Selective B3 adrenergic agonists

A method of treating obesity which comprises administering to a patient in need thereof a compound of Formula I:

• 248
• wherein:
• X1 is —OCH2—, —SCH2—, or a bond;
• X2 is a bond, or a 1 to 5 carbon straight or branched alkylene;
• X3 is O, S. or a bond;
• R1 is a fused heterocycle of the formula:
• 249
• the A1 groups are independently carbon or nitrogen, provided that no more than 2 nitrogens may be contained in either fused 6 membered ring and those 2 nitrogens may not be adjacent;
• R2 is independently hydrogen, C1-C4 alkyl, or aryl;
• R3 is hydrogen or C1-C4 alkyl;
• R4 is an optionally substituted heterocycle or a moiety selected from the group consisting of:
• 250
• R5 is hydrogen or C1-C4 alkyl;
• R6 is hydrogen, C1-C4 alkyl, or CO2(C1-C4 alkyl);
• or R5 and R6 combine with the carbon to which each is attached to form a C3-C6 cycloalkyl;
• or R6 combines with X2 and the carbon to which each is attached to form a C3-C8 cycloalkyl;
• or R6 combines with X2, R4, and the carbon to which each is attached to form:
• 251
• provided that R5 is hydrogen;
• R7 is independently hydrogen, halo, hydroxy, OR2, C1-C4 alkyl, C1-C4 haloalkyl, aryl, COOR2, CONR2R2, NHCOR2, C1-C4 alkoxy, NHR2, SR2, CN, SO2R2, SO2NHR2, or SOR2;
• R8 is independently hydrogen, halo, or C1-C4 alkyl;
• R9 is hydrogen, halo, hydroxy, CN, OR10, C1-C4 alkyl, C1-C4 haloalkyl, CO2R2, CONR11R12, CONH(C1-C4 alkyl or C1-C4 alkoxy), SR2, CSNR2 CSNR11R12, NR2SO2R2, SO2R2, SO2NR11R12, SOR2, NR11R12, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12;
• R10 is C1-C4 alkyl, C1-C4 haloalkyl, (CH2)nC3-C8 cycloalkyl, (CH2)naryl, (CH2)nheterocycle, (CH2)nC3-C8 optionally substituted cycloalkyl, (CH2)n optionally substituted aryl, (CH2)n optionally substituted heterocycle, or (CH2)nCO2R2;
• R11 and R12 are independently hydrogen, C1-C4 alkyl, aryl, (CH2)naryl, or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl;
• m is 0 or 1;
• n is independently 0, 1, 2, or 3;
• or a pharmaceutically acceptable salt or solvate thereof.

A method of treating Type II diabetes which comprises administering to a patient in need thereof a compound of Formula I:

• 258
• wherein:
• X1 is —OCH2—, —SCH2—, or a bond;
• X2 is a bond, or a 1 to 5 carbon straight or branched alkylene;
• X3 is O, S, or a bond;
• R1 is a fused heterocycle of the formula:
• 259
• the A1 groups are independently carbon or nitrogen, provided that no more than 2 nitrogens may be contained in either fused 6 membered ring and those 2 nitrogens may not be adjacent;
• R2 is independently hydrogen, C1-C4 alkyl, or aryl;
• R3 is hydrogen or C1-C4 alkyl;
• R4 is an optionally substituted heterocycle or a moiety selected from the group consisting of:
• 260
• R5 is hydrogen or C1-C4 alkyl;
• R6 is hydrogen, C1-C4 alkyl, or CO2(C1-C4 alkyl);
• or R5 and R6 combine with the carbon to which each is attached to form a C3-C6 cycloalkyl;
• or R6 combines with X2 and the carbon to which each is attached to form a C3-C8 cycloalkyl;
• or R6 combines with X2, R4, and the carbon to which each is attached to form:
• 261
• provided that R5 is hydrogen;
• R7 is independently hydrogen, halo, hydroxy, OR2, C1-C4 alkyl, C1-C4 haloalkyl, aryl, COOR2, CONR2R2, NHCOR2, C1-C4 alkoxy, NHR2, SR2, CN, SO2R2, SO2NHR2, or SOR2;
• R8 is independently hydrogen, halo, or C1-C4 alkyl;
• R9 is hydrogen, halo, hydroxy, CN, OR10, C1-C4 alkyl, C1-C4 haloalkyl, CO2R2, CONR11R12, CONH(C1-C4 alkyl or C1-C4 alkoxy), SR2, CSNR2, CSNR11R12, NR2SO2R2, SO2R2, SO2NR11R12, SOR2, NR11R12, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12;
• R10 is C1-C4 alkyl, C1-C4 haloalkyl, (CH2)nC3-C8 cycloalkyl, (CH2)naryl, (CH2)nheterocycle, (CH2)nC3-C8 optionally substituted cycloalkyl, (CH2)n optionally substituted aryl, (CH2)n optionally substituted heterocycle, or (CH2)nCO2R2;
• R11 and R12 are independently hydrogen, C1-C4 alkyl, aryl, (CH2)naryl, or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl;
• m is 0 or 1;
• n is independently 0, 1, 2, or 3;
• or a pharmaceutically acceptable salt or solvate thereof.

A compound of the Formula II

• 268
• wherein:
• X1 is —OCH2—, —SCH2—, or a bond;
• X3 is O, S, or a bond;
• R1 is a fused heterocycle of the formula:
• 269
• the A1 groups of said heterocycle are independently carbon or nitrogen, provided that no more than 2 nitrogens may be contained in either fused 6 membered ring and those 2 nitrogens may not be adjacent;
• R2 is independently hydrogen, C1-C4 alkyl, or aryl;
• R3 is hydrogen or C1-C4 alkyl;
• R4 is an optionally substituted heterocycle or a moiety selected from the group consisting of:
• 270
• X2 is a bond, or a 1 to 5 carbon straight-or branched alkylene;
• R5 is hydrogen or C1-C4 alkyl;
• R6 is hydrogen, C1-C4 alkyl, or CO2(C1-C4 alkyl);
• or R5 and R6 combine with the carbon to which each is attached to form a C3-C6 cycloalkyl;
• or R6 combines with X2 and the carbon to which each is attached to form a C3-C8 cycloalkyl;
• or R6 combines with X2, R4, and the carbon to which each is attached to form:
• 271
• provided that R5 is hydrogen;
• R7 is independently hydrogen, halo, hydroxy, OR2, C1-C4 alkyl, C1-C4 haloalkyl, aryl, COOR2, CONHR2, NHCOR2, C1-C4 alkoxy, NHR2, SR2, CN, SO2R2, SO2NHR2, or SOR2;
• R8 is independently hydrogen, halo or C1-C4 alkyl;
• R9 is halo, CN, OR10, C1-C4 alkyl, C1-C4 haloalkyl, CO2R2, CONR11R12, CONH(C1-C4 alkyl or C0-C4 alkoxy), SR2, CSNR2, CSNR11R12, NR2SO2R2, SO2R2, SO2NR11R12, SOR2, NR11R12, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12;
• R10 is C1-C4 alkyl, C1-C4 haloalkyl, lCH2)nC3-C8 cycloalkyl, (CH2)naryl, (CH2)nheterocycle, (CH2)nC3-C8 optionally substituted cycloalkyl, (CH2)n optionally substituted aryl, (CH2)n optionally substituted heterocycle, or (CH2)nCO2R2;
• R11 and R12 are independently hydrogen, C1-C4 alkyl, aryl, (CH2)naryl, or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl;
• m is 0 or 1;
• n is independently 0, 1, 2, or 3;
• provided:
• when R5 or R6 is hydrogen;
• either
• 1) one or more A1 must be nitrogen, or
• 2) R9 is CN, OR10, CO2R2, CSNR2, CSNR11R12, NR2SO2R2, SO2NR11R12, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12;
• and
• R10 is C1-C4 haloalkyl, (CH2)nC3-C8 cycloalkyl, (CH2)nheterocycle, (CH2)nC3-C8 optionally substituted cycloalkyl, (CH2)n optionally substituted aryl, or (CH2)n optionally substituted heterocycle;
• or a pharmaceutically acceptable salt or solvate thereof.