Bicyclic heterocycle compounds and their uses in therapy

Patent metadata

Field	Value
Publication number	US-2021122749-A1
Application number	US-202017034926-A
Country	US
Kind code	A1
Filing date	Sep 28, 2020
Priority date	Apr 21, 2011
Publication date	Apr 29, 2021
Grant date	—

Abstract

or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R1, R2a, R2b, R3a, R3b, R5, R6, R7, R8, R9, p and E are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

First claim

1 . A pharmaceutical composition comprising a compound of formula (I):

or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof; wherein
Ring E represents phenyl, pyrimidinyl, pyridazinyl, pyridyl, or pyridinonyl;
G and J are independently selected from C and N;
Q is CR 4 or N;
R 1 is selected from C 1-4 alkyl, C 2-4 alkenyl and —(CH 2 ) s —C 3-8 cycloalkyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, and C 3-8 cycloalkyl may be optionally substituted by one or more R a groups;
R a is selected from halogen, —OH and —O—C 1-6 alkyl;
R 2a and R 2b are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(═O)NH (2-q) (C 1-6 alkyl) q , —(CH 2 ) s -(3-12 membered heterocyclyl), and —(CH 2 ) s —C 3-12 carbocyclyl, or R 2a and R 2b groups, together with the carbon atom to which they are attached, can join to form a 3-10 membered saturated carbocyclyl or heterocyclyl group, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heterocyclyl and carbocyclyl groups may be optionally substituted by one or more R b groups;
R 3a and R 3b are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(═O)NH (2-q) (C 1-6 alkyl) q , —(CH 2 ) s -(3-12 membered heterocyclyl), —(CH 2 ) s —C 3-12 carbocyclyl, —C(═O)-(3-12 membered heterocyclyl), and —C(═O)—C 3-12 carbocyclyl,
or R 3a and R 3b groups, together with the carbon atom to which they are attached, can join to form a 3-10 membered saturated carbocyclyl or heterocyclyl group, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heterocyclyl and carbocyclyl groups may be optionally substituted by one or more R b groups;
R 4 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(═O)NH (2-q) (C 1-6 alkyl) q , —(CH 2 ) s -(3-12 membered heterocyclyl), —(CH 2 ) s —C 3 carbocyclyl, —C(═O)-(3-12 membered heterocyclyl), and —C(═O)—C 3-12 carbocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heterocyclyl and carbocyclyl groups may be optionally substituted by one or more R b groups;
R 5 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) s —C 3-8 cycloalkyl and —(CH 2 ) s —C 3-8 cycloalkenyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and C 3-8 cycloalkenyl may be optionally substituted by one or more R a groups;
R 6 and R 7 are independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —Y—C 3-12 carbocyclyl, —Z-(3-12 membered heterocyclyl), —(CR x R y ) s —O—R z , —O—(CR x R y ) n —OR z , —(CH 2 ) s —CN, —S(O) q —R x , —C(═O)R x , —C(═S)R x , —C(═N)R x , —(CR x R y ) s —C(═O)OR z , —(CR x R y ) s —O—C(═O)—R z , —(CR x R y ) s —C(═O)NR x R y , —(CH 2 ) s —NR x C(═O)R y , —(CH 2 ) s —OC(═O)NR x R y , —(CH 2 ) s —NR x C(═O)OR y , —(CH 2 ) s —NR x R y , —NR x —(CH 2 ) s —R z , —(CR x R y ) s —C(═S)NR z , —(CR x R y ) s —C(═N)NR z , —(CH 2 ) s —O—C(═O)—C 1-4 alkyl-NR x R y , —(CH 2 ) s —NR x —(CH 2 ) n —O—C(═O)—R z , —(CH 2 ) s —NR x —(CH 2 ) s —SO 2 —R y , —(CH 2 ) s —NH—SO 2 —NR x R y and —(CH 2 ) s —SO 2 NR x R y groups,
or R 6 and R 7 groups, together with the carbon atom to which they are attached, can join to form a 3-10 membered fully or partially saturated carbocyclyl or heterocyclyl group, which may be optionally fused to a 5-6 membered aromatic carbocyclyl or heterocyclyl ring, wherein said C 1-8 alkyl, C 2-8 alkenyl and C 2-8 alkynyl groups may be optionally substituted by one or more R b groups and wherein said carbocyclyl and heterocyclyl groups may be optionally substituted by one or more R b groups;
R 8 and R 9 are independently selected from hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —Y—C 3-12 carbocyclyl, —Z-(3-12 membered heterocyclyl), —(CR x R y ) s —O—R z , —O—(CR x R y ) n —OR z , ═O, ═S, nitro, Si(R x ) 4 , —(CH 2 ) s —CN, —S(O) q —(CR x R y ) s —R z , —C(═O)R x , —C(═S)R x , —C(═N)R x , —(CR x R y ) s —C(═O)OR z , —(CR x R y ) s —O—C(═O)—R z , —(CR x R y ) s —C(═O)NR x R y , —(CH 2 ) s —NR x C(═O)R y , —(CH 2 ) s —OC(═O)NR x R y , —(CH 2 ) s —NR x C(═O)OR y , —(CH 2 ) s —NR x R y , —NR x —(CH 2 ) s —R z , —(CR x R y ) s -C(═S)NR z , —(CR x R y ) s —C(═N)NR x , —S(O)(═NR x )R y , —(CH 2 ) s —O—C(═O)—C 1-4 alkyl-NR x R y , —(CH 2 ) s —NR x —(CH 2 ) n —O—C(═O)—R z , —(CH 2 ) s —NR x —(CH 2 ) s —SO 2 —R y , —(CH 2 ) s —NH—SO 2 —NR x R y , —(CH 2 ) s —SO 2 NR x R y groups and —P(═O)(R x ) 2 , wherein said C 1-8 alkyl, C 2-8 alkenyl and C 2-8 alkynyl groups may be optionally substituted by one or more R b groups and wherein said carbocyclyl and heterocyclyl groups may be optionally substituted by one or more R b groups;
R b is independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) s —C 3-8 cycloalkyl, —(CH 2 ) s —C 3-8 cycloalkenyl, —(CH 2 ) s -phenyl, —(CH 2 ) s -(4-7 membered saturated heterocyclyl), —(CR x R y ) s —O—R z , —O—(CR x R y ) n —OR z , haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkanol, ═O, ═S, nitro, Si(R x ) 4 , —(CH 2 ) s —CN, —S(O) q —R x , —C(═O)R x , —(CR x R y ) s —C(═O)OR z , —(CR x R y ) s —O—C(═O)—R z , —(CR x R y ) s —C(═O)NR x R y , —(CH 2 ) s —NR x C(═O)R, —(CH 2 ) s —OC(═O)NR x R y , —(CH 2 ) s —NR x C(═O)OR y —(CH 2 ) s —NR x R y , —NR x —(CH 2 ) s —R z , —(CH 2 ) s —O—C(═O)—C 1-4 alkyl-NR x R y , —(CH 2 ) s —NR x —(CH 2 ) n —O—C(═O)—R z , —(CH 2 ) s —NR x —(CH 2 ) s —SO 2 —R y , —(CH 2 ) s —NH—SO 2 —NR x R y , —(CH 2 ) s —SO 2 NR x R y groups and —P(═O)(R x ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl and heterocyclyl groups may be optionally substituted by one or more R groups;
R x , R y and R z independently represent halogen, hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) s —C 3-8 cycloalkyl, —(CH 2 ) s —C 3-8 cycloalkenyl, —(CH 2 ) s -phenyl, —(CH 2 ) s -(4-7 membered saturated heterocyclyl), C 1-6 alkanol optionally substituted with one or more halo, —C(═O)OC 1-6 alkyl, hydroxy, C 1-6 alkoxy, haloC 1-6 alkyl, —(CH 2 ) n —O—C 1-6 alkyl, —C(═O)—(CH 2 ) n —C 1-6 alkoxy, —C(═O)—C 1-6 alkyl, —(CH 2 ) s —CN, C 1-6 alkyl-N(H) 2-q (C 1-6 alkyl) q , —N(H) 2-q (C 1-6 alkyl) q , —C(═O)—N(H) 2-q (C 1-6 alkyl) q , —(CH 2 )—NH—SO 2 —N(H) 2-q (C 1-6 alkyl) q , —(CH 2 ) s —N(C 1-4 alkyl)-SO 2 —N(H) 2-q (C 1-6 alkyl) q or —(CH 2 ) s —O—C(═O)—C 1-4 alkyl-N(H) 2-q (C 1-6 alkyl) q , and when attached to nitrogen, carbon, silicon or phosphorus atom R x and R y may join to form a 3-7 membered ring optionally containing one or two additional heteroatoms selected from O, N, S and oxidised forms of N or S;
Y and Z are independently selected from a bond, —(CR x R y ) m —, —C(═CR x )—, —C(═O)—, —NR x , —C(═O)NR x —, —NR x C(═O)—, —(CR x R y ) q -O—, —O—(CR x R y ) q —, —S(O) 2 —NH, NH—S(O) 2 — and —S(O) q —;
s independently represents an integer from 0-4;
n independently represents an integer from 1-4;
p independently represents an integer from 0-4;
q represents an integer from 0-2; and
m represents an integer from 1-2.

2 . A pharmaceutical composition as defined in claim 1 , wherein Q represents N.

3 . A pharmaceutical composition as defined in claim 1 , wherein ring E represents pyridyl, pyridazinyl or phenyl.

4 . A pharmaceutical composition as defined in claim 1 , wherein R 1 represents methyl.

5 . A pharmaceutical composition as defined in claim 1 , wherein R 2a and R 2b are hydrogen.

6 . A pharmaceutical composition as defined in claim 1 , wherein:
(i) R 3a and R 3b are independently selected from hydrogen, C 1-6 alkyl, —C(═O)NH (2-q) (C 1-6 alkyl) q , —(CH 2 ) s -(3-

Assignees

• Astex Therapeutics Ltd

Inventors

• Woolford Alison Jo-Anne
• Howard Steven
• Buck Ildiko Maria
• Chessari Gianni
• Johnson Christopher Norbert
• Tamanini Emiliano
• Day James Edward Harvey
• Chiarparin Elisabetta
• Heightman Thomas Daniel
• Frederickson Martyn
• Griffiths-Jones Charlotte Mary

Classifications

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/12

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