WO2005047297A1 - Heterocyclic boronic acid compounds - Google Patents

Heterocyclic boronic acid compounds Download PDF

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Publication number
WO2005047297A1
WO2005047297A1 PCT/US2004/037820 US2004037820W WO2005047297A1 WO 2005047297 A1 WO2005047297 A1 WO 2005047297A1 US 2004037820 W US2004037820 W US 2004037820W WO 2005047297 A1 WO2005047297 A1 WO 2005047297A1
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Prior art keywords
alkyl
independently
phenyl
optionally mono
cycloalkyl
Prior art date
Application number
PCT/US2004/037820
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French (fr)
Inventor
David Alan Campbell
David T. Winn
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Phenomix Corporation
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Publication date
Priority to BRPI0416444A priority Critical patent/BRPI0416444B8/en
Priority to US10/514,575 priority patent/US7674913B2/en
Priority to PL04810839T priority patent/PL1689757T3/en
Application filed by Phenomix Corporation filed Critical Phenomix Corporation
Priority to NZ547752A priority patent/NZ547752A/en
Priority to AU2004288831A priority patent/AU2004288831B2/en
Priority to ES04810839.3T priority patent/ES2524916T3/en
Priority to CA2545311A priority patent/CA2545311C/en
Priority to EA200600935A priority patent/EA013684B1/en
Priority to EP04810839.3A priority patent/EP1689757B1/en
Priority to DK04810839.3T priority patent/DK1689757T3/en
Priority to CN200480037257.9A priority patent/CN1894261B/en
Priority to JP2006539906A priority patent/JP5435841B2/en
Priority to SI200432201T priority patent/SI1689757T1/en
Publication of WO2005047297A1 publication Critical patent/WO2005047297A1/en
Priority to US11/381,082 priority patent/US7576121B2/en
Priority to US11/381,085 priority patent/US7317109B2/en
Priority to US11/381,090 priority patent/US7767828B2/en
Priority to IL175550A priority patent/IL175550A/en
Priority to NO20062711A priority patent/NO337818B1/en
Priority to US11/556,944 priority patent/US20070185061A1/en
Priority to US11/833,063 priority patent/US7906658B2/en
Priority to US11/930,337 priority patent/US7884217B2/en
Priority to US12/692,276 priority patent/US8415295B2/en
Priority to HRP20141155TT priority patent/HRP20141155T1/en
Priority to NO20160635A priority patent/NO340063B1/en

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Definitions

  • the present invention relates to boronic acid compounds and their use as inhibitors of post-proline/alanine cleaving amino-dipeptidases.
  • the invention also relates to methods of employing such inhibitors, alone or with another therapeutic agent, to treating DPP-IV-related diseases, such as Type II diabetes and diabetic complications, hyperglycemia, Syndrome X, hyperinsulinemia, obesity, atherosclerosis and related diseases, as well as various immunomodulatory diseases and chronic inflammatory bowel disease.
  • DPP-IV-related diseases such as Type II diabetes and diabetic complications, hyperglycemia, Syndrome X, hyperinsulinemia, obesity, atherosclerosis and related diseases, as well as various immunomodulatory diseases and chronic inflammatory bowel disease.
  • the invention has applications in the medicinal chemical, pharmacological, and medical arts.
  • DPP-IV 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.
  • 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.
  • DPP-IV has been implicated in the control of glucose metabolism because its substrates include the insulinotropic hormones, glucagon like peptide- 1 (GLP-1) and gastric inhibitory peptide (GIP), which are inactivated by removal of their two N- terminal amino acids.
  • GLP-1 glucagon like peptide- 1
  • GIP gastric inhibitory peptide
  • Post-proline/alanine cleaving amino-dipeptidases have been discovered, including DPP7, DPP8, DPP9, and fibroblast activation protein (FAP), that have the substrate- and inhibitor-specificity of DPP-IV.
  • FAP fibroblast activation protein
  • inhibitors of this sort may affect multiple members of the enzyme group.
  • the precise physiological role of each of these post-proline/alanine cleaving enzymes is not well defined. Consequently, inhibiting each of them separately, a subset of them, or all of them at the same time would have uncertain physiological effect(s).
  • Diabetic dyslipidemia is characterized by multiple lipoprotein defects, including moderately high serum levels of cholesterol and triglycerides, small LDL particles, and low levels of HDL cholesterol.
  • the results of recent clinical trials reveal beneficial effects of cholesterol-lowering therapy in diabetic and nondiabetic patients, thus supporting increased emphasis on treatment of diabetic dyslipidemia. This need for intensive treatment of diabetic dyslipidemia was advocated by the National Cholesterol Education Program's Adult Treatment Panel III.
  • 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.
  • Even mild obesity increases the risk for premature death, diabetes, hypertension, atherosclerosis, gallbladder disease and certain types of cancer.
  • 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.
  • 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.
  • the present invention provides DPP-IV inhibitors that are effective in treating conditions that may be regulated or normalized by inhibition of DPP-IV. More particularly, the invention relates to boronic acid-containing heterocycles and their derivatives that inhibit DPP-IV, and to methods for making such compounds.
  • 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.
  • FIG. 1 shows the pH dependence of the percentage of linear and cyclic isomeric forms present in aqueous solution of a compound of the invention.
  • n 1 to 3; X is CH 2 ; S; O; CF 2 or C(CH 3 ) 2 ; Z is H; halogen; hydroxyl; (C 1-6 )alkoxy; (C ⁇ - ⁇ 2 )alkyl; (C 3- ⁇ 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 1 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;
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C 1-6 )alkylcarbonyl; (C 3- 12 )cycloalkyl ring; (C 3- ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3-12 )cycloalkyl ring; and
  • R 16 and R 17 are each independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(C ⁇ _ 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 12 ; or R 16 and R 17 together form a (C 3- ⁇ 2 )cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
  • R 18 and R 19 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(C ⁇ . 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 12 ; or R 18 and R 19 together form a (C 3- ⁇ 2 )cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phen
  • R 20 is hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(C 1-6 )alkylaminocarbonyl; (C 3- 8 )cyclo alkylcarbonyl; 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 R ; R x is hydrogen; (C ⁇ -8 )alkyl; (C 3- ⁇ 2
  • R 21 is hydrogen; (C ⁇ -8 )alkyl; benzyl; or phenyl; 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 1 , R", 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
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; (C 3- ⁇ )cycloalkyl ring; (C 3- ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3- ⁇ 2 )cycloalkyl
  • R 16 and R 17 are each independently hydrogen; (C 1-8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(C ⁇ _ 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 12 ; or R 16 and R 17 together form a (C 3- ⁇ 2 )cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
  • R 18 and R 19 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(C). 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 12 ; or R 18 and R 19 together form a (C 3- ⁇ 2 )cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (pheny
  • R 20 is hydrogen; (C 1-8 )alkyl; (C 1-6 )alkylcarbonyl; di-(C 1-6 )alkylaminocarbonyl; (C 3- 8 )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 R 12 ; R x is hydrogen; (C 1-8 )alkyl; (C 3- ⁇ 2 )
  • R 21 is hydrogen; (C ⁇ -8 )alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 12 ; 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, aral
  • R 1 and R 2 independently or together are the boronic acid protecting group formed from (+)-pinanediol; pinacol; 1,2- dicyclohexyl-ethanediol; 1 ,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3- butanediol, diisopropyl tartrate; 1 ,4-butanediol; diisopropylethanediol; (S,S,)-5,6- decanediol; 1 ,1 ,2-triphenyl-l ,2-ethanediol; (2R,3R)-1 ,4-dimethyoxy-l ,1 ,4,4-tetraphenyl- 2,3-butanediol; methanol; ethanol; isopropanol; catechol; or 1-butanol.
  • R and R represent a single protecting group attached to both boronic ester oxygens when diols such as (+)-pinanediol and pinacol are used, whereas R 1 and R 2 represent separate moieties on the boronic ester oxygens such as methyl or ethyl when the esters are formed from methanol and ethanol, respectively.
  • R and R independently or together are a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids and are formed from 1,2-dicyclohexylethanediol; 1,2-ethanediol; 1,3-propanediol; 2,3-butanediol, 1,4-butanediol; diisopropylethanediol; methanol; ethanol; isopropanol; or 1-butanol.
  • R 1 and R 2 are each formed from methanol, the resulting R 1 and R 2 groups are methyl.
  • the resulting R 1 and R 2 groups are a single group and the resulting boronic ester has the following structure:
  • Compounds of formula I include those wherein if CR R is absent, then R 3 , r R>4 and R , 5 are selected from (dd), (ee) or (ff): (dd) R 3 and R 4 are hydrogen; and R 5 is a) (C ⁇ -12 )alkyl; (C 2-12 )alkenyl; (C 2-12 )alkynyl; (C 3-12 ) cycloalkyl; or (C - ⁇ 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; R 6 is (C ⁇ -6 )alkyl; (C ⁇ -6 )alkoxy; cycloalkyl; carboxy;
  • R 7 is halogen; (C ⁇ - ⁇ o)alkyl; (C ⁇ -10 )alkoxy; (C ⁇ - ⁇ o)alkylamino; (C ⁇ -10 ) dialkylamino; benzyl; benzyloxy; hydroxyl(C ⁇ -6 )alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethyl thio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R 8 is (C 1- ⁇ o)alkyl; (C 2-H) )alkenyl; (C 2-10 )alkynyl; (C 3- ⁇ o)cycloalkyl; (C 5- ⁇ 0 )cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C 1-6 )alkylcarbonyl; (C 3- ]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 ⁇ - 6 )alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3- ⁇ 2 )cycloalkyl ring;
  • R 16 and R 17 are each independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(C ⁇ _ 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 12 ; or R 16 and R 17 together form a (C 3-12 )cycloalkyl ring; and s is 1 to 6; h) a group of the formula:
  • R 18 and R 19 are independently hydrogen; (C ⁇ -8 )alkyl; (C 1-6 )alkylcarbonyl; di-(C ⁇ 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 12 ; or R 18 and R 19 together form a (C - ⁇ 2 )cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; i) a group of the formula: (phenyl
  • R 20 is hydrogen; (C ⁇ -8 )alkyl; (C 1-6 )alkylcarbonyl; di-(C ⁇ -6 )alkylaminocarbonyl; (C 3- 8 )cycloalkylcarbonyl; benzyl; benzoyl; (C 1-6 )alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; R x is hydrogen; (C ⁇ -8 )alkyl; (C 3-12 )
  • R is hydrogen; (C ⁇ -8 )alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 12 ; 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;
  • Compounds of formula I also include those wherein X is CH 2 ; the ring containing X is saturated; CR'R* 1 is absent, R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is (C 2 )alkyl; (C 2- ⁇ 2 )alkenyl; (C 2- ⁇ 2 )alkynyl; (C - ⁇ 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 5 is a (C ⁇ _ 12 )alkyl or (C 3- ⁇ 2 )cycloalkyl, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, or adamantyl.
  • X is CH 2 ; the ring containing X is saturated; CR'R iJ is absent, R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is indanyl; 1,2,3,4- tetrahydronaphthyl; (CH 2 ) j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]-oct-l-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, (C ⁇ .
  • R 9 and R 10 are independently ( . 8 )alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C ⁇ _ 8 )alkyl, (C]. 8 )alkoxy, halogen, or trifluoromethyl, or R 9 and R 10 together are (C 3-6 )alkylene.
  • X is CH 2 ; the ring containing X is saturated; CR'R" is absent, R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is R ⁇ (CH 2 ) p - where R 11 is 2-oxopyrrolidinyl; (C ⁇ -6 )alkoxy; phenyl; phenoxy; (C ⁇ -8 )cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2- oxopyrrolidinyl, (C ⁇ -6 )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 disubstituted with (C ⁇ -4 ;
  • X is CH 2 ; the ring containing X is saturated; CR'R" is absent; R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is (R 13 ) 2 CH(CH 2 ) q -, where R 13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R 12 ; and q is 0 to 3.
  • X is CH 2 ; the ring containing X is saturated; CR'R" is absent, R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula:
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ - 6 )alkylcarbonyl; (C 3- ⁇ 2 )cycloalkyl ring; (C 3- ⁇ 2 )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 12 ; or R 14 and R 15 together form a (C - ⁇ 2 )cycloalkyl
  • Compounds of formula I include those wherein X is CH 2 ; the ring containing X is saturated; CR'R" is absent, R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula:
  • R 16 and R 17 are each independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ . 6 )alkylcarbonyl; di-(C ⁇ . 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 12 ; or R 16 and R 17 together form a (C 3- ⁇ 2 )cycloalkyl ring; and s is 1 to 6.
  • R 18 and R 19 are independently hydrogen; (C ⁇ -8 )alkyl; (C 1-6 )alkylcarbonyl; di-(C ⁇ . 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 12 ; or R 18 and R 19 together form a (C 3-12 )cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3.
  • R 5 has formula:
  • X is CH ; the ring containing
  • XX i iss ssaattuurated; CR'R" is absent, R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula: (phenyl-CH 2 -C(CH 3 ) 2 -), where the phenyl group is optionally mono- or independently plurisubstituted with R 12 .
  • Compounds of Formula I include those having the following structure, Formula IA:
  • R 5 is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricyclo alkyl; 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, alkoxycarbony
  • R 5 is alkyl; alkenyl; cycloalkyl; cycloalkylalkyl; hydroxyalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted as described above (in, e.g., (ee)).
  • R 5 is alkyl, cycloalkyl or cycloheteroalkyl, optionally mono- or independently plurisubstituted as described above.
  • R 3 and R 4 are both hydrogen.
  • n is 1. In some embodiments of compounds of Formula IA where n is 1 and R 1 , R 2 , R 3 , and R 4 are hydrogen, R 5 is not methyl.
  • Compounds of formula I include those wherein X is CH 2 ; the ring containing X is saturated; CR'R" is absent, R , R , R and R are hydrogen; and R is a group of the formula:
  • R 20 is hydrogen; (C ⁇ _ 8 )alkyl; (C ⁇ - 6 )alkylcarbonyl; di-(C ⁇ -6 )alkylaminocarbonyl; (C - 8 )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 R 12 ; R x is hydrogen; (C ⁇ -8 )alkyl; (C 3-
  • R 5 has formula:
  • R is
  • the compound has the formula
  • R ,21 is hydrogen; (C ⁇ -8 )alkyl; benzyl; or phenyl; in which the benzyl and phenyl 19 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.
  • R 5 has formula:
  • Compounds of formula I include those wherein R 1 and R 2 are hydrogen; n is 1 ; X together with an adjacent ring carbon and Z form a fused cyclopropyl; CR'R" is absent; 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 cycloheter
  • R 1 , R 2 , R 3 and R 4 are hydrogen; n is 1; X is CH 2 ; CR'R" is absent; and R 5 is aryl or aralkyl.
  • compounds of formula I have the formula:
  • Compounds of formula I include those wherein, if CR'R" 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, O, 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 if CR'R" is absent, then R 3 is hydrogen; and R 4 and R 5 together with the atoms to which they are attached form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO 2 , and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently pluri
  • each R 24 is independently: a) hydrogen; b) (C 1-12 )alkyl; (C 2-12 )alkenyl; (C 2-12 )alkynyl; (C 3-12 ) cycloalkyl; or (C 3- 12 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are 19 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 pluri
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; (C - ⁇ 2 )cycloalkyl ring; (C 3- ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3- ⁇ 2 )cycloalky
  • R 21 is hydrogen; (C ⁇ -8 )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 25 is: a) hydrogen; b) (C 1-12 )alkyl; (C 2-12 )alkenyl; (C 2- ⁇ 2 )alkynyl; (C 3-12 ) cycloalkyl; or (C 3- 12 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are 19 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
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; (C 3- ⁇ 2 )cycloalkyl ring; (C 3- ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3- ⁇ 2 )cycloalkyl
  • R 21 is hydrogen; (C ⁇ -s)alkyl; benzyl; or phenyl; in which the benzyl and phenyl 19 groups are optionally mono- or independently di-substituted on the ring with R ; and t is 0 to 6; and R 26 is: a) hydrogen; b) (C, -12 )alkyl; (C 2- ⁇ 2 )alkenyl; (C 2-12 )alkynyl; (C 3-12 ) cycloalkyl; or (C 3- ⁇ 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; c) aryl; or heteroaryl; where the aryl and heteroaryl groups
  • R 14 and R 15 are independently hydrogen; (C 1-8 )alkyl; (C ⁇ -6 )alkylcarbonyl; (C 3- ⁇ 2 )cycloalkyl ring; (C - ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3- ⁇ 2 )cycloalkyl
  • X is CH 2 ; the ring containing 1 9 9* ⁇
  • X is saturated; and R , R and R are hydrogen.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 25 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.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 25 are hydrogen; and R 24 is (C ⁇ - ⁇ 2 )alkyl; (C 2- ⁇ 2 )alkenyl; (C 2- ⁇ 2 )alkynyl; (C - ⁇ 2 ) cycloalkyl; or (C 3 . ⁇ 2 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 12 , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 25 are hydrogen; and R 24 is phenyl optionally mono- or independently plurisubstituted with R 12 .
  • Compounds of formula II include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 25 are hydrogen; and R 24 is R U (CH 2 ) P - where R 11 is 2- oxopyrrolidinyl; (C 1-6 )alkoxy; phenyl; phenoxy; (C ⁇ -8 )cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Ci ⁇ alkylcarbonyl; (C .
  • cycloalkylcarbonyl 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 ⁇ -6 )alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R 12 ; where the phenoxy group is optionally mono- or independently disubstituted with (Ci- 4 )alkyl, (C 1-4 )alkoxy, or
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 25 are hydrogen; and R 24 is (R 13 ) 2 CH(CH 2 ) q -, where R is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R 12 ; and q is 0 to 3.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 25 are hydrogen; and R 24 is a group of the formula: R 15 I R 14 ⁇ ⁇ (CH 2 ) S -
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (d ⁇ alkylcarbonyl; (C - ⁇ 2 )cycloalkyl ring; (C - ⁇ 2 )cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-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 12 ; or R 14 and R 15 together form a (C 3-12 )cycloalkyl ring; and
  • R 21 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 R 12 ; and t is 1 to 6.
  • Compounds of formula II include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 24 are hydrogen.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 25 is (Ci- ⁇ 2 )alkyl; (C 2- ⁇ 2 )alkenyl; (C 2- ⁇ 2 )alkynyl; (C 3- ⁇ 2 ) cycloalkyl; or (C 3- ⁇ 2 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 12 , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are 9 ⁇ 1 hydrogen; and R is phenyl optionally mono- or independently plurisubstituted with R .
  • Compounds of formula II include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 25 is R n (CH 2 ) p - where R 1 ' is 2-oxopy ⁇ olidinyl, (C ⁇ -6 )alkoxy, phenyl; phenoxy; (C ⁇ -g)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopy ⁇ olidinyl, (C ⁇ -6 )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 disubstituted with (C ⁇ -4 )alkyl, or halogen
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 25 is (R 13 ) 2 CH(CH 2 ) q -, where R 13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R 12 ; and q is 0 to 3.
  • Compounds of formula II include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 25 is a group of the formula:
  • R 14 and R 15 are independently hydrogen; (C 1-8 )alkyl; (C ⁇ -6 )alkylcarbonyl; (C 3- 1 )cycloalkyl ring; (C 3- ⁇ 2 )cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-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 12 ; or R 14 and R 15 together form a (C 3- ⁇ 2 )cycloalkyl ring; and
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 25 is a group of the formula: R 21 — 0-(CH 2 ) t — where R 21 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 R 12 ; and t is 0 to 6.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 and R 26 are hydrogen.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 26 is (C ⁇ - ⁇ 2 )alkyl; (C 2- ⁇ 2 )alkenyl; (C 2- ⁇ 2 )alkynyl; (C 3- ⁇ 2 ) cycloalkyl; or (C 3- ⁇ 2 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 12 , 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 1 , R 2 , R 24 are hydrogen; and R 26 is phenyl optionally mono- or independently plurisubstituted with R 12 .
  • Compounds of formula II include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 26 is (R 13 ) 2 CH(CH 2 ) q -; where R 13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R 12 ; and q is 0 to 3.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 26 is a group of the formula: R 15 R 14 ⁇ ⁇ (CH 2 ) r
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; (C 3- ⁇ 2 )cycloalkyl ring; (C 3- ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3- ⁇ 2 )cycloalkyl
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 26 is a group of the formula: where R 21 is hydrogen; (C ⁇ -8 )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 0 or 2 to 6.
  • Compounds of formula II include those that have the formula:
  • R ,25 is phenyl optionally mono- or independently plurisubstituted with R 12
  • the compound has the formula:
  • R 28 and R 29 are each independently hydrogen, hydroxy, alkyl, alkoxy, aryloxy, or halogen.
  • Y is O, S, CHR 25 or NR 26 ; k is 0 to 3 and m is 0 to 3 when Y is CHR 2"5.; k is 1 to 3 and m is 0 to 3 when Y is NR 26 ; k is 1 to 3 and m is 0 to 3 when Y is O;
  • R is a) hydrogen; b) (C, -12 )alkyl; (C 2- ⁇ 2 )alkenyl; (C 2-12 )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 6 , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R 6 is (C ⁇ -6)alkyl
  • ⁇ 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 R 7 ; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; c) aryl optionally fused to a (C 3- ⁇ o)cycloalkyl; or heteroaryl optionally fused to a (C 3- i 0 )cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH )
  • R 1 and R 17 are each independently hydrogen; (C ⁇ .g)alkyl; (Ci. 6 )alkylcarbonyl; di-(C ⁇ -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 12 ; or R 16 and R 17 together form a (C 3- ⁇ 2 )cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
  • R 18 and R 19 are independently hydrogen; (C 1-8 )alkyl; (C). 6 )alkylcarbonyl; di-(C ⁇ -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 disubstituted with R 12 ; or R 18 and R 19 together form a (C 3- ⁇ 2 )cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-
  • R ,20 is hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(C 1-6 )alkylaminocarbonyl; (C - 8 )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 R 12 ; R x is hydrogen; (C ⁇ -8 )alkyl; (C
  • R 21 is hydrogen; (C ⁇ -8 )alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 12 ; each t is independently 0 to 6; and u is 0 to 3; each R 24 is independently: a) hydrogen; b) (C 2 )alkyl; (C 2-12 )alkenyl; (C 2-12 )alkynyl; (C 3-12 ) cycloalkyl; or (C 3 , ⁇ 2 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 12 , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; c) aryl; or heteroaryl
  • phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R 12 ; 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 12 is halogen; trifluoromethyl; cyano; nitro; (C 1-6 )alkyl; (C ⁇ -6 )alkoxy; cycloalkyl; carboxy; acetamido; hydroxy;
  • R 14 and R 15 are independently hydrogen; (C 1- )alkyl; (C ⁇ -6 )alkylcarbonyl; (C 3- )2 )cycloalkyl ring; (C 3- ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3- ⁇ 2 )cycloalkyl ring
  • R 21 is hydrogen; (C ⁇ -8 )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 0 to 6;
  • R 25 is: a) hydrogen; b) (C ⁇ -12 )alkyl; (C 2-12 )alkenyl; (C 2-12 )alkynyl; (C 3-12 ) cycloalkyl; or (C 3 .
  • alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 12 , 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 • 19 mono- or independently plu ⁇ substituted with R ; d) R n (CH 2 )p- where R 11 is 2-oxopy ⁇ olidinyl; (C ⁇ -6 )alkoxy; phenyl; phenoxy; (C ⁇ -8 )cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (C ⁇ .g)alkylcarbonyl; (C . ⁇ 2
  • phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R 12 ; 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 1-8 )alkyl; p is 0 to 3; and R 12 is halogen; trifluoromethyl; cyano; nitro; (C 1-6 )alkyl; (C ⁇ -6 )alkoxy; cycloalkyl; carboxy; acetamido; hydroxy;
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (Ci -6 )alkylcarbonyl; (C 3- 12 )cycloalkyl ring; (C 3- ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3-12 )cycloalkyl ring; and
  • R 21 is hydrogen; (C ⁇ -8 )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 0 to 6; and R 26 is: a) hydrogen; b) (C, -12 )alkyl; (C 2-12 )alkenyl; (C 2- ⁇ 2 )alkynyl; (C 3-12 ) cycloalkyl; or (C 3- ⁇ 2 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 12 , 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 heteroary
  • R 14 and R 15 are independently hydrogen; (C 1-8 )alkyl; (C ⁇ -6 )alkylcarbonyl; (C 3- ⁇ 2 )cycloalkyl ring; (C 3- ⁇ 2 )cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C ⁇ - 6 )alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfony
  • R 21 is hydrogen; (C ⁇ -8 )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 0 or 2 to 6.
  • Compounds of formula III include those wherein X is CH 2 ; the ring containing X 1 9 9 • is saturated; and R , R and R are hydrogen; those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 25 are hydrogen; and R 24 is hydrogen; and those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 25 are hydrogen; and R 24 is (C ⁇ _ ⁇ 2 )alkyl; (C 2- 12 )alkenyl; (C 2- ⁇ 2 )alkynyl; (C 3- ⁇ 2 ) cycloalkyl; or (C 3- ⁇ 2 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently 1 plurisubstituted with R , and where the alkyl, alkenyl, alkynyl,
  • X is CH ; the ring containing X is saturated; R 1 , R 2 and R 25 are hydrogen; and R 24 is phenyl optionally mono- or independently plurisubstituted with R 12 .
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 25 are hydrogen; and R 24 is R H (CH 2 ) P - where R 11 is 2-oxopyrrolidinyl, (C ⁇ -6 )alkoxy, phenyl; phenoxy; (C 1-8 )cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2- oxopy ⁇ olidinyl, (C ⁇ -6 )alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- • • 1 or independently di- or independently trisubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with (C ⁇ -4 )alkyl, (C ⁇ -4 )alkoxy, or halogen;
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 25 are hydrogen; and R 24 is (R 13 ) 2 CH(CH 2 ) q -, where R 13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R 12 ; and q is 0 to 3.
  • Compounds of formula III include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 25 are hydrogen; and R 24 is a group of the formula: R 15 I R 14 ⁇ ⁇ (CH 2 ) S —
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; (C 3- ⁇ 2 )cycloalkyl ring; (C 3- ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3- ⁇ 2 )cycloalkyl
  • Compounds of formula III also include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 25 are hydrogen; and R 24 is a group of the formula:
  • R 21 is hydrogen; (C ⁇ -8 )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 0 to 6.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 and R 24 are hydrogen.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 25 is (C ⁇ .] 2 )alkyl; (C 2- ⁇ 2 )alkenyl; (C 2- ⁇ 2 )alkynyl; (C 3- ⁇ 2 ) cycloalkyl; or (C 3-12 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 12 , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 25 is phenyl optionally mono- or independently plurisubstituted with R 12 .
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 25 is R ⁇ (CH 2 ) p - where R n is 2- oxopy ⁇ olidinyl, (C 1-6 )alkoxy, phenyl; phenoxy; (C ⁇ -8 )cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2- oxopyrrolidinyl, (C ⁇ -6 )alkoxy, phenyl, pyridinyl, and nap
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 25 is (R 13 ) 2 CH(CH 2 ) q -, where R 13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R 12 ; and q is 0 to 3.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 25 is a group of the formula: R 15 .
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C 1-6 )alkylcarbonyl; (C 3- 12 )cycloalkyl ring; (C 3- ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C - ⁇ 2 )cycloalkyl ring;
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 25 is a group of the formula: R 21 -0-(CH 2 ) t 1
  • R 21 is hydrogen; (C ⁇ -8 )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 0 to 6.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 and R 26 are hydrogen.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 26 is (C ⁇ -12 )alkyl; (C 2- ⁇ 2 )alkenyl; (C 2- ⁇ 2 )alkynyl; (C - ⁇ 2 ) cycloalkyl; or (C 3- ⁇ 2 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 12 , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 and R 26
  • Compounds of formula III include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 26 is R 27 (CH 2 ) P -, where R 27 is 2-oxopyrrolidinyl; (C ⁇ -6 )alkoxy; phenyl; phenoxy; (C 1-8 )cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (C 1-8 )alkylcarbonyl; (C 3- ⁇ 2 )cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C ⁇ -6 )alkyl; where
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 26 is (R 13 ) 2 CH(CH 2 ) q -; where R 13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R 12 ; and q is 0 to 3.
  • Compounds of formula III include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 26 is a group of the formula:
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ - )alkylcarbonyl; (C 3- ⁇ 2 )cycloalkyl ring; (C 3- ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C - ⁇ 2 )cycloalkyl
  • Compounds of formula III also include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 24 are hydrogen; and R 26 is a group of the formula:
  • R 21 is hydrogen; (C ⁇ -8 )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 0 or 2 to 6.
  • CR'R is present.
  • the compound has formula IVA or IVB:
  • R is a) hydrogen; b) (C ⁇ - ⁇ 2 )alkyl; (C 2-12 )alkenyl; (C 2-12 )alkynyl; (C 3-12 ) cycloalkyl; or (C 3- i 2 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are 19 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 R 12 ; d) R ⁇ (CH 2 ) p - where R 11 is 2-oxopyrrolidinyl; (C ⁇ -6 )alkoxy; phenyl;
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; (C 3- i 2 )cycloalkyl ring; (C -i2)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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3- ⁇ 2 )cycloalkyl ring
  • R 21 is hydrogen; (C ⁇ -8 )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 0 to 6;
  • boronic acid compounds of the invention can exist as either linear or cyclic isomers. Typically, such compounds form an equilibrium mixture in aqueous solution. As shown in Figure 1, the concentration of the two isomers of such compounds is typically pH dependent. Thus, it is expected that such inventive compounds will exist as a mixture of linear and cyclic isomers in vivo. Moreover, the cyclic forms of inventive compounds may serve as novel, orally available prodrugs. Hence, in this aspect of the invention, there are provided compounds that have the formula VA, VB, or a mixture thereof:
  • VA VB including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein: n is 1 to 3; X is CH 2 ; S; O; CF 2 or C(CH 3 ) 2 ; Z is H; halogen; hydroxyl; (C ⁇ -6 )alkoxy; (C]. ⁇ 2 )alkyl; (C 3- ⁇ 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 1 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
  • R 14 and R 15 are independently hydrogen; (C 1-8 )alkyl; (C ⁇ -6 )alkylcarbonyl; (C 3- ⁇ 2 )cycloalkyl ring; (C 3- ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C - ⁇ 2 )cycloalkyl
  • R and R are each independently hydrogen; (C ⁇ -8 )alkyl; (Ci -6 )alkylcarbonyl; di-(C ⁇ 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 12 ; or R 16 and R 17 together form a (C 3- ⁇ 2 )cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
  • R 18 and R 19 are independently hydrogen; (C 1-8 )alkyl; (Cj -6 )alkylcarbonyl; di-(C ⁇ _ 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 12 ; or R 18 and R 19 together form a (C 3- ⁇ 2 )cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phen
  • R 20 is hydrogen; (C ]-8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(Ci -6 )alkylaminocarbonyl; (C 3- 8 )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 R 12 ; R x is hydrogen; (C ⁇ -8 )alkyl; (C -
  • R is hydrogen; (C ⁇ -8 )alkyl; benzyl; or phenyl; in which the benzyl and phenyl * 1 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; 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, a
  • R 1 and R 2 independently or together are the boronic acid protecting group formed from (+)-pinanediol; pinacol; 1,2-dicyclohexyl-ethanediol; 1 ,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3-butanediol, diisopropyl tartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6- decanediol; 1 , 1 ,2-triphenyl- 1 ,2-ethanediol; (2R,3R)- 1 ,4-dimethyoxy- 1 , 1 ,4,4-tetraphenyl- 2,3-butanediol; methanol; ethanol; isopropanol; catechol; or 1-butanol.
  • 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-butanediol; diisopropylethanediol; methanol; ethanol; isopropanol; or 1-butanol.
  • 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
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is (C 1-12 )alkyl; (C 2- 1 )alkenyl; (C 2- ⁇ 2 )alkynyl; (C 3- ⁇ 2 ) cycloalkyl; or (C 3- ⁇ 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 5 is (C 3-12 ) cycloalkyl such as cyclopentyl.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is indanyl; 1,2,3,4- tetrahydronaphthyl; (CH 2 )j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]-oct-l-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, (C ⁇ -8 )alkyl, (C ]-8 )alkoxy, (C ⁇ -8 )alkanoy
  • Compounds of formula VA or VB include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is R ⁇ (CH 2 ) p - where R 11 is 2-oxopyrrolidinyl; (C ]-6 )alkoxy; phenyl; phenoxy; (C ⁇ -8 )cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2- oxopyrrolidinyl, (C 1-6 )alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- 19 or independently di- or independently trisubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with (C ⁇ -4 )alkyl, (
  • Compounds of VA or VB further include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is (R 13 ) 2 CH(CH 2 ) q -, where R 13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R 12 ; and q is 0 to 3.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula:
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C 3- 12 )cycloalkyl ring; (C - ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3-12 )cycloalkyl ring; and r is 2 to 6.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula:
  • R 16 and R 17 are each independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(C ⁇ _ 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 12 ; or R 16 and R 17 together form a (C 3-12 )cycloalkyl ring; and s is 1 to 6.
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula:
  • R 18 and R 19 are independently hydrogen; (C ⁇ -8 )alkyl; (C 1-6 )alkylcarbonyl; di-(C ⁇ - 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 12 ; or R 18 and R 19 together form a (C 3- ⁇ 2 )cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3.
  • R 5 has formula:
  • Compounds of formula VA or VB further include those wherein X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula:
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula:
  • R 20 is hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(C ⁇ -6 )alkylaminocarbonyl; (C - 8 )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 R 12 ; R x is hydrogen; (C ⁇ -8 )alkyl; (C 3-
  • R has formula:
  • X is CH 2 ; the ring containing X is saturated; R 1 , R 2 , R 3 and R 4 are hydrogen; and R 5 is a group of the formula:
  • R ,21 is hydrogen; (C ⁇ -8 )alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 12 ; each t is independently 0 to 6; and u is 0 to 3.
  • R 5 has formula:
  • Compounds of formula VA or VB further include those wherein R 1 and R 2 are hydrogen; n is 1 ; X together with an adjacent ring carbon and Z form a fused cyclopropyl;
  • 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, alk
  • compounds of formual VA or VB include those having the formula:
  • compounds of formula VA or VB have the formula:
  • compounds of formual VA or VB have the formula:
  • the invention provides boronic acid inhibitors of dipeptidyl peptidase-IV having an inhibition constant of 10 micromolar or less for dipeptidyl peptidase-IV.
  • Such inhibitors comprises a boroproline (including boropyrrolidines, boropiperidines, and boroazepanes) attached to an amino acid through an amide bond.
  • the amino acid can be a beta-amino acid (including cyclic forms such as , an N-cycloalkyl-alpha-amino acid, an N-heterocyclyl-alpha amino acid, a cyclic alpha-amino acid having at least one substituent on the alpha-amino acid ring or having a ring other than pyrrolidine, or N-substituted glycine.
  • the boronic acid inhibitor is of Formula I:
  • n 1 to 2
  • X is CH 2 ; S; O; CF 2 or C(CH 3 ) 2
  • Z is H; halogen; hydroxyl; (C ⁇ -6 )alkoxy; (Q. ⁇ alkyl; (C -12 )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 1 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"
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; (C 3- )2 )cycloalkyl ring; (C 3- ⁇ 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3- ⁇ 2 )cycloalkyl
  • R 16 and R 17 are each independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(d 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 12 ; or R 16 and R 17 together form a (C - ⁇ 2 )cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
  • R 18 and R 19 are independently hydrogen; (C 1-8 )alkyl; (C 1- )alkylcarbonyl; di-(C ⁇ - 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 12 ; or R 18 and R 19 together form a (C 3- ⁇ 2 )cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-
  • R 20 is hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(C ⁇ -6 )alkylaminocarbonyl; (C 3- 8 )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 R 12 ; R x is hydrogen; (C ⁇ -8 )alkyl; (C 3-
  • R 21 is hydrogen; (C ⁇ -8 )alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 12 ; each t is independently 0 to 6; and u is 0 to 3; (bb) R', R", 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
  • R 14 and R 15 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; (C 3- i 2 )cycloalkyl ring; (C 3- i 2 )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, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14 and R 15 together form a (C 3-12 )cycloalkyl ring
  • R 16 and R 17 are each independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(C ⁇ . 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 12 ; or R 16 and R 17 together form a (C -i 2 )cycloalkyl ring; and s is 1 to 6; h) a group of the formula:
  • R 18 and R 19 are independently hydrogen; (C ⁇ -8 )alkyl; (C ⁇ -6 )alkylcarbonyl; di-(d. 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 12 ; or R 18 and R 19 together form a (C 3- i 2 )cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; i) a group of the formula: (pheny
  • R 20 is hydrogen; (C ⁇ -8 )alkyl; (Ci ⁇ alkylcarbonyl; di-(C ⁇ -6 )alkylaminocarbonyl; (C 3- 8 )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 R 12 ; R x is hydrogen; (C ⁇ -8 )alkyl; (C 3- ⁇ 2
  • R 21 is hydrogen; (C ⁇ -8 )alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 12 ; 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; hetero
  • the invention also relates to methods for preparing the above-described compounds.
  • the compounds of formula I and II are prepared by reacting a cyclic amine (e.g., py ⁇ olidine or piperidine), suitably protected with a standard protecting group such as Boc-, Fmoc-, CBz- or the like, with sec-BuLi/TMEDA followed by B(OCH 3 ) 3 , to provide the methyl boronic ester derivative.
  • Acid hydrolysis of the methyl esters with 2N HC1 provides the boronic acid intermediate 1.
  • Reaction of 1 with (+) pinanediol, deprotection of the amino protecting group, and recrystallization provides the pinanediol ester 2 as an isomerically pure salt.
  • Intermediate 2 is useful for the synthesis of both series A and series B compounds.
  • N-acylation of 2 with chloroacetyl chloride provides the ⁇ - chloro amide 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.
  • coupling of intermediate 2 with N-Boc-5-phenyl-Pro using EDAC/HOBT provides amide 5.
  • Deprotection of the amino group and hydrolysis of the boronic esters provides a compound of formula II, 6.
  • This synthetic scheme is adaptable for the preparation of all the compounds of the invention, by reacting the appropriate cyclic amine (py ⁇ ollidine, piperidine, and other cyclic amines) 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.
  • Another aspect of the invention provides a process for preparing the compounds of formula I:
  • R 5 -NH 2 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 ⁇ l , r R»2 , ⁇ R> 3 , ⁇ R»4 , T R» I , ⁇ R, " , n, X, and Z are as defined herein.
  • Prefe ⁇ ed 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.
  • Still another aspect of the invention provides a process for preparing the compounds of formula II:
  • R'and R 2 are not hydrogen, and n, X, and Z are as defined herein.
  • the 2-boroheterocycle is a 2-boropy ⁇ olidino or 2-boropiperidino.
  • the N-protected cyclic amino acid is N-Boc-4-phenyl-boroPro-OH.
  • 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.
  • salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
  • Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like.
  • Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • 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.
  • 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.
  • the invention extends to all of the stereoisomeric forms of the claimed compounds, including enantiomers and diastereomers, as well as the racemates.
  • Methods/Uses [0097] Another aspect of the invention provides methods and uses for the compounds of the invention.
  • the invention compounds can be administered to an individual suffering from a disease or condition mediated by a post-proline/alanine cleaving amino-dipeptidase.
  • the individual is administered an amount of the invention compound effective in reducing the activity of the post-proline/alanine cleaving amino-dipeptidase and, thereby, reducing or alleviating symptoms of the disease or condition.
  • the administered compound reduces the activtity of DPP- IV.
  • the disease or condition is selected from the group consisting of diabetes, diabetec complications, hyperglycemia, Syndrome X, hyperinsulinemia, obesity, atherosclerosis and related diseases.
  • the invention compounds to be administered may be one or more of the inventive bronic acid compounds, which may be formulated in any manner as described here, including combination with "other type(s) of therapeutic agents" identified further below.
  • 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;
  • 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;
  • Methods for treating controlling, or preventing diabetes comprising administering to a patient of an effective amount of a compound of the invention
  • 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;
  • Methods for treating, controlling or preventing hyperglycemia in a mammalian patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of the invention;
  • Methods for treating to enhance islet neo genesis, 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;
  • 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
  • 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;
  • 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;
  • 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;
  • 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;
  • 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;
  • Methods for treating, controlling or preventing in a mammalian patient in need of such treatment one or more disorders selected from the group consisting of neutropenia, anemia, neuronal disorders, tumor growth and metastasis, benign prostatic hypertrophy, gingivitis, hypertension and osteoporosis, comprising administering to the patient a therapeutically effective amount of a compound of the invention;
  • Methods for reducing sperm motility in a male in a mammalian patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of the invention;
  • Methods for treating, controlling or preventing in a mammalian patient in need of such treatment one or more conditions selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) rheumatoid arthritis, (17) other inflammatory conditions, (18) pancreatitis, (19) abdominal obesity, (20) neurodegenerative disease, (21) multiple sclerosis, (22) retinopathy, (23) nephropathy, (24) neuropathy, (25) Syndrome X, (26) ovarian hyperandrogenism, (27) allograft rejection in transplantation, and other conditions where insulin
  • Methods for treating, controlling or preventing in a mammalian patient in need of such treatment one or more conditions selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) rheumatoid arthritis, (17) other inflammatory conditions, (18) pancreatitis, (19) abdominal obesity, (20) neurodegenerative disease, (21) multiple sclerosis, (22) retinopathy, (23) nephropathy, (24) neuropathy, (25) Syndrome X, (26) ovarian hyperandrogenism, (27) allograft rejection in transplantation, (28) Type II diabetes
  • Methods for the treatment, control, or prevention of one or more conditions selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of the invention and an HMG-CoA reductase inhibitor;
  • HMC-CoA reductase inhibitor is a statin
  • statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin;
  • 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;
  • 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;
  • 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;
  • anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and or mazindol;
  • 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;
  • 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;
  • Methods for the treatment, control, or prevention of anemia wherein the erythropoietin agonist is EPO, an EPO mimetic, or an EPO receptor agonist;
  • the compounds of the invention may be used in combination with one or more other types of antidiabetic agents (employed to treat diabetes and related diseases) and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in a separate oral dosage form or by injection.
  • the other type of antidiabetic agent which may be optionally employed in combination with the DPP-IV inhibitors of the invention may be 1,2,3 or more antidiabetic agents or antihyperglycemic agents including insulin secretagogues or insulin sensitizers, or other antidiabetic agents preferably having a mechanism of action different from DPP-IV inhibition and may include biguanides, sulfonyl ureas, glucosidase inhibitors, PPAR ⁇ agonists, such as thiazolidinediones, SGLT2 inhibitors, PPAR ⁇ / ⁇ dual agonists, aP2 inhibitors, glycogen phosphorylase inhibitors, advanced glycosylation end (AGE) products inhibitors, and/or meglitinides, as well as insulin, and or glucagon-like peptide- 1 (GLP-1) or mimetics thereof.
  • biguanides such as thiazolidinediones, SGLT2 inhibitors, PPAR
  • the other antidiabetic agent may be an oral antihyperglycemic agent preferably a biguanide such as metformin or phenformin or salts thereof, preferably metformin HC1.
  • 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.
  • 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 ⁇ -cells, with glyburide and glipizide being preferred, which may be administered in the same or in separate oral dosage forms.
  • the compounds of the invention will be employed in a weight ratio to the sulfonyl urea in the range from about 0.01 :1 to about 100:1, preferably from about 0.05:1 to about 5:1.
  • the oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. patent No. 4,904,769) or miglitol (disclosed in U.S. patent No. 4,639,436), which may be administered in the same or in a separate oral dosage forms.
  • acarbose disclosed in U.S. patent No. 4,904,769
  • miglitol disclosed in U.S. patent No. 4,639,436
  • the compounds of the invention will be employed in a weight ratio to the glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.2:1 to about 50:1.
  • the compounds of the invention may be employed in combination with a PPAR ⁇ agonist such as a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner- Lambert's Rezulin®, disclosed in U.S. patent No. 4,572,912), rosiglitazone (en), pioglitazone (Takeda), Mitsubishi MCC-555 (disclosed in U.S. patent No.
  • a PPAR ⁇ agonist such as a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner- Lambert's Rezulin®, disclosed in U.S. patent No. 4,572,912), rosiglitazone (en), pioglitazone (Takeda), Mitsubishi MCC-555 (disclosed in
  • 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-l 19702 (Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone.
  • 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.
  • the sulfonyl urea and thiazolidinedione in amounts of less than about 150 mg oral antidiabetic agent may be inco ⁇ orated in a single tablet with the compounds of the invention.
  • 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-10-36) amide, GLP-l(7-36) amide, GLP-l(7-36) (as disclosed in U.S. Patent No. 5,614,492 to Habener, disclosure of which is inco ⁇ orated herein by reference), or a GLP-1 mimic such as AC2993 or Exendin-4 (Amylin) and LY-315902 or LY-307167 (Lilly) and NN2211 (Novo-Nordisk), which may be administered via injection, intranasal, or by transdermal or buccal devices.
  • GLP-1 such as GLP-10-36) amide, GLP-l(7-36) amide, GLP-l(7-36)
  • GLP-1 mimic such as AC2993 or Exendin-4 (Amylin) and LY-315902 or
  • metformin the sulfonyl ureas, such as glyburide, glimepiride, glipyride, glipizide, chlo ⁇ ropamide and gliclazide and the glucosidase inhibitors acarbose or miglitol or insulin (injectable, pulmonary, buccal, or oral) may be employed in formulations as described above and in amounts and dosing as indicated in the PHYSICIAN'S DESK REFERENCE (PDR).
  • PDR PHYSICIAN'S DESK REFERENCE
  • 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.
  • 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.
  • 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 inco ⁇ orated herein by reference.
  • the other antidiabetic agent may also be a PPAR ⁇ / ⁇ dual agonist such as AR- HO39242 (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.
  • the other antidiabetic agent may be an SGLT2 inhibitor, as disclosed in U.S. Application Ser. No. 09/679,027, filed Oct. 4, 2000 (attorney file LA49NP), which is inco ⁇ orated herein by reference, employing dosages as set out herein.
  • Prefe ⁇ ed are the compounds designated as prefe ⁇ ed in the above application.
  • the other antidiabetic agent which may be employed in combination with the DPP-IV inhibitors in accordance with the present invention, can be an aP2 inhibitor,09/519,079, filed Mar. 6, 2000 (attorney file LA27NP), which are each inco ⁇ orated herein by reference, employing dosages as set out herein.
  • Prefe ⁇ ed antidiabetic agents to be used in combination with the invention compounds are those indicated as prefe ⁇ ed in the above cited patents.
  • 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.
  • the meglitinide which may optionally be employed in combination with the compound of the invention may be repaglinide, nateglinide (Novartis) or KADI 229 (PF/Kissei), with repaglinide being preferred.
  • the DPP-IV inhibitors of the invention will be employed in a weight ratio to the meglitinide, PPAR ⁇ agonist, PPAR ⁇ / ⁇ 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.
  • 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 abso ⁇ tion 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.
  • MTP inhibitors employed herein include MTP inhibitors disclosed in U.S. patents No. 5,595,872, No. 5,739,135, No. 5,712,279, No. 5,760,246, No. 5,827,875, No. 5,885,983, and No. 5,962,440.
  • MTP inihibitors prefe ⁇ ed herein are thos identified as being prefe ⁇ ed in the above referenced patents.
  • MTP inhibitors 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 pefe ⁇ ed MTP inhibitor in this context is 9-[4-[4-[[2-(2,2,2- Trifluoroethoxy)-benzoyl]amino]-l-piperidinyl] butyl]-N-(2,2,2-trifluoroethyl)-9H- fluorene-9-carboxamide.
  • the hypolipidemic agent may be an HMG CoA reductase inhibitor which includes, but is not limited to, mevastatin and related compounds as disclosed in U.S. patent No. 3,983,140, lovastatin (mevinolin) and related compounds disclosed in U.S. patent No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Patent No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Patent Nos. 4,448,784 and 4,450,171.
  • 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.
  • the squalene synthetase inhibitors suitable for use herein include, but are not limited to, ⁇ -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., Cu ⁇ ent Pharmaceutical Design, 2, 1-40 (1996).
  • squalene synthetase inhibitors suitable for use herein include the te ⁇ enoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc, 1976, 98, 1291- 1293, phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987, 10, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstracts Table of Contents, pp 16, 17, 40-43, 48-51, Summary.
  • hypohpidemic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezaf ⁇ brate, ciprofibrate, clinofibrate, and the like, probucol, and related compounds as disclosed in U.S. Patent No.
  • the other hypohpidemic 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, frel). (1998), 137(1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypohpidemic activity mediated by selective suppression of the hepatic secretion of ApoBlOO-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev.
  • the hypohpidemic agent may be an upregulator of LD2 receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).
  • the hypohpidemic agent may be a cholesterol abso ⁇ tion inhibitor preferably Schering-Plough's SCH48461 as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).
  • the hypohpidemic agent may be an ileal Na + /bile acid cotransporter inhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).
  • the lipid-modulating agent may be a cholesteryl ester transfer protein (CETP) inhibitor such as Pfizer's CP 529,414 (WO/0038722 and EP 818448) and Pharmacia's SC- 744 and SC-795.
  • CETP cholesteryl ester transfer protein
  • 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.
  • Prefe ⁇ ed hypohpidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin and ZD-4522.
  • the compounds of the invention will be employed in a weight ratio to the hypohpidemic agent (where present), within the range from about 500:1 to about 1 :500, preferably from about 100:1 to about 1:100.
  • 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.
  • the dosages and formulations for the hypohpidemic agent will be as disclosed in the various patents and applications discussed above. [0167] The dosages and formulations for the other hypohpidemic agent to be employed, where applicable, will be as set out in the latest edition of the Physicians' Desk Reference.
  • MTP inhibitor for oral administration, a satisfactory result may be obtained employing the MTP inhibitor in an amount within the range of from about 0.01 mg/kg to about 500 mg and preferably from about 0.1 mg to about 100 mg, one to four times daily.
  • 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.
  • an HMG CoA reductase inhibitor for example, pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin in dosages employed as indicated in the PHYSICIAN'S DESK REFERENCE, such as in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.
  • 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.
  • a prefe ⁇ ed 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.
  • a prefe ⁇ ed 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.
  • the other hypohpidemic agent may also be a lipoxygenase inhibitor including a 15-lipoxygenase (15-LO) inhibitor such as benzimidazole derivatives as disclosed in WO 97/12615, 15-LO inhibitors as disclosed in WO 97/12613, isothiazolones as disclosed in WO 96/38144, and 15-LO inhibitors as disclosed by Sendobry et al "Attenuation of diet- induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties", Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al, "15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease", Current Pharmaceutical Design, 1999, 5, 11-20.
  • 15-LO 15-lipoxygenase
  • 15-LO 15-lipoxygenase
  • benzimidazole derivatives as disclosed in WO 97/12615
  • the compounds of the invention and the hypohpidemic agent may be employed together in the same oral dosage form or in separate oral dosage forms taken at the same time.
  • 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.
  • the prefe ⁇ ed hypohpidemic agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin.
  • the other type of therapeutic agent which may be optionally employed with the DPP-IV inhibitors of the invention may be 1, 2, 3 or more of an anti-obesity agent including a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta drug, an anorectic agent and/or a fatty acid oxidation upregulator.
  • 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.
  • the beta 3 adrenergic agonist which may be optionally employed in combination with a compound of the invention may be AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. patents No. 5,541,204, No. 5,770,615, No. 5,491,134, No. 5,776,983 and No. 5,488,064, with AJ9677, L750,355 and CP331648 being prefe ⁇ ed.
  • 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 prefe ⁇ ed.
  • the serotonin (and dopamine) reuptake inhibitor which may be optionally employed in combination with a compound of the invention may be sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramine and topiramate being prefe ⁇ ed.
  • the thyroid receptor beta compound which may be optionally employed in combination with a compound of the invention may be a thyroid receptor ligand as disclosed in WO97/21993 (U. Cal SF), WO099/00353 (KaroBio) and GB98/284425 (KaroBio), with compounds of the KaroBio applications being prefe ⁇ ed.
  • the anorectic agent which may be optionally employed in combination with a compound of the invention may be dexamphetamine, phentermine, phenylpropanolamine or mazindol, with dexamphetamine being prefe ⁇ ed.
  • the fatty acid oxidation upregulator which may be optionally employed in combination with the compound of the invention can be famoxin (Genset).
  • 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.
  • 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.
  • GnRH gonadotropin releasing hormone
  • Lupron® leuprolide
  • 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.
  • 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 inco ⁇ orated herein by reference, which may be employed in amounts specified in the PDR, where applicable.
  • 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 inco ⁇ orated herein by reference, which may be employed in amounts specified in the
  • the agent for treating arthritis which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be 1, 2, or more of aspirin, indomethacin, ibuprofen, diclofenac sodium, naproxen, nabumetone (Relafen®, SmithKline Beecham), tolmetin sodium (Tolectin®, Ortho-McNeil), piroxicam (Feldene®, Pfizer), ketorolac tromethamine (Toradol®, Roche), celecoxib (Celebrex®, Searle), rofecoxib (Vioxx®, Merck) and the like, which may be employed in amounts specified in the PDR.
  • autoimmune diseases such as multiple sclerosis and immunomodulatory diseases such as lupus erythematosis, psoriasis, for example, azathioprine, Immuran, cyclophosphamide, NSAIDS such as ibuprofen, cox 2 inhibitors such as Vioxx and Celebrex, glucocorticoids and hydroxychloroquine, may be optionally employed in combination with the DPP-IV inhibitor of the invention, which may be employed in amounts specified in the PDR.
  • 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), in
  • the above anti-AIDS agents may be employed in amounts specified in the PDR.
  • 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.
  • the agent for treating osteoporosis which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be 1, 2, or more of alendronate sodium (Fosamax®, Merck, tiludronate (Skelid®, Sanofi), etidronate disodium (Didronel®, P&G), raloxifene HC1 (E vista®, Lilly), which may be employed in amounts specified in the PDR.
  • a pharmaceutical composition may be employed containing the compounds of the invention, with or without another antidiabetic agent and/or other type therapeutic agent, in association with a pharmaceutical vehicle or diluent.
  • the pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration.
  • the compounds can be administered to mammalian species including humans, monkeys, dogs, etc. by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations.
  • the dose for adults is preferably between 10 and 1,000 mg per day, which can be administered in a single dose or in the form of individual doses from 1-4 times per day.
  • a typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.
  • a typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.
  • 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.
  • compositions containing a compound of the invention of the invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19th Ed., 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include a compound of the invention which inhibits the enzymatic activity of DPP-IV or a pharmaceutically acceptable basic addition salt or prodrug or hydrate thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • 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.
  • the carrier 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.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, te ⁇ a alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpy ⁇ olidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • 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.
  • the route of administration may be any route, which effectively transports the active compound of the invention which inhibits the enzymatic activity of DPP-IV to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being prefe ⁇ ed.
  • 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.
  • a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of the invention which inhibits the enzymatic activity of DPP-IV, dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, abso ⁇ tion enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • 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.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt thereof) 250 mg Colloidal silicon dioxide (Aerosil)® 1.5 mg Cellulose, microcryst. (Avicel)® 70 mg Modified cellulose gum (Ac-Di-Sol)® 7.5 mg Magnesium stearate Ad.
  • 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.
  • 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.
  • the compounds of the invention are effective over a wide dosage range.
  • 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.
  • 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.
  • 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.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.05 mg to about 1000 mg, preferably from about 0.5 mg to about 250 mg of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
  • 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.
  • 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.
  • the invention also encompasses active metabolites of a compound of the invention.
  • compositions of the compounds of the invention alone or in combination with another type antidiabetic agent and/or other type therapeutic agent.
  • 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;
  • 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;
  • compositions comprising a compound of formula VA, VB, or a mixture thereof and a pharmaceutically acceptable carrier or diluent;
  • Pharmaceutical compositions comprising: a. a substantially pure preparation of a compound of formula VB as described herein; and b. a pharmaceutically acceptable carrier or diluent;
  • 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;
  • 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;
  • 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
  • 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;
  • 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; iii) Insulin or insulin mimetics; iv) Sulfonylureas or other insulin secretagogues; v) ⁇ -glucosidase inhibitors; vi) glucagons receptor agonists; vii) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; viii) GIP, GIP mimetics, and GIP receptor agonists; ix) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; x) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists
  • compositions 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.
  • compositions 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 ⁇ agonist, a PPAR ⁇ / ⁇ 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; [0230] Pharmaceutical combinations comprising a compound of the invention and an antidiabetic agent wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlo ⁇ ropamide, gliclazide, acarbose, miglitol,
  • compositions 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;
  • compositions comprising a compound of the invention and an antidiabetic agent wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, an anorectic agent, and/or a fatty acid oxidation upregulator;
  • 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
  • compositions 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;
  • the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol;
  • compositions comprising a compound of the invention and a lipid-modulating agent wherein the lipid-modulating agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, an ACAT inhibitor, a cholesteryl ester transfer protein inhibitor, or an ATP citrate lyase inhibitor;
  • compositions comprising a compound of the invention and a lipid-modulating agent wherein the lipid-modulating agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529,414, avasimibe, TS-962, MD-700, and/or LY295427; [0236] Pharmaceutical combinations comprising a compound of the invention and a lipid-modulating agent wherein the compound is present in a weight ratio to the lipid- modulating agent within the range from about 0.01 to about 100:1;
  • compositions comprising a compound of the invention and an agent for treating infertility, an agent for treating polycystic ovary syndrome, an agent for treating a growth disorder and/or frailty, an anti-arthritis agent, an agent for preventing inhibiting allograft rejection in transplantation, an agent for treating autoimmune disease, an anti-AIDS agent, an agent for treating inflammatory bowel disease/syndrome, an agent for treating anorexia nervosa, an anti-osteoporosis agent and/or an anti-obesity agent.
  • 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.
  • 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.
  • DPP-IV enzyme activity was determined by a fluorometric assay with the substrate Gly-Pro-AMC which is cleaved by DPP-IV to release the fluorescent AMC leaving group.
  • Free AMC (7-amino-4-methyl coumarin) was measured using an excitation wavelength of 380 nm and an emission wavelength of 460 nm with a Victor-II fluorescent reader.
  • Stock solutions of DPP-IV (1 ng/ ⁇ l, pH 8.0) and Gly-Pro-AMC substrate (400 ⁇ M) in 25 mM Tris buffer (pH 8.0) were prepared separately. Test compounds were dissolved in DMSO or in 50 mM glycine buffer (pH 3.0).
  • the assay was performed by diluting the DPP-IV stock (10 ⁇ l) into 25 mM Tris buffer (77.5 ⁇ l) followed by addition of test compound (2.5 ⁇ l) at 26°C. After 10-minutes substrate was added (10 ⁇ l) and allowed to react for 20-minutes at 26°C before free AMC was measured. IC50 values were determined in triplicate, using a minimum of six different inhibitor concentrations. IC 50 values were calculated using Nonlinear Regression Analysis (GraphPad, Prism, San Diego, CA).
  • the Zucker Diabetic Fatty (ZDF) rat model can be used to investigate the effects of the compounds of the invention on both the treatment and prevention of diabetes as rats of this sub-strain are initially pre-diabetic although they develop severe type 2 diabetes characterized by increased 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.
  • the model predicts the potency and limited clinical efficacy of thiazolidinedione insulin sensitizer compounds.
  • porcine DPP-IV The purification of porcine DPP-IV and the enzyme assay under steady state conditions are described in (1) Rahfeld, J. Schutkowski, M., Faust, J., Neubert., Barth, A., and Heins, J. (1991) Biol. Chem. Hoppe-Seyler, 372, 313-318; and (2) Nagatsu, T., Hino, M., Fuyamada, H., Hayakawa, T., Sakakibara, S., Nakagawa, Y., and Takemoto, T. (1976) Anal. Biochem., 74, 466-476, respectively.
  • 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.
  • 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.
  • diabetes complications include retinopathy, neuropathy and nephropathy, and other known complications of diabetes.
  • other type(s) of therapeutic agents refers to one or more antidiabetic agents (other than DPP-IV inhibitors of the invention), one or more anti-obesity agents, and/or one or more lipid-modulating agents (including anti- atherosclerosis agents), and/or one or more infertility agents, one or more agents for treating polycystic ovary syndrome, one or more agents for treating growth disorders, one or more agents for treating frailty, one or more agents for treating arthritis, one or more agents for preventing allograft rejection in transplantation, one or more agents for treating autoimmune diseases, one or more anti-AIDS agents, one or more anti-osteoporosis agents, one or more agents for treating immunomodulatory diseases, one or more agents for treating chronic inflammatory bowel disease or syndrome and/or one or more agents for treating anorexia nervosa.
  • lipid-modulating agent 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.
  • treatment is defined as the management and care of a patient for the pu ⁇ ose 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.
  • 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.
  • substantially pure in relation to compounds of the invention such as, but not limited to, those of formula VA and VB, it is meant that one isomer or the other, including all enantiomers, diastereoisomers, solvates, hydrates, and pharmaceutically acceptable salts thereof, represents at least 90% by weight of the composition. In some embodiments one isomer represents at least 98% by weight of the composition.
  • boronic acid protecting group refers to a moiety employed to block or protect the boronic acid functionality while reactions involving other functional sites of the compound are carried out.
  • the boronic acid OH groups are protected as boronic acid esters derived from alchohols such as (+)-pinanediol; pinacol; 1,2- dicyclohexyl-ethanediol; 1,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3- butanediol, diisopropyl tartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6- decanediol; 1 , 1 ,2-triphenyl- 1 ,2-ethanediol; (2R,3R)- 1 ,4-dimethyoxy- 1 , 1 ,4,4-tetra
  • 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 ).
  • diols such as pinacol form cyclic boronic diesters with -B(OH) 2 in which the organic moiety (e.g., -C(Me) 2 -C(Me) -)is attached to both oxygens.
  • 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, 3 rd Ed.” (John Wiley & Sons, New York (1999)), which is hereby inco ⁇ orated by reference.
  • N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p- toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- nitrobenzyloxycarbonyl, p-bromobenzy
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • alkyl or "(d- ⁇ 2 )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.
  • (C ⁇ . ⁇ o)alkyl 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.
  • (C ⁇ -4 )alkyl 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.
  • (C 2- ⁇ 2 )alkenyl and “(C 2- ⁇ o)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.
  • (C 2- ⁇ 2 )alkynyl and “(C 2- ⁇ o)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 C ⁇ CH, - CH 2 -CH 2 -C ⁇ CH, -CH(CH 3 )C ⁇ CH, and the like.
  • (C 3-12 )cycloalkyl and “(C 3- ⁇ 0 )cycloalkyl” refers to one or more saturated cyclic hydrocarbons having from 3-12 or 3-10 carbon atoms, respectively, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
  • (C 5 . ⁇ o)cycloalkenyl refers to a radical of one or more cyclic hydrocarbon having at least one double bond having from 5-10 carbon atoms such as, but not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • cycloalkylene refers to a “cycloalkyl” group which has single bonds for attachment at two different carbon atoms.
  • exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like.
  • exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like.
  • Exemplary cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • (C ⁇ -10 )alkoxy refers to "O" 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.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.
  • branched alkoxy include but are not limited to isop ⁇ oxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • aryloxy refers to an aryl group bonded to O.
  • alkanoyl alone or as part of another group, refers to alkyl linked to a carbonyl group.
  • alkylene refers to alkyl groups which have single bonds for attachment at two different carbon atoms.
  • alkenylene refers to alkenyl groups which have single bonds for attachement at two different carbon atoms.
  • alkynylene refers to alkynyl groups which have single bonds for attachement at two different carbon atoms.
  • aryl refers to monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring systems having 6 to 14 carbon atoms in the ring portion.
  • 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.
  • heteroaryl as used herein includes heterocyclic unsaturated ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur.
  • heteroaryl groups include but are not limited to furyl, thienyl, py ⁇ olyl, and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.
  • aryl and “heteroaryl” includes but are not limited to phenyl, biphenyl, indenyl, naphthyl (1 -naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1 -anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, py ⁇ olyl (2-py ⁇ olyl), pyrazolyl (3-pyrazolyl), imi
  • arylalkenyl and “arylalkynyl” alone or as part of another group refer to alkenyl and alkynyl groups as described above having an aryl substituent.
  • halogen and halo refers to chloro, fluoro, bromo or iodo.
  • alkylamino alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
  • substituted amino 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.
  • amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-py ⁇ olidinyl, 1 -piperidinyl, 1-azepinyl, 4-mo ⁇ holinyl, 4- thiamo ⁇ holinyl, 1-piperazinyl, 4-alkyl-l-piperazinyl, 4-arylalkyl-l-piperazinyl, 4- diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1 -piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
  • alkylthio alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.
  • 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.
  • cycloheteroalkyl alone or as part of another group refers to a 3-, 4-,
  • cycloheteroalkylalkyl alone or as part of another group refers cycloheteroalkyl groups as defined above linked through a carbon atom or heteroatom to a (CH 2 ) r chain.
  • heteroarylalkyl or “heteroarylalkenyl” alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to a (CH 2 ) r chain, alkylene or alkenylene as defined above.
  • sidechains attached to the ⁇ -amino carbon in the following naturally occu ⁇ ing ⁇ -amino acids: glycine, alanine, 2-aminobutyric acid, valine, leucine, isoleucine, tert-leucine, serine, threonine, cysteine, asparagine, aspartic acid, glutamine, glutamic acid, phenylalanine, histidine, tryptophan, tyrosine, phenylglycine, lysine, methionine, and arginine.
  • the side chains of these amino acids are well known in the art.
  • the ⁇ -amino acid sidechain of alanine is methyl
  • the sidechain of phenylalanine is benzyl
  • the sidechain of tert-leucine is tert-butyl.
  • 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 .
  • 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 O, CF 3 O or CF 3 CF 2 CH 2 O.
  • polycyclic and “polycycle” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls, heteroaryls and or cycloheteroalkyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings.” Fused rings that are joined through nonadjacent atoms, are also known as “bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, trifluoromethyl, cyano, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, si
  • a flame dried round bottom flask equipped with a magnetic stir bar was charged with N-Boc-py ⁇ olidine (20 g, 117 mmol, 1 eq) and dry THF (60 mL) under a nitrogen atmosphere.
  • the clear colorless solution was cooled to -78 °C and a solution of s- BuLi (100 mL of a 1.4 M solution in cyclohexane, 140 mmol) was added slowly over a 30 minute period.
  • the light orange colored solution was sti ⁇ ed at -78°C for 3 hours followed by treatment with B(OMe) 3 (39 mL, 350 mmol) after which the cooling bath was removed and the clear colorless solution slowly warmed to 0°C.
  • the reaction Upon reaching 0°C, the reaction was quenched with a small amount of water ( ⁇ 2 mL), allowed to warm to room temp then extracted into 2 N NaOH (250 mL) and backwashed with additional EtOAc (150 mL). The aqueous phase was acidified to pH 3 by the addition of 2 N HC1 and then extracted with EtOAc (3 x 120 mL). The organic extracts were combined and dried over Na 2 SO and concentrated to produce the free boronic acid (22.08 g, 103 mmol) as a sticky white solid in 88% yield.
  • Crystallization and isolation of the desired isomer was performed by dissolving the HC1 salt in a minimal amount of dichloromethane (250 mL) with gentle heating to facilitate a homogenous solution followed by continuous stirring for 8 hours to yield a fluffy white precipitate that was collected by vacuum filtration, dried and then dissolved in minimal 2-propanol (-200 mL) with gentle heating until homogenous. The alcoholic solution was sti ⁇ ed 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).
  • Step 1 (2R)-l-(2-ChloroacetyI)-boroPro-(lS,2S,3R,5S)-pinanediol ester (3 A).
  • 2 36.7 g, 129.3 mmol
  • chloroacetyl chloride 12.34 mL, 155.2 mmol
  • 4-methylmo ⁇ holine 42.4 mL, 182 mmol
  • Step 2 (2R)-l-(2-Cyclopentylamino-acetyl)-boroPro-(lS,2S,3R,5S)-pinanedioI ester (3B).
  • reaction mixture was then allowed to warm to room temperature and sti ⁇ ed overnight.
  • Step 1 N-Boc-5-phenylPro-(2R)-boroPro-(lS,2S,3R,5S)-pinanediol ester (5):
  • Step 2 l-(5R-Phenyl-pyrrolidine-2S-carbonyl)-pyrro!idine-(2R)-boronic acid (6):
  • 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 Bl (76 mg, 0.26 mmol) as an amo ⁇ hous white solid.
  • Step 1 (2R)-l- ⁇ 2-[(3S)-l-tert-Butoxycarbonyl-pyrroIidin-3-ylamino]-acetyI ⁇ - pyrrolidine- 2-boronic acid (lS,2S,3R,5S)-pinanediol ester (7)
  • Step 1 (2R)-l- ⁇ 2-[(3R)-l-tert-Butoxycarbonyl-pyrrolidin-3-ylamino]-acetyl ⁇ - pyrrolidine-
  • Step 1 (2R)-l-[(2S)-l-tert-ButoxycarbonyI-azetidine-2-carbonyl]-boroPro- (lS,2S,3R,5S)-pinanediol ester (11)
  • Step 1 (2R)-l-[(25,4S)-l-tert-Butoxycarbonyl-4-benzyloxycarbonyIamino- pyrrolidine-2-carbonyl]-boroPro-(lS,25,3R,55)-pinanediol ester (13)
  • Step 2 (2R)-l-[(2S,45)-l-tert-Butoxycarbonyl-4-amino-pyrrolidine-2-carbonyl]- boroPro-(lS,2S,3R,5S)-pinanediol ester (14)
  • Step 1 (2R)-l-[(2S)-l-tert-ButoxycarbonyI-4-benzyloxycarbonyl-piperazine-2- carbonyl]-boroPro-(lS,2S,3R,5S)-pinanedioI ester (16)
  • Step 3 (2R)-l-[(2S)-l-tert-Butoxycarbonyl-4-methanesulfonyl-piperazine-2- carbonyl]-boroPro-(lS,2S,3R,5S)-pinanediol ester (18)
  • Step 1 (2R)-l- ⁇ 2-[(3S)-l-tert-Butoxycarbonyl-pyrrolidin-3-ylamino]-acetyl ⁇ -boroPro- (lS,2S,3R,5S)-pinanediol ester (20)
  • Step 2 (2R)-l- ⁇ 2-[(3S)-Pyrrolidin-3-ylamino]-acetyl ⁇ -boroPro-OH (21) [0305]
  • the protocol described above for the N-Boc deprotection and pinanediol ester deprotection of compound 12 was applied to 20.
  • Compound 21 was obtained as a white solid.
  • 21-TFA salt 1H-NMR (500 MHz, CD 3 OD) ⁇ 4.12 (m, 3H), 3.76 (m, IH), 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 mlz (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).
  • Example 17 Dependence of Aminoboronate and Boronic Acid Forms of Inventive Compounds on pH [0307]
  • 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 O. pH was adjusted to the desired value by dropwise addition of either 20% DC1 in D O or 5% DC1 in D 2 O. 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 ⁇ -NMR spectra in a Varian AS 500 MHz instrument and measuring the ratio of the integrals of the peaks at 2.90-2.95 ppm and 2.40-2.50 ppm characteristic of the open and closed forms, respectively.
  • FIG. 1 shows that the closed form predominates at higher pHs such as physiological pH, whereas the open form predominates at lower pHs.

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Abstract

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

Description

HETEROCYCLIC BORONIC ACID COMPOUNDS
FIELD OF THE INVENTION
[0001] The present invention relates to boronic acid compounds and their use as inhibitors of post-proline/alanine cleaving amino-dipeptidases. The invention also relates to methods of employing such inhibitors, alone or with another therapeutic agent, to treating DPP-IV-related diseases, such as Type II diabetes and diabetic complications, hyperglycemia, Syndrome X, hyperinsulinemia, obesity, atherosclerosis and related diseases, as well as various immunomodulatory diseases and chronic inflammatory bowel disease. Thus, the invention has applications in the medicinal chemical, pharmacological, and medical arts.
BACKGROUND OF THE INVENTION
[0002] The following background commentary is an aid to in understanding the present invention. Inclusion of this commentary is not an admission concerning the nature or content of the prior art.
[0003] Dipeptidyl peptidase-IV (DPP-IV) is a serine protease that belongs to a group of post-proline/alanine cleaving amino-dipeptidases. DPP-IV catalyzes the release of an N- terminal dipeptide only from proteins with N-terminal penultimate proline or alanine.
[0004] The physiological role of DPP-IV has not been established fully. It is believed to play an important role in neuropeptide metabolism, T-cell activation, gastric ulceration, functional dyspepsia, obesity, appetite regulation, impaired fasting glucose (IFG), and diabetes. In particular, DPP-IV has been implicated in the control of glucose metabolism because its substrates include the insulinotropic hormones, glucagon like peptide- 1 (GLP-1) and gastric inhibitory peptide (GIP), which are inactivated by removal of their two N- terminal amino acids.
[0005] In vivo administration of synthetic inhibitors of DPP-IV prevents N-terminal degradation of GLP-1 and GIP, resulting in higher plasma concentrations of these hormones, increased insulin secretion and, therefore, improved glucose tolerance. Therefore, such inhibitors have been proposed for the treatment of patients with type II diabetes, a disease characterized by decreased glucose tolerance and insulin resistance.
[0006] Post-proline/alanine cleaving amino-dipeptidases have been discovered, including DPP7, DPP8, DPP9, and fibroblast activation protein (FAP), that have the substrate- and inhibitor-specificity of DPP-IV. Thus, inhibitors of this sort may affect multiple members of the enzyme group. The precise physiological role of each of these post-proline/alanine cleaving enzymes is not well defined. Consequently, inhibiting each of them separately, a subset of them, or all of them at the same time would have uncertain physiological effect(s).
[0007] Diabetic dyslipidemia is characterized by multiple lipoprotein defects, including moderately high serum levels of cholesterol and triglycerides, small LDL particles, and low levels of HDL cholesterol. The results of recent clinical trials reveal beneficial effects of cholesterol-lowering therapy in diabetic and nondiabetic patients, thus supporting increased emphasis on treatment of diabetic dyslipidemia. This need for intensive treatment of diabetic dyslipidemia was advocated by the National Cholesterol Education Program's Adult Treatment Panel III.
[0008] Obesity is a well-known risk factor for the development of many very common diseases such as atherosclerosis, hypertension and diabetes. The incidence of obese people and thereby also these diseases is increasing throughout the entire industrialized world. Except for exercise, diet and food restriction no convincing pharmacological treatment for reducing body weight effectively and acceptably currently exist. However, due to its indirect but important effect as a risk factor in mortal and common diseases it will be important to find treatment for obesity or appetite regulation. Even mild obesity increases the risk for premature death, diabetes, hypertension, atherosclerosis, gallbladder disease and certain types of cancer. In the industrialized western world the prevalence of obesity has increased significantly in the past few decades. Because of the high prevalence of obesity and its health consequences, its prevention and treatment should be a high public health priority. [0009] At present a variety of techniques are available to effect initial weight loss. Unfortunately, initial weight loss is not an optimal therapeutic goal. Rather, the problem is that most obese patients eventually regain their weight. An effective means to establish and/or sustain weight loss is the major challenge in the treatment of obesity today.
[0010] Accordingly, a need exists for compounds that are useful for inhibiting DPP-IV without suppressing the immune system.
[0011] Several compounds have been shown to inhibit DPP-IV, but all of these have limitations in relation to the potency, stability, selectivity, toxicity, and/or pharmacodynamic properties. Such compounds have been disclosed, for example, in WO 98/19998, WO 00/34241, U.S. patent No. 6,124,305 (Novartis AG), and WO 99/38501 (Trustees of Tufts University).
SUMMARY OF THE INVENTION
[0012] The present invention provides DPP-IV inhibitors that are effective in treating conditions that may be regulated or normalized by inhibition of DPP-IV. More particularly, the invention relates to boronic acid-containing heterocycles and their derivatives that inhibit DPP-IV, and to methods for making such compounds. In addition, the invention provides pharmaceutical compositions comprising compounds of the invention, and combinations thereof including one or more other types of antidiabetic agents; methods for inhibiting DPP-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.
BRIEF DESCRIPTION OF THE DRAWING
[0013] FIG. 1 shows the pH dependence of the percentage of linear and cyclic isomeric forms present in aqueous solution of a compound of the invention. DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention provides compounds of formula I:
Figure imgf000005_0001
including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein: n is 1 to 3; X is CH2; S; O; CF2 or C(CH3)2; Z is H; halogen; hydroxyl; (C1-6)alkoxy; (Cι-ι2)alkyl; (C3-ι2)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; R1 and R2 independently or together are hydrogen; a boronic acid protecting group; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; CR'R" may be present or absent, wherein if CR'R" is present, then R1, R",R3, R4 and R5 are selected from (aa), (bb) or (cc): (aa) R1, R", R3 and R4 are hydrogen; and R5 is a) hydrogen; b) (C 2)alkyl; (C2-ι2)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cι-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8) 2; -OR8; or -S-R8; R7 is halogen; (Cι-1o)alkyl; (Cι-ιo)alkoxy;
Figure imgf000006_0001
(Ci-io) dialkylamino; benzyl; benzyloxy; hydroxyl(C1- )alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (Cι.ιo)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3. ιo)cycloalkyl; (Cs-1o)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; c) aryl optionally fused to a (C -10)cycloalkyl; or heteroaryl optionally fused to a (C3-ι0)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4- pentylbicyclo[2.2.2]oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH )j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (Cι-8)alkoxy,
Figure imgf000006_0002
or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (Cι- )alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene; e) Rπ(CH2)p- where R11 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Cι-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
Figure imgf000007_0001
(Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; and p is 0 to 3; R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Ci. 6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; g) a group of the formula: R15 I >1 " ^(CH2)r-
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; (C3- 12)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6; h) a group of the formula:
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι_ 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
Figure imgf000008_0001
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι. 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl, or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH2-C(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R ; k) a group of the formula:
Figure imgf000008_0002
where R20 is hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3- 8)cyclo alkylcarbonyl; benzyl; benzoyl; (Cι-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 R ; Rx is hydrogen; (Cι-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (Cι-8)alkyl, (Cι-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
Figure imgf000009_0001
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; 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) R1, R", R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R' together with R3 or R4, or R" together with R3 or R4, and the atoms to which they are attached form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2; and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa); or R4 and R5 together form -(CR22R23)m- where m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl; halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino; arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylamino; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (cc) R1 and R3 are hydrogen; and R" and R4 together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa) or (bb) and R5 is any of the groups in (aa) or (bb); and if CR'R" is absent, then R3, R4 and R5 are selected from (dd), (ee) or (fit): (dd) R3 and R4 are hydrogen; and R5 is a) hydrogen, provided that R5 is not hydrogen when n is 1 , X is CH2, and Z is H; b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C -ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cι-6)alkyl; (Cι-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 R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8)2; -OR8; or -S-R8; R7 is halogen; (Cι-ιo)alkyl; (Cι-ιo)alkoxy; (Cι-ιo)alkylamino; (Ci-io) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (Cι-ιo)alkyl; (C2-ι0)alkenyl; (C2-,0)alkynyl; (C3- ιo)cycloalkyl; (C5-ιo)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R ; c) aryl optionally fused to a (C3-10)cycloalkyl; or heteroaryl optionally fused to a (C3-ιo)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R ; 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-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (Cι-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene; e) Rπ(CH2)p- where Ru is 2-oxopyπolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Cι-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 (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; and p is 0 to 3; 1 "7 R is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; g) a group of the formula: R15 I R14^ ^(CH2)r 1-
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι )cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 2 to 6; h) a group of the formula:
Figure imgf000012_0001
where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι_ 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
Figure imgf000012_0002
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(C). 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH2-C(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; k) a group of the formula:
Figure imgf000013_0001
where R20 is hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (C1-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R ; R is absent or is halogen, (Cι-8)alkyl, (C1-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
Figure imgf000013_0002
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; or (ee) R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfmyl, sulfonamido or sulfonyl, provided that when n is 1, X is CH2, the ring containing X is saturated, and Z, R3 and R5 are H, R4 is not a side chain of a naturally occurring α-amino acid, and provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R5 are H, R3 and R4 are not both methyl; or R and R together form -(CR R )m - where m is 2 to 6, and R and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl; halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino; arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylamino; provided that when n is 1, X is CH2, the ring containing X is saturated, Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (ff) R3 is hydrogen; and R4 and R5 together with the atoms to which they are attached form a 4 to 8 member mono- or polycyclic heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, wherein the heterocyclic ring system is optionally mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; and wherein the bond containing the wavy line signifies the point of attachment.
[0015] In some embodiments of compounds of formula I, R1 and R2 independently or together are the boronic acid protecting group formed from (+)-pinanediol; pinacol; 1,2- dicyclohexyl-ethanediol; 1 ,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3- butanediol, diisopropyl tartrate; 1 ,4-butanediol; diisopropylethanediol; (S,S,)-5,6- decanediol; 1 ,1 ,2-triphenyl-l ,2-ethanediol; (2R,3R)-1 ,4-dimethyoxy-l ,1 ,4,4-tetraphenyl- 2,3-butanediol; methanol; ethanol; isopropanol; catechol; or 1-butanol. Thus, it will be 1 understood by those of skill in the art that R and R represent a single protecting group attached to both boronic ester oxygens when diols such as (+)-pinanediol and pinacol are used, whereas R1 and R2 represent separate moieties on the boronic ester oxygens such as methyl or ethyl when the esters are formed from methanol and ethanol, respectively. In 1 9 other embodiments of compounds of formula I, R and R independently or together are a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids and are formed from 1,2-dicyclohexylethanediol; 1,2-ethanediol; 1,3-propanediol; 2,3-butanediol, 1,4-butanediol; diisopropylethanediol; methanol; ethanol; isopropanol; or 1-butanol. For example, when R1 and R2 are each formed from methanol, the resulting R1 and R2 groups are methyl. When 2,3-butanediol is used, the resulting R1 and R2 groups are a single group and the resulting boronic ester has the following structure:
Figure imgf000015_0001
[0016] Compounds of formula I include those wherein if CR R is absent, then R 3 , r R>4 and R ,5 are selected from (dd), (ee) or (ff): (dd) R3 and R4 are hydrogen; and R5 is a) (Cι-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C -ι2)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; R6 is (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8) 2; -OR8; or
-S-R8; R7 is halogen; (Cι-ιo)alkyl; (Cι-10)alkoxy; (Cι-ιo)alkylamino; (Cι-10) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethyl thio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (C1-ιo)alkyl; (C2-H))alkenyl; (C2-10)alkynyl; (C3- ιo)cycloalkyl; (C5-ι0)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; b) aryl optionally fused to a (C3-ιo)cycloalkyl; or heteroaryl optionally fused to a (C3-ι0)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; c) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)jadamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4- pentylbicyclo[2.2.2]oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (Cι-8)alkoxy, (Cι-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (Cι-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Cι-8)alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene; d) Rn(CH2)p- where R11 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyπolidinyl,
Figure imgf000016_0001
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 (Cι- )alkyl, ( ^alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; and p is 0 to 3; R12 is halogen; trifluoromethyl; cyano; nitro;
Figure imgf000016_0002
(Cι_ 6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (Rl3)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula: R15 I R1 ^ ^(CH2)r 1-
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; (C3- ]2)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 2 to 6; g) a group of the formula:
Figure imgf000017_0001
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι_ 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6; h) a group of the formula:
Figure imgf000017_0002
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; di-(Cι 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C -ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; i) a group of the formula: (phenyl-CH2-C(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; j) a group of the formula:
Figure imgf000018_0001
where R20 is hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (C1-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (Cι-8)alkyl; (C3-12) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (Cι-8)alkyl, (Cι-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or k) a group of the formula:
Figure imgf000018_0002
91 where R is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; or (ee) R3 and R4 are independently hydrogen, alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; R5 is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R4 and R5 together form -(CR22R23)m - wherein m is 2 to 6, and R22 and 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; provided that when n is 1, X is CH2, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (ff) R3 is hydrogen; and R4 and R5 together with the atoms to which they are attached form a 4 to 8 member mono- or polycyclic heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, wherein the heterocyclic ring system is optionally mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-.
[0017] Compounds of formula I also include those wherein X is CH2; the ring containing X is saturated; CR'R*1 is absent, R1, R2, R3 and R4 are hydrogen; and R5 is (C 2)alkyl; (C2- ι2)alkenyl; (C2-ι2)alkynyl; (C -ι2) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions. In some such embodiments, R5 is a (Cι_ 12)alkyl or (C3-ι2)cycloalkyl, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, or adamantyl.
[0018] In some embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CR'RiJ is absent, R1, R2, R3 and R4 are hydrogen; and R5 is indanyl; 1,2,3,4- tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]-oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι.8)alkyl, (Cι-8)alkoxy, (Cι-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently ( . 8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Cι_8)alkyl, (C].8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene. [0019] In other embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is Rπ(CH2)p- where R11 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2- oxopyrrolidinyl, (Cι-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 (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently 19 plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι- 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 .
[0020] In certain embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CR'R" is absent; R1, R2, R3 and R4 are hydrogen; and R5 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
[0021] In some embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
R15
> 14' ^(CH2)r-
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Ci_6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C -ι2)cycloalkyl ring; and r is 2 to 6. [0022] Compounds of formula I include those wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000022_0001
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Cι.6)alkylcarbonyl; di-(Cι. 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6.
[0023] Compounds of formula I wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000022_0002
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; di-(Cι. 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-12)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3. In some such embodiments, R5 has formula:
Figure imgf000022_0003
[0024] In some embodiments of compounds of formula I, X is CH ; the ring containing
XX iiss ssaattuurated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula: (phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12.
[0025] Compounds of Formula I include those having the following structure, Formula IA:
Figure imgf000023_0001
IA In some such embodiments, R5 is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricyclo alkyl; 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. In other such embodiments, R5 is alkyl; alkenyl; cycloalkyl; cycloalkylalkyl; 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, R5 is alkyl, cycloalkyl or cycloheteroalkyl, optionally mono- or independently plurisubstituted as described above. In some embodiments of compounds of Formula IA, R3 and R4 are both hydrogen. In other embodiments, n is 1. In some embodiments of compounds of Formula IA where n is 1 and R1, R2, R3, and R4 are hydrogen, R5 is not methyl.
[0026] Compounds of formula I include those wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R , R , R and R are hydrogen; and R is a group of the formula:
Figure imgf000024_0001
where R20 is hydrogen; (Cι_8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; (C - 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (Cι-8)alkyl; (C3-ι ) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (Cι-8)alkyl, (Cι-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3. In some such embodiments, R5 has formula:
Figure imgf000024_0002
[0027] In other such embodiments, R is
Figure imgf000024_0003
including for example, the following structures:
Figure imgf000025_0001
[0028] In still other such embodiments, the compound has the formula
Figure imgf000025_0002
[0029] Compounds of formula I wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000025_0003
where R ,21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl 19 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. In some such embodiments, R5 has formula:
Figure imgf000025_0004
[0030] Compounds of formula I include those wherein R1 and R2 are hydrogen; n is 1 ; X together with an adjacent ring carbon and Z form a fused cyclopropyl; CR'R" is absent; R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R4 and R5 together form -(CR22R23)m- where m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl; halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino; arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylamino; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto.
[0031] In some embodiments of compounds of Formula I, R1, R2, R3 and R4 are hydrogen; n is 1; X is CH2; CR'R" is absent; and R5 is aryl or aralkyl. [0032] In some embodiments, compounds of formula I have the formula:
Figure imgf000027_0001
[0033] In other embodiments, compounds of formula I have the formula:
Figure imgf000027_0002
[0034] In still other embodiments, compounds of formula I have the formula:
Figure imgf000027_0003
[0035] In still other embodiments, compounds of formula I have the formula:
Figure imgf000027_0004
[0036] Compounds of formula I include those wherein, if CR'R" is present, R' and R3 are hydrogen; R" and R4 together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa) or (bb) and R5 is any of the groups in (aa) or (bb); or if CR'R" is absent, then R3 is hydrogen; and R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are hydrogen, R4 and R5 together are not -(CH2)2- or -(CH2)3-.
[0037] In some such embodiments, compounds of formula I have formula II:
Figure imgf000028_0001
wherein: Y is O, S, CHR25 or NR26; k is 0 to 3 and m is 0 to 3 when Y is CHR25; k is 2 to 3 and m is 1 to 3 when Y is O or NR ; each R24 is independently: a) hydrogen; b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3- 12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are 19 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 R12; d) Rn(CH2)p- where R11 is 2-oxopyrrolidinyl; (C].6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2-oxopyπolidinyl, (Cι_ 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, 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 (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι- )alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula: R15
R14^ ^(CH2)S )•
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C - ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6; or g) a group of the formula:
R21— o— (CH2),-
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 1 to 6; R25 is: a) hydrogen; b) (C1-12)alkyl; (C2-12)alkenyl; (C2-ι2)alkynyl; (C3-12) cycloalkyl; or (C3- 12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are 19 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 19 mono- or independently plurisubstituted with R ; d) Ru(CH2)p- where R1 1 is 2-oxopyπolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (C1-8)alkylcarbonyl; (C -ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2-oxopyrrolidinyl, (C\. 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and 19 R is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula:
Figure imgf000030_0001
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and t is 0 to 6; or g) a group of the formula: R2i_0 — (CH2)t-
where R21 is hydrogen; (Cι-s)alkyl; benzyl; or phenyl; in which the benzyl and phenyl 19 groups are optionally mono- or independently di-substituted on the ring with R ; and t is 0 to 6; and R26 is: a) hydrogen; b) (C,-12)alkyl; (C2-ι2)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3- ι2)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 R12; d) R27(CH2)P-, where R27 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (C1-8)alkylcarbonyl; (C3-ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2-oxopyrrolidinyl, (Cι_ 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and 19 R is halogen; tπfluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R )2CH(CH2)q-, where R is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula: R15 R1 ^ ^(CH2)r
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C -ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 0 or 2 to 6; or g) a group of the formula:
Figure imgf000032_0001
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl 19 groups are optionally mono- or independently di-substituted on the ring with R ; and t is 0 or 2 to 6.
[0038] In some embodiments of compounds of formula II, X is CH2; the ring containing 1 9 9*ϊ
X is saturated; and R , R and R are hydrogen. In other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is hydrogen, provided that if k, n, and m are each 1, and Y is CHR25, Z is not H. In still other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is (Cι-ι2)alkyl; (C2-ι2)alkenyl; (C2-ι2)alkynyl; (C -ι2) cycloalkyl; or (C3.ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions. In some embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is phenyl optionally mono- or independently plurisubstituted with R12.
Compounds of formula II include those wherein X is CH2; the ring containing X is saturated; R1, R2 and R25are hydrogen; and R24 is RU(CH2)P- where R11 is 2- oxopyrrolidinyl; (C1-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Ci ^alkylcarbonyl; (C . ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2-oxopyrrolidinyl, (Cι-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Ci- 4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
[0039] In certain embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is (R13)2CH(CH2)q-, where R is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
[0040] In other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is a group of the formula: R15 I R14^ ^(CH2)S -
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (d ^alkylcarbonyl; (C - ι2)cycloalkyl ring; (C -ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and s is 1 to 6. [0041 ] In some embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is a group of the formula:
R21— O— (CH2) -ζ
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 1 to 6.
[0042] Compounds of formula II include those wherein X is CH2; the ring containing X is saturated; R1, R2 and R24 are hydrogen. In some embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is (Ci- ι2)alkyl; (C2-ι2)alkenyl; (C2-ι2)alkynyl; (C3-ι2) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions. In other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2, R24 are 9^ 1 hydrogen; and R is phenyl optionally mono- or independently plurisubstituted with R .
[0043] Compounds of formula II include those wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is Rn(CH2)p- where R1 ' is 2-oxopyπolidinyl, (Cι-6)alkoxy, phenyl; phenoxy; (Cι-g)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyπolidinyl, (Cι-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 (Cι-4)alkyl,
Figure imgf000034_0001
or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Ci- 8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C\. 6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι.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. [0044] In other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
[0045] Compounds of formula II include those wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is a group of the formula:
Figure imgf000035_0001
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (Cι-6)alkylcarbonyl; (C3- 1 )cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and t is 0 to 6.
[0046] In some embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is a group of the formula: R21— 0-(CH2)t — where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6. In other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2, R24 and R26 are hydrogen. In still other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is (Cι-ι2)alkyl; (C2-ι2)alkenyl; (C2-ι2)alkynyl; (C3-ι2) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions. Compounds of formula II include those wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is phenyl optionally mono- or independently plurisubstituted with R12. [0047] Compounds of formula II wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is R27(CH2)P-, where R27 is 2-oxopyπolidinyl; (C,. 6)alkoxy; phenyl; phenoxy; (Cι- )cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι-8)alkylcarbonyl; (C -ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2- oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι_4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and p is 0 to 3.
[0048] Compounds of formula II include those wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is (R13)2CH(CH2)q-; where R13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
[0049] In some embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula: R15 R14^ ^(CH2)r
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 0 or 2 to 6.
[0050] In other embodiments of compounds of formula II, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula:
Figure imgf000037_0001
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 or 2 to 6.
[0051] Compounds of formula II include those that have the formula:
Figure imgf000037_0002
In some such embodiments, R ,25 is phenyl optionally mono- or independently plurisubstituted with R 12
[0052] In other embodiments of compounds of formula II, the compound has the formula:
Figure imgf000037_0003
[0053] Compounds of formula II also include those that have the formula:
Figure imgf000038_0001
wherein: R28 and R29 are each independently hydrogen, hydroxy, alkyl, alkoxy, aryloxy, or halogen.
[0054] In some embodiments of compounds of formula I wherein CR'R" is present, the compound has formula III:
Figure imgf000038_0002
wherein:
Y is O, S, CHR25 or NR26; k is 0 to 3 and m is 0 to 3 when Y is CHR 2"5.; k is 1 to 3 and m is 0 to 3 when Y is NR26; k is 1 to 3 and m is 0 to 3 when Y is O; R is a) hydrogen; b) (C,-12)alkyl; (C2-ι2)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3- 12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(Cι-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 plurisubstituted with R8; -SOR8; -SO2R8; - COR8; -CO2R8, -CONHR8; -CON(R8) 2; -OR8; or -S-R8; R7 is halogen; (Cι-ι0)alkyl; (Cι-ιo)alkoxy; (Cι-ιo)alkylamino; (Ct.io) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (CMo)alkyl; (C2-10)alkenyl; (C2-ι0)alkynyl; (C3-ι0)cycloalkyl; (C5. ιo)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; c) aryl optionally fused to a (C3-ιo)cycloalkyl; or heteroaryl optionally fused to a (C3-i0)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH )j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-l- yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (Cι-8)alkoxy, (Cι-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (Cι-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Cι-8)alkyl, (Cι- )alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C -6)alkylene; e) R"(CH2)P- where Rπ is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Ci ^cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Cι-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 (Cι-4)alkyl,
Figure imgf000039_0001
or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; and p is 0 to 3; R12 is halogen; trifluoromethyl; cyano; nitro;
Figure imgf000040_0001
(Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are • • • 19 independently optionally mono- or independently disubstituted with R ; and q is 0 to 3; g) a group of the formula: R15 I R1 ^ ^(CH2)r - where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι_ 6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C -ι2)cycloalkyl ring; and r is 2 to 6; h) a group of the formula:
Figure imgf000040_0002
where R1 and R17 are each independently hydrogen; (Cι.g)alkyl; (Ci. 6)alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
Figure imgf000041_0001
where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C). 6)alkylcarbonyl; di-(Cι-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 disubstituted with R12; or R18 and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH2-C(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; k) a group of the formula:
Figure imgf000041_0002
where R ,20 is hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C - 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (Cι-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (Cι_8)alkyl, (Cι-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
Figure imgf000042_0001
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; each R24 is independently: a) hydrogen; b) (C 2)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3, ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R ; d) Ru(CH2)p- where R11 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι-8)alkylcarbonyl; (C3-ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2-oxopyπolidinyl, (Ci. 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι.g)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R )2CH(CH2)q-, where R is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R ; and q is 0 to 3; f) a group of the formula: R15
R14^ ^(CH2)S f-
where R14 and R15 are independently hydrogen; (C1- )alkyl; (Cι-6)alkylcarbonyl; (C3- )2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and s is 0 to 6; or g) a group of the formula:
R21— O— (CH2)t-|
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6; R25 is: a) hydrogen; b) (Cι-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3. )2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally • 19 mono- or independently pluπsubstituted with R ; d) Rn(CH2)p- where R11 is 2-oxopyπolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι.g)alkylcarbonyl; (C .ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2-oxopyπolidinyl, (C\. 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι- )alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula:
Figure imgf000044_0001
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Ci-6)alkylcarbonyl; (C3- 12)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and t is 0 to 6; or g) a group of the formula:
R21— o— (CH2),-
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6; and R26 is: a) hydrogen; b) (C,-12)alkyl; (C2-12)alkenyl; (C2-ι2)alkynyl; (C3-12) cycloalkyl; or (C3- ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally 19 mono- or independently plurisubstituted with R ; d) R27(CH2)P-, where R27 is 2-oxopyπolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2-oxopyrrolidinyl, (Ci. 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and 19 R is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R13)2CH(CH2)q-, where R13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula:
Figure imgf000045_0001
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 0 or 2 to 6; or g) a group of the formula:
R21— o— (CH2) -
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 or 2 to 6.
[0055] Compounds of formula III include those wherein X is CH2; the ring containing X 1 9 9 • is saturated; and R , R and R are hydrogen; those wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is hydrogen; and those wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is (Cι_ι2)alkyl; (C2- 12)alkenyl; (C2-ι2)alkynyl; (C3-ι2) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently 1 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 ; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is phenyl optionally mono- or independently plurisubstituted with R12. In other embodiments, X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is RH(CH2)P- where R11 is 2-oxopyrrolidinyl, (Cι-6)alkoxy, phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2- oxopyπolidinyl, (Cι-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- • • 1 or independently di- or independently trisubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι. 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 . In still other embodiments, X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
[0057] Compounds of formula III include those wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is a group of the formula: R15 I R14^ ^(CH2)S—
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6.
[0058] Compounds of formula III also include those wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is a group of the formula:
R21— o— (CH2)t-5
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6.
[0059] In some embodiments of compounds of formula III, X is CH2; the ring containing X is saturated; R1, R2 and R24 are hydrogen. In other embodiments, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is (Cι.]2)alkyl; (C2-ι2)alkenyl; (C2-ι2)alkynyl; (C3-ι2) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions. In still other embodiments, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is phenyl optionally mono- or independently plurisubstituted with R12. [0060] In some embodiments of compounds of formula III, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is Rπ(CH2)p- where Rn is 2- oxopyπolidinyl, (C1-6)alkoxy, phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2- oxopyrrolidinyl, (Cι-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- 19 or independently di- or independently trisubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1- 6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
[0061] In other embodiments of compounds of formula III, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3. In still other embodiments, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is a group of the formula: R15 .
,14' ^(CH2)t
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; (C3- 12)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C -ι2)cycloalkyl ring; and t is 0 to 6.
[0062] In certain embodiments of compounds of formula III, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is a group of the formula: R21-0-(CH2)t 1
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6.
[0063] In some embodiments of compounds of formula III, X is CH2; the ring containing X is saturated; R1, R2, R24 and R26 are hydrogen. In other embodiments, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is (Cι-12)alkyl; (C2-ι2)alkenyl; (C2-ι2)alkynyl; (C -ι2) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions. In yet other embodiments, X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is phenyl optionally mono- or independently plurisubstituted with R12.
Compounds of formula III include those wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is R27(CH2)P-, where R27 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (C1-8)alkylcarbonyl; (C3-ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2- oxopyrrolidinyl, (Cι-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with
Figure imgf000049_0001
(Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-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; R1, R2, R24 are hydrogen; and R26 is (R13)2CH(CH2)q-; where R13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
[0064] Compounds of formula III include those wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula:
Figure imgf000050_0001
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι- )alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C -ι2)cycloalkyl ring; and r is 0 or 2 to 6.
[0065] Compounds of formula III also include those wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula:
R21— O— (CH2),-S
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 or 2 to 6.
[0066] In some embodiments of compounds of formula I, CR'R" is present. In other embodiments of compounds of formula I where CR'R" is present, the compound has formula IVA or IVB:
Figure imgf000050_0002
(IVA) (IVB) wherein R is a) hydrogen; b) (Cι-ι2)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3- i2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are 19 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 R12; d) Rπ(CH2)p- where R11 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Cι- )alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently 19 trisubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R ; e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula: R15 I R14^ ^(CH2)S
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- i2)cycloalkyl ring; (C -i2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and s is 0 to 6; or g) a group of the formula: >21_ -O- "(CH2)t-
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6;
[0067] It has further been discovered that certain boronic acid compounds of the invention can exist as either linear or cyclic isomers. Typically, such compounds form an equilibrium mixture in aqueous solution. As shown in Figure 1, the concentration of the two isomers of such compounds is typically pH dependent. Thus, it is expected that such inventive compounds will exist as a mixture of linear and cyclic isomers in vivo. Moreover, the cyclic forms of inventive compounds may serve as novel, orally available prodrugs. Hence, in this aspect of the invention, there are provided compounds that have the formula VA, VB, or a mixture thereof:
Figure imgf000052_0001
VA VB including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein: n is 1 to 3; X is CH2; S; O; CF2 or C(CH3)2; Z is H; halogen; hydroxyl; (Cι-6)alkoxy; (C].ι2)alkyl; (C3-ι2)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; R1 and R2 independently or together are hydrogen; a boronic acid protecting group; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; R3, R4 and R5 are selected from (dd) or (ee): (dd) R3 and R4 are hydrogen; and R5 is a) hydrogen, provided that R5 is not hydrogen when n is 1, X is CH2, and Z is H; b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8) 2; -OR8; or -S-R8; R7 is halogen; (Cι-ιo)alkyl; (Cι.ιo)alkoxy; (Cι.ιo)alkylamino; (Ci-io) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3- ιo)cycloalkyl; (C5-ιo)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R ; c) aryl optionally fused to a (C3-ι0)cycloalkyl; or heteroaryl optionally fused to a (C3-ι0)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R ; d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4- pentylbicyclo[2.2.2]oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (Cι-8)alkoxy, (Cι-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (d-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene; e) Rn(CH )p- where Rn is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyπolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (Ci^alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; and p is 0 to 3; R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; g) a group of the formula: R15 I R14^ ^(CH2)r 1
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C -ι2)cycloalkyl ring; and r is 2 to 6; h) a group of the formula:
Figure imgf000055_0001
where R and R are each independently hydrogen; (Cι-8)alkyl; (Ci-6)alkylcarbonyl; di-(Cι 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
Figure imgf000055_0002
where R18 and R19 are independently hydrogen; (C1-8)alkyl; (Cj-6)alkylcarbonyl; di-(Cι_ 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl;; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH2-C(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; k) a group of the formula:
Figure imgf000055_0003
where R20 is hydrogen; (C]-8)alkyl; (Cι-6)alkylcarbonyl; di-(Ci-6)alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (Cι-8)alkyl; (C -ι ) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (Cι-8)alkyl, (Cι.g)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
Figure imgf000056_0001
1 where R is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl * 1 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; or (ee) R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; provided that when n is 1 , X is CH2, the ring containing X is saturated, and Z, R3 and R5 are H, R4 is not a side chain of a naturally occuπing α-amino acid; and provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R5 are H, R3 and R4 are not both methyl; and wherein the bond containing the wavy line signifies the point of attachment.
[0068] In some embodiments of compounds of formula VA and VB, R1 and R2 independently or together are the boronic acid protecting group formed from (+)-pinanediol; pinacol; 1,2-dicyclohexyl-ethanediol; 1 ,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3-butanediol, diisopropyl tartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6- decanediol; 1 , 1 ,2-triphenyl- 1 ,2-ethanediol; (2R,3R)- 1 ,4-dimethyoxy- 1 , 1 ,4,4-tetraphenyl- 2,3-butanediol; methanol; ethanol; isopropanol; catechol; or 1-butanol. In other embodiments, R1 and R2 independently or together are a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids formed from 1,2-dicyclohexylethanediol; 1,2-ethanediol; 1,3-propanediol; 2,3-butanediol, 1,4-butanediol; diisopropylethanediol; methanol; ethanol; isopropanol; or 1-butanol.
[0069] In some embodiments of compounds of formula VA or VB,
R3 and R4 are independently hydrogen, alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; and R5 is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl.
[0070] In still other embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is (C1-12)alkyl; (C2- 1 )alkenyl; (C2-ι2)alkynyl; (C3-ι2) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions. In some such embodiments, R5 is (C3-12) cycloalkyl such as cyclopentyl.
[0071] In some embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is indanyl; 1,2,3,4- tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]-oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (C]-8)alkoxy, (Cι-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (Ci. 8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Cι-8)alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C -6)alkylene.
[0072] Compounds of formula VA or VB include those wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is Rπ(CH2)p- where R11 is 2-oxopyrrolidinyl; (C]-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2- oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- 19 or independently di- or independently trisubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl, (Cι- )alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι_ 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.
[0073] Compounds of VA or VB further include those wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
[0074] In some embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
R15 I -N. >14" ^(CH2)r-
where R14 and R15 are independently hydrogen; (Cι-8)alkyl;
Figure imgf000059_0001
(C3- 12)cycloalkyl ring; (C -ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6.
[0075] In other embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000059_0002
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι_ 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6.
[0076] In certain embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000060_0001
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; di-(Cι- 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3. In some such embodiments, R5 has formula:
Figure imgf000060_0002
[0077] Compounds of formula VA or VB further include those wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
(phenyl-CH2-C(CH3)2-),
where the phenyl group is optionally mono- or independently plurisubstituted with R 12 [0078] In some embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000061_0001
where R20 is hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; (C - 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (Cι-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently 19 di-substituted on the ring with R ; R is absent or is halogen, (C1-8)alkyl, (C1-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or
In some such embodiments, R has formula:
Figure imgf000061_0002
[0079] In other embodiments of compounds of formula VA or VB, X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000061_0003
where R ,21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3. In some such embodiments, R5 has formula:
Figure imgf000062_0001
[0080] Compounds of formula VA or VB further include those wherein R1 and R2 are hydrogen; n is 1 ; X together with an adjacent ring carbon and Z form a fused cyclopropyl;
R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl.
[0081] In certain embodiments of compounds of formula VA or VB, the compoundshave the formula:
Figure imgf000062_0002
or a mixture thereof. [0082] Compounds of formula VA or VB include those having the formula:
Figure imgf000063_0001
or a mixture thereof.
[0083] In other embodiments, compounds of formual VA or VB include those having the formula:
Figure imgf000063_0002
or a mixture thereof; or the formula:
Figure imgf000063_0003
or a mixture thereof. [0084] Compounds of formula VA or VB further include those having the formula:
Figure imgf000064_0001
or a mixture thereof.
[0085] In still other embodiments, compounds of formula VA or VB have the formula:
Figure imgf000064_0002
or a mixture thereof.
[0086] In yet other embodiments, compounds of formual VA or VB have the formula:
Figure imgf000064_0003
or a mixture thereof. [0087] In still another aspect, the invention provides boronic acid inhibitors of dipeptidyl peptidase-IV having an inhibition constant of 10 micromolar or less for dipeptidyl peptidase-IV. Such inhibitors comprises a boroproline (including boropyrrolidines, boropiperidines, and boroazepanes) attached to an amino acid through an amide bond. The amino acid can be a beta-amino acid (including cyclic forms such as , an N-cycloalkyl-alpha-amino acid, an N-heterocyclyl-alpha amino acid, a cyclic alpha-amino acid having at least one substituent on the alpha-amino acid ring or having a ring other than pyrrolidine, or N-substituted glycine. In some embodiments, the boronic acid inhibitor is of Formula I:
Figure imgf000065_0001
including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein: n is 1 to 2; X is CH2; S; O; CF2 or C(CH3)2; Z is H; halogen; hydroxyl; (Cι-6)alkoxy; (Q.^alkyl; (C -12)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; R1 and R2 independently or together are hydrogen; a boronic acid protecting group; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; CR'R" may be present or absent, wherein if CR'R" is present, then R', R", R3, R4 and R5 are selected from (aa), (bb) or (cc): (aa) R', R", R3 and R4 are hydrogen; and R5 is a) hydrogen; b) (C,.i2)alkyl; (C2-i2)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cι-6)alkyl;
Figure imgf000066_0001
cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8) 2; -OR8; or -S-R8; R7 is halogen; (Cι.ι0)alkyl; (Cι-10)alkoxy; (C1-1o)alkylamino; (Ci-io) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (Cι.ιo)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3- 10)cycloalkyl; (C5-ι0)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; c) aryl optionally fused to a (C3-ι0)cycloalkyl; or heteroaryl optionally fused to a (C3-ι0)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH^adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4- pentylbicyclo[2.2.2]oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (Cι-8)alkoxy, (Cι-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (Cι-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Cι-8)alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene; e) Rn(CH2)p- where Rn is 2-oxopyπolidinyl; (Ct-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyπolidinyl, (Cι-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 (Cι-4)alkyl, (C1- )alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; and p is 0 to 3; 19 R is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Q. 6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-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 ; f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; g) a group of the formula: R15 I R14^ ^(CH2)r 1
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- )2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 2 to 6; h) a group of the formula:
Figure imgf000067_0001
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(d 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C -ι2)cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
Figure imgf000068_0001
where R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1- )alkylcarbonyl; di-(Cι- 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH2-C(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; k) a group f:
Figure imgf000068_0002
where R20 is hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (Cι-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (Cι-8)alkyl, (Cι.g)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
Figure imgf000069_0001
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; (bb) R', R", R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R' together with R3 or R4, or R" together with R3 or R4, and the atoms to which they are attached form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2; and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa); or R4 and R5 together form -(CR22R23)m- where m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl; halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino; arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylamino; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (cc) R' and R3 are hydrogen; and R" and R4 together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa) or (bb) and R5 is any of the groups in (aa) or (bb); and if CR'R" is absent, then R3, R4 and R5 are selected from (dd), (ee) or (ff): (dd) R3 and R4 are hydrogen; and R5 is a) (C,-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cι-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8)2; -OR8; or -S-R8; R7 is halogen; (d-ιo)alkyl; (Cι-ιo)alkoxy; (Cι-10)alkylamino; (Ci-io) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethyl thio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-1o)alkynyl; (C3- 10)cycloalkyl; (C5-ι0)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; b) aryl optionally fused to a (C3-ι0)cycloalkyl; or heteroaryl optionally fused to a (C3-ιo)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; c) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4- pentylbicyclo[2.2.2]oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (Cι-8)alkoxy, (Ci-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (Cι-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Cι- )alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene; d) Rn(CH2)p- where R11 is 2-oxopyrrolidinyl; (Cι.6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Cι-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently 19 trisubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with
Figure imgf000071_0001
or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; and p is 0 to 3; R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Ci. 6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cj-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula: R15 I ? 14' ^(CH2)r-
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- i2)cycloalkyl ring; (C3-i2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6; g) a group of the formula:
Figure imgf000072_0001
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι. 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C -i2)cycloalkyl ring; and s is 1 to 6; h) a group of the formula:
Figure imgf000072_0002
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(d. 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-i2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; i) a group of the formula: (phenyl-CH2-C(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; j) a group of the formula:
Figure imgf000073_0001
where R20 is hydrogen; (Cι-8)alkyl; (Ci ^alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (Cι-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (C1-8)alkyl, (Cι-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or k) a group of the formula:
Figure imgf000073_0002
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; or (ee) R3 and R4 are independently hydrogen, alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; R5 is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R4 and R5 together form -(CR22R23)m - wherein m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl; halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino; arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylamino; provided that when n is 1, X is CH2, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (ff) R3 is hydrogen; and R4 and R5 together with the atoms to which they are attached form a 4 to 8 member mono- or polycyclic heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, wherein the heterocyclic ring system is optionally mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; and wherein a bond containing a wavy line signifies a point of attachment.
[0088] The invention also relates to methods for preparing the above-described compounds. As shown below and as described in the EXAMPLES, the compounds of formula I and II are prepared by reacting a cyclic amine (e.g., pyπolidine or piperidine), suitably protected with a standard protecting group such as Boc-, Fmoc-, CBz- or the like, with sec-BuLi/TMEDA followed by B(OCH3)3, to provide the methyl boronic ester derivative. Acid hydrolysis of the methyl esters with 2N HC1 provides the boronic acid intermediate 1. Reaction of 1 with (+) pinanediol, deprotection of the amino protecting group, and recrystallization provides the pinanediol ester 2 as an isomerically pure salt.
[0089] Intermediate 2 is useful for the synthesis of both series A and series B compounds. For example, N-acylation of 2 with chloroacetyl chloride provides the α- chloro amide 3. Treatment of 3 with Na2CO3 and cyclopentylamine, and hydrolysis of the pinanediol boronic ester, provides a compound of formula I, 4. Alternatively, coupling of intermediate 2 with N-Boc-5-phenyl-Pro using EDAC/HOBT provides amide 5. Deprotection of the amino group and hydrolysis of the boronic esters, provides a compound of formula II, 6.
1) (+)-Pinanediol, Et20
Figure imgf000076_0001
2) HCI, Et20 then re crystallize (2X) leaving only R isomer
ic Acid
Figure imgf000076_0002
[0090] This synthetic scheme is adaptable for the preparation of all the compounds of the invention, by reacting the appropriate cyclic amine (pyπollidine, piperidine, and other cyclic amines) with sec-BuLi/B(OCH3)3, and coupling the boronic ester intermediate with the desired acid chloride or acid via routes A or B, respectively. The appropriate cyclic amine may either be commercially available or is easily synthesized through known procedures, for example, those procedures disclosed in U.S. Patent Nos. 6,617,340; 6,432,969; 6,380,398; 6,172,081; 6,166,063; 6,124,305; 6,110,949; 6,107,317; 6,011,155; and 6,395,767, which are hereby incoφorated by reference in their entirety.
[0091] Thus, another aspect of the invention provides a process for preparing the compounds of formula I:
Figure imgf000077_0001
by coupling a reactive compound of formula:
Figure imgf000077_0002
with an amine of formula: R5-NH2; 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 ι l , r R»2 , Γ R> 3 , Γ R»4 , T R» I , Γ R, " , n, X, and Z are as defined herein. Prefeπed embodiments are those where R3 and R4 are hydrogen, L is halogen, including but not limited to Cl, and R5-NH2 is cyclopentylamine.
[0092] Still another aspect of the invention provides a process for preparing the compounds of formula II:
Figure imgf000077_0003
by coupling a 2-boroheterocycle having the formula:
Figure imgf000078_0001
with the coπesponding N-protected cyclic amino acid; optionally deprotecting the boronic acid ester; and recovering the resultant compound as a free acid or as an acid addition salt. R'and R2 are not hydrogen, and n, X, and Z are as defined herein. Typically the 2-boroheterocycle is a 2-boropyπolidino or 2-boropiperidino. In some such embodiments, the N-protected cyclic amino acid is N-Boc-4-phenyl-boroPro-OH.
[0093] The compounds of the invention may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan.
[0094] The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
[0095] The compounds of this invention may form solvates with standard low molecular weight solvents, including water to yield hydrates, using methods known to the skilled artisan.
[0096] It is to be understood that the invention extends to all of the stereoisomeric forms of the claimed compounds, including enantiomers and diastereomers, as well as the racemates. Methods/Uses [0097] Another aspect of the invention provides methods and uses for the compounds of the invention. In one approach, the invention compounds can be administered to an individual suffering from a disease or condition mediated by a post-proline/alanine cleaving amino-dipeptidase. In this embodiment, the individual is administered an amount of the invention compound effective in reducing the activity of the post-proline/alanine cleaving amino-dipeptidase and, thereby, reducing or alleviating symptoms of the disease or condition. In some embodiments, the administered compound reduces the activtity of DPP- IV. In some embodiments, the disease or condition is selected from the group consisting of diabetes, diabetec complications, hyperglycemia, Syndrome X, hyperinsulinemia, obesity, atherosclerosis and related diseases. The invention compounds to be administered may be one or more of the inventive bronic acid compounds, which may be formulated in any manner as described here, including combination with "other type(s) of therapeutic agents" identified further below.
[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; [00103] Methods for treating, controlling or preventing hyperglycemia in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention;
[00104] Methods for treating, controlling or preventing obesity in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention;
[00105] Methods for treating to enhance islet neo genesis, b-cell survival, and insulin biosynthesis in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention;
[00106] Methods for treating, controlling or preventing insulin resistance in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention;
[00107] Methods for treating, controlling or preventing one or more lipid disorders selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, and high LDL in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention;
[00108] Methods for treating, controlling or preventing atherosclerosis in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention;
[00109] Methods for treating or controlling growth hormone deficiency in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention;
[00110] Methods for modulating the immune response in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention;
[00111] Methods for treating, or controlling HIV infection in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention; [00112] Methods for treating, controlling or preventing in a mammalian patient in need of such treatment one or more disorders selected from the group consisting of neutropenia, anemia, neuronal disorders, tumor growth and metastasis, benign prostatic hypertrophy, gingivitis, hypertension and osteoporosis, comprising administering to the patient a therapeutically effective amount of a compound of the invention;
[00113] Methods for reducing sperm motility in a male in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention;
[00114] Methods for treating, controlling or preventing in a mammalian patient in need of such treatment one or more conditions selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) rheumatoid arthritis, (17) other inflammatory conditions, (18) pancreatitis, (19) abdominal obesity, (20) neurodegenerative disease, (21) multiple sclerosis, (22) retinopathy, (23) nephropathy, (24) neuropathy, (25) Syndrome X, (26) ovarian hyperandrogenism, (27) allograft rejection in transplantation, and other conditions where insulin resistance is a component, comprising administering to the patient a therapeutically effective amount of a compound of the invention;
[00115] Methods for treating, controlling or preventing in a mammalian patient in need of such treatment one or more conditions selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) rheumatoid arthritis, (17) other inflammatory conditions, (18) pancreatitis, (19) abdominal obesity, (20) neurodegenerative disease, (21) multiple sclerosis, (22) retinopathy, (23) nephropathy, (24) neuropathy, (25) Syndrome X, (26) ovarian hyperandrogenism, (27) allograft rejection in transplantation, (28) Type II diabetes, (29) growth hormone deficiency, (30) neutropenia, (31) anemia, (32) neuronal disorders, (33) tumor growth and metastasis, (34) benign prostatic hypertrophy, (35) gingivitis, (36) hypertension, (37) osteoporosis, and other conditions that may be treated by inhibition of dipeptidyl peptidase-IV, comprising administering to the patient of a therapeutically effective amount of a first compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more other compounds selected from the group consisting of: a) Other dipeptidyl peptidase-IV inhibitors; b) Insulin sensitizers selected from the group consisting of (i) PPAR agonists, (ii) biguanides, and (iii) protein phosphatase- IB inhibitors; c) Insulin or insulin mimetics; d) Sulfonylureas or other insulin secretagogues; e) α-glucosidase inhibitors; f) glucagons receptor agonists; g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; h) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists; i) GIP, GIP mimetics, and GIP receptor agonists; j) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; k) Cholesterol lowering agents selected from the group consisting of (i) HMG- CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists, (v) PPARα/γ dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoAxholesterol acyltransferase inhibitors, and (viii) anti-oxidants; 1) PPARδ agonists; m) Anti-obesity compounds; n) An ileal bile acid transporter inhibitor; o) Anti-inflammatory agents; p) G-CSF, G-CSF mimetics, and G-CSF receptor agonists; and q) EPO, EPO mimetics, and EPO receptor agonists.
[00116] Methods for the treatment, control, or prevention of one or more conditions selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of the invention and an HMG-CoA reductase inhibitor;
[00117] Methods wherein the HMC-CoA reductase inhibitor is a statin;
[00118] Methods wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin;
[00119] Methods for treating, controlling or preventing atherosclerosis, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of the invention and an HMG-CoA reductase inhibitor;
[00120] Methods for treating, controlling or preventing obesity, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of the invention and an anti-obesity agent;
[00121] Methods wherein the anti-obesity agent is a beta-3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, an anorectic agent, and/or a fatty acid oxidation upregulator;
[00122] Methods wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and or mazindol;
[00123] Methods for the treatment, control, or prevention of neutropenia comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of the invention and a neutrophilic agent;
[0100] Methods for the treatment, control, or prevention of neutropenia wherein the neutrophilic agent is G-CSF, a G-CSF mimetic, or a G-CSF receptor agonist;
[0101] Methods for the treatment, control, or prevention of neutropenia wherein the neutrophilic agent is pegfilgrastim, filgrastim, lenograstim, or nartograstim;
[0102] Methods for the treatment, control, or prevention of anemia, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of the invention and a erythropoietin agonist; [0103] Methods for the treatment, control, or prevention of anemia wherein the erythropoietin agonist is EPO, an EPO mimetic, or an EPO receptor agonist;
[0104] Methods for the treatment, control, or prevention of anemia wherein the erythropoietin agonist is epoetin alfa, or darbepoetin alfa;
[0105] Methods for treating diabetes, insulin resistance, hyperglycemia, hyperisulinemia, or elevated blood levels of free fatty acids or glycerol, obesity, Syndrome X, dysmetabolic syndrome, diabetic complications, hypertriglyceridemia, hyperinsulinemia, atherosclerosis, impaired glucose homeostasis, impaired glucose tolerance, infertility, polycystic ovary syndrome, growth disorders, frailty, arthritis, allograft rejection in transplantation, autoimmune diseases, AIDS, intestinal diseases, inflammatory bowel syndrome, nervosa, osteoporosis, or an immunomodulatory disease or a chronic inflammatory bowel disease, comprising administering to a mammalian species in need of treatment a therapeutically effective amount of a compound of the invention;
[0106] Methods for treating type II diabetes and/or obesity;
[0107] A variety of uses of the invention compounds are possible along the lines of the various methods of the treating an individual such as a mammal described above. Exemplary uses of the invention methods are represented by:
[0108] Use of a compound of the invention for the manufacture of a medicament for treating a condition that may be regulated or normalized via inhibition of DPP-IV;
[0109] Use of a compound of the invention for the manufacture of a medicament for treatment of metabolic disorders;
[0110] Use of a compound of the invention for the manufacture of a medicament for blood glucose lowering;
[0111] Use of a compound of the invention for the manufacture of a medicament for treatment of type II diabetes;
[0112] Use of a compound of the invention for the manufacture of a medicament for the treatment of impaired glucose tolerance (IGT); [0113] Use of a compound of the invention for the manufacture of a medicament for the treatment of impaired fasting glucose (IFG);
[0114] Use of a compound of the invention for the manufacture of a medicament for prevention of hyperglycemia;
[0115] Use of a compound of the invention for the manufacture of a medicament for delaying the progression of impaired glucose tolerance (IGT) to type II diabetes;
[0116] Use of a compound of the invention for the manufacture of a medicament for delaying the progression of non-insulin requiring type II diabetes to insulin requiring type II diabetes;
[0117] Use of a compound of the invention for the manufacture of a medicament for increasing the number and/or the size of beta cells in a mammalian subject;
[0118] Use of a compound of the invention for the manufacture of a medicament for treatment of beta cell degeneration, in particular apoptosis of beta cells.
[0119] Use of a compound of the invention for the manufacture of a medicament for the treatment of disorders of food intake;
[0120] Use of a compound of the invention for the manufacture of a medicament for the treatment of obesity;
[0121] Use of a compound of the invention for the manufacture of a medicament for appetite regulation or induction of satiety;
[0122] Use of a compound of the invention for the manufacture of a medicament for the treatment of dyslipidemia;
[0123] Use of a compound of the invention for the manufacture of a medicament for treatment of functional dyspepsia, in particular iπitable bowel syndrome; and
[0124] Methods for treating the conditions mentioned above by administering to a subject in need thereof an effective amount of a compound of the invention. Combination Treatments
[0125] The compounds of the invention may be used in combination with one or more other types of antidiabetic agents (employed to treat diabetes and related diseases) and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in a separate oral dosage form or by injection.
[0126] The other type of antidiabetic agent which may be optionally employed in combination with the DPP-IV inhibitors of the invention may be 1,2,3 or more antidiabetic agents or antihyperglycemic agents including insulin secretagogues or insulin sensitizers, or other antidiabetic agents preferably having a mechanism of action different from DPP-IV inhibition and may include biguanides, sulfonyl ureas, glucosidase inhibitors, PPAR γ agonists, such as thiazolidinediones, SGLT2 inhibitors, PPAR α/ γ dual agonists, aP2 inhibitors, glycogen phosphorylase inhibitors, advanced glycosylation end (AGE) products inhibitors, and/or meglitinides, as well as insulin, and or glucagon-like peptide- 1 (GLP-1) or mimetics thereof.
[0127] The use of the compounds of the invention in combination with 1, 2, 3 or more other antidiabetic agents may produce antihyperglycemic results greater than that possible from each of these medicaments alone and greater than the combined additive antihyperglycemic effects produced by these medicaments.
[0128] The other antidiabetic agent may be an oral antihyperglycemic agent preferably a biguanide such as metformin or phenformin or salts thereof, preferably metformin HC1.
[0129] Where the other antidiabetic agent is a biguanide, the compounds of the invention will be employed in a weight ratio to biguanide within the range from about 0.01 :1 to about 100: 1 , preferably from about 0.1 : 1 to about 5:1.
[0130] Preferably, the other antidiabetic agent can be a sulfonyl urea such as glyburide (also known as glibenclamide), glimepiride (disclosed in U.S. patent No. 4,379,785), glipizide, gliclazide or chlorpropamide, other known sulfonylureas or other antihyperglycemic agents which act on the ATP-dependent channel of the γ-cells, with glyburide and glipizide being preferred, which may be administered in the same or in separate oral dosage forms. [0131] The compounds of the invention will be employed in a weight ratio to the sulfonyl urea in the range from about 0.01 :1 to about 100:1, preferably from about 0.05:1 to about 5:1.
[0132] The oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. patent No. 4,904,769) or miglitol (disclosed in U.S. patent No. 4,639,436), which may be administered in the same or in a separate oral dosage forms.
[0133] The compounds of the invention will be employed in a weight ratio to the glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.2:1 to about 50:1.
[0134] The compounds of the invention may be employed in combination with a PPAR γ agonist such as a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner- Lambert's Rezulin®, disclosed in U.S. patent No. 4,572,912), rosiglitazone (en), pioglitazone (Takeda), Mitsubishi MCC-555 (disclosed in U.S. patent No. 5,594,016), Glaxo-Wellcome's GL-262570, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer), isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-l 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.
[0136] The sulfonyl urea and thiazolidinedione in amounts of less than about 150 mg oral antidiabetic agent may be incoφorated in a single tablet with the compounds of the invention.
[0137] 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-10-36) amide, GLP-l(7-36) amide, GLP-l(7-36) (as disclosed in U.S. Patent No. 5,614,492 to Habener, disclosure of which is incoφorated herein by reference), or a GLP-1 mimic such as AC2993 or Exendin-4 (Amylin) and LY-315902 or LY-307167 (Lilly) and NN2211 (Novo-Nordisk), which may be administered via injection, intranasal, or by transdermal or buccal devices.
[0138] Where present, metformin, the sulfonyl ureas, such as glyburide, glimepiride, glipyride, glipizide, chloφropamide and gliclazide and the glucosidase inhibitors acarbose or miglitol or insulin (injectable, pulmonary, buccal, or oral) may be employed in formulations as described above and in amounts and dosing as indicated in the PHYSICIAN'S DESK REFERENCE (PDR).
[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 incoφorated herein by reference.
[0143] The other antidiabetic agent may also be a PPAR α/γ dual agonist such as AR- HO39242 (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 incoφorated herein by reference, employing dosages as set out therein, which compounds designated as prefeπed are preferred for use herein. [0144] The other antidiabetic agent may be an SGLT2 inhibitor, as disclosed in U.S. Application Ser. No. 09/679,027, filed Oct. 4, 2000 (attorney file LA49NP), which is incoφorated herein by reference, employing dosages as set out herein. Prefeπed are the compounds designated as prefeπed in the above application.
[0145] The other antidiabetic agent, which may be employed in combination with the DPP-IV inhibitors in accordance with the present invention, can be an aP2 inhibitor,09/519,079, filed Mar. 6, 2000 (attorney file LA27NP), which are each incoφorated herein by reference, employing dosages as set out herein. Prefeπed antidiabetic agents to be used in combination with the invention compounds are those indicated as prefeπed in the above cited patents.
[0146] The other antidiabetic agent that may employed with the DPP-IV inhibitors of the invention can be a glycogen phosphorylase inhibitor as disclosed, for instance, in WO 96/39384, WO 96/39385, WO 99/26659, WO 99/43663, WO 2000/47206, EP 978279, EP 1041068, and U.S. patents No. 5,952,322 and No. 5,998,463.
[0147] The meglitinide which may optionally be employed in combination with the compound of the invention may be repaglinide, nateglinide (Novartis) or KADI 229 (PF/Kissei), with repaglinide being preferred.
[0148] The DPP-IV inhibitors of the invention will be employed in a weight ratio to the meglitinide, PPAR γ agonist, PPAR α/ γ 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 absoφtion 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. 5,885,983, and No. 5,962,440. MTP inihibitors prefeπed herein are thos identified as being prefeπed in the above referenced patents.
[0151] Most prefeπed 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 pefeπed MTP inhibitor in this context is 9-[4-[4-[[2-(2,2,2- Trifluoroethoxy)-benzoyl]amino]-l-piperidinyl] butyl]-N-(2,2,2-trifluoroethyl)-9H- fluorene-9-carboxamide.
[0152] The hypolipidemic agent may be an HMG CoA reductase inhibitor which includes, but is not limited to, mevastatin and related compounds as disclosed in U.S. patent No. 3,983,140, lovastatin (mevinolin) and related compounds disclosed in U.S. patent No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Patent No. 4,346,227, 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, α-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., Cuπent Pharmaceutical Design, 2, 1-40 (1996).
[0154] In addition, other squalene synthetase inhibitors suitable for use herein include the teφenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc, 1976, 98, 1291- 1293, phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987, 10, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstracts Table of Contents, pp 16, 17, 40-43, 48-51, Summary.
[0155] Other hypohpidemic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafϊbrate, ciprofibrate, clinofibrate, and the like, probucol, and related compounds as disclosed in U.S. Patent No. 3,674,836, probucol and gemfibrozil being prefeπed, bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL- 283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p- aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives such as disclosed in U.S. Patent No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes such as disclosed in U.S. Patent No. 4,027,009, and other known serum cholesterol lowering agents.
[0156] The other hypohpidemic 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, frel). (1998), 137(1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypohpidemic activity mediated by selective suppression of the hepatic secretion of ApoBlOO-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; "RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor", Smith, C, et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; "ACAT inhibitors: physiologic mechanisms for hypohpidemic 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, Cuπ. Med. Chem. (1994), 1(3), 204-25; "Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N'-[(l- phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity", Stout et al, Chemtracts: Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd).
[0157] The hypohpidemic agent may be an upregulator of LD2 receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).
[0158] The hypohpidemic agent may be a cholesterol absoφtion inhibitor preferably Schering-Plough's SCH48461 as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).
[0159] The hypohpidemic agent may be an ileal Na+/bile acid cotransporter inhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).
[0160] The lipid-modulating agent may be a cholesteryl ester transfer protein (CETP) inhibitor such as Pfizer's CP 529,414 (WO/0038722 and EP 818448) and Pharmacia's SC- 744 and SC-795.
[0161] The ATP citrate lyase inhibitor which may be employed in the combination of the invention may include, for example, those disclosed in U.S. patent No. 5,447,954.
[0162] Prefeπed hypohpidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin and ZD-4522.
[0163] The above-mentioned U.S. patents are incoφorated 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 hypohpidemic 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.
[0166] The dosages and formulations for the hypohpidemic agent will be as disclosed in the various patents and applications discussed above. [0167] The dosages and formulations for the other hypohpidemic agent to be employed, where applicable, will be as set out in the latest edition of the Physicians' Desk Reference.
[0168] For oral administration, a satisfactory result may be obtained employing the MTP inhibitor in an amount within the range of from about 0.01 mg/kg to about 500 mg and preferably from about 0.1 mg to about 100 mg, one to four times daily.
[0169] An oral dosage form, such as tablets or capsules, will contain the MTP inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg, one to four times daily.
[0170] For oral administration, a satisfactory result may be obtained employing an HMG CoA reductase inhibitor, for example, pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin in dosages employed as indicated in the PHYSICIAN'S DESK REFERENCE, such as in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.
[0171] The squalene synthetase inhibitor may be employed in dosages in an amount within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg.
[0172] A prefeπed 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 prefeπed oral dosage form, such as tablets or capsules will contain the squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg.
[0174] The other hypohpidemic agent may also be a lipoxygenase inhibitor including a 15-lipoxygenase (15-LO) inhibitor such as benzimidazole derivatives as disclosed in WO 97/12615, 15-LO inhibitors as disclosed in WO 97/12613, isothiazolones as disclosed in WO 96/38144, and 15-LO inhibitors as disclosed by Sendobry et al "Attenuation of diet- induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties", Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al, "15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease", Current Pharmaceutical Design, 1999, 5, 11-20.
[0175] The compounds of the invention and the hypohpidemic agent may be employed together in the same oral dosage form or in separate oral dosage forms taken at the same time.
[0176] The compositions described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination.
[0177] The prefeπed hypohpidemic agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin.
[0178] The other type of therapeutic agent which may be optionally employed with the DPP-IV inhibitors of the invention may be 1, 2, 3 or more of an anti-obesity agent including a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta drug, an anorectic agent and/or a fatty acid oxidation upregulator.
[0179] The beta 3 adrenergic agonist which may be optionally employed in combination with a compound of the invention may be AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. patents No. 5,541,204, No. 5,770,615, No. 5,491,134, No. 5,776,983 and No. 5,488,064, with AJ9677, L750,355 and CP331648 being prefeπed.
[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 prefeπed.
[0181] The serotonin (and dopamine) reuptake inhibitor which may be optionally employed in combination with a compound of the invention may be sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramine and topiramate being prefeπed.
[0182] The thyroid receptor beta compound which may be optionally employed in combination with a compound of the invention may be a thyroid receptor ligand as disclosed in WO97/21993 (U. Cal SF), WO099/00353 (KaroBio) and GB98/284425 (KaroBio), with compounds of the KaroBio applications being prefeπed.
[0183] The anorectic agent which may be optionally employed in combination with a compound of the invention may be dexamphetamine, phentermine, phenylpropanolamine or mazindol, with dexamphetamine being prefeπed.
[0184] The fatty acid oxidation upregulator which may be optionally employed in combination with the compound of the invention can be famoxin (Genset).
[0185] The various anti-obesity agents described above may be employed in the same dosage form with the compound of the invention or in different dosage forms, in dosages and regimens as generally known in the art or in the PDR.
[0186] The infertility agent which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be 1, 2, or more of clomiphene citrate (Clomid®, Aventis), bromocriptine mesylate (Parlodel®, Novartis),LHRH analogs, Lupron (TAP Pharm.), danazol, Danocrine (Sanofi), progestogens or glucocorticoids, which may be employed in amounts specified in the PDR.
[0187] The agent for polycystic ovary syndrome which may be optionally employed in combination with the DPP-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 incoφorated herein by reference, which may be employed in amounts specified in the PDR, where applicable.
[0189] The agent for treating arthritis which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be 1, 2, or more of aspirin, indomethacin, ibuprofen, diclofenac sodium, naproxen, nabumetone (Relafen®, SmithKline Beecham), tolmetin sodium (Tolectin®, Ortho-McNeil), piroxicam (Feldene®, Pfizer), ketorolac tromethamine (Toradol®, Roche), celecoxib (Celebrex®, Searle), rofecoxib (Vioxx®, Merck) and the like, which may be employed in amounts specified in the PDR.
[0190] Conventional agents for preventing allograft rejection in transplantation such as cyclosporin, Sandimmune (Novartis), azathioprine, Immuran (Faro) or methotrexate may be optionally employed in combination with the DPP-IV inhibitor of the invention, which may be employed in amounts specified in the PDR.
[0191] Conventional agents for treating autoimmune diseases such as multiple sclerosis and immunomodulatory diseases such as lupus erythematosis, psoriasis, for example, azathioprine, Immuran, cyclophosphamide, NSAIDS such as ibuprofen, cox 2 inhibitors such as Vioxx and Celebrex, glucocorticoids and hydroxychloroquine, may be optionally employed in combination with the DPP-IV inhibitor of the invention, which may be employed in amounts specified in the PDR.
[0192] The AIDS agent which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be a non-nucleoside reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a protease inhibitor and/or an AIDS adjunct anti- infective and may be 1, 2, or more of dronabinol (Marinol®, Roxane Labs), didanosine (Videx®, Bristol-Myers Squibb), megestrol acetate (Megace®, 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).
[0193] The above anti-AIDS agents may be employed in amounts specified in the PDR.
[0194] The agent for treating inflammatory bowel disease or syndrome which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be 1, 2, or more of sulfasalazine, salicylates, mesalamine (Asacol®, P&G) or Zelmac®, (Bristol- Myers Squibb), which may be employed in amounts specified in the PDR or otherwise known in the art. [0195] The agent for treating osteoporosis which may be optionally employed in combination with the DPP-IV inhibitor of the invention may be 1, 2, or more of alendronate sodium (Fosamax®, Merck, tiludronate (Skelid®, Sanofi), etidronate disodium (Didronel®, P&G), raloxifene HC1 (E vista®, Lilly), which may be employed in amounts specified in the PDR.
[0196] In carrying out the methods of the invention, a pharmaceutical composition may be employed containing the compounds of the invention, with or without another antidiabetic agent and/or other type therapeutic agent, in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration. The compounds can be administered to mammalian species including humans, monkeys, dogs, etc. by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations. The dose for adults is preferably between 10 and 1,000 mg per day, which can be administered in a single dose or in the form of individual doses from 1-4 times per day.
[0197] A typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.
[0198] DPP-IV inhibitor activity of the compounds of the invention may be determined by use of an in vitro assay system which measures the potentiation of inhibition of DPP-IV. Inhibition constants (Ki values) for the DPP-IV inhibitors of the invention may be determined by the method described below.
Pharmaceutical Compositions
[0199] Pharmaceutical compositions containing a compound of the invention of the invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19th Ed., 1995. The compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
[0200] Typical compositions include a compound of the invention which inhibits the enzymatic activity of DPP-IV or a pharmaceutically acceptable basic addition salt or prodrug or hydrate thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, teπa alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyπolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
[0201] The pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and or coloring substances and the like, which do not deleteriously react with the active compounds.
[0202] The route of administration may be any route, which effectively transports the active compound of the invention which inhibits the enzymatic activity of DPP-IV to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being prefeπed.
[0203] If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
[0204] For nasal administration, the preparation may contain a compound of the invention which inhibits the enzymatic activity of DPP-IV, dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absoφtion enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
[0205] For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
[0206] Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
[0207] A typical tablet that may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt thereof) 250 mg Colloidal silicon dioxide (Aerosil)® 1.5 mg Cellulose, microcryst. (Avicel)® 70 mg Modified cellulose gum (Ac-Di-Sol)® 7.5 mg Magnesium stearate Ad.
Coating: HPMC approx. 9 mg *Mywacett 9-40 T approx. 0.9 mg
*Acylated monoglyceride used as plasticizer for film coating.
[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.
[0209] 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.
[0210] Generally, the compounds of the invention are dispensed in unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage. [0211] Usually, dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.05 mg to about 1000 mg, preferably from about 0.5 mg to about 250 mg of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
[0212] The invention also encompasses prodrugs of a compound of the invention which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of a compound of the invention which are readily convertible in vivo into a compound of the invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
[0213] The invention also encompasses active metabolites of a compound of the invention.
[0214] Thus, another aspect of the invention provides pharmaceutical compositions of the compounds of the invention, alone or in combination with another type antidiabetic agent and/or other type therapeutic agent.
[0215] In one example, the embodiments of the invention are represented by:
[0216] Pharmaceutical compositions comprising, as an active ingredient, at least one compound of the invention which inhibits the enzymatic activity of DPP-IV or a pharmaceutically acceptable salt or prodrug or hydrate thereof together with a pharmaceutically acceptable carrier or diluent;
[0217] Pharmaceutical compositions comprising a compound of the invention as described herein, in free form or in pharmaceutically acceptable acid addition salt form, together with at least one pharmaceutically acceptable carrier or diluent;
[0218] Pharmaceutical compositions comprising a compound of formula VA, VB, or a mixture thereof and a pharmaceutically acceptable carrier or diluent; [0219] Pharmaceutical compositions comprising: a. a substantially pure preparation of a compound of formula VB as described herein; and b. a pharmaceutically acceptable carrier or diluent;
[0220] Methods of making a pharmaceutical composition comprising mixing a substantially pure preparation of a compound of formula VB with a pharmaceutically acceptable carrier or diluent;
[0221] Methods of making a pharmaceutical composition of a compound described herein wherein the pharmaceutically acceptable carrier or diluent is suitable for oral administration;
[0222] Methods of making a pharmaceutical composition of a compound described herein suitable for for oral administration further comprising the step of formulating the composition into a tablet or capsule;
[0223] Methods of making a pharmaceutical composition of a compound described herein wherein the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration;
[0224] Methods of making a pharmaceutical composition of a compound described herein suitable for parenteral administration further comprising the step of lyophilizing the composition to form a lyophilized preparation;
[0225] Pharmaceutical compositions for the treatment, prevention or control of atherosclerosis, comprising: (1) a compound of the invention, (2) an HMG-CoA reductase inhibitor, and (3) a pharmaceutically acceptable carrier;
[0226] Pharmaceutical compositions, comprising: a) A compound of the invention; b) One or more compounds selected from the group consisting of: i) Other dipeptidyl peptidase-IV inhibitors; ii) Insulin sensitizers selected from the group consisting of (i) PPAR agonists, (ii) biguanides, and (iii) protein phosphatase- IB inhibitors; iii) Insulin or insulin mimetics; iv) Sulfonylureas or other insulin secretagogues; v) α-glucosidase inhibitors; vi) glucagons receptor agonists; vii) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; viii) GIP, GIP mimetics, and GIP receptor agonists; ix) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; x) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists; xi) Cholesterol lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists, (v) PPARα/γ dual agonists, (vi) inhibitors of cholesterol absoφtion, (vii) acyl CoAxholesterol acyltransferase inhibitors, and (viii) anti-oxidants; xii) PPARδ agonists; xiii) Anti-obesity compounds; xiv) An ileal bile acid transporter inhibitor; xv) Anti-inflammatory agents; xvi) G-CSF, G-CSF mimetics, and G-CSF receptor agonists; xvii) EPO, EPO mimetics, and EPO receptor agonists; and c) a pharmaceutically acceptable carrier.
[0227] Pharmaceutical combinations comprising a compound of the invention, an antidiabetic agent other than a DPP-IV inhibitor for treating diabetes and related diseases, and an anti-obesity agent or a lipid-modulating agent or both.
[0228] Pharmaceutical combinations comprising a compound of the invention and an antidiabetic agent;
[0229] Pharmaceutical combinations comprising a compound of the invention and an antidiabetic agent wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γ 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; [0230] Pharmaceutical combinations comprising a compound of the invention and an antidiabetic agent wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chloφropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, Gl -262570, isaglitazone, JTT-501, NN- 2344, L895645, YM-440, R-l 19702, AJ9677, repaglinide, nateglinide, KADI 129, APR- HO39242, GW-409544, KRP297, AC2993, Exendin-4, LY307161, NN2211, and/or LY315902;
[0231] Pharmaceutical combinations comprising a compound of the invention and an antidiabetic agent wherein the compound is present in a weight ratio to the antidiabetic agent within the range from about 0.01 to about 100:1;
[0232] Pharmaceutical combinations comprising a compound of the invention and an antidiabetic agent wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, an anorectic agent, and/or a fatty acid oxidation upregulator;
[0233] Pharmaceutical combinations comprising a compound of the invention and an anti-obesity agent wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol;
[0234] Pharmaceutical combinations comprising a compound of the invention and a lipid-modulating agent wherein the lipid-modulating agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, an ACAT inhibitor, a cholesteryl ester transfer protein inhibitor, or an ATP citrate lyase inhibitor;
[0235] Pharmaceutical combinations comprising a compound of the invention and a lipid-modulating agent wherein the lipid-modulating agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529,414, avasimibe, TS-962, MD-700, and/or LY295427; [0236] Pharmaceutical combinations comprising a compound of the invention and a lipid-modulating agent wherein the compound is present in a weight ratio to the lipid- modulating agent within the range from about 0.01 to about 100:1;
[0237] Pharmaceutical combinations comprising a compound of the invention and an agent for treating infertility, an agent for treating polycystic ovary syndrome, an agent for treating a growth disorder and/or frailty, an anti-arthritis agent, an agent for preventing inhibiting allograft rejection in transplantation, an agent for treating autoimmune disease, an anti-AIDS agent, an agent for treating inflammatory bowel disease/syndrome, an agent for treating anorexia nervosa, an anti-osteoporosis agent and/or an anti-obesity agent.
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/μl, pH 8.0) and Gly-Pro-AMC substrate (400 μM) 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 μl) into 25 mM Tris buffer (77.5 μl) followed by addition of test compound (2.5 μl) at 26°C. After 10-minutes substrate was added (10 μl) and allowed to react for 20-minutes at 26°C before free AMC was measured. IC50 values were determined in triplicate, using a minimum of six different inhibitor concentrations. IC50 values were calculated using Nonlinear Regression Analysis (GraphPad, Prism, San Diego, CA).
[0240] To determine the DPP-IV activity in the plasma of mice dosed with test compounds, plasma (10 μl) was diluted into 25 mM Tris buffer (80 μl, pH 8.0) followed by addition of Gly-Pro-AMC stock solution (10 μl) and the free AMC measured after 20- minutes at 26°C. Analysis was performed as described above.
[0241] The Zucker Diabetic Fatty (ZDF) rat model can be used to investigate the effects of the compounds of the invention on both the treatment and prevention of diabetes as rats of this sub-strain are initially pre-diabetic although they develop severe type 2 diabetes characterized by increased 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, J. Schutkowski, M., Faust, J., Neubert., Barth, A., and Heins, J. (1991) Biol. Chem. Hoppe-Seyler, 372, 313-318; and (2) Nagatsu, T., Hino, M., Fuyamada, H., Hayakawa, T., Sakakibara, S., Nakagawa, Y., and Takemoto, T. (1976) Anal. Biochem., 74, 466-476, respectively.
DEFINITIONS
[0236] The term "DPP-IV" denotes dipeptidyl peptidase IV (EC 3.4.14.5; DPP-IV), also known as "CD-26." DPP-IV cleaves a dipeptide from the N terminus of a polypeptide chain containing a proline or alanine residue in the penultimate position.
[0237] The term "diabetes and related diseases" refers to Type II diabetes, Type I diabetes, impaired glucose tolerance, obesity, hyperglycemia, Syndrome X, dysmetabolic syndrome, diabetic complications, diabetic dyslipidemia, hyperinsulinemia, and the like. [0238] The conditions, diseases and maladies collectively referred to as "diabetic complications" include retinopathy, neuropathy and nephropathy, and other known complications of diabetes.
[0239] The term "other type(s) of therapeutic agents" as employed herein refers to one or more antidiabetic agents (other than DPP-IV inhibitors of the invention), one or more anti-obesity agents, and/or one or more lipid-modulating agents (including anti- atherosclerosis agents), and/or one or more infertility agents, one or more agents for treating polycystic ovary syndrome, one or more agents for treating growth disorders, one or more agents for treating frailty, one or more agents for treating arthritis, one or more agents for preventing allograft rejection in transplantation, one or more agents for treating autoimmune diseases, one or more anti-AIDS agents, one or more anti-osteoporosis agents, one or more agents for treating immunomodulatory diseases, one or more agents for treating chronic inflammatory bowel disease or syndrome and/or one or more agents for treating anorexia nervosa.
[0240] The term "lipid-modulating" agent as employed herein refers to agents which lower LDL and or raise HDL and/or lower triglycerides and/or lower total cholesterol and/or other known mechanisms for therapeutically treating lipid disorders.
[0241] The term "treatment" is defined as the management and care of a patient for the puφose 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.
[0243] By "substantially pure" in relation to compounds of the invention such as, but not limited to, those of formula VA and VB, it is meant that one isomer or the other, including all enantiomers, diastereoisomers, solvates, hydrates, and pharmaceutically acceptable salts thereof, represents at least 90% by weight of the composition. In some embodiments one isomer represents at least 98% by weight of the composition.
[0244] The term "boronic acid protecting group" as used herein refers to a moiety employed to block or protect the boronic acid functionality while reactions involving other functional sites of the compound are carried out. Typically, the boronic acid OH groups are protected as boronic acid esters derived from alchohols such as (+)-pinanediol; pinacol; 1,2- dicyclohexyl-ethanediol; 1,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3- butanediol, diisopropyl tartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6- decanediol; 1 , 1 ,2-triphenyl- 1 ,2-ethanediol; (2R,3R)- 1 ,4-dimethyoxy- 1 , 1 ,4,4-tetraphenyl- 2,3-butanediol; methanol; ethanol; isopropanol; catechol; 1-butanol; and the like. As will be understood by those skilled in the art, alcohols having only a single hydroxy group, such as methanol, form diesters having the structure -B(OR)2 in which R is the organic moiety from the alcohol (e.g., -B(OMe)2). By comparison, diols such as pinacol form cyclic boronic diesters with -B(OH)2 in which the organic moiety (e.g., -C(Me)2-C(Me) -)is attached to both oxygens.
[0245] 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, 3rd Ed." (John Wiley & Sons, New York (1999)), which is hereby incoφorated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p- toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l -methyl ethoxycarbonyl, α,α-di methyl - 3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Prefeπed N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
[0246] The term "alkyl" or "(d-ι2)alkyl", alone or in combination, refers to linear or branched chains and may include cyclic portions, having from 1-12 (the use of 1-12 herein implies each of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl, and the like.
[0247] The terms "(Cι.ιo)alkyl", "(C]-8)alkyl" and "(C1-6)alkyl", alone or in combination, refers to linear or branched chains and may include cyclic portions, having from 1-10, 1-8, or 1-6 carbon atoms, respectively, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl, and the like.
[0248] The term "(Cι-4)alkyl", alone or in combination, refers to linear or branched chains and may include cyclic portions, having from 1-4 carbon atoms, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
[0249] The terms "(C2-ι2)alkenyl" and "(C2-ιo)alkenyl", alone or in combination, refers to a straight or branched, unsaturated hydrocarbon chain having from 2-12 or 2-10 carbon atoms, respectively, and at least one double bond, such as, but not limited to, vinyl, 1- propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl, n-hexenyl, and the like.
[0250] The terms "(C2-ι2)alkynyl" and "(C2-ιo)alkynyl", alone or in combination, refers to an unsaturated hydrocarbon chain having from 2-12 or 2-10 carbon atoms, respectively, and at least one triple bond, such as but not limited to -C≡CH, -C≡C-CH3, -CH2C≡CH, - CH2-CH2-C≡CH, -CH(CH3)C≡CH, and the like. [0251] The terms "(C3-12)cycloalkyl" and "(C3-ι0)cycloalkyl" refers to one or more saturated cyclic hydrocarbons having from 3-12 or 3-10 carbon atoms, respectively, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
[0252] The term "(C5.ιo)cycloalkenyl" refers to a radical of one or more cyclic hydrocarbon having at least one double bond having from 5-10 carbon atoms such as, but not limited to, cyclopentenyl, cyclohexenyl, and the like.
[0253] The term "cycloalkylene" refers to a "cycloalkyl" group which has single bonds for attachment at two different carbon atoms.
[0254] The terms "(Cι-6)alkylaminocarbonyl" and "di-(Cι_6)alkylaminocarbonyl" refer to straight or branched chain hydrocarbon groups having 1 to 6 carbon atoms connected to NC(=O). Exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like.
[0255] The term "(Cι- )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 (C3-8)cycloalkylcarbonyl refers to cyclic hydrocarbon groups having 3 to 8 carbon atoms connected to C(=O). Exemplary cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[0257] The terms "(Cι-10)alkoxy", "(C,-8)alkoxy" and "(d-6)alkoxy", alone or in combination, refers to "O" 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 isopφoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
[0258] The term "aryloxy" refers to an aryl group bonded to O.
[0259] The term "alkanoyl", alone or as part of another group, refers to alkyl linked to a carbonyl group.
[0260] The term "alkylene" refers to alkyl groups which have single bonds for attachment at two different carbon atoms.
[0261] The term "alkenylene" refers to alkenyl groups which have single bonds for attachement at two different carbon atoms.
[0262] The terms "alkynylene" refers to alkynyl groups which have single bonds for attachement at two different carbon atoms.
[0263] The term "aryl" refers to monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring systems having 6 to 14 carbon atoms in the ring portion. Examples of aryl groups include but are not limited to phenyl, naphthyl, biphenyl, anthracenyl, azulenyl, and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems including 1,2,3,4-tetrahydro-naphthyl, indanyl and the like.
[0264] The term "heteroaryl" as used herein includes heterocyclic unsaturated ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur. Examples of heteroaryl groups include but are not limited to furyl, thienyl, pyπolyl, and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.
[0265] Examples of "aryl" and "heteroaryl" includes but are not limited to phenyl, biphenyl, indenyl, naphthyl (1 -naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1 -anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyπolyl (2-pyπolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1 -imidazolyl, 2-imidazolyl, 4- imidazolyl, 5 -imidazolyl), triazolyl (1,2,3-triazol-l-yl, l,2,3-triazol-2-yl l,2,3-triazol-4-yl, l,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2 -pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5 -pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2- benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro- benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro- benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro- benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro- benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro- benzo[b]thiophenyl), indolyl (1 -indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1 -indazolyl, 3 -indazolyl, 4-indazolyl, 5 -indazolyl, 6-indazolyl, 7- indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5- benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1- benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4- benzothiazolyl, 5 -benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1- carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H- dibenz[b,f]azepin-l-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H- dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,1 l-dihydro-5H-dibenz[b,f]azepine (10,1 l-dihydro-5H-dibenz[b,f]azepine-l-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,l l-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.
[0266] The terms "arylalkenyl" and "arylalkynyl" alone or as part of another group refer to alkenyl and alkynyl groups as described above having an aryl substituent.
I l l [0267] The terms "halogen" and "halo" refers to chloro, fluoro, bromo or iodo.
[0268] The term "alkylamino", "arylamino", or "arylalkylamino" alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
[0269] The term "substituted amino" as employed herein alone or as part of another group refers to amino substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted with any of the groups as set out above. In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyπolidinyl, 1 -piperidinyl, 1-azepinyl, 4-moφholinyl, 4- thiamoφholinyl, 1-piperazinyl, 4-alkyl-l-piperazinyl, 4-arylalkyl-l-piperazinyl, 4- diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1 -piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
[0270] The terms "alkylthio", "arylthio" or "aralkylthio" alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.
[0271] The term "acyl" by itself or part of another group refers to an organic radical linked to a carbonyl group; examples of acyl groups include any of the groups attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl, and the like.
[0272] The term "cycloheteroalkyl" alone or as part of another group refers to a 3-, 4-,
5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)g (where g is 1, 2 or 3). The above groups may include 1 to 4 substituents such as alkyl, halo, oxo, and the like. In addition, any of the cycloheteroalkyl rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring. [0273] The term "cycloheteroalkylalkyl" alone or as part of another group refers cycloheteroalkyl groups as defined above linked through a carbon atom or heteroatom to a (CH2)r chain.
[0274] The term "heteroarylalkyl" or "heteroarylalkenyl" alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to a (CH2)r chain, alkylene or alkenylene as defined above.
[0275] The phrase "naturally occuπing α-amino acid sidechain" refers to the moieties
(sidechains) attached to the α-amino carbon in the following naturally occuπing α-amino acids: glycine, alanine, 2-aminobutyric acid, valine, leucine, isoleucine, tert-leucine, serine, threonine, cysteine, asparagine, aspartic acid, glutamine, glutamic acid, phenylalanine, histidine, tryptophan, tyrosine, phenylglycine, lysine, methionine, and arginine. The side chains of these amino acids are well known in the art. For example, the α-amino acid sidechain of alanine is methyl; the sidechain of phenylalanine is benzyl; and the sidechain of tert-leucine is tert-butyl.
[0276] The term "polyhaloalkyl" refers to an "alkyl" group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF3CH2, CF3 or CF3CF2CH2.
[0277] The term "polyhaloalkoxy" refers to an "alkoxy" or "alkyloxy" group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF3CH2O, CF3O or CF3CF2CH2O.
[0278] The terms "polycyclic" and "polycycle" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls, heteroaryls and or cycloheteroalkyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings." Fused rings that are joined through nonadjacent atoms, are also known as "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, trifluoromethyl, cyano, or the like.
EXAMPLES
[0279] A further detailed description of the invention is given with reference to the following non-limiting examples.
Example 1 Synthesis of (2R)-boroPro-(lS,2S,3R,5S)-pinanedιol ester, hydrochloride (2)
[0280] A flame dried round bottom flask equipped with a magnetic stir bar was charged with N-Boc-pyπolidine (20 g, 117 mmol, 1 eq) and dry THF (60 mL) under a nitrogen atmosphere. The clear colorless solution was cooled to -78 °C and a solution of s- BuLi (100 mL of a 1.4 M solution in cyclohexane, 140 mmol) was added slowly over a 30 minute period. The light orange colored solution was stiπed at -78°C for 3 hours followed by treatment with B(OMe)3 (39 mL, 350 mmol) after which the cooling bath was removed and the clear colorless solution slowly warmed to 0°C. Upon reaching 0°C, the reaction was quenched with a small amount of water (~2 mL), allowed to warm to room temp then extracted into 2 N NaOH (250 mL) and backwashed with additional EtOAc (150 mL). The aqueous phase was acidified to pH 3 by the addition of 2 N HC1 and then extracted with EtOAc (3 x 120 mL). The organic extracts were combined and dried over Na2SO and concentrated to produce the free boronic acid (22.08 g, 103 mmol) as a sticky white solid in 88% yield. Without further purification the boronic acid was dissolved in tert-butyl methyl ether (150 mL) and with constant stirring (+)-pinanediol (17.5 g, 103 mmol) was added at room temperature. After 18 hr the ether was removed and the (+)-pinanediol boronic ester was purified by column chromatography (silica gel, 1 :3 hexanes/EtOAc) to give a clear thick oil (26.84 g, 76.8 mmol, 76% yield, Rf = 0.6 using a 2:1 hexane/ethyl acetate eluant, made visual via I and/or PMA stain). Removal of the Boc protecting group was achieved by dissolving the oil in dry ether, cooling to 0°C in an ice bath and with constant stiπing dry HC1 (g) was bubbled into the solution for 10 minutes. After 2 hours a white precipitate developed in the flask and the ether and excess HC1 were removed in vacuo to afford the racemic HC1 salt as a white solid. Crystallization and isolation of the desired isomer was performed by dissolving the HC1 salt in a minimal amount of dichloromethane (250 mL) with gentle heating to facilitate a homogenous solution followed by continuous stirring for 8 hours to yield a fluffy white precipitate that was collected by vacuum filtration, dried and then dissolved in minimal 2-propanol (-200 mL) with gentle heating until homogenous. The alcoholic solution was stiπed 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). 1H NMR (400 MHz, D2O) δ 4.28 (d, J= 8.0 Hz, IH), 3.06 (m, 3H), 2.18 (m, IH), 1.96 (m, 2H), 1.78 (m, 3 H), 1.62 (m, 2H), 1.21 (s, 3H), 1.05 (m, 5H), 0.84 (d, 7=12 Hz, 2H), 0.71 (s, 2H), 0.62 (s, 3H).
Example 2 Synthesis Of Series A Compounds: (2R)-l-(2-Cvclopentylamino-acetyl)-boroPro-OH { )
Step 1: (2R)-l-(2-ChloroacetyI)-boroPro-(lS,2S,3R,5S)-pinanediol ester (3 A). [0281] To a solution of 2 (36.7 g, 129.3 mmol) dissolved in dry CH2C12 (200 mL) cooled to 0°C was added chloroacetyl chloride (12.34 mL, 155.2 mmol) under a blanket of N2. To this was slowly dripped 4-methylmoφholine (42.4 mL, 182 mmol) to give an almost clear light orange solution that was warmed to room temp. After 30 minutes the solution was cooled again to 0°C and 200 mL of a 0.2 N solution of HC1 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, Rf = 0.22, made visual via I2 and/or PMA stain) and was used in the next step without further purification. 1H NMR (400 MHz, CDC13) δθ.80 (s, 3 H), 1.25 (m, 1 H), 1.26 (s, 3 H), 1.42 (s, 3H), 1.75-1.96 (m, 4 H), 1.98-2.10 (m, 3 H), 2.12-2.20 (m, 1 H), 2.29- 2.35 (m, 1 H), 3.12-3.16 (m, 1 H), 3.47-3.53 (m, 1 H), 3.58-3.63 (m, 1 H), 3.97-4.05 (q, 2 H), 4.30-4.32 (d, 1 H).
Step 2: (2R)-l-(2-Cyclopentylamino-acetyl)-boroPro-(lS,2S,3R,5S)-pinanedioI ester (3B).
[0282] Compound 3A was dissolved in dry THF (-150 mL) followed by addition of
K2CO3 (35 g) and cooled to 0°C before addition of cyclopentylamine (21.93 g, 258 mmol).
The reaction mixture was then allowed to warm to room temperature and stiπed overnight.
TLC indicated all starting material was consumed. The mixture was filtered through a celite and silica pad, washed with 5% MeOH in CH2CI2 (200 mL) and concentrated to yield a sticky, light orange solid. The red sticky solid was dissolved in CH2CI2 (150 mL) followed by addition of Et2θ (-200 mL) and the solution was stiπed overnight. The resulting milky white solution was then filtered and the precipitate was washed with cold EtOAc (2 x 60 mL) and hexane (2 x 50 mL) and dried to give 3B (28.92 g, 120.5 mmol) as a fluffy white solid. The dark red mother liquor filtrate was concentrated and subjected to the previous recrystallization conditions to obtain a second crop of 3B (6.17 g, 25.7 mmol) for a combined overall yield of 3B (35.09 g, 93.8 mmol) of 73% yield. Rf = 0.45 (10% MeOH in CH2C12). Η NMR (400 MHz, CDC13) δ 4.18 (d, IH), 3.95 (d, J= 16 Hz, IH), 3.6 (d, J= 16 Hz, IH), 3.46 (m, 3H), 2.74 (m, IH), 2.36 (m, IH), 2.16 (m, 2H), 2.04 (m, 4H), 1.90 (s, IH), 1.74 (m, 6H), 1.61 (s, IH), 1.46 (m, 2H), 1.34 (s, 3H), 1.30 (s, 3H), 0.88 (s, 3H).
Step 3: (2R)-l-(2-Cyclopentylamino-acetyl)-boroPro-OH (4)
[0283] To a solution of 3B (40.59 g, 108.5 mmol) in H2O (200 mL, adjusted to pH 2 by addition of 2 N HC1) was added hexane (200 mL) and phenyl boronic acid (13.37 g, 109.5 mmol) and the bi-phasic mixture was stiπed 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+ foπn) 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 1H NMR (400 MHz, D2O) δ 3.88 (dd, J= 8.0 Hz, 2H), 3.54 (m, IH), 3.42 (m, IH), 3.28 (m, IH), 2.96 (m, IH), 1.96 (m, 4H), 1.85 (m, 2H), 1.63 (m, 7H); MS (ESI) m/z 223 (M+H-H2O)+.
Example 3 Synthesis of l-(2-CvcIopropylamino-acetyl)-pyrrolidine-(2R)-boronic acid. (A2):
[0284] The title compound was prepared according to the procedure of Example 2 using appropriate starting materials. 1H NMR (D2O) δ 4.08 (dd, j = 12 Hz, 2 H), 3.54 (m, IH), 3.38 (m, IH), 3.07 (m, IH), 2.26 (m, IH), 2.09 (m, 2H), 1.94 (m, IH), 1.71 (m, IH), 0.88 (s, 4H); MS (ESI) m/z 195.13 (MH+-H2O).
Example 4 Synthesis of l-[2-(3-Hvdroxy-adamantan-l-ylamino)-acetyll- pyrrolidine-(2/?)-boronic acid (A3):
[0285] The title compound was prepared according to the procedure of Example 2 using appropriate starting materials. 1H NMR (D2O) δ 3.94 (d, J= 8 Hz, 2H), 3.54 (m, IH), 3.40 (m, IH), 3.09 (m, IH), 2.41 (s, 2H), 2.09 (m, 3H), 1.93 (m, 2H), 1.87 (m, 7H), 1.71 (m, 6H), 1.56 (m, 2 H); MS (ESI) m/z 305.21 (MH+-H2O).
Example 5 Synthesis of l-(5R-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (6):
Step 1: N-Boc-5-phenylPro-(2R)-boroPro-(lS,2S,3R,5S)-pinanediol ester (5):
[0286] To an ice-cooled (0°C) solution of N-Boc-5-phenyl-Pro-OH (0.84 mmol) in dry
CH2C12 was added EDAC (174 mg, 0.91 mmol) and HOBt (105 mg, 0.775 mmol). The reaction was stiπed at 0°C for 15-minutes and then 2 (200 mg, 0.7 mmol) and N-methyl moφhiline (0.25 mL, 2.1 mmol) was added and the reaction was slowly warmed to room temperature and the reaction continued for 8 hours. The coupling reaction was then quenched with the addition of NaHCO3 (10 mL), extracted into EtOAc (2 15 mL), washed with brine (15 mL), dried over Na2SO4, 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: l-(5R-Phenyl-pyrrolidine-2S-carbonyl)-pyrro!idine-(2R)-boronic acid (6):
[0287] An ice-cooled solution of 5 (320 mg, 0.62 mmol) in dry ether was saturated with dry HC1 (g) and allowed to stir for 1-hour. The solution was then concentrated under vacuum to afford a sticky white solid that was taken up in H2O (10 mL, adjusted to pH 2 by addition of 2 N HC1) and hexane (10 mL) and phenyl boronic acid (74 mg, 0.62 mmol) and the bi-phasic mixture was stiπed 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 Bl (76 mg, 0.26 mmol) as an amoφhous white solid. Η NMR (D2O) δ 7.46 (m, 5H), 3.65 (m, IH), 3.44 (m, IH), 3.04 (m, IH), 2.54 (m, IH), 2.38 (m, 2H), 2.20 (m, IH), 2.06 (m, 2H), 1.86 (m, IH), 1.66 (m, IH); MS (ESI) m/z 271 (MH+-H2O). Example 6 Synthesis of l-(Piperidine-2S-carbonvI)-pyrrolidin-(2R)-boronic acid (B2):
[0288] The title compound was prepared according to the procedure of Example 5 using appropriate starting materials. Η NMR (D2O) δ 4.07 (m, IH), 3.61 (m, IH), 3.34 (m, 2H), 2.94 (m, 2H), 2.16 (m, IH), 2.03 (m, 2H), 1.87 (m, 3H), 1.56 (m, 4H); MS (ESI) m/z 209 (MH+-H2O).
Example 8 Synthesis of l-(2,3-Dihvdro-lH-indole-2S-carbonyl)-pyrrolidine-(2R)-boronic acid {Mil
[0289] The title compound was prepared according to the procedure of Example 5 using appropriate starting materials. Η NMR (D2O) δ 4.54 (m, IH), 3.73 (m, IH), 3.58 (m, IH), 3.34 (m, IH), 2.48 (m, IH), 2.37 (m, IH), 2.06 (m, 3H), 1.83 (m, 3H), 1.58 (m, 4H), 1.32 (m, 4H); MS (ESI) m/z 249 (MH+-H2O).
Example 9 Synthesis of l-(4S-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid ΪM
[0290] The title compound was prepared according to the procedure of Example 5 using appropriate starting materials. 1H NMR (D2O) δ 7.34 (d, J = 13 Hz, 2H), 7.27 (m, 3H), 4.79 (m, IH), 3.83 (m, 1H),3.59 (m, IH), 3.34 (m, 2H), 3.06 (m, IH), 2.53 (m, 2H), 2.08 (m, 2H) 1.77 (m, IH), 1.64 (m, IH); MS (ESI) m/z 271 (MH+-H2O).
Example 10 Synthesis of (2R)-l-{2-[(3S)-Pyrrolidin-3-yIamino]-acetyl}-pyrrolidine-2-boronic acid (8)
Figure imgf000120_0001
Step 1 : (2R)-l-{2-[(3S)-l-tert-Butoxycarbonyl-pyrroIidin-3-ylamino]-acetyI}- pyrrolidine- 2-boronic acid (lS,2S,3R,5S)-pinanediol ester (7)
[0291] The protocol described above for the synthesis of 3B was followed employing
(3S)-3-amino-pyπolidine-l -carboxylic acid tert-butyl ester in place of cyclopentylamine. Compound 7 was obtained as an oil.
(2R)-l-{2-[(3S)-Pyrrolidin-3-ylamino]-acetyl}-pyrroIidine-2-boronic acid (8)
[0292] The protocol described above for the deprotection of the pinanediol boronic ester 3B (Example 2, Step 3) was applied to 7. Compound 8 was obtained as a white solid. 8-TFA salt. 1H-NMR (500 MHz, CD3OD) δ 4.12 (m, 3H), 3.76 (m, IH), 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 mlz (rel intensity) 241 (M) (27), 224 (100), 209 (73), 155 (47). Example 11 Synthesis of (2R -{2-[(3R)-Pyrrolidin-3-ylaminol-acetyl}-pyrrolidine-2-boronic acid (10)
Figure imgf000121_0001
Step 1 : (2R)-l-{2-[(3R)-l-tert-Butoxycarbonyl-pyrrolidin-3-ylamino]-acetyl}- pyrrolidine-
2-boronic acid (lS,2S,3R,5S)-pinanediol ester (9).
[0293] The protocol described above for the synthesis of 3B was followed employing
(3i?)-3-amino-pyπolidine-l-carboxylic acid tert-butyl ester in place of cyclopentylamine. Compound 9 was obtained as an oil. MS mlz (rel intensity) 476 (M + 1)+ (100), 376 (74), 239 (38), 224 (67), 155 (55).
Step 2: (2R)-l-{2-[(3R)-Pyrrolidin-3-yIamino]-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. 1H-NMR (500 MHz, CD3OD) δ 4.13 (m, IH), 4.08 (bs, 2H), 3.76 (dd, J= 13.0, 8.0 Hz, IH), 3.55 (m, 3H), 3.41 (m, 2H), 3.27 (m, IH), 2.53 (m, IH), 2.26 (m, IH), 2.10 (m, 2H), 1.99 (m, IH), 1.75 (m, IH). MS mlz (rel intensity) 224 (M-17) (100), 206 (25), 180 (29), 155 (70). Example 12 Synthesis of Series B Compounds: (2R)-l-f(2S)-Azetidine-2-carbonyll-boroPro-OH (12)
Step 1 : (2R)-l-[(2S)-l-tert-ButoxycarbonyI-azetidine-2-carbonyl]-boroPro- (lS,2S,3R,5S)-pinanediol ester (11)
[0295] To a solution of (2S)-azetidine- 1 ,2-dicarboxylic acid 1 -tert-butyl ester (169 mg,
0.8 mmol) in CH2C12 (5 mL) was added HOBt (105 mg, 0.8 mmol) and EDC (174 mg, 0.9 mmol). The reaction solution was then cooled to 0 °C in an ice bath for 10 min followed by sequential addition of 2 (200 mg, 0.7 mmol) and NMM (0.25 mL, 2.1 mmol). The reaction solution was allowed to warm up to room temperature and stiπed overnight. The reaction mixture was diluted with additional CH2C12 (5 mL), washed with NaHCO3 (2 x 10 mL), 0.1 M aqueous HC1 (5 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The resulting oily residue was purified by column chromatography (silica gel, solvent eluent gradient from 1 :4 EtOAc/hexane to 1 :2 EtOAc/hexane) to afford 11 as a clear viscous oil.
Step 2: (2R)-l-[(2S)-Azetidine-2-carbonyl]-boroPro-OH (12)
[0296] A solution of compound 11 in 4N HC1 in dioxane was stiπed at room temperature for 4 h. The solvent was removed under vacuum and the resulting residue was submitted to the pinanediol ester deprotection protocol described above for the preparation of boronic acid 4. Compound 12 was obtained as a white solid. 12-TFA salt Η-NMR (500 MHz, D2O) δ 5.23 (m, IH), 4.11 (m, IH), 3.90 (m, IH), 3.42 (m, IH), 3.18 (m, IH), 2.99 (m, IH), 2.79 (m, IH), 2.55 (m, IH), 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: (2R)-l-[(2S,4S)-4-Amino- pyrrolidine-2-carbonvn-boroPro-OH (15)
Step 1 : (2R)-l-[(25,4S)-l-tert-Butoxycarbonyl-4-benzyloxycarbonyIamino- pyrrolidine-2-carbonyl]-boroPro-(lS,25,3R,55)-pinanediol ester (13)
[0297] The protocol described for the synthesis of 11 was followed employing (2S,4S)-
Fmoc-4-amino-l-boc-pyπOlidine-2-carboxylic acid (628 mg, 2.2 mmol) in place of azetidine-l,2-dicarboxylic acid 1 -tert-butyl ester. Compound 13 was obtained as a clear colorless oil that was used in the next step without further purification.
Step 2: (2R)-l-[(2S,45)-l-tert-Butoxycarbonyl-4-amino-pyrrolidine-2-carbonyl]- boroPro-(lS,2S,3R,5S)-pinanediol ester (14)
[0298] To a solution of 13 dissolved in DCM (10 ml) was added diethyl amine (5 ml) at once and the resulting colorless solution was stiπed overnight at room temperature. The reaction was evaporated to dryness and additional DCM was added followed by evaporation once again to dryness. The resulting oil was purified by column chromatography (silica gel, eluted with a gradient of 2.5 to 5% MeOH in DCM, made visible by I2 and/or PMA) to give 14 as a clear colorless oil in a 48% yield over 2 steps.
Step 3: (2R)-l-[(2S,4S)-4-Amino-pyrroIidine-2-carbonyl]-boroPro-OH (15)
[0299] The protocol described above for the N-Boc deprotection and pinanediol ester hydrolysis in the synthesis of compound 12 was applied to 14. Compound 15 was obtained as a white solid. 15-TFA salt Η-NMR (500 MHz, D2O) δ 4.42 (dd, IH), 3.87 (m, IH), 3.5 (dd, IH), 3.28 (m, 2H), 3.07 (m, IH), 2.73 (m, IH), 2.64 (m, IH), 1.86 (m, IH), 1.72 (br m, 2H), 1.55 (br m, 2H), 1.34 (m, 2H). MS mlz (rel intensity) 228 (M + 1) (55), 210 (M + 1 - H2O) (95).
Example 14 Synthesis of Series D Compounds: (2R)-l-f(2S)-4-Methanesulfonyl- piperazine-2-carbonvn-boroPro-OH (19)
Step 1 : (2R)-l-[(2S)-l-tert-ButoxycarbonyI-4-benzyloxycarbonyl-piperazine-2- carbonyl]-boroPro-(lS,2S,3R,5S)-pinanedioI ester (16)
[0300] The protocol described above for the synthesis of 11 was followed employing
(2S)-N-l-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 mlz (rel intensity) 618 (M + 23)+ (17), 596 (M + 1)+ (100), 496 (38).
Step 2: (2R)-l-[(2S)-l-tert-Butoxycarbonyl-piperazine-2-carbonyl]-boroPro- (15,2S,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 stiπed under a H2 atmosphere for 2 h. Upon completion of the reaction, it was filtered through a plough of Celite. The solvents were removed under reduced pressure and the oily residue used in the next step without further purification. MS mlz (rel intensity) 462 (M + 1)+ (100), 406 (12), 362 (11).
Step 3: (2R)-l-[(2S)-l-tert-Butoxycarbonyl-4-methanesulfonyl-piperazine-2- carbonyl]-boroPro-(lS,2S,3R,5S)-pinanediol ester (18)
[0302] To a solution of compound 17 (214mg, 0.46 mmol) in CH2C12 (5 mL) cooled to
0 °C was sequentially added N-methylmoφholine (204 μL, 1.9 mmol) and methanesulfonyl chloride (72 μL, 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 CH2C1 (6 ml) and water (6 mL). The organic phase was isolated and dried over MgSO4. After filtration, solvents were removed under reduced pressure. The oily residue was purified by column chromatography (silica gel) using a mixture of EtOAc/Hexanes as eluent. Compound 18 (112 mg, 0.21 mmol) was obtained in 45% yield. MS mlz (rel intensity) 562 (M + 23)+ (14), 540 (M + l) (100), 388 (75).
Step 4: (2R)-l-[(2S)-4-Methanesulfonyl-piperazine-2-carbonyl]-boroPro-OH (19)
[0303] The protocol described above for the N-Boc deprotection and pinanediol ester hydrolysis in the synthesis of compound 12 was applied to 18 (112 mg, 0.21 mg). Compound 19 (32 mg, 0.11 mmol) was obtained in 53% yield. 19 TFA salt Η-NMR (500 MHz, D2O) δ 4.32 (dd, J= 11.0, 3.5 Hz, IH), 4.05 (m, IH), 3.93 (m, IH), 3.77 (m, IH), 3.60 (ddd, J= 10.5, 8.0, 2.5 Hz, IH), 3.47 (ddd, J= 12.5, 3.0, 3.0, IH), 3.35 (m, 2H), 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, IH), 1.72 (m, IH), 1.56 (m, IH). MS mlz (rel intensity) 575 (12), 328 (M + 23)+ (6), 288 (M - 17) (100).
Example 15 Synthesis of Series F Compounds: (2R)-l-{2-f(3S)-Pyrrolidin-3-ylamino1- acetyll-boroPro-OH (21)
Step 1 : (2R)-l-{2-[(3S)-l-tert-Butoxycarbonyl-pyrrolidin-3-ylamino]-acetyl}-boroPro- (lS,2S,3R,5S)-pinanediol ester (20)
[0304] The protocol described above for the synthesis of 3B was followed employing
(3S)-3-amino-pyπolidine-l -carboxylic acid tert-butyl ester in place of cyclopentylamine. Compound 20 was obtained as an oil.
Step 2: (2R)-l-{2-[(3S)-Pyrrolidin-3-ylamino]-acetyl}-boroPro-OH (21) [0305] The protocol described above for the N-Boc deprotection and pinanediol ester deprotection of compound 12 was applied to 20. Compound 21 was obtained as a white solid. 21-TFA salt 1H-NMR (500 MHz, CD3OD) δ 4.12 (m, 3H), 3.76 (m, IH), 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 mlz (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
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Example 17 Dependence of Aminoboronate and Boronic Acid Forms of Inventive Compounds on pH [0307] A 0.4 M stock solution of Na2HPO4 was prepared by dissolving 909 mg of salt in 16 mL of D2O. pH was adjusted to the desired value by dropwise addition of either 20% DC1 in D O or 5% DC1 in D2O. 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 Η-NMR spectra in a Varian AS 500 MHz instrument and measuring the ratio of the integrals of the peaks at 2.90-2.95 ppm and 2.40-2.50 ppm characteristic of the open and closed forms, respectively. FIG. 1 shows that the closed form predominates at higher pHs such as physiological pH, whereas the open form predominates at lower pHs.
Example 18
[0308] The final compounds of Examples 1-16 were tested in vitro as described herein and each displayed an IC50 or K, of 10 μM or less.
[0309] 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 incoφorated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
[0311] 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.
[0312] In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described.
[0313] Other embodiments are set forth within the following claims.

Claims

CLAIMS What is claimed is:
1. A compound of formula I:
Figure imgf000140_0001
including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein: n is 1 to 3; X is CH2; S; O; CF2 or C(CH3)2; Z is H; halogen; hydroxyl; (Cι-6)alkoxy; (Cι-ι2)alkyl; (C3-ι2)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; R1 and R2 independently or together are hydrogen; a boronic acid protecting group; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; CR'R" may be present or absent, wherein if CR'R" is present, then R1, R", R3, R4 and R5 are selected from (aa), (bb) or (cc): (aa) R", R", R3 and R4 are hydrogen; and R5 is a) hydrogen; b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cι-6)alkyl; (C[.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 R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8) 2; -OR8; or -S-R8; R is halogen; (Cι-1o)alkyl; (Cι-ιo)alkoxy; (C1-10)alkylamino; (Cι-10) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluorornethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3- 10)cycloalkyl; (C5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R ; c) aryl optionally fused to a (C3-ι0)cycloalkyl; or heteroaryl optionally fused to a (C3-ι0)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4- pentylbicyclo[2.2.2]oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (Cι-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene; e) Rn(CH2)p- where R11 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Cι-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently 17 • trisubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; and p is 0 to 3; R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Ci- 6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; g) a group of the formula: R15 I > 14' ^(CH2)r-
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (Cι-6)alkylcarbonyl; (C - ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 2 to 6; h) a group of the formula:
Figure imgf000142_0001
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι_ 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
Figure imgf000143_0001
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι. 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and 1 1 8 phenylsulfonyl groups are optionally mono- or independently di-substituted with R ; or R and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH2-C(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; k) a group f:
Figure imgf000143_0002
where R20 is hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (C1-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (Cι-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (Cι-8)alkyl, (Cι-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
Figure imgf000143_0003
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; (bb) R1, R", R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R1 together with R3 or R4, or R" together with R3 or R4, and the atoms to which they are attached form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2; and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa); or R4 and R5 together form -(CR 2R23)m- where m is 2 to 6, and R22 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 R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (cc) R1 and R3 are hydrogen; and R" and R4 together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa) or (bb) and R5 is any of the groups in (aa) or (bb); and if CR'R" is absent, then R3, R4 and R5 are selected from (dd), (ee) or (ff): (dd) R3 and R4 are hydrogen; and R5 is a) hydrogen, provided that R5 is not hydrogen when n is 1, X is CH2, and Z is H; b) (C,-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3- ι2)cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8)2; -OR8; or -S-R8; R is halogen; (Cι-ιo)alkyl; (Cι-ιo)alkoxy;
Figure imgf000145_0001
(Ci-io) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (C,-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3- ιo)cycloalkyl; (C5-ι0)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R ; c) aryl optionally fused to a (C3-ι0)cycloalkyl; or heteroaryl optionally fused to a (C3-ι0)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R ; 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-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (Cι-8)alkoxy, (Cι-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (Cι.g)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene; e) Rn(CH2)p- where R11 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι- )alkyl, (C1- )alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; and p is 0 to 3; 1 ") R is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; g) a group of the formula:
Figure imgf000147_0001
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 2 to 6; h) a group of the formula:
Figure imgf000147_0002
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-ι )cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
Figure imgf000147_0003
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι. 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; k) a group of the formula:
Figure imgf000148_0001
where R20 is hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (Cι-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (C^alkyl, (Cι-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
Figure imgf000148_0002
where R2' is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; or (ee) R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl, provided that when n is 1, X is CH2, the ring containing X is saturated, and Z, R3 and R5 are H, R4 is not a side chain of a naturally occurring α-amino acid, and provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R5 are H, R3 and R4 are not both methyl; or R4 and R5 together form -(CR22R23)m - where m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl; halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino; arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylamino; provided that when n is 1, X is CH2, the ring containing X is saturated, Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2) -; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (ff) R3 is hydrogen; and R4 and 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, O, S, SO and SO2, wherein the heterocyclic ring system is optionally mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; and wherein a bond containing a wavy line signifies a point of attachment.
2. The compound of claim 1 wherein R1 and R2 independently or together are the boronic acid protecting group formed from (+)-pinanediol; pinacol; 1,2-dicyclohexyl- ethanediol; 1,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3-butanediol, dusopropyl tartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6-decanediol; 1,1,2-triphenyl- 1,2- ethanediol; (2R,3R)-l,4-dimethyoxy-l,l,4,4-tetraphenyl-2,3-butanediol; methanol; ethanol; isopropanol; catechol; or 1-butanol.
3. The compound of claim 1 wherein R and R independently or together are a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids formed from 1,2-dicyclohexylethanediol; 1,2- ethanediol; 1,3-propanediol; 2,3-butanediol, 1,4-butanediol; diisopropylethanediol; methanol; ethanol; isopropanol; or 1-butanol.
4. The compound of claim 1 wherein if CR'R" is absent, then R3, R4 and R5 are selected from (dd), (ee) or (ff): (dd) R3 and R4 are hydrogen; and R5 is a) (C,-12)alkyl; (C2-ι2)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8)2; -OR8; or -S-R8; R7 is halogen; (Cι-ιo)alkyl; (Cι-1o)alkoxy; (Cι.ιo)alkylamino; (Ci-io) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3- ιo)cycloalkyl; (C5-ι0)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; b) aryl optionally fused to a (C3-ι0)cycloalkyl; or heteroaryl optionally fused to a (C3-ιo)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R ; c) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4- pentylbicyclo[2.2.2]oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (Cι-8)alkoxy, (Cι-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (Cι-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Cι- )alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene; d) Rn(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Cι-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 (C1-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; and p is O to 3; R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Q. 6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is O to 3; f) a group of the formula: R15 I R1 ^ ^(CH2)r -
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 2 to 6; g) a group of the formula:
Figure imgf000152_0001
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Q^alkylcarbonyl; di-(Cι. 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6; h) a group of the formula:
Figure imgf000152_0002
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι- 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; i) a group of the formula: (phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; j) a group of the formula:
Figure imgf000152_0003
where R20 is hydrogen; (Cι- )alkyl; (Cι-6)alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-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 19 independently di-substituted with R ; Rx is hydrogen; (Cι-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently 1 di-substituted on the ring with R ; R is absent or is halogen, (Cι-8)alkyl, (Cι-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or k) a group of the formula:
Figure imgf000153_0001
1 * where R is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; or (ee) R3 and R4 are independently hydrogen, alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; R5 is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R4 and R5 together form -(CR22R23)m - wherein m is 2 to 6, and R22 9" 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; provided that when n is 1, X is CH2, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (ff) R3 is hydrogen; and R4 and R5 together with the atoms to which they are attached form a 4 to 8 member mono- or polycyclic heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, wherein the heterocyclic ring system is optionally mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-.
5. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is (C 2)alkyl; (C2- ι2)alkenyl; (C2-ι2)alkynyl; (C3-ι2)cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
6. The compound of claim 5 wherein R5 is (Cι-12)alkyl or (C3-ι )cycloalkyl.
7. The compound of claim 6 wherein R5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, or adamantyl.
8. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is indanyl; 1,2,3,4- tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]-oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (Cι-8)alkoxy, (Cι-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (Cι_ 8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Cι-8)alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C -6)alkylene.
9. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is RU(CH2)P- where R11 is 2-oxopyrrolidinyl;
Figure imgf000155_0001
phenyl; phenoxy; (C1- )cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2- oxopyrrolidinyl, ( -6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- • 19 or independently di- or independently trisubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl,
Figure imgf000155_0002
or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι_ 6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
10. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR'R" is absent; R1, R2, R3 and R4 are hydrogen; and R5 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
11. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
R15
> 14" ^(CH2)r-
where R14 and R15 are independently hydrogen; (C1-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C -ι2)cycloalkyl ring; and r is 2 to 6.
12. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000156_0001
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(C 1- 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C -ι2)cycloalkyl ring; and s is 1 to 6.
13. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000157_0001
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; di-(Cι_ 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 R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3.
14. The compound of claim 13 wherein R5 has formula:
Figure imgf000157_0002
15. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
(phenyl-CH2-C(CH3)2-),
where the phenyl group is optionally mono- or independently plurisubstituted with R12.
16. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000158_0001
where R20 is hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; (C - )cycloalkylcarbonyl; benzyl; benzoyl; (Cι.6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (Cι-8)alkyl; (C3-12) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (C1-8)alkyl, (C1-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or
17. The compound of claim 16 wherein R has formula:
Figure imgf000158_0002
18. The compound of claim 16 wherein R is
Figure imgf000158_0003
19. The compound of claim 18 wherein R5 is
Figure imgf000159_0001
H or H
20. The compound of claim 16 that has the formula:
OH N \ N OH OH
HN^ or HN^
21. The compound of claim 16 that has the formula:
Figure imgf000159_0002
22. The compound of claim 1 wherein X is CH2; the ring containing X is saturated; CR'R" is absent, R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000159_0003
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3.
23. The compound of claim 22 wherein R5 has formula:
Figure imgf000160_0001
1 9 24. The compound of claim 1 wherein R and R are hydrogen; n is 1; X together with an adjacent ring carbon and Z form a fused cyclopropyl; CR'R" is absent; are hydrogen; and R5 R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R4 and R5 together form -(CR22R23)m- where m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl; halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino; arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylamino; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto.
25. The compound of claim 1 that has formula:
Figure imgf000161_0001
26. The compound of claim 1 that has formula:
Figure imgf000161_0002
27. The compound of claim 1 that has formula:
Figure imgf000161_0003
28. The compound of claim 1 that has formula:
Figure imgf000161_0004
29. The compound of claim 1 wherein R 1 , R r> 2 , R τ>3 a „n„dj R D 4 are hydrogen; n is 1 ; X is CH2; CR'R" is absent; and R5 is aryl or aralkyl.
30. The compound of claim 1 wherein if CR'R" is present, R' and R3 are hydrogen; R" and R4 together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa) or (bb) and R5 is any of the groups in (aa) or (bb); or if CR'R" is absent, then R3 is hydrogen; and R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X is CH , the ring containing X is saturated, and Z and R3 are hydrogen, R4 and R5 together are not -(CH2)2- or -(CH2)3-.
31. The compound of claim 30 that has formula II:
Figure imgf000162_0001
wherein: Y is O, S, CHR25 or NR26; k is 0 to 3 and m is 0 to 3 when Y is CHR25; k is 2 to 3 and m is 1 to 3 when Y is O or NR26; each R24 is independently: a) hydrogen; b) (C,-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3- ]2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are 19 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 R12; d) Rπ(CH2)p- where R11 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι- )alkylcarbonyl; (C3-ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2-oxopyrrolidinyl, (Ci. 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently 19 • di- or independently trisubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with (Cι- )alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are 19 independently optionally mono- or independently disubstituted with R ; and q is 0 to 3; f) a group of the formula:
Figure imgf000163_0001
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6; or g) a group of the formula:
Figure imgf000163_0002
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 1 to 6; R25 is: a) hydrogen; b) (Ci-i2)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3- 12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are 19 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 19 mono- or independently plurisubstituted with R ; d) Rπ(CH2)p- where R11 is 2-oxopyrrolidinyl; (Cj-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι-8)alkylcarbonyl; (C3-ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2-oxopyrrolidinyl, (Cι_ 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-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 ; e) (R )2CH(CH2)q-, where R is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula: R15 I < ^(CH2)t — % where R14 and R15 are independently hydrogen; (C] -8)alkyl; (Cι-6)alkylcarbonyl; (C - ι2)cycloalkyl ring; (C -ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-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 R14 and R15 together form a (C3-ι2)cycloalkyl ring; and t is 0 to 6; or g) a group of the formula:
R21— o— (CH2),-
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6; and R26 is: a) hydrogen; b) (Cι-ι2)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3.12) cycloalkyl; or (C3- ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally 19 mono- or independently plurisubstituted with R ; d) R27(CH2)P-, where R27 is 2-oxopyπolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι-6)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsufonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2-oxopyrrolidinyl, (Ci- 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsufonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C^alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι.8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-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 ; e) (R13)2CH(CH2)q-, where R13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula:
Figure imgf000166_0001
where R14 and R15 are independently hydrogen; (Cι.8)alkyl; (Cι-6)alkylcarbonyl; (C3- !2)cycloalkyl ring; (C3-i2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C -i2)cycloalkyl ring; and r is 0 or 2 to 6; or g) a group of the formula:
R2I_O_ (CH2),- 1 where R is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 or 2 to 6.
32. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; and R1, R2 and R25 are hydrogen.
33. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is hydrogen, provided that if k, n, and m are each 1, and Y is CHR25, Z is not H.
34. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is (Cι-]2)alkyl; (C2-ι2)alkenyl; (C2-)2)alkynyl; (C -ι2) cycloalkyl; or (C3-i2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
35. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25are hydrogen; and R24 is phenyl optionally mono- or independently plurisubstituted with R12.
36. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25are hydrogen; and R24 is Rπ(CH2)p- where R11 is 2- oxopyrrolidinyl;
Figure imgf000167_0001
phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι-8)alkylcarbonyl; (C3- ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)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 R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι_ )alkyl,
Figure imgf000167_0002
or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
37. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is (Rl3)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
38. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is a group of the formula:
Figure imgf000168_0001
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6.
39. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is a group of the formula:
R 2i_o_ (CH2) -
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 1 to 6.
40. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2 and R24 are hydrogen.
41. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is (Cι-]2)alkyl; (C2-]2)alkenyl; (C2-]2)alkynyl; (C3-ι2) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
42. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is phenyl optionally mono- or independently • 19 plurisubstituted with R .
43. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is Rπ(CH2)p- where R11 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2- oxopyπolidinyl, (Cι-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or • 19 independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
44. The compound of claim 31 wherein X is CH ; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is O to 3.
45. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is a group of the formula:
R15
>14' "\ (CH2)t
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- i2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-i2)cycloalkyl ring; and t is 0 to 6.
46. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is a group of the formula:
R21— 0-(CH2)t — I 91 where R is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6.
47. The compound of claim 31 wherein X is CH ; the ring containing X is saturated; R1, R2, R24 and R26 are hydrogen.
48. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is (d.ι2)alkyl; (C2-ι2)alkenyl; (C2-ι2)alkynyl; (C3-ι2) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
49. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is phenyl optionally mono- or independently 19 plurisubstituted with R .
50. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is R27(CH2)P-, where R27 is 2-oxopyrrolidinyl; (C|-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2- oxopyrrolidinyl, (Cι-6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with
Figure imgf000171_0001
(C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and p is 0 to 3.
51. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is (R13)2CH(CH2)q-; where R13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is O to 3.
52. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula:
R 15
R 14' -(CH2)r-
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- i2)cycloalkyl ring; (C -ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι- )alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 0 or 2 to 6.
53. The compound of claim 31 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula:
R 2i_0 — (CH2),-S
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl 19 groups are optionally mono- or independently di-substituted on the ring with R ; and t is 0 or 2 to 6.
54. The compound of claim 31 that has formula:
Figure imgf000172_0001
55. The compound of claim 54 wherein R25 is phenyl optionally mono- or independently plurisubstituted with R12.
56. The compound of claim 31 that has formula:
Figure imgf000173_0001
57. The compound of claim 31 that has formula:
Figure imgf000173_0002
wherein: 98 90 R and R are each independently hydrogen, hydroxy, alkyl, alkoxy, aryloxy, or halogen.
58. The compound of claim 30 that has formula III:
Figure imgf000174_0001
wherein:
Y is O, S, CHR25 orNR26; k is 0 to 3 and m is 0 to 3 when Y is CHR25; k is 1 to 3 and m is 0 to 3 when Y is NR26; k is 1 to 3 and m is 0 to 3 when Y is O; R is a) hydrogen; b) (C 2)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3- i2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cj-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; - COR8; -CO2R8, -CONHR8; -CON(R8)2; -OR8; or-S-R8; R7 is halogen; (Cι-10)alkyl; (Cι-10)alkoxy; (Cι.ιo)alkylamino; (CMO) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (Cι-ιo)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3-10)cycloalkyl; (C5- ιo)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; c) aryl optionally fused to a (C3-ιo)cycloalkyl; or heteroaryl optionally fused to a (C3-ιo)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)jadamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-l- yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (Cι-8)alkoxy, (Cι-8)alkanoyloxy, or R9R10N-CO-O-5 where R9 and R10 are independently (Cι-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Cι-8)alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3.6)alkylene; e) Rn(CH2)p- where R11 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3>3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Cι-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently 19 trisubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl,
Figure imgf000175_0001
or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; and p is 0 to 3; 19 R is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; f) (R,3)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; g) a group of the formula: R15 I R14^ ^(CH2)r i where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (C\. 6)alkylcarbonyl; (C3.ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 2 to 6; h) a group of the formula:
Figure imgf000176_0001
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (C\. 6)alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C -12)cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
Figure imgf000176_0002
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (Ci. 6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di- 1 18 10 substituted with R ; or R and R together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH2-C(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; k) a group of the formula:
Figure imgf000177_0001
where R20 is hydrogen; (Cι-8)alkyl; (C]-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (Ci-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (Cι- )alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (Cι-8)alkyl, (Cι-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
Figure imgf000177_0002
91 where R is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; each R24 is independently: a) hydrogen; b) (Cι.ι2)alkyl; (C2-ι2)alkenyl; (C2-12)alkynyl; (C3-ι2) cycloalkyl; or (C3- ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R12; d) Ru(CH2)p- where Ru is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι-8)alkylcarbonyl; (C3-ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2-oxopyrrolidinyl, (Cι_ 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; 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; e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula:
Figure imgf000178_0001
where R14 and R15 are independently hydrogen; (Cι_8)alkyl; (C1-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι )cycloalkyl ring; and s is 0 to 6; or g) a group of the formula:
R21— o— (CH2),-
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6; R25 is: a) hydrogen; b) (C 2)alkyl; (C2-12)alkenyl; (C2-i2)alkynyl; (C3-ι2) cycloalkyl; or (C3- ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally 1 mono- or independently plurisubstituted with R ; d) Rn(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cj-8)alkylcarbonyl; (C3-ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2-oxopyrrolidinyl, (Ci. 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with (C1- )alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and 19 R is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula:
Figure imgf000179_0001
where R14 and R15 are independently hydrogen; (Cj-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3.ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι- )alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C -ι2)cycloalkyl ring; and t is 0 to 6; or g) a group of the formula:
R2 — o— (CH2),-
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6; and R26 is: a) hydrogen; b) (Cι-12)alkyl; (C2-ι2)alkenyl; (C2-]2)alkynyl; (C3-12) cycloalkyl; or (C3- 12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R12; d) R27(CH2)P-, where R27 is 2-oxopyπolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι- )alkylcarbonyl; (C3-ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Ci-6)alkyl; where the 2-oxopyrrolidinyl, (Cj. 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R13)2CH(CH2)q-, where R13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula: R15 R1 ^ ^(CH2)r 1
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C]-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 0 or 2 to 6; or g) a group of the formula: ?21_ O— (CH2)t-|
where R21 is hydrogen; (Cι- )alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 or 2 to 6.
59. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; and R1, R2 and R25 are hydrogen.
60. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 and R25 are hydrogen.
61. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25are hydrogen; and R24 is (Cι-ι2)alkyl; (C2-i2)alkenyl; (C2-i2)alkynyl; (C3-ι2) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
62. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is phenyl optionally mono- or independently plurisubstituted with R12.
63. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is R11(CH2)P- where R1 ' is 2- oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cι-8)alkylcarbonyl; (C3- i2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2-oxopyrrolidinyl, (C1- )alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, 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 (Cι_ 4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is 19 optionally mono-or independently plurisubstituted with (C1-8)alkyl; p is 0 to 3; and R is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
64. The compound of claim 58 wherein wherein X is CH2; the ring containing X is saturated; R1, R2 and R25 are hydrogen; and R24 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
65. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R , R and R are hydrogen; and R is a group:
R 15 I .N. R 14' ^(CH2)S
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C - i2)cycloalkyl ring; (C3-i2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-i2)cycloalkyl ring; and s is 0 to 6.
66. The compound of claim 58 wherein X is CH2; the ring containing X is 1 9S 94 saturated; R , R and R are hydrogen; and R is a group of the formula:
R21— o— (CH2),- 1 where R is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6.
67. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2 and R24 are hydrogen.
68. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is (Cι-ι2)alkyl; (C2-ι2)alkenyl; (C2-ι2)alkynyl; (C3-ι2) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
69. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24are hydrogen; and R25 is phenyl optionally mono- or independently 19 plurisubstituted with R .
70. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24are hydrogen; and R25 is Rπ(CH2)p- where Ru is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (Cj-8)alkylcarbonyl; (C3-]2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)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 R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(G-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 .
71. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is O to 3.
72. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is a group of the formula:
R 15
)14' -(CH2)t
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-i2)cycloalkyl ring; and t is 0 to 6.
73. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R25 is a group of the formula:
R21— 0-(CH2)t —
where R21 is hydrogen; (G-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl 19 groups are optionally mono- or independently di-substituted on the ring with R ; and t is 0 to 6.
74. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 and R26 are hydrogen.
75. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is (Cι-ι2)alkyl; (C2-ι2)alkenyl; (C2-ι2)alkynyl; (C .]2) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
76. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is phenyl optionally mono- or independently 19 plurisubstituted with R .
77. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is R27(CH2)P-, where R27 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (G-8)alkylcarbonyl; (C -12)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl; where the 2- oxopyrrolidinyl, (G.6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Ci-^alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (G.8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and p is 0 to 3.
78. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is (R13)2CH(CH2)q-; where R13 is phenyl, in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
79. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula:
15
.N. ?14' ^(CH2)r-
where R14 and R15 are independently hydrogen; (G-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 0 or 2 to 6.
80. The compound of claim 58 wherein X is CH2; the ring containing X is saturated; R1, R2, R24 are hydrogen; and R26 is a group of the formula:
R21— O— (CH2) -ζ
where R21 is hydrogen; (G-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 or 2 to 6.
81. The compound of claim 30 that has formula IVA:
Figure imgf000188_0001
(IVA)
wherein R is a) hydrogen; b) (C1-12)alkyl; (C2-12)alkenyl; (C2-ι2)alkynyl; (C3-12) cycloalkyl; or (C3- ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally 19 mono- or independently plurisubstituted with R ; d) Ru(CH2)p- where R11 is 2-oxopyrrolidinyl; (G-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (G-8)alkylcarbonyl; (C -ι2)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(G-6)alkyl; where the 2-oxopyrrolidinyl, (Q. 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι-4)alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (G-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R13)2CH(CH )q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula:
Figure imgf000189_0001
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C -12)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and s is 0 to 6; or g) a group of the formula: R2I— o— (CH2) -
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6;
82. The compound of claim 30 that has formula IVB:
Figure imgf000190_0001
(IVB)
wherein R is a) hydrogen; b) (C1-12)alkyl; (C2-I2)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3. ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R12, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; c) aryl; or heteroaryl; where the aryl and heteroaryl groups are optionally • 1 mono- or independently plurisubstituted with R ; d) Rπ(CH2)p- where Rn is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (G-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; (C1-8)alkylcarbonyl; (C3-12)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl; where the 2-oxopyrrolidinyl, (Ci- 6)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (Cι- )alkyl, (Cι-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (G-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (G-6)alkyl; (G-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3; f) a group of the formula:
Figure imgf000191_0001
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (G-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and s is 0 to 6; or g) a group of the formula:
Figure imgf000191_0002
91 where R is hydrogen; (G-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; and t is 0 to 6;
83. The compound of claim 1 wherein CR'R" is present.
84. A process for preparing the compound of formula I in claim 1 , comprising: a) coupling a reactive compound of formula:
Figure imgf000192_0001
wherein L is a leaving group; R1 and R2 are independently a boronic acid protecting group or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; and n, X, Z, R', R", R3, and R4 are as defined in claim 1; with an amine of formula: R5-NH2; b) optionally deprotecting the boronic acid ester; and c) recovering the resultant compound as a free acid or as an acid addition salt.
85. The process of claim 84 wherein Ri and Rii are not present; R3 and R4 are hydrogen; the leaving group is Cl; and the amine is a cyclopentylamine or an aminopyrrolidine.
86. The process of claim 85 wherein the aminopyrrolidine is N-protected at the pyrrolidine nitrogen.
87. A process for preparing the compound of formula II of claim 31 , comprising: a) coupling a 2-boroheterocycle of formula:
Figure imgf000193_0001
wherein R1 and R2 are not hydrogen, and n, X, and Z are as defined in claim 31 ; with the corresponding N-protected amino acid; b) optionally deprotecting the boronic acid ester; and c) recovering the resultant compound as a free acid or as an acid addition salt.
88. The process of claim 87 wherein the N-protected cyclic amino acid is N- Boc-4-phenyl-proline.
89. A pharmaceutical composition comprising a compound according to claim 1 in free form or in pharmaceutically acceptable acid addition salt form, together with at least one pharmaceutically acceptable carrier or diluent.
90. A method for inhibiting dipeptidyl peptidase-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable acid addition salt thereof.
91. A method for treating conditions mediated by dipeptidyl peptidase-IV inhibition comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable acid addition salt thereof.
92. A method for treating controlling, or preventing diabetes comprising administering to a patient of an effective amount of a compound of claim 1.
93. A method for treating, controlling, or preventing non-insulin dependent (Type 2) diabetes mellitus in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
94. A method for treating, controlling, or preventing insulin dependent (Type 1) diabetes mellitus in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
95. A method for treating, controlling or preventing hyperglycemia in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
96. A method for treating, controlling or preventing obesity in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
97. A method for treating to enhance islet neogenesis, b-cell survival, and insulin biosynthesis in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
98. A method for treating, controlling or preventing insulin resistance in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
99. A method for treating, controlling or preventing one or more lipid disorders selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, and high LDL in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
100. A method for treating, controlling or preventing atherosclerosis in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
101. A method for treating or controlling growth hormone deficiency in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
102. A method for modulating the immune response in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
103. A method for treating, or controlling HIV infection in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
104. A method for treating, controlling or preventing in a mammalian patient in need of such treatment one or more disorders selected from the group consisting of neutropenia, anemia, neuronal disorders, tumor growth and metastasis, benign prostatic hypertrophy, gingivitis, hypertension and osteoporosis, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
105. A method reducing sperm motility in a male in a mammalian patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
106. A method for treating, controlling or preventing in a mammalian patient in need of such treatment one or more conditions selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) rheumatoid arthritis, (17) other inflammatory conditions, (18) pancreatitis, (19) abdominal obesity, (20) neurodegenerative disease, (21) multiple sclerosis, (22) retinopathy, (23) nephropathy, (24) neuropathy, (25) Syndrome X, (26) ovarian hyperandrogenism, (27) allograft rejection in transplantation, and other conditions where insulin resistance is a component, comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
107. A method for treating, controlling or preventing in a mammalian patient in need of such treatment one or more conditions selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) rheumatoid arthritis, (17) other inflammatory conditions, (18) pancreatitis, (19) abdominal obesity, (20) neurodegenerative disease, (21) multiple sclerosis, (22) retinopathy, (23) nephropathy, (24) neuropathy, (25) Syndrome X, (26) ovarian hyperandrogenism, (27) allograft rejection in transplantation, (28) Type II diabetes, (29) growth hormone deficiency, (30) neutropenia, (31) anemia, (32) neuronal disorders, (33) tumor growth and metastasis, (34) benign prostatic hypertrophy, (35) gingivitis, (36) hypertension, (37) osteoporosis, and other conditions that may be treated by inhibition of dipeptidyl peptidase-IV, comprising administering to the patient of a therapeutically effective amount of a first compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more other compounds selected from the group consisting of: a) Other dipeptidyl peptidase-IV inhibitors; b) Insulin sensitizers selected from the group consisting of (i) PPAR agonists, (ii) biguanides, and (iii) protein phosphatase- IB inhibitors; c) Insulin or insulin mimetics; d) Sulfonylureas or other insulin secretagogues; e) α-glucosidase inhibitors; f) glucagons receptor agonists; g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; h) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists; i) GIP, GIP mimetics, and GIP receptor agonists; j) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; k) Cholesterol lowering agents selected from the group consisting of (i) HMG- CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists, (v) PPARα/γ dual agonists, (vi) inhibitors of cholesterol absoφtion, (vii) acyl CoAxholesterol acyltransferase inhibitors, and (viii) anti-oxidants; 1) PPARδ 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.
108. A method for the treatment, control, or prevention of one or more conditions selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of claim 1 and an HMG-CoA reductase inhibitor.
109. The method of claim 108 wherein the HMC-CoA reductase inhibitor is a statin.
110. The method of claim 109 wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD- 4522 and rivastatin.
111. A method for treating, controlling or preventing atherosclerosis, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of claim 1 and an HMG-CoA reductase inhibitor.
112. The method of claim 111 wherein the HMC-CoA reductase inhibitor is a statin.
113. The method of claim 112 wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD- 4522 and rivastatin.
114. A pharmaceutical composition for the treatment, prevention or control of atherosclerosis, comprising: (1) a compound of claim 1, (2) an HMG-CoA reductase inhibitor, and (3) a pharmaceutically acceptable carrier.
115. A method for treating, controlling or preventing obesity, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of claim 1 and an anti-obesity agent.
116. The method of claim 115 wherein the anti-obesity agent is a beta-3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, an anorectic agent, and/or a fatty acid oxidation upregulator.
117. The method of claim 116 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol.
118. A method for the treatment, control, or prevention of neutropenia, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of claim 1 and a neutrophilic agent.
119. The method of claim 118 wherein the neutrophilic agent is G-CSF, a G-CSF mimetic, or a G-CSF receptor agonist.
120. The method of claim 115 wherein the neutrophilic agent is pegfϊlgrastim, filgrastim, lenograstim, or nartograstim.
121. A method for the treatment, control, or prevention of anemia, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of claim 1 and a erythropoietin agonist.
122. The method of claim 121 wherein the erythropoietin agonist is EPO, an EPO mimetic, or an EPO receptor agonist.
123. The method of claim 122 wherein the erythropoietin agonist is epoetin alfa, or darbepoetin alfa.
124. A pharmaceutical composition, comprising: a) A compound of claim 1 ; b) One or more compounds selected from the group consisting of: i) Other dipeptidyl peptidase-IV inhibitors; ii) Insulin sensitizers selected from the group consisting of (i) PPAR agonists, (ii) biguanides, and (iii) protein phosphatase- IB inhibitors; iii) Insulin or insulin mimetics; iv) Sulfonylureas or other insulin secretagogues; v) α-glucosidase inhibitors; vi) glucagons receptor agonists; vii) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; viii) GIP, GIP mimetics, and GIP receptor agonists; ix) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; x) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists; xi) Cholesterol lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists, (v) PPARα/γ dual agonists, (vi) inhibitors of cholesterol absoφtion, (vii) acyl CoA holesterol acyltransferase inhibitors, and (viii) anti-oxidants; xii) PPARδ 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.
125. A pharmaceutical combination comprising a DPP-IV inhibitor compound according to claim 1 , an antidiabetic agent other than a DPP-IV inhibitor for treating diabetes and related diseases, and an anti-obesity agent or a lipid-modulating agent or both.
126. The combination according to claim 125 comprising the DPP-IV inhibitor compound and an antidiabetic agent.
127. The combination according to claim 126 wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/ γ dual agonist, an SGLT2 inhibitor, an aP2 inhibitor, a glycogen phosphorylase inhibitor, an AGE inhibitor, an insulin sensitizer, a glucagon-like peptide- 1 (GLP-1) or mimetic thereof, insulin and/or a meglitinide.
128. The combination according to claim 127 wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chloφropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, Gl -262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-l 19702, AJ9677, repaglinide, nateglinide, KADI 129, APR-HO39242, GW-409544, KRP297, AC2993, Exendin-4, LY307161, NN2211, and/or LY315902.
129. The combination according to claim 128 wherein the DPP-IV inhibitor compound is present in a weight ratio to the antidiabetic agent within the range from about 0.01 to about 100:1.
130. The combination according to claim 129 wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, an anorectic agent, and/or a fatty acid oxidation upregulator.
131. The combination according to claim 130 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol.
132. The combination according to claim 125 wherein the lipid-modulating agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, an ACAT inhibitor, a cholesteryl ester transfer protein inhibitor, or an ATP citrate lyase inhibitor.
133. The combination according to claim 132 wherein the lipid-modulating agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529,414, avasimibe, TS-962, MD-700, and/or LY295427.
134. The combination according to claim 133 wherein the DPP-IV inhibitor is present in a weight ratio to the lipid-modulating agent within the range from about 0.01 to about 100:1.
135. A pharmaceutical combination comprising a DPP-IV inhibitor compound according to claim 1 and an agent for treating infertility, an agent for treating polycystic ovary syndrome, an agent for treating a growth disorder and/or frailty, an anti-arthritis agent, an agent for preventing inhibiting allograft rejection in transplantation, an agent for treating autoimmune disease, an anti-ADDS agent, an agent for treating inflammatory bowel disease/syndrome, an agent for treating anorexia nervosa, an anti-osteoporosis agent and/or an anti-obesity agent.
136. A method for treating diabetes, insulin resistance, hyperglycemia, hyperisulinemia, or elevated blood levels of free fatty acids or glycerol, obesity, Syndrome X, dysmetabolic syndrome, diabetic complications, hypertriglyceridemia, hyperinsulinemia, atherosclerosis, impaired glucose homeostasis, impaired glucose tolerance, infertility, polycystic ovary syndrome, growth disorders, frailty, arthritis, allograft rejection in transplantation, autoimmune diseases, AIDS, intestinal diseases, inflammatory bowel syndrome, nervosa, osteoporosis, or an immunomodulatory disease or a chronic inflammatory bowel disease, comprising administering to a mammalian species in need of treatment a therapeutically effective amount of a compound according to claim 1.
137. The method according to claim 136 for treating type II diabetes and/or obesity.
138. A compound that has the formula VA, VB, or a mixture thereof:
Figure imgf000202_0001
VA VB including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein: n is 1 to 3; X is CH2; S; O; CF2 or C(CH3)2 Z is H; halogen; hydroxyl; (Cι-6)alkoxy; (G-ι )alkyl; (C3-ι2)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; 1 9 R 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; R3, R4 and R5 are selected from (dd) or (ee): (dd) R3 and R4 are hydrogen; and R5 is a) hydrogen, provided that R is not hydrogen when n is 1, X is CH2, and Z is H; b) (C 2)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
R6 is (C]-6)alkyl; (C]-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8)2; -OR8; or -S-R8; R7 is halogen; (Cι-1o)alkyl; (Cι.ιo)alkoxy; (C1-10)alkylamino; (Ci-io) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (Cι-ιo)alkyl; (C2-10)alkenyl; (C2-ι0)alkynyl; (C3- !o)cycloalkyl; (C5-ιo)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; c) aryl optionally fused to a (C3-ι0)cycloalkyl; or heteroaryl optionally fused to a (C -ιo)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH )j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4- pentylbicyclo[2.2.2]oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (G-8)alkyl, (Cι-8)alkoxy, (Cι-8)alkanoyloxy, or R9R,0N-CO-O-, where R9 and R10 are independently (G-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (G-8)alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-ό)alkylene; e) Rπ(CH2)p- where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl; phenoxy; (G-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (G-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently 19 tπsubstituted with R ; where the phenoxy group is optionally mono- or independently disubstituted with (C!-4)alkyl, (G-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (G-8)alkyl; and p is O to 3; R12 is halogen; trifluoromethyl; cyano; nitro; (G-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; 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; f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is O to 3; g) a group of the formula:
Figure imgf000204_0001
where R14 and R15 are independently hydrogen; (C]-8)alkyl; (G-6)alkylcarbonyl; (C3- 12)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(G-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 2 to 6; h) a group of the formula:
Figure imgf000204_0002
where R16 and R17 are each independently hydrogen; (G-8)alkyl; (G-6)aιkylcarbonyl; di-(Cι_ 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
Figure imgf000205_0001
where R18 and R19 are independently hydrogen; (C]-8)alkyl; (Cι.6)alkylcarbonyl; di-(G- 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH2-C(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; k) a group of the formula:
Figure imgf000205_0002
90 where R is hydrogen; (C1-8)alkyl; (Q ^alkylcarbonyl; di-(Q ^alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (Ci-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (G-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (G-8)alkyl, (G-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
Figure imgf000205_0003
where R21 is hydrogen; (G-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; or (ee) R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; provided that when n is 1 , X is CH2, the ring containing X is saturated, and Z, R3 and R5 are H, R4 is not a side chain of a naturally occurring α-amino acid; and provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R5 are H, R3 and R4 are not both methyl; and wherein the bond containing the wavy line signifies the point of attachment. 1 9 139. The compound of claim 138 wherein R and R independently or together are the boronic acid protecting group formed from (+)-pinanediol; pinacol; 1,2-dicyclohexyl- ethanediol; 1,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3-butanediol, dusopropyl tartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6-decanediol; 1,1,2-triphenyl- 1,2- ethanediol; (2R,3R)-l,4-dimethyoxy-l,l,4,4-tetraphenyl-2,3-butanediol; methanol; ethanol; isopropanol; catechol; or 1-butanol. 1 9 140. The compound of claim 138 wherein R and R independently or together are a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids formed from 1,2-dicyclohexylethanediol; 1,2- ethanediol; 1,3-propanediol; 2,3-butanediol, 1,4-butanediol; diisopropylethanediol; methanol; ethanol; isopropanol; or 1-butanol.
141. The compound of claim 138 wherein R3 and R4 are independently hydrogen, alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; and R5 is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl.
142. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is (Cι-ι2)alkyl; (C2-]2)alkenyl; (C2- ι2)alkynyl; (C3-ι2) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions.
143. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]-oct-l-yl)amine; where the indanyl, 1,2,3,4- tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cj-8)alkyl, (Q. 8)alkoxy, (G-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (Q. 8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (Cj-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene.
144. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is Rn(CH2)p- where Rn is 2- oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2- oxopyrrolidinyl, (Cι-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 (Cι-4)alkyl, (G- )alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (G-8)alkyl; p is 0 to 3; and R12 is halogen; trifluoromethyl; cyano; nitro; (G-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι- 6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7.
145. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3.
146. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
R 15 I -N. R 14' -(CH2)r-
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Q ^alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C -ι2)cycloalkyl ring; and r is 2 to 6.
147. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000209_0001
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Ci ^alkylcarbonyl; di-(G. 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6.
148. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000210_0001
where R18 and R19 are independently hydrogen; (G-8)alkyl; (Cι-6)alkylcarbonyl; di-(G- 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3.
149. The compound of claim 148 wherein R5 has formula:
Figure imgf000210_0002
150. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
(phenyl-CH2-C(CH3)2-),
where the phenyl group is optionally mono- or independently plurisubstituted with R12.
151. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
Figure imgf000211_0001
where R20 is hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-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 19 independently di-substituted with R ; Rx is hydrogen; (C1-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (C1-8)alkyl, (Cι-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3;.
152. The compound of claim 151 wherein R has formula:
Figure imgf000211_0002
153. The compound of claim 151 wherein R 5 i •s
Figure imgf000211_0003
154. The compound of claim 151 that has the formula:
Figure imgf000212_0001
155. The compound of claim 151 that has the formula:
Figure imgf000212_0002
156. The compound of claim 138 wherein X is CH2; the ring containing X is saturated; R , 1 , r R>2 , τ Rι3 and R are hydrogen; and R is a group of the formula:
Figure imgf000212_0003
where R >21 i ■s hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3.
157. The compound of claim 156 wherein R has formula:
Figure imgf000212_0004
1 9 158. The compound of claim 138 wherein R and R are hydrogen; n is 1; X together with an adjacent ring carbon and Z form a fused cyclopropyl; R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl.
159. The compound of claim 138 wherein the compound has the formula:
Figure imgf000213_0001
or a mixture thereof.
160. The compound of claim 138 wherein the compound has the formula:
Figure imgf000214_0001
or a mixture thereof.
161. The compound of claim 138 wherein the compound has the formula:
Figure imgf000214_0002
or a mixture thereof.
162. The compound of claim 138 wherein the compound has the formula:
Figure imgf000214_0003
or a mixture thereof.
163. The compound of claim 138 wherein the compound has the formula:
Figure imgf000215_0001
or a mixture thereof.
164. The compound of claim 138 wherein the compound has the formula:
Figure imgf000215_0002
or a mixture thereof.
165. The compound of claim 138 wherein the compound has the formula:
Figure imgf000215_0003
or a mixture thereof.
166. A pharmaceutical composition comprising a compound of claim 138 and a pharmaceutically acceptable carrier or diluent.
167. The pharmaceutical composition of claim 166 wherein the compound has the formula VB.
168. A pharmaceutical composition comprising: a. a substantially pure preparation of a compound of formula VB:
Figure imgf000216_0001
VB including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein: n is 1 to 3; X is CH2; S; O; CF2 or C(CH3)2; Z is H; halogen; hydroxyl; (Cι-6)alkoxy;
Figure imgf000216_0002
(C3-12)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; R1 and R2 independently or together are hydrogen; a boronic acid protecting group; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; R3, R4 and R5 are selected from (dd) or (ee): (dd) R3 and R4 are hydrogen; and R5 is a) hydrogen, provided that R5 is not hydrogen when n is 1 , X is CH2, and Z is H; b) (C,-12)alkyl; (C2-,2)alkenyl; (C2-ι2)alkynyl; (C3-12) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cι-6)alkyl; (Cι-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 R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8) 2; -OR8; or
-S-R8 R7 is halogen; (Cι-ιo)alkyl; (Cι-10)alkoxy; (Cι-ιo)alkylamino;
(Ci-io) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (Cι.ιo)alkyl; (C2-U,)alkenyl; (C2-10)alkynyl; (C3- 10)cycloalkyl; (C5-ιo)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; c) aryl optionally fused to a (C3-ι0)cycloalkyl; or heteroaryl optionally fused to a (C3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)jadamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4- pentylbicyclo[2.2.2]oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (Cι-8)alkoxy, (Cι-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (Cι-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Cι-8)alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene; e) Rπ(CH2)p- where R11 is 2-oxopyrrolidinyl; (C] -6)alkoxy; phenyl; phenoxy; (C] -8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with
Figure imgf000218_0001
or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; and p is O to 3; R12 is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl 19 groups are independently optionally mono- or independently disubstituted with R ; and q is O to 3; g) a group of the formula:
Figure imgf000218_0002
where R14 and R15 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; (C3- i2)cycloalkyl ring; (C3-i2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C -i2)cycloalkyl ring; and r is 2 to 6; h) a group of the formula:
Figure imgf000219_0001
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-i2)cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
Figure imgf000219_0002
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι- )alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and 19 1 phenylsulfonyl groups are optionally mono- or independently di-substituted with R ; or R and R19 together form a (C -12)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH2-C(CH3) 2-), 19 where the phenyl group is optionally mono- or independently plurisubstituted with R ; k) a group of the formula:
Figure imgf000219_0003
where R20 is hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι-6)alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-6)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl; phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; Rx is hydrogen; (C1-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently 19 di-substituted on the ring with R ; R is absent or is halogen, (Cι-8)alkyl, (Cι-8)alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
Figure imgf000220_0001
where R21 is hydrogen; (Cι-g)alkyl; benzyl; or phenyl; in which the benzyl and phenyl 19 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; or (ee) R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; provided that when n is 1, X is CH2, the ring containing X is saturated, and Z, R3 and R5 are H, R4 is not a side chain of a naturally occuπing α-amino acid; and provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R5 are H, R3 and R4 are not both methyl; and wherein the bond containing the wavy line signifies the point of attachment; and b. a pharmaceutically acceptable earner or diluent.
169. A method of making a pharmaceutical composition, comprising mixing a substantially pure preparation of the compound of formula VB of claim 138 with a pharmaceutically acceptable carrier or diluent.
170. The method of claim 169 wherein the pharmaceutically acceptable carrier or diluent is suitable for oral administration.
171. The method of claim 170 further comprising the step of formulating the composition into a tablet or capsule.
172. The method of claim 170 wherein the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration.
173. The method of claim 172 further comprising the step of lyophilizing the composition to form a lyophilized preparation.
174. A compound that is a boronic acid inhibitor of dipeptidyl peptidase-IV having an inhibition constant of 10 micromolar or less for dipeptidyl peptidase-IV wherein the inhibitor comprises a boropyrrolidine, boropiperidine, or boroazepane attached to an amino acid through an amide bond wherein the amino acid is a beta-amino acid, an N-cycloalkyl-alpha-amino acid, an N-heterocyclyl-alpha amino acid, a cyclic alpha-amino acid (also known as an imino acid) having at least one substituent on the alpha-amino acid ring, a cyclic alpha-amino acid having a ring other than pyrrolidine, or an N-substituted glycine.
175. The compound of claim 174 wherein the boronic acid inhibitor is of Formula I:
Figure imgf000222_0001
including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein: n is 1 to 2; X is CH2; S; O; CF2 or C(CH3)2; Z is H; halogen; hydroxyl; (C1-6)alkoxy;
Figure imgf000222_0002
(C3-ι2)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; R1 and R2 independently or together are hydrogen; a boronic acid protecting group; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; CR'R" may be present or absent, wherein if CR'R" is present, then R', R", R3, R4 and R5 are selected from (aa), (bb) or (cc): (aa) R', R", R3 and R4 are hydrogen; and R5 is a) hydrogen; b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-ι2)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8) 2; -OR8; or -S-R8; R7 is halogen; (Cι-ιo)alkyl;
Figure imgf000223_0001
(Cι.ιo)alkylamino; (Ci-io) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethyl thio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (Cι-ιo)alkyl; (C2-ιo)alkenyl; (C2-ι0)alkynyl; (C3. ιo)cycloalkyl; (C5-ι0)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; c) aryl optionally fused to a (C3-ιo)cycloalkyl; or heteroaryl optionally fused to a (C3-ι0)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4- pentylbicyclo[2.2.2]oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (Cι-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (C]-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (Cι-8)alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C -6)alkylene; e) RU(CH2)P- where R11 is 2-oxopyrrolidinyl; (Cι-6)alkoxy; phenyl; phenoxy; (Cι-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Cι-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 (Cι-4)alkyl,
Figure imgf000223_0002
or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (Cι-8)alkyl; and p is O to 3; 19 R is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Ci. 6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; f) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is O to 3; g) a group of the formula: R15 I R14^ ^(CH2)r -
where R and R are independently hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; (C3- ι2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 2 to 6; h) a group of the formula:
Figure imgf000224_0001
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-ι2)cycloalkyl ring; and s is 1 to 6; i) a group of the formula:
Figure imgf000224_0002
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (C1-6)alkylcarbonyl; di-(Cι_ 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R18 and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; j) a group of the formula: (phenyl-CH2-C(CH3) 2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; k) a group f:
Figure imgf000225_0001
where R20 is hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C3- 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-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 R ; Rx is hydrogen; (d- )alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (C1- )alkyl, (C1- )alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or 1) a group of the formula:
Figure imgf000225_0002
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; (bb) R, R", R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R1 together with R3 or R4, or R" together with R3 or R4, and the atoms to which they are attached form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2; and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa); or R4 and R5 together form -(CR22R23)m- where m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl; halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino; arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylamino; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (cc) R1 and R3 are hydrogen; and R" and R4 together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, and includes single rings, fused bicyclic and tricyclic rings, which are optionally mono- or independently plurisubstituted with any of the groups set forth in (aa) or (bb) and R5 is any of the groups in (aa) or (bb); and if CRR" is absent, then R3, R4 and R5 are selected from (dd), (ee) or (ff): (dd) R3 and R4 are hydrogen; and R5 is a) (0,-12)3 !; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12) cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (Cι-6)alkyl; (Cι-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; -SOR8; -SO2R8; -COR8; -CO2R8, -CONHR8; -CON(R8) 2; -OR8; or -S-R8; R7 is halogen; (Cι.ιo)alkyl;
Figure imgf000227_0001
(Cι-10)alkylamino; (Ci-io) dialkylamino; benzyl; benzyloxy; hydroxyl(Cι-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (Cι-10)alkyl; (C2-10)alkenyl; (C2-ι0)alkynyl; (C3- ιo)cycloalkyl; (C5-ιo)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; and where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; b) aryl optionally fused to a (C3-1o)cycloalkyl; or heteroaryl optionally fused to a (C -ιo)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; c) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4- pentylbicyclo[2.2.2]oct-l-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (Cι-8)alkyl, (Cι-8)alkoxy, (Cι-8)alkanoyloxy, or R9R10N-CO-O-, where R9 and R10 are independently (Cι-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (Cι-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C -6)alkylene; d) Rn(CH2)p- where Rn is 2-oxopyrrolidinyl; (C]-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (Cι-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 (Cι-4)alkyl,
Figure imgf000228_0001
or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-or independently plurisubstituted with (C1-8)alkyl; and p is O to 3; 19 R is halogen; trifluoromethyl; cyano; nitro; (Cι-6)alkyl; (Ci. )alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(Cι-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; e) (R13)2CH(CH2)q-, where R13 is phenyl; in which the phenyl 19 groups are independently optionally mono- or independently disubstituted with R ; and q is O to 3; f) a group of the formula: R15
R1 ^ ^(CH2)r
where R14 and R15 are independently hydrogen; (Cι-8)alkyl;
Figure imgf000228_0002
(C3- i2)cycloalkyl ring; (C3-ι2)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(Cι-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-ι2)cycloalkyl ring; and r is 2 to 6; g) a group of the formula:
Figure imgf000229_0001
where R16 and R17 are each independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι. 6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-ι )cycloalkyl ring; and s is 1 to 6; h) a group of the formula:
Figure imgf000229_0002
where R18 and R19 are independently hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(Cι- 6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and 19 18 phenylsulfonyl groups are optionally mono- or independently di-substituted with R ; or R and R19 together form a (C3-ι2)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3; i) a group of the formula: (phenyl-CH2-C(CH3)2-), where the phenyl group is optionally mono- or independently plurisubstituted with R12; j) a group of the formula:
Figure imgf000229_0003
9fl where R is hydrogen; (Cι-8)alkyl; (Cι-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; (C - 8)cycloalkylcarbonyl; benzyl; benzoyl; (Cι-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 19 independently di-substituted with R ; Rx is hydrogen; (Cι-8)alkyl; (C3-ι2) cycloalkyl; benzyl; phenyl; where the benzyl and phenyl, groups are optionally mono- or independently di-substituted on the ring with R12; R is absent or is halogen, (Cι-8)alkyl, (Cj- )alkoxy,
O-alkylcarboxylate, O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; or k) a group of the formula:
Figure imgf000230_0001
where R21 is hydrogen; (Cι-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl 19 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; or (ee) R3 and R4 are independently hydrogen, alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; R5 is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino- carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; or R4 and R5 together form -(CR22R23)m - wherein m is 2 to 6, and R22 and R23 are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl; halo; amino; substituted amino; cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino; arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylamino; provided that when n is 1, X is CH2, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; or R4 and R5 together with the atoms to which they are attached form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to 7 membered cycloalkyl ring fused thereto; or (ff) R3 is hydrogen; and R4 and R5 together with the atoms to which they are attached form a 4 to 8 member mono- or polycyclic heterocyclic ring system containing 1 to 3 heteroatoms selected from N, O, S, SO and SO2, wherein the heterocyclic ring system is optionally mono- or independently plurisubstituted with any of the groups set forth in (dd) or (ee); provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are H, R4 and R5 together are not -(CH2)2- or -(CH2)3-; and wherein a bond containing a wavy line signifies a point of attachment.
176. A method for inhibiting dipeptidyl peptidase-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 174, or a pharmaceutically acceptable acid addition salt thereof.
177. A method for treating conditions mediated by dipeptidyl peptidase-IV inhibition comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 174, or a pharmaceutically acceptable acid addition salt thereof.
178. A method for treating controlling, or preventing diabetes comprising administering to a patient of an effective amount of a compound of claim 174.
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COUTTS ET AL.: "Structure-activity relationships of boronic acid inhibitors of dipeptidyl peptidase IV. 1. Variation of the P2 position of Xaa-boroPro dipeptides", J. MED. CHEM., vol. 39, no. 10, 10 May 1996 (1996-05-10), pages 2087 - 2094, XP002092856 *
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SI1689757T1 (en) 2015-01-30
EP1997533B8 (en) 2014-10-29
BRPI0416444B8 (en) 2021-05-25
US7674913B2 (en) 2010-03-09
US20070185061A1 (en) 2007-08-09
KR100918322B1 (en) 2009-09-22
CA2545311C (en) 2012-01-03
US8415295B2 (en) 2013-04-09
EP1997533B1 (en) 2014-09-24
NO20160635L (en) 2006-05-15
KR20070054762A (en) 2007-05-29
NO337818B1 (en) 2016-06-27
EP1689757A4 (en) 2007-01-10
AU2004288831A1 (en) 2005-05-26
JP5435841B2 (en) 2014-03-05
JP2007512254A (en) 2007-05-17
JP5398199B2 (en) 2014-01-29
NO20062711L (en) 2006-08-14
BRPI0416444B1 (en) 2019-02-19
US20070060547A1 (en) 2007-03-15
EP1743676A1 (en) 2007-01-17
EA200600935A1 (en) 2006-10-27
AU2004288831B2 (en) 2010-08-26
NO340063B1 (en) 2017-03-06
CA2545311A1 (en) 2005-05-26
BRPI0416444A (en) 2007-02-27
US20100120661A1 (en) 2010-05-13
HRP20141155T1 (en) 2015-01-16
TW200608969A (en) 2006-03-16
EA013684B1 (en) 2010-06-30
PT1689757E (en) 2014-12-09
TWI337078B (en) 2011-02-11
NZ547752A (en) 2009-12-24
SG134333A1 (en) 2007-08-29
ES2524916T3 (en) 2014-12-15
AR046778A1 (en) 2005-12-21
IL175550A (en) 2011-11-30
KR20060121170A (en) 2006-11-28
JP2009007377A (en) 2009-01-15
DK1689757T3 (en) 2014-12-08
IL175550A0 (en) 2006-09-05
EP1689757B1 (en) 2014-08-27
EP1689757A1 (en) 2006-08-16
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PL1689757T3 (en) 2015-05-29
JP2008019261A (en) 2008-01-31

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