CA2545311A1 - Heterocyclic boronic acid compounds - Google Patents

Heterocyclic boronic acid compounds Download PDF

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CA2545311A1
CA2545311A1 CA002545311A CA2545311A CA2545311A1 CA 2545311 A1 CA2545311 A1 CA 2545311A1 CA 002545311 A CA002545311 A CA 002545311A CA 2545311 A CA2545311 A CA 2545311A CA 2545311 A1 CA2545311 A1 CA 2545311A1
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alkyl
independently
phenyl
optionally mono
cycloalkyl
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CA2545311C (en
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David Alan Campbell
David T. Winn
Juan M. Betancort
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Phenomix Corp
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Phenomix Corporation
David Alan Campbell
David T. Winn
Juan M. Betancort
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Abstract

Dipeptidyl peptidase IV (DPP-IV)-inhibiting compounds are provided that have formula I: wherein n is 1 to 3; X is CH2; S; O; CF2 or C (CH3)2; Z is H; halogen; hydroxyl; (C1-6)alkoxy; (C1-12)alkyl; (C3-12)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; and CriRii, R1, R1, R3, R4 and R5 are as described herein. Methods for preparing these compounds, an d methods for treating diabetes, especially Type II diabetes, and other relate d diseases are described using the compounds of formula I in pharmaceutical compositions which contain these compounds. Pharmaceutical compositions whic h contain combinations of these compounds with other antidiabetic agents are also described herein.

Claims (178)

1. A compound of formula I:
including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:
n is 1 to 3;
X is CH2; S; O; CF2 or C(CH3)2;
Z is H; halogen; hydroxyl; (C1-6)alkoxy; (C1-12)alkyl; (C3-12)cycloalkyl;
phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl;
and optionally, one of the bonds in the ring containing X is a double bond;
R1 and R2 independently or together are hydrogen; a boronic acid protecting group;
or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids;
CR i R ii may be present or absent, wherein if CR i R ii is present, then R i, R ii, R3, R4 and R5 are selected from (aa), (bb) or (cc):
(aa) R i, R ii, R3 and R4 are hydrogen; and R5 is a) hydrogen;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
R6 is (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy;
acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;

trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl;
heteroaryl;
where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8)2; -OR8; or -S-R8;
R7 is halogen; (C1-10)alkyl; (C1-10)alkoxy; (C1-10)alkylamino;
(C1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C1-6)alkyl; hydroxymethyl;
nitro;
trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano;
carboxy;
acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3-10)cycloalkyl; (C5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl;
where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
c) aryl optionally fused to a (C3-10)cycloalkyl; or heteroaryl optionally fused to a (C3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene;
e) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy;
phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;
pyridinyl; naphthyl;
cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl;
and p is 0 to 3;
R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl;
hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
g) a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6;
h) a group of the formula:
where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6;
i) a group of the formula:

where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine;
phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-12)cycloalkyl ring; each t is independently 0 to 6; and a is 0 to 3;
j) a group of the formula:
(phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12;
k) a group f:
where R20 is hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3-8)cycloalkylcarbonyl; benzyl; benzoyl; (C1-6)alkyloxycarbonyl;
arlkyloxycarbonyl, pyridine;
pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl;
alkylsulfonyl;
or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; R x is hydrogen; (C1-8)alkyl; (C3-12) cycloalkyl;
benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R y is absent or is halogen, (C1-8)alkyl, (C1-8)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
s is 1 to 6; t is 0 to 6; and u is 0 to 3; or l) a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and a is 0 to 3;
(bb) R i, R ii, R3, R4 and R5 are independently hydrogen; alkyl; alkenyl;
alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl;
alkylcycloalkyl;
hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;
hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl;
arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl;
cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R i together with R3 or R4, or R ii together with R3 or R4, and the atoms to which they are attached form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2; and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa); or R4 and R5 together form -(CR22R23)m where m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl;
cycloalkyl; halo;
amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl;
heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino;
arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino;
alkoxycarbonyl;
aryloxycarbonyl; or alkylaminocarbonylamino; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the,cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (cc) R i and R3 are hydrogen; and R ii and R4 together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa) or (bb) and R5 is any of the groups in (aa) or (bb); and if CR i R ii is absent, then R3, R4 and R5 are selected from (dd), (ee) or (ff):
(dd) R3 and R4 are hydrogen; and R5 is a) hydrogen, provided that R5 is not hydrogen when n is 1, X
is CH2, and Z is H;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12)cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
R6 is (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy;
acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl;
heteroaryl;
where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8)2; -OR8; or -S-R8;
R7 is halogen; (C1-10)alkyl; (C1-10)alkoxy; (C1-10)alkylamino;
(C1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C1-6)alkyl; hydroxymethyl;
nitro;
trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano;
carboxy;
acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3-10)cycloalkyl; (C5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl;
where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
c) aryl optionally fused to a (C3-10)cycloalkyl; or heteroaryl optionally fused to a (C3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene;
e) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy;
phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;
pyridinyl; naphthyl;
cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl;
and p is 0 to 3;
R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl;
(C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl;
hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
g) a group of the formula:

where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6;
h) a group of the formula:

where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6;
i) a group of the formula:

where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine;
phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-12)cycloalkyl ring; each t is independently 0 to 6; and a is 0 to 3;
j) a group of the formula:
(phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12;

k) a group of the formula:
where R20 is hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3-8)cycloalkylcarbonyl; benzyl; benzoyl; (C1-6)alkyloxycarbonyl;
arlkyloxycarbonyl, pyridine;
pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl;
alkylsulfonyl;
or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; R x is hydrogen; (C1-8)alkyl; (C3-12) cycloalkyl;
benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R y is absent or is halogen, (C1-8)alkyl, (C1-8)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
sis 1 to 6; t is 0 to 6; and u is 0 to 3; or l) a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and a is 0 to 3; or (ee) R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl;
cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl;
hydroxyalkyl;
hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;
hydroxytricycloalkyl;
bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl;
cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl, provided that when n is 1, X is CH2, the ring containing X is saturated, and Z, R3 and R5 are H, R4 is not a side chain of a naturally occurring a-amino acid, and provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R5 are H, R3 and R4 are not both methyl; or R4 and R5 together form -(CR22R23)m - where m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl;
cycloalkyl; halo;
amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl;
heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino;
arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino;
alkoxycarbonyl;
aryloxycarbonyl; or alkylaminocarbonylamino; provided that when n is 1, X is CH2, the ring containing X is saturated, Z and R3 are H, R4 and R5 together are not -(CH2)2-or -(CH2)3-;
or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (ff) R3 is hydrogen; and R4 and R5 together with the atoms to which they are attached form a 4 to 8 member mono- or polycyclic heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, wherein the heterocyclic ring system is optionally mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; and wherein a bond containing a wavy line signifies a point of attachment.
2. The compound of claim 1 wherein R1 and R2 independently or together are the boronic acid protecting group formed from (+)-pinanediol; pinacol; 1,2-dicyclohexyl-ethanediol; 1,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3-butanediol, diisopropyl tartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6-decanediol; 1,1,2-triphenyl-1,2-ethanediol; (2R,3R)-1,4-dimethyoxy-1,1,4,4-tetraphenyl-2,3-butanediol;
methanol; ethanol;
isopropanol; catechol; or 1-butanol.
3. The compound of claim 1 wherein R1 and R2 independently or together are a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids formed from 1,2-dicyclohexylethanediol; 1,2-ethanediol; 1,3-propanediol; 2,3-butanediol, 1,4-butanediol;
diisopropylethanediol;
methanol; ethanol; isopropanol; or 1-butanol.
4. The compound of claim 1 wherein if CR i R ii is absent, then R3, R4 and R5 are selected from (dd), (ee) or (ff):
(dd) R3 and R4 are hydrogen; and R5 is a) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
R6 is (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy;
acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl;
heteroaryl;
where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8) 2; -OR8; or -S-R8;
R7 is halogen; (C1-10)alkyl; (C1-10)alkoxy; (C1-10)alkylamino;
(C1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C1-6)alkyl; hydroxymethyl;
nitro;
trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano;
carboxy;
acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3-10)cycloalkyl; (C5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl;
where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;

b) aryl optionally fused to a (C3-10)cycloalkyl; or heteroaryl optionally fused to a (C3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
c) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene;
d) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy;
phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;
pyridinyl; naphthyl;
cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl;
and p is 0 to 3;
R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl;
hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
f) a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;

phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6;
g) a group of the formula:
where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6;
h) a group of the formula:
where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine;
phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-12)cycloalkyl ring; each t is independently 0 to 6; and a is 0 to 3;
i) a group of the formula:
(phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12;
j) a group of the formula:
where R20 is hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3-8)cycloalkylcarbonyl; benzyl; benzoyl; (C1-6)alkyloxycarbonyl;
arlkyloxycarbonyl, pyridine;
pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl;
alkylsulfonyl;
or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; R x is hydrogen; (C1-8)alkyl; (C3-12) cycloalkyl;
benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R y is absent or is halogen, (C1-8)alkyl, (C1-8)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
s is 1 to 6; t is 0 to 6; and u is 0 to 3; or k) a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and a is 0 to 3; or (ee) R3 and R4 are independently hydrogen, alkyl; alkenyl; alkynyl;
cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl;
hydroxyalkyl;
hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;
hydroxytricycloalkyl;
bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl;
cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl;

R5 is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl;
bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl;
hydroxyalkylcycloalkyl;
hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl;
bicycloalkylalkyl;
alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl;
heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R4 and R5 to ether form -(CR22R23)m- wherein m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl;
cycloalkyl;
halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl;
arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino;
arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino;
alkoxycarbonyl;
aryloxycarbonyl; or alkylaminocarbonylamino; provided that when n is 1, X is CH2, and Z
and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (ff) R3 is hydrogen; and R4 and R5 together with the atoms to which they are attached form a 4 to 8 member mono- or polycyclic heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, wherein the heterocyclic ring system is optionally mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-.
5. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR i R ii is absent, R1, R2, R3 and R4 are hydrogen; and R5 is (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12)cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
6. The compound of claim 5 wherein R5 is (C1-12)alkyl or (C3-12)cycloalkyl.
7. The compound of claim 6 wherein R5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, or adamantyl.
8. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR i R ii is absent, R1, R2, R3 and R4 are hydrogen; and R5 is indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]-oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene.
9. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR i R ii is absent, R1, R2, R3 and R4 are hydrogen; and R5 is R11(CH2)p where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3]
bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono-or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen;
and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen;
trifluoromethyl; cyano;
nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy;
hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido;

alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
10. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR i R ii is absent; R1, R2, R3 and R4 are hydrogen; and R5 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
11. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR i R ii is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-
12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6.

12. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR i R ii is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6.
13. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR i R ii is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine;
phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-12)cycloalkyl ring; each t is independently 0 to 6; and a is 0 to 3.
14. The compound of claim 13 wherein R5 has formula:
15. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR i R ii is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
(phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12.
16. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR i R ii is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
where R20 is hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3-8)cycloalkylcarbonyl; benzyl; benzoyl; (C1-6)alkyloxycarbonyl;
arlkyloxycarbonyl, pyridine;
pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl;
alkylsulfonyl;
or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; R x is hydrogen; (C1-8)alkyl; (C3-12) cycloalkyl;
benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R y is absent or is halogen, (C1-8)alkyl, (C1-8)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
s is 1 to 6; t is 0 to 6; and u is 0 to 3; or
17. The compound of claim 16 wherein R5 has formula:
18. The compound of claim 16 wherein R5 is
19. The compound of claim 18 wherein R5 is
20. The compound of claim 16 that has the formula:
21. The compound of claim 16 that has the formula:
22. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR i R ii is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3.
23. The compound of claim 22 wherein R5 has formula:
24. The compound of claim 1 wherein R1 and R2 are hydrogen; n is 1; X together with an adjacent ring carbon and Z form a fused cyclopropyl; CR'R" is absent;
are hydrogen; and R5 R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl;
cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl;
hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;
hydroxytricycloalkyl;
bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl;
cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R4 and R5 together form -(CR22R23)m where m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl;
cycloalkyl; halo;
amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl;
heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino;
arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino;
alkoxycarbonyl;
aryloxycarbonyl; or alkylaminocarbonylamino; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto.
25. The compound of claim 1 that has formula:
26. The compound of claim 1 that has formula:
27. The compound of claim 1 that has formula:
28. The compound of claim 1 that has formula:
29. The compound of claim 1 wherein R1, R2, R3 and R4 are hydrogen; n is 1; X
is CH2; CR i R ii is absent; and R5 is aryl or aralkyl.
30. The compound of claim 1 wherein if CR i R ii is present, R i and R3 are hydrogen; R ii and R4 together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa) or (bb) and R5 is any of the groups in (aa) or (bb); or if CR i R ii is absent, then R3 is hydrogen; and R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono-or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X
is CH2, the ring containing X is saturated, and Z and R3 are hydrogen, R4 and R5 together are not -(CH2)2- or -(CH2)3-.
31. The compound of claim 30 that has formula II:
wherein:
Y is O, S, CHR25 or NR26;
k is 0 to 3 and m is 0 to 3 when Y is CHR25;
k is 2 to 3 and m is 1 to 3 when Y is O or NR26;
each R24 is independently:
a) hydrogen;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R12;

d) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl;
phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl;
naphthyl;
cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl;
pyrimidinyl;
phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono-or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy;
cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
f) a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and s is 1 to 6; or g) a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 1 to 6;
R25 is:
a) hydrogen;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R12;
d) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl;
phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl;
naphthyl;
cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl;
pyrimidinyl;
phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono-or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy;
cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
f) a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and t is 0 to 6; or g) a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6; and R26 is:
a) hydrogen;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R12;
d) R27(CH2)p-, where R27 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl;
phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl;
naphthyl;
cyclohexenyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl;
pyrimidinyl;
phenylaminocarbonyl; alkylsufonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsufonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono-or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy;
cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
e) (R13)2CH(CH2)q-, where R13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
f) a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 0 or 2 to 6; or g) a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 or 2 to 6.
32. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; and R1, R2 and R25 are hydrogen.
33. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is hydrogen, provided that if k, n, and m are each 1, and Y is CHR25, Z is not H.
34. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl;
(C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
35. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is phenyl optionally mono- or independently plurisubstituted with R12.
36. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3]
bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (C1-8)alkylcarbonyl;
(C3-12)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl;
alkylsulfonyl;
phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12;
where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl;
carboxy;
acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy;
sulfamoyl;
carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
37. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
38. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and s is 1 to 6.
39. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 1 to 6.
40. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R24 are hydrogen.
41. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is (C1-12)alkyl; (C2-12)alkenyl;
(C2-12)alkynyl;
(C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
42. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is phenyl optionally mono- or independently plurisubstituted with R12.
43. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is R11(CH2)p- where R11 is 2-oxopyrrolidinyl;
(C1-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;
pyridinyl; naphthyl; cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl;
benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl;
where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl;
where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen;
trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy;
acetamido;
hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;
carbamoyl;
sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
44. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
45. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and t is 0 to 6.
46. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6.
47. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 and R26 are hydrogen.
48. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is (C1-12)alkyl; (C2-12)alkenyl;
(C2-12)alkynyl;
(C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
49. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is phenyl optionally mono- or independently plurisubstituted with R12.
50. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is R27(CH2)p-, where R27 is 2-oxopyrrolidinyl;
(C1-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;
pyridinyl; naphthyl; cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl;
benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl;
where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl;
where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen;
trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy;
acetamido;
hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;
carbamoyl;
sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and p is 0 to 3.
51. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is (R13)2CH(CH2)q-; where R13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
52. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula:

where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3--12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 0 or 2 to 6.
53. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula:

where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 or 2 to 6.
54. The compound of claim 31 that has formula:

55. The compound of claim 54 wherein R25 is phenyl optionally mono- or independently plurisubstituted with R12.
56. The compound of claim 31 that has formula:

57. The compound of claim 31 that has formula:

wherein:
R28 and R29 are each independently hydrogen, hydroxy, alkyl, alkoxy, aryloxy, or halogen.
58. The compound of claim 30 that has formula III:
wherein:
Y is O, S, CHR25 or NR26;
k is 0 to 3 and m is 0 to 3 when Y is CHR25;
k is 1 to 3 and m is 0 to 3 when Y is NR26;
k is 1 to 3 and m is 0 to 3 when Y is O;
R is a) hydrogen;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
R6 is (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro;
halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethyl;
trifluoromethoxy;
sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8)2; -OR8; or -S-R8;
R7 is halogen; (C1-10)alkyl; (C1-10)alkoxy; (C1-10)alkylamino; (C1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C1-6)alkyl; hydroxymethyl; nitro;
trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano;
carboxy;
acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3-10)cycloalkyl; (C5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono-or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;

c) aryl optionally fused to a (C3-10)cycloalkyl; or heteroaryl optionally fused to a (C3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene;
e) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl;
phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl;
naphthyl;
cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl;
and p is 0 to 3;
R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy;
cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
g) a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl;
benzoyl; pyridine;
pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl;
where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6;
h) a group of the formula:

where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine;
pyrimidine;
phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6;
i) a group of the formula:

where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl;
pyridine;
pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl;
where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-12)cycloalkyl ring;
each t is independently 0 to 6; and a is 0 to 3;
j) a group of the formula:

(phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12;
k) a group of the formula:

where R20 is hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3-8)cycloalkylcarbonyl; benzyl; benzoyl; (C1-6)alkyloxycarbonyl;
arlkyloxycarbonyl, pyridine;
pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl;
alkylsulfonyl;
or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; R x is hydrogen; (C1-8)alkyl; (C3-12) cycloalkyl;
benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R y is absent or is halogen, (C1-8)alkyl, (C1-8)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
s is 1 to 6; t is 0 to 6; and u is 0 to 3; or l) a group of the formula:

where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3;
each R24 is independently:
a) hydrogen;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R12;
d) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl;
phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl;
naphthyl;
cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl;
pyrimidinyl;
phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono-or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy;
cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
f) a group of the formula:

where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and s is 0 to 6; or g) a group of the formula:

where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6;
R25 is:
a) hydrogen;

b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R12;
d) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl;
phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl;
naphthyl;
cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl;
pyrimidinyl;
phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono-or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy;
cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
f) a group of the formula:

where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and t is 0 to 6; or g) a group of the formula:

where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6; and R26 is:
a) hydrogen;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R12;
d) R27(CH2)p-, where R27 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl;
phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl;
naphthyl;
cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl;
pyrimidinyl;
phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono-or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy;
cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;

e) (R13)2CH(CH2)q-, where R13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
f) a group of the formula:

where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 0 or 2 to 6; or g) a group of the formula:

where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 or 2 to 6.
59. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; and R1, R2 and R25 are hydrogen.
60. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 and R25 are hydrogen.
61. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl;
(C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
62. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is phenyl optionally mono- or independently plurisubstituted with R12.
63. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3]
bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (C1-8)alkylcarbonyl;
(C3-12)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl;
alkylsulfonyl;
phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12;
where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl;
carboxy;
acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy;
sulfamoyl;
carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
64. The compound of claim 58 wherein wherein X is CH2; the ring containing X
is saturated; R1, R2 and R25 are hydrogen; and R24 is (R13)2CH(CH2)q-, where R13 is phenyl;
in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
65. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is a group:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and s is 0 to 6.
66. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6.
67. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2 and R24 are hydrogen.
68. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is (C1-12)alkyl; (C2-12)alkenyl;
(C2-12)alkynyl;
(C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
69. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is phenyl optionally mono- or independently plurisubstituted with R12.
70. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is R11(CH2)p- where R11 is 2-oxopyrrolidinyl;
(C1-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;
pyridinyl; naphthyl; cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl;
benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl;
where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl;
where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen;
trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy;
acetamido;
hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;
carbamoyl;
sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
71. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
72. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and t is 0 to 6.
73. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6.
74. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 and R26 are hydrogen.
75. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is (C1-12)alkyl; (C2-12)alkenyl;
(C2-12)alkynyl;
(C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
76. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is phenyl optionally mono- or independently plurisubstituted with R12.
77. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is R27(CH2)p-, where R27 is 2-oxopyrrolidinyl;
(C1-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;
pyridinyl; naphthyl; cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl;
benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl;
where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl;
where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen;
trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy;
acetamido;
hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;
carbamoyl;
sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and p is 0 to 3.
78. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is (R13)2CH(CH2)q-; where R13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
79. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 0 or 2 to 6.
80. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 or 2 to 6.
81. The compound of claim 30 that has formula IVA:
wherein R is a) hydrogen;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R12;
d) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl;
phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl;
naphthyl;
cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl;
pyrimidinyl;
phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono-or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy;
cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;

e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
f) a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and s is 0 to 6; or g) a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6;
82. The compound of claim 30 that has formula IVB:
wherein R is a) hydrogen;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R12;
d) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl;
phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl;
naphthyl;
cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl;
pyrimidinyl;
phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono-or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy;
cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;

e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
f) a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and s is 0 to 6; or g) a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6;
83. The compound of claim 1 wherein CR i R ii is present.
84. A process for preparing the compound of formula I in claim 1, comprising:
a) coupling a reactive compound of formula:
wherein L is a leaving group; R1 and R2 are independently a boronic acid protecting group or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; and n, X, Z, R i, R ii, R3, and R4 are as defined in claim 1;
with an amine of formula: R5-NH2;
b) optionally deprotecting the boronic acid ester; and c) recovering the resultant compound as a free acid or as an acid addition salt.
85. The process of claim 84 wherein Ri and Rii are not present; R3 and R4 are hydrogen; the leaving group is Cl; and the amine is a cyclopentylamine or an aminopyrrolidine.
86. The process of claim 85 wherein the aminopyrrolidine is N-protected at the pyrrolidine nitrogen.
87. A process for preparing the compound of formula II of claim 31, comprising:
a) coupling a 2-boroheterocycle of formula:
wherein R1 and R2 are not hydrogen, and n, X, and Z are as defined in claim 31;
with the corresponding N-protected amino acid;
b) optionally deprotecting the boronic acid ester; and c) recovering the resultant compound as a free acid or as an acid addition salt.
88. The process of claim 87 wherein the N-protected cyclic amino acid is N-Boc-4-phenyl-proline.
89. A pharmaceutical composition comprising a compound according to claim 1 in free form or in pharmaceutically acceptable acid addition salt form, together with at least one pharmaceutically acceptable carrier or diluent.
90. A method for inhibiting dipeptidyl peptidase-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable acid addition salt thereof.
91. A method for treating conditions mediated by dipeptidyl peptidase-IV
inhibition comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable acid addition salt thereof.
92. A method for treating controlling, or preventing diabetes comprising administering to a patient of an effective amount of a compound of claim 1.
93. A method for treating, controlling, or preventing non-insulin dependent (Type 2) diabetes mellitus in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
94. A method for treating, controlling, or preventing insulin dependent (Type 1) diabetes mellitus in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
95. A method for treating, controlling or preventing hyperglycemia in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
96. A method for treating, controlling or preventing obesity in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
97. A method for treating to enhance islet neogenesis, b-cell survival, and insulin biosynthesis in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
98. A method for treating, controlling or preventing insulin resistance in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
99. A method for treating, controlling or preventing one or more lipid disorders selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, and high LDL in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
100. A method for treating, controlling or preventing atherosclerosis in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
101. A method for treating or controlling growth hormone deficiency in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
102. A method for modulating the immune response in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
103. A method for treating, or controlling HIV infection in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
104. A method for treating, controlling or preventing in a mammalian patient in need of such treatment one or more disorders selected from the group consisting of neutropenia, anemia, neuronal disorders, tumor growth and metastasis, benign prostatic hypertrophy, gingivitis, hypertension and osteoporosis, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
105. A method reducing sperm motility in a male in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
106. A method for treating, controlling or preventing in a mammalian patient in need of such treatment one or more conditions selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) rheumatoid arthritis, (17) other inflammatory conditions, (18) pancreatitis, (19) abdominal obesity, (20) neurodegenerative disease, (21) multiple sclerosis, (22) retinopathy, (23) nephropathy, (24) neuropathy, (25) Syndrome X, (26) ovarian hyperandrogenism, (27) allograft rejection in transplantation, and other conditions where insulin resistance is a component, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
107. A method for treating, controlling or preventing in a mammalian patient in need of such treatment one or more conditions selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) rheumatoid arthritis, (17) other inflammatory conditions, (18) pancreatitis, (19) abdominal obesity, (20) neurodegenerative disease, (21) multiple sclerosis, (22) retinopathy, (23) nephropathy, (24) neuropathy, (25) Syndrome X, (26) ovarian hyperandrogenism, (27) allograft rejection in transplantation, (28) Type II diabetes, (29) growth hormone deficiency, (30) neutropenia, (31) anemia, (32) neuronal disorders, (33) tumor growth and metastasis, (34) benign prostatic hypertrophy, (35) gingivitis, (36) hypertension, (37) osteoporosis, and other conditions that may be treated by inhibition of dipeptidyl peptidase-IV, comprising administering to the patient of a therapeutically effective amount of a first compound of claim 1, or a pharmaceutically acceptable salt thereof, and one or more other compounds selected from the group consisting of:
a) Other dipeptidyl peptidase-IV inhibitors;
b) Insulin sensitizers selected from the group consisting of (i) PPAR
agonists, (ii) biguanides, and (iii) protein phosphatase-1B inhibitors;
c) Insulin or insulin mimetics;
d) Sulfonylureas or other insulin secretagogues;
e) .alpha.-glucosidase inhibitors;
f) glucagons receptor agonists;
g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;
h) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists;
i) GIP, GIP mimetics, and GIP receptor agonists;
j) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;
k) Cholesterol lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR.alpha. agonists, (v) PPAR.alpha./.gamma. dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterol acyltransferase inhibitors, and (viii) anti-oxidants;
1) PPAR.delta. agonists;

m) Anti-obesity compounds;
n) An deal bile acid transporter inhibitor;
o) Anti-inflammatory agents;
p) G-CSF, G-CSF mimetics, and G-CSF receptor agonists; and q) EPO, EPO mimetics, and EPO receptor agonists.
108. A method for the treatment, control, or prevention of one or more conditions selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL
levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of claim 1 and an HMG-CoA
reductase inhibitor.
109. The method of claim 108 wherein the HMC-CoA reductase inhibitor is a stator.
110. The method of claim 109 wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin.
111. A method for treating, controlling or preventing atherosclerosis, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of claim 1 and an HMG-CoA reductase inhibitor.
112. The method of claim 111 wherein the HMC-CoA reductase inhibitor is a statin.
113. The method of claim 112 wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin.
114. A pharmaceutical composition for the treatment, prevention or control of atherosclerosis, comprising: (1) a compound of claim 1, (2) an HMG-CoA
reductase inhibitor, and (3) a pharmaceutically acceptable carrier.
115. A method for treating, controlling or preventing obesity, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of claim 1 and an anti-obesity agent.
116. The method of claim 115 wherein the anti-obesity agent is a beta-3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, an anorectic agent, and/or a fatty acid oxidation upregulator.
117. The method of claim 116 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol.
118. A method for the treatment, control, or prevention of neutropenia, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of claim 1 and a neutrophilic agent.
119. The method of claim 118 wherein the neutrophilic agent is G-CSF, a G-CSF
mimetic, or a G-CSF receptor agonist.
120. The method of claim 115 wherein the neutrophilic agent is pegfilgrastim, filgrastim, lenograstim, or nartograstim.
121. A method for the treatment, control, or prevention of anemia, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of claim 1 and a erythropoietin agonist.
122. The method of claim 121 wherein the erythropoietin agonist is EPO, an EPO
mimetic, or an EPO receptor agonist.
123. The method of claim 122 wherein the erythropoietin agonist is epoetin alfa, or darbepoetin alfa.
124. A pharmaceutical composition, comprising:
a) A compound of claim 1;
b) One or more compounds selected from the group consisting of:
i) Other dipeptidyl peptidase-IV inhibitors;
ii) Insulin sensitizers selected from the group consisting of (i) PPAR
agonists, (ii) biguanides, and (iii) protein phosphatase-1B inhibitors;
iii) Insulin or insulin mimetics;
iv) Sulfonylureas or other insulin secretagogues;
v) .alpha.-glucosidase inhibitors;
vi) glucagons receptor agonists;
vii) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;
viii) GIP, GIP mimetics, and GIP receptor agonists;
ix) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;
x) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists;
xi) Cholesterol lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR.alpha. agonists, (v) PPAR.alpha./.gamma. dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterol acyltransferase inhibitors, and (viii) anti-oxidants;
xii) PPAR.delta. agonists;
xiii) Anti-obesity compounds;
xiv) An deal bile acid transporter inhibitor;
xv) Anti-inflammatory agents;
xvi) G-CSF, G-CSF mimetics, and G-CSF receptor agonists;
xvii) EPO, EPO mimetics, and EPO receptor agonists; and c) a pharmaceutically acceptable carrier.
125. A pharmaceutical combination comprising a DPP-IV inhibitor compound according to claim 1, an antidiabetic agent other than a DPP-IV inhibitor for treating diabetes and related diseases, and an anti-obesity agent or a lipid-modulating agent or both.
126. The combination according to claim 125 comprising the DPP-IV inhibitor compound and an antidiabetic agent.
127. The combination according to claim 126 wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR
.gamma. agonist, a PPAR .alpha./ .gamma. dual agonist, an SGLT2 inhibitor, an aP2 inhibitor, a glycogen phosphorylase inhibitor, an AGE inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) or mimetic thereof, insulin and/or a meglitinide.
128. The combination according to claim 127 wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, G1 -262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, APR-H039242, GW-409544, KRP297, AC2993, Exendin-4, LY307161, NN2211, and/or LY315902.
129. The combination according to claim 128 wherein the DPP-N inhibitor compound is present in a weight ratio to the antidiabetic agent within the range from about 0.01 to about 100:1.
130. The combination according to claim 129 wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, an anorectic agent, and/or a fatty acid oxidation upregulator.
131. The combination according to claim 130 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol.
132. The combination according to claim 125 wherein the lipid-modulating agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, an ACAT inhibitor, a cholesteryl ester transfer protein inhibitor, or an ATP
citrate lyase inhibitor.
133. The combination according to claim 132 wherein the lipid-modulating agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529,414, avasimibe, TS-962, MD-700, and/or LY295427.
134. The combination according to claim 133 wherein the DPP-IV inhibitor is present in a weight ratio to the lipid-modulating agent within the range from about 0.01 to about 100:1.
135. A pharmaceutical combination comprising a DPP-IV inhibitor compound according to claim 1 and an agent for treating infertility, an agent for treating polycystic ovary syndrome, an agent for treating a growth disorder and/or frailty, an anti-arthritis agent, an agent for preventing inhibiting allograft rejection in transplantation, an agent for treating autoimmune disease, an anti-AIDS agent, an agent for treating inflammatory bowel disease/syndrome, an agent for treating anorexia nervosa, an anti-osteoporosis agent and/or an anti-obesity agent.
136. A method for treating diabetes, insulin resistance, hyperglycemia, hyperisulinemia, or elevated blood levels of free fatty acids or glycerol, obesity, Syndrome X, dysmetabolic syndrome, diabetic complications, hypertriglyceridemia, hyperinsulinemia, atherosclerosis, impaired glucose homeostasis, impaired glucose tolerance, infertility, polycystic ovary syndrome, growth disorders, frailty, arthritis, allograft rejection in transplantation, autoimmune diseases, AIDS, intestinal diseases, inflammatory bowel syndrome, nervosa, osteoporosis, or an immunomodulatory disease or a chronic inflammatory bowel disease, comprising administering to a mammalian species in need of treatment a therapeutically effective amount of a compound according to claim 1.
137. The method according to claim 136 for treating type II diabetes and/or obesity.
138. A compound that has the formula VA, VB, or a mixture thereof including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:
n is 1 to 3;
X is CH2; S; O; CF2 or C(CH3)2 Z is H; halogen; hydroxyl; (C1-6)alkoxy; (C1-12)alkyl; (C3-12)cycloalkyl;
phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl;
and optionally, one of the bonds in the ring containing X is a double bond;
R1 and R2 independently or together are hydrogen; a boronic acid protecting group;
or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids;
R3, R4 and R5 are selected from (dd) or (ee):
(dd) R3 and R4 are hydrogen; and R5 is a) hydrogen, provided that R5 is not hydrogen when n is 1, X
is CH2, and Z is H;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;

R6 is (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy;
acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl;
heteroaryl;
where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8)2; -OR8; or -S-R8;
R7 is halogen; (C1-10)alkyl; (C1-10)alkoxy; (C1-10)alkylamino;
(C1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C1-6)alkyl; hydroxymethyl;
nitro;
trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano;
carboxy;
acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3-10)cycloalkyl; (C5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl;
where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
c) aryl optionally fused to a (C3-10)cycloalkyl; or heteroaryl optionally fused to a (C3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene;
e) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy;
phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;
pyridinyl; naphthyl;
cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl;
and p is 0 to 3;
R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl;
(C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl;
hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
g) a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6;
h) a group of the formula:
where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6;
i) a group of the formula:

where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine;
phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-12)cycloalkyl ring; each t is independently 0 to 6; and a is 0 to 3;
j) a group of the formula:
(phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12;
k) a group of the formula:
where R20 is hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3-8)cycloalkylcarbonyl; benzyl; benzoyl; (C1-6)alkyloxycarbonyl;
arlkyloxycarbonyl, pyridine;
pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl;
alkylsulfonyl;
or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; R x is hydrogen; (C1-8)alkyl; (C3-12) cycloalkyl;
benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R y is absent or is halogen, (C1-8)alkyl, (C1-8)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
s is 1 to 6; t is 0 to 6; and u is 0 to 3; or l) a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and a is 0 to 3; or (ee) R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl;
cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl;
hydroxyalkyl;
hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;
hydroxytricycloalkyl;
bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl;
cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; provided that when n is 1, X is CH2, the ring containing X is saturated, and Z, R3 and R5 are H, R4 is not a side chain of a naturally occurring .alpha.-amino acid; and provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R5 are H, R3 and R4 are not both methyl; and wherein the bond containing the wavy line signifies the point of attachment.
139. The compound of claim 138 wherein R1 and R2 independently or together are the boronic acid protecting group formed from (+)-pinanediol; pinacol; 1,2-dicyclohexyl-ethanediol; 1,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3-butanediol, diisopropyl tartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6-decanediol; 1,1,2-triphenyl-1,2-ethanediol; (2R,3R)-1,4-dimethyoxy-1,1,4,4-tetraphenyl-2,3-butanediol;
methanol; ethanol;
isopropanol; catechol; or 1-butanol.
140. The compound of claim 138 wherein R1 and R2 independently or together are a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids formed from 1,2-dicyclohexylethanediol; 1,2-ethanediol; 1,3-propanediol; 2,3-butanediol, 1,4-butanediol;
diisopropylethanediol;
methanol; ethanol; isopropanol; or 1-butanol.
141. The compound of claim 138 wherein R3 and R4 are independently hydrogen, alkyl; alkenyl; alkynyl; cycloalkyl;
cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl;
hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;
hydroxytricycloalkyl;
bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl;
cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; and R5 is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl;
tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl;
hydroxycycloalkyl;
hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl;
alkylbicycloalkyl;
alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl;
heteroarylalkyl;
cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl.
142. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
143. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is indanyl; 1,2,3,4-tetrahydronaphthyl;
(CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]-oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene.
144. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3]
bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono-or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen;
and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen;
trifluoromethyl; cyano;
nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy;
hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido;
alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
145. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is (R13)2CH(CH2)q-, where R13 is phenyl;
in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
146. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6.
147. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6.
148. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine;
phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-12)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3.
149. The compound of claim 148 wherein R5 has formula:
150. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
(phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12
151. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
where R20 is hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3-8)cycloalkylcarbonyl; benzyl; benzoyl; (C1-6)alkyloxycarbonyl;
arlkyloxycarbonyl, pyridine;
pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl;
alkylsulfonyl;
or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; R x is hydrogen; (C1-8)alkyl; (C3-12) cycloalkyl;
benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R y is absent or is halogen, (C1-8)alkyl, (C1-8)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
s is 1 to 6;t is 0 to 6; and u is 0 to 3;.
152. The compound of claim 151 wherein R5 has formula:.
153. The compound of claim 151 wherein R5 is
154. The compound of claim 151 that has the formula:
or
155. The compound of claim 151 that has the formula:
or
156. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a goup of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and a is 0 to 3.
157. The compound of claim 156 wherein R5 has formula:
158. The compound of claim 138 wherein R1 and R2 are hydrogen; n is 1; X
together with an adjacent ring carbon and Z form a fused cyclopropyl;
R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl;
cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl;
hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;
hydroxytricycloalkyl;
bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl;
cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl.
159. The compound of claim 138 wherein the compound has the formula:
or a mixture thereof.
160. The compound of claim 138 wherein the compound has the formula:

or a mixture thereof.
161. The compound of claim 138 wherein the compound has the formula:

or a mixture thereof.
162. The compound of claim 138 wherein the compound has the formula:

or a mixture thereof.
163. The compound of claim 138 wherein the compound has the formula:

or a mixture thereof.
164. The compound of claim 138 wherein the compound has the formula:

or a mixture thereof.
165. The compound of claim 138 wherein the compound has the formula:

or a mixture thereof.
166. A pharmaceutical composition comprising a compound of claim 138 and a pharmaceutically acceptable carrier or diluent.
167. The pharmaceutical composition of claim 166 wherein the compound has the formula VB.
168. A pharmaceutical composition comprising:
a. a substantially pure preparation of a compound of formula VB:

including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:
n is 1 to 3;
X is CH2; S; O; CF2 or C(CH3)2;
Z is H; halogen; hydroxyl; (C1-6)alkoxy; (C1-12)alkyl; (C3-12)cycloalkyl;
phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl;
and optionally, one of the bonds in the ring containing X is a double bond;
R1 and R2 independently or together are hydrogen; a boronic acid protecting group;
or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids;
R3, R4 and R5 are selected from (dd) or (ee):
(dd) R3 and R4 are hydrogen; and R5 is a) hydrogen, provided that R5 is not hydrogen when n is 1, X
is CH2, and Z is H;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl, (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
R6 is (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy;
acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl;
heteroaryl;
where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8)2; -OR8; or -S-R8;
R7 is halogen; (C1-10)alkyl; (C1-10)alkoxy; (C1-10)alkylamino;
(C1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C1-6)alkyl; hydroxymethyl;
nitro;
trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano;
carboxy;
acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3-10)cycloalkyl; (C5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl;
where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
c) aryl optionally fused to a (C3-10)cycloalkyl; or heteroaryl optionally fused to a (C3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene;
e) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C3-6)alkoxy;
phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;
pyridinyl; naphthyl;
cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3]
bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl;
and p is 0 to 3;
R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl;
(C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl;
hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
g) a group of the formula:

where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6;

h) a group of the formula:

where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6;
i) a group of the formula:

where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine;
phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-12)cycloalkyl ring; each t is independently 0 to 6; and a is 0 to 3;
j) a group of the formula:

(phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12;
k) a group of the formula:

where R20 is hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3-8)cycloalkylcarbonyl; benzyl; benzoyl; (C1-6)alkyloxycarbonyl;
arlkyloxycarbonyl, pyridine;
pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl;
alkylsulfonyl;
or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; R x is hydrogen; (C1-8)alkyl; (C3-12) cycloalkyl;
benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R y is absent or is halogen, (C1-8)alkyl, (C1-8)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
s is 1 to 6; t is 0 to 6; and u is 0 to 3; or l) a group of the formula:

where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and a is 0 to 3; or (ee) R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl;
cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl;
hydroxyalkyl;
hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;
hydroxytricycloalkyl;
bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl;
cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; provided that when n is 1, X is CH2, the ring containing X is saturated, and Z, R3 and R5 are H, R4 is not a side chain of a naturally occurring .alpha.-amino acid; and provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R5 are H, R3 and R4 are not both methyl; and wherein the bond containing the wavy line signifies the point of attachment;
and b. a pharmaceutically acceptable carrier or diluent.
169. A method of making a pharmaceutical composition, comprising mixing a substantially pure preparation of the compound of formula VB of claim 138 with a pharmaceutically acceptable carrier or diluent.
170. The method of claim 169 wherein the pharmaceutically acceptable carrier or diluent is suitable for oral administration.
171. The method of claim 170 further comprising the step of formulating the composition into a tablet or capsule.
172. The method of claim 170 wherein the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration.
173. The method of claim 172 further comprising the step of lyophilizing the composition to form a lyophilized preparation.
174. A compound that is a boronic acid inhibitor of dipeptidyl peptidase-IV
having an inhibition constant of 10 micromolar or less for dipeptidyl peptidase-IV wherein the inhibitor comprises a boropyrrolidine, boropiperidine, or boroazepane attached to an amino acid through an amide bond wherein the amino acid is a beta-amino acid, an N-cycloalkyl-alpha-amino acid, an N-heterocyclyl-alpha amino acid, a cyclic alpha-amino acid (also known as an imino acid) having at least one substituent on the alpha-amino acid ring, a cyclic alpha-amino acid having a ring other than pyrrolidine, or an N-substituted glycine.
175. The compound of claim 174 wherein the boronic acid inhibitor is of Formula I:

including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:
n is 1 to 2;
X is CH2; S; O; CF2 or C(CH3)2;
Z is H; halogen; hydroxyl; (C1-6)alkoxy; (C1-12)alkyl; (C3-12)cycloalkyl;
phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl;
and optionally, one of the bonds in the ring containing X is a double bond;
R1 and R2 independently or together are hydrogen; a boronic acid protecting group;
or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids;
CR i R ii may be present or absent, wherein if CR i R ii is present, then R i, R ii, R3, R4 and R5 are selected from (aa), (bb) or (cc):
(aa) R i, R ii, R3 and R4 are hydrogen; and R5 is a) hydrogen;
b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
R6 is (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy;
acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl;
heteroaryl;

where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8) 2; -OR8; or -S-R8;
R7 is halogen; (C1-10)alkyl; (C1-10)alkoxy; (C1-10)alkylamino;
(C1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C1-6)alkyl; hydroxymethyl;
nitro;
trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano;
carboxy;
acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3-10)cycloalkyl; (C5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl;
where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
c) aryl optionally fused to a (C3-10)cycloalkyl; or heteroaryl optionally fused to a (C3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene;
e) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy;
phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;
pyridinyl; naphthyl;
cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R'2; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl;
and p is 0 to 3;

R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl;
hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
f) (R13 )2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
g) a group of the formula:

where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6;
h) a group of the formula:

where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6;
i) a group of the formula:

where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine;
phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-12)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3;
j) a group of the formula:
(phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12;
k) a group f:

where R20 is hydrogen; (1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3-8)cycloalkylcarbonyl; benzyl; benzoyl; (C1-6)alkyloxycarbonyl;
arlkyloxycarbonyl, pyridine;
pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl;
alkylsulfonyl;
or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; R x is hydrogen; (C1-8)alkyl; (C3-12) cycloalkyl;
benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R y is absent or is halogen, (C1-8)alkyl, (C1-8)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
s is 1 to 6; t is 0 to 6; and u is 0 to 3; or l) a group of the formula:

where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3;
(bb) R i, R ii, R3, R4 and R5 are independently hydrogen; alkyl; alkenyl;
alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl;
alkylcycloalkyl;

hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;
hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl;
arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl;
cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R i together with R3 or R4, or R ii together with R3 or R4, and the atoms to which they are attached form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2; and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa); or R4 and R5 together form -(CR22R23)m- where m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl;
cycloalkyl; halo;
amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl;
heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino;
arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino;
alkoxycarbonyl;
aryloxycarbonyl; or alkylaminocarbonylamino; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (cc) R i and R3 are hydrogen; and R ii and R4 together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa) or (bb) and R5 is any of the groups in (aa) or (bb); and if CR i R ii is absent, then R3, R4 and R5 are selected from (dd), (ee) or (ff):
(dd) R3 and R4 are hydrogen; and R5 is a) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
R6 is (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy;
acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl;
trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl;
heteroaryl;
where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8 )2; -OR8; or -S-R8;
R7 is halogen; (C1-10)alkyl; (C1-10)alkoxy; (C1-10)alkylamino;
(C1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C1-6)alkyl; hydroxymethyl;
nitro;
trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano;
carboxy;
acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3-10)cycloalkyl; (C5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl;
where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
b) aryl optionally fused to a (C3-10)cycloalkyl; or heteroaryl optionally fused to a (C3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
c) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene;
d) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy;
phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;
pyridinyl; naphthyl;
cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl;
and p is 0 to 3;
R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl;
hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
f) a group of the formula:

where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6;

g) a group of the formula:

where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6;
h) a group of the formula:

where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine;
phenyl;
phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-12)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3;
i) a group of the formula:
(phenyl-CH2-C(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12;
j) a group of the formula:

where R20 is hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3-8)cycloalkylcarbonyl; benzyl; benzoyl; (C1-6)alkyloxycarbonyl;
arlkyloxycarbonyl, pyridine;
pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl;
alkylsulfonyl;
or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; R x is hydrogen; (C1-8)alkyl; (C3-12) cycloalkyl;
benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R y is absent or is halogen, (C1-8)alkyl, (C1-8)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
s is 1 to 6; t is 0 to 6; and u is 0 to 3; or k) a group of the formula:

where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; or (ee) R3 and R4 are independently hydrogen, alkyl; alkenyl; alkynyl;
cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl;
hydroxyalkyl;
hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;
hydroxytricycloalkyl;
bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl;
cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl;
R5 is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl;
bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl;
hydroxyalkylcycloalkyl;
hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl;
bicycloalkylalkyl;
alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl;
heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R4 and R5 together form -(CR22R23)m - wherein m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl;
cycloalkyl;
halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl;
arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino;
arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino;
alkoxycarbonyl;
aryloxycarbonyl; or alkylaminocarbonylamino; provided that when n is 1, X is CH2, and Z
and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (ff) R3 is hydrogen; and R4 and R5 together with the atoms to which they are attached form a 4 to 8 member mono- or polycyclic heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, wherein the heterocyclic ring system is optionally mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; and wherein a bond containing a wavy line signifies a point of attachment.
176. A method for inhibiting dipeptidyl peptidase-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 174, or a pharmaceutically acceptable acid addition salt thereof.
177. A method for treating conditions mediated by dipeptidyl peptidase-IV
inhibition comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 174, or a pharmaceutically acceptable acid addition salt thereof.
178. A method for treating controlling, or preventing diabetes comprising administering to a patient of an effective amount of a compound of claim 174.
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