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US 10,472,376 B2Granted
Amide compound
AssigneeTakeda Pharmaceutical Company Limited
InventorsSatoshi Yamamoto, Junya Shirai, Mitsunori Kono, Yoshihide Tomata, Ayumu Sato, Atsuko Ochida, Yoshiyuki Fukase, Shoji Fukumoto, Tsuneo Oda, Hidekazu Tokuhara, Naoki Ishii, Yusuke Sasaki
Life of this patent
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Abstract
The present invention relates to compound (I) or a salt thereof which has a RORγt inhibitory action. In the formula (I), each symbol is as defined in the specification.
Claims13
A compound represented by the following formula (I):
- wherein
- Ring A is a 6-membered aromatic ring optionally further substituted by 1 to 3 substituents selected from
- (1) a halogen atom, and
- (2) a cyano group;
- R1 is
- (1) a group represented by the formula:
- -Q(R1a)(R1b)(R1c)
- wherein
- Q is a carbon atom, a silicon atom or a germanium atom, and
- R1a, R1b and R1c are each independently
- (a) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
- (i) a halogen atom, and
- (ii) a C1-6 alkoxy group,
- (b) a hydroxy group,
- (c) a C6-14 aryl group,
- (d) a C3-10 cycloalkyl group,
- (e) a cyano group,
- (f) a carbamoyl group optionally mono- or di-substituted by C3-10 cycloalkyl group(s), or
- (g) a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl group, or
- R1a and R1b in combination form, together with the adjacent Q, a C3-10 cycloalkane ring,
- (2) a neopentyl group, or
- (3) a trimethylsilylmethyl group;
- R2 is
- (1) a group represented by the formula:
- wherein
- R5 is
- (A) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
- (a) a C1-6 alkoxy group optionally substituted by 1 to 3 substituents selected from
- (i) a halogen atom, and
- (ii) a C1-6 alkoxy group, and
- (b) a hydroxy group, or
- (B) a C1-6 alkoxy group optionally substituted by 1 to 3 C1-6 alkoxy groups, and
- the benzene ring in the formula optionally has, besides R5, additional 1 to 3 substituents selected from
- (A) a C1-6 alkyl group, and
- (B) a C1-6 alkoxy group,
- (2) a bicyclic fused heterocyclic group optionally substituted by 1 to 3 C1-6 alkyl groups, or
- (3) a group represented by the formula -L-Z1:
- wherein
- L is a bond;
- and
- Z1 is
- (A) a C3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from
- (a) a halogen atom, and
- (b) a hydroxy group, or
- (B) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by C1-6 alkyl group(s) optionally substituted by 1 to 3 halogen atoms;
- R3 is
- (1) a hydrogen atom, or
- (2) a C1-6 alkyl group optionally substituted by 1 to 3 cyano groups;
- and
- R4 is
- (1) a C1-6 alkyl group optionally substituted by 1 to 7 substituents selected from
- (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from
- (i) an oxo group,
- (ii) a C1-6 alkyl group,
- (iii) a hydroxy group, and
- (iv) a cyano group,
- (b) a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from
- (i) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C6-14 aryl group,
- (ii) a hydroxy group, and
- (iii) a C1-6 alkoxy group optionally substituted by 1 to 3 C6-14 aryl groups,
- (c) a 8- to 14-membered fused polycyclic aromatic heterocyclic group,
- (d) a 9- to 14-membered fused polycyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 oxo groups,
- (e) a halogen atom,
- (f) a hydroxy group,
- (g) a cyano group,
- (h) a carboxy group,
- (i) a carbamoyl group,
- (j) a C1-6 alkylsulfonyl group,
- (k) a C3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from
- (i) a hydroxy group, and
- (ii) a cyano group,
- (l) an amino group optionally mono- or di-substituted by substituent(s) selected from
- (i) a C1-6 alkyl group,
- (ii) a C1-6 alkyl-carbonyl group, and
- (iii) a C1-6 alkoxy-carbonyl group,
- (m) an imino group optionally substituted by a hydroxy group, and
- (n) a 5- or 6-membered monocyclic aromatic heterocyclyloxy group optionally substituted by 1 to 3 C1-6 alkyl groups,
- (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group selected from the group consisting of pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, imidazolidinyl, tetrahydrofuryl, 1,1-dioxidotetrahydrothienyl, morpholinyl, dihydrooxazolyl, dihydrothiazolyl, piperazinyl and dihydrooxadiazolyl, each optionally substituted by 1 to 3 substituents selected from
- (a) an oxo group,
- (b) a hydroxy group,
- (c) a cyano group,
- (d) a halogen atom,
- (e) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups,
- (f) a C1-6 alkoxy group optionally substituted by 1 to 3 C6-14 aryl groups,
- (g) a C1-6 alkyl-carbonyl group, and
- (h) a C1-6 alkylidene group optionally substituted by 5- or 6-membered monocyclic aromatic heterocyclic group(s) optionally substituted by 1 to 3 substituents selected from
- (i) a C1-6 alkyl group, and
- (ii) a halogenated boryl group,
- (3) a 5-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from
- (a) a hydroxy group,
- (b) a cyano group,
- (c) a carboxy group,
- (d) a halogen atom,
- (e) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups,
- (f) a C1-6 alkoxy group,
- (g) a C1-6 alkoxy-carbonyl group, and
- (h) an amino group optionally mono- or di-substituted by C1-6 alkyl-carbonyl group(s),
- (4) a C3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from
- (a) a halogen atom,
- (b) a hydroxy group,
- (c) an oxo group,
- (d) a cyano group,
- (e) a carboxy group, and
- (f) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups,
- (5) a C2-6 alkenyl group optionally substituted by 1 to 3 substituents selected from
- (a) a carbamoyl group, and
- (b) a hydroxy group,
- (6) a C6-14 aryl group optionally substituted by 1 to 3 hydroxy groups,
- (7) a 9- to 14-membered fused polycyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 oxo groups,
- (8) a 8- to 14-membered fused polycyclic aromatic heterocyclic group,
- (9) a C1-6 alkoxy-carbonyl group,
- (10) a 5- to 14-membered spiro heterocyclic group,
- (11) a 3- to 8-membered monocyclic non-aromatic heterocyclyloxy group, or
- (12) an amino group optionally mono- or di-substituted by substituent(s) selected from
- (a) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, and
- (b) a 5- or 6-membered monocyclic aromatic heterocyclic group;
- or
- when R3 is a substituent, R3 and R4 in combination form, together with the nitrogen atom adjacent to R3 and the carbon atom adjacent to R4, a 3- to 14-membered non-aromatic heterocycle selected from the group consisting of pyrrolidine and 2,7-diazaspiro[4.4]nonane, each substituted by one oxo group and each optionally further substituted by 1 to 3 oxo groups,
- provided that
- α-(acetylamino)-N-[4-(1,1-dimethylettyl)phenyl]-cyclopentaneacetamide
- is excluded,
- or a salt thereof.
119 more elements
(3S)-N-((1 R)-2-((4-tert-Butyl-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide or a salt thereof.
N-((1R)-2-((3,5-Difluoro-4-(trimethylsilyl)phenyl)amino)-1- (4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide or a salt thereof.
(2R)-N-(4-tert-Butyl-3,5-difluorophenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(1-methyl-1H-indazol-5-yl)acetamide or a salt thereof.
A compound selected from the group consisting of:
- (3S)-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide,
- N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide,
- N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide,
- (2R)-2-(((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)amino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide,
- (2R)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((4-oxopyridazin-1(4H)-yl)acetyl)amino)acetamide,
- 1-acetyl-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)piperidine-4-carboxamide,
- (2R)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide,
- (2R)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((4-oxopyridin-1(4H)-yl)acetyl)amino)acetamide,
- (2R)-N-(4-tert-butyl-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)-2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide,
- (3R)-N-((1R)-2-((4-tert-butyl-3-fluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide,
- N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide,
- N-((1R)-2-((4-tert-butyl-3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3,3,3-trifluoro-2-hydroxypropanamide,
- (2R)-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)acetamide, and
- (2R)-N-(4-tert-butyl-3-fluorophenyl)-2-(((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide,
- or a salt thereof.
12 more elements
A compound of (3R)-N-((1R)-2-((3-fluoro-4-(trimethylsily) phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)5-oxopyrrolidine-3-carboxamide, or a salt thereof.
Dependencies are inferred from the claim text.