Kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10100050-B2
Application number	US-201615388350-A
Country	US
Kind code	B2
Filing date	Dec 22, 2016
Priority date	Dec 23, 2015
Publication date	Oct 16, 2018
Grant date	Oct 16, 2018

Abstract

Compounds of formula (I) defined herein are p38 MAPK inhibitors and are useful as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
R 1 is H or selected from the group consisting of (C 1 -C 4 )alkyl-, (C 3 -C 7 )cycloalkyl-, (C 4 -C 7 )heterocycloalkyl-, R A O—, (R A R B )NC(O)—, R C CO(R A )N—, R A O(C 1 -C 4 )alkylene-, (R A R B )N—, R C O(O)C—, (R A R B )NSO 2 —, R C SO 2 (C 1 -C 4 )alkylene-, R C (O)CO(C 1 -C 4 )alkylene-, R C OC(O)(R A )N—, (R A R B )NCO(R D )N—, and (R A R B )N(C 1 -C 6 )alkylene-, wherein any of said alkyl, alkylene, cycloalkyl, heterocycloalkyl or heteroaryl may be optionally substituted by one or more groups selected from the group consisting of (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl,
(C 4 -C 7 )heterocycloalkyl, —OR A , halo, and CN;
R 2 is H or selected from the group consisting of halo, (C 1 -C 6 )alkyl, R A O—, (R A R B )N(C 1 -C 6 )alkylene-, and R A O(C 1 -C 4 )alkylene-;
R A and R B are at each occurrence independently H or selected from the group consisting of (C 1 -C 4 )alkyl-, (C 3 -C 7 )cycloalkyl-, and (C 4 -C 7 )heterocycloalkyl-, wherein any of said alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted;
or R A and R B may form together with the nitrogen atom to which they are attached an optionally substituted 5-11-membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is oxygen or nitrogen;
R C is selected from the group consisting of (C 1 -C 4 )alkyl-, (C 3 -C 7 )cycloalkyl-, and (C 4 -C 7 )heterocycloalkyl-, wherein any of said alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted;
R D is I-1 or is selected from the group consisting of (C 1 -C 4 )alkyl-,
(C 3 -C 7 )cycloalkyl-, and (C 4 -C 7 )heterocycloalkyl-, wherein any of said alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted;
R 3 is a group of one of formula (IIa) to (IIf):

R 4 and R 5 are at each occurrence independently H or optionally substituted
(C 1 -C 4 )alkyl-; or R 4 and R 5 may form together with the carbon atom to which they are attached an optionally substituted 3-6-membered saturated heterocyclic monocyclic ring system;
R 6 and R 7 are at each occurrence independently H or optionally substituted (C 1 -C 4 )alkyl-;
or R 5 and R 6 may form together with the carbon or nitrogen atom to which they are attached 4-6-membered saturated heterocyclic monocyclic ring system;
or R 6 and R 7 may form together with the nitrogen atom to which they are attached an optionally substituted 4-6-membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is oxygen or nitrogen wherein said nitrogen may be optionally substituted with (C 1 -C 6 )alkyl-;
R 8 is H or optionally substituted (C 1 -C 4 )alkyl-;
X is —CH 2 , —O—, or —NR 8 ;
wherein “optionally substituted” means substitution by one or more groups selected from the group consisting of (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl,
(C 4 -C 7 )heterocycloalkyl, OH, (C 1 -C 6 )alkyl-O, —NH 2 , (C 1 -C 4 )HN—,
(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl(N)—, halo, and CN;
with the proviso that—
when R 1 is H, then R 2 is not H, halo or CH 3 ;
or a pharmaceutically acceptable salt thereof.

2. A compound or pharmaceutically acceptable salt according to claim 1 , which is a compound of formula (Ia) wherein a carbon stereogenic centers on the cycloalkylene portion linked to group —NH and —O— and identified, respectively, with numbers (1) and (2), have the absolute configuration shown below

3. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is H or is selected from the group consisting of (C 1 -C 4 )alkyl-, R C SO 2 —, (R A R B )NCO—, R C CO(R A )N—, R A O(C 1 -C 4 )alkylene-, (R A R B )N—, R C O(O)C—, (R A R B )NSO 2 —, R C SO 2 (C 1 -C 4 )alkylene-, R C (O)CO(C 1 -C 4 )alkylene-, and R C OC(O)(R A )N—, wherein any of said alkyl or alkylene may be optionally substituted by one or more groups —OR A ; wherein R A and R B are at each occurrence independently H or (C 1 -C 4 )alkyl-, which may be optionally substituted by —OH or R A and R B may form together with the nitrogen atom to which they are attached an optionally substituted 6 membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is oxygen; R C is selected from the group consisting of (C 1 -C 4 )alkyl- and (C 3 -C 7 )cycloalkyl-, wherein any of such alkyl or cycloalkyl may be optionally substituted by one or more groups selected from the group consisting of (C 1 -C 6 )alkyl-O— and halo.

4. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is H or selected from the group consisting of (C 1 -C 6 )alkyl and R A O—; wherein R A is H or (C 1 -C 4 )alkyl-.

5. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is a group of formula (IIb)

wherein R 4 and R 5 are at each occurrence independently H or (C 1 -C 4 )alkyl- optionally substituted by —OH; R 7 is H or (C 1 -C 4 )alkyl-; R 8 is H or (C 1 -C 4 )alkyl- optionally substituted by —OH.

6. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is a group of formula (IIa):

wherein R 4 and R 5 are (C 1 -C 4 )alkyl-; and R 6 and R 7 are (C 1 -C 4 )alkyl-.

7. A compound or pharmaceutically acceptable salt according to claim 1 , wherein
R 1 is H or selected from the group consisting of (C 1 -C 4 )alkyl-, R C SO 2 —, (R A R B )NC(O)—, R C CO(R A )N—, (R A R B )N—, R C O(O)C—, (R A R B )NSO 2 —, R C SO 2 (C 1 -C 4 )alkylene-, R C (O)CO(C 1 -C 4 )alkylene-, R C OC(O)(R A )N—, and (R A R B )N(C 1 -C 6 )alkylene- wherein any of said alkyl or alkylene may be optionally substituted by one or more groups —OR A ;
R 2 is H or selected from the group consisting of (C 1 -C 6 )alkyl-, R A O—, and R A O(C 1 -C 4 )alkylene-;
wherein R A and R B are at each occurrence independently H or (C 1 -C 4 )alkyl-, wherein any of such alkyl may be optionally substituted by
(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl(N)—;
R C is selected from the group consisting of (C 1 -C 4 )alkyl- and (C 3 -C 7 )cycloalkyl-, wherein any of such alkyl may be optionally substituted by (C 1 -C 6 )alkylO—;
R 3 is a group of formulae (IIa), (III)), (IIc), or (IIe)

wherein X is —CH 2 ,
R 4 and R 5 are at each occurrence independently H or (C 1 -C 4 )alkyl-;
R 6 and R 7 are at each occurrence (C 1 -C 4 )alkyl-;
R 8 is H or (C 1 -C 4 )alkyl-.

8. A compound selected from the group consisting of
1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((S)-1,2-dimethyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea hydrochloride salt;
1-(5-tert-butyl-3-hydroxymethyl-2-methoxy-phenyl)-3-{(1S,4R)-4-[-3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;
1-(5-tert-butyl-3-hydroxymethyl-2-methoxy-phenyl)-3-{(1S,4R)-4-[-3-((S)-1,2-dimethyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4

Assignees

• Chiesi Farm Spa

Inventors

• Capaldi Carmelida
• Armani Elisabetta
• Jennings Andrew Steven Robert
• Hurley Christopher

Classifications

• A61P11/06

  Antiasthmatics · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title