Heterobicyclic compounds for inhibiting the activity of SHP2

Patent metadata

Field	Value
Publication number	US-12037345-B2
Application number	US-201917262341-A
Country	US
Kind code	B2
Filing date	Jul 23, 2019
Priority date	Jul 24, 2018
Publication date	Jul 16, 2024
Grant date	Jul 16, 2024

Abstract

The invention provides a compound of formula (I):wherein Ring A, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, X, a, b, c and d are as defined in the specification, useful for inhibiting the activity of SHP2.

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 —CH 3 ;
R 2 and R 3 are independently selected from hydrogen and C 1-4 alkyl;
Q is C or N;
wherein when Q is C then either:
(i) R 4 is amino, aminoC 1-4 alkyl or monoC 1-4 alkylamino;
R 5 is hydrogen, C 1-4 alkyl, halogen, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl or C 1-4 alkoxyC 1-4 alkyl;
or
(ii) R 4 and R 5 together with Q form a four- to six-membered ring that can optionally contain 1 to 3 heteroatoms or groups independently selected from N, O, S, NH, C(O) and S(O) m , and said ring formed by R 4 and R 5 can be unsubstituted or substituted with 1 to 4 groups independently selected from amino, halogen, haloC 1-4 alkyl, hydroxyl, methoxy, methylamino, and C 1-4 alkyl, and m is selected from 1 and 2; and

wherein when Q is N then:
R 4 is absent; and
R 5 is hydrogen;

R 6 and R 7 are independently selected from halogen, C 1-4 alkyl, hydroxyC 1-4 alkyl and hydroxyl provided that when Q is N then R 6 or R 7 are not halogen or hydroxyl;
Or, any two groups selected from R 2 , R 3 , R 6 and R 7 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, R 4 and R 7 form a four- to six-membered ring containing a N atom;
Or, R 5 and R 7 form a three- to six-membered ring;
Or, R 6 and R 7 form a direct bond;
a is selected from 0, 1 and 2;
b is selected from 0, 1 and 2;
c is selected from 0, 1 and 2;
Or, Q is C, c is 2, R 4 is hydrogen and the two R 7 join to form a 4 to 6 membered nitrogen containing ring;
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 hydrogen, C 1-4 alkyl, haloC 1-4 alkyl and halogen;
R 9 is selected from hydrogen and halogen;
R 10 is selected from haloC 1-4 alkyl, C 1-4 alkyl, halogen, hydrogen and C 1-4 alkoxy;
R 11 are independently selected from halogen, cyano, cyanoC 1-4 alkyl, hydroxyl, oxo (═O), C 1-4 alkyl optionally substituted with five- or six-membered heterocyclic group containing 1 or 2 heteroatoms selected from O, N, and S, haloC 1-4 alkyl, C 1-4 alkoxy, hydroxylC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylsulfone, amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, aminoC 1-4 alkyl, —C 1-4 alkylene-C(═O)NH (2-q) (C 1-6 alkyl) q ), —C 1-4 alkylene-NHC(═O)C 1-6 alkyl, sulfonamide, sulfonamideC 1-4 alkyl, 3 to 6 membered cycloalkyl, C 1-4 alkyl substituted with 3 to 6 membered cycloalkyl, five- or six-membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O, N, and S, 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
d is selected from 0, 1 and 2.

2. A compound according to claim 1 or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein Ring A is a five-membered or six-membered nitrogen-containing heteroaromatic ring wherein the ring optionally contains one or two additional heteroatoms selected from N, O and S.

3. A compound according to claim 1 , or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein any two groups selected from R 2 , R 3 , R 6 and R 7 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.

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

5. A compound according to claim 1 , or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein
R 4 is amino, aminoC 1-4 alkyl or monoC 1-4 alkylamino; and
R 5 is hydrogen, C 1-4 alkyl, halogen, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl or C 1-4 alkoxyC 1-4 alkyl.

6. A compound according to claim 1 , or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein
R 4 and R 5 together with Q form a four- to six-membered ring that can optionally contain 1 to 3 heteroatoms or groups independently selected from N, O, S, NH, C(O) and S(O) m , and said ring formed by R 4 and R 5 can be unsubstituted or substituted with 1 to 4 groups independently selected from amino, halogen, halo C1-4 alkyl, hydroxyl, methoxy, methylamino, and C 1-4 alkyl, and m is selected from 1 and 2.

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

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

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

10. A compound according to claim 1 , or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,
2-(4-(aminomethyl)-4-methylpiperidin-1-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,
2-(4-amino-4-methylpiperidin-1-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,
2-(exo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,
2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,
2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(7-chloro-2-ethylbenzo[d]thiazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,
2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,
2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,
2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(2-(tert-butyl)-4-chloro-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,
2-(exo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,
(R)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,
(S)-2-(4-amino-2-oxa-8-a

Assignees

• Taiho Pharmaceutical Co Ltd
• Otsuka Pharma Co Ltd

Inventors

• Shimamura Tadashi
• Kato Ryo
• Miura Risako
• Mita Takashi
• Ogawa Takahiro
• Sagara Yufu
• Johnson Christopher Norbert
• Howard Steven
• Day James Edward Harvey
• St Denis Jeffrey David
• Liebeschuetz John Walter

Classifications

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title