Therapeutic agents II

A compound of formula IA

• in which
• R1 represents chloro, fluoro, methoxy or a group NRaRb in which Ra and Rb independently represent a C1-4alkyl group or Ra and Rb together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring optionally including an O;
• n represents 0 or 1, and when n=1 the substituent is attached to either position 6 or 7;
• R2 represents H or cyano or a C1-4alkyl group, a C1-4alkoxy group optionally substituted by one or more fluoro, a group NRaRb in which Ra and Rb independently represent H or a C1-4alkyl group or Ra and Rb together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring optionally including an O, a group CONRcRd in which Rc and Rd independently represent H or a C1-4alkyl group or Rc and Rd together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring;
• m represents 0 or 1;
• R3 represents H;
• A represents CH2 and t is 1;
• R4 represents H;
• L2 represents CH2, C(CH3)2 or CF2;
• and
• R5 represents aryl or a heterocyclic group selected from thienyl, furyl, pyridyl, pyrrolyl, quinolinyl, indolyl, benzofuranyl, benzo[b]thienyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, pyrazolyl, oxazolyl, imidazo[1,2-a]pyridine, 5H-pyrrolo[2,3-b]pyrazine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[2,3-b]pyridine, 1H-indazole each of which is optionally substituted by one or more of the following:
• cyano, halo, a C1-4 alkyl group optionally substituted by one or more fluoro, a C1-4 alkoxy group optionally substituted by one or more fluoro, or by a group S(O)aRy in which a is 0, 1 or 2 and Ry is phenyl optionally substituted by cyano, halo, a C1-4alkyl group optionally substituted by one or more fluoro or a C1-4alkoxy group optionally substituted by one or more fluoro, or a group (CH2)zRz in which z is 0 or 1 and Rz represents phenyl or a heterocyclic group selected from thienyl, pyridyl, thiazolyl, pyrazolyl, wherein each Rz is optionally substituted by one or more cyano, halo, a C1-4 alkyl group optionally substituted by one or more fluoro, a C1-4alkoxy group optionally substituted by one or more fluoro;
• as well as optical isomers and racemates thereof as well as pharmaceutically acceptable salts thereof.

A compound of formula IB

• in which
• R1 represents H, cyano, methoxy, isopropoxy, dimethylamino, chloro or fluoro;
• R2 represents H, cyano, a C1-4alkyl group optionally substituted by one or more fluoro or a C1-4 alkoxy group optionally substituted by one or more fluoro, a group NRaRb in which Ra and Rb independently represent H or a C1-4alkyl group or Ra and Rb together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring optionally including an O;
• R3 represents H;
• A represents CH2 and t is 1;
• R4 represents H;
• L2 represents CH2, C(CH3)2 or CF2;
• and
• R5 represents aryl or a heterocyclic group selected from thienyl, furyl, pyridyl, pyrrolyl, quinolinyl, indolyl, benzofuranyl, benzo[b]thienyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, pyrazolyl, oxazolyl, imidazo[1,2-a]pyridine, 5H-pyrrolo[2,3-b]pyrazine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[2,3-b]pyridine, 1H-indazole each of which is optionally substituted by one or more of the following:
• cyano, halo, a C1-4 alkyl group optionally substituted by one or more fluoro, a C1-4 alkoxy group optionally substituted by one or more fluoro, or by a group S(O)aRy in which a is 0, 1 or 2 and Ry is phenyl optionally substituted by cyano, halo, a C1-4alkyl group optionally substituted by one or more fluoro or a C1-4alkoxy group optionally substituted by one or more fluoro, or a group (CH2)zRz in which z is 0 or 1 and Rz represents phenyl or a heterocyclic group selected from thienyl, pyridyl, thiazolyl, pyrazolyl, wherein each Rz is optionally substituted by one or more cyano, halo, a C1-4 alkyl group optionally substituted by one or more fluoro, a C1-4alkoxy group optionally substituted by one or more fluoro;
• as well as optical isomers and racemates thereof as well as pharmaceutically acceptable salts thereof.

A compound as represented by formula IC

• in which
• R1 represents cyano or a C1-4 alkoxy group optionally substituted by one or more fluoro, a C1-4 alkyl group optionally substituted by one or more fluoro, halo, a group NRaRb in which Ra and Rb independently represent H or a C1-4alkyl group or Ra and Rb together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring optionally including an O, a group CONRcRd in which Rc and Rd independently represent H or a C1-4alkyl group or Rc and Rd together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring;
• n represents 0, 1, 2 or 3;
• R2 represents H, cyano, a C1-4alkyl group optionally substituted by one or more fluoro or a C1-4alkoxy group optionally substituted by one or more fluoro, a group NRaRb in which Ra and Rb independently represent H or a C1-4 alkyl group or Ra and Rb together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring optionally including an O, a group CONRcRd in which Rc and Rd independently represent H or a C1-4alkyl group or Rc and Rd together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring;
• R3 represents H or a C1-4 alkyl group;
• L1 represents a (CH2)pC7-10 cycloalkyl group in which p is 0 or 1 and in which the cycloalkyl group is fused bicyclic or bridged bicyclic provided that the two nitrogens bearing R3 and R4, respectively, are not linked to the same carbon atom, and wherein one of the carbons may be replaced by O;
• R4 represents H or a C1-4 alkyl group optionally substituted by one or more of the following:
• fluoro or C1-4 alkoxy, optionally substituted by one or more fluoro;
• L2 represents an alkylene chain (CH2)s in which s represents 1, 2 or 3 wherein the alkylene chain is optionally substituted by one or more of the following:
• fluoro or C1-4 alkyl;
• or L2 may also represent a 5-6 membered carbocyclic ring fused to R5;
• R5 represents aryl or a heterocyclic group selected from thienyl, furyl, pyridyl, pyrrolyl, quinolinyl, indolyl, benzofuranyl, benzo[b]thienyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, pyrazolyl, oxazolyl, imidazo[1,2-a]pyridine, 5H-pyrrolo[2,3-b]pyrazine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[2,3-b]pyridine, 1H-indazole each of which is optionally substituted by one or more of the following:
• cyano, halo, a C1-4 alkyl group optionally substituted by one or more fluoro, a C1-4 alkoxy group optionally substituted by one or more fluoro, or by a group S(O)aRy in which a is 0, 1 or 2 and Ry is phenyl optionally substituted by cyano, halo, a C1-4alkyl group optionally substituted by one or more fluoro or a C1-4alkoxy group optionally substituted by one or more fluoro, or a group (CH2)zRz in which z is 0 or and Rz represents phenyl or a heterocyclic group selected from thienyl, pyridyl, thiazolyl, pyrazolyl, wherein each Rz is optionally substituted by one or more cyano, halo, a C1-4 alkyl group optionally substituted by one or more fluoro, a C1-4alkoxy group optionally substituted by one or more fluoro;
• as well as optical isomers and racemates thereof as well as pharmaceutically acceptable salts thereof.

One or more of the following compounds:

• N-(4-methylquinazolin-2-yl)-N′-(3-thienylmethyl)-trans-cyclohexane-1,3-diamine;
• N4,N4-dimethyl-N2-{-3-[(3-thienylmethyl)amino]-trans-cyclohexyl}quinazoline-2,4-diamine;
• N2-{-3-[(1-benzothien-3-ylmethyl)amino]-trans-cyclohexyl}-N4,N4-dimethylquinazoline-2,4-diamine;
• N4,N4-dimethyl-N2-(-3-{[(1-methyl-1H-indol-3-yl)methyl]amino}-trans-cyclohexyl)quinazoline-2,4-diamine,
• N4,N4-dimethyl-N2-((1S,3S)-3-{[2-(trifluoromethoxy)benzyl]amino}cyclohexyl)-quinazoline-2,4-diamine;
• N4,N4-dimethyl-N2-[(1S,3S)-3-({[6-(trifluoromethyl)pyridin-3-yl]methyl}amino)-cyclohexyl]quinazoline-2,4-diamine;
• and
• N2-{(1S,3S)-3-[(3,4-dichlorobenzyl)amino]cyclohexyl}-N4-N4-dimethylquinazoline-2,4-diamine;
• and pharmaceutically acceptable salts thereof.

A process for the preparation of a compound of formula I

• comprising reacting a compound of formula
• in which
• R1 represents a) a C1-4 alkoxy group optionally substituted by one or more fluoro, b) a C1-4 alkyl group optionally substituted by one or more fluoro, c) halo, d) cyano, e) a group NRaRb in which Ra and Rb independently represent H or a C1-4alkyl group or Ra and Rb together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring optionally including an O atom, f) a group CONRcRd in which Rc and Rd independently represent H or a C1-4alkyl group or Rc and Rd together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring, or g) a group —OSO2C1-4alkyl optionally substituted by one or more fluoro;
• R2 represents H or cyano or a C1-4alkyl group optionally substituted by one or more fluoro or a C1-4alkoxy group optionally substituted by one or more fluoro, a group NRaRb in which Ra and Rb independently represent H or a C1-4 alkyl group or Ra and Rb together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring optionally including an O, a group CONRcRd in which Rc and Rd independently represent H or a C1-4alkyl group or Rc and Rd together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring;
• R3 represents H or a C1-4alkyl group;
• R4 represents H or a C1-4alkyl group optionally substituted by one or more of the following:
• fluoro or C1-4alkoxy optionally substituted by one or more fluoro;
• L1 represents a (CH2)pC3-10 cycloalkyl group in which p is 0 or 1 and in which the cycloalkyl group may be monocyclic or bicyclic and optionally may be bridged provided that the two nitrogens bearing R3 and R4, respectively, are not linked to the same carbon atom, and wherein one of the carbons may be replaced by O;
• with the proviso that L1 does not represent 1,3-cyclopentyl or 1,4-cyclohexyl;
• and
• n represents 0, 1, 2 or 3;
• with a compound of formula III
• R5-L2′=O III
• in which
• R5 represents phenyl or naphthyl or a heterocyclic group selected from thienyl, furyl, pyridyl, pyrrolyl, quinolinyl, indolyl, benzofuranyl, benzo[b]thienyl, imidazolyl, benzimidazolyl thiazolyl, thiadiazolyl, pyrimidinyl, pyrazolyl, oxazolyl, imidazo[1,2-a]pyridinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-indazolyl, wherein each R5 is optionally substituted by one or more of the following:
• a) cyano, b) halo, c) a C1-4alkyl group optionally substituted by one or more fluoro, d) a C1-4 alkoxy group optionally substituted by one or more fluoro, e) a group S(O)aRy in which a is 0, 1 or 2 and Ry is phenyl optionally substituted by cyano, halo, a C1-4alkyl group optionally substituted by one or more fluoro or a C1-4alkoxy group optionally substituted by one or more fluoro, f) or by a group (CH2)zRz in which z and w is 0 or 1 and Rz represents phenyl or a heterocyclic group selected from thienyl, pyridyl, thiazolyl, pyrazolyl, wherein each Rz is optionally substituted by one or more of the following:
• cyano, halo, a C1-4 alkyl group optionally substituted by one or more fluoro, or a C1-4alkoxy group optionally substituted by one or more fluoro;
• and
• L2′ represents a group which after reaction of compounds II and III gives L2 on reduction, under reductive alkylation conditions.

A compound of formula II

• in which
• R1 represents a) a C1-4 alkoxy group optionally substituted by one or more fluoro, b) a C1-4 alkyl group optionally substituted by one or more fluoro, c) halo, d) cyano, e) a group NRaRb in which Ra and Rb independently represent H or a C1-4alkyl group or Ra and Rb together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring optionally including an O atom, f) a group CONRcRd in which Rc and Rd independently represent H or a C1-4alkyl group or Rc and Rd together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring, or g) a group —OSO2C1-4alkyl optionally substituted by one or more fluoro;
• R2 represents H or cyano or a C1-4alkyl group optionally substituted by one or more fluoro or a C1-4alkoxy group optionally substituted by one or more fluoro, a group NRaRb in which Ra and Rb independently represent H or a C1-4 alkyl group or Ra and Rb together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring optionally including an O, a group CONRcRd in which Rc and Rd independently represent H or a C1-4alkyl group or Rc and Rd together with the nitrogen atom to which they are attached represent a saturated 3 to 7 membered heterocyclic ring;
• R3 represents H or a C1-4alkyl group;
• R4 represents H or a C1-4alkyl group optionally substituted by one or more of the following:
• fluoro or C1-4alkoxy optionally substituted by one or more fluoro;
• L1 represents a (CH2)pC3-10 cycloalkyl group in which p is 0 or 1 and in which the cycloalkyl group may be monocyclic or bicyclic and optionally may be bridged provided that the two nitrogens bearing R3 and R4, respectively, are not linked to the same carbon atom, and wherein one of the carbons may be replaced by O;
• with the proviso that L1 does not represent 1,3-cyclopentyl or 1,4-cyclohexyl;
• and
• n represents 0, 1, 2 or 3.