Fused pyrrolecarboxamides; a new class of GABA brain receptor ligands

A compound of the formula:

• 107
• where
• R3, R5, and R6 independently represent hydrogen, or alkyl;
• Ra represents hydrogen or alkyl where the alkyl is optionally halogenated;
• and
• e is an integer of 1-3.

A compound of the formula:

• 108
• where
• R3, R5, and R6 independently represent hydrogen, or alkyl;
• Ra and Rb independently represent hydrogen or alkyl;
• and
• e is an integer of 2-3.

A compound of the formula:

• 109
• where
• R3, R5, and R6 independently represent hydrogen, or alkyl;
• Ra represents hydrogen, alkyl, or C3-7 cycloalkyl;
• Rb represents hydrogen, alkyl, or acyl;
• Y represents hydrogen or halogen;
• and
• e is an integer of 1-3.

A compound of the formula:

• 110
• where
• R3, R5, and R6 independently represent hydrogen, or alkyl;
• Ra represents hydrogen or alkyl where the alkyl is optionally halogenated;
• and
• e is an integer of 1-3.

A compound of the formula:

• 111
• where G represents
• 112
• where Ra represents hydrogen, alkyl, or C3-7 cycloalkyl;
• Rb represents hydrogen, alkyl, or acyl;
• Y and Y′ independently represent hydrogen or halogen;
• and
• e is an integer of 1-3.

A compound of the formula:

• 113
• where G represents:
• 114
• where Z is oxygen, nitrogen, or methylene;
• and m is 1 or 2.

A compound of the formula:

• 115
• or the pharmaceutically acceptable non-toxic salts thereof wherein:
• Q is phenyl or 3-pyridyl, each of which may be mono or disubstituted with hydroxy or halogen;
• W is oxygen or nitrogen;
• Z is
• hydroxy, C3-C7 cycloalkylC1-C6 alkoxy, or C1-C6 alkoxy where the alkyl portion is optionally substituted with amino, mono- or diC1-C6alkylamino, or azaC1-C6cycloalkyl;
• amino, or mono- or diC1-C6alkylamino, (trifluoromethyl)methyl, C3-C7 cycloalkyl optionally substituted with C1-C6 alkyl, or C3-C7cycloalkylC1-C6alkyl;
• phenyl or phenyl(C1-C6)alkyl where the phenyl portion is optionally substituted with C1-C6 alkyl, hydroxy, C1-C6 alkoxy, triflouromethyl, halogen, amino, or mono- or diC1-C6 alkylamino;
• p2 2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl, or adamantane-2-yl;
• each of which may be substituted on a tertiary carbon or a secondary nitrogen with C1-C6alkyl;
• NR9COR10 where R9 and R10 are the same or different and represent hydrogen or C1-C6 alkyl or C3-C7 cycloalkyl;
• or
• Z is connected, optionally through W, to Q to from a 1-6 membered ring;
• or
• Z represents
• a group of the formula:
• 116
• where
• p is 1, 2, or 3;
• D and D′ independently represent oxygen, NRy or CHRy provided that only one of D and D′ may be NRy where each Ry is hydrogen or C1-C6 alkyl;
• or and
• Rz is hydrogen or C1-C6 alkyl;
• a group of the formula:
• 117
• where
• p is 1, 2, or 3;
• q is 0, 1, or 2;
• Rz is hydrogen or C1-C6 alkyl;
• or
• a group of the formula:
• 118
• where
• s is 0, 1, 2 or 3, and the sum of s and m is not less than 1;
• Ro is hydroxy, C1-C6alkoxy, amino, mono- or diC1-C6alkylamino where each alkyl is independently optionally substituted with amino, mono- or diC1-C6alkylamino, or
• Ro is a group of the formula
• 119
• where p, D, D′, and Rz are as defined above;
• 120
• and
• 121
• independently represent a carbon chain optionally substituted with hydrogen, halogen, or straight or branched chain lower alkyl having 1-6 carbon atoms;
• wherein
• k is 0, 1, 2, or 3;
• m is 0, 1, 2, or 3;
• and
• n is 1 or 2;
• and
• R3, R4, R5, and R6 are the same or different and are selected from hydrogen, alkyl, —COR11 or -CO2R11 where R11 is alkyl or cycloalkyl having 3-7 carbon atoms;
• or —CONR12R13 where R12 and R13 are selected independently from hydrogen, alkyl, cycloalkyl having 3-7 carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, or NR12R13 forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl;
• or
• R3-R4 may be taken together to form a cyclic moiety having 3-7 carbon atoms;
• or
• R5-R6 may be taken together to form a cyclic moiety having 3-7 carbon atoms;
• and where each alkyl group forming an R3, R4, R5, or R6 substitutent or portion thereof may be substituted independently with hydroxy or mono- or dialkylamino where each alkyl is independently alkyl or cycloalkyl having 3-7 carbon atoms.

A compound of formula A or formula B:

• 122
• or a pharmaceutically acceptable salt thereof wherein
• R3, R4, R5, and R6 are the same or different and are selected from hydrogen, alkyl, —COR11 or —CO2R11 where R11 is alkyl or cycloalkyl having 3-7 carbon atoms;
• or —CONR12R13 where R12 and R13 are selected independently from hydrogen, alkyl, cycloalkyl having 3-7 carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, or NR12R13 forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl;
• or
• R3-R4 may be taken together to form a cyclic moiety having 3-7 carbon atoms;
• or
• R5-R6 may be taken together to form a cyclic moiety having 3-7 carbon atoms;
• and
• where each alkyl group forming an R3, R4, R5, or R6 substituent or portion thereof may be substituted independently with hydroxy or mono- or dialkylamino where each alkyl is independently alkyl or cycloalkyl having 3-7 carbon atoms.;
• and
• G represents
• 123
• where
• Rh is hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, or trifluoromethyl;
• s is 0, 1, 2 or 3, and the sum of s and m is not less than 1;
• Ro is hydroxy, C1-C6alkoxy, amino, mono- or diC1-C6alkylamino where each alkyl is independently optionally substituted with amino, mono- or diC1-C6alkylamino, or
• Ro is a group of the formula
• 124
• p is 1, 2, or 3;
• D and D′ independently represent oxygen, NRy or CHRy provided that only one of D and D′ may be NRy where each Ry is hydrogen or C1-C6 alkyl;
• or and
• Rz is hydrogen or C1-C6 alkyl.