Azabicyclic amine derivatives and their use as therapeutic agents

A compound of the formula (I):

• wherein
• X represents hydrogen or a C1-4alkyl group optionally substituted by a hydroxy group;
• Y represents hydrogen, C1-6alkyl or C3-7cycloalkyl;
• Z is —CR9R10CH2— or —CH2CR9R10—;
• R represents hydrogen, fluorine, hydroxy, C1-6alkyl or C1-6alkoxy;
• R1 represents hydrogen, hydroxy, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, fluoroC1-6alkoxy, hydroxyC1-6alkyl, C1-6alkoxyC1-4alkyl, C1-6alkoxyC1-4alkoxy, fluoroC1-6alkoxyC1-4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, phenoxy, benzyloxy, cyano, halogen, NRaRb, SRa, SORa, SO2Ra, OSO2Ra, NRaCOR12, CORa, CO2Ra or CONRaRb where Ra and Rb each independently represent hydrogen, C1-4alkyl or fluoroC1-4alkyl;
• R2 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy;
• or when R2 is adjacent to R1, they may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen, sulphur, NH or NRc, which ring is optionally substituted by one, two or three groups selected from hydroxy, C1-4alkyl, C1-3alkoxyC1-3alkyl, fluoroC1-4alkyl, phenyl, =O or =S, where Rc represents C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, fluoroC1-4alkyl, phenyl or benzyl,
• R3 represents hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, cyano, SRa, SORa, SO2Ra, NRaRb, NRaCOR12, CORa, CO2Ra, CONRaRb or C1-4alkyl substituted by cyano, CO2Ra or CONRaRb where Ra and Rb are as previously defined;
• or R3 represents a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, trifluoromethyl, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, phenyl, (CH2)rNRaRb, (CH2)rNRaCORb, (CH2)rCONRaRb, or CH2C(O)Ra, where Ra and Rb are as previously defined and r is zero, 1 or 2;
• R4 represents hydrogen, halogen, C1-6alkyl, C1-6alkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, where Ra and Rb are as previously defined;
• R5 represents hydrogen, halogen, C1-6alkyl, CF3 or C1-6alkoxy substituted by C1-4alkoxy;
• R6 represents hydrogen, hydroxy, CORa, CO2Ra, COCONRaRb, COCO2Ra, C1-6alkyl optionally substituted by a group selected from (CO2Ra, CONRaRb, hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONHphenyl(C1-4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaC1-6alkylR14, CONR11C2-6alkenyl, CONR11C2-6alkynyl, COCONRaRb, CONRaC(NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from C1-6alkyl, C1-6alkoxy, halogen and trifluoromethyl);
• or R6 represents a group of the formula —CH2C≡CCH2NR7R8 where R7 and R8 are as defined below;
• or R6 represents C1-6alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by =O or =S and optionally substituted by a group of the formula —W—NR7R8 where
• W is C1-6alkylene or C3-6cycloalkyl;
• R7 represents hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
• R8 represents hydrogen or C1-4alkyl, C1-4alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by a group selected from C1-4alkoxy, hydroxyl, CO2Ra, NRaRb, aryl, aryloxy, heteroaryl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
• or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy, phenyl, benzyl or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NRC moiety where Rc is as previously defined;
• or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
• or W, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
• R9 represents hydrogen, hydroxy, oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, fluoroC1-6alkyl, C1-6alkoxy, fluoroC1-6alkoxy, hydroxyC1-6alkyl, C1-6alkoxyC1-4alkyl, C1-6alkoxyC1-4alkoxy, fluoroC1-6alkoxyC1-4alkyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, aryl, aryl(CH2), aryloxy, aryl(CH2)oxy, cyano, halogen, NR7R8, CH2NR7R8, SR12, SOR12, SO2R12, OSO2R12, NRaCOR12, CH(OH)R12, COR12, CO2R12, CONR7R8, CH20R13, heteroaryl or heteroarylC1-4alkyl, wherein Ra is as previously defined;
• R10 represents hydrogen, halogen or hydroxy;
• R11 represents hydrogen or C1-6alkyl;
• R12 represents hydrogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl or phenyl optionally substituted by one, two or three substituents selected from C1-6alkyl, C1-6alkoxy, halogen or trifluoromethyl;
• R13 represents C1-4alkyl substituted by a group selected from hydroxy, CORa, CO2Ra, CONRaRb and heteroaryl, where Ra is as previously defined;
• R14 represents ORa, CONRaRb or heteroaryl;
• or a pharmaceutically acceptable salt or N-oxide thereof;
• provided that when R, R4, R5, R6, X and Y are hydrogen, and Z is —CR9R10CH2— or —CH2CR9R10— wherein R9 and R10 are hydrogen, then at least one of R1, R2, and R3 is not hydrogen;
• and
• provided that when R, R4, R5, X and Y are hydrogen, Z is —CR9R10CH2— or —CH2CR9R10— wherein R9 and R10 are hydrogen, and R6 is —CO2tBu, then at least one of R1, R2, and R3 is not hydrogen;
• and
• provided that when R1 is 2-methoxy, and R, R2, R4, R5, R6, X and Y are hydrogen, and Z is —CR9R10CH2— or —CH2CR9R10— wherein R9 and R10 are hydrogen, then R3 is not 5-trifluoromethoxy.