Tetrahydroindazoles and medical uses thereof

A method of treating cancer and/or treating a viral infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of:

• soft tissue cancers, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, cancers of the head and/or nervous system, gynecological cancers, haematologic cancers, skin cancers, and neuroblastomas;
• wherein formula I is:
• and wherein:
• A1 represents aryl optionally substituted by one or more groups independently selected from G1 or heteroaryl optionally substituted by one or more groups independently selected from G2;
• A2 represents aryl optionally substituted by one or more groups independently selected from G3 or heteroaryl optionally substituted by one or more groups independently selected from G4;
• L1 represents —C(O)—, —C(O)N(R3)—, —C(O)O—, —S(O)j— or —S(O)kN(R4)—;
• R1 represents H or C1-3 alkyl optionally substituted by one or more halo;
• R2 represents F;
• R3 and R4 each independently represents H or C1-3 alkyl optionally substituted by one or more halo;
• each G1 independently represents halo, Ra1, —CN, -Aa1-C(Qa1)Rb1, -Ab1-C(Qb1)N(Rc1)Rd1, -Ac1-C(Qc1)ORe1, -Ad1-S(O)pRf1, -Ae1-S(O)qN(Rg1)Rh1, -Af1-S(O)pORi1, —N3, —N(Rj1)Rk1, —N(H)CN, —NO2, —ONO2, —ORl1 or —SRm1;
• each Qa1 to Qc1 independently represents ═O, ═S, ═NRa1 or ═N(ORo1);
• each Aa1 to Af1 independently represents a single bond, —N(Rp1)— or —O—;
• each G2 independently represents halo, Ra2, —CN, -Aa2-C(Qa2)Rb2-Ab2-C(Qb2)N(Rc2)Rd2, -Ac2-C(Qc2)ORe2, -Ad-S(O)pRf2, -Ae2-S(O)qN(Rg2)Rh2, -Af2-S(O)pORi2, —N3, —N(Rj2)Rk2, —N(H)CN, —NO2, —ONO2, —ORl2 or —SRm2;
• each Qa2 to Qc2 independently represents ═O, ═S, ═NRn2 or ═N(ORo2);
• each Aa2 to Af2 independently represents a single bond, —N(Rp2)— or —O—;
• each G3 independently represents halo, Ra3, —CN, -Aa3-C(Qa3)Rb3, -Ab3-C(Qb3)N(Rc3)Rd3, -Ac3-C(Qc3)ORe3, -Ad3-S(O)pRf3, -Ae3-S(O)qN(Rg3)Rh3, -A-S(O)pORi3, —N3, —N(Rj3)Rk3, —N(H)CN, —NO2, —ONO2, —ORl3 or —SRm3;
• each Qa3 to Qc3 independently represents ═O, ═S, ═NRn3 or ═N(ORo3);
• each Aa3 to Af3 independently represents a single bond, —N(Rp3)— or —O—;
• each G4 independently represents halo, Ra4, —CN, -Aa4-C(Qa4)Rh4, -Ab4-C(Qb4)N(Rc4)Rd4, -Ac4-C(Qc4)ORe4, -Ad4-S(O)pRf4, -Ae4-S(O)qN(Rg4)Rh4, -Af4-S(O)pORi4, —N3, —N(Rj4)Rk4, —N(H)CN, —NO2, —ONO2, —ORl4 or —SRm4;
• each Qa4 to Qc4 independently represents ═O, ═S, ═NRn4 or ═N(ORo4);
• each Aa4 to Af4 independently represents a single bond, —N(Rp4)— or —O—;
• each Ra1 and Rf1 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G5a, heterocycloalkyl optionally substituted by one or more groups independently selected from G5b, aryl optionally substituted by one or more groups independently selected from G5c, or heteroaryl optionally substituted by one or more groups independently selected from G5d;
• each Rp1 independently represents H or C1-6 alkyl optionally substituted by one or more halo;
• each Rb1, Rc1, Rd1, Re1, Rf1, Rh1, Ri1, Rj1, Rk1, Rl1, Rm1, Rn1 and Ro1 independently represents H, C1-6 alkyl optionally substituted by one or more groups independently selected from G5a, heterocycloalkyl optionally substituted by one or more groups independently selected from G5b, aryl optionally substituted by one or more groups independently selected from G5c, or heteroaryl optionally substituted by one or more groups independently selected from G5d;
• or
• alternatively any of Rc1 and Rd1, Rg1 and Rh1 and/or Rj1 and Rk1 are linked together to form, together 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, and ═O;
• each Ra2 and Rf2 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G6a, heterocycloalkyl optionally substituted by one or more groups independently selected from G6b, aryl optionally substituted by one or more groups independently selected from G6c, or heteroaryl optionally substituted by one or more groups independently selected from G6d;
• each Rp2 independently represents H or C1-6 alkyl optionally substituted by one or more F;
• each Rb2, Rc2, Rd2, Re2, Rg2, Rh2, Ri2, Rj2, Rk2, Rl2, Rm2, Rn2 and Ro2 independently represents H, C1-6alkyl optionally substituted by one or more groups independently selected from G6a, heterocycloalkyl optionally substituted by one or more groups independently selected from G6b, aryl optionally substituted by one or more groups independently selected from G6c, or heteroaryl optionally substituted by one or more groups independently selected from G6d;
• or
• alternatively any of Rc2 and Rd2, Rg2 and Rh2 and/or Rj2 and Rk2 are linked together to form, together 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, and ═O;
• each Ra3 and Rf3 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G7a, heterocycloalkyl optionally substituted by one or more groups independently selected from G7b, aryl optionally substituted by one or more groups independently selected from G7c, or heteroaryl optionally substituted by one or more groups independently selected from G7d;
• each Rp3 independently represents H or C1-6 alkyl optionally substituted by one or more F;
• each Rb3, Rc3, Rd3, Re3, Rg3, Rh3, Ri3, Rj3, Rk3, Rl3, Rm3, Rn3 and Ro3 independently represents H, C1-6 alkyl optionally substituted by one or more groups independently selected from G7a, heterocycloalkyl optionally substituted by one or more groups independently selected from G7b, aryl optionally substituted by one or more groups independently selected from G7c, or heteroaryl optionally substituted by one or more groups independently selected from G7d;
• or
• alternatively any of Rc3 and Rd3, Rg3 and Rh3 and/or Rj3 and Rk3 are linked together to form, together 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, and ═O;
• each Ra4 and Rf4 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G8a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G8b, aryl optionally substituted by one or more groups independently selected from G8c, or heteroaryl optionally substituted by one or more groups independently selected from G8d;
• each Rp4 independently represents H or C1-6 alkyl optionally substituted by one or more F;
• each Rb4, Rc4, Rd4, Re4, Rg4, Rh4, Ri4, Rj4, Rk4, Rl4, Rm4, Rn4 and Ro4 independently represents H, C1-6alkyl optionally substituted by one or more groups independently selected from G8a or heterocycloalkyl optionally substituted by one or more groups independently selected from G8b;
• or
• alternatively any of Rc4 and Rd4, Rg4 and Rh4 and/or Rj4 and Rk4 are linked together to form, together 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, and ═O;
• each G5a, G5b, G6a, G6b, G7a, G7b, G8a and G8b independently represents halo, —CN, —N(Rb5)Rc5, —ORd5, —SRe5 or ═O;
• each G5c, G5d, G6c, G6d, G7c, G7d, G8c and G8d independently represents halo, Ra5, —CN, —N(Rb5)Rc5, —ORd5, —SRe5 or ═O;
• each Ra5 independently represents C1-6 alkyl optionally substituted by one or more F;
• each Rb5, Rc5, Rd5 and Re5 independently represents H or C1-6 alkyl optionally substituted by one or more F;
• or Rb5 and Rc5 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 F, C1-3 alkyl optionally substituted by one or more F, and ═O;
• each j independently represents 0, 1 or 2;
• each k, p and q independently represents 1 or 2;
• and
• n represents 0 to 7.

A compound of formula Ib:

• or a pharmaceutically acceptable salt thereof, wherein:
• A1 represents aryl optionally substituted by one or more groups independently selected from G1 or heteroaryl optionally substituted by one or more groups independently selected from G2;
• A2 represents aryl optionally substituted by one or more groups independently selected from G3 or heteroaryl optionally substituted by one or more groups independently selected from G4;
• L1 represents —C(O)—, —C(O)N(R3)—, —C(O)O—, —S(O)j— or —S(O)kN(R4)—;
• R1 represents H or C1-3 alkyl optionally substituted by one or more halo;
• R2 represents F;
• R3 and R4 each independently represents H or C1-3 alkyl optionally substituted by one or more halo;
• each G1 independently represents halo, Ra1, —CN, -Aa1-C(Qa1)Rb1, -Ab1-C(Qb1)N(Rc1)Rd1, -Ac1-C(Qc1)ORe1, -Ad1-S(O)pRf1, -Ae1-S(O)qN(Rg1)Rh1, -Af1-S(O)pORi1, —N3, —N(Rj1)Rk1, —N(H)CN, —NO2, —ONO2, —ORl1 or —SRm1;
• each Qa1 to Qc1 independently represents ═O, ═S, ═NRn1 or ═N(ORo1);
• each Aa1 to Af1 independently represents a single bond, —N(Rp1)— or —O—;
• each G2 independently represents halo, Ra2, —CN, -Aa2-C(Qa2)Rb2-Ab2-C(Qb2)N(Rc2)Rd2, -Ac2-C(Qc2)ORe2, -Ad2-S(O)pRf2, -Ae2-S(O)qN(Rg2)Rh2, -Af2-S(O)pORi2, —N3, —N(Rj2)Rk2, —N(H)CN, —NO2, —ONO2, —ORl2 or —SRm2;
• each Qa2 to Qc2 independently represents ═O, ═S, ═NRn2 or ═N(ORo2);
• each Aa2 to Af2 independently represents a single bond, —N(Rp2)— or —O—;
• each G3 independently represents halo, Ra3, —CN, -Aa3-C(Qa3)Rb3, -Ab3-C(Qb3)N(Rc3)Rd3, -Ac3-C(Qc3)ORe3, -Ad3-S(O)pRf3, -Ae3-S(O)qN(Rg3)Rh3, -Af3-S(O)pORi3, —N3, —N(Rj3)Rk3, —N(H)CN, —NO2, —ONO2, —ORl3 or —SRm3;
• each Qa3 to Qc3 independently represents ═O, ═S, ═NRn3 or ═N(ORo3);
• each Aa3 to Af3 independently represents a single bond, —N(Rp3)— or —O—;
• each G4 independently represents halo, Ra4, —CN, -Aa4-C(Qa4)Rb4, -Ab4-C(Qb4)N(Rc4)Rd4, -Ac4-C(Qc4)ORe4, -Ad4-S(O)pRf4, -Ae4S(O)qN(Rg4)Rh4, -Af4-S(O)pORi4, —N3, —N(Rj4)Rk4, —N(H)CN, —NO2, —ONO2, —ORl4 or —SRm4;
• each Qa4 to Qc4 independently represents ═O, ═S, ═NRn4 or ═N(ORo4;
• each Aa4 to Af4 independently represents a single bond, —N(Rp4)— or —O—;
• each Ra1 and Rf1 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G5a, heterocycloalkyl optionally substituted by one or more groups independently selected from G5b, aryl optionally substituted by one or more groups independently selected from G5c, or heteroaryl optionally substituted by one or more groups independently selected from G5d;
• each Rp1 independently represents H or C1-6 alkyl optionally substituted by one or more halo;
• each Rb1, Rc1, Rd1, Re1, Rg1, Rh1, Ri1, Rj1, Rk1, Rl1, Rm1, Rn1 and Ro1 independently represents H, C1-6 alkyl optionally substituted by one or more groups independently selected from G5a, heterocycloalkyl optionally substituted by one or more groups independently selected from G5b, aryl optionally substituted by one or more groups independently selected from G5c, or heteroaryl optionally substituted by one or more groups independently selected from G5d;
• or
• alternatively any of Rc1 and Rd1, Rg1 and Rh1 and/or Rj1 and Rk1 are linked together to form, together 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, and ═O;
• each Ra2 and Rf2 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G6a, heterocycloalkyl optionally substituted by one or more groups independently selected from G6b, aryl optionally substituted by one or more groups independently selected from G6c, or heteroaryl optionally substituted by one or more groups independently selected from G6d;
• each Rp2 independently represents H or C1-6 alkyl optionally substituted by one or more F;
• each Rb2, Rc2, Rd2, Re2, Rg2, Rh2, Ri2, Rj2, Rk2, Rl2, Rm2, Rn2 and Ro2 independently represents H, C1-6alkyl optionally substituted by one or more groups independently selected from G6a, heterocycloalkyl optionally substituted by one or more groups independently selected from G6b, aryl optionally substituted by one or more groups independently selected from G6c, or heteroaryl optionally substituted by one or more groups independently selected from G6d;
• or
• alternatively any of Rc2 and Rd2, Rg2 and Rh2 and/or Rj2 and Rk2 are linked together to form, together 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, and ═O;
• each Ra3 and Rf3 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G7a, heterocycloalkyl optionally substituted by one or more groups independently selected from G7b, aryl optionally substituted by one or more groups independently selected from G7c, or heteroaryl optionally substituted by one or more groups independently selected from G7d;
• each Rp3 independently represents H or C1-6 alkyl optionally substituted by one or more F;
• each Rb3, Rc3, Rd3, Re3, Rf3, Rh3, Ri3, Rj3, Rk3, Rl3, Rm3, Rn3 and Ro3 independently represents H, C1-6 alkyl optionally substituted by one or more groups independently selected from G7a, heterocycloalkyl optionally substituted by one or more groups independently selected from G7b, aryl optionally substituted by one or more groups independently selected from G7c, or heteroaryl optionally substituted by one or more groups independently selected from G7d;
• or
• alternatively any of Rc3 and Rd3, Rg3 and Rh3 and/or Rj3 and Rk3 are linked together to form, together 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, and ═O;
• each Ra4 and Rf4 independently represents C1-6 alkyl optionally substituted by one or more groups independently selected from G8a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G8b, aryl optionally substituted by one or more groups independently selected from G8c, or heteroaryl optionally substituted by one or more groups independently selected from G8d;
• each Rp4 independently represents H or C1-6 alkyl optionally substituted by one or more F;
• each Rb4, Rc4, Rd4, Re4, Rh4, Ri4, Rj4, Rk4, Rl4, Rm4, Rn4 and Ro4 independently represents H, C1-6alkyl optionally substituted by one or more groups independently selected from G8a or heterocycloalkyl optionally substituted by one or more groups independently selected from G8b;
• or
• alternatively any of Rc4 and Rd4, Rg4 and Rh4 and/or Rj4 and Rk4 are linked together to form, together 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, and ═O;
• each G5a, G5b, G6a, G6b, G7a, G7b, G8a and G8b independently represents halo, —CN, —N(Rb5)Rc5, —ORd5, —SRe5 or ═O;
• each G5c, G5d, G6c, G6d, G7c, G7d, G8c and G8d independently represents halo, Ra5, —CN, —N(Rb5)Rc5, —ORd5, —SRe5 or ═O;
• each Ra5 independently represents C1-6 alkyl optionally substituted by one or more F;
• each Rb5, Rc5, Rd5 and Re5 independently represents H or C1-6 alkyl optionally substituted by one or more F;
• or Rb5 and Rc5 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 F, C1-3 alkyl optionally substituted by one or more F, and ═O;
• each j independently represents 0, 1 or 2;
• each k, p and q independently represents 1 or 2;
• and
• n represents 0 to 7;
• with the proviso that the compound of formula Ib is not (S)-N-(1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)picolinamide.