Novel heteroaromatic derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
OwnerChristelle Boléa, Sylvain Calanireinventors
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Abstract
The present invention relates to novel compounds of Formula (I), wherein X1, X2, X3, X4, Y1, Y2, Y3, Y4, M1, M2, M3, Am and Bn are defined as in Formula (I); invention compounds are modulators of metabotropic glutamate receptors—subtype 4 (“mGluR4”) which are useful for the treatment or prevention of central nervous system disorders as well as other disorders modulated by mGluR4 receptors. The invention is also directed to pharmaceutical compositions and the use of such compounds in the manufacture of medicaments, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR4 is involved.
Claims34
(canceled)
A compound according to the general Formula (I),
- a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof, wherein:
- X1, X2 and X3 are each independently selected from the group of C, N, O, S and C═C representing a 5 or 6 membered heteroaryl ring which may further be substituted by 1 to 3 radicals Am;
- m is an integer ranging from 1 to 3;
- Am radicals are each independently selected from the group of hydrogen, halogen, —CN, —OH, —NO2, —CF3, —SH, —NH2 and an optionally substituted radical selected from the group of —(C1-C6)alkyl, —(C1-C6)alkylhalo, —(C2-C6)alkynyl, —(C2-C6)alkenyl, —(C3-C7)cycloalkyl, —(C3-C8)cycloalkenyl, —(C1-C6)alkylcyano, —(C1-C6)alkylheteroaryl, —(C1-C6)alkylaryl, aryl, heteroaryl, heterocycle, —(C0-C6)alkyl-OR1, —O—(C2-C6)alkyl-OR1, —NR1(C2-C6)alkyl-OR2, —(C3-C7)cycloalkyl-(C1-C6)alkyl, —O—(C3-C7)cycloalkyl-(C1-C6)alkyl, —NR1—(C3-C7)cycloalkyl-(C1-C6)alkyl, —(C1-C6)alkylhalo-OR1, —(C1-C6)alkylhalo-NR1R2, —(C3-C6)alkynyl-OR1, —(C3-C6)alkynyl-NR1R2, —(C3-C6)alkenyl-OR1, —(C3-C6)alkenyl-NR1R2, —(C0-C6)alkyl-S—R1, —O—(C2-C6)alkyl-S—R1, —NR1—(C2-C6)alkyl-S—R2, —(C0-C6)alkyl-S(═O)—R1, —O—(C1-C6)alkyl-S(═O)—R1, —NR1—(C1-C6)alkyl-S(═O)—R2, —(C0-C6)alkyl-S(═O)2—R1, —O—(C1-C6)alkyl-S(═O)2—R1, —NR1—(C1-C6)alkyl-S(═O)2—R2, —(C0-C6)alkyl-NR1R2, —O—(C2-C6)alkyl-NR1R2, —NR1—(C2-C6)alkyl-NR2R3, —(C0-C6)alkyl-S(═O)2NR1R2, —O—(C1-C6)alkyl-S(═O)2NR1R2, —NR1—(C1-C6)alkyl-S(═O)2NR2R3, —(C0-C6)alkyl-NR1—S(═O)2R2, —O—(C2-C6)alkyl-NR1—S(═O)2R2, —NR1—(C2-C6)alkyl-NR2—S(═O)2R3, —(C0-C6)alkyl-C(═O)—NR1R2, —O—(C1-C6)alkyl-C(═O)—NR1R2, —NR1—(C1-C6)alkyl-C(═O)—NR2R3, —(C0-C6)alkyl-NR1C(═O)—R2, —O—(C2-C6)alkyl-NR1C(═O)—R2, —NR1—(C2-C6)alkyl-NR2C(═O)—R3, —(C0-C6)alkyl-OC(═O)—R1, —O—(C2-C6)alkyl-OC(═O)—R1, —NR1—(C2-C6)alkyl-OC(═O)—R2, —(C0-C6)alkyl-C(═O)—OR1, —O—(C1-C6)alkyl-C(═O)—OR1, —NR1—(C1-C6)alkyl-C(═O)—OR2, —(C0-C6)alkyl-C(═O)—R1, —O—(C1-C6)alkyl-C(═O)—R1, —NR1—(C1-C6)alkyl-C(═O)—R2, —(C0-C6)alkyl-NR1—C(═O)—OR2, —(C0-C6)alkyl-O—C(═O)—NR1R2, —(C0-C6)alkyl-NR1—C(═NR2)—NR3R4, —(C0-C6)alkyl-NR1—C(═O)—NR2R3, —O—(C2-C6)alkyl-NR1—C(═O)—NR2R3, —NR1—(C2-C6)alkyl-NR2—C(═O)—NR3R4 and —(C0-C6)alkyl-NR1—C(═S)—NR2R3;
- Any two radicals of Am (A1 and A2) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- R1, R2, R3 and R4 are each independently hydrogen or an optionally substituted radical selected from the group of —(C1-C6)alkylhalo, —(C1-C6)alkyl, —(C1-C6)alkylcyano, —(C3-C7)cycloalkyl, —(C4-C10)alkylcycloalkyl, heteroaryl, —(C1-C6)alkylheteroaryl, aryl, heterocycle and —(C1-C6)alkylaryl;
- Any two radicals of R (R1, R2, R3 or R4) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- n is an integer ranging from 1 to 2;
- Bn radicals are each independently selected from the group of hydrogen, halogen, —CN, —OH, —NO2, —CF3, —SH, —NH2 and an optionally substituted radical selected from the group of —(C1-C6)alkyl, —(C1-C6)alkylhalo, —(C2-C6)alkynyl, —(C2-C6)alkenyl, —(C3-C7)cycloalkyl, —(C3-C8)cycloalkenyl, —(C1-C6)alkylcyano, —(C1-C6)alkylheteroaryl, —(C1-C6)alkylaryl, aryl, heteroaryl, heterocycle, —(C0-C6)alkyl-OR5, —O—(C2-C6)alkyl-OR5, —NR5(C2-C6)alkyl-OR6, —(C3-C7)cycloalkyl-(C1-C6)alkyl, —O—(C3-C7)cycloalkyl-(C1-C6)alkyl, —NR5—(C3-C7)cycloalkyl-(C1-C6)alkyl, —(C1-C6)alkylhalo-OR5, —(C1-C6)alkylhalo-NR5R6, —(C3-C6)alkynyl-OR5, —(C3-C6)alkynyl-NR5R6, —(C3-C6)alkenyl-OR5, —(C3-C6)alkenyl-NR5R6, —(C0-C6)alkyl-S—R5, —O—(C2-C6)alkyl-S—R5, —NR5—(C2-C6)alkyl-S—R6, —(C0-C6)alkyl-S(═O)—R5, —O—(C1-C6)alkyl-S(═O)—R5, —NR5—(C1-C6)alkyl-S(═O)—R6, —(C0-C6)alkyl-S(═O)2—R5, —O—(C1-C6)alkyl-S(═O)2—R5, —NR5—(C1-C6)alkyl-S(═O)2—R6, —(C0-C6)alkyl-NR5R6, —O—(C2-C6)alkyl-NR5R6, —NR5—(C2-C6)alkyl-NR6R7, —(C0-C6)alkyl-S(═O)2NR5R6, —O—(C1-C6)alkyl-S(═O)2NR5R6, —NR5—(C1-C6)alkyl-S(═O)2NR6R7, —(C0-C6)alkyl-NR5—S(═O)2R6, C6)alkyl-NR5—S(═O)2R6, —NR5—(C2-C6)alkyl-NR6—S(═O)2R7, —(C0-C6)alkyl-C(═O)—NR5R6, —O—(C1-C6)alkyl-C(═O)—NR5R6, —NR5—(C1-C6)alkyl-C(═O)—NR6R7, —(C0-C6)alkyl-NR5C(═O)—R6, —O—(C2-C6)alkyl-NR5C(═O)—R6, —NR5—(C2-C6)alkyl-NR6C(═O)—R7, —(C0-C6)alkyl-OC(═O)—R5, —O—(C2-C6)alkyl-OC(═O)—R5, —NR5—(C2-C6)alkyl-OC(═O)—R6, —(C0-C6)alkyl-C(═O)—OR5, —O—(C1-C6)alkyl-C(═O)—OR5, —NR5—(C1-C6)alkyl-C(═O)—OR6, —(C0-C6)alkyl-C(═O)—R5, —O—(C1-C6)alkyl-C(═O)—R5, —NR5—(C1-C6)alkyl-C(═O)—R6, —(C0-C6)alkyl-NR5—C(═O)—OR6, —(C0-C6)alkyl-O—C(═O)—NR5R6, —(C0-C6)alkyl-NR5—C(═NR6)—NR7R8, —(C0-C6)alkyl-NR5—C(═O)—NR6R7, —O—(C2-C6)alkyl-NR5—C(═O)—NR6R7, —NR5—(C2-C6)alkyl-NR6—C(═O)—NR7R8 and —(C0-C6)alkyl-NR5—C(═S)—NR6R7;
- Any two radicals of Bn (B1 and B2) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- R5, R6, R7 and R8 are each independently hydrogen or an optionally substituted radical selected from the group of —(C1-C6)alkylhalo, —(C1-C6)alkyl, —(C1-C6)alkylcyano, —(C3-C7)cycloalkyl, —(C4-C10)alkylcycloalkyl, heteroaryl, —(C1-C6)alkylheteroaryl, aryl, heterocycle and —(C1-C6)alkylaryl;
- Any two radicals of R (R5, R6, R7 or R8) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- M1 is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;
- M2 is selected from the group of a hydrogen or an optionally substituted radical selected from the group of —(C0-C6)alkyl-R9, —(C1-C6)alkylhalo, —(C2-C6)alkyl-NR9R10, —(C2-C6)alkyl-OR9, —(C2-C6)alkyl-SR9, —(C0-C6)alkyl-C(═O)—R9, —(C2-C6)alkyl-S(O)—R9, —(C0-C6)alkyl-C(═O)NR9R10 and —(C0-C6)alkyl-S(O)2—R9;
- M3 is selected from the group of a hydrogen or an optionally substituted radical selected from the group of —(C0-C6)alkyl-C(═O)—R11, —(C2-C6)alkyl-S(O)—R11, —(C0-C6)alkyl-C(═O)NR11R12 and —(C0-C6)alkyl-S(O)2—R11;
- R9, R10, R11 and R12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of —(C1-C6)alkylhalo, —(C1-C6)alkyl, —(C1-C6)alkylcyano, —(C3-C7)cycloalkyl, —(C4-C10)alkylcycloalkyl, heteroaryl, —(C1-C6)alkylheteroaryl, aryl, heterocycle and —(C1-C6)alkylaryl;
- provided that:
- (i) when M2 and M3 are H, X1 is S, X2 and X3 are C, m and n are both 1, A1 is H and B1 is —CN then M1 cannot be an aryl optionally substituted by —O—(C1-C8)alkyl;
- and provided that:
- (ii) when M1 is aryl, M2 is H, X1 is S, X2 is N, X3 is C, n is 1 and B1 is alkyl then M3 can cannot be an optionally substituted —S(O)2aryl;
- and provided that:
- (iii)
- cannot be
- and provided that the compound is not:
- (iv) 3-(3-methyl-1H-pyrazol-4-yl)-N-phenyl-1,2,4-thiadiazol-5-amine, (3-methyl-4-(5-(phenylamino)-1,2,4-thiadiazol-3-yl)-1H-pyrazol-1-yl)(phenyl)methanone, 1-(3-methyl-4-(5-(phenylamino)-1,2,4-thiadiazol-3-yl)-1H-pyrazol-1-yl)ethanone and (3-methyl-4-(5-(phenylamino)-1,2,4-thiadiazol-3-yl)-1H-pyrazol-1-yl)(thiophen-2-yl)methanone.
A compound according to claim 34 having the Formula (III),
- a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof, wherein:
- X1 is selected from C or N which may further be substituted by A1;
- A1 radical is selected from the group of hydrogen, halogen, —CN, —OH, —CF3, —SH, —NH2 and an optionally substituted radical selected from the group of —(C1-C6)alkyl, —(C1-C6)alkylhalo, —(C2-C6)alkynyl, —(C2-C6)alkenyl, —(C3-C7)cycloalkyl, —(C3-C8)cycloalkenyl, —(C1-C6)alkylcyano, —(C1-C6)alkylheteroaryl, —(C1-C6)alkylaryl, aryl, heteroaryl, heterocycle, —(C0-C6)alkyl-OR1, —O—(C2-C6)alkyl-OR1, —NR1(C2-C6)alkyl-OR2, —(C3-C7)cycloalkyl-(C1-C6)alkyl, —O—(C3-C7)cycloalkyl-(C1-C6)alkyl, —NR1—(C3-C7)cycloalkyl-(C1-C6)alkyl, —(C1-C6)alkylhalo-OR1, —(C1-C6)alkylhalo-NR1R2, —(C3-C6)alkynyl-OR1, —(C3-C6)alkynyl-NR1R2, —(C3-C6)alkenyl-OR1, —(C3-C6)alkenyl-NR1R2, —(C0-C6)alkyl-S—R1, —O—(C2-C6)alkyl-S—R1, —NR1—(C2-C6)alkyl-S—R2, —(C0-C6)alkyl-S(═O)—R1, —O—(C1-C6)alkyl-S(═O)—R1, —NR1—(C1-C6)alkyl-S(═O)—R2, —(C0-C6)alkyl-S(═O)2—R1, —O—(C1-C6)alkyl-S(═O)2—R1, —NR1—(C1-C6)alkyl-S(═O)2—R2, —(C0-C6)alkyl-NR1R2, —O—(C2-C6)alkyl-NR1R2, —NR1—(C2-C6)alkyl-NR2R3, —(C0-C6)alkyl-S(═O)2NR1R2, —O—(C1-C6)alkyl-S(═O)2NR1R2, —NR1—(C1-C6)alkyl-S(═O)2NR2R3, —(C0-C6)alkyl-NR1—S(═O)2R2, —O—(C2-C6)alkyl-NR1—S(═O)2R2, —NR1—(C2-C6)alkyl-NR2—S(═O)2R3, —(C0-C6)alkyl-C(═O)—NR1R2, —O—(C1-C6)alkyl-C(═O)—NR1R2, —NR1—(C1-C6)alkyl-C(═O)—NR2R3, —(C0-C6)alkyl-NR1C(═O)—R2, —O—(C2-C6)alkyl-NR1C(═O)—R2, —NR1—(C2-C6)alkyl-NR2C(═O)—R3, —(C0-C6)alkyl-C(═O)—R1, —O—(C1-C6)alkyl-C(═O)—R1, —NR1—(C1-C6)alkyl-C(═O)—R2, —(C0-C6)alkyl-NR1—C(═O)—NR2R3, —O—(C2-C6)alkyl-NR1—C(═O)—NR2R3, —NR1—(C2-C6)alkyl-NR2—C(═O)—NR3R4 and —(C0-C6)alkyl-NR1—C(═S)—NR2R3;
- R1, R2, R3 and R4 are each independently hydrogen or an optionally substituted radical selected from the group of —(C1-C6)alkylhalo, —(C1-C6)alkyl, —(C1-C6)alkylcyano, —(C3-C7)cycloalkyl, —(C4-C10)alkylcycloalkyl, heteroaryl, —(C1-C6)alkylheteroaryl, aryl, heterocycle and —(C1-C6)alkylaryl;
- Any two radicals of R (R1, R2, R3 or R4) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- n is an integer ranging from 1 to 2;
- Bn radicals are each independently selected from the group of hydrogen, halogen, —CN, —OH, —CF3, —SH, —NH2 and an optionally substituted radical selected from the group of —(C1-C6)alkyl, —(C1-C6)alkylhalo, —(C2-C6)alkynyl, —(C2-C6)alkenyl, —(C3-C7)cycloalkyl, —(C3-C8)cycloalkenyl, —(C1-C6)alkylcyano, —(C1-C6)alkylheteroaryl, —(C1-C6)alkyl aryl, aryl, heteroaryl, heterocycle, —(C0-C6)alkyl-OR5, —O—(C2-C6)alkyl-OR5, —NR5(C2-C6)alkyl-OR6, —(C3-C7)cycloalkyl-(C1-C6)alkyl, —O—(C3-C7)cycloalkyl-(C1-C6)alkyl, —NR5—(C3-C7)cycloalkyl-(C1-C6)alkyl, —(C1-C6)alkylhalo-OR5, —(C1-C6)alkylhalo-NR5R6, —(C3-C6)alkynyl-OR5, —(C3-C6)alkynyl-NR5R6, —(C3-C6)alkenyl-OR5, —(C3-C6)alkenyl-NR5R6, —(C0-C6)alkyl-S—R5, —O—(C2-C6)alkyl-S—R5, —NR5—(C2-C6)alkyl-S—R6, —(C0-C6)alkyl-S(═O)—R5, —O—(C1-C6)alkyl-S(═O)—R5, —NR5—(C1-C6)alkyl-S(═O)—R6, —(C0-C6)alkyl-S(═O)2—R5, —O—(C1-C6)alkyl-S(═O)2—R5, —NR5—(C1-C6)alkyl-S(═O)2—R6, —(C0-C6)alkyl-NR5R6, —O—(C2-C6)alkyl-NR5R6, —NR5—(C2-C6)alkyl-NR6R7, —(C0-C6)alkyl-S(═O)2NR5R6, —O—(C1-C6)alkyl-S(═O)2NR5R6, —NR5—(C1-C6)alkyl-S(═O)2NR6R7, —(C0-C6)alkyl-NR5—S(═O)2R6, —O—(C2-C6)alkyl-NR5—S(═O)2R6, —NR5—(C2-C6)alkyl-NR6—S(═O)2R7, —(C0-C6)alkyl-C(═O)—NR5R6, —O—(C1-C6)alkyl-C(═O)—NR5R6, —NR5—(C1-C6)alkyl-C(═O)—NR6R7, —(C0-C6)alkyl-NR5C(═O)—R6, —O—(C2-C6)alkyl-NR5C(═O)—R6, —NR5—(C2-C6)alkyl-NR6C(═O)—R7, —(C0-C6)alkyl-C(═O)—R5, —O—(C1-C6)alkyl-C(═O)—R5, —NR5—(C1-C6)alkyl-C(═O)—R6, —(C0-C6)alkyl-NR5—C(═O)—NR6R7, —O—(C2-C6)alkyl-NR5—C(═O)—NR6R7, —NR5—(C2-C6)alkyl-NR6—C(═O)—NR7R8 and —(C0-C6)alkyl-NR5—C(═S)—NR6R7;
- R5, R6, R7 and R8 are each independently hydrogen or an optionally substituted radical selected from the group of —(C1-C6)alkylhalo, —(C1-C6)alkyl, —(C1-C6)alkylcyano, —(C3-C7)cycloalkyl, —(C4-C10)alkylcycloalkyl, heteroaryl, —(C1-C6)alkylheteroaryl, aryl, heterocycle and —(C1-C6)alkylaryl;
- Any two radicals of R (R5, R6, R7 or R8) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
- M1 is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;
- M3 is selected from the group of a hydrogen or an optionally substituted radical selected from the group of —(C0-C6)alkyl-C(═O)—R9, —(C2-C6)alkyl-S(O)—R9, —(C0-C6)alkyl-C(═O)NR9R10 and —(C0-C6)alkyl-S(O)2—R9;
- R9 and R10 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of —(C1-C6)alkylhalo, —(C1-C6)alkyl, —(C1-C6)alkylcyano, —(C3-C7)cycloalkyl, —(C4-C10)alkylcycloalkyl, heteroaryl, —(C1-C6)alkylheteroaryl, aryl, heterocycle and —(C1-C6)alkylaryl;
- provided that:
- (i) when M3 is H, X1 is C, n is 1, A1 is H and B1 is —CN then M1 cannot be an aryl optionally substituted by —O—(C1-C8)alkyl;
- and provided that:
- (ii) when M1 is aryl, X1 is N, n is 1 and B1 is alkyl then M3 cannot be an optionally substituted —S(O)2aryl;
- and provided that the compound is not:
- (iv) 3-(3-methyl-1H-pyrazol-4-yl)-N-phenyl-1,2,4-thiadiazol-5 (3-methyl-4-(5-(phenylamino)-1,2,4-thiadiazol-3-yl)-1H-pyrazol-1-yl)(phenyl)methanone, 1-(3-methyl-4-(5-(phenylamino)-1,2,4-thiadiazol-3-yl)-1H-pyrazol-1-yl)ethanone and (3-methyl-4-(5-(phenylamino)-1,2,4-thiadiazol-3-yl)-1H-pyrazol-1-yl)(thiophen-2-yl)methanone.
A compound as in any of claims 2-7 or 34, in which can exist as optical isomers, wherein said compound is either the racemic mixture or one or both of the individual optical isomers.
A compound as in claim 2, 3 or 34, wherein said compound is selected from:
- N-(2-Chlorophenyl)-3-(3-methyl-1H-pyrazol-4-yl)-1,2,4-thiadiazol-5-amine
- N-(2-Fluorophenyl)-3-(3-methyl-1H-pyrazol-4-yl)-1,2,4-thiadiazol-5-amine
- 3-(3-Methyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine
- N-Phenyl-3-(1H-pyrazol-4-yl)-1,2,4-thiadiazol-5-amine
- 4-(3-Methyl-1H-pyrazol-4-yl)-N-phenylthiazol-2-amine
- N-Phenyl-3-(3-propyl-1H-pyrazol-4-yl)-1,2,4-thiadiazol-5-amine
- 3-(3-Propyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine
- N-(Pyridin-2-yl)-3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazol-5-amine
- 4-(3-Methyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
- N-(Pyridin-2-yl)-4-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazol-2-amine and
- 4-(3-Isopropyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
- and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof.
A compound according to claims 2 or 34, wherein said compound is selected from:
- N-(2,6-Difluorophenyl)-4-(3-methyl-1H-pyrazol-4-yl)thiazol-2-amine
- 5-Methyl-4-(3-methyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
- 5-Methyl-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
- N-(2,5-Difluorophenyl)-4-(3-methyl-1H-pyrazol-4-yl)thiazol-2-amine
- 5-Methyl-N-(6-methylpyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
- 5-Methyl-N-(4-methylpyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
- N-(3,5-Difluoropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
- 4-(3-Methyl-1H-pyrazol-4-yl)-N-(4-methylpyridin-2-yl)thiazol-2-amine
- 5-Ethyl-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
- 4-(3-Methyl-1H-pyrazol-4-yl)-N-(6-methylpyridin-2-yl)thiazol-2-amine
- N-(5-Fluoropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
- 4-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
- 2-Methyl-1-(4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazol-1-yl)propan-1-one
- 4-(5-Methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazole-1-carboxamide
- Cyclohexyl(4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazol-1-yl)methanone
- N-Cyclohexyl-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
- 2-Methyl-1-(4-(5-methyl-2-(6-methylpyridin-2-ylamino)thiazol-4-yl)-1H-pyrazol-1-yl)propan-1-one
- N-(6-Chloropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
- 5-Chloro-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
- N-(6-Fluoropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
- (4-(5-Methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazol-1-yl)(piperidin-1-yl)methanone
- 3-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine
- 2-Methyl-1-(4-(5-(pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-1H-pyrazol-1-yl)propan-1-one
- N-Cyclopentyl-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
- N-(6-Methylpyridin-2-yl)-3-(1H-pyrazol-4-yl)-1,2,4-thiadiazol-5-amine
- 5-Methyl-N-(pyrazin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
- 3-(3-Methyl-1H-pyrazol-4-yl)-N-(6-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine
- N-(6-Chloropyridin-2-yl)-3-(3-methyl-1H-pyrazol-4-yl)-1,2,4-thiadiazol-5-amine
- N-(6-Chloropyridin-2-yl)-3-(1H-pyrazol-4-yl)-1,2,4-thiadiazol-5-amine
- N-(6-Fluoropyridin-2-yl)-3-(3-methyl-1H-pyrazol-4-yl)-1,2,4-thiadiazol-5-amine
- N-(3,5-Difluoropyridin-2-yl)-3-(3-methyl-1H-pyrazol-4-yl)-1,2,4-thiadiazol-5-amine
- 5-Methyl-4-(1-(methylsulfonyl)-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
- N-(3-Fluoropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine 4-(1H-Pyrazol-4-yl)-2-(pyridin-2-ylamino)thiazol-5-carbonitrile
- N-(6-Ethylpyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
- N-(6-Chloropyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
- N-Isopropyl-4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazole-1-carboxamide
- N-(6-Fluoropyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
- 5-Chloro-N-(6-methylpyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
- N-(2,5-Difluorophenyl)-6-(1H-pyrazol-4-yl)pyridin-2-amine
- N-(6-Methylpyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
- 4-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)-5-(trifluoromethyl)thiazol-2-amine
- 5-Phenyl-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
- 5-Fluoro-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
- (4-(1H-Pyrazol-4-yl)-2-(pyridin-2-ylamino)thiazol-5-yl)methanol
- N-(6-Methoxypyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine
- N-Cyclopropyl-4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazole-1-carboxamide
- 4-(3-Cyclopropyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
- 4-(3-Ethyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine
- 4-(2-(6-Fluoropyridin-2-ylamino)-5-methylthiazol-4-yl)-1H-pyrazole-1-carboxamide
- and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof.
A pharmaceutical composition comprising a therapeutically effective amount of a compound as in any of claims 2-10 or 34 and a pharmaceutically acceptable carrier and/or excipient.
A method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR4 allosteric modulators, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR4 positive allosteric modulators, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating or preventing central nervous system disorders selected from the group consisting of:
- addiction, tolerance or dependence, affective disorders, such as depression and anxiety, psychiatric disease such as psychotic disorders, attention-deficit/hyperactivity disorder and bipolar disorder;
- Parkinson's disease, memory impairment, Alzheimer's disease, dementia, delirium tremens, other forms of neurodegeneration, neurotoxicity, and ischemia, comprising administering to a mammalian patient in need of such treatment an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating or preventing central nervous system disorders selected from the group consisting of Parkinson's disease and movement disorders such as bradykinesia, rigidity, dystonia, drug-induced parkinsonism, dyskinesia, tardive dyskinesia, L-DOPA-induced dyskinesia, dopamine agonist-induced dyskinesia, hyperkinetic movement disorders, Gilles de la Tourette syndrome, resting tremor, action tremor, akinesia, akinetic-rigid syndrome, akathisia, athetosis, asterixis, tics, postural instability, postencephalitic parkinsonism, muscle rigidity, chorea and choreaform movements, spasticity, myoclonus, hemiballismus, progressive supranuclear palsy, restless legs syndrome, periodic limb movement disorder, comprising administering to a mammalian patient in need of such treatment an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating or preventing central nervous system disorders selected from the group consisting of cognitive disorders:
- delirium, substance-induced persisting delirium, dementia, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, Parkinsonian-ALS demential complex, dementia of the Alzheimer's type, substance-induced persisting dementia and mild cognitive impairment comprising administering to a mammalian patient in need of such treatment an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating affective disorders, anxiety, Agoraphobia, Generalized Anxiety Disorder (GAD), Obsessive-Compulsive Disorder (OCD), Panic Disorder, Posttraumatic Stress Disorder (PTSD), Social Phobia, Other Phobias, Substance-Induced Anxiety Disorder, acute stress disorder comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating or preventing neurological disorders selected from the group of neurodegeneration, neurotoxicity or ischemia such as stroke, spinal cord injury, cerebral hypoxia, intracranial hematoma, Parkinson's disease, memory impairment, Alzheimer's disease, dementia, delirium tremens comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating or preventing inflammatory central nervous system disorders selected from multiple sclerosis forms such as benign multiple sclerosis, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, progressive-relapsing multiple sclerosis, comprising administering an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating migraine comprising administering an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating or preventing epilepsy and tremor, temporal lobe epilepsy, epilepsy secondary to another disease or injury e.g., chronic encephalitis, traumatic brain injury, stroke or ischemia comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating or preventing inflammation and/or neurodegeneration resulting from traumatic brain injury, stroke, ischemia, spinal cord injury, cerebral hypoxia or intracranial hematoma, comprising administering to a mammal in need of such treatment an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating or preventing sensory, motor or cognitive symptoms resulting from traumatic brain injury, stroke, ischemia, spinal cord injury, cerebral hypoxia or intracranial hematoma, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating medulloblastomas comprising administering an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating or preventing inflammatory or neuropathic pain comprising administering to a mammalian patient in need of such treatment an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating, or preventing, ameliorating, controlling or reducing the risk of various metabolic disorders associated with glutamate dysfunction comprising administering to a mammalian patient in need of such treatment an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating or preventing type 2 diabetes comprising administering to a mammalian patient in need of such treatment an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating or preventing diseases or disorders of the retina, retinal degeneration or macular degeneration, comprising administering to a mammalian patient in need of such treatment an effective amount of a compound/composition as in any of claims 2-11 or 34.
A method useful for treating or preventing diseases or disorders of the gastrointestinal tract including gastro-esophageal reflux disease (GERD), lower esophageal sphincter diseases or disorders, diseases of gastrointestinal motility, colitis, Crohn's disease or irritable bowel syndrome (IBS), comprising administering to a mammalian patient in need of such treatment an effective amount of a compound/composition as in any of claims 2-11 or 34.
Use of a compound as in any of claims 2-10 or 34 in the manufacture of a medicament for a treatment or prevention as in one of claims 12-30.
Use of a compound as in any of claims 2-10 or 34 to prepare a tracer for imaging a metabotropic glutamate receptor.
Use of a compound as in any of claims 2-10 or 34 as a taste agent, flavour agent, flavour enhancing agent or a food or beverage additive.
Dependencies are inferred from the claim text.