Benzolactam compounds as protein kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10457669-B2
Application number	US-201615767775-A
Country	US
Kind code	B2
Filing date	Oct 20, 2016
Priority date	Oct 21, 2015
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

The invention provides a compound of formula (0):

or a pharmaceutically acceptable salt, N-oxide or tautomer thereof; wherein:
n is 1 or 2;
X is CH or N;
Y is selected from CH and C—F;
Z is selected from C—R z and N;
R 1 is selected from:
-(Alk 1 ) t -Cyc 1 ; wherein t is 0 or 1; Optionally substituted C 1-6 acyclic hydrocarbon groups

R 2 is selected from hydrogen; halogen; and C 1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms;
R 3 is hydrogen or a group L 1 -R 7 ;
R 4 is selected from hydrogen; methoxy; and optionally substituted C 1-3 alkyl; and
R 4a is selected from hydrogen and a C 1-3 alkyl group;
wherein R z , Alk 1 , Cyc 1 , L 1 and R 7 are defined herein;
provided that the compound is other than 6-benzyl-3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and 3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and salts and tautomers thereof.

The compounds are inhibitors of ERK1/2 kinases and will be useful in the treatment of ERK1/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.

First claim

The invention claimed is:

1. A compound selected from:
(a) a compound having the formula (2):

or a pharmaceutically acceptable salt or tautomer thereof; and
(b) a compound having the formula (5):

or a pharmaceutically acceptable salt or tautomer thereof;

wherein
n is 1 or 2;
Z is selected from C—R z and N;
R z is selected from hydrogen; halogen; methoxy; and C 1-3 alkyl optionally substituted with hydroxy or methoxy;
R 1 is selected from:
-(Alk 1 ) t -Cyc 1 ; wherein t is 0 or 1; and Alk 1 is a C 1-4 straight chain or branched alkylene group optionally substituted with 1 or 2 hydroxy groups; and
C 1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R 5 selected from hydroxy; oxo; fluorine; and cyano; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N;

Cyc 1 is a cyclic group selected from (a) 3 to 9 membered non-aromatic monocyclic and bicyclic carbocyclic and heterocyclic groups containing 0, 1, 2, or 3 heteroatom ring members selected from O, N, S, S(O) and S(O) 2 ; (b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and (c) 3 to 7 membered monocyclic carbocyclic groups; wherein each cyclic group (a), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R 6 selected from hydroxy; oxo; fluorine; amino; NH(Hyd 1 ); N(Hyd 1 ) 2 ; O-Hyd 1 ; —C(═O)—Hyd 1 ; —C(═O)—O—Hyd 1 and Hyd 1 ; where Hyd 1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy;
R 2 is selected from hydrogen; halogen; and C 1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms;
R 3 is hydrogen or a group L 1 -R 7 ;
R 4 is selected from hydrogen; methoxy; and C 1-3 alkyl optionally substituted with hydroxy, amino, mono- or di-C 1-2 alkylamino, a cyclic amino group or methoxy; wherein the cyclic amino group is a saturated 4-7 membered heterocyclic group containing a nitrogen ring member and optionally a second heteroatom ring member selected from O, N and S, wherein the cyclic amino group is linked via a nitrogen ring member thereof to the C 1-3 alkyl, and wherein the cyclic amino group is optionally substituted with one or two methyl groups;
provided that no more than one R 4 can be other than hydrogen or methyl;
L 1 is selected from a bond; Alk 2 , Alk 2 -O and Alk 2 -C(═O) wherein Alk 2 is a C 1-4 straight chain or branched alkylene group which is optionally substituted with one or more substituents selected from hydroxy, methoxy, amino, methylamino, dimethylamino and fluorine;
R 7 is selected from:
hydrogen;
CO 2 H;
NR 8 R 9 ;
a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R 10 ; and
an acyclic C 1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C 1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R 10 ; wherein one or two but not all of the carbon atoms of the acyclic C 1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO 2 or NR 11 ;

R 8 is selected from hydrogen and a C 1-4 hydrocarbon group, the C 1-4 hydrocarbon group being optionally substituted with 1-2 substituents selected from hydroxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and 4-7 membered saturated heterocyclic rings containing 1-2 heteroatom ring members selected from O and N, wherein the mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and 4-7 membered saturated heterocyclic rings are each optionally substituted with 1-2 hydroxy or C 1-3 alkyl substituents;
R 9 is selected from:
hydrogen;
a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R 10 ; and
an acyclic C 1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C 1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R 10 ; wherein one or two but not all of the carbon atoms of the acyclic C 1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO 2 or NR 11 ;

or NR 8 R 9 forms a heterocyclic group having from 4 to 12 ring members wherein, in addition to the nitrogen atom of NR 8 R 9 , the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O, N and S and oxidised forms of S; and wherein the heterocyclic group is optionally substituted with one or more substituents R 10 ;
R 10 is selected from:
halogen; hydroxy; oxo; cyano;
OR 12 wherein R 12 is C 1-6 alkyl or C 3-6 cycloalkyl, each being optionally substituted with halogen;
an acyclic C 1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C 1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R 13 selected from hydroxy; halogen; cyano; amino; —NH(Hyd 1 ); —N(Hyd 1 ) 2 ; and —(O) v - Hyd 1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C 1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO 2 or NR 11 ; and
carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R 13 ; and

R 11 is selected from hydrogen and a C 1-4 hydrocarbon group.

2. A compound according to claim 1 , having the formula (2), or (5), or a pharmaceutically acceptable salt or tautomer thereof, wherein
R z is selected from hydrogen; halogen; and C 1-3 alkyl optionally substituted with hydroxy or methoxy;
Cyc 1 is a cyclic group selected from (a) 3 to 9 membered non-aromatic monocyclic and bicyclic carbocyclic and heterocyclic groups containing 0, 1, 2, or 3 heteroatom ring members selected from O, N, S and S(O) 2 ; (b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and (c) 3 to 7 membered monocyclic carbocyclic groups; wherein each cyclic group (a), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R 6 selected from hydroxy; oxo; fluorine; amino; NH(Hyd 1 ); N(Hyd 1 ) 2 ; O-Hyd 1 ; —C(═O)—Hyd 1 ;

Assignees

• Otsuka Pharma Co Ltd

Inventors

• Berdini Valerio
• Buck Ildiko Maria
• Day James Edward Harvey
• Griffiths-Jones Charlotte Mary
• Heightman Thomas Daniel
• Howard Steven
• Murray Christopher William
• Norton David
• O'Reilly Marc
• Woolford Alison Jo-Anne
• Cooke Michael Liam
• Cousin David
• Onions Stuart Thomas
• Shannon Jonathan Martin
• Watts John Paul

Classifications

• C07D471/08

  Bridged systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title