2,4-dioxo-quinazoline-6-sulfonamide derivatives as inhibitors of PARG

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

• wherein:
• R1a is selected from fluoro, chloro, cyano, formyl, (1-2C)alkyl, (1-2C) haloalkyl, (2C)alkenyl, or (2C)alkynyl;
• R1b, R1c, R1d, and R1e are each independently selected from H, fluoro or methyl;
• X1 is selected from CR2 or N;
• wherein R2 is H or fluoro;
• X2 is selected from CR3 or N;
• wherein R3 is H or fluoro;
• X3 is selected form 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
• R4 is selected from a group of the formula:
• -L4-L4C-Q4C
• wherein
• L4 is absent or a (1-3C)alkylene, (2-4C)alkenylene, or (2-4C)alkynylene, each of which is optionally substituted by (1-2C)alkyl or oxo;
• L4C is absent or selected from O, S, SO, SO2, N(R4b), C(O), C(O)O, OC(O), C(O)N(R4b), N(R4b)C(O), N(R4b)C(O)O, C(O)N(R4b)O, N(R4b)C(O)N(R4C), S(O)2N(R4b), or N(R4b)SO2, wherein R4b and R4c are each independently selected from hydrogen or (1-2C)alkyl;
• and
• Q4c is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl;
• and wherein Q6C is optionally substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR4dR4e, OR4d, C(O)R4d, C(O)OR4d, OC(O)R4d, C(O)N(R4e)R4d, N(R4e)C(O)R4d, S(O)yR4d (where y is 0, 1 or 2), SO2N(R4e)R4d, N(R4e)SO2R4d or (CH2)zNR4eR4d (where z is 1, 2 or 3), wherein R4d and R4e are each independently selected from H or (1-4C)alkyl;
• wherein HET is a structure of Formula (III), (IV), (V), (VI), (VII), (VIII) or (IX):
• R5c is selected from H, halo, (1-2C)alkyl, (1-2C)alkoxy, amino, (1-2C)alkylamino, (1-2C)dialkylamino, cyano or (2C)alkynyl, wherein said (1-2C)alkyl is optionally substituted by one or more substituents selected from amino or halo;
• R5N is selected from H, (1-2C)alkyl or (1-2C)haloalkyl;
• R6c is selected from hydrogen, cyano, halo or a group of the formula:
• -L6-L6C-Q6C
• wherein
• L6 is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;
• L6C is absent or selected from O, S, SO, SO2, N(Rb), C(O), C(O)O, OC(O), C(O)N(Rb), N(Rb)C(O), N(Rb)C(O)N(Rc), S(O)2N(Rb), or N(Rb)SO2, wherein Rb and Rc are each independently selected from hydrogen or (1-2C)alkyl;
• and
• Q6C is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl;
• and wherein Q6C is optionally substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NRdRe, ORd, C(O)Rd, C(O)ORd, OC(O)Rd, C(O)N(Re)Rd, N(Re)C(O)Rd, S(O)yRd (where y is 0, 1 or 2), SO2N(Re)Rd, N(Re)SO2Rd or (CH2)zNReRd (where z is 1, 2 or 3), wherein Rd and Re are each independently selected from H or (1-4C)alkyl;
• R6N is selected from hydrogen, or a group of the formula:
• -L6-L6N-Q6N
• wherein
• L6 is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;
• L6N is absent or selected from O, S, SO, SO2, N(Rf), C(O), C(O)O, OC(O), C(O)N(Rg), N(Rf)C(O), N(Rf)C(O)N(Rg), S(O)2N(Rf), or N(Rf)SO2, wherein Rf and Rg are each independently selected from hydrogen or (1-2C)alkyl;
• and
• Q6N is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NRhRi, ORh, C(O)Rh, C(O)ORh, OC(O)Rh, C(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)ORi, S(O)yRh (where y is 0, 1 or 2), SO2N(Rh)Ri, N(Rh)SO2Ri or (CH2)zNRhRi (where z is 1, 2 or 3), wherein Rh and Ri are each independently selected from H or (1-4C)alkyl;
• or
• Q6N is optionally substituted by a group of formula:
• —W6N—Z6N
• wherein
• W6N is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;
• Z6N is selected from (3-5C)cycloalkyl, (3-6C)heterocycyl, (2C)alkynyl, phenyl, 5 or 6 membered heteroaryl, carboxy, carbamoyl or cyano, wherein Z6N is substituted by one or more substituents selected from (1-2C)alkyl, (1-2C)alkoxy or halo;
• R7c is selected from hydrogen, cyano, halo or 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(Rj), C(O), C(O)O, OC(O), C(O)N(Rj), N(Rj)C(O), N(Rj)C(O)N(Rk), S(O)2N(Rj), or N(Rj)SO2, wherein Rj and Rk are each independently selected from hydrogen or (1-2C)alkyl;
• and
• Q7C is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocycyl-(1-2C)-alkyl, heteroaryl or heteroaryl-(1-2C)alkyl;
• and wherein Q7c is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, NRlRm, ORl, C(O)Rm, C(O)ORl, OC(O)Rm, C(O)N(Rl)Rm, N(Rl)C(O)Rm, S(O)yRl (where y is 0, 1 or 2), SO2N(Rl)Rm, N(Rl)SO2Rm or (CH2)zNRlRm (where z is 1, 2 or 3), wherein Rl and Rm are each independently selected from H or (1-4C)alkyl;
• R8c is selected from hydrogen, cyano, halo or a group of the formula:
• -L8-L8C-Q8C
• wherein
• L8 is absent or (1-3C)alkylene, (3-4C)cycloalkylene, optionally substituted by one or more substituents selected from (1-2C)alkyl, halo, or oxo;
• L8C is absent or selected from O, S, SO, SO2, N(Rr), C(O), C(O)O, OC(O), C(O)N(Rr), N(Rr)C(O), N(Rr)C(O)N(Rs), S(O)2N(Rr), or N(Rr)SO2, wherein Rr and Rs are each independently selected from hydrogen or (1-2C)alkyl;
• and
• Q8C is hydrogen, cyano, (1-6C)alkyl, (3-6C)cycloalkyl, (2-3C)alkenyl, (2-3C)alkynyl, aryl, heterocyclyl or heteroaryl;
• and wherein Q8C is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, NRtRu, ORt, C(O)Rt, C(O)ORt, OC(O)Rt, C(O)N(Rt)Ru, N(Rt)C(O)Ru, S(O)yRt (where y is 0, 1 or 2), SO2N(Rt)Ru, N(Rt)SO2R, or (CH2)zNRtRu (where z is 1, 2 or 3), wherein Rt and Ru are each independently selected from H or (1-4C)alkyl;
• or
• Q8C is optionally substituted by a group of the formula:
• —W8C-L8′-Z8C
• wherein
• W8C is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;
• L8′ is absent or selected from C(O), C(O)O, OC(O), C(O)N(Rv), N(Rv)C(O), N(Rv)C(O)N(Rw), S(O)2N(Rv), or N(Rv)SO2, wherein Rv and Rw are each independently selected from hydrogen or (1-2C)alkyl;
• and
• Z8C is phenyl or 5-6 membered heteroaryl;
• wherein Z8C is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl or sulphamoyl;
• Q8C and R4 are linked, such that, together with the carbon atom to which they are attached, they form a group of the formula;
• wherein
• X7 is C;
• Rz is selected from (1-4C)alkyl, (1-4C)haloalkyl, or a group of the formula:
• -LRz-ZRz
• wherein
• LRz is absent or (1-3C)alkylene, optionally substituted by one or more substituents selected from (1-2C)alkyl, halo or oxo;
• and
• ZRz is aryl, carbocyclyl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, haloalkyl, amino, cyano, hydroxyl, carboxy, carbamoyl or sulphamoyl;
• R8N is selected from hydrogen or a group of the formula:
• -L8-L8N-Q8N
• wherein
• L8 is absent or (1-3C)alkylene, (3-4C)cycloalkyl optionally substituted by one or more substituents selected from (1-2C)alkyl;
• halo or oxo;
• L8N is absent or selected from O, S, SO, SO2, N(Rx), C(O), C(O)O, OC(O), C(O)N(Rx), N(Rx)C(O), N(Rx)C(O)N(Ry), N(Rx)C(O)O, S(O)2N(Rx), or N(Rx)SO2, wherein Rxand Ry are each independently selected from hydrogen or (1-2C)alkyl;
• Q8N is hydrogen, cyano, (1-6C)alkyl, (3-6C)cycloalkyl, (2-3C)alkenyl, (2-3C)alkynyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, haloalkyl, amino, cyano, aryl, hydroxyl, carboxy, carbamoyl, sulphamoyl, NRzRa′, ORz, C(O)Rz, C(O)ORz, OC(O)Rz, C(O)N(Rz)Ra′, N(Rz)C(O)Ra′, S(O)yRz (where y is 0, 1 or 2), SO2N(Rz)Ra′, N(Rz)SO2Ra′ or (CH2)zNRzRa′ (where z is 1, 2 or 3), wherein Rz and Ra′ are each independently selected from H or (1-4C)alkyl;
• or
• Q8N is optionally substituted by a group of the formula:
• —W8N-L8′-Z8N
• wherein
• W8N is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;
• L8′ is absent or selected C(O), C(O)O, OC(O), C(O)N(Rb′), N(Rb′)C(O), N(Rb′)C(O)N(Rc′), S(O)2N(Rb′), or N(Rb′)SO2, wherein Rb′ and Rc′, are each independently selected from hydrogen or (1-2C)alkyl;
• and
• Z8N is phenyl, (1-4C)alkyl, (4-6C)heterocycyl or a 5-6 membered heteroaryl;
• wherein Z8N is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl or sulphamoyl.