Substituted benzene compound

A compound of the general formula (1a) or a pharmaceutically acceptable salt thereof:

• wherein
• A is a nitrogen atom,
• R1 is a halogen atom, a cyano group, a C1-C3 alkyl group optionally substituted with 1 to 3 fluorine atoms, or a C1-C3 alkoxy group optionally substituted with 1 to 3 fluorine atoms,
• R1′ is a hydrogen atom, a halogen atom, or a C1-C3 alkyl group, or
• R1 and R1′ are bonded to each other to form a C1-C4 alkylene group optionally substituted with 1 to 3 substituents selected from substituent group a′, thereby constituting a ring structure,
• R1″ is a hydrogen atom, or a halogen atom,
• R1′″ is a hydrogen atom, a halogen atom, a cyano group, or a methyl group,
• R2 and A are bonded to each other to form any partial structure selected from the group shown below:
• wherein the left end of the partial structure is a bond to R2, and the right end of the partial structure is a bond to A, and for convenience, the partial structure is shown as being substituted with R3, and optionally, the partial structure may be substituted with 1 to 3 substituents selected from substituent group a′,
• R2′ is a hydrogen atom, or a C1-C3 alkyl group, or
• R2′ and R2 are bonded to each other to form —NH—(CH2)n- (n is an integer of 1, 2 or 3), thereby constituting a ring structure,
• R3 is
• a C1-C3 alkyl group optionally substituted with 1 to 3 substituents selected from substituent group b′,
• a C3-C6 cycloalkyl group optionally substituted with 1 to 3 substituents selected from substituent group b′,
• a C5-C8 bicycloalkyl group optionally substituted with 1 to 3 substituents selected from substituent group b′,
• a C5-C8 azabicycloalkyl group optionally substituted with 1 to 3 substituents selected from substituent group b′,
• a C5-C8 oxabicycloalkyl group optionally substituted with 1 to 3 substituents selected from substituent group b′,
• a 3-6-membered nitrogen-containing saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b′, or
• a 5-6-membered nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b′,
• the substituent group a′ consists of
• a halogen atom, a cyano group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group optionally substituted with 1 to 3 fluorine atoms, a C1-C3 alkoxy group optionally substituted with 1 to 3 fluorine atoms, a C1-C4 alkylene group, a C2-C4 alkanediyl group (including a 1,3-butadiene-1,4-diyl group), a C1-C3 oxyalkylene group, and a cyclopropylacethylene group, and
• the substituent group b′ consists of
• a hydroxyl group, a halogen atom, a C1-C3 alkyl group, a hydroxy C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, and a 5-membered oxygen-containing saturated heterocyclic group.

A compound of the general formula (1b) or a pharmaceutically acceptable salt thereof:

• wherein
• R1 is a halogen atom, a C1-C3 alkyl group optionally substituted with 1 to 3 fluorine atoms, or a C1-C3 alkoxy group optionally substituted with 1 to 3 fluorine atoms,
• R2 and the nitrogen atom are bonded to each other to form any partial structure selected from the group shown below:
• wherein the left end of the partial structure is a bond to R2, and the right end of the partial structure is a bond to the nitrogen atom, and for convenience, the partial structure is shown as being substituted with R3, and optionally, the partial structure may be substituted with 1 to 3 substituents selected from substituent group a″,
• R3 is
• a C3-C6 cycloalkyl group optionally substituted with 1 to 3 substituents selected from substituent group b″,
• a C6-C7 bicycloalkyl group optionally substituted with 1 to 3 substituents selected from substituent group b″,
• a 3-6-membered nitrogen-containing saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b″, or
• a 5-6-membered nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b″,
• the substituent group a″ consists of
• a halogen atom, a cyano group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group optionally substituted with 1 to 3 fluorine atoms, a C1-C3 alkoxy group optionally substituted with 1 to 3 fluorine atoms, a C1-C4 alkylene group, and a C1-C3 oxyalkylene group, and
• the substituent group b″ consists of
• a hydroxyl group, a halogen atom, and a C1-C3 alkyl group.

A compound selected from the group consisting of:

• 3-methyl-2-{7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol,
• 3-methyl-2-{7-[(3R)-1-methylpiperidin-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol,
• 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,
• 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,
• 2-{5-fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,
• 5-chloro-2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol,
• 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,
• 2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,
• 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,
• 2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,
• 5-(difluoromethoxy)-2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol,
• 2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethoxy) phenol,
• 5-{3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol,
• 5-chloro-2-{5-fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol,
• 5-chloro-2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol,
• 5-chloro-2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol,
• 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-6H-furo[2′,3′:
• 4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,
• 7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine-5-carbonitrile,
• 2-[7-(5-fluoropyrimidin-2-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol,
• 2-[(4bR,7aR)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2′,3′:
• 4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol,
• 2-[(4bS,7aS)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2′,3′:
• 4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol,
• 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-5H-furo[3′,4′:
• 4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol;
• and
• pharmaceutically acceptable salts thereof.

A compound selected from the group consisting of:

• 2-{5-Fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,
• 2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,
• 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-6H-furo[2′,3′:
• 4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,
• 2-[(4bR,7aR)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2′,3′:
• 4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol,
• 2-[(4bS,7aS)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2′,3′:
• 4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol,
• 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-5H-furo[3′,4′:
• 4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, and
• or a pharmaceutically acceptable salt pharmaceutically acceptable salts thereof.

A compound of the general formula (1c) or a pharmaceutically acceptable salt thereof:

• wherein
• A is a single bond, or a carbon atom,
• R1 is a halogen atom, a C1-C3 alkyl group optionally substituted with 1 to 3 fluorine atoms, or a C1-C3 alkoxy group optionally substituted with 1 to 3 fluorine atoms,
• R2 is a hydrogen atom, or a C1-C3 alkyl group optionally substituted with 1 to 3 substituents selected from substituent group c, or
• R2 and A are bonded to each other to form any partial structure selected from the group shown below:
• wherein the left end of the partial structure is a bond to R2, and the right end of the partial structure is a bond to A, and for convenience, the partial structure is shown as being substituted with R3, and optionally, the partial structure may be substituted with 1 to 3 substituents selected from substituent group c,
• R3 is
• a C3-C6 cycloalkyl group optionally substituted with 1 to 3 substituents selected from substituent group d,
• a C6-C7 bicycloalkyl group optionally substituted with 1 to 3 substituents selected from substituent group d, or
• a 3-6-membered nitrogen-containing saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group d,
• the substituent group c consists of
• a halogen atom, a C1-C3 alkyl group optionally substituted with 1 to 3 fluorine atoms, a C1-C3 alkoxy group optionally substituted with 1 to 3 fluorine atoms, a C1-C4 alkylene group, and a C1-C3 oxyalkylene group, and
• the substituent group d consists of
• a hydroxyl group, and a C1-C3 alkyl group.

A compound selected from the group consisting of:

• 3-methyl-2-{6-[(1-methylpiperidin-3-yl)methyl]pyridazin-3-yl}-5-(trifluoromethyl)phenol,
• 3-methyl-2-[5-methyl-7-(1-methylpiperidin-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol,
• 3-methyl-2-[7-(1-methylpiperidin-3-yl) thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol,
• 3-methyl-2-{8-[(3R)-1-methylpiperidin-3-yl]cinnolin-3-yl}-5-(trifluoromethyl)phenol,
• 2-{8-[(3R)-1-ethylpiperidin-3-yl]cinnolin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, and
• pharmaceutically acceptable salts thereof.

The method according to claim 41, wherein the autoinflammatory disease, autoimmune disease, and/or inflammatory disease is a disease selected from the diseases listed below:

• cryopyrin-associated periodic syndrome (CAPS), systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriasis, systemic scleroderma (SSc), vasculitis syndrome, systemic amyloidosis, alcoholic liver disease (ALD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), viral hepatitis, non-alcoholic fatty liver disease (NAFLD), chronic obstructive pulmonary diseases (COPD), asthma, acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis, diabetic nephropathy, lupus nephritis, primary hyperoxaluria, interstitial cystitis, inflammatory bowel disease (IBD), gout, pseudogout, osteoarthritis, atherosclerosis, diabetes type 1/type 2, heart failure, SARS-COV-2 infection, EBV infection, viral encephalitis, glaucoma, optic neuritis, age-related macular degeneration, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colorectal cancer, tumor lysis syndrome, multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, frontotemporal dementia, epilepsy, major depressive disorder, schizophrenia, insomnia, autism spectrum disorder, bipolar disorder, panic disorder, anxiety disorder, phobia, obsessive-compulsive disorder, posttraumatic stress disorder (PTSD), postoperative delirium, substance related disorder, eating disorder, ischemic stroke, hemorrhagic stroke, and traumatic brain injury.