Pyridine and pyrimidine derivatives as MGLUR2 antagonists

A compound of formula (Ia):

• wherein
• X and Y are N;
• Q is S, O, —CH═N— or —N═CH—;
• B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of:
• halo,
• nitro,
• C1-6-alkyl optionally substituted by hydroxy,
• NRaRb, wherein Ra and Rb are independently H, C1-6-alkyl or —(CO)—C1-6-alkyl,
• —S—C1-6-alkyl,
• —(SO2)—OH,
• —(SO2)—C1-6-alkyl,
• —(SO2)—NRcRd, wherein Rc and Rd are independently:
• H,
• C1-6-alkyl optionally substituted by hydroxy,
• C1-6-haloalkyl,
• C1-6-alkoxy,
• —(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,
• —(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
• —(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy,
• —(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1, 5 or 6-membered heterocycloalkyl,
• —(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of:
• hydroxy, C1-6-alkyl, C1-6-alkoxy which is optionally substituted by
• hydroxy, and 5 or 6 membered heteroaryloxy,
• NHSO2—C1-6-alkyl, and
• NHSO2—NRhRi wherein Rh and Ri are independently H, C1-6-alkyl, —(CO)O—C1-6-alkyl, or Rh and Ri together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by C1-6-alkyl,
• R1 is H, halogen, C1-6-alkyl optionally substituted by hydroxy, C1-6-alkoxy, C1-6-haloalkyl, or C3-6-cycloalkyl;
• and
• R2 is selected from the group consisting of cyano, halogen, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C1-6-alkyl and C3-6-cycloalkyl;
• or is NRjRk wherein Rj and Rk are each independently selected from the group consisting of
• H, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and C1-6-alkyl which optionally substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and —NRlRm, wherein Rl and Rm are independently selected from the group consisting of H and C1-6-alkyl;
• or Rl and Rm can, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic group comprising 5 to 12 ring atoms optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, wherein said heterocyclic group is optionally substituted by one, two, three, four or five substituents are selected from the group consisting of halogen, hydroxy, C1-6-alkyl and C1-6-haloalkyl;
• or a pharmaceutically acceptable salt thereof.

A compound of formula (Ib):

• wherein
• X and Y are N;
• Q is S, O, —CH═N— or —N═CH—;
• B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of:
• halo,
• nitro,
• C1-6-alkyl optionally substituted by hydroxy,
• NRaRb, wherein Ra and Rb are independently H, C1-6-alkyl or —(CO)—C1-6-alkyl,
• —S—C1-6-alkyl,
• —(SO2)—OH,
• —(SO2)—C1-6-alkyl,
• —(SO2)—NRcRd, wherein Rc and Rd are independently:
• H,
• C1-6-alkyl optionally substituted by hydroxy,
• C1-6-haloalkyl,
• C1-6-alkoxy,
• —(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy, —(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
• —(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy,
• —(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1, 5 or 6-membered heterocycloalkyl,
• —(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of
• hydroxy, C1-6-alkoxy which is optionally substituted by
• hydroxy, and 5 or 6 membered heteroaryloxy,
• NHSO2—C1-6-alkyl, and
• NHSO2—NRhRl wherein Rh and Ri are independently H, —(CO)O—C1-6-alkyl, or Rh and Ri together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by C1-6-alkyl,
• R1 is H, halogen, C1-6-alkyl optionally substituted by hydroxy, C1-6-alkoxy, C1-6-haloalkyl, or C3-6-cycloalkyl;
• and
• R2 is selected from the group consisting of cyano, halogen, C1-6-haloalkyl, O1-6-alkoxy, C1-6-haloalkoxy, C1-6-alkyl and C3-6-cycloalkyl;
• or is NRjRk wherein Rj and Rk are each independently selected from the group consisting of
• H, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and C1-6-alkyl which optionally substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and —NRlRm, wherein Rl and Rm are independently selected from the group consisting of H and C1-6-alkyl;
• or Rl and Rm can, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic group comprising 5 to 12 ring atoms optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur, wherein said heterocyclic group is optionally substituted by one, two, three, four or five substituents are selected from the group consisting of halogen, hydroxy, C1-6-alkyl and C1-6-haloalkyl;
• or a pharmaceutically acceptable salt thereof.

A compound of formula (Ic):

• wherein
• X and Y are N;
• Q is S, O, —CH═N— or —N═CH—;
• B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of:
• halo,
• nitro,
• C1-6-alkyl optionally substituted by hydroxy,
• NRaRb, wherein Ra and Rb are independently H, C1-6-alkyl or —(CO)—C1-6-alkyl,
• —S—C1-6-alkyl,
• —(SO2)—OH,
• —(SO2)—C1-6-alkyl,
• —(SO2)—NRcRd, wherein Rc and Rd are independently:
• H,
• C1-6-alkyl optionally substituted by hydroxy,
• C1-6-haloalkyl,
• C1-6-alkoxy,
• —(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,
• —(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
• —(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy,
• —(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1, 5 or 6-membered heterocycloalkyl,
• —(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of:
• hydroxy, C1-6-alkyl, C1-6-alkoxy which is optionally substituted by
• hydroxy, and 5 or 6 membered heteroaryloxy,
• NHSO2—C1-6-alkyl, and
• NHSO2—NRhRi wherein Rh and Ri are independently H, C1-6-alkyl, —(CO)O—C1-6-alkyl, or Rh and Ri together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by C1-6-alkyl,
• R1 is H, halogen, C1-6-alkyl optionally substituted by hydroxy, C1-6-alkoxy, C1-6-haloalkyl, or C3-6-cycloalkyl;
• and
• R2 is selected from the group consisting of cyano, halogen, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C1-6-alkyl and C3-6-cycloalkyl;
• or is NRjRk wherein Rj and Rk are each independently selected from the group consisting of
• H, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and C1-6-alkyl which optionally substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and —NRlRm, wherein Rl and Rm are independently selected from the group consisting of H and C1-6-alkyl;
• or Rl and Rm can, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic group comprising 5 to 12 ring atoms optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur, wherein said heterocyclic group is optionally substituted by one, two, three, four or five substituents are selected from the group consisting of halogen, hydroxy, C1-6-alkyl and C1-6-haloalkyl;
• or a pharmaceutically acceptable salt thereof.

A compound of formula (Id):

• wherein
• X and Y are N;
• Q is S, O, —CH═N— or —N═CH—;
• B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of:
• halo,
• nitro,
• C1-6-alkyl optionally substituted by hydroxy,
• NRaRb, wherein Ra and Rb are independently H, C1-6-alkyl or —(CO)—C1-6-alkyl,
• —S—C1-6-alkyl,
• —(SO2)—OH,
• —(SO2)—C1-6-alkyl,
• —(SO2)—NRcRd, wherein Rc and Rd are independently:
• H,
• C1-6-alkyl optionally substituted by hydroxy,
• C1-6-haloalkyl,
• C1-6-alkoxy,
• —(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,
• —(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
• —(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy,
• —(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1, 5 or 6-membered heterocycloalkyl,
• —(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of:
• hydroxy, C1-6-alkoxy which is optionally substituted by
• hydroxy, and 5 or 6 membered heteroaryloxy,
• NHSO2—C1-6-alkyl, and
• NHSO2—NRhRi wherein Rh and Ri are independently H, —(CO)O—C1-6-alkyl, or Rh and Ri together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by C1-6-alkyl,
• R1 is H, halogen, C1-6-alkyl optionally substituted by hydroxy, C1-6-alkoxy, O1-6-haloalkyl, or C3-6-cycloalkyl;
• and
• R2 is selected from the group consisting of cyano, halogen, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C1-6-alkyl and C3-6-cycloalkyl;
• or is NRjRk wherein Rj and Rk are each independently selected from the group consisting of
• H, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and C1-6-alkyl which optionally substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and —NRlRm, wherein Rl and Rm are independently selected from the group consisting of H and C1-6-alkyl;
• or Rl and Rm can, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic group comprising 5 to 12 ring atoms optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur, wherein said heterocyclic group is optionally substituted by one, two, three, four or five substituents are selected from the group consisting of halogen, hydroxy, C1-6-alkyl and C1-6-haloalkyl;
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising a compound of formula I

• wherein
• X and Y are N;
• Q is S, O, —CH═N— or —N═CH—;
• A is aryl or 5 or 6 membered heteroaryl each of which is optionally substituted by C1-6-alkyl;
• B is an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of:
• halo,
• nitro,
• C1-6-alkyl optionally substituted by hydroxy,
• NRaRb, wherein Ra and Rb are independently H, C1-6-alkyl or —(CO)—C1-6-alkyl,
• —S—C1-6-alkyl,
• —(SO2)—OH,
• —(SO2)—C1-6-alkyl,
• —(SO2)—NRcRd, wherein Rc and Rd are independently:
• H,
• C1-6-alkyl optionally substituted by hydroxy,
• C1-6-haloalkyl,
• C1-6-alkoxy,
• —(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,
• —(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
• —(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy,
• —(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1, 5 or 6-membered heterocycloalkyl,
• —(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of:
• hydroxy, C1-6-alkyl, C1-6-alkoxy which is optionally substituted by
• hydroxy, and 5 or 6 membered heteroaryloxy,
• NHSO2—C1-6-alkyl, and
• NHSO2—NRhRi wherein Rh and Ri are independently H, C1-6-alkyl, —(CO)O—C1-6-alkyl, or Rh and Ri together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by C1-6-alkyl,
• R1 is H, halogen, C1-6-alkyl optionally substituted by hydroxy, C1-6-alkoxy, C1-6-haloalkyl, or C3-6-cycloalkyl;
• and
• R2 is selected from the group consisting of cyano, halogen, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C1-6-alkyl and C3-6-cycloalkyl;
• or is NRjRk wherein Rj and Rk are each independently selected from the group consisting of
• H, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and C1-6-alkyl which optionally substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and —NRlRm, wherein Rl and Rm are independently selected from the group consisting of H and C1-6-alkyl;
• or Rl and Rm can, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic group comprising 5 to 12 ring atoms optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur, wherein said heterocyclic group is optionally substituted by one, two, three, four or five substituents are selected from the group consisting of halogen, hydroxy, C1-6-alkyl and C1-6-haloalkyl;
• or a pharmaceutically acceptable salt thereof
• and a pharmaceutically acceptable carrier.