AR074862A1 - BICYCLE HETEROCICLE DERIVATIVES AND THEIR METHODS OF USE - Google Patents

Abstract

This refers to bicyclic heterocycle derivatives, compositions comprising a bicyclic heterocycle derivative and methods of using bicyclic heterocycle derivatives to treat or prevent obesity, diabetes, a metabolic disorder, a cardiovascular disease or an activity related disorder. of a GPCR in a patient. Claim 1: A compound having the formula (1): or one of its pharmaceutically acceptable salts, solvates, esters, prodrugs or stereoisomers, wherein: A is aryl or heteroaryl, each of which may be optionally substituted with up to 4 groups, which may be the same or different and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycloakenyl, haloalkyl, hydroxyalkyl, halo, -OH, -O-haloalkyl, -O-alkyl, -O-alkyl-OH, - O-alkyl-O-alkyl, -O-aryl, -alkylene-O-alkyl, -CN, -N (R4) 2, -C (O) H, -C (O) R4, C (O) OR4, C (O) N (R4) 2, NHC (O) R4, NHS (O) mR4, S (O) nR4 and -S (O) mN (R4) 2; B is aryl or heteroaryl, each of which may be optionally substituted with up to 4 groups, which may be the same or different and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, heteroaryl, halo, - OH, -O-haloalkyl, -O-alkyl, -O-aryl, -alkylene-O-alkyl, -alkylene-S (O) 2-alkyl, -SF5, -CN, -N (R4) 2, -C (O) H, -C (O) R4, C (O) OR4, -C (O) N (R4) 2, -NHC (O) R4, -NHS (O) mR4, -S (O) nR4 and -S (O) mN (R4) 2, wherein a cycloalkyl, aryl or heteroaryl substituent group may not be substituted or may be optionally substituted with R9 and where, when B is aryl, the aryl group may optionally be fused with a cycloalkyl group or a cycloalkanoyl group of 4 to 7 members; G is -C (R1) - or -N-; W is a bond, -O-, -C (O) O-, -C (R12) -, -alkylene-O-, alkylene, -C (O) -, -S (O) -, -S (O ) 2-, -S (O) 2-N (R10) -, -N (R12) -, -NHC (O) - or -C (O) -N (R10) -, so that W is other than -O- when G is -N- and so that, when G is -C (R1) - and W is -C (R12) -, tese R1 and R12 groups can be combined to form a C1-3 alkylene bridge between G and W and form a spirocycle; X is a bond, -C (R1) 2-, -O-, -N (R10) - or -S-; Z is a single bond, a double bond, -C (O) -, -C (= NOR12) -, -C = C (R14) 2, -C (R1) 2-, -O-, -N (R10 ) - or -S (O) n-, so that, when q is 0, Z is different from a double bond; each occurrence of R1 is, independently, H, alkyl, cycloalkyl, halo or -OR7 where an alkyl group may not be substituted or may be optionally substituted with one or more of the following groups: -O-alkyl, -OH or -N (R4); and wherein any two R1 geminal groups, together with the common carbon atom to which they are attached, can be joined to form a 3 to 6 membered spirocyclic cycloalkyl group, a 3 to 6 membered spirocyclic heterocycloalkyl group or a spirocyclic heterocycloalkenyl group from 3 to 6 members; and wherein any two R1 groups present in separate ring carbon atoms can be joined to form an alkylene or heteroalkylene bridge between the ring carbon atoms to which they are attached; and where, when any group R1 is -OR7, then the carbon atom to which the group R1 is attached is also not attached to another oxygen atom or a nitrogen or halogen atom; each occurrence of R2 is, independently, H or alkyl; R3 is alkyl, - (alkylene) t-alkenyl, - (alkylene) t-alkynyl, - (alkylene) tC (O) R4, - (alkylene) t-haloalkyl, -alkylene-O-alkyl, -alkylene-O- (alkylene) t-aryl, -alkylene-S-aryl, -alkylene-N (R4) C (O) O-alkyl, -CH (cycloalkyl) 2, -CH (heterocycloalkyl) 2, - (alkylene) t-aryl , - (alkylene) t-cycloalkyl, - (alkylene) t-cycloalkenyl, - (alkylene) t-heterocycloalkyl, - (alkylene) t-heterocycloalkenyl or - (alkylene) t-heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl group , heterocycloalkyl, heterocycloalkenyl or heteroaryl may not be substituted or may be optionally substituted with R9; Each occurrence of R4 is H, alkyl, haloalkyl, cycloalkyl, heteroaryl, aryl or alkenyl, any of which is unsubstituted or optionally substituted with one or more groups, which may be the same or different and are selected from halo, alkyl, -OH and -O-alkyl; each occurrence of R7 is, independently, H or alkyl; R9 represents 1 to 4 optional substituents, which may be the same or different and are selected from alkyl, hydroxyalkyl, - (alkylene) tO-R13, alkenyl, alkynyl, halo, haloalkyl, -CN, -NO2, -O- ( rent) t-R13, -S (rent) t-R13, -N (R13) - (rent) t-R13, - (rent) t-R13, - (rent) tN (R7) 2, -C (O ) - (alkylene) t-R13, -C (O) O- (alkylene) t-R13, -N (R7) C (O) - (alkylene) t-R13, -C (O) N (R7) - (alkylene) t-R13, -OC (O) - (alkylene) t-R13, -N (R7) C (O) N (R7) - (alkylene) t-R13, -N (R7) C (O) O- (alkylene) t-R13, -SF5, -S (O) - (alkylene) t-R13 or -S (O) 2 (alkylene) t-R13; R10 is H, alkyl, aryl or -C (O) OR4, wherein an alkyl group is not substituted or is optionally substituted with -OH or -O-alkyl; R12 is H, alkyl or aryl; each occurrence of R13 is, independently, H, haloalkyl, aryl, cycloalkyl, cycloalkanoyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl or heteroaryl group may optionally be substituted for 3 groups , which may be the same or different and are selected from alkyl, alkenyl, halo, haloalkyl, -CN, -N (R7) 2, -OH, -O-alkyl or -O-haloalkyl; each occurrence of R14 is, independently, H, alkyl or aryl or both groups and the carbon atom to which they are attached, combine to form a cycloalkyl or heterocycloalkyl group; each occurrence of m is, independently, 1 or 2; each occurrence of n is, independently, 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2, so that when Z is -O- or -N (R10) -, then at least one of p and q is different from 0; r is 0, 1 or 2, so that when G is -N-, then at least one of p and r is different from 0; s is 0, 1 or 2; each occurrence of t is, independently, 0 or 1; and u is 0, 1 or 2, so that when G is -N-, then at least one of s and u is different from 0.