RU2808435C2 - Heterocyclic compound - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to compounds represented by the general formula (I), in which A represents

R₁ represents 1) a hydrogen atom, 2) a halogen atom, 3) a cyano group, 4) a C_1-3 alkyl group, which may be substituted by 1 to 3 halogen atoms, 5) a C_1-3 alkoxy group, 6) C_{3 -6} cycloalkyl group or 7) phenyl group; R₂ represents 1) a hydrogen atom or 2) a halogen atom; R₃ represents 1) a C_1-6 alkyl group, which may be substituted with 1 to 3 substituents selected from a C_1-3 alkoxy group, a hydroxyl group and a halogen atom, 2) a pyrazolyl group, which may be substituted with 1 to 3 substituents selected from a C_1-3 alkyl group and a halogen atom, 3) a C_3-6 cycloalkyl group, 4) an amino group disubstituted with a C_1-3 alkyl group, or 5) a phenyl group, which may be substituted by 1 to 3 atoms halogen; R₄ and R₆ represent 1) a hydrogen atom, 2) a halogen atom, 3) a C_1-3 alkyl group which may be substituted by 1 to 3 substituents selected from a) a hydroxyl group, b) a C_1-3 alkoxy group , which may be substituted by a 4-methoxyphenyl group and c) a halogen atom or 4) a C_1-3 alkoxy group, which may be substituted by 1 to 3 halogen atoms; R₅, R₇ and R₉ represent 1) a C_1-6 alkyl group, which may be substituted by 1 to 3 C_1-3 alkoxy groups, or 2) a phenyl group, which may be substituted by 1 to 3 halogen atoms; R₈ represents a C_1-3 alkyl group; and B represents 1) a phenyl group, which may be substituted by 1 to 3 substituents selected from a) a halogen atom, b) a cyano group, c) a C_1-3 alkoxy group, which may be substituted by 1 to 3 halogen atoms, and d) a triazolyl group, 2) a C_3-6 cycloalkyl group, which may be substituted with 1 to 3 substituents selected from a) a C_1-3 alkyl group, which may be substituted with 1 to 3 halogen atoms, and b) a halogen, 3) a pyridyl group, which may be substituted by 1 to 3 substituents selected from a) a halogen atom, b) a cyano group, c) a C_1-3 alkyl group, which may be substituted by 1 to 3 halogen atoms, d) C_1-3 alkoxy group, which may be substituted with 1 to 3 substituents selected from a halogen atom and a C_1-3 alkoxy group, e) pyrazolyl group, which may be substituted with 1 to 3 C_1-3 alkyl groups, f) imidazolyl group group which may be substituted with 1 to 3 C_1-3 alkyl groups, g) triazolyl group which may be substituted with 1 to 3 C_1-3 alkyl groups which may be substituted with 1 to 3 substituents selected from C_1-3 alkoxy groups and halogen atoms, h) an azetidinyl group, i) a pyrrolidonyl group, j) a tetrazolyl group, which may be substituted with 1 to 3 C_1-3 alkyl groups, k) a pyrimidinyl group and l) an oxazolyl group, 4) a pyrazolyl group, which may be substituted with 1 to 3 substituents selected from a) a C_1-3 alkyl group, which may be substituted with 1 to 3 halogen atoms, b) a C_1-3 alkoxy group, which may be substituted with 1 to 3 halogen atoms, c) a cyano group and d) a halogen atom, or 5) an imidazopyridyl group, which may be substituted by 1 to 3 halogen atoms, or pharmaceutically acceptable salts thereof.

EFFECT: production of new compounds that can be used in medicine as a preventive or therapeutic agent for the treatment of MALT1-mediated cancer.

9 cl, 4 tbl, 270 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0001]

The present invention relates to a heterocyclic compound which can have the effect of inhibiting MALT1 (mucosal lymphoid tissue protein 1), and is expected to be useful as a preventive or therapeutic agent for the treatment of cancer, etc.

[0002]

BACKGROUND OF THE ART

In the major T cells and B cells responsible for cell-mediated immunity, the T cell receptor signal and the B cell receptor signal play important roles in their function. Impaired transduction of these signals causes various diseases such as cancer and inflammatory disease. In fact, in the case of cancer, it has been reported that genetic analysis of patients with T-cell leukemia lymphoma such as TCL (Adult T-cell leukemia lymphoma), which is one of the refractory lymphomas, reveals a genetic abnormality in T-cell receptor signaling/NF- κB pathway, and that the B-cell receptor signaling pathway/NF-κB pathway is also consistently activated in other B-cell lymphomas, such as DLBCL type ABC (diffuse large B-cell lymphoma) and MCL (mantle cell lymphoma).

The CBM protein complex, which fuses the signals of these T-cell and B-cell receptors, consists of the scaffolding protein CARD11, the adapter protein BCL10 and MALT1, which has paracaspase activity. The formation of the CBM protein complex is promoted by the T-cell receptor signal and the B-cell receptor signal, which leads to increased paracaspase activity of MALT1 and activation of the transcription factor NF-κB.

Accordingly, it is expected that an inhibitor that inhibits MALT1 activity will be able to correct the increase in MALT1 activity caused by abnormalities in T cell receptor signal and B cell receptor signal, and is considered useful as a prophylactic or therapeutic agent for the treatment of cancer, inflammatory disease and the like caused by MALT1 activity.

[0003]

It is expected that the compound of the present invention will be useful for the prevention or treatment of diseases that may be affected by MALT1 (sometimes abbreviated herein as "MALT1-related diseases"). It is expected to be useful for the prevention or treatment of diseases including, but not limited to, cancer [eg, colorectal cancer (eg, colon cancer, rectal cancer, anal cancer, hereditary colorectal cancer, hereditary nonpolyposis colorectal cancer and gastrointestinal stromal tumor), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, and malignant mesothelioma), mesothelioma, pancreatic cancer (eg, pancreatic duct cancer and endocrine pancreatic tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, cancer stomach (eg, papillary adenocarcinoma, mucinous adenocarcinoma, and adenosquamous carcinoma), duodenal cancer, small bowel cancer, breast cancer (eg, invasive ductal carcinoma of the breast, ductal carcinoma in situ, and inflammatory breast cancer), ovarian cancer (eg, epithelial ovarian cancer, extragonadal germinal cell tumor, ovarian germinal cell tumor and low-grade ovarian tumor), testicular cancer, prostate cancer (for example, hormone-dependent prostate cancer, hormone-independent prostate cancer and castration-resistant prostate cancer), liver cancer (eg, hepatocellular carcinoma, primary liver cancer, and extrahepatic cholangiocarcinoma), thyroid cancer (eg, medullary thyroid cancer), kidney cancer (eg, renal cell carcinoma (eg, clear cell renal cell carcinoma), transitional cell carcinoma renal pelvic and ureteral carcinoma), uterine cancer (eg, cervical cancer, endometrial cancer, and uterine sarcoma), uterine choriocarcinoma, brain tumor (eg, medulloblastoma, glioma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, and pituitary adenoma ), retinoblastoma, skin cancer (eg, basal cell carcinoma and malignant melanoma (eg, melanoma)), sarcomas (eg, rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma, and osteosarcoma), malignant bone tumor, bladder cancer, hematopoietic tumors (eg, multiple myeloma, leukemia (eg, acute myeloid leukemia and acute lymphocytic leukemia)), malignant lymphoma (eg, diffuse large B-cell lymphoma, mantle cell lymphoma, adult T-cell leukemia/lymphoma, and chronic myeloproliferative disease), Hodgkin's disease and cancer of unknown primary site], inhibiting cancer growth, suppressing metastasis, promoting apoptosis, or preventing or treating a premalignant condition (for example, bone marrow atypia syndrome). It is further expected that the compound of the present invention will be useful for the prevention or treatment of autoimmune and/or inflammatory diseases (eg, encephalomyelitis, colitis, atopic disease, rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus), bone disease, metabolic disease, neurological disease and neurodegenerative diseases, cancer, cardiovascular disease, allergies and asthma, Alzheimer's disease, hormone-dependent disease, inflammatory disease, viral infection (eg, human immunodeficiency viral infections) and bacterial infection (eg, sepsis).

[0004]

Patent literature 1 discloses the following compounds as having a MALT1 inhibitory effect and useful for the treatment of autoimmune disorders and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and vasculitic conditions, cancers originating from the hematopoietic system, including chronic myelogenous leukemia , myeloid leukemia, non-Hodgkin's lymphoma and other B-cell lymphomas or solid tumors and the like.

[0005]

[0006]

[in which each symbol represents as defined in the literature.]

Patent literature 2 discloses the following compounds as having a MALT1 inhibitory effect and useful for the treatment of autoimmune disorders and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, Sjögren's syndrome, systemic lupus erythematosus and vasculitic conditions, cancers originating from the hematopoietic systems, including chronic myeloid leukemia, myelogenous leukemia, non-Hodgkin's lymphoma and other B-cell lymphomas or solid tumors and the like.

[0007]

[0008]

[in which each symbol represents as defined in the literature.]

Patent Literature 3 discloses the following compounds as compounds having a MALT1 inhibitory effect and useful for the treatment of autoimmune disorders, inflammatory diseases, cancers and the like.

[0009]

[0010]

[in which each symbol represents as defined in the literature.]

Patent literature 4 discloses the following compounds as having both the effects of inhibiting MALT1 and promoting the degradation of MALT1 protein through the addition of E3 ubiquitin ligase, and are useful for the treatment of cancers such as hematologic tumor, lymphocytic malignancy, leukemia, lymphoma, and multiple myeloma, and the like.

[0011]

[0012]

[in which each symbol represents as defined in the literature.]

list of opposed materials

Patent literature

[0013]

Patent Literature 1: WO 2015/181747

Patent Literature 2: WO 2017/081641

Patent Literature 3: WO 2018/020474

Patent Literature 4: WO 2018/085247

essence of the invention

TECHNICAL CHALLENGES

[0014]

An object of the present invention is to provide a new compound which can have a MALT1 inhibitory effect and is expected to be useful as a prophylactic or therapeutic agent for the treatment of cancer, etc., and a medicament containing the same.

SOLUTIONS TO PROBLEMS

[0015]

As a result of careful research aimed at solving the above objects, the present inventors have discovered that the compound represented by the following formula (I) can have an excellent MALT1 inhibition effect, thereby completing the present invention.

In other words, the present invention is as follows.

[1] The compound represented by formula (I):

[0016]

[0017]

(wherein

A represents

[0018]

[0019]

R ₁ represents 1) a hydrogen atom, 2) a halogen atom, 3) a cyano group, 4) a C _1-3 alkyl group, which may be substituted by 1 to 3 halogen atoms, 5) a C _1-3 alkoxy group, 6) C _{3 -6} cycloalkyl group or 7) phenyl group;

R ₂ represents 1) a hydrogen atom or 2) a halogen atom;

R ₃ represents 1) a C _1-6 alkyl group, which may be substituted with 1 to 3 substituents selected from a C _1-3 alkoxy group, a hydroxyl group and a halogen atom, 2) a pyrazolyl group, which may be substituted with 1 to 3 substituents selected from a C _1-3 alkyl group and a halogen atom, 3) a C _3-6 cycloalkyl group, 4) an amino group disubstituted with a C _1-3 alkyl group, or 5) a phenyl group, which may be substituted by 1 to 3 atoms halogen;

R ₄ and R ₆ represent 1) a hydrogen atom, 2) a halogen atom, 3) a C _1-3 alkyl group which may be substituted by 1 to 3 substituents selected from a) a hydroxyl group, b) a C _1-3 alkoxy group , which may be substituted by a 4-methoxyphenyl group and c) a halogen atom or 4) a C _1-3 alkoxy group, which may be substituted by 1 to 3 halogen atoms;

R ₅ , R ₇ and R ₉ represent 1) a C _1-6 alkyl group, which may be substituted by 1 to 3 C _1-3 alkoxy groups, or 2) a phenyl group, which may be substituted by 1 to 3 halogen atoms;

R ₈ represents a C _1-3 alkyl group; And

B represents

1) a phenyl group which may be substituted by 1 to 3 substituents selected from a) a halogen atom, b) a cyano group, c) a C _1-3 alkoxy group which may be substituted by 1 to 3 halogen atoms, and d) a triazolyl group ,

2) a C _3-6 cycloalkyl group, which may be substituted by 1 to 3 substituents selected from a) a C _1-3 alkyl group, which may be substituted by 1 to 3 halogen atoms, and b) a halogen atom,

3) a pyridyl group, which may be substituted by 1 to 3 substituents selected from a) a halogen atom, b) a cyano group, c) a C _1-3 alkyl group, which may be substituted by 1 to 3 halogen atoms, d) C _{1 -3} alkoxy group, which may be substituted by 1 to 3 substituents selected from a halogen atom and a C _1-3 alkoxy group, e) a pyrazolyl group, which may be substituted by 1 to 3 C _1-3 alkyl groups, f) an imidazolyl group, which may be substituted with 1 to 3 C _1-3 alkyl groups, g) a triazolyl group, which may be substituted with 1 to 3 C _1-3 alkyl groups, which may be substituted with 1 to 3 substituents selected from C _{1- 3} alkoxy groups and halogen atoms, h) an azetidinyl group, i) a pyrrolidonyl group, j) a tetrazolyl group, which may be substituted with 1 to 3 C _1-3 alkyl groups, k) a pyrimidinyl group and l) an oxazolyl group,

4) a pyrazolyl group, which may be substituted by 1 to 3 substituents selected from a) a C _1-3 alkyl group, which may be substituted by 1 to 3 halogen atoms, b) a C _1-3 alkoxy group, which may be substituted by 1 to 3 halogen atoms, c) a cyano group and d) a halogen atom, or

5) imidazopyridyl group, which can be replaced by 1 to 3 halogen atoms)

or a salt thereof, or a cocrystalline, hydrate, or solvate thereof (sometimes abbreviated in the specification as “Compound (I)”).

[2] The connection according to [1], in which A is

[0020]

[0021]

[3] The connection according to [1], in which A is

[0022]

[0023]

[4] The connection according to [1], in which A is

[0024]

[0025]

R ₁ represents 1) a halogen atom or 2) a C _1-3 alkyl group;

R ₂ represents a hydrogen atom;

R ₃ represents a C _1-6 alkyl group, which may be substituted by 1 to 3 C _1-3 alkoxy groups;

R ₄ represents 1) a halogen atom or 2) a C _1-3 alkyl group;

R ₅ represents a C _1-6 alkyl group, which may be substituted by 1 to 3 C _1-3 alkoxy groups; And

B represents a pyridyl group which may be substituted by 1 to 3 substituents selected from a) a halogen atom, b) a cyano group, c) a C _1-3 alkyl group which may be substituted by 1 to 3 halogen atoms, d) C _{1 to 3} alkoxy groups, which may be substituted by 1 to 3 halogen atoms, and e) a triazolyl group.

[5] The compound according to [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,

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

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

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

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

(S)-N-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazole)- 2-yl)-5-(trifluoromethylpyridin-3-yl)urea,

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(2-methoxypropan-2-yl)-2-methylimidazo [1,2-b]pyridazin-7-yl)urea,

N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl) urea or

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

[6] The compound according to [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] The compound according to [1], which is (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H- 1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea.

[8] A medicinal product containing the compound of [1], or a salt thereof, or a cocrystalline substance, hydrate, or solvate thereof.

[9] The drug according to [8], which is a MALT1 inhibitor.

[10] A drug according to [8], which is a prophylactic or therapeutic agent for the treatment of cancer.

PREFERABLE EFFECTS OF THE INVENTION

[0026]

The compound of the present invention may have a MALT1 inhibitory effect and be useful as a drug such as a prophylactic or therapeutic agent for the treatment of cancer, etc.

[0027]

DESCRIPTION OF IMPLEMENTATION OPTIONS

The following is a detailed description of the definition of each substituent used in the description. Unless otherwise stated, each substituent is defined as follows.

In the specification, examples of “halogen atom” include fluorine, chlorine, bromine and iodine.

In the specification, examples of the "C _1-6 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1- dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.

In the specification, examples of the "C _3-6 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the specification, examples of "C _1-3 alkoxy groups" include methoxy, ethoxy, propoxy and isopropoxy.

[0028]

In the specification, examples of "an amino group disubstituted with a C _1-3 alkyl group" include dimethylamino, ethylmethylamino, diethylamino, ethylpropylamino and dipropylamino.

[0029]

In the specification, "C _1-3 alkyl group" includes the above-mentioned "C _1-6 alkyl group" having 1 to 3 carbon atoms.

[0030]

The following is a detailed description of the definition of each symbol in formula (I).

A represents

[0031]

[0032]

A is preferably

[0033]

[0034]

In one preferred embodiment of the invention, A is

[0035]

[0036]

In another preferred embodiment of the present invention, A is

[0037]

[0038]

.

[0039]

R ₁ represents 1) a hydrogen atom, 2) a halogen atom (for example, a chlorine atom, a bromine atom), 3) a cyano group, 4) a C _1-3 alkyl group (for example, methyl), which may be substituted by 1 to 3 atoms a halogen (eg fluorine atom), 5) a C _1-3 alkoxy group (eg methoxy), 6) a C _3-6 cycloalkyl group (eg cyclopropyl) or 7) a phenyl group.

R ₁ is more preferably 1) a halogen atom (eg chlorine atom) or 2) a C _1-3 alkyl group (eg methyl).

[0040]

R ₂ represents 1) a hydrogen atom or 2) a halogen atom (eg fluorine atom, chlorine atom).

R ₂ preferably represents a hydrogen atom.

[0041]

R ₃ represents 1) a C _1-6 alkyl group (eg ethyl, isopropyl, sec-butyl) which may be substituted with 1 to 3 substituents selected from a C _1-3 alkoxy group (eg methoxy), hydroxyl group and halogen atom (for example, fluorine atom), 2) a pyrazolyl group (for example, 4-pyrazolyl), which may be substituted with 1 to 3 substituents selected from a C _1-3 alkyl group (for example, methyl) and a halogen atom (for example, chlorine atom), 3) a C _3-6 cycloalkyl group (for example, cyclopropyl), 4) an amino group disubstituted with a C _1-3 alkyl group (for example, methyl), or 5) a phenyl group, which can be substituted with 1 to 3 atoms halogen (for example, a chlorine atom).

R ₃ is preferably a C _1-6 alkyl group (eg ethyl, isopropyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (eg methoxy).

[0042]

R ₄ and R ₆ represent 1) a hydrogen atom, 2) a halogen atom (eg chlorine atom), 3) a C _1-3 alkyl group (eg methyl, ethyl) which may be substituted with 1 to 3 substituents selected of a) a hydroxyl group, b) a C _1-3 alkoxy group (eg methoxy), which may be substituted by a 4-methoxyphenyl group, and c) a halogen atom (eg fluorine atom), or 4) a C _1-3 alkoxy group (eg , methoxy, ethoxy), which may be replaced by 1 to 3 halogen atoms (for example, a fluorine atom).

R ₄ preferably represents 1) a halogen atom (eg chlorine atom) or 2) a C _1-3 alkyl group (eg methyl).

R ₆ preferably represents 1) a hydrogen atom, 2) a halogen atom (eg chlorine atom), 3) a C _1-3 alkyl group (eg methyl) or 4) a C _1-3 alkoxy group (eg methoxy).

[0043]

R ₅ , R ₇ and R ₉ represent 1) a C _1-6 alkyl group (eg, ethyl, isopropyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (eg, methoxy, ethoxy), or 2) a phenyl group, which may be substituted by 1 to 3 halogen atoms (for example, a chlorine atom).

R ₅ is preferably a C _1-6 alkyl group (eg ethyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (eg methoxy).

R ₇ preferably represents 1) a C _1-6 alkyl group (eg, ethyl, isopropyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (eg, methoxy), or 2) a phenyl group, which may be substituted from 1 to 3 halogen atoms (for example, a chlorine atom).

R ₉ is preferably a C _1-3 alkyl group (eg ethyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (eg methoxy).

[0044]

R ₈ represents a C _1-3 alkyl group (eg, methyl).

[0045]

B represents

1) a phenyl group, which may be substituted with 1 to 3 substituents selected from a) a halogen atom (for example, fluorine atom, chlorine atom), b) a cyano group, c) a C _1-3 alkoxy group (for example, methoxy), which can be substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and d) a triazolyl group,

2) a C _3-6 cycloalkyl group (eg cyclohexyl), which may be substituted with 1 to 3 substituents selected from a) C _1-3 alkyl group (eg methyl), which may be substituted with 1 to 3 halogen atoms (for example, a fluorine atom) and b) a halogen atom (for example, a fluorine atom),

3) a pyridyl group, which may be substituted with 1 to 3 substituents selected from a) a halogen atom (for example, fluorine atom, chlorine atom, bromine atom), b) a cyano group, c) a C _1-3 alkyl group (for example, methyl ), which may be substituted with 1 to 3 halogen atoms (eg fluorine atom), d) C _1-3 alkoxy group (eg methoxy, ethoxy), which may be substituted with 1 to 3 substituents selected from a halogen atom (eg , fluorine atom) and a C _1-3 alkoxy group (for example, methoxy), e) a pyrazolyl group, which may be substituted with 1 to 3 C _1-3 alkyl groups (for example, methyl), f) an imidazolyl group, which may be substituted 1 to 3 C _1-3 alkyl groups (eg methyl), g) triazolyl group which may be substituted by 1 to 3 C _1-3 alkyl groups (eg methyl) which may be substituted by 1 to 3 substituents selected from a C _1-3 alkoxy group (eg methoxy) and a halogen atom (eg fluorine atom), h) an azetidinyl group, i) a pyrrolidonyl group, j) a tetrazolyl group, which may be substituted with 1 to 3 C _1-3 alkyl groups (eg methyl), k) pyrimidinyl group and l) oxazolyl group,

4) a pyrazolyl group, which may be substituted with 1 to 3 substituents selected from a) a C _1-3 alkyl group (for example, methyl, ethyl, isopropyl), which may be substituted with 1 to 3 halogen atoms (for example, a fluorine atom ), b) a C _1-3 alkoxy group (eg methoxy), which may be substituted by 1 to 3 halogen atoms (eg fluorine atom), c) a cyano group and d) a halogen atom (eg chlorine atom), or

5) an imidazopyridyl group, which may be substituted by 1 to 3 halogen atoms (for example, a chlorine atom).

B is preferably a pyridyl group, which may be substituted with 1 to 3 substituents selected from a) a halogen atom (eg chlorine atom), b) a cyano group, c) a C _1-3 alkyl group (eg methyl), which may be substituted with 1 to 3 halogen atoms (for example, a fluorine atom), d) a C _1-3 alkoxy group (for example, methoxy), which may be substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and e) a triazolyl group .

[0046]

Suitable examples of compound (I) include the following compounds.

[Connection I-1]

Compound (I) in which A is

[0047]

[0048]

R ₁ represents 1) a hydrogen atom, 2) a halogen atom (for example, a chlorine atom, a bromine atom), 3) a cyano group, 4) a C _1-3 alkyl group (for example, methyl), which may be substituted by 1 to 3 atoms a halogen (eg fluorine atom), 5) a C _1-3 alkoxy group (eg methoxy), 6) a C _3-6 cycloalkyl group (eg cyclopropyl) or 7) a phenyl group;

R ₂ represents 1) a hydrogen atom or 2) a halogen atom (eg fluorine atom, chlorine atom);

R ₃ represents 1) a C _1-6 alkyl group (eg ethyl, isopropyl, sec-butyl) which may be substituted with 1 to 3 substituents selected from a C _1-3 alkoxy group (eg methoxy), hydroxyl group and halogen atom (for example, fluorine atom), 2) a pyrazolyl group (for example, 4-pyrazolyl), which may be substituted with 1 to 3 substituents selected from a C _1-3 alkyl group (for example, methyl) and a halogen atom (for example, chlorine atom), 3) a C _3-6 cycloalkyl group (for example, cyclopropyl), 4) an amino group disubstituted with a C _1-3 alkyl group (for example, methyl), or 5) a phenyl group, which can be substituted with 1 to 3 atoms halogen (for example, a chlorine atom);

R ₄ represents 1) a hydrogen atom, 2) a halogen atom (eg chlorine atom), 3) a C _1-3 alkyl group (eg methyl, ethyl), which may be substituted with 1 to 3 substituents selected from a) hydroxyl group, b) a C _1-3 alkoxy group (for example, methoxy), which may be substituted by a 4-methoxyphenyl group, and c) a halogen atom (for example, a fluorine atom), or 4) a C _1-3 alkoxy group (for example, methoxy, ethoxy), which may be replaced by 1 to 3 halogen atoms (for example, a fluorine atom);

R ₅ represents 1) a C _1-6 alkyl group (eg, ethyl, isopropyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (eg, methoxy, ethoxy), or 2) a phenyl group, which may be substituted with 1 to 3 halogen atoms (for example, a chlorine atom);

R ₆ represents 1) a hydrogen atom, 2) a halogen atom (eg, chlorine atom), 3) a C _1-3 alkyl group (eg, methyl) or 4) a C _1-3 alkoxy group (eg, ethoxy);

R ₇ represents 1) a C _1-6 alkyl group (ethyl, isopropyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (for example, methoxy), or 2) a phenyl group, which may be substituted with 1 to 3 halogen atoms (for example, a chlorine atom);

R ₈ represents a C _1-3 alkyl group (eg methyl);

R ₉ represents a C _1-3 alkyl group (eg, ethyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (eg, methoxy); And

B represents

1) a phenyl group, which may be substituted with 1 to 3 substituents selected from a) a halogen atom (for example, fluorine atom, chlorine atom), b) a cyano group, c) a C _1-3 alkoxy group (for example, methoxy), which can be substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and d) a triazolyl group,

2) a C _3-6 cycloalkyl group (eg cyclohexyl), which may be substituted with 1 to 3 substituents selected from a) C _1-3 alkyl group (eg methyl), which may be substituted with 1 to 3 halogen atoms (for example, a fluorine atom) and b) a halogen atom (for example, a fluorine atom),

3) a pyridyl group, which may be substituted with 1 to 3 substituents selected from a) a halogen atom (for example, fluorine atom, chlorine atom, bromine atom), b) a cyano group, c) a C _1-3 alkyl group (for example, methyl ), which may be substituted with 1 to 3 halogen atoms (eg fluorine atom), d) C _1-3 alkoxy group (eg methoxy, ethoxy), which may be substituted with 1 to 3 substituents selected from a halogen atom (eg , fluorine atom) and a C _1-3 alkoxy group (for example, methoxy), e) a pyrazolyl group, which may be substituted with 1 to 3 C _1-3 alkyl groups (for example, methyl), f) an imidazolyl group, which may be substituted 1 to 3 C _1-3 alkyl groups (eg methyl), g) triazolyl group which may be substituted by 1 to 3 C _1-3 alkyl groups (eg methyl) which may be substituted by 1 to 3 substituents selected from a C _1-3 alkoxy group (eg methoxy) and a halogen atom (eg fluorine atom), h) an azetidinyl group, i) a pyrrolidonyl group, j) a tetrazolyl group, which may be substituted with 1 to 3 C _1-3 alkyl groups (eg methyl), k) pyrimidinyl group and l) oxazolyl group,

4) a pyrazolyl group, which may be substituted with 1 to 3 substituents selected from a) a C _1-3 alkyl group (for example, methyl, ethyl, isopropyl), which may be substituted with 1 to 3 halogen atoms (for example, a fluorine atom ), b) a C _1-3 alkoxy group (eg methoxy), which may be substituted by 1 to 3 halogen atoms (eg fluorine atom), c) a cyano group and d) a halogen atom (eg chlorine atom), or

5) an imidazopyridyl group, which may be substituted by 1 to 3 halogen atoms (for example, a chlorine atom).

[0049]

[Connection I-2]

Compound (I) in which A is

[0050]

[0051]

R ₁ represents 1) a halogen atom (eg chlorine atom) or 2) a C _1-3 alkyl group (eg methyl);

R ₂ represents a hydrogen atom;

R ₃ represents a C _1-6 alkyl group (eg, ethyl, isopropyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (eg, methoxy);

R ₄ represents 1) a halogen atom (eg chlorine atom) or 2) a C _1-3 alkyl group (eg methyl);

R ₅ represents a C _1-6 alkyl group (eg, ethyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (eg, methoxy); And

B represents a pyridyl group which may be substituted with 1 to 3 substituents selected from a) a halogen atom (eg chlorine atom), b) a cyano group, c) a C _1-3 alkyl group (eg methyl) which may be substituted with 1 to 3 halogen atoms (eg fluorine atom), d) a C _1-3 alkoxy group (eg methoxy) which may be substituted with 1 to 3 halogen atoms (eg fluorine atom), and e) triazolyl group.

[0052]

[Connection I-3]

Compound (I) in which A is

[0053]

[0054]

R ₁ represents a C _1-3 alkyl group (eg methyl);

R ₂ represents a hydrogen atom;

R ₃ represents a C _1-6 alkyl group (eg, ethyl, isopropyl) that is substituted with 1 to 3 C _1-3 alkoxy groups (eg, methoxy);

R ₄ represents 1) a halogen atom (eg chlorine atom) or 2) a C _1-3 alkyl group (eg methyl);

R ₅ represents a C _1-6 alkyl group (eg, ethyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (eg, methoxy); And

B represents a pyridyl group which may be substituted with 1 to 3 substituents selected from a) a halogen atom (eg chlorine atom), b) a C _1-3 alkyl group (eg methyl) which may be substituted with 1 to 3 halogen atoms (eg fluorine atom), c) a C _1-3 alkoxy group (eg methoxy) which may be substituted by 1 to 3 halogen atoms (eg fluorine atom), and d) a triazolyl group.

[0055]

[Connection I-4]

Compound (I) in which A is

[0056]

[0057]

R ₁ represents 1) a hydrogen atom, 2) a halogen atom (for example, a chlorine atom, a bromine atom), 3) a cyano group, 4) a C _1-3 alkyl group (for example, methyl), which may be substituted by 1 to 3 atoms a halogen (eg fluorine atom), 5) a C _1-3 alkoxy group (eg methoxy), 6) a C _3-6 cycloalkyl group (eg cyclopropyl) or 7) a phenyl group;

R ₂ represents 1) a hydrogen atom or 2) a halogen atom (eg fluorine atom, chlorine atom);

R ₃ represents 1) a C _1-6 alkyl group (eg ethyl, isopropyl, sec-butyl) which may be substituted with 1 to 3 substituents selected from a C _1-3 alkoxy group (eg methoxy), hydroxyl group and halogen atom (for example, fluorine atom), 2) a pyrazolyl group (for example, 4-pyrazolyl), which may be substituted with 1 to 3 substituents selected from a C _1-3 alkyl group (for example, methyl) and a halogen atom (for example, chlorine atom), 3) a C _3-6 cycloalkyl group (for example, cyclopropyl), 4) an amino group disubstituted with a C _1-3 alkyl group (for example, methyl), or 5) a phenyl group, which can be substituted with 1 to 3 atoms halogen (for example, a chlorine atom); And

B represents

1) a phenyl group, which may be substituted with 1 to 3 substituents selected from a) a halogen atom (for example, fluorine atom, chlorine atom), b) a cyano group, c) a C _1-3 alkoxy group (for example, methoxy), which can be substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and d) a triazolyl group,

2) a pyridyl group, which may be substituted with 1 to 3 substituents selected from a) a halogen atom (for example, chlorine atom, bromine atom), b) a cyano group, c) a C _1-3 alkyl group (for example, methyl), which may be substituted with 1 to 3 halogen atoms (for example, a fluorine atom), d) a C _1-3 alkoxy group (for example, methoxy), which may be substituted with 1 to 3 halogen atoms (for example, a fluorine atom), e) a pyrazolyl group , which may be substituted with 1 to 3 C _1-3 alkyl groups (for example, methyl), f) an imidazolyl group, which may be substituted with 1 to 3 C _1-3 alkyl groups (for example, methyl), g) a triazolyl group which may be substituted with 1 to 3 C _1-3 alkyl groups (eg methyl), which may be substituted with 1 to 3 substituents selected from a C _1-3 alkoxy group (eg methoxy) and a halogen atom (eg fluorine), and h) an oxazolyl group,

3) a pyrazolyl group, which may be substituted with 1 to 3 substituents selected from a) a C _1-3 alkyl group (eg methyl), which may be substituted with 1 to 3 halogen atoms (eg fluorine atom), b) a C _1-3 alkoxy group (eg methoxy), which may be substituted with 1 to 3 halogen atoms (eg fluorine atom), c) a cyano group and d) a halogen atom (eg chlorine atom), or

4) an imidazopyridyl group, which may be substituted by 1 to 3 halogen atoms (for example, a chlorine atom).

[0058]

[Connection I-5]

Compound (I) in which A is

[0059]

[0060]

R ₄ represents 1) a hydrogen atom, 2) a halogen atom (eg chlorine atom), 3) a C _1-3 alkyl group (eg methyl, ethyl), which may be substituted with 1 to 3 substituents selected from a) hydroxyl group, b) a C _1-3 alkoxy group (for example, methoxy), which may be substituted by a 4-methoxyphenyl group, and c) a halogen atom (for example, a fluorine atom), or 4) a C _1-3 alkoxy group (for example, methoxy, ethoxy), which may be replaced by 1 to 3 halogen atoms (for example, a fluorine atom);

R ₅ represents 1) a C _1-6 alkyl group (eg, ethyl, isopropyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (eg, methoxy, ethoxy), or 2) a phenyl group, which may be substituted with 1 to 3 halogen atoms (for example, a chlorine atom); And

B represents

1) a phenyl group, which can be replaced by 1 to 3 halogen atoms (for example, a fluorine atom),

2) a C _3-6 cycloalkyl group (eg cyclohexyl), which may be substituted with 1 to 3 substituents selected from a) C _1-3 alkyl group (eg methyl), which may be substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and b) a halogen atom (for example, a fluorine atom),

3) a pyridyl group, which may be substituted with 1 to 3 substituents selected from a) a halogen atom (for example, fluorine atom, chlorine atom, bromine atom), b) a cyano group, c) a C _1-3 alkyl group (for example, methyl ), which may be substituted with 1 to 3 halogen atoms (eg fluorine atom), d) C _1-3 alkoxy group (eg methoxy, ethoxy), which may be substituted with 1 to 3 substituents selected from a halogen atom (eg , fluorine atom) and a C _1-3 alkoxy group (for example, methoxy), e) a triazolyl group, which can be substituted with 1 to 3 C _1-3 alkyl groups (for example, methyl), which can be substituted with 1 to 3 substituents selected from a C _1-3 alkoxy group (eg methoxy) and a halogen atom (eg fluorine atom), f) an azetidinyl group, g) a pyrrolidonyl group, h) a tetrazolyl group, which may be substituted with 1 to 3 substituents selected from a C _1-3 alkyl group (eg methyl), i) a pyrimidinyl group and j) an oxazolyl group, or

4) a pyrazolyl group, which may be substituted with 1 to 3 C _1-3 alkyl groups (eg, methyl, ethyl, isopropyl), which may be substituted with 1 to 3 halogen atoms (eg, fluorine atom).

[0061]

[Connection I-6]

Compound (I) in which A is

[0062]

[0063]

R ₆ represents 1) a hydrogen atom, 2) a halogen atom (eg, chlorine atom), 3) a C _1-3 alkyl group (eg, methyl) or 4) a C _1-3 alkoxy group (eg, ethoxy);

R ₇ represents 1) a C _1-6 alkyl group (ethyl, isopropyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (for example, methoxy), or 2) a phenyl group, which may be substituted with 1 to 3 halogen atoms (for example, a chlorine atom); And

B represents

1) a phenyl group, which may be substituted by 1 to 3 halogen atoms (for example, a fluorine atom), or

2) a pyridyl group, which may be substituted with 1 to 3 substituents selected from a) a halogen atom (for example, a chlorine atom), b) a cyano group, c) a C _1-3 alkyl group (for example, methyl), which may be substituted 1 to 3 halogen atoms (eg fluorine atom), d) a C _1-3 alkoxy group (eg methoxy) which may be substituted by 1 to 3 halogen atoms (eg fluorine atom), and e) a triazolyl group.

[0064]

[Connection I-7]

Compound (I) in which A is

[0065]

[0066]

R ₈ represents a C _1-3 alkyl group (eg methyl);

R ₉ represents a C _1-3 alkyl group (eg, ethyl), which may be substituted with 1 to 3 C _1-3 alkoxy groups (eg, methoxy); And

B represents a pyridyl group which may be substituted with 1 to 3 substituents selected from a) a halogen atom (eg chlorine atom), b) a C _1-3 alkyl group (eg methyl) which may be substituted with 1 to 3 halogen atoms (eg fluorine atom), c) C _1-3 alkoxy group (eg methoxy) and d) triazolyl group.

[0067]

[Connection I-8]

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

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

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

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

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

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

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(2-methoxypropan-2-yl)-2-methylimidazo [1,2-b]pyridazin-7-yl)urea,

N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl) urea or

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

[0068]

[Connection I-9]

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

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

[0069]

The salt of the compound represented by formula (I) is preferably a pharmacologically acceptable salt. Examples of such a salt 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.

[0070]

Suitable examples of salts with inorganic bases include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and ammonium salt.

[0071]

Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], t-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine and N,N-dibenzylethylenediamine.

[0072]

Suitable examples of salts with inorganic acids include salts with hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid and phosphoric acid.

[0073]

Suitable examples of salts with 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. acids.

[0074]

Suitable examples of basic amino acid salts include arginine, lysine and ornithine salts.

[0075]

Suitable examples of acidic amino acid salts include salts with aspartic acid and glutamic acid.

[0076]

The following is a description of the method for producing the compound of the present invention.

The starting materials and reagents used in each step in the following production methods and the resulting compounds may each form a salt. Examples of such a salt include salts similar to the above-mentioned salts of the compound of the present invention.

[0077]

When the compound obtained in each step is a free compound, it can be converted into the desired salt by a well-known method. In contrast, when the compound obtained in each step is a salt, it can be converted to the free form or other desired salt form by a well-known method.

[0078]

The compound obtained in each step as a reaction solution or crude product can be used in the next reaction. Alternatively, the compound obtained in each step can be isolated and/or purified from the reaction mixture by separation methods such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation or chromatography in accordance with a standard method.

[0079]

When the starting material or compound reagent for each step is commercially available, the commercially available product can be used as such.

[0080]

In each reaction step, the reaction time may vary depending on the reagent or solvent used, but unless otherwise specified, is usually from 1 minute to 48 hours, preferably from 10 minutes to 24 hours.

[0081]

In each reaction step, the reaction temperature may vary depending on the reagent or solvent used, but unless otherwise specified, is typically -78°C to 300°C, preferably -78°C to 150°C.

[0082]

In each reaction step, the pressure may vary depending on the reagent or solvent used, but unless otherwise specified, it is usually from 1 atm to 20 atm, preferably from 1 atm to 3 atm.

[0083]

Each reaction step, for example, may use a microwave synthesis device such as the Initiator from Biotage. The reaction temperature may vary depending on the reagent or solvent used, but unless otherwise specified, it is typically between room temperature and 300°C, preferably between 50°C and 250°C. The reaction time may vary depending on the reagent or solvent used, but unless otherwise specified, it is usually from 1 minute to 48 hours, preferably from 1 minute to 8 hours.

[0084]

In each reaction step, the reagent is used in an amount of from 0.5 equivalents to 20 equivalents, preferably from 0.8 equivalents to 5 equivalents, relative to the substrate, unless otherwise specified. When the reactant is used as a catalyst, the reactant is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. When a reagent also serves as a reaction solvent, the amount of reagent used is the amount of solvent.

[0085]

Unless otherwise specified for each reaction step, reactions are carried out without solvent or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include those described in the Examples or the following.

Alcohols: methanol, ethanol, tert-butyl 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.;

Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.;

Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.;

Nitriles: acetonitrile, etc.;

Sulfoxides: 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.

As a solvent for use, two or more kinds can be mixed in an appropriate ratio.

[0086]

When a base is used in the reaction of each step, for example, the base shown below or the base described in the Examples is used.

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 and etc.;

Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.;

Alkali metal hydrides: sodium hydride, etc.;

Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.;

Organolithium compounds: n-butyllithium, etc.

[0087]

When an acid or acid catalyst is used in the reaction of each step, for example, the acid or acid catalyst shown below or the acid or acid catalyst described in the Examples is used.

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.

[0088]

Unless otherwise indicated, the reaction of each step is carried out in accordance with a well-known method described, for example, in The fifth series of experimental chemistry, Volumes 13 to 19 (Edited by Chemical Society of Japan); New experimental chemistry, Volumes 14 to 15 (Edited by Chemical Society of Japan); Precise Organic Chemistry, Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankodo Co., Ltd.); Revised Organic Name Reactions; The Reaction Mechanism and Essence (written by Hideo Togo, Kodansha, Ltd.); ORGANIC SYNTHESES Collective Volume I to VII (John Wiley & Sons Inc); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (written by Jie Jack Li, published by OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14 (Elsevier Japan); Strategic applications of named reactions in organic synthesis (the translation supervised by Kiyoshi Tomioka, published by Kagaku-Dojin Publishing Company, Inc.); Comprehensive Organic Transformations (VCH Publishers Inc.) published in 1989, etc., or in the manner described in the Examples.

[0089]

In each step, the reaction to protect or deprotect a functional group is carried out in accordance with a well known method described, for example, in "Protective Groups in Organic Synthesis, 4th Ed." (written by Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; "Protecting Groups 3rd Ed." (written by P.J. Kocienski), published by Thieme in 2004, etc., or in the manner described in the Examples.

Examples of the protecting group for the alcohol hydroxyl group, and the phenolic hydroxyl group, and the like include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether; carboxylate ester protecting groups such as acetate ester; sulfonate ester type protecting groups such as methanesulfonate ester; and carbonate ester type protecting groups such as tert-butyl carbonate.

Examples of the protecting group for the carbonyl group of an aldehyde include acetal type protecting groups such as dimethyl acetal; and cyclic acetal type protecting groups such as 1,3-dioxane.

Examples of the protecting group for the carbonyl group of the ketone include ketal type protecting groups such as dimethyl ketal; cyclic ketal type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone type protecting groups such as N,N-dimethylhydrazone.

Examples of the protecting group for the carboxyl group include ester type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide.

Examples of the thiol protecting group include ether type protecting groups such as benzyl thioether; and ester-type protecting groups such as thioacetic acid ester, thiocarbonate and thiocarbamate.

Examples of the protecting group for the amino group and the aromatic heterocycle such as imidazole, pyrrole or indole include carbamate type protecting groups such as benzyl carbamate; amide-type protecting groups such as acetamide; alkylamine type protecting groups such as N-triphenylmethylamine, and sulfonamide type protecting groups such as methanesulfonamide.

Removal of the protecting group can be carried out using a well known method, for example, methods using acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or trialkylsilyl halides (for example, trimethylsilyl iodide, trimethylsilyl bromide) or reduction method .

[0090]

In each step of the reduction reaction, the reducing agent used includes metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride and tetramethylammonium triacetoxyborohydride; boranes such as borane-tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid and triethylsilane. Reducing a carbon-carbon double or triple bond involves a process that uses a catalyst such as palladium-on-carbon or Lindlar catalyst.

[0091]

In each step of the oxidation reaction, the oxidizing agent used includes peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodic acids such as sodium periodate; high valence iodine-based reagents such as iodosylbenzene; reagents containing manganese such as manganese dioxide and potassium permanganate; lead-based compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC) and Jones' reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0092]

In each step of the radical cyclization reaction, the radical initiator used includes azo compounds such as azobisisobutyronitrile (AIBN); water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA); triethylboron in the presence of air or oxygen and benzoyl peroxide. In addition, the radical reaction reagent used includes tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane and samarium iodide.

[0093]

In each step of the Wittig reaction, the Wittig reagent used includes alkylidene phosphoranes. Alkylidene phosphoranes can be prepared by a well-known method, for example by reacting a phosphonium salt with a strong base.

[0094]

In each step of the Horner-Emmons reaction, the reagents used include phosphonoacetate esters such as methyl dimethyl phosphonoacetate and ethyl diethyl phosphonoacetate; and bases such as alkali metal hydrides and organolithium compounds.

[0095]

In each step of the Friedel-Crafts reaction, the reagents used include a combination of a Lewis acid and an acid chloride or a combination of a Lewis acid and an alkylating agent (eg, alkyl halides, alcohols, olefins, etc.). Alternatively, instead of a Lewis acid, an organic acid or an inorganic acid can be used, and instead of an acid chloride, an acid anhydride such as acetic anhydride can be used.

[0096]

Each step of an aromatic nucleophilic substitution reaction uses a nucleophilic reagent (e.g., amines, imidazole, etc.) and a base (e.g., organic bases, etc.) as reactants.

[0097]

In each step of a nucleophilic addition reaction with a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) with a carbanion, or a nucleophilic substitution reaction with a carbanion, the base used to form the carbanion includes organolithium compounds, metal alkoxides, inorganic bases, and organic bases .

[0098]

In each step of the Grignard reaction, the Grignard reagent includes arylmagnesium halides such as phenylmagnesium bromide; and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a well known method, for example by reacting an alkyl halide or aryl halide with magnesium metal using ether or tetrahydrofuran as a solvent.

[0099]

In each step of the Knoevenagel condensation reaction, an active methylene compound located between two electron-attracting groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and bases (e.g., organic bases, metal alkoxides, inorganic bases) is used as reagents.

[0100]

In each step of the Vilsmeyer-Haack reaction, phosphoryl chloride and an amide derivative (for example, N, N-dimethylformamide, etc.) are used as reactants.

[0101]

In each step of the azide reaction of alcohols, alkyl halides and sulfonate esters, the azidating agent used includes diphenylphosphoryl azide (DPPA), trimethylsilyl azide and sodium azide. For example, in the azidation of alcohols, a method using diphenylphosphoryl azide (DPPA) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a method using trimethylsilyl azide, and a Lewis acid, and the like are used.

[0102]

In each step of the reductive amination reaction, the reducing agent used includes sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen and formic acid. When the substrate is an amine compound, the carbonyl compound used includes aldehydes such as paraformaldehyde and acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, the amines used include ammonia; primary amines such as methylamine; and secondary amines such as dimethylamine.

[0103]

Each step of the Mitsunobu reaction uses azodicarboxylate esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD)) and triphenylphosphine as reagents.

[0104]

In each step of the esterification reaction, amidation reaction or urea formation reaction, the reagent used includes acyl halides such as acid chloride and acid bromide; and activated carboxylic acids such as acid anhydrides, active esters and sulfate esters. The carboxylic acid activator includes carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM); carbonate ester condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Mukayama reagent); thionyl chloride; lower alkyl haloformate such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid or a combination thereof. When using a carbodiimide-based coupling agent, an additional excipient such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu) or 4-dimethylaminopyridine (DMAP) may be added to the reaction.

[0105]

In each coupling reaction step, the metal catalyst used includes palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris (dibenzylideneacetone)dipalladium(0) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel (0); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; and platinum compounds. In addition, a base may be added to the reaction, and such base includes inorganic bases.

[0106]

In each step of the thiocarbonylation reaction, diphosphorus pentasulfide is typically used as the thiocarbonylating agent. In addition to diphosphorus pentasulfide, reagents having the structure of 1,3,2,4-dithiadiphosphetane-2,4-disulfide, such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane- 2,4-disulfide (Lavesson's reagent).

[0107]

In each step of the Wohl-Ziegler reaction, the halogenating agent used includes N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine and sulfuryl chloride. Additionally, the reaction can be accelerated by adding a radical initiator to the reaction, such as heat, light, benzoyl peroxide, or azobisisobutyronitrile.

[0108]

In each step of the hydroxy group halogenation reaction, the halogenating agent used includes hydrohalides and inorganic acids, in particular hydrochloric acid, thionyl chloride and phosphorus oxychloride for chlorination and 48% hydrobromic acid for bromination. Moreover, the method can be used to produce an alkyl halide from an alcohol by reacting triphenylphosphine with carbon tetrachloride, carbon tetrabromide or the like. Alternatively, the method can be used to synthesize an alkyl halide through a two-step reaction involving conversion of the alcohol to a sulfonate ester followed by reaction with lithium bromide, lithium chloride or sodium iodide.

[0109]

In each step of the Arbuzov reaction, the reagent used includes alkyl halides such as ethyl bromoacetate; and phosphites such as triethylphosphite and tri(isopropyl)phosphite.

[0110]

In each step of the sulfonate esterification reaction, the sulfonylating agent used includes methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride and p-toluenesulfonic anhydride.

[0111]

In each step of the hydrolysis reaction, an acid or base is used as a reactant. In addition, in the acid hydrolysis reaction of tert-butyl ether, formic acid, triethylsilane or the like may be added to reductively capture the by-product tert-butyl cation.

[0112]

In each step of the dehydration reaction, the dehydrating agent used includes sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina and polyphosphoric acid.

When the compound obtained in each step has amino groups, imidazoles, pyrroles, aromatic heterocycles such as indole, carboxyl groups, hydroxyl group and the like as substituents, these groups can be protected by a protecting group such as those listed above. In this case, the target compound can be obtained by removing the protecting group at the desired stage. The introduction or removal of these protecting groups is carried out in the same manner as described above.

In addition, the above-mentioned reaction and the like may optionally be included in each step.

[0113]

The following is a description of the method for preparing compound (I).

Unless otherwise noted, each symbol in the following reaction formula has the same meaning as described above. The starting compound can be easily obtained in the market or can be obtained by a well-known method or a similar method if no specific production method is described.

[0114]

Compound (I) can be prepared from compound (II) using the following method.

[0115]

[0116]

Compound (II) may be a commercially available product or may be prepared using a well known method.

Compound (IV) can be prepared by amination reaction of compound (III) with a hydroxylamine derivative in the presence of a base or acid. The hydroxylamine derivative includes O-(4-nitrobenzoyl)hydroxylamine, hydroxylamine-O-sulfonic acid and O-diphenylphosphinylhydroxylamine.

Compound (V) can be prepared by reacting compound (IV) with an acrylate ester under an oxygen atmosphere in the presence of a palladium catalyst and an inorganic salt such as lithium bromide. The palladium catalyst includes palladium(II) acetate, and the acrylate ester includes methyl acrylate and ethyl acrylate. Alternatively, compound (V) can also be prepared by reacting compound (IV) with methyl 3,3-dimethoxypropanoate in the presence of an acid, followed by intramolecular cyclization in the presence of a base.

Compound (VIII) may be a commercially available product as is, or may be prepared using a well known method or a similar method.

Compound (I) can be prepared by reacting compound (VIII) with compound (VII) prepared by reacting compound (VI) in the presence of diphenylphosphoryl azide (DPPA), optionally a base, using a Curtius rearrangement. The solvent used in addition to the above includes 2-methyltetrahydrofuran.

Compound (IX) can be prepared by reacting compound (VI) in the presence of diphenylphosphoryl azide (DPPA), optionally a base, using a Curtius rearrangement. The solvent used in addition to the above includes 2-methyltetrahydrofuran.

Compound (I) can be prepared by formation of urea in the presence of compound (IX), compound (VIII), an activator and optionally a base. The activator includes chloroformate ester derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate or p-nitrophenyl chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole or N,N'-disuccinimidyl carbonate. Among them, triphosgene and 2,2,2-trichloroethyl chloroformate are preferred.

In the above step, the substituents R ₁ and R ₂ can be converted into other types of substituents by electrophilic substitution reaction, coupling reaction or a well-known method in the desired step. For example, compound (IV) in which R ₁ represents a halogen atom can be prepared by performing an electrophilic substitution reaction of compound (IV) in which R ₁ represents a hydrogen atom. Electrophiles used in this reaction include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine and sulfuryl chloride. In addition, the compound (V) in which R ₁ represents a C _1-3 alkyl group (for example, a methyl group) can be obtained by allowing the compound (V) in which R ₁ represents a leaving group (for example, a halogen atom ), react with an organic boronic acid or an organic boronate ester reagent (for example, 2,4,6-trimethylboroxine). This reaction can be carried out in the presence of a base or inorganic salt (eg tripotassium phosphate), the aforementioned metal complex such as palladium, or in the presence of a phosphine ligand. Examples of the phosphine ligand include 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos).

[0117]

Compound (V) can also be obtained using the following method.

[0118]

[0119]

Compound (X) may be a commercially available product or may be prepared using a well known method.

Compound (XI) can be prepared by an amination reaction of compound (X). The amination method includes the same method as the method for producing compound (IV) from compound (III).

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

X ₁ of compound (XIV) represents a halogen atom. The halogenating agent used in the halogenation reaction to prepare compound (XIV) in addition to the above includes phosphorus oxybromide.

Compound (V) can be prepared from compound (XIV) by coupling reaction, substitution reaction or a well-known method.

In the above step, the substituents R ₁ and R ₂ can be converted into other types of substituents by electrophilic substitution reaction or a well-known method in the desired step.

[0120]

Compound (I) can also be obtained using the following method.

[0121]

[0122]

Compound (XV) may be a commercially available product or may be prepared using a well known method. X ₁ represents a halogen atom.

Compound (XVII) can be prepared by subjecting compound (XVI) and a nitroenamine derivative to a nucleophilic substitution reaction in the presence of an acid. The nitroenamine derivative includes (E)-4-(2-nitrovinyl)morpholine.

Compound (XVIII) can be prepared by an intramolecular cyclization reaction of compound (XVII). This reaction may optionally be carried out in the presence of a base.

Compound (XIX) can be prepared by reducing compound (XVIII). In addition to the above, the reducing agent includes iron, tin(II) chloride and tin(II) chloride dihydrate.

Compound (I) can be prepared by formation of urea in the presence of compound (XIX), compound (VIII), an activator and optionally a base. The activator includes chloroformate ester derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate or p-nitrophenyl chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole or N,N'-disuccinimidyl carbonate. Among them, triphosgene and 2,2,2-trichloroethyl chloroformate are preferred.

In the above steps, the substituents R ₄ and R ₅ can be converted by incorporating a coupling reaction, a substitution reaction or a well known method in the desired step.

[0123]

Compound (I) can also be obtained using the following method.

[0124]

[0125]

Compound (XX) may be a commercially available product or may be prepared using a well known method.

Compound (XXI) can be prepared by subjecting compound (XX) and a nitroenamine derivative to a nucleophilic substitution reaction in the presence of an acid. The nitroenamine derivative includes (E)-4-(2-nitrovinyl)morpholine.

Compound (XXII) can be prepared by an intramolecular cyclization reaction of compound (XXI). This reaction may optionally be carried out in the presence of a base.

X ₁ of compound (XXIII) represents a halogen atom. The halogenating agent used in the halogenation reaction to obtain compound (XXIII) in addition to the above includes phosphorus tribromide.

Compound (XVIII) can be prepared from compound (XXIII) by coupling reaction, substitution reaction or a multi-step well-known method. The catalyst used in the coupling reaction to obtain compound (XVIII) in addition to the above includes PdCl ₂ (Amphos) ₂ .

Compound (XIX) can be prepared by reducing compound (XVIII). In addition to the above, the reducing agent includes iron, tin(II) chloride and tin(II) chloride dihydrate.

Compound (I) can be prepared by formation of urea in the presence of compound (XIX), compound (VIII), an activator and optionally a base. The activator includes chloroformate ester derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate or p-nitrophenyl chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole or N,N'-disuccinimidyl carbonate. Among them, triphosgene and 2,2,2-trichloroethyl chloroformate are preferred.

In the above steps, the substituents R ₄ and R ₅ can be converted by incorporating a coupling reaction, a nucleophilic substitution reaction or a well known method in the desired step.

[0126]

Compound (I) can also be obtained using the following method.

[0127]

[0128]

Compound (XXIV) may be a commercially available product or may be prepared using a well known method.

Compound (XXVI) can be prepared by subjecting compound (XXV) and a 3-oxopropanoic acid derivative to a nucleophilic substitution reaction in the presence of an acid. The 3-oxopropanoic acid derivative includes methyl 3,3-dimethoxypropanoate.

Compound (XXVII) can be prepared by an intramolecular cyclization reaction of compound (XXVI). This reaction may optionally be carried out in the presence of a base.

Compound (I) can be prepared by reacting compound (VIII) with compound (XXIX) prepared by reacting compound (XXVIII) in the presence of diphenylphosphoryl azide (DPPA), optionally a base, using a Curtius rearrangement. The solvent used in addition to the above includes 2-methyltetrahydrofuran.

Compound (XXX) can be prepared by reacting compound (XXVIII) in the presence of diphenylphosphoryl azide (DPPA), optionally a base, using a Curtius rearrangement. The solvent used in addition to the above includes 2-methyltetrahydrofuran.

Compound (I) can be prepared by formation of urea in the presence of compound (XXX), compound (VIII), an activator and optionally a base. The activator includes chloroformate ester derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate or p-nitrophenyl chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole or N,N'-disuccinimidyl carbonate. Among them, triphosgene and 2,2,2-trichloroethyl chloroformate are preferred.

In the above steps, the substituents R ₆ and R ₇ can be converted by incorporating a coupling reaction, a substitution reaction or a well known method in the desired step.

[0129]

Compound (I) can also be obtained using the following method.

[0130]

[0131]

Compound (XXXI) may be a commercially available product or may be prepared using a well known method.

Compound (XXXII) can be prepared by subjecting compound (XXXI) and an alkoxymethylenemalonic acid derivative to a nucleophilic substitution reaction in the presence of an acid. The alkoxymethylenemalonic acid derivative includes diethylethoxymethylenemalonate.

Compound (XXXIII) can be prepared by an intramolecular cyclization reaction of compound (XXXII).

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

Compound (XXXV) can be prepared by reacting compound (XXXIV) with cesium fluoride.

X ₁ of compound (XXXVI) represents a halogen atom. The halogenating agent used in the halogenation reaction to prepare compound (XXXVI) in addition to the above includes phosphorus tribromide.

Compound (I) can be prepared by reacting compound (VIII) with compound (XXXIX) prepared by reacting compound (XXXVIII) in the presence of diphenylphosphoryl azide (DPPA), optionally a base, using a Curtius rearrangement. The solvent used in addition to the above includes 2-methyltetrahydrofuran.

Compound (XXXX) can be prepared by reacting compound (XXXVIII) in the presence of diphenylphosphoryl azide (DPPA), optionally a base, using a Curtius rearrangement. The solvent used in addition to the above includes 2-methyltetrahydrofuran.

Compound (I) can be prepared by formation of urea in the presence of compound (XXXX), compound (VIII), an activator and optionally a base. The activator includes chloroformate ester derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate or p-nitrophenyl chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole or N,N'-disuccinimidyl carbonate. Among them, triphosgene and 2,2,2-trichloroethyl chloroformate are preferred.

In the above steps, the substituent R ₉ can be converted by incorporating a coupling reaction, a substitution reaction or a well-known method in the desired step.

[0132]

Compound (I) can also be obtained using the following method.

[0133]

[0134]

Compound (XXXXI) may be a commercially available product or may be prepared using a well known method or the same method as for compound (XXVII).

Compound (XXXXIII) can be prepared by alkylation of compound (XXXXII) in the presence of a base. The base in addition to the above includes lithium hydroxide.

Compound (I) can be prepared by reacting compound (VIII) with compound (XXXXV) prepared by reacting compound (XXXXIV) in the presence of diphenylphosphoryl azide (DPPA), optionally a base, using a Curtius rearrangement. The solvent used in addition to the above includes 2-methyltetrahydrofuran.

Compound (XXXXVI) can be prepared by reacting compound (XXXXIV) in the presence of diphenylphosphoryl azide (DPPA), optionally a base, using a Curtius rearrangement. The solvent used in addition to the above includes 2-methyltetrahydrofuran.

Compound (I) can be prepared by formation of urea in the presence of compound (XXXXVI), compound (VIII), an activator and optionally a base. The activator includes chloroformate ester derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate or p-nitrophenyl chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole or N,N'-disuccinimidyl carbonate. Among them, triphosgene and 2,2,2-trichloroethyl chloroformate are preferred.

In the above steps, the substituents R ₈ and R ₉ can be converted by incorporating a coupling reaction, a substitution reaction or a well known method in the desired step.

[0135]

Substituting the resulting compound (I) using well known means (ie, introducing a substituent or converting a functional group) can also produce another compound or a salt thereof included in compound (I).

As a method for introducing a substituent or converting a functional group, known general methods are used. Examples of these include the conversion of a halogen atom (e.g., fluorine, chlorine, bromine, iodine) or a C _1-6 alkylsulfonyloxy group, which may be halogenated [e.g., methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy (triflate)], into a methyl group, a cyclopropyl group, vinyl group, cyano group, formyl group, carbonyl group, carboxyl group, hydroxyl group, amino group or boryl group, conversion of a formyl group to an ethynyl group by Seyfert-Gilbert homologation, conversion of an ester to a carboxyl group by hydrolysis, conversion of a carboxyl group to a carbamoyl group by amidation, conversion of a carboxyl group to a hydroxymethyl group by reduction, conversion of a carbonyl group to an alcohol by reduction or alkylation, reductive amination of a carbonyl group, formation of an oxime of a carbonyl group, acylation of an amino group, urea formation of an amino group, sulfonylation of an amino group, alkylation of an amino group, substitution or amination of the active halogen with an amine, alkylation of the hydroxy group, and substitution or amination of the hydroxy group.

In the case where there is a reaction center in which a reaction other than the intended one occurs when introducing a substituent or converting a functional group is carried out, the compound included in the scope of the present invention can also be prepared by introducing a protecting group into the reaction center by well known methods in advance. and removing the protecting group by well known methods after completion of the desired reaction, if necessary.

For example, when the starting material compound or intermediate has an amino group, a carboxyl group or a hydroxyl group as a substituent, these groups may be protected by a protecting group commonly used in peptide chemistry and the like. In this case, the target compound can be obtained by removing the protecting group after the reaction, if necessary.

[0136]

Compound (I) obtained by the above production method can be isolated and purified by known methods such as solvent extraction, changing the pH of the solution, transfer dissolution, crystallization, recrystallization and chromatography.

[0137]

When compound (I) contains optical isomers, steric isomers, positional isomers and rotational isomers, these isomers are also included as compound (I), and each of them can be obtained as a separate product using well-known synthesis methods and separation methods. For example, when compound (I) has an optical isomer, the optical isomer separated from the compound is also included in compound (I).

In the present description, the optical isomer can be obtained using a well-known method.

[0138]

Compound (I) may be a crystalline substance.

A crystalline substance of compound (I) (hereinafter sometimes abbreviated as “crystalline substance of the present invention”) can be obtained by applying a well-known crystallization method to compound (I) to crystallize it.

The crystalline substance of the present invention is expected to have excellent physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, in vivo kinetics (absorption, distribution, metabolism, excretion), drug efficacy) and be useful as a medicine.

Compound (I) may be a pharmaceutically acceptable cocrystal or a cocrystal salt. As used herein, a cocrystalline substance or cocrystalline salt means a crystalline substance consisting of two or more individual solids at room temperature, wherein the solids differ in physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility and stability) from each other. friend. The cocrystalline substance or cocrystalline salt can be prepared according to a well-known cocrystallization method.

Compound (I) may be a hydrate, non-hydrate, non-solvate or solvate.

In addition, a converted deuterium compound in which ¹ H has been converted to ² H (D) is also included in compound (I).

Compound (I) may be labeled with an isotope (eg, ³ H, ¹³ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I) or the like. The isotopically labeled or substituted compound (I) can be used, for example, as a tracer (PET (positron emission tomography) tracer) used in PET and is expected to be useful in fields such as medical diagnostics.

[0139]

Compound (I) can be used as a prodrug.

A prodrug of compound (I) is a compound that is converted to compound (I) by reaction with an enzyme, gastric juice or the like under physiological conditions in a living body, that is, a compound that is enzymatically subject to oxidation, reduction, hydrolysis, etc. to become the compound (I), or a compound that undergoes hydrolysis or the like under the action of gastric juice or the like to become the compound (I).

[0140]

A prodrug of compound (I) includes a compound having an amino group of compound (I) acylated, alkylated or phosphorylated (for example, a compound having an amino group of compound (I) eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene -4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated); a compound having the hydroxy group of compound (I) acylated, alkylated, phosphorylated or borated (for example, a compound having the hydroxy group of compound (I) acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated); a compound having a carboxy group of compound (I) esterified or amidated (for example, a compound having a carboxy group of compound (I) ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioc salty -4-yl)methylesterified, cyclohexyloxycarbonylethylesterified or methylamidated). These compounds can be prepared from compound (I) using a well-known method.

[0141]

In addition, a prodrug of compound (I) may be a prodrug that is converted to compound (I) under physiological conditions, as described in Molecular Design, pp. 163 to 198 in "Pharmaceutical research and development", Vol. 7, by Hirokawa Shoten in 1990.

In the description, the prodrug may form a salt. Such a salt includes the salt exemplified as the salt of the compound represented by the above formula (I).

[0142]

Compound (I) or a prodrug thereof (hereinafter sometimes simply abbreviated as “the compound of the present invention”) may have MALT1 inhibitory activity and may be useful as a prophylactic or therapeutic agent for the treatment of cancer, a cancer growth inhibitor and a cancer metastasis inhibitor.

The compound of the present invention may be useful as a drug because the compound of the present invention exhibits selective MALT1 inhibitory activity and also has excellent drug efficacy, pharmacokinetics (eg, absorption, distribution, metabolism, excretion), solubility (eg, water solubility ), interactions with other pharmaceutical products (e.g. drug metabolizing enzyme inhibition effect), safety (e.g. acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central toxicity) and stability (e.g. chemical stability, stability against the enzyme).

Accordingly, the compound of the present invention can be used to inhibit the excessive (abnormal) effect of MALT1 in mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cattle, sheep, monkey, human).

[0143]

The compound of the present invention can be administered orally or parenterally to a mammal (preferably a human) as a drug, either alone or in combination with a pharmacologically acceptable carrier.

The following is a detailed description of a medicinal product containing a compound of the present invention (sometimes abbreviated as “the medicinal product of the present invention”). Examples of the dosage form of the drug of the present invention include oral preparations such as tablets (eg, sugar-coated tablet, film-coated tablet, sublingual tablet, buccal tablet, oral disintegrating tablet), pills, granules, powders, capsules (eg , soft capsule, microcapsule), syrups, emulsions, suspensions and film preparations (eg, oral disintegrating film, oral adhesive film). Moreover, examples of dosage forms of the drug of the present invention include parenteral preparations such as injections, infusions, transdermal agents (eg, transdermal iontophoresis agent), suppositories, ointments, nasal agents, transpulmonary agents and eye drops. In addition, the drug of the present invention may be controlled release drugs, such as immediate release drugs and sustained release drugs (eg, sustained release microcapsule).

[0144]

The drug of the present invention can be produced by a known production method generally used in the pharmaceutical field (for example, by the method described in the Japanese Pharmacopoeia). In addition, the drug preparation of the present invention may contain an excipient, such as an excipient, a binder, a disintegrating agent, a glidant, a sweetener, a surfactant, a suspending agent, an emulsifier, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a stabilizer or a thickening agent, typically used in the pharmaceutical field, in appropriate quantities if necessary.

The pharmacologically acceptable carrier described above includes these excipients.

[0145]

For example, tablets can be prepared using an excipient, a binder, a disintegrant, a glidant and the like, and pills and granules can be prepared using an excipient, a binder, a disintegrant and the like. In addition, powders and capsules can be prepared using an excipient and the like, syrups can be prepared using a sweetener and the like, and emulsions or suspensions can be prepared using a suspending agent, a surfactant, an emulsifier and the like.

[0146]

Examples of the excipient include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate and calcium sulfate.

Examples of the binder include 5 to 10 wt% starch paste, 10 to 20 wt% gum acacia solution or gelatin solution, 1 to 5 wt% tragacanth solution, carboxymethylcellulose solution, sodium alginate solution or glycerin.

Examples of leavening agents include starch and calcium carbonate.

Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate and purified talc.

Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin and simple syrup.

Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan fatty acid ester and polyoxyl 40 stearate.

Examples of the suspending agent include gum acacia, sodium alginate, sodium carboxymethylcellulose, methylcellulose and bentonite.

Examples of the emulsifier include gum acacia, tragacanth, gelatin and polysorbate 80.

[0147]

For example, in the case where the drug of the present invention is a tablet, the tablet can be prepared by adding to the compound of the present invention, for example, an excipient (for example, lactose, sucrose, starch), a disintegrant (for example, starch, calcium carbonate), a binder (eg, starch, gum acacia, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose) or glidant (eg, talc, magnesium stearate, polyethylene glycol 6000) followed by compression in accordance with a well known method and then optionally subjected to a taste masking, enteric or long lasting coating with a well known method way. The coating agent used for coating includes hydroxypropyl methylcellulose, such as ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by ROHM, Germany, methacrylic acid-acrylic acid copolymer ) and dyes (eg red iron oxide, titanium dioxide) can be used.

[0148]

Injections include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, intraperitoneal injection and drip injection.

[0149]

Such injections are prepared by a well known method, that is, by dissolving, suspending or emulsifying the compound of the invention in a sterile aqueous or oily liquid. Aqueous fluid includes saline and isotonic solutions containing glucose or other excipients (eg, D-sorbitol, D-mannitol, sodium chloride). The aqueous liquid may contain a suitable solubilizer such as an alcohol (eg, ethanol), a polyalcohol (eg, propylene glycol, polyethylene glycol), or a nonionic surfactant (eg, polysorbate 80, HCO-50). The oily liquid includes sesame oil and soybean oil. The oily liquid may contain a suitable solubilizer. The solubilizer includes benzyl benzoate and benzyl alcohol. Additionally, the injection may be formulated with a mixture of a buffer (eg, phosphate buffer, sodium acetate buffer), a sedative (eg, benzalkonium chloride, procaine hydrochloride), a stabilizer (eg, human serum albumin, polyethylene glycol), a preservative (eg, benzyl alcohol) , phenol) or the like. The prepared injection solution can usually be filled into an ampoule.

[0150]

The content of the compound of the present invention in the drug preparation of the present invention varies depending on the form of the preparation, but is typically from about 0.01 to about 100 wt%, preferably from about 2 to about 85 wt%, more preferably from about 5 to about 70 wt.% relative to the entire drug.

[0151]

The excipient content of the drug formulation of the present invention varies depending on the form of the formulation, but is typically from about 1 to about 99.9% by weight, preferably from about 10 to about 90% by weight, based on the total formulation.

[0152]

The compound of the present invention is stable, has low toxicity, and can be safely used. The daily dosage of the compound of the present invention varies depending on the condition and weight of the patient, the type of compound, route of administration, etc. For example, when administered orally to a patient for the purpose of treating cancer, the daily dosage for an adult (body weight of approximately 60 kg) is from about 1 to about 1000 mg, preferably from about 3 to about 300 mg, more preferably from about 10 to about 200 mg of a compound of the present invention. The daily dose can be administered once or in 2-3 divided doses.

[0153]

When a compound of the present invention is administered parenterally, it is typically administered in the form of a liquid preparation (eg, injection). The single dose of the compound of the present invention varies depending on the purpose of administration, target organ, symptom, route of administration, etc. For example, it is generally preferable to administer from about 0.01 to about 100 mg, preferably from about 0.01 to about 50 mg more preferably from about 0.01 to about 20 mg of a compound of the present invention per kg of body weight by intravenous injection.

[0154]

The compound of the present invention can be used in combination with other drugs. In particular, the compound of the present invention can be used in combination with drugs such as a hormonal therapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent or a drug that inhibits the action of a cell growth factor and its receptor. Hereinafter, a drug that can be used in combination with a compound of the present invention is abbreviated as “concomitant drug”.

[0155]

As a "hormonal therapeutic agent" you can use, for example, fosfestrol diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, antiestrogens (for example , tamoxifen citrate, toremifene citrate), pills, mepithiostane, testololactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, buserelin, leuprorelin acetate), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitors (eg, fadrozole hydrochloride, anastrozole, letrozole, exemestane , vorozol , formestane), antiandrogens (for example, flutamide, bicalutamide, nilutamide, enzalutamide), 5α-reductase inhibitors (for example, finasteride, epristeride, dutasteride), adrenocortical hormonal drugs (for example, dexamethasone, prednisolone, betamethasone, triamcinolone), androgen synthesis inhibitors ( for example, abiraterone), retinoids and drugs that slow the metabolism of retinoids (for example, liarozole), thyroid hormone and their drug delivery system (DDS) preparations.

[0156]

As "chemotherapeutic agents", for example, alkylating agents, antimetabolites, anti-cancer antibiotics and anti-cancer herbal agents can be used.

[0157]

As "alkylating agents" you can use, for example, nitrogen mustard, nitrogen mustard N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate , triethylenemelamine, carmustine, lomustine, streptozocin, pipobromane, etoglucide, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustine, temozolomide, treosulfan, trofosfamide, zinostatin, stimalamer, adozelesin, cystemustin , bizelezin and their DDS preparations.

[0158]

As "antimetabolites" you can use, for example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enocytabine, cytarabine, cytarabine oxphosphate, ancytabine hydrochloride, 5-FU drugs (for example, fluorouracil, tegafur, UFT, doxyfluridine, carmofur, halocitabine, emitefur, capecitabine), aminopterin, nelarabine, calcium leucovorin, tabloid, butocin, calcium folinate, calcium levofolinate, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexim, idoxuridine, mitoguazone, tiazofurin, ambamustine, bendamustine and their drugs DDS.

[0159]

As "antitumor antibiotics" you can use, for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, not ocarcinostatin, mithramycin , sarcomycin, carzinophiline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS preparations (eg, PEG ribosome encapsulating doxorubicin).

[0160]

As "herbal anti-cancer agents", for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, cabazitaxel, vinorelbine and their DDS preparations can be used.

[0161]

As an "immunotherapeutic agent" you can use, for example, picibanil, crestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony-stimulating factors, granulocyte colony-stimulating factors, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibodies (eg, ipilimumab, tremelimumab), anti-PD-1 antibodies (eg, nivolumab, pembrolizumab) and anti-PD-L1 antibodies.

[0162]

The “cell growth factor” in “a drug that inhibits the action of a cell growth factor and its receptor” can be any substance that promotes cell growth and typically includes factors that are peptides with a molecular weight of 20,000 or less and exert their action at low concentrations by binding to the receptor. In particular, (1) EGF (epidermal growth factor) or substances having essentially the same activity [for example, TGFα], (2) insulin or substances having essentially the same activity [for example, insulin, IGF (insulin-like growth factor )-1, IGF-2], (3) FGF (fibroblast growth factor) or substances having substantially the same activity [for example, acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10] and (4 ) other cell growth factors [eg, CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PGF (platelet growth factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), heregulin and angiopoietin].

[0163]

A “cell growth factor receptor” may be any receptor having the ability to bind to the aforementioned cell growth factor. In particular, EGF receptor, heregulin receptor (for example, HER3), insulin receptor, IGF-1 receptor, IGF-2 receptor, FGF-1 receptor or FGF-2 receptor, VEGF receptor, angiopoietin receptor (for example, Tie2), can be used. PSF receptor and the like.

[0164]

As a "drug that inhibits the action of cell growth factor and its receptor", EGF inhibitors, TGFα inhibitors, heregulin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitors, IL-2 inhibitors can be used. , NGF inhibitors, PRT 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-1 receptor inhibitors , FGF-2 receptor inhibitors, FGF-3 receptor inhibitors, FGF-4 receptor inhibitors, VEGF receptor inhibitors, Tie-2 inhibitors, PRT receptor inhibitors, TLR receptor inhibitors, Abl inhibitors, Raf inhibitors, FLT3 inhibitors, c-Kit inhibitors, Src inhibitors, PLC inhibitors, PKC inhibitors, Smo inhibitors, ALK inhibitors, ROR1 inhibitors, Trk inhibitors, Ret inhibitors, mTOR inhibitors, Aurora inhibitors, PLK inhibitors, MEK inhibitors (MEK1/2), MET inhibitors, CDK inhibitors, Akt inhibitors, ERK inhibitors, PI3K inhibitors, IKK inhibitors, BTK inhibitors, IRAK inhibitors, HDAC inhibitors, TAK1 inhibitors, TBK1 inhibitors, ZAP inhibitors, SYK inhibitors, LCK inhibitors, TYK2 inhibitors, SYK inhibitors, JAK inhibitors, FAK inhibitors, LYN inhibitors and the like. More specifically, anti-VEGF antibodies (eg, bevacizumab, ramukurumab), anti-HER2 antibodies (eg, trastuzumab, pertuzumab), anti-EGFR antibodies (eg, cetuximab, panitumumab, matuzumab, nimotuzumab), anti-HFR antibodies, imatinib may be used. , erlotinib, gefitinib, sorafenib, sunitinib, dasatinib, lapatinib, vatalanib, ibrutinib, bosutinib, cabozantinib, crizotinib, alectinib, vismodegib, axitinib, motesanib, nilotinib, 6-[4-(4-ethylpiperazin-1-ylmethyl)phenyl]- N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE-788), vandetanib, temsirolimus, everolimus, enzastaurin, tosasertib, 2-[N-[3- [4-[5-[N-(3-fluorophenyl)carbamoylmethyl]-1H-pyrazol-3-ylamino]quinazolin-7-yloxy]propyl]-N-ethylamino]ethyl phosphate ester (AZD-1152), 4-[9 -chloro-7-(2,6-difluorophenyl)-5H-pyrimide[5,4-d][2]benzazepin-2-ylamino]benzoic acid, N-[2-methoxy-5-[(E)-2 -(2,4,6-trimethoxyphenyl)vinylsulfonylmethyl]phenyl]glycine sodium salt (ON-1910Na), volasertib, selumetinib, trametinib, N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2- (2-fluoro-4-iodophenylamino)benzamide (PD-0325901), bosutinib, regorafenib, afatinib, idelalisib, ceritinib, dabrafenib and the like.

[0165]

In addition to the above drugs, asparaginase, aceglatone, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, hematoporphyrin mercury-sodium, topoisomerase I inhibitors (for example, irinotecan, topotecan, indothecan, indimithecan), topoisomerase II inhibitors can also be used as concomitant drugs (eg, sobuzoxan) differentiation inducers (eg, retinoids, vitamin D), other angiogenesis inhibitors (eg, fumagillin, shark extract, COX-2 inhibitors), α-blockers (eg, tamsulosin hydrochloride), bisphosphonic acid (eg, pamidronate, zoledronate), thalidomide, lenalidomide, pomalidomide, 5-azacytidine, decitabine, proteasome inhibitors (eg, bortezomib, carfilzomib, ixazomib), NEDD8 inhibitors (eg, pevonedistat), UAE inhibitors, PARP inhibitors (eg, olaparib, niraparib, veliparib), BCL2 inhibitors (eg, venetoclax, obatoclax, oblimersen), antitumor antibodies such as anti-CD20 antibody (eg, rituximab, obinutuzumab) and anti-CCR4 antibody (eg, mogamulizumab), antibody-drug conjugates (eg, trastuzumab emtansine, brentuximab vedotin), gene-modified T-cell therapies using chimeric antigen receptors (CARs) (CAR-T therapies) (eg, tisagenlecleucel, axicabtagene ciloleucel) and the like.

[0166]

The combination of the compound of the present invention with a concomitant drug can provide excellent effects. For example, (1) the dose may be reduced compared to the case where the compound of the present invention or a concomitant drug is administered alone, (2) the drug to be used in combination with the compound of the present invention may be selected depending on the patient's symptom (mild , severe, etc.), (3) the duration of treatment can be prolonged, (4) the therapeutic effect can be sustained, and (5) a synergistic effect can be achieved by using the compound of the present invention in combination with a concomitant drug.

[0167]

Hereinafter, the case where the compound of the present invention is used in combination with a concomitant drug is referred to as a “concomitant drug of the present invention.”

When using the concomitant drug of the present invention, the administration time of the compound of the present invention and the concomitant drug is not limited, but the compound of the present invention and the concomitant drug can be administered to the subject to be administered at the same time or with a delay in time. When administered with a time delay, the time delay will vary depending on the active ingredient administered, dosage form and route of administration. For example, when the concomitant drug is administered first, the compound of the present invention can be administered within 1 minute to 3 days, preferably within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour after administration of the concomitant drug. When the compound of the present invention is administered first, the concomitant drug can be administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administration of the compound of the present invention. The dose of the concomitant drug may be based on a clinically used dose and may be appropriately selected depending on the subject to be administered, the route of administration, the disease, the combination and the like.

[0168]

Examples of the administration form where the compound of the present invention and the concomitant drug are used in combination include (1) administration of one drug obtained by simultaneous preparation of the compound of the present invention and the concomitant drug, (2) simultaneous administration of two drugs obtained by separate preparation the compound of the present invention and the concomitant drug by the same route of administration, (3) administration of two drugs obtained by separately preparing the compound of the present invention and the concomitant drug by the same route of administration with a time delay, (4) simultaneous administration of two drugs obtained by separately formulating the compound of the present invention and the concomitant drug through different routes of administration, and (5) administering two drugs obtained by separately formulating the compound of the present invention and the concomitant drug through different routes of administration with a time delay ( for example, administration in the order of the compound of the present invention and the concomitant drug or administration in the reverse order).

The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the mixture ratio of the compound of the present invention and the concomitant drug can be suitably selected depending on the subject to be administered, the route of administration, the target disease, symptom, combination and the like. For example, when the subject to be administered is a human, 0.01 to 100 parts by weight of the concomitant drug to 1 part by weight of the compound of the present invention can be used.

[0169]

In addition, the compound of the present invention or the concomitant drug of the present invention can be used in combination with non-drug treatments. In particular, the compound of the present invention or the concomitant drug of the present invention can be combined with non-drug therapy, for example, (1) surgery, (2) hypertension-induced chemotherapy using angiotensin II or the like, (3) gene therapy, (4) thermotherapy, (5) cryotherapy, (6) laser ablation and (7) radiation therapy.

[0170]

For example, by using a compound of the present invention or a concomitant drug of the present invention before or after surgery or the like, or before or after treatment with a combination of these two or three, effects such as inhibiting the development of resistance, prolonging disease-free survival, suppressing metastasis or recurrence of cancer can be achieved. and life extension.

[0171]

In addition, it is possible to combine treatment with a compound of the present invention or a concomitant drug of the present invention and supportive therapy [(i) administration of an antibiotic (eg, β-lactams such as pansporin, macrolides such as clarithromycin) against complications associated with various infectious diseases, (ii) administering a high-calorie infusion, an amino acid drug, and a multivitamin to improve malnutrition, (iii) administering morphine to relieve pain, (iv) administering a drug that improves side effects such as nausea, vomiting, loss of appetite, diarrhea, leukopenia, thrombocytopenia, decreased hemoglobin concentration, hair loss, liver damage, kidney damage, DIC and fever, and (v) administration of a drug to suppress multidrug-resistant cancer, etc.].

EXAMPLES

[0172]

The present invention is described in detail below with reference to the following Examples, Preparation Examples and Research Examples, but the present invention is not limited to them. The present invention may be modified without departing from the scope of the present invention.

"Room temperature" in the following Examples generally means from about 10°C to about 35°C. The ratio presented in the mixed solvent is the volume ratio unless otherwise stated. Percentage (%) means % by weight unless otherwise stated.

Silica gel column chromatography used silica gel bound to aminopropyl silane when described as NH, used silica gel bound to 3-(2,3-dihydroxypropoxy)propylsilane when described as diol, and silica gel bound to N-(2-aminoethyl )-3-aminopropylsilane when described as DiNH. When described as C18 in HPLC (high performance liquid chromatography) silica gel coupled with octadecyl was used. The elution solvent ratio is a volume ratio unless otherwise noted.

In the following Examples the following abbreviations are used.

Boc ₂ O: Di-tert-butyl dicarbonate

CDCl ₃ : Deuterated chloroform

DMSO-d ₆ : Deuterated dimethyl sulfoxide

¹ H NMR: Proton Nuclear Magnetic Resonance

LC/MS: Liquid Chromatograph/Mass Spectrometer

ESI: Electrospray ionization

APCI: Atmospheric Pressure Chemical Ionization

DBU: 1,8-Diazabicyclo[5.4.0]undeca-7-ene

DIEA: Diisopropylethylamine

DMAP: 4-Dimethylaminopyridine

DMF: N,N-Dimethylformamide

Mp: Melting point

DPPA: Diphenylphosphoryl azide

MS: Mass spectrum

[M+H] ⁺ , [MH] ^- : Molecular ion peak

M: Molarity

N: Normality

Pd(OAc) ₂ : Palladium(II) acetate

SPhos: 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

TEA: Triethylamine

TFA: Trifluoroacetic acid

THF: tetrahydrofuran

¹ H NMR was measured using Fourier transform NMR. ACD/SpecManager (trade name) and the like were used for analysis. The description does not give a peak for very weak protons, for example, for hydroxyl groups and amino groups.

MS was measured using LC/MS. The ionization method used was the ESI method or the APCI method. The data described are measured (found) values. Typically a molecular ion peak ([M+H] ⁺ , [MH] ^- etc.) is observed, but in the case of a compound having a tert-butoxycarbonyl group as a fragment ion, a peak of the removed tert-butoxycarbonyl group or tert may be observed. -butyl group. In addition, in the case of a compound having a hydroxyl group as a fragment ion, an abstracted H ₂ O peak may be observed. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.

[0173]

Reference Example 1

5-Chloro-6-(difluoromethoxy)pyridin-3-amine

A) 3-Chloro-2-(difluoromethoxy)-5-nitropyridine

To a mixture of 3-chloro-5-nitropyridin-2-ol (10 g) and acetonitrile (300 ml) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (11.86 ml) and sodium sulfate (3.26 d) at room temperature, followed by stirring at the same temperature overnight. To the resulting reaction mixture, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (11.86 ml) and sodium sulfate (3.26 g) were further added at room temperature, followed by stirring at the same temperature for 3 days. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture to make it basic, followed by concentration under reduced pressure. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (4.31 g).

^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.84 (1H, t, J=70.8 Hz), 8.97 (1H, d, J=2.6 Hz), 9.11 (1H , d, J=2.3 Hz).

[0174]

B) 5-Chloro-6-(difluoromethoxy)pyridin-3-amine

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

MS: [M+N] ⁺ 194.9.

[0175]

Reference example 2

6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine

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

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

MS: [M+N] ⁺ 259.9.

[0176]

B) 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine

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

MS: [M+H] ⁺ 229.9.

[0177]

Reference Example 3

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

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

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 temperature for 3 hours. The resulting reaction mixture was poured into ice water, followed by double extraction with ethyl acetate. The organic layer was washed twice with water and brine, and then dried over sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.5 g).

MS: [M+H] ⁺ 225.9.

[0178]

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

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

MS: [M+H] ⁺ 195.9.

[0179]

Reference example 4

5-Amino-2-(difluoromethoxy)nicotinonitrile

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

MS: [M+H] ⁺ 185.9.

[0180]

Example 1

(S)-N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea

[0181]

[0182]

A) 2-Methoxy-1-(1-(triphenylmethyl)-1H-imidazol-2-yl)propan-1-one

A 1.6 M solution of n-butyllithium/hexane (100 ml) was added dropwise to a mixture of 1-(triphenylmethyl)-1H-imidazole (50 g) and THF (600 ml) at -10°C, followed by increasing the temperature to 0° C. The resulting reaction mixture was then stirred at the same temperature for 30 minutes. The reaction mixture was cooled to -78°C followed by the addition of methyl 2-methoxypropanoate (20.94 g) dropwise. The resulting reaction mixture was stirred at the same temperature for 1 hour, followed by raising the temperature to room temperature over 3 hours. A saturated aqueous ammonium chloride solution (10 ml) was added to the reaction mixture, followed by extraction of the aqueous layer with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the precipitate was collected by filtration to give the title compound (50 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.90 (3H, d, J=6.8 Hz), 2.83 (3H, s), 4.88-4.93 (1H, m) , 6.89-7.43 (17H, m).

[0183]

B) 1-(1H-Imidazol-2-yl)-2-methoxypropan-1-one

A mixture of 2-methoxy-1-(1-(triphenylmethyl)-1H-imidazol-2-yl)propan-1-one (150 g) and 5% acetic acid/methanol solution (500 ml) was heated to reflux within 16 hours. After cooling the resulting reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (44 g).

MS: [M+N] ⁺ 154.8.

[0184]

C) 1-(1-Amino-1H-imidazol-2-yl)-2-methoxypropan-1-one

To a mixture of 1-(1H-imidazol-2-yl)-2-methoxypropan-1-one (20 g) and DMF (100 ml) was added a solution of 1 M potassium tert-butoxide in THF (143 ml) at room temperature. The resulting reaction mixture was then stirred at the same temperature for 30 minutes. O-(4-nitrobenzoyl)hydroxylamine (26 g) was added to the reaction mixture at room temperature, followed by stirring at the same temperature for 16 hours. Ice water (40 ml) was added to the reaction mixture, and the solvent was distilled off under reduced pressure. Ethyl acetate (200 ml) was added to the residue, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (17 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.32 (3H, d, J=6.8 Hz), 3.24 (3H, s), 4.94-4.99 (1H, m) , 6.86 (2H, br.s), 7.06 (1H, s), 7.47 (1H, s).

[0185]

D) tert-Butyl-(2-(2-methoxypropanoyl)-1H-imidazol-1-yl)carbamate

To a mixture of 1-(1-amino-1H-imidazol-2-yl)-2-methoxypropan-1-one (17 g) and DMF (50 ml) was added DMAP (6.1 g) at room temperature, followed by addition Boc ₂ O (22.3 ml) at the same temperature. The resulting reaction mixture was stirred at 80°C for 1 hour and then cooled to room temperature. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13 g).

MS: [M+N] ⁺ 270.1.

[0186]

E) tert-Butyl-(4-bromo-2-(2-methoxypropanoyl)-1H-imidazol-1-yl)carbamate

A solution of N-bromosuccinimide (5.2 g) in DMF was added dropwise to a mixture of tert-butyl(2-(2-methoxypropanoyl)-1H-imidazol-1-yl)carbamate (8.0 g) and DMF (40 ml). (10 ml) at room temperature. The resulting reaction mixture was then stirred at the same temperature for 16 hours. The reaction mixture was diluted with water (80 ml), followed by extraction of the aqueous layer with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.5 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.28 (3H, d, J=6.8 Hz), 1.46 (9H, s), 3.21 (3H, s), 4.83 -4.85 (1H, m), 7.93 (1H, s), 10.80 (1H, s).

[0187]

F) 1-(1-Amino-4-bromo-1H-imidazol-2-yl)-2-methoxypropan-1-one

To a mixture of tert-butyl(4-bromo-2-(2-methoxypropanoyl)-1H-imidazol-1-yl)carbamate (10 g) and dichloromethane (100 ml) was added TFA (20 ml) at 0°C. The resulting reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the residue. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. n-pentane was added to the residue, and the precipitate was collected by filtration to give the title compound (7.0 g).

MS: [M+N] ⁺ 248.2.

[0188]

G) Methyl 2-bromo-8-(1-methoxyethyl)imidazo[1,2-b]pyridazine-7-carboxylate

To a mixture of 1-(1-amino-4-bromo-1H-imidazol-2-yl)-2-methoxypropan-1-one (7.0 g) and THF (50 ml) was added methyl acrylate (5.1 ml) and lithium bromide (9.71 g) at room temperature. The resulting reaction mixture was degassed with oxygen, and then Pd(OAc) ₂ (1.27 g) was added to the reaction mixture at the same temperature, followed by stirring at 50°C for 16 hours under an oxygen atmosphere. The reaction mixture was diluted with ice water (50 ml), followed by extraction of the aqueous layer with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.0 g).

MS: [M+N] ⁺ 314.0.

[0189]

H) Methyl 8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylate

After degassing the mixture of methyl 2-bromo-8-(1-methoxyethyl)imidazo[1,2-b]pyridazine-7-carboxylate (8.0 g), toluene (70 ml) and water (10 ml), phosphate was added with nitrogen tripotassium (17.6 g) and 2,4,6-trimethylboroxine (7.12 ml) at room temperature. After further degassing the mixture with nitrogen, Pd(OAc) ₂ (571 mg) and SPhos (1.57 g) were added at room temperature, followed by stirring at 80°C for 3 hours. The resulting reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate (50 ml), followed by extraction of the aqueous layer with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.0 g).

MS: [M+H] ⁺ 250.2

[0190]

I) (S)-methyl-8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylate

Methyl 8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4.36 g) was fractionated by HPLC (CHIRALCEL OD-H (VJ002), 20 mm ID × 250 mm L, mobile phase: hexane/2-propanol=950/50). The shorter retention time fraction containing the target product was concentrated under reduced pressure to give the title compound (2034 mg).

Optical purity: 99.9% e.i., retention time: 6.845 minutes (CHIRALCEL OD-H (VK069), 4.6 mm ID × 250 mm L, mobile phase: hexane/2-propanol=950/50)

MS: [M+N] ⁺ 250.0.

The absolute configuration was determined using a single crystal diffractometer.

[0191]

J) (S)-8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid trifluoroacetate

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

MS: [M+N] ⁺ 236.0.

[0192]

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

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

MS: [M+N] ⁺ 207.0.

[0193]

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

Triphosgene ( 679.1 mg) at 0°C followed by stirring at room temperature for 1 hour. 5-chloro-6-(difluoromethoxy)pyridin-3-amine (1.17 g) obtained in Reference Example 1 was added to the resulting reaction mixture at room temperature, followed by stirring at 60°C for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) followed by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (1.83 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.52 (3H, d, J=6.8 Hz), 2.35 (3H, d, J=0.8 Hz), 3.30 (3H , s), 5.26 (1H, kV, J=6.8 Hz), 7.40-7.91 (1H, m), 7.92 (1H, d, J=0.8 Hz), 8 .21 (1H, d, J=2.3 Hz), 8.33 (1H, d, J=2.3 Hz), 8.69 (1H, br.s), 9.01 (1H, s) , 10.27 (1H, br.s).

MS: [M+N] ⁺ 427.0.

The absolute configuration was determined using a single crystal diffractometer.

[0194]

Example 2

(S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea

[0195]

[0196]

A) tert-Butyl-(6-chloro-2-(2-methoxypropanoyl)pyridin-3-yl)carbamate

To a mixture of tert-butyl-(2-bromo-6-chloropyridin-3-yl)carbamate (20.0 g) and THF (160 ml) was added a 1.08 M solution of methyllithium/diethyl ether (72.3 ml) at - 78°C followed by stirring at the same temperature for 15 minutes. A 1.6 M n-butyllithium/hexane solution (52.8 ml) was added to the resulting reaction mixture at -78°C, followed by stirring at the same temperature for 15 minutes. A solution of 2-methoxy-1-morpholinopropan-1-one (16.9 g) in THF (60 ml) was added to the reaction mixture at -78°C, followed by stirring for 2 hours while raising the temperature to room temperature. A solution of acetic acid (15 ml) in water (150 ml) was added to the reaction mixture at room temperature, followed by extraction of the aqueous layer with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15.81 g).

MS: [M+H-tBu] ⁺ 258.9.

[0197]

B) 1-(6-Chloro-3-((2-nitrovinyl)amino)pyridin-2-yl)-2-methoxypropan-1-one

A solution of 4N was added to a mixture of tert-butyl-(6-chloro-2-(2-methoxypropanoyl)pyridin-3-yl)carbamate (15.7 g) and ethyl acetate (100 ml). hydrogen chloride in cyclopentyl methyl ether (200 ml) at room temperature, followed by stirring at the same temperature for 2 hours. A 4 N solution was additionally added to the resulting reaction mixture. hydrogen chloride in cyclopentyl methyl ether (100 ml) at room temperature, followed by stirring overnight at the same temperature and the solvent was distilled off under reduced pressure. A mixture of the resulting residue, (E)-4-(2-nitrovinyl)morpholine (9.47 g), 6 N. a solution of hydrochloric acid (36 ml) and acetone (120 ml) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (240 ml), followed by stirring at 0°C for 1 hour. The precipitate was collected by filtration and washed with water, and the resulting solid was dried under reduced pressure to obtain the title compound (12.55 g).

MS: [M+N] ⁺ 286.0.

[0198]

C) 2-Chloro-8-(1-methoxyethyl)-7-nitro-1,5-naphthyridine

To a mixture of DBU (6.62 ml) and THF (120 ml) was added a solution of 1-(6-chloro-3-((2-nitrovinyl)amino)pyridin-2-yl)-2-methoxypropan-1-one (12 .55 g) in THF (280 ml) at room temperature, followed by stirring at the same temperature for 1 hour. After adjusting the pH to slightly acidic by adding 2N. a solution of hydrochloric acid to the resulting reaction mixture, the mixture was diluted with water, followed by extraction of the aqueous layer with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (9.82 g).

MS: [M+N] ⁺ 267.9.

[0199]

D) 6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridine-3-amine

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

MS: [M+H] ⁺ 238.0.

[0200]

E) (S)-6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridine-3-amine

6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (3.84 g) was fractionated by HPLC (CHIRALPAK IG (VJ003), 20 mm ID × 250 mm L, mobile phase: hexane /ethanol=900/100). The longer retention time fraction containing the target product was concentrated under reduced pressure to give the title compound (1865 mg).

Optical purity: 99.9% e.i., retention time: 7.359 minutes (CHIRALPAK AD-H (VJ019), 4.6 mm ID × 250 mm L, mobile phase: hexane/2-propanol=850/150)

MS: [M+H] ⁺ 238.0.

The absolute configuration was determined using a single crystal diffractometer.

[0201]

F) (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2 -yl)-5-(trifluoromethyl)pyridin-3-yl)urea

The reaction was carried out in the following 4 divided stages.

Reaction mixture 1: To a mixture of triphosgene (62 mg) and THF (5 ml) was added a solution of (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (100 mg) and DIEA (0.220 ml) in THF (2 ml) at 0°C, followed by stirring at the same temperature for 1 hour. To the resulting reaction mixture, 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (106 mg) obtained in Reference Example 2 was added at 0°C, followed by stirring at 60°C overnight.

Reaction mixture 2: To a mixture of triphosgene (187 mg) and THF (12 ml) was added a solution of (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (300 mg) and DIEA (0.660 ml) in THF (6 ml) at 0°C, followed by stirring at the same temperature for 1 hour. To the resulting reaction mixture, 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (318 mg) obtained in Reference Example 2 was added at 0°C, followed by stirring at 60°C for 2 hours. 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (29 mg) was added to the reaction mixture at the same temperature, followed by stirring overnight.

Reaction mixture 3: To a mixture of triphosgene (375 mg) and THF (24 ml) was added a solution of (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (600 mg) and DIEA (1.32 ml) in THF (12 ml) at 0°C, followed by stirring at the same temperature for 1 hour. To the resulting reaction mixture, 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (636 mg) obtained in Reference Example 2 was added at 0°C, followed by stirring at 60°C for 2 hours. 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (116 mg) was added to the reaction mixture at the same temperature, followed by stirring overnight.

Reaction mixture 4: To a mixture of triphosgene (531 mg) and THF (34 ml) was added a solution of (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (850 mg) and DIEA (1.87 ml) in THF (17 ml) at 0°C, followed by stirring at the same temperature for 1 hour. To the resulting reaction mixture, 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (901 mg) obtained in Reference Example 2 was added at 0°C, followed by stirring at 60°C for 2 hours. 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (164 mg) was added to the reaction mixture at the same temperature, followed by stirring overnight.

Reaction mixtures 1 to 4 were combined and the combined mixture was diluted with saturated aqueous sodium hydrogen carbonate, followed by extraction of the aqueous layer with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. THF and ethyl acetate were added to the residue, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give a crude crystalline material (3.46 g). The resulting crude crystalline material was 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 and then cooled to room temperature, followed by stirring at the same temperature overnight. The precipitate was collected by filtration, washed with a mixed solution of ethyl acetate and n-heptane, and then dried under reduced pressure to obtain the title compound (3.35 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.56 (3H, d, J=6.4 Hz), 3.36 (3H, s), 5.85 (1H, q, J=6, 7 Hz), 7.77 (1H, d, J=8.7 Hz), 8.18 (2H, s), 8.46 (1H, d, J=9.1 Hz), 8.74 (1H , d, J=2.6 Hz), 8.89 (1H, d, J=2.3 Hz), 9.24 (1H, s), 9.68 (1H, s), 10.89 (1H , With).

MS: [M-N] ^- 491.1.

The absolute configuration was determined using a single crystal diffractometer.

[0202]

Example 3

(S)-N-(4-(1-Methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea

[0203]

[0204]

A) 8-(1-Methoxyethyl)-2-methyl-7-nitro-1,5-naphthylene

A mixture of 2-chloro-8-(1-methoxyethyl)-7-nitro-1,5-naphthyridine (500 mg), 2,4,6-trimethylboroxine (0.39 ml), Pd(dppf)Cl ₂ /CH ₂ Cl ₂ (153 mg), tripotassium phosphate (793 mg) and 1,2-dimethoxyethane (20 ml) were heated at 100°C for 1.5 hours under microwave irradiation. The resulting reaction mixture was diluted with ethyl acetate. Insoluble material was filtered through celite 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).

MS: [M+H] ⁺ 247.9.

[0205]

B) 4-(1-Methoxyethyl)-6-methyl-1,5-naphthyridin-3-amine

A mixture of 8-(1-methoxyethyl)-2-methyl-7-nitro-1,5-naphthyridine (470 mg), tin(II) chloride dihydrate (2.57 g), THF (3 ml) and ethanol (12 ml ) was stirred at room temperature overnight at 60°C for 7 hours. The resulting reaction mixture was diluted with ethyl acetate and neutralized with saturated aqueous sodium hydrogen carbonate. Insoluble material was filtered off and washed with ethyl acetate. The filtrate was extracted twice with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) followed by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (306 mg).

MS: [M+H] ⁺ 217.9.

[0206]

C) N-(4-(1-Methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)- 5-(trifluoromethyl)pyridin-3-yl)urea

To a solution of 4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3-amine (80 mg), 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl )pyridin-3-amine (101 mg) obtained in Reference Example 2 and pyridine (0.089 ml) in THF (5 ml), a solution of triphosgene (54.6 mg) in THF (1 ml) was added at 0°C. The resulting reaction mixture was stirred at 0°C for 30 minutes and 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 resulting reaction mixture was stirred at 0°C for 30 minutes and at room temperature for 4 hours. The mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, followed by double extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (127 mg).

MS: [M+N] ⁺ 473.1.

[0207]

D) (S)-N-(4-(1-Methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2 -yl)-5-(trifluoromethyl)pyridin-3-yl)urea

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

MS: [M+H] ⁺ 473.1.

[0208]

Example 4

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

[0209]

[0210]

An 8 M aqueous solution of sodium hydroxide (4 ml) at room temperature. The resulting reaction mixture was stirred for 2 days. The reaction mixture was concentrated under reduced pressure, and then the residue was extracted with ethyl acetate. The aqueous layer was adjusted to pH 4 with 6N. hydrochloric acid solution and concentrated under reduced pressure. The residue was suspended in ethanol, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To a solution of the residue (848 mg) and triethylamine (1.51 ml) in toluene (50 ml) was added DPPA (1.16 ml) at room temperature. After stirring the mixture at room temperature for 40 minutes, 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (705 mg) obtained in Reference Example 3 was added. the mixture was stirred at 100°C for 2 hours and then poured into a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was separated and washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off 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 give the title compound (488 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.54 (3H, d, J=6.4 Hz), 2.37 (3H, s), 3.33 (3H, s), 5.29 (1H, kv, J=6.8 Hz), 7.96 (1H, d, J=0.8 Hz), 8.16 (2H, s), 8.47-8.52 (1H, m) , 8.54 (1H, d, J=2.3 Hz), 8.75 (1H, br.s), 9.04 (1H, s), 10.59 (1H, br.s).

MS: [M+N] ⁺ 428.0.

[0211]

Example 5

(S)-N-(5-Cyano-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea

[0212]

[0213]

To a mixture of (S)-8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid trifluoroacetate (80 mg), TEA (0.17 ml) and toluene (5 ml) DPPA (0.12 ml) at room temperature, followed by stirring the resulting reaction mixture at the same temperature for 30 minutes. In addition, DPPA (0.12 ml) was added at room temperature, followed by stirring the reaction mixture at the same temperature for 30 minutes. 5-amino-2-(difluoromethoxy)nicotinonitrile (57.9 mg) obtained in Reference Example 4 was added, followed by stirring the reaction mixture at 110°C for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and suspended and washed with ethyl acetate/hexane to give the title compound (65 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.53 (3H, d, J=6.8 Hz), 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=0.8 Hz), 8.51-8.57 (2H, m ), 8.68 (1H, br.s), 9.01 (1H, s), 10.33 (1H, br.s).

MS: [M+N] ⁺ 418.1.

[0214]

Example 6

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

[0215]

[0216]

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

To a solution of methyl 8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (262 mg) in methanol was added 8 M aqueous sodium hydroxide (0.53 ml) at room temperature with followed by stirring at the same temperature for 5 hours. The resulting reaction mixture was neutralized with 2 N. hydrochloric acid solution and concentrated under reduced pressure. The residue was suspended in ethyl acetate and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (256 mg).

MS: [M+H] ⁺ 235.9.

[0217]

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

DPPA (0.18 ml) at room temperature. After stirring the mixture at room temperature for 40 minutes, 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (162 mg) obtained in Reference Example 2 was added. The resulting reaction mixture was stirred at 100°C for 2 hours, and then poured into a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was separated and washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and suspended and washed with ethyl acetate/hexane to give the title compound (183 mg).

MS: [M+N] ⁺ 462.1.

[0218]

C) (S)-N-(8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazole -2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

N-(8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)- 5-(trifluoromethyl)pyridin-3-yl)urea (183 mg) was fractionated by HPLC (CHIRALPAK IC (VB004), 20 mm ID × 250 mm L, mobile phase: hexane/2-propanol=300/700). The shorter retention time fraction containing the target product was concentrated under reduced pressure. The concentrate was washed with ethyl acetate/hexane to give the title compound (62 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.55 (3H, d, J=6.8 Hz), 2.37 (3H, d, J=0.8 Hz), 3.33 (3H , s), 5.24-5.34 (1H, m), 7.96 (1H, d, J=0.8 Hz), 8.17 (2H, s), 8.72 (1H, d, J=2.3 Hz), 8.80 (1H, br.s), 8.83 (1H, d, J=2.3 Hz), 9.06 (1H, s), 10.75 (1H, ush.s).

MS: [M+N] ⁺ 462.1.

[0219]

Example 7

N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(2-methoxypropan-2-yl)-2-methylimidazo [1,2-b]pyridazin-7-yl)urea

[0220]

[0221]

A) 1-(Triphenylmethyl)-1H-imidazole

To a solution of imidazole (25 g) in methylene chloride (300 ml) was added TEA (77 ml) at 0°C. After stirring the mixture for 5 minutes, triphenyl methyl chloride (102 g) was gradually added at the same temperature. The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and then extracted twice with methylene chloride. The organic layer was washed with water, then with brine, dried over sodium sulfate and then concentrated under reduced pressure. The residue was washed with hexane to give the title compound (110 g).

^1H NMR (300 MHz, CDCl ₃ ) 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).

[0222]

B) 2-Methoxy-2-methyl-1-(1-(triphenylmethyl)-1H-imidazol-2-yl)propan-1-one

To a solution of 1-(triphenylmethyl)-1H-imidazole (1.0 g) in THF (15 ml), a solution of 1.4 M n-butyllithium/hexane (2.3 ml) was added dropwise at -10°C, followed by stirring at 0°C for 30 minutes. After cooling the resulting reaction mixture to -78°C, methyl 2-methoxy-2-methylpropionate (0.5 g) was added dropwise, followed by stirring at the same temperature for 1 hour and then at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by double extraction with ethyl acetate. The organic layer was washed with water, then with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was suspended and washed with hexane to give the title compound (650 mg).

^1H NMR (300 MHz, CDCl ₃ ) δ 1.38 (6H, s), 2.67 (3H, s), 7.02-7.15 (12H, m), 7.25-7.35 ( 5H, m).

[0223]

C) 1-(1H-Imidazol-2-yl)-2-methoxy-2-methylpropan-1-one

A mixture of 2-methoxy-2-methyl-1-(1-(triphenylmethyl)-1H-imidazol-2-yl)propan-1-one (4.2 g) and 5% acetic acid-methanol solution (50 ml) was heated reflux for 16 hours. The resulting reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.2 g).

MS: [M+N] ⁺ 169.2.

[0224]

D) 1-(1-Amino-1H-imidazol-2-yl)-2-methoxy-2-methylpropan-1-one

To a solution of 1-(1H-imidazol-2-yl)-2-methoxy-2-methylpropan-1-one (1.4 g) in DMF (15 ml), a solution of 1 M potassium tert-butoxide in THF (9. 2 ml) followed by stirring at the same temperature for 30 minutes. O-(4-nitrobenzoyl)hydroxylamine (1.7 g) was added to the resulting mixture at room temperature, followed by stirring at the same temperature for 16 hours. Cold water was added to the reaction mixture, followed by concentration under reduced pressure. The residue was diluted with ethyl acetate and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.0 g).

MS: [M+N] ⁺ 184.1.

[0225]

E) N-(2-(2-(2-Methoxy-2-methylpropanoyl)-1H-imidazol-1-yl)(tert-butoxy)formamide

DMAP (0.34 g) was added to a solution of 1-(1-amino-1H-imidazol-2-yl)-2-methoxy-2-methylpropan-1-one (1.0 g) in DMF (10 ml), then Boc ₂ O (1.2 ml) at room temperature. The resulting reaction mixture was stirred at 80°C for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.1 g).

MS: [M+H]+ 284.2.

[0226]

F) N-(4-Bromo-2-(2-(2-methoxy-2-methylpropanoyl)-1H-imidazol-1-yl)(tert-butoxy)formamide

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

MS: [M+N] ⁺ 362.0.

[0227]

G) 1-(1-Amino-4-bromo-1H-imidazol-2-yl)-2-methoxy-2-methylpropan-1-one

Trifluoroacetic acid was added to a solution of N-(4-bromo-2-(2-(2-methoxy-2-methylpropanoyl)-1H-imidazol-1-yl)(tert-butoxy)formamide (700 mg) in methylene chloride (10 ml). acid (3 ml) at 0°C followed by stirring at room temperature for 1 hour. The resulting reaction mixture was concentrated under reduced pressure and the residue was neutralized with saturated aqueous sodium hydrogen carbonate. The mixture was extracted twice with ethyl acetate. The organic layer was washed with water, then with saturated saline , washed with sodium sulfate and then concentrated under reduced pressure.The residue was washed with pentane to give the title compound (450 mg).

MS: [M+N] ⁺ 262.0.

[0228]

H) Methyl 2-bromo-8-(2-methoxypropan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate

To a solution of 1-(1-amino-4-bromo-1H-imidazol-2-yl)-2-methoxy-2-methylpropan-1-one (400 mg) in THF (5 ml) was added methyl acrylate (0.3 ml ) and lithium bromide (531 mg) at room temperature. The mixture was placed under an oxygen atmosphere, Pd(OAc) ₂ (69 mg) was added and the mixture was stirred under an oxygen atmosphere at 50°C for 16 hours. The resulting reaction mixture was poured into water, followed by double extraction with ethyl acetate. The organic layer was washed with water, then with brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (250 mg).

MS: [M+H] ⁺ 328.1.

[0229]

I) Methyl 2-methyl-8-(2-methoxypropan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate

To a solution of methyl 2-bromo-8-(2-methoxypropan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (200 mg) in toluene (6 ml) and water (0.4 ml) 2,4,6-trimethylboroxine (0.15 ml) and tripotassium phosphate (390 mg) were added. The mixture was then placed under a nitrogen atmosphere. Pd(OAc) ₂ (28 mg) and SPhos (101 mg) were added and the mixture was stirred at 80°C for 3 hours. The resulting reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, followed by double extraction with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (120 mg).

MS: [M+N] ⁺ 264.0.

[0230]

J) Methyl-2-methyl-8-(2-methoxypropan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid

To a solution of methyl 2-methyl-8-(2-methoxypropan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (300 mg) in ethanol (10 ml) was added 8 M aqueous sodium hydroxide 0.72 ml) followed by stirring the resulting reaction mixture at 60°C overnight. 8 M aqueous sodium hydroxide solution (1.44 ml) was added, followed by stirring at 80°C overnight. 6 M hydrochloric acid was added to the reaction mixture to make it acidic to pH 4, followed by concentration under reduced pressure. The residue was suspended in ethanol, and the insoluble material was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure by boiling azeotropically with toluene to give the title compound (406 mg).

MS: [M+N] ⁺ 250.0.

[0231]

K) N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(2-methoxypropan-2-yl)-2 -methylimidazo[1,2-b]pyridazin-7-yl)urea

To a mixture of methyl 2-methyl-8-(2-methoxypropan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (50 mg) and triethylamine (0.04 ml) in DMF (5 ml ) DPPA (0.05 ml) was added, followed by stirring at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. Toluene (5 ml), triethylamine (0.04 ml) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (27.5 mg) were added to the residue. obtained in Reference Example 3, followed by stirring at 110°C for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (2 mg).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.95 (6H, s), 2.44 (3H, d, J=0.8 Hz), 3.29 (3H, s), 7.64 (1H , d, J=0.8 Hz), 7.70 (1H, s), 7.88-7.99 (2H, m), 8.38 (1H, d, J=2.6 Hz), 8 .57 (1H, d, J=2.6 Hz), 9.17 (1H, s), 9.58 (1H, s).

MS: [M+N] ⁺ 442.1.

[0232]

Example 8

N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl) urea

[0233]

[0234]

A) Ethyl 1-amino-1H-imidazole-2-carboxylate

A solution of 1 M lithium hexamethyldisilazide in THF (171 ml) was added dropwise to a solution of ethylimidazole-2-carboxylate (20 g) in anhydrous DMF (400 ml) at -10°C under a nitrogen atmosphere, followed by stirring at the same temperature for 30 minutes. A solution of O-diphenylphosphinylhydroxylamine (39.9 g) in anhydrous DMF (1000 ml) was added at 0°C. The resulting reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with methylene chloride 4 times. The extract was washed twice with saturated saline, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (23.0 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.31 (3H, t, J=7.2 Hz), 4.30 (2H, q, J=7.2 Hz), 6.59 (2H , br.s), 6.98 (1H, d, J=0.8 Hz), 7.39 (1H, d, J=0.8 Hz).

[0235]

B) Ethyl 1-((tert-butoxycarbonyl)amino)-1H-imidazole-2-carboxylate

To a solution of ethyl 1-amino-1H-imidazole-2-carboxylate (23.0 g) and DMAP (8.72 g) in anhydrous DMF (250 ml) was added dropwise Boc ₂ O (28.0 g). The mixture was stirred under nitrogen atmosphere at 80-85°C for 4 hours and then concentrated under reduced pressure. The residue was diluted with methylene chloride, and washed with saturated aqueous citric acid, then with saturated saline. Drying was carried out over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methylene chloride) to give the title compound (26.6 g).

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

[0236]

C) Ethyl 1-((tert-butoxycarbonyl)amino)-4-chloro-1H-imidazole-2-carboxylate

To a solution of ethyl 1-((tert-butoxycarbonyl)amino)-1H-imidazole-2-carboxylate (80.0 g) in anhydrous DMF (800 ml), N-chlorosuccinimide (50.2 g) was gradually added, followed by stirring at room temperature for 16 hours under nitrogen atmosphere. The resulting reaction mixture was diluted with water and extracted 3 times with ethyl acetate. The organic layer was washed twice with water and twice with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (16.8 g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J=7.2 Hz), 1.49 (9H, s), 4.39 (2H, q, J=7.2 Hz ), 7.16 (1H, s), 8.07 (1H, br.s).

[0237]

D) Ethyl 3-(1-((tert-butoxycarbonyl)amino)-4-chloro-1H-imidazol-2-yl)-3-oxopropanate

To a solution of ethyl 1-((tert-butoxycarbonyl)amino)-4-chloro-1H-imidazole-2-carboxylate (22.0 g) and ethyl acetate (33.5 g) in anhydrous THF (250 ml) was added dropwise a solution of 1 M lithium hexamethyldisilazide in THF (266 ml) at -10°C under nitrogen atmosphere. The resulting reaction mixture was stirred at the same temperature for 30 minutes and then at room temperature for 4.5 hours. After cooling the reaction mixture to 0°C, acetic acid was added to adjust the pH to 5, and then the pH was adjusted to 8 with saturated aqueous sodium hydrogen carbonate. After extraction with ethyl acetate three times, the organic layer was washed twice with brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methylene chloride) to give the title compound (19.7 g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.26 (3H, t, J=7.2 Hz), 1.50 (9H, s), 4.05 (2H, s), 4.19 (2H , kV, J=6.8 Hz), 7.25 (1H, s), 8.31 (1H, br.s).

[0238]

E) Ethyl 2-chloro-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate

To a solution of ethyl 3-(1-((tert-butoxycarbonyl)amino)-4-chloro-1H-imidazol-2-yl)-3-oxopropanate (31.0 g) in anhydrous methylene chloride (400 ml) was added N-dimethylformamide dimethyl acetal (13.4 g). The resulting reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/methylene chloride) to give the title compound (16.0 g).

MS: [M+N] ⁺ 241.9.

[0239]

F) Ethyl 8-bromo-2-chlorimidazo[1,2-b]pyridazine-7-carboxylate

Phosphorus oxybromide (30.4 g) was added to a solution of ethyl 2-chloro-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (16.0 g) in acetonitrile (150 ml), followed by stirring the resulting reaction mixture at 80-90°C for 2 hours in a nitrogen atmosphere. After cooling the mixture to room temperature, ice water was added, followed by neutralization with a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted 3 times with ethyl acetate. The organic layer was washed twice with water and twice with brine, dried over sodium sulfate and then 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).

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.45 (3H, t, J=7.2 Hz), 4.47 (2H, sq, J=7.2 Hz), 8.03 (1H, s ), 8.71 (1H, s).

[0240]

G) Ethyl 2-chloro-8-(propen-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate

A mixture of ethyl 8-bromo-2-chlorimidazo[1,2-b]pyridazine-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-dioxane (15 ml) were stirred at 80-85°C for 16 hours under a nitrogen atmosphere. The resulting reaction mixture was cooled to room temperature and then diluted with ethyl acetate. The organic layer was washed twice with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (715 mg).

MS: [M+N] ⁺ 265.9.

[0241]

H) Ethyl 2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate

A mixture of ethyl 2-chloro-8-(propen-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (1.20 g) and tris(triphenylphosphine)rhodium(I) chloride (418 mg) in anhydrous ethanol (30 ml) was stirred at 10-15°C for 40 hours under a hydrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (955 mg).

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

[0242]

I) 2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid

To a solution of ethyl 2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (955 mg) in methanol (10 ml), THF (10 ml) and water (10 ml) sodium hydroxide (571 mg) was added, followed by stirring the mixture at 10°C for 1 hour under a nitrogen atmosphere. After adding 2 N to the resulting reaction mixture. hydrochloric acid solution to bring the pH to 5, the mixture was extracted 3 times with ethyl acetate. The organic layer was washed twice with brine, dried over sodium sulfate and then concentrated under reduced pressure. The residue was washed with ethyl acetate/petroleum ether to give the title compound (800 mg).

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

[0243]

J) N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7- silt)urea

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

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

MS: [M+N] ⁺ 430.9.

[0244]

Example 9

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

[0245]

[0246]

A) Methyl 2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate

A solution of 0.6 M trimethylsilyldiazomethane in hexane (9.6 ml) was added to a solution of 2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (462 mg) in methanol. at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to obtain the title compound (475 mg).

MS: [M+H] ⁺ 254.1.

[0247]

B) Methyl 2-methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate

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

MS: [M+N] ⁺ 234.2.

[0248]

C) 2-Methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid

A 2 M aqueous solution of sodium hydroxide (1.5 ml) followed by stirring the mixture at room temperature for 2 hours. An 8M sodium hydroxide aqueous solution (0.76 ml) was added to the mixture, followed by stirring at room temperature for 4 hours. After adding 1 N. hydrochloric acid solution to the resulting reaction mixture at 0°C to neutralize the mixture was extracted with ethyl acetate. The organic layer was washed with water, then with brine, dried over magnesium sulfate and then concentrated under reduced pressure to give the title compound (254 mg).

MS: [M+N] ⁺ 220.2.

[0249]

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

Diphenylphosphoryl azide ( 0.09 ml). After stirring the mixture at the same temperature for 40 minutes, 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (71 mg) obtained in Reference Example 3 was added followed by stirring at 100°C for 2 hours. The resulting reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and suspended and washed with ethyl acetate/hexane to give the title compound (83 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.49 (6H, d, J=7.2 Hz), 2.38 (3H, s), 3.48 (1H, quin, J=6, 9 Hz), 7.93 (1H, d, J=0.8 Hz), 8.12-8.16 (2H, m), 8.46 (1H, d, J=2.3 Hz), 8 .49 (1H, s), 8.57 (1H, d, J=2.3 Hz), 8.82 (1H, s), 9.73 (1H, br.s).

MS: [M+N] ⁺ 412.2.

[0250]

The following compounds of Examples 10 to 270 were synthesized in the same manner.

[0251]

[Table 1-1]

Example No. Salt MS 1 (S)-N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea 427.0 2 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea 491.1 3 (S)-N-(4-(1-Methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea 473.0 4 (S)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo [1,2-b]pyridazin-7-yl)urea 428.1 5 (S)-N-(5-Cyano-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea 418.1 6 (S)-N-(8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazol-2 -yl)-5-(trifluoromethyl)pyridin-3-yl)urea 461.9 7 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(2-methoxypropan-2-yl)-2-methylimidazo [1,2-b]pyridazin-7-yl)urea 442.1 8 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl) urea 429.0 9 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(2-methyl-8-(propan-2-yl)imidazo[ 1,2-b]pyridazin-7-yl)urea 412.0 10 (R)-N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea HCI 427.1 eleven (R)-N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea _{H2SO4 _} 427.1 12 (S)-N-(6-Chloro-4(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl) -5-(trifluoromethyl)pyridin-3-yl)urea HCI 493.1 13 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea _{0.5H2SO4 _} 493.1 14 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)urea 427.1

[0252]

[Table 1-2]

15 (R)-N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea 427.0 16 N-(5-Cyanopyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)urea 350.1 17 N-(8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)- 5-(trifluoromethyl)pyridin-3-yl)urea 462.0 18 (R)-N-(8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazol-2 -yl)-5-(trifluoromethyl)pyridin-3-yl)urea 461.9 19 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2 -b]pyridazin-7-yl)urea 428.0 20 (R)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo [1,2-b]pyridazin-7-yl)urea 428.2 21 (S)-N-(5-Chloro-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl) -2-methylimidazo[1,2-b]pyridazin-7-yl)urea 442.2 22 (S)-N-(8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-(2-methyl-6-(2H-1,2,3 -triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 475.9 23 (S)-N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl) -2-methylimidazo[1,2-b]pyridazin-7-yl)urea 442.2 24 (S)-N-(5-Chloro-6-(1,3-oxazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2 -b]pyridazin-7-yl)urea 428.1 25 (S)-N-(5-Chloro-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1 ,2-b]pyridazin-7-yl)urea 441.1 26 (S)-N-(8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-(6-(1,3-oxazol-2-yl)- 5-(trifluoromethyl)pyridin-3-yl)urea 462.2 27 (S)-N-(8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-(5-methyl-6-(2H-1,2,3 -triazol-2-yl)pyridin-3-yl)urea 408.1 28 (S)-N-(6-(Difluoromethoxy)-5-methylpyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl) urea 407.1

[0253]

[Table 1-3]

29 (S)-N-(5-Chloro-6-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl) -2-methylimidazo[1,2-b]pyridazin-7-yl)urea 442.1 thirty (S)-N-(8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-(6-(4-methyl-2H-1,2,3 -triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 476.2 31 (S)-N-(5-(Difluoromethyl)-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2 -methylimidazo[1,2-b]pyridazin-7-yl)urea 444.2 32 (S)-N-(8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-[6-(4-(methoxymethyl)-2H-1,2 ,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl]urea 506.3 33 (S)-N-(8-(1-Methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-(6-(3-methyl-1H-1,2,4 -triazol-1-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 476.2 34 (S)-N-[6-(4-(Difluoromethyl)-2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl]-N'-(8-( 1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)urea 512.2 35 (S)-N-(5-Bromo-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea 471.1 36 (S)-N-[5-Chloro-6-(4-(methoxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1- methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)urea 472.2 37 (S)-N-(5-Chloro-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl) -2-methylimidazo[1,2-b]pyridazin-7-yl)urea 442.1 38 (S)-N-(6-(Difluoromethoxy)-5-(difluoromethyl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7 -yl)urea 443.1 39 (S)-N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo [1,2-b]pyridazin-7-yl)urea 418.9 40 (S)-N-(5-Chloro-6-(difluoromethoxy)-2-methylpyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin- 7-yl)urea 441.1 41 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-cyanopyridin-3-yl)urea 381.0 42 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5- (trifluoromethyl)pyridin-3-yl)urea 491.0

[0254]

[Table 1-4]

43 (R)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea 491.1 44 (R)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea HCI 493.1 45 (R)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea _{0.5H2SO4 _} 493.1 46 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea 427.1 47 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-6-(2H-1,2,3-triazol-2-yl )pyridin-3-yl)urea 459.1 48 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-6-(2H-1,2,3-triazol-2-yl )pyridin-3-yl)urea 459.1 49 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-6-(2H-1,2,3-triazol-2-yl )pyridin-3-yl)urea 459.1 50 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-cyano-6-(2H-1,2,3-triazol-2-yl )pyridin-3-yl)urea 448.1 51 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-6-methoxypyridin-3-yl)urea 421.9 52 N-(5-Chloro-6-(2-methoxyethoxy)pyridin-3-yl)-N'-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)urea 465.9 53 N-(6-(Azetidin-1-yl)-5-chloropyridin-3-yl)-N'-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)urea 447.0 54 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl )urea 474.9 55 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea 443.0 56 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)urea 411.0

[0255]

[Table 1-5]

57 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-fluoro-6-methoxypyridin-3-yl)urea 406.0 58 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(2-cyano-5-methylpyridin-4-yl)urea 397.2 59 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)urea 456.0 60 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)urea 458.1 61 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)urea 458.1 62 N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(2-methyl-6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea 507.1 63 (R)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(2-methyl-6-(2H-1,2,3-triazole -2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 507.1 64 (R)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-2-methyl-6-(2H-1,2 ,3-triazol-2-yl)pyridin-3-yl)urea 473.1 65 (R)-N-(5-Chloro-6-(difluoromethoxy)-2-methylpyridin-3-yl)-N'-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3- silt)urea 472.0 66 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(2-methyl-6-(2H-1,2,3-triazole -2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 507.2 67 (S)-N-(5-Chloro-6-(difluoromethoxy)-2-methylpyridin-3-yl)-N'-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3- silt)urea 472.1 68 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-2-methyl-6-(2H-1,2 ,3-triazol-2-yl)pyridin-3-yl)urea 473.2 69 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(1,3-oxazol-2-yl)-5- (trifluoromethyl)pyridin-3-yl)urea 493.1 70 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-methyl-6-(2H-1,2,3-triazole -2-yl)pyridin-3-yl)urea 439.1

[0256]

[Table 1-6]

71 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-6-(3-methyl-1H-1,2 ,4-triazol-1-yl)pyridin-3-yl)urea 473.1 72 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-6-(1,3-oxazol-2-yl )pyridin-3-yl)urea 459.1 73 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-6-(1-methyl-1H-1,2 ,4-triazol-3-yl)pyridin-3-yl)urea 473.1 74 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(difluoromethoxy)-5-methylpyridin-3-yl)urea 438.1 75 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-cyano-6-(difluoromethoxy)pyridin-3-yl)urea 449.1 76 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(4-methyl-2H-1,2,3-triazole -2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 507.2 77 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-{6-(4-(methoxymethyl)-2H-1,2,3 -triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl}urea 537.2 78 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(3-methyl-1H-1,2,4-triazole -1-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 507.2 79 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(5-(difluoromethyl)-6-(2H-1,2,3 -triazol-2-yl)pyridin-3-yl)urea 475.1 80 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(4-(difluoromethyl)-2H-1,2,3 -triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 543.2 81 (S)-N-(6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(difluoromethoxy)-5-(difluoromethyl)pyridin-3-yl )urea 474.1 82 (S)-N-(5-Bromo-6-(difluoromethoxy)pyridin-3-yl)-N'-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)urea 502.1 83 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-methyl-1,5 -naphthyridin-3-yl)urea 439.1 84 N-(4-(1-Methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5- (trifluoromethyl)pyridin-3-yl)urea 473.1

[0257]

[Table 1-7]

85 (R)-N-(4-(1-Methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea 472.9 86 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)urea 438.1 87 N-(2-Cyano-5-methylpyridin-4-yl)-N'-(4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)urea 377.2 88 (R)-N-(4-(1-Methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(2-methyl-6-(2H-1,2,3-triazole -2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 487.2 89 (R)-N-(5-Chloro-6-(difluoromethoxy)-2-methylpyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3- silt)urea 452.1 90 (R)-N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl) -6-methyl-1,5-naphthyridin-3-yl)urea 453.2 91 (R)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-methyl -1,5-naphthyridin-3-yl)urea 439.2 92 (R)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-methyl -1,5-naphthyridin-3-yl)urea HCI 439.2 93 (S)-N-(4-(1-Methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(2-methyl-6-(2H-1,2,3-triazole -2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 487.2 94 (S)-N-(5-Chloro-6-(difluoromethoxy)-2-methylpyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3- silt)urea 452.2 95 (S)-N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl) -6-methyl-1,5-naphthyridin-3-yl)urea 453.2 96 (S)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-methyl -1,5-naphthyridin-3-yl)urea 439.2 97 (S)-N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-methyl -1,5-naphthyridin-3-yl)urea HCI 439.2 98 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyanopyridin-3-yl)urea 353.9

[0258]

[Table 1-8]

99 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazol-2- yl)-5-(trifluoromethyl)pyridin-3-yl)urea HCOOH 464.1 100 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-chloro-6-(2H-1,2,3- triazol-2-yl)pyridin-3-yl)urea HCOOH 430.0 101 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyano-6-(2H-1,2,3- triazol-2-yl)pyridin-3-yl)urea HCOOH 421.1 102 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(3-cyano-1-methyl-1H-pyrazol-5-yl )urea HCOOH 357.0 103 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5 -yl)urea HCOOH 400.0 104 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(3,4-dicyanophenyl)urea 378.1 105 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyano-6-methoxypyridin-3-yl)urea 384.0 106 N-(5-Chloro-6-methoxypyridin-3-yl)-N'-(2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)urea 395.1 107 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(3-(difluoromethoxy)-1-methyl-1H-pyrazol-5 -yl)urea 398.0 108 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(1-(difluoromethyl)-1H-pyrazol-4-yl)urea 368.0 109 N-(5-Chloro-6-cyanopyridin-3-yl)-N'-(2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)urea 388.0 110 N-(8-Chloroimidazo[1,2-a]pyridin-6-yl)-N'-(2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl )urea 404.0 111 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(6-cyano-5-(trifluoromethyl)pyridin-3-yl) urea 422.0 112 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(6-cyano-5-(trifluoromethyl)pyridin-3-yl) urea 422.0

[0259]

[Table 1-9]

113 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5 -yl)urea 382.0 114 N-(3-Chloro-1-methyl-1H-pyrazol-5-yl)-N'-(2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl )urea 366.0 115 N-(2-Chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4 -yl)urea 384.0 116 N-(2-Methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazol-2- yl)-5-(trifluoromethyl)pyridin-3-yl)urea 446.0 117 N-(6-Chloro-5-(trifluoromethyl)pyridin-3-yl)-N'-(2-methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl) urea 413.1 118 N-(2-Methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(6-(1-methyl-1H-pyrazol-4-yl) -5-(trifluoromethyl)pyridin-3-yl)urea 459.1 119 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl) urea 410.9 120 N-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-N'-(2-methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl) urea 404.2 121 N-(3-Chloro-4-methoxyphenyl)-N'-(2-methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)urea 374.1 122 N-(2-methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(2-(trifluoromethyl)pyridin-4-yl)urea 379.2 123 N-(3-Chloro-4-(trifluoromethoxy)phenyl)-N'-(2-methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)urea 427.9 124 N-(3-Chloro-4-(difluoromethoxy)phenyl)-N'-(2-methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)urea 409.9 125 N-(5-Chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-N'-(2-methyl-8-(propan-2-yl)imidazo[1, 2-b]pyridazin-7-yl)urea 425.0 126 N-(3-Chloro-4-(1H-1,2,4-triazol-1-yl)phenyl)-N'-(2-methyl-8-(propan-2-yl)imidazo[1,2- b]pyridazin-7-yl)urea 411.0

[0260]

[Table 1-10]

127 N-(5-Cyano-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl) urea 402.0 128 N-(2-Chloro-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(3,4-dicyanophenyl)urea 394.0 129 N-(2-Chloro-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyanopyridin-3-yl)urea 370.0 130 N-(2-Chloro-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyano-6-methoxypyridin-3-yl)urea 400.0 131 N-(2-Chloro-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyano-6-(2H-1,2,3-triazol- 2-yl)pyridin-3-yl)urea 437.1 132 N-(2-Chloro-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl )urea 415.9 133 N-(2-Chloro-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-chloro-6-(2H-1,2,3-triazol- 2-yl)pyridin-3-yl)urea 447.9 134 N-(2-Chloro-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl) -5-(trifluoromethyl)pyridin-3-yl)urea 479.9 135 N-(2-Chloro-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl) -5-(trifluoromethyl)pyridin-3-yl)urea 479.9 136 N-(2-Chloro-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl) -5-(trifluoromethyl)pyridin-3-yl)urea 479.9 137 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-chloro-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)urea 444.9 138 N-(2-Bromo-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyanopyridin-3-yl)urea 414.0 139 N-(5-Cyanopyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-phenylimidazo[1,2-b]pyridazin-7-yl)urea 414.1 140 N-(5-Cyanopyridin-3-yl)-N'-(2-cyclopropyl-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)urea 378.1

[0261]

[Table 1-11]

141 N-(5-Cyanopyridin-3-yl)-N'-(2-methoxy-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)urea 366.0 142 N-(2-Cyano-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyanopyridin-3-yl)urea 361.1 143 N-(5-Chloro-6-methoxypyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-7-yl)urea 445.1 144 N-(5-Chloro-6-methoxypyridin-3-yl)-N'-(2-(difluoromethyl)-8-(1-methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)urea 427.2 145 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(2-(difluoromethyl)-8-(1-methoxyethyl)imidazo[ 1,2-b]pyridazin-7-yl)urea 464.1 146 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(2-(difluoromethyl)-8-(1-methoxyethyl)imidazo[ 1,2-b]pyridazin-7-yl)urea 464.1 147 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(3-fluoro-8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea 445.1 148 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(3-fluoro-8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea 445.1 149 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(3-fluoro-8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea 445.1 150 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(2-methoxypropan-2-yl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea 441.1 151 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)imidazo[1,2-b] pyridazin-7-yl)urea 413.9 152 N-(8-(1-Methoxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-( trifluoromethyl)pyridin-3-yl)urea 447.9 153 N-(8-(2-Chlorophenyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(2,4-difluorophenyl)urea 400.1 154 N-(8-(2-Chlorophenyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(2,4-difluorophenyl)urea HCI 400.1

[0262]

[Table 1-12]

155 N-(3-Chloro-8-(2-chlorophenyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(2,4-difluorophenyl)urea 434.0 156 N-(2-Chloro-8-(dimethylamino)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyanopyridin-3-yl)urea 355.0 157 N-(2-Chloro-8-cyclopropylimidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyanopyridin-3-yl)urea 351.9 158 N-(2-Chloro-8-ethylimidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyanopyridin-3-yl)urea 339.9 159 N-(8-(Butan-2-yl)-2-chloroimidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyanopyridin-3-yl)urea 367.9 160 N-(8-(Butan-2-yl)-2-chloroimidazo[1,2-b]pyridazin-7-yl)-N'-(5-chloro-6-(1H-1,2,3-triazole -1-yl)pyridin-3-yl)urea 444.0 161 N-(8-(Butan-2-yl)-2-chloroimidazo[1,2-b]pyridazin-7-yl)-N'-(5-chloro-6-(2H-1,2,3-triazole -2-yl)pyridin-3-yl)urea 444.0 162 N-(8-(Butan-2-yl)-2-chloroimidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea 478.1 163 N-(8-(Butan-2-yl)-2-chloroimidazo[1,2-b]pyridazin-7-yl)-N'-(6-(1H-1,2,3-triazol-1-yl )-5-(trifluoromethyl)pyridin-3-yl)urea 478.1 164 N-(8-(Butan-2-yl)-2-chloroimidazo[1,2-b]pyridazin-7-yl)-N'-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5- silt)urea 414.0 165 N-(8-(Butan-2-yl)-2-chloroimidazo[1,2-b]pyridazin-7-yl)-N'-(3-cyano-1-methyl-1H-pyrazol-5-yl) urea 373.1 166 N-(8-(Butan-2-yl)-2-chloroimidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyano-6-(2H-1,2,3-triazole -2-yl)pyridin-3-yl)urea 435.0 167 N-(8-(Butan-2-yl)-2-chloroimidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyano-6-(2H-1,2,3-triazole -2-yl)pyridin-3-yl)urea 435.1 168 N-(8-(Butan-2-yl)-2-chloroimidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyano-6-(2H-1,2,3-triazole -2-yl)pyridin-3-yl)urea 435.1

[0263]

[Table 1-13]

169 N-(8-(Butan-2-yl)-2-chloroimidazo[1,2-b]pyridazin-7-yl)-N'-(3-(difluoromethoxy)-1-methyl-1H-pyrazol-5- silt)urea 412.1 170 N-(8-(Butan-2-yl)-2-chloroimidazo[1,2-b]pyridazin-7-yl)-N'-(3-chloro-1-methyl-1H-pyrazol-5-yl) urea 380.1 171 N-(2-Chloro-8-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyanopyridin-3-yl)urea 408.0 172 N-(2-Chloro-8-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(3-cyano-1-methyl-1H -pyrazol-5-yl)urea 411.1 173 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-chloro-8-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b] pyridazin-7-yl)urea 483.0 174 N-(2-Chloro-8-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2, 3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 518.1 175 N-(2-Chloro-8-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyano-6-(2H- 1,2,3-triazol-2-yl)pyridin-3-yl)urea 475.1 176 N-(5-Chloro-6-methoxypyridin-3-yl)-N'-(2-chloro-8-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazin-7 -yl)urea 447.0 177 N-(2-Chloro-8-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(1-methyl-3-(trifluoromethyl) -1H-pyrazol-5-yl)urea 454.0 178 N-(2-Chloro-8-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(3-(difluoromethoxy)-1-methyl -1H-pyrazol-5-yl)urea 452.0 179 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(2-chloro-8-(1,1,1-trifluoropropan- 2-yl)imidazo[1,2-b]pyridazin-7-yl)urea 484.0 180 N-(3-Chloro-1-methyl-1H-pyrazol-5-yl)-N'-(2-chloro-8-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b ]pyridazin-7-yl)urea 419.9 181 N-(2-Chloro-8-(1-hydroxyethyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(2,4-difluorophenyl)urea 368.0 182 N-(2-Chloro-8-(1-methoxypropan-2-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyanopyridin-3-yl)urea HCOOH 384.0

[0264]

[Table 1-14]

183 N-(2-Chloro-8-(3-chloro-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyanopyridin-3 -yl)urea HCOOH 428.1 184 N-(2-Chloro-8-(3-chloro-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-cyano-6 -methoxypyridin-3-yl)urea 458.0 185 N-(2-Chloro-8-(3-chloro-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-7-yl)-N'-(5-chloro-6 -methoxypyridin-3-yl)urea 466.9 186 N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N'-(8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl)urea 366.0 187 N-(6-Methoxy-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea 425.1 188 N-(6-Methoxy-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5- (trifluoromethyl)pyridin-3-yl)urea 489.1 189 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(6-methoxy-4-(1-methoxyethyl)-1,5 -naphthyridin-3-yl)urea 455.1 190 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(6-methoxy-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)urea 454.0 191 N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(6-methoxy-4-(1-methoxyethyl)-1,5 -naphthyridin-3-yl)urea 446.2 192 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-(trifluoromethyl)-1,5-naphthyridin-3-yl)urea 490.1 193 N-(4-(1-Methoxyethyl)-6-(trifluoromethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)- 5-(trifluoromethyl)pyridin-3-yl)urea 525.1 194 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-(trifluoromethyl)-1 ,5-naphthyridin-3-yl)urea 491.1 195 N-(4-(1-Methoxyethyl)-6-(trifluoromethyl)-1,5-naphthyridin-3-yl)-N'-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl) urea 461.1 196 N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-(trifluoromethyl)-1 ,5-naphthyridin-3-yl)urea 482.1

[0265]

[Table 1-15]

197 N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-(trifluoromethyl)-1 ,5-naphthyridin-3-yl)urea 484.1 198 N-(5-Cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-(trifluoromethyl)-1 ,5-naphthyridin-3-yl)urea 484.1 199 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)urea 424.1 200 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-1,5-naphthyridin-3 -yl)urea 425.1 201 N-(4-(1-Methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridine -3-yl)urea 459.2 202 N-(6-Chloro-4-(1-ethoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5- (trifluoromethyl)pyridin-3-yl)urea 506.8 203 N-(6-(Difluoromethyl)-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)- 5-(trifluoromethyl)pyridin-3-yl)urea 509.2 204 N-(6-Ethyl-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5- (trifluoromethyl)pyridin-3-yl)urea 487.2 205 N-(6-Ethyl-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5- (trifluoromethyl)pyridin-3-yl)urea 487.2 206 N-(6-Chloro-4-(2-methoxypropan-2-yl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea 507.2 207 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)- 5-(trifluoromethyl)pyridin-3-yl)urea 476.9 208 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(3-(1,1-difluoroethyl)-1-methyl-1H-pyrazol- 5-yl)urea 409.2 209 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(3-methyl-1-(2,2,2-trifluoroethyl)-1H- pyrazol-5-yl)urea 427.1 210 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(5-(difluoromethyl)-6-methoxypyridin-3-yl)urea 422.1

[0266]

[Table 1-16]

211 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(1-(propan-2-yl)-3-(trifluoromethyl)-1H- pyrazol-5-yl)urea 441.1 212 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(3,3-difluorocyclohexyl)urea 383.2 213 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(3-(trifluoromethyl)cyclohexyl)urea 415.1 214 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-6-(2H-1,2,3-triazol-2 -yl)pyridin-3-yl)urea 443.1 215 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(2-(trifluoromethyl)pyridin-4-yl)urea 409.9 216 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(2-cyanopyridin-4-yl)urea 366.9 217 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(6-chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)urea 441.9 218 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(5-(trifluoromethyl)pyridin-3-yl)urea 409.9 219 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)urea 439.9 220 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(5-cyanopyridin-3-yl)urea 366.9 221 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3 -yl)urea 473.8 222 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(2-(difluoromethyl)pyridin-4-yl)urea 390.1 223 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(2-(difluoromethoxy)pyridin-4-yl)urea 408.1 224 N-(5-Chloro-6-(difluoromethyl)pyridin-3-yl)-N'-(6-chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)urea 426.1

[0267]

[Table 1-17]

225 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(2-cyano-5-methylpyridin-4-yl)urea 380.9 226 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(2-cyano-6-methylpyridin-4-yl)urea 380.9 227 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(2-cyano-3-methylpyridin-4-yl)urea 380.9 228 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(5-methyl-2-(trifluoromethyl)pyridin-4-yl)urea 424.1 229 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(2-methyl-5-(trifluoromethyl)pyridin-3-yl)urea 424.0 230 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(6-(1H-terazol-5-yl)-5-(trifluoromethyl)pyridine -3-yl)urea 477.9 231 N-(5-Bromo-2-(trifluoromethyl)pyridin-4-yl)-N'-(6-chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)urea 487.7 232 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(5-fluoro-2-(trifluoromethyl)pyridin-4-yl)urea 427.9 233 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)urea 443.9 234 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(2-methyl-6-(2H-1,2,3-triazol-2 -yl)-5-(trifluoromethyl)pyridin-3-yl)urea 490.9 235 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(5-chloro-6-(pyrimidin-2-yl)pyridin-3-yl )urea 453.9 236 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(6-(1-methyl-1H-tetrazol-5-yl)-5- (trifluoromethyl)pyridin-3-yl)urea 491.9 237 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'(6-(2-methyl-2H-tetrazol-5-yl)-5-( trifluoromethyl)pyridin-3-yl)urea 491.9 238 N-(5-Chloro-6-(difluoromethoxy)-2-methylpyridin-3-yl)-N'-(6-chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl) urea 454.1

[0268]

[Table 1-18]

239 N-(5-Chloro-2-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(6-chloro-4-(propan-2- yl)-1,5-naphthyridin-3-yl)urea 457.1 240 N-(6-Chloro-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)urea 438.1 241 N-(4-(Propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl )pyridin-3-yl)urea 443.2 242 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(propan-2-yl)-1,5-naphthyridine -3-yl)urea 409.1 243 N-(6-Methyl-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)- 5-(trifluoromethyl)pyridin-3-yl)urea 456.9 244 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(6-methyl-4-(propan-2-yl)-1 ,5-naphthyridin-3-yl)urea 422.9 245 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(6-methyl-4-(propan-2-yl)-1,5-naphthyridin-3-yl)urea 422.0 246 N-(2-Cyano-5-methylpyridin-4-yl)-N'-(6-methyl-4-(propan-2-yl)-1,5-naphthyridin-3-yl)urea 361.1 247 N-(6-(2,2-Difluoroethoxy)-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazole -2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 522.9 248 N-(6-(Difluoromethoxy)-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea 508.9 249 N-(6-(Methoxymethyl)-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea 487.1 250 N-(6-{((4-Methoxyphenyl)methoxy)methyl}-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2 ,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 593.2 251 N-(6-(Hydroxymethyl)-4-(propan-2-yl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea 473.2 252 N-(4-(2-Chlorophenyl)-1,5-naphthyridin-3-yl)-N'-(2,4-difluorophenyl)urea 411.1

[0269]

[Table 1-19]

253 N-(2-Chloro-8-(2-chlorophenyl)imidazo[1,2-b]pyridazin-7-yl)-N'-(2,4-difluorophenyl)urea 434.0 254 N-(4-(2-Chlorophenyl)-1,6-naphthyridin-3-yl)-N'-(2,4-difluorophenyl)urea 411.1 255 N-(5-Methoxy-4-(1-methoxyethyl)-1,6-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5- (trifluoromethyl)pyridin-3-yl)urea 487.1 256 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(5-methoxy-4-(1-methoxyethyl)-1,6 -naphthyridin-3-yl)urea 453.1 257 N-(5-Cyanopyridin-3-yl)-N'-(5-methoxy-4-(1-methoxyethyl)-1,6-naphthyridin-3-yl)urea 377.1 258 N-(5-Chloro-4-(1-methoxyethyl)-1,6-naphthyridin-3-yl)-N'-(5-chloro-6-(2H-1,2,3-triazol-2-yl )pyridin-3-yl)urea 457.0 259 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(5-methyl-4-(propan-2-yl)-1,6-naphthyridin-3-yl)urea 422.2 260 N-(5-Chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-5-methyl-1,6-naphthyridin-3-yl)urea 438.1 261 N-(4-(1-Methoxyethyl)-5-methyl-1,6-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5- (trifluoromethyl)pyridin-3-yl)urea 473.2 262 N-(4-(1-Methoxyethyl)-5-methyl-1,6-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5- (trifluoromethyl)pyridin-3-yl)urea 473.2 263 N-(4-(1-Methoxyethyl)-5-methyl-1,6-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5- (trifluoromethyl)pyridin-3-yl)urea 473.2 264 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-5-methyl-1,6 -naphthyridin-3-yl)urea 439.1 265 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-5-methyl-1,6 -naphthyridin-3-yl)urea 439.1 266 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-5-methyl-1,6 -naphthyridin-3-yl)urea 439.1

[0270]

[Table 1-20]

267 N-(5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(4-(1-methoxyethyl)-5-methyl-6-oxo -5,6-dihydro-1,5-naphthyridin-3-yl)urea 455.2 268 N-(4-(1-Methoxyethyl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3 -triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 489.2 269 N-(4-(1-Methoxyethyl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3 -triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea 489.2 270 N-(5-Chloro-6-methoxypyridin-3-yl)-N'-(4-(1-methoxyethyl)-6-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3- silt)urea 418.0

[0271]

Receiving example 1 (receiving capsules)

1) Connection of Example 1 30 mg 2) Fine powdered cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60 mg

1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0272]

Receipt example 2 (receipt of tablets)

1) Connection of Example 1 30 g 2) Lactose 50 g 3) Corn starch 15 g 4) Calcium carboxymethylcellulose 44 g 5) Magnesium stearate 1 g 1000 tablets Total quantity

All quantities of 1), 2), and 3), and 30 g of 4) are mixed with water and dried under vacuum, followed by granulation. 14 g 4) and 1 g 5) are mixed with this grain size powder followed by tableting using a tablet machine. In this way, 1000 tablets are obtained containing 30 mg of the compound of Example 1 per tablet.

[0273]

Case study 1

Preparation of recombinant human MALT1 protein

For the human MALT1 gene, PCR was performed using GC-030-D09 (pENTR221/MALT1, GeneCopoeia) as a template with primers containing the BamH I restriction enzyme at the N-terminus and the Not I restriction enzyme at the C-terminus to form a MALT1 dimer (340 -789aa) person. For the yeast leucine zipper gene GCN4, PCR was performed using yeast DNA as a template with primers containing the Nde I restriction enzyme at the N-terminus and the linker sequence (GGAAGTGGCTCAGGTAGC (SEQ ID NO: 1)), and the BamH I restriction enzyme at the C-terminus. end to produce yeast GCN4 (251-281aa). Both resulting fragments were treated with restriction enzymes and inserted between Nde I and Not I of vector pET28a (Novagen) to obtain the recombinant human MALT1 protein expression vector pET28a/His-LZ-hMALT1v1 (340-789)-His.

Recombinant human MALT1 protein was produced by transforming the expression plasmid obtained as described above with ECOS Competent E. coli BL21 (DE3) (Nippon Gene Co., Ltd.). Escherichia coli obtained by transformation was inoculated into 300 ml of LB medium (1% tryptone, 0.5% yeast extract, 0.5% sodium chloride, 0.01% ampicillin) and cultured at 30°C for 16 hours. The resulting culture solution was transferred to a culture vessel containing 6 L of basic fermentation medium (0.3% potassium dihydrogen phosphate, 0.6% disodium hydrogen phosphate, 0.1% ammonium chloride, 0.05% sodium chloride, 0.024% magnesium sulfate, 0. .01% PE-L defoamer, 1.5% sorbitol, 1.5% casamino acid, 0.5% yeast extract and 0.01% ampicillin), and cultivation was started at 37°C, aeration rate 5 l/min and mixer rotation speed 400 rpm. When the turbidity of the culture solution reached approximately 500 Klett units, the culture temperature was reduced to 16°C and then isopropyl-β-D-thiogalactopyranoside (IPTG) was added to a final concentration of 0.1 mM. In addition, culture was carried out for 16 hours to induce the expression of human MALT1 protein. After completion of cultivation, the culture solution was centrifuged at 5000 rpm for 10 minutes. After suspending the resulting Escherichia coli expressing human MALT1 protein 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, sonication was performed using Sonifier (Branson). This ground liquid was centrifuged (15300×G, 30 min, TOMY MX-301) and the resulting supernatant was passed and adsorbed onto a Ni-NTA Superflow column (QIAGEN) pre-equilibrated with 50 mM Tris-HCl pH 8.0, 300 mM NaCl.5 mM DTT and 10% glycerol, followed by elution in a buffer containing 50 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 10% glycerol and 250 mM imidazole. In addition, gel filtration was performed on a Superdex 200 pg column, pre-equilibrated with a buffer solution containing 50 mM Tris-HCl pH 8.0, 150 mM NaCl, 5 mM DTT and 10% glycerol to collect the target fraction and equal amounts of 50 mM Tris-HCl pH 8.0, 150 mM NaCl, 5 mM DTT, and 90% glycerol were added to obtain purified human MALT1 protein. The resulting protein was stored at -30°C and the protein concentration was measured using a BCA protein assay kit (PIERCE) using BSA as a standard.

[0274]

Measurement of MALT1 enzyme inhibitory activity

To a 384-well black plate (Greiner), 2 μl of a compound solution diluted in assay buffer (20 mM HEPES (Dojin Laboratories), 10 mM KCl (Wako Pure Chemical Industries, Ltd.), 1.5 mM MgCl ₂ (Sigma- Aldrich), 1 mM EDTA (pH 8.0) (Nippon Gene Co., Ltd.), 0.01% Triton X-100 (Sigma-Aldrich), and 1 mM DTT (Wako Pure Chemical Industries, Ltd.)). Subsequently, 2 μL of purified recombinant human MALT1 enzyme solution was added, followed by incubation for 60 minutes at room temperature. 2 μL of substrate solution (75 μM Ac-LRSR-AFC (SM Biochemicals), 20 mM HEPES (Dojin Laboratories), 10 mM KCl (Wako Pure Chemical Industries, Ltd.), 1.5 mM MgCl ₂ (Sigma-Aldrich), 1 mM EDTA (pH 8.0) (Nippon Gene Co., Ltd.), 0.01% Triton X- 100 (Sigma-Aldrich) and 1 mM DTT (Wako Pure Chemical Industries, Ltd.) followed by incubation for 60 minutes at room temperature.The excitation fluorescence values of 400 nm and emission 485 nm immediately after the addition of the substrate and after the enzymatic reaction were measured using Envision plate reader (PerkinElmer), and the fluorescence values increased by the enzymatic reaction were used to calculate the degree of inhibition (%). The degree of inhibition (%) was calculated relative to the value without adding enzyme as 100% and the value without adding compound as 0%.

The results of measuring the inhibitory activity against the MALT1 enzyme are shown below.

[0275]

[Table 2]

Example No. The degree of MALT1 enzyme inhibition (%) at 3 μM compound 1 104 2 99 3 101 4 111 5 99 6 108 7 98 8 94 9 99 22 104 31 103 35 105 36 101 59 95 66 99 133 99 173 99 255 97 261 98 269 99 270 94

[0276]

Based on these results, it was shown that the compound of the present invention has MALT1 enzyme inhibitory activity.

[0277]

Case Study 2

Measurement of growth inhibitory activity using OCI-Ly3 cells

OCI-Ly3 cells were seeded in IMDM cell culture medium (Fujifilm Wako Pure Chemical Corporation) containing 20% FBS (fetal bovine serum, Thermo Fisher Scientific) and monothioglycerol (Fujifilm Wako Pure Chemical Corporation) to yield 1.25 × 10 ³ cells/well in a 96-well plate. Cell Titer-Glo solution (Promega) was added to cells to which no test compound had been added, followed by stirring at room temperature for 15 minutes. The luminescence value was subsequently measured using Envision (PerkinElmer) on the day of sowing. Cells to which the test compound was added dissolved in dimethyl sulfoxide (Fujifilm Wako Pure Chemical Corporation) were allowed to stand in a CO ₂ incubator (37°C) for 6 days. Subsequently, the luminescence value was measured in the same way. The degree of inhibition (%) of the test compound on OCI-Ly3 cell growth was calculated using the following formula.

Degree of cell growth inhibition (%) = (1 - (Luminescent value on day 6 of treatment with test compound - Luminescent value before treatment with test compound)/(Luminescent value on day 6 without addition of compound - Luminescent value before treatment with test compound)) × 100

The results of measuring the degree of cell growth inhibition are shown below.

[0278]

[Table 3]

Example No. Degree of cell growth inhibition (%) at 3 µM compound 1 96 2 97 3 99 4 97 5 93 6 99 7 95 9 99 22 102 31 96 35 95 36 96 59 98 66 100 133 98 173 85 255 99 261 88 269 95 270 40

[0279]

Based on these results, it was shown that the compound of the present invention inhibits cell growth.

[0280]

Case Study 3

Antitumor effect in a cancer model bearing OCI-Ly3 cells

Human diffuse large B-cell lymphoma OCI-Ly3 cells (DSMZ, German Collection of Microorganisms and Cell Cultures) were suspended in Matrigel (BD Biosciences):HBSS (Thermo Fisher Scientific) = 1:1 solution and 1 × 10 ⁷ cells were transplanted subcutaneously into the peritoneal cavity of female NOG mice (CLEA Japan, Inc.). The diameter of the grafted tumor was measured and the tumor volume was calculated using the following formula.

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

Objects with a grafted tumor having a tumor volume of approximately 120 mm ³ were selected, and 6 animals per group were used in the experiment. A suspension of the test compound in 0.5% methylcellulose solution (Fujifilm Wako Pure Chemical Corporation) was administered orally at a dose of 10 mg/kg (10 ml/kg) twice daily for 3 weeks. Tumor volume was measured the day before the start of administration and every 3-4 days over time, and tumor diameter was finally measured the day after the end of administration for 21 days to calculate tumor volume. Tumor growth in the test compound-administered group compared with the control compound-administered group was calculated using the following formula as the average tumor volume increase ratio T/C.

T/C = ((Tumor volume at the end of administration for the test compound group - Tumor volume on the day before the start of administration for the test compound group)/(Tumor volume at the end of administration for the control compound group - Volume tumors the day before the start of administration for the group that received the control compound)) × 100

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

[0281]

[Table 4]

Example No. Dose (mg/kg) T/C (%) 1 10 13.4 2 10 2.0 3 10 38.7 4 10 43.3

[0282]

Based on these results, the compound of the present invention was shown to have an antitumor effect in subcutaneously transplanted human OCI-Ly3 diffuse large B-cell lymphoma cell models.

INDUSTRIAL APPLICABILITY

[0283]

The compound of the present invention may have the effect of inhibiting MALT1, and is expected to be useful as a prophylactic or therapeutic agent for the treatment of cancer, etc.

This application is based on Japanese Patent Application No. 2018-222530 filed in Japan, the contents of which are incorporated herein by reference in their entirety.

--->

LIST OF SEQUENCES

<110> Takeda Pharmaceutical Company Limited

<120> HETEROCYCLIC COMPOUND

<130> 092968

<150> JP2018-222530

<151> 2018-11-28

<160> 1

<170> PatentIn version 3.5

<210> 1

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> linker sequence

<400> 1

ggaagtggct caggtagc

<---

Claims (42)

1. The compound represented by formula (I) in which A represents R ₁ represents 1) a hydrogen atom, 2) a halogen atom, 3) a cyano group, 4) a C _1-3 alkyl group, which may be substituted by 1 to 3 halogen atoms, 5) a C _1-3 alkoxy group, 6) C _{3 -6} cycloalkyl group or 7) phenyl group; R ₂ represents 1) a hydrogen atom or 2) a halogen atom; R ₃ represents 1) a C _1-6 alkyl group, which may be substituted with 1 to 3 substituents selected from a C _1-3 alkoxy group, a hydroxyl group and a halogen atom, 2) a pyrazolyl group, which may be substituted with 1 to 3 substituents selected from a C _1-3 alkyl group and a halogen atom, 3) a C _3-6 cycloalkyl group, 4) an amino group disubstituted with a C _1-3 alkyl group, or 5) a phenyl group, which may be substituted by 1 to 3 atoms halogen; R ₄ and R ₆ represent 1) a hydrogen atom, 2) a halogen atom, 3) a C _1-3 alkyl group which may be substituted by 1 to 3 substituents selected from a) a hydroxyl group, b) a C _1-3 alkoxy group , which may be substituted by a 4-methoxyphenyl group and c) a halogen atom or 4) a C _1-3 alkoxy group, which may be substituted by 1 to 3 halogen atoms; R ₅ , R ₇ and R ₉ represent 1) a C _1-6 alkyl group, which may be substituted by 1 to 3 C _1-3 alkoxy groups, or 2) a phenyl group, which may be substituted by 1 to 3 halogen atoms; R ₈ represents a C _1-3 alkyl group; And B represents 1) a phenyl group which may be substituted by 1 to 3 substituents selected from a) a halogen atom, b) a cyano group, c) a C _1-3 alkoxy group which may be substituted by 1 to 3 halogen atoms, and d) a triazolyl group , 2) a C _3-6 cycloalkyl group, which may be substituted by 1 to 3 substituents selected from a) a C _1-3 alkyl group, which may be substituted by 1 to 3 halogen atoms, and b) a halogen atom, 3) a pyridyl group, which may be substituted by 1 to 3 substituents selected from a) a halogen atom, b) a cyano group, c) a C _1-3 alkyl group, which may be substituted by 1 to 3 halogen atoms, d) C _{1 -3} alkoxy group, which may be substituted by 1 to 3 substituents selected from a halogen atom and a C _1-3 alkoxy group, e) a pyrazolyl group, which may be substituted by 1 to 3 C _1-3 alkyl groups, f) an imidazolyl group, which may be substituted with 1 to 3 C _1-3 alkyl groups, g) a triazolyl group, which may be substituted with 1 to 3 C _1-3 alkyl groups, which may be substituted with 1 to 3 substituents selected from C _{1- 3} alkoxy groups and halogen atoms, h) an azetidinyl group, i) a pyrrolidonyl group, j) a tetrazolyl group, which may be substituted with 1 to 3 C _1-3 alkyl groups, k) a pyrimidinyl group and l) an oxazolyl group, 4) a pyrazolyl group, which may be substituted by 1 to 3 substituents selected from a) a C _1-3 alkyl group, which may be substituted by 1 to 3 halogen atoms, b) a C _1-3 alkoxy group, which may be substituted by 1 to 3 halogen atoms, c) a cyano group and d) a halogen atom, or 5) an imidazopyridyl group, which may be substituted by 1 to 3 halogen atoms, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein A is 3. The compound according to claim 1, wherein A is 4. The compound according to claim 1, wherein A is R ₁ represents 1) a halogen atom or 2) a C _1-3 alkyl group; R ₂ represents a hydrogen atom; R ₃ represents a C _1-6 alkyl group, which may be substituted by 1 to 3 C _1-3 alkoxy groups; R ₄ represents 1) a halogen atom or 2) a C _1-3 alkyl group; R ₅ represents a C _1-6 alkyl group, which may be substituted by 1 to 3 C _1-3 alkoxy groups; And B represents a pyridyl group which may be substituted by 1 to 3 substituents selected from a) a halogen atom, b) a cyano group, c) a C _1-3 alkyl group which may be substituted by 1 to 3 halogen atoms, d) C _{1 to 3} alkoxy groups, which may be substituted by 1 to 3 halogen atoms, and e) a triazolyl group. 5. A compound according to claim 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, (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea, (S)-N-(4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl )-5-(trifluoromethyl)pyridin-3-yl)urea, (S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo [1,2-b]pyridazin-7-yl)urea, (S)-N-(5-cyano-6-(difluoromethoxy)pyridin-3-yl)-N'-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl )urea, (S)-N-(8-(1-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-7-yl)-N'-(6-(2H-1,2,3-triazole)- 2-yl)-5-(trifluoromethylpyridin-3-yl)urea, N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(8-(2-methoxypropan-2-yl)-2-methylimidazo [1,2-b]pyridazin-7-yl)urea, N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-N'-(2-chloro-8-(propan-2-yl)imidazo[1,2-b]pyridazin-7-yl) urea or N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-N'-(2-methyl-8-(propan-2-yl)imidazo[ 1,2-b]pyridazin-7-yl)urea. 6. A compound according to claim 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. The compound according to claim 1, which is (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1 ,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea. 8. A medicinal product containing a compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a MALT1 inhibitor. 9. A medicinal product containing a compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a prophylactic or therapeutic agent for the treatment of cancer caused by MALT1 activity.