AU2008229787B9

AU2008229787B9 - Heterocyclic boronic acid compounds

Info

Publication number: AU2008229787B9
Application number: AU2008229787A
Authority: AU
Inventors: Juan M. Betancort; David Alan Campbell; David Winn
Original assignee: Phenomix Corp
Current assignee: Phenomix Corp
Priority date: 2003-11-12
Filing date: 2008-10-03
Publication date: 2010-10-14
Anticipated expiration: 2024-11-12
Also published as: AU2007201757A1; AU2008229787A1; AU2008229787B2

Description

AUSTRALIA Patents Act COMPLETE SPECIFICATION (ORIGINAL) Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Phenomix Corporation Actual Inventor(s): Juan M. Betancort, David Alan Campbell, David Winn Address for Service and Correspondence: PHILLIPS ORMONDE & FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: HETEROCYCLIC BORONIC ACID COMPOUNDS Our Ref: 839913 POF Code: 221787/477531 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- FIELD OF THE INVENTION The present application is a divisional application from Australian Patent Application No. 2004288831, the entire disclosure of which is incorporated herein by reference. [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-lV-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 [00021 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. [00031 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. [00041 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- I (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. W:\IFQ\772449772449 DIVISIONAL 30I9.doc 2 Theefre, such hiltors have -- en proposed for the treatment of-patients with type 11 diabetes, a disease oh thctermed by deereasd glneose tolerance and insulin resistance. [0061 Psstprotine/alaninoeoloaying agino-dipeptidases have been discovered, includIng DP7, DPPS, DPP9, and finroblast activation protein,(AP), that have the subsrate- and inhibitor-specificity of DPP-IV. Thus, inhibitors of this sort may affect multiple netbes offthe eryne gop. The precise physiological role of ach ofthese post-prein/alantn1~ealving enzymes is not well defined. Consequently, inhibiting each of them separAtely, a subset ofthemn, or all ofthem at the same time would have uncertain -physfolo.gical effect(s) [00]7j Diabetic dyslipidemia is characterized by multiple lipoprotein defects, including moderately high serum levels of cholesterol and triglycerides, small LDL particles, and low levels 6f 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 dyslipidernia was advocated by the National Cholesterol Education Program's Adult Treatment Panel III. [00081 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. 3 tuuuyi m present a variety 01 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, US patent No. 6,124,305 (Novartis AG), and WO 99/38501 (Trustees of Tufts University). The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge as at the priority date of any of the claims. Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification (including the claims) they are to be interpreted as specifying the presence of the stated features, integers, steps or components, but not precluding the presence of one or more other features, integers, steps or components, or group thereof. SUMMARY OF THE INVENTION [00121 The present invention provides DPP-1V 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-1V, 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 IV 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. Viewed from one aspect, the present invention provides a compound of formula (VI): W.%FQ%7?244gM772449 DMSIONAL 3OOMO dc 4 Rx HN b N N a H B R2 (VI) including all cyclic isomers thereof, stereoisomers thereof, solvates thereof, hydrates thereof 5 and pharmaceutically acceptable salts thereof, any prodrug thereof wherein: R' and R 2 independently or together are -OH, -O~ M* wherein M+ is a pharmaceutically acceptable cation, 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; 10 RX is hydrogen, (Ci.s)alkyl, (C 3

.

12 ) cycloalkyl, benzyl, or phenyl; wherein the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 2 ; R is halogen, trifluoromethyl, cyano, nitro, (Ci.

6 )alkyl, (CI.

6 )alkoxy, cycloalkyl, carboxy, acetamido, hydroxy, hydroxy(CI_ 6 )alkyl, hydroxymethyl, trifluoromethoxy, sulfamoyl, carbamoyl, sulfonamido, alkylsulfonyl, phenylsulfonyl, aryl, or heteroaryl; wherein 15 the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R';

R

7 is halogen, (C.io)alkyl, (CI 1 io)alkoxy, (Ciio)alkylamino, (Ci.jo)dialkylamino, benzyl, benzyloxy, hydroxy(CI.

6 )alkyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N-hydroxyamino, cyano, carboxy, acetamido, hydroxy, sulfamoyl, sulfonamido, carbamoyl; 20 the wavy lines at asymmetric carbons C" 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. BRIEF DESCRIPTION OF THE DRAWING 100131 FIG. I shows the pH dependence of the percentage of linear and cyclic isomeric 25 forms present in aqueous solution of a compound of the invention. T -UFO\8399I3\8399I3_caims_ 11 5.09 doc 5 UETAJ1uJ DR-SC PTION OF THE INVKNTION [01014] The pteleht invention provides cympounds of formalah I,

W

4

R-

3 B-O R6(1 z includiig all enantioniers, diastereoisomers, solvates, hydrates and pharmaceutically aceptble salts thereof, wherein n is I to 3; X is CHZ; 8; 0; CF o-C(CHj*; Z is H; halogen; hydroxyl; (C 1 a)alkoxy; (Ci.Ia)alkyl; (C3.

1 2)yCloalkyl; 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; aid optionally, one of the bonds in the ring containing X is a double bond; R1 and R 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 CRIR l is present, then R', R, R, R 4 and R are selected from (aa), (bb) or (cc): (aa) R', R, R' and 1W are hydrogen; and R is a) hydrogen; b) (Ci.1 2 )alkyl; (C 2 4.)alkenyl; (C2.1)alkynyl; (C 3

,

12 ) cycloalkyl; or (C 3 .. i)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with 1R, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; 6

R

6 is (C .

6 )ajkyl; (C .)alkoy; cyqloalkyl; cahoxy; oetamit; yant itro; halogen; hydroxy; hydoxy(C,.)alkyl; hydruxymnthyl tfifluoromathyI; trilluoroethoxy; aulfamoyl; sulfonamido; tarbamoyl aryl; hetoroaryl; Where the arylad heteroaryl groups are optionally mono- or independently plurisubstituted with R; arino, whqee the amino group is optionally mono- or independently pluisubstituted with -0; -SOR 8 ; -40%e; -COR,; -CoR, -CONHR ; -CON(R 2; -O; o 4-R; R3 it halogea; (Cj910)a1ky!; (Cw~alkoxy; (C,.,Iogl mino; (Ci 0 ) ialkylamin_; benzyl; benzyloxy; hydroxy1(C,~alky1; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy-, trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetarnido; hydroxy; sulfarnoyl; sulfonanido; or catbanoyl; R' is (C 1 .to)alkyl; (C2,o)alkenyl;

(C

2

-

10 )alkynyl; (C 3 . ,o)cycloalkyl; (Cs.jo)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 R'; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; c) aryl optionally fused to a (C 3 .io)cycloalkyl; or heteroaryl optiohally fused to a (C 3 .)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)jadamantyl in which is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4 pentylbicyclo[2.2.2]oet-1 -yl)axnine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adanantyl, and [2.2.1] or [3.1.11 bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (CIs)alkyl, (C,.s)alkoxy, (C,.s)alkanoyloxy, or

R

9 R'ON-CO-O-, where R 9 and R' 0 are independently (C1..)alkyl, or phenyl, where the alkyl and pheryl groups are optionally m6no- or independently plurisubstituted with (Cl-B)alkyl,

(C

1 .g)olkoxy, halogen, or trifluoromethyl, or R? and R' 0 together are (C3- 6 )alkylene; e) R '(CH 2 )p- where R" is 2 -oxopyrrolidinyl; (C1.

6 )alkoxy; phenyl; phenoxy-, (Ci.s)cycloalkyl; (3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (CI.)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R 12 ; where the phenoxy group is optionally mono- or independently 71 disubsitutoed with (Cim)akyl, (C1)alkoxy, od hlogen; and wherethe .1:5) beya1je carbveyclic moiety is optionatly rmono-or idependetitly.plutisuhtittted with (Ci.ai)lky; and p is 0 to 3;

R"

2 is haoge; tt fluotoethyl, oyano; nirn; (.4alky; (C,. 6 )alkoxy; eycloalkyl; earboxy; aetaindo; hydroy; hydroxy(Ci)aikyl; hydroymethy; trifluoromethoxy; sulfamoyl; carbaMoyl; sulfbnamido; alkylsufonyl; phenylsulfenyl; aryl; heteroaryl; where the aryl and heteroaryl groups arte optionallyfiono- or independently plutisubstituted with WI; f) &(I) CU(rI6)ywhere R is phenyl; in which the phenyl groups are independently optionglly mono- or independently disubstituted with R.; and q is 0 to 3; g) a .group of the formula: R141 (CH 2 )r' where R 4 and R' 5 are independently hydrogen; (Ci..)alkyl; (C,.4)alkycarbonyl; (C. 12 )cycloalkyl ring; (C 3

.

1 )cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C.6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaninocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R' 4 and R" together form a

(C

3

..

2 )cycloalkyl ring; and r is 2 to 6; h) a group of the formula:

R

17 R1- (CH 2

)

8 where R 6 and R 7 are each independently hydrogen; (CI.S)alkyl; (Ci-)alkylcarbonyl; di-(C,. 6)alkylaminocarbonyl; benzyl; berizoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, dine, pine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R4; or R 16 and R" together form a (C 3

.

12 )cycloalkyl ring; and s is I to 6; 8, i.)a toup of th~ obM14~al where R' 3 and R 9 are independently hydrogen; (CI 4 )alkyIe;(CI- 4 )alkylearbonyl; di-(C alkylaminoearbonyl benzyl; eothiaZOl; benOy4 pyrdIne; pyrinidine; phenyl; phenylaedfQCab~ny1; 4kylsulfonyl, or phenylsuMfyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine% phenyl, phenylartinoourbonyl, alkylsilfbnyl, and phenylsulfonyl groups ato optionally mno- or independently di-substituted with R 2 ; or R .anid R' 9 together farn a (Co 2 )oyolwalkyl ting; each t is idependently 0 to 6; and u is 0 to 3; ) a group of the formula: (phenyl-CHrC(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R1 2 ; k) a group of the forrnula: Ro0R (CH:.).4 o N F.(CH2)1-4 Ry R (CH2)t 20 R20 or RN7 or NK RRy"'tu F where R 20 is hydrogen; (C, 4 e)alkyl; (C,4alkyliarbonyl; di-(C,-6)alkylminocarbonyl;

(C

3 . s)cycloalkyloarbonyl; benzyl; benzoyl; (C,.6)alkyloxycarbonyj; arikyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyI, pyridine. pyritnidine, phenyl, phenylamninocarbonyl, alkylsulfonyl, and phenyls.lfonyl groups are optionally mono- or independently di-substituted with R 2 ; R, is hydrogen; (C, 4 8)alkyl; (C 3

.

2 ) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R1 2 ; R is absent or is halogen, (C, 4 )alkyl, (Ci. s)alkoxy, 0-alkylcarboxylate, 0-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxanido; or phenyl; 9 sis i to!6; tis o to. ; and u is-0 to3;-a 1) a groups of the fo rMugla; where R 2 is. hydrogen; C-.)lkyl benzy; or PgIenyl;:in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R1; each t is independently 0 to 6; and u:is 0 to 3; (bb) R 1 , R",, R 3 1 4 and R are independently hydrogen alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; trycloalkyl; alkylcycl aikyl; 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, alkynylanino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylanino, alkylaminocarbonyl-amino, alkoxycarbonylarnino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R' together with R) or R 4 , or R" together with R 3 or R 4 , and the atoms to which they are attached form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing I to 3 heteroatoms selected from N, 0, S, SO or S0 2 6 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

R

4 and R together form -(CR 22 R2)m- where m is 2 to 6, and RP and

R

23 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; aryloxydarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylamino; or 10 #iid R 5 together with the atoms to whidh they are attached.formb a 5 ta7 ttieaibe6A fig tMataining a tda1 6f~ to 4 htmatseled from'N, 0, S, S0, ot SQ2 or uRd R together with the toems to whiph they are attached fbim a 4 to 8 meremb d cyqtohetwrgjcyl ring wherein the pydloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 memubered cycloaikyl ring fied thertn; or (0) R' anil R arehydrogen; and R 1 ' and R together form: a 4 to 8 m bnbered oyW1iplyoyolic er etraocyoe ring system containing 1 to 3'heteroatoms soloep from ,, SO and 402, and includes single rings, fbsed bicyolic and tricyclic rings, which &e optionally mono- or itdependntly pltdaubstituted with any of the groups set forth i (aa)OYr (bh) and R5 is any of the groups in (aa) or (bb); and if C01R 1s absent, then R 3 , R 4 and R are selected from (dd), (ee) or (fo: (dd) R' and R are hydrogen; and

R

5 is a) hydrogen, provided that R 5 is not hydrogen when n is 1, X is CH 2 , and Z is H; b) (C.

1 2)alkyl; (C2-1 2 )alkenyl; (C 2 -12)alkynyl; .(C 3 -1 2 ) cycloalkyl; or (C 3 .12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 6 , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R is (C4)alkyl; (CI)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nito; halogen; hydroxy; hydroxy(C)4alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy, sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR 8 ; -S0 2 R; COR; -CO 2 R', -CONHRK; -CON(R')2; -OR'; or

R

7 is halogen; (C,.,o)alkyl; (Ci.,o)alkoxy; (Ca..o)alIkylamino; (C,.to) dialkylamino; benzyl; benzyloxy; hydroxyl(Ca.6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; 11 8 is (C 1 .1)alky; (C2)alkelyl; (C2.)alkynyl;

(C

3 . %)yQlmikyl(CswtoyloalkrW boazyl; phenethyl; aryl; or heterqaryl; where -thg lkyl. alkenyl, 'atkiynyl,oygloalkiy, gyoloalkenyl groups are optionally mono, or independently pigrisubstituted with aryl or heteroaryl where the aryl and heteroaryl grups are optionally thono- orindependotly plurisibstituted with R; and where the aryl and hetermaryl groups are optionally mono- or independently plurisubstituted with R 7 ; 0 ary1 optionally fused to a (C3.io)oyoloalkyl; or heteroaryl optiongily fuse to o Ca.Io)qyoloalkyl; where the aryl and heteroaryl groups are optionally monio- or indepenidently plurisnbstituted with R 7 ; 4) indanyl; 1;2,3,4.tetrahydronaphthyl; (CH2)Iadamantyl in whiehj is 0Q-; or a [2.2.1] or [3.1.11 bicycijo carbocyclic moiety, including (4 pentylbicyclo[2.2.2]oct- I-yl)aniine; where the indanyl, I,2,3,4-tetrahydronaphthyl,

(CH

2 )j adamantyl, and [2.2.1) or (3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Ci.s)alkyl, (C .g)alkoxy, (Ci.s)alkanoyloxy, or

R

9 R'N-CO-O-, where R' and R' 0 are independently (C,.g)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (CI.)alkyl, (Cs)alkoxy, halogen, or trifluoromethyl, or R 9 and R' 0 together are (C3-6)alkylene; e) R"(CH 2 )p- where R" is 2-oxopyrrolidinyl; (CO)alkoxy; phenyl; phenoxy; (C, 4 g)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Ci.,)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R 1 2 ; where the phenoxy group is optionally mono- or independently disubstituted with (C,4)alkyl, (C)4alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C.g)alkyl; and p is 0 to 3; Ri2 is halogen; trifluoromethyl; cyano; nitro; (Cl.,)alkyl; (C,)alkoxy; cydloalkyl; carboxy; acetamido; hydroxy; hydroxy(C,)alkyl; hydroxymethyl; trifluoromethoxy; sulfanoyi; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; f) (R 1 )2CH(CH 2 )q-, where R1 3 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R 12 ; and q is Oto 3; 12 g) a group of the fogaufa;

R

1 where P and 1' are independentlyhydrogen;(Ci)alkyl;(Ci~all arbonyl; (Ca

,

2 )tycloalkyl ring; (C 3 .d)cylDoalkyl riag; benzyl, benzoy pyridine; pyrimidine; phenyl; phenylnino-oarhony; alkyla~f'onyi; or pheYlIulfonyl; where the oycloalkyl rhig is optionally sabstititd with hydroxy(sCa)ayl, and where the begazyl, bcnzoyl, pyridie, pyrimiiine, phenyl phenyamninocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mnd- or independently di-substituted with R2; or R and R'f together form a (Ca1)yCloalkyl ring;and r is 2 to 6; h) a group of the formula; R17

R'

6 (CI where R' 6 and R' 7 are each independently hydrogen; (CI 4 )alkyl; (Ci.6)alkylcarbonyl; di-(Ci. 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyritnidine, phenyl, phenylaminodarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 1; or R1 6 and R" together form a (C.3.I)eycloalkyl ring; and s is 1 to 6; i) a group of the formula: (CHAh

R

1 where R" and R" are independently hydrogen; (Cjg)alkyl; (Ci-6)alkylcarbonyl; di-(C. 6)alkylaninocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl;. where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbony, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R"; or R's and R' 9 together form a (C3.I)cyoloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH 2

-C(CHI

3 ) 2), 13 whae the Ohenyl groap is optitally rlno- or independenfty plurisubstitated with R 1; k) group dthe fannula: o or .

or u ~f~j(H2)iARy )hU' where Ra is hydrogen; (C,.s)alkil; (Ci~aiyledbonyll di4Ci)alkylaminovatbonyl;

(C

3 . 8a)yo2llkylIOatbonyl; benZyl; benzoyl; (C(2 )ialkyloxye ony; ailkylaxycarbony1, pyridine; pydmidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfbnyl; or phenylsulfonyl; where the befizyl, betzdyl, pyridne pyrhmidine, phnyI, phylanh~oarbodyl, alkylsulfbayl, and phenyIsulfAnyl groups are Optionally mono- or independently di-substituted with R12; R. is hydrogen; (C..s)alkyl; (CM) cyoGAlkyl; benzyl; phenyl; Where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R1 2 ; RY is absent br is halogen, (CI, 4 )alkyl, (C,.g)alkoxy, 0-alkylcarboxylate, 0-arakylcarboxylate, 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:

(CH

2 )t where R1 2 is hydrogen; (CI..s)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R1 2 ; each t is independently 0 to 6; and u is 0 to 3; or (ee) R 3 , R 4 and R 5 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, cyclohetetoalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino 14 oarbonyl, alkylahtinocabody1, aflketylarinoatbonyl, alylcanheonyl-oiy, akylerbnylatiinm, aryltborylamino, olkytsulfonylminor alkylamnoarboylr ino, 4lkoxycarhonylamino, alkylsulfany1, anminosuffinyl, aminosulfonyi, alklylsulfmyl, sulfonamido r sulfonyl, provided that when ni X i s CH, the ting ontaining X is saturted, and Z, R 3 and 1 are fI, R 4 'is niota side ehain of a nahtlly' o ring a-amino MAid, and provided that when n is 1, X is CHIj the ring containing X is saturated and Z and R' are H, R 3 and R 4 are not both methyl; or R' and together form4C1 2 R -where m is 2 to 6, and 14 and R are independently hydrogen; hydroxyl; aikoxy alkyl; alkehyl; alkynyl; eyoloalkyl; halo; amino; substituted arnino; qyoloalkylalkyl cyoloalkenyl; aryl; ,arylaky1; heterolaryl, hetetoarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbopylamrino; arylcarbonylaming; alkoxyoarbonyl-amino; aryloxycarbonyl-aiino; alkoxytarbontyl; aryloxytarbonyl; or alkylamiiodarbonylainino; provided that when n is 1. X is CH 2 , the ring containing X is saturated, Z and RWare H, R 4 and Rstogether aren't -(CH 2

)

2 or -(CHi); or

R

4 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

SO

2 ; or

R

4 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) R2 is hydrogen; and R 4 and Rs 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, 80 and SO 2 , wherein the heterocyclic ring system is optionally mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ec); provided that when n is 1, X is CH 2 , the ring containing X is saturated, and Z and R3 are H, RW and R together are not -(CHZ) 2 - or -(C1 2

)

3 ; and wherein the bond containing the wavy line signifies the point of attachment. [O015] In some embodiments of compounds of formula I, R' and R2 independently or together are the boronic acid protecting, group formed from (+)-pinanediol; pinacol' 1,2 dicyclohexyl-ethanediol; I.,2-ethanediol; 2,2-diethanolainine; 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 15 M anedio1 methanol; ethanol;.isopropanl; catechot er 1-butandl. Thus, it will be underatoad by those ofskill In the at that R' and Re represdat a singleProte-ng glup ottaohed to both boronio ostor oxygens when diola such as (+)-pinanediol and pinaal are usedwhereas 1O andR-represent separate moieties on the boronic ester oxygens such as methyl or ethyl when the esters are forned ftom methanol and ethanol, respectively. In other embodiments ofacompounds 6f fornhAla I, R' and R 2 ilidependently r-together are a group capable ofbeing,hydrolyzed to a hydroxyl group in an aqueous galation at physiological pH or in biblogieAl fluids and are formed from 1,ZdioyoIhexylethanediol; 142ethapediol; 1,-propanediol; 2,3-butanediol, 1,4-butanediol; dlsopropylethanedigl; ethanol; ethanol; isopropanol;-at 1-butanol. For example, when R' and R 2 are each fornmid from Methanol, the resulting R' and R 2 groups are rnethyl. When 2,3-butanediol is used, the resulting R' and R 2 groups are a single group and the reaulting boronic ester has the following structure: 0. [0016) Compounds of formula I include those wherein if CRR" is absent, then R 3 , R 4 and R 5 are selected from (dd), (ee) or (ff): (dd) R 3 and R 4 are hydrogen; and R' is a) (C.

1

-

2 )alkyl; (C 2 -1 2 )alkenyl; (C24, 2 )alkynyl; (C 3

.

1 2) cycloalkyl; or (C 3

.

1 2 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally ruono- or independently plurisubstituted with R 6 , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;

R

6 is (Ci-6)alkyl; (Ci.

6 )alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C.

6 )alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R'; amino, where the amino group is optionally mono- or independently 16 pluriftjtuted with R 8 ; -SOR 8 ; -OIRs. -COl; -C0 1

R

8 ,-CONHR: -CON(Rt); -. 01; or

R

7 is halgen; (Cwto)alkyl; (Ci.,o)alkoxy; (C -oalkylamino (Cvti) di kylamin; benzyl; benzytoxy; hydroxy(CtI.)aikyl; hydroxymethyl;nitro; trifluoroMethyl; trifluoromethoxy, trifluoroinethylthio; -,hy&dxyififino; cyaho; carboxy; aoetamnido; hydroXY; sulfeMoyl4 sulfonamido; or oarbanoy;

R

8 is (C 1 .io)alkyl- (C_-to)awkenyl; (Cz.o)alkynyl;.(C. o)eyaloagky4; (Cs.io)-yeloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alky, alkenyl, alkynyl, cydloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl orheteroaryl where the aryl and heteroaryl groups are optionally mono- or Independently plurisubstituted with R 7 ; and where the aryl and heterogryl groups are optionally mono- or independently plurisubstituted with R 7 ; b) aryl optionally fused to a (C 3 ..i)cycloalkyl; or heteroaryl optionally fused to a (C3.)cycloalkyl; where the aryl and heteroaryl groups are optionally nonomkor independently pluri substituted with R 7 ; c) indanyl; 1,2,3,4-tetrahydronaphthyl;

(CH

2 )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,

(CH

2 )j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Ci 4 )alkyl, (Ci.s)alkoxy, (Ci.s)alkanoyloxy, or

R

9 R'N-CO-0-, where R 9 and R' 0 are independently (CI.s)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C I 4 )alkyl, (CI S)alkoxy, halogen, or trifluoromethyl, or R 9 and R' 0 together are (C3-6)alkylene; d) R' '(CH 2 )p- where R" is 2-oxopyrrolidinyl; (CI-6)alkoxy, phenyl; phenoxy; (Cis)cyoloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl,

(CI

4 )alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono. or independently di- or independently trisubstituted with R"; where the phenoxy group is optionally mono- or independently disubstituted with (CI.4)alkyl, (C,.4)alkoxy, or halogen; and where the [33.31 bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (CIs)alkyl; and p is 0 to 3;

R

2 is halogen; trifluoromethyl; cyano; nitro; (Ci,)alkyl; (C. 6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(CI.4)alkyl; hydroxymethyl; 17 triflueromethoxy; sulfamyl; oarbamoyl; sulfonaMido; alkylutfhnyl;phenylsulfony; aryl; heteroatyl; where the aryl and hoterbaryl groUps are optioally mono- or inpe leadly plirisubstituted with R; e) (R')2CH(C%)q-, where RI.is phenyl; inwhich ths phenyl groups are independently optionally mono- or independently disubstituted with P 1 -; and q is 0 tto 3; f) a group of the formula: where R 4 and R" are independently hydrogen; (CIM)alkyl; (C,)alkylcarbonyl;

(C

3 . z)eycloalkyl ring; (C3.1 2 )ryloalkenyl ring; benyl; benmoyli pyridine; pyriMidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cyolealkyl ring is optionallysubstituted with hydroxy(O 1 -~lky1, and where the benzyi, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groUps are optionally mono- or independently di-substituted with R1 2 ; or R 14 and R' 5 together form a

(C

3

.

12 )cycloalkyl ring; and r is 2 to 6; g) a group of the formula; R17 RI6_ "(CHY) where R' 6 and R" are each independently hydrogen; (C 1 s)alkyl; (CI.6)alkylcarbonyl; di-(Cr. 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'; or R' and R 7 together form a (C 3

.

12 )cycloalkyl ring; and s is 1 to 6; h) a group of the formula:

R

19 R - ,-(C u R where R' 8 and R' 9 are independently hydrogen; (C 1 .s)alkyl; (Cl-6)alkylcarbonyl; di-(C 1 . )alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; 18 phenyhmfrcag~ny1; atkyisulfonyl; or phenylsulfonyl; where the bemyly benzoyl, 'benzothiazale, pytidinej pydinditto, phenyl, phenylaninooabonyl, alyiuifonyl, and PhenyludnFonyl group& ar optioiIlly mono' or independently di-substituted with R"; or R" attdRitogetkhr form a (Ca, )yoJ1lkyl ring; each t is Independently 0 to 6 and 0 is 0 to 3; 1) agoraIp of the formula; (phenyl-CflrC(CHI) 2), wherbi he phenyl group isoptionally tono- or-independonly plurisubstitited with R' 2 ; group ofthe fornla: R(CH2)H (GH2%4 Ry Ryo R or where 106 is hydrogen; (C.

1 s)alkyl; (C 1 -6)alkylcarbonyl; di-(CI, )alkylaminocatbonyl;

(C

3 . s)oyeloalkyloarbonyl; benzyl; benzoyl; (Ci.O)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyriinidine; phenyl; phenyl substituted thiazole ring; phenylarninocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl,'benzoyl, pyridine, pyrimidine, phonyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 2 ; R, is hydrogen; (CI-s)alkyl; (C 3 -1 2 ) 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, (Ci.s)alkyl,.(CI 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: (CHAhi R2'O--(CH2ht where R 2 ' is hydrogen; (Ci-s)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) R 3 and R 4 are independently hydrogen, alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyi; bitycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, 19 .&alkyl; heteroaryl; hetezoaryld1ky; cyc1oheteroalkyl of cyeloheterallylaky1; al opgenaly So mnd endntly pludsubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, halk41kxy, gdlyhaloalkoxy, alkoxycarbonyl, alkehyl, alkynyl, cyaloalkyl, Oyolbalkylalkyl, polyqycloalkyl, heterOarylaiino, aiylamino, CyClobtroalkyl, tyclohetmralkylalkyl hydroxy, hydroxyallkyl, nitro, cyanto, amino, Substituted amino, alkylamino, dialkylamino, thiol. alkyltbioalkyloarbonyl, -ay, alkoxycarbonyl, aminocarbonyl, Ikynylanino carbonyl, alkiylaminoarbonyl, alkenylaminocarbonyl, alkyloarbonyloxy, alkylearbonylamino; arylearbonylamino, alkylsulfonylaniinaogalkylaftniioatbnyl-amino, alkaXyoarbotiylamitid, lkylsulfbnyI, aninosulfiyl, aminosulfonyl, alkyjsu!Anytl, sulfonamido or sulfonyl;

R

5 is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcyoloalkyl; hydroxyalkyl; hydroxyalkyleyeloalkyt hydroxycycloalkyl; hydroxybicyoloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independentlyplurisubstituted 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, alkynylatnino carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylanino, alkylsulfonylamino, alkylaminocarbonyl-anino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or

R

4 and R 5 together form -(CR 22

R

2 3 )m - wherein M is 2 to 6, and Ra and R 23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl; cycloalIyl; halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino; arylcarbonylamino; alkoxycarbonyl-amino; aryloxyearbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylamino; provided that when n is 1, X is CH 2 , and Z and R' are H, R 4 and R' together are not -(CH 2

)

2 - or -(CH 2

)

3 -; or 20 1e t1d R togthor with tho atoms. to .Wikh they are attached f a 5 to7 memstbered ring contarng A total of2 to-4heteroatoms selected Nrom N, 0, -, -90, or SO2; or 4 iand R 5 together with the atoms to wlfieh they ae attached form a 4 to 8 riembored oyelllterealkyl ring whoein the cyloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered.yglogky ring fuse4tihereto; or (ft) Qis hydrogen; and R and R 5 together with the atoms to which they are attached form a 4-to S: ietber miono- t polyoyolfe heterecyliG ring system ,containing 1 to 3 heteroatoms selected from N, 0, S, SO and 802, wherein the hoterocyclic ring system Is optionaly mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X is CH, the ring containing X is saturated, and Z and R 3 are H, R 4 and R 5 together are not -(CH 2

)

2 - or -(CH 2

)

3 -. [0017] Compounds of formula I also include those wherein X is C1I; the ring containing X is saturated; CRWR is absent, R', k 2 , A 3 and R 4 are hydrogen; and Ris (C,..

2 )alkyl; (C 2 1 2 )alkenyl; (C 2

.

12 )alkynyl; (C 3

.

1 2 ) cycloalkyl; or (C3.j)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 6 , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions. In some such embodiments, R 5 is a (C 1 . 1 2 )alkyl or (C3..n)Cyeloalkyl, including, but riot limited to, miethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, or adarnantyl. [00181 In some embodiments of compounds of formula I, X is CH 2 ; the ring containing X is saturated; CRR" is absent, R, R, R 3 and R 4 are hydrogen; and R 5 is indanyl; 1,2,3,4 tetrahydronaphthyl; (CH2)j adaniantyl 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,

(CH

2 )jadamantyl, and [2.2.11 or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cu.s)alkyl, (CI.g)alkoxy, (C,1S)alkanoyloxy, or RR' 0 N-CO-O-, where R? and R' 0 are independently (C,. s)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C 1 .s)alkyl, (Ci.s)alkoxy, halogen, or trifluoromethyl, or R 9 and R'6 together are (C 3 .3)alkylene. 21 [00191 In other embodiments of tompounds of formula ]I X is CHI 2 ; the rinig containing X iWsatiWratedNR" is absent, R.' R, 3 axO d R 4 are hydrqgn; and is R (CH 2 )/where 1s ?-oxopyrroli inyCN ) (Cikgxy phenyl; phenoxy; (Cj-8)eycloaky1; [3.3.3] bigyclic carbQcyclic moiety; pyridinyl; naphthyl; tycloheXenyl; dr adamanityl; where the2 uxopyitolidinyl, (C01allkcxy, phenyl, pyridinyl, and taphthyl groups are optionally mono orindependently di- or independently trisubstituted with R.

2 ; where the phenoxy group is optionally mono- or independently disubstituted with(Ci4)aIkyl, (Ci4alkoxy, or halogen; and where the [3.3.1] bicyclic carbocyolic moiety is optionally mono-or independently plurisubstituted with (Ct 4 )alky49 V is 0 to 3; and R 2 is halogen triflutoomethyl; cyano; nitro; (CI4)alky; (Cw)alloy; eyeloalkyl; oarboxy; acetamido; hydroxy; hydroxy(Cl. 6)alkyl; 4ydroxymethy; trifluoromethoxy; sulfamoyl; carbanoyl; sulfonamido; alkylsUf6nyl; phenylsulfonyl; aryl, heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R'. [0020] In certain embodiments of compounds of formula I, X is CH 2 ; the ring containing X is saturated; CRWR' is absent; R', R 2 , R' and R 4 are hydrogen; and R' is (RG)2CH(CH)q-, where R1 3 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R ; and q is 0 to 3. [0021] In some embodiments of compounds of formula I, X is CH 2 ; the ring containing X is saturated; CRR" is absent, R', R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula: R's R14 (CH2)i where R 4 and R" are independently hydrogen; (Ci.s)alkyl; (CI-6)alkylcarbonyl; (C3. 1 2 )oycloalkyl ring; (C..

12 )cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cs)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocatbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R"; or R1 4 and R1 5 together form a

(C

3

.

12 )cycloalkyl ring; and r is 2 to 6. 224 [0D2-] Compounds of formula I include those wherein Xis CI the ring contiing X is satiurated: CRR is absent, iP, R 2 Ra 0nd R 4 Arelydrogen; and, 5 is a group of the fonnule: R 17 where R' and R' 7 are each independently hydrogen; (Ci.;)alig1; (Ci 4 )alkyabony; diarC,4 A)aikylaminocarbonyl; benzyl;;benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; whore the benzyli benzoyl, pyridiie, pyrimidine, phenyl, phenylaminocarbonylalkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R; or R' 6 and R together form a (C 3

.

1 2 )cycloalkyl ring; and s is I to 6. 10:023] Compounds of formula I wherein X is CH 2 ; the ring containing X is saturated; CR'R is absent, R', R 2 , R 3 and R 4 9re hydrogen; and R is a group of the formula:

(CH(

R -- ( u

R

18 where R1 8 and R 19 are independently hydrogen; (C 1 .)alkyl; (C1.4)alkylcarbonyl; di-(Cl. 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 R'; or R" and R1 9 together form a (C3..2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3. In some such embodiments, R 5 has formula:

(CH

2

)

or NN 23 (p94 In same diingis afvoinpends of fonnula-I, Xis CH 2 ; the ring containing X satptated; . is se, R, and 4 are hydrogen; and "~is a group of the for iula: (phAyKC 2

-C(CH)

2 -), Where the phonyl group .i eptnatlly Mono- or independently lurisubstitued withf 2 . [0025) CQmpo'unds, ofFonula I include those having the following structure, Formula LA: 0 N R4 R 3 N IA It some such emboditnets, RS is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyI; 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, alkylanino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino carbonyl, alkylaminacar'bonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl. In other such embodiments, R 5 is alkyl; alkenyl; cycloalkyl; cycloalkylalkiyl; hydroxyalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted as described above (in, e.g., (ee)). In still other such embodiments, R is alkyl, cycloalkyl or cycloheteroalkyl, optionally mono- or independently plurisubstituted as described above. In some embodiments of compounds of Formula IA, R 3 and R 4 are both 24 hIydntget. IWother smlbodimiitsOn -is 1. In some emibbdiment of co pounds of Fomiala Mhbrme Wis 1 and ', k.61, and R 4 pre hydrogen, R' is not methy. [.002] Compound of formula Iinclude those wherein X is CH 2 ; the ring containing is saturated; Q- is absent, RI, R 2 , R' and R4 are hydrogen; and A 5 is a group of the formula:

R

2 R (CH2) (Dgh Ry. or . or Ry 20 where R 2 0 is hydrogen; (C,.)aIkyi; (Ci4)alkylcarbonyl; di-(C 1.)alkylaminocarbonyl;

(C

3 . )oyeloalkylcatboxnyl; benzyl; bentoyl; (Ct.)alkyloxycarbonyl; arlkyloxyearbonyl, pyridine; pyritmidine; phenyl;Phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfoniyl groups are optionally mono- or independently di-substituted with R1 2 ; Rx is hydrogen; (C 1 .e)alkyl; (C 3

.

2 ) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R1 2 ; R, is absent or is halogen, (C,.s)alkyl, (C..)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. In some such embodiments, R 5 has formula: Rr x(CHh__I C: (CH2)td4 R2O-N or 2 100271 In other such embodiments, Rs is Rx(CH2)A 20 2 5 including for oxemple, th. following structures: N H or H [09281 In still other such embodiments, the compound has the formula OH OH OH OH H3L- O' H r3 o OH NH NH HN ,or HN [0029] Compounds of formula I wherein X is CH 2 ; the ring containing X is saturated; CR'RE is absent, R', R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula ,(CH2)t-l R21-O--(C6 P u where R 2 ' is hydrogen; (Ci.s)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R1 2 ; each t is independently 0 to 6; and u is 0 to 3. In some such embodiments, R 5 has formula:

(CH

2

)

or R21-0" R O (CH2 26 [03.0] Canponds of formula . include those wherein R axi R are hydrogen; n is 1; X together withadjcent ing oarbn -nd Z form a fused oyalopropyl; QRRi"s absent; ,f and R are independently hykrogen; alkyl; alkenyl ;alkynyl;t ycloalkyl; cyoloalkylalky, bi1yclo1alkyl; tricydlbalkyl; alkyloycloalkyl hydroxyalkyl; hydrollyalkyycykloalkyl; hydroxyoyeloalkylk hydroxybicycloalkyl; hydoxMytripycloalkyl; bicycloalkylalkyl; alkylbicyna0lkyl; akylthioalkyl; arytalkylthioalkyl; cyoIgalkenyl; aryl, aralkyl; heteroaryl; heterory alkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurinubstituted'witlh halogen, alkyl, polyhnloalkyl, alkoxy, haloalkoxy, polghaoalkoxy% alkoxycarbonyl, alkenyl, alkynyl, cyoloalkyl, oyoloalkylalkyl, polyeycloalkyJ, heteroarylainno, arylanino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, eyano, amino, substituted amin6, alkylamino, dialkylamino, thiol, alkylthio, alkylcarboiiyl, acyl, alkoxycarbonyl, atninoctarbonyl, alkytylamino carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsalfinyl, sulfonamido or sulfonyl; or

R

4 and R 5 together form -(CR 2 R 23 )m_ where m is 2 to 6, and R" and R are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; akynyl; cycloalkyl; halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylaniino; arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylanino; or

R

4 and Wt 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 SOz; or

R

4 and R 5 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. [00311 In some embodiments of compounds of Formula I, R', R 2 , R 3 and R 4 are hydrogen; n is 1; X is CH 2 ; CRR" is absent; and R 5 is aryl or aralkyl.

100321 In soso embodiments, aompoUnds of fonnula I have the formula: H 0 -QOR R, 100331 In other embodinents, compounds 9f formula I have the formula: OR R B--OR 0 B-OR 2

R

5 N RN [0034] In still other embodiments, compounds of formula I have the formula: OR' H B--OR2 R N6 [0035] In still other embodiments, compounds of formula I have the formula:

R

1 O R'O H 0 B-OR 2 H 0 B-OR 2 NN Rs N R§ N

R

4 4 F or. OH [0036] Compounds of formula I include those wherein, if CRWR is present, R' and R 3 are hydrogen; R"' and R 4 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 SO 2 , 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 R 5 is any of the groups in (aa) or (bb); or 28 if CR'R" is absent, then R is hydrqge; andi and R 5 tgdlerwith the atoms to which they are aligched form a 4 to 8 mernbered cyolic, polycyclib or htocyclic ring system containing 1 to 3 heterOatoms selected from N, 0, S, 80 and SO 2 , and includes single rings, fused bicylicy and tricyclic rings, which are optionally mono- or independently plutisubstitutod with any of the groups set forth in.(dd) oT(ee); provided that when n is 1, X is CH 2 , the ring containing X is saturated, and Z and I 3 are hydrogen, K and R together are not -(CI 2

)

2 - or -(CH 2

)

3 -. 10037] In some such embodiments, compounds of formula I have formula II: OR, H GR2 N ('IN R24 ) Y )i X n/ z wherein: Y is 0, S, CHR2 or N6 k is 0 to 3 and m is 0 to 3 when Yis CHR"; k is 2 to 3 and m is 1 to 3 when Y is O or NR 26 ; each R2 is independently: a) hydrogen; b) (C 1 12 )alkyl; (C2.

1 2)alkenyl; (C 2 .)alkynyl; (C 3

.

12 ) cycloalkyl; or (C 3 . 12 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R , 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 R1 2 ; d) R"(CH2)p- where R" is 2-oxopyrrolidinyl; (Ci-6)alkoxy; phenyl; phenoxy; (C 1 .s)cycloalkyl; [3.3.1} bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (C 1 .8)alkylcarbonyl; (C3.1 2 )cycloalkylarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C.

6 )alkyl; where the 2 -oxopyrrolidinyl, (C 1 . 6 )alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently 29 di- O idependeIty trisubstitUtd with R"; where the phPnoxy goup is optionally Mnoso 'ixidependently disubstituted with (C.)alkyI, (Ci.4)ilkoxy, or halogen; and where the (313] biQyptic carbooyolio moiety is optionally iono-or independently plurigubstituted with (C,.g)alkyl; p ig 0 to 3; and

R

2 1is halogen; trifluoromethyl; ;yano; nitro; (CI.6)akyh (C.aalk xy; cyoloalkyl; carhtoy; asetamido; hydroxy; hydroxy(Cj._)akyl; hydroxymethyl; trifluorometboxy; sulfamoyl; earbamoyl; sulforiamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heterbaryl groups are optionally mono- or independently plurisubstituted with Ri e) (R 13

)

2

CH(CH

2 )n-, where R1 3 is pheayl; in whidh the phenyl groups are independently optionally mono- or independently disubstituted with R' 2 ; and q is 0 to 3; f) a group of the forndula: R N (CH 2

)

where R' 4 and R1 5 are independently hydrogen; (Ci..)alkyl; (C1.-)alkylcarbonyl; (Cj. 1 2)cycloalkyl ring; (C3-j2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaniino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cia)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 2 ; or R' 4 and R1 5 together form a

(C

3

.

1 2 )cycloalkyl ring; and s is 1 to 6; or g) a group of the formula: where Rat is hydrogen; (Ci.s)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 12 ; and t is 1 to 6; R" is: a) hydrogen; b) (CI.1 2 )alkyl; (C2.12)alkenyl;

(C

2

,

12 )alkynyl; (C 3

.

12 ) cycloalkyl; or (C 3 . 1 2 1cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are 30 ptionally teono Or itidepeindently plurisubstituted with R' 2 , and where the alkyI, Ellrouy), alkynYgportions inlude linearr branehed chains and may include cyclic portions; c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally iono- or independently plurisubstituted with R; d) R '(CH 2 ), where R" is 2-oxopyrrolidinyl; (Ci_)alkoxyg phenyli phenoxy; (C 1 s)cyOloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cydoahexenyl; (O 1 .s)alkyicarbonyl; (C 3 a 1 2)cycloalkylcarbonyl; benzyl; benzoyl; pytjnidinyl; phenylaminocarbonyl; alkylsulfonyl; phenyisalfonyl; or adamantyl; where 4heeyiloalkyl ting is optionally substituted with hydroxy(Cj 4 )alkyl; where the 2-oxopyrrodinyl, (C 1 .

.

6 )alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrintidinyl, phenylaminocatbonyl alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R"; where the phenoxy group is optionally noo or independently disubstituted with (CI.4)alkyl, (Ci.

4 )alkoxy, or halogen; and where the (3,3.3i bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Ci ,g)alkyl; p is 0 to 3; and

R

2 is halogen; trifluoromethyl; cyano; nitro; (C,4-)alkyl; (Ct1-)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Ci.4)alkyl; hydroxyinethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfbnyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; e) (R 1 )2CH(CH 2 )q-, where R1 3 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R1 2 ; and q is 0 to 3; f) a group of the formula: R's R14 N (CHA)rA where R1 4 and R1 5 are independently hydrogen; (CI-s)alkyl; (CI.4)alkylcarbonyl;

(C

3 . 1)cycloalkyl ring; (C3.

1 2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylanino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C 1 .6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 1 2 ; or R1 4 and together form a

(C

3 )cycloalkyl ring; and t is 0 to 6; or 31 g)a tipfthfobia where is hydrogen; (Cie)alky1; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-aubstimted Qn the ring with Ru; and t is 0 to 6; and R1 6 is: a) hydrgen; b) (Ci.

12 )acyl; (C2.)alkenyI; (C 2 1 2 )alkynyl; (C 3 4 2 ) cyoloalkyl; or (C 3 . )cycloalkenyl; where the alkyl, alkenyl, alkynyl, ey loalkyl and cycloalkenyl groups ate optionally mono- or independently plurisubstituted with R"', and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and.may include cyclic portions; d) aryl; or heteroaryl; where the aryl and heteroaiyl groups are optionally moho- or independently plurisubstituted with R; d) R 2

(CH

2 ),-, where R 27 is 2-oxopyrrolidinyl; (Cia)alkoxy; phenyl; phenoxy, (Ci.s)cycloalkyl; (3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Ci.s)alkylcarbonyl; (C 3

.

1 )cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(CI-)alkyl; where the 2-oxopyrrolidinyl, (C 1 . 6 )alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R1 2 ; where the phenoxy group is optionally mono or independently disubstituted with (Ci4)alkyl, (Ci4)alkoxy, or halogen; and where the (3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Ci.s)alkyl; p is 0 to 3; and R1 2 is halogen; trifluoromethyl; cyano; nitro; (CI)alkyl; (Ci4alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C 1 a)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl, sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; e) (R 1 )2CH(CH2)q,, where R' 3 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R1 2 ; and q is 0 to 3; 32 Sa group (f the formula: R 14 where R' 4 and R are independently hydrogen; (C, 4 )alkyl; (Ci-)alkyltarbonyl; (C 3 . )cydloalkyl ring; (C 3 .j2)oyloalkenyl ring; benzyl; henzojl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonylb or phoeylsulfonyI; where thecycloalkyl ring is optionally substituted with hydroxy(C 1 . 4alkyl, and where the benzyl, bentoyl, pyridine, pyimidin-e, phenyl, phenylaminooarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R4; or R 4 and R 5 together form a

(C

3

.

2 )YeOloalkyl ring; and r is 0 or 2 to 6; or g) a group of the formula: R2'-_(CH2.)A where R 2 is hydrogen; (Ci.s)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R"; and t is 0 or 2 to 6. 100381 In some embodiments of compounds of formula II, X is CH 2 ; the ring containing X is saturated; and R', R 2 and R, are hydrogen. In other embodiments of compounds of formula U, X is CH 2 ; the ring containing X is saturated; R', R 2 and R" are hydrogen; and

R

24 is hydrogen, provided that if k, n, and m are each 1, and Y is CHR 25 , Z is not H. In still other embodiments of compounds of formula U, X is CH 2 ; the ring containing X is saturated; R', R 2 and R are hydrogen; and R 4 is (C.,)alkyl; (C2.I 2 )alkenyl; (C 2

..

2 )alkynyl; (C.,1 2 )' cycloalkyl; or (C3.,2)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. In some embodiments of compounds of formula II, X is CH 2 ; the ring containing X is saturated; RI, R 2 and R2 are hydrogen; and R" is phenyl optionally mono or independently plurisubstituted with R. Compounds of formula 11 include those wherein X is CH 2 ; the ring containing X is saturated; R', R 2 and R 2 are hydrogen; and R 24 is R"(CH 2 )p- where R" is 2 33 oxopyrrbolidiny1; (Ci.)koxy; phenyl; phenoxy; (Cis)yoloIlkyI; [333]iylic earbogglie .indiety; pyridinyl; tiaphthyl; cyclohexenyl; (C, )alkylcarbony (C. iz)cycloaikylcarbonyl;. benzyl; benzoyl; pyrimidinyl; phenylaminocatbonyl; alkylsufonyl; phenylsulfonyl; or adwaantyl; where the tysloalkyl ring is optionally substituted with hydroxy(C 1 4Oilkyl; where the 2-oxopyrrolidinyl,(Ci-.)alko.y, phenyl, pyridinyl, bnyl, benzoyl.,pyrimidinyl, phenylaminocarbonyl, alkyisulfonyl, phenylsulfonyl, an(, naphthyl groups are optiQnally mono- or independently di- or Independently trisubstituted with R1 2 6 where the phenoxy group is optionally-mono- or independently disubstituted With (C. 4 )alkyl, (C .4)alkoy, or halogen; and where the [3.3;3] bicylic tarbocyclie moiety is optionallynono-or independently plurisubstituted with.(C,.8)alkyl; p is 0 to 3; and R' 2 is halogen; trifluoromethyl; cyano; nitro; (C,-)alkyl; (C,4)alkoxy; cycloalkyl; carboxy, acetainido; hydtoxy; hydroxy(C, 4 )alkyl; hydroxymethyl; trifluoromethoxy; sulfamyl; carbamoyl; sulfonanido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and beteroaryl groups are optionally mono- or independently plurisubstituted with R 7 . [00391 In certain embodiments of compounds of formula H, X is CH 2 ; the ring containing X is saturated; R', R2 and R 2 5 are hydrogen; and R 4 is (R1 3 )2CH(CH2),-, where R1 3 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R1 2 ; and q is 0 to 3. [00401 In other embodiments of compounds of formula U, X is CH 2 ; the ring containing X is saturated; R', R2 and R 25 are hydrogen; and R 24 is a group of the formula: RIS R',- N CH2)A-' where R' 4 and R" are independently hydrogen; (Cl.g)alkyl; (C.)alkylcarbonyl; (C 3 . 1 2)cycloalkyl ring; (C3.12)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cyclo4lkyl ring is optionally substituted with hydroxy(C.)alkyl, and where the henzyl, benzoyl, pyridine, pyrinidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 2 ; or R' 4 and R' 5 together form a

(C

3 ,1 2 )cycloalkyl ring; and s is I to 6. 34 [00411 In some ombodimonts .eaMpQunds oforInula , X is C-16; the ring containing X is saturated; R I 2 and R e hysragen; and 4 is a groip of the formula: whret R"' is hydrogen; (C 4 )alkyl benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with RI 2 ; and is 1 ,to 6. [00421 Compounds of formula U1 include those wherein X is CH 2 ; the ring containing X is saturated; R', R 2 and W 4 are hydrogen. In some enbodiments 6f compounds of formtula II, X is. CH2; the ring coritainiug X is saturated; R R 2 , R are hydrogen; and R2 5 is (Ci. 12 )alkyl; (C 2 1 )alkenyl (C )alkynyl; (C312) cycloalky1; or (C3.a.)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R1 2 , 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 CH 2 ; the ring containing X is saturated; R', R2, R 24 are hydrogen; and R 25 is phenyl optionally mono- or independently plurisubstituted with R". [0043] Compounds of formula II include those wherein X is CH 2 ; the ring containing X is saturated; R' W, R243 are hydrogen; and R 25 is R"(CH 2 ),- where R" is 2-oxopyrrolidinyl, (Ci.6alkoxy, phenyl; phenoxy, (Cig)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Ci.

6 )alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R"; where the phenoxy group is optionally mono- or independently disubstituted with (C,.

4 )alkyl, (C1.4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Ci. g)alkyl; p is 0 to 3; and R1 2 is halogen; trifluoromethyl; cyano; nitro; (CI-6)alkyl; (C. 6 )alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C.4)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 . 35 (.0441 In other erihediments ofe pounds of formula IL X is CH2; the ing containing X in satuattd; R$, R~ R 24 Me hydrgen; and Ris f(R')ZCH(C 2 )- where R- is phenyl; in which the phenyl groups Are independently optionally mono- or independently disubstituted with R 2 ; andq is eto3 100451 Coinpounds of formula I include those wherein X is C1 2 ; the ring containing X is saturated; R', R 4 , R 4 are hydrogen; and 10 is a group of the formula: R 14N>_ CH2A where R and R are independently hydrogen; (CI 8 )alkyl; (C,.6)alkylcarbonyl; (C3. 1 I)cycloalkyl ring; (C 3

-

12 )yCloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C.

6 )alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylamiinocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R1 2 ; or R' 4 and R" together fornm a

(C

3 .1 2 )cycloalkyl ring; and t is 0 to 6. [00461 In some embodiments of compounds of formula II, X is CH 2 ; the ring containing X is saturated; R', A 2 , RN are hydrogen; and R 25 is a group of the formula: R21-0-(CH2)1i_ where R21 is hydrogen; (Cj.s)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 2 ; and t is 0 to 6. In other embodiments of compounds of formula II, X is CH 2 ; the ring containing X is saturated; R', R, R and RM are hydrogen. In still other embodiments of compounds of formula II, X is CHR 2 ; the ring containing X is saturated; R', R 2 , R 24 are hydrogen; and R 26 is

(C,.,

2 )alkyl; (C2.12)alkenyl; (C 2 -nz)alkynyl; (C 3 .12) cycloalkyl; or (C 3

.

1 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R1 2 , 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 CH 2 ; the ring containing X is saturated; R', R2, R 2 ' are hydrogen; and R 2 is phenyl optionally mono- or independently plurisubstituted with R'. 36 [0,047I COmp~unds of foriula HI whemrin X is CH 2 , the ring containing X is saturated; R', R 2 , 1seihydrzgen; ~azi R is 1

(CI

2 ). where 7 s 2-oxopyrrolidiny); (C. 6 )allkoy; pbony; phenoxy; (ti 4 )oycioalkyl; [3.3.3] bioyclinoarbzocyclic roiety; pyidinyl; naphthyl; cycloh6Xcenyj; (Ct .g)alkylcarbonyli; (C3.I2)cyloalkyloarbobfyl benzyl; hentoyl; pyritnidinyl; phenylamino-atbonyl; alkylsulfonyl; pheylsulfOiyl; or admantyl; where the cycloalkyl ring is optionally sabatituted with hyeroxy(C.4)alkyl; Where the 2 oxopyrrolidinyl, (C 1 4alkocy, pheny pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocaibonylalkylsullony, phanyltulfontyl, and naphthyl groups are optionally mono- or independently di- ot indepehdeuitly trisubstituted with R1 2 ; where the phenoxy group is optionally mono- or independently disubstituted with (Cj4)akyI (Ci.4)akoxy, or halogen; and where the [3.3,11) bicyclir carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1.s)alkyl; p is 0 to 3; and R' 2 is halogen; trifluoromethyl;cyano; nitro; (C4alkyl; (C 1 )alkoxy; Gycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C 1

.

6 )alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonanido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; and p is 0 to 3. [0048] Compounds of formula H include those wherein X is CH 2 ; the ring containing X is saturated; R', R 2 , R 24 are hydrogen; and R 26 is (R' 3

)

2

CH(CH

2 )q-; where R 3 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R1 2 ; and q is 0 to 3. [0049] In some embodiments of compounds of formula U, X is CH 2 ; the ring containing X is saturated; R', R 2 , R 24 are hydrogen; and R 26 is a group of the formula:

R

15 R14/N>CHzh where R'4 and R'S are independently hydrogen; (CI.s)alkyl; (C1 )alkylcarbonyl; (C3. 1 2)cycloalkyl ring; (C3.a 2 )Cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylarnino-carbonyl; alkyisulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C..)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phonylamninocarbonyl, alkylsulfonyl, and phenyisulfonyl groups are 37 rtionally miono- 9r ind~ederttly di-sstituted with R 1 ; or R- nd R together fom a (t3a2)yoloaikyl ing; and r is-0 or .2 o '6. [01)501 i dther eimbodirnents of compounds of formula II, X is. CHI; the ting containing X Is aturated; R', R, R 24 are hydrogen; and R 6 is a groupof the formula: where'R" is hydrogen;:(C 14 )alkyl; benzyl; or phenyl; in which the benzyl and phenyl gtoups are optionally mnho- or independently di-substituted on thd ring With R'; and t is 0 or2to 6. 1.00511 Compounds of forinula II include those that have the formula: OR' 0 2 H m

R

2 5 In sone such embodiments, R is phenyl optionally mono- or independently plurisubstituted with R11. [00521 In other embodiments of compounds of formula II, the compound has the formula: OR'

B-OR

2 Nn N

R

2 3 [0093] Compounds of formula .I alSo include those that have the fornrula: OR' H B-OR 2 ROW

R

28 wherein: R and , Are each iNdependetly hydrogen, hydroxy, alkyl, alkoxy, aryloxy, or halogen. MN4 kh some embodiments ofweOmpounds of formula I wherein CR'R is present, the compound has formula Ill: k is 0 to 3 and m is 0 to 3 when Y is C0; ROis a) hydrogen; b) (C 1

.

2 )alkyl; (C 2

.

1 )alkenyl; (C 2

.

12 )alkynyl; (C 3

.

12 ) cyclo alkyl; or (C 3 . 1 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 6 , and where-the ailkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;

R

6 is (Ci~ealkyl; (C 1 .)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C 1 .,)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups 39 are optignally mono- or indlpendo ny plurisubstituted with A' 7 ; amino, where' the amino group is optionally inOna.- or independefitly plusldibstituted with R") -80; -S0IR'; COR; -C 2 R, CONHIe, -CON(R), OR orS-R!; R is halogen, (Ci.q)alky; (C 1 )allxy; (C.

1 o)alkylaMin, (Cmo) dialkylamino; benzyl; benzyloxy; hydoyl(C 1 , alkyll; hydroxymIethyl; nitro; trifluoromethyl; trifluoromethoxy; trifAoromethylthio; N-hydroxyimino;:cyano; carboxy; acetamido; hydroxy; sulfamoyl;k ulfonamido, t earbatuoyl; R is (CI.ie)alkys (C 2 1)alknyl; (Cg.)alkynyl; (CMo)eyeloalkylI (Cs. 10)cyoloalkenyl; benzyl; phenethyl; aryl; or beteroary; where the alkyl, alkenyl, alkynyl, cycloalkyl, eyaloalkenyl 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.w)oycloalkyl; or heteroaryl optionally fused to a (C 3 -io)cycloalkyl; where the aryl and heteroatyl 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 yI)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 pilunrisubstituted with hydroxy, (Ci-s)alkyl, (CI,4)akoxy, (Ct.g)alkanoyloxy, or R'R>N-CO-O-, where R! and R1* are independently (CI-s)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (CiS 4 )alkyl, (C 1 .s)alkoxy, halogen, or trifluoromethyl, or R 9 and R'" together are (C3.6)alkylene; e) R"'(CHz),- where R"' is 2-oxopyrrolidinyl; (Cj,)alkoxy; phenyl; phenoxy; (C,.s)cycloalkyl; [.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexanyl; or adamantyl; where the 2-oxopyrrolidinyl, (Ci -)alkoxy, phenyl,. pyridihyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R'; where the phenoxy group is optionally mono- or independently disubstituted with (Ci.4)akyl, (C.

4 )alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Ci.s)alkyl; and p is 0 to 3; 40 W is haloge); t jfluoromdth4l; Gyano; nitro; (C,.&)alkyl; (Ct.-)alkoxy; cycloalkyl; caboxy;.acetamido; hydroxy; hydtoxy(CI.4)alkyl; hydroxymethyl; trifluoromethxy; sulfamoyl; eaarboyl; sulfQoamidD; alkylsufonyl; phenylsulfonYl; aryl; heteroaryl; where the aryl and hetetoaryl groups are opionally mono- or indpendently plurisubstituted with W; S(W )2CH(CI)4-, where R' 3 is phnyl; in which the phenyl grups are independently optionally miono- or independently disubstitutedwith R 2 ; and q is 0 to 3; g) a group of the formulate RW R14 (CH 2

)

where R1 4 and R" areindependently hydrogen; (Ci.,s)alkyl; (C. 6)alkylearbonyl; (C3.

12 )cycloalkyl ring; (C3.1.)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 R"; or R 4 and R' 5 together form. a (C 3

.

12 )cycloalkyl ring; and r is 2 to 6; h) a group of the formula:

R

17 R16 8 A (CH) 6 where R1 6 and R" are each independently hydrogen; (C,-A)alkyl; (C,. 6 )alkylcarbonyl; di-(C IO)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylarminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 2 ; or R1 6 and R4 together form a (C 3 .1 2 )cycloalkyl ring; and s is I to 6; 41 i) a group of the formula: R .* RU where )kI and R1 9 are independently hydrogen; (C,.a)alkyl; (C 6 )alkylearbotiyl; di-(CI4)alkylamidcarbonyl; bexayl; benzothiazole; betnzoyl; pyridine; pyrimidinei phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl;where the benzyl, benzoyil, benzothiazole, pyridine, pyriniidine, phenyl,.phenylaminoqarbony, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently.di substituted with R' 2 ; or R' 8 and R' together form a (C 3 .)cycl6alkyl ing; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH 2

-C(CH

3 ) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R1 2 ; k) a group of the formula: (CH )&_4 r 2 (CH2)t- o Ry RY/ or O N u where R 20 is hydrogen; (C..s)alkyl; (CI.

4 )alkylcarbonyl; di-(CI.6)alkylaminocarbonyl;

(C

3 , g)cycloalkylcarbonyl; benzyl; benzoyl; (CI-6)alkyloxycarbonyl; arikyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaninocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R1 2 ; R, is hydrogen; (C,.s)alkyl; (C 3

.

2 ) cycloaikyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R1 2 ; R, is absent or is halogen, (C,.s)alkyl, (CI,)alkojy, 0-alkylcarboxylate, 0-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; 421 s is i to: 6 t is to 6i nti ais04to 3; 6r 1) a group af the frinula: where l 2 is hydrogen; (C,.s)alkyl; benzy; or Ohenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the rign with A'z; eaeh t is ind6pendently 0 to 6; and u is 0 to 3; each R 2 is independently: a) hydrogen; b) (,., 2 )alkyl; (C2-.,)alkenyl; (C.1,)ailkynyl; (C, ) cycloalkyl; or (C 3 . 12 )6yciatlkenyl; *here the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R" 2 , and where the alkyl, alkenyl, alkyny! 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 R 12 ; d) R"(CH 2 )p- where R1 is 2-oxopyrrolidinyl; (C1 )alkoxy; phenyl; phenoxy; (C .8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (C, s)alkylcarbonyl; (C 3

.,

2 )cycloalkylcarbonyl; benzyl; benzoyl; pyrimiidinyl; phenylamitiocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C,4)alkyl; where the 2-oxopyrrolidinyl, (C. 6 )alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R1 2 ; where the phenoxy group is optionally mono or independently-disubstituted with (CIA)alkyl, (C.

4 )alkoxy, or halogen; and where the [3.3.3] bicyclic catbocyclic moiety is optionally mono-or independently plurisubstituted with (C,.s)alkyl; p is 0 to 3; and R1 2 is halogen; trifluoromethyl; cyano; nitro; (CI-,alkyl; (C,4)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C,4)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R?; 43

(R

13 )2C(CH 2 )q, where R.

3 is phenyl; in which the phenyl groups ae independently optionaly mon-r independently disubstituted with R'; and q is 0ta 3; f) a group of the formula:

R

15 where A" and R'" are independently hydrogen; (Ci.8)ayl; (Ci.

6 )alkylcarbonyl; (C 3 . 12)oYelOalkyl ring; (C 3 .I)cgycloalkeiyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylanino-.arbonyl; akylsulonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(CW.,)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R"; or R" and R 5 together form a

(C

3 .12)cycloalkyl ring; and s is 0 to 6; or g) a group of the formula: R21-0--(CH2)t where R 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 R 2 ; and t is 0 to 6;

R'

5 is: a) hydrogen; b) (Ct 12 )alkyl; (C 2

-

12 )alkenyl; (C 2

-

12 )alkynyl; (C 3 12 ) cycloalkyl; or (C 3 . I2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 1 2 , 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 mtono- or independently pluritubstituted with R1 2 ; d) R1(CH 2 )- where R" is 2-oxopyrrolidinyl; (C1.6)alkoxy; phenyl; phenoxy; (C 1 .,s)cycloalkyl; [3.3.31 bicyclic carbocyclic moiety, pyridinyl; naphthyl; cyclohexenyl; (C,.s)alkylcarbonyl; (C3.12)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C 1 -6)alkyl; where the 2-oxopyrrolidinyl, (C 1 . 6 )alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, 44 alkylsulfonyl,, phenylsulfonyl, a -d IpAphthyl groups &e optionally anWeo- rf independently di- or.independefttly trsubstituted with R' 2 ; whoe the-phenoXy group is optionally mono or independently disubstituted with (Ci.4)alky (C, 4 )alkxy, or halogen; and whore the [3.3.3] bicyclic carbooyli o moiety is optionAlly mono-or independently pluisubstituted with (C 14 )alkyl; p is 0 to 3; and R" isihalogen; trifluorormethyl; oyano; nitM; (Cia)alkyl; (C.

4 )alkoxy; cycloalkyl; carboxy; acetainido; hydroxy; hydroxy(CIo)alkyli hydrtxyurethyl; trifluoromethoxy; sulfamoyl4 carh=nyl; sulfonamido; aicylsutbnyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; e) (R 1 )2CH(CHj)q, Where Rt 3 is phenyl; in which the pbe.yl groups are independently optionally mono- or independently disubstituted with R 2 ; and q is 0 to 3; f) a group of the formula: R15 R N14 CH 2 )twhere R 4 and R" are independently hydrogen; (C,.s)alkyl; (Cji)alkyldarbony; (C 3 . 1 2 )cycloalkyl ring; (C 3

.

12 )cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C 1 .)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 2 ; or R 4 and R' 5 together form a

(C

3

.,

2 )cycloalkyl ring; and t is 0 to 6; or g) a group of the formula: R2'-- (CH2)i where R is hydrogen; (Ci.s)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 2 ; and t is 0 to 6; and

R

26 is: a) hydrogen; b) (CI-iz)alkyl; (C2.12)alkenyl; (C 2 )alkynyl; (C 3

.

12 ) cycloalkyl; or (C 3 . 1 2 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are 45 6ptionally tonO- 0r'independently plurisubstituted with R'ird where the alkyl, alkenyl, alkynyl portions include linear or branohed chains and may include cyclic portions; d) aryl;.Qr heteroaryl; where-the atyl:and heteroaryl groups are optionally mono- or independently-pItitisubstituted with R ; d) R'(CH 2 )g-, where Rais 2-oxo'pyrrolidinyl; (C, 4 )alkoxy; phenyl; phenoxy; (Ci.g)vyaloalkyl; f33.31 bicyclic carbocychlo moiety; pyrkin yI; naphthyl; cyclbohxenyi) (C, g)alkyloarbonyl; (Osy)cycloalkylcarony1; benayl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfbnyl; or adahil* where the cycloalkyl ting is optionally substituted with hydroxy(C 1 ,.)alkyl; where the 2-6xcpyrrolidinyl, (Cl. 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenyIaminocarbonyl, alkylsulf'onyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R1 2 ; where the phenoxy group is optionally mono or independently disubstituted with (C,4)alkyl, (C.4)alkoXy, or halogen; and where the [3.3,3) bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C,.g)alkyl; p is 0 to 3; and R is halogen; trifluorornethyl; cyano; nitro; (C,4)alkyl; (CI-6)alkoxy; cycloalkyl; carboxy; acetarnido; 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 R 7 ; e) (R' 3 )2CH(CH 2 )q-, where R1 3 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R; and q is 0 to 3; fagroup of the formula: R N " (CH2)r__ 14 1 where R 4 and R1 5 are independently hydrogen; (C..s)alkyl; (C4)alkycarbonyl; (C 3 . 2 )cycloalkyl ring; (C 3 .12)cycloalkenyl ring; benzyl; behzoyl; pyridine; pyrimidine; phenyl; phanylamino-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 46 optionally miono or independently di-substituted with R' 2 ; or R' 4 and k- together formT a (C.ta)cyoloalkyl ring; and r is 6 or2 -to 6; or g) a group of the formula: RE'-.C-(CH2)1 where R" is hydrogen; (Ci.g)alkyl; benzyl; or phenyl; in which the benzyL and phenyl groups We optionally mono- or independently di-substituted on the ring with R"; and t is 0 br.2 to 6. [0055] Compounds of formula M include those wherein X is CH 2 ; the ring coitaining X is saturated; and R1, R 2 and R are hydrogen; those wherein X is CH 2 ; th ring containing X is saturated; R), R and R 25 are hydrogen; and R 24 is hydrogen; and those wherein X is CU 2 ; the ring containing X is saturated; R', R 2 and R 5 are hydrogen; and R 24 is (C1.i 2 )alkyl; (C2 I)alkenyl; (C 2

-

12 )alkynyl; (C 3

.

12 ) cycloalkyl; or (C3.

1 2 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R', 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 CH 2 ; the ring containing X is saturated; R', R 2 and R2 are hydrogen; and R 24 is phenyl optionally mono- or independently plurisubstituted with R . In other embodiments, X is CH2; the ring containing X is saturated; R', R 2 and Rare hydrogen; and R 24 is R"(CH 2 )- where R" is 2-oxopyrrolidinyl, (Ci.6)alkoxy, phenyl; phenoxy; (Cl.s)cycloalkyl; [33.3] bicyclic carbocyclic moiety, pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2 oxopyrrolidinyl, (Ci.6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono or independently di- or independently trisubstituted with R1 2 ; where the phenoxy group is optionally mono- or independently disubstituted with (C.4)alkyl, (CJ4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Ci.g)alkyl; p is 0 to 3; and R 2 is halogen; trifluoromethyl; cyano; nitro; (C 14 )alkyl; (Ci.

6 )alkoxy; cycloalkyl; carboxy; acetarnido; hydroxy; hydroxy(C 6 )alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamide; alkylsufonyl; phenylsulfonyl; aryl; heteroaryI; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 . In still other embodiments, X is CH 2 ; the ring containing X is saturated; R', R 2 and R 2 3 are hydrogen; and R 24 is 47 (R1)2CH{Cl)q, where' is phenyl; in which the phenyl groups are indepenterttly optionally Mon- or independently substituted with P'; and q is 0 to 3. (00511 ConWdutids of fornula III include those Wherein X is CH 2 ; the ring containing X is saturated; R 2 and RS are hydrogen; and R isa group of the formula:

R

15 R14' 'CH 2

)_

where R1 4 and R" 5 are independently hydrogen; (C 1 .s)alkyl; (Ci_)alkylcarbonyl; (C 3 . t2)cyel0alkyl ring; (C3-i.)Pycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino,carbonyl; alkylsulfony1; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C.6)alkyl, and where the benzyl, benzoyl, pyridine, pyrinidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R' 2 ; or R 4 and R 15 together form a

(C

3

.

12 )cycloalkyl ring; and s is 1 to 6. [00581 Compounds of formula III also include those wherein X is CH 2 ; the ring containing X is saturated; R', R 2 and R are hydrogen; and R 4 is a group of the formula: R1-O--(CH2)t where R 2 1 is hydrogen; (C.s)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R1 2 ; and t is 0 to 6. [00591 In some embodiments of compounds of fonnula III, X is CH 2 ; the ring containing X is saturated; R1, R 2 and R 24 are hydrogen. In other embodiments, X is CH 2 ; the ring containing X is saturated; R', R 2 , R 24 are hydrogen; and R 5 is (Ci.

12 )alkyl; (C 2

.

1 2)alkenyl;

(C

2 .1 2 )alkynyl; (C 3

.

12 ) cycloalkyl; or (C3.

1 2)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. In still other embodiments, X is CH 2 ; the ring containing X is saturated; R', R 2 , R1 4 are hydrogen; and R 25 is phenyl optionally mono- or independently plurisubstituted with R4. 48 [10A60 In soine efmboditbat8 of compounds of formula III, X is CH 2 ; the ring winaining X isstured; R', R, R 24 e hydrogen; and R 25 is R1(CH 2 ),- where R" is 2 0xppyrrol yJ, (C 1 s)alkoxy, phenyl; phenoxy; ( s)cycloalkyl; [3.3.3) bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; Where the 2 oxopyrrolidinyl, (Cdj)alkoxy, phenyl, pyridinyl, and haphthyl groups are optionally rnono or idependently di- or indepenrdently trisubstituted with R; where the phenoxy group is optionally mono- or independently disubstituted with (CIA)alkyl, (CIA)alkoxy, or halogen; and where the [3.3bigyolic carbocyelio moiety is optionally mono-or independently plurisubstituted with.(C.g)alkyl; p is 0 to 3; and R1 2 is halogen; trifluoromethyl; cyano; nitr (C,.

6 )alkylI; (CI-ailoxy; ycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C. 6 )alkyl; hydroxymethyl; trifluorometboxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally rhoio- or independently plurisubstituted with R. [00611 In other embodiments of compounds of formula III, X is CH 2 ; the ring containing X is saturated; R', R 2 , R 24 are hydrogen; and R 2 ' is (Rs) 2

CH(CH

2 )q-, where R1 3 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R ; and q is 0 to 3. In still other embodiments, X is CH 2 ; the ring containing X is saturated; R, R , R 24are hydrogen; and R is a group of the formula: R16. R14 N (CH 2 )A where R 14 and R 5 are independently hydrogen; (C 1 .s)alkyl; (C 1 .4)alkylcarbonyl; (C 3 . 12 )ycloalkyl ring; (C 3 .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 R 2 ; or R1 4 and R 5 together forth a

(C,.

12 )cycloalkyl ring; and t is 0 to 6. [0062] In certain embodiments of compounds of formula III, X is CH 2 ; the ring containing X is saturated; R', R 2 , R 24 are hydrogen; and R 25 is a group of the formula: 49 where R 2 ' is hydrogen; (C.s)alkyl; benzyl; or phenyl; in which the bentyl and phenyl groups are optionally mono- or independeitly di-substituted on the ringwith R1 2 ; and. t is 0 to 6. [0063] In some embodiments of congpounds of formula III, X is CHi; the ring containing X is saturated; R', R2, R 2 4 and are hydrogeh. In other embodiments, X is CH 2 ; the ring containing X is saturated; RI , R2 4 are hydrogen; and R2 6 is (Ci.

12 )alkyi; (C.ujalkenyl;

(C

2 .)alkynyl; (C 3

.

1 z) cycloalkyl; or (C3-.)Qycloalkenyl; where the alky, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R1 , 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; R', R 2 , R 2 4 are hydrogen; and R 26 is phenyl optionally mono- or independently plurisubstituted with R' 2 . Compounds of formula III include those wherein X is CH 2 ; the ring containing X is saturated; R', R2, R are hydrogen; and R 26 is R 27

(CH

2 )p-, where R 27 is 2-oxopyrrolidinyl; (C .

4 )alkoxy; phenyl; phenoxy; (Ci.s)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (C-s)alkylcarbonyl; (C 3

.

1 2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C 1

.

4 )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 R1 2 ; where the phenoxy group is optionally mono- or independently disubstituted with (C .4akyl, (C14)alkoxy, or halogen; and where the [3.3,3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Ci.s)alkyl; p is 0 to 3; and R 1 2 is halogen; trifluoromethyl; cyano; nitro; (CI.

4 )allkyl; (C1-6)9lkoxy; cycloalkyl; catboxy; acetarnido; hydroxy; hydroxy(C.

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 CH2; the ring containing X is saturated; R', R 2 , R 2 are hydrogen; and R 26 is (' 3

)

2

CH(CH

2 )4-; where R is phenyl, in 50 which the phenyl otoupsiare independently optionaly finbo- 6r independexitly disubstituted With R 12 ;nd e Is o to 3, [00641 Compounds of fornula III include those wherein X is CH 2 ; the ring containing X is. saturated; R , Rk, R 4 4 are hydrogen; and R 2 6 is a group of the formula:

R

15 R14""(CH2)r whee R' 4 antd R" lare independently hydrogen; (C 1 g)alkyl; (C I 6 )alkylearbonyl; (C.. 2 )cyloalkyl ring; (C.)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloaikyl ring is optionally substituted with hydroxy(C.3)alkyl, and where the ben2zyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R"; or R1 4 and R' 5 together form a

(C

3

-

12 )cycloalkyl ring; and r is 0 or 2 to 6. [00651 Compounds of formula III also include those wherein X is CH 2 ; the ring containing X is saturated; R', R 2 , R 24 are hydrogen; and R 26 is a group of the formula: R21-O--(CH2)t where R 2 1 is hydrogen; (C I-)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. f00661 In soie 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: RIO RIO 0 B-OR 2 0 B-OR 2

H

2 N N H 2 N N Ll L R- R- I - z z (IVA) (IVB) 51 wherein Ris a) hydrogen; b) (Ciai2)alkyl;(C 2

.,

2 )alkenyl; (C 2 a.

2 )alkynyl; (C 3 4)yclotky1; or (C 3 . 1 )cycloalkenyl; where the alkyI, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R' 2 , and where the alkyl, slkenyl, alkynyl portions include linear or branched chains and may include oyolickportions; e) aryl; or heteroaryl; where the aryl and heteroaryl groups ar optionally mono- or independently plurisubstituted with P 2 ; d) R" (CH 2 ),- where R1 is 2-oxopyrrolidinyl; (CIaalkoky; phenyl; phenoxy; (CI-s)cycloalkyli [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidnyl, (Cl-&)akoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R"; where the phenoxy gtoup is optionally mono- or-independently disubstituted with (CI4)alkyl, (C 1 4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Ci-g)alkyl; p is 0 to 3; and

R

2 is halogen; trifluoromethyl; cyano; nitro; (Ci.

6 )alkyl; (CI-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cl.6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; e) (R") 2

CH(CH

2 )q-, where R1 3 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R 2 ; and q is 0 to 3; f) a group of the formula:

R

15 R4N>(CH 2 )s' where R1 4 and RIS are independently hydrogen; (Ci.s)alkyl; (Ci1.4)alkylcarbonyl; (C 3 . 12 )cycloalkyl ring; (C 3 .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, pyimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are 52 'optionally mono- or independently di-substituted with R 2 ; pr R' and R 5 together fem a

(C

3

,.

2 )ycloalkyl ring; and s is 0 to 6; or g) a group of the formula: R2--' (CHZ)t whee R2' is hydrogen; (C 1 .8)alkyl; benzyl; orphenyl; in which the benzyl aInd phenyl groups are optionally mono- or independently di-substituted on the ring'with'; and t is 0 to 6; [0067] It has further been discovered that certain boronic acid comopounds ofthe invention .an exist as either linear or cyclic isomers. Typically, such compounds form an equilibrium mixture in aqueous solution. As shown in Figure 1, the doncentration of 'the two isomers of such compounds is typically pH dependent, Thus, it is expdated 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:

R

5 H R OR' R \/ OR'

R

5 HN R 4 I OR2 R 4 1 N I OR2 B e B 0 N n X X z z VA VB including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein: n is 1 to 3; X is CH 2 ; S; 0; CF 2 or C(CH 3

)

2 ; Z is H; halogen; hydroxyl; (C.)alkoxy; (Ci.

12 )alkyl; (C 3

-

12 )cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; 53: optionally, X together with an adjacent ring carbon and Z form -a fused cycloprpyl; and optionally, one of the bonds in the ring containing X is a double bond; R and R 2 independently or together are hydrogen; a boronic acid protecting gmup; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; RI, R and 1W are selected from (dd) or (ee): (4d) R' and A 4 are hydrogen; and R' is a) hydrogen, provided that R 5 is not hydrogen when n i's 1, X is CH 2 , and Z is H; b) (C.

12 )alkyl; (C 2

.

12 )alkenyl; (C2- 12 )alkynyl; (C 3 12 ) cyoloalkyl; or (C).-)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with k 6 , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (C 1

.

6 )alkyl; (CI-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(CI-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 R 8 ; -SOR 8 ; -SO 2 Re; -COR 8 ; -C0 2 R, -CONHIR 8 ; -CON(R 8 ) 2; -OR 8 ; or -S-R8;

R

7 is halogen; (C 1

.

1 o)alkyl; (CI.,o)alkoxy; (C,.,o)alkylamino;

(C

1

.

1 0 ) dialkylamino; benzyl; benzyloxy; hydroxyl(C.

6 )alkyl; hydroxymtiethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;

R

8 is (Cj.io)alkyl; (C 2 -o)alkenyl; (C 2 .io)alkynyl; (C 3 . 1 6)cycloalkyl; (C 5

.

1 o)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; 54 Idy - I ) aryl optioMally fUsed to a (CaO)ycloallyl; or heteroaryl optionally fused to a (C.o)cypIlalky; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; d) indanyl; 1,2,34-tetrAhydronaphthyl; (CH2)jadanantyl in whichj is 0-3; or a [2.2.1]tor [3..1)] bicyclic carbocyclic moiety, including (4 pentylbicyelo[2.2.2]oct- I -yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl,

(CH

2 )j adamantyl, and [2.2.1) or [3.1.1] bicyclic carbocydlic moieties are optionally mnono- or independently plurisubstituted with hydroxy, (C..)alkyl, (C 1 .s)alkoxy, (Ct.S)alkanoyloxy, or RR"ON-CO-0-, where R 9 and R' 0 are independently (C.s)alkyl, or Ohenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Cs)alkyl, (Ciag)alkoxy, halogen, or trifluoromethyl, or R 9 and R' 0 together are (C 3 .)alkylene; e) R"(CHg)- where R" is 2-oxopyrrolidinyl; (CI-6)alkoxy; phenyl; phenoxy; (Ci-s)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Ct.6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R1 2 ; where the phenoxy group -is optionally mono- or independently disubstituted with (C.4)alkyl, (C.4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (CI 4 )alkyl; and p is 0 to 3;

R

2 is halogen; trifluoromethyl; cyano; nitro; (C 1 -4)alkyl; (C 1 4 )alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Ci.6)alky); hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R; f) (R4)2CH(CH2)q, where R 3 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R1 2 ; and q is 0 to 3; g) a group of the formula: R's R14N(CH 2 )r ' where R1 4 and R's are independently hydrogen; (Cl.a)alkyl; (C,._)alkylcarbonyl; (C 3 . 1 2 )cycloalkyl ring; (C 3 1 2 )cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; 55 phehylanihio-Oab'nYl; alky1gulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionallysubstitute4d with ydroxy(Ci- )alkyl, and where the benzyl, benzoyl, pyridine, pyrnmidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R; or R and R' together form a (CAi 2 )cycloalkyl ring; end r is 2 to 6; h) a group of the formula: (RH1) 3 (I where R 6 and R1 7 are each independently hydrogen; (C,.S)alkyl; (Cj_6)alkylcarbouyl; di-(C,. 6)alkylalainotarbcknyl; bonzyl; benzoyl; pyridino; pyrimidine; phenyl; phenylamino.arbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R; or R' 6 and R" together form a (C 3

.

12 )cyloalkyl ring; and s is I to 6; i) a group of the formula: CH2)td R18 where R' 8 and R' 9 are independently hydrogen; (Ci.s)alkyl; (CI.

4 )alkylcarbonyl; di-(Cj. 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 R1 2 ; or R 8 and R' 9 together form a (C 3

.

1 2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH 2

-C(CH

3 ) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R1 2 ; k) a group of the formula: R20 o(CH2) R (CH 2 )-A R R (CH 2 )-4 RyIuor R 25N uor 56 where R 20 is hydrogen; (Ci alkylyl; (Ci.

6 )alkylcarbonyl; di-(C i-)alkylarninocarbony; (C. 8 )cycloalkylcarbonyl; benzyl; benzoyl; (Cr.

6 )alkyloxycarbonyl; arlkyloyoarbdnyI, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylarninoOarhonyl; 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 ; R, is hydrogen; (Ci.e)AlkYl; (C 3

,

2 ) CyCloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally rmono- or independently di-substituted on the ring with R'; R, is absent or is halogen, (C -g)alkyl, (C 1s)alkoxy, 0-alkylcarboxylate, 0-aralkylcarboxylate, N-alkylcarboxamnido, N-aralkylcarbokarnido; 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:

(CH

2

)

R

2 1 -O-(CH u where R 2 1 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 R1 2 ; each t is independently 0 to 6; and u is 0 to 3; or (ee) R , R 4 and R 5 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-aminio, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aninosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; provided that when n is 1, X is CH 2 , the ring containing X is saturated, and Z, R 3 and R 5 are H, R 4 is not a side chain of a naturally occurring ca~amino 57 acidg, and provided that when n is I, X is CH 2 , the ring containing X is saturated, and 2 and R g'e,5lI, R 3 'and R4 are not both mnethyl;.and wherein the bond containing the Vavy line signifies-the point of attachment. 106681 In soxne embodiments of compounds of fobnula VA and VB, R' and R 2 independently or together are the boronic acid protecting group formed from (+)-pinanediol; 'pinao.ul; 1,2-dioyolohexyl-ethanediol; 1 2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3ibutnediol, diisopropyl tartrate; 1,4-butanediol; diisopropylethanedioi; (S,S,)-5,6 eg-anediol; 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 R 2 independently or together are a group capable of being hydrolyzed to a hydroxyl group in an aqueous soluton at physiological pH or in biological fluids formed from 1,2-dicyclohexylethanediol; 1,2-ethanediol; 1,3-propanedidl; 2,3-butanediol, '14-butanediol; diisopropylethanediol; methanol; ethanol; isopropanol; or 1-butanol. [0069] In some embodiments of compounds of formula VA or VB,

R

3 and R 4 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, alkynylanino carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylarnino, alkylsulfonyl, aminosulfinyl, aninosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; and R' is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; 58 alkylthioalkyl; Arylalkylthioalklyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or eyeldheotwallkylalkyl; all optionally mono- or independently pilurisubstituted with halogen) lkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, ycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, ycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyliacyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcbononyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl. [0070] In still other eibodiments of compouids of formula VA or VB, X is CH 2 ; the ring containing X is saturated; R', 1, R 3 and R 4 are hydrogen; and R5 is (Ci- 1 2 )alkyl; (C 2 12)alkenyl; (C2-12)alkynyl; (C 3

.

1 2 ) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions. In some such embodiments, R 5 is (C 3

-

12 ) cycloalkyl such as cyclopentyl. [00711 In some embodiments of compounds of formula VA or VB, X is CH 2 ; the ring containing X is saturated; R', R 2 , R 3 and R 4 are hydrogen; and R 5 is indanyl; 1,2,3,4 tetrahydronaphthyl; (CH 2 )j adamantyl in whichj is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]-oct- I -yl)arpine; 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, (Ct.s)alkyl,

(C

1 .e)alkoxy, (CI.)alkanoyloxy, or R 9

R'

0 N-CO-O-, where R 9 and R'* are independently (C 1 . s)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C .s)alkyl, (CI.

8 )alkoxy, halogen, or trifluoromethyl, or R' and R'* together are (C 3

.

6 )alkylene. [0072] Compounds of formula VA or VB include those wherein X is CH 2 ; the ring containing X is saturated; R', R 2 , R and R 4 are hydrogen; and R 5 is R"(CH 2 )p- where R" is 2-oxopyrrolidinyl; (Ci- 6 )alkoxy; phenyl; phenoxy; (C1.s)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2 59 oxopyrrolidinyI, (Cs)alkoxypheny, pyridinyl, and naphthyl groups are-optionally mono or independently di- or independently trisubstituted with R' 2 ; whertihe phenoxygroup is optionally moho- or indep.fidently disubstituted with (.C.)aikyl, (C )alkoxy, or halogen; and where the [3.3.3] bioYcli carbocyclic moiety is optgnally rnono-Qr independently plurisubstituted with (C 14 )ulkyl; p i 0 to 3; and 1 2 is halIgen; trifluoromethyl; ryano; nitro; (Co)alky; (CI.

6 )?ikoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C. 6 )alkyl; hydroxcymathpl; triflu6romethoxy, sulfanloyl; earbatanyl; sitifonarido; alkylsufonyl; phentylsulfonyl aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 . [00731 Compounds of VA or VB further include those wherein X is CH 2 ; the ring containing X is saturated; R', RE,. and R 4 are hydrogen; and R' is (RD)1CH(CH 2 )q-, where R 3 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R' 2 ; and q is 0 to 3. [00741 In some embodiments of compounds of formula VA or VB, X is CH 2 ; the ring containing X is saturated; R', R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula: R14N (CH 2 )r * where R' 4 and R 5 are independently hydrogen; (Ci.s)alkyl; (C.6)alkylcarbonyl; (C 3 . 12 )cycloalkyl ring; (C3.1 2 )cydloalkenyl 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, phenylarninocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R' 4 and R' 5 together form a

(C

3

.

2 )cycloalkyl ring; and r is 2 to 6. [0075] In other embodiments of compounds of formula VA or VB, X is CH 2 ; the ring containing X is saturated; R', R 2

R

3 and R 4 are hydrogen; and R 5 is a group of the formula: R17

R'

6

(CH

2

)

5 60 where R and '' are each independently hydrogen; (C,.s)alkyl; (Ci.6)alkylcarbonyl; d[(C, S)ikylaminobai-on94 benzyl benzoyl; pyridinel pyrimidine; phenyl; phenylanincarbonyl; slkylsulfoztyl; or phenytsulfonyl; where the benzy1, beuzoyl, pyridine pyriddine, phpenyl, phenylaminocarbottyl, alkylsulfenyl, and phenylsulfonyl groups ae optionally mono- or independently di-substituted with ); or R' and R" together form a (C 3 4)cydloalkyl ring; and s is I to 6. [0076) in certain embodiments of compounds of formula VA or VS, X is CH 2 ; the ring containing X is saturated; R', R2, R 3 and R 4 are hydrogen; and R 5 is a group of the formula: (CH2)II71I -RI where RiS and R 9 are independently hydrogen; (C 1 8 )alkyl; (Cj_)alkylcarbonyl; di-(Cj. 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 R 2 ; or R's and R' 9 together form a (C 3

.

12 )cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3. In some such embodiments, RS has formula:

(CH

2

)

Rig or N N I RIB [00771 Compounds of formula VA or VB further include those wherein X is CH 2 ; the ring containing X is saturated; R', R2, R3 'and R 4 are hydrogen; and R3 is a group of the formula: (phenyl-CH2-C(CH 3

)

2 -), where the phenyl group is optionally mono- or independently plurisubstituted with R 2 . 61 [0078] In some enibodiments of compounds of formula VA gr VB, X is CH 2 ; the ritg containing Xis saturated; R 1 , R', k' and R are hydrogen; and R' ita gtoup of the formula; WOAH2s or R 20

-

orx CH X(CH2)(CH 2 y2 Or RJ20 I4 Nou where R 20 is. hydrogen; (C 1 s)alkyl; (C .

6 )alkylcorbonyl; di-(C..-).alkylaminoearbonyl; (C 3 . s)cycloalkylcarbonyl benzyl; benzoyl; (Ci.)alkyloxycarbonyl; arkyloxycarbony, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocabonyl; ailkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R1 2 ; R. is hydrogen; (CO.s)alkyl; (C3.j2') cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R1 2 ; R, is absent or is halogen, (C.s)Alkyl, (Cis)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, R 5 has formula:. S (CH2)(CH 2 -4 N F20- or 20 [00791 In other embodiments of compounds of formula VA or VB, X is CH 2 ; the ring containing X is saturated; R1, R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula: (CH2) R2'O- _(CH u where R 2 ' is hydrogen; (Ci.s)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. In some such embodiments, R 5 has formula: 62 or [00801 Compourtdt of frmula VA or VB further include those wherein R' and R 2 are hydrogen; n is 1; X together with an adjacent ring carbon and Z forn a fused cyclopropyl; R', R and 1W are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cyncalkylalkyl; bi ycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroary; heteroarylaikyl; cycloheteroatkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxyearbonyl, 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: RI H R OR' R \/ OR' RSHN R 4 j OR 2 R N I OR 2 Be 0 N N -XX z , z or a mixture thereof. 63 100821 Compounds of formula VA or VB include thope having the formula:

R

5 H

R

3 OR' R \/ OR'

R

5 HN R 4 2QR2 RNo2 O 0N S ,S or a mixture thereof. [00831 In other embodiments, compounds of formual VA or VB include those having the formula:

R

3 O R '3 3 H \

R

5 HN R 4

OR

2 4 N OR2 O N 0 N or a mixture thereof; or the formula:

R

5 H R R OR'

R

3 \/ OR'

R

5 HN R 4

QOR

2

R

4 N I OR2 B eB O N 0 N or a mixture thereof. 64 [0084] Compounds of formula VA or VB further include those having the formula.:

R

3 1

R

5 H

R

5 HN R 4 I R2 R 4 '2 REORH O N 0 N or a mixture thereof. [00851 In still other embodiments, compounds of formula VA or VB have the formula:

R

3 OR R 3

R

5 1

R

5 HN R 4 IOR2 R 4 N OR2 B e O N O N F , F or a mixture thereof. [00861 In yet other embodiments, compounds of formual VA or VB have the formula: R5 H

R

3

OR

1

R

3 OR'

R

5 HN R 4 L.,OR2 R 4 N OR2 B 0 N N OH, OH, or a mixture thereof. 65 [6007] In still another aspect, the invention provides boronic acid inhibitors of dipptidyl peptidase-IV having an inhibition constantof 10 micromolar or less for dipeptidyl peptidase-IV. Suoh inhibitors comprises a bofaproline (including boropyrrolidines, boropiperidines, and boroazepanet) attached to an amino acid through an anide bond. The amino add cati be a beta-amino aid (including cyclic fonns such as , an N-eyeloalkyl-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. Ii some embodiments, the boronic acid inhibitor is of Formula I: OW

R

4

R

3 0 B-OR 2 z including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein: n is 1 to 2; X is CH 2 ; S; 0; CF 2 or C(CH 3

)

2 ; Z is H; halogen; hydroxyl; (C 14 )alkoxy; (CI- 1 2 )alkyl; (C 3 -1 2 )cycloalkyl; phenyl; or heteroaryl; where the phenyl. and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; 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; R' and R 2 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", R 3 , R 4 and 1- are selected from (aa), (bb) or (cc): (aa) R', R!, R 3 and R 4 are hydrogen; and R' is a) hydrogen; 66 b) (CI42)alkyl; (C2_:)aikenyl; (C2,12)alkygyl; (C3.12) cycloalkyl; or (CP 3 2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, oycloalkyi and oyoloalkenyl groups. are optionally mono- or independently plurisubstituted with R 6 ,:and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyelie portions;

R

6 is (C.6)aIkyI; (Ci.6)alkoxy; cycloalkyl; carboxy; acetamido; pyano; nitro; halogen; hydroxy; hydroxy(C 1 .4)alkyl; hydbxynethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R; amino, where aminoamino group is optionally mono- or independently plurisubstituted with R 8 ; -SOR'; -SO 2 R'; -COR; -CO 2 R!, -CONHR'; -CON(R) 2;. -OR'; or -S-R';,

R

7 is halogen; (C 1

.

1 )alkyl; (Ci.jo)alkoxy; (C.,o)alkylarnino; (Ci.

1 o) dialkylamino; benzyl; benzyloxy; hydroxyl(C-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;

R

8 is (Ci.

10 )alkyl; (C2-o)alkenyl; (C2-io)alkynyl;

(C

3 . io)cycloalkyl; (C5.io)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 R 7 ; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; c) aryl optionally fused to a (C3.Io)cycloalkyl; or heteroaryl optionally fused to a (C3.lo)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; 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)anine; where the indanyl, 1,2,3,4-tetrahydranaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally nono- or independently plurisubstituted with hydroxy, (C.s)alkyl, (CI.)alkoxy, (Ci.)alkanoyloxy, or

R

9

R'

0 N-CO-O-, where R9 and R" are independently (Ci.s)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Ci.s)alkyl, (Cj.s)alkoxy, halogen, or trifluoromethyl, or R9 and..R' 0 together are (C 3 -6)alkylene; 67 e) R"(CH 2 ), where R" is 2-oxopyrrolidilyl; (C,)aikoxy; phenyl; pherioXy; (Cig)yoyloalkyl; [3.33 bicyelio earbocydlie moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxo'pyrrolidinyl, (C,)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R' 2 ; where the phenoxy group is -optionally mono- or independently disubstituted with (Cd)alkyI, (C4)alkoxy, orhalogen; and where the [3.3.3] bicyclic ,carbobyclic moiety is optionally nono-or independently plurisubstituted with (C 1 .g)alkyl; and p is Oto 3; R1 2 is halpgen; trifluoromethyl; cyano; nitro; (C 1 )alkyl; (.. 6 )alkoxy; cycloalkyl; darboxy; acetamnido; hydroxy; hydroxy(C 1 )alkyl; hydroxymethyl; trifluoromethoxy; sulfathoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R; f) (R 1

)

2 CH(CH2)q-, where R1 3 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R2; and q is 0 to 3; g) a group of the formula:

R'

5 R14IN'-(CH2)r 'I where R 14 and R1 5 are independently hydrogen; (C 1 .)alkyl; (C 1 .)alkylcarbonyl; (C 3 . 12 )cycloalkyl ring; (C 3

,

12 )cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylarnino-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 R 1 2 ; or R' 4 and R' 5 together form a

(C

3

.

1 )cycloalkyl ring; and r is 2 to 6; h) a group of the formula:

R

17 Rie N (CH 2 )s where R 16 and R1 7 are each independently hydrogen; (C 1 .s)alkyl; (C.4)alkylcarbonyl; di-(Ci. 6 )alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, 68 pyidine, pyrimidine, phenylphenylamino arbonyl, alkylsulfonyl, and phenylsulfonyi groups ue optionally mono- or independently di-substituted with R"; or R and -R' 7 together form a (C. i)cycloalkyl ring; and s is I to 6; i) agroup of the formula:

(CH

2 )t 19 18 where R' 8 and R' are independently hydrogen; (Ci-g)alkyl; (C, )alyloarbonyl; di-(Ci )lkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenyisulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrinidinej phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R1 2 ; or R1 8 and R1 9 together form a (C 3

.

12 )cycloalky ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH2-C(CH 3 ) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R1 2 ; k) a group f: 20 Rx(CH2)

(CH

2 )t-4 Ry R (CH2) or R20-N o (r Ry" u . Ry u 1420 where R 20 is hydrogen; (C 1 .)alkyl; (C 1 .6)alkylcarbonyl; di-(C 1 4)alkylaminocarbonyl; (C 3 . .g)cycloalkylcarbonyl; benzyl; benzoyl; (C.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 R1 2 ; R, is hydrogen; (C,.s)alkyl; (C 3

.

12 ) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R' 2 ; R, is absent or is halogen, (C,.&)alkyl, (CI.s)alkoxy, 0-alkylcarboxylate, 0-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; 69 s is I to 6;'t is 0 to 6; and u is Oto 3; or 1) a group of the formula:

.(CH

2 )t-l R2'O--(CI 2) U wheiR 21 is hydrogen; (C .s)aIkyl; benzyl; or phenil; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R" ; each t is independently 0 to 6; and u is 0 to 3; (bb) R', R", 1W, R 4 and R5 are iidpendently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkyloycloalkyl; 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 R 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 I to 3 heteroatoms selected from N, 0, S, SO or SO 2 ; 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 RW and R5 together form -(CR 22

R

23 )m- where m is 2 to 6, and R 22 and R 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 70

R

4 and R' together with the atoms to which they are attached form a 5 to 7 mernbered ring containing a total of 2 to 4 heteroatoms selectegl from N, 0, $ SO, or

SO

2 ; or

R

4 and R 5 together with the atoms to Which they are attached form a 4 to 8emnenbered cyclohetetalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (cc) 1 and R 3 are hydrogen; ad R and R 4 together form a 4 to 8 membered pyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatorhs selected from. N, 0, S, SO and S0 2 , and includes single ring$, fused bicyclic and tricyclic rings, which are optionally monQ- or independently p'lurisubstituted with any of the groups set forth in (aa) or (bb) and

R

5 is any of the groups in (aa) or (bb); and if CR' is absent, then R 3 , R 4 and R 5 are selected from (dd), (ee) or (ff): (dd) R 3 and R 4 are hydrogen; and R' is a) (CI.

12 )alkyl; (C 2

.

12 )alkenyl; (C2- 12 )alkynyl; (C 3

-

1 2 ) cycloalkyl; or (C3.2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 6 , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R' is (CI-6)alkyl; (CI.6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(CI 4 )alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; amino, where the amino group is optionally mono- or independently plurisubstituted with RB; -SOR'; -S0 2

R

8 ; -COR; -C0 2 R, -CONHR 8 ; -CON(R) 2; -OR'; or -S-R;

R

7 is halogen; (Ci.io)alkyl; (Ci.io)alkoxy; (C1.1o)alkylamino;

(C

1

.

1 o) dialkylamino; benzyl; benzyloxy; hydroxyl(C.

6 )alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;

R

8 is (Ci.

10 )alkyl; (C 2 -io)alkenyl; (C2-o)alkynyl; (C 3 . 10 )cycloalkyl; (Cs.io)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, 71 aikenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono or independently pluribstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R'; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; b) aryl optionally fused to a (C 3 10 )eycloalkyl; or heteroaryl optionally fused to a (Ca..

1 o)cycloalkyl; where the aryl and heteroaryl groups are: optionally iono- or independently plurisubstituted with R 7 ; c) indanyl; 1,,3,4-tetrahydronaphthyl; (CI)adamantyl in which j is 0-3; or a (2,21] 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, (CH 2 )j adaiantyl, and [2.2.1] or [3.1.1) bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Ci.)alkyl, (C 1 )alkoxy, (C 1

.

8 )alkanoyloxy, or

R

9 "'N-CO-O-, where R 9 and R' 0 are independently (Ci.S)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently-plurisubstituted with (C 1 .s)alkyl, (Ci.s)alkoxy, halogen, or trifluoromethyl, or R 9 and R' 0 together are (C 3

.

4 )alkylene; d) R"(CH 2 ),- where R" is 2-oxopyrolidihyl; (C,.

6 )alkoxy; phenyl; phenoxy; (Ct.s)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adanantyl; where the 2-oxopyrrolidinyl, (CI-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, (CI.4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C, 4 8)alkyl; and p is 0 to 3; R1 2 is halogen; trifluoromethyl; cyano; nitro; (C 1 46)alkyl; (C 1 . 6 )alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C 1 .4)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; e) (R )2zCH(CH2)q-, where R1 3 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R1 2 ; and q is 0 to 3; 72 f) a group of the fornnulat where R1 4 and R' 5 areindependently hydrogen; (C1,s)alkyl; (CI.6)alkylcarbony; (C 3 . iz)cycloalkyl ring; (C3.i1)eycloalkenyl 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, pyriimidine, phenyl, pheniAminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R"; or R' 4 and R" together form a

(C

3 ...)cycloalkyl ring; and r is 2 to 6; g) a group of the formula: R16 (CIY where R 16 and R 7 are each independently hydrogen; (Ci-s)alkyl; (CI.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 R 2 ; or R1 6 and R1 7 together form a (C 3

.

12 )cycloalkyl ring; and s is I to 6; h) a group of the formula: S(CH2) R19 R --- (C 2t 1R 18 R where R1 8 and R' 9 are independently hydrogen; (Ci 8 )alkyl; (Ci.6)alkylcarbonyl; di-(C. 6 )alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaninocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 2 ; or R'S and R 19 -together form a (C 3 .,)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; i) a group of the formula: (phenyl-CH 2

-C(CH

3 ) 2), 73 where the phenyl group is optionally mono- or independently plurisubstituted with' 2; j) a group of the formula:

R

20 Rx{) R x '(CH 2

)

1 -A Rx{G g (CH A -t Ry . (C 2) Ry or W2ONJ' or N where, R 2 0 is hydrogen; (C..g)afkyl; (CI-6)alkylcarbonyl; di-(C1.6)alkylaminocarbonyl;

(C

3 . )cycloalkyloarbonyl; benzyl; benzoyl; (CI.6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl -substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phetiylamibcarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally rhono- or independently di-substituted with R 12 ; R, is hydrogen; (Ci.s)alkyl; (C 3

.

12 ) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R'; RY is absent or is halogen, (Ci.

8 )alkyl, (C.)alkoxy, 0-alkylcarboxylate, 0-aralkyicarboxylate, 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:

(CH

2

-

R2'O-(CH) )u where R 2 ' is hydrogen; (Ci.g)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R1 2 ; each t is independently 0 to 6; and u is 0 to 3; or (ee) R 3 and R 4 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 74 carbonyl, alkyliminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfdnylamiho, alkylaminocarbnyl-anmino, alkoxycarbonylarmino, alkylsulfonyl, aminosulfinyl, aininosulfonyl, alkylsulfinyl, sulfonatido or sulfonyl; RS is alkyl; alkenyl; alkynyl; cygloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalky; alkyloycloalkyl; hydroxyalkyl; hydroxyalkylcydloalkyl; hydroxycycloalkyl; hydroxybicyeloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycioheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloralkylalkyl, polycycloalkyl, heteroarylarnino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyi, hydroxy, hydroxyalkyl, nitro, eyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycatbonyl, aminocarbonyl, alkynylamino carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylarnino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or

R

4 and R together form -(CR 22

R

23 )m - wherein m is 2 to 6, and R2 and R3 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 CH 2 , and Z and R 3 are H, R 4 and Rs together are not -(CH 2

)

2 - or -(CH 2

)

3 -; or

R

4 and R 5 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

SO

2 ; or

R

4 and R 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; of (ff) R3 is hydrogen; and R 4 and R 5 together with the atoms to which they are attached form a 4 to 8 member mono- or polycyclic heterocyclic ring system 75 containing 1 to 3 heteraatom seledted frojn N, 0, S, SO and SO 2 , wherein the heterocyclic fihg system is optionall-y mono- or independently plutisubstituted with ay of the groups set forth in (dd) or (ce); provided that when n is 1, X is CH 2 , the rirtg containing X is saturated, and .Z and R 3 are 1, R 4 and R 5 together are not -(CH 2

)

2 - or -(CH 2

)

3 -; and wherein a bond containing a wavy line signifies a point of attachrrent. [0081] The invention also relates to methods for preparing the above-described compounds. As shown below and as descibed in the EXAMPLES, the corrpounds of formula I and 11 are prepared by reacting a cyclic amine (p.g., pyrrolidine or pipeline), suitably protected with a standard protecting group such as Boc-, Fmoc-, CBz- or the like, with sec-BuLifTMEDA followed by B(OCH3) 3 , to provide the methyl boronic ester derivative. Acid hydrolysis of the methyl esters with 2N HCI provides the boronic acid intermediate 1. R eaction 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 aide 3. Treatment of 3 with Na 2

CO

3 and cyclopentylamine, and hydrolysis of the pinanediol boronic ester, provides a compound of formula I, 4. Alternatively, coupling of intennediate 2 with N-Boc-5-phenyl-Pro using EDAC/HOBT provides amide S. Deprotection of the amino group and hydrolysis of the boronic esters, provides a compound of formula 11, 6. 76 1) s-.uLi, TMEDA -40 0 C HO-OH B 2)MeO) 1) (+)BPinoandih EtO 3) O~ NBoc 2) IO-ii Et 2 O then re crystallize (2X) leaving Only P Isomer C0 eNH-HCI 2 C N 01 0 A00 0 0" 3 5 1) Na 2

CO

3

NH

2 1) HCI, Et 2 O 2) Phenyl Boronic Acid 2) Phenyl Boronic Acid Hexane / H 2 0 Hexane / H 2 0 aN- N N4 OHO 4 6 [0090] 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 anmines) with sec-BuLi/B(OCH 3

)

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; 77 6,432,969; 6,380,398; 6,172,081; 6,166,063;, 6,124 305; 6-110%949; 6,107,3,17; 6,01 t,155; and 6,395,767, which are hereby Inerporated by reference in their entirety. [00911 Thus, another aspect of the invention provides a process for preparing the compounds of formula I: OR' k 4 W' 0 B- OR 2 z by coupling a reactive compound of formula: OR'

R

4

R

3 0 _O2 LN RL ' R x with an amine of formula: R 5

-NH

2 ; 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', R 2 , R 3 , R 4 , R', R!, n, X, and Z are as defined herein. Preferred embodiments are those where R 3 and R 4 are hydrogen, L is halogen, including but not limited to Cl, and R 5

-NH

2 is cyclopentylamine. 106921 Still another aspect of the invention provides a process for preparing the compounds of formula II: OR' H 0

B-OR

2 R24N z 78 by coupling a 2-borohetoroeydle having thefennula:

B-OR

2 .z with the corresponding N-protested cyclic amino acid; optionally deprotecting the boronic acid ester; and recovering the resultant compound as a free acid or as an acid atidition salt. R'and 1 2 .re not hydrogen, and n, X, and Z are as defined herein. Typically the 2-boroheterocycle is a 2-boropyrrolidino or 2-boropipetidino. In some such embodiments, the N-protected cyclic amino acid is N-Boc-4-phenyl-boroPro-OH. [00931 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, ialic 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. [00941 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. [00951 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 diastereorners, as well as the radernates. 79 Methods/Uses 100971 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 -r'oline/alanine cleaving amino-dipeptidase. In this embodiment, the individual administered an amount of the invention compound effectivein reducing the activity of the post-proline/alaine cleaving amino-dipeptidase and, thereby, reducing or alleviatig symptoms of the disease or condition. In some embodiments, the administered compound reduces the activity of DPP IV. In some embodiments, the disease or condition is selected from the group consisting of diabetes, diabetes 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. [0098] Other exemplary embodiments of the invention methods are represented by: [0099] 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; [00100] 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; [00102] 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; 80 j00103] 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 ofthe 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; [001051 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; [001071 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; [001081 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; 1001091 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; [001101 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; 81 [00112] Methods for treating, controlling or preventing in amammalian 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 prostatoid hypertrophy, gingivitis,hypertension and osteoporosis, comprising administering to the patient a therapeutically effective antount of a compound of the invention; [001131 Methods for reducing spermi 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 syndtome, (15) inflarmatory 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; [001151 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) dyslipidernia, (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 82 transplantation, (28) Type IU diabetes, (29) growth hormop-e deficien0y, (30) heutropenia, (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 invdetion, o- 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-lB inhibitors; c) Insulin or insulin mimetics; d) Sulfonylureas or other insulin secretagogues; e) c-glucosidase inhibitors; f) glucagonsreceptor 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) PPARt 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. 100116] 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 83 therapeutically effective amount of a compound of the invention and an IMG-CoA reductase inhibitor; [00117] Methods wherein the HMC-CoA reductase inhibitor is a statin; 1001181 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; [01201 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; [001211 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, sibuttamine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol; [001231 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; [01001 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; 10101] Methods for the treatment, control, or prevention of neutropenia wherein the neutrophilic agent is pegfilgrastin, filgrastim, lenograstim, or nartograstim; [01021 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; 84 [0103] Methods for the treatrment control, or prevention of anemia wherein the erythropoietin agonist is EPO, an EPO mimetic, or an 8PO: receptor agonist; [0104] Methods for the treatment, control, or prevention of' anemia wherein the erythropoietin agonist is epoetin dig, or darbep6etin alfa; [01051 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, allografi rejection in transplantation, autoimmune diseasss, 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; [01061 Methods for treating type H diabetes and/or obesity; [01071 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; [01101 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 I diabetes; [0112] Use of a compound of the invention for the manufacture of a medicament for the treatment of impaired glucose tolerance (IGT); 85 01.13] Use of a compound of the invention for the manufacture of a medicament for the tteatment of Impaired fasting glucose (IFG); [0114] Use of a compound of the invention for the manufacture of a medicament for prevention of hyperglycemia; .101151 Use ofa compound of the invention for the manufacture of a medicament for delaying the progression of impaired glucose tolerance (IGT) to type II diabetes; [01161 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; [01181 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. 10119] Use of a compound of the invention for the manufacture of a medicament for the treatment of disorders of food intake; [01201 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; 101231 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. 86 Combination Tretneits [012-51 The compounds of the invention may be used in combination with one ornore 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, 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 ct/ y dual agonists, .P2 inhibitors, glycogen phosphorylase inhibitors, advanced glycosylation end (AGE) products inhibitors, and/or ieglitinides, as well as insulin, and/or glucagon-like peptide-l (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. [01281 The other antidiabetic agent may be an oral antihyperglycemic agent preferably a biguanide such as metformin or phenformin or salts thereof, preferably metformin HCL. [01291 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. [01301 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. 87 10131) The coIounds of the invention will be employed in a weight ratio to the sulfenyl urea in the range orom about 0.01:1 to about 100:1, preferably from-about .05:1 to about 5:1. [012- The oral antidiabetic agent may also be a glueosidase 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 aspate oral dosage forms. [0133] The compounds of the invention will be eniployed 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), tosiglitazone (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 19702 (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. 10136] 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, disclosure of which is incorporated herein by reference), or a GLP-1 mimic such as AC2993 or Exendin-4 (Amylin) and LY-315902 or LY-307167 (Lilly) and 88 NN22 11 (Novo-Nordisk), which may be administered via injection, intranasal, or by transderntal or buccal devices. [01381 Where present, metformin, the sulfonyl ureas, such as glyburide, glimepiride, glipyride, glipitide, 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 RE FERENCE (PDR). [0139] 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. [0140] 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. [0141] Where present insulin may be employed in formulations, amounts and dosing as indicated by the PHYSICIAN'S DESK REFERENCE. [0142] 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 which are incorporated herein by reference. [01431 The other antidiabetic agent may also be a PPAR g/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), and in U.S. application Ser. No. 09/664,598, filed Sep. 18, 2000, (attorney file LA29NP), the disclosure of which is incorporated herein by reference, employing dosages as set out therein, which compounds designated as preferred are preferred for use herein. 89 [01441 The. other antidiahetic. agent may be an SGLT2 inhibitor, as disclosed in U.S. Applioation Ser. No. 091679,f027, filed Oct. 4, 2000 (attorney file LA49NP), whieh is incorporated herein by reference employing dosages as set out herein.Preferred are the comtpounds designated as preferred in the above application. [01451 The other antidiabetic agent, whiqh may be employed in combination with the DPP-W inhibitors in Accordance with the present invention, can be an aP2 inhibitor,09/5 19,079, filed Mar. 6, 2000 (attorney file LA27NP), which are eath incorporated herein by reference, 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. 101471 The meglitinide which may optionally be employed in combination with the compound of the invention may be repaglinide, nateglinide (Novartis) or KAD 1229 (PF/Kissei), with repaglinide being preferred. [01481 The DPP-IV inhibitors of the invention will be employed in a weight ratio to the meglitinide, PPAR y agonist, PPAR cx/ 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, ileal 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. 90 5,885,983, and No, S;962,440. MTP inihibitors preferred herein are thos identified as being preferred in the above referenced patents. [01.511 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 hfluorne-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 (rmevinolin) 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, simvastatin 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). [01541 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 famesyl 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 91 and cyclopropan6sre-prted by Capson, T. L., PhD disstrtation,Jutie, 1987, Dept. Med. Chem. U of UtahbA tracts Table of Contenits, pp 16, 17, 4043, 48-51, Summary. [0155] Other hypolipidemnic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate, and the like,-probucond related compounds as disclosed in U.S. Patent No. 3,674,836, probucol and gemfibrozil being preferred, bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (Seeholex@, Policexide@), as well as lipostabil (Rhone-Pouleoo), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402),;tetrahydrotipstatin (THL), istigmastanyliphos.phorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azuldne 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 anine poly(diallyldimethylanimonium chloride) and ionenes such as disclosed in U.S. Patent No. 4,027,009, and other known serum cholesterol lowering agents. 101561 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, Cl-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 ApoB 100-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(t), 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'-[(1 92 Phefylcylopenrtyl)methyllureas with enhanced hypocholesterolemic activity" Stout et al, ChemtrActs: Org. Chem. (1995), 8(6), 359-62, or TS-9 (Taisho Phafmaceutidai Co. Ltd). [01571 The hypolipidemic agent may be an upregulatr of LD2 receptor activity such as MD-7Q (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly). [01581 The hypolipidemic agent may be a cholesterol absorption inhibitor preferably Schering-Plough's SCH148461 as well as those disclosed in Atherosclerosis I15, 45-63 (1995) and J. Med, Chem 41, 973 (199&). [0159] The hypolipidemic agent may be an ileal Na/bile acid cotransporter inhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999). [01601 The lipid-modulating agent may be a ch6lesteryl 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. [01611 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. [0162] Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin and ZD-4522. [0163]. The above-mentioned U.S. patents are incorporated herein by reference. The amounts and dosages employed will be as indicated in the Physician's Desk Reference and/or in the patents set out above. [0164] 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. [0165] 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. [01661 The dosages and formulations for the hypolipidemic agent will be as disclosed in the various patents and applications discussed above. 93 101671 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 Ieference. [01681 For oral administration a satisfactory result may be obtained employing the M 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. [01691 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, sinvastatin, atorvastatin, fluvastatin, or cerivastatin in dosages employed as indicated in the PHYSICIAN'S DESK REFERENCE, such Is in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg. 101711 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. [01741 The other hypolipidemic agent may also be a lipoxygenase inhibitor including a 15-lipoxygenase (1 5-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 94 Comicelii et a1 "15-Ljpox.ygengse and its Inhibition A Novel ThOrngeutic Target for Vascular Disease", Current Pharmaceutical Design, 1999, 5, 11-20. (01751 The compounds of theinvention and the hypolipidemie agent may be employed together in the same oral dosage form or in separate oral dosage forms taken at the same time [01761 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, sirmvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin. (01781 The other type of therapeutic agent which may be optionally employed with the DPP-1W 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. [01791 The beta 3 adrenergic agonist which may be optionally employed in combination with a compound of the invention may be A19677 (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. [01811 The serotonin (and dopamine) reuptake inhibitor which may be optionally employed in combination with a compound of the invention maybe sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramine and topiramate being preferred. [01821 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 95 disclosed in W097/21-90 (U. Cal SF), W0099/00353 (KatoBio) -and GB98/284425 -(aroBid), With compounds of the KaroBio applications being preferred. (01831 The ahiorettic 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. [01841 The fatty acid oxidation upregulator which may be optionally employed in combination with the compound of the invention can be famoxin (Geasdt). [015] The various anti-obesity agents described above may be employed in the same dosage forn 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. [01871 The agent for polycystic ovary syndrome which may be optionally employed in combination with the DPP-IV 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 U.S. Ser. No. 09/506,749 filed Feb. 18, 2000 (attorney docket LA26), as well as selective androgen receptor modulators (SARMs), which is incorporated herein by reference, which may be employed in amounts specified in the PDR, where applicable. (01891 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, 96 ibuprofeo, di soofenansodium, naproxen, nabumetoxe (Rllafen@, SmithKine Beecham), tolmietin sodin,(Toleofthi Ortho-McNeil), piroxicam (Fldene@, Pfizer), ketorolac tromethamine (Toradl@ Roche), celecoxib (C.ebrex@, 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 cyclospotin, Sandimmune (Novartis), azathioprine, Immuran (Faro) or methotrexate may be optionally employed in combination with the DPP-1V inhibitor of the invention, which may be employed in aniounts 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, lhunuran, cyclophosphamide, NSAIDS such as ibuprofen, cox 2 inhibitors such as Vioxx and Celebrex, glueocorticoids 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@, 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@, Roche), ritonavir (Norvir@, Abbott), nelfinavir (Viracept@, Agouron). [01931 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. 97 101951 The agent for treating Osteoporosis which may beoptionally employed in Poinbm.4tion with the DPP-IV inhibitor of the invention may be 1, 2, or more of alendronate sodium (Fosamax@, Merck, tiludronate (Skelid@, Sanofi), etidronate disodium (Didrone1@, P&G), raloxifene HCI (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 Vehioile 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 img), 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 98 conventional forms, fbr example capsules, tablets, aerosols, solutions, suspensions or topical applications. [0206. Typical compositions include a compound ofthe invention which inhibits.the enzymatic activity of DPP-IV or a pharmaceutically acceptable basic addition salt or prodrug or hydrates 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 ofa capsule, sachet, paper orother container. In making the compositions, cofVefitiotial 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. gome 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, tale, 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 ofthe 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. 102011 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 99 appropriate or desired site of action, such as oral, nasal, puhnonary, buccal, subdermal, intradernal, transderm or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramusculdr, intranasal, ophthalmic solution or an ointment, the oral route being preferred. [02031 If a solid caifier 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, soit gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. [02041 For nasal administration, the preparation may contain a compound of the invention which inhibits the enzymatic activity of DPP-TV, 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. [02061 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. 10207] A typical tablet that may be prepared by conventional tabletting techniques may contain: 100 Core: Active compound (as free compound or salt thereof) 250 mg Colloidal silicon dioxide (Aerosil)@ i. 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. [0208] 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. 101 102111 Usually, dosage forms suitable for oral,, nasal, pulmonal or transdenmal adniltistration 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 dilent. [02,12] 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; 102 102191 Pharmaceutical compOsitions comprising: a. a substantially pure preparation of a compound of formula VB as described herein; and b. a pharnaceitically acceptable carier 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; 10222] 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; [02231 Methods of making a pharmaceutical composition of a compound described herein wherein the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration; [02241 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; [02251 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-IB inhibitors; 103 ii?) Insulitt or insulin iim ties; iv) Sulfonylureas or other insulin seoretagogues; v)' o.ghtoosidase inhibitors; vi) glucagons receptor agonists; vii) GLP-1, GLP-1 miMetics, and GLP-1 receptor agonists; viii) 61p),y GP mimetics, and GIP receptor agonists; ix) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; x) GLP-2, GLP-2 niimetics, 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 OoA:cholesterol acyltransferase inhibitors, and (viii) anti-oxidants; xii) PPARS 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. [02281 Pharmaceutical combinations comprising a compound of the invention and an antidiabetic agent; [02291 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 SGLT2 inhibitor, an aP2 inhibitor, a glycogen phosphorylase inhibitor, an AGE inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) or mimetic thereof, insulin and/or a meglitinide; 104 [02301 Pharmaceutical combinations comprising a compound of the invention and an antidibetic agent wherein the antidiabetic agent is 1, 2, 3 or more of metfortnin, glyburide, glimepiride, glipyride, glipizide, chlorpropatnide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, GI -262570, isaglitazone, JTT-501, NN 2344, L895645, YM-440, R-1 19702, AJ9677, repaglinide, nateglinide, KAil129, APR H039242, GW-409544, WRP297, AC2993, Exendin-4, LY507161, NN221 1, and/or LY3 15902; [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 .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 FMG 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, sinvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529,414, avasimibe, TS-962, MD-700, and/or LY295427; 105 [02361 Pharmaceutical coribinatidais comprising a compound of the invention and a lipid-modulating agent wherein the compound ispresent in a weight ratio to the lipid modulating agent within the range from about 0.01 to about 100:1; [02371 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 atlograft rejection in transplantation, an agent for treating autoimmune disease, an anti-AIDS ageht, an agent for treating inflammatory bowel disease/syndromte, an agent for treating anorexia nervosa, an anti-osteoporosis agent and/or an anti-obesity agent. Methods For Measuring Activity [0238] 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. [0239] 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/gl, pH 8.0) and Gly-Pro-AMC substrate (400 lM) 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 pl) into 25 mM Tris buffer (77.5 p1) followed by addition of test 106 compoundd (2.5 pl) at 26'C. -Ater 10-minutds substrate was added (10 pl) and allowed to tract for 20-minutes at 26C before free AMC was measured. ICso values were determined in triplicate, using a minimum of six different inhibitor concentrations. IC 5 o values were calculated using Nonlinear Regression Analysis (GraphPad, Prism, San Diego, CA). 102401 To determine the DPP-IV activity in the plasma of mice dosed with test compounds, plasma (10 pl) was diluted into 25 mM Tris buffer (80 pA, pH 8.0) followed by addition of Gly-Pro-AMC stock solution (10 pl) and the free AMC measured after 20 minutes at 26'C. Analysis was peffonned 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 sevete type 2 diabetes characterized by increased HbAl 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, 1. 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 [02361 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. [02371 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. 107 102581 The conditions, diseases and maladies collectively referred to as "diabetic complications" include retinopathy, neuropatby- and nephropathy, and other known complications of diabetes. 102391 The term "other type(s) of therapeutic agents" a 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 er 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 of more anti-ost6oporosis agents, one or more agents for treating immunornodulatory 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. [02411 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 term "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. [02431 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 108 acceptable salts thereof, representsat least 90% by weight of the composition. In some embodiments one isomer rapreats at least 98% by weight of the composition. 10244] The term "boronic acid protecting group" as used herein refers toa moiety employed to block or protect the borordc 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-ethanadiol; 2, 2 -diethanolamine; 1,3-propancdiol; 2,3 butanediol, diisopropyl tartrate; 1,4-butanediol; diisopropylethanediol; (SS,)-5,6 decanediol; 1,1,2-triphenyl-1,24ethenedio1; (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, 3d Ed." (John Wiley & Sons, New York (1999)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaly, o-nitrophenoxyacetyl, a-chlor6butyryl, 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, 2 nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3

,

4 -dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2

,

4 -dimethoxybenzyloxycarbonyl, 4 methoxybenzyloxycarbohyl, 2 -nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5 triniethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-I-methylethoxycarbonyl, a,a-di methyl 3 ,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, 109 allyloxycarbonyl, 2,2,2,-rtichloroethoxycarbonyl, phenoxycarboniy, 4 nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, oyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxytmiethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are frmyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). [0246] The term "alkyl" or "(Cijz)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. [02471 The terms "(Cio)alkyl", "(C 1 .s)alkyl" and "(CI-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 "(Ct.

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 "(C 2

.

1 2 )alkenyl" and "(C2-io)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. [02501 The terms "(C2-12)alkynyl" and "(C2-io)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-CH 3 , -CH 2 CCH, CH 2

-CH

2 -C CH, -CH(CH 3 )C1CH, and the like. 110 [O25) The t0rms "(Cs-3.)oyoloalkyl" and "(C 3 -1o)cyeloalkyl" refers to one or more saturated qyelic hydrearbons having from 3-12 or 3- 0 carbon atoms, respectively, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,.cyclohexyl, adamantyl, and the like. [0252 The term "(Cs.o)cycloalkenyl" refers to a radical of one or more cyclic hydroathon having at least one double bond having frQm 5-10 carbon atoms such as, but not limited to, cyalopentenyl, cyclohexenyl, and the like. [02531 The term "cycloalkylene" refers to a "cycloalkyl" group which has single bonds for attachment at two different carbon atoms. 10254J The terms "(Cj_6)alkylaminocarbonyl" and "di-(CI-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. [02551 The term "(Ci.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. [02571 The terms "(C.io)alkoxy",

"(CI.

8 )alkoxy" and "(C,.

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 Ill AlkOxy ihlude but are not limited to cyclopropyloxy, cyclobutyloXy, cyclopentyloxy, cyclohexyloxy, and the like. [02581 The term "aryloxy'' refers to an aryl group bonded to 0. 10259] The term "alkanoyl", alone or as part of another group, refers to alkyl linked to a carboqyl 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 (I-naphthyl, 2-naphthyl), N-hydroxytetrazolyl,

N

hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2 -anthracenyl, 3 anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, 112 isoxzol qJnpzolinyl1, fluorenyl, xantheny1, isoindanyl, benthydryl, acridiytizll pyrrolyl- (2 -pyrol1), pyrazolyl (3-pyrazolyl), imidazolyl (I -imfidazolyl, 2-imidazoy,4 imidazolyl, 5-imidazolyl), triazolyl (1 ,2,3-triazol- l-yI, I ,2,3riazo]-2-yl 1,2,3'-triat-ol-4-yI, l,.2,4-t-iazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4 thiazly, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyidyl, 4-pyridyp niny(2prmdn, 4-pyrimidiny1, 5-pyrimidinyl, 6-pyrimnidinyl), p yrazinyl, pyrldazinyl (3- pyridazinyl, 4 pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quincolyl, 4.quinholyl, 5-qUinolyl, 6 qulniolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1 -isoquinolyl,. 3-isoquinolyl, 4-isoquinolyl, 5 isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinoly), b-enzQolbfuranyI (2 benzo~b~furanyl, 3-benzo [1,)furanyl, 4-benzo[b]furanyl, 5-benzo[b]ffiranyl, 6-benzo[b]fuiranyl, 7-benzo(bjfuranyl), 2,3-dihydro-benizo[b]fiiranyl (2-(2,3-dihydro benzo[b~furany1), 3-(2,3-dihydro-benzo[b]furanyl1), 4-(2,3-dihydro-b~nzo[b]fuany), 5-(2,3-dihydro-benzo[b] furanyl), 6-(2,3-dihydro-benzo[b] furanyl), 7-(2,5-dihydro benzo[b~furanyl), benzo I[blthiophenyl (2-benzo(b]thiophenyl, 3-benzo[b~thiophenyl, 4-benfzo[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-indoly], 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 -benzixnidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5 benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (I1 benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1 -benzothiazolyl, 2-benzothiazolyl, 4 benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyi), carbazolyl (1 carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzb,*flazepine (5H dibenz[b,flazepin- l-yI, SH1-dibenz[b,flazepine-2-yi, 514-dibenz~b,flazepine-3-yi, 5dibenz[b,flazepine-4-yI, 5H-dibenz[b,flazepine-5-yl), 10, 11 -dihydro-5H-dibenzljb,flazepine (10,11 -dihydro-5H-dibenz[b,flazepine- 1-yl, 10,11 -dihydro-5H-dibenz[b,flazepine-2-yI, 10,1 1-dihydro-5H-dibenz[b,flazepine-3-yl, 10,1 1-dihydro-SH-dibenz*,fqazepine-.4-yl, 10,1 1-dihydro-51--dibenz[b,flazepine-5-yl), and the like. [02661 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. 113 [0267j The terms "halogen" and "halo" refers to chloro, fluoro, bromo or iodo. [0268] Thoterm "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. [02691 The term "substituted amino" a 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 thiarnorpholinyl, 1 -piperazinyl, 4-alkyl-l-piperazinyl, 4-arylalkyl- 1 -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. [02711 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. [02721 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 (CH 2 )s (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. 114 [9271j The term "cycloheteroalkylalkyl" alone or as part ofeanother group refers cyoloheteroalkyl groups as defned bove linked through a carbon atom or heteroatorn to a (CH2), ohain. [.02*4] The termI "hetefoarylalkyl" or "heteroarylalkenyl" alone or as pan of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to a (CH 2 )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, phenylalaaine, histidine, tryptophan, tyrosine, phenylglycine, lysine, nethionine, 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. 102761 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 CF 3

CH

2 , CF 3 or CF 3

CF

2

CH

2 . 102771 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 CF 3

CH

2 0, CFO or CF 3

CF

2

CH

2 0. [02781 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 substittients as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, 115 alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an arrnatio ot heteroaromatic moiety, trifluorotnthyl 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) [02,O] A flame dried round bottom flask equipped with a magnetic stir bar was charged with N-Boc-pyrrolidine (20 g, 117 mmol, I eq) and dry TIF (60 mL) under a nitrogen atmosphere. The clear colorless solution was cooled to -78C and a solution of s BuLi (100 mL of a 1 4 M solution in cyclohexane, 140 mml) 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 O'C. Upon reaching O'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 HCl and then extracted with EtOAc (3 x 120 mL). The organic extracts were combined and dried over Na 2

SO

4 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, Rr= 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 O'C in an ice bath and with constant stirring dry HCI (g) was bubbled into the solution for 10 minutes. After 2 hours a white precipitate developed in the flask and the ether and excess ICI were removed in vacuo to afford the racemic HCl salt as a white solid. Crystallization and isolation of the desired isomer was performed by dissolving the HCI salt in a minimal amount of dichloromethane (250 mL) with gentle heating to facilitate a homogenous solution followed by continuous stirring for 8 116 hours to yield a fluffy white precipitate that was collected by vasuun frltratioh, 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). 'H NMR (400 Mzt, D 2 0) 84.28 (d, J=8.0 Hz, 11-1), 3.06 (m, 31), 2.18 (n, IH), 1.96 (in, 2H), 1.78 (in, 3 H), 1.62 (in, 2H), 1.21 (s, 3H), 1.05 (in, 5II), 0.84 (d, J=12 Hz, 2H), 0.71 (s, 2H), 0.62 (s, 31). Example 2 Synthesis Of Series A Compounds: (2RF142-Cylopentylamino acetlbboroProoH (4) Step 1: (2R)--(2-Chloroacetyl)-boroPro-(1S,2S,3R,S.)-pinanediol ester (3A). [0281] To a solution of 2 (36.7 g, 129.3 mmol) dissolved in dry CH 2

C

2 (200. mL) cooled to O'C was added chloroacetyl chloride (12.34 mL, 155.2 mmol) under a blanket of

N

2 . 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 O'C and 200 mL of a 0.2 N solution of HCI 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 hex/EtOAc, Rr= 0.22, made visual via 12 and/or PMA stain) and was used in the next step without further purification. 'H NMR (400 MHz, CDCl 3 ) 80.80 (s, 3 H), 1.25 (m, I 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 (in, 1 H), 2.29 2.35 (m, 1 H), 3.12-3.16 (in, 1 H), 3.47-3.53 (in, 1 H), 3.58-3.63 (in, 1 H), 3.97-4.05 (q, 2 H), 4.30-4.32 (d, I H). Step 2: ( 2 R)-1-(2-Cyclopentylamino-acetyl)-boroPro-(iS,2S,3R5S)-pinanediol ester (3B). [02821 Compound 3A was dissolved in dry THF (-150 mL) followed by addition of

K

2 C0 3 (35 g) and cooled to O'C before addition of cyclopentylamine (21.93 g, 258 minmol). The reaction mixture was then allowed to warm to room temperature and stirred overnight. TLC indicated all starting material was consumed. The mixture was filtered through a celite and silica pad, washed with 5% MeOH in CH 2 C1 2 (200 mL) and concentrated to yield a sticky, light orange solid. The red sticky solid was dissolved in CH2Cl 2 (150 mL) followed by addition of Et 2 0 (-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 60 117 mL) and hexane (2 x 50 mL) and dried to give. 3B(28.91g, 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, 2:5.7 mimol) for a combined overall yield of 3B (35.09 g, 93.8 mmol) of 73% yield R= 0.45 (10% MeOH in

CH

2 C-1). 'H NMR (400 MHz, CDC 3 ) 8 4.18 (d, 111), 3.95 (d, J= 16 Hz, 1H), 3.6 (d, J= 16 Hz, 11), 3.46 (in,3H),.2.74 (im, H), 2.36 (n, IH), 2.16 (m, 2H), 2.04 (i, 41H), 1.90 (s, 1H), 1.74 (in, 611), 1.61 (s, 1H), 1.46 (m, 2H), 1.34 (s, 3-H), 130(s, 311), 0.88(s, 3H). Step 3: (2RE)--(2-Cyclopentylamino-acetyl)-boroPro-OH (4) {0281] To a solution of 5B (40.59 g, 108.5 Mmol) in H20 (2001nL, adjusted to pH 2 by addition of 2 N HCI) was added hexane (200 mL) and phenyl boronic acid (13.37 g, 109,5 miol) 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 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,

D

2 0) 5 3.88 (dd, J= 8.0 Hz, 2H), 3.54 (in, 1H), 3.42 (in, 1H), 3.28 (m, 1H), 2.96 (in, 1H), 1.96 (in, 4H), 1.85 (in, 2H), 1.63 (in, 7H); MS (ESI) m/z 223 (M+H-H 2 0)*. 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. 11 NMR (D 2 0) S 4.08 (dd, J = 12 Hz, 2 H), 3.54 (in, 1H), 3.38 (in, 1H), 3.07 (in, 1H), 2.26 (in, 1H), 2.09 (in, 2H), 1.94 (n, 111), 1.71 (in, 111), 0.88 (s, 4H); MS (ESI) m/z 195.13 (MH-H 2 0). Example 4 Synthesis of 1-[2-(3-Rydroxy-adamantan-1-ylamino)-acetyll 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) 8 3.94 (d, J 8 Hz, 2H), 3.54 (in, 1H), 118 3.40 (in, lH), 3.09 (M, IH), 2.41 (s, 2H), 2.09 (M, 311), 1.93 (M, 2H), 1.7 (i, 7R), 1.7.1 (i, 6H), 1.56 (m, 2 1J); MS (ESI) Mz 305.21 (MH*-H 2 Q), Example 5 SYnthesis of .. 5R-Ph.enyl-pyrrolidine-2S-pathonv)-Dyrrolidine-2R)-boranitiacid (6): Step 1: N-Boc-5-ph enylPro-(2R)-boroPro-(1S2S,3R,S.)-pinanedioI ester (5): [02861 To an ice-cooled (OC) solution of N-Boc-5-phenyl-ProI-H (0.84 mnl) in dry

CH

2

C

2 was added EDAC (174 mg, 0.91 minol) and HOBt (105 mg, 0.775 miaol). The reaction was stirred at O'C for 15-minutes and then 2 (200 nig, 0.7 nmol) and.N-methyl morphiline (0.25 mL, 2.1 nmol) 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 NaHCO 3 (10 mnL), extracted into EtOAc (2 x 15 mL), washed with brine (15 mL), dried over Na 2

SO

4 , 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-(SR-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (6): [02871 An ice-cooled solution of 5 (320 mg, 0.62 mmol) in dry ether was saturated with dry HCI (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 H20 (10 mL, adjusted to pH 2 by addition of 2 N HCl) 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 B (76 mg, 0.26 mmol) as an amorphous white solid. 'H NMR (D20) 8 7.46 (m, 5H), 3.65 (m, 1H), 3.44 (m, 1H), 3.04 (in, 1H), 2.54 (m, 1H), 2.38 (m, 2H), 2.20 (rn, 1H), 2.06 (m, 2H), 1.86 (m, 1H), 1.66 (m, 1H); MS (ESI) m/z 271 (MH*-H 2 0). 119 Exaniple 6 Slntheis rof i- Ipbridi, ge- 2 SelathoiyI-pyrroidin(R ~brouie acid (B2): (0f)88] The title t0mpound was prepared according to the procedure of Example 5 using appropriate starting materials. 'H NMR (D 2 0) S 4.07 (m, lH)j 3.61 (m, iH), 3.34 (in, 21J), 2.94 (m, 2), 2.16 (in, 1H), 2.03 (in, 2H), 1.87 (m, 31), 1.56 (m, 4H); MS (ES,) m/z 209 (MH*-H{ 2 0). Example 8 Synthesis of 1)(2,3-oihndro-aHindole-2S-carbcindiotrolidine-(2R);-boronic acid 102891 The title compound was prepared according to the procedure of Example 5 -using appropriate starting materials. 'H NMR (D20) 8 4.54 (in, 1H), 3.73 (m, MH), 3.58 (in, 1H), 3.34 (m, 1H), 2.48 (in, IH), 2.37 (in, 1H), 2,06 (in, 3H), 1.83 (in, 3H), 1.58 (m, 4H), 1.32 (m, 4H); MS (ESI) m/z 249(Mf-H 2 0). Example 9 Synthesis of 1-( 4 S-Phenyi-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid [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, lH), 3.83 (in, IH),3.59 (in, 1H), 3.34 (i, 2H), 3.06 (m, 1H), 2.53 (m, 2H), 2.08 (in, 2H) 1.77 (in, 1H), 1.64 (m, 1H); MS (ESI) m/z 271 (MH*-H 2 0). 120 Example 10 Syothesis ot (2R)-1-2-(3S)-PyrrolIdin-3-yiamino-acetyl}-pyrrolidine-2-boronic acid (8)

,NH

2 N oc k C b , THF ..,,NHN " PhB(OH) 2 ,

H

3 O*, Hexanes OH -_ OQH HN . 8 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. 'H-NMR (500 MHz, CD 3 OD) 8 4.12 (m, 3H), 3.76 (m, 1H), 3.54 (m, 3H), 3.41 (m, 2H), 3.26 (m, IH), 2.55 (m, IH), 2.28 (m, IH), 2.05 (m, 3H), 1.74 (m, IH). MS m/z (rel intensity) 241 (M) (27), 224 (100), 209 (73), 155 (47). 121 Example la $ynthesis off2R)--(-I(3)-Prblidin-ylaminol-acetylkpyrrolidine boron ic acid

NH

2 ,0 N C1

OQK

2 C0 3 , THF H I PhB(OH) 2 , HjO*, Hexanes C) ' B'O N % OH NH 10 Step 1: (2R)-l12-[(3R)-1-tert-Butoxycarbonyi-pyrrolidin-3-ylaminol-acetyl} pyrrolidine 2-bororic acid (1S,2S,3R,5S)-pinanediol ester (9). [02931 The protocol described above for the synthesis of 3B was followed employing

(

3 R)-3-amino-pyrrolidine-1 -carboxylic acid tert-butyl ester in place of cyclopentylamine. Compound 9 was obtained as an oil. MS m/z (rel intensity) 476 (M + 1)* (100), 376 (74), 239 (38), 224 (67), 155 (55). Step 2: (2R)-l12-[(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, CD 3 0D) 8 4.13 (m, 111), 4.08 (bs, 211), 3.76 (dd, J= 13.0, 8.0 Hz, 1H), 3.55 (m, 3H), 3.41 (m, 2H), 3.27 (m, 1H), 2.53 (m, 1H), 2.26 (m, 1H), 2.10 (m, 211), 1.99 (m, 1H), 1.75 (m, 1H). MS m/z (rel intensity) 224 (M-17)(100), 206 (25), 180 (29), 155 (70). 122 Ex ample 12 Synthesis Of Series B Compounds- ( (12) Step 1: (2R)- [( 2 )1-tert-utoxycarbonyl-azeidine-2-carbonyl]-boroPro OS,2S,3Pi5)-jinaardiol ester (11) [02951 To a solution of (2S)-azetidine-1,2-dicarboxylic acid 1-teft-butyl ester (169 mg, 0:8 f&mmol) in CHIC1 2 (5 mL) was added I4D8t (105 mg, 0.8 mmn1) and EDC (174 mg, 0.9 tumol). The reaction solution was then cooled to 0 *C in an ice bath for 10 min followed by sequential addition of 2 (200 rg, 0.7 mmol) and NMM (0.25 mL, 2. mmol). The reaction solution was allowed to warm up to room temperature and stirred overnight. The reaction mixture was diluted with additional

CH

2

C

2 (5 mL), washed with NaHCO 3 (2 x 10 mL), 0.1 M aqueous HCI (5 mL) and brine (10 mL). The organic layer was dried over Na 2

SO

4 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-[( 2 S)-Azetidine-2-carbonyl]-boroPro-OH (12) [0296] A solution of compound 11 in 4N HCI 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. Cornpound 12 was obtained as a white solid. 12-TFA salt 'H-NMR (500 MHz, D 2 0) 8 5.23 (m, I H), 4.11 (m, IH), 3.90 (m, IH), 3.42 (m, IH), 3.18 (m, 1H), 2.99 (m, 1H), 2.79 (m, IH), 2.55 (m, 1H), 1.92 (m, 3H), 1.63 (m, IH). MS mlz (rel intensity) 199 (M + 1)* (7), 181 (M-17) (100), 152 (53). Example 13 Synthesis of Series C Compounds:

(

2 R)-i-l(2S,4S)-4-Ainno. pyrrolidine-2carbonyl-boroPro-OH (15) Step 1: (2R)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-benzyloxycarbonylamino pyrrolidine-2-carbonyl]-boroPro-(IS,2S,3R,5S)-pinanediol ester (13) [0297] The protocol described for the synthesis of 11 was followed employing (2S,4S) Fmoc-4-amino-1 -boc-pyrrolidine-2-carboxylic acid (628 mg, 2.2 mmol) in place of 123 azetidine-1,2-dicarboxylic acid 1-tert-butyl ester. Compound 13 was obtained as a -ear colorless oil that was used in the next step without further purification. S tep) 2: (2A)-1-b2-crbony boroPro-(1S,2S,3R,-S)-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.ovemight 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 12 and/or.PMA)-to give 14 as a clear dolorless oil in a 48% yield over 2 steps. Step 3: (2R)-1-[( 2

S,

4

S)-

4 -Amino-pyrrolidine-2-carbonyIj-boroPro-OH (15) [0299] The protocol described above for the N-Boe 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, D 2 0) 8 4.42 (dd, 1H), 3.87 (in, IH), 3.5 (dd, 1H), 3.28 (in, 21), 3.07 (m, 1H), 2.73 (m, 1H), 2.64 (m, 1H), 1.86 (m, 1H), 1.72 (br m, 2H), 1.55 (br m, 211), 1.34 (m, 2H). MS m/z (rel intensity) 228 (M + 1) (55), 210 (M + 1 H 2 0) (95). Example 14 Synthesis of Series D Compounds: ( 2 R--(2S)-4-Methanesufonyl piperazine-2-carbonyll-boroPro-OH (19) Step 1: (2R)-1 -[( 2 S)-l-tert-Butoxycarbonyl-4-benzyloxycarbonyl-piperazine-2 carbonyll-boroPro-(1S,2S,3R,5S)-pinanediol ester (16) 10300] The protocol described above for the synthesis of 11 was followed employing

(

2 S)-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 -carbonyll-boroPro (IS,2S,3R,5S)-pinanediol ester (17) [0301] 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 124 completion of the reaction, it was filtered through a plough of Celite. The solvents were renioved wider reduced pressure and the oily residue used in the next step withoutfurther purification. MS m/z (ret intensity) 462 (M + 1)* (100), 406 (12), 362 (11). Step 3: (2R)-1-((2)-1-tert-Butoxycarbonyl-4-muth aesulfonyl-piperazine-2 carbonylJ-bor0Pro-(1S,2S,3R,5S)-pinanediol ester (14) [03021 To a solution of compound 17 (214mg, 0.46 mmol) in CH 2 C1 2 (5 mL) cooled to 0 "C was sequentially added N-methylnorpholine (204 pL, 1.9 mnimi) and methanesulfonyl chloride (72 pL, 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 CH 2 Cit (6 ml) and water (6 rnL). The organic phase was isolated and dried over MgSO 4 . After filtration, solvents were removed under reduced pressure. The oily residue was purified by column phromatography (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-Methanesulfony-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 mug, 0.11 mmol) was obtained in 53% yield. 19-TFA salt 'H-NMR (500 MHz, D 2 0) 8 4.32 (dd, J= 11.0, 3.5 Hz, 1H), 4.05 (m, 111), 3.93 (m, IH), 3.77 (in, 1H), 3.60 (ddd, J= 10.5, 8.0, 2.5 Hz, 1H), 3.47 (ddd, J= 12.5, 3.0, 3.0, IH), 3.35 (m, 211), 3.16 (m, 2H), 3.02 (dd, J= 13.8, 11.3 Hz, IH), 2.93 (s, 3H), 1.96 (m, 2H), 1.81 (m, 1H), 1.72 (m, Ii), 1.56 (in, 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-vlamino] acetyll-boroPro-OH (21) Step 1: ( 2 R)-l-{ 2

-[(

3 S)--tert-Butoxycarbony-pyrrolidin-3-ylamino]-acetyl}-horoPro (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) 125 [03051 The protocol described above for the N-Boc deprotection and pinanediol ester deprotection ofontpud 12 was applied to 20. Compound 21 was Otained as a white solid. 2.-TFA salt 'H-NMR (500 MHz, CD 3 OD) & 412 (m, 31H), 3.76 (m, 1H), 3.54 (m, 3H), 3.41 (m, 2H), 3.261(m, IH), 2.55 (m, 1H), 2.28 (m, 1H), 2.05 (m, 311), 1.74 (M, H). 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 ,OH 255 (M+1)(13), 237 O OH).3 N % H OH OH 23 AO 227 (M+1)(18), 209 C,' BO (100) H OH 24 A 229 (M+I)(18). 211 2 OH (100) H N O OH 25 A OH 215 (M1)(12), 197 H0N B' (100) O OH 26126 26 A/OH263 (M+1)(5). 245 (100) -' H N B 27 A (\q ,H277 (M+1)(4), 259 (100) 7 H ON QIHNAo OH 126 Compound Series Structure LC-MS No.._ _ _ _ _ __ _ _ _ _ 38 A 8\0H 283 (M+1)(22),2 25 (1.00) 29 A OH 277 (M41)(1), 25 10 H H 31 A H 26396, 8 (M+1)(100) 29 A ~ OH27 32~~~~ A, 76 6, 8 M+)i PhSO 2 N 33 A 284 (M+1)(19). 266(100) 0N N,.,B..OH 34 A 651 (28), 326 (M+1)(57) 308 (100) O H,B'OH OHO 35 A -691 (22), 346 32 A H0(M+1)(100), 328 (86) O N~K H 0 ,B-OH H2 N __________ ~H HOB'oH_______ 37 A 691 (49), 346 (M+1)(14), BzN N 328(100) H o QH 127 nipud Series Structure LC-MS 38 A 0 703 (27), 352-(M )(3). N 334 (100) H d 0 OH AH A 651 (48), 326 (13), 308 N (100) H_____ HOrBO 40 A 382 (M+1)(100), 364 (7) -4H _ _ _ _ _ HOr 41 A 332 (M+1)(100), 314 (10) 01'N\ Nq 2HCI H H Or OH 42 A 531 (15), 266 (M AcN, /3 N 17)(100) H o ,B-OH 43 A HO 271 (M+1)(100), 253 a N (16) H 0 HOB'OH 44 A H2N '270 (M+1)(100), 252 (17) H o HOB-OH 45 A H 0HOBO 731 (42), 366 'B-OH (M+1)(1 00), 348 (43) OHCI 46 A HCI H O HO OH 791 (12),396 (M+1) 47 A 721 (10), 361 (M+1)(100) H 0 HOB'OH 128 Series Structure LC-MS 48 A 285 (M41)(100), 207 (12) N N H o HO OH 49 A 0 595 (48), 298 N (M+1)(100), 280 (80) HCl H H B-OH 50 A 0 679 (29), 340 (0.) Na CI OHO'B-OH $1 A 719 (92), 360 (M+1)(65), z N342 (100) HCI H HO BOH 52 A 791 (35), 396 N N(M+1)(100). 378 (14) Ho H 0 HO, B'OH 53 A N\ 595 (89), 298 (M+1)(44), 280 (100) H 0 HO,B'OH 54 A 719 (72), 360 (M+1)(40), _ ,OyNQ 342 (100) BzN H _ HOB'OH 55 A Nq 731 (100), 366 (M+1)(34), 348 (86) (D O .H 0 H

O

B-OH Hci 56 A 340 (M+1)(5), 322 (100), N) N 304 (18) O H O HO H 57 A 731 (100),$66 ()y'NN ( Nq (M+1)(52), 348 (94) 58 A - 773 (33), 396 " , N N (M+1)(100), 378 (16) l H HOB'OH 129 Compound Series.Srcur CM 59 A 695(93). 2*98 +1)(26, MID 280.(100). V q 60A 079 10-);340(98), 22 o HOrBOH 61A 34'&7 (M+1)(od) NfNH 2 12) O'HO 62 'O L\,N29MI7major, NH 2(M)minor 0 NN OH 64 B F 'OH 289(M+1 )minor, 271 (M 17)major OH 0 NH 65 B OH213(M_17), 425(2M+1) N _____ _____ \__NH 66 B Q rH282(M-1 7) major NH01 ~N H 67 2 5 7(M-17)major, 275(M+1 )mlnor ________HNK yq 130 . M-pob~nd Sreries StructureL-M B, ~ OH 209.(M-1 7)mapjor, 227(M+1 )minor OH f 0 303(M+1 )minor 70 H OBO 209(M-1 7)major, N Nq227(M+1 )mlnor H o HdB-OH 71 BHO : 211( (-1 7)mnajor, 229(M+1 )mlnlor 72 B H 0H" 2 0 9(M-1 7)mjr 9 _,r Nq227(M+1 )minor

H

2 N 0 MYB-OH ___________(cis) 73 B 0 209(M-17)major, -N ,227(M+1)minor

H

2 N 4%FH2 " B-OH ____ ____IR,2R 74 B HCA 257(M.1 7)major. 2 75(M+l)minor 75 B 209(M-1 7)major, 112N N?227(M+1 )minor HdB-OH lS.2S_ 131 compundSeries Strudture LM 76 B 223(M-i 7)mojor, Nq 241 l(M+1)minor

NH

2 0 ,B="OH "77 B23M17mjr Nr 2 4 '1(M*1)mino~r

NH

2 0 1BO HO' 24-1(M.1 )mlnrr HN yN _________HO' BOH 79 23$(M-1 7)mjor, Nq .253(.M+1)mlnor B-OH 80 BN2M"23 _M-17)Major, ell, N253(M+1 )minor

_____NH

2 0 HO BOH 81 B HO, ,OH 23 .5(M-1 7)major, B 253(M-I-)minor 82BHO,.S OH 251 (M-1 7)major, 0 269(M+1)minor 83N d:4 H 2 235(M-1 7)m-aor, OH 253(M+1)minor -B-OH 84 B- 0 -233(-1 7)major. N? 251 (M+1 )minor 85 B

NH

2 0 H'B- OH 85 B 233(M-1 7)major, N 251 (M+1 )minor ____ ____NH 2 0BOH 132 CompbouhdSeisSrctrL-M NO. ___ __ ___ __ ___ _s 'B ~~7S Mmajor,

NH

2 .B=OH HOr 87 ~~B O 1(-7mj HdB'329+(Mifl)minor ND 70 -P,30% 6-Ph ______________ P =edo Int i er drawn B 209(M-1 7)major. Nq .227(M+1 minorr < NH 0 HOB- 'OH 89 B 434(M-1 7) majo-r

H

2 N 0 Hf1-OH 90 B OH 46 (M +1) (23), 42 8 Ho - (1 0 0 ) 0 O=s=O O,Me 91 B HOH 350(M-1 7)m-aJor. HO.B/368(M+1)minor ZN 0=6=0 133 Somes Structure Nd. LC-MS 92 B

*

1 H434(M-17-) major H2N~~G ==0 N OCFa 93 B 346 (M+1)(100), 328 k l ,(14) 2HCI HH -BOH 94 B 511 (9), 256 (M+i)(100) HN N N Q238 (19) HO H HO, B 2HCI 95 B 201 (M+I)(100), 183 N (22) H O HO B-OH 96 B 255 (M+1)(100), 237 N N (100) H OHBO 97 B HOH . 187 (M+1)(5), 169 (100) OH 98 B OH 243(M+1)(5), 225 (71) OH 0 NH 99 B ,OH 449(5),.243(M+1)(7), B. 225(100) OH .NH 100 B

HCO

2 H 223(M+23)(3), 183(48) Me

H

2 N NKI O ,B-OH 134 C mbulfd Series Struoture LC-MS No._______ _ 16HOH 224(M+23)(4 183(10) Me- r

NH

2 0 HOQH 102 C H 2 N '2-8(M+1)'(5), 210 (M N 2 1 7)(95) H o B=OH HO' 103 C + 210(M-17)major, N 228(M+1)Mitfor H

-

BOH 104 c H2N 210(M-i7)major, HN Nq 228(M+1)minor H O HO'BOH 105 D OH 575 (12),.328 (M423)(6), O B 288 (100) N O OH OH K NH.HCI 106 D 452 (M+1)(3), 434 (100) N OH SOCF3 107 D OH 368 (M+1)(2), 350 (100) N * OH N 108 D BOH 428 (M-17)(100) N OH o ,NH.HCI 109 D F OH 386 (M-17)(100) F N O H F 0 L. NH.HCI 135 mpond Series Struoture LC-M5 No. ___________ 1.100- .. \ H 436 (M+i )(l0),.4.18 OH 00 0 NHHCI 111 D 436 (M+1)(4), 418 (100) lo N F OH o K.NH.HCI 112 D Hc 627 (25), 332 (M+1)(10), B OH314(100) NH HO O N formic acid salt 113 D 07yPH 368(M+1)(38), 350 (100) N O OH HCI 114 D OH 350 (M-17)(100), 332 N 3 (22) d OH 0 N 0 HI NH 115 D NH 332(M+1)(4), 314 (93) \ / HCI H HO B 116 D 338(M+1)(3), 320 (98) NH HCI H O ,BOH HON 117 D NH 332(M+1)(27), 314 (100) 118 D 338 (M+1)(21), 320 (100) HCI H 0 B'OH 136 No. e Series Structure 105 D O2NOH 119 ~7~oH 77(8) ~64(Mf7f(56) S O H 120 D OH 603(24), 302 (M-17)(73)

H

2 N N S O H 0 121 F HO HO 242 (M+1)(100), 224 H Q L OH (19) H O HCI 122 F HN N 242 (M+1)(100), 224 (9) HO T2 - F :N a:H 0HO B-OH 123 F 0 300(M+1)(11), 282 (100) HN§ N N H o H' B-OH 124 F 371(M-17)major, 38 9(M+1)minor NH HN N 0 OH 125 F -256 (M+1)(100) HN N H 126 F H N 256 (M+1)(100). 238(8) HCI 0H B-OH HOr 127 F

--

Q256 (M+1)(100), 238(10) HN - N 0 HBOH HCIH 137 G~rnoun -series StructUreLCM 128 F -A (M+1 minorr ) 0 BO F 0(M+1)( ),i23n 8 HN D N5 6M (+1)(' 0) (28) HCI HO (100), 294 (30) H O 2o H( ) 3 ( 1 131 G H 819 (20), 410 (100) H O OI-H H 374 (M+1)(100), 356 N,,a (67) 0 N ,VNq O HO'B'OH 133 G H 759 (57), 380 0 N N Nq (M+I)(100). 362 (64) H 0 HO,1'OH Example 17 Dependence of Aminoboronate and Boronic Acid Forms of Inventive Compounds on [03071 A 0.4 M stock solution of Na 2

HPO

4 was prepared by dissolving 909 mg of salt in 16 mL of D 2 0. pH was adjusted to the desired value by dropwise addition of either 20% DC in D 2 0 or 5% DC 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 138 integrals of the peaks at 2.90-2.95 ppmt atid 2.4042.50 ppm characteristic of the open and closed fortns, respectively. FIG. 1 shows that the closed form predoimihates at higher pffs such as physiological pH, whereas the open form predominates at lower pHs. Example 18 103081 The final compounds of Examples 1-16 were tested in vitro as described herein and each displayed an ICso or Ki of 10 iM or less. 103091 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] All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. [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, 13'9 chlorine, and iodine, claims for X being bromine and claims for X being komine and chloiine are fully described. 103131 Other embodiments are set forth within the following claims 140

Claims

1. A compound of formula (VI): HN Rx N a b N H R2 5 (VI) or a cyclic isomer thereof of formula VIb, HN Rx H-N R2 e Be 0 N (VIb). stereoisomers thereof, solvates thereof, hydrates thereof and pharmaceutically 10 acceptable salts thereof, any prodrug thereof, or any mixture thereof, wherein: R 1 and R 2 independently or together are -OH, -0 M* wherein M* is a pharmaceutically acceptable cation, 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; 15 RX is hydrogen, (C1. 8 )alkyl, (C3-12) cycloalkyl, benzyl, or phenyl; wherein the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 12 ; R 12 is halogen, trifluoromethyl, cyano, nitro, (C 1 . 6 )alkyl, (C 1 . 6 )alkoxy, cycloalkyl, carboxy, acetamido, hydroxy, hydroxy(C 1 . 6 )alkyl, hydroxymethyl, trifluoromethoxy, 20 sulfamoyl, carbamoyl, sulfonamido, alkylsufonyl, phenylsulfonyl, aryl, or heteroaryl; """"'' 141 wherein the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; R 7 is halogen, (C 1 .10)alkyl, (C 1 . 1 0 )alkoxy, (C 1 . 10 )alkylamino, (C 1 . 10 )dialkylamino, benzyl, benzyloxy, hydroxy(C 1 . 6 )alkyl, hydroxymethyl, nitro, trifluoromethyl, 5 trifluoromethoxy, trifluoromethylthio, N-hydroxyamino, cyano, carboxy, acetamido, hydroxy, sulfamoyl, sulfonamido, carbamoyl; 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. 0

2. The compound of claim 1 having the formula (VIl): HN aN a b N H R (VII), or a cyclic isomer thereof of formula VIllb HN H-Ne /- R 2 0 N (VIIb). 15 , or any pharmaceutically acceptable salt thereof, any prodrug thereof, or any solvate thereof, or any mixture thereof; wherein 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 20 mixtures are included. '"""""m 142

3. The compound of claim 1 having the formula (VIII): HN Rx N a b N H or a cyclic isomer thereof of formula Vlb, HN Rx - B e O N (VIIIb) 5 or any pharmaceutically acceptable salt thereof, any prodrug thereof, or any solvate thereof, or any mixture thereof; wherein Rx is (C 1 . 8 )alkyl, (C3-12) cycloalkyl, benzyl, or phenyl. 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 10 configurations such that all stereoisomers and all stereomeric mixtures are included.

4. A compound of claim 3 wherein Rx is methyl, benzyl, i-butyl, i-propyl or ethyl.

5. A compound of any one of claims 1 to 4 wherein R1 and R 2 independently or 15 together are hydroxyl bearing 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; 20 catechol; or 1-butanol. "lame, 143

6. A compound of any one of claims 1 to 4 wherein R 1 and R 2 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 5 butanediol; diisopropylethanediol; methanol; ethanol; isopropanol; or 1-butanol.

7. A compound of any one of claims 1 to 4, wherein R 1 and R 2 are hydroxyl.

8. A pharmaceutical composition comprising a compound of any of claims 1 to 7 0 and at least one pharmaceutically acceptable carrier or diluent.

9. A method for inhibiting dipeptidyl peptidase-IV comprising contacting dipeptidyl peptidase-IV with an effective amount of a compound of any of claims 1 to 7. 15

10. The use of a compound of any one of claims 1 to 7 for the manufacture of a medicament for the treatment of the malcondition of a mammal that can be regulated or normalized via inhibition of dipeptidyl peptidase-IV.

11. The use of claim 10, wherein the malcondition is a metabolic disorder. ?0

12. The use of claim 10, wherein the malcondition is diabetes.

13. The use of claim 10 further comprising administering a therapeutically effective amount of an antidiabetic agent selected from the group consisting of a second 25 medicament 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, proteins that affect glycemic control, or any combination thereof. 30

14. The use of a therapeutically effective amount of a first compound of any one of claims 1 to 7 and one or more second medicaments selected from the group consisting of a) Other dipeptidyl peptidase-IV inhibitors; """M 144 b) Insulin sensitizers selected from the group consisting of (i) PPAR agonists, (ii) biguanides, and (iii) protein phosphatase-1 B inhibitors; c) Insulin or insulin mimetics; d) Sulfonylureas or other insulin secretagogues; 5 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; 0 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) PPARc/y dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterol acyltransferase inhibitors, and (viii) 15 anti-oxidants; I) PPARS agonists; m) Anti-obesity compounds; n) An ileal bile acid transporter inhibitor; o) Anti-inflammatory agents; ?0 p) G-CSF, G-CSF mimetics, and G-CSF receptor agonists; and q) EPO, EPO mimetics, and EPO receptor agonists for the manufacture of a medicament 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 25 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) 30 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 il diabetes, (29) growth hormone deficiency, (30) neutropenia, (31) anemia, (32) neuronal disorders, (33) tumor growth and metastasis, (34) benign prostatic 0e..e 145 hypertrophy, (35) gingivitis, (36) hypertension, (37) osteoporosis, and other conditions that may be treated by inhibition of dipeptidyl peptidase-IV.

15. A pharmaceutical combination comprising a compound of any one of claims 1 5 to 7; 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, provides a replacement for endogenous peptides or proteins that affect glycemic control, or any 0 combination thereof.

16. The pharmaceutical combination of claim 15 wherein the weight ratio of the compound and the antidiabetic agent is from about 0.01:1 to about 100:1. 15

17. The pharmaceutical combination of claim 15, wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, nateglinide, pioglitazone, troglitazone, rosiglitazone, insulin, GI -262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-1 19702, AJ9677, repaglinide, nateglinide, KAD1 129, APR-H039242, GW-409544, ?0 KRP297, AC2993, Exendin-4, LY307161, NN221 1, and/or LY315902.

18. The pharmaceutical combination of claim 15 wherein the second medicament is suitable for treatment of a diabetes condition. 25

19. A method of preparing a compound of formula (VI) of claim 1, comprising: contacting a compound of Formula (XXX) N 0 R2 R (XXX) and a compound of Formula (XXXI) .e.m' 146 Rx HN NH 2 (XXXI) wherein L comprises a leaving group, under conditions suitable to provide the compound of formula (VI). 5

20. The method of claim 19 wherein L is halo.

21. The method of claim 19 wherein L is chloro.

22. The method of claim 19 further comprising preparing a compound of the 0 Formula (VI) wherein R 1 and R 2 are each OH by contacting acid and a compound of the Formula (VI) wherein R 1 and R 2 are each hydroxyl bearing a boronic acid protecting group.

23. The method of claim 22 further comprising contacting with phenylboronic acid. 15

24. A method of preparing a compound of Formula (VI) of claim 1: HN Rx N N H B R2 (VI) comprising contacting a compound of Formula (XXXII): GN Rx G 0 (XXXII) 20 with a compound of Formula (XXXIII): 4''""" 147 HN B 2 R R 2 (XXXIII) wherein G comprises a protecting group and L comprises a leaving group, under conditions suitable to provide a G protected compound of Formula (VIG), NG Rx N a b N G B O R / NR1 R2R 5 (VIG) then treating the G protected compound of Formula (VIG) under conditions suitable to remove group G to provide the compound of Formula (VI).

25. The method of claim 24 wherein G is a group such as an acyl group; a sulfonyl 10 group; a carbamate forming group; an alkyl group; or a silyl group.

26. The method of claim 24 further comprising preparing a compound of Formula (VI) wherein R 1 and 2 are each OH by contacting acid and a compound of Formula (VI) wherein R 1 and R 2 are each hydroxyl bearing a boronic acid protecting group. 15

27. The method of claim 26 further comprising contacting with phenylboronic acid.

28. The method of any one of claims 19-27, wherein Rx is hydrogen, (C 1 . 8 )alkyl, (C 3 - 1 2 ) cycloalkyl, benzyl, or phenyl. 20

29. The method of any one of claims 19-27, wherein Rx is hydrogen, methyl, benzyl, i-butyl, i-propyl or ethyl.

30. The method of any one of claims 19-27, wherein Rx is hydrogen. "''"""' 148

31. A compound of formula (VI) of claim 1 wherein the compound is of the formula HN N N O ,B R 3 R 2 5 or a cyclic isomer thereof of formula, o N 1:I Gn- OR2 NB R 3 H NH or any pharmaceutically acceptable salt thereof, any prodrug thereof, or any hydrate or solvate thereof, or any mixture thereof; wherein R 2 and R 3 each independently is OH, -0 M* wherein M+ is a cation, a hydroxyl bearing a boronic acid protecting 10 group, or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids.

32. The compound of claim 31 wherein R 2 and R 3 are each hydroxyl, comprising a compound of formula (VIRR): HN N N H O B 15 HO OH (VIRR) or any pharmaceutically acceptable salt thereof.

33. A cyclic isomer of the compound of formula (VIRR) of claim 32, having formula 20 (VIRRC): "''"''"" 149 O N 0 B(OH) 2 N H NH (VIRRC) or any pharmaceutically acceptable salt thereof. 5

34. A mixture of the compound of formula (VIRR) of claim 32 or any pharmaceutically acceptable salt thereof and the cyclic isomer of formula (VIRRC) of claim 33 or any pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition comprising the compound of formula (1) of claim 10 31, the compound of formula (VIRR) of claim 32, the cyclic isomer of formula (VIRRC) of claim 33, or the mixture of claim 34, and a pharmaceutically acceptable carrier.

36. The composition of claim 35 further comprising a second medicament comprising a known second medicament that increases insulin secretion, increases 15 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. 20

37. Use of the compound of formula (1) of claim 31, the compound of formula (VIRR) of claim 32, the cyclic isomer of formula (VIRRC) of claim 33, or the mixture of claim 34, for preparation of a medicament adapted for the treatment of a malcondition that can be regulated or normalized via inhibition of dipeptidyl peptidase-IV. 25

38. The use of claim 37 further comprising the use of a known second medicament 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, for "'""""n 150 preparation of a medicament adapted for the treatment of a malcondition that can be regulated or normalized via inhibition of dipeptidyl peptidase-IV.

39. A method for inhibiting dipeptidyl peptidase-IV comprising contacting dipeptidyl 5 peptidase-IV with an effective amount of a compound of any one of claims 1 to 7 or 31 to 34.

40. The method of claim 39 further comprising administering a therapeutically effective amount of a second medicament selected from the group consisting of a 0 second medicament 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. 5

41. The method according to claim 39 wherein one or more second medicaments are administered and are selected from the group consisting of a) Other dipeptidyl peptidase-IV inhibitors; b) Insulin sensitizers selected from the group consisting of (i) PPAR ?0 agonists, (ii) biguanides, and (iii) protein phosphatase-1 B inhibitors; c) Insulin or insulin mimetics; d) Sulfonylureas or other insulin secretagogues; e) a-glucosidase inhibitors; f) glucagons receptor agonists; 25 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) 30 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; I) PPAR6 agonists; """ame' 151 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 5 q) EPO, EPO mimetics, and EPO receptor agonists.

42. A method of treatment of a malcondition in a mammal wherein inhibition of DPP-IV is medically indicated, comprising administering an effective amount of a compound of any one of claims 1 to 7 or 31 to 34 to the patient. 0

43. The method of claim 42 further comprising administering a therapeutically effective amount of a second medicament selected from the group consisting of a second medicament that increases insulin secretion, increases insulin sensitivity, reduces the uptake of sugar from the gastrointestinal tract, enhances the effect of 15 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. 152