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

A method of treating metabolic disorders mediated by insulin resistance or hyperglycemia in a mammal in need thereof which comprises administering to said mammal, a compound of formula I having the structure 15

• wherein:
• B and D are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, aralkyl of 6-12 carbon atoms, or heteroaralkyl of 6-12 carbon atoms except where B and D both are hydrogen;
• R1 is hydrogen, alkyl of 1-6 carbon atoms, —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 alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, —CONR6R7, —NR3CONR6R7, —NR3COR6, —OR6, —O2CNR6R7, —NR3CO2R6, —O2CR6, —CH2OR6, —NR6R7, —CR3═CR3R8, —CPh3, —CH2NR6R7, or 16
• 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, —(CH)mA or R6 and R7 are, together, —(CH2)p—, —(CH2)2N(CH3)(CH2)4—, —(CH2)2N(R8)(CH2)2—, or —(CH 2)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, —(CH 2CH2O)nCH3, —(CH2CH2CH2O)nCH3 or —(CH2)mA;
• A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl, heteroarylsulfonyl, —CHF2, —CH2F, —CF3, —(CH 2CH2O)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 or inhibiting type II diabetes in a mammal in need thereof which comprises administering to said mammal, a compound of formula I having the structure 17

• wherein:
• B and D are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, aralkyl of 6-12 carbon atoms, or heteroaralkyl of 6-12 carbon atoms except where B and D both are hydrogen;
• R1 is hydrogen, alkyl of 1-6 carbon atoms, —SO2Ph(OH)(CO2H), —CH(R2)W, —CH 2CH2Y, 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, —NR′(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 alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, —CONR6R7, —NR3CONR6R7, —NR3COR6,
• —OR6, O2CNR6R7, —NR3CO2R6, —O2CR6, —CH2OR6, —NR6R7, —CR3═CR3R8, —CPh3, —CH2NR6R7, or 18
• 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 —(CH 2)2CH(R8)—(CH2)2—;
• R8 is hydrogen, allyl 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, —(CH 2CH2O)nCH3, —(CH2CH2CH2O)nCH3, or —(CH2)mA;
• A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl, heteroarylsulfonyl, —CHF2, —CH2F, —CF3, —(CH 2CH2O)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 modulating glucose levels in a mammal in need thereof which comprises administering to said mammal, a compound of formula I having the structure 19

• wherein:
• B and D are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, aralkyl of 6-12 carbon atoms, or heteroaralkyl of 6-12 carbon atoms except where B and D both are hydrogen;
• 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, —NR 3(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 alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, —CONR6R7, —NR3CONR6R7, —NR3COR6, —OR 6, —O2CNR6R7, —NR3CO2R6, —O2CR6, —CH2OR6, —NR6R7, —CR3═CR3R8, —CPh3, —CH2NR6R7, or 20
• R6 and R7 are each, independently, hydrogen, alkyl of 1-18 carbon atoms, aryl, heteroaryl, arakl 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 —(CH 2)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, —(CH 2CH2O)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 21

• wherein:
• B and D are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, aralkyl of 6-12 carbon atoms, or heteroaralkyl of 6-12 carbon atoms except where B and D both are hydrogen;
• R1 is hydrogen, alkyl of 1-6 carbon atoms, —SO2Ph(OH)(CO2H), —CH(R2)W, —CH 2CH2Y, 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, —NR 3(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)n13 , or —CH2CH2XCH2CH2—;
• X is O, S, SO, SO2, NR3 or CH2;
• n is 2 to 5;
• C is alkyl of 1-18 carbon atoms, aryl, heteroaryl, aralkyl of 6-20 carbon atoms, heteroaralkyl of 6-20 carbon atoms, —CONR6R7, —NR3CONR6R7, —NR3COR6, —OR 6, —O2CNR6R7, —NR3CO2R6, —O2CR6, —CH2OR6, —NR6R7, —CR3═CR3R8, —CPh3, —CH2NR6R7, or 22
• 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 —(CH 2)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, —(CH 2CH2O)nCH3, —(CH2CH2CH2O)nCH3, or —(CH2)mA;
• A is aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfoxy, heteroarylsulfoxy, arylsulfonyl, heteroarylsulfonyl, —CHF2, —CH2F, —CF3, —(CH 2CH2O)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.