Heterocyclic compound
The present invention provides a heterocyclic compound having an IRAK-4 inhibitory action, which is useful for the prophylaxis or treatment of inflammatory disease, autoimmune disease, osteoarticular degenerative disease, neoplastic disease and the like, and a medicament containing thereof. The present invention relates to a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.
1. A compound represented by the formula (I):
wherein
R 1 is an aromatic heterocyclic group or a C 6-14 aryl group, each of which is optionally substituted by 1 to 3 substituents selected from
(1) a halogen atom,
(2) a C 1-6 alkyl group optionally having substituent(s) selected from Substituent Group A,
(3) a C 6-14 aryl group optionally having substituent(s) selected from Substituent Group A,
(4) a heterocyclic group optionally having substituent(s) selected from Substituent Group A and a thioxo group (the substituent is optionally further substituted by substituent(s) selected from Substituent Group A, an azido group and a mono- or di-C 1-6 alkylamino group (the alkyl is substituted by substituent(s) selected from a C 3-10 cycloalkyl group and a halogen atom)),
(5) a C 3-10 cycloalkylsulfonyl group,
(6) a C 1-6 alkyl-carbonyl group,
(7) an aromatic heterocyclylsulfonyl group, and
(8) a halogenated sulfanyl group;
R 2 is
(1) a C 1-6 alkyl group optionally having substituent(s) selected from Substituent Group A, and a non-aromatic heterocyclic group having oxo group(s),
(2) a C 3-10 cycloalkyl group optionally having substituent(s) selected from Substituent Group A, or
(3) a non-aromatic heterocyclic group optionally having substituent(s) selected from Substituent Group A;
R 3 and R 4 are independently a hydrogen atom or a C 1-6 alkyl group optionally having substituent(s) selected from Substituent Group A;
R 5 and R 6 are independently
(1) a hydrogen atom,
(2) a hydroxy group,
(3) a C 1-6 alkyl group optionally having substituent(s) selected from (1) Substituent Group A, and (2) an amino group mono- or di-substituted by substituent(s) selected from (a) a C 1-6 alkyl group, (b) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, (c) a non-aromatic heterocyclic group, (d) a C 1-6 alkylsulfonyl group, and (e) a C 3-10 cycloalkyl-carbonyl group,
(4) a C 1-6 alkoxy group optionally having substituent(s) selected from Substituent Group A,
(5) an amino group optionally mono- or di-substituted by substituent(s) selected from
(i) a C 1-6 alkyl group optionally having substituent(s) selected from Substituent Group A,
(ii) a C 1-6 alkyl-carbonyl group optionally having substituent(s) selected from Substituent Group A, and
(iii) a C 1-6 alkylsulfonyl group optionally having substituent(s) selected from Substituent Group A,
(6) a non-aromatic heterocyclic group optionally having substituent(s) selected from Substituent Group A,
(7) a carboxy group, or
(8) a carbamoyl group optionally mono- or di-substituted by C 1-6 alkyl group(s), or
R 5 and R 6 in combination optionally form
(1) a non-aromatic heterocycle optionally having substituent(s) selected from Substituent Group A, or
(2) a C 3-10 cycloalkane optionally having substituent(s) selected from Substituent Group A;
X is CR 7 R 8 , NR 9 , O or S;
R 7 and R 8 are independently
(1) a hydrogen atom,
(2) a cyano group,
(3) a C 1-6 alkyl group optionally having substituent(s) selected from Substituent Group A, or
(4) a hydroxy group, or
R 7 and R 8 in combination optionally form
(1) a C 3-10 cycloalkane optionally having substituent(s) selected from Substituent Group A, or
(2) a non-aromatic heterocycle optionally having substituent(s) selected from Substituent Group
A and a C 7-16 aralkyl group; and
R 9 is
(1) a hydrogen atom,
(2) a C 1-6 alkyl group optionally having substituent(s) selected from Substituent Group A,
(3) a C 2-6 alkenyl group optionally having substituent(s) selected from Substituent Group A, or
(4) a C 7-16 aralkyl group optionally having substituent(s) selected from Substituent Group A, or a salt thereof;
wherein Substituent Group A consists of
(1) a halogen atom,
(2) a nitro group,
(3) a cyano group,
(4) an oxo group,
(5) a hydroxy group,
(6) an optionally halogenated C 1-6 alkoxy group,
(7) a C 6-14 aryloxy group,
(8) a C 7-16 aralkyloxy group,
(9) a 5- to 14-membered aromatic heterocyclyloxy group,
(10) a 3- to 14-membered non-aromatic heterocyclyloxy group,
(11) a C 1-4 alkyl-carbonyloxy group,
(12) a C 6-14 aryl-carbonyloxy group,
(13) a C 3-6 alkoxy-carbonyloxy group,
(14) a mono- or di-C 1-6 alkyl-carbamoyloxy group,
(15) a C 6-14 aryl-carbamoyloxy group,
(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group,
(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group,
(18) an optionally halogenated C 1-6 alkylsulfonyloxy group,
(19) a C 6-14 arylsulfonyloxy group optionally substituted by a C 1-6 alkyl group,
(20) an optionally halogenated C 1-6 alkylthio group,
(21) a 5- to 14-membered aromatic heterocyclic group,
(22) a 3- to 14-membered non-aromatic heterocyclic group,
(23) a formyl group,
(24) a carboxy group,
(25) an optionally halogenated C 1-6 alkyl-carbonyl group,
(26) a C 6-14 aryl-carbonyl group,
(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,
(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,
(29) a C 1-6 alkoxy-carbonyl group,
(30) a C 6-14 aryloxy-carbonyl group,
(31) a C 7-16 aralkyloxy-carbonyl group,
(32) a carbamoyl group,
(33) a thiocarbamoyl group,
(34) a mono- or di-C 1-6 alkyl-carbamoyl group,
(35) a C 6-14 aryl-carbamoyl group,
(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group,
(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group,
(38) an optionally halogenated C 1-6 alkylsulfonyl group,
(39) a C 6-14 arylsulfonyl group,
(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group,
(41) an optionally halogenated C 1-6 alkylsulfinyl group,
(42) a C 6-14 arylsulfinyl group,
(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group,
(44) an amino group,
(45) a mono- or di-C 1-6 alkylamino group,
(46) a mono- or di-C 6-14 arylamino group,
(47) a 5- to 14-membered aromatic heterocyclylamino group,
(48) a C 7-16 aralkylamino group,
(49) a formylamino group,
(50) a C 1-6 alkyl-carbonylamino group,
(51) a (C 1-6 alkyl)(C 1-6 alkyl-carbonyl)amino group,
(52) a C 6-14 aryl-carbonylamino group,
(53) a C 1-6 alkoxy-carbonylamino group,
(54) a C 7-16 aralkyloxy-carbonylamino group,
(55) a C 1-6 alkylsulfonylamino group,
(56) a C 6-14 arylsulfonylamino group optionally substituted by a C 1-6 alkyl group,
(57) an optionally halogenated C 1-6 alkyl group,
(58) a C 2-6 alkenyl group,
(59) a C 2-6 alkenyl group,
(60) a C 3-10 cycloalkyl group,
(61) a C 3-10 cycloalkenyl group and
(62) a C 6-14 aryl group.
2. The compound or salt of claim 1 , wherein
X is CR7R8 or NR9; and
R3 and R4 are both hydrogen atoms.
3. N-(3-(3-(2-Hydroxyethyl)-2-oxoimidazolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxamide or a salt thereof.
4. N-(1-Methyl-3-(2-oxoimidazolidin-1-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxamide or a salt thereof.
5. N-(1-Methyl-3-((3 S)-3-methyl-2-oxopyrrolidin-1-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxamide or a salt thereof.
6. A medicament comprising the compound or salt of claim 1 .
7. The medicament of claim 6 , which is an interleukin 1 receptor-associated kinase 4 inhibitor.
8. The medicament of claim 6 , which is an agent for the treatment of autoimmune disease and/or inflammatory disease.
9. The medicament of claim 8 , wherein the medicament is an agent for the treatment of multiple sclerosis, systemic lupus erythematosus, gout or hay fever.
10. A method of inhibiting interleukin 1 receptor-associated kinase 4 in a mammal, which comprises administering an effective amount of the compound or salt of claim 1 to the mammal.
11. A method for the treatment of autoimmune disease and/or inflammatory disease in a mammal, which comprises administering an effective amount of the compound or salt of claim 1 to the mammal.
12. The method of claim 11 , wherein the method is for the treatment of multiple sclerosis, systemic lupus erythematosus, gout or hay fever.
13. A compound represented by the formula (I):
wherein
R 1 is an aromatic heterocyclic group or a C 6-14 aryl group, each of which is optionally substituted by 1 to 3 substituents selected from
(1) a halogen atom,
(2) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom, and
(ii) a hydroxy group,
(3) a C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms,
(4) an aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from
(i) an amino group optionally mono- or di-substituted by C 1-6 alkyl group(s) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom, and
(b) a C 3-10 cycloalkyl group,
(ii) a halogen atom,
(iii) a C 1-6 alkoxy group,
(iv) a cyano group,
(v) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(a) an azido group,
(b) an amino group optionally mono- or di-substituted by C 1-6 alkyl group(s) optionally substituted by 1 to 3 substituents selected from a halogen atom and a C 3-10 cycloalkyl group,
(c) a hydroxy group, and
(d) a halogen atom,
(vi) a formyl group,
(vii) a carboxy group,
(viii) a carbamoyl group,
(ix) a C 3 -C 10 cycloalkyl group, and
(x) a non-aromatic heterocyclic group,
(5) a non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from
(i) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(a) a hydroxy group,
(b) an amino group optionally mono- or di-substituted by C 1-6 alkyl group(s),
(c) a cyano group, and
(d) a C 6-14 aryl group,
(ii) an oxo group,
(iii) a hydroxy group,
(iv) a carbamoyl group, and
(v) a thioxo group,
(6) a C 3-10 cycloalkylsulfonyl group,
(7) a C 1-6 alkyl-carbonyl group,
(8) an aromatic heterocyclylsulfonyl group, and
(9) a halogenated thio group;
R 2 is
(1) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(i) a C 1-6 alkoxy-carbonyl group,
(ii) a C 1-6 alkylsulfonyl group,
(iii) a carbamoyl group,
(iv) a cyano group,
(v) a non-aromatic heterocyclic group optionally substituted by 1 to 3 oxo groups, and
(vi) a halogen atom,
(2) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups, or
(3) a non-aromatic heterocyclic group;
R 3 and R 4 are independently
(1) a hydrogen atom, or
(2) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from an amino group optionally mono- or di-substituted by C 1-6 alkyl group(s);
R 5 and R 6 are independently
(1) a hydrogen atom,
(2) a hydroxy group,
(3) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(i) a hydroxy group,
(ii) an amino group optionally mono- or di-substituted by substituent(s) selected from
(a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(b) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 halogen atoms,
(c) a non-aromatic heterocyclic group,
(d) a C 1-6 alkylsulfonyl group,
(e) a C 1-6 alkyl-carbonyl group, and
(f) a C 3-10 cycloalkyl-carbonyl group,
(iii) a halogen atom,
(iv) a C 1-6 alkylsulfanyl group,
(v) a C 1-6 alkylsulfinyl group, and
(vi) a C 1-6 alkylsulfonyl group,
(4) a C 1-6 alkoxy group,
(5) an amino group optionally mono- or di-substituted by substituent(s) selected from
(i) a C 1-6 alkyl group,
(ii) a C 1-6 alkyl-carbonyl group, and
(iii) a C 1-6 alkylsulfonyl group,
(6) a non-aromatic heterocyclic group,
(7) a carboxy group, or
(8) a carbamoyl group optionally mono- or di-substituted by C 1-6 alkyl group(s), or
R 5 and R 6 in combination optionally form
(1) a non-aromatic heterocycle, or
(2) a C 3-10 cycloalkane;
X is CR 7 R 8 , NR 9 , O or S;
R 7 and R 8 are independently
(1) a hydrogen atom,
(2) a cyano group,
(3) a C 1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, or
(4) a hydroxy group, or
R 7 and R 8 in combination optionally form
(1) a C 3-10 cycloalkane optionally substituted by 1 to 3 substituents selected from
(i) an oxo group, and
(ii) a hydroxy group, or
(2) a non-aromatic heterocycle optionally substituted by 1 to 3 C 7-16 aralkyl groups; and
R 9 is
(1) a hydrogen atom,
(2) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(i) a hydroxy group,
(ii) a C 1-6 alkoxy group optionally substituted by 1 to 3 C 6-14 aryl groups, and
(iii) an amino group optionally mono- or di-substituted by C 1-6 alkyl group(s),
(3) a C 2-6 alkenyl group, or
(4) a C 7-16 aralkyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups,
or a salt thereof.