Kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10364245-B2
Application number	US-201815987277-A
Country	US
Kind code	B2
Filing date	May 23, 2018
Priority date	Jun 7, 2017
Publication date	Jul 30, 2019
Grant date	Jul 30, 2019

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:
A is a group of formula (Ia), (Ib), (Ic), or (Id):

B is a group of formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (II h), or (Iii):

R 1 is H, —CN, linear or branched (C 1 -C 4 )alkyl-, (R 8 )(R 9 )NC(O)—, R 12 O—(C 1 -C 4 )alkylene-, (R 8 )(R 9 )N—(C 1 -C 4 )alkylene-, (C 1 -C 4 )alkyl-C(O)O—(C 1 -C 4 )alkylene-, (R 8 )C(O)O—; (C 1 -C 4 )alkyl-S(O) 2 NH—, (C 1 -C 4 )alkyl-S—, (R 8 )(R 9 )N—, (R 8 )(R 9 )N—(C 1 -C 4 )alkylene-C(O)NH—(C 1 -C 4 )alkylene-, optionally substituted (C 3 -C 7 )heterocycloalkyl-C(O)NH—(C 1 -C 4 )alkylene-, (C 1 -C 4 )alkyl-OC(O)—, or (R 8 )(R 9 )N—(C 1 -C 4 )alkylene-O—(C 1 -C 4 )alkylene-;
R 2 is H, linear or branched (C 1 -C 4 )alkyl-, or (C 1 -C 4 )alkyl-O—;
R 3 is H or linear or branched (C 1 -C 4 )alkyl-;
R 4 is H or linear or branched (C 1 -C 4 )alkyl-;
R 5 is H, linear or branched (C 1 -C 4 )alkyl-, R 12 O—(C 1 -C 4 )alkylene-, or R 12 O—;
R 6 is H or linear or branched (C 1 -C 4 )alkyl-;
R 7 is H or linear or branched (C 1 -C 4 )alkyl-; or
R 6 and R 7 may form, together with the nitrogen atom to which they are attached, an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom;
X is —CH 2 —, —(R 3 )N—, or —O—;
R 8 is H, linear or branched —(C 1 -C 4 )alkyl-, or R 12 O—(C 1 -C 4 )alkylene-;
R 9 is H, linear or branched (C 1 -C 4 )alkyl-, optionally substituted (C 3 -C 7 )heterocycloalkyl-, optionally substituted (C 3 -C 7 )cycloalkyl-, R 12 O—(C 1 -C 4 )alkylene-, (R 10 )(R 11 )N—(C 1 -C 4 )alkylene-, or (R 10 )(R 11 )N—(C 1 -C 4 )alkylene-O—(C 1 -C 4 )alkylene-, wherein said (C 1 -C 4 )alkylene- in (C 3 -C 7 )cycloalkyle-, R 12 O—(C 1 -C 4 )alkylene-, (R 10 )(R 11 )N—(C 1 -C 4 )alkylene-, and (R 10 )(R 11 )N—(C 1 -C 4 )alkylene-O—(C 1 -C 4 )alkylene may be optionally substituted with one or more groups selected from the group consisting of linear or branched (C 1 -C 4 )alkyl-, spiro-(C 1 -C 6 )cycloalkyl, and spiro-(C 1 -C 6 )heterocycloalkyl;
or R 8 and R 9 may form, together with the nitrogen atom to which they are attached, an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom;
R 10 is H, linear or branched (C 1 -C 4 )alkyl-, R 12 O—(C 1 -C 4 )alkylene-, (C 3 -C 7 )cycloalkyl-, or (C 3 -C 7 )heterocycloalkyl-;
R 11 is H, linear or branched (C 1 -C 4 )alkyl-, or R 12 O—(C 1 -C 4 )alkylene-;
or R 10 and R 11 may form, together with the nitrogen atom to which they are attached, an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom;
n is an integer from 1 to 4;
m is an integer from 1 to 2;
z is an integer from 1 to 2;
wherein “optionally substituted” means substitution by one or more groups selected from the group consisting of linear or branched (C 1 -C 4 )alkyl-, halo, R 12 O—(C 1 -C 4 )alkylene-, R 12 O—, oxo, and (C 1 -C 4 )alkyl(C 1 -C 4 )alkyl)N—;
R 12 is H or linear or branched (C 1 -C 4 )alkyl-; and
the symbol * indicates the point of attachment to the rest of the molecule;
with the proviso that when A is (Ib) then R 1 is not H, CH 3 or CN;
or a pharmaceutically acceptable salt thereof.

2. A compound or pharmaceutically acceptable salt according to claim 1 , wherein B is a group of formula (IIa), (IIb), (IIc), (IId), (IIe), (IIg), (IIh), or (IIi):

R 1 is H, —CN, linear or branched (C 1 -C 4 )alkyl, (R 8 )(R 9 )NC(O)—, R 12 O—(C 1 -C 4 )alkylene-, (R 8 )(R 9 )N—(C 1 -C 4 )alkylene-, (C 1 -C 4 )alkyl-S(O) 2 NH—, (C 1 -C 4 )alkyl-S—, (C 1 -C 4 )alkyl-OC(O)—, or (R 8 )(R 9 )N—(C 1 -C 4 )alkylene-O—(C 1 -C 4 )alkylene-;
R 6 and R 7 form, together with the nitrogen atom to which they are attached, an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom;
R 8 is H, linear or branched —(C 1 -C 4 )alkyl-;
R 9 is linear or branched (C 1 -C 4 )alkyl-, optionally substituted (C 3 -C 7 )cycloalkyl-, R 12 O—(C 1 -C 4 )alkylene-, or (R 10 )(R 11 )N—(C 1 -C 4 )alkylene-, wherein said (C 1 -C 4 )alkylene- in (R 10 )(R 11 )N—(C 1 -C 4 )alkylene- may be optionally substituted with one or more groups selected from the group consisting of linear or branched (C 1 -C 4 )alkyl-, spiro-(C 1 -C 6 )cycloalkyl, and spiro-(C 1 -C 6 )heterocycloalkyl;
or R 8 and R 9 may form, together with the nitrogen atom to which they are attached, an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom;
R 10 is linear or branched (C 1 -C 4 )alkyl- or (C 3 -C 7 )cycloalkyl-;
R 11 is linear or branched (C 1 -C 4 )alkyl- or R 12 O—(C 1 -C 4 )alkylene-;
or R 10 and R 11 may form, together with the nitrogen atom to which they are attached, an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom;
n is 3;
m is 1; and
z is 1.

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

B is a group of formula (IIa) or (IIe):

R 1 is H or (R 8 )(R 9 )NC(O)—;
R 3 is linear or branched (C 1 -C 4 )alkyl-;
R 5 is linear or branched (C 1 -C 4 )alkyl-, R 12 O—(C 1 -C 4 )alkylene-, or R 12 O—;
R 8 is H;
R 9 is (R 10 )(R 11 )N—(C 1 -C 4 )alkylene-, wherein said (C 1 -C 4 )alkylene- in
(R 10 )(R 11 )N—(C 1 -C 4 )alkylene- may be optionally substituted with one or more linear or branched (C 1 -C 4 )alkyl- groups;
R 10 is linear or branched (C 1 -C 4 )alkyl-;
R 11 is linear or branched (C 1 -C 4 )alkyl- or and R 12 O—(C 1 -C 4 )alkylene-;
or R 10 and R 11 may form, together with the nitrogen atom to which they are attached, an optionally substituted 4-7 membered saturated heterocyclic monocyclic ring system, optionally containing a further oxygen or nitrogen heteroatom.

4. A compound or pharmaceutically acceptable salt according to claim 1 , wherein A is group of formula (Ib):

B is a group of formula (IIa) or (IIe):

R 1 is H or (R 8 )(R 9 )NC(O)—;
R 3 is linear or branched (C 1 -C 4 )alkyl-;
R 5 is linear or branched (C 1 -C 4 )alkyl-, R 12 O—(C 1 -C 4 )alkylene-, or R 12 O—;
R 8 is H;
R 9 is (R 10 )(R 11 )N—(C 1 -C 4 )alkyl

Assignees

• Chiesi Farm Spa

Inventors

• Capaldi Carmelida
• Armani Elisabetta
• Hurley Christopher
• Avitabile-Woo Barbara Giuseppina
• Lanaro Roberta
• Jennings Neil Stuart

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title