Mglu2/3 antagonists for the treatment of intellectual disabilities

A method for the treatment of an intellectual developmental disorder in a subject in need of such treatment, the method comprising administering to said subject a therapeutically effective amount of a mGlu2/3 negative allosteric modulator selected from a compound of formula (I) or formula (II):

• or a pharmaceutically acceptable salt thereof, wherein:
• E, J, G, L and M are:
• either:
• E and J are N, G is C and one of L or M is N and the other is CH;
• or:
• L and G are N, E is C, and J and M are CH;
• or:
• J, G and L are N, E is C and M is CH;
• or:
• E and L are N, J and M are CH and G is C;
• A is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridine-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-2-yl, pyridazin-3-yl, thiazol-2-yl, thiazol-5-yl, and thiophen-2-yl which are optionally substituted by one to four Ra;
• B is selected from the group consisting of imidazolyl, [1,2,4]oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4]triazolyl, thiazolyl, pyrimidinyl and thiophenyl, each of which is optionally substituted by C1-6-alkyl;
• C is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of (i)-(xi):
• xii. Halo;
• xiii. Nitro;
• xiv. C1-6-alkyl optionally substituted by hydroxyl;
• xv. NRaaRbb, wherein Raa and Rbb are independently H, C1-6-alkyl or —(CO)—C1-6-alkyl;
• xvi. —S—C1-6-alkyl;
• xvii. —(SO2)—OH;
• xviii. —(SO2)—C1-6-alkyl;
• xix. —(SO2)—NRccRdd, wherein Rcc and Rdd are independently selected from the group consisting of (a)-(i):
• a. H;
• b. C1-6-alkyl optionally substituted by hydroxyl;
• c. C1-6-haloalkyl;
• d. C1-6-alkoxy;
• e. —(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy;
• f. —(CH2CH2O)nCHRcc, wherein Rcc is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
• g. —(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy;
• h. —(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1;
• and
• i. 5 or 6-membered heterocycloalkyl;
• xx. —(SO2)—NRffRgg, wherein Rff and Rgg 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 or a 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;
• xxi. NHSO2—C1-6-alkyl;
• and
• xxii. NHSO2—NRhhRii wherein Rhh and Rii are independently H, C1-6-alkyl, —(CO)O—C1-6-alkyl, or Rhh and Rii 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, halo, CF3, CHF2, or C1-6-alkyl;
• R2 is H, halo, C1-6-alkyl, C1-6-alkoxy, CF3 or CHF2;
• R3 is H, —C(CH3)2OH;
• linear C1-4-alkyl or C3-4-cycloalkyl, which are optionally substituted by one or more substituents selected from the group consisting of 1 to 6 F and 1 to 2 OH;
• R4 is H, halogen, C1-6-alkyl optionally substituted by hydroxy, C1-6-alkoxy, C1-6-haloalkyl, C3-6-cycloalkyl;
• R5 is H, cyano, halogen, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C1-6-alkyl or C3-6-cycloalkyl;
• R6 is halogen, H, C1-6-alkoxy, C1-6-haloalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-haloalkoxy, or NRjjRkk wherein Rjj and Rkk are 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 —NRllRkk, wherein Rll and Rmm are independently selected from the group consisting of H and C1-6-alkyl;
• or Rjj and Rkk 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 heteroaryl group is optionally substituted by one, two, three, four or five substituents selected from the group consisting of halogen, hydroxy, C1-6-alkyl and C1-6-haloalkyl;
• or R5 and R6 can together form a dioxo bridge;
• R7 is H or halo;
• Ra is halo;
• hydroxy;
• cyano;
• CF3;
• NReRf;
• C1-6-alkyl optionally substituted by amino or by hydroxy;
• C1-6-alkoxy;
• C3-4-cycloalkyl;
• CO—NRbRc, SO2—NRbRc;
• or SO2—Rd;
• Rb and Rc may be the same or different and are selected from the group consisting of (i)-(v):
• i. H;
• ii. straight or branched C1-6-alkyl optionally substituted by one or more substituents selected from the group consisting of F, cyano, hydroxy, C1-6-alkoxy, —NH—C(O)—O—C1-6-alkyl, amino, (C1-6-alkyl)amino, di(C1-6-alkyl)amino, C3-6-cycloalkyl, heterocycloalkyl having 5 or 6 ring atoms, aryl and 5 or 6-membered heteroaryl;
• iii. C3-6-cycloalkyl;
• iv. aryl;
• and
• v. heteroaryl;
• or Rb and Rc may, together with the nitrogen atom to which they are attached, form an heterocyclic ring of 4 to 6 ring members which may be substituted by hydroxy or by C1-6-alkyl;
• Rd is OH or C1-6-alkyl;
• and
• Re and Rf are H, C1-6-alkyl optionally substituted by hydroxy, —C(O)—C1-6-alkyl;
• or S(O)2—C1-6-alkyl;
• wherein the intellectual developmental disorder is characterized by significant limitations in intellectual functioning and adaptive behavior.