US 12,129,236 B2
PARG inhibitory compounds
Alison E. McGonagle, Manchester (GB); Allan M. Jordan, Manchester (GB); Bohdan Waszkowycz, Manchester (GB); Colin P. Hutton, Manchester (GB); Ian D. Waddell, Manchester (GB); James R. Hitchin, Manchester (GB); Kate M. Smith, Manchester (GB); and Niall M. Hamilton, Manchester (GB)
Assigned to CANCER RESEARCH TECHNOLOGY LIMITED, London (GB)
Filed by CANCER RESEARCH TECHNOLOGY LIMITED, London (GB)
Filed on Mar. 17, 2021, as Appl. No. 17/204,206.
Application 16/662,997 is a division of application No. 15/533,819, granted, now 10,508,086, previously published as PCT/GB2015/054064, filed on Dec. 17, 2015.
Application 17/204,206 is a continuation of application No. 16/662,997, filed on Oct. 24, 2019, granted, now 10,995,073.
Claims priority of application No. 1422771 (GB), filed on Dec. 19, 2014.
Prior Publication US 2021/0380539 A1, Dec. 9, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 235/26 (2006.01); A61P 35/00 (2006.01); C07D 307/85 (2006.01); C07D 401/06 (2006.01); C07D 403/04 (2006.01); C07D 403/06 (2006.01); C07D 405/04 (2006.01); C07D 405/06 (2006.01); C07D 409/04 (2006.01); C07D 413/04 (2006.01); C07D 413/06 (2006.01); C07D 413/14 (2006.01); C07D 417/04 (2006.01); C07D 417/06 (2006.01); C07D 417/14 (2006.01)
CPC C07D 235/26 (2013.01) [A61P 35/00 (2018.01); C07D 307/85 (2013.01); C07D 401/06 (2013.01); C07D 403/04 (2013.01); C07D 403/06 (2013.01); C07D 405/04 (2013.01); C07D 405/06 (2013.01); C07D 409/04 (2013.01); C07D 413/04 (2013.01); C07D 413/06 (2013.01); C07D 413/14 (2013.01); C07D 417/04 (2013.01); C07D 417/06 (2013.01); C07D 417/14 (2013.01)] 14 Claims
 
1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structural formula (II) shown below:

OG Complex Work Unit Chemistry
wherein:
R1a is selected from fluoro, chloro, cyano, formyl, (1-2C)alkyl, (1-2C) haloalkyl, (2C)alkenyl, and (2C)alkynyl;
R1b, R1c, R1d, and R1e are each independently selected from H, fluoro, and methyl;
X1 is CR2 or N; wherein R2 is H or fluoro;
X2 is CR3 or N; wherein R3 is H or fluoro;
X3 is CR4 or N; wherein R4 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:

OG Complex Work Unit Chemistry
wherein
bond a is a single bond;
R5 is H, (1-4C)alkyl, or a group of the formula:
-L1-L5-Q5
wherein
L1 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;
L5 is absent or selected from C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), S(O)2N(Ra), and N(Ra)SO2, wherein Ra and Rb are each independently selected from hydrogen and (1-2C)alkyl; and
Q5 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 Q5 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, amino, cyano, carboxy, carbamoyl, sulphamoyl, trifluoromethoxy, haloalkyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1, or 2), SO2N(Rc)Rd, N(Rc)SO2Rd, and (CH2)zNRcRd (where z is 1, 2, or 3), wherein Rc and Rd are each independently selected from H and (1-4C)alkyl;
X4 is C(═O);
X5 is selected from CHR7C and N—R7N;
wherein
R7c is selected from hydrogen, cyano, halo, and a group of the formula:
-L7-L7C-Q7C
wherein
L7 is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;
L7C is absent or selected from O, S, SO, SO2, N(Ro), C(O), C(O)O, OC(O), C(O)N(Ro), N(Ro)C(O), N(Ro)C(O)N(Rp), S(O)2N(Ro), and N(Ro)SO2, wherein Ro and Rp are each independently selected from hydrogen and (1-2C)alkyl; and
Q7C is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl; and wherein Q7C is optionally substituted by one or more substituents selected from -(1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, NRqRr, ORq, C(O)Rq, C(O)ORq, OC(O)Rq, C(O)N(Rq)Rr, N(Rq)C(O)Rr, S(O)yRq (where y is 0, 1, or 2), SO2N(Rq)Rr, N(Rq)SO2Rr, and (CH2)zNRqRr (where z is 1, 2, or 3), wherein Rq and Rr are each independently selected from H and (1-4C)alkyl; or
R7N is selected from hydrogen and a group of the formula:
-L7-L7N-Q7N
wherein
L7 is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl;
L7N is absent or selected from O, S, SO, SO2, N(Ru), C(O), C(O)O, OC(O), C(O)N(Ru), N(Ru)C(O), N(Ru)C(O)N(Rv), S(O)2N(Ru), and N(Ru)SO2, wherein Ru and Rv are each independently selected from hydrogen and (1-2C)alkyl; and
Q7N 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, NRwRx, ORw, C(O)Rw, C(O)ORw, OC(O)Rw, C(O)N(Rw)Rx, N(Rw)C(O)Rx, S(O)yRw (where y is 0, 1, or 2), SO2N(Rw)Rx, N(Rw)SO2Rx, and (CH2)zNRwRx (where z is 1, 2, or 3), wherein Rw and Rx are each independently selected from H and (1-4C)alkyl;
with the proviso that:
(i) only one or two of R1b-e can be selected from any substituents other than H; and
(ii) only one or two of X1, X2, and X3 can be N.