US 2010/0137336 A1Published application

Novel amido derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors

OwnerChristelle Boléainventor

Life of this patent

Estimating the term…

Abstract

The present invention relates to novel compounds of Formula (I), wherein X1, X2, X3, X4, 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.

Claims30

Dependent claims

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 is selected from the group of N, O and S and X2, X3 and X4 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, —(C3-C7)cycloalkyl, —(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, —(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, —(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 3;
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, —(C3-C7)cycloalkyl, —(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, —(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-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)—NR2R8, —(C0-C6)alkyl-NR5—C(═O)—NR6R7, —O—(C2-C6)alkyl-NR5—C(═O)—NR6R2, —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;
provided that:
(i) Formula (I)
can not be
and provided that:
(ii) Formula (I)
can not be
when B1 is NR5R6 and CH2NR5R6;
and provided that:
(iii) Formula (I)
can not be
and provided that:
(iv) Formula (I)
can not be
and provided that:
(v) when X1 is O or S and X2, X3 and X4 are C then in Formula (I)
can not be

25 more elements

Dependencies are inferred from the claim text.

patentgrep

Loading patent…

Abstract

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 is selected from the group of N, O and S and X2, X3 and X4 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, —(C3-C7)cycloalkyl, —(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, —(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, —(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 3;
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, —(C3-C7)cycloalkyl, —(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, —(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-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)—NR2R8, —(C0-C6)alkyl-NR5—C(═O)—NR6R7, —O—(C2-C6)alkyl-NR5—C(═O)—NR6R2, —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;
provided that:
(i) Formula (I)
can not be
and provided that:
(ii) Formula (I)
can not be
when B1 is NR5R6 and CH2NR5R6;
and provided that:
(iii) Formula (I)
can not be
and provided that:
(iv) Formula (I)
can not be
and provided that:
(v) when X1 is O or S and X2, X3 and X4 are C then in Formula (I)
can not be

25 more elements