2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia

A method of treating type II diabetes in a mammal in need thereof which comprises administering to said mammal, a therapeutically effective amount of a compound of formula I having the structure

• wherein:
• B is aryl;
• D is halogen or aryl;
• R1 is hydrogen, alkyl of 1–6 carbon atoms, —SO2Ph(OH)(CO2H), —CH(R2)W, —CH2CH2Y, or —CH2CH2CH2Y;
• R2 is hydrogen, alkyl of 1–6 carbon atoms, aralkyl of 6–12 carbon atoms, —CH2(1H-imidazol-4-yl), —CH2(3-1H-indolyl), —CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), —CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), or —CH2(3-pyridyl);
• W is —CO2R3, —CONHOH, —CN, —CONHR3, aryl, heteroaryl, —CHO, —CH═NOR3, or —CH═NHNHR3;
• Y is —W, —OCH2CO2R3, aryl, heteroaryl, —C(═NOH)NH2, —OR3, —O(C═O)NR4R5, —NR3(C═O)OR3, —NR3(C═O)NR4R5, or —NR4R5;
• R3 is hydrogen or alkyl of 1–6 carbon atoms;
• R4 R5 are each, independently, hydrogen, or alkyl of 1–6 carbon atoms or R4 and R5 are, together, —(CH2)n—, or —CH2CH2XCH2CH2—;
• X is O, S, SO, SO2, NR3, or CH2;
• n is 2 to 5;
• C is —OR6, or —NR6R7;
• R6 and R7 are each, independently, hydrogen, alkyl of 1–18 carbon atoms, aryl, heteroaryl, aralkyl of 6–20 carbon atoms, heteroaralkyl of 6–20 carbon atoms, cycloalkyl of 3–10 carbon atoms, —(CH2CH2O)nCH3, —(CH2)mA or R6 and R7 are, together, —(CH2)p—, —(CH2)2N(CH3)(CH2)4—, —(CH2)2N(R8)(CH2)2—, or —(CH2)2CH(R8)—(CH2)2—;
• R8 is hydrogen, alkyl of 1–18 carbon atoms, aryl, heteroaryl, aralkyl of 6–20 carbon atoms, heteroaralkyl of 6–20 carbon atoms, cycloalkyl of 3–10 carbon atoms, —(CH2CH2O)nCH3, —(CH2CH2CH2O)nCH3, or —(CH2)mA;
• A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl, heteroarylsulfonyl, —CHF2, —CH2F, —CF3, —(CH2CH2O)nCH3, —(CH2CH2CH2O)nCH3, —CO2R3, —O(C═O)NR6R7, aralkyloxy, or heteroaralkyloxy;
• m is 2 to 16
• p is 2 to 12
• or a pharmaceutically acceptable salt thereof.

A method of lowering glucose levels in a mammal in need thereof which comprises administering to said mammal, a therapeutically effective amount of a compound of formula I having the structure

• wherein:
• B is aryl;
• D is halogen or aryl;
• R1 is hydrogen, alkyl of 1–6 carbon atoms, —SO2Ph(OH)(CO2H), —CH(R2)W, —CH2CH2Y, or —CH2CH2CH2Y;
• R2 is hydrogen, alkyl of 1–6 carbon atoms, aralkyl of 6–12 carbon atoms, —CH2(1H-imidazol-4-yl), —CH2(3-1H-indolyl), —CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), —CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), or —CH2(3-pyridyl);
• W is —CO2R3, —CONHOH, —CN, —CONHR3, aryl, heteroaryl, —CHO, —CH═NOR3, or —CH═NHNHR3;
• Y is —W, —OCH2CO2R3, aryl, heteroaryl, —C(═NOH)NH2, —OR3, —O(C═O)NR4R5, —NR3(C═O)OR3, —NR3(C═O)NR4R5, or —NR4R5;
• R3 is hydrogen or alkyl of 1–6 carbon atoms;
• R4 and R5 are each, independently, hydrogen, or alkyl of 1–6 carbon atoms or R4 and R5 are, together, —(CH2)n—, or —CH2CH2XCH2CH2—;
• X is O, S, SO, SO2, NR3, or CH2;
• n is 2 to 5;
• C is —OR6, or —NR6R7;
• R6 and R7 are each, independently, hydrogen, alkyl of 1–18 carbon atoms, aryl, heteroaryl, aralkyl of 6–20 carbon atoms, heteroaralkyl of 6–20 carbon atoms, cycloalkyl of 3–10 carbon atoms, —(CH2CH2O)nCH3, —(CH2)mA or R6 and R7 are, together, —(CH2)p—, —(CH2)2N(CH3)(CH2)4—, —(CH2)2N(R8)(CH2)2—, or —(CH2)2CH(R8)—(CH2)2—;
• R8 is hydrogen, alkyl of 1–18 carbon atoms, aryl, heteroaryl, aralkyl of 6–20 carbon atoms, heteroaralkyl of 6–20 carbon atoms, cycloalkyl of 3–10 carbon atoms, —(CH2CH2O)nCH3, —(CH2CH2CH2O)nCH3, or (CH2)mA;
• A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl, heteroarylsulfonyl, —CHF2, —CH2F, —CF3, —(CH2CH2O)nCH3, —(CH2CH2CH2O)nCH3, —CO2R3, —O(C═O)NR6R7, aralkyloxy, or heteroaralkyloxy;
• m is 2 to 16
• p is 2 to 12
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition which comprises a compound of formula I having the structure

• wherein:
• B is aryl;
• D is halogen or aryl;
• R1 is hydrogen, alkyl of 1–6 carbon atoms, —SO2Ph(OH)(CO2H), —CH(R2)W, —CH2CH2Y, or —CH2CH2CH2Y;
• R2 is hydrogen, alkyl of 1–6 carbon atoms, aralkyl of 6–12 carbon atoms, —CH2(1H-imidazol-4-yl), —CH2(3-1H-indolyl), —CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), —CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), or —CH2(3-pyridyl);
• W is —CO2R3, —CONHOH, —CN, —CONHR3, aryl, heteroaryl, —CHO, —CH═NOR3, or —CH═NHNHR3;
• Y is —W, —OCH2CO2R3, aryl, heteroaryl, —C(═NOH)NH2, —OR3, —O(C═O)NR4R5, —NR3(C═O)OR3, —NR3(C═O)NR4R5, or —NR4R5;
• R3 is hydrogen or alkyl of 1–6 carbon atoms;
• R4 and R5 are each, independently, hydrogen, or alkyl of 1–6 carbon atoms or R4 and R5 are, together, —(CH2)n—, or —CH2CH2XCH2CH2—;
• X is O, S, SO, SO2, NR3, or CH2;
• n is 2 to 5;
• C is —OR6, or —NR6R7;
• R6 and R7 are each, independently, hydrogen, alkyl of 1–18 carbon atoms, aryl, heteroaryl, aralkyl of 6–20 carbon atoms, heteroaralkyl of 6–20 carbon atoms, cycloalkyl of 3–10 carbon atoms, —(CH2CH2O)nCH3, —(CH2)mA or R6 and R7 are, together, —(CH2)p—, —(CH2)2N(CH3)(CH2)4—, —(CH2)2N(R8)(CH2)2—, or —(CH2)2CH(R8)—(CH2)2—;
• R8 is hydrogen, alkyl of 1–18 carbon atoms, aryl, heteroaryl, aralkyl of 6–20 carbon atoms, heteroaralkyl of 6–20 carbon atoms, cycloalkyl of 3–10 carbon atoms, —(CH2CH2O)nCH3, —(CH2CH2CH2O)nCH3, or —(CH2)mA;
• A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl, heteroarylsulfonyl, —CHF2, —CH2F, —CF3, —(CH2CH2O)nCH3, —(CH2CH2CH2O)nCH3, —CO2R3, —O(C═O)NR6R7, aralkyloxy, or heteroaralkyloxy;
• m is 2 to 16
• p is 2 to 12
• or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

A method of treating insulin resistance in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound of formula I having the structure

• wherein:
• B is aryl;
• D is halogen or aryl;
• R1 is hydrogen, alkyl of 1–6 carbon atoms, —SO2Ph(OH)(CO2H), —CH(R2)W, —CH2CH2Y, or —CH2CH2CH2Y;
• R2 is hydrogen, alkyl of 1–6 carbon atoms, aralkyl of 6–12 carbon atoms, —CH2(1H-imidazol-4-yl), —CH2(3-1H-indolyl), —CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), —CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), or —CH2(3-pyridyl);
• W is —CO2R3, —CONHOH, —CN, —CONHR3, aryl, heteroaryl, —CHO, —CH═NOR3, or —CH═NHNHR3;
• Y is —W, —OCH2CO2R3, aryl, heteroaryl, —C(═NOH)NH2, —OR3, —O(C═O)NR4R5, —NR3(C═O)OR3, —NR3(C═O)NR4R5, or —NR4R5;
• R3 is hydrogen or alkyl of 1–6 carbon atoms;
• R4 and R5 are each, independently, hydrogen, or alkyl of 1–6 carbon atoms or R4 and R5 are, together, —(CH2)n—, or —CH2CH2XCH2CH2—;
• X is O, S, SO, SO2, NR3, or CH2;
• n is 2 to 5;
• C is —OR6 or —NR6R7;
• R6 and R7 are each, independently, hydrogen, alkyl of 1–18 carbon atoms, aryl, heteroaryl, aralkyl of 6–20 carbon atoms, heteroaralkyl of 6–20 carbon atoms, cycloalkyl of 3–10 carbon atoms, —(CH2CH2O)nCH3, —(CH2)mA or R6 and R7 are, together, —(CH2)p—, —(CH2)2N(CH3)(CH2)4—, —(CH2)2N(R8)(CH2)2—, or —(CH2)2CH(R8)—(CH2)2—;
• R8 is hydrogen, alkyl of 1–18 carbon atoms, aryl, heteroaryl, aralkyl of 6–20 carbon atoms, heteroaralkyl of 6–20 carbon atoms, cycloalkyl of 3–10 carbon atoms, —(CH2CH2O)nCH3, —(CH2CH2CH2O)nCH3, or —(CH2)mA;
• A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl, heteroarylsulfonyl, —CHF2, —CH2F, —CF3, —(CH2CH2O)nCH3, —(CH2CH2CH2O)nCH3, —CO2R3, —O(C═O)NR6R7, aralkyloxy, or heteroaralkyloxy;
• m is 2 to 16
• p is 2 to 12
• or a pharmaceutically acceptable salt thereof.

A method of treating hypergycemia in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound of formula I having the structure

• wherein:
• B is aryl;
• D is halogen or aryl;
• R is hydrogen, alkyl of 1–6 carbon atoms, —SO2Ph(OH)(CO2H), —CH(R2)W, —CH2CH2Y, or —CH2CH2CH2Y;
• R2 is hydrogen, alkyl of 1–6 carbon atoms, aralkyl of 6–12 carbon atoms, —CH2(1H-amidazol-4-yl), —CH2(3-1H-indolyl), —CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), —CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), or —CH2(3-pyridyl);
• W is —CO2R3, —CONHOH, —CN, —CONHR3, aryl, heteroaryl, —CHO, —CH═NOR3, or —CH═NHNHR3;
• Y is —W, —OCH2CO2R3, aryl, heteroaryl, —C(═NOH)NH2, —OR3, —O(C═O)NR4R5, —NR3(C═O)OR3, —NR3(C═O)NR4R5, or —NR4R5;
• R3 is hydrogen or alkyl of 1–6 carbon atoms;
• R4 R5 are each, independently, hydrogen, or alkyl of 1–6 carbon atoms or R4 and R5 are, together, —(CH2)n—, or —CH2CH2XCH2CH2—;
• X is O, S, SO, SO2, NR3, or CH2;
• n is 2 to 5;
• C is —OR6, or —NR6R7;
• R6 and R7 are each, independently, hydrogen, alkyl of 1–18 carbon atoms, aryl, heteroaryl, aralkyl of 6–20 carbon atoms, heteroaralkyl of 6–20 carbon atoms, cycloalkyl of 3–10 carbon atoms, —(CH2CH2O)nCH3, —(CH2)mA or R6 and R7 are, together, —(CH2)p—, —(CH2)2N(CH3)(CH2)4—, —(CH2)2N(R8)(CH2)2—, or —(CH2)2CH(R8)—(CH2)2—;
• R8 is hydrogen, alkyl of 1–18 carbon atoms, aryl, heteroaryl, aralkyl of 6–20 carbon atoms, heteroaralkyl of 6–20 carbon atoms, cycloalkyl of 3–10 carbon atoms, —(CH2CH2O)nCH3, —(CH2CH2CH2O)nCH3, or —(CH2)mA;
• A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl, heteroarylsulfonyl, —CHF2, —CH2F, —CF3, —(CH2CH2O)nCH3, —(CH2CH2CH2O)nCH3, —CO2R3, —O(C═O)NR6R7, aralkyloxy, or heteroaralkyloxy;
• m is 2 to 16
• p is 2 to 12
• or a pharmaceutically acceptable salt thereof.