents a halogen atom.

[0310] Compound (XVII) can be prepared by reacting compound (XVI) with a nitroenamine derivative in the presence of an acid via a nucleophilic substitution reaction. Examples of nitroenamine derivatives include (E)-4-(2-nitrovinyl)morpholine.

[0311] Compound (XVIII) can be prepared by an intramolecular cyclization reaction of compound (XVII). This reaction can be carried out in the presence of a base as desired.

[0312] Compound (XIX) can be manufactured by reducing compound (XVIII). In addition to the above, iron, tin(II) chloride, or tin(II) chloride dihydrate can also be used as reducing agents.

[0313] Compound (I) can be prepared by ureation of compound (XIX) and compound (VIII) in the presence of an activator and a desired base. Examples of activators include chloroformate derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, or p-nitrobenzene chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole, or N,N'-disuccinimidyl carbonate, with triphosgene and 2,2,2-trichloroethyl chloroformate being preferred.

[0314] In the above steps, substituents R4 and R5 can be converted by combination coupling or substitution reactions at the desired stage, or by methods known to the public.

[0315] In addition, compound (I) can also be manufactured by the following methods.

[0316]

[0317]

[0318] The compound (XX) can be manufactured using commercially available products or by methods known to the public.

[0319] Compound (XXI) can be prepared by reacting compound (XX) with a nitroenamine derivative in the presence of an acid via a nucleophilic substitution reaction. Examples of nitroenamine derivatives include (E)-4-(2-nitrovinyl)morpholine.

[0320] Compound (XXII) can be prepared by an intramolecular cyclization reaction of compound (XXI). This reaction can be carried out in the presence of a base as desired.

[0321] In compound (XXIII), X1 represents a halogen atom. In addition to those mentioned above, phosphorus tribromide and other halogenating agents used in the halogenation reaction during the manufacture of compound (XXIII) can also be listed as halogenating agents.

[0322] Compound (XVIII) can be produced from compound (XXIII) by a combination coupling reaction or substitution reaction, or by a number of well-known methods. In addition to those mentioned above, PdCl2(Amphos)2 and other catalysts used as catalysts for the coupling reaction in the production of compound (XVIII) can also be listed.

[0323] Compound (XIX) can be manufactured by reducing compound (XVIII). In addition to the above, iron, tin(II) chloride, or tin(II) chloride dihydrate can also be used as reducing agents.

[0324] Compound (I) can be prepared by ureation of compound (XIX) and compound (VIII) in the presence of an activator and a desired base. Examples of activators include chloroformate derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, or p-nitrobenzene chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole, or N,N'-disuccinimidyl carbonate, with triphosgene and 2,2,2-trichloroethyl chloroformate being preferred.

[0325] In the above steps, substituents R4 and R5 can be converted by combination coupling reaction or nucleophilic substitution reaction at the desired stage, or by methods known to the public.

[0326] In addition, compound (I) can also be manufactured by the following methods.

[0327]

[0328]

[0329] The compound (XXIV) can be commercially available or manufactured using methods known to the public.

[0330] Compound (XXVI) can be prepared by reacting compound (XXV) with a 3-side-oxypropane acid derivative in the presence of an acid via a nucleophilic substitution reaction. Examples of 3-side-oxypropane acid derivatives include methyl 3,3-dimethoxypropionate.

[0331] Compound (XXVII) can be prepared by an intramolecular cyclization reaction of compound (XXVI). This reaction can be carried out in the presence of a base as desired.

[0332] Compound (I) can be prepared by reacting compound (XXIX) with compound (VIII), wherein compound (XXIX) is obtained by reacting compound (XXVIII) with diphenylphosphide azide (DPPA) in the presence of a desired base using Curtius transposition. In addition to the above, 2-methyltetrahydrofuran and other solvents may be used as solvents.

[0333] Compound (XXX) can be prepared by reacting compound (XXVIII) with diphenylphosphide azide (DPPA) in the presence of a desired base using Curtius transposition. In addition to the above-mentioned solvents, 2-methyltetrahydrofuran and other solvents can also be used.

[0334] Compound (I) can be prepared by ureation of compound (XXX) and compound (VIII) in the presence of an activator and a desired base. Examples of activators include chloroformate derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, or p-nitrobenzene chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole, or N,N'-disuccinimidyl carbonate, with triphosgene and 2,2,2-trichloroethyl chloroformate being preferred.

[0335] In the above steps, substituents R6 and R7 can be converted by combination coupling or substitution reactions at the desired stage, or by methods known to the public.

[0336] In addition, compound (I) can also be manufactured by the following methods.

[0337]

[0338]

[0339] The compound (XXXI) can be manufactured using commercially available products or by methods known to the public.

[0340] Compound (XXXII) can be prepared by reacting compound (XXXI) with an alkoxymethylene malonate derivative in the presence of an acid via a nucleophilic substitution reaction. Examples of alkoxymethylene malonate derivatives include diethyl ethoxymethylene malonate.

[0341] Compound (XXXIII) can be manufactured by intramolecular cyclization reaction of compound (XXXII).

[0342] Compound (XXXIV) can be prepared by reacting compound (XXXIII) with chloro(chloromethyl)dimethylsilane in the presence of a base.

[0343] Compound (XXXV) can be produced by reacting compound (XXXIV) with cesium fluoride.

[0344] In compound (XXXVI), X1 represents a halogen atom. In the manufacture of compound (XXXVI), halogenating agents used in the halogenation reaction, besides those mentioned above, include phosphorus tribromide, etc.

[0345] Compound (I) can be prepared by reacting compound (XXXIX) with compound (VIII), wherein compound (XXXIX) is obtained by reacting compound (XXXVIII) with diphenylphosphide azide (DPPA) in the presence of a desired base using Curtius transposition. In addition to the above, 2-methyltetrahydrofuran can also be used as a solvent.

[0346] Compound (XXXX) can be prepared by reacting compound (XXXVIII) with diphenylphosphide azide (DPPA) in the presence of a desired base using Curtius transposition. In addition to the above-mentioned solvents, 2-methyltetrahydrofuran and other solvents can also be used.

[0347] Compound (I) can be prepared by ureation of compound (XXXX) and compound (VIII) in the presence of an activator and a desired base. Examples of activators include chloroformate derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, or p-nitrobenzene chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole, or N,N'-disuccinimidyl carbonate, with triphosgene and 2,2,2-trichloroethyl chloroformate being preferred.

[0348] In the above steps, the substituent R9 can be converted by a combination coupling reaction or substitution reaction at the desired stage, or by a method known to the public.

[0349] In addition, compound (I) can also be manufactured by the following methods.

[0350]

[0351]

[0352] Compound (XXXXI) can be manufactured using commercially available products or by methods known to the public or by the same methods as compound (XXVII).

[0353] Compound (XXXXIII) can be produced by alkylating compound (XXXXII) in the presence of a base. In addition to those mentioned above, lithium hydroxide and other similar bases can also be used.

[0354] Compound (I) can be prepared by reacting compound (XXXXV) with compound (VIII), wherein compound (XXXXV) is obtained by reacting compound (XXXXIV) with diphenylphosphide azide (DPPA) in the presence of a desired base using Curtius transposition. In addition to the above, 2-methyltetrahydrofuran can also be used as a solvent.

[0355] Compound (XXXXVI) can be prepared by reacting compound (XXXXIV) with diphenylphosphine azide (DPPA) in the presence of a desired base using Curtius transposition. In addition to the above, 2-methyltetrahydrofuran can also be used as a solvent.

[0356] Compound (I) can be prepared by ureation of compound (XXXXVI) and compound (VIII) in the presence of an activator and a desired base. Examples of activators include chloroformate derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, or p-nitrobenzene chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole, or N,N'-disuccinimidyl carbonate, with triphosgene and 2,2,2-trichloroethyl chloroformate being preferred.

[0357] In the above steps, the substituents R8 and R9 can be converted by coupling or substitution reactions at the desired stage, or by methods known to the public.

[0358] Another compound or its salt contained in compound (I) can also be produced by applying known means to the substituents of the compound (I) thus obtained (i.e., the introduction of substituents or the conversion of functional groups).

[0359] The methods for introducing substituents or converting functional groups are well-known general methods, such as the conversion of halogen atoms (e.g., fluorine, chlorine, bromine, iodine) or halogenatable C1-6 alkyl sulfonyl-oxy groups [e.g., methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy (trifluoromethanesulfonate (ester))] to methyl, cyclopropyl, vinyl, cyano, methyl, carbonyl, carboxyl, hydroxyl, amino, oxoboroyl, etc. The methyl group is converted via Se... The conversion of the yferth-Gilbert carbide group to acetylene, the conversion of the ester to the carboxyl group via hydrolysis, the conversion of the carboxyl group to the aminomethyl group via acetylation, the conversion of the carboxyl group to the hydroxymethyl group via reduction, the conversion of the carbonyl group to the alcohol via reduction or alkylation, the reducing aminoation of the carbonyl group, the oximeation of the carbonyl group, the acetylation of the amino group, the ureation of the amino group, the sulfonylation of the amino group, the alkylation of the amino group, the substitution or aminoation of the amino group via the active halogen of the amine, the alkylation of the hydroxyl group, and the substitution or aminoation of the hydroxyl group.

[0360] When introducing this substituent or performing a functional group conversion, there may be reactive sites that can undergo reactions other than the target reaction. If necessary, a protecting group may be introduced into the reactive site in advance by means known in the invention. After the target reaction is performed, the protecting group may be removed by means known in the invention to produce a compound included in the scope of the invention.

[0361] For example, when the starting compound or intermediate has amine, carboxyl, or hydroxyl groups as substituents, these groups can be protected using protecting groups commonly used in peptide chemistry. In this case, the target compound can be obtained by removing the protecting group as needed after the reaction.

[0362] The compound (I) obtained by the above manufacturing method can be purified by known means, such as solvent extraction, pH change of solution, resolution, crystallization, recrystallization, and chromatography.

[0363] In the case where compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and each can be obtained as a single product by known synthetic or separation methods. For example, if an optical isomer is present in compound (I), the optical isomer resolved from that compound is also included in compound (I).

[0364] Here, optical isomers can be manufactured using methods known to the public.

[0365] Compound (I) can also be crystalline.

[0366] The crystallization of compound (I) (hereinafter, sometimes referred to as the crystallization of the present invention) can be produced by crystallizing compound (I) using a crystallization method known herein.

[0367] The crystal system of this invention exhibits excellent physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., in vivo dynamics (absorption, distribution, metabolism, excretion), and pharmacological effects), and is expected to be used in medicine.

[0368] Compound (I) may also be a pharmaceutically permissible co-crystallization or co-crystallized salt. Here, co-crystallization or co-crystallized salt means a crystalline substance consisting of two or more distinct solids, each possessing different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability), at room temperature. Co-crystallization or co-crystallized salts may be prepared by co-crystallization methods known to the public.

[0369] Compound (I) can be a hydrate, a non-hydrate, a solvent-free compound, or a solvent compound.

[0370] Furthermore, the deuterium conversion product obtained by converting 1H to 2H(D) is also included in compound (I).

[0371] Compound (I) can also be labeled with isotopes (e.g., 3H, 13C, 14C, 18F, 35S, 125I). Isotopically labeled or substituted compounds (I) can be used as tracers (PET tracers) for example in positron emission tomography (PET) and are expected to have applications in fields such as medical diagnostics.

[0372] Compound (I) can also be used in the form of a prodrug.

[0373] Compound (I) is a compound that is converted into compound (I) under physiological conditions in the body through reactions such as enzymes or gastric acid. That is, it is a compound that is transformed into compound (I) through enzymatic oxidation, reduction, hydrolysis, etc., or a compound that is transformed into compound (I) through hydrolysis by gastric acid, etc.

[0374] As a prodrug of compound (I), examples include compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of compound (I) is eicosylated, propylaminolated, pentylaminocarbonylated, (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methoxycarbonylated, tetrahydrofuranized, pyrrolidone methylated, trimethylacetylated, or tributylated); and compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxyl group of compound (I) is acetylated, alkylated, phosphorylated, or borated). Compounds that are palmitylated, propionic, trimethylacetylated, succinylated, fumarate-acylated, propylaminoacetylated, or dimethylaminomethylcarbonylated; compounds in which the carboxyl group of compound (I) is esterified or amylated (e.g., compounds in which the carboxyl group of compound (I) is ethylated, phenyl esterified, carboxymethylated, dimethylaminomethylated, trimethylacetylated oxymethylated, ethoxycarbonyloxyethylated, phthaloyl esterified, (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methylated, cyclohexyloxycarbonylethylated, or methylamylated). These compounds can be manufactured from compound (I) by methods known herein.

[0375] In addition, the prodrug of compound (I) can also be the one that changes into compound (I) under physiological conditions, as described in Volume 7 of "Pharmaceutical Development" published by Hirokawa Shoten in 1990, pages 163 to 198.

[0376] In this specification, the prodrug may also form a salt, and the salts of the compounds shown in formula (I) can be listed as examples of such salts.

[0377] Compound (I) or its prodrug (hereinafter, sometimes simply referred to as the compound of the present invention) may have MALT1 inhibitory activity and may be used as a cancer prevention or treatment agent, a cancer proliferation inhibitor, or a cancer metastasis inhibitor.

[0378] The compounds of the present invention exhibit selective inhibitory activity against MALT1, and also demonstrate excellent pharmacodynamics (e.g., absorption, distribution, metabolism, excretion), solubility (e.g., water solubility), interactions with other pharmaceuticals (e.g., inhibition of drug-metabolizing enzymes), safety (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central nervous system toxicity), and stability (e.g., chemical stability, stability to enzymes), thus making them suitable for use as pharmaceuticals.

[0379] Therefore, the compounds of the present invention can be used to inhibit excessive (abnormal) MALT1 activity in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, and humans).

[0380] The compounds of the present invention can be formulated into pharmaceuticals, either as is or with the addition of a pharmacologically permissible carrier, and administered orally or non-orally to mammals (preferably humans).

[0381] The following describes in detail pharmaceuticals containing the compounds of the present invention (sometimes abbreviated as "the pharmaceuticals of the present invention"). Examples of dosage forms for the pharmaceuticals of the present invention include, for example, tablets (e.g., sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, intraoral disintegrating tablets), pills, granules, powders, capsules (e.g., soft capsules, microcapsules), syrups, emulsions, suspensions, and films (e.g., intraoral disintegrating films, oral mucosal adhesive films), etc. Furthermore, examples of dosage forms for the pharmaceuticals of the present invention include, for example, injections, drops, transdermal preparations (e.g., iontophoresis transdermal preparations), suppositories, ointments, nasal preparations, pulmonary preparations, eye drops, etc. In addition, the pharmaceuticals of the present invention can also be release-controlled preparations such as immediate-release formulations and sustained-release formulations (e.g., sustained-release microcapsules).

[0382] The pharmaceutical of this invention can be manufactured using well-known manufacturing methods commonly used in the field of pharmaceutical formulation (e.g., methods described in the Japanese Pharmacopoeia). Furthermore, the pharmaceutical of this invention may contain, as needed, appropriate amounts of additives commonly used in the pharmaceutical field, such as excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, flavoring agents, stabilizers, and thickeners.

[0383] Examples of such additives can be listed as pharmacologically permissible carriers.

[0384] For example, tablets can be manufactured using excipients, binders, disintegrants, lubricants, etc., while pills and granules can be manufactured using excipients, binders, disintegrants, etc. In addition, powders and capsules can be manufactured using excipients, syrups can be manufactured using sweeteners, etc., and emulsions or suspensions can be manufactured using suspending agents, surfactants, emulsifiers, etc.

[0385] Examples of excipients include lactose, white sugar, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate.

[0386] Examples of adhesives include 5 to 10% by weight starch paste, 10 to 20% by weight gum arabic or gelatin, 1 to 5% by weight tragacanth gum, carboxymethyl cellulose, sodium alginate, and glycerin.

[0387] Examples of disintegrants include starch and calcium carbonate.

[0388] Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, and refined talc.

[0389] Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerol, and simple syrup.

[0390] Examples of surfactants include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and stearic acid polyoxyester 40.

[0391] Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, and bentonite.

[0392] Examples of emulsifiers include gum arabic, gum tragali, gelatin, and polysorbate 80.

[0393] For example, in the case of a tablet form of the present invention, the tablet can be manufactured by adding excipients (e.g., lactose, sugar, starch), disintegrants (e.g., starch, calcium carbonate), binders (e.g., starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose), or lubricants (e.g., talc, magnesium stearate, polyethylene glycol 6000) to the compound of the present invention according to known methods, followed by compression molding, and then coating as needed for the purposes of flavor masking, enteric coagulation, or persistence, using known methods. Coating agents used as coatings may include, for example, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, methacrylic acid / acrylic acid copolymer), and pigments (e.g., red iron oxide, titanium dioxide).

[0394] In addition to intravenous injections, the aforementioned injectable drugs also include subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, and intravenous drip injections.

[0395] This injectable preparation is formulated by a method known to the public, namely, by dissolving, suspending, or emulsifying the compound of the present invention in a sterile aqueous or oily solution. Examples of aqueous solutions include physiological saline, glucose, or isotonic solutions containing other adjuvants (e.g., D-sorbitol, D-mannitol, sodium chloride). The aqueous solution may also contain suitable dissolving agents, such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants (e.g., polysorbate 80, HCO-50). Examples of oily solutions include sesame oil and soybean oil. The oily solution may also contain suitable dissolving agents. Examples of dissolving agents include benzyl benzoate and benzyl alcohol. In addition, buffers (such as phosphate buffer, sodium acetate buffer), analgesics (such as benzalkonium chloride, procaine hydrochloride), stabilizers (such as human serum albumin, polyethylene glycol), and preservatives (such as benzyl alcohol, phenol) may also be incorporated into this injection. The prepared injection solution is usually filled into ampoules.

[0396] The content of the compound of the present invention in the pharmaceutical product varies depending on the form of the preparation. Generally, it is about 0.01 to about 100% by weight relative to the whole preparation, preferably about 2 to about 85% by weight, and more preferably about 5 to about 70% by weight.

[0397] The content of the additives in the pharmaceuticals of the present invention varies depending on the form of the preparation. Generally, it is about 1 to about 99.9% by weight relative to the whole preparation, and preferably about 10 to about 90% by weight.

[0398] The compounds of this invention are stable and have low toxicity, and can be used safely. The daily dosage of the compounds of this invention varies depending on the patient's condition or weight, the type of compound, the route of administration, etc. For example, in the case of oral administration to a patient for the purpose of treating cancer, the daily dosage for an adult (weighing about 60 kg) is about 1 to about 1000 mg, more preferably about 3 to about 300 mg, and even more preferably about 10 to about 200 mg, which can be administered once or divided into 2 to 3 doses.

[0399] In cases where the compounds of the present invention are not administered orally, they are typically administered in liquid form (e.g., injection). The dosage of the compounds of the present invention administered at one time varies depending on the recipient, the organ of the recipient, the symptoms, the method of administration, etc. For example, it is generally preferred to administer about 0.01 to about 100 mg per kg of body weight via intravenous injection, more preferably about 0.01 to about 50 mg, and even more preferably about 0.01 to about 20 mg of the compounds of the present invention.

[0400] The compounds of this invention can be used in combination with other drugs. Specifically, the compounds of this invention can be used in combination with drugs such as hormone therapy agents, chemotherapy agents, immunotherapy agents, or agents that inhibit the action of cell proliferation factors and their receptors. Hereinafter, drugs that can be used in combination with the compounds of this invention will be abbreviated as combined drugs.

[0401] As "hormonal therapy agents," those such as fosfestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, and anti-estrogens (such as tamoxifen citrate and toremifene citrate) can be used. citrate), oral contraceptives, mepitiostane, testololactone, aminoglutethimide, LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin acetate), droloxifene, epitiostanol, ethinylestradiol sulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride)Hydrochloride, anastrozole, letrozole, exemestane, vorozole, formestane, antiandrogens (e.g., flutamide, bicalutamide, nilutamide, enzalutamide), 5α-reductase inhibitors (e.g., finasteride, epristeride, dutasteride), adrenocorticotropic hormones (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone), androgen synthesis inhibitors (e.g., abiraterone), rhodopsin and drugs that delay rhodopsin metabolism (e.g., liarozole), thyroid hormones, and their drug delivery systems (DDS). System) preparations.

[0402] As "chemotherapy agents", alkylating agents, metabolic antagonists, anticancer antibiotics, and plant-derived anticancer agents can be used.

[0403] As "alkylating agents," those used include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, and estramustine phosphate. Sodium, trivinyltricyanate, carmustine, lomustine, streptozocin, pipebroman, etoglucid, carboplatin, cisplatin, miboplatin Nadaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustin, temozolomide, treosulfan, trofosfamide, zinostatin stimalamer, adozelesin, cystemustine, bizelesin, and their DDS formulations.

[0404] As "metabolic antagonists," substances such as mercaptopurines, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine octadecyl phosphate, ancitabine hydrochloride, 5-FU agents (such as fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallotabine, emmitefur, capecitabine), and aminopterin can be used. Nelzarabine, leucovorin calcium, tabloid, butocine, leucovorin calcium, leucovorin calcium, cladribine, emmitefur, fludarabine, gemcitabine, hydroxymethylamine, pentostatin, piritraxim, idoxuridine, mitoguazone, thiazophrine, ambamustine, bendamustine, and their DDS formulations.

[0405] As "anticancer antibiotics," the following can be used: Actinomycin D, Actinomycin C, Mitomycin C, Chromomycin A3, Bleomycin Hydrochloride, Bleomycin Sulfate, Peplomycin Sulfate, Daunorubicin Hydrochloride, Doxorubicin Hydrochloride, Aclarubicin Hydrochloride, Pirarubicin Hydrochloride, Epirubicin Hydrochloride, Neocarzinostatin, Mithramycin, Sarkomycin, Carzinophillin, Mitotane, Zorubicin Hydrochloride, Mitoxantrone Hydrochloride, Idarubicin Hydrochloride. hydrochloride and its DDS formulations (e.g., PEG ribosomes containing doxorubicin).

[0406] As "plant-derived anticancer agents", etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, cabazitaxel, vinorelbine, and their DDS formulations can be used.

[0407] As "immunotherapy agents," the following can be used: picibanil, krestin, sizofiran, lentinan, ubenimex, interferon, interleukin, macrophage community-stimulating factor, granulocyte community-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazol, anti-CTLA4 antibodies (e.g., ipilimumab, tremelimumab), anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab), and anti-PD-L1 antibodies.

[0408] As "agents that inhibit the action of cell proliferation factors and their receptors," "cell proliferation factors" can refer to any substance that promotes cell proliferation. Generally, peptides with a molecular weight of less than 20,000 that exert their effects at low concentrations by binding to receptors can be listed. Specifically, (1) EGF (epidermal growth factor) or substances with essentially the same activity [e.g., TGFα], (2) insulin or substances with essentially the same activity [e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2], (3) FGF (fibroblast growth factor) or substances with essentially the same activity [e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10], (4) other cell proliferation factors [e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor)]. factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor), VEGF (vascularendothelial growth factor), heregulin, angiopoietin].

[0409] As a "receptor for cell proliferation factors", any receptor that has the ability to bind to the aforementioned cell proliferation factors can be used. Specifically, EGF receptor, modulatory receptor (e.g., HER3), insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (e.g., Tie2), PDGF receptor, etc.

[0410] As "agents that inhibit the action of cell proliferation factors and their receptors," the following can be used: EGF inhibitors, TGFα inhibitors, cytokinin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitors, IL-2 inhibitors, NGF inhibitors, PDGF inhibitors, TGFβ inhibitors, HGF inhibitors, VEGF inhibitors, angiopoietin inhibitors, EGF receptor inhibitors, HER2 inhibitors, HER4 inhibitors, insulin receptor inhibitors, IGF-1 receptor inhibitors, IGF-2 receptor inhibitors, FGF receptor-1 inhibitors, FGF receptor-2 inhibitors, FGF receptor-3 inhibitors, FGF receptor-4 inhibitors, VEGF receptor inhibitors, Tie-2 inhibitors, PDGF receptor inhibitors, TLR receptor inhibitors, Abl inhibitors, Raf inhibitors, FLT3 inhibitors, c-Kit inhibitors, Src inhibitors, PLC inhibitors, and PK inhibitors. C-blockers, Smo blockers, ALK blockers, ROR1 blockers, Trk blockers, Ret blockers, mTOR blockers, Aurora blockers, PLK blockers, MEK (MEK1 / 2) blockers, MET blockers, CDK blockers, Akt blockers, ERK blockers, PI3K blockers, IKK blockers, BTK blockers, IRAK blockers, HDAC blockers, TAK1 blockers, TBK1 blockers, ZAP blockers, SYK blockers, LCK blockers, TYK2 blockers, SYK blockers, JAK blockers, FAK blockers, LYN blockers, etc.More specifically, anti-VEGF antibodies (such as bevacizumab and ramucurumab), anti-HER2 antibodies (such as trastuzumab and pertuzumab), anti-EGFR antibodies (such as cetuximab, panitumumab, matuzumab, and nimotuzumab), anti-HGF antibodies, imatinib, erlotinib, and gefitinib can be used. Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, Ibrutinib, Bosutinib, Cabozantinib, Crizotinib, Alectinib, Vismodegib, Axitinib, Motesanib, Nilotinib, 6-[4-(4-ethylpiperazine) [-1-ylmethyl)phenyl]-N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE-788), Vandetanib, Temsirolimus, Everolimus, Enzastaurin, Tozasertib, 2-[N-[3-[4-[5-[N-(3-fluorophenyl)aminomethylmethyl]-1H-pyrazol-3-ylamino]quinazolin-7-yloxy]propyl]-N-ethylamino]ethyl phosphate (AZD-1152), 4-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimidino[5,4-d][2]benzozahexacyclohepten-2-ylamino]amino] Sodium glycine, N-[2-methoxy-5-[(E)-2-(2,4,6-trimethoxyphenyl)vinylsulfonylmethane]phenyl]glycine sodium salt (ON-1910Na), Volasetib, Selumetinib, Trametinib, N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoamide (PD-0325901), Bosutinib, Regorafenib, Afatinib, Idelalisib, Ceritinib, Dabrafenib, etc.

[0411] In addition to the drugs mentioned above, asparaginase, aceglatone, procarbazine hydrochloride, prorocin / cobalamin salt, mercuric hemosiderin / sodium, topoisomerase I inhibitors (e.g., irinotecan, topotecan, indotecan, indimitecan), topoisomerase II inhibitors (e.g., sobuzoxane), differentiation inducers (e.g., visual pigments, vitamin D derivatives), other angiogenesis inhibitors (e.g., fumagillin, shark extract, COX-2 inhibitors), and alpha-blockers (e.g., tamsulosin hydrochloride) can also be used. Hydrochlorides, bisphosphonates (e.g., pamidronate, zoledronate), thalidomide, lenalidomide, pomalidomide, 5-azacitidine, decitabine, proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib), and NEDD8 inhibitors (e.g., pevonedistat). Anti-tumor antibodies and antibody-drug complexes (e.g., trastuzumab-metazidine) include: UAE inhibitors, PARP inhibitors (e.g., olaparib, niraparib, veliparib), BCL2 inhibitors (e.g., venetoclax, obatoclax, oblimersen), anti-CD20 antibodies (e.g., rituximab, obinutuzumab), and anti-CCR4 antibodies (e.g., mogamulizumab). emtansine), brentuximab vedotin, and gene-modified T-cell therapy using chimeric antigen receptors (CAR-T therapy) (such as tisagenlecleucel and axicabtagene ciloleucel) are used as concomitant drugs.

[0412] By combining the compounds of the present invention with other drugs, the following excellent effects can be obtained: (1) the dosage can be reduced compared to administering the compounds of the present invention alone or the other drugs alone; (2) the drugs used in combination with the compounds of the present invention can be selected according to the patient's symptoms (mild, severe, etc.); (3) the treatment period can be set for a longer period of time; (4) the therapeutic effect can be sustained; and (5) the synergistic effect can be obtained by using the compounds of the present invention in combination with other drugs.

[0413] Hereinafter, the use of compounds of the present invention in combination with drugs will be referred to as "combinations of the present invention".

[0414] When using the combined formulations of this invention, there is no limitation on the timing of administration of the compound and the combined drug. The compound and the combined drug can be administered to the target simultaneously or at time intervals. In the case of time-interval administration, the time interval varies depending on the active ingredient, dosage form, and administration method. For example, if the combined drug is administered first, the compound can be administered within 1 minute to 3 days after the administration of the combined drug, preferably within 10 minutes to 1 day, and more preferably within 15 minutes to 1 hour. If the compound is administered first, the combined drug can be administered within 1 minute to 1 day after the administration of the compound, preferably within 10 minutes to 6 hours, and more preferably within 15 minutes to 1 hour. The dosage of the combined drug should be based on clinically used dosages and can be appropriately selected according to the target, route of administration, disease, and combination.

[0415] Examples of administration methods for using the compound of the present invention in combination with the drug can be listed as follows: (1) administering a single formulation obtained by simultaneously formulating the compound of the present invention and the drug; (2) administering two formulations obtained by simultaneously formulating the compound of the present invention and the drug individually via the same administration route; (3) administering two formulations obtained by separately formulating the compound of the present invention and the drug individually via the same administration route with a time difference; (4) administering two formulations obtained by separately formulating the compound of the present invention and the drug individually via different administration routes; and (5) administering two formulations obtained by separately formulating the compound of the present invention and the drug individually via different administration routes with a time difference (e.g., administering in the order of compound of the present invention → drug, or in the reverse order).

[0416] The dosage of the concurrent drug can be appropriately selected based on the dosage used clinically. Furthermore, the blending ratio of the compound of the present invention to the concurrent drug can be appropriately selected according to the target population, route of administration, target disease, symptoms, and combination. For example, in the case of a human target population, 0.01 to 100 parts by weight of the concurrent drug relative to 1 part by weight of the compound of the present invention is sufficient.

[0417] Furthermore, the compounds of the present invention or their adjuvants may be used in combination with non-pharmacological therapies. Specifically, the compounds of the present invention or their adjuvants may be combined with, for example, the following non-pharmacological therapies: (1) surgery, (2) vasopressor chemotherapy using angiotensin II, (3) gene therapy, (4) thermotherapy, (5) cryotherapy, (6) laser ablation, and (7) radiation therapy.

[0418] For example, by using the compound of the present invention or the combination of the present invention before or after the aforementioned surgery, or before or after combining two or three of these treatments, effects such as preventing resistance, prolonging disease-free survival, inhibiting cancer metastasis or recurrence, and extending life can be achieved.

[0419] In addition, treatment and supportive therapy using the compounds of the present invention or their combined use [(i) administration of antibiotics (e.g., β-lactams such as pansporin, macrocyclic lactones such as clarithromycin) for the complications of various infectious diseases, (ii) administration of high-calorie infusions, amino acid preparations, and multivitamins to improve nutritional deficiencies, (iii) administration of morphine to relieve pain, (iv) administration of drugs to improve side effects such as nausea, vomiting, loss of appetite, diarrhea, leukopenia, thrombocytopenia, low hemoglobin concentration, hair loss, liver dysfunction, kidney dysfunction, DIC, fever, etc., and (v) administration of drugs to inhibit multi-dose tolerance to cancer, etc.] can be combined.

[0420] [Example]

[0421] The present invention will be further described in detail by way of the following examples, formulation examples and test examples, but these do not limit the present invention. In addition, variations may be made without departing from the scope of the present invention.

[0422] In the following examples, "room temperature" generally refers to about 10°C to about 35°C. Ratios shown in mixed solvents are by volume unless otherwise specified. % are by weight unless otherwise specified.

[0423] In silica gel column chromatography, when labeled NH, aminopropylsilane-bound silica gel is used; when labeled Diol, 3-(2,3-dihydroxypropoxy)propylsilane-bound silica gel is used; and when labeled DiNH, N-(2-aminoethyl)-3-aminopropylsilane-bound silica gel is used. In HPLC (high performance liquid chromatography), when labeled C18, octadecyl-bound silica gel is used. Unless otherwise specified, the solvent ratio is expressed as a volumetric ratio.

[0424] In the following embodiments, the following abbreviations are used.

[0425] Boc2O: Ditert-butyl dicarbonate

[0426] CDCl3: Dichloroform

[0427] DMSO-d6: Dimethyl sulfoxide

[0428] 1H NMR: Proton Nuclear Magnetic Resonance

[0429] LC / MS: Liquid Chromatography Mass Analyzer

[0430] ESI: Electro-injection ionization

[0431] APCI: Atmospheric Pressure Chemical Ionization

[0432] DBU:1,8-diazabicyclo[5.4.0]undec-7-ene

[0433] DIEA: Diisopropylethylamine

[0434] DMAP: 4-Dimethylaminopyridine

[0435] DMF: N,N-Dimethylformamide

[0436] mp: melting point

[0437] DPPA: Diphenylphosphide azide

[0438] MS: Mass Spectrometry

[0439] [M+H]+,[MH]-: Molecular ion peaks

[0440] M: molar concentration

[0441] N: Equivalent

[0442] Pd(OAc)2:Palladium(II) acetate

[0443] SPhos:2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0444] TEA: Triethylamine

[0445] TFA: Trifluoroacetic acid

[0446] THF: Tetrahydrofuran

[0447] The ¹H NMR was determined using Fourier transform NMR. ACD / SpecManager (trade name) was used for analysis. Peaks with very flat proton groups, such as hydroxyl or amino groups, were not recorded.

[0448] MS is determined by LC / MS. As an ionization method, ESI or APCI is used. Data are recorded as found values. Typically, molecular ion peaks ([M+H]+, [MH]-, etc.) are observed. In the case of compounds containing a terbutoxycarbonyl group, peaks resulting from the removal of the terbutoxycarbonyl or terbutyl group can sometimes be observed as fragment ions. Furthermore, in the case of compounds containing a hydroxyl group, peaks resulting from the removal of H2O can sometimes be observed as fragment ions. In the case of salts, molecular ion peaks or fragment ion peaks of the free phase are usually observed.

[0449] Reference Example 1

[0450] 5-Chloro-6-(difluoromethoxy)pyridine-3-amine

[0451] A) 3-Chloro-2-(difluoromethoxy)-5-nitropyridine

[0452] To a mixture of 10 g of 3-chloro-5-nitropyridine-2-ol and 300 mL of acetonitrile, 11.86 mL of 2,2-difluoro-2-(fluorosulfonyl)acetic acid and 3.26 g of sodium sulfate were added at room temperature, and the reaction mixture was stirred overnight at the same temperature. Further addition of 11.86 mL of 2,2-difluoro-2-(fluorosulfonyl)acetic acid and 3.26 g of sodium sulfate to the reaction mixture at room temperature was carried out, and the reaction mixture was stirred for 3 days at the same temperature. The reaction mixture was adjusted to alkalinity by adding a saturated aqueous solution of sodium bicarbonate, and the mixture was concentrated under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (NH₃, ethyl acetate / hexane) to give the title compound (4.31 g).

[0453] 1H NMR(300MHz,DMSO-d6)δ 7.84(1H,t,J=70.8Hz),8.97(1H,d,J=2.6Hz),9.11(1H,d,J=2.3Hz).

[0454] B) 5-Chloro-6-(difluoromethoxy)pyridine-3-amine

[0455] A mixture of 2.57 g of 3-chloro-2-(difluoromethoxy)-5-nitropyridine, 12.91 g of tin(II) chloride dihydrate, and 100 mL of ethanol was stirred overnight at 70 °C. The reaction mixture was diluted with an aqueous solution of ethyl acetate and saturated sodium bicarbonate, and the insoluble matter was filtered off. The aqueous layer of the filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.17 g).

[0456] MS:[M+H]+ 194.9.

[0457] See Example 2

[0458] 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridine-3-amine

[0459] A) 5-Nitro-2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridine

[0460] To a mixture of 3.0 g of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine and 15 mL of THF, 0.921 mL of 2H-1,2,3-triazole was added at room temperature, and the reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.75 g).

[0461] MS:[M+H]+ 259.9.

[0462] B) 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridine-3-amine

[0463] In a mixture of 3.54 g of 5-nitro-2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridine, 101 mL of 10% hydrochloric acid / methanol solution, and 100 mL of methanol, 12.95 g of tin(II) chloride was added at room temperature, and the reaction mixture was stirred at the same temperature for 2 hours. The solvent was removed by distillation under reduced pressure, and ethyl acetate was added to the residue. The mixture was then neutralized by adding 2N sodium hydroxide aqueous solution. The precipitate was filtered, and the aqueous layer of the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.95 g).

[0464] MS:[M+H]+ 229.9.

[0465] See Example 3

[0466] 5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine

[0467] A) 3-Chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine

[0468] A mixture of 2,3-dichloro-5-nitropyridine (5.0 g), 2H-1,2,3-triazole (1.7 mL), potassium carbonate (4.3 g), and DMF (25 mL) was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. The organic layer was washed twice with water, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (3.5 g).

[0469] MS:[M+H]+ 225.9.

[0470] B) 5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine

[0471] A mixture of 3-chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine (3.3 g), stannous(II) chloride dihydrate (16.3 g), and ethanol (100 mL) was stirred overnight at 70 °C. The reaction mixture was diluted with ethyl acetate, and after adding a saturated aqueous solution of sodium bicarbonate, the insoluble residue was filtered off. The organic layer was separated, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.4 g).

[0472] MS:[M+H]+ 195.9.

[0473] See Example 4

[0474] 5-Amino-2-(difluoromethoxy)nicotinamide

[0475] A mixture of 5-chloro-6-(difluoromethoxy)pyridine-3-amine (319 mg), tris(dibenzylacetone)dipalladium (0) (300 mg), Sphos (269 mg), zinc cyanide (1.54 g), and DMF (10 mL) was stirred at 120 °C under microwave irradiation for 1 hour. The reaction mixture was poured into a 10% ammonia solution and extracted with ethyl acetate. The organic layer was washed with a 10% ammonia solution, water, and then saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (205 mg).

[0476] MS:[M+H]+ 185.9.

[0477] Example 1

[0478] (S)-N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil) -7-base) urea

[0479]

[0480]

[0481] A) 2-Methoxy-1-(1-(triphenylmethyl)-1H-imidazol-2-yl)prop-1-one

[0482] In a mixture of 50 g of 1-(triphenylmethyl)-1H-imidazole and 600 mL of THF, 100 mL of 1.6 M n-butyllithium / hexane solution was added dropwise at -10 °C, and the mixture was heated to 0 °C while stirring at the same temperature for 30 minutes. The mixture was then cooled to -78 °C, and 20.94 g of methyl 2-methoxypropionate was added dropwise. The mixture was stirred at the same temperature for 1 hour, followed by stirring at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride (10 mL) was added to the mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and distilled off the solvent under reduced pressure. Hexane was added to the residue, and the precipitate was filtered off to obtain the title compound (50 g).

[0483] 1H NMR(400MHz, DMSO-d6)δ 0.90(3H,d,J=6.8Hz),2.83(3H,s),4.88-4.93(1H,m),6.89-7.43(17H,m).

[0484] B) 1-(1H-imidazol-2-yl)-2-methoxyprop-1-one

[0485] A mixture of 150 g of 2-methoxy-1-(1-(triphenylmethyl)-1H-imidazol-2-yl)prop-1-one and 5% acetic acid / methanol solution (500 mL) was heated under reflux for 16 hours. After cooling the reaction mixture to room temperature, the solvent was removed by distillation under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (44 g).

[0486] MS:[M+H]+ 154.8.

[0487] C) 1-(1-amino-1H-imidazol-2-yl)-2-methoxyprop-1-one

[0488] A mixture of 20 g of 1-(1H-imidazol-2-yl)-2-methoxyprop-1-one and 100 mL of DMF was added to a 1 M potassium trioxide THF solution (143 mL) at room temperature, and the reaction mixture was stirred at the same temperature for 30 minutes. 26 g of O-(4-nitrobenzoyl)hydroxyamine was added to the reaction mixture at room temperature, and the reaction mixture was stirred at the same temperature for 16 hours. 40 mL of ice-cold water was added to the reaction mixture, and the solvent was removed by distillation under reduced pressure. 200 mL of ethyl acetate was added to the residue, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (17 g).

[0489] 1H-NMR(400MHz,DMSO-d6)δ 1.32(3H,d,J=6.8Hz),3.24(3H,s),4.94-4.99(1H,m),6.86(2H,brs),7.06(1H,s),7.47(1H,s).

[0490] D)(2-(2-methoxypropyl)-1H-imidazol-1-yl)carbamate tributyl ester

[0491] DMAP (6.1 g) was added to a mixture of 1-(1-amino-1H-imidazol-2-yl)-2-methoxyprop-1-one (17 g) and DMF (50 mL) at room temperature, followed by Boc2O (22.3 mL) at the same temperature. The reaction mixture was stirred at 80 °C for 1 hour and cooled to room temperature. The solvent was removed by distillation under reduced pressure, and the residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (13 g).

[0492] MS:[M+H]+ 270.1.

[0493] E)(4-bromo-2-(2-methoxypropyl)-1H-imidazol-1-yl)carbamate tributyl ester

[0494] A mixture of 8.0 g of (2-(2-methoxypropionic acid)-1H-imidazol-1-yl)carbamate tributyl ester and DMF (40 mL) was added dropwise to a DMF solution of 5.2 g of N-bromosuccinimide (10 mL) at room temperature, and the reaction mixture was stirred at the same temperature for 16 hours. The reaction mixture was diluted with water (80 mL), and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (5.5 g).

[0495] 1H-NMR(400MHz,DMSO-d6)δ 1.28(3H,d,J=6.8Hz),1.46(9H,s),3.21(3H,s),4.83-4.85(1H,m),7.93(1H,s),10.80(1H,s).

[0496] F)1-(1-amino-4-bromo-1H-imidazol-2-yl)-2-methoxyprop-1-one

[0497] In a mixture of 10 g of tert-butyl (4-bromo-2-(2-methoxypropionic)-1H-imidazol-1-yl)carbamate and 100 mL of dichloromethane, 20 mL of TFA was added at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and 50 mL of saturated sodium bicarbonate aqueous solution was added to the residue. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and distilled off the solvent under reduced pressure. n-Pentane was added to the residue, and the precipitate was filtered off to obtain the title compound (7.0 g).

[0498] MS:[M+H]+ 248.2.

[0499] G)2-Bromo-8-(1-Methoxyethyl)imidazo[1,2-b]tadalafil 7-Carboxylic Acid Methyl Ester

[0500] A mixture of 7.0 g of 1-(1-amino-4-bromo-1H-imidazol-2-yl)-2-methoxyprop-1-one and 50 mL of THF was added to methyl acrylate (5.1 mL) and lithium bromide (9.71 g) at room temperature. After degassing the reaction mixture with oxygen, Pd(OAc)₂ (1.27 g) was added to the reaction mixture at the same temperature, and the reaction mixture was stirred at 50 °C for 16 hours under oxygen. The reaction mixture was diluted with ice-cold water (50 mL), and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (5.0 g).

[0501] MS:[M+H]+ 314.0.

[0502] H)8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]tadalafil 7-Carboxylic Acid Methyl Ester

[0503] 2-Bromo-8-(1-Methoxyethyl)imidazo[1,2-b]tadalafil A mixture of methyl 7-carboxylate (8.0 g), toluene (70 mL), and water (10 mL) was degassed with nitrogen, and then tripotassium phosphate (17.6 g) and 2,4,6-trimethyltriborane trioxane (7.12 mL) were added at room temperature. The mixture was further degassed with nitrogen, and then Pd(OAc)₂ (571 mg) and SPhos (1.57 g) were added at room temperature. The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was diluted with saturated sodium bicarbonate aqueous solution (50 mL), and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (4.0 g).

[0504] MS:[M+H]+ 250.2

[0505] I)(S)-8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]tadalafil 7-Carboxylic acid methyl ester 8-(1-methoxyethyl)-2-methylimidazo[1,2-b] ester Methyl 7-carboxylic acid ester (4.36 g) was separated by HPLC (CHIRALCEL OD-H (VJ002), 20 mm I D × 250 mm L, mobile phase: hexane / 2-propanol = 950 / 50), and the fraction containing the target compound with a shorter retention time was concentrated under reduced pressure to obtain the title compound (2034 mg).

[0506] Optical purity: 99.9% ee, holding time: 6.845 minutes (CHIRALCEL OD-H(VK069), 4.6mm ID × 250mm L, mobile phase: hexane / 2-propanol = 950 / 50)

[0507] MS:[M+H]+ 250.0.

[0508] The absolute configuration is determined using a single-crystal X-ray diffraction device.

[0509] J)(S)-8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]tadalafil -7-Carboxylic acid trifluoroacetate

[0510] (S)-8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil A mixture of methyl 7-carboxylate (1.71 g) and acetic acid (17 mL) was added to 6N hydrochloric acid (17.15 mL) at room temperature, and the reaction mixture was stirred overnight at 100 °C. The reaction mixture was concentrated under reduced pressure, and the residue was separated by HPLC (C18, mobile phase: water / acetonitrile (system containing 0.1% TFA)). The fraction obtained was concentrated under reduced pressure and dried under reduced pressure to obtain the title compound (2.6 g).

[0511] MS:[M+H]+ 236.0.

[0512] K)(S)-8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]tadalafil 7-amine

[0513] (S)-8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil In a mixture of 2.6 g of 7-carboxylic acid trifluoroacetate, 5.3 mL of TEA, and 150 mL of toluene, 4.9 mL of DPPA was added at room temperature, and the reaction mixture was stirred at the same temperature for 2 hours. Acetic acid (50 mL) and water (50 mL) were added to the reaction mixture, and the reaction mixture was stirred overnight at 80 °C. After concentrating the reaction mixture under reduced pressure, the residue was diluted with a saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (NH4, ethyl acetate / hexane) to give the title compound (1.38 g).

[0514] MS:[M+H]+ 207.0.

[0515] L)(S)-N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil) -7-base) urea

[0516] (S)-8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil A mixture of 7-amine (1180 mg), DIEA (3.49 mL), and THF (10 mL) was added to triphosgene (679.1 mg) at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. 5-Chloro-6-(difluoromethoxy)pyridine-3-amine (1.17 g) obtained in Reference Example 1 was added to the reaction mixture at room temperature, and the reaction mixture was stirred at 60 °C for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (NH₃, ethyl acetate / hexane), followed by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (1.83 g).

[0517] 1H NMR(300MHz,DMSO-d6)δ 1.52(3H,d,J=6.8Hz),2.35(3H,d,J=0.8Hz),3.30(3H,s),5.26(1H,q,J=6.8Hz),7.40-7. 91(1H,m),7.92(1H,d,J=0.8Hz),8.21(1H,d,J=2.3Hz),8.33(1H,d,J=2.3Hz),8.69(1H,br s),9.01(1H,s),10.27(1H,br s).

[0518] MS:[M+H]+ 427.0.

[0519] The absolute configuration is determined using a single-crystal X-ray diffraction device.

[0520] Example 2

[0521] (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5- (Pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

[0522]

[0523]

[0524] A)(6-chloro-2-(2-methoxypropyl)pyridin-3-yl)carbamate tributyl ester

[0525] A mixture of 20.0 g of tributyl (2-bromo-6-chloropyridin-3-yl)carbamate and 160 mL of THF was added to a 1.08 M lithium methyl ether solution (72.3 mL) at -78 °C, and the reaction mixture was stirred at the same temperature for 15 minutes. A 52.8 mL solution of 1.6 M n-butyllithium / hexane was added to the reaction mixture at -78 °C, and the reaction mixture was stirred at the same temperature for 15 minutes. A 60 mL solution of THF containing 16.9 g of 2-methoxy-1-N-morpholinylprop-1-one was added to the reaction mixture at -78 °C, and the reaction mixture was stirred while being heated to room temperature for 2 hours. A 150 mL solution of acetic acid and water was added to the reaction mixture at room temperature, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (15.81 g).

[0526] MS:[M+H-tBu]+ 258.9.

[0527] B) 1-(6-chloro-3-((2-nitrovinyl)amino)pyridin-2-yl)-2-methoxyprop-1-one

[0528] A mixture of 15.7 g of tributyl (6-chloro-2-(2-methoxypropyl)pyridin-3-yl)carbamate and 100 mL of ethyl acetate was added to a solution of 200 mL of 4N cyclopentyl methyl ether hydrochloride at room temperature, and the reaction mixture was stirred at the same temperature for 2 hours. Another 100 mL solution of 4N cyclopentyl methyl ether hydrochloride was added to the reaction mixture at room temperature, and the mixture was stirred overnight at the same temperature. The solvent was then distilled off under reduced pressure. The resulting residue, a mixture of (E)-4-(2-nitrovinyl)morpholine (9.47 g), 36 mL of 6N hydrochloric acid, and 120 mL of acetone was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (240 mL) and stirred at 0 °C for 1 hour. The precipitate was filtered off, washed with water, and the solid obtained was dried under reduced pressure to give the title compound (12.55 g).

[0529] MS:[M+H]+ 286.0.

[0530] C) 2-Chloro-8-(1-Methoxyethyl)-7-nitro-1,5- pyridine

[0531] A mixture of DBU (6.62 mL) and THF (120 mL) was added at room temperature to a THF solution of 1-(6-chloro-3-((2-nitrovinyl)amino)pyridin-2-yl)-2-methoxyprop-1-one (12.55 g) in 280 mL. The reaction mixture was stirred at the same temperature for 1 hour. 2N hydrochloric acid was added to the reaction mixture to adjust the pH to weakly acidic, and then it was diluted with water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (9.82 g).

[0532] MS:[M+H]+ 267.9.

[0533] D)6-Chloro-4-(1-Methoxyethyl)-1,5- pyridine-3-amine

[0534] 2-Chloro-8-(1-Methoxyethyl)-7-nitro-1,5- A mixture of pyridine (5.00 g), stannous(II) chloride dihydrate (21.1 g), and ethyl acetate (150 mL) was stirred at 60 °C for 2 hours, then stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and neutralized with 2 M potassium carbonate aqueous solution. The precipitate was filtered, and the aqueous layer of the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (NH4, ethyl acetate / hexane) to give the title compound (3.91 g).

[0535] MS:[M+H]+ 238.0.

[0536] E)(S)-6-chloro-4-(1-methoxyethyl)-1,5- pyridine-3-amine

[0537] 6-Chloro-4-(1-Methoxyethyl)-1,5- The 3-pyridylamine (3.84 g) was separated by HPLC (CHIRALPAK IG (VJ003), 20 mm ID × 250 mm L, mobile phase: hexane / ethanol = 900 / 100), and the fraction containing the target compound with a longer retention time was concentrated under reduced pressure to obtain the title compound (1865 mg).

[0538] Optical purity: 99.9% ee, holding time: 7.359 minutes (CHIRALPAK AD-H(VJ019), 4.6 mm ID × 250 mm L, mobile phase: hexane / 2-propanol = 850 / 150)

[0539] MS:[M+H]+ 238.0.

[0540] The absolute configuration is determined using a single-crystal X-ray diffraction device.

[0541] F)(S)-N-(6-chloro-4-(1-methoxyethyl)-1,5- (Pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

[0542] The reaction is carried out in four separate steps, as shown below.

[0543] Reaction mixture 1: (S)-6-chloro-4-(1-methoxyethyl)-1,5- A solution of 100 mg pyridin-3-amine and 0.220 mL DIEA in 2 mL of THF was added, and the reaction mixture was stirred at the same temperature for 1 hour. 106 mg of 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine obtained in Reference Example 2 was added to the reaction mixture at 0 °C, and the reaction mixture was stirred at 60 °C overnight.

[0544] Reaction mixture 2: (S)-6-chloro-4-(1-methoxyethyl)-1,5- A solution of 300 mg pyridin-3-amine and 0.660 mL DIEA in 6 mL of THF was added, and the reaction mixture was stirred at the same temperature for 1 hour. 318 mg of 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine obtained in Reference Example 2 was added to the reaction mixture at 0 °C, and the reaction mixture was stirred at 60 °C for 2 hours. 29 mg of 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine was added to the reaction mixture at the same temperature, and the reaction mixture was stirred overnight.

[0545] Reaction mixture 3: (S)-6-chloro-4-(1-methoxyethyl)-1,5- A solution of 600 mg of pyridin-3-amine and 1.32 mL of DIEA in 12 mL of THF was added, and the reaction mixture was stirred at the same temperature for 1 hour. 636 mg of 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine obtained in Reference Example 2 was added to the reaction mixture at 0 °C, and the reaction mixture was stirred at 60 °C for 2 hours. 116 mg of 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine was added to the reaction mixture at the same temperature, and the reaction mixture was stirred overnight.

[0546] Reaction mixture 4: (S)-6-chloro-4-(1-methoxyethyl)-1,5- A solution of 850 mg of pyridin-3-amine and 1.87 mL of DIEA in THF (17 mL) was added, and the reaction mixture was stirred at the same temperature for 1 hour. 901 mg of 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine obtained in Reference Example 2 was added to the reaction mixture at 0 °C, and the reaction mixture was stirred at 60 °C for 2 hours. 164 mg of 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine was added to the reaction mixture at the same temperature, and the reaction mixture was stirred overnight.

[0547] Reaction mixtures 1-4 were combined into one, diluted with a saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled off the solvent under reduced pressure. THF and ethyl acetate were added to the residue, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH₃, ethyl acetate / hexane) to obtain crude crystals (3.46 g). The obtained crude crystals were dissolved in ethyl acetate (20 mL) at 80 °C, and n-heptane (180 mL) was added dropwise to the mixed solution at the same temperature. The mixed solution was stirred at the same temperature for 1 hour, cooled to room temperature, and stirred overnight at the same temperature. The precipitate was filtered off, washed with a mixed solution of ethyl acetate and n-heptane, and dried under reduced pressure to obtain the title compound (3.35 g).

[0548] 1H NMR(300MHz,DMSO-d6)δ1.56(3H,d,J=6.4Hz),3.36(3H,s),5.85(1H,q,J=6.7Hz),7.77(1H,d,J=8.7Hz),8.18(2H ,s),8.46(1H,d,J=9.1Hz),8.74(1H,d,J=2.6Hz),8.89(1H,d,J=2.3Hz),9.24(1H,s),9.68(1H,s),10.89(1H,s).

[0549] MS:[MH]- 491.1.

[0550] The absolute configuration is determined using a single-crystal X-ray diffraction device.

[0551] Example 3

[0552] (S)-N-(4-(1-methoxyethyl)-6-methyl-1,5- (Pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

[0553]

[0554]

[0555] A) 8-(1-Methoxyethyl)-2-methyl-7-nitro-1,5- pyridine

[0556] 2-Chloro-8-(1-Methoxyethyl)-7-nitro-1,5- A mixture of pyridine (500 mg), 2,4,6-trimethyltriborazine trioxane (0.39 mL), Pd(dppf)Cl2‧CH2Cl2 (153 mg), tripotassium phosphate (793 mg), and 1,2-dimethoxyethane (20 mL) was heated at 100 °C for 1.5 hours under microwave irradiation. The reaction mixture was diluted with ethyl acetate. The insoluble matter was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (439 mg).

[0557] MS:[M+H]+ 247.9.

[0558] B) 4-(1-Methoxyethyl)-6-methyl-1,5- pyridine-3-amine

[0559] 8-(1-Methoxyethyl)-2-methyl-7-nitro-1,5- A mixture of pyridine (470 mg), tin(II) dihydrate (2.57 g), THF (3 mL), and ethanol (12 mL) was stirred overnight at room temperature and then stirred at 60 °C for 7 hours. The reaction mixture was diluted with ethyl acetate and neutralized with a saturated aqueous sodium bicarbonate solution. The insoluble matter was filtered off and washed with ethyl acetate. The filtrate was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), followed by silica gel column chromatography (NH₃, ethyl acetate / hexane) to give the title compound (306 mg).

[0560] MS:[M+H]+ 217.9.

[0561] C)N-(4-(1-methoxyethyl)-6-methyl-1,5- (Pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

[0562] In 4-(1-methoxyethyl)-6-methyl-1,5- A solution of pyridine-3-amine (80 mg), 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridine-3-amine (101 mg) obtained in Reference Example 2, and pyridine (0.089 mL) in THF (5 mL) was added at 0 °C to a solution of triphosgene (54.6 mg) in THF (1 mL). The reaction mixture was stirred at 0 °C for 30 minutes, then at room temperature for 30 minutes. Pyridine (0.089 mL) was added at 0 °C, followed by a solution of triphosgene (54.6 mg) in THF (1 mL). The reaction mixture was stirred at 0 °C for 30 minutes, then at room temperature for 4 hours. The mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silicone column chromatography (NH, ethyl acetate / hexane) to give the title compound (127 mg).

[0563] MS:[M+H]+ 473.1.

[0564] D)(S)-N-(4-(1-methoxyethyl)-6-methyl-1,5- (Pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

[0565] N-(4-(1-methoxyethyl)-6-methyl-1,5- (Pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea (119.8 mg) was separated by HPLC (CHIRALPAK AD-H(VA001), 20 mm ID × 250 mm L, mobile phase: hexane / ethanol = 700 / 300). The fraction containing the target compound with a shorter retention time was concentrated under reduced pressure to obtain the title compound (55.6 mg).

[0566] MS:[M+H]+ 473.1.

[0567] Example 4

[0568] (S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil) -7-base) urea

[0569]

[0570]

[0571] In (S)-8-(1-methoxyethyl)-2-methylimidazo[1,2-b] 4 mL of 8 M sodium hydroxide aqueous solution was added to a THF (30 mL) solution of methyl 7-carboxylic acid (743 mg) at room temperature. The reaction mixture was stirred for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The aqueous layer was adjusted to pH 4 with 6 N hydrochloric acid and concentrated under reduced pressure. The residue was suspended in ethanol, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. 1.16 mL of DPPA was added to a toluene (50 mL) solution of the residue (848 mg) and triethylamine (1.51 mL) at room temperature. After stirring at room temperature for 40 minutes, 705 mg of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridine-3-amine obtained in Reference Example 3 was added. The reaction mixture was stirred at 100 °C for 2 hours, poured into a saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (488 mg).

[0572] 1H NMR(300MHz,DMSO-d6)δ 1.54(3H,d,J=6.4Hz),2.37(3H,s),3.33(3H,s),5.29(1H,q,J=6.8Hz),7.96(1H,d,J=0.8Hz),8. 16(2H,s),8.47-8.52(1H,m),8.54(1H,d,J=2.3Hz),8.75(1H,brs),9.04(1H,s),10.59(1H,brs).

[0573] MS:[M+H]+ 428.0.

[0574] Example 5

[0575] (S)-N-(5-cyano-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil) -7-base) urea

[0576]

[0577]

[0578] (S)-8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil A mixture of 7-carboxylic acid trifluoroacetate (80 mg), TEA (0.17 mL), and toluene (5 mL) was added, and DPPA (0.12 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. DPPA (0.12 mL) was further added at room temperature, and the reaction mixture was stirred at the same temperature for 30 minutes. 5-amino-2-(difluoromethoxy)nicotinamide (57.9 mg) obtained in Reference Example 4 was added, and the reaction mixture was stirred at 110 °C for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (NH₃, ethyl acetate / hexane), and washed with ethyl acetate / hexane suspension to give the title compound (65 mg).

[0579] 1H NMR(300MHz,DMSO-d6)δ 1.53(3H,d,J=6.8Hz),2.36(3H,s),3.31(3H,s),5.22-5.31(1H,m),7.47-7.98(1H,m), 7.93(1H,d,J=0.8Hz),8.51-8.57(2H,m),8.68(1H,brs),9.01(1H,s),10.33(1H,brs).

[0580] MS:[M+H]+ 418.1.

[0581] Example 6

[0582] (S)-N-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil -7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

[0583]

[0584]

[0585] A)8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]tadalafil -7-carboxylic acid

[0586] In 8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil A methanol solution of methyl 7-carboxylic acid (262 mg) was dissolved in 0.53 mL of 8 M sodium hydroxide solution at room temperature and stirred for 5 hours. The reaction mixture was neutralized with 2 N hydrochloric acid and concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the insoluble matter was filtered off. The title compound (256 mg) was obtained by concentrating the filtrate under reduced pressure.

[0587] MS:[M+H]+ 235.9.

[0588] B)N-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil -7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

[0589] In 8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil DPPA (0.18 mL) was added to a toluene (10 mL) solution of 7-carboxylic acid (166 mg) and triethylamine (0.30 mL) at room temperature. After stirring at room temperature for 40 minutes, 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridine-3-amine (162 mg) obtained in Reference Example 2 was added. The reaction mixture was stirred at 100 °C for 2 hours, then poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (NH4, methanol / ethyl acetate), and washed with ethyl acetate / hexane suspension to give the title compound (183 mg).

[0590] MS:[M+H]+ 462.1.

[0591] C)(S)-N-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil -7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

[0592] N-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]tadalafil (-7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea (183 mg) was separated by HPLC (CHIRALPAK IC (VB004), 20 mmID × 250 mmL, mobile phase: hexane / 2-propanol = 300 / 700), and the fraction containing the shorter retention time of the target compound was concentrated under reduced pressure. Washed with ethyl acetate / hexane, the title compound (62 mg) was obtained.

[0593] 1H NMR(300MHz,DMSO-d6)δ1.55(3H,d,J=6.8Hz),2.37(3H,d,J=0.8Hz),3.33(3H,s),5.24-5.34(1H,m),7.96(1H,d, J=0.8Hz),8.17(2H,s),8.72(1H,d,J=2.3Hz),8.80(1H,brs),8.83(1H,d,J=2.3Hz),9.06(1H,s),10.75(1H,brs).

[0594] MS:[M+H]+ 462.1.

[0595] Example 7

[0596] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(2-methoxypropyl-2-yl)-2-methylimidazo[1,2-b]tadalafil -7-base) urea

[0597]

[0598]

[0599] A) 1-(triphenylmethyl)-1H-imidazolium

[0600] TEA (77 mL) was added to a solution of imidazole (25 g) in dichloromethane (300 mL) at 0 °C. After stirring for 5 minutes, triphenylmethyl chloride (102 g) was added in small, incremental amounts at the same temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted twice with dichloromethane. The organic layer was washed with water, then with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The title compound (110 g) was obtained by washing the residue with hexane.

[0601] 1H NMR(300MHz, CDCl3)δ 6.82(1H,s),7.06(1H,s),7.08-7.15(6H,m),7.26-7.34(9H,m),7.45(1H,s).

[0602] B) 2-Methoxy-2-methyl-1-(1-(triphenylmethyl)-1H-imidazol-2-yl)prop-1-one

[0603] In a THF (15 mL) solution of 1-(triphenylmethyl)-1H-imidazole (1.0 g), a 1.4 M n-butyllithium hexane solution (2.3 mL) was added dropwise at -10 °C, and the mixture was stirred at 0 °C for 30 min. After cooling the reaction mixture to -78 °C, methyl 2-methoxy-2-methylpropionate (0.5 g) was added dropwise, and the mixture was stirred at the same temperature for 1 h, followed by stirring at room temperature for 3 h. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water, then with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The title compound (650 mg) was obtained by washing the residue with hexane suspension.

[0604] 1H NMR (300MHz, CDCl3) δ1.38(6H,s),2.67(3H,s),7.02-7.15(12H,m),7.25-7.35(5H,m).

[0605] C) 1-(1H-imidazol-2-yl)-2-methoxy-2-methylprop-1-one

[0606] A mixture of 4.2 g of 2-methoxy-2-methyl-1-(1-(triphenylmethyl)-1H-imidazol-2-yl)prop-1-one and 5% acetic acid-methanol solution (50 mL) was refluxed for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (1.2 g).

[0607] MS:[M+H]+ 169.2.

[0608] D)1-(1-amino-1H-imidazol-2-yl)-2-methoxy-2-methylprop-1-one

[0609] A solution of 1-(1H-imidazol-2-yl)-2-methoxy-2-methylprop-1-one (1.4 g) in DMF (15 mL) was added to a 1M potassium tert-butoxide solution in THF (9.2 mL), and the mixture was stirred at the same temperature for 30 minutes. O-(4-nitrobenzoyl)hydroxylamine (1.7 g) was added to the resulting mixture at room temperature, and the mixture was stirred at the same temperature for 16 hours. Cold water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (1.0 g).

[0610] MS:[M+H]+ 184.1.

[0611] E)N-(2-(2-(2-methoxy-2-methylpropionic acid)-1H-imidazol-1-yl)(tert-butoxy)methamide

[0612] DMAP (0.34 g) was added to a DMF (10 mL) solution of 1-(1-amino-1H-imidazol-2-yl)-2-methoxy-2-methylprop-1-one (1.0 g) at room temperature, followed by Boc₂O (1.2 mL). The reaction mixture was stirred at 80 °C for 1 hour, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (1.1 g).

[0613] MS:[M+H]+ 284.2.

[0614] F)N-(4-bromo-2-(2-(2-methoxy-2-methylpropionic acid)-1H-imidazol-1-yl)(tert-butoxy)methamide

[0615] A solution of N-bromosuccinimide (0.82 g) in DMF (5 mL) was added dropwise to a solution of N-(2-(2-(2-methoxy-2-methylpropionic acid)-1H-imidazol-1-yl)(tert-butoxy)methoxyamine (1.0 g) in 10 mL of DMF. The reaction mixture was stirred at room temperature for 16 hours. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was extracted twice with ethyl acetate, the organic layer was washed with water, then with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (700 mg).

[0616] MS:[M+H]+ 362.0.

[0617] G)1-(1-amino-4-bromo-1H-imidazol-2-yl)-2-methoxy-2-methylprop-1-one

[0618] In a solution of N-(4-bromo-2-(2-(2-methoxy-2-methylpropionic acid)-1H-imidazol-1-yl)(tert-butoxy)methamide (700 mg) in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with a saturated aqueous sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate. The organic layer was washed with water, then with saturated brine, and then with sodium sulfate, followed by concentration under reduced pressure. The title compound (450 mg) was obtained by washing the residue with pentane.

[0619] MS:[M+H]+ 262.0.

[0620] H)2-Bromo-8-(2-methoxypropyl-2-yl)imidazo[1,2-b]tadalafil 7-Carboxylic Acid Methyl Ester

[0621] Methyl acrylate (0.3 mL) and lithium bromide (531 mg) were added to a THF solution (400 mg) of 1-(1-amino-4-bromo-1H-imidazol-2-yl)-2-methoxy-2-methylprop-1-one (5 mL) at room temperature. The mixture was then placed in an oxygen-rich environment, and Pd(OAc)₂ (69 mg) was added. The mixture was stirred at 50 °C for 16 hours under oxygen conditions. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layer was washed with water, followed by saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to give the title compound (250 mg).

[0622] MS:[M+H]+ 328.1.

[0623] I) 2-Methyl-8-(2-methoxypropyl-2-yl)imidazo[1,2-b]tadalafil 7-Carboxylic Acid Methyl Ester

[0624] In 2-bromo-8-(2-methoxypropyl-2-yl)imidazo[1,2-b] In a solution of methyl 7-carboxylic acid (200 mg) in toluene (6 mL) and water (0.4 mL), 2,4,6-trimethyltriborane (0.15 mL) and tripotassium phosphate (390 mg) were added to create a nitrogen environment. Pd(OAc)₂ (28 mg) and SPhos (101 mg) were added, and the mixture was stirred at 80 °C for 3 hours. The reaction mixture was poured into an aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (120 mg).

[0625] MS:[M+H]+ 264.0.

[0626] J)2-Methyl-8-(2-methoxypropyl-2-yl)imidazo[1,2-b]tadalafil 7-Carboxylic Acid Methyl Ester

[0627] In 2-methyl-8-(2-methoxypropyl-2-yl)imidazo[1,2-b] A solution of methyl 7-carboxylate (300 mg) in ethanol (10 mL) was dissolved in 0.72 mL of 8 M sodium hydroxide solution, and the reaction mixture was stirred overnight at 60 °C. Then, 1.44 mL of 8 M sodium hydroxide solution was added, and the mixture was stirred overnight at 80 °C. 6 M hydrochloric acid was added to the reaction mixture to make it acidic at pH 4, and the mixture was concentrated under reduced pressure. The residue was suspended in ethanol, and the insoluble matter was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure while azeotropically reacting with toluene to obtain the title compound (406 mg).

[0628] MS:[M+H]+ 250.0.

[0629] K)N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(2-methoxypropyl-2-yl)-2-methylimidazo[1,2-b]tadalafil) -7-base) urea

[0630] In 2-methyl-8-(2-methoxypropyl-2-yl)imidazo[1,2-b] A mixture of methyl 7-carboxylic acid (50 mg) and triethylamine (0.04 mL) in DMF (5 mL) was added to DPPA (0.05 mL), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Toluene (5 mL), triethylamine (0.04 mL), and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridine-3-amine (27.5 mg) obtained in Reference Example 3 were added to the residue, and the reaction mixture was stirred at 110 °C for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to obtain the title compound (2 mg).

[0631] 1H NMR (300MHz, CDCl3)δ 1.95(6H,s),2.44(3H,d,J=0.8Hz),3.29(3H,s),7.64(1H,d,J=0.8Hz),7.70(1H,s),7. 88-7.99(2H,m),8.38(1H,d,J=2.6Hz),8.57(1H,d,J=2.6Hz),9.17(1H,s),9.58(1H,s).

[0632] MS:[M+H]+ 442.1.

[0633] Example 8

[0634] N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-chloro-8-(prop-2-yl)imidazo[1,2-b]tadalafil -7-base) urea

[0635]

[0636]

[0637] A) Ethyl 1-amino-1H-imidazol-2-carboxylate

[0638] A 1M lithium hexamethyldisilamide THF solution (171 mL) was added dropwise to an anhydrous DMF solution (400 mL) of ethyl imidazole-2-carboxylate (20 g) under nitrogen at -10 °C, and stirred at the same temperature for 30 min. An anhydrous DMF solution (1000 mL) of O-diphenyloxyphosphine hydroxylamine (39.9 g) was added at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted four times with dichloromethane. The extract was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (23.0 g).

[0639] 1H NMR(400MHz,DMSO-d6)δ 1.31(3H,t,J=7.2Hz),4.30(2H,q,J=7.2Hz),6.59(2H,brs),6.98(1H,d,J=0.8Hz),7.39(1H,d,J=0.8Hz).

[0640] B) Ethyl 1-((tert-butoxycarbonyl)amino)-1H-imidazol-2-carboxylate

[0641] Boc₂O (28.0 g) was added dropwise to an anhydrous DMF (250 mL) solution of ethyl 1-amino-1H-imidazolium-2-carboxylate (23.0 g) and DMAP (8.72 g). The mixture was stirred at 80–85 °C for 4 hours under nitrogen, and then concentrated under reduced pressure. The residue was diluted with dichloromethane, washed with saturated citric acid aqueous solution, and then washed with saturated brine. After drying with anhydrous sodium sulfate, the residue was concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / dichloromethane) to give the title compound (26.6 g).

[0642] 1H NMR(400MHz,MeOD)δ 1.40(3H,t,J=7.2Hz),1.52(9H,s),4.39(2H,q,J=7.2Hz),7.15(1H,d,J=1.2Hz),7.39(1H,d,J=1.2Hz).

[0643] C) 1-((tert-butoxycarbonyl)amino)-4-chloro-1H-imidazol-2-carboxylic acid ethyl ester

[0644] N-chlorosuccinimide (50.2 g) was added incrementally to an anhydrous DMF (800 mL) solution of ethyl 1-((tert-butoxycarbonyl)amino)-1H-imidazolium-2-carboxylate (80.0 g). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was washed twice with water and twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / petroleum ether) to give the title compound (16.8 g).

[0645] 1H NMR(400MHz, CDCl3)δ 1.39(3H,t,J=7.2Hz),1.49(9H,s),4.39(2H,q,J=7.2Hz),7.16(1H,s),8.07(1H,brs).

[0646] D)Ethyl 3-(1-((tert-butoxycarbonyl)amino)-4-chloro-1H-imidazol-2-yl)-3-sideoxypropionate

[0647] A 1M hexamethyldisilamide lithium THF solution (266 mL) was added dropwise to an anhydrous THF solution of 1-((tert-butoxycarbonyl)amino)-4-chloro-1H-imidazol-2-carboxylic acid ethyl ester (22.0 g) and ethyl acetate (33.5 g) at -10 °C under nitrogen. The reaction mixture was stirred at the same temperature for 30 min, followed by stirring at room temperature for 4.5 h. After cooling to 0 °C, acetic acid was added to adjust the pH to 5, and then the pH was adjusted to 8 with a saturated sodium bicarbonate aqueous solution. After extraction three times with ethyl acetate, the organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane) to give the title compound (19.7 g).

[0648] 1H NMR(400MHz, CDCl3)δ 1.26(3H,t,J=7.2Hz),1.50(9H,s),4.05(2H,s),4.19(2H,q,J=6.8Hz),7.25(1H,s),8.31(1H,brs).

[0649] E)2-Chloro-8-hydroxyimidazo[1,2-b]tadalafil 7-Carboxylic acid ethyl ester

[0650] Ethyl 3-(1-((tert-butoxycarbonyl)amino)-4-chloro-1H-imidazol-2-yl)-3-sideoxypropionate (31.0 g) was added to anhydrous dichloromethane (400 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by silicone column chromatography (methanol / dichloromethane) to give the title compound (16.0 g).

[0651] MS:[M+H]+ 241.9.

[0652] F)8-Bromo-2-chloroimidazole[1,2-b]tartrate 7-Carboxylic acid ethyl ester

[0653] In 2-chloro-8-hydroxyimidazo[1,2-b]tadalafil Phosphorus bromide (30.4 g) was added to a solution of ethyl 7-carboxylate (16.0 g) in acetonitrile (150 mL). The reaction mixture was stirred at 80–90 °C for 2 hours under nitrogen. After cooling to room temperature, ice water was added, and the mixture was neutralized with a saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with ethyl acetate. The organic layer was washed twice with water and twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (8.24 g).

[0654] 1H NMR(400MHz, CDCl3)δ 1.45(3H,t,J=7.2Hz),4.47(2H,q,J=7.2Hz),8.03(1H,s),8.71(1H,s).

[0655] G)2-Chloro-8-(propen-2-yl)imidazo[1,2-b]tadalafil 7-Carboxylic acid ethyl ester

[0656] 8-Bromo-2-chloroimidazole[1,2-b]tadalafil Ethyl 7-carboxylate (1.0 g), potassium isopropenyl trifluoroborate (534 mg), tripotassium phosphate (2.09 g), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (240 mg), anhydrous DMF (5 mL), and anhydrous 1,4-di-carboxylate The mixture of alkane (15 mL) was stirred at 80–85 °C for 16 hours under nitrogen. After cooling the reaction mixture to room temperature, it was diluted with ethyl acetate. The organic layer was washed twice with water, then with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / petroleum ether) to give the title compound (715 mg).

[0657] MS:[M+H]+ 265.9.

[0658] H)2-Chloro-8-(propyl-2-yl)imidazo[1,2-b]tadalafil 7-Carboxylic acid ethyl ester

[0659] 2-Chloro-8-(propen-2-yl)imidazo[1,2-b]tadalafil A mixture of ethyl 7-carboxylate (1.20 g) and rhodium(I) chloride (418 mg) in anhydrous ethanol (30 mL) was stirred at 10–15 °C for 40 hours under hydrogen conditions. The mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / petroleum ether) to give the title compound (955 mg).

[0660] 1H NMR(400MHz, CDCl3)δ 1.43(3H,t,J=7.2Hz),1.59(6H,d,J=7.2Hz),4.09-4.22(1H,m),4.43(2H,q,J=7.2Hz),7.88(1H,s),8.59(1H,s).

[0661] I) 2-Chloro-8-(propyl-2-yl)imidazo[1,2-b]tadalafil -7-carboxylic acid

[0662] In 2-chloro-8-(prop-2-yl)imidazo[1,2-b] Sodium hydroxide (571 mg) was added to a solution of ethyl 7-carboxylate (955 mg) in methanol (10 mL), THF (10 mL), and water (10 mL). The mixture was stirred at 10 °C for 1 hour under nitrogen. The reaction mixture was adjusted to pH 5 by adding 2N hydrochloric acid and then extracted three times with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate / petroleum ether to give the title compound (800 mg).

[0663] 1H NMR(400MHz,DMSO-d6)δ 1.49(6H,d,J=6.8Hz),4.09-4.24(1H,m),8.57(1H,s),8.72(1H,s),13.97(1H,brs).

[0664] J)N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-chloro-8-(prop-2-yl)imidazo[1,2-b]tadalafil -7-base) urea

[0665] In 2-chloro-8-(prop-2-yl)imidazo[1,2-b] -7-carboxylic acid (60mg) and triethylamine (51mg) DPPA (130 mg) was added to a mixture of alkane (3 mL) at 10 °C. After stirring at the same temperature for 30 minutes, 5-chloro-6-(difluoromethoxy)pyridine-3-amine (58 mg) obtained in Reference Example 1 was added, and the mixture was stirred at 100 °C for 1 hour under nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / petroleum ether) followed by HPLC to give the title compound (31 mg).

[0666] 1H NMR(400MHz,DMSO-d6)δ 1.46(6H,d,J=6.8Hz),3.41-3.57(1H,m),7.67(1H,t,J=72.8Hz),8.20-8.40(3H,m),8.71(1H,s),9.03(1H,brs),9.62(1H,brs).

[0667] MS:[M+H]+ 430.9.

[0668] Example 9

[0669] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(2-methyl-8-(prop-2-yl)imidazo[1,2-b]tadalafil -7-base) urea

[0670]

[0671]

[0672] A) 2-Chloro-8-(prop-2-yl)imidazo[1,2-b]tadalafil 7-Carboxylic Acid Methyl Ester

[0673] In 2-chloro-8-(prop-2-yl)imidazo[1,2-b] A methanol solution of 7-carboxylic acid (462 mg) was dissolved in 0.6 M trimethylsilyldiazomethane in hexane (9.6 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure to give the title compound (475 mg).

[0674] MS:[M+H]+ 254.1.

[0675] B) 2-Methyl-8-(propyl-2-yl)imidazo[1,2-b]tadalafil 7-Carboxylic Acid Methyl Ester

[0676] In 2-chloro-8-(prop-2-yl)imidazo[1,2-b] Pd(OAc)₂ (84 mg) was added to a mixture of methyl 7-carboxylic acid (475 mg), 2,4,6-trimethyltriborane trioxane (0.52 mL), tripotassium phosphate (1.92 g), SPhos (307 mg), toluene (3 mL), and water (0.3 mL) under argon atmosphere. The reaction mixture was heated at 130 °C for 1 hour, then poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (356 mg).

[0677] MS:[M+H]+ 234.2.

[0678] C) Imidazolidine[1,2-b]dal 2-Methyl-8-(propyl-2-yl)-7-carboxylic acid ester

[0679] In 2-methyl-8-(propyl-2-yl)imidazo[1,2-b] A 15 mL methanol solution of methyl 7-carboxylate (356 mg) was added, followed by 1.5 mL of 2 M sodium hydroxide solution. The mixture was stirred at room temperature for 2 hours. An 0.76 mL solution of 8 M sodium hydroxide was then added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized at 0 °C with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (254 mg).

[0680] MS:[M+H]+ 220.2.

[0681] D)N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(2-methyl-8-(prop-2-yl)imidazo[1,2-b]tadalafil -7-base) urea

[0682] In imidazo[1,2-b] dapoxetine A solution of 2-methyl-8-(propyl-2-yl)-7-carboxylic acid (80 mg) and triethylamine (0.15 mL) in toluene (10 mL) was added to diphenylphosphine azide (0.09 mL). After stirring at the same temperature for 40 minutes, 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridine-3-amine (71 mg) obtained in Reference Example 3 was added, and the mixture was stirred at 100 °C for 2 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and washed with ethyl acetate / hexane suspension to give the title compound (83 mg).

[0683] 1H NMR(300MHz,DMSO-d6)δ1.49(6H,d,J=7.2Hz),2.38(3H,s),3.48(1H,quin,J=6.9Hz),7.93(1H,d,J=0.8Hz) ,8.12-8.16(2H,m),8.46(1H,d,J=2.3Hz),8.49(1H,s),8.57(1H,d,J=2.3Hz),8.82(1H,s),9.73(1H,brs).

[0684] MS:[M+H]+ 412.2.

[0685] The compounds of Examples 10-270 were synthesized using the same method.

[0686] [Table 1-1]

[0687] [Table 1-2]

[0688] [Table 1-3]

[0689] [Table 1-4]

[0690] [Table 1-5]

[0691] [Table 1-6]

[0692] [Table 1-7]

[0693] [Table 1-8]

[0694] [Table 1-9]

[0695] [Table 1-10]

[0696] [Table 1-11]

[0697] [Table 1-12]

[0698] [Table 1-13]

[0699] [Table 1-14]

[0700] [Table 1-15]

[0701] [Table 1-16]

[0702] [Table 1-17]

[0703] [Table 1-18]

[0704] [Table 1-19]

[0705] [Table 1-20]

[0706] Formulation Example 1 (Capsule Manufacturing)

[0707]

[0708] Mix 1), 2), 3) and 4) and fill them into gelatin capsules.

[0709] Formulation Example 2 (Manufacturing of Tablets)

[0710]

[0711] The total amounts of 1), 2), and 3) and 30g of 4) were mixed with water, vacuum dried, and then granulated. 14g of 4) and 1g of 5) were mixed into this granulated powder and granulated using a tablet-making machine. Thus, 1000 tablets were obtained, each containing 30mg of the compound from Example 1.

[0712] Experimental Example 1

[0713] Modulation of recombinant human MALT1 protein

[0714] The human MALT1 gene line was used as a template with GC-030-D09 (pENTR221 / MALT1, GeneCopoeia) as a template. PCR was performed using a primer with BamHI added to the N-terminus and NotI added to the C-terminus to obtain human MALT1 (340-789aa). To form a dimer, the yeast GCN4 leucine zipper gene line was used as a template with yeast DNA as a template. PCR was performed using a primer with NdeI added to the N-terminus and a linker sequence (GGAAGTGGCTCAGGTAGC (sequence number 1)) and BamHI added to the C-terminus to obtain yeast GCN4 (251-281aa). The two obtained restriction enzyme fragments were processed and inserted between Nde I and Not I of the pET28a(Novagen) vector to obtain the recombinant human MALT1 protein expression vector pET28a / His-LZ-hMALT1v1(340-789)-His.

[0715] The modulation of recombinant human MALT1 protein involved transforming the aforementioned phenoplasts into ECOS Competent E. coli BL21(DE3) (Nippon Gene). The resulting E. coli were inoculated into 300 mL of LB medium (1% pancreatic acid, 0.5% yeast extract, 0.5% sodium chloride, 0.01% ampicillin) and incubated at 30°C for 16 hours. The obtained culture medium was transferred to a 6L fermentation tank containing 0.3% potassium dihydrogen phosphate, 0.6% disodium hydrogen phosphate, 0.1% ammonium chloride, 0.05% sodium chloride, 0.024% magnesium sulfate, 0.01% Antifoam PE-L, 1.5% sorbitol, 1.5% casein amino acids, 0.5% yeast extract, and 0.01% ampicillin. Incubation was initiated at 37°C, with an aeration rate of 5L / min and a stirring speed of 400 rpm. When the turbidity of the culture medium reached approximately 500 kletts, the culture temperature was lowered to 16°C, and isopropyl-β-D-thiogalactopyranoside (IPTG) was added at a final concentration of 0.1 mM. Human MALT1 protein was induced by further incubation for 16 hours. After the culture was completed, the culture medium was centrifuged at 5,000 rpm for 10 min. The obtained human MALT1 protein-expressing E. coli was suspended in a buffer solution containing 50 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 5 U / ml Benzonase, 20 mM Imidazole, 10% glycerol, and 0.1% NP-40, and then subjected to ultrasonic treatment using Sonifier (Branson). The lysate was centrifuged (15, 300×G, 30 min, TOMY MX-301). The resulting supernatant was passed through a Ni-NTA Superflow (QIAGEN) column, which had been pre-equilibrated with 50 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, and 10% glycerol. After adsorption, the supernatant was dissolved in a buffer solution containing 50 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 10% glycerol, and 250 mM Imidazole. The target fraction was further recovered by gel filtration using a Superdex 200pg column pre-equilibrated with a buffer containing 50mM Tris-HCl pH8.0, 150mM NaCl, 5mM DTT, and 10% glycerol. An equal amount of 50mM Tris-HCl pH8.0, 150mM NaCl, 5mM DTT, and 90% glycerol was then added to prepare purified human MALT1 protein.The prepared protein was stored at -30°C, and the protein concentration was determined using the BCA Protein Assay Kit (PIERCE) with BSA as the standard.

[0716] Determination of MALT1 enzyme inhibition activity

[0717] Two μL of a compound solution diluted with experimental buffer (20 mM HEPES (Dongjin Chemical), 10 mM KCl (Wako Pure Chemical), 1.5 mM MgCl2 (Sigma-Aldrich), 1 mM EDTA (pH 8.0) (Nippon Gene), 0.01% Triton X-100 (Sigma-Aldrich), 1 mM DTT (Wako Pure Chemical)) was added to each 384-well Greiner disc. Next, 2 μL of purified recombinant human MALT1 enzyme solution was added, and the discs were incubated at room temperature for 60 minutes. Then, a matrix solution (75 μM Ac-LRSR-AFC (SM Biochemicals), 20 mM HEPES (Dongjin Chemical), 10 mM KCl (Wako Pure Chemical), 1.5 mM MgCl2 (Sigma-Aldrich), 1 mM EDTA (pH 8.0) (Nippon Gene)) was added. Gene), 0.01% Triton X-100 (Sigma-Aldrich), 1mM DTT (purified by Heguang) 2uL, were incubated at room temperature for 60 minutes. The fluorescence values ​​at Excitation 400nm and Emission 485nm were measured immediately after the addition of the substrate and immediately after the enzyme reaction using an Envision (PerkinElmer) reader. The increase in fluorescence value due to the enzyme reaction was used to calculate the inhibition rate (%). The inhibition rate (%) was calculated with the value without added enzyme set as 100% and the value without added compound set as 0%.

[0718] The following shows the results of the determination of MALT1 enzyme inhibition activity.

[0719] [Table 2]

[0720] The results show that the compounds of the present invention have MALT1 enzyme-inhibiting activity.

[0721] Experimental Example 2

[0722] Assay for proliferation inhibition activity of OCI-Ly3 cells

[0723] OCI-Ly3 cells were seeded at a density of 1.25 × 10³ cells / well in 96-well plates in IMDM cell culture medium containing 20% ​​FCS (fetal bovine serum, Thermo Fisher Scientific) and monothioglycerol (Fuji Film and Koden Chemical). Cell Titer-Glo solution (Promega) was added to cells without the test compound, and after stirring at room temperature for 15 minutes, the luminescence value was measured on the day of seeding using Envision (PerkinElmer). Cells with the test compound dissolved in dimethyl sulfoxide (Fuji Film and Koden Chemical) were incubated in a CO2 incubator (37°C) for 6 days, and the luminescence value was measured similarly. The inhibition rate (%) of the test compound on OCI-Ly3 cell proliferation was calculated using the following formula.

[0724] Cell proliferation inhibition rate (%) = (1 - (luminescence value on day 6 after treatment with the test compound - luminescence value before treatment with the test compound) ÷ (luminescence value on day 6 without compound - luminescence value before compound treatment)) × 100

[0725] The results of the cell proliferation inhibition rate determination are shown below.

[0726] [Table 3]

[0727] The results show that the compounds of the present invention inhibit cell proliferation.

[0728] Experimental Example 3

[0729] Antitumor effect on OCI-Ly3 cell carcinogenic model

[0730] Human diffuse large cell B-cell lymphoma cells OCI-Ly3 (DSMZ, German Collection of Microorganisms and Cell Cultures) were suspended in a Matrigel (BD Biosciences):HBSS (Thermo Fisher Scientific) solution at a ratio of 1:1. One × 10⁷ cells were transplanted subcutaneously into the abdomen of NOG female mice (CLEA, Japan). The tumor diameter of the transplanted tumors was measured, and the tumor volume was calculated using the following formula.

[0731] Tumor volume = major axis × minor axis × minor axis × (1 / 2)

[0732] Six individuals were selected from each group, with tumors reaching a size of approximately 120 mm³ after successful implantation, for use in the experiment. The test compound was administered orally twice daily at a dose of 10 mg / kg (10 mL / kg) in a 0.5% methylcellulose solution suspension (Fuji Film and Koei Tecmo Chemicals) for three weeks. Tumor volume was measured periodically on the day before administration began and every 3-4 days. The final tumor diameter was measured on the day following the end of administration (day 21), and the tumor volume was calculated. The tumor proliferation in the test compound administration group compared to the control group was defined as the average tumor volume increase rate (T / C), calculated using the following formula.

[0733] T / C = ((Tumor volume at the end of administration in the test compound group - Tumor volume on the day before administration in the test compound group) / (Tumor volume at the end of administration in the control group - Tumor volume on the day before administration in the control group)) × 100

[0734] The T / C of the test compound is shown below.

[0735] [Table 4]

[0736] These results demonstrate that the compounds of the present invention possess antitumor activity in a subcutaneous transplantation model of human diffuse large cell B-cell lymphoma cells OCI-Ly3.

[0737] [Industrial Applicability]

[0738] The compounds of this invention may have MALT1 inhibitory activity and are expected to be used as preventive or therapeutic agents for cancer, etc.

[0739] This application is based on Japanese Patent Application No. 2018-222530, which is entirely incorporated herein by reference.

[0740]

Claims

1. Use of (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5-pyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea or its salts or hydrates thereof for the manufacture of cancer prevention and / or treatment agents.

2. The use as described in claim 1, wherein, The aforementioned cancer is mantle cell lymphoma.

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