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US 8,273,741 B2Granted
Imidazo-pyridazinyl compounds and uses thereof
AssigneeTakeda Pharmaceutical Company Limited
InventorsNozomu Sakai, Shinichi Imamura, Naoki Miyamoto, Takaharu Hirayama
Life of this patent
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Abstract
The present invention provides a fused heterocyclic derivative having a potent kinase inhibitory activity and use thereof. A compound represented by the formula (I): wherein each symbol is as defined in the specification, except a particular compound, or a salt thereof, and a pharmaceutical agent containing the compound or a prodrug thereof, which is a kinase (VEGFR, VEGFR2, PDGFR, Raf) inhibitor, an angiogenesis inhibitor, an agent for the prophylaxis or treatment of cancer, a cancer growth inhibitor or a cancer metastasis suppressor.
Claims23
A compound represented by the formula (II):
- wherein
- ring Ya is
- (1) C6-10 aryl optionally substituted by 1 to 3 substituents selected from
- (a) a halogen atom,
- (b) C1-4 alkyl,
- (c) C1-4 alkoxy,
- (d) amino optionally substituted by the substituents selected from
- (i) C1-4 alkyl optionally substituted by a 5-membered aromatic heterocyclic group optionally substituted by 1 to 3 C1-4 alkyl,
- (ii) C1-4 alkyl-carbonyl optionally substituted by 1 to 3 substituents selected from
- (i′) hydroxy,
- (ii′) C1-4 alkylsulfonyl, and
- (iii′) a 6-membered aromatic heterocyclic group,
- (iii) C2-4 alkenyl-carbonyl optionally substituted by C6-10 aryl,
- (iv) C2-4 alkynyl-carbonyl optionally substituted by C6-10 aryl,
- (v) C3-6 cycloalkyl-carbonyl,
- (vi) C3-6 cycloalkenyl-carbonyl,
- (vii) C6-10 aryl-carbonyl optionally substituted by 1 to 3 substituents selected from
- (i′) a halogen atom,
- (ii′) C1-4 alkyl optionally substituted by 1 to 3 substituents selected from a halogen atom, cyano, hydroxy and C3-6 cycloalkyl,
- (iii′) C3-6 cycloalkyl optionally substituted by cyano,
- (iv′) C1-4 alkoxy optionally substituted by 1 to 5 halogen atoms,
- (v′) C1-4 alkoxy-carbonyl, and
- (vi′) a 5- or 6-membered heterocyclic group optionally substituted by cyano or oxo,
- (viii) 5- or 6-membered heterocyclyl-carbonyl containing, as ring-constituting atom, 1 to 3 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom besides carbon atoms, which is optionally substituted by 1 to 3 substituents selected from
- (i′) a halogen atom,
- (ii′) C1-4 alkyl optionally substituted by 1 to 3 substituents selected from a halogen atom, cyano, hydroxy and C1-4 alkoxy,
- (iii′) C6-10 aryl,
- (iv′) C6-10 aryl-C1-4 alkyl,
- (v′) C1-4 alkoxy optionally substituted by C1-4 alkoxy,
- (vi′) C1-4 alkylsulfonyl,
- (vii′) C1-4 alkyl-carbonyl, and
- (viii′) oxo,
- (ix) aromatic fused heterocyclyl-carbonyl,
- (x) C1-4 alkyl-aminocarbonyl,
- (xi) C6-10 aryl-aminocarbonyl optionally substituted by C1-4 alkyl optionally substituted by 1 to 3 halogen atoms,
- (xii) C1-4 alkoxy-aminocarbonyl,
- (xiii) 5-membered heterocyclyl-aminocarbonyl optionally substituted by 1 to 3 substituents selected from C1-4 alkyl and C6-10 aryl, and
- (xiv) 5-membered aromatic heterocyclyl-sulfonyl optionally substituted by 1 to 3 C1-4 alkyl,
- (e) C1-4 alkyl-aminocarbonyl optionally having C6-10 aryl,
- (f) 5-membered heterocyclyl-aminocarbonyl optionally substituted by 1 to 3 substituents selected from C1-4 alkyl and C6-10 aryl,
- (g) C6-10 aryl-aminocarbonyl optionally substituted by C1-4 alkyl optionally substituted by 1 to 3 substituents selected from a halogen atom and cyano,
- (h) carboxy, and
- (i) nitro,
- (2) monocyclic aromatic heterocycle optionally substituted by 1 to 3 substituents selected from
- (a) a halogen atom, and
- (b) C6-10 aryl-carbonylamino optionally substituted by C1-4 alkyl optionally substituted by 1 to 3 halogen atoms, or
- (3) fused aromatic heterocycle optionally substituted by 1 to 3 substituents selected from
- (a) C1-4 alkyl, and
- (b) C6-10 arylamino optionally substituted by C1-4 alkyl optionally substituted by 1 to 3 halogen atoms;
- Xa is —O—, —S—, —S(O)—, —S(O)2— or —NH—;
- R1a is
- (1) amino,
- (2) C1-4 alkyl-carbonylamino optionally substituted by 1 to 3 substituents selected from
- (a) a halogen atom,
- (b) hydroxy,
- (c) C1-4 alkoxy,
- (d) C1-4 alkyl-carbonyloxy,
- (e) C1-4 alkylamino,
- (f) di-C1-4 alkylamino,
- (g) C1-4 alkylsulfonyl, and
- (h) a 6-membered heterocyclic group optionally having 1 to 3 C1-4 alkyl,
- (3) C2-4 alkenyl-carbonylamino optionally having C1-4 alkoxy,
- (4) C2-4 alkynyl-carbonylamino,
- (5) C3-6 cycloalkyl-carbonylamino optionally substituted by 1 to 4 substituents selected from
- (a) a halogen atom,
- (b) hydroxy,
- (c) C1-4 alkyl optionally having hydroxy,
- (d) C1-4 alkoxy,
- (e) C1-4 alkoxy-carbonyl, and
- (f) C1-4 alkyl-carbonyloxy,
- (6) C3-6 cycloalkyl-C1-4 alkyl-carbonylamino,
- (7) 6-membered heterocyclyl-carbonylamino optionally substituted by 1 to 3 substituents selected from
- (a) a halogen atom,
- (b) cyano, and
- (c) C1-4 alkyl optionally having 1 to 3 halogen atoms,
- (8) aminocarbonylamino optionally substituted by 1 or 2 substituents selected from
- (a) C1-4 alkyl optionally having 1 to 3 C1-4 alkoxy optionally having 1 to 3 hydroxy, and
- (b) C1-4 alkoxy,
- (9) C1-4 alkoxy-carbonylamino optionally substituted by 1 to 3 halogen atoms,
- (10) C1-4 alkylsulfonylamino,
- (11) C3-6 cycloalkylsulfonylamino,
- (12) C6-10 arylamino, or
- (13) heterocyclylamino optionally substituted by 1 to 3 substituents selected from
- (a) a halogen atom, and
- (b) C 1-4 alkylamino;
- R2a is a hydrogen atom;
- R3a is a hydrogen atom;
- R4a is a hydrogen atom;
- provided that
- methyl [6-(phenylthio)imidazo[1,2-b]pyridazin-2-yl]carbamate and
- methyl [6-(phenylsulfinyl)imidazo[1,2-b]pyridazin-2-yl]carbamate are excluded, or a salt thereof.
88 more elements
A compound selected from the group consisting of:
- N-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide;
- N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;
- N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2,5-dimethyl-1,3-oxazole-4-carboxamide;
- N-[3-({2-[(N,N-dimethylglycyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide;
- N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}sulfanyl)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide;
- N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide;
- N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]benzamide;
- N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-4-carboxamide;
- N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-1H-pyrazole-5-carboxamide;
- N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-methoxy-1-methyl-1H-pyrazole-5-carboxamide;
- N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide;
- N-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide;
- N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-methyl-1H-pyrazole-5-carboxamide;
- N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-2,4-dimethyl-1,3-oxazole-5-carboxamide;
- N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-2-ethyl-4-methyl-1,3-oxazole-5-carboxamide;
- N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide;
- 3-(1-cyano-1-methylethyl)-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]benzamide;
- N-[3-({2-[(N,N-dimethylglycyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide;
- N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)phenyl]-3-(trifluoromethyl)benzamide;
- and
- N-{6-[3-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide, or a salt thereof.
18 more elements
Dependencies are inferred from the claim text.