Pharmaceutical compounds

Patent metadata

Field	Value
Publication number	US-11466016-B2
Application number	US-201916976631-A
Country	US
Kind code	B2
Filing date	Mar 1, 2019
Priority date	Mar 2, 2018
Publication date	Oct 11, 2022
Grant date	Oct 11, 2022

Abstract

The invention provides new pyrazine derivatives of formula (I):or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the substituents are as defined herein. The invention also provides pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

First claim

The invention claimed is:

1. A compound of formula (I):

or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R 1 is hydrogen, —CH 3 or —CH 2 OH but when X is N then R 1 is selected from —CH 3 and —CH 2 OH;
R 2 and R 3 are either:
(i) independently selected from hydrogen and C 1-4 alkyl; or
(ii) together form a one- to three-membered bridge group selected from C 1-3 alkylene, C 2-3 alkenylene, methylene-NR q -methylene and methylene-O-methylene, wherein the bridge group is optionally substituted by a group selected from C 1-4 alkyl, hydroxyl and halogen and R q is selected from hydrogen, C 1-4 alkyl, hydroxyl and halogen;

Q is C or N;
wherein when Q is C then either:
(i) R 4 is hydrogen or C 1-4 alkyl optionally substituted by amino;
R 5 is hydrogen, amino, hydroxyl or C 1-4 alkyl optionally substituted by 1 or 2 groups selected from halogen, hydroxyl and amino;
provided that R 4 and R 5 must not both be selected from amino and C 1-4 alkyl substituted by amino; or
(ii) R 4 and R 5 together with Q form a four- to six-membered nitrogen-containing heterocyclic ring; and

wherein when Q is N then:
R 4 is absent;
R 5 is hydrogen; and
R 2 and R 3 together form the one- to three-membered bridge group;

R 6 and R 7 are independently selected from halogen, C 1-4 alkyl and hydroxyl provided that when Q is N then R 6 or R 7 are not halogen or hydroxyl;
a is selected from 0, 1 and 2;
b is selected from 0, 1 and 2;
Ring A is either:
(i) a five-membered nitrogen-containing heterocyclic ring wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S, or
(ii) a six-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or
(iii) a six-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S;

R 8 is selected from haloC 1-4 alkyl, —CH 3 and halogen;
R 9 is selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl and halogen;
R 10 is independently selected from halogen, cyano, cyanoC 1-4 alkyl, hydroxyl, ═O (oxo), C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, hydroxylC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkylene, amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, aminoC 1-4 alkylene, —C 1-4 alkylene-C(═O)NH (2-q) (C 1-6 alkyl) q ), —C 0-4 alkylene-NHC(═O)C 1-6 alkyl, sulfonamideC 0-4 alkylene, 3 to 6 membered cycloalkyl, optionally substituted five- or six-membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O, N, and S where the optional substituent is selected from C 1-4 alkyl, C 1-4 alkyl substituted with 3 to 6 membered cycloalkyl, C 1-4 alkyl substituted with optionally substituted five- or six-membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O, N, and S where the optional substituent is selected from C 1-4 alkyl, C 1-4 alkyl substituted with optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, and S where the optional substituent is selected from C 1-4 alkyl and optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, and S where the optional substituent is selected from C 1-4 alkyl;
q is selected from 0, 1 and 2; and
c is selected from 0, 1, 2 and 3.

2. A compound according to claim 1 , or a tautomer, pharmaceutically acceptable salt or solvate thereof, wherein:
X is CH or N;
R 1 is hydrogen, —CH 3 or —CH 2 OH but when X is N then R 1 is selected from —CH 3 and —CH 2 OH;
R 2 and R 3 are either:
(i) independently selected from hydrogen and C 1-4 alkyl; or
(ii) together form a one- to three-membered bridge group selected from C 1-3 alkylene, C 2-3 alkenylene, methylene-NR q -methylene and methylene-O-methylene, wherein the bridge group is optionally substituted by a group selected from C 1-4 alkyl, hydroxyl and halogen and R q is selected from hydrogen, C 1-4 alkyl, hydroxyl and halogen;

Q is C or N;
wherein when Q is C then either:
(i) R 4 is hydrogen or C 1-4 alkyl optionally substituted by amino;
R 5 is hydrogen, amino, or C 1-4 alkyl optionally substituted by 1 or 2 groups selected from halogen, hydroxyl and amino;
provided that R 4 and R 5 must not both be selected from amino and C 1-4 alkyl substituted by amino; or
(ii) R 4 and R 5 together with Q form a four- to six-membered nitrogen-containing heterocyclic ring; and

wherein when Q is N then:
R 4 is absent;
R 5 is hydrogen; and
R 2 and R 3 together form the one- to three-membered bridge group;

R 6 and R 7 are independently selected from halogen, C 1-4 alkyl and hydroxyl provided that when Q is N then R 6 or R 7 are not halogen or hydroxyl;
a is selected from 0, 1 and 2;
b is selected from 0, 1 and 2;
Ring A is either:
(i) a five-membered nitrogen-containing heterocyclic ring wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S, or
(ii) a six-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or
(iii) a six-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S;

R 8 is selected from haloC 1-4 alkyl, —CH 3 and halogen;
R 9 is selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl and halogen;
R 10 is independently selected from halogen, cyano, cyanoC 1-4 alkyl, hydroxyl, ═O (oxo), C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, hydroxylC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkylene, C 1-4 alkylsulfone, amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, aminoC 1-4 alkylene, —C 1-4 alkylene-C(═O)NH (2-q) (C 1-6 alkyl) q ), —C 1-4 alkylene-NHC(═O)C 1-6 alkyl, sulfonamideC 0-4 alkylene, and optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, and S where the optional substituent is selected from C 1-4 alkyl;
q is selected from 0, 1 and 2; and
c is selected from 0, 1 and 2.

3. A compound according to claim 1 , or a tautomer, pharmaceutically acceptable salt or solvate thereof, wherein X is CH.

4. A compound according to claim 1 , or a tautomer, pharmaceutically acceptable salt or solvate thereof, wherein X is N.

5. A compound according claim 1 , or a tautomer, pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H.

6. A compound according to claim 1 , or a tautomer, N oxido, pharmaceutically acceptable salt or solvate thereof, wherein R 2 and R 3 together form:
a one- to three-membered bridge group selected from C 1-3 alkylene, C 2-3 alkenylene, methylene-NR q -methylene and methylene-O-methylene, wherein the bridge group is optionally substituted by a group selected from C 1-4 alkyl, hydroxyl and halogen and R q is selected from hydrogen and C 1-4 alkyl; or
a one- to three-membered bridge group which is C 1-3 alkylene.

7. A compound according to claim 1 , or a tautomer, pharmaceutically acceptable salt or solvate thereof, wherein Q is C.

8. A compound according to claim 1 , or a tautomer, pharmaceutically acceptable salt or solvate thereof, wherein:
R 4 is hydrogen or C 1-4 alkyl; and/or
R 5 is hydr

Assignees

• Otsuka Pharma Co Ltd
• Taiho Pharmaceutical Co Ltd

Inventors

• Johnson Christopher Norbert
• Buck Ildiko Maria
• Chessari Gianni
• Day James Edward Harvey
• Fujiwara Hideto
• Hamlett Christopher Charles Frederick
• Hiscock Steven Douglas
• Holvey Rhian Sara
• Howard Steven
• Liebeschuetz John Walter
• Palmer Nicholas John
• St Denis Jeffrey David
• Twigg David Geoffrey
• Woodhead Andrew James

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07B2200/07

  Optical isomers · CPC title