Conformationally constrained analogs useful as antidiabetic and antiobesity agents and method

A compound which has the structure

• wherein Xm is a bond, C1-2 alkylene, C2 alkenylene, allenyl or C2 alkynylene;
• Xn is a bond, C1-2 alkylene, C2 alkenylene, allenyl or C2 alkynylene;
• Q is C or N;
• A is C1-5 alkylene, C2-5 alkenylene, allenyl or C2-5 alkynylene;
• or A is (CH2)x1, where x1 is 2 to 5, with an alkenyl bond or an alkynyl bond embedded in the chain;
• or A is Xx2—O—Xx3 where Xx2 is a bond, C1-5 alkylene, C2-5 alkenylene, allenyl or C2-5 alkynylene and Xx3 is a bond, C1-5 alkylene, C2-5 alkenylene, allenyl or C2-5 alkynylene, provided that at least one of Xx2 and Xx3 is other than a bond;
• wherein
• X1 is CH or N;
• X2 is C, N, O or S;
• X3 is C or N;
• X4 is C, N, O or S, provided that at least one of X2, X3 and X4 is N;
• in each of X1 through X4, as defined above, C may include CH;
• R1 is H or alkyl;
• R2 is H, alkyl, alkoxy, halogen, amino or substituted amino;
• R2a, R2b and R2c may be the same or different and are selected from H, alkyl, alkoxy, halogen, amino or substituted amino;
• R3 is selected from H, alkyl, arylalkyl, aryloxycarbonyl, alkyloxycarbonyl, alkynyloxycarbonyl, alkenyloxycarbonyl, arylcarbonyl, alkylcarbonyl, aryl, heteroaryl, cycloheteroalkyl, heteroarylcarbonyl, heteroaryl-heteroarylalkyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, heteroaryl-heteroarylcarbonyl, alkylsulfonyl, alkenylsulfonyl, heteroaryloxycarbonyl, cycloheteroalkyloxycarbonyl, heteroarylalkyl, aminocarbonyl, substituted aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylalkenyl, cycloheteroalkyl-heteroarylalkyl;
• hydroxyalkyl, alkoxy, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, arylheteroarylalkyl, arylalkylarylalkyl, aryloxyarylalkyl, haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, aryloxyaryloxycarbonyl, arylsulfinylarylcarbonyl, arylthioarylcarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, heteroaryloxyarylalkyl, aryloxyarylcarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl, aryloxyalkyloxycarbonyl, arylalkylsulfonyl, arylthiocarbonyl, arylalkenylsulfonyl, heteroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl, heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl, aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl, arylalkenylarylalkyl, arylalkoxyarylalkyl, arylcarbonylarylalkyl, alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl, heteroarylarylalkyl, arylcarbonylheteroarylalkyl, heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkyl, or aminocarbonylarylarylalkyl;
• Y is CO2R4 (where R4 is H or alkyl, or a prodrug ester) or Y is a C-linked 1-tetrazole, a phosphinic acid of the structure P(O)(OR4a)R5 (where R4a is H or a prodrug ester which is methyl, ethyl or benzyl ester, R5 is alkyl or aryl) or a phosphonic acid of the structure P(O)(OR4a)2;
• Z is (CH2)x4 where x4 is 3;
• including all stereoisomers thereof, and a pharmaceutically acceptable salt thereof,
• wherein the term prodrug ester refers to carboxylic acid esters, phosphorus acid esters, and esters where R4 is
• wherein Ra, Rb and Rc are H, alkyl, aryl or arylalkyl;
• provided that RaO cannot be HO,
• or R4 is
• wherein Ra is H, alkyl, arylalkyl or aryl;
• Rd is H, alkyl, halogen or alkoxy, Re is alkyl, aryl, arylalkyl or alkoxyl, and n1 is 0, 1 or 2.