Heterocyclic amide compounds having RORyT inhibitory action

Patent metadata

Field	Value
Publication number	US-11053262-B2
Application number	US-201916576293-A
Country	US
Kind code	B2
Filing date	Sep 19, 2019
Priority date	Jul 3, 2013
Publication date	Jul 6, 2021
Grant date	Jul 6, 2021

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.

First claim

The invention claimed is:

1. A method of inhibiting RORγt, which comprises administering an effective amount of a compound represented by the following formula (I):

wherein

Ring A is a benzene ring optionally further substituted by 1 to 3 substituents selected from
(1) a halogen atom, and
(2) a cyano group;

R 1 is
(1) a group represented by the formula: -Q(R 1a )(R 1b )(R 1c )
wherein
Q is a carbon atom or a silicon atom, and
R 1a , R 1b and R 1c are each independently a C 1-6 alkyl group, or

(2) a neopentyl group;
R 2 is
(1) a group represented by the formula:

wherein
R 5 is
(A) a C 1-6 alkyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups, or
(B) a C 1-6 alkoxy group,

(2) a bicyclic fused heterocyclic group selected from dihydrobenzofuryl and indazolyl, each optionally substituted by 1 to 3 C 1-6 alkyl groups, or
(3) a group represented by the formula -L-Z 1 :
wherein
L is a bond; and
Z 1 is
(A) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, or
(B) tetrahydropyranyl;

R 3 is
(1) a hydrogen atom, or
(2) a C 1-6 alkyl group; and
R 4 is
(1) a C 1-6 alkyl group optionally substituted by 1 to 7 substituents selected from
(a) a 3- to 8-membered monocyclic non-aromatic heterocyclic group selected from dihydropyrimidinyl, dihydropyridyl, dihydropyridazinyl, imidazolidinyl, tetrahydropyranyl, morpholinyl, piperidyl and tetrahydropyrimidinyl, each optionally substituted by 1 to 3 substituents selected from
(i) an oxo group, and
(ii) a C 1-6 alkyl group,

(b) a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from
(i) a C 1-6 alkyl group, and
(ii) a hydroxy group,

(c) a 8- to 14-membered fused bicyclic aromatic heterocyclic group selected from indazolyl and benzimidazolyl,
(d) a halogen atom,
(e) a hydroxy group,
(f) a cyano group,
(g) a carboxy group,
(h) a C 1-6 alkylsulfonyl group, and
(i) an amino group optionally mono- or di-substituted by C 1-6 alkyl-carbonyl group(s),

(2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group selected from pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl and tetrahydropyranyl, each optionally substituted by 1 to 3 substituents selected from
(a) an oxo group,
(b) a hydroxy group,
(c) a halogen atom, and
(d) a C 1-6 alkyl-carbonyl group,

(3) a 5-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups,
(4) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, or
(5) an amino group optionally mono- or di-substituted by C 1-6 alkyl group(s),
provided that
α-(acetylamino)-N-[4-(1,1-dimethylethyl)phenyl]-cyclopentaneacetamide is excluded,
or a salt thereof, to a mammal.

2. The method of claim 1 , wherein the substituent that Ring A optionally further has is a fluorine atom or a chlorine atom.

3. The method of claim 1 , wherein R 1 is a tert-butyl group, a neopentyl group or a trimethylsilyl group.

4. The method of claim 1 , wherein R 2 is
(1) a group represented by the formula:

wherein R 5 is an alkoxy group or an alkoxyalkyl group,

(2) a tetrahydro-2H-pyran-4-yl group,
(3) a 4,4-difluorocyclohexyl group,
(4) a 1-methyl-1H-indazol-5-yl group, or
(5) a 2,3-dihydro-1-benzofuran-5-yl group.

5. The method of claim 1 , wherein R 3 is a hydrogen atom or a methyl group.

6. The method of claim 1 , wherein the compound is (3S)—N-((1R)-2-((4-tert-Butyl-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide or a salt thereof.

7. The method of claim 1 , wherein the compound is 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.

8. The method of claim 1 , wherein the compound is (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.

9. The method of claim 1 , wherein the compound is (3R)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide or a salt thereof.

10. The method of claim 1 , wherein the compound is 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.

11. A method for the treatment of psoriasis, which comprises administering an effective amount of a compound represented by the following formula (I):

wherein

Ring A is a benzene ring optionally further substituted by 1 to 3 substituents selected from
(1) a halogen atom, and
(2) a cyano group;

R 1 is
(1) a group represented by the formula: -Q(R 1a )(R 1b )(R 1c )
wherein
Q is a carbon atom or a silicon atom, and
R 1a , R 1b and R 1c are each independently a C 1-6 alkyl group, or

(2) a neopentyl group;
R 2 is
(1) a group represented by the formula:

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Yamamoto Satoshi
• Shirai Junya
• Kono Mitsunori
• Tomata Yoshihide
• Sato Ayumu
• Ochida Atsuko
• Fukase Yoshiyuki
• Fukumoto Shoji
• Oda Tsuneo
• Tokuhara Hidekazu
• Ishii Naoki
• Sasaki Yusuke

Classifications

• A61P1/04 Primary

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• C07D309/06

  Radicals substituted by oxygen atoms · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D205/04

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07D261/12

  Oxygen atoms · CPC title