WO2006012441A1 - Peptidase inhibitors - Google Patents

Abstract

The present invention relates to a series of novel compounds having the formula: [INSERT FORMULA I] wherein A is a bicyclic carbocycle and R1 and R2 are independently [INSERT MOLECULE FROM CLAIM 1] The compounds are useful as DPP-IV inhibitors and for treating diabetes.

Description

PEPTIDASE INHIBITORS

Field of the Invention

The present invention relates to a series of novel compounds that are inhibitors of the enzyme dipeptidyl peptidase IV (DPP-IV), as well as their salts, and isomers, and pharmaceutical formulations containing the same, and to methods of use thereof, particularly for treating diabetes.

Background of the Invention

The gut incretin hormones, glucagon-like peptide- 1 (GLP-I) and gastric inhibitory polypeptide (GIP) are responsible for >50% of nutrient stimulated insulin release and have roles in β-cell glucose competence, stimulating β-cell growth, differentiation, proliferation and cell survival. On release, these hormones are rapidly inactivated (GLP-I; ty₂ = 1.5 min) by a ubiquitous serine protease, dipeptidyl peptidase IV (DPP-IV) which acts by specifically cleaving Pro or Ala terminal amino acid residues. Inhibition of DPP-IV has been shown to extend the half-life of GLP-I with favorable effects on stimulation of insulin secretion, inhibition of glucagon release and slowing gastric emptv ing.

DPP-IV inhibition, through the preservation of active GLP-I levels, has the potential to slow or even prevent the progression of type 2 diabetes by stimulating insulin gene expression and biosynthesis, increasing the expression of the β-cell's glucose-sensing mechanism and promoting genes involved in the differentiation of β-cells. As the glucose lowering effects of GLP-I are dependent on elevated blood glucose and subside as glucose levels return to normal, the probability of hypoglycemia during treatment with a DPP-IV inhibitor is expected to be very low. Indeed; studies on the long term inhibition of DPP-FV and with DPP-IV knock-out mice have shown no adverse effects.

Application of DPP-IV inhibitors delays the inactivation of GIP and GLP-I thereby allowing increased insulin secretion and improved blood glucose control. It could be shown in animal models and diabetic patients that the overall blood sugar control of the body is improved due to a restoration of proper insulin secretion and action. Such a mode of action is unique to this therapeutic principle. The above studies suggest the possibility of long term safe treatment of type-2 diabetes with DPP-IV inhibitors.

Summary of the Invention

A first aspect of the present invention is a compound of Formula I:

wherein: n and v are independently 1 or 2;

A is a monocyclic, bicyclic or tricyclic carbocycle of 5 to 20 atoms wherein each bridge of the bicycle has at least one atom; R¹ and R² are independently

wherein: p and q are independently 0 or 1 ;

R⁸ is H or cyano, preferably cyano;

Y is CH₂, CHF, CF₂, O, or S(O)_m;

W and Z are independently CH₂, CHF, or CF₂; and wherein the ring formed by N, W, Y, Z and the carbon atoms to which they are attached is saturated or optionally contains one double bond; and R¹¹ and R¹² are independently selected from the group consisting of H, alkylcarbonyl, alkoxycarbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, and sulfone; m is 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof. A further aspect of the present invention is a compound of Formula XI:

wherein:

X is NH or a covalent bond; n is 1 or 2;

A is a bicyclic carbocycle of 5 to 20 atoms wherein each bridge of the bicycle has at least one atom;

R¹ is

wherein: p and q are independently OΌΓ 1;

Y is CH₂, CHF, CF₂, O, or S(O)_m;

W and Z are independently CH?. CHF. or CF₂; and wherein the ring formed by N. W. Y. Z and the carbon atoms to which they are attached is saturated or optionally contains one double bond; and R² is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, and heterocycloalkyl, each of which is unsubstituted or optionally substituted with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, haloalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O)_m, haloalkyl-S(O)_m, cycloalkyl-S(O)_m, cycloalkylalkyl-S(O)_m, aryl-S(O)_m, arylalkyl- S(O)_m, heterocyclo-S(O)_m, heterocycloalkyl-S(O)_m, amino, alkylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano; or R⁸ is H or cyano; m is 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.

A further aspect of the present invention is a compound of Formula XII:

wherein: n is 1 or 2;

A is a bicyclic or tricyclic carbocycle of 5 to 20 atoms wherein each bridge of the bicycle has at least one atom;

R¹ is

wherein: p and q are independently 0 or 1 , Y is CH₂, CHF, CF₂, O, or S(O)₀₁; W and Z are independently CH₂, CHF, or CF₂; and wherein the ring formed by N, W, Y, Z and the carbon atoms to which they are attached is saturated or optionally contains one double bond; R²³ is -NR⁵R⁶, or -OR⁶ or OH, R⁵ is H or alkyl;

R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, and heterocycloalkyl, each of which is unsubstituted or optionally substituted with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, haloalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O)_m, haloalkyl-S(O)_m, cycloalkyl-S(O)_m, cycloalkylalkyl-S(O)_m, aryl-S(O)_m, arylalkyl- S(O)_m, heterocyclo-S(O)_m, heterocycloalkyl-S(O)_m, amino, alkylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano; or R⁵ and R⁶ together form a C4-C6 alkylene bridge to which may be fused a substituted or unsubstituted cyclic or heterocyclic group;

R⁸ is H or cyano; m is 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.

A further aspect of the present invention is a compound of Formula XIII or Formula XIV:

wherein: n is 1 or 2;

A is a bicyclic or tricyclic carbocycle of 5 to 20 atoms wherein each bridge of the bicycle has at least one atom;

R¹ is

wherein: p and q are independently 0 or l; Y is CH₂, CHF, CF₂, O, or S(O)_m;

W and Z are independently CH₂, CHF, or CF₂; and wherein the ring formed by N, W, Y, Z and the carbon atoms to which they are attached is saturated or optionally contains one double bond;

R⁸ is H or cyano; m is 0, 1 or 2;

R²⁰ is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heterocyclo, heterocycloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, alkylamino, arylalkylamino, heterocycloamino, cycloalkylamino, cycloalkylalkylamino, or disubstituted-amino;

R²¹ and R²² are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, and heterocycloalkyl, each of which is unsubstituted or optionally substituted with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, haloalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O)_m, haloalkyl-S(O)_m, cycloalkyl-S(O)_m, cycloalkylalkyl-S(O)_m, aryl-S(O)_m, arylalkyl- S(O)_m, heterocyclo-S(O)_m, heterocycloalkyl-S(O)_m, amino, alkylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano; or R²¹ and R²² together form a C4-C6 alkylene linkage; or a pharmaceutically acceptable salt or prodrug thereof.

A further aspect of the present invention is a pharmaceutical composition comprising a compound as described herein in combination with a pharmaceutically acceptable carrier.

A third aspect of the present invention is a method of inhibiting DPP-IV in a subject in need thereof, comprising administering said subject a compound as described herein in an amount effective to inhibit DPP-IV in said subject.

A fourth aspect of the present invention is a method of treating diabetes (particularly type II diabetes) in a subject in need thereof, comprising administering said subject a compound as described herein in an amount effective to treat said diabetes. A fifth aspect of the present invention is the use of a compound or active compound as described herein for the preparation of a medicament useful for a method of use or treatment as described herein.

In some embodiments, the administering step is a transdermal administering step (e.g., an active transdermal administering step, such as an iontophoresis, electroporation, sonophoresis, thermal energy, or magnetophoresis, or is carried out by applying a patch containing said active agent to the skin of said subject).

In some embodiments, the administering step is carried out by inhalation administration (e.g., by intranasal spray, and/or by inhalation to the lungs of said subject)

A further aspect of the invention is, in a transdermal drug delivery device, the improvement comprising employing an active compound as described herein as the active agent in the device. Such devices include a patch (e.g., a patch comprising a backing and at least one adhesive layer carried by said backing, with said adhesive layer further comprising said active agent; a patch comprising a backing, a reservoir connected to said backing, and an adhesive layer, with said reservoir further comprising said active agent; a patch comprising a backing, a matrix connected to said backing, and an adhesive layer, with said matrix further comprising said active agent) and in some embodiments optionally further comprise a plurality of microneedles operatively associated therewith and configured for increasing flux of said active agent across the skin of a subject.

A further aspect of the invention is, in an inhalation drug delivery device, the improvement comprising employing an active agent as described herein as the active agent in the device. Suitable devices include a nasal spray devices and lung administration devices.

The foregoing and other objects and aspects of the present invention are explained in greater detail in the specification set forth below.

Detailed Description of the Preferred Embodiments

"Halo" as used herein refers to any suitable halogen, including -F, -Cl, -Br, and -I. "Mercapto" as used herein refers to an -SH group. "Azido" as used herein refers to an -N₃ group. "Cyano" as used herein refers to a -CN group. "Hydroxyl" as used herein refers to an -OH group.

"Nitro" as used herein refers to an -NO₂ group.

"Alkyl" as used herein alone or as part of another group, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. "Loweralkyl" as used herein, is a subset of alkyl, in some embodiments preferred, and refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like. The term "akyl" or "loweralkyl" is intended to include both substituted and unsubstituted alkyl or loweralkyl unless otherwise indicated and these groups may be substituted with groups selected from halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O)_m, haloalkyl-S(O)_m, alkenyl-S(O)_m, alkynyl-S(O)_m, cycloalkyl-S(O)_m, cycloalkylalkyl-S(O)_m, aryl-S(O)_m, arylalkyl-S(O)_m, heterocyclo-S(O)_m, heterocycloalkyl-S(O)_m, amino, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino. arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano where m= 0, 1 or 2.

"Alkenyl" as used herein alone or as part of another group, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms (or in loweralkenyl 1 to 4 carbon atoms) which include 1 to 4 double bonds in the normal chain. Representative examples of Alkenyl include, but are not limited to, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentyl, 3- pentyl, 2-hexenyl, 3-hexenyl, 2,4-heptadiene, and the like. The term "alkenyl" or "loweralkenyl" is intended to include both substituted and unsubstituted alkenyl or loweralkenyl unless otherwise indicated and these groups may be substituted with groups as described in connection with alkyl and loweralkyl above. "Alkynyl" as used herein alone or as part of another group, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms (or in loweralkynyl 1 to 4 carbon atoms) which include 1 triple bond in the normal chain. Representative examples of Alkynyl include, but are not limited to, 2-propynyl, 3-butynyl, 2- butynyl, 4-pentenyl, 3- pentenyl, and the like. The term "alkynyl" or "loweralkynyl" is intended to include both substituted and unsubstituted alkynyl or loweralknynyl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl and loweralkyl above.

"Alkoxy," as used herein alone or as part of another group, refers to an alkyl or loweralkyl group, as defined herein, appended to the parent molecular moiety through an oxy group, -O-. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

"Acyl" as used herein alone or as part of another group refers to a -C(O)R radical, where R is any suitable substituent such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl or other suitable substituent as described herein.

"Haloalkyl," as used herein alone or as part of another group, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.

"Alkylthio," as used herein alone or as part of another group, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.

"Aryl," as used herein alone or as part of another group, refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like. The term "aryl" is intended to include both substituted and unsubstituted aryl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl and loweralkyl above. "Arylalkyl," as used herein alone or as part of another group, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylallcyl include, but are not limited to, benzyl, 2- phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.

"Amino" as used herein means the radical -NH₂.

"Alkylamino" as used herein alone or as part of another group means the radical -NHR, where R is an alkyl group.

"Arylalkylamino" as used herein alone or as part of another group means the radical - NHR, where R is an arylalkyl group.

"Disubstituted-amino" as used herein alone or as part of another group means the radical -NR_aR_b, where R_a and R_b are independently selected from the groups alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.

"Acylamino" as used herein alone or as part of another group means the radical -NR₃R_b, where R₃ is an acyl group as defined herein and R_b is selected from the groups hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.

" Acyloxy" as used herein alone or as part of another group means the radical -OR, where R is an acyl group as defined herein.

"Ester" as used herein alone or as part of another group refers to a -C(O)OR radical, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Amide" as used herein alone or as part of another group refers to a -C(O)NR₃R_b radical, where R_a and R_b are any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Sulfone" as used herein alone or as part of another group refers to a -S(O)₂R radical, where R is any suitable substituent, such as H, alkyl, aryl, alkylaryl, etc.

"Sulfonamide" as used herein alone or as part of another group refers to a -S(O)₂NR_aR_b radical, where R_a and R_b are any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Urea" as used herein alone or as part of another group refers to an -N(Rc)C(O)NR₃R_b radical, where R₃, R_b and R₀ are any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl. "Alkoxyacylamino" as used herein alone or as part of another group refers to an - N(R_a)C(O)OR_b radical, where R_a, R_b are any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Aminoacyloxy" as used herein alone or as part of another group refers to an - OC(O)NR₃R_b radical, where R₂ and R_b are any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

"Cycloalkyl," as used herein alone or as part of another group, refers to a saturated or partially unsaturated cyclic hydrocarbon group containing from 3, 4 or 5 to 6, 7 or 8 carbons (which may be replaced in a heterocyclic group as discussed below). Representative examples of cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. These rings may be optionally substituted with halo or loweralkyl.

"Heterocyclic group" or "heterocyclo" as used herein alone or as part of another group, refers to a monocyclic- or a bicyclic-ring system. Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. The 5 membered ring has from 0-2 double bonds and the 6 membered ring has from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like. These rings may be optionally substituted with groups selected from halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O)_m, haloalkyl-S(O)_m, alkenyl-S(O)_m, alkynyl- S (O)_m, cycloalkyl-S(O)_m, cycloalkylalkyl-S(O)_m, aryl-S(O)_m, arylalkyl- S(O)_m, heterocyclo-S(0)_m, heterocycloalkyl-S(O)_m, amino, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano where m = 0, 1 or 2.

"Carbonyl" as used herein refers to a -C(=O)- group.

"Alkoxycarbonyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like.

"Alkylcarbonyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-l- oxopropyl, 1-oxobutyl, 1-oxopentyl, and the like.

"Treat" as used herein refers to any type of treatment that imparts a benefit to a patient afflicted with a disease, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the disease, etc.

"Pharmaceutically acceptable" as used herein means that the compound or composition is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.

"Pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable risk/benefit ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated by reference herein. See also US Patent No. 6,680,299 Examples include a prodrug that is metabolized in vivo by a subject to an active drug having an activity of active compounds as described herein, wherein the prodrug is an ester of an alcohol or carboxylic acid group, if such a group is present in the compound; an acetal or ketal of an alcohol group, if such a group is present in the compound; an N-Mannich base or an imine of an amine group, if such a group is present in the compound; or a Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidine of a carbonyl group, if such a group is present in the compound, such as described in US Patent No. 6,680,324 and US Patent No. 6,680,322.

Prodrugs of the present invention include esters or compositions as described in US Patent No. 6,548,668 to Adams et al., US Patent No. 6,083,903 to Adams et al., or US Patent No. 6,699,835 to Plamondon et al., the disclosures of which are incorporated by reference herein in their entirety.

1. Active compounds.

Active compounds of the present invention (this term including pharmaceutically acceptable salts and prodrugs thereof) can be made in accordance with known techniques (see, e.g., U.S. Patent No. 6,166,063 to Villhauer et al.) or variations thereof which will be apparent to those skilled in the art based on the disclosure provided herein.

Thus compounds or active compounds of the present invention are illustrated by Formula I:

wherein: n and v are independently 1 or 2;

A is a monocyclic, bicyclic or tricyclic carbocycle of 5 to 20 atoms wherein each bridge of the bicycle has at least one atom;

R¹ and R² are independently

wherein: p and q are independently 0 or 1 ;

R⁸ is cyano;

Y is CH₂, CHF, CF₂, O, or S(O)₁₇₁;

W and Z are independently CH₂, CHF, or CF₂; and wherein the ring formed by N, W, Y, Z and the carbon atoms to which ihey are attached is saturated or optionally contains one double bond; and

R¹¹ and R¹² are independently selected from the group consisting of FI, alkylcarbonyl, alkoxycarbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, and sulfone; m is 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof. Examples of compounds of the present invention include but are not limited to:

Active compounds of the invention include compounds of Formula XI:

wherein:

X is NH or a covalent bond; n is 1 or 2;

A is a bicyclic carbocycle of 5 to 20 atoms wherein each bridge of the bicycle has at least one atom;

R¹ is

wherein: p and q are independently 0 or 1 ;

Y is CH₂, CHF, CF₂, O, or S(O)_m;

W and Z are independently CH₂, CHF, or CF₂; and wherein the ring formed by N, W, Y, Z and the carbon atoms to which they are attached is saturated or optionally contains one double bond; and R² is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, and heterocycloalkyl, each of which is unsubstituted or optionally substituted with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, haloalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O)_m, haloalkyl-S(O)_m, cycloalkyl-S(O)_m, cycloalkylalkyl-S(O)_m, aryl-S(O)_m, arylalkyl- S(O)_m, heterocyclo-S(O)_m, heterocycloalkyl-S(O)_m, amino, alkylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano; or

R⁸ is H or cyano; m is 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.

Active compounds of the present invention include compounds of Formula XII:

wherein: n is 1 or 2;

A is a bicyclic or tricyclic carbocycle of 5 to 20 atoms wherein each bridge of the bicycle has at least one atom;

R' is

wherein: p and q are independently 0 or 1 ; Y is CH₂, CHF, CF₂, O, or S(O)_m; W and Z are independently CH₂, CHF, or CF₂; and wherein the ring formed by N, W, Y, Z and the carbon atoms to which they are attached is saturated or optionally contains one double bond;

R²³ is -NR⁵R⁶, or -OR⁶ or OH,

R⁵ is H or alkyl;

R⁶ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, and heterocycloalkyl, each of which is unsubstituted or optionally substituted with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, haloalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O)_m, haloalkyl-S(O)_m, cycloalkyl-S(O)_m, cycloalkylalkyl-S(O)_m, aryl-S(O)_m, arylalkyl- S(O)_m, heterocyclo-S(O)_m, heterocycloalkyl-S(O)_m, amino, alkylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano; or R⁵ and R⁶ together form a C4-C6 alkylene bridge to which may be fused a substituted or unsubstituted cyclic or heterocyclic group;

R⁸ is H or cyano; m is 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.

Active compounds of the present invention include compounds of Formula XIII or Formula XIV:

wherein: n is 1 or 2; A is a bicyclic or tricyclic carbocycle of 5 to 20 atoms wherein each bridge of the bicycle has at least one atom; R¹ is

wherein: p and q are independently 0 or 1 ;

Y is CH₂, CHF, CF₂, O, or S(O)_m;

W and Z are independently CH₂, CHF, or CF₂; and wherein the ring formed by N, W, Y, Z and the carbon atoms to which they are attached is saturated or optionally contains one double bond;

R is H or cyano; m is 0, 1 or 2;

R²⁰ is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heterocyclo, heterocycloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, hetcrocycloalkyloxy, alkylamino, arylalkylamino, heterocycloamino, cycloalkylamino, cycloalkylalkylamino, or disubstituted-amino;

R²¹ and R²² are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl. cycloalkylalkyl, aryl, arylalkyl, heterocyclo, and heterocycloalkyl, each of which is unsubstituted or optionally substituted with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, haloalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O)_m, haloalkyl-S(O)_m, cycloalkyl-S(O)_m, cycloalkylalkyl-S(O)_m, aryl-S(O)_m, arylalkyl- S(O)_n,, heterocyclo-S(O)_m, heterocycloalkyl-S(O)_m, amino, alkylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano; or R²¹ and R²² together form a C4-C6 alkylene linkage; or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments of compounds of Formulas XI-XIV, or salts thereof, n is 1 ; in other embodiments of the foregoing n is 2.

In some embodiments of the foregoing compounds of Formula XI-XIV, or salts thereof, Y is selected from the group consisting of CHF, CF₂, O, and S(O)_m; or q is 1 and W is selected from the group consisting of CHF and CF₂; or p is 1 and Z is selected from the group consisting of CHF and CF₂.

In some embodiments of compounds of Formulas XI-XIV, or salts thereof, Y is selected from the group consisting of CHF, CF₂, O, and S(O)_n,; q is 1 and W is CH₂; and p is O.

In some embodiments of the compounds of Formulas XI-XIV, or salts thereof, Y is selected from the group consisting of CHF, CF₂, O, and S(O)₁₁₁; or q is o; and p is 1 and Z is CH₂.

In some embodiments of the foregoing, Y is CH₂ q is 1 and W is selected from the group consisting of CHF and CF₂; and p is O.

In some embodiments of the foregoing, Y is CH₂; q is O; and p is 1 and Z is selected from the group consisting of CHF and CF₂.

Suitable groups "A" for carrying out the present invention include adamantyl, which may be optionally include one or more double bonds. Examples of suitable adamantyl groups, with linkages, include the following:

Suitable groups "A" for carrying out the present invention include bicyclo[2.1.1]hexane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and bicyclo[3.3.1]nonane, which may be optionally include one or more double bonds.

Particular examples of suitable groups'Α" for carrying out the present invention, with linkages, include the following:

(a bicyclo[2.2.2]octane) (a bicyclo[3.2.1]octane) (a bicyclo[3.1.1]heptane)

Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. The scope of the present invention includes pure stereoisomers as well as mixtures of stereoisomers, such as purified enantiomers/diastereomers, enantiomerically/diastereomerically enriched mixtures or racemates.

The active compounds disclosed herein can, as noted above, be prepared in the form of their pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of such salts are (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; (b) salts formed from elemental anions such as chlorine, bromine, and iodine, and (c) salts derived from bases, such as ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.

2. Pharmaceutical formulations.

The active compounds described above may be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (9^th Ed. 1995). In the manufacture of a pharmaceutical formulation according to the invention, the active compound (including the physiologically acceptable salts thereof) is typically admixed with, inter alia, an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.01 or 0.5% to 95% or 99% by weight of the active compound. One or more active compounds may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy consisting essentially of admixing the components, optionally including one or more accessory ingredients.

The formulations of the invention include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), topical (i.e., both skin and mucosal surfaces, including airway surfaces) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used.

Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above). In general, the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.

Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the active compound in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations of the present invention suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents. The formulations may be presented in unit\dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. For example, in one aspect of the present invention, there is provided an injectable, stable, sterile composition comprising a compound of Formula (I), or a salt thereof, in a unit dosage form in a sealed container. The compound or salt is provided in the form of a lyophilizate which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject. The unit dosage form typically comprises from about 10 mg to about 10 grams of the compound or salt. When the compound or salt is substantially water-insoluble, a sufficient amount of emulsifying agent which is physiologically acceptable may be employed in sufficient quantity to emulsify the compound or salt in an aqueous carrier. One such useful emulsifying agent is phosphatidyl choline.

Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof. Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. Suitable formulations comprise citrate or bis\tris buffer (pH 6) or ethano I/water and contain from 0.1 to 0.2M active ingredient.

Further, the present invention provides liposomal formulations of the compounds disclosed herein and salts thereof. The technology for forming liposomal suspensions is well known in the art. When the compound or salt thereof is an aqueous-soluble salt, using conventional liposome technology, the same may be incorporated into lipid vesicles. In such an instance, due to the water solubility of the compound or salt, the compound or salt will be substantially entrained within the hydrophilic center or core of the liposomes. The lipid layer employed may be of any conventional composition and may either contain cholesterol or may be cholesterol-free. When the compound or salt of interest is water-insoluble, again employing conventional liposome formation technology, the salt may be substantially entrained within the hydrophobic lipid bilayer which forms the structure of the liposome. In either instance, the liposomes which are produced may be reduced in size, as through the use of standard sonication and homogenization techniques. Liposomal formulations containing the compounds disclosed herein or salts thereof, may be lyophilized to produce a lyophilizate which may be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.

Other pharmaceutical compositions may be prepared from the water-insoluble compounds disclosed herein, or salts thereof, such as aqueous base emulsions. In such an instance, the composition will contain a sufficient amount of pharmaceutically acceptable emulsifying agent to emulsify the desired amount of the compound or salt thereof. Particularly useful emulsifying agents include phosphatidyl cholines, and lecithin.

In addition to the active compounds, the pharmaceutical compositions may contain other additives, such as pH-adjusting additives. In particular, useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. Further, the compositions may contain microbial preservatives. Useful microbial preservatives include methylparaben, propylparaben, and benzyl alcohol. The microbial preservative is typically employed when the formulation is placed in a vial designed for multidose use. Of course, as indicated, the pharmaceutical compositions of the present invention may be lyophilized using techniques well known in the art.

3. Subjects.

The present invention is primarily concerned with the treatment of human subjects, but the invention may also be carried out on animal subjects, particularly mammalian subjects such as mice, rats, dogs, cats, livestock and horses for veterinary purposes, and for drug screening and drug development purposes. The subjects may be male or female and may be of any suitable age, including infant, juvenile, adolescent, and adult subjects.

Subjects to be treated with active compounds, or administered active compounds, of the present invention are, in general, subjects in which dipeptidyl peptidase IV (DPP-IV) is to be inhibited.

Subjects in need of such treatment include, but are not limited to, subjects afflicted with diabetes, especially Type II diabetes, as well as 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, anorexia nervosa, osteoporosis, hyperglycemia, Syndrome X, diabetic complications, hyperinsulinemia, obesity, atherosclerosis and related diseases, as well as various immunomodulatory diseases and chronic inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), glucosuria, metabolic acidosis, cataracts, Type 1 diabetes, hypertension, hyperlipidemia, osteopenia, bone loss, bone fracture, acute coronary syndrome, short bowel syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy, chronic pain, alcohol addiction, ulcers, irritable bowel syndrome. Subjects afflicted with such diseases are administered the active compound of the present invention (including salts thereof), alone or in combination with other compounds used to treat the said disease, in an amount effective to combat or treat the disease. A particularly preferred category of diseases for treatment by the methods of the present invention is Type II diabetes.

4. Dosage and routes of administration.

As noted above, the present invention provides pharmaceutical formulations comprising the active compounds (including the pharmaceutically acceptable salts thereof), in pharmaceutically acceptable carriers for oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, or intravenous, and transdermal administration.

The therapeutically effective dosage of any specific compound, the use of which is in the scope of present invention, will vary somewhat from compound to compound, and patient to patient, and will depend upon the condition of the patient and the route of delivery. In general, a dosage from about 0.05 or 0.1 to about 20 or 50 mg/kg subject body weight may be utilized to carry out the present invention. For example, a dosage from about 0.1 mg/kg to about 50 mg/kg may be employed for oral administration; or a dosage of about 0.05 mg/kg to 20 mg/kg may be employed for intramuscular injection. The duration of the treatment may be one or two dosages per day for a period of two to three weeks, or until the condition is controlled or treated. In some embodiments lower doses given less frequently can be used prophylactically to prevent or reduce the incidence of recurrence of the condition being treated.

Transdermal delivery. Numerous different systems for the transdermal delivery of active agents are known. Transdermal delivery systems include but are not limited to passive devices such as drug-in-adhesive transdermal patches and "active" transdermal technologies such as iontophoresis, electroporation, sonophoresis, magnetophoresis, microneedle devices and those devices that use thermal energy to make the skin more permeable.

Transdermal drug delivery devices are available from the 3M Drug Delivery Systems Division (St. Paul, Minnesota, USA), Noven Pharmaceuticals, Inc. (Miami, Florida, USA), ImaRx (Tucson, Arizona, USA), Elan Corporation (Dublin, Ireland), Novosis AG (Miesbach, Germany), Ultrasonic Technologies (St. Albans, Vermont, USA), Antares Pharma (Exton, Pennsylvania, USA), Altea Therapeutics (Tucker, Georgia, USA), Iomed, Inc. (Salt Lake City, Utah, USA), MacroChem Corp (Lexington, Massachusetts, USA), Sontra Medical Corporation (Franklin, Massachusetts, USA), Vyteris, Inc. (Fair Lawn, New Jersey, USA), BioChemics, Inc. (Danvers, Massachusetts, USA), A.P Pharma (Redwood, City, California, USA), MIKA Pharma GmbH (Limburgerhof, Germany), NexMed, Inc. (Robbinsville, New Jersey, USA), Encapsulation Systems, Inc. (Springfield, Pennsylvania, USA), Acrux Ltd (Elgin, Illinois, USA), Jenapharm GmbH (Berlin, Germany), Norwood Abbey (Victoria, Australia), Novavax (Columbia, Maryland, USA), Genetronics Biomedical Corporation (San Diego, California, USA), Adherex Technologies (Research Triangle Park, North Carolina, USA), and AlphaRx (Ontario, Canada).

Transdermal drug delivery using patch technology is typically accomplished by using a covering element in the form of a transdermal patch device that is attached to the host at the desired drug delivery site. A typical transdermal patch structure includes a drug-in-adhesive layer sandwiched between an impermeable backing and a release liner. At the time of use, the release liner is easily removed so that the patch can be attached to the host, adhesive side down. The impermeable backing thus traps the drug-in-adhesive layer between the backing and the attachment site of the host. Over time, the drug penetrates into the host, or is topically active, in accordance with the desired therapeutic treatment. Optionally, the drug-in-adhesive formulation may include one or more compounds known as penetration enhancers that increase the delivery of the drug to the subject. (See U.S. Patent No. 6,627,216).

Some examples of transdermal patch technology include but are not limited to those described in U.S. Patent No. 6,592,893; U.S. Patent No. 6,267,983 to Fuji et al.; U.S. Patent No. 6,238,693 to Luther et al.; U.S. Patent No.6,211,425 to Takayasu et al.; U.S. Patent No. 6,159,497 to LaPrade et al.; U.S. Patent No. 6,153,216 to Cordes et al.; U.S. Patent No. 5,948,433 to Burton et al.; U.S. Patent No. 5.508,035 to Wang et al.; U.S. Patent No. 5,284,660 to Lee et al.; U.S.Patent No. 4,942,037 to Bondi et al.; and U.S. Patent No. 4,906,463 to Cleary et al.

Iontophoresis, an active transdermal technology, uses low voltage electrical current to drive charged drugs through the skin. Those molecules with a positive charge are driven into the skin at the anode and those with a negative charge are driven into the skin at the cathode. See U.S. Patent No. 6,622,037 to Kasamo. Additional examples of iontophoretic delivery devices for the transdermal delivery of active agents include but are not limited to those described in U.S. Pat. No.6,564,903 to Ostrow et al.; U.S. Pat. No. 5,387,189 to Gory et al; U.S. Pat. No. 5,358,483 to Sibalis; U.S. Pat. No. 5,356,632 to Gross et al; U.S. Pat. No. 5,312,325 to Sibalis; U.S. Pat. No. 5,279,544 to Gross et al; U.S. Pat. No. 5,167,479 to Sibalis; U.S. Pat. No. 5,156,591 to Gross et al, U.S. Pat. No. 5,135,479 to Sibalis et al; U.S. Pat. No. 5,088,977 to Sibalis; U.S. Pat. No. 5,057,072 to Phipps; U.S. Pat. No. 5,053,001 to Reller et al; and U.S. Pat. No. 4,942,883 to Newman.

Electroporation is similar to iontophoresis in that it uses electrical fields to aid in transport of molecules across the stratum corneum. However, rather than driving the molecules through the skin, electroporation uses high-voltage electric field pulses to create transient pores which permeabilize the stratum corneum (SC) (Prausnitz et al., Proc. Natl. Acad. Sci. 90:10504- 10508 (1993); Murthy et al. J. Control. Release 98:307-315 (2004); U. S. Patent No. 5,947,921)). Examples of electroporation technology for transdermal delivery include but are not limited to U.S. Pat. No. 6,692,456 to Eppstein et al.; U.S. Pat. No. 6,564,093 to Ostrow et al.; U.S. Pat. No. 6,517,864 to Orup Jacobsen et al.; U.S. Pat. No. 6,512,950 to Li et al.; U.S. Pat. No. 5,968,006 to Hofmann; and U.S. Pat. No. 5,749,847 to Zewart et al.

The technique of sonophoresis utilizes ultrasound to disrupting the stratum corneum, creating cavitations which disorder the lipid bilayers resulting increased drug transport. Although a variety of ultrasound conditions have been used for sonophoresis, the most commonly used conditions correspond to frequencies in the range of between one MHz and three MHz. and intensity in the range of between above zero and two W/cm² (U.S. Pat. No. 4,767,402 to Kost, et al.). Other devices use low frequency ultrasound that is less than one MHz (U.S. Patent No 6,234,990). Other examples of sonophoretic devices include but are not limited to those described in U.S. Pat. No. 6,491,657 to Rowe et al.; U.S. Pat. No. 6,487,447 to Weimann et al.; U.S. Pat. No. 6,190, 315 to Kost et al.; U.S. Pat. No. 6,041, 253 to Kost et al.; U.S. Pat. No. 5,947,921 to Johnson et al.; U.S. Pat. No. 5,906,580 to Kline-Schoder et al.; and U.S. Pat. No. 5,445,61 1 to Eppstein et al.

An additional method used to facilitate the transport of compounds across the stratum corneum is the use of thermal energy. Examples of the use of thermal energy technology to facilitate transport of compounds across the stratum corneum include but are not limited to those described in U.S. Patent No. 6,780,426 to Zhang et al.; U.S. Patent No. 6,613,350 to Zhang et al.; U.S. Patent No. 6,465,006 to Zhang et al.; U.S. Patent No. 6284,266 to Zhang et al.; U.S. Patent No. 6261,595 to Stanley et al.; U.S. Patent No. 6, 048,337 to Svedman; U.S. Patent No. 4,898,592 to Latzke et al.; U.S. Patent No. 4,685,911 to Konno et al.; and U.S. Patent No. 4,230,105 to Harwood.

Magnetophoresis, the use of magnetic energy, is an additional method used to increase drug transport across the stratum corneum. Some examples of magnetophoretic delivery devices include but are not limited to those disclosed in U.S. Patent No. 6,564,093 to Ostrow et al.; U.S. Patent No. 5,983,134 to Ostrow; U.S. Patent No. 5,947,921 to Johnson et al.; U.S. Patent No. 4,702,732 to Powers et al.

Microneedles or microstructured arrays are used to create micropores in the stratum corneum to aid in the flux of drugs across the skin. Examples of microneedle technology includes but is not limited to the disclosure in U.S. Patent No. 6,331,310 to Roser et al. and H. Sebastien, et al, J. Pharm. Sci. 87:922-925 (1998).

Inhalation delivery. Devices for inhalation delivery of active agents, whether to the lungs or to nasal passages, are known and described in, for example, 6,080,762 to Allen et al. For example, dry powder formulations will typically comprise active agent in a dry, usually lyophilized, form of an appropriate particle size or within an appropriate particle size range. Minimum particle size appropriate for deposition within the lung is typically 0.5 μm mass median equivalent aerodynamic diameter (MMEAD), but is preferably 1 μm MMEAD. and is most preferably 2 μm MMEAD. Maximum particle size appropriate for deposition within the lung is typically 10 μm MMEAD, but is preferably 8 μm MMEAD, and is most preferably 4 μm MMEAD. A particle size of about 3 μm MMEAD is most preferred. Minimum particle size appropriate for deposition within the nose is typically 0.5 μm MMEAD, but is preferably 3 μm MMEAD, and is most preferably 5 μm MMEAD. Maximum particle size appropriate for deposition within the nose is typically 100 μm MMEAD, but is preferably 50 μm MMEAD, and is most preferably 20 μm MMEAD. Respirable powders of the active agent within the preferred size range can be produced by a variety of conventional techniques, such as jet milling, spray drying, solvent precipitation, supercritical fluid condensation, and the like. Because particle size is less important for nasal delivery, crystallization from solution may be sufficient. If it is not sufficient, it could be augmented by jet milling or ball milling. These dry powders of appropriate MMEAD can be administered to a patient via a conventional dry powder inhalers (DPI's) which rely on the patient's breath, upon inhalation, to disperse the power into an aerosolized amount. Alternatively, the dry powder may be administered via air assisted devices that use an external power source to disperse the powder into an aerosolized amount, e.g., a piston pump.

Dry powder devices typically require a powder mass in the range from about 1 mg to 20 mg to produce a single aerosolized dose ("puff). If the required or desired dose of the active agent is lower than this amount, as discussed below, the active agent powder will typically be combined with a pharmaceutical dry bulking powder to provide the required total powder mass. Preferred dry bulking powders include sucrose, lactose, dextrose, mannitol, glycine, trehalose, human serum albumin (HSA), and starch. Other suitable dry bulking powders include cellobiose, dextrans, maltotriose, pectin, sodium citrate, sodium ascorbate, and the like.

When the dry powder is prepared by solvent precipitation, buffers and salts are typically used to stabilize the active agent in solution prior to particle formation. Suitable buffers include, but are not limited to, ascorbate, phosphate, citrate, acetate, and tris-HCl, typically at concentrations from about 5 mM to 50 miM. Suitable salts include sodium chloride, sodium carbonate, calcium chloride, and the like.

Liquid formulations of active agent for use in a nebulizer system, e.g., compressed air-, jet-, ultrasonic-, and piezoelectric nebulizers, can employ active agent dissolved or suspended in a pharmaceutical solvent, e.g., water, ethanol, or a mixture thereof. Typically, the minimum concentration of active agent dissolved/suspended is about 1 mg/mL, but is preferably 5 mg/mL, and is most preferably 10 mg/mL. Generally, the maximum concentration of active agent dissolved/suspended is about 100 mg/mL, but is preferably 60 mg/mL, and is most preferably 20 mg/mL. The total volume of nebulized liquid needed to deliver the aerosolized amount is generally in the range from about 0.1 mL to 5 mL.

The pharmaceutical solvent employed can also be a slightly acidic aqueous buffer (pH 4- 6). Suitable buffers are as described above. Other components may be added to enhance or maintain chemical stability, including preservatives, surfactants, dispersants, or gases. Suitable preservatives include, but are not limited to, phenol, methyl paraben, paraben, m-cresol, thiomersal, benzylalkonimum chloride, and the like. Suitable surfactants include, but are not limited to, oleic acid, sorbitan trioleate, polysorbates, lecithin, phosphotidyl cholines, and various long chain diglycerides and phospholipids. Suitable dispersants include, but are not limited to, ethylenediaminetetraacetic acid, and the like. Suitable gases include, but are not limited to, nitrogen, helium, carbon dioxide, air, and the like.

Sprayer systems for respiratory and/or nasal delivery of active agent employ formulations similar to that described for nebulizers. For a description of such lung systems and others described herein, see e.g., Wolff, R. K. and Niven, R. W., "Generation of Aerosolized Drugs," J. Aerosol Med., 7:89, 1994. Nasal delivery systems have been described in Transdermal Systemic Medication, Y. W. Chien Ed., Elsevier Publishers, New York, 1985 and in U.S. Pat. No. 4,778,810, the teachings of which are herein incorporated by reference.

For use in MDI's, active agent may be dissolved or suspended in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Such suspensions will contain between 10 mg to 100 mg of active agent per aerosol dose. Suitable CFCs include trichloromonofluoromethane (propellant 11), dichlorotetrafluoromethane (propellant 1 14), and dichlorodifluoromethane (propellant 12). Suitable HFC's include tetrafluoroethane (HFC- 134a) and heptafluoropropane (HFC-227).

For incorporation into the aerosol propellant, active agent is preferably processed into particles of the sizes described above for the dry powder formulations. The particles may then be suspended in the propellant as is, but are typically coated with a surfactant to enhance/facilitate their dispersion. Suitable surfactants are as defined above for liquid formulation. A propellant formulation may further include a lower alcohol, such as ethanol (up to 30% by weight) and other additives to maintain or enhance chemical stability and physiological acceptability. Additives suitable for propellant formulations include a surfactant as described above, such as sorbitals, oleic acid, and lecithins. For further information on such addivitives, see G. W. Hallworth. "The formulation and evaluation of pressurised metered-dose inhalers," Drug Delivery to the Lung, D. Ganderton and T. Jones (eds), Ellis Horword, Chichester, U.K., pg's 87- 1 18.

The precise dosage of active agent necessary will vary with the age, size, sex and condition of the subject, the nature and severity of the disorder to be treated, and the like; thus, a precise effective amount should be determined by the caregiver. However, the total aerosolized dosage of active agent for the treatment of the disorder will typically be in the range from about 1 or 2 mg to 20, 50 or 100 mg/per day. Typically, the total dosage of active agent will be delivered in a few separate aerosolized doses.

The present invention is explained in greater detail in the following non-limiting Examples.

EXAMPLE 1 l,3-bis-(2-((S)-2-cyanopyrrolidin-l-yl)-2-oxoethylamino)-adamantane

A solution of 1,3-diaminoadamantane (1.328 g, 8 mmol) was dissolved in 50 mL DMF with stirring. Cesium carbonate (3.25 g, 10 mmol) was then added in one portion and the reaction stirred for 20 minutes. The (S)-I -(2-chloroacetyl)pyrrolidine-2-carbonitrile (1.38 g, 8 mmol) was dissolved in 10 mL DMF and added drop wise to the stirring reaction over 5 minutes. The reaction was allowed to stir at room temperature for 18 hrs, and then analyzed by LC/MS. The mono-alkylated product ([M+H]⁺= 303), the di-alkylated product ([M+H]⁺= 439) and the starting diamine ([M+H]⁺=167) were present in a 2:1 :1 ratio and the reaction was stopped. The crude reaction mixture was diluted to 500 mL with dichloromethane and filtered. The filtrate was evaporated to an amber oil that was purified by flash chromatography using 20% methanol/dichloromethane to elute the l,3-bis-(2-((S)-2-cyanopyrrolidin-l-yl)-2- oxoethylamino)-adamantane (540 mg, 15.4% yield) as an off-white foam. Next 50% methanol/dichloromethane was used to elute the (S)-l-[(3-amino-l -adamantyl)amino]-acetyl-2- cyano-pyrrolidine (992 mg, 41% yield) as a yellow foam. ¹H NMR (DMSO, 400MHz) δ 4.71 (dd, 2H, J=3.9, 7.2Hz), 3.59 (m, 2H), 3.35 to 3.44 (m, 2H), 1.94 to 2.15 (m, 12H), 1.45 (bs, 10H)

EXAMPLE 2 l,3-bis(2-((R)-4-cyanothiazolidin-3-yl)-2-oxoethylamino)-adamantane

This compound was prepared similarly to example 1 using (R)-3-(2- chloroacetyl)thiazolidine-4-carbonitrile in 2% yield. EXAMPLES 3-11 Synthesis of Precursor Compounds

EXAMPLE 3 1,4-Dicarbomethoxybicyclo[2.2.2]octane

A cooled (-67⁰C) solution of dry diisopropylamine (54.6mL, 0.39 mole) in anhydrous THF (30OmL) under nitrogen in a 3 -neck 2L round bottom flask equipped with a mechanical stirrer,, addition funnel, and gas inlet/thermometer adapter was treated via syringe with 2.4N n- butyllithium/hexane (15OmL, 0.36 mole) at a rate to keep the pot temperature <-45°C, warmed to 0⁰C for 5 minutes, then recooled (-67⁰C). l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU, 182mL, 1.5 mole, dried over molecular seives) was added dropwise so as to keep pot temp <-60 °C (solid formed), then a solution of dimethyl cyclohexane-l,4-dicarboxylate (60.06g, 0.30 mole) in anhydrous THF (9OmL) was likewise added dropwise. After Ih at -67 ⁰C, a solution of l-bromo-2-chloroethane (60.2g, 0.42 mole) in anhydrous THF (6OmL) was added dropwise so as to keep pot temp <-55⁰C, then the mixture was warmed to room temperature over one hour (solid formed), and stirred at room temperature for 1.5 hours (solid dissolved). The mixture was cooled on an ice bath and quenched with saturated aqueous ammonium chloride (225mL), and the THF was removed in vacuo. The residue was extracted with 9:1 hexane/ethyl acetate (60OmL, then 30OmL, then 2X15OmL), and the combined organic extracts were washed with water (25OmL), dried (MgSO4), and concentrated in vacuo. The residual oil was taken up in methylene chloride (~300mL), filtered through a pad of alumina in a 35OmL coarse fritted glass funnel, further eluted with methylene chloride, and the filtrate concentrated in vacuo to afford 81. Ig of a pale yellow oil (103% of theoretical) which contained primarily desired product and just a little DMPU and starting diester (by LCMS-mass spec). The product could also be visualized on TLC plate eluted with 10%EtOAc/hexane and developed with Hanessian stain.

A solution of l-(2-chloroethyl)-l,4-dicarbomethoxycyclohexane (all of semi-purified from 0.3 moles dimethyl cyclohexane-l,4-dicarboxylate) and DMPU (18ImL, 1.5 moles) in anhydrous THF (70OmL) under nitrogen in a 2L 3 -neck flask equipped with mechanical stirrer, thermometer with nitrogen inlet, and rubber septum was cooled to -67⁰C. Meanwhile, a cooled (-67⁰C) solution of dry diisopropylamine (54.6mL, 0.39 moles) in anhydrous tetrahydrofuran (30OmL) under nitrogen was treated via syringe with 2.4N n-butyllithium/hexane (15OmL, 0.36 moles), the mixture warmed to 0 ⁰C for 5 min, and recooled (-67⁰C). The LDA solution was cannulated in portions (about 6) into the diester solution so as to keep pot temp<-60°C, then the mixture was stirred at -67⁰C for 30 min, warmed to room temperature over 75 min, then stirred at room temperature 3-4h and cooled on an ice bath and quenched with saturated aqueous ammonium chloride (225mL). The THF was removed in vacuo, and the residue was extracted with 9:1 hexane/ethyl acetate (60OmL, 30OmL, 2X200mL). The combined extracts were washed with water (25OmL), dried (MgSO4), and concentrated in vacuo. The residue was dissolved in methylene chloride and filtered through a pad of alumina (in a 150 mL fritted glass filter, eluted with methylene chloride). The filtrate was concentrated to a crude solid (~77g), and this was taken up in petroleum ethers (30°-60°) or pentane, cooled for awhile, filtered and the solid dried in vacuo to afford 26.76g of the subject material as white crystals. The concentrated mother liquor was dissolved in hexane and chromato graphed on silica gel (eluted with 40%, 50%, and 60% methylene chloride/hexane, then 100% methylene chloride) to afford additional subject material (5.4Ig). The total yield was 32.17g (47% for two steps from dimethyl cyclohexane-1,4- dicarboxylate). [M+H]⁺=227.3. ¹H NMR (CDCl₃) δ 3.64 (s, 6H), 1.80 (s, 12H).

EXAMPLE 4

1,4-Dicarboxybicyclo[2.2.2]octane

A stirred solution of l,4-dicarbomethoxybicyclo[2.2.2]octane (31.7g, 0.14 mole) in tetrahydrofuran (20OmL) and isopropanol (7OmL) was treated with a solution of lithium hydroxide hydrate (17.7g, 0.42 mole) in water (20OmL), and the mixture was heated to 60°-70°C for 2.5h with stirring. The organic solvents were removed in vacuo, and the alkaline aqueous solution was filtered, then the filtrate was cooled on an ice bath and acidified with concentrated hydrochloric acid (4OmL). The solid was filtered, rinsed with cold water, and partially air dried overnight, then further dried under vacuum, triturated from acetonitrile, and redried in vacuo to afford 27.19g (98%) of subject material as a white solid. No MS could be obtained. ¹H NMR (d6-DMSO) δ 12.09 (br s, 2H), 1.66 (s, 12H).

EXAMPLE 5 1,4-Diaminobicyclo[2.2.2]octane dihydrochloride

2HCl

A suspension of l,4-dicarboxybicyclo[2.2.2]octane (9.91g, 50 mmol) in toluene (225mL) was azeotroped under a Dean-Stark trap to dryness, then cooled to room temperature under nitrogen and treated with triethylamine (2OmL, 143 mmol) and diphenylphosphoryl azide (33.Og, 120 mmol). The solution was slowly and cautiously warmed to 8O⁰C (some exotherm and much evolution of gas observed) and stirred at 80°-90°C for 3h, then concentrated in vacuo to remove toluene and the residue cooled on an ice bath and treated with 6N hydrochloric acid (15OmL, 900 mmol). The bath was removed and the mixture stirred at room temperature for 3h, then partially concentrated to remove most water. Acetonitrile (60OmL) was added, and the suspension was cooled for an hour in a refrigerator, filtered, and the solid rinsed with acetonitrile and dried in vacuo to afford 9.3 Ig (87%) of subject material as a white solid. [M+H]⁺=141.3. ¹H NMR (d6- DMSO) δ 8.24 (br s, 6H), 1.81 (s, 12H).

EXAMPLE 6 1,3-Dicarbomethoxybicyclo[3.2.1]octane

A cooled (-67⁰C) solution of dry diisopropylamine (11.OmL, 78 mmol) in anhydrous THF (6OmL) in a 3-neck 50OmL round bottom flask equipped with magnetic stirring, addition funnel, and gas inlet/thermometer was treated via syringe with 2.4N n-butyllithium/hexane (3OmL, 72 mmol) at a rate to keep the pot temperature <-50°C, warmed to O⁰C for 5 minutes, then recooled (-67 ⁰C). l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU, 36.3mL, 300 mmole, dried over molecular seives) was added dropwise so as to keep pot temp < -60⁰C, then a solution of dimethyl cyclohexane-l,3-dicarboxylate (12.01g, 60 mmol) in anhydrous THF (2OmL) was likewise added dropwise. After Ih at -67 ⁰C, a solution of l-bromo-2-chloroethane (12.05g, 84 mmol) in anhydrous THF (15mL) was added dropwise so as to keep pot temp <-50 ⁰C, and the mixture was warmed to room temperature over 1.5h and stirred at room temperature for 18h, then cooled on an ice bath and quenched with saturated aqueous ammonium chloride (5OmL). The organic solvent was removed in vacuo and the aqueous residue was extracted with 9:1 hexane/ethyl acetate (15OmL, 10OmL, 2X50mL). The combined organic extracts were washed with water (10OmL), dried (MgSO₄), and concentrated in vacuo. The residue was dissolved in methylene chloride and passed through a pad of alumina in a 6OmL fritted glass funnel (eluted with methylene chloride) to afford 15.36g (97% of theoretical) of a pale yellow oil which was essentially the desired intermediate with minor impurities.

A solution of l-(2-chloroethyl)-l,3-dicarbomethoxycyclohexane (all of semi-purified from 60 mmol dimethyl cyclohexane-l,3-dicarboxylate) and DMPU (36.3mL, 300 mmol) in anhydrous THF (15OmL) under nitrogen in a 50OmL 3 -neck flask equipped with magnetic stirring, addition funnel, and gas inlet/thermometer was cooled to -67⁰C. Meanwhile, a cooled (- 67⁰C) solution of dry diisopropylamine (11.OmL, 78 mmol) in anhydrous THF (75mL) under nitrogen was treated via syringe with 2 4N n-butyllithium/hexane (3OmL, 72 mmol), the mixture was warmed to O⁰C for 5 min, then recooled (-67⁰C). The LDA solution was cannulated in portions (~6) into the other solution at a rate to keep pot temperature <-60 ⁰C, then the mixture was stirred at -67 ⁰C for 30 min, warmed to room temperature over 1.5h, then stirred at room temperature for 18h, cooled on an ice bath and quenched with saturated aqueous ammonium chloride (5OmL). The organic solvent was removed in vacuo and the aqueous residue was extracted with 9:1 hexane/ethyl acetate (15OmL, 10OmL, 2X50mL). The combined organic extracts were washed with water (10OmL), dried (MgSO₄), and concentrated in vacuo. The residue was dissolved in methylene chloride and passed through a pad of alumina in a 6OmL fritted glass funnel (eluted with methylene chloride) to afford crude subject material (9.52g) as a pale yellow oil. Chromatography on silica gel (~400cc) eluted with 40%, then 50% methylene chloride/hexane, then methylene chloride alone, then 10% ethyl acetate/methylene chloride afforded 8.32g (61% for two steps from dimethyl cyclohexane-l,3-dicarboxylate) purified subject material as a very pale yellow oil. [M+H]⁺=226.9. ¹H NMR (CDCl₃) δ 3.66 (s,6H), 2.20-2.30 (m,lH), 2.00-2.10 (m,2H), 1.70-1.80 (m,5H), 1.55-1.65 (m,4H).

EXAMPLE 7 1,3-Dicarboxybicyclo [3.2.1] octane

A stirred solution of l,3-dicarbomethoxybicyclo[3.2.1]octane (8.26g, 36.5 mmol) in tetrahydrofuran (5OmL) and isopropanol (16mL) was treated with a solution of lithium hydroxide hydrate (4.2Og, 100 mmol) in water (5OmL), and the mixture was heated to 60°-70°C for 2h with stirring. The organic solvents were removed in vacuo, and the alkaline aqueous solution was cooled on an ice bath and acidified with concentrated hydrochloric acid (1OmL). The solid was filtered, rinsed with cold water, and partially air dried overnight, then further dried under vacuum, triturated from acetonitrile, and redried in vacuo to afford 6.25g (86%) of subject material as a white solid. No MS could be obtained. ¹H NMR (CDCl₃+drop d6-DMSO) δ 2.15- 2.25 (m, IH), 1.95-2.05 (m, 2H), 1.40-1.70 (m, 9H).

EXAMPLE 8 1 ,3-Diaminobicy clo [3.2.1] octane dihydrochloride

2HCl

A suspension of l,3-dicarboxybicyclo[3.2.1]octane (6.15g, 31 mmol) in toluene (15OmL) was azeotroped under a Dean-Stark trap to dryness, then cooled to room temperature under nitrogen and treated with triethylamine (12.2mL, 87.5 mmol) and diphenylphosphoryl azide (20.4g, 74 mmol). The solution was slowly and cautiously warmed to 8O⁰C (some exotherm and much evolution of gas observed) and stirred at 80°-90°C for 3h, then concentrated in vacuo to remove toluene and the residue cooled on an ice bath and treated with 6N hydrochloric acid (6OmL, 360 mmol). The bath was removed and the mixture stirred at room temperature for 3h, then partially concentrated to remove most water. Acetonitrile (15OmL) was added, and the suspension was cooled for an hour in a refrigerator, filtered, and the solid rinsed with acetonitrile and dried in vacuo to afford 5.25g (79%) of subject material as a white solid. [M+H]⁺=141.3. ¹H NMR (d6-DMSO) δ 8.55 (br s, 6H), 2.23 (m, IH), 1.91 (m, 2H), 1.55-1.75 (m, 9H).

EXAMPLE 9 1,3-Dicarbomethoxybicyclo[3.1.1]heptane

A cooled (-67⁰C) solution of dry diisopropylamine (3.65mL, 26 mmol) in anhydrous THF (2OmL) under nitrogen was treated via syringe with 2.5N n-butyllithium/hexane (9.6mL, 24 mmol), warmed to O⁰C for 5 min, then recooled (-67⁰C). DMPU (12.ImL, 100 mmol) was added dropwise via addition funnel so as to keep pot temp < -60 ⁰C, then a solution of dimethyl cyclohexane-l,3-dicarboxylate (4.0Og, 20 mmol) in anhydrous THF (1OmL) was likewise added dropwise. After Ih at -67⁰C, diiodomethane (7.23g, 27 mmol) in THF (1OmL) was added dropwise, then the mixture was warmed to room temperature over Ih stirred Ih, cooled on an ice bath, and quenched with saturated aqueous ammonium chloride (2OmL). The organic solvents were removed in vacuo and water (3OmL) was added, and the aqueous was extracted with hexane (10OmL, then 2X5 OmL). The combined organic extracts were washed with water (75mL), dried (MgSO₄), and concentrated in vacuo, then dissolved in methylene chloride and passed through a pad of alumina in a fritted (3OmL) funnel. The concentrated filtrate was chromatographed on silica gel (~200cc, eluted with 1 :1 hexane/methylene chloride) to afford 4.65g (68%) of l-iodomethyl-l,3-dicarbomethoxycyclohexane as a colorless oil.

The above intermediate (4.59g, 13.5 mmol) and DMPU (7.25mL, 60mmol) in anhydrous THF (3OmL) under nitrogen was cooled to -67⁰C. Meanwhile, a cooled (-67⁰C) solution of dry diisopropylamine (2.6mL, 18 mmol) in anhydrous THF (2OmL) under nitrogen was treated via syringe with 2.4N n-butyllithium/-hexane (6.25mL, 15 mmol), warmed to 0⁰C for 5 minutes, and recooled (-67 ⁰C). The LDA solution was transferred via cannula in portions into the other solution at a rate to keep the pot temperature <-60⁰C, and the combined solution was stirred at - 67 ⁰C for 30 minutes, warmed to room temperature over 75 minutes, and stirred 4h at room temperature. The mixture was cooled on an ice bath and quenched with saturated aqueous ammonium chloride (2OmL), then partially concentrated in vacuo to remove organics and extracted with hexane (3X50mL). The combined extracts were washed with water (5OmL), dried (MgSO₄), and concentrated in vacuo, dissolved in methylene chloride and filtered through a pad of alumina in a 30 mL fritted glass funnel. The concentrated filtrate was chromatographed on silica gel (~120cc, eluted with 10% ethyl acetate/hexane) to afford 1.97g (69%) of subject material as a colorless oil. [M+H]⁺=213.2. ¹H NMR (CDCl₃) δ 3.66 (s, 6H), 2.45-2.55 (m, 2H), 1.75-2.00 (m, 8H).

EXAMPLE 10 1,3-Dicarboxybicyclo[3.1.1]heptane

A stirred solution of l,3-dicarbomethoxybicyclo[3.1.1]heptane (1.9Og, 8.95mmol) in tetrahydrofuran (25mL) and isopropanol (8mL) was treated with a solution of lithium hydroxide hydrate (2.1g, 50 mmol) in water (25mL), and the mixture was heated to 60°-70°C for 3h with stirring. The organic solvents were removed in vacuo, and the alkaline aqueous solution was cooled on an ice bath and acidified with 6N hydrochloric acid (1OmL). The solid was filtered, rinsed with cold water, and partially air dried overnight, then further dried under vacuum to afford 6.25g (86%) of subject material as a white solid. No MS could be obtained. ¹H NMR (CDCl₃) δ 2.40-2.50 (m, 2H), 1.90-2.00 (m, 4H), 1.80-1.90 (m, 2H), 1.70-1.80 (m, 2H).

EXAMPLE 11 1,3-Diaπ.inobicyclo[3.1.1]heptane dihydrochloride

2HCl

A suspension of l,3-dicarboxybicyclo[3.1.1]heptane (1.0Og, 5.43 mmol) in anhydrous toluene (35mL) under nitrogen was treated with triethylamine (2.65mL, 19 mmol) and diphenylphosphoryl azide (3.72g, 13.5 mmol) and warmed to 80 ⁰C and stirred at 80-90 ⁰C for 3h. The solution was concentrated in vacuo, cooled on an ice bath, and treated with 6N HCl (16mL). The mixture was stirred at room temperature for 16h, extracted with ether (2X25mL), and concentrated in vacuo, then the residue was triturated from acetonitrile and dried to afford 560mg (52%) of the subject material as a white solid. [M+H]⁺=127.5.

¹H NMR (d6-DMSO) δ 8.66 (br s, 6H), 2.30-2.40 (m, 2H), 1.90-2.00 (m, 2H), 1.70-1. '90 (m, 6H).

EXAMPLE 12

General Procedure for Generating Diamine Free Base From Dihydrochloride Salt: 1,4-Diaminobicyclo[2.2.2]octane

DOWEX^® 550A-OH hydroxide resin (Aldrich, 75g) was suspended in methanol, filtered, rinsed with methanol, and partially air dried. A portion of 1 ,4-diamino- bicyclo[2.2.2]octane dihydrochloride (1Og, 46.8 mmol) was taken up in methanol (20OmL), then treated with the above hydro xyl resin and stirred for 30 min (making sure all white clumps were dissolved). The mixture was filtered, the resin rinsed with methanol, and the filtrate concentrated in vacuo to afford 6.46g (98%) of l,4-diaminobicyclo[2.2.2]octane free base as a white solid (caution: compound readily carbonates in air and must be stored under nitrogen).

EXAMPLE 13-15

Additional Examples of Intermediates and Active Compounds

EXAMPLE 13

(S)-(l-(l-Aminobicyclo[2.2.2]oct-4-yl)aminoacetyl)-2-cyanopyrrolidine and (S,S)-l,4-bis[(2-(2-cyanopyrrolidin-l-yl)-2-oxo)ethylamino]bicyclo[2.2.2]-octane

A solution of l,4-diaminobicyclo[2.2.2]octane free base (1.07g, 7.6 mmol) and potassium carbonate (4.5g, 32.6mmol) in anhydrous N,N-dimethylformamide (DMF, 15mL) under nitrogen was treated with (S)-l-chloroacetyl-2-cyano-pyrrolidine (690mg, 4.0 mmol) and stirred at room temperature for 16h. The mixture was combined with methylene chloride (5OmL), filtered through Celite^®, the filter cake rinsed with methylene chloride, and the filtrate concentrated in vacuo (exhaustively to remove DMF). The crude residue was loaded onto a silica gel column (~125cc) and eluted with 4:1 methylene chloride/methanol to afford (S,S)-l,4-bis[(2-(2- cyanopyrrolidin-l-yl)-2-oxo)ethylamino]bicyclo[2.2.2]-octane (160mg, 10%) as a white solid, then eluted with 83:15:2 methylene chloride/methanol/ammonium hydroxide to afford (S)-(I- (laminobicyclo[2.2.2]oct-4-yl)aminoacetyl)-2-cyanopyrrolidine (715mg, 65%) as a waxy white solid. Finally, the column was eluted with 70:23:7 methylene chloride/methanol/-ammonium hydroxide to afford recovered l,4-diaminobicyclo[2.2.2]octane free base 373mg).

(S,S)-l,4-bis[(2-(2-cyanopyrrolidin-l-yl)-2-oxo)ethylamino]bicyclo[2.2.2]octane: [M+H]⁺=413.4. ¹H NMR (CDCl₃) δ 4.70-4.90 (m, 2H), 3.25-3.75 (m, 8H), 2.00-2.40 (m, 8H), 1.60 (br s, 12H).

(S)-(l-(l-aminobicyclo[2.2.2]oct-4-yl)aminoacetyl)-2-cyanopyrrolidine: [M+H]⁺=277.3. ¹H NMR (d6-DMSO) δ 4.70 (m, IH), 3.57 (m, IH), 3.37 (m,lH), 3.24 (m, 2H), 1.85-2.20 (m, 4H), 1.45 (br s, 12H).

EXAMPLE 14

(S)-(l-(l-Aminobicyclo[3.2.1]oct-3-yI)aminoacetyl)-2-cyanopyrrolidine and (S,S)-l,3-bis[(2-(2-cyanopyrroIidin-l-yl)-2-oxo)ethylamino]bicyclo[3.2.1]-octane

A solution of l,3-diaminobicyclo[3.2.1]octane free base (743mg, 5.3 mmol) and potassium carbonate (3.18g, 23mmol) in anhydrous N,N-dimethylformamide (DMF, 1OmL) under nitrogen was treated with (S)-l-chloroacetyl-2-cyano-pyrrolidine (483mg, 2.8 mmol) and stirred at room temperature for 18h. The mixture was combined with methylene chloride (35mL), filtered through Celite^®, the filter cake rinsed with methylene chloride, and the filtrate concentrated in vacuo (exhaustively to remove DMF). The crude residue was loaded onto a silica gel column (-lOOcc) and eluted with 4:1 methylene chloride/methanol to afford (S₅S)-1, 3- bis[(2-(2-cyanopyrrolidin-l-yl)-2-oxo)ethylamino]bicyclo[3.2.1]-octane (204mg, 18%) as a pale yellow foam, then eluted with 83:15:2 methylene chloride/methanol/ammonium hydroxide to afford (S)-(l-(laminobicyclo[3.2.1]oct-3-yl)aminoacetyl)-2-cyanopyrrolidine (568mg, 73%) as a pale yellow oil. Finally, the column was eluted with 70:23:7 methylene chloride/methanol/- ammonium hydroxide to afford recovered l,3-diaminobicyclo[3.2.1]octane free base (210mg).

(S,S)-l,3-bis[(2-(2-cyanopyrrolidin-l-yl)-2-oxo)ethylamino]bicyclo[3.2.1]octane: [M+H]⁺=413.3. ¹H NMR (CDCl₃) δ 4.70-4.85 (m, 2H), 3.30-3.70 (m, 8H), 2.00-2.40 (m, 8H), 1.40-1.80 (m, 12H).

(S)-(I -(l-aminobicyclo[3.2. l]oct-3-yl)aminoacetyl)-2-cyanopyrrolidine: [M+H]⁺=277.4. ¹H NMR (CDCl₃) δ 4.70-4.85 (m, IH), 3.30-3.70 (m, 4H), 2.00-2.40 (m, 4H), 1.40-1.80 (m, 12H).

EXAMPLE 15

(S)-(I-(I - Aminobicyclo [3.1.1 ] hept-3-yl)aminoacetyl)-2-cy anopy rrolidine and (S,S)-l,3-bis[(2-(2-cyanopyrrolidin-l-yl)-2-oxoethyIamino]bicycIo[3.1.1]-heptane

A solution of l,3-diaminobicyclo[3.1.1]heptane free base (316mg, 2.5 mmol) and potassium carbonate (1.66g, 12mmol) in anhydrous N,N-dimethylformamide (DMF, 5mL) under nitrogen was treated with (S)-l-chloroacetyl-2-cyano-pyrrolidine (242mg, 1.4 mmol) and stirred at room temperature for 18h. The mixture was combined with methylene chloride (15mL), filtered through Celite^®, the filter cake rinsed with methylene chloride, and the filtrate concentrated in vacuo (exhaustively to remove DMF). The crude residue was loaded onto a silica gel column (~100cc) and eluted with 9:1 methylene chloride/methanol to afford (S, S)- 1,3- bis[(2-(2-cyanopyrrolidin-l-yl)-2-oxo)ethylamino]bicyclo[3.1.1]-heptane (47mg, 17%) as a colorless glass, then eluted with 90:9:1 methylene chloride/rnethanol/ammonium hydroxide to afford (S)-(l-(l-aminobicyclo[3.1.1]- hept-3-yl)aminoacetyl)-2-cyanopyrrolidine (194mg,

53%) as a viscous oil. Finally, the column was eluted with 60:30:10 methylene chloride/methanol/-ammonium hydroxide to afford recovered l,3-diaminobicyclo[3.1.1]heptane free base (60mg).

(S,S)-l,3-bis[(2-(2-cyanopyrrolidin-l-yl)-2-xo)ethylamino]bicyclo[3.1.1]heptane: [M+H]⁺=399.5. ¹H NMR (CDCl₃) δ 4.70-4.85 (m, 2H), 3.30-3.70 (m, 8H), 1.60-2.40 (m, 18H).

(S)-(I-(I -aminobicyclo [3.1.1 ]hept-3 -yl)aminoacetyl)-2-cyanopyrrolidine : [M+H]⁺=263.2. ¹H NMR (CDCl₃) δ 4.70-4.80 (m, IH), 3.30-3.70 (m, 4H), 2.00-2.45 (m, 4H), 1.50-1.90 (m, 10H).

EXAMPLE 16-20 Additional Examples of Active Compounds

EXAMPLE 16

3-(2-(4-(2-((S)-2-cyanopyrrolidin-l-yl)-2- oxoethylamino)adamantylamino)acetyl)thiazolidine-4-carbonitrile

To a solution of the (S)-l-[(3-amino-l-adamantyl)amino]acetyl-2-cyanopyrrolidine (lOOmg, 0.33 mmol) in DMF (4 ml) was added potassium carbonate ( 136.6 mg, 0.99mmol) followed by the addition of 3-(2-chloroacetyl)thiazolidine-4-carbonitrile ( 94 mg, 0.495 mmol). Reaction mixture was stirred for 18 hours. The crude was checked by LCMS and showed conversion to product M+l= 457. The crude was concentrated and purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 140 mg of the bis TFA salt of 3-(2-(4-(2-((S)-2-cyanopyrrolidin-l-yl)-2- oxoethylamino) adamantylamino) acetyl)thiazolidine-4-carbonitrile was isolated (62 % yield). MS (ESI) m/z = 457 (M+H)⁺.

EXAMPLE 17

(S)-l-(2-(4-(2-oxo-2-(thiazolidin-3-yl)ethylamino)adamantylamino)acetyl)pyrrolidine-2- carbonitrile

Compound was synthesized the same way as described for 3-(2-(4-(2-((S)-2- cyanopyrrolidin- 1 -yl)-2-oxoethylamino)adamantylamino)acetyl)thiazolidine-4-carbonitrile. MS (ESI) m/z = 432 (M+H)⁺. 32 % yield.

EXAMPLE 18

(S)-l-(2-(4-(2-oxo-2-(pyrroIidin-l-yl)ethylamino) adamantylamino)acetyl)pyrrolidine-2-carbonitriIe

To a solution of the (S)-I -[(3 -amino- l-adamantyl)amino]acetyl-2-cyanopyrrolidine (lOOmg, 0.33 mmol) in DMF (4 ml) was added potassium carbonate ( 136.6 mg, 0.99mmol) followed by the addition of 2-chloro-l-(pyrrolidin-l-yl)ethanone (72.8 mg, 0.495 mmol). Reaction mixture was stirred for 18 hours. The crude was checked by LCMS and showed conversion to product M+l=414. The crude was concentrated and purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions bis TFA salt of 3-(2-(4-(2-((S)-2-cyanopyrrolidin-l-yl)-2- oxoethylamino)adamantylamino)acetyl) thiazolidine-4-carbonitrile was isolated. ¹H NMR (CD₃CN, 400 MHz), δ 4.805 (t, IH, J=5.57Hz), 3.889(q, 2H, J=14.9Hz), 3.848(s, 2H), 3.676 to 3.611 (m, IH), 3.506 to 3.393 (m, 6H), 2.710 (dd, IH, J=39.8Hz, J=I LlHz), 2.492 (s, 2H), 2.274 to 2.193 (m, 2H), 2.183 to 2.090 (m, 2H), 2.066 to 1.776(m, 14H), 1.661 (s, 2H). MS (ESI) m/z = 414 (M+H)⁺. 28.3 % yield

EXAMPLE 19

(S)-l-(2-(4-(2-(3,3-difluoropyrrolidin-l-yl)-2- oxoethylamino)adamantylamino)acetyl)pyrrolidine-2-carbonitrile

This compound was synthesized in substantially the same way as described for 3-(2-(4- (2-((S)-2-cyanopyrrolidin- 1 -yl)-2-oxoethylamino)adamantylamino)acetyl) thiazolidine-4- carbonitrile. MS (ESI) m/z = 450 (M+H)⁺. 54 % yield

EXAMPLE 20 (S)-N-(2-cyanoethyl)-2-(4-(2-(2-cyanopyrroIidin-l-yl) -2-oxoethylamino)adamantylamino)-N-cyclopentylacetamide

This compound was synthesized in substantially the same way as described for 3-(2-(4- (2-((S)-2-cyanopyrrolidin-l-yl)-2-oxoethylamino)adamantylamino)acetyl)thiazolidine-4- carbonitrile. MS (ESI) m/z = 481 (M+H)⁺. 51 % yield

EXAMPLES 21-24 Active Compounds with Modified Side-Chains

EXAMPLE 21

(S,S)-l-[(2-(2-cyanopyrroIidin-l-yI)-2-oxo)ethyl(ethoxycarbonyl)amino]-4- [(2-(2-cyanopyrrolidin-l-yl)-2-oxo)ethyIamino]bicyclo [2.2.2] octane and HCl salt

A cooled (5⁰C) solution of (S₅S)- l,4-bis[(2-(2-cyanopyrrolidin-l-yl)-2- oxo)ethylarnino]bicyclo[2.2.2]octane (103mg, 0.25mmol) in anhydrous acetonitrile (1.OmL) and potassium carbonate (200mg, 1.45mmol) under nitrogen was treated dropwise with ethyl chloroformate (30mg, 0.276mmol) in anhydrous acetonitrile (0.5mL). The mixture was stirred at 5⁰C for 4h, diluted with methylene chloride (1OmL), treated with triethylamine (0.1 OmL), filtered, and the filtrate concentrated in vacuo. The residue was dissolved in methylene chloride and loaded onto a silica gel (~20cc) column and eluted with 10% methanol/ethyl acetate, then 7% methanol/methylene chloride to afford the subject compound (41mg, 34%) as a colorless glass. [M+H]⁺=485.4. ¹H NMR (CDCl₃) δ 4.65-4.85 (m, IH), 3.95-4.25 (m, 4H), 3.50-3.70 (m, 2H), 3.25-3.50 (m, 4H), 2.00-2.40 (m, 14H), 1.65 (m, 6H), 1.20 (m, 3H). A solution of the subject free base (41mg, 0.085 mmol) in anhydrous THF (ImL) was treated with 0.25N ethereal HCl (0.4mL, 0.1 mmol), diluted with ether, stirred a few minutes, filtered, and the solid was rinsed with ether, collected, and dried in vacuo to afford 38.4mg (87%) of the subject HCl salt as a white solid.

EXAMPLE 22

3-(2-(4-(2-((S)-2-cyanopyrrolidin-l-yl)-2-oxoethylamino)-adamantyl- l-N-ethoxycarbonyl-N-(arainoethyloxo-2-(4-(2-((S)-cyanopyrrolidin-lyl)))

A solution of the l,3-bis-(2-((S)-2-cyanopyrrolidin-l-yl)-2-oxoethylamino)-adamantane (200mg, 0.46 mmole) in 4mls of acetonitrile with triethylamine ( 140 ul, l.Ommole) and cooled to O⁰C in the freezer. The ethyl chloroformate was prepared in advance as a 0.33M solution in dry THF. The ethyl chloroformate solution (2.8ml, 0.9 mmole) was added dropwise to the cooled amine solution and stirred at O⁰C for 2 hours. The crude was checked by LCMS and showed complete conversion to product M+l= 511. The crude was evaporated to dryness and diluted to 2 mis in 3/1 acetonitrile: water. The sample was purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 30 mg of the mono TFA salt was isolated. 10% yield . ¹H NMR (CD₃N, 400MHz) δ 4.73 (t, IH, J=5.6Hz), 4.68 (t, IH, 5.5Hz), 4.13 (d, 2H, J=5.2Hz), 4.05 (m, 2H), 3.91 (s, 2H), 3.64 (m, 2H), 3.46 (m, 2H), 2.54 (s, 2H), 2.37 (s, 2H), 2.28 to 2.08 (m, 8H), 1.96 (m 7H), 1.62 (m, 2H), 1.21 (t, 3H, J=7.0Hz).

EXAMPLE 23 3-(2-(4-(2-((S)-2-cyanopyrrolidin-l-yl)-2-oxoethylamino)-adamantyl- l-N-methoxycarbonyl-N-(aminoethyloxo-2-(4-(2-((S)-cyanopyrrolidin-lyl)))

A solution of the l,3-bis-(2-((S)-2-cyanopyrrolidin-l-yl)-2-oxoethylamino)-adamantane (200mg, 0.46 mmole) in 4mls of acetonitrile with triethylamine ( 140 ul, l.Ommole) and cooled to O⁰C in the freezer. The methyl chloroformate was prepared in advance as a 0.5M solution in dry THF. The methyl chloroformate solution (2. ml, 1.0 mmole) was added dropwise to the cooled amine solution and stirred at O⁰C for 2 hours. The crude was checked by LCMS and showed complete conversion to product M+l= 497. The crude was evaporated to dryness and diluted to 2 mis in 3/1 acetonitrile: water. The sample was purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 58 mg of the mono TFA salt was isolated. 21% yield . ¹H NMR (CD₃N, 400MHz) δ 4.73 (t, IH, J=5.6Hz), 4.67 (t, IH, J=5.6Hz), 4.15 (s, 2H), 3.89 (d, 2H, J=6.4Hz), 3.63 (m, 2H), 3.60 (s, 3H), 3.45 (m, 2H), 2.56 (s, 2H), 2.38 (s, 2H), 2.28 to 2.10 (m, 8H), 1.98 to 1.88 (m, 7H), 1,62 ( m, 2H)

EXAMPLE 24

3-(2-(4-(2-((S)-2-cyanopyrrolidin-l-yl)-2-oxoethylamino)- adamantyl-l-N-acetyl-N-(aminoethyloxo-2-(4-(2-((S)-cyanopyrroIidin-lyl)))

A solution of the l,3-bis-(2-((S)-2-cyanopyrrolidin-l-yl)-2-oxoethylarαino)-adamantane (140mg, 0.32 mmole) in 4mls of acetonitrile with triethylamine ( 140 ul, l.Ommole) and cooled to O⁰C in the freezer. The acetyl chloride was prepared in advance as a 0.33M solution in dry THF. The acetyl chloride solution (0.5 ml, 0.16 mmole) was added dropwise to the cooled amine solution and stirred at O⁰C for 2 hours. The crude was checked by LCMS and showed . complete conversion to product M+l= 481. The crude was evaporated to dryness and diluted to 2 mis in 3/1 acetonitrile: water. The sample was purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 32 mg of the mono TFA salt was isolated. 17% yield. MS (ESI) m/z = 481 (M+H)⁺.

EXAMPLES 25-26 Compounds with Alternate Groups "A"

EXAMPLE 25 l-(2-((l,3,3-trimethyl-4-(2-oxo-2-(pyrrolidin-l-yl-2- carbonitrile)ethylamino)cyclohexyl)methylamino)acetyl)pyrrolidine-2-carbonitrile

To a solution of 5-amino-l,3,3-trimethylcycloxexanemethylamine (49.5 mg, 0.29 mmol) in DMF (2 ml) potassium carbonate (200 mg, 1.45 mmol) was added followed by the addition of l-(2-chloroacetyl)pyrrolidine-2-carbonitrile(100 mg, 0.58 mmol). Reaction mixture was stirred for 18 hours. The crude was checked by LCMS and showed conversion to product M+l= 441. Then crude was concentrated and purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 24 mg of the mono TFA salt was isolated. (15% yield). MS (ESI) m/z = 443 (M+H)⁺.

EXAMPLE 26 l-(2-(2-(4-methyI-4-(2-oxo-2-(pyrrolidin-l-yl-2-carbonitrile) ethylamino)cyclohexyl)propan-2-ylamino)acetyl)pyrrolidine-2-carbonitrile

Compound was synthesized the same way as described for l-(2-((l,3,3-trimethyl-4-(2- oxo-2-(pyrrolidin- 1 -yl-2-carbonitrile)ethylamino)cyclohexyl)methylamino)acetyl) pyrrolidine-2- carbonitrile. MS (ESI) m/z = 441 (M+H)⁺. 18 % yield.

EXAMPLE 27

1 ,3-di [2-oxo-(thiazolidin-3-yl)ethy lamino)adamantine and 2-(3-aminoadamantylamino)-l-(thiazolidin-3-yl)ethanone

A solution of diaminoadamantane free base ( 332mg, 2mmol) and potassium carbonate (414 mg, 3mmol) in anhydrous N,N-dimethylformamide was treated with 2-chloro-l- (tetrahydrothiophen-3-yl)ethanone (247 mg, 1.5 mmol) and stirred at room temperature for 18h. The reaction mixture was combined with methylene chloride, filtered through Celite^®, then filtrate was concentrated in vacuo and the crude was purified by column silica gel chromatography using DCM/ MeOH as eluting solvent to afford 134 mg ( 26% yield) of 2-(3- aminoadamantylamino)-l-(thiazolidin-3-yl)ethanone and 116 mg of crude l,3-di[2-oxo- (thiazolidin-3-yl)ethylamino)adamantine. Then crude l,3-di[2-oxo-(thiazolidin-3- yl)ethylamino)adamantine was purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 45 mg (7% yield) of 1,3- di[2-oxo-(thiazolidin-3-yl)ethylamino)adamantine was isolated. l,3-di[2-oxo-(thiazolidin-3-yl)ethylamino)adamantine; MS (ESI) m/z = 425 (M+H)⁺, 2-(3-aminoadamantylamino)-l-(thiazolidin-3-yl)ethanone; MS (ESI) m/z =296 (M+H)⁺.

EXAMPLE 28 l,3-di[2-oxo-(3,3-difluoropyrrolidin-3-yl)ethylamino)adamantine and 2-(3-aminoadamantylamino)-l-(3,3-difluoropyrrolidin-l-yl)ethanone

These ompounds were synthesized the same way as described for l,3-di[2-oxo- (thiazolidin-3-yl)ethylamino)adamantine and 2-(3-aminoadamantylamino)-l -(thiazolidin-3- yl)ethanone. l,3-di[2-oxo-(3,3-difluoropyrrolidin-3-yl)ethylamino)adamantine; MS (ESI) m/z = 461 (M+H)⁺. 2% yield

2-(3-aminoadamantylamino)-l-(3,3-difluoropyrrolidin-l-yl)ethanone; MS (ESI) m/z = 314 (M+H)⁺. 17 % yield EXAMPLE 29-30 Inhibition of dipeptidyl peptidase IV (DPP-IV) activity

Porcine dipeptidyl peptidase IV (Sigma, D-7052) is used. Test compound and/or vehicle is pre-incubated with enzyme (70 μU /ml) in Tris-HCl pH 8.0 for 15 minutes at 37⁰C. Ala-Pro- AFC (20 μM) is then added for a further 30 minutes incubation period. The concentration of proteolytic product, AFC, is then read spectrofiuorimetrically. 8 point concentration curves in duplicate are used to calculate IC₅₀ values, or percent inhibition is measured in duplicate at two dose levels.

Table 1 - DPP-IV IC₅₀ values

Table 2 - Percent Inhibition of DPP-IV

EXAMPLES 31-34 Amides and Urea Active Compounds

EXAMPLE 31

(S)-(2-Cyano-l-(l-(4-fluorobenzamido) bicyclo[2.2.2]oct-4-yl)aminoacetyl)-pyrrolidine

An ice-cooled solution of (S)-(l-(l-aminobicyclo[2.2.2]oct-4-yl)aminoacetyl)-2- cyanopyrrolidine (55.3mg, 0.20 mmol) and triethylamine (0.14mL, 1.0 mmol) in anhydrous methylene chloride (1.OmL) under nitrogen was treated with 4-fluorobenzoyl chloride (40mg, 0.25 mmol). The mixture was warmed to room temperature and stirred for 16h, then concentrated in vacuo. The residue was dissolved in methylene chloride and loaded onto a silica gel column (~15cc) and eluted with 1.5% methanol/methylene chloride, then 5% methanol/methylene chloride to afford (S)-(2-cyano-l-(l-(4-fluorobenzamido)bicyclo[2.2.2]oct- 4-yl)-aminoacetyl)pyrrolidine (51mg, 64%) as a white foam. [M+H]⁺=399.5. ¹H NMR (CDCl₃) δ 7.69 (dd, 2H, J=9Hz, 6Hz), 7.07 (t, 2H, J=9Hz), 5.71 (s, IH), 4.73-4.85 (m, IH), 3.33- 3.63 (m, 4H), 2.05-2.20 (m, 4H), 2.09 (m, 6H), 1.72 (m, 6H).

EXAMPLE 32

(S)-(2-Cyano-l-(l-(4-fluorophenyl) aminocarboxamidobicyclo [2.2.2] oct-4-yl)aminoacetyl)pyrrolidine

An ice-cooled solution of (S)-(l-(l-aminobicyclo[2.2.2]oct-4-yl)aminoacetyl)-2- cyanopyrrolidine (55.3mg, 0.20 mmol) in anhydrous tetrahydrofuran (1.OmL) under nitrogen was treated with 4-fluorophenyl isocyanate (31.5mg, 0.23 mmol), warmed to room temperature, stirred for 16h, and concentrated in vacuo. The residue was dissolved in methylene chloride and loaded onto a silica gel column (~15cc) and eluted with 2%, then 10% methanol/methylene chloride to afford (S)-(2-cyano-l-(l-(4-fluorophenyl)aminocarboxamidobicyclo[2.2.2]oct-4- yl)aminoacetyl)pyrrolidine (40mg, 48%) as a white foam. [M+H]⁺=414.5. ¹H NMR (CDC13) δ 7.21 (dd, 2H, J=9Hz, 6Hz), 6.97 (t, 2H, J=9Hz), 6.29 (br s, IH), 4.72-4.84 (m, IH), 4.49 (br s, IH), 3.30-3.62 (m, 4H), 2.00-2.20 (m, 4H), 1.96 (m, 6H), 1.64 (m, 6H).

EXAMPLE 33

(S)-(2-Cyano-l -(I -(4-fluorobenzamido) bicyclo [3.2.1] oct-3-yl)aminoacetyl)-pyrrolidine

An ice-cooled solution of (S)-(l-(l-aminobicyclo[3.2.1]oct-3-yl)aminoacetyl)-2- cyanopyrrolidine (55.3mg, 0.20 mmol) and triethylamine (0.14mL, 1.0 mmol) in anhydrous methylene chloride (1.OmL) under nitrogen was treated with 4-fluorobenzoyl chloride (35mg, 0.22 mmol). The mixture was warmed to room temperature and stirred for 2h, then concentrated in vacuo. The residue was dissolved in methylene chloride and loaded onto a silica gel column (~15cc) and eluted with 3% methanol/methylene chloride, then 5% methanol/methylene chloride to afford (S)-(2-cyano-l-(l-(4-fluorobenzamido)bicyclo[3.2.1]oct-3-yl)-aminoacetyl)pyrrolidine (46mg, 58%) as a white foam. [M+H]⁺=399.3. ¹H NMR (CDCl₃) δ 7.72 (dd, 2H, J=9Hz, 6Hz), 7.08 (t, 2H, J=9Hz), 6.17 (br s, IH), 4.73-4.85 (m, IH), 3.37-3.67 (m, 4H), 1.95-2.35 (m, 8H), 1.50-1.85 (m, 8H).

EXAMPLE 34

(S)-(2-Cyano-l-(l-(4-fluorophenyl) aminocarboxamidobicyclo [3.2.1] oct-3-yl)aminoacetyl)pyrrolidine

An ice-cooled solution of (S)-(l-(l-aminobicyclo[3.2.1]oct-3-yl)aminoacetyl)-2- cyanopyrrolidine (69mg, 0.25 mmol) in anhydrous methylene chloride (1.5mL) under nitrogen was treated with 4-fluorophenyl isocyanate (34mg, 0.25 mmol) in anhydrous methylene chloride (0.5mL), warmed to room temperature for Ih, then loaded directly onto a silica gel column (~15cc) and eluted with 4% methanol/ethyl acetate, then 7% methanol/methylene chloride to afford (S)-(2-cyano- 1 -( 1 -(4-fiuorophenyl)aminocarboxamidobicyclo [3.2.1 ] oct-3 - yl)aminoacetyl)pyrrolidine (40mg, 39%) as a white foam. [M+H]⁺=414.4. IH NMP (XΔXλ3) δ 7.26 (dd, 2H, J=9Hz, 6Hz), 7.10 (d, IH, J=8.5Hz), 6.93 (t, 2H, J=9Hz), 5.41 (br s, IH), 4.68^4.85 (m, IH), 3.32-3.62 (m, 4H), 2.10-2.35 (m, 4H), 1.90-2.05 (m, 4H), 1.40-1.75 (m, 8H).

EXAMPLES 35-36 Alpha-Carbonyl Active Compounds

EXAMPLE 35

3-(2-(4-(2-((S)-2-cyanopyrrolidin-l-yl)-2-oxoethyIamino) adamantylamino) acetamido)-N-(5-cyanopyridin-2-yl)

A solution of the (S)-l-[(3-amino-l-adamantyl)amino]acetyl-2-cyano-pyrrolidine (lOOmg, 0.33 mmole) was dissolved in 2 mis DMF with stirring, potassium carbonate (69mg, 0.5 mmole) was then added in one portion and the reaction was stirred for 20 minutes. The 2-chloro- N-(5-cyanopyridin-2-yl)acetamide (52mg, 0.27 mmole) was dissolved in 1 ml DMF and added drop wise to the stirring reaction over 2 minutes. The reaction was allowed to stir at room temperature for 18 hrs, and then checked by LCMS. The reaction was checked by LCMS and the product was present with a retention time of 2.2 minutes with M+ 1=462. The crude was diluted to 2OmIs with DCM and filtered. The crude was evaporated to dryness and diluted to 1 mls in 3/1 acetonitrile: water. The sample was purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 40 mg of the mono TFA salt was isolated. 26% yield. ¹H NMR (CD₃N, 400MHz) δ 8.63 (s, IH), 8.07 (s, 2H), 4.79 (t, IH, J=5.6Hz), 4.14 (s, 2H), 3.95 (dd, 2H, J=15.9, 24.6Hz), 3.66 (dt, IH, J=5.8, 9.8Hz), 3.49 (dt, IH, J=7.7, 9.6Hz), 2.59 (dd, 2H, J=I l, 18.6Hz), 2.50 (s, 2H), 2.23 (t, 2H, J=6.2Hz), 2.14 (m, 2H), 1.96 (m, 9H), 1.67 (bs, 2H)

EXAMPLE 36

3-(2-(4-(2-((S)-2-cyanopyrrolidin-l-yl)-2-oxoethylamino) adamantylamino) acetamido)-l-(3, 4-dihydroisoquinolin-2(lH)-yl)

A solution of the (S)-l-[(3-amino-l-adamantyl)amino]acetyl-2-cyano-pyrrolidine (lOOmg, 0.33 mmole) was dissolved in 2 mis DMF with stirring, potassium carbonate (69mg, 0.5 mmole) was then added in one portion and the reaction was stirred for 20 minutes. The 2-chloro- N-(3, 4-dihydroisoquinolin-2(lH)-yl))acetamide (53mg, 0.25mmole) was dissolved in 1 ml DMF and added dropwise to the stirring reaction over 2 minutes. The reaction was allowed to stir at room temperature for 18 hrs. The reaction was checked by LCMS and the product was present with a retention time of 2.75 minutes with M+l=476.The crude was diluted to 2OmIs with DCM and filtered. The crude was evaporated to dryness and diluted to 1 mis in 3/1 acetonitrile: water. The sample was purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 40 mg of the mono TFA salt was isolated. 68% yield ¹H NMR (CD₃N, 400MHz) δ 7.22 (m, 4H), 4.76 (q, IH, J=5.7Hz), 4.69 (d, IH, J=9.7Hz), 4.64 (s, IH), 4.06 (s, 2H), 3.92 (dd, 2H, J=I 6.2, 26.2Hz), 3.66 (m, 2H), 3.48 (dt, IH, J=7.6, 9.4Hz), 2.96 (t, IH, J=5.8Hz), 2.84 (t, IH, J=5.8), 2.73 (m, 2H), 2.50 (s, 2H), 2.22 (m, 2H), 2.14 (m, 2H), 1.96 (m,9H), 1.67 (s, 2H). EXAMPLES 37-41 Additional Active Compounds

Examples 8-12 show additional active compounds, with different structures, that are useful in like manner as the active compounds set forth above.

EXAMPLE 37

(S)-l-[3-(tert-butyl-methylcarbamoylsulfamoyl- l-adamantyl)-amino]acetyl-2-cyanopyrrolidine

To a solution of the (S)-l-{(3-amino-l adamantyl)anino]acetyl-2-cyano-pyrrolidine (500 mg, 1.65 mmol) in 5 ml of methylene chloride N-(l-(tert-butoxycarbonyl)pyridin-4(lH)- ylidene)-N-methylmethanaminium (596 mg, 1.98 mmol) was added. Reaction mixture was stirred for 18 hours. The crude was checked by LCMS and showed complete conversion to product M+l=482. Then crude material was concentrated and purified by column silica gel chromatography using DCM/ MeOH as eluting solvent to afford 287 mg of [3-(tert-butyl- methylcarbamoylsulfamoyl-l-adamantyl)-amino]acetyl-2-cyanopyrrolidine (36% yield). ¹H NMR (CD₃CN, 400 MHz), δ 5.608(broad, IH), 4.67 (t, IH, J=5.27Hz), 3.628 to 3.538 (m, IH), 3,44 to 3.35 (m, IH), 2.0 to 2.3 (m, 7H), 1.5 to 1.85 (m, HH), 1.490 (s, 9 H)

EXAMPLE 38 (S)-l-[(3-pivaIsuIfamoyI-l-adamantyl)-amino]acetyl-2-cyanopyrrolidine

To a solution of (S)-l-[(3-aminosulfamoyl-l-adamantyl)-amino]acetyl-2- cyanopyrrolidine (80 mg, 0.209 mmol) in DMF (3 ml) DMAP ( 51 mg, 0.42 mmol) , DIEA ( 73 μl, 0.42 mmol) and trimethylacetyl chloride ( 75 μl, 0.63 mmol) were added. The reaction mixture was stirred for 2 hours. The crude was checked by LCMS and showed complete conversion to product M+l= 466. The crude was concentrated and purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 9 mg of the mono TFA salt was isolated. (10% yield). MS (ESI) m/z = 466 (M+H)⁺.

EXAMPLE 39

N'-(3-(2-(S)-2-cyanopyrrolidine-l-yl)-2 -oxoethylamino)-adamantyl)-trimethylacetylsulfamide

To a cooled with ice bath solution of (S)-l-[(3-aminosulfamoyl-l-adamantyl)- amino]acetyl-2-cyanopyrrolidine (80 mg 0.21 mmol) in DMF (3ml) was added DMAP (51 mg, 0.42 mmol), DIEA (73 μL, 0.42 mmol) and trimethylacetyl chloride (75μL, 0.63). Reaction mixture was stirred for 18 hours. The crude was checked by LCMS and showed conversion to product M+l= 424. Then crude was concentrated and purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 9 mg of the mono TFA salt was isolated (10 % yield). MS (ESI) m/z = 424 (M+H)⁺.

EXAMPLE 40

(E)-N'-cyano-N-[(3-adamantyl-amino}acetyI-2- cyanopyrrolidine]piperidine-l-carboxamidine

To a solution of the N-(3-aminoadamantyl)-N'-cyanopiperidine-l-carboxamidine (37 mg, 0.123 mmol) in 2 ml of DMF 3 equivalents of potassium carbonate (50.9 mg, 0.369 mmol) was added followed by the addition of l-(2-chloroacetyl)pyrrolidine-2-carbonitrile (31.7 mg, 1.85 mmol). Reaction mixture was stirred for 18 hours. The crude was checked by LCMS and showed complete conversion to product M+l= 438. Then crude was concentrated and purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 12 mg of the mono TFA salt of (E)-N'-cyano-N-[(3-adamantyl- amino}acetyl-2-cyanopyrrolidine]piperidine-l-carboxamidine was isolated (18 % yield). ¹H NMR (CD₃CN, 400 MHz), δ 4.714 (t, IH, J=5.56), 3.98 to 3.905 (m, IH), 3.72 to 3.58 (m, IH), 2.5 (s, IH), 2.44 to 2.045 (m, 5H), 2.045 to 1.82 (m, 10H), 1.744 to 1.541 (m, 5H).

EXAMPLE 41

(S,E)-l-(2-(4-(2-cyano-l-(pyrrolidin-l-yI)vinylamino) adamantylamino)acetyl)pyrrolidine-2-carbonitrile

This compound was synthesized in substantially the same way as described for (E)-N'- cyano-N- [(3 -adamantyl-amino } acetyl-2-cyanopyrrolidine]piperidine- 1 -carboxamidine. MS (ESI) m/z = 424 (M+H)⁺. 63 % yield. EXAMPLE 42

(S)-l-[3-(3-(3-chlorophenyl)ureayl suIfamoyl- l-adamantyl)-amino]acetyI-2-cyanopyrrolidine

A solution of 3-chloro-aniline (45mg, 0.35 mmole) in 2.5 mL acetonitrile was added dropwise to a solution of chlorosulfonyl isocyanate (50 mg, 0.35 mmole) in 0.5 mL acetonitrile at 0 ⁰C under nitrogen. The reactions stirred for 30 minutes when LC/MS analysis showed formation of the intermediate was complete. This reaction mixture was then added dropwise to a solution of (S)-I -[(3 -amino- l-adamantyl)amino]acetyl-2-cyano-pyrrolidine (107mg, 0.35 mmole) and triethylamine (54 μL, 0.39 mmole) in 1 mL acetonitrile at room temperature. The reaction stirred overnight. The crude reaction mixture was evaporated to dryness and diluted to 1 mL in 3/1 acetonitrile: water. The sample was purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 20 mg of the mono TFA salt was isolated. 9% yield. MS (ESI) m/z = 535 (M+H)⁺.

EXAMPLE 43

(S)-l-[3-(3-(5-cyanopyridin-2-yl)ureayl sulfamoyl- l-adamantyl)-amino]acetyl-2-cyanopyrrolidine

This compound was prepared similarly to that described in Example 12 above. After lyophilization of the fractions 16 mg of the mono TFA salt was isolated. 7% yield. MS (ESI) m/z - 527 (M+H)⁺.

EXAMPLE 44

7er/-butyI 2-(3-(2-((S)-2-cyanopyrrolidin- l-yl)-2-oxoethylamino)-adamantylamino)acetate

To a solution of (S)-I -[(3 -amino- l-adamantyl)amino]acetyl-2-cyano-pyrro Ii dine (219mg, 0.73 mmole) in 2 mL of dichloromethane was added 200 μL triethylamine then tert-butyl bromoacetate (107 μL, 0.73 mmole). After 2 hours the crude reaction mixture was evaporated to dryness and diluted to 1 mL in 3/1 acetonitrile: water. The sample was purified by mass directed fractionation with an acetonitrile/water gradient and TFA as a modifier. After lyophilization of the fractions 87 mg of the mono TFA salt was isolated. 22.5% yield. MS (ESI) m/z = 417 (M+H)⁺.

EXAMPLE 45

Methyl 2-(3-(2-((S)-2-cyanopyrrolidin-l-yl)- 2-oxoethylamino)-adamantylamino)acetate

To a solution of (S)-l-[(3-amino-l-adamantyl)amino]acetyl-2-cyano-pyrrolidine (367mg, 1.2 mmole) in 2 mL of dichloromethane was added 200 μL triethylamine then methyl bromoacetate (115 μL, 1.2 mmole). After 2 hours the crude reaction mixture was evaporated to dryness and dissolved in dichloromethane. The product was purified by flash chromatography on a silica gel column (~15g SiO₂) eluting with a solvent gradient from 100 % dichloromethane to 98:2 dichloromethane:methanol to afford 87 mg of the product. 55% yield. MS (ESI) m/z = 375 (M+H)⁺.

EXAMPLE 46

2-(3-(2-((S)-2-cyanopyrrolidin-l-yl)-2- oxoethylamino)-adamantylamino)acetic acid

To a solution of tert-butyl 2-(3-(2-((S)-2-cyanopyrrolidin-l-yl)-2-oxoethylamino)- adamantylamino)acetate (17 mg, 0.045 mmol) in 1 mL dichloromethane was added 200 mL of trifluoroacetic acid. The mixture was stirred for 2 hours. The trifluoroacetic acid was removed by evaporating the reaction mixture to dryness then redissolving in dichloromethane. This was repeated four times to give 21 mg of the bis-TFA salt. 81% yield. MS (ESI) m/z = 361 (M+H)⁺.

EXAMPLE 47

(S,E)-l-(2-(4-(2-cyano-l-(methyl-l-yl)vinylamino) adamantylamino)acetyl)pyrrolidine-2-carbonitrile

This compound was prepared similarly to Example 41 but purified by flash chromatography using a stepwise gradient from 100% ethyl acetate to 20% ethanol/ ethyl acetate with a final elution with 10% methanol/ methylene chloride. This gave 44 mg of the desired product. 54% yield. MS (ESI) m/z = 384 (M+H)⁺.

EXAMPLE 48

(S,E)-l-(2-(4-(2-cyano-l-((4-fluorophenyl)-l- yl)vinylamino)adamantylamino)acetyl)pyrrolidine-2-carbonitrile

This compound was prepared similarly to that described in example 47 above. 14 mg of product was isolated. 29% yield. MS (ESI) m/z = 478 (M+H)⁺.

EXAMPLE 49 Inhibition of dipeptidyl peptidase IV (DPP-IV) activity

Porcine dipeptidyl peptidase IV (Sigma, D-7052) is used. Test compound and/or vehicle is pre-incubated with enzyme (70 μU ^f/ml) in Tris-HCl pH 8.0 for 15 minutes at 37⁰C. Ala-Pro- AFC (20 μM) is then added for a further 30 minutes incubation period. The concentration of proteolytic product, AFC, is then read spectrofluorimetrically. 8 point concentration curves in duplicate are used to calculate IC₅₀ values, or percent inhibition is measured in duplicate at two dose levels. Active compounds as described herein are found to inhibit DPP-IV activity in the foregoing test.

The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

THAT WHICH IS CLAIMED IS:

1. A compound of Formula I:

wherein: n and v are independently 1 or 2;

A is a monocyclic, bicyclic or tricyclic carbocycle of 5 to 20 atoms wherein each bridge of the bicycle has at least one atom;

R¹ and R² are independently

wherein: p and q are independently 0 or 1 ;

R⁸ is cyano;

Y is CH₂, CHF, CF₂, O, or S(O)_m;

W and Z are independently CH₂, CHF, or CF₂; and wherein the ring formed by N, W, Y, Z and the carbon atoms to which they are attached is saturated or optionally contains one double bond; and subject to the proviso that one of R¹ or R² may be -C(O)NR⁷R⁸, where R⁷ is alkyl, cycloalkyl, or cycloalkylalkyl and R is cyanoalkyl or cyanocycloalkyl; R¹¹ and R¹² are independently selected from the group consisting of H, alkylcarbonyl, alkoxycarbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, and sulfone; m is 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.

2. The compound of claim 1, wherein A is adamantyl.

3. The compound of claim 1, wherein A is

4. The compound of claim 1, wherein A is selected from the group consisting of bicyclo[2.1.1]hexane, bicyclo[3.2.1]octane, bicyclo[3.1.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.3.1]nonane, which may be optionally include one or more double bonds.

5. The compound of claim 1, wherein A is selected from the group consisting of

6. The compound of claim 1, wherein n is 1.

7. The compound of claim 1, wherein n is 2.

8. The compound of claim 1, wherein v is 1.

9. The compound of claim 1, wherein v is 2.

10. The compound of claim 1, wherein, for both Ri and R₂:

Y is selected from the group consisting of CHF, CF₂, O, and S(O)_m; or q is 1 and W is selected from the group consisting of CHF and CF₂; or p is 1 and Z is selected from the group consisting of CHF and CF₂.

11. The compound of claim 1 , wherein, for both R₁ and R₂:

Y is selected from the group consisting of CHF, CF₂, O, and S(O)₁₇₁; q is 1 and W is CH₂; and p is O.

12. The compound of claim 1, wherein, for both R₁ and R₂:

Y is selected from the group consisting of CHF, CF₂, O, and S(0)_m; or q is o; and p is 1 and Z is CH₂.

13. The compound of claim 1, wherein, for both Ri and R₂:

Y is CH₂; q is 1 and W is selected from the group consisting of CHF and CF₂; and p is 0.

14. The compound of claim 1, wherein, for both Ri and R₂:

Y is CH₂; q is 0; and p is 1 and Z is selected from the group consisting of CHF and CF₂.

15. The compound of claim 1 wherein R¹¹ and R¹² are both H.

16. The compound of claim 1 wherein R¹¹ and R¹² are both selected from the group consisting of alkylcarbonyl and alkoxycarbonyl.

17. The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts and prodrugs thereof.

18. The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts and prodrugs thereof.

19. The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts and prodrugs thereof.

20. The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts and prodrugs thereof.

21. The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts and prodrugs thereof.

22. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22, wherein said composition is in the form of a tablet or capsule.

24. The pharmaceutical composition of claim 22, wherein said composition is a parenterally injectable composition.

25. A method of inhibiting DPP-IV in a subject in need thereof, comprising administering said subject a compound of claim 1 in an amount effective to inhibit DPP-IV in said subject.

26. The method of claim 25, wherein said subject is a human subject.

27. A method of treating diabetes in a subject in need thereof, comprising administering said subject a compound of claim 1 in an amount effective to treat said diabetes.

28. The method of claim 27, wherein said subject is a mammalian subject.

29. The method of claim 27, wherein said subject is a human subject.

30. The method of claim 27, wherein said diabetes is type II diabetes.

31. A compound of Formula XI:

wherein:

X is NH or a covalent bond; n is 1 or 2;

A is a bicyclic carbocycle of 5 to 20 atoms wherein each bridge of the bicycle has at least one atom; R¹ is

wherein: p and q are independently 0 or 1 ; Y is CH₂, CHF, CF₂, O, or S(O)_m; W and Z are independently CH₂, CHF, or CF₂; • and wherein the ring formed by N, W, Y, Z and the carbon atoms to which they are attached is saturated or optionally contains one double bond; and R² is selected from the group consisting of alkyl, alkeriyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, and heterocycloalkyl, each of which is unsubstituted or optionally substituted with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, haloalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O)_m, haloalkyl-S(O)_m, cycloalkyl-S(O)_m, cycloalkylalkyl-S(O)_m, aryl-S(O)_m, arylalkyl- S(O)_m, heterocyclo-S(O)_m, heterocycloalkyl-S(O)_m, amino, alkylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano; or R⁸ is H or cyano; m is 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.

32. The compound of claim 31, wherein A is selected from the group consisting of bicyclo[2.1.1]hexane, bicyclo[3.1.1]heptane, bicyclo [3.2.1] octane, bicyclo[2.2.2]octane and bicyclo[3.3.1]nonane, which may be optionally include one or more double bonds.

33. The compound of claim 31, wherein A is selected from the group consisting of:

34. The compound of claim 31, wherein n is 1.

35. The compound of claim 31, wherein n is 2.

36. The compound of claim 31, wherein:

Y is selected from the group consisting of CHF, CF₂, O, and S(O)_m; or q is 1 and W is selected from the group consisting of CHF and CF₂; or p is 1 and Z is selected from the group consisting of CHF and CF₂.

37. The compound of claim 31, wherein:

Y is selected from the group consisting of CHF, CF₂, O, and S(O)_m; q is 1 and W is CH₂; and p is 0.

38. The compound of claim 31, wherein:

Y is selected from the group consisting of CHF, CF₂, O, and S(O)₁₁₁; or q is o; and p is 1 and Z is CH₂.

39. The compound of claim 31, wherein:

Y is CH₂; q is 1 and W is selected from the group consisting of CHF and CF₂; and p is O.

40. The compound of claim 31, wherein: Y is CH₂; q is 0; and p is 1 and Z is selected from the group consisting of CHF and CF₂.

41. The compound of claim 31 selected from the group consisting of:

and pharmaceutically acceptable salts and prodrugs thereof.

42. A pharmaceutical composition comprising a compound of claim 31 in combination with a pharmaceutically acceptable carrier.

43. The pharmaceutical composition of claim 42, wherein said composition is in the form of a tablet or capsule.

44. The pharmaceutical composition of claim 42, wherein said composition is a parenterally injectable composition.

45. A method of inhibiting DPP-IV in a subject in need thereof, comprising administering said subject a compound of claim 31 in an amount effective to inhibit DPP-IV in said subject.

46. The method of claim 45, wherein said subject is a human subject.

47. A method of treating diabetes in a subject in need thereof, comprising administering said subject a compound of claim 31 in an amount effective to treat said diabetes.

48. The method of claim 47, wherein said subject is a human subject.

49. The method of claim 47, wherein said diabetes is type II diabetes.

50. A compound of Formula XII:

wherein: n is 1 or 2;

A is a bicyclic or tricyclic carbocycle of 5 to 20 atoms wherein each bridge of the bicycle has at least one atom;

R¹ Is

wherein: p and q are independently 0 or 1 ;

Y is CH₂, CHF, CF₂, O, or S(O)_m;

W and Z are independently CH₂, CHF, or CF₂; and wherein the ring formed by N, W, Y, Z and the carbon atoms to which they are attached is saturated or optionally contains one double bond; R²³ is -NR⁵R⁶, or -OR⁶ or OH₃

R⁵ is H or alkyl;

R⁶ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, and heterocycloalkyl, each of which is unsubstituted or optionally substituted with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, haloalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O)_m, haloalkyl-S(O)_m, cycloalkyl-S(O)_m, cycloalkylalkyl-S(O)_m, aryl-S(O)_m, arylalkyl- S(O)_m, heterocyclo-S(O)_m, heterocycloalkyl-S(O)_m, amino, alkylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano; or R⁵ and R⁶ together form a C4-C6 alkylene bridge to which may be fused a substituted or unsubstituted cyclic or heterocyclic group;

R⁸ is H or cyano; m is 0, 1 or 2; or a pharmaceutically acceptable salt or prodrug thereof.

51. The compound of claim 50, wherein A is adamantyl.

52. The compound of claim 50, wherein A is selected from the group consisting of bicyclo[2.1.1]hexane, bicyclo[3.1.1]heptane, bicyclo [3.2.1] octane, bicyclo[2.2.2]octane and bicyclo[3.3.1]nonane, which may be optionally include one or more double bonds.

53. The compound of claim 50, wherein A is selected from the group consisting of:

V — / .

54. The compound of claim 50, wherein n is 1.

55. The compound of claim 50, wherein n is 2.

56. The compound of claim 50, wherein:

Y is selected from the group consisting of CHF, CF₂, O, and S(O)_m; or q is 1 and W is selected from the group consisting of CHF and CF₂; or p is 1 and Z is selected from the group consisting of CHF and CF₂.

57. The compound of claim 50, wherein:

Y is selected from the group consisting of CHF, CF₂, O, and S(O)_m; q is 1 and W is CH₂; and p is 0.

58. The compound of claim 50, wherein:

Y is selected from the group consisting of CHF, CF₂, O, and S(O)_m; or q is o; and p is 1 and Z is CH₂.

59. The compound of claim 50, wherein:

Y is CH₂; q is 1 and W is selected from the group consisting of CHF and CF₂; and p is 0.

60. The compound of claim 50, wherein:

Y is CH₂; q is 0; and p is 1 and Z is selected from the group consisting of CHF and CF₂.

61. The compound of claim 50 selected from the group consisting of:

and pharmaceutically acceptable salts and prodrugs thereof.

62. A pharmaceutical composition comprising a compound of claim 50 in combination with a pharmaceutically acceptable carrier.

63. The pharmaceutical composition of claim 62, wherein said composition is in the form of a tablet or capsule.

64. The pharmaceutical composition of claim 62, wherein said composition is a parenterally injectable composition.

65. A method of inhibiting DPP-IV in a subject in need thereof, comprising administering said subject a compound of claim 50 in an amount effective to inhibit DPP-IV in said subject.

66. The method of claim 65, wherein said subject is a human subject.

67. A method of treating diabetes in a subject in need thereof, comprising administering said subject a compound of claim 50 in an amount effective to treat said diabetes.

68. The method of claim 67, wherein said subject is a human subject.

69. The method of claim 67, wherein said diabetes is type II diabetes.

70. A compound of Formula XIII or Formula XTV:

wherein: n is 1 or 2;

A is a bicyclic or tricyclic carbocycle of 5 to 20 atoms wherein each bridge of the bicycle has at least one atom;

R¹ is

wherein: p and q are independently 0 or 1 ;

Y is CH₂, CHF, CF₂, O, or S(O)₀₁;

W and Z are independently CH₂, CHF, or CF₂; and wherein the ring formed by N, W, Y, Z and the carbon atoms to which they are attached is saturated or optionally contains one double bond; R⁸ is H or cyano; m is 0, 1 or 2;

R²⁰ is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heterocyclo, heterocycloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, alkylamino, arylalkylamino, heterocycloamino, cycloalkylamino, cycloalkylalkylamino, or disubstituted-amino;

R²¹ and R²² are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, and heterocycloalkyl, each of which is unsubstituted or optionally substituted with halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, haloalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O)_m, haloalkyl-S(O)_m, cycloalkyl-S(O)_m, cycloalkylalkyl-S(O)_m, aryl-S(O)_m, arylalkyl- S(O)_m, heterocyclo-S(O)_m, heterocycloalkyl-S(0)_m, amino, alkylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano; or R²¹ and R²² together form a C4-C6 alkylene linkage; or a pharmaceutically acceptable salt or prodrug thereof.

71. The compound of claim 70, wherein A is adamantyl.

72. The compound of claim 70, wherein A is selected from the group consisting of bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane bicyclo[3.3.1]nonane, bicyclo[3.2.1]octane, and bicyclo[3.1.1] -heptane, which may optionally include one or more double bonds.

73. The compound of claim 70, wherein A is selected from the group consisting of:

74. A pharmaceutical composition comprising a compound of claim 70 in combination with a pharmaceutically acceptable carrier.

75. A method of inhibiting DPP-IV in a subject in need thereof, comprising administering said subject a compound of claim 40 in an amount effective to inhibit DPP-IV in said subject.

76. A method of treating diabetes in a subject in need thereof, comprising administering said subject a compound of claim 70 in an amount effective to treat said diabetes.