Tricyclic compounds and their use in the treatment of cancer

A compound of formula I

• or a pharmaceutically acceptable salt thereof, wherein:
• X represents C1-12 alkyl optionally substituted by one or more groups independently selected from G1a, C2-12 alkenyl optionally substituted by one or more groups independently selected from G1a, C2-12 alkynyl optionally substituted by one or more groups independently selected from G1a, heterocycloalkyl optionally substituted by one or more groups independently selected from G1b, aryl optionally substituted by one or more groups independently selected from G1c, or heteroaryl optionally substituted by one or more groups independently selected from G1d;
• Y represents C1-12 alkyl optionally substituted by one or more groups independently selected from G2a;
• C2-12 alkenyl optionally substituted by one or more groups independently selected from G2a, C2-12 alkynyl optionally substituted by one or more groups independently selected from G2a, heterocycloalkyl optionally substituted by one or more groups independently selected from G2b, aryl optionally substituted by one or more groups independently selected from G2c, or heteroaryl optionally substituted by one or more groups independently selected from G2d;
• Z represents O, S, NRa or N(ORb);
• R1 and R2 independently represents H, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted by one or more groups independently selected from halo, —OC1-6 alkyl optionally substituted by one or more halo, —OC2-6 alkenyl optionally substituted by one or more halo, and —OC2-6 alkynyl optionally substituted by one or more halo;
• each G1a, G1b, G1c and G1d independently represents halo, Ra1, —CN, -Aa1—C(Qa1)Rb1, -Ab1—C(Qb1)N(Rc1)Rd1, -Ac1—C(Qc1)ORe1, -Ad1—S(O)nRf1, -Ae1-S(O)nC(O)Rg1, -Af1—S(O)nN(Rh1)Ri1, -Ag1—S(O)nORj1, —N3, —N(Rk1)Rl1, —N(H)CN, —NO2, —ORm1, —SRn1 or ═Qd1;
• each Aa1 to Ag1 independently represents a single bond, —N(Ro1)—, —C(Qe1)N(Rp1)— or —O—;
• each Qa1 to Qe1 independently represents ═O, ═S, ═NRq1 or ═N(ORr1);
• Ra and Rb each independently represent H, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted by one or more groups independently selected from halo, —OC1-6 alkyl optionally substituted by one or more halo, —OC2-6 alkynyl optionally substituted by one or more halo;
• each Ra1 and Rf1 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G3a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G3a, C2-6 alkynyl optionally substituted by one or more groups independently selected from G3a, heterocycloalkyl optionally substituted by one or more groups independently selected from G3b, aryl optionally substituted by one or more groups independently selected from G3c, or heteroaryl optionally substituted by one or more groups independently selected from G3d;
• each Rb1, Rc1, Rd1, Re1, Rg1, Rh1, Ri1, Rj1, Rk1, Rl1, Rm1, Rn1, Rq1 and Rr1 independently represents H, C1-6 alkyl optionally substituted by one or more groups independently selected from G3a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G3a, C2-6 alkynyl optionally substituted by one or more groups independently selected from G3a, heterocycloalkyl optionally substituted by one or more groups independently selected from G3b, aryl optionally substituted by one or more groups independently selected from G3c, or heteroaryl optionally substituted by one or more groups independently selected from G3d;
• or any two Rc1 and Rd1, Rh1 and Rj1 and/or Rk1 and Rl1 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C1-3 alkyl optionally substituted by one or more halo, C2-3 alkenyl optionally substituted by one or more halo, C2-3 alkynyl optionally substituted by one or more halo, and ═O;
• each Ro1 and Rp1 independently represents H, C1-6 alkyl optionally substituted by one or more halo, C2-3 alkenyl optionally substituted by one or more halo, or C2-3 alkynyl optionally substituted by one or more halo;
• each G2a, G2b, G2c and G2d independently represents halo, Ra2, —CN, -Aa2-(Qa2)Rb2, -Ab2—C(Qb2)N(Rc2)Rd2, -Ac2—C(Qc2)ORe1, -Ad2—S(O)pRf2, -Ae2—S(O)pC(O)Rg2, -Af2—S(O)pN(Rh2)Ri2, -Ag2—S(O)pORj2, —N3, —N(Rk2)Rl2, —N(H)CN, —NO2, —ORm2, —SRn2 or ═Qd2;
• each Aa2 to Ag2 independently represents a single bond, —N(Ro2)—, —C(Qe2)N(Rp2)— or —O—;
• each Qa2 to Qe3 independently represents ═O, ═S, ═NRq2 or ═N(ORr2);
• each Ra2 independently represents heterocycloalkyl optionally substituted by one or more groups independently selected from G4b, aryl optionally substituted by one or more groups independently selected from G4c, or heteroaryl optionally substituted by one or more groups independently selected from G4d;
• each Rf2 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G4a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G4a, C2-6 alkynyl optionally substituted by one or more groups independently selected from G4a, heterocycloalkyl optionally substituted by one or more groups independently selected from G4b, aryl optionally substituted by one or more groups independently selected from G4c, or heteroaryl optionally substituted by one or more groups independently selected from G4d;
• each Rb2, Rc2, Rd2, Re2, Rg2, Rh2, Ri2, Rj2, Rk2, Rl2, Rm2, Rn2, Rq2 and Rr2 independently represents H, C1-6 alkyl optionally substituted by one or more groups independently selected from G4a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G4a, C2-6 alkynyl optionally substituted by one or more groups independently selected from G4a, heterocycloalkyl optionally substituted by one or more groups independently selected from G4b, aryl optionally substituted by one or more groups independently selected from G4c, or heteroaryl optionally substituted by one or more groups independently selected from G4d;
• or any two Rc2 and Rd2, Rh2 and Ri2 and/or Rk2 and Rl2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C1-3 alkyl optionally substituted by one or more halo, C2-3 alkenyl optionally substituted by one or more halo, C2-3 alkynyl optionally substituted by one or more halo, and ═O;
• each Ro2 and Rp2 independently represents H, C1-6 alkyl optionally substituted by one or more halo, C2-6 alkenyl optionally substituted by one or more halo, or C2-6 alkynyl optionally substituted by one or more halo;
• each G3a independently represents halo, —CN, -Aa3—C(Qa3)Rb3, -Ab3—C(Qb3)N(Rc3)Rd3, -Ac3—C(Qc3)ORe3, -Ad3—S(O)qRf3, -Ae3-S(O)qC(O)Rg3, -Af3—S(O)qN(Rh3)Ri3, -Ag3—S(O)qORj3, —N3, —N(Rk3)Rl3, —N(H)CN, —NO2, —ORm3, —SRn3 or ═Qd3;
• each G3b, G3c and G3d independently represents halo, Ra3, —CN, -A3—C(Qa3)Rb3, -Ab3—C(Qb3)N(Rc3) Rd3, -Ac3—C(Qc3)ORe3, -Ad3—S(O)qRf3, -Ae3—S(O)qC(O) Rg3, -Af3—S(O)N(Rh3)Ri3, -Ag3—S(O)qORj3, —N3, —N(Rk3)Rl3, —N(H)CN, —NO2, —ORm3, —SRn3 or ═Qd3;
• each Aa3 to Ag3 independently represents a single bond, —N(Ro3)—, —C(Qe3)N(Rp3)— or —O—;
• each Qa3 to Qe3 independently represents ═O, ═S, ═NRq3 or ═N(ORr3);
• each Ra3 and Rf3 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G5a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G5a, C2-6 alkynyl optionally substituted by one or more groups independently selected from G5a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G5b;
• each Rb3, Rc3, Rd3, Re3, Rg3, Rh3, Ri3, Rj3, Rk3, Rl3, Rm3, R, Rq3 and Rr3 independently represents H, C1-6 alkyl optionally substituted by one or more groups independently selected from G5a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G5a, C2-6 alkynyl optionally substituted by one or moree groups independently selected from G5a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G5b;
• or any two Rc3 and Rd3, Rh3 and Ri3 and/or Rk3 and Rl3 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C1-3 alkyl optionally substituted by one or more halo, C2-3 alkenyl optionally substituted by one or more halo, C2-3 alkynyl optionally substituted by one or more halo, and ═O;
• each Ro3 and Rp3 independently represents H, C1-6 alkyl optionally substituted by one or more halo, C2-6 alkenyl optionally substituted by one or more halo, or C2-6 alkynyl optionally substituted by one or more halo;
• each G4a independently represents halogen, —CN, -Aa4—C(Qa4)Rb4, -Ab4—C(Qb4)N(Rc4)Rd4, -Ac4—C(Qc4)ORe4, -Ad4—S(O)rRf4, -Ae4—S(O)rC(O)Rg4, -Af4—S(O)rN(Rh4) Ri4, -Ag4—S(O)ORj4, —N3, —N(Rk4)Rl4, —N(H)CN, —NO2, —ORm4, —SRn4 or ═Qd4;
• each G4b, G4c and G4d independently represents halo, Ra4, —CN, -Aa4—C(Qa4)Rb4-Ab4—C(Qb4)N(Rc4) Rd4, -Ac4—C(Qc4)ORe4, -Ad4-S(O)rRf4, -Ae4—S(O)rC(O)Rg4, -Af4—S(O)rN(Rh4)Ri4, -Ag4—S(O)rORj4, —N3, —N(Rk4)Rl4, —N(H)CN, —NO2, —ORm4, —SRn4 or ═Qd4;
• each Aa4 to Ag4 independently represents a single bond, —N(Ro4)—, —C(Qe4)N(Rp4)— or —O—;
• each Qa4 to Qe4 independently represents ═O, ═S, ═NRq4 or ═N(ORr4);
• each Ra4 and Rf4 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G6a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G6a, C2-6 alkynyl optionally substituted by one or more groups independently selected from G6a, heterocycloalkyl optionally substituted by one or more groups independently selected from G6b, or aryl optionally substituted by one or more groups independently selected from G6c;
• each Rb4, Rc4, Rd4, Re4, Rg4, Rh4, Ri4, Rj4, Rk4, Rl4, Rm4, Rn4, Rq4 and Rr4 independently represents H, C1-6 alkyl optionally substituted by one or more groups independently selected from G6a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G6a, C2-6 alkynyl optionally substituted by one or more groups independently selected from G6a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G6b;
• or any two Rc4 and Rd4, Rh4 and Ri4 and/or Rk4 and Rl4 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C1-3 alkyl optionally substituted by one or more halo, C2-3 alkenyl optionally substituted by one or more halo, C2-3 alkynyl optionally substituted by one or more halo and ═O;
• each Ro4 and Rp4 independently represents H, C1-6 alkyl optionally substituted by one or more halo, C2-6 alkenyl optionally substituted by one or more halo, or C2-6 alkynyl optionally substituted by one or more halo;
• each G5a and G6a independently represents halo or —OC1-6 alkyl optionally substituted by one or more halo, —OC2-6 alkenyl optionally substituted by one or more halo, and —OC2-6 alkynyl optionally substituted by one or more halo;
• each G5b, G6b and G6c represents halo, C1-6 alkyl optionally substituted by one or more halo, C2-6 alkenyl optionally substituted by one or more halo, or C2-6 alkynyl optionally substituted by one or more halo, —OC1-6 alkyl optionally substituted by one or more halo, —OC2-6 alkenyl optionally substituted by one or more halo, or —OC2-6 alkynyl optionally substituted by one or more halo;
• each n independently represents 1 or 2;
• each p independently represents 1 or 2;
• each q independently represents 1 or 2;
• and
• each r independently represents 1 or 2,
• with the proviso that the compound of formula I is not a compound selected from:
• exo-11-methyl-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• 11-methyl-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-methyl 3,5,10-trioxo-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-8-en-11-carboxylate;
• exo-methyl 3,5,10-trioxo-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-8-en-11-carboxylate;
• exo-4,11-diphenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-4,11-diphenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• diphenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• 11-(4-bromobenzyl)-4-methyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-4-phenyl-11-(4-pyridyl)-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-4-phenyl-11-(2-pyridyl)-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-11-(2-iodobenzyl)-4-methyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-11-(2-iodobenzyl)-4-methyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-11-benzyl-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• 11-benzyl-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-4-methyl-11-(2-vinylphenyl)-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-4-methyl-11-(2-vinylphenyl)-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-4-phenyl-11-(2-pyridyl)-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-11-(3-oxocyclohex-1-en-1-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-4-(3,5,10-trioxo-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-8-en-11-yl)pyridine-1-oxide;
• exo-4-phenyl-11-styryl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-11-(6,6-dimethyl-3-oxocyclohex-1-en-1-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• 11-(4-tert-butylbenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-11-(2-iodobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-11-(4,6-dimethylpyrimidin-2-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-11-(4,6-dimethylpyrimidin-2-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-11-(4,4-dimethyl-3-oxopent-1-ene-1-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-4-(4-ethylphenyl)-11-(2-iodobenzyl)-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-11-(6-chloropyridazin-3-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-11-(6-chloropyridazin-3-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-11-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-11-(2-pyridylmethyl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-11-(2,4-dinitrophenyl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-4-phenyl-11-(6-phenylpyridazin-3-yl)-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-11-(4,6-diphenyl-1,3,5-triazin-2-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-4-(2,6-diisopropylphenyl)-11-(2-iodobenzyl)-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-4-(2,6-diisopropylphenyl)-11-(2-iodobenzyl)-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-11-((E)-3-(4-bromophenyl)-3-oxoprop-1-en-1-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-11-((E)-3-(4-chlorophenyl)-3-oxoprop-1-en-1-yl)-4-phenyl-4,11-diazatricyclo-[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-11-((E)-3-(2,4-dinitrophenyl)-3-oxoprop-1-en-1-yl)-4-phenyl-4,11-diazatricyclo-[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo,exo-1,2-bis-(4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione-11-yl)-ethane;
• endo,exo-1,2-bis-(4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione-11-yl)-ethane;
• exo,exo-1,3-bis-(4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione-11-yl)-propane;
• endo,exo-1,3-bis-(4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione-11-yl)-propane;
• 4-phenyl-11-(3-phenyl-1,2,4-thiadiazol-5-yl)-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• exo-11-(5,6-diphenyl-1,2,4-triazin-3-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• endo-11-(5,6-diphenyl-1,2,4-triazin-3-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione;
• and
• endo-11-(1,2-bis(3-nitrophenyl)vinyl)-4-phenyl-4,11-diazatricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione.