N-(4-sulfonylaryl)Cyclylamine 2-hydroxyethylamines as beta-3 adrenergic receptor agonists

A method of treating metabolic disorders mediated by insulin resistance or hyperglycemia resulting from insulin resistance in a mammal in need thereof which comprises providing to said mammal, an effective amount of a compound of formula I having the structure

• wherein:
• W is (CH2)m;
• X is (CH2)n;
• Y is OCH2, SCH2, or a bond;
• R1 is phenyl substituted with R5 and R6, or Het substituted with R5 and R6;
• R2 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms;
• R4 is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, aryl substituted with R5 and R6, Het substituted with R5 and R6, aryloxy, —NHCOR7, —NR8R8, —CR3R5R6, arylamino, Het-amino, arylalkylamino having 1-6 carbon atoms in the alkyl chain, Het-alkylamino having 1-6 carbon atoms in the alkyl chain, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl of 3-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms, arylaminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain, phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6 carbon atoms;
• R3, R5, and R6, are each, independently, hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having 1-6 carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon atoms in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in the alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino, Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain, Het-alkylamino having 1-6 carbon atoms in the alkyl chain, hydroxyamino, —NHCOR7, —NHSO2R7, —NHP(O)(R7)2, —COR8, —SO2R8, —NR8R8, carboxy, alkylcarbonyl of 2-7 carbon atoms, formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms, arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6 carbon atoms;
• or R5 and R6 may be alkylene groups that are taken together to form a 3-8 membered cycloalkyl ring when R5 and R6 are attached to a common carbon atom;
• R7 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon atoms, —NR8R9, or —NR9(CH2)p—R8
• R8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, hydroxy, aryl substituted with R5 and R6, arylalkoxy having 1-6 carbon atoms in the alkyl chain, —CR3R5R6, —(CH2)p—COR9, or —(CH2)p—R9;
• R9 is hydrogen, hydroxy, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, aryl substituted with R5 and R6, Het substituted with R5 and R6, arylalkoxy having 1-6 carbon atoms in the alkyl chain, or —NR10R10;
• R10 is hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, hydroxy, aryl substituted with R5 and R6, or Het substituted with R5 and R6;
• Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;
• wherein the heterocycle may be saturated, unsaturated, or partially unsaturated;
• and may be optionally fused to a phenyl ring;
• m is 1-3;
• n is 1-3;
• and m+n=4;
• p is 0-6;
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting type II diabetes in a mammal in need thereof which comprises providing to said mammal, an effective amount of a compound of Formula I having the structure

• wherein:
• W is (CH2)m;
• X is (CH2)n;
• Y is OCH2, SCH2, or a bond;
• R1 is phenyl substituted with R5 and R6, or Het substituted with R5 and R6;
• R2 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms;
• R4 is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, aryl substituted with R5 and R6, Het substituted with R5 and R6, aryloxy, —NHCOR7, —NR8R8, —CR3R5R6, arylamino, Het-amino, arylalkylamino having 1-6 carbon atoms in the alkyl chain, Het-alkylamino having 1-6 carbon atoms in the alkyl chain, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl of 3-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms, arylaminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain, phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6 carbon atoms;
• R3, R5, and R6, are each, independently, hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having 1-6 carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon atoms in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in the alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino, Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain, Het-alkylamino having 1-6 carbon atoms in the alkyl chain, hydroxyamino, —NHCOR7, —NHSO2R7, —NHP(O)(R7)2, —COR8, —SO2R8, —NR8R8, carboxy, alkylcarbonyl of 2-7 carbon atoms, formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms, arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6 carbon atoms;
• or R5 and R6 may be alkylene groups that are taken together to form a 3-8 membered cycloalkyl ring when R5 and R6 are attached to a common carbon atom;
• R7 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon atoms, —NR8R9, or —NR9(CH2)p—R8
• R8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, hydroxy, aryl substituted with R5 and R6, arylalkoxy having 1-6 carbon atoms in the alkyl chain, —CR3R5R6, —(CH2)p—COR9, or —(CH2)p—R9;
• R9 is hydrogen, hydroxy, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, aryl substituted with R5 and R6, Het substituted with R5 and R6, arylalkoxy having 1-6 carbon atoms in the alkyl chain, or —NR10R10;
• R10 is hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, hydroxy, aryl substituted with R5 and R6, or Het substituted with R5 and R6;
• Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;
• wherein the heterocycle may be saturated, unsaturated, or partially unsaturated;
• and may be optionally fused to a phenyl ring;
• m is 1-3;
• n is 1-3;
• and m+n=4;
• p is 0-6;
• or a pharmaceutically acceptable salt thereof.

A method of modulating glucose levels in a mammal in need thereof which comprises providing to said mammal, an effective amount of a compound of formula I having the structure

• wherein:
• W is (CH2)m;
• X is (CH2)n;
• Y is OCH2, SCH2, or a bond;
• R1 is phenyl substituted with R5 and R6, or Het substituted with R5 and R6;
• R2 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms;
• R4 is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, aryl substituted with R5 and R6, Het substituted with R5 and R6, aryloxy, —NHCOR7, —NR8R8, —CR3R5R6, arylamino, Het-amino, arylalkylamino having 1-6 carbon atoms in the alkyl chain, Het-alkylamino having 1-6 carbon atoms in the alkyl chain, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl of 3-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms, arylaminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain, phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6 carbon atoms;
• R3, R5, and R6, are each, independently, hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having 1-6 carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon atoms in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in the alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino, Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain, Het-alkylamino having 1-6 carbon atoms in the alkyl chain, hydroxyamino, —NHCOR7, —NHSO2R7, —NH P(O)(R7)2, —COR8, —SO2R8, —NR8R8, carboxy, alkylcarbonyl of 2-7 carbon atoms, formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms, arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6 carbon atoms;
• or R5 and R6 may be alkylene groups that are taken together to form a 3-8 membered cycloalkyl ring when R5 and R6 are attached to a common carbon atom;
• R7 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon atoms, —NR8R9, or —NR9(CH2)p—R8
• R8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, hydroxy, aryl substituted with R5 and R6, arylalkoxy having 1-6 carbon atoms in the alkyl chain, —CR3R5R6, —(CH2)p—COR9, or —(CH2)p—R9;
• R9 is hydrogen, hydroxy, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, aryl substituted with R5 and R6, Het substituted with R5 and R6, arylalkoxy having 1-6 carbon atoms in the alkyl chain, or —NR10R10;
• R10 is hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, hydroxy, aryl substituted with R5 and R6, or Het substituted with R5 and R6;
• Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;
• wherein the heterocycle may be saturated, unsaturated, or partially unsaturated;
• and may be optionally fused to a phenyl ring;
• m is 1-3;
• n is 1-3;
• and m+n=4;
• p is 0-6;
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting urinary incontinence in a mammal in need thereof which comprises providing to said mammal an effective amount of a compound of formula I having the structure

• wherein:
• W is (CH2)m;
• X is (CH2)n;
• Y is OCH2, SCH2, or a bond;
• R1 is phenyl substituted with R5 and R6, or Het substituted with R5 and R6;
• R2 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms;
• R4 is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, aryl substituted with R5 and R6, Het substituted with R5 and R6, aryloxy, —NHCOR7, —NR8R8, —CR3R5R6, arylamino, Het-amino, arylalkylamino having 1-6 carbon atoms in the alkyl chain, Het-alkylamino having 1-6 carbon atoms in the alkyl chain, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl of 3-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms, arylaminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain, phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6 carbon atoms;
• R3, R5, and R6, are each, independently, hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having 1-6 carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon atoms in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in the alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino, Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain, Het-alkylamino having 1-6 carbon atoms in the alkyl chain, hydroxyamino, —NHCOR7, —NHSO2R7, —NHP(O)(R7)2, —COR8, —SO2R8, —NR8R8, carboxy, alkylcarbonyl of 2-7 carbon atoms, formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms, arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6 carbon atoms;
• or R5 and R6 may be alkylene groups that are taken together to form a 3-8 membered cycloalkyl ring when R5 and R6 are attached to a common carbon atom;
• R7 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon atoms, —NR8R9, or —NH9(CH2)p—R8
• R8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, hydroxy, aryl substituted with R5 and R6, arylalkoxy having 1-6 carbon atoms in the alkyl chain, —CR3R5R6, —(CH2)p—COR9, or —(CH2)p—R9;
• R9 is hydrogen, hydroxy, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, aryl substituted with R5 and R6, Het substituted with R5 and R6, arylalkoxy having 1-6 carbon atoms in the alkyl chain, or —NR10R10;
• R10 is hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, hydroxy, aryl substituted with R5 and R6, or Het substituted with R5 and R6;
• Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;
• wherein the heterocycle may be saturated, unsaturated, or partially unsaturated;
• and may be optionally fused to a phenyl ring;
• m is 1-3;
• n is 1-3;
• and m+n=4;
• p is 0-6;
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting atherosclerosis, gastrointestinal disorders, neurogenic inflammation, glaucoma, or ocular hypertension in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula I having the structure

• wherein:
• W is (CH2)m;
• X is (CH2)n;
• Y is OCH2, SCH2, or a bond;
• R1 is phenyl substituted with R5 and R6, or Het substituted with R5 and R6;
• R2 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms;
• R4 is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, aryl substituted with R5 and R6, Het substituted with R5 and R6, aryloxy, —NHCOR7, —NR8R8, —CR3R5R6, arylamino, Het-amino, arylalkylamino having 1-6 carbon atoms in the alkyl chain, Het-alkylamino having 1-6 carbon atoms in the alkyl chain, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl of 3-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms, arylaminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain, phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6 carbon atoms;
• R3, R5, and R6, are each, independently, hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having 1-6 carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon atoms in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in the alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino, Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain, Het-alkylamino having 1-6 carbon atoms in the alkyl chain, hydroxyamino, —NHCOR7, —NHSO2R7, —NHP(O)(R7)2, —COR8, —SO2 R8, —NR8R8, carboxy, alkylcarbonyl of 2-7 carbon atoms, formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms, arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6 carbon atoms;
• or R5 and R6 may be alkylene groups that are taken together to form a 3-8 membered cycloalkyl ring when R5 and R6 are attached to a common carbon atom;
• R7 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon atoms, —NR8R9, or —NR9(CH2)p—R8
• R8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, hydroxy, aryl substituted with R5 and R6, arylalkoxy having 1-6 carbon atoms in the alkyl chain, —CR3R5R6, —(CH2)p—COR9, or —(CH2)p—R9;
• R9 is hydrogen, hydroxy, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, aryl substituted with R5 and R6, Het substituted with R5 and R6, arylalkoxy having 1-6 carbon atoms in the alkyl chain, or —NR10R10;
• R10 is hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, hydroxy, aryl substituted with R5 and R6, or Het substituted with R5 and R6;
• Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;
• wherein the heterocycle may be saturated, unsaturated, or partially unsaturated;
• and may be optionally fused to a phenyl ring;
• m is 1-3;
• n is 1-3;
• and m+n=4;
• p is 0-6;
• or a pharmaceutically acceptable salt thereof.

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

• wherein:
• W is (CH2)m;
• X is (CH2)n;
• Y is OCH2, SCH2, or a bond;
• R1 is phenyl substituted with R5 and R6, or Het substituted with R5 and R6;
• R2 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms;
• R4 is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, aryl substituted with R5 and R6, Het substituted with R5 and R6, aryloxy, —NHCOR7, —NR8R8, —CR3R5R6, arylamino, Het-amino, arylalkylamino having 1-6 carbon atoms in the alkyl chain, Het-alkylamino having 1-6 carbon atoms in the alkyl chain, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl of 3-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms, arylaminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain, phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6 carbon atoms;
• R3, R5, and R6, are each, independently, hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having 1-6 carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon atoms in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in the alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino, Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain, Het-alkylamino having 1-6 carbon atoms in the alkyl chain, hydroxyamino, —NHCOR7, —NHSO2R7, —NHP(O)(R7)2, —COR8, —SO2R8, —NR8R8, carboxy, alkylcarbonyl of 2-7 carbon atoms, formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms, arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6 carbon atoms;
• or R5 and R6 may be alkylene groups that are taken together to form a 3-8 membered cycloalkyl ring when R5 and R6 are attached to a common carbon atom;
• R7 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon atoms, —NR8R9, or —NH9(CH2)p—R8
• R8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, hydroxy, aryl substituted with R5 and R6, arylalkoxy having 1-6 carbon atoms in the alkyl chain, —CR3R5R6, —(CH2)p—COR9, or —(CH2)p—R9;
• R9 is hydrogen, hydroxy, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, aryl substituted with R5 and R6, Het substituted with R5 and R6, arylalkoxy having 1-6 carbon atoms in the alkyl chain, or —NR10R10;
• R10 is hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, hydroxy, aryl substituted with R5 and R6, or Het substituted with R5 and R6;
• Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;
• wherein the heterocycle may be saturated, unsaturated, or partially unsaturated;
• and may be optionally fused to a phenyl ring;
• m is 1-3;
• n is 1-3;
• and m+n=4;
• p is 0-6;
• or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.