CA2545311C - Heterocyclic boronic acid compounds - Google Patents

Heterocyclic boronic acid compounds Download PDF

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CA2545311C
CA2545311C CA2545311A CA2545311A CA2545311C CA 2545311 C CA2545311 C CA 2545311C CA 2545311 A CA2545311 A CA 2545311A CA 2545311 A CA2545311 A CA 2545311A CA 2545311 C CA2545311 C CA 2545311C
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alkyl
independently
formula
compound
phenyl
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CA2545311A1 (en
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David Alan Campbell
David T. Winn
Juan M. Betancort
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Phenomix Corp
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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, and methods for treating diabetes, especially Type II diabetes, and other related diseases are described using the compounds of formula I in pharmaceutical compositions which contain these compounds. Pharmaceutical compositions which contain combinations of these compounds with other antidiabetic agents are also described herein.

Description

HETEROCYCLIC BORONIC ACID COMPOUNDS
FIELD OF THE INVENTION

[00011 The present invention relates to boronic acid compounds and their use as inhibitors of post-proline/alanine cleaving amino-dipeptidases. The invention also relates to methods of employing such inhibitors, alone or with another therapeutic agent, to treating DPP-IV-related diseases, such as Type II diabetes and diabetic complications, hyperglycemia, Syndrome X, hyperinsulinemia, obesity, atherosclerosis and related diseases, as well as various immunomodulatory diseases and chronic inflammatory bowel disease. Thus, the invention has applications in the medicinal chemical, pharmacological, and medical arts.

BACKGROUND OF THE INVENTION
[0002] The following background commentary is an aid to in understanding the present invention. Inclusion of this commentary is not an admission concerning the nature or content of the prior art.
[0003] Dipeptidyl peptidase-IV (DPP-IV) is a serine protease that belongs to a group of post-proline/alanine cleaving amino-dipeptidases. DPP-IV catalyzes the release of an N-terminal dipeptide only from proteins with N-terminal penultimate proline or alanine.
[0004] The physiological role of DPP-IV has not been established fully. It is believed to play an important role in neuropeptide metabolism, T-cell activation, gastric ulceration, functional dyspepsia, obesity, appetite regulation, impaired fasting glucose (IFG), and diabetes. In particular, DPP-IV has been implicated in the control of glucose metabolism because its substrates include the insulinotropic hormones, glucagon like peptide-1 (GLP- 1) and gastric inhibitory peptide (GIP), which are inactivated by removal of their two N-terminal amino acids.
[0005] In vivo administration of synthetic inhibitors of DPP-IV prevents N-terminal degradation of GLP-1 and GIP, resulting in higher plasma concentrations of these hormones, increased insulin secretion and, therefore, improved glucose tolerance.

Therefore, such inhibitors have been proposed for the treatment of patients with type II
diabetes, a disease characterized by decreased glucose tolerance and insulin resistance.
[0006] Post-proline/alanine cleaving amino-dipeptidases have been discovered, including DPP7, DPP8, DPP9, and fibroblast activation protein (FAP), that have the substrate- and inhibitor-specificity of DPP-IV. Thus, inhibitors of this sort may affect multiple members of the enzyme group. The precise physiological role of each of these post-proline/alanine cleaving enzymes is not well defined. Consequently, inhibiting each of them separately, a subset of them, or all of them at the same time would have uncertain physiological effect(s).
[0007] Diabetic dyslipidemia is characterized by multiple lipoprotein defects, including moderately high serum levels of cholesterol and triglycerides, small LDL
particles, and low levels of HDL cholesterol. The results of recent clinical trials reveal beneficial effects of cholesterol-lowering therapy in diabetic and nondiabetic patients, thus supporting increased emphasis on treatment of diabetic dyslipidemia. This need for intensive treatment of diabetic dyslipidemia was advocated by the National Cholesterol Education Program's Adult Treatment Panel III.
[0008] Obesity is a well-known risk factor for the development of many very common diseases such as atherosclerosis, hypertension and diabetes. The incidence of obese people and thereby also these diseases is increasing throughout the entire industrialized world.
Except for exercise, diet and food restriction no convincing pharmacological treatment for reducing body weight effectively and acceptably currently exist. However, due to its indirect but important effect as a risk factor in mortal and common diseases it will be important to find treatment for obesity or appetite regulation. Even mild obesity increases the risk for premature death, diabetes, hypertension, atherosclerosis, gallbladder disease and certain types of cancer. In the industrialized western world the prevalence of obesity has increased significantly in the past few decades. Because of the high prevalence of obesity and its health consequences, its prevention and treatment should be a high public health priority.
[0009] At present a variety of techniques are available to effect initial weight loss.
Unfortunately, initial weight loss is not an optimal therapeutic goal. Rather, the problem is that most obese patients eventually regain their weight. An effective means to establish and/or sustain weight loss is the major challenge in the treatment of obesity today.
[0010] Accordingly, a need exists for compounds that are useful for inhibiting DPP-IV
without suppressing the immune system.
[0011] Several compounds have been shown to inhibit DPP-IV, but all of these have limitations in relation to the potency, stability, selectivity, toxicity, and/or pharmacodynamic properties. Such compounds have been disclosed, for example, in WO
98/19998, WO 00/34241, U.S. patent No. 6,124,305 (Novartis AG), and WO

(Trustees of Tufts University).

SUMMARY OF THE INVENTION
[0012] The present invention provides DPP-IV inhibitors that are effective in treating conditions that may be regulated or normalized by inhibition of DPP-IV. More particularly, the invention relates to boronic acid-containing heterocycles and their derivatives that inhibit DPP-IV, and to methods for making such compounds. In addition, the invention provides pharmaceutical compositions comprising compounds of the invention, and combinations thereof including one or more other types of antidiabetic agents;
methods for inhibiting DPP-1V comprising administering to a patient in need of such treatment a therapeutically effective amount thereof, and compounds for use as a pharmaceutical, and their use in a process for the preparation of a medicament for treating a condition that are regulated or normalized via inhibition of DPP-IV.

BRIEF DESCRIPTION OF THE DRAWING
[0013] FIG. 1 shows the pH dependence of the percentage of linear and cyclic isomeric forms present in aqueous solution of a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION
(0014] The present invention provides compounds of formula I:
ORS

R5111 I) N

Ri; R1 L/-X )n Z
including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:
nisIto3;
X is CH2; S; 0; 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 pluri substituted 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'R" may be present or absent, wherein if CR'R" is present, then R', R", R3, Ra and R5 are selected from (aa), (bb) or (cc):
(aa) R', R", 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 pluri substituted 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; -SORB; -S02R8; -CORE; -C02R8, -CONHRB; -CON(R8) 2; -OR8; or -S-R8;
R7 is halogen; (C1_10)alkyl; (C1_10)alkoxy; (C1_1o)alkylamino;
(C1.1o) 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 R';
c) aryl optionally fused to a (C3_1o)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))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, (C
1_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 O to 3;
g) a group of the formula:

R14,."-N (CH2r_i where R14 and R15 are independently hydrogen; (C1_5)alkyl; (C I -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 R'5 together form a (C3_12)cycloalkyl ring; and r is 2 to 6;
h) a group of the formula:

R16~ (CHz)S

where R16 and R17 are each independently hydrogen; (C1_8)alkyl; (C
1_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:

(CH2)t R N-(CH2)t )U

where R'8 and R19 are independently hydrogen; (C1_8)alkyl; (C
1_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 R' 9 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 of the formula:
Rx R 20 Rx(CH2)s ~ Rx (CH2)t 3 RYC (CH2)t or R20 _N or '~~r) RyX u RY u 120 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; RX 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; RY 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 1) a group of the formula:
(CH2)t l R21_p-(CP)t ) u 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', R", 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' together with R3 or R4, or R" 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, 0, 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)", where in 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, 0, 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' and R3 are hydrogen; and R" and R4 together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, 0, 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'R" 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 RB; -SORB; -S02R8; -CORE; -CO2R8, -CONHRB; -CON(R) 2; -ORB; or -S-RB;
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_lo)alkyl; (C2_1o)alkenyl; (C2_1o)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 pluri substituted 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)jadamantyl 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 (CI.8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently pluri substituted with (C1_8)alkyl, (CI.8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3_6)alkylene;
e) R' 1(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 (CI.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 O to 3;

g) a group of the formula:

R14~ (CH2)r-i where R14 and R15 are independently hydrogen; (C1.8)alkyl; (C
1.6)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 R'5 together form a (C3_12)cycloalkyl ring; and r is 2 to 6;
h) a group of the formula:

R16~N (CHZ)s s' where R16 and R17 are each independently hydrogen; (C1.8)alkyl; (C
1.6)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:
(CHA

R I
--,N-(CHz)c ) u 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 R'9 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 of the formula:

R20 Rx Rx(CH2)t l Ry Rx (CH2)t 1 N (CH2)9 or R2oN l or JN
/~ ~) Ry/ U Ry / U 120 U

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,, 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; RY is absent or is halogen, (C1_8)alkyl, (C1.8)alkoxy, 0-alkylcarboxylate, 0-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
sis 1 to 6;tisOto 6; anduisOto 3; or 1) a group of the formula:
(CH2)t R21-0-(Cz)t ) u 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, 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)n, - where in 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, 0, 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, 0, 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 the bond containing the wavy line signifies the point of attachment.
[0015] In some embodiments of compounds of formula I, Rl 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. Thus, it will be understood by those of skill in the art that R' and R2 represent a single protecting group attached to both boronic ester oxygens when diols such as (+)-pinanediol and pinacol are used, whereas R' and R2 represent separate moieties on the boronic ester oxygens such as methyl or ethyl when the esters are formed from methanol and ethanol, respectively. In other embodiments of compounds of formula I, 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 and are formed from 1,2-dicyclohexylethanediol;
1,2-etanediol; 1,3-propanediol; 2,3-butanediol, 1,4-butanediol;
diisopropylethanediol;
methanol; ethanol; isopropanol; or 1-butanol. For example, when R' and R2 are each formed from methanol, the resulting R' and R2 groups are methyl. When 2,3-butanediol is used, the resulting R' and R2 groups are a single group and the resulting boronic ester has the following structure:

B\
o [00161 Compounds of formula I include those wherein if CR'R" 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 pluri substituted 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 pluri substituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -CORE; -CO2R8, -CONHR8; -CON(R8) 2; -OR8; or -S-R8;
R7 is halogen; (C1_IO)alkyl; (C1_10)alkoxy; (C1_lo)alkylamino;
(C1_10) dialkylamino; benzyl; benzyloxy; hydroxyl(CI.6)alkyl; hydroxymethyl;
nitro;
trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano;
carboxy;
acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
R8 is (C1_IO)alkyl; (C2_10)alkenyl; (C2_10)alkynyl; (C3-1 o)cycloalkyl; (C5_10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl;
where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently pluri substituted 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 pluri substituted with R';
c) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2))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 pluri substituted with hydroxy, (C1_8)alkyl, (C1.8)alkoxy, (C
1_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 pluri substituted with (C1.8)alkyl, (C1 8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3_6)alkylene;
d) R11(CH2)p- where R' is 2-oxopyrrolidinyl; (CI.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.)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;
Rig is halogen; trifluoromethyl; cyano; nitro; (C1.6)alkyl; (C1_ 6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(CI.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 O to 3;
f) a group of the formula:

R14~ (CHz)r where R14 and R15 are independently hydrogen; (C1_5)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:

R16~ (CHz)s where R16 and R17 are each independently hydrogen; (C 1.8)alkyl; (C
1.6)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:
(CHA

N-(CH2)t 1 u where R18 and R19 are independently hydrogen; (C1.8)alkyl;
(C1.6)alkylcarbonyl; di-(C1_ 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine;
phenyl;
16 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 R'9 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:

20 (CHz)s Rx R Rx(CH2)t Rye (CHA
N ~ C
or R20-_ N/~r) or N
Ry/ U Ry U R20 u 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; Rx 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; Ry is absent or is halogen, (C1.8)alkyl, (C1.8)alkoxy, 0-alkylcarboxylate, 0-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:
(CH2)1 R21-0-(C6 P)t )U

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 R' 2; 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,
17 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)n, - wherein in 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
18 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, 0, 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, 0, 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-.

[0017] Compounds of formula I also include those wherein X is CH2i the ring containing X is saturated; CR'R" is absent, R', 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. In some such embodiments, R5 is a (C1_ 12)alkyl or (C3_12)cycloalkyl, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, or adamantyl.

[0018] In some embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2) 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) adamantyl, and [2.2.1 ] or [3.1.1 ] bicyclic carbocyclic moieties are optionally mono- or independently pluri substituted with hydroxy, (C1.8)alkyl, (C1.8)alkoxy, (C 1_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 pluri substituted with (C1_8)alkyl, (C1.8)alkoxy, halogen, or trifluoromethyl, or R9 and R'0 together are (C3.6)alkylene.
19 [0019] In other embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is R"(CH2)p where R" 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 pluri substituted with R7.
[0020] In certain embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CR'R" 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.
[0021] In some embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CR'R" is absent, R', R2, R3 and R4 are hydrogen; and R5 is a group of the formula:

R14~ (CH2)r 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.
[0022] Compounds of formula I include those wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R', R2, R3 and R4 are hydrogen; and R5 is a group of the formula:

R16/ (CHz)s where R16 and R17 are each independently hydrogen; (C1.8)alkyl; (C
1.6)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 R'7 together form a (C3_12)cycloalkyl ring; and s is 1 to 6.
[0023] Compounds of formula I wherein X is CH2; the ring containing X is saturated;
CR'R" is absent, R', R2, R3 and R4 are hydrogen; and R5 is a group of the formula:

(CHA

t U

where R18 and R' 9 are independently hydrogen; (C1.8)alkyl; (C
1.6)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.
In some such embodiments, R5 has formula:

(CHz)-~
R1 zc)-111 or N R\
N
[0024] In some embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CR'R" 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.
[0025] Compounds of Formula I include those having the following structure, Formula IA:

0 R1 O\B~,OR2 H

R5/ N ) n IA
In some such embodiments, 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 pluri substituted 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. In other such embodiments, R5 is alkyl; alkenyl;
cycloalkyl;
cycloalkylalkyl; hydroxyalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl;
heteroarylalkyl;
cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently pluri substituted as described above (in, e.g., (ee)). In still other such embodiments, R5 is alkyl, cycloalkyl or cycloheteroalkyl, optionally mono- or independently plurisubstituted as described above. In some embodiments of compounds of Formula IA, R3 and R4 are both hydrogen. In other embodiments, n is 1. In some embodiments of compounds of Formula IA where n is 1 and R', R2, R3, and R4 are hydrogen, R5 is not methyl.
[0026] Compounds of formula I include those wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R', R2, R3 and R4 are hydrogen; and R5 is a group of the formula:

(CHA
R20 Rx (CH~ Rx(CH2)t 1 Ry Rx 2)s or R20-N or N 1 J u Ry/ U Ry R20 where R20 is hydrogen; (CI_8)alkyl; (C1.6)alkylcarbonyl; di-(C1_6)alkylaminocarbonyl; (C3_ 8)cycloalkylcarbonyl; benzyl; benzoyl; (C 1.6)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,, 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; Ry is absent or is halogen, (C1_8)alkyl, (C1_8)alkoxy, O-alkylcarboxylate, 0-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
s is 1 to 6; t is 0 to 6; and u is 0 to 3. In some such embodiments, R5 has formula:
Rx Rx (CH2)t~
(CH2t R20 N or R20
[0027] In other such embodiments, R5 is Rx(CH2)t 3 1N `"

including for example, the following structures:

N
CN
H or H .
[0028] In still other such embodiments, the compound has the formula 01 ,OH n OH
N % N %

r--~O OH r-~O OH
HNO.,,%NH HN::~NH
0~1 ,OH OH
N B N B
OH OH
H3C ~O H3C
NH ,%NH
HN , or HN
[0029] Compounds of formula I wherein X is CH2; the ring containing X is saturated;
CR'R" is absent, R', R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
(CHz)r R21-O-(C6P)t) u where R21 is hydrogen; (C 1.8)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. In some such embodiments, R5 has formula:

(CH2)-I
or R21-O R21_O
[0030] Compounds of formula I include those wherein R' and R2 are hydrogen; n is 1; X
together with an adjacent ring carbon and Z form a fused cyclopropyl; CR'R" is absent;
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 pluri substituted 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 in 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, 0, 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.
[0031] In some embodiments of compounds of Formula I, R', R2, R3 and R4 are hydrogen; n is 1; X is CH2; CR'R" is absent; and R5 is aryl or aralkyl.

[00321 In some embodiments, compounds of formula I have the formula:

I
H O B-OR

T_,_ L
RS~N N

[00331 In other embodiments, compounds of formula I have the formula:

O B-OR z O
R5/ N N RS"I N kN
R4 R3 or R3 [00341 In still other embodiments, compounds of formula I have the formula:

I

R5~N
N

[00351 In still other embodiments, compounds of formula I have the formula:

R5-- N jj~ N RS'- N N

F or OH

[00361 Compounds of formula I include those wherein, if CR'R" is present, R' and R3 are hydrogen; R" and R4 together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, 0, 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 CR1R" 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, 0, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono-or independently pluri substituted 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-.

[00371 In some such embodiments, compounds of formula I have formula II:
OR' X/N
R24~tV ~ )n kkk "~~~Y n, X
z wherein:
Y is 0, S, CHR25 or NR26;
k is 0 to 3 and in 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 pluri substituted with R12;
d) R11(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1_6)alkoxy; phenyl;
phenoxy; (C 1_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:

R14~ (CH2)s 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; or g) a group of the formula:
R21-0-(CH2)t_ 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 pluri substituted 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) R' 1(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 pluri substituted 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 pluri substituted 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:

R1 4",.-. (CH2)t 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:

R21_O-(CH2)t_~

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; (C 1_8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl;
naphthyl;
cyclohexenyl; (C 1.8)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 pluri substituted 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 pluri substituted with R';
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:

R14~ (CH2)r 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:
R21_O-(CH2)t_~
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.

[0038) In some embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; and R', R2 and R25 are hydrogen. In other embodiments of compounds of formula II, X is CH2i the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is hydrogen, provided that if k, n, and in are each 1, and Y is CHR25, Z
is not H. In still other embodiments of compounds of formula II, X is CH2; the ring containing X
is saturated; R', 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 pluri substituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions. In some embodiments of compounds of formula II, 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.

Compounds of formula II include those 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 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 pluri substituted 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.

[0039] In certain embodiments of compounds of formula II, 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.

[0040] In other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is a group of the formula:

R14~ (CHz)s where R14 and R15 are independently hydrogen; (C1.8)alkyl; (C
1.6)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.
32 [0041] In some embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is a group of the formula:

R21-O-(CH2)t_ 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.

[0042] Compounds of formula II include those wherein X is CH2; the ring containing X
is saturated; R', R2 and R24 are hydrogen. In some embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R', R2, R24 are hydrogen;
and R25 is (Cl_ 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. In other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R', R2, R24 are hydrogen; and R25 is phenyl optionally mono- or independently plurisubstituted with R12.
[0043] Compounds of formula II include those wherein X is CH2; the ring containing X
is saturated; R', R2, R24 are hydrogen; and R25 is R11(CH2)p- where R' 1 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; 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.
33 [0044] In other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R', R2, R24 are hydrogen; and R25 is (R13)2CH(CH2)a-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.

[0045] Compounds of formula II include those wherein X is CH2; the ring containing X
is saturated; R', R2, R24 are hydrogen; and R25 is a group of the formula:

R14~ (CH2)t where R14 and R15 are independently hydrogen; (C1.8)alkyl; (C
t_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.

[0046] In some embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R', R2, R24 are hydrogen; and R25 is a group of the formula:
R21-O-(CH2)t 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. In other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2, R24 and R26 are hydrogen. In still other embodiments of compounds of formula II, X is CHZ; the ring containing X is saturated; R', 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. Compounds of formula II include those wherein X is CH2; the ring containing X is saturated; R', R2, R24 are hydrogen; and R26 is phenyl optionally mono- or independently pluri substituted with R12.
34 [0047] Compounds of formula II wherein X is CH2; the ring containing X is saturated;
R', R2, R24 are hydrogen; and R26 is R27(CH2)p , where R27 is 2-oxopyrrolidinyl; (Cl-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 ti substituted with Rig; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C
1 -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.
[0048] Compounds of formula II include those wherein X is CH2; the ring containing X
is saturated; R', 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.

[0049] In some embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R', R2, R24 are hydrogen; and R26 is a group of the formula:

R14~ (CH2)r 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.

[0050] In other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R', R2, R24 are hydrogen; and R26 is a group of the formula:
R21_O-(CH2)t-~

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 Rig; and t is 0 or 2 to 6.

[0051] Compounds of formula II include those that have the formula:
ORS

Rea v)m N ) n In some such embodiments, R25 is phenyl optionally mono- or independently plurisubstituted with R12.

[0052] In other embodiments of compounds of formula II, the compound has the formula:

0 B_OR2 H
N N

n N
I

[00531 Compounds of formula II also include those that have the formula:

ORS

H
N
N

-X n z wherein:
R28 and R29 are each independently hydrogen, hydroxy, alkyl, alkoxy, aryloxy, or halogen.

[00541 In some embodiments of compounds of formula I wherein CR'R" is present, the compound has formula III:

N-R' N l" `~~ (III) R2 k " )m Z-X n R
wherein:

Y is 0, 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 O 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 pluri substituted 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 pluri substituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -S02R8; -COR8; -C02R8, -CONHR8; -CON(R8) 2; -OR8; or -S-R8;
R7 is halogen; (C1_10)alkyl; (C1_10)alkoxy; (C 1_lo)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_ 1o)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 pluri substituted with R7;
d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)jadamantyl 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 pluri substituted with hydroxy, (C1.8)alkyl, (C1_8)alkoxy, (C I -8)alkanoyloxy, or R9R'0N-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 R'1 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, (C14)alkoxy, or halogen; and where the [3.3.3]
bicyclic carbocyclic moiety is optionally mono-or independently pluri substituted with (C1.8)alkyl;
and p is 0 to 3;

R' 2 is halogen; trifluoromethyl; cyano; nitro; (C i _6)alkyl; (C i _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) (R' 3)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:

R74,~ (CH2)r-I

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:

R16~ (CH2)s where R16 and R17 are each independently hydrogen; (C1_8)alkyl; (C1_ 6)alkylcarbonyl; di-(C 1.6)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:

(CHA
1 19 N-(CH2)t / u where R18 and R' 9 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 of the formula:

20 2 1 R-x 1"(CH2)s ~ 1"(CH2)t RyC (CH )t or 120-N or N 1 1yz ) U 1Y U R2o u where R20 is hydrogen; (C1_8)alkyl; (C1.6)alkylcarbonyl; di-(C1_6)alkylaminocarbonyl; (C3_ 8)cycloalkylcarbonyl; benzyl; benzoyl; (C 1.6)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, 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; Ry 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 1) a group of the formula:

(CH2)ti R21-0-(CH tt u 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 pluri substituted 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 (C14)alkyl, (C1.4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently pluri substituted 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:

R14~ (CHZ)s_i 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:
R21_O-(CH2)t-~
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; (C I -6)alkoxy; phenyl;
phenoxy; (C1_8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl;
naphthyl;
cyclohexenyl; (C 1_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 tisubstituted 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 pluri substituted with (C1_8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (CI.6)alkyl; (CI.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:

R14""-N,_1 (CH2)t where R14 and R15 are independently hydrogen; (C1 8)alkyl; (C
I.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, alkylsiilfonyl, 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:
R21_O-(CH2)I_~
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) (CI_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; (CI.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(CI.6)alkyl; where the 2-oxopyrrolidinyl, (CI
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 (CI-4)alkyl, (C1_4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently pluri substituted with (C1_8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C 1.6)alkyl; (C I.6)alkoxy;
cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(CI.6)alkyl; hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently pluri substituted 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:

R14~ (CH2)r where R14 and R15 are independently hydrogen; (C18)alkyl; (C I -6)alkylcarbonyl; (C3_ 12)cycloalkyl ring; (C3_12)cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; cycloalkenyl ring; benzyl; benzoyl; pyridine;
pyrimidine; phenyl;
phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(CI.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:
Rea-O-(CH2)t_ where R21 is hydrogen; (CI-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 or2to6.

[0055] Compounds of formula III include those wherein X is CH2; the ring containing X
is saturated; and R', R2 and R25 are hydrogen; those wherein X is CH2; the ring containing X
is saturated; R', R2 and R25 are hydrogen; and R24 is hydrogen; and those wherein X is CH2;
the ring containing X is saturated; R', 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 R'2, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.

[0056] In some embodiments of compounds of formula III, X is CH2; the ring containing X is saturated; R', R2 and R25 are hydrogen; and R24 is phenyl optionally mono-or independently plurisubstituted with R12. In other embodiments, X is CH2; the ring containing X is saturated; R', R2 and R25 are hydrogen; and R24 is R"(CH2)p-where R" is 2-oxopyrrolidinyl, (C1.6)alkoxy, phenyl; phenoxy; (C 1_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, (C I -4)alkoxy, or halogen;
and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently pluri substituted 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. In still other embodiments, 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.

(0057] Compounds of formula III include those wherein X is CH2; the ring containing X
is saturated; R1, R2 and R25 are hydrogen; and R24 is a group of the formula:

R14~ (CH2)s_I

where R14 and R15 are independently hydrogen; (C1_8)alkyl; (C
1.6)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.

[0058] Compounds of formula III also include those wherein X is CH2; the ring containing X is saturated; R', R2 and R25 are hydrogen; and R24 is a group of the formula:
R21-O-(CH2)t_ 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.

[0059] In some embodiments of compounds of formula III, X is CH2; the ring containing X is saturated; R', R2 and R24 are hydrogen. In other embodiments, X is CH2;
the ring containing X is saturated; R', 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 pluri substituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions. In still other embodiments, X is CH2; the ring containing X is saturated; R', R2, R24 are hydrogen; and R25 is phenyl optionally mono-or independently pluri substituted with R12.

[0060] In some embodiments of compounds of formula III, X is CH2; the ring containing X is saturated; R', R2, R24 are hydrogen; and R25 is R"(CH2)p- where R" 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.

[0061] In other embodiments of compounds of formula III, X is CH2i the ring containing X is saturated; R', 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. In still other embodiments, X is CH2; the ring containing X is saturated; R', R2, R24 are hydrogen; and R25 is a group of the formula:

R14~N 1~1 (CH2)t where R14 and R15 are independently hydrogen; (C1.8)alkyl; (C
1.6)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.

[0062] In certain embodiments of compounds of formula III, X is CH2; the ring containing X is saturated; R', R2, R24 are hydrogen; and R25 is a group of the formula:

R21-O-(CH2)t 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.

[0063] In some embodiments of compounds of formula III, X is CH2; the ring containing X is saturated; R1, R2, R24 and R26 are hydrogen. In other embodiments, 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. In yet other embodiments, 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.

Compounds of formula III include those wherein X is CH2; the ring containing X
is 24 26 27 where R27 is 2-oxo olidiny1 saturated; R', R2, R are hydrogen; and R is R (CH2)p-, pyrr ;
(C1_6)alkoxy; phenyl; phenoxy; (C1.8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;
pyridinyl; naphthyl; cyclohexenyl; (C 1.8)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, (C14)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. In some embodiments of compounds of formula III, X is CH2i the ring containing X
is saturated; R', R2, R24 are hydrogen; and R26 is (R' 3)2CH(CH2)q-; where R13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and g is O to 3.

[0064] Compounds of formula III include those wherein X is CH2; the ring containing X
is saturated; R', R2, R24 are hydrogen; and R26 is a group of the formula:

R14/N 1-1 (CH2)r where R14 and R15 are independently hydrogen; (C1_8)alkyl; (C
1.6)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.

[0065] Compounds of formula III also include those wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula:
R21-O-(CH2)t-l 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.

[0066] In some embodiments of compounds of formula I, CR'R" is present. In other embodiments of compounds of formula I where CR'R" is present, the compound has formula IVA or IVB:

N N
R- LI R- LI
z z (IVA) (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 pluri substituted with R12;
d) R"(CH2)p- where R1 1 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; 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 pluri substituted 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:

R14~ (CHz)s where R14 and R15 are independently hydrogen; (C1.8)alkyl; (C
1.6)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:
R21_O-(CH2)t-~
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;

[0067] It has further been discovered that certain boronic acid compounds of the invention can exist as either linear or cyclic isomers. Typically, such compounds form an equilibrium mixture in aqueous solution. As shown in Figure 1, the concentration of the two isomers of such compounds is typically pH dependent. Thus, it is expected that such inventive compounds will exist as a mixture of linear and cyclic isomers in vivo. Moreover, the cyclic forms of inventive compounds may serve as novel, orally available prodrugs.
Hence, in this aspect of the invention, there are provided compounds that have the formula VA, VB, or a mixture thereof:

R3 OR1 R3 `/ ORS
R5HN R4 I ,OR2 RNO R
e O N ) O
n N n X
Z Z
VA VB
including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:
n is 1 to 3;
X is CH2; S; 0; 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 pluri substituted 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; -SORB; -S02R8; -CORE; -C02R8, -CONHRB; -CON(R) 2; -ORB; or -S-R8;
R7 is halogen; (C1_10)alkyl; (C1_lo)alkoxy; (C 1_lo)alkylamino;
(C1_'o) 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; (C3-1 O)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_lo)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2))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 pluri substituted with hydroxy, (C1_g)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 pluri substituted 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 (C14)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(CI.6)alkyl;
hydroxymethyl;
trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl;
phenylsulfonyl; aryl;
heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently pluri substituted 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 O to 3;
g) a group of the formula:

R14/ (CH2)r-i 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(CI.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:

R16~ (CH)s where R16 and R17 are each independently hydrogen; (C1.8)alkyl; (C
1.6)alkylcarbonyl; di-(CI
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 R'6 and R17 together form a (C3_12)cycloalkyl ring; and s is 1 to 6;
i) a group of the formula:
(CH2)t N--(CH) U

where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C
I.6)alkylcarbonyl; di-(CI
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 of the formula:

(CHA-A Rye (CH2)t I
R20 Rx(CH2)s Rx Rx N or R20_N) or N
C
j 1 Ry ) u Ry U R20 U

where R20 is hydrogen; (C1_8)alkyl; (C1.6)alkylcarbonyl; di-(C1.6)alkylaminocarbonyl; (C3_ 8)cycloalkylcarbonyl; benzyl; benzoyl; (C 1.6)alkyloxycarbonyl;
arikyloxycarbonyl, 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,, 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; RY is absent or is halogen, (C1.8)alkyl, (C1.8)alkoxy, 0-alkylcarboxylate, 0-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
s is I to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
(CHz)t R21-O-(C)t )u 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, 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 pluri substituted 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; and wherein the bond containing the wavy line signifies the point of attachment.
[0068] In some embodiments of compounds of formula VA and VB, R' 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. In other embodiments, R' 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.

[0069] In some embodiments of compounds of formula VA or VB, 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.

[0070] In still other embodiments of compounds of formula VA or VB, X is CH2;
the ring containing X is saturated; R', 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 pluri substituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions. In some such embodiments, R5 is (C3-12) cycloalkyl such as cyclopentyl.

[0071] In some embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R', R2, R3 and R4 are hydrogen; and R5 is indanyl;
1,2,3,4-tetrahydronaphthyl; (CH2) 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) 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 pluri substituted with (C1_8)alkyl, (C1_8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3_6)alkylene.

[0072] Compounds of formula VA or VB include those wherein X is CH2i the ring containing X is saturated; R', R2, R3 and R4 are hydrogen; and R5 is R11(CH2)p-where Rl 1 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, (C14)alkoxy, or halogen;
and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently pluri substituted with (CI_8)alkyl; p is 0 to 3; and R12 is halogen;
trifluoromethyl; cyano;
nitro; (CI.6)alkyl; (CL6)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 pluri substituted with R7.

[0073] Compounds of VA or VB further include those wherein X is CH2; the ring containing X is saturated; R', 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.

[0074] In some embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:

R14~N (CH2)r_I

where R14 and R15 are independently hydrogen; (C1_g)alkyl; (C
I.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.

[0075] In other embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:

~(CH2)s f where R16 and R17 are each independently hydrogen; (C1_8)alkyl; (C
I.6)alkylcarbonyl; di-(CI
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 R'7 together form a (C3_12)cycloalkyl ring; and s is 1 to 6.

[0076] In certain embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R', R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
(CHA

R \
N-(CH2)t u where R18 and R19 are independently hydrogen; (C1.8)alkyl; (C
1.6)alkylcarbonyl; di-(CI_ 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 R'9 together form a (C3_12)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3.
In some such embodiments, R5 has formula:

(CH2)_ R 1 or Rig N N

[0077] Compounds of formula VA or VB further include those wherein X is CH2;
the ring containing X is saturated; R', 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.

[0078] In some embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R', R2, R3 and R4 are hydrogen; and R5 is a group of the formula:

3 Rx R20 Rx(CH2)s 3 Rx (CHA Rye (CHA
~N or R2o_N or CN
u RyX U Ry R20 where R20 is hydrogen; (C1.8)alkyl; (C1_6)alkylcarbonyl; di-(C1.6)alkylaminocarbonyl; (C3_ 8)cycloalkylcarbonyl; benzyl; benzoyl; (C 1.6)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, 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; Ry is absent or is halogen, (C1_8)alkyl, (C1.8)alkoxy, 0-alkylcarboxylate, 0-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
s is I to 6; t is 0 to 6; and u is 0 to 3; or In some such embodiments, R5 has formula:.

Rx (CH2)t Rx (CH2)t R2o N or R20 [0079] In other embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
(CHz)i R21_O-(CH2)t ) 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. In some such embodiments, R5 has formula:

(CH2)-J
or R21-p R21-p [0080] Compounds of formula VA or VB further include those wherein R' 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.

[0081] In certain embodiments of compounds of formula VA or VB, the compoundshave the formula:

R3 OR' R3 \ / OR1 RSHN R I /OR2 R4 ~ I OR2 e O N O N

X
Z Z

or a mixture thereof.

[00821 Compounds of formula VA or VB include those having the formula:

R3 OR1 R3 \ / OR1 e O N O N

S S
or a mixture thereof.

[00831 In other embodiments, compounds of formual VA or VB include those having the formula:

R3 OR1 R3 \ / OR1 R5HN R4 I ",OR R4 N OR2 e or a mixture thereof, or the formula:

R3 OR1 R3 \ / OR1 e or a mixture thereof.

[0084] Compounds of formula VA or VB further include those having the formula:

R3 OR1 R3 \ / OR1 O

O N O N
or a mixture thereof.

[0085] In still other embodiments, compounds of formula VA or VB have the formula:

R3 OR1 R3 \ / OR1 e O N O N
F F
or a mixture thereof.

[0086] In yet other embodiments, compounds of formual VA or VB have the formula:

R3 OR' R3 \ / OR' R5HN R4 B/OR2 R4 ~ I /OR2 E) O N O N

OH , OH , or a mixture thereof.

[00871 In still another aspect, the invention provides boronic acid inhibitors of dipeptidyl peptidase-IV having an inhibition constant of 10 micromolar or less for dipeptidyl peptidase-IV. Such inhibitors comprises a boroproline (including boropyrrolidines, boropiperidines, and boroazepanes) attached to an amino acid through an amide bond. The amino acid can be a beta-amino acid (including cyclic forms such as, an N-cycloalkyl-alpha-amino acid, an N-heterocyclyl-alpha amino acid, a cyclic alpha-amino acid having at least one substituent on the alpha-amino acid ring or having a ring other than pyrrolidine, or N-substituted glycine. In some embodiments, the boronic acid inhibitor is of Formula I:

ORS

R ~1 N N (1) H
R" R' I-/- X
Z
including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:
nisIto2;
X is CH2; S; 0; 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 pluri substituted 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'R" may be present or absent, wherein if CR'R" is present, then R', R", R3, R4 and R5 are selected from (aa), (bb) or (cc):
(aa) R', R", 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 (CI.6)alkyl; (CI.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; -S02R8; -CORE; -CO2R8, -CONHRB; -CON(R) 2; -ORB; or -S-R8;
R7 is halogen; (CI_10)alkyl; (CI_lo)alkoxy; (C 1.10)alkylamino;
(CI-1o) 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.IO)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)jadamantyl 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)) 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, (C
1_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 pluri substituted with (CI.8)alkyl, (C1.8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3_6)alkylene;

e) R11(CH2)p- where R1' 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 (C14)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3]
bicyclic carbocyclic moiety is optionally mono-or independently pluri substituted 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 Oto3;
g) a group of the formula:

R14",-N (CHZr_i where R14 and R15 are independently hydrogen; (C1.8)alkyl; (C
1.6)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:

R16~ (CH2)s where R16 and R17 are each independently hydrogen; (C1.8)alkyl; (C
1.6)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:
(CHA

N-(CH )t U

where R18 and R19 are independently hydrogen; (C1.8)alkyl; (C
1.6)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:

R Rx(CH2t Ry Rx 20 Rx(CH2)s I" (CH2)t l or R20_N or CN
Ry/ / u RY u 20 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,, 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; Ry is absent or is halogen, (C1_8)alkyl, (C1.8)alkoxy, O-alkylcarboxylate, 0-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;

s is 1 to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
(CHA
R21-O-(CH2)t ) u 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', R", 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' together with R3 or R4, or R" 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, 0, 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)", where in 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, 0, 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' and R3 are hydrogen; and R" and R4 together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, 0, 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'R" 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 pluri substituted 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(C 1.6)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 pluri substituted with R8; -SOR8; -SO2R8; -CORE; -CO2R8, -CONHRB; -CON(R) 2; -ORB; or -S-R8;
R7 is halogen; (C1_10)alkyl; (C1_10)alkoxy; (C 1.1o)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 pluri substituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently pluri substituted 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 pluri substituted with R7;
c) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)jadamantyl 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 pluri substituted with hydroxy, (C1.8)alkyl, (C1_8)alkoxy, (C
1.8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R'0 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 R'0 together are (C3_6)alkylene;
d) R' 1(CH2)p- where R" is 2-oxopyrrolidinyl; (C 1.6)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 (C14)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;
andpisOto3;
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 Oto3;

f) a group of the formula:

R14~ N ~(CH2r_i where R14 and R15 are independently hydrogen; (C1.8)alkyl; (C
1.6)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:

N
R16/ (CH2)S s where R16 and R17 are each independently hydrogen; (C1_8)alkyl; (C
1.6)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 R' 2; or R16 and R17 together form a (C3_12)cycloalkyl ring; and s is 1 to 6;
h) a group of the formula:
(CHA

N-(CH )t u 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:

R 20 Rx Rx (CH2)t Rye (CH2)t N Rx(CH2)s or R20--N or N 1 ,Z~r Rye ~õ Ry / u 20 J u where R20 is hydrogen; (C1_8)alkyl; (C1.6)alkylcarbonyl; di-(C1.6)alkylaminocarbonyl; (C3_ 8)cycloalkylcarbonyl; benzyl; benzoyl; (C 1.6)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; RX 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; Ry is absent or is halogen, (C1_8)alkyl, (C1.8)alkoxy, 0-alkylcarboxylate, 0-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl;
sis 1 to 6;tis0to6;anduis0to3;or k) a group of the formula:
(CHA
R21-O-(CH2 tt ) u 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, 0, 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, 0, 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.
[0088] The invention also relates to methods for preparing the above-described compounds. As shown below and as described in the EXAMPLES, the compounds of formula I and II are prepared by reacting a cyclic amine (e.g., pyrrolidine or piperidine), suitably protected with a standard protecting group such as Boc-, Fmoc-, CBz-or the like, with sec-BuLi/TMEDA followed by B(OCH3)3, to provide the methyl boronic ester derivative. Acid hydrolysis of the methyl esters with 2N HCl provides the boronic acid intermediate 1. Reaction of 1 with (+) pinanediol, deprotection of the amino protecting group, and recrystallization provides the pinanediol ester 2 as an isomerically pure salt.
[0089] Intermediate 2 is useful for the synthesis of both series A and series B
compounds. For example, N-acylation of 2 with chloroacetyl chloride provides the a-chloro amide 3. Treatment of 3 with Na2CO3 and cyclopentylamine, and hydrolysis of the pinanediol boronic ester, provides a compound of formula I, 4. Alternatively, coupling of intermediate 2 with N-Boc-5-phenyl-Pro using EDAC/HOBT provides amide 5.
Deprotection of the amino group and hydrolysis of the boronic esters, provides a compound of formula II, 6.

1) s-BuLi, TMEDA -40 C HO`B-OH
2) (MeO)3B 1) (+)-Pinanediol, Et20 C NBoc 3) H30+ NBoc 2) HCI, Et20 then re crystallize (2X) leaving only R isomer lj~CI jNHHCI
CI
CI/~N
O B,, N
N
O
/ O OA 0 (:~B'O
3 o 1) Na2CO3 1) HCI, Et20 2) Phenyl Boronic Acid 2) Phenyl Boronic Acid Hexane / H2O
Hexane / H20 N N N N
H

[00901 This synthetic scheme is adaptable for the preparation of all the compounds of the invention, by reacting the appropriate cyclic amine (pyrrollidine, piperidine, and other cyclic amines) with sec-BuLi/B(OCH3)3, and coupling the boronic ester intermediate with the desired acid chloride or acid via routes A or B, respectively. The appropriate cyclic amine may either be commercially available or is easily synthesized through known procedures, for example, those procedures disclosed in U.S. Patent Nos.
6,617,340;

6,432,969; 6,380,398; 6,172,081; 6,166,063; 6,124,305; 6,110,949; 6,107,317;
6,011,155;
and 6,395,767.

[0091] Thus, another aspect of the invention provides a process for preparing the compounds of formula I:

OR' R ~ N N (1) H
R" R' X
Z
by coupling a reactive compound of formula:

ORS

L ~
R" ) R' Z X n with an amine of formula: R5-NH2i optionally deprotecting the boronic acid ester;
and recovering the resultant compound as a free acid or as an acid addition salt; wherein L
is a leaving group. R', R2, R3, R4, R', R", n, X, and Z are as defined herein.
Preferred embodiments are those where R3 and R4 are hydrogen, L is halogen, including but not limited to Cl, and R5-NH2 is cyclopentylamine.

[00921 Still another aspect of the invention provides A process for preparing the compounds of formula II:

ORS

R24 n Y lM I X

by coupling a 2-boroheterocycle having the formula:

OR' HN ) X n z with the corresponding N-protected cyclic amino acid; optionally deprotecting the boronic acid ester; and recovering the resultant compound as a free acid or as an acid addition salt. Rand R2 are not hydrogen, and n, X, and Z are as defined herein. Typically the 2-boroheterocycle is a 2-boropyrrolidino or 2-boropiperidino. In some such embodiments, the N-protected cyclic amino acid is N-Boc-4-phenyl-boroPro-OH.

[0093] The compounds of the invention may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan.

[0094] The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.

[0095] The compounds of this invention may form solvates with standard low molecular weight solvents, including water to yield hydrates, using methods known to the skilled artisan.

[0096] It is to be understood that the invention extends to all of the stereoisomeric forms of the claimed compounds, including enantiomers and diastereomers, as well as the racemates.

Methods/Uses [00971 Another aspect of the invention provides methods and uses for the compounds of the invention. In one approach, the invention compounds can be administered to an individual suffering from a disease or condition mediated by a post-proline/alanine cleaving amino-dipeptidase. In this embodiment, the individual is administered an amount of the invention compound effective in reducing the activity of the post-proline/alanine cleaving amino-dipeptidase and, thereby, reducing or alleviating symptoms of the disease or condition. In some embodiments, the administered compound reduces the activtity of DPP-IV. In some embodiments, the disease or condition is selected from the group consisting of diabetes, diabetec complications, hyperglycemia, Syndrome X, hyperinsulinemia, obesity, atherosclerosis and related diseases. The invention compounds to be administered may be one or more of the inventive bronic acid compounds, which may be formulated in any manner as described here, including combination with "other type(s) of therapeutic agents"
identified further below.

[00981 Other exemplary embodiments of the invention methods are represented by:
[00991 Methods for inhibiting DPP-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable acid addition salt thereof, [001001 Methods for treating conditions mediated by DPP-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable acid addition salt thereof;

[00101] Methods for treating controlling, or preventing diabetes comprising administering to a patient of an effective amount of a compound of the invention;

[001021 Methods for treating, controlling, or preventing insulin dependent (Type I) and/or 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 the invention;

[00103] Methods 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 the invention;

[00104] Methods 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 the invention;

[00105] Methods 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 the invention;

[00106] Methods 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 the invention;

[00107] Methods 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 the invention;

[00108] Methods 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 the invention;

[00109] Methods 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 the invention;

[00110] Methods 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 the invention;

[00111] Methods 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 the invention;

[00112] Methods 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 the invention;

[00113] Methods for 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 the invention;

[00114] Methods 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 the invention;

[00115] Methods 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 the invention, 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) a-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) PPARa agonists, (v) PPARa/y dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterol acyltransferase inhibitors, and (viii) anti-oxidants;
1) PPARS agonists;
m) Anti-obesity compounds;
n) An ileal 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.

[00116] Methods 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 the invention and an HMG-CoA
reductase inhibitor;

[00117] Methods wherein the HMC-CoA reductase inhibitor is a statin;

[00118] Methods wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin;
[00119] Methods 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 the invention and an HMG-CoA reductase inhibitor;

[00120] Methods 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 the invention and an anti-obesity agent;

[00121] Methods 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;

[00122] Methods wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol;

[00123] Methods 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 the invention and a neutrophilic agent;

[0100] Methods for the treatment, control, or prevention of neutropenia wherein the neutrophilic agent is G-CSF, a G-CSF mimetic, or a G-CSF receptor agonist;

[0101] Methods for the treatment, control, or prevention of neutropenia wherein the neutrophilic agent is pegfilgrastim, filgrastim, lenograstim, or nartograstim;

[0102] Methods 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 the invention and a erythropoietin agonist;

[0103] Methods for the treatment, control, or prevention of anemia wherein the erythropoietin agonist is EPO, an EPO mimetic, or an EPO receptor agonist;

[0104] Methods for the treatment, control, or prevention of anemia wherein the erythropoietin agonist is epoetin alfa, or darbepoetin alfa;

[0105] Methods 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 of the invention;

[0106] Methods for treating type II diabetes and/or obesity;

[0107] A variety of uses of the invention compounds are possible along the lines of the various methods of the treating an individual such as a mammal described above.
Exemplary uses of the invention methods are represented by:

[0108] Use of a compound of the invention for the manufacture of a medicament for treating a condition that may be regulated or normalized via inhibition of DPP-IV;
[0109] Use of a compound of the invention for the manufacture of a medicament for treatment of metabolic disorders;

[0110] Use of a compound of the invention for the manufacture of a medicament for blood glucose lowering;

[0111] Use of a compound of the invention for the manufacture of a medicament for treatment of type II diabetes;

[0112] Use of a compound of the invention for the manufacture of a medicament for the treatment of impaired glucose tolerance (IGT);

[0113] Use of a compound of the invention for the manufacture of a medicament for the treatment of impaired fasting glucose (IFG);

[0114] Use of a compound of the invention for the manufacture of a medicament for prevention of hyperglycemia;

[0115] Use of a compound of the invention for the manufacture of a medicament for delaying the progression of impaired glucose tolerance (IGT) to type II
diabetes;

[0116] Use of a compound of the invention for the manufacture of a medicament for delaying the progression of non-insulin requiring type II diabetes to insulin requiring type II
diabetes;

[0117] Use of a compound of the invention for the manufacture of a medicament for increasing the number and/or the size of beta cells in a mammalian subject;

[0118] Use of a compound of the invention for the manufacture of a medicament for treatment of beta cell degeneration, in particular apoptosis of beta cells.

[0119] Use of a compound of the invention for the manufacture of a medicament for the treatment of disorders of food intake;

[0120] Use of a compound of the invention for the manufacture of a medicament for the treatment of obesity;

[0121] Use of a compound of the invention for the manufacture of a medicament for appetite regulation or induction of satiety;

[0122] Use of a compound of the invention for the manufacture of a medicament for the treatment of dyslipidemia;

[0123] Use of a compound of the invention for the manufacture of a medicament for treatment of functional dyspepsia, in particular irritable bowel syndrome; and [0124] Methods for treating the conditions mentioned above by administering to a subject in need thereof an effective amount of a compound of the invention.

Combination Treatments [0125] The compounds of the invention may be used in combination with one or more other types of antidiabetic agents (employed to treat diabetes and related diseases) and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in a separate oral dosage form or by injection.

[0126] The other type of antidiabetic agent which may be optionally employed in combination with the DPP-IV inhibitors of the invention may be 1,2,3 or more antidiabetic agents or antihyperglycemic agents including insulin secretagogues or insulin sensitizers, or other antidiabetic agents preferably having a mechanism of action different from DPP-IV
inhibition and may include biguanides, sulfonyl ureas, glucosidase inhibitors, PPAR y agonists, such as thiazolidinediones, SGLT2 inhibitors, PPAR a/ y dual agonists, aP2 inhibitors, glycogen phosphorylase inhibitors, advanced glycosylation end (AGE) products inhibitors, and/or meglitinides, as well as insulin, and/or glucagon-like peptide-1 (GLP-1) or mimetics thereof.

[0127] The use of the compounds of the invention in combination with 1, 2, 3 or more other antidiabetic agents may produce antihyperglycemic results greater than that possible from each of these medicaments alone and greater than the combined additive antihyperglycemic effects produced by these medicaments.

[0128] The other antidiabetic agent may be an oral antihyperglycemic agent preferably a biguanide such as metformin or phenformin or salts thereof, preferably metformin HCI.
[0129] Where the other antidiabetic agent is a biguanide, the compounds of the invention will be employed in a weight ratio to biguanide within the range from about 0.01:1 to about 100:1, preferably from about 0.1:1 to about 5:1.

[0130] Preferably, the other antidiabetic agent can be a sulfonyl urea such as glyburide (also known as glibenclamide), glimepiride (disclosed in U.S. patent No.
4,379,785), glipizide, gliclazide or chlorpropamide, other known sulfonylureas or other antihyperglycemic agents which act on the ATP-dependent channel of the y-cells, with glyburide and glipizide being preferred, which may be administered in the same or in separate oral dosage forms.

[01311 The compounds of the invention will be employed in a weight ratio to the sulfonyl urea in the range from about 0.01:1 to about 100:1, preferably from about 0.05:1 to about 5:1.

[0132] The oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. patent No. 4,904,769) or miglitol (disclosed in U.S. patent No.
4,639,436), which may be administered in the same or in a separate oral dosage forms.
[01331 The compounds of the invention will be employed in a weight ratio to the glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.2:1 to about 50:1.

[01341 The compounds of the invention may be employed in combination with a PPAR y agonist such as a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner-Lambert's Rezulin , disclosed in U.S. patent No. 4,572,912), rosiglitazone (en), pioglitazone (Takeda), Mitsubishi MCC-555 (disclosed in U.S. patent No.
5,594,016), Glaxo-Wellcome's GL-262570, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer), isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-1 (Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone.

[0135] The compounds of the invention will be employed in a weight ratio to the thiazolidinedione in an amount within the range from about 0.01:1 to about 100:1, preferably from about 0.1:1 to about 10:1.

[0136] The sulfonyl urea and thiazolidinedione in amounts of less than about 150 mg oral antidiabetic agent may be incorporated in a single tablet with the compounds of the invention.

[01371 The compounds of the invention may also be employed in combination with a antihyperglycemic agent such as insulin or with glucagon-like peptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-36) (as disclosed in U.S. Patent No.
5,614,492 to Habener) or a GLP-1 mimic such as AC2993 or Exendin-4 or its synthetic version exenatide (Amylin) and LY-315902 or LY-307167 (Lilly) and NN2211 (Novo-Nordisk), which may be administered via injection, intranasal, or by transdermal or buccal devices.

[0138] Where present, metformin, the sulfonyl ureas, such as glyburide, glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and the glucosidase inhibitors acarbose or miglitol or insulin (injectable, pulmonary, buccal, or oral) may be employed in formulations as described above and in amounts and dosing as indicated in the PHYSICIAN'S
DESK REFERENCE (PDR).

[01391 Where present, metformin or salt thereof may be employed in amounts within the range from about 500 to about 2000 mg per day which may be administered in single or divided doses one to four times daily.

[01401 Where present, the thiazolidinedione anti-diabetic agent may be employed in amounts within the range from about 0.01 to about 2000 mg/day which may be administered in single or divided doses one to four times per day.

[01411 Where present insulin may be employed in formulations, amounts and dosing as indicated by the PHYSICIAN'S DESK REFERENCE.

[01421 Where present GLP-1 peptides may be administered in oral buccal formulations, by nasal administration (for example inhalation spray) or parenterally as described in U.S.
Patent Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224.

[0143] The other antidiabetic agent may also be a PPAR a/y dual agonist such as AR-H039242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck), as well as those disclosed by Murakami et al., "A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation--Activated Receptor Alpha (PPAR alpha) and PPAR
gamma.
Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats," Diabetes 47: 1841-47 (1998), employing dosages as set out therein, which compounds designated as preferred are preferred for use herein.

[0144] The other antidiabetic agent may be an SGLT2 inhibitor, as disclosed in USP 6,414,126 B1, employing dosages as set out herein. Preferred are the compounds designated as preferred in the above application.

[0145] The other antidiabetic agent, which may be employed in combination with the DPP-IV inhibitors in accordance with the present invention, can be an aP2 inhibitor, USP 6,548,529 B1, employing dosages as set out herein. Preferred antidiabetic agents to be used in combination with the invention compounds are those indicated as preferred in the above cited patents.

[0146] The other antidiabetic agent that may employed with the DPP-IV
inhibitors of the invention can be a glycogen phosphorylase inhibitor as disclosed, for instance, in WO
96/39384, WO 96/39385, WO 99/26659, WO 99/43663, WO 2000/47206, EP 978279, EP
1041068, and U.S. patents No. 5,952,322 and No. 5,998,463.

[0147] The meglitinide which may optionally be employed in combination with the compound of the invention may be repaglinide, nateglinide (Novartis) or (PF/Kissei), with repaglinide being preferred.

[0148] The DPP-IV inhibitors of the invention will be employed in a weight ratio to the meglitinide, PPAR y agonist, PPAR of y dual agonist, SGLT2 inhibitor, aP2 inhibitor, or glycogen phosphorylase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.1:1 to about 10:1.

[0149] The hypolipidemic agent or lipid-modulating agent which may be optionally employed in combination with the compounds of the invention may include 1,2,3 or more MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ilea] Na+/bile acid cotransporter inhibitors, upregulators of LDL receptor activity, ATP
citrate lyase inhibitors, cholesteryl ester transfer protein inhibitors, bile acid sequestrants, and/or nicotinic acid and derivatives thereof.

[0150] MTP inhibitors employed herein include MTP inhibitors disclosed in U.S.
patents No. 5,595,872, No. 5,739,135, No. 5,712,279, No. 5,760,246, No. 5,827,875, No.

5,885,983, and No. 5,962,440. MTP inihibitors preferred herein are thos identified as being preferred in the above referenced patents.

[0151] Most preferred MTP inhibitors, in accordance with the present invention, are implitapide (Bayer) and those set out in U.S. patents No. 5,739,135, No.
5,712,279, and No.
5,760,246. A particularly peferred MTP inhibitor in this context is 9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)-benzoyl] amino] -1 -piperidinyl] butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide.

[0152] The hypolipidemic agent may be an HMG CoA reductase inhibitor which includes, but is not limited to, mevastatin and related compounds as disclosed in U.S. patent No. 3,983,140, lovastatin (mevinolin) and related compounds disclosed in U.S.
patent No. 4,231,938, pravastatin and related compounds such as disclosed in U.S.
Patent No.
4,346,227, smvastatin and related compounds as disclosed in U.S. Patent Nos.
4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Patent No.
5,354,772, cerivastatin disclosed in U.S. patents No. 5,006,530 and No. 5,177,080, atorvastatin disclosed in U.S. patents No. 4,681,893, No. 5,273,995, No. 5,385,929 and No.
5,686,104, atavastatin (Nissan/Sankyo nisvastatin (NK-104)), disclosed in U.S. patent No.
5,011,930, and Shionogi-Astra/Zeneca visastatin (ZD-4522), disclosed in U.S. patent No.
5,260,440.
[0153] The squalene synthetase inhibitors suitable for use herein include, but are not limited to, a-phosphono-sulfonates disclosed in U.S. Patent No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 11, No. 10, pp 1869-1871, including isoprenoid (phosphinyl-methyl)phosphonates as well as other known squalene synthetase inhibitors, for example, as disclosed in U.S. Patent Nos. 4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996).

[0154] In addition, other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J.
Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987, 10, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med.
Chem. U of Utah, Abstracts Table of Contents, pp 16, 17, 40-43, 48-5 1, Summary.

[0155] Other hypolipidemic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, cliofbrate, and the like, probucol, and related compounds as disclosed in U.S.
Patent No.
3,674,836, probucol and gemfibrozil being preferred, bile acid sequestrants such as TM
cholestyramine, colestipol and DEAE-Sephadex (Secholex(b, Policexide ), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives such as disclosed in U.S.
Patent No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes such as disclosed in U.S. Patent No. 4,027,009, and other known serum cholesterol lowering agents.

[01561 The other hypolipidemic agent may be an ACAT inhibitor such as disclosed in 24 DRUGS OF THE FUTURE 9-15 (Avasimibe 1999), "The ACAT inhibitor, C1-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters", Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; "RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor", Smith, C., et al, Bioorg.
Med. Chem.
Lett. (1996), 6(1), 47-50; "ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals", Krause et al, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla.; "ACAT inhibitors: potential anti-atherosclerotic agents", Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; "Inhibitors of acyl-CoA:cholesterol 0-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT
inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N'-[(l-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity", Stout et al, Chemtracts: Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd).
[01571 The hypolipidemic agent may be an upregulator of LD2 receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

[01581 The hypolipidemic agent may be a cholesterol absorption inhibitor preferably Schering-Plough's SCH48461 as well as those disclosed in Atherosclerosis 115, (1995) and J. Med. Chem. 41, 973 (1998).

[01591 The hypolipidemic agent may be an ilea] Na+/bile acid cotransporter inhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).

[0160] The lipid-modulating agent may be a cholesteryl ester transfer protein (CETP) inhibitor such as Pfizer's CP 529,414 (WO/0038722 and EP 818448) and Pharmacia's SC-744 and SC-795.

[0161] The ATP citrate lyase inhibitor which may be employed in the combination of the invention may include, for example, those disclosed in U.S. patent No.
5,447,954.

[01621 Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin and ZD-4522.

[01631. The amounts and dosages employed will be as indicated in the Physician's Desk Reference and/or in the patents set out above.

[01641 The compounds of the invention will be employed in a weight ratio to the hypolipidemic agent (where present), within the range from about 500:1 to about 1:500, preferably from about 100:1 to about 1:100.

[01651 The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.

101661 The dosages and formulations for the hypolipidemic agent will be as disclosed in the various patents and applications discussed above.

[0167] The dosages and formulations for the other hypolipidemic agent to be employed, where applicable, will be as set out in the latest edition of the Physicians' Desk Reference.
[0168] For oral administration, a satisfactory result may be obtained employing the MTP
inhibitor in an amount within the range of from about 0.01 mg/kg to about 500 mg and preferably from about 0.1 mg to about 100 mg, one to four times daily.

[0169] An oral dosage form, such as tablets or capsules, will contain the MTP
inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg, one to four times daily.

[0170] For oral administration, a satisfactory result may be obtained employing an HMG
CoA reductase inhibitor, for example, pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin in dosages employed as indicated in the PHYSICIAN'S DESK
REFERENCE, such as in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.

[0171] The squalene synthetase inhibitor may be employed in dosages in an amount within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg.

[0172] A preferred oral dosage form, such as tablets or capsules, will contain the HMG
CoA reductase inhibitor in an amount from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 to about 40 mg.

[0173] A preferred oral dosage form, such as tablets or capsules will contain the squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg.

[0174] The other hypolipidemic agent may also be a lipoxygenase inhibitor including a 15-lipoxygenase (15-LO) inhibitor such as benzimidazole derivatives as disclosed in WO
97/12615, 15-LO inhibitors as disclosed in WO 97/12613, isothiazolones as disclosed in WO 96/38144, and 15-LO inhibitors as disclosed by Sendobry et al "Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties", Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al, "15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease", Current Pharmaceutical Design, 1999, 5, 11-20.

[0175] The compounds of the invention and the hypolipidemic agent may be employed together in the same oral dosage form or in separate oral dosage forms taken at the same time.

[0176] The compositions described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination.
[0177] The preferred hypolipidemic agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin.

[0178] The other type of therapeutic agent which may be optionally employed with the DPP-IV inhibitors of the invention may be 1, 2, 3 or more of an anti-obesity agent including a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta drug, an anorectic agent and/or a fatty acid oxidation upregulator.

[0179] The beta 3 adrenergic agonist which may be optionally employed in combination with a compound of the invention may be AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S.
patents No.
5,541,204, No. 5,770,615, No. 5,491,134, No. 5,776,983 and No. 5,488,064, with AJ9677, L750,355 and CP331648 being preferred.

[0180] The lipase inhibitor which may be optionally employed in combination with a compound of the invention may be orlistat or ATL-962 (Alizyme), with orlistat being preferred.

[0181] The serotonin (and dopamine) reuptake inhibitor which may be optionally employed in combination with a compound of the invention may be sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramine and topiramate being preferred.

[0182] The thyroid receptor beta compound which may be optionally employed in combination with a compound of the invention may be a thyroid receptor ligand as disclosed in W097/21993 (U. Cal SF), W0099/00353 (KaroBio) and GB98/284425 (KaroBio), with compounds of the KaroBio applications being preferred.

[0183] The anorectic agent which may be optionally employed in combination with a compound of the invention may be dexamphetamine, phentermine, phenylpropanolamine or mazindol, with dexamphetamine being preferred.

[0184] The fatty acid oxidation upregulator which may be optionally employed in combination with the compound of the invention can be famoxin (Genset).

[0185] The various anti-obesity agents described above may be employed in the same dosage form with the compound of the invention or in different dosage forms, in dosages and regimens as generally known in the art or in the PDR.

[0186] The infertility agent which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be 1, 2, or more of clomiphene citrate (Clomid(&, Aventis), bromocriptine mesylate (Parlodel , Novartis),LHRH analogs, Lupron (TAP
Pharm.), danazol, Danocrine (Sanofi), progestogens or glucocorticoids, which may be employed in amounts specified in the PDR.

[0187] The agent for polycystic ovary syndrome which may be optionally employed in combination with the DPP-1V inhibitor of the invention may be 1, 2, or more of gonadotropin releasing hormone (GnRH), leuprolide (Lupron ), Clomid , Parlodel , oral contraceptives or insulin sensitizers such as PPAR agonists, or other conventional agents for such use which may be employed in amounts specified in the PDR.

[0188] The agent for treating growth disorders and/or frailty which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be 1, 2, or more of a growth hormone or growth hormone secretagogue such as MK-677 (Merck), CP-424,391 (Pfizer), and compounds disclosed in USP 6,518,292 B 1, as well as selective androgen receptor modulators (SARMs) which may be employed in amounts specified in the PDR, where applicable.

[0189] The agent for treating arthritis which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be 1, 2, or more of aspirin, indomethacin, ibuprofen, diclofenac sodium, naproxen, nabumetone (Relafen , SmithKline Beecham), tolmetin sodium (Tolectin , Ortho-McNeil), piroxicam (Feldene , Pfizer), ketorolac tromethamine (Toradol , Roche), celecoxib (Celebrex , Searle), rofecoxib (Vioxx , Merck) and the like, which may be employed in amounts specified in the PDR.

[0190] Conventional agents for preventing allograft rejection in transplantation such as cyclosporin, Sandimmune (Novartis), azathioprine, Immuran (Faro) or methotrexate may be optionally employed in combination with the DPP-IV inhibitor of the invention, which may be employed in amounts specified in the PDR.

[0191] Conventional agents for treating autoimmune diseases such as multiple sclerosis and immunomodulatory diseases such as lupus erythematosis, psoriasis, for example, azathioprine, Immuran, cyclophosphamide, NSAIDS such as ibuprofen, cox 2 inhibitors such as Vioxx and Celebrex, glucocorticoids and hydroxychloroquine, may be optionally employed in combination with the DPP-IV inhibitor of the invention, which may be employed in amounts specified in the PDR.

[0192] The AIDS agent which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be a non-nucleoside reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a protease inhibitor and/or an AIDS adjunct anti-infective and may be 1, 2, or more of dronabinol (Marinol , Roxane Labs), didanosine (Videx , Bristol-Myers Squibb), megestrol acetate (Megace(b, Bristol-Myers Squibb), stavudine (Zerit , Bristol-Myers Squibb), delavirdine mesylate (Rescriptor , Pharmacia), lamivudine/zidovudine (Combivir.TM., Glaxo), lamivudine (Epivir.TM., Glaxo), zalcitabine (Hivid , Roche), zidovudine (Retrovir , Glaxo), indinavir sulfate (Crixivan , Merck), saquinavir (Fortovase.TM., Roche), saquinovir mesylate (Invirase(ID, Roche), ritonavir (Norvir , Abbott), nelfinavir (Viracept , Agouron).

[0193] The above anti-AIDS agents may be employed in amounts specified in the PDR.
[0194] The agent for treating inflammatory bowel disease or syndrome which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be 1, 2, or more of sulfasalazine, salicylates, mesalamine (Asacol , P&G) or Zelmac , (Bristol-Myers Squibb), which may be employed in amounts specified in the PDR or otherwise known in the art.

[0195] The agent for treating osteoporosis which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be 1, 2, or more of alendronate sodium (Fosamax , Merck, tiludronate (Skelid , Sanofi), etidronate disodium (Didronel , P&G), raloxifene HC1(Evista , Lilly), which may be employed in amounts specified in the PDR.

[0196] In carrying out the methods of the invention, a pharmaceutical composition may be employed containing the compounds of the invention, with or without another antidiabetic agent and/or other type therapeutic agent, in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration. The compounds can be administered to mammalian species including humans, monkeys, dogs, etc. by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations. The dose for adults is preferably between 10 and 1,000 mg per day, which can be administered in a single dose or in the form of individual doses from 1-4 times per day.

[0197] A typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL
of physiological saline, to produce an injectable preparation.

[0198] DPP-IV inhibitor activity of the compounds of the invention may be determined by use of an in vitro assay system which measures the potentiation of inhibition of DPP-IV.
Inhibition constants (Ki values) for the DPP-IV inhibitors of the invention may be determined by the method described below.

Pharmaceutical Compositions [0199] Pharmaceutical compositions containing a compound of the invention of the invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19th Ed., 1995. The compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.

[0200] Typical compositions include a compound of the invention which inhibits the enzymatic activity of DPP-IV or a pharmaceutically acceptable basic addition salt or prodrug or hydrate thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.

[0201] The pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
[0202] The route of administration may be any route, which effectively transports the active compound of the invention which inhibits the enzymatic activity of DPP-IV to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.

[0203] If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

[0204] For nasal administration, the preparation may contain a compound of the invention which inhibits the enzymatic activity of DPP-IV, dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.

[0205] For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

[0206] Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A
syrup or elixir can be used in cases where a sweetened vehicle can be employed.

[0207] A typical tablet that may be prepared by conventional tabletting techniques may contain:

Core:

Active compound (as free compound or salt thereof) 250 mg Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcryst. (Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium stearate Ad.
Coating:
HPMC approx. 9 mg *Mywacett 9-40 T approx. 0.9 mg *Acylated monoglyceride used as plasticizer for film coating.

[02081 The compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of the various diseases as mentioned above, e.g., type II diabetes, IGT, IFG, obesity, appetite regulation or as a blood glucose lowering agent, and especially type II
diabetes. Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.

[02091 The compounds of the invention are effective over a wide dosage range.
For example, in the treatment of adult humans, dosages from about 0.05 to about 1000 mg, preferably from about 1 to about 500 mg, per day may be used. A typical dosage is about 10 mg to about 500 mg per day. In choosing a regimen for patients it may frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.

[02101 Generally, the compounds of the invention are dispensed in unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.

[0211] Usually, dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.05 mg to about 1000 mg, preferably from about 0.5 mg to about 250 mg of the compounds admixed with a pharmaceutically acceptable carrier or diluent.

[0212] The invention also encompasses prodrugs of a compound of the invention which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of a compound of the invention which are readily convertible in vivo into a compound of the invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H.
Bundgaard, Elsevier, 1985.

[0213] The invention also encompasses active metabolites of a compound of the invention.

[0214] Thus, another aspect of the invention provides pharmaceutical compositions of the compounds of the invention, alone or in combination with another type antidiabetic agent and/or other type therapeutic agent.

[0215] In one example, the embodiments of the invention are represented by:

[0216] Pharmaceutical compositions comprising, as an active ingredient, at least one compound of the invention which inhibits the enzymatic activity of DPP-IV or a pharmaceutically acceptable salt or prodrug or hydrate thereof together with a pharmaceutically acceptable carrier or diluent;

[0217] Pharmaceutical compositions comprising a compound of the invention as described herein, in free form or in pharmaceutically acceptable acid addition salt form, together with at least one pharmaceutically acceptable carrier or diluent;

[0218] Pharmaceutical compositions comprising a compound of formula VA, VB, or a mixture thereof and a pharmaceutically acceptable carrier or diluent;

[0219] Pharmaceutical compositions comprising:

a. a substantially pure preparation of a compound of formula VB as described herein; and b. a pharmaceutically acceptable carrier or diluent;

[0220] Methods of making a pharmaceutical composition comprising mixing a substantially pure preparation of a compound of formula VB with a pharmaceutically acceptable carrier or diluent;

[0221] Methods of making a pharmaceutical composition of a compound described herein wherein the pharmaceutically acceptable carrier or diluent is suitable for oral administration;

[0222] Methods of making a pharmaceutical composition of a compound described herein suitable for for oral administration further comprising the step of formulating the composition into a tablet or capsule;

[0223] Methods of making a pharmaceutical composition of a compound described herein wherein the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration;

[0224] Methods of making a pharmaceutical composition of a compound described herein suitable for parenteral administration further comprising the step of lyophilizing the composition to form a lyophilized preparation;

[0225] Pharmaceutical compositions for the treatment, prevention or control of atherosclerosis, comprising: (1) a compound of the invention, (2) an HMG-CoA
reductase inhibitor, and (3) a pharmaceutically acceptable carrier;

[0226] Pharmaceutical compositions, comprising:
a) A compound of the invention;
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) a-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) PPARa agonists, (v) PPARa/y dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterol acyltransferase inhibitors, and (viii) anti-oxidants;

xii) PPAR8 agonists;
xiii) Anti-obesity compounds;
xiv) An ileal 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.

[0227] Pharmaceutical combinations comprising a compound of the invention, 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.

[0228] Pharmaceutical combinations comprising a compound of the invention and an antidiabetic agent;

[0229] Pharmaceutical combinations comprising a compound of the invention and an antidiabetic agent wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR y agonist, a PPAR a/y dual agonist, an 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;

[0230] Pharmaceutical combinations comprising a compound of the invention and an antidiab tic agent wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, GI -262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, APR-H039242, GW-409544, KRP297, AC2993, Exendin-4 or its synthetic version exenatide, LY307161, NN221 1, and/or LY315902;

[0231] Pharmaceutical combinations comprising a compound of the invention and an antidiabetic agent wherein the compound is present in a weight ratio to the antidiabetic agent within the range from about 0.01 to about 100:1;

[0232] Pharmaceutical combinations comprising a compound of the invention and an antidiabetic agent 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;

[0233] Pharmaceutical combinations comprising a compound of the invention and an anti-obesity agent wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol;

[0234] Pharmaceutical combinations comprising a compound of the invention and a lipid-modulating agent 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;

[0235] Pharmaceutical combinations comprising a compound of the invention and a lipid-modulating agent 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;

[0236] Pharmaceutical combinations comprising a compound of the invention and a lipid-modulating agent wherein the compound is present in a weight ratio to the lipid-modulating agent within the range from about 0.01 to about 100:1;

[0237] Pharmaceutical combinations comprising a compound of the invention 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.
[0237.0001] The invention relates to a compound of the formula (VI):

HN R "
N
b N a H
~B--_ R
O
R2 (VI), or any pharmaceutically acceptable salt thereof, or any solvate thereof;
wherein:
R' and R2 independently or together are -OH, a hydroxyl bearing 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;
Rx is hydrogen or a substituted or unsubstituted (CI-8) alkyl, (C2.8) alkenyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, or heterocyclylalkyl group; and the wavy lines at asymmetric carbons Ca and Cb independently indicate for each asymmetric carbon an R configuration, an S configuration, or a mixture of both configurations such that all stereoisomers and all stereomeric mixtures are included.

Methods For Measuring Activity 10238] The following methods were used to measure the activities of the compounds of the invention which inhibit the enzymatic activity of DPP-IV. The compounds of the invention are tested for their ability to inhibit the enzyme activity of purified DPP-IV.
Briefly, the activity of DPP-IV is measured in vitro by its ability to cleave the synthetic substrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavage of Gly-Pro-pNA by DPP-IV

liberates the product p-nitroanilide (pNA), whose rate of appearance is directly proportional to the enzyme activity. Inhibition of the enzyme activity by specific enzyme inhibitors slows down the generation of pNA. Stronger interaction between an inhibitor and the enzyme results in a slower rate of generation of pNA. Thus, the degree of inhibition of the rate of accumulation of pNA is a direct measure of the strength of enzyme inhibition. The accumulation of pNA is measured spectrophotometrically. The inhibition constant, Ki, for each compound is determined by incubating fixed amounts of enzyme with several different concentrations of inhibitor and substrate.

[02391 Thus, DPP-IV enzyme activity was determined by a fluorometric assay with the substrate Gly-Pro-AMC which is cleaved by DPP-IV to release the fluorescent AMC
leaving group. Free AMC (7-amino-4-methyl coumarin) was measured using an excitation wavelength of 380 nm and an emission wavelength of 460 nm with a Victor-II
fluorescent reader. Stock solutions of DPP-IV (1 ng/ l, pH 8.0) and Gly-Pro-AMC substrate (400 M) in 25 mM Tris buffer (pH 8.0) were prepared separately. Test compounds were dissolved in DMSO or in 50 mM glycine buffer (pH 3.0). The assay was performed by diluting the DPP-IV stock (10 l) into 25 mM Tris buffer (77.5 l) followed by addition of test 104a compound (2.5 l) at 26 C. After 10-minutes substrate was added (10 l) and allowed to react for 20-minutes at 26 C before free AMC was measured. IC50 values were determined in triplicate, using a minimum of six different inhibitor concentrations. IC50 values were calculated using Nonlinear Regression Analysis (GraphPad, Prism, San Diego, CA).

[0240] To determine the DPP-IV activity in the plasma of mice dosed with test compounds, plasma (10 l) was diluted into 25 mM Tris buffer (80 l, pH 8.0) followed by addition of Gly-Pro-AMC stock solution (10 l) and the free AMC measured after minutes at 26 C. Analysis was performed as described above.

[0241] The Zucker Diabetic Fatty (ZDF) rat model can be used to investigate the effects of the compounds of the invention on both the treatment and prevention of diabetes as rats of this sub-strain are initially pre-diabetic although they develop severe type 2 diabetes characterized by increased HbAI c levels over a period of 6 weeks. The same strain can be used to predict the clinical efficacy of other anti-diabetic drug types. For example, the model predicts the potency and limited clinical efficacy of thiazolidinedione insulin sensitizer compounds.

[0242] The purification of porcine DPP-IV and the enzyme assay under steady state conditions are described in (1) Rahfeld, J. Schutkowski, M., Faust, J., Neubert., Barth, A., and Heins, J. (1991) Biol. Chem. Hoppe-Seyler, 372, 313-318; and (2) Nagatsu, T., Hino, M., Fuyamada, H., Hayakawa, T., Sakakibara, S., Nakagawa, Y., and Takemoto, T.
(1976) Anal. Biochem., 74, 466-476, respectively.

DEFINITIONS
[0236] The term "DPP-IV" denotes dipeptidyl peptidase IV (EC 3.4.14.5; DPP-IV), also known as "CD-26." DPP-IV cleaves a dipeptide from the N terminus of a polypeptide chain containing a proline or alanine residue in the penultimate position.

[0237] The term "diabetes and related diseases" refers to Type II diabetes, Type I
diabetes, impaired glucose tolerance, obesity, hyperglycemia, Syndrome X, dysmetabolic syndrome, diabetic complications, diabetic dyslipidemia, hyperinsulinemia, and the like.

[0238] The conditions, diseases and maladies collectively referred to as "diabetic complications" include retinopathy, neuropathy and nephropathy, and other known complications of diabetes.

[0239] The term "other type(s) of therapeutic agents" as employed herein refers to one or more antidiabetic agents (other than DPP-IV inhibitors of the invention), one or more anti-obesity agents, and/or one or more lipid-modulating agents (including anti-atherosclerosis agents), and/or one or more infertility agents, one or more agents for treating polycystic ovary syndrome, one or more agents for treating growth disorders, one or more agents for treating frailty, one or more agents for treating arthritis, one or more agents for preventing allograft rejection in transplantation, one or more agents for treating autoimmune diseases, one or more anti-AIDS agents, one or more anti-osteoporosis agents, one or more agents for treating immunomodulatory diseases, one or more agents for treating chronic inflammatory bowel disease or syndrome and/or one or more agents for treating anorexia nervosa.

[0240] The term "lipid-modulating" agent as employed herein refers to agents which lower LDL and/or raise HDL and/or lower triglycerides and/or lower total cholesterol and/or other known mechanisms for therapeutically treating lipid disorders.

[0241] The term "treatment" is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes administering a compound of the present invention to prevent the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.

[0242] The tern "beta cell degeneration" is intended to mean loss of beta cell function, beta cell dysfunction, and death of beta cells, such as necrosis or apoptosis of beta cells.
[0243] By "substantially pure" in relation to compounds of the invention such as, but not limited to, those of formula VA and VB, it is meant that one isomer or the other, including all enantiomers, diastereoisomers, solvates, hydrates, and pharmaceutically acceptable salts thereof, represents at least 90% by weight of the composition. In some embodiments one isomer represents at least 98% by weight of the composition.

10244] The term "boronic acid protecting group" as used herein refers to a moiety employed to block or protect the boronic acid functionality while reactions involving other functional sites of the compound are carried out. Typically, the boronic acid OH groups are protected as boronic acid esters derived from alchohols such as (+)-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; 1-butanol; and the like. As will be understood by those skilled in the art, alcohols having only a single hydroxy group, such as methanol, form diesters having the structure -B(OR)2 in which R is the organic moiety from the alcohol (e.g., -B(OMe)2). By comparison, diols such as pinacol form cyclic boronic diesters with -B(OH)2 in which the organic moiety (e.g., -C(Me)2-C(Me)2-)is attached to both oxygens.

[02451 The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures.
Commonly used N-protecting groups are disclosed in T.W. Greene, P. G. Wuts, "Protective Groups In Organic Synthesis, 3ta Ed." (John Wiley & Sons, New York (1999)), N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, a,a-di methyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like;
alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

[0246] The term "alkyl" or "(C1_12)alkyl", alone or in combination, refers to linear or branched chains and may include cyclic portions, having from 1-12 (the use of 1-12 herein implies each of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl, and the like.

[0247] The terms "(C1_10)alkyl", "(C1_$)alkyl" and "(C1.6)alkyl", alone or in combination,' refers to linear or branched chains and may include cyclic portions, having from 1-10, 1-8, or 1-6 carbon atoms, respectively, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl, and the like.
[0248] The term "(C1-4)alkyl", alone or in combination, refers to linear or branched chains and may include cyclic portions, having from 1-4 carbon atoms, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.

[0249] The terms "(C2_12)alkenyl" and "(C2_10)alkenyl", alone or in combination, refers to.a straight or branched, unsaturated hydrocarbon chain having from 2-12 or 2-10 carbon atoms, respectively, and at least one double bond, such as, but not limited to, vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl, n-hexenyl, and the like.

[0250] The terms "(C2_12)alkynyl" and "(C2_1o)alkynyl", alone or in combination, refers to an unsaturated hydrocarbon chain having from 2-12 or 2-10 carbon atoms, respectively, and at least one triple bond, such as but not limited to -C=CH, -C=C-CH3, -CH2C CH, -CH2-CH2-C=CH, -CH(CH3)C CH, and the like.

[0251] The terms "(C3_12)cycloalkyl" and "(C3_10)cycloalkyl" refers to one or more saturated cyclic hydrocarbons having from 3-12 or 3-10 carbon atoms, respectively, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.

[0252] The term "(C5_lo)cycloalkenyl" refers to a radical of one or more cyclic hydrocarbon having at least one double bond having from 5-10 carbon atoms such as, but not limited to, cyclopentenyl, cyclohexenyl, and the like.

[0253] The term "cycloalkylene" refers to a "cycloalkyl" group which has single bonds for attachment at two different carbon atoms.

[0254] The terms "(C1_6)alkylaminocarbonyl" and "di-(C1.6)alkylaminocarbonyl"
refer to straight or branched chain hydrocarbon groups having 1 to 6 carbon atoms connected to NC(=O). Exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like.

[0255] The term "(C1_6)alkylcarbonyl" refers to linear or branched chain and cyclic hydrocarbon groups having 1 to 6 carbon atoms connected to C(=O). Exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like.

[0256] The term (C3_s)cycloalkylcarbonyl refers to cyclic hydrocarbon groups having 3 to 8 carbon atoms connected to C(=O). Exemplary cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0257] The terms "(C1_lo)alkoxy", "(C1-8)alkoxy" and "(C1.6)alkoxy", alone or in combination, refers to "0" connected to alkyl, having linear or branched chains and may include cyclic portions, having from 1-10, 1-8 or 1-6 carbon atoms, respectively. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy include but are not limited to isoprpoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like.
Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0258] The term "aryloxy" refers to an aryl group bonded to 0.

[0259] The term "alkanoyl", alone or as part of another group, refers to alkyl linked to a carbonyl group.

[0260] The term "alkylene" refers to alkyl groups which have single bonds for attachment at two different carbon atoms.

[0261] The term "alkenylene" refers to alkenyl groups which have single bonds for attachement at two different carbon atoms.

[0262] The terms "alkynylene" refers to alkynyl groups which have single bonds for attachement at two different carbon atoms.

[0263] The term "aryl" refers to monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring systems having 6 to 14 carbon atoms in the ring portion. Examples of aryl groups include but are not limited to phenyl, naphthyl, biphenyl, anthracenyl, azulenyl, and the like.
Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems including 1,2,3,4-tetrahydro-naphthyl, indanyl and the like.

[0264] The term "heteroaryl" as used herein includes heterocyclic unsaturated ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur.
Examples of heteroaryl groups include but are not limited to furyl, thienyl, pyrrolyl, and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.

[0265] Examples of "aryl" and "heteroaryl" includes but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), fury] (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-l-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-l-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

[0266] The terms "arylalkenyl" and "arylalkynyl" alone or as part of another group refer to alkenyl and alkynyl groups as described above having an aryl substituent.

[0267] The terms "halogen" and "halo" refers to chloro, fluoro, bromo or iodo.
[0268] The term "alkylamino", "arylamino", or "arylalkylamino" alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.

[0269] The term "substituted amino" as employed herein alone or as part of another group refers to amino substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted with any of the groups as set out above. In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-l-piperazinyl, 4-arylalkyl-l-piperazinyl, 4-diarylalkyl-l-piperazinyl, 1-pyrrolidinyl, 1 -piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.

[0270] The terms "alkylthio", "arylthio" or "aralkylthio" alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.
[0271] The term "acyl" by itself or part of another group refers to an organic radical linked to a carbonyl group; examples of acyl groups include any of the groups attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl, and the like.

[0272] The term "cycloheteroalkyl" alone or as part of another group refers to a 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)g (where g is 1, 2 or 3). The above groups may include 1 to 4 substituents such as alkyl, halo, oxo, and the like. In addition, any of the cycloheteroalkyl rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

[0273] The term "cycloheteroalkylalkyl" alone or as part of another group refers cycloheteroalkyl groups as defined above linked through a carbon atom or heteroatom to a (CH2)r chain.

[0274] The term "heteroarylalkyl" or "heteroarylalkenyl" alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to a (CH2)r chain, alkylene or alkenylene as defined above.

[0275] The phrase "naturally occurring a-amino acid sidechain" refers to the moieties (sidechains) attached to the a-amino carbon in the following naturally occurring a-amino acids: glycine, alanine, 2-aminobutyric acid, valine, leucine, isoleucine, tert-leucine, serine, threonine, cysteine, asparagine, aspartic acid, glutamine, glutamic acid, phenylalanine, histidine, tryptophan, tyrosine, phenylglycine, lysine, methionine, and arginine. The side chains of these amino acids are well known in the art. For example, the a-amino acid sidechain of alanine is methyl; the sidechain of phenylalanine is benzyl; and the sidechain of tert-leucine is tert-butyl.

[0276] The term "polyhaloalkyl" refers to an "alkyl" group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF3CH2, CF3 or CF3CF2CH2.

[0277] The term "polyhaloalkoxy" refers to an "alkoxy" or "alkyloxy" group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF3CH2O, CF3O or CF3CF2CH2O.

[0278] The terms "polycyclic" and "polycycle" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls, heteroaryls and/or cycloheteroalkyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings." Fused rings that are joined through nonadjacent atoms, are also known as "bridged"
rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, trifluoromethyl, cyano, or the like.

EXAMPLES
[02791 A further detailed description of the invention is given with reference to the following non-limiting examples.

Example 1 Synthesis of (2R)-boroPro-(1S,2S,3R,5S)-pinanediol ester, hydrochloride (2) [02801 A flame dried round bottom flask equipped with a magnetic stir bar was charged with N-Boc-pyrrolidine (20 g, 117 mmol, 1 eq) and dry THE (60 mL) under a nitrogen atmosphere. The clear colorless solution was cooled to -78 C and a solution of s-BuLi (100 mL of a 1.4 M solution in cyclohexane, 140 mmol) was added slowly over a 30 minute period. The light orange colored solution was stirred at -78 C for 3 hours followed by treatment with B(OMe)3 (39 mL, 350 mmol) after which the cooling bath was removed and the clear colorless solution slowly warmed to 0 C. Upon reaching 0 C, the reaction was quenched with a small amount of water (-2 mL), allowed to warm to room temp then extracted into 2 N NaOH (250 mL) and backwashed with additional EtOAc (150 mL). The aqueous phase was acidified to pH 3 by the addition of 2 N HC1 and then extracted with EtOAc (3 x 120 mL). The organic extracts were combined and dried over Na2SO4 and concentrated to produce the free boronic acid (22.08 g, 103 mmol) as a sticky white solid in 88% yield. Without further purification the boronic acid was dissolved in tert-butyl methyl ether (150 mL) and with constant stirring (+)-pinanediol (17.5 g, 103 mmol) was added at room temperature. After 18 hr the ether was removed and the (+)-pinanediol boronic ester was purified by column chromatography (silica gel, 1:3 hexanes/EtOAc) to give a clear thick oil (26.84 g, 76.8 mmol, 76% yield, Rf = 0.6 using a 2:1 hexane/ethyl acetate eluant, made visual via 12 and/or PMA stain). Removal of the Boc protecting group was achieved by dissolving the oil in dry ether, cooling to 0 C in an ice bath and with constant stirring dry HCl (g) was bubbled into the solution for 10 minutes. After 2 hours a white precipitate developed in the flask and the ether and excess HCl were removed in vacuo to afford the racemic HC1 salt as a white solid. Crystallization and isolation of the desired isomer was performed by dissolving the HCl salt in a minimal amount of dichloromethane (250 mL) with gentle heating to facilitate a homogenous solution followed by continuous stirring for 8 hours to yield a fluffy white precipitate that was collected by vacuum filtration, dried and then dissolved in minimal 2-propanol (-200 mL) with gentle heating until homogenous. The alcoholic solution was stirred over night and the resulting white precipitate was collected by vacuum filtration affording isomerically pure 1 as a white solid. (7.0 g, 27 mmol, 23%
yield). 111 NMR (400 MHz, D20) S 4.28 (d, J= 8.0 Hz, 1H), 3.06 (m, 3H), 2.18 (m, 1H), 1.96 (m, 2H), 1.78 (m, 3 H), 1.62 (m, 2H), 1.21 (s, 3H), 1.05 (m, 5H), 0.84 (d, J=12 Hz, 2H), 0.71 (s, 2H), 0.62 (s, 3H).

Example 2 Synthesis Of Series A Compounds: (2R)-1-(2-Cyclopentylamino-acetyl)-boroPro-OH
Step 1: (2R)-1-(2-Chloroacetyl)-boroPro-(1S,2S,3R,5S)-pinanediol ester (3A).
[0281] To a solution of 2 (36.7 g, 129.3 mmol) dissolved in dry CH2Cl2 (200 mL) cooled to 0 C was added chloroacetyl chloride (12.34 mL, 155.2 mmol) under a blanket of N2. To this was slowly dripped 4-methylmorpholine (42.4 mL, 182 mmol) to give an almost clear light orange solution that was warmed to room temp. After 30 minutes the solution was cooled again to 0 C and 200 mL of a 0.2 N solution of HCl was added and the organic layers separated, dried and concentrated to give a dark red oil that was a single spot by TLC
(2:1 hexfEtOAc, Rf = 0.22, made visual via 12 and/or PMA stain) and was used in the next step without further purification. 'H NMR (400 MHz, CDCl3) 50.80 (s, 3 H), 1.25 (m, 1 H), 1.26 (s, 3 H), 1.42 (s, 3H), 1.75-1.96 (m, 4 H), 1.98-2.10 (m, 3 H), 2.12-2.20 (m, I H), 2.29-2.35 (m, I H), 3.12-3.16 (m, 1 H), 3.47-3.53 (m, 1 H), 3.58-3.63 (m, 1 H), 3.97-4.05 (q, 2 H), 4.30-4.32 (d, 1 H).

Step 2: (2R)-1-(2-Cyclopentylamino-acetyl)-boroPro-(1S,2S,3R,5S)-pinanediol ester (3B)-102821 Compound 3A was dissolved in dry THE (-150 mL) followed by addition of K2C03 (35 g) and cooled to 0 C before addition of cyclopentylamine (21.93 g, 258 mmol).
The reaction mixture was then allowed to warm to room temperature and stirred overnight.
T
TLC indicated all starting material was consumed. The mixture was filtered through a celite m and silica pad, washed with 5% MeOH in CH2C12 (200 mL) and concentrated to yield a sticky, light orange solid. The red sticky solid was dissolved in CH2C12 (150 mL) followed by addition of Et2O (-200 mL) and the solution was stirred overnight. The resulting milky white solution was then filtered and the precipitate was washed with cold EtOAC (2 x 60 mL) and hexane (2 x 50 mL) and dried to give 3B (28.92 g, 120.5 mmol) as a fluffy white solid. The dark red mother liquor filtrate was concentrated and subjected to the previous recrystallization conditions to obtain a second crop of 3B (6.17 g, 25.7 mmol) for a combined overall yield of 3B (35.09 g, 93.8 mmol) of 73% yield. Rf = 0.45 (10%
MeOH in CH2C12). 'H NMR (400 MHz, CDC13) S 4.18 (d, 1H), 3.95 (d, J= 16 Hz, 1H), 3.6 (d, J= 16 Hz, 1H), 3.46 (m, 3H), 2.74 (m, 1H), 2.36 (m, 1H), 2.16 (m, 2H), 2.04 (m, 4H), 1.90 (s, 1H), 1.74 (m, 6H), 1.61 (s, 1H), 1.46 (m, 2H), 1.34 (s, 3H), 1.30 (s, 3H), 0.88 (s, 3H).

Step 3: (2R)-1-(2-Cyclopentylamino-acetyl)-boroPro-OH (4) [02831 To a solution of 3B (40.59 g, 108.5 mmol) in H2O (200 mL, adjusted to pH 2 by addition of 2 N HCl) was added hexane (200 mL) and phenyl boronic acid (13.37 g, 109.5 mmol) and the bi-phasic mixture was stirred vigorously. The hexane layer was periodically removed and replaced with fresh hexane 6 times over a 24-hour period. The TM
aqueous layer was separated and applied to a Dowex 50-X2-100 ion exchange column (H+
form) and eluted with water until the eluate was neutral. Elution with aqueous ammonium hydroxide (2 wt %) followed by lyophilization of the appropriate fractions yielded 4 (23.91 g, 99.6 mmol) as a white crystalline solid in a 92% yield. 4-TFA salt 'H NMR
(400 MHz, D20) S 3.88 (dd, J= 8.0 Hz, 2H), 3.54 (m, 1H), 3.42 (m, 1H), 3.28 (m, 1H), 2.96 (m, 1H), 1.96 (m, 4H), 1.85 (m, 2H), 1.63 (m, 7H); MS (ESI) m/z 223 (M+H-H2O)+.

Example 3 Synthesis of 1-(2-Cyclopropylamino-acetyl)-pyrrolidine-(2R)-boronic acid.
(A2):
(02841 The title compound was prepared according to the procedure of Example 2 using appropriate starting materials. 'H NMR (1)20) 6 4.08 (dd, J = 12 Hz, 2 H), 3.54 (m, I H), 3.38 (m, I H), 3.07 (m, I H), 2.26 (m, I H), 2.09 (m, 2H), 1.94 (m, I
H), 1.71 (m, I H), 0.88 (s, 4H); MS (ESI) m/z 195.13 (MH+-H2O).

Example 4 Synthesis of 1-12-(3-Hydroxy-adamantan-1-ylamino)-acetyil pyrrolidine-(2R)-boronic acid (A3):

[02851 The title compound was prepared according to the procedure of Example 2 using appropriate starting materials. 'H NMR (D20) S 3.94 (d, J= 8 Hz, 2H), 3.54 (m, 1H), 3.40 (m, 1H), 3.09 (m, 1H), 2.41 (s, 2H), 2.09 (m, 3H), 1.93 (m, 2H), 1.87 (m, 7H), 1.71 (m, 6H), 1.56 (m, 2 H); MS (ESI) m/z 305.21 (MH+-H20).

Example 5 Synthesis of 1-(5R-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (6):
Step 1: N-Boc-5-phenylPro-(2R)-boroPro-(1S,2S,3R,5S)-pinanediol ester (5):

[0286] To an ice-cooled (0 C) solution of N-Boc-5-phenyl-Pro-OH (0.84 mmol) in dry CH2C12 was added EDAC (174 mg, 0.91 mmol) and HOBt (105 mg, 0.775 mmol). The reaction was stirred at 0 C for 15-minutes and then 2 (200 mg, 0.7 mmol) and N-methyl morphiline (0.25 mL, 2.1 mmol) was added and the reaction was slowly warmed to room temperature and the reaction continued for 8 hours. The coupling reaction was then quenched with the addition of NaHCO3 (10 mL), extracted into EtOAc (2 x 15 mL), washed with brine (15 mL), dried over Na2SO4i concentrated and further purified via column chromatography (silica gel, eluted with a gradient of EtOAc in hexanes, 30-50%) to afford 5 (320 mg, 0.62 mmol, 88%) as an off-white solid.

Step 2: 1-(5R-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (6):
[0287] An ice-cooled solution of 5 (320 mg, 0.62 mmol) in dry ether was saturated with dry HCl (g) and allowed to stir for 1-hour. The solution was then concentrated under vacuum to afford a sticky white solid that was taken up in H2O (10 mL, adjusted to pH 2 by addition of 2 N HC1) and hexane (10 mL) and phenyl boronic acid (74 mg, 0.62 mmol) and the bi-phasic mixture was stirred vigorously. The hexane layer was periodically removed and replaced with fresh hexane 6 times over a 24-hour period. The aqueous layer was separated and applied to a Dowex 50-X2-100 ion exchange column (H+ form) and eluted with water until the eluate was neutral. Elution was continued with aqueous ammonium hydroxide (2 wt%) and the appropriate fractions were lyophilized to afford the free boronic acid B1 (76 mg, 0.26 mmol) as an amorphous white solid. 'H NMR (D20) b 7.46 (m, 5H), 3.65 (m, 1H), 3.44 (m, I H), 3.04 (m, I H), 2.54 (m, I H), 2.38 (m, 2H), 2.20 (m, 1H), 2.06 (m, 2H), 1.86 (m, 1H), 1.66 (m, 1H); MS (ESI) m/z 271 (MH+-H2O).

Example 6 Synthesis of 1-(Piperidine-2S-carbonyl)-pyrrolidin-(2R)-boronic acid (B2):
[0288] The title compound was prepared according to the procedure of Example 5 using appropriate starting materials. IH NMR (D20) 8 4.07 (m, 1H), 3.61 (m, 1H), 3.34 (m, 2H), 2.94 (m, 2H), 2.16 (m, 1H), 2.03 (m, 2H), 1.87 (m, 3H), 1.56 (m, 4H); MS
(ESI) m/z 209 (MH+-H2O).

Example 8 Synthesis of 1-(2,3-Dihydro-1H-indole-2S-carbonyl)-pyrrolidine-(2R)-boronic acid [0289] The title compound was prepared according to the procedure of Example 5 using appropriate starting materials. 1H NMR (D20) 6 4.54 (m, 1H), 3.73 (m, 1H), 3.58 (m, 1H), 3.34 (m, 1H), 2.48 (m, 1H), 2.37 (m, 1H), 2.06 (m, 3H), 1.83 (m, 3H), 1.58 (m, 4H), 1.32 (m, 4H); MS (ESI) m/z 249 (MH+-H20).

Example 9 Synthesis of 1-(4S-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (B

[0290] The title compound was prepared according to the procedure of Example 5 using appropriate starting materials. 'H NMR (D20) 8 7.34 (d, J = 13 Hz, 2H), 7.27 (m, 3H), 4.79 (m, 1H), 3.83 (m, 1H),3.59 (m, 1H), 3.34 (m, 2H), 3.06 (m, 1H), 2.53 (m, 2H), 2.08 (m, 2H) 1.77 (m, 1H), 1.64 (m, 1H); MS (ESI) m/z 271 (MH+-H2O).

Example 10 Synthesis of (2R)-1-{2-[(3S)-Pyrrolidin-3-ylamino]-acetyl}-pyrrolidine-2-boronic acid (8) BO ~Bo Boc rO
CI\ O < - .NH
\O K2CO3, THE ON" 7 Boc PhB(OH)2, H3O+, Hexanes ,OH
~i- B
OH
O
AH

Step 1: (2R)-1-{2-[(3S)-1-tert-Butoxycarbonyl-pyrrolidin-3-ylamino]-acetyl}-pyrrolidine-2-boronic acid (1S,2S,3R,5S)-pinanediol ester (7) [02911 The protocol described above for the synthesis of 3B was followed employing (3S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester in place of cyclopentylamine.
Compound 7 was obtained as an oil.

(2R)-1-{2-[(3S)-Pyrrolidin-3-ylamino]-acetyl}-pyrrolidine-2-boronic acid (8) [0292] The protocol described above for the deprotection of the pinanediol boronic ester 3B (Example 2, Step 3) was applied to 7. Compound 8 was obtained as a white solid.
8-TFA salt. 1H-NMR (500 MHz, CD3OD) S 4.12 (m, 3H), 3.76 (m, 1H), 3.54 (m, 3H), 3.41 (m, 2H), 3.26 (m, 1H), 2.55 (m, 1H), 2.28 (m, 1H), 2.05 (m, 3H), 1.74 (m, 1H).
MS m/z (rel intensity) 241 (M) (27), 224 (100), 209 (73), 155 (47).

Example 11 Synthesis of (2R)-1-{2-1(3R)-Pyrrolidin-3-ylaminol-acetyl}-pyrrolidine-2-boronic acid CI 0 Boc rO
C
0 K2CO3, THE ON- NH 9 Boc PhB(OH)2, H30+, Hexanes N B %
OH
O
~NH

Step 1: (2R)-1-{2-[(3R)-1-tert-Butoxycarbonyl-pyrrolidin-3-ylamino]-acetyl}-pyrrolidine-2-boronic acid (1S,2S,3R,5S)-pinanediol ester (9).

[0293] The protocol described above for the synthesis of 3B was followed employing (3R)-3-amino-pyrrolidine-l-carboxylic acid tert-butyl ester in place of cyclopentylamine.
Compound 9 was obtained as an oil. MS mlz (rel intensity) 476 (M + 1)+ (100), 376 (74), 239 (38), 224 (67), 155 (55).

Step 2: (2R)-1-{2-[(3R)-Pyrrolidin-3-ylamino]-acetyl}-pyrrolidine-2-boronic acid (10) [0294] The protocol described above for the deprotection of the pinanediol boronic ester 3B (Example 2, Step 3) was applied to 9. Compound 10 was obtained as a white solid.
10=TFA salt. 'H-NMR (500 MHz, CD3OD) b 4.13 (m, 1H), 4.08 (bs, 2H), 3.76 (dd, J=
13.0, 8.0 Hz, I H), 3.55 (m, 3H), 3.41 (m, 2H), 3.27 (m, I H), 2.53 (m, I H), 2.26 (m, 1H), 2.10 (m, 2H), 1.99 (m, 1H), 1.75 (m, 1H). MS m/z (rel intensity) 224 (M-17) (100), 206 (25), 180 (29), 155 (70).

Example 12 Synthesis of Series B Compounds: (2R)-1-[(2S)-Azetidine-2-carbonyll-boroPro-OH

Step 1: (2R)-1-[(2S)-1-tert-Butoxycarbonyl-azetidine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (11) [0295] To a solution of (2S)-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester (169 mg, 0.8 mmol) in CH2C12 (5 mL) was added HOBt (105 mg, 0.8 mmol) and EDC (174 mg, 0.9 mmol). The reaction solution was then cooled to 0 C in an ice bath for 10 min followed by sequential addition of 2 (200 mg, 0.7 mmol) and NMM (0.25 mL, 2.1 mmol). The reaction solution was allowed to warm up to room temperature and stirred overnight. The reaction mixture was diluted with additional CH2C12 (5 mL), washed with NaHCO3 (2 x 10 mL), 0.1 M aqueous HCl (5 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The resulting oily residue was purified by column chromatography (silica gel, solvent eluent gradient from 1:4 EtOAc/hexane to 1:2 EtOAc/hexane) to afford 11 as a clear viscous oil.

Step 2: (2R)-1-[(2S)-Azetidine-2-carbonyl]-boroPro-OH (12) [0296] A solution of compound 11 in 4N HCl in dioxane was stirred at room temperature for 4 h. The solvent was removed under vacuum and the resulting residue was submitted to the pinanediol ester deprotection protocol described above for the preparation of boronic acid 4. Compound 12 was obtained as a white solid. 12-TFA salt'H-NMR (500 MHz, D2O) S 5.23 (m, I H), 4.11 (m, I H), 3.90 (m, I H), 3.42 (m, I H), 3.18 (m, I H), 2.99 (m, 1H), 2.79 (m, 1H), 2.55 (m, 1H), 1.92 (m, 3H), 1.63 (m, 1H). MS m/z (rel intensity) 199 (M + 1)+ (7), 181 (M-17) (100), 152 (53).

Example 13 Synthesis of Series C Compounds: (2R)-1-[(2S,4S)-4-Amino-pyrrolidine-2-carb onyll-boroPro-OH (15) Step 1: (2R)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-benzyloxycarbonylamino-pyrrolidine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (13) [0297] The protocol described for the synthesis of 11 was followed employing (2S,4S)-Fmoc-4-amino-l-boc-pyrrolidine-2-carboxylic acid (628 mg, 2.2 mmol) in place of azetidine-1,2-dicarboxylic acid 1-tert-butyl ester. Compound 13 was obtained as a clear colorless oil that was used in the next step without further purification.

Step 2: (2R)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-amino-pyrrolidine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (14) [0298] To a solution of 13 dissolved in DCM (10 ml) was added diethyl amine (5 ml) at once and the resulting colorless solution was stirred overnight at room temperature. The reaction was evaporated to dryness and additional DCM was added followed by evaporation once again to dryness. The resulting oil was purified by column chromatography (silica gel, eluted with a gradient of 2.5 to 5% MeOH in DCM, made visible by I2 and/or PMA) to give 14 as a clear colorless oil in a 48% yield over 2 steps.

Step 3: (2R)-1-[(2S,4S)-4-Amino-pyrrolidine-2-carbonyl]-boroPro-OH (15) [0299] The protocol described above for the N-Boc deprotection and pinanediol ester hydrolysis in the synthesis of compound 12 was applied to 14. Compound 15 was obtained as a white solid.15-TFA salt 'H-NMR (500 MHz, D20) S 4.42 (dd, 1H), 3.87 (m, 1H), 3.5 (dd, I H), 3.28 (m, 2H), 3.07 (m, I H), 2.73 (m, I H), 2.64 (m, I H), 1.86 (m, I H), 1.72 (br in, 2H), 1.55 (br in, 2H), 1.34 (m, 2H). MS m/z (rel intensity) 228 (M + 1) (55), 210 (M + 1 -H2O) (95).

Example 14 Synthesis of Series D Compounds: (2R)-1-[(2S)-4-Methanesulfonyl-piperazine-2-carbonyll-boroPro-OH (19) Step 1: (2R)-1-[(2S)-1-tert-Butoxycarbonyl-4-benzyloxycarbonyl-piperazine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (16) [03001 The protocol described above for the synthesis of 11 was followed employing (2S)-N-1-Boc-N-4-Cbz-2-piperazine carboxylic acid (1 g, 2.6 mmol) in place of azetidine-1,2-dicarboxylic acid 1-tert-butyl ester. Compound 16 (690 mg, 1.5 mmol) was obtained in 57% yield as an oil after silica gel column chormatography. MS m/z (rel intensity) 618 (M +
23)+ (17), 596 (M + 1)+ (100), 496 (38).

Step 2: (2R)-1-[(2S)-1-tert-Butoxycarbonyl-piperazine-2-carbonyl]-boroPro-(IS,2S,3R,5S)-pinanediol ester (17) [03011 To a solution of compound 16 (314 mg, 0.53 mmol) in MeOH (6 mL) was added Pd/C (40 mg). The mixture was stirred under a H2 atmosphere for 2 h.
Upon completion of the reaction, it was filtered through a plough of Celite. The solvents were removed under reduced pressure and the oily residue used in the next step without further purification. MS m/z (rel intensity) 462 (M + 1)+ (100), 406 (12), 362 (11).

Step 3: (2R)-1-[(2S)-1-tert-Butoxycarbonyl-4-methanesulfonyl-piperazine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (18) [0302] To a solution of compound 17 (214mg, 0.46 mmol) in CH2C12 (5 mL) cooled to 0 C was sequentially added N-methylmorpholine (204 L, 1.9 mmol) and methanesulfonyl chloride (72 L, 0.93 mmol). The reaction mixture was allowed to warm up to room temperature and stir for 3 hours. The reaction was then diluted with CH2C12 (6 ml) and water (6 mL). The organic phase was isolated and dried over MgSO4. After filtration, solvents were removed under reduced pressure. The oily residue was purified by column chromatography (silica gel) using a mixture of EtOAc/Hexanes as eluent.
Compound 18 (112 mg, 0.21 mmol) was obtained in 45% yield. MS m/z (rel intensity) 562 (M +
23)+ (14), 540 (M + 1) (100), 388 (75).

Step 4: (2R)-1-[(2S)-4-Methanesulfonyl-piperazine-2-carbonyl]-boroPro-OH (19) [0303] The protocol described above for the N-Boc deprotection and pinanediol ester hydrolysis in the synthesis of compound 12 was applied to 18 (112 mg, 0.21 mg).
Compound 19 (32 mg, 0.11 mmol) was obtained in 53% yield. 19=TFA salt 'H-NMR
(500 MHz, D20) 6 4.32 (dd, J= 11.0, 3.5 Hz, 1H), 4.05 (m, 1H), 3.93 (m, 1H), 3.77 (m, 1H), 3.60 (ddd, J= 10.5, 8.0, 2.5 Hz, I H), 3.47 (ddd, J= 12.5, 3.0, 3.0, I H), 3.35 (m, 2H), 3.16 (m, 2H), 3.02 (dd, J= 13.8, 11.3 Hz, 1H), 2.93 (s, 3H), 1.96 (m, 2H), 1.81 (m, 1H), 1.72 (m, 1H), 1.56 (m, 1H). MS m/z (rel intensity) 575 (12), 328 (M + 23)+ (6), 288 (M -17) (100).

Example 15 Synthesis of Series F Compounds: (2R)-1-{2-[(3S)-Pyrrolidin-3-ylaminol-acetyl}-boroPro-OH (21) Step 1: (2R)-1-{2-[(3S)-1-tert-Butoxycarbonyl-pyrrolidin-3-ylamino]-acetyl}-boroPro-(1S,2S,3R,5S)-pinanediol ester (20) [0304] The protocol described above for the synthesis of 3B was followed employing (3S)-3-amino-pyrrolidine- 1 -carboxylic acid tert-butyl ester in place of cyclopentylamine.
Compound 20 was obtained as an oil.

Step 2: (2R)-1-{2-[(3S)-Pyrrolidin-3-ylamino]-acetyl}-boroPro-OH (21) [0305] The protocol described above for the N-Boc deprotection and pinanediol ester deprotection of compound 12 was applied to 20. Compound 21 was obtained as a white solid. 21-TFA salt 'H-NMR (500 MHz, CD3OD) S 4.12 (m, 3H), 3.76 (m, 1H), 3.54 (m, 3H), 3.41 (m, 2H), 3.26 (m, 1H), 2.55 (m, 1H), 2.28 (m, 1H), 2.05 (m, 3H), 1.74 (m, 1H).
MS m/z (rel intensity) 241 (M) (27), 224 (100), 209 (73), 155 (47).

Example 16 [0306] Using the procedures illustrated above, the following compounds in the Table were prepared and characterized using liquid chromatography-mass spectroscopy (LC-MS).
TABLE

Compound Series Structure LC-MS
No.
22 A SOH 255 (M+1)(13), 237 \N^B (100) %
H
H O
NO
23 A /~ OH 227 (M+1)(10), 209 ~B (100) H~ OH
~N O
24 A ~ BOH 229 (M+1)(18), 211 (100) H OH

C~' OH 215 (M+1)(12),197 B' (100) N OH
H
N O

26 A 'OH 263 (M+1)(5), 245 (100) H OH
N 'A-0 27 A OH 277 (M+1)(4), 259 (100) B
H H
O
N O

Compound Series Structure LC-MS
No.
28 A N_,O H 283 (M+1)(22), 265 H OH ) 0-~ N ,-~O

OH 277 (M+1)(5), 259 (100) 29 A ` \ B

N OH

30 A OH 283 (M+1)(21), 265 B (100) OYHN

31 A .' -B OH 269 0(M+1)(16), 251 ~N l OH
N O
32 A H 0 HO OH 763 (6), 382 (M+1)(100) PhSOZN N~ \g-33 A 284 (M+1)(19), 266(100) \N

H 0 HO B`OH

34 A 651 (28), 326 (M+1)(57), 308 (100) N N
N
35 A 691 (22), 346 0 (M+1)(100), 328 (86) N~ N N

H 0 HO B_OH
36 A 703 (28), 352 (M+1)(18), 334 (100) 0 Na Nq N"-( H 0 HO B`OH
37 A ~ 691 (49), 346 (M+1)(14), BzN/\ N 328 (100) N
H 0 HO' B-OH

Compound Series Structure LC-MS
No.
38 A 0 703 (27), 352 (M+1)(3), N
B-OH 334(100) N~
H O HO
39 A 651 (48), 326 (13), 308 ND ."'N -~y N (100) H O HO B -OH
40 A 0 382 (M+1)(100), 364 (7) b "N N
H HO B-OH
41 A / 332 (M+1)(100), 314 N (10) N J'N~

2HCI H O HO'B-OH
42 A 531 (15), 266 (M-AcN/D N 17)(100) N
H OHO B-OH
43 A HO 271 (M+1)(100), 253 "a"'-~ N (16) N
H OHO B`OH
44 A H N N 270 (M+1)(100), 252 2 (17)
45 A HO 731 (42), 366 0 H ~`B-OH (M+1)(100), 348 (43) N~ N ) O HCI
46 A HCI N HO g-OH 791 (12), 396 (M+1) 0Nr N) O
47 A 721 (10), 361 (M+1)(100) ON N
H 0 HO=B-OH

Compound Series Structure LC-MS
No.
48 A /O 285 (M+1)(100), 267 N (12) N
H OHOB OH
49 A o 595 (48), 298 (M+1)(100), 280 (80) N
N
HCI H OHO B-OH
50 A 0 679 (29), 340 (100) aN"f"q HCI H 0 HdB_OH
51 A 719 (92), 360 (M+1)(65), BzN ,N^ N 342 (100) HCI
52 A 791 (35), 396 0 'N (M+1)(100), 378 (14) N' ~( HCI H O HO B-OH
i
53 A 595 (89), 298 (M+1)(44), ~N, q 280 (100) O
54 A 719 (72), 360 (M+1)(40), N 342 (100) BzN N
H O HO B`OH
55 A 731 (100), 366 ar(ND""N~ N (M+1)(34), 348 (86) H 0 HO B_OH
56 A 340 (M+1)(5), 322 (100), oN,- N--_I( q 304 (18)
57 A 731 (100), 366 C~r ~N~N (M+1)(52), 348 (94)
58 A 773 (33), 396 0 Nq (M+1)(100), 378 (16) N/'N~

Compound Series Structure LC-MS
No.
59 A 595 (93), 298 (M+1)(26), N NN 280 (100) O H O HO,B-OH
60 A 679 (100), 340 (98), 322 ~ II >N N (70)
61 A 346 (M+1)(100), NH N 328 (12) N
g-OH
OHO
62 B OH 249(M-17)major, N 267(M+1)minor OH

NH
63 B OH 289(M+1)minor, 271(M-01B 17)major OH
NH
64 B OH 289(M+1)minor, 271(M-N 17)major OH
O
NH
65 B OH 213(M-17), 425(2M+1) N i3 OH
S, O
\---NH
66 B CH 282(M-17) major OH
O
NH
H
67 257(M-17)major, f 275(M+1)minor HN N

O
HO' B, OH

Compound Series Structure LC-MS
No.
68 B OH 209(M-17)major, OlB 227(M+1)minor OH
co O
?NH~~
69 B 285(M-17)major, 303(M+1)minor ~ Nq "' 11 H OHO B-OH
70 B 209(M-1 7)major, N 227(M+1)minor N
H O HO,B-OH
71 B HQ 211 (M-1 7)major, 229(M+1)minor N
N
72 B 209(M-1 7)major, N 227(M+1)minor (cis)
73 B 0 209(M-1 7)major, N 227(M+1)minor HzN
B-OH
HO

IR,2R
74 B HCI 257(M-17)major, NHZ 275(M+1)minor HO
,<
-oH
N
75 B Q 209(M-17)major, 227(M+1)minor H2N,, B-OH
HO

1S,2S

Compound Series Structure LC-MS
No.
76 B 223(M-17)major, IIIIIIIIIL...NII 241(M+1)minor
77 B 223(M-17)major, N 241(M+1)minor NH2 O HOB B'OH
78 B 223(M-1 7)major, N 241(M+1)minor O
HOB B, OH
79 B 235(M-1 7)major, N 253(M+1)minor
80 B 235(M-17)major, 253(M+1)minor Ir 4
81 B HO, B,OH 235(M-17)major, O 253(M+1)minor No (1R, 2S)
82 B HO.. ,OH 251(M-17)major, O B 269(M+1)minor L*No L,?NH2 'OH
83 B NOH 235(M-17)major, 2 253(M+1)minor OH
N :1B-OH
84 B 233(M-17)major, N 251(M+1)minor
85 B e(NfII? 233(M-1 7)major, 251(M+1)minor _ INH
2 0 ~B-OH
O

Compound Series Structure LC-MS
No.
86 B 275(M-17)major, 293(M +1)minor N

,B-OH
H
87 B HO-i3 OH 311(M-17)major, 329(M+1)minor 70% 6-Ph, 30% 5-Ph Predominate isomer drawn
88 B 209(M-1 7)major, N 227(M+1)minor CN~~HO HO'B-OH
89 B o 3 434(M-1 7) major /
,o O N
N
Jr B-OH
90 B HO,B OH 446 (M+1)(23), 428 0 (100) H2N0~L

O=S=O
SO Me
91 B HO-B OH 350(M-17)major, 0 368(M+1)minor H2N No N
0=S=O

Compound Series Structure LC-MS
No.
92 B HO_e 434(M-17) major o N
0=S=O
93 B 346 (M+1)(100), 328 N (14) Nlj~ N
94 B ^ 511 (9), 256 (M+1)(100), NI , 238 (19) HN N ~ 11 H O HO,B-OH
95 B 201 (M+1)(100), 183 N (22) --N H OHO B-OH
96 B 255 (M+1)(100), 237 l-r N (100) N
H O HO B -OH
97 B OH 187(M+1)(5),169(100) H OH
N O
98 B243(M+1)(5), 225 (71) N D'..IB' OH
O
NH
99 B ~g'OH 225((15),200)43(M+1)(7), O
~NH
100 B HCO2H 223(M+23)(3),183(48) Me HZN t /N
0 Hd Compound Series Structure LC-MS
No.
101 B HCO2H 223(M+23)(4), 183(10) Me-1 / N

NH2 0 HO'B-OH
102 C H2N 228(M+1)(55), 210 (M-17)(95) N N
H 0 HO B_OH
103 C H 210(M-17)major, CN 228(M+1)minor N?
N:~r pHO' OH
H
104 C H2N 210(M-17)major, 228(M+1)minor N N

H O HdB OH
105 D OH 575 (12), 328 (M+23)(6), N B/ 288 (100) 0 O%
H
S\N 0 ~.NH.HCI
106 D OH 452 (M+1)(3),434 (100) Na H OH
CNJ O
N _ C, % OCF3
107 D 1 OH 368 (M+1)(2), 350 (100) H OH
O
N

O' O
108 D O SO/ OH 428 (M-17)(100) N
I " o OH
OS\N 0 NH.HCI
109 D F O OH 386 (M-17)(100) O N O%
H
iS,NO
F 0 LNH.HCI

Compound Series Structure LC-MS
No.
110 D OH 436 (M+1)(10), 418 B (100) % 0 O
~NH.HCI
111 D
0113 436 (M+1)(4), 418 (100) SOH

F # N OH
S, N
// ~O
IINH.HCI
112 D HO 627 (25), 332 (M+1)(10), B,OH 314 (100) CN( 0 "
TNH
N J formic acid salt 0--r
113 D OH 368(M+1)(38), 350 (100) OH
O FiN,. 0 CNH
HCI
114 D OH 350 (M-17)(100), 332 N' -B (22) S~ OH
OF N~ O
~NH
115 D O 332(M+1)(4), 314 (93) NH

/ ' II
116 D O 338(M+1)(3), 320 (98) NH

C N~ Nq HCI H O /B-OH
HO
117 D O 332(M+1)(27), 314 (100) NH

N H
B,
118 _dO,NR
HCI OHO OH
0 NH 338 (M+1)(21),320 (100) N
HCI H O /B`OH
HO

Compound Series Structure LC-MS
No.
119 D ( OH 727(8), 364 (M-17)(56) HzN OH
O
/SAO
120 D SOH 603(24), 302 (M-17)(73) B
HZN O
H
N
121 F 242 (M+1)(100), 224 HHO B-OH (19) HNJ
HCI
122 F HNa 242 (M+1)(100), 224 (9) N N
123 F O~j 300 (M+1)(11), 282 (100) HNa N

H HO ,B-OH
124 F 371(M-17)major, 389(M+1)minor NH

HNQ NQ
125 F 256 (M+1)(100) HNaN Nq H OHO B`OH
126 F 256 (M+1)(100), 238(8) HN N,, N4 HCI H OHO B`OH
127 F 256 (M+1)(100), 238(10) HN ,N^ /N

H O HO,B-OH
HCI

Compound Series Structure LC-MS
No.
128 F HNN 210(M-17)(major), 228 N-'~- N (M+1)(minor) O HO~B'OH
129 F HN/~ 256 (M+1)(100), 238 ~~\/N N (28) H OHO B_OH
HCI
130 G H 623 (28), 312 (M+1) O N~N N~ (100), 294 (30)
131 G i H 819 (20), 410 (100) IN
SI -a N
132 G 0--~ H 374 (M+1)(100), 356 N (67) O N
133 G
cl-~- H 759 (57), 380 O
N N (M+1)(100), 362 (64) Example 17 Dependence of Aminoboronate and Boronic Acid Forms of Inventive Compounds on PH
103071 A 0.4 M stock solution of Na2HPO4 was prepared by dissolving 909 mg of salt in 16 mL of D20. pH was adjusted to the desired value by dropwise addition of either 20% DC1 in D20 or 5% DCl in D20. The pH values were measured with a Fisher Scientific Accumet AB15 pH meter. Aliquots of the stock solution (4 mL) were prepared and 8 mg of compound 4 in the closed form (aminoboronate) were added to each one.
The scintillation vials were capped, sealed with parafilm and allowed to stand in the dark for three days. After this time pH was measured again. The open/closed (i.e., linear/cyclic) ratio of compound 4 isomers at each pH was determined by recording the corresponding 'H-NMR spectra in a Varian AS 500 MHz instrument and measuring the ratio of the integrals of the peaks at 2.90-2.95 ppm and 2.40-2.50 ppm characteristic of the open and closed forms, respectively. FIG. 1 shows that the closed form predominates at higher pHs such as physiological pH, whereas the open form predominates at lower pHs.

Example 18 [03081 The final compounds of Examples 1-16 were tested in vitro as described herein and each displayed an IC50 or K; of 10 p.M or less.

[03091 While the invention has been described and exemplified in sufficient detail for those skilled in this art to make and use it, various alternatives, modifications, and improvements will be apparent to those skilled in the art without departing from the spirit and scope of the claims.

[0310) [03111 The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of and "consisting of may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

[03121 In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described.

[03131 Other embodiments are set forth within the following claims.

Claims (41)

CLAIMS:
1. A compound of the formula (VI):

or any pharmaceutically acceptable salt thereof, or any solvate thereof;
wherein:
R1 and R2 independently or together are -OH, a hydroxyl bearing 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;

R x is hydrogen or a substituted or unsubstituted (C1-8) alkyl, (C2-8) alkenyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, or heterocyclylalkyl group; and the wavy lines at asymmetric carbons C a and C b independently indicate for each asymmetric carbon an R configuration, an S configuration, or a mixture of both configurations such that all stereoisomers and all stereoisomeric mixtures are included.
2. A cyclic isomer of the compound of formula VI of claim 1 having formula (VIb):

wherein R1, R2, and R x and variables defined therein, are as is specified in claim 1.
3. A mixture of the compound of formula VI of claim 1 and its cyclic isomer of formula VIb of claim 2.
4. The compound of claim 1 having the formula (VII):
or any pharmaceutically acceptable salt thereof, or any solvate thereof;
wherein the wavy lines at asymmetric carbons C a and C b independently indicate for each asymmetric carbon an R configuration, an S configuration, or a mixture of both configurations such that all stereoisomers and all stereoisomeric mixtures are included.
5. The cyclic isomer of the compound of formula VII of claim 4 having formula (VIIb):

wherein R1 and R2 and variables defined therein, are as is specified in claim 4.
6. A mixture of the compound of formula VII of claim 4 and its cyclic isomer of formula VIIb of claim 5.
7. The compound of claim 1 having the formula (VIII):
or any pharmaceutically acceptable salt thereof, or any solvate thereof;
wherein R x is methyl or ethyl, and the wavy lines at asymmetric carbons C a and C b independently indicate for each asymmetric carbon an R configuration, an S configuration, or a mixture of both configurations such that all stereoisomers and all stereoisomeric mixtures are included.
8. The cyclic isomer of the compound of formula VIII of claim 7 having formula (VIIIb):

wherein R1, R2, and R x and variables defined therein, are as is specified in claim 7.
9. A mixture of the compound of formula VIII of claim 7 and its cyclic isomer of formula VIIIb of claim 8.
10. A pharmaceutical composition comprising a compound of any one of claims 1-2, 4-5 and 7-8 or the mixture of any one of claims 3, 6 and 9 and a pharmaceutically acceptable carrier.
11. Use of the compound of any one of claims 1-2, 4-5 and 7-8 or the mixture of any one of claims 3, 6 and 9 for inhibiting dipeptidyl peptidase-IV.
12. Use of the compound of any one of claims 1-2, 4-5 and 7-8 or the mixture of any one of claims 3, 6 and 9 for the manufacture of a medicament for the treatment of a malcondition of a mammal that can be regulated or normalized via inhibition of dipeptidyl peptidase-IV.
13. The use of claim 12, wherein the malcondition is impaired glycemic control.
14. The use of claim 12, wherein the malcondition is diabetes.
15. The use of claim 12, wherein said medicament is adapted for administration with a therapeutically effective amount of a pharmaceutical agent that increases insulin secretion, increases insulin sensitivity, reduces the uptake of sugar from the gastrointestinal tract, enhances the effect of endogenous peptides or proteins that affect glycemic control, or provides a replacement for endogenous peptides or proteins that affect glycemic control, or any combination thereof.
16. Use of the compound of any one of claims 1-2, 4-5 and 7-8 or the mixture of any one of claims 3, 6 and 9 and one or more pharmaceutical agents, said pharmaceutical agent being:
a) another dipeptidyl peptidase-IV inhibitors;
b) an insulin sensitizer, said insulin sensitizer being(i) a PPAR agonist, (ii) a biguanide, or (iii) a protein phosphatase-1B inhibitor;
c) insulin or an insulin mimetic;
d) a sulfonylurea or another insulin secretagogue;
e) an .alpha.-glucosidase inhibitor;

f) a glucagons receptor agonist;
g) GLP-1, a GLP-1 mimetic, or a GLP-1 receptor agonist;
h) GLP-2, a GLP-2 mimetic, or a GLP-2 receptor agonists;
i) GIP, a GIP mimetic, or a GIP receptor agonist;
j) PACAP, a PACAP mimetic, or a PACAP receptor 3 agonist;
k) a cholesterol lowering agent, said cholesterol lowering agent being (i) a HMG-CoA reductase inhibitor, (ii) a sequestrant, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) a PPAR.alpha. agonist, (v) a PPAR.alpha./.gamma. dual agonist, (vi) an inhibitor of cholesterol absorption, (vii) an acyl CoA:cholesterol acyltransferase inhibitor, or (viii) an anti-oxidants;

l) a PPAR.delta. agonist;

m) an anti-obesity compound;
n) an ileal bile acid transporter inhibitor;
o) an anti-inflammatory agent;
p) G-CSF, a G-CSF mimetic, or a G-CSF receptor agonist; or q) EPO, a EPO mimetic, or a EPO receptor agonist, for the manufacture of a medicament for treating, controlling or preventing in a mammalian patient in need of such treatment one or more conditions, the condition being hyperglycemia, low glucose tolerance, insulin resistance, obesity, a lipid disorder, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, another inflammatory conditions, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X, ovarian hyperandrogenism, allograft rejection in transplantation, Type II diabetes, growth hormone deficiency, neutropenia, anemia, a neuronal disorder, tumor growth and metastasis, benign prostatic hypertrophy, gingivitis, hypertension, osteoporosis, or a condition that may be treated by inhibition of dipeptidyl peptidase-IV.
17. The use of claim 16, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
18. The use of claim 16, wherein the other inflammatory conditions is rheumatoid arthritis.
19. The use of claim 16, wherein the neurodegenerative disease is multiple sclerosis.
20. A pharmaceutical combination comprising the compound of any one of claims 1-2, 4-and 7-8 or the mixture of any one of claims 3, 6 and 9; and a pharmaceutical agent that increases insulin secretion, increases insulin sensitivity, reduces the uptake of sugar from the gastrointestinal track, enhances the effect of endogenous peptides or proteins that affect glycemic control, or provides a replacement for endogenous peptides or proteins that affect glycemic control, or any combination thereof.
21. The pharmaceutical combination of claim 20 wherein the pharmaceutical agent is an antidiabetic agent.
22. The pharmaceutical combination of claim 21 wherein the weight ratio of the compound of any one of claims 1-2, 4-5 and 7-8 or the mixture of any one of claims 3, 6 and 9 and the antidiabetic agent is from about 0.01:1 to about 100:1.
23. The pharmaceutical combination of claim 21, wherein the antidiabetic agent is glyburide, glipizide, nateglinide, repaglinide, metformin, pioglitazone, rosiglitazone, acarbose, miglitol, exenatide, insulin, glimepiride, glipyride, chlorpropamide, gliclazide, troglitazone, Gl -262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, KAD1129, APR-HO39242, GW-409544, KRP297, AC2993, Exendin-4, LY307161, NN2211, or LY315902 or any combination thereof.
24. The pharmaceutical combination of claim 20 wherein the pharmaceutical agent is suitable for treatment of a diabetes-associated condition.
25. The pharmaceutical combination according to claim 24 wherein the compound of any one of claims 1-2, 4-5 and 7-8 or the mixture of any one of claims 3, 6 and 9 is present in a weight ratio to the pharmaceutical agent from about 0.01:1 to about 100:1.
26. A compound of formula (VI) of claim 1, wherein the compound is of the formula (VI-RR) or any pharmaceutically acceptable salt thereof, or any hydrate or solvate thereof.
27. A cyclic isomer of the compound of claim 26 having formula (VI-RR-b):

or any pharmaceutically acceptable salt thereof.
28. A mixture of the compound of formula VI-RR as defined in claim 26 and the cyclic isomer of formula VI-RR-b as defined in claim 27.
29. A pharmaceutical composition comprising the compound of formula VI-RR of claim 26, the cyclic isomer of formula VI-RR-b of claim 27, or the mixture of claim 28, and at least one pharmaceutically acceptable carrier or diluent.
30. Use of the compound of formula VI-RR of claim 26, the cyclic isomer of formula VI-RR-b of claim 27, or the mixture of claim 28 for inhibiting dipeptidyl peptidase-IV.
31. Use of the compound of formula VI-RR of claim 26, the cyclic isomer of formula VI-RR-b of claim 27, or the mixture of claim 28 for the manufacture of a medicament for the treatment of a malcondition of a mammal that can be regulated or normalized via inhibition of dipeptidyl peptidase-IV.
32. The use of claim 31, wherein the malcondition is a metabolic disorder.
33. The use of claim 31, wherein the malcondition is diabetes.
34. The use of claim 31, wherein the medicament is adapted for administration with a therapeutically effective amount of an antidiabetic agent that increases insulin secretion, increases insulin sensitivity, reduces the uptake of sugar from the gastrointestinal tract, enhances the effect of endogenous peptides or proteins that affect glycemic control, or provides a replacement for endogenous peptides or proteins that affect glycemic control, or any combination thereof.
35. Use of the compound of formula VI-RR of claim 26, the cyclic isomer of formula VI-RR-b of claim 27 or the mixture of claim 28, and one or more pharmaceutical agents, the pharmaceutical agent being:

a) another dipeptidyl peptidase-IV inhibitor;
b) an insulin sensitizer, the insulin sensitizer, being (i) a PPAR agonist, (ii) a biguanide, or (iii) a protein phosphatase-1B inhibitor;
c) insulin, an insulin mimetic;
d) a sulfonylureas or another insulin secretagogue;
e) an .alpha.-glucosidase inhibitor;

f) a glucagons receptor agonist;

g) GLP-1, a GLP-1 mimetic, or a GLP-1 receptor agonist;
h) GLP-2, a GLP-2 mimetic, or a GLP-2 receptor agonist;
i) GIP, a GIP mimetic, or a GIP receptor agonist;
j) PACAP, a PACAP mimetic, or a PACAP receptor 3 agonist;

k) a cholesterol lowering agent, the cholesterol lowering agent being (i) a HMG-CoA reductase inhibitor, (ii) a sequestrant, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) a PPAR.alpha. agonist, (v) a PPAR.alpha./.gamma. dual agonist, (vi) an inhibitor of cholesterol absorption, (vii) an acyl CoA:cholesterol acyltransferase inhibitor, or (viii) an anti-oxidants;

l) a PPAR.delta. agonist;

m) an anti-obesity compound;

n) an ileal bile acid transporter inhibitor;
o) an anti-inflammatory agent;
p) G-CSF, a G-CSF mimetic, or a G-CSF receptor agonist; or q) EPO, a EPO mimetic, or a EPO receptor agonist, for the manufacture of a medicament for treating, controlling or preventing in a mammalian patient in need of such treatment one or more conditions, the condition being hyperglycemia, low glucose tolerance, insulin resistance, obesity, a lipid disorder, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, another inflammatory condition, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X, ovarian hyperandrogenism, allograft rejection in transplantation, Type II diabetes, growth hormone deficiency, neutropenia, anemia, a neuronal disorder, tumor growth and metastasis, benign prostatic hypertrophy, gingivitis, hypertension, osteoporosis, or a condition that may be treated by inhibition of dipeptidyl peptidase-IV.
36. The use of claim 35, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
37. The use of claim 35, wherein the other inflammatory conditions is rheumatoid arthritis.
38. The use of claim 35, wherein the neurodegenerative disease is multiple sclerosis.
39. A pharmaceutical combination comprising the compound of formula VI-RR of claim 26, the cyclic isomer of formula VI-RR-b of claim 27, or the mixture of claim 28; and an antidiabetic agent that increases insulin secretion, increases insulin sensitivity, reduces the uptake of sugar from the gastrointestinal track, enhances the effect of endogenous peptides or proteins that affect glycemic control, or provides a replacement for endogenous peptides or proteins that affect glycemic control, or any combination thereof.
40. The pharmaceutical combination of claim 39 wherein the weight ratio of the compound and the antidiabetic agent is from about 0.01:1 to about 100:1.
41. The pharmaceutical combination of claim 39, wherein the antidiabetic agent is at least one of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, nateglinide, pioglitazone, troglitazone, rosiglitazone, exenatide, insulin, GI-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, KAD1129, APR-HO39242, GW-409544, KRP297, AC2993, Exendin-4, LY307161, NN2211, or LY315902.
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