PARG inhibitory compounds

Patent metadata

Field	Value
Publication number	US-12129236-B2
Application number	US-202117204206-A
Country	US
Kind code	B2
Filing date	Mar 17, 2021
Priority date	Dec 19, 2014
Publication date	Oct 29, 2024
Grant date	Oct 29, 2024

Abstract

The present invention relates to compounds of formula I that function as inhibitors of PARG (Poly ADP-ribose glycohydrolase) enzyme activity: wherein R1a, R1b, R1c, R1d, W, X1, X2, X3, X4, X5, X6, X7, c are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which PARG activity is implicated.

First claim

The invention claimed is:

1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structural formula (II) shown below:

wherein:
R 1a is selected from fluoro, chloro, cyano, formyl, (1-2C)alkyl, (1-2C) haloalkyl, (2C)alkenyl, and (2C)alkynyl;
R 1b , R 1c , R 1d , and R 1e are each independently selected from H, fluoro, and methyl;
X 1 is CR 2 or N; wherein R 2 is H or fluoro;
X 2 is CR 3 or N; wherein R 3 is H or fluoro;
X 3 is CR 4 or N; wherein R 4 is H, halo, cyano, (1-2C)alkyl, (1-2C) haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, or (2C)alkynyl; or
HET is a fused 5-membered saturated, partially saturated or unsaturated heterocyclic ring of formula:

wherein
bond a is a single bond;
R 5 is H, (1-4C)alkyl, or a group of the formula:
-L 1 -L 5 -Q 5

wherein
L 1 is absent, (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo, or a (2-3C)alkenylene or (2-3C)alkynylene linker that is optionally substituted by (1-2C)alkyl;
L 5 is absent or selected from C(O), C(O)O, OC(O), C(O)N(R a ), N(R a )C(O), N(R a )C(O)N(R b ), S(O) 2 N(R a ), and N(R a )SO 2 , wherein R a and R b are each independently selected from hydrogen and (1-2C)alkyl; and
Q 5 is selected from hydrogen, (1-4C)alkyl, aryl, 5-6 membered heteroaryl, (4-6C)cycloalkyl, (4-6C)cycloalkenyl, (2C)alkenyl, and 5-6 membered heterocyclyl;
wherein Q 5 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, amino, cyano, carboxy, carbamoyl, sulphamoyl, trifluoromethoxy, haloalkyl, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R c )R d , N(R c )C(O)R d , S(O) y R c (where y is 0, 1, or 2), SO 2 N(R c )R d , N(R c )SO 2 R d , and (CH 2 ) z NR c R d (where z is 1, 2, or 3), wherein R c and R d are each independently selected from H and (1-4C)alkyl;
X 4 is C(═O);
X 5 is selected from CHR 7C and N—R 7N ;
wherein
R 7c is selected from hydrogen, cyano, halo, and a group of the formula:
-L 7 -L 7C -Q 7C

wherein
L 7 is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;
L 7C is absent or selected from O, S, SO, SO 2 , N(R o ), C(O), C(O)O, OC(O), C(O)N(R o ), N(R o )C(O), N(R o )C(O)N(R p ), S(O) 2 N(R o ), and N(R o )SO 2 , wherein R o and R p are each independently selected from hydrogen and (1-2C)alkyl; and
Q 7C is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl; and wherein Q 7C is optionally substituted by one or more substituents selected from -(1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, NR q R r , OR q , C(O)R q , C(O)OR q , OC(O)R q , C(O)N(R q )R r , N(R q )C(O)R r , S(O) y R q (where y is 0, 1, or 2), SO 2 N(R q )R r , N(R q )SO 2 R r , and (CH 2 ) z NR q R r (where z is 1, 2, or 3), wherein R q and R r are each independently selected from H and (1-4C)alkyl; or

R 7N is selected from hydrogen and a group of the formula:
-L 7 -L 7N -Q 7N
wherein
L 7 is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl;
L 7N is absent or selected from O, S, SO, SO 2 , N(R u ), C(O), C(O)O, OC(O), C(O)N(R u ), N(R u )C(O), N(R u )C(O)N(R v ), S(O) 2 N(R u ), and N(R u )SO 2 , wherein R u and R v are each independently selected from hydrogen and (1-2C)alkyl; and
Q 7N is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted by one or more substituents selected from -(1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, NR w R x , OR w , C(O)R w , C(O)OR w , OC(O)R w , C(O)N(R w )R x , N(R w )C(O)R x , S(O) y R w (where y is 0, 1, or 2), SO 2 N(R w )R x , N(R w )SO 2 R x , and (CH 2 ) z NR w R x (where z is 1, 2, or 3), wherein R w and R x are each independently selected from H and (1-4C)alkyl;

with the proviso that:
(i) only one or two of R 1b-e can be selected from any substituents other than H; and
(ii) only one or two of X 1 , X 2 , and X 3 can be N.

2. A compound according to claim 1 , wherein R 1a is cyano or (1-2C)alkyl.

3. A compound according to claim 1 , wherein X 1 is CR 2 ; wherein R 2 is H or fluoro.

4. A compound according to claim 3 , wherein X 1 is C—H.

5. A compound according to claim 1 , wherein X 2 is CR 3 ; wherein R 3 is H or fluoro.

6. A compound according to claim 1 , wherein X 3 is CR 4 or N; wherein R 4 is H, halo, cyano, or (1-2C)haloalkyl.

7. A compound according to claim 6 , wherein X 3 is C—H, C—F, or C—CF 3 .

8. A compound according to claim 1 , wherein R 1b , R 1c , R 1d and R 1e are each H.

9. A compound according to claim 1 , wherein R 5 is H, (1-4C)alkyl, or a group of the formula:
-L 1 -L 5 -Q 5
wherein
L 1 is absent or selected from (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;
L 5 is absent or selected from C(O), C(O)O, OC(O), C(O)N(R a ), and N(R a )C(O), wherein R a is selected from hydrogen and (1-2C)alkyl; and
Q 5 is selected from hydrogen, (1-4C)alkyl, aryl, 5-6 membered heteroaryl, (4-6C)cycloalkyl, (4-6C)cycloalkenyl, (2C)alkenyl, and 5-6 membered heterocyclyl;
wherein Q 5 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, amino, cyano, amino, carboxy, carbamoyl, sulphamoyl, trifluoromethoxy, haloalkyl, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R c )R d , and N(R c )C(O)R d , wherein R c and R d are each independently selected from H and (1-4C)alkyl.

10. A compound of claim 1 , wherein R 5 is H, (1-4C)alkyl, or a group of the formula:
L 1 -L 5 -Q 5
wherein
L 1 is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;
L 5 is absent or selected from C(O), C(O)O, OC(O), C(O)N(R a ), and N(R a )C(O), wherein R a and R b are each independently selected from hydrogen and (1-2C)alkyl; and
Q 5 is selected from hydrogen, (1-4C)alkyl, aryl, 5-6 membered heteroaryl, (4-6C)cycloalkyl, (4-6C)cycloalkenyl, (2C)alkenyl, and 5-6 membered heterocyclyl;
wherein Q 5 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, amino, cyano, amino, haloalkyl, NR c R d , OR c , and C(O)R c , wherein R c and R d are each independently selected from H and (1-2C)alkyl.

11. A compound according to claim 1 , wherein X 5 is selected from CHR 7C and N-R 7N ;
wherein
R 7C is selected from hydrogen, cyano, halo, and a group of the formula:
-L 7 -L 7C -Q 7C

wherein
L 7 is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;
L 7C is absent or selected from O, S, SO, SO 2 , N(R o ), C(O), C(O)O, OC(O), C(O)N(R o ), and N(R o )C(O), wherein R o is selected from hydrogen and (1-2C)alkyl; and
Q 7C is hydrogen, cyano, (1-4C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl; and wherein Q 7C is optionally substituted by one or more substituents selected from -(1-2C)alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl and sulphamoyl;
R 7N is selected from hydrogen or a group of the formula:
-L 7 -Q 7N

wherein
L 7 is absent or (1-3C)alkylene optionally substituted by (1-2C)alky

Assignees

• Cancer Research Tech Ltd

Inventors

• Mcgonagle Alison E
• Jordan Allan M
• Waszkowycz Bohdan
• Hutton Colin P
• Waddell Ian D
• Hitchin James R
• Smith Kate M
• Hamilton Niall M

Classifications

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D307/85

  attached in position 2 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title