1,2,4-triazine-4-amine derivatives

A method of treatment of cancer, comprising administering an effective amount of a compound to a patient in need of such treatment, wherein the compound is represented by formula A1:

• wherein:
• A represents CyAA or HetAA;
• CyAA represents a 6-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system, which CyAA group is substituted, in the 3-position relative to the point of attachment to the triazine ring, with a R4a substituent and is optionally substituted by one or more additional R4a substituents;
• HetAA represents a 6-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, and which HetAA group is substituted, in the 3-position relative to the point of attachment to the triazine ring, with a R4b substituent and is optionally substituted by one or more additional R4b substituents;
• B represents a CyBB or HetBB;
• CyBB represents phenyl optionally substituted by one or more R4c substituents;
• HetBB represents a 6-membered aromatic heterocyclic group which contains one or more N atoms, and which HetBB group is optionally substituted by one or more R4d substituents;
• R4a to R4d represent, independently at each occurrence,
• (a) halo,
• (b) CN,
• (c) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, which latter three groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR5a, S(O)qR5b, S(O)2N(R5cR5d), N(R5e)S(O)2R5f, N(R5g)(R5h), B1—C(G1)-B2—R5i, aryl and Het1,
• (d) Cy3, which Cy3 group is optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR6a, S(O)qR6b, S(O)2N(R6cR6d), N(R6e)S(O)2R6f, N(R6g)(R6h), B3—C(G1)-B4—R6i, aryl and Het2,
• (e) Heta, which Heta group is optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR7a, S(O)gR7b, S(O)2N(R7c)(R7d), N(R7e)S(O)2R7f, N(R7g)(R7h), B5—C(G1)-B6—R7i, aryl and Het3,
• (f) OR8,
• (g) S(O)rR9,
• (h) S(O)2N(R9b)(R9c),
• (i) N(R9d)S(O)2R9e,
• (j) N(R9f)(R9g),
• (k) B7—C(G1)-B8—R9h,
• (l) ═O,
• (m) ═S,
• or when two R4a, R4b, R4c or R4d groups are attached to the same carbon atom in a non-aromatic portion of a CyAA, HetA, CyBB or HetBB group, they may form, together with the carbon atom to which they are attached, a saturated or unsaturated 3 to 6-membered ring, which ring optionally contains one to three heteroatoms selected from O, S and N, and which ring is optionally substituted by one or more R9i substituents;
• G1 represents, independently at each occurrence, O, S or NR5j;
• R8 represents, independently at each occurrence,
• H,
• Cy3, Heta, aryla, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, which latter seven groups are optionally substituted by one or more substituents selected from halo, —CN, C3-6 cycloalkyl, aryl, Het4, —C(O)OR10, —C(O)R11, —C(O)N(RN1)(RN2), S(O)rR9aa, S(O)2N(R9ba)(R9ca), N(R9da)S(O)2R9ea and N(R9fa)(R9ga);
• Cy3 represents, independently at each occurrence, a 3- to 6-membered aromatic, fully saturated or partially unsaturated carbocyclic ring;
• Heta represents, independently at each occurrence, a 3- to 6-membered heterocyclic ring that may be aromatic, fully saturated or partially unsaturated and which contains one or more heteroatoms selected from O, S and N;
• R10 and R11 independently represent
• (a) H,
• (b) C1-6 alkyl optionally substituted by one or more substituents selected from halo, aryl, —N(RN3)(RN4) and —ORa,
• (c) aryl or
• (d) C3-7 cycloalkyl (which group is optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy);
• B1 to B8 independently represent, at each occurrence, a direct bond, O, S or N(RN3);
• each aryla independently represents a C6-14 carbocyclic aromatic group, which group may comprise one, two or three rings;
• each aryl independently represents a C6-14 carbocyclic aromatic group, which group may comprise one, two or three rings and may be substituted by one or more substituents selected from
• halo,
• C1-6 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, —N(RN4)(RN5) and —ORa, and
• —ORa;
• Het1 to Het4 independently represent 4- to 14-membered heterocyclic groups containing one or more heteroatoms selected from O, S and N, which heterocyclic groups may comprise one, two or three rings and may be substituted by one or more substituents selected from
• halo,
• C1-6 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, —N(RN6)(RN7) and —ORa, and
• —ORa;
• RN1 to RN7 independently represent
• H,
• C1-6 alkyl or C3-6 cycloalkyl, which latter two groups are optionally substituted by one or more substituents selected from halo and —ORa;
• Ra represents, independently at each occurrence,
• (a) H;
• (b) C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR12a, S(O)gR12b, S(O)2N(R12c)(R12d), N(R12e)S(O)2R12f, N(R12g)(R12h), B9—C(G2)-B10—R12i, aryl1 and Hetb, and which C3-12 cycloalkyl or C4-12 cycloalkenyl groups may additionally be substituted by ═O,
• (c) S(O)rR13a,
• (d) S(O)2N(R13b)(R13c) or
• (e) C(O)—B11—R13d;
• R5a to R5j, R6a to R6i, R7a to R7i, R9a to R9i, R9aa to R9ga, R12a to R12i and R13a to R13d independently represent, at each occurrence,
• (a) H,
• (b) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl which latter three groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR5aa, S(O)gR5ab, S(O)2N(R5ac)(R5ad), N(R5ae)S(O)2R5af, N(R5ag)(R5ah), B12—C(G2)-B13—R5ai, aryl1 and Hetc;
• (c) C3-10 cycloalkyl, or C4-10 cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from halo, OH, ═O, C1-6 alkyl and C1-6 alkoxy),
• (d) Hetd;
• G2 represents, independently at each occurrence, O, S, or NR5aj;
• R5aa to R5aj independently represent at each occurrence,
• (a) H,
• (b) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl which latter three groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy),
• (c) C3-6 cycloalkyl, or C4-6 cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from halo, OH, ═O, C1-4 alkyl and C1-4 alkoxy),
• (d) Hete,
• or R5ag and R5ah may represent, together with the nitrogen atom to which they are attached, a 3- to 10-membered heterocyclic ring that may be aromatic, fully saturated or partially unsaturated and which may additionally contain one or more heteroatoms selected from O, S and N, which heterocyclic ring is optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy);
• B9 to B13 independently represent a direct bond, O, S or N(RN8);
• aryl1 represents, independently at each occurrence, a C6-10 carbocyclic aromatic group, which group may comprise one or two rings and may be substituted by one or more substituents selected from
• halo,
• C1-6 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, —N(RN10)(RN11) and C1-6 alkoxy (which latter substituent is optionally substituted by one or more halo atoms), and
• C1-6 alkoxy (which latter substituent is optionally substituted by one or more halo atoms);
• RN8, RN10 and RN11 independently represent
• H,
• C1-6 alkyl or C3-6 cycloalkyl, which latter two groups are optionally substituted by one or more halo atoms;
• Hetb represents a 5- or 6-membered that may be aromatic, fully saturated or partially unsaturated and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may be substituted by one or more substituents selected from halo, ═O and C1-6 alkyl;
• Hetc to Hete independently represent, a 3- to 6-membered heterocyclic ring that may be aromatic, fully saturated or partially unsaturated and which contains one or more heteroatoms selected from O, S and N, which Hetc to Hete groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy);
• q and r independently represent at each occurrence 0, 1 or 2;
• and
• unless otherwise specified alkyl, alkenyl, alkynyl, cycloalkyl and the alkyl part of alkoxy groups may be substituted by one or more halo atoms;
• or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof,
• provided that the compound is not:
• (a) 5-(2-chlorophenyl)-6-(3,4-dimethoxyphenyl)-[1,2,4]triazin-3-ylamine;
• or
• (b) 5-(2-chlorophenyl)-6-(3,4,5-trimethoxyphenyl)-[1,2,4]triazin-3-ylamine.