Cyclic amine phenyl beta-3 adrenergic receptor agonists

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

• 27
• wherein
• A is Ar or Het;
• X is —OCH2—, —SCH2—, or a bond;
• T1 is (CH2)m;
• T2 is (CH2)n;
• T is a bond, alkyl of 1-6 carbon atoms optionally substituted with R11, alkenyl of 2-7 carbon atoms optionally substituted with R11, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety, alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7 carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms;
• R1, R2, and R3are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, dihydroxyphosphorylamino, —CO2-alkyl of 1-6 carbon atoms, or Ar optionally substituted with R11;
• R4 is hydrogen, alkyl of 1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbon atoms,
• R5 is
• 28
• Aa is (i) an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5;
• or (ii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms;
• Y and Z are each, independently, NR7, O, or S;
• X1 and x2 are each, independently, CO or SO2,
• a dotted line represents and optional double bond;
• R6, R7, and R8 are each, independently, hydrogen;
• alkyl of 1-6 carbon atoms optionally substituted by R11, R12;
• and R13;
• alkenyl of 2-7 carbon atoms optionally substituted by R11, R12, and R13;
• alkynyl of 2-7 carbon atoms optionally substituted with Ra11;
• cycloalkyl of 3-8 carbon atoms optionally substituted by R11, R12, and R13;
• bicycloalkyl of 7-11 carbon atoms optionally substituted by R11, R12, and R13;
• —CO2-alkyl of 1-6 carbon atoms;
• Het optionally substituted by R11, R12, or R13;
• or Ar optionally substituted by R11, R12, and R13;
• or when R6 and R7 are contained on a common nitrogen, they may be taken together to form a saturated 5-7 membered heterocycle that is optionally substituted with R11;
• R9 and R10 are each, independently, alkyl optionally substituted by R11, R12, and R13;
• Ar optionally mono-, di-, or tri-substituted by R15;
• Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-, di-, or tri-substituted by R15;
• Het optionally mono-, di-, or tri-substituted by R15;
• R11, R12, or R13 are each, independently, alkyl of 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atoms in the alkyl moiety, Ar optionally substituted with R14, Het optionally substituted with R14, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo, —CN, —CHO, —CO2H, —OCO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, —CO2-Ar, —CO2-alkyl-Ar wherein the alkyl moiety has 1-6 carbon atoms, —OCO2-Ar, —CONH2, —CONHOH, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO2-alkyl of 1-6 carbon atoms, —NHSO2—Ar, or —NHSO2—Het;
• or when R11 and R12 are contained on a common carbon atom of an alkyl moiety, they may be taken together to form a spiro cycloalkyl ring of 3-8 carbon atoms;
• R14 is halogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7 carbon atoms, —SO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbon atoms;
• R15 is
• (a) hydroxy, halogen, —CN, —NR16R16, —OR16, —SR16, triflouromethyl, alkyl of 1-6 carbon atoms, —SO2R17, —O-alkyl-CO2R17 wherein the alkyl moiety contains 1-6 carbon atoms, —CO2R17, —OCOR17, —NR16COR17, —COR17, —NR16SO2R17, or —NR16CO2R16;
• or
• (b) alkyl of 1-6 carbon atoms mono-, or di-substituted with hydroxy;
• halogen;
• —CN;
• —NR16NR16;
• —OR16;
• —SR16;
• triflouromethyl;
• alkyl of 1-6 carbon atoms;
• —SO2R17;
• —CO2R17;
• —OCOR17;
• —NR16COR17;
• —COR17;
• —NR16SO2R17;
• —NR16;
• Ar which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or Het which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• (c) Het optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or
• (d) Ar optionally mono- or di-substituted-by R16, OR16, —NR16R16, or halogen;
• R16 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Ar or Het moieties may be optionally mono-, di-, or tri- substituted with halogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO2H, —CO2alkyl of 1-6 carbon atoms, or —SO2alkyl of 1-6 carbon atoms;
• R17 is R16 or NR16R16;
• 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;
• Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms;
• m=1-3;
• n=1-3;
• 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

• 29
• wherein
• A is Ar or Het;
• X is —OCH2—, —SCH2—, or a bond;
• T1 is (CH2)m;
• T2 is (CH2)n;
• T is a bond, alkyl of 1-6 carbon atoms optionally substituted with R11, alkenyl of 2-7 carbon atoms optionally substituted with R11, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety, alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkyloxoalkyl of.1-6 carbon atoms per alkyl, moiety, acyl of 2-7 carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms;
• R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, dihydroxyphosphorylamino, —CO2-alkyl of 1-6 carbon atoms, or Ar optionally substituted with R11;
• R4 is hydrogen, alkyl of 1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbon atoms,
• R5 is
• 30
• Aa is (i) an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5;
• or (ii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms;
• Y and Z are each, independently, NR7, O, or S;
• X1 and X2 are each, independently, CO or SO2;
• a dotted line represents and optional double bond;
• R6, R7, and R8 are each, independently, hydrogen;
• alkyl of 1-6 carbon atoms optionally substituted by R11, R12, and R13;
• alkenyl of 2-7 carbon atoms optionally substituted by R11, R12, and R13;
• alkynyl of 2-7 carbon atoms optionally substituted with R11;
• cycloalkyl of 3-8 carbon atoms optionally substituted by R11, R12, and R13;
• bicycloalkyl of 7-11 carbon atoms optionally substituted by R11, R12, and R13;
• —CO2-alkyl of 1-6 carbon atoms;
• Het optionally substituted by R11, R12, or R13;
• or Ar optionally substituted by R11, R12, and R13;
• or when R6 and R7 are contained on a common nitrogen, they may be taken together to form a saturated 5-7 membered heterocycle that is optionally substituted with R11;
• R9 and R10 are each, independently, alkyl optionally substituted by R11, R12, and R13;
• Ar optionally mono-, di-, or tri-substituted by R15;
• Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-, di-, or tri-substituted by R15;
• Het optionally mono-, di-, or tri-substituted by R15;
• R11, R12, or R13 are each, independently, alkyl of 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atoms in the alkyl moiety, Ar optionally substituted with R14, Het optionally substituted with R14, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo, —CN, —CHO, —CO2H, —OCO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, —CO2—Ar, —CO2-alkyl-Ar wherein the alkyl moiety has 1-6 carbon atoms, —OCO2—Ar, —CONH2, —CONHOH, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO2-alkyl of 1-6 carbon atoms, —NHSO2-Ar, or —NHSO2—Het;
• or when R,11 and R12 are contained on a common carbon atom of an alkyl moiety, they may be taken together to form a spiro cycloalkyl ring of 3-8 carbon atoms;
• R14 is halogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7 carbon atoms, —SO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbon atoms;
• R15 is
• (a) hydroxy, halogen, —CN, —NR16R16, —OR16, —SR16, triflouromethyl, alkyl of 1-6 carbon atoms, —SO2R17, —O-alkyl-CO2R17 wherein the alkyl moiety contains 1-6 carbon atoms, —CO2R17, —OCOR17, —NR16COR17, —COR17, —NR16SO2R17 or —NR16CO2R16;
• or
• (b) alkyl of 1-6 carbon atoms mono-, or di-substituted with hydroxy;
• halogen;
• —CN;
• —NR16NR16;
• —OR16;
• —SR16;
• triflouromethyl;
• alkyl of 1-6 carbon atoms;
• —SO2R17;
• —CO2R17;
• —OCOR17;
• —NR16COR17;
• —COR17;
• —NR16SO2R17;
• —NR16;
• Ar which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or Het which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• (c) Het optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or
• (d) Ar optionally mono- or di-substituted by R16, —OR16, —NR16R16 or halogen;
• R16 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Ar or Het moieties may be optionally mono-, di-, or tri- substituted with halogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO2H, —CO2alkyl of 1-6 carbon atoms, or —SO2alkyl of 1-6 carbon atoms;
• R17is R16or —NR16R16;
• 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;
• Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms;
• m=1-3;
• n=1-3;
• 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

• 31
• wherein
• A is Ar or Het;
• X is —OCH2—, —SCH2—, or a bond;
• T1 is (CH2)m;
• T2 is (CH2)n;
• T is a bond, alkyl of 1-6 carbon atoms optionally substituted with R11, alkenyl of 2-7 carbon atoms optionally substituted with R11, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety, alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety,acyl of 2-7 carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms;
• R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, dihydroxyphosphorylamino, —CO2-alkyl of 1-6 carbon atoms, or Ar optionally substituted with R11;
• R4 is hydrogen, alkyl of 1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbon atoms,
• R5 is
• 32
• Aa is (i) an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5;
• or (ii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms;
• Y and Z are each;
• independently, NR6, O, or S;
• X1 and X2 are each, independently, CO or SO2;
• a dotted line represents and optional double bond;
• R6, R7, and R8 are each, independently, hydrogen;
• alkyl of 1-6 carbon atoms optionally substituted by R11, R12, and R13;
• alkenyl of 2-7 carbon atoms optionally substituted by R11, R12, and R13;
• alkynyl of 2-7 carbon atoms optionally substituted with R11;
• cycloalkyl of 3-8 carbon atoms optionally substituted by R11, R12, and R13;
• bicycloalkyl of 7-11 carbon atoms optionally substituted by R11, R12, and R13;
• —CO2-alkyl of 1-6 carbon atoms;
• Het optionally substituted by R11, R12, or R13;
• or Ar optionally substituted by R11, R12, and R13;
• or when R6 and R7 are contained on a common nitrogen, they may be taken together to form a saturated 5-7 membered heterocycle that is optionally substituted with R11;
• R9 and R10 are each, independently, alkyl optionally substituted by by R11, R12, and R13;
• Ar optionally mono-, di-, or tri-substituted by R15;
• Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-, di-, or tri-substituted by R15;
• Het optionally mono-, di-, or tri-substituted by R15;
• R11, R12, or R13 are each, independently, alkyl of 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atoms in the alkyl moiety, Ar optionally substituted with R14, Het optionally substituted with R14, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo, —CN, —CHO, —CO2H, —OCO2-alkyl of 1-6 carbon atoms, —OCO2-alkyl of 1-6 carbon atoms, —CO2-Ar, —CO2-alkyl-Ar wherein the alkyl moiety has 1-6 carbon atoms, —OCO2—Ar, —CONH2, —CONHOH, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO2-alkyl of 1-6 carbon atoms, —NHSO2—Ar, or —NHSO2—Het;
• or when R11 and R12 are contained on a common carbon atom of an alkyl moiety, they may be taken together to form a spiro cycloalkyl ring of 3-8 carbon atoms;
• R14 is halogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7 carbon atoms, —SO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbon atoms;
• R15 is
• (a) hydroxy, halogen, —CN, —NR16R16, —OR16, —SR16, triflouromethyl, alkyl of 1-6 carbon atoms, —SO2R17, —O-alkyl-CO2R17 wherein the alkyl moiety contains 1-6 carbon atoms, —CO2R17, —OCOR17, —NR16COR17, —COR17, —NR16SO2R17, or —NR16CO2R16;
• or
• (b) alkyl of 1-6 carbon atoms mono-, or di-substituted with hydroxy;
• halogen;
• —CN;
• —NR16NR16;
• —OR16;
• —SR16;
• triflouromethyl;
• alkyl of 1-6 carbon atoms;
• —SO2R17;
• —CO2R17;
• —OCOR17;
• —NR16COR17;
• —COR17;
• —NR16SO2R17;
• —NR16CO2R16;
• Ar which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or Het which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• (c) Het optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or
• (d) Ar optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• R16 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Ar or Het moieties may be optionally mono-, di-, or tri- substituted with halogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO2H, —CO2alkyl of 1-6 carbon atoms, or —SO2alkyl of 1-6 carbon atoms;
• R17 is R16 or —NR16R16;
• 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;
• Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms;
• m=1-3;
• n=1-3;
• or a pharmaceutically acceptable salt thereof wherein
• A is Ar or Het;
• X is —OCH2—, —SCH2—, or a bond;
• T1 is (CH2)m;
• T2 is (CH2)n;
• T is a bond, alkyl of 1-6 carbon atoms optionally substituted with R11, alkenyl of 2-7 carbon atoms optionally substituted with R11, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety, alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7 carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms;
• R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, dihydroxyphosphorylamino, —CO2-alkyl of 1-6 carbon atoms, or Ar optionally substituted with R11;
• R4 is hydrogen, alkyl of 1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbon atoms,
• R5 is
• 33
• Aa is (i) an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5;
• or (ii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5, and the alkyl moiety of the alkyl -ester contains 1-6 carbon atoms;
• Y and Z are each, independently, NR7, O, or S;
• X1 and X2 are each, independently, CO or SO2;
• a dotted line represents and optional double bond;
• R6, R7, and R8 are each, independently, hydrogen;
• alkyl of 1-6 carbon atoms optionally substituted by R11, R12, and R13;
• alkenyl of 2-7 carbon atoms optionally substituted by R11, R12, and R13;
• alkynyl of 2-7 carbon atoms optionally substituted with R11 cycloalkyl of 3-8 carbon atoms optionally substituted by R11, R12, and R13;
• bicycloalkyl of 7-11 carbon atoms optionally substituted by R11, R12, and R13;
• —CO2-alkyl of 1-6 carbon atoms;
• Het optionally substituted by R11, R12, or R13;
• or Ar optionally substituted by R11, R12, and R13;
• or when R6 and R7 are contained on a common nitrogen, they may be taken together to form a saturated 5-7 membered heterocycle that is optionally substituted with R11;
• p1 R9 and R10 are each, independently, alkyl optionally substituted by R11, R12, and R13;
• Ar optionally mono-, di-, or tri-substituted by R15;
• Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-, di-, or tri-substituted by R15;
• Het optionally mono-, di-, or tri-substituted by R15;
• R11, R12, or R13 are each, independently, alkyl of 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atoms in the alkyl moiety, Ar optionally substituted with R14, Het optionally substituted with R14, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo, —CN, —CHO, —CO2H, —OCO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, —CO2—Ar, —CO2-alkyl-Ar wherein the alkyl moiety has 1-6 carbon atoms, —OCO2—Ar, —CONH2, —CONHOH, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO2-alkyl of 1-6 carbon atoms, —NHSO2—Ar, or —NHSO2-Het;
• or when R11 and R12 are contained on a common carbon atom of an alkyl moiety, they may be taken together to form a spiro cycloalkyl ring of 3-8 carbon atoms;
• R14 is halogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7 carbon atoms, -SO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbon atoms;
• R15 is
• (a) hydroxy, halogen, —CN, —NR16R16, —OR16, —SR16, triflouromethyl, alkyl of 1-6 carbon atoms, —SO2R17, —O-alkyl-CO2R17 wherein the alkyl moiety contains 1-6 carbon atoms, —CO2R17, —OCOR17, —NR16COR17, —COR17, —NR16SO2R17, or —NR16CO2R16;
• or
• (b) alkyl of 1-6 carbon atoms mono-, or di-substituted with hydroxy;
• halogen;
• —CN;
• —NR16NR16;
• —OR16;
• —SR16;
• triflouromethyl;
• alkyl of 1-6 carbon atoms;
• —SO2R17;
• CO2R17;
• —OCOR17;
• NR16COR17;
• COR17;
• —NR16SO2R17;
• —NR16CO2R16;
• Ar which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or Het which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• (c) Het optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or
• (d) Ar optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• R16 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Ar or Het moieties may be optionally mono-, di-, or tri- substituted with halogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO2H, —CO2alkyl of 1-6 carbon atoms, or —SO2alkyl of 1-6 carbon atoms;
• R17 is R16 or —NR16R16;
• 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;
• Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms;
• m=1-3;
• n=1-3;
• 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

• 34
• wherein
• A is Ar or Het;
• X is —OCH2—, —SCH2—, or a bond;
• T1 is (CH2)m;
• T2 is (CH2)n;
• T is a bond, alkyl of 1-6 carbon atoms optionally substituted with R11, alkenyl of 2-7 carbon atoms optionally substituted with R11, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety, alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7 carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms;
• R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, dihydroxyphosphorylamino, —CO2-alkyl of 1-6 carbon atoms, or Ar optionally substituted with R11;
• R4 is hydrogen, alkyl of 1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbon atoms,
• R5 is
• 35
• Aa is (i) an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5;
• or (ii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms;
• Y and Z are each, independently, NR7, O, or S;
• X1 and X2 are each, independently, CO or SO2;
• a dotted line represents and optional double bond;
• R6, R7, and R8 are each, independently, hydrogen;
• alkyl of 1-6 carbon atoms optionally substituted by R11, R12, and R13;
• alkenyl of 2-7 carbon atoms optionally substituted by R11, R12, and R13;
• alkynyl of 2-7 carbon atoms optionally substituted with R11;
• cycloalkyl of 3-8 carbon atoms optionally substituted by R11, R12 and R13;
• bicycloalkyl of 7-11 carbon atoms optionally substituted by R11, R12, and R13;
• —CO2-alkyl of 1-6 carbon atoms;
• Het optionally substituted by R11, R12, or R13;
• or Ar optionally substituted by R11, R12, and R13;
• or when R6 and R7 are contained on a common nitrogen, they may be taken together to form a saturated 5-7 membered heterocycle that is optionally substituted with R11;
• R9 and R10 are each, independently, alkyl optionally substituted by R11, R12, and R13;
• Ar optionally mono-, di-, or tri-substituted by R15;
• Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-, di-, or tri-substituted by R15;
• Het optionally mono-, di-, or tri-substituted by R15;
• R11, R12, or R13 are each, independently, alkyl of 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atoms in the alkyl moiety, Ar optionally substituted with R14, Het optionally substituted with R14, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo, —CN, —CHO, —CO2H, —OCO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, —CO2—Ar, —CO2-alkyl-Ar wherein the alkyl moiety has 1-6 carbon atoms, —OCO2—Ar, —CONH2, —CONHOH, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO2-alkyl of 1-6 carbon atoms, —NHSO2—Ar, or —NHSO2—Het;
• or when R11 and R12 are contained on a common carbon atom of an alkyl moiety, they may be taken together to form a spiro cycloalkyl ring of 3-8 carbon atoms;
• R14 is halogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7 carbon atoms, —SO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbon atoms;
• R15 is
• (a) hydroxy, halogen, —CN, —NR16R16, —OR16, —SR16, triflouromethyl, alkyl of 1-6 carbon atoms, —SO2R17, —O-alkyl-CO2R17 wherein the alkyl moiety contains 1-6 carbon atoms, —CO2R17, —OCOR17, —NR16COR17, —COR17, —NR16SO2R17, or —NR16CO2R16;
• or
• (b) alkyl of 1-6 carbon atoms mono-, or di-substituted with hydroxy;
• halogen;
• —CN;
• —NR16NR16;
• —OR16;
• —SR16;
• triflouromethyl;
• alkyl of 1-6 carbon atoms;
• —SO2R17;
• —CO2R17;
• —OCOR17;
• —NR16COR17;
• —COR17;
• —NR16SO2R17;
• —NR16CO2R16;
• Ar which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or Het which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• (c) Het optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or
• (d) Ar optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• R16 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Ar or Het moieties may be optionally mono-, di-, or tri- substituted with halogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO2H, —CO2alkyl of 1-6 carbon atoms, or —SO2alkyl of 1-6 carbon atoms;
• R17 is R16 or —NR16R16;
• 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;
• Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms;
• m=1-3;
• n 1-3;
• or a pharmaceutically acceptable salt thereof.

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

• 36
• wherein
• A is Ar or Het;
• X is —OCH2—, —SCH2—, or a bond;
• T1 is (CH2)m;
• T2 is (CH2)n;
• T is a bond, alkyl of 1-6 carbon atoms optionally substituted with R11, alkenyl of 2-7 carbon atoms optionally substituted with R11, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety, alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbonatoms per alkyl moiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7 carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms;
• R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, dihydroxyphosphorylamino, —CO2-alkyl of 1-6 carbon atoms, or Ar optionally substituted with R11;
• R4 is hydrogen, alkyl of 1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbon atoms,
• R5 is
• 37
• Aa is (i) an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5;
• or (ii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms;
• Y and Z are each, independently, NR7, O, or S;
• X1 and X2 are each, independently, CO or SO2;
• a dotted line represents and optional double bond;
• R6, R7, and R8 are each;
• independently, hydrogen;
• alkyl of 1-6 carbon atoms optionally substituted by R11, R12, and R13;
• alkenyl of 2-7 carbon atoms optionally substituted by R11 R12, and R13;
• alkynyl of 2-7 carbon atoms optionally substituted with R11;
• cycloalkyl of 3-8 carbon atoms optionally substituted by R11, R12, and R13;
• bicycloalkyl of 7-11 carbon atoms optionally substituted by R11, R12, and R13;
• —CO2-alkyl of 1-1-6 carbon atoms;
• Het optionally substituted by R11;
• R12, or R13;
• or Ar optionally substituted by R11, R12, and R13;
• or when R6 and R7 are contained on a common nitrogen, they may be taken together to form a saturated 5-7 membered heterocycle that is optionally substituted with R11;
• R9 and R10 are each, independently, alkyl optionally substituted by R11, R12, and R13;
• Ar optionally mono-, di-, or tri-substituted by R15;
• Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-, di-, or tri-substituted by R15;
• Het optionally mono-, di-, or tri-substituted by R15;
• R11, R12, or R13 are each, independently, alkyl of 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atoms in the alkyl moiety, Ar optionally substituted with R14, Het optionally substituted with R14, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo, —CN, —CHO, —CO2H, —OCO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, —CO2—Ar, —CO2-alkyl-Ar wherein the alkyl moiety has 1-6 carbon atoms, —OCO2—Ar, —CONH2, —CONHOH, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO2-alkyl of 1-6 carbon atoms, —NHSO2—Ar, or —NHSO2—Het;
• or when R11 and R12 are contained on a common carbon atom of an alkyl moiety, they may be taken together to form a spiro cycloalkyl ring of 3-8 carbon atoms;
• R14 is halogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7 carbon atoms, —SO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbon atoms;
• R15 is
• (a) hydroxy, halogen, —CN, —NR16R16, —OR16, —SR16, triflouromethyl, alkyl of 1-6 carbon atoms, —SO2R17, —O-alkyl-CO2R17 wherein the alkyl moiety contains 1-6 carbon atoms, —CO2R17, —OCOR17, —NR16COR17, —COR17, —NR16SO2R17, or —NR16CO2R16;
• or
• (b) alkyl of 1-6 carbon atoms mono-, or di-substituted with hydroxy;
• halogen;
• —CN;
• —NR16NR16;
• —OR16;
• —SR16;
• triflouromethyl;
• alkyl of 1-6 carbon atoms;
• —SO2R17—CO2R17;
• —OCOR17;
• —NR16COR17;
• —COR17;
• —NR16SO2R17;
• —NR16CO2R16;
• Ar which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or Het which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• (c) Het optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or
• (d) Ar optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• R16 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Ar or Het moieties may be optionally mono-, di-, or tri- substituted with halogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO2H, —CO2alkyl of 1-6 carbon atoms, or —SO2alkyl of 1-6 carbon atoms;
• R17 is R16 or —NR16R16;
• 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;
• Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms;
• m=1-3;
• n=1-3;
• or a pharmaceutically acceptable salt thereof.

A method of increasing the lean meat to fat ratio in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula I having the structure

• 38
• wherein
• A is Ar or Het;
• X is —OCH2—, —SCH2—, or a bond;
• T1 is (CH2)m;
• T2 is (CH2)n;
• T is a bond, alkyl of 1-6 carbon atoms optionally substituted with R11, alkenyl of 2-7 carbon atoms optionally substituted with R11, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety, alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7 carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms;
• R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, dihydroxyphosphorylamino, —CO2-alkyl of 1-6 carbon atoms, or Ar optionally substituted with R11;
• R4 is hydrogen, alkyl of 1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbon atoms,
• R5 is
• 39
• Aa is (i) an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5;
• or (ii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms;
• Y and Z are each, independently, NR7, O, or S;
• X1 and X2 are each, independently, CO or SO2;
• a dotted line represents and optional double bond;
• R6, R7, and R8 are each, independently, hydrogen;
• alkyl of 1-6 carbon atoms optionally substituted by R11, R12 and R13;
• alkenyl of 2-7 carbon atoms optionally substituted by R11, R12, and R13;
• alkynyl of 2-7 carbon atoms optionally substituted with R11;
• cycloalkyl of 3-8 carbon atoms optionally substituted by R11, R12, and R13;
• bicycloalkyl of 7-11 carbon atoms optionally substituted by R11, R12, and R13;
• —CO2-alkyl of 1-6 carbon atoms;
• Het optionally substituted by R11, R12, or R13;
• or Ar optionally substituted by R11, R12, and R13;
• or when R6 and R7 are contained on a common nitrogen, they may be taken together to form a saturated 5-7 membered heterocycle that is optionally substituted with R11;
• R9 and R10 are each, independently, alkyl optionally substituted by R11, R12, and R13;
• Ar optionally mono-, di-, or tri-substituted by R15;
• Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-, di-, or tri-substituted by R15;
• Het optionally mono-, di-, or tri-substituted by R15;
• R11, R12, or R13 are each, independently, alkyl of 1-6 carbon atoms,, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atoms in the alkyl moiety, Ar optionally substituted with R14, Het optionally substituted with R14, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo, —CN, —CHO, —CO2H, —OCO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, —CO2—Ar, —CO2-alkyl-Ar wherein the alkyl moiety has 1-6 carbon atoms, —OCO2—Ar, —CONH2, —CONHOH, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO2-alkyl of 1-6 carbon atoms, —NHSO2—Ar, or —NHSO2—Het;
• or when R11 and R12 are contained on a common carbon atom of an alkyl moiety, they may be taken together to form a spiro cycloalkyl ring of 3-8 carbon atoms;
• R14 is halogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7 carbon atoms, —SO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbon atoms;
• R15 is
• (a) hydroxy, halogen, —CN, —NR16R16, —OR16, —SR16, triflouromethyl, alkyl of 1-6 carbon atoms, —SO2R17, —O-alkyl-CO2R17 wherein the alkyl moiety contains 1-6 carbon atoms, —CO2R17, —OCOR17, —NR16COR17;
• —COR17, —NR16SO2R17;
• or —NR16CO2R16;
• or
• (b) alkyl of 1-6 carbon atoms mono-, or di-substituted with hydroxy;
• halogen;
• —CN;
• —NR16NR16;
• —OR16;
• —SR16;
• triflouromethyl;
• alkyl of 1-6 carbon atoms;
• —SO2R17;
• —CO2R17;
• —OCOR17;
• —NR16COR17;
• —COR17;
• —NR16SO2R17;
• —NR16CO2R16, Ar which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or Het which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• (c) Het optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or
• (d) Ar optionally mono- or di-substituted R16, —OR16, —NR16, or halogen;
• R16 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het wherein the Ar or Het moieties may be optionally mono, di-, or tri- substituted with halogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoromethyl, alkyl of, 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms;
• —CO2H, —CO2alkyl of 1-6 carbon atoms, or —SO2alkyl of 1-6 carbon atoms;
• R17 is R16 or —NR16R16;
• Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, sand sulfur;
• wherein the heterocycle may be saturated, unsaturated, or partially unsaturated;
• and may be optionally fused to a phenyl ring;
• Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms;
• m=1-3;
• n=1-3;
• or a pharmaceutically acceptable salt thereof.

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

• 40
• wherein
• A is Ar or Het;
• X is —OCH2—, —SCH2—, or a bond;
• T1 is (CH2)m;
• T2 is (CH2)n;
• T is a bond, alkyl of 1-6 carbon atoms optionally substituted with R11, alkenyl of 2-7 carbon atoms optionally substituted with R11, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety, alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7 carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms;
• R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, dihydroxyphosphorylamino, —CO2-alkyl of 1-6 carbon atoms, or Ar optionally substituted with R11;
• R4 is hydrogen, alkyl of 1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbon atoms,
• R5 is
• 41
• Aa is (i) an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5;
• or (ii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms;
• Y and Z are each, independently, NR7, O, or S;
• X1 and X2 are each, independently, CO or SO2;
• a dotted line represents and optional double bond;
• R6, R7, and R8 are each, independently, hydrogen;
• alkyl of 1-6 carbon atoms optionally substituted by R11, R12, and R13;
• alkenyl of 2-7 carbon atoms optionally substituted by R11, R12, and R13;
• alkenyl of 2-7 carbon atoms optionally substituted with R11;
• cycloalkyl of 3-8 carbon atoms optionally substituted by R11, R12, and R13;
• bicycloalkyl of 7-11 carbon atoms optionally substituted;
• by R11, R12, and R13;
• —CO2-alkyl of 1-6 carbon atoms;
• Het optionally substituted by R11, R12, or R13;
• or Ar optionally substituted by R11, R12, and R13;
• or when R6 and R7 are contained on a common nitrogen, they may be taken together to form a saturated 5-7 membered heterocycle that is optionally substituted with R11;
• R9 and R10 are each, independently, alkyl optionally substituted by R11, R12, and R13;
• Ar optionally mono-, di-, or tri-substituted by R15;
• Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-, di-, or tri-substituted by R15;
• Het optionally mono-, di-, or tri-substituted by R15;
• R11, R12, or R13 are each, independently, alkyl of 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atoms in the alkyl moiety, Ar optionally substituted with R14, Het optionally substituted with R14, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo, —CN, —CHO, —CO2H, —OCO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, —CO2—Ar, —CO2-alkyl-Ar wherein the alkyl moiety has 1-6 carbon atoms, —OCO2—Ar, —CONH2, —CONHOH, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO2-alkyl of 1-6 carbon atoms, —NHSO2—Ar, or —NHSO2—Het;
• or when R11 and R12 are contained on a common carbon atom of an alkyl moiety, they may be taken together to form a spiro cycloalkyl ring of 3-8 carbon atoms;
• R14 is halogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7 carbon atoms, -SO2-alkyl of 1-6 carbon atoms, —CO2-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbon atoms;
• R15 is
• (a) hydroxy, halogen, —CN, —NR16R16, —OR16, —SR16, triflouromethyl, alkyl of 1-6 carbon atoms, —SO2R17, —O-alkyl-CO2R17 wherein the alkyl moiety contains 1-6 carbon atoms, —CO2R17, —OCOR17, -NR16COR17, —COR17, —NR16SO2R17, or —NR16CO2R16;
• or
• (b) alkyl of 1-6 carbon atoms mono-, or di-substituted with hydroxy;
• halogen;
• —CN;
• —NR16NR16;
• —OR16;
• —SR16;
• triflouromethyl;
• alkyl of 1-6 carbon atoms;
• —SO2R17;
• —CO2R17;
• —OCOR17;
• —NR16COR17;
• —COR17;
• —NR16SO2R17;
• —NR16CO2R16;
• Ar which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or Het which may be optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• (c) Het optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• or
• (d) Ar optionally mono- or di-substituted by R16, —OR16, —NR16R16, or halogen;
• R16 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Ar or Het moieties may be optionally mono-, di-, or tri- substituted with halogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO2H, —CO2alkyl of 1-6 carbon atoms, or —SO2alkyl of 1-6 carbon atoms;
• R17 is R16 or —NR16R16;
• 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;
• Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms;
• m=1-3;
• n=1-3;
• or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.