Pyridazinones and their use in the treatment of cancer

A method of treating cancer, wherein the cancer is selected from pharyngeal squamous cell carcinoma, colorectal carcinoma, epidermoid (skin) carcinoma and lung carcinoma comprising administering to a patient in need thereof a therapeutically effective amount of a compound, wherein the compound is represented by formula I

• or a pharmaceutically acceptable salt thereof, wherein:
• W represents C1 alkylene optionally substituted by one or more groups independently selected from R4;
• X represents O;
• Y represents C1-6 alkyl optionally substituted by one or more groups independently selected from G1a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G1a, C2-6 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;
• Z represents O, S or NR5;
• R1 represents H, halo, Ra1, —CN, —C(Qa1)Rb1, —C(Qb1)N(Rc1)Rd1, —C(Qc1)ORe1, —S(O)nRf1, —S(O)pN(Rg1)Rh1, —S(O)pORi1 or —NO2;
• R2 represents H, halo, —CN or —N3;
• R3 represents H, halo or Rj1;
• R4 represents halo, C1-6 alkyl optionally substituted by one or more groups independently selected from G1e, C2-6 alkenyl optionally substituted by one or more groups independently selected from G1e, or C2-6 alkynyl optionally substituted by one or more groups independently selected from G1e;
• R5 represents H, Rk1, —ORl1 or —N(Rm1)Rn1;
• Qa1 to Qc1 each independently represents ═O, ═S, ═NRo1 or ═N(ORp1);
• each Ra1, Rf1, Rj1 and Rk1 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G2a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G2a, C2-6 alkynyl optionally substituted by one or more groups independently selected from G2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G2b;
• each Rb1, Rc1, Rd1, Re1, Rg1, Rh1, Ri1, Rl1, Rm1, Rn1, Ro1 and Rp1 independently represents H, C1-6 alkyl optionally substituted by one or more groups independently selected from G2a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G2a, C2-6 alkynyl optionally substituted by one or more groups independently selected from G2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G2b;
• or any two Rc1 and Rd1, Rg1 and Rh1 and/or Rm1 and Rn1 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 halogen, C1-3 alkyl optionally substituted by one or more halogens, C2-3 alkenyl optionally substituted by one or more halogens, C2-3 alkynyl optionally substituted by one or more halogens, and ═O;
• each G1a, G1b, G1c and G1d represent halogen, RA2, —CN,-Aa1-C(Qa2)Rb2, -Ab1-C(Qb2)N(Rc2)Rd2, -Ac1-C(Qc2)ORe2, -Ad1-S(O)qRf2, -Ae1-S(O)qC(O)Rg2, -Af1-S(O)qN(Rh2)Ri2, -Ag1-S(O)qORj2, —N3, —N(Rk2)Rl2, —N(H)CN, —NO2, —ORm2, —SRn2 or ═Qd2;
• Aa1 to Ag1 each independently represents a single bond, —N(R6)—, —C(Qe2)N(R7)— or —O—;
• Qa2 to Qe2 each independently represents ═O, ═S, ═NRo2 or ═N(ORp2);
• each R6 and R7 independently represents H, C1-6 alkyl optionally substituted by one or more F, C2-6 alkenyl optionally substituted by one or more F, or C2-6 alkynyl optionally substituted by one or more F;
• each Ra2 and Rf2 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, or heterocycloalkyl optionally substituted by one or more groups independently selected from G3b;
• each Rb2, Rc2, Rd2, Re2, Rg2, Rh2, Ri2, Rj2, Rk2, Rl2, Rm2, Rn2, Ro2 and Rp2 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, or heterocycloalkyl optionally substituted by one or more groups independently selected from G3b;
• 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 halogen, C1-3 alkyl optionally substituted by one or more halogens, C2-3 alkenyl optionally substituted by one or more halogens, C2-3 alkynyl optionally substituted by one or more halogens, and ═O;
• each G1e independently represents halo, Ra2, —CN, —N(Ra3)Rb3, —ORc3 or —SRd3;
• Ra3, Rb3, Rc3 and Rd3 each independently represents H, C1-6 alkyl optionally substituted by one or more F, C2-6 alkenyl optionally substituted by one or more F, or C2-6 alkynyl optionally substituted by one or more F;
• or Ra3 and Rb3 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 fluoro, C1-3 alkyl optionally substituted by one or more fluoro, C2-3 alkenyl optionally substituted by one or more fluoro, C2-3 alkynyl optionally substituted by one or more fluoro, and ═O;
• each G2a and G2b independently represents halo, —CN, —N(Ra4)Rb4, —ORc4, —SRd4 or ═O;
• each Ra4, Rb4, Rc4 and Rd4 independently represents H, C1-6 alkyl optionally substituted by one or more fluoro, C2-6 alkenyl optionally substituted by one or more fluoro, or C2-6 alkynyl optionally substituted by one or more fluoro;
• or Ra4 and Rb4 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 fluoro, C1-3 alkyl optionally substituted by one or more fluoro, C2-3 alkenyl optionally substituted by one or more fluoro, C2-3 alkynyl optionally substituted by one or more fluoro, and ═O;
• each G3a and G3b independently represents halo, —CN, —N(Ra5)Rb5, —ORc5, —SRd5 or ═O;
• each Ra5, Rb5, Rc5 and Rd5 independently represents H, C1-6 alkyl optionally substituted by ONE OR MORE FLUORO, C2-6 ALKENYL OPTIONALLY SUBSTITUTED BY ONE OR MORE FLUORO, OR C2-6 ALKYNYL optionally substituted by one or more fluoro;
• or Ra5 and Rb5 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 fluoro, C1-3 alkyl optionally substituted by one or more fluoro, C2-3 alkenyl optionally substituted by one or more fluoro, C2-3 alkynyl optionally substituted by one or more fluoro, and ═O;
• each n independently represents 0, 1 or 2,
• each p independently represents 1 or 2, and
• each q independently represents 1 or 2.

A pharmaceutical composition comprising a compound, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier, wherein the compound is represented by formula I

• or a pharmaceutically acceptable salt thereof, wherein:
• W represents C1 alkylene optionally substituted by one or more groups independently selected from R4;
• X represents O;
• Y represents C1-6 alkyl optionally substituted by one or more groups independently selected from G1a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G1a, C2-6 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;
• Z represents O, S or NR5;
• R1 represents H, halo, Ra1, —CN, —C(Qa1)Rb1, —C(Qb1)N(Rc1)Rd1, —C(Qc1)ORe1, —S(O)nRf1, —S(O)pN(Rg1)Rh1, —S(O)pORi1 or —NO2;
• R2 represents H, halo, —CN or —N3;
• R3 represents H, halo or Rj1;
• R4 represents halo, C1-6 alkyl optionally substituted by one or more groups independently selected from G1e, C2-6 alkenyl optionally substituted by one or more groups independently selected from G1e, or C2-6 alkynyl optionally substituted by one or more groups independently selected from G1e;
• R5 represents H, Rk1, —ORl1 or —N(Rm1)Rn1;
• Qa1 to Qc1 each independently represents ═O, ═S, ═NRo1 or ═N(ORp1);
• each Ra1, Rf1, Rj1 and Rk1 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G2a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G2a, C2-6 alkynyl optionally substituted by one or more groups independently selected from G2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G2b;
• each Rb1, Rc1, Rd1, Re1, Rg1, Rh1, Ri1, Rl1, Rm1, Rn1, Ro1 and Rp1 independently represents H, C1-6 alkyl optionally substituted by one or more groups independently selected from G2a, C2-6 alkenyl optionally substituted by one or more groups independently selected from G2a, C2-6 alkynyl optionally substituted by one or more groups independently selected from G2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G2b;
• or any two Rc1 and Rd1, Rg1 and Rh1 and/or Rm1 and Rn1 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 halogen, C1-3 alkyl optionally substituted by one or more halogens, C2-3 alkenyl optionally substituted by one or more halogens, C2-3 alkynyl optionally substituted by one or more halogens, and ═O;
• each G1a, G1b, G1c and G1d represent halogen, Ra2, —CN, -Aa1-C(Qa2)Rb2, -Ab1-C(Qb2)N(Rc2)Rd2, -Ac1-C(Qc2)ORe2, -Ad1-S(O)qRf2, -Ae1-S(O)qC(O)Rg2, -Af1-S(O)qN(Rh2)Ri2, -Ag1-S(O)qORj2, —N3, —N(Rk2)Rl2, —N(H)CN, —NO2, —ORm2, —SRn2 or ═Qd2;
• Aa1 to Ag1 each independently represents a single bond, —N(R6)—, —C(Qe2)N(R7)— or —O—;
• Qa2 to Qc2 each independently represents ═O, ═S, ═NRo2 or ═N(ORp2);
• each R6 and R7 independently represents H, C1-6 alkyl optionally substituted by one or more F, C2-6 alkenyl optionally substituted by one or more F, or C2-6 alkynyl optionally substituted by one or more F;
• each Ra2 and Rf2 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, or heterocycloalkyl optionally substituted by one or more groups independently selected from G3b;
• each Rb2, Rc2, Rd2, Re2, Rg2, Rh2, Ri2, Rj2, Rk2, Rl2, Rm2, Rn2, Ro2 and Rp2 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, or heterocycloalkyl optionally substituted by one or more groups independently selected from G3b;
• 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 halogen, C1-3 alkyl optionally substituted by one or more halogens, C2-3 alkenyl optionally substituted by one or more halogens, C2-3 alkynyl optionally substituted by one or more halogens, and ═O;
• each G1e independently represents halo, Ra2, —CN, —N(Ra3)Rb3, —ORc3 or —SRd3;
• Ra3, Rb3, Rc3 and Rd3 each independently represents H, C1-6 alkyl optionally substituted by one or more F, C2-6 alkenyl optionally substituted by one or more F, or C2-6 alkynyl optionally substituted by one or more F;
• or Ra3 and Rb3 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 fluoro, C1-3 alkyl optionally substituted by one or more fluoro, C2-3 alkenyl optionally substituted by one or more fluoro, C2-3 alkynyl optionally substituted by one or more fluoro, and ═O;
• each G2a and G2b independently represents halo, —CN, —N(Ra5)Rb5, —ORc5, —SRd5 or ═O;
• each Ra4, Rb4, Rc4 and Rd4 independently represents H, C1-6 alkyl optionally substituted by one or more fluoro, C2-6 alkenyl optionally substituted by one or more fluoro, or C2-6 alkynyl optionally substituted by one or more fluoro;
• or Ra4 and Rb4 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 fluoro, C1-3 alkyl optionally substituted by one or more fluoro, C2-3 alkenyl optionally substituted by one or more fluoro, C2-3 alkynyl optionally substituted by one or more fluoro, and ═O;
• each G3a and G3b independently represents halo, —CN, —N(Ra5)Rb5, —ORc5, —SRd5 or ═O;
• each Ra5, Rb5, Rc5 and Rd5 independently represents H, C1-6 alkyl optionally substituted by one or more fluoro, C2-6 alkenyl optionally substituted by one or more fluoro, or C2-6 alkynyl optionally substituted by one or more fluoro;
• or Ra5 and Rb5 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 fluoro, C1-3 alkyl optionally substituted by one or more fluoro, C2-3 alkenyl optionally substituted by one or more fluoro, C2-3 alkynyl optionally substituted by one or more fluoro, and ═O;
• each n independently represents 0, 1 or 2,
• each p independently represents 1 or 2, and
• each q independently represents 1 or 2.