WO2005097103A2 - Diabetes and metabolic syndrome therapy utilizing cathepsin b inhibitors - Google Patents

Abstract

The present invention is directed to the treatment of Type II diabetes by administering a cathepsin B inhibitor(s).

Description

BACKGROUND OF THE INVENTION

Cross-Reference

[001] The Applicants claim priority under 35 U.S.C. 119(e) to copending Provisional Application No. 60/558,933 filed on April 1, 2004, the disclosure of which is incorporated herein by reference in its entirety.

FIELD OF INVENTION

[002] The present invention is directed to the use of cathepsin B inhibitors in treatment of Type II diabetes mellitus.

STATE OF THE ART

[003] Cysteine proteases such as cathepsins B, H, K, L, O, and S represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g., as a result of increase or enhanced activation, however, may have pathological consequences. For example, increased cathepsin B levels and redistribution of the enzyme are found in tumors thus suggesting a role for the enzyme in tumor invasion and metastasis. In addition, aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteoarthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders.

[004] Type II diabetes and impaired glucose tolerance are one of the main causes of morbidity and mortality (Saltiel and KahnNαtwre 2001, 414, 799-806 ). Type II diabetes affects over 18 million people in the United States, of which 95% have Type II (statistics for 2002, South, S.A. Journal of Applied Research 2004, 4(3), 396-409) and over 170 million worldwide (statistics for 2000 for both Type I and II, Diabetes Care 2004, 27(5), 1047-53). Type II diabetes mellitus is characterized by tissue resistance or lack of responsiveness to the glucose-lowering effects of insulin {id.). Insulin resistance results in dysregulation of cell growth and differentiation and of substrate storage (promotion of lipid, glycogen, and protein syntheses and inhibition of their breakdown) (id.). As a result of the failure of insulin to stimulate uptake of glucose into cells, blood glucose levels become elevated to the extent that glucose is also seen in urine, which serves as an indicator for the disease.

[005] Insulin resistance is also one of a group of abnormalities associated with Metabolic syndrome. In addition to insulin resistance, the syndrome is characterized by obesity, hyperglycemia, dyslipidemia, thrombotic disorders, and hypertension. (See Pi- Sunyer FX., Obes Res. 2004, 12 Suppl,174$-80S; and Caglayan E, Blaschke F, Takata Y, Hsueh WA., Curr Opin Pharmacol. 2005, 5(2), 135-142.). Metabolic Syndrome, which affects about 25% of the United States population (Shields, T. M.; Hennekens, C. H. Endocrinology and Metabolism Clinics of North America 2004, 33(3), 577-593), is associated with increased risk for Type II diabetes, hypertension, coronary artery disease, stroke, and early mortality. (See Firdaus M., J Okla State MedAssoc. 2005, 98(2), 63-6; and Pi-Sunyer FX., Obes Res. 2004, 12 Suppl, 174S-80S.) In fact, the syndrome is a strong risk factor for diabetes (Streja D., Clin Cornerstone 2004, 6 Suppl 3, S 14-29). [006] Insulin resistance and dyslipidemia in diabetes has been linked to increases in basal serum TNF-α, suggesting the latter as a causative factor for non-insulin dependent diabetes mellititus (NIDDM) (Moller, TEM 2000, 11(6), 212-217). Free fatty acids induce TNF-α secretion in hepatocytes in an NFkB-mediated process. Inhibiting the effects of TNF-α has been suggested as a therapy for NIDDM (Ueki, K.; Kadowaki, T., Adiposcience 2004, 1(3), 281-287). Selective inhibition of cathepsin B lowers serum TNF-α levels in mice which have been fed high sucrose diet (Figure 1 and Table 1) and restores insulin sensitivity. Therefore, cathepsin B has a role in Type II diabetes mellitus which has not previously been suggested.

[007] Incretins are small peptides that may augment the body's capacity to use insulin to maintain glucose homeostasis (Creutzfeldt, W. Exp. Clin. Endocrinol. Diabetes 2001, 109 (Suppl 2), S288-S303; Sprangler, J., et. al. Lancet 2003, 361, 226-228). Thus, treatments that inhibit the degradation of GLP-1, preserving it for longer periods of time, would serve as another point at which to affect blood sugar level and may aid in the treatment of Type II diabetes and/or Metabolic Syndrome (Sinclair, E.; Drucker, D. Current Opinion in Endocrinology & Diabetes 2005, 12(2), 146-151). In particular, the incretin GLP-1, as a major stimulator of pancreatic insulin secretion (Expert Opinions on Therapeutic Patents 2000, 10(12), 1937-1942), acts to lower blood sugar. DPP-IN has been shown to degrade and inactivate GLP-1. Inhibitors of DPP-IN increase postprandial active GLP-1 and have shown success in the clinic in treating Type II diabetes. [008] The present invention relates to the discovery, previously unknown in the art, that cathepsin B has a role in the degradation of the acid (Figure 2.), but not the amide, form of the incretin GLP-1 in vitro (Figure 3.). As a result, inhibition of cathepsin B can improve the action of incretins in general, and GLP-1 in particular, and therefore serve as a way to treat Type II diabetes and/or Metabolic Syndrome.

[009] In Type 2 diabetes, free fatty acids (FFA) accumulate in microvascular cells, but the consequences of this accumulation is not completely understood. (Please see Mishra, R. and Simonson, M. Cardiovascular Diabetology 2005, 4:2; and Lam T.K., Carpentier A., Lewis G.F., van de Werve G., Fantus I.G., Giacca A. Am J Physiol Endocrinol Metab. 2003, 284(5), E863-73). Saturated FFA induce apoptosis in human microvascular mesangial cells and might contribute to the microvascular remodeling that leads to numerous complications in type 2 diabetes (id.). The present invention relates to the discovery that inhibition of cathepsin B leads to a reduction in free fatty acid (Figure 1.) and, as a result, can lower FFA levels and/or free-fatty-acid-induced damage in the pancreas and/or the liver and thus can have a role in treatment of ΝIDDM and Metabolic syndrome.

[010] Current anti-diabetic therapy includes lifestyle changes like alteration of diet, weight loss, and exercise. Antidiabetic drugs are administered in conjunction with behavior modification or where diet alteration and exercise are insufficient to control blood glucose. The main classes of drug treatment include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (alpha- glucosidase inhibitors) or improve insulin action (thiazolidinediones) (Krentz AJ, Bailey CJ., Drugs 2005, 65(3), 385-411). Insulin therapy may also be required in addition to lifestyle changes and drug therapy.

[011] While current methods of treatment of Type II diabetes are effective, a substantial number of patients continue to have difficulty in achieving and maintaining satisfactory control of blood glucose. (Sinclair, E.; Drucker, D. Current Opinion in Endocrinology & Diabetes 2005, 12(2), 146-151). In addition, drugs in the thiazolidinedione family, which includes rosiglitazone, have undesirable side effects - hypoglycemia, significant weight gain, water retention, cardiac failure, and reversible liver dysfunction (Hussein, Z.; Wentworth, J.M.; Nankervis, A.J.; Proietto, J. Colman PG. Med JAust. 2004, 181(10), 536-9). Sulfonylureas and meglitinides, because they stimulate the release of insulin, have a risk of hypoglycemia. Combination of drugs used in treatment may be helpful but taking more than one drug is costly and can increase the risk of side effects. [012] Therefore, there is need for improved treatments of Type II diabetes and related diseases. The present invention fulfills these and related needs. Inhibition of cathepsin B can decrease insulin levels, lower leptin, lower glucose levels, decrease free fatty acid levels and/or free-fatty-acid-induced damage in the liver or pancreas, and/or restore insulin sensitivity; and therefore inhibition of cathepsin B can be useful as an antidiabetic treatment.

SUMMARY OF THE INVENTION [013] In one aspect, this invention is directed to a method of treating an animal with Type II diabetes, comprising administering to said animal a cathepsin B inhibitor. [014] In another aspect, this invention is directed to a method of treating an animal with Type II diabetes, comprising administering to said animal a cathepsin B inhibitor in combination with another anti-diabetic therapy to said animal.

[015] In yet another aspect, this invention is directed to a method of treating an animal with Metabolic Syndrome, comprising administering to said animal a cathepsin B inhibitor.

[016] In another aspect, this invention is directed to a method of treating an animal with Metabolic Syndrome, comprising administering to said animal a cathepsin B inhibitor in combination with another anti-diabetic therapy to said animal.

[017] In another aspect, this invention is directed to a method of treating an animal with hyperinsulinemia, comprising administering to said animal a cathepsin B inhibitor. Preferably, a cathepsin B inhibitor is given to said animal in a dosage sufficient to restore glucose homeostasis. More preferably, the cathepsin B inhibitor is given in a dosage sufficient to restore insulin sensitivity or decrease insulin resistance. [018] In another aspect, this invention is directed to a method of treating an animal with hyperinsulinemia, comprising administering to said animal a cathepsin B inhibitor in combination with another anti-diabetic therapy to said animal.

[019] In another aspect, this invention is directed to a method of treating an animal with hyperglycemia, comprising administering to the animal a cathepsin B inhibitor. Preferably, a cathepsin B inhibitor is given to said animal in a dosage sufficient to restore glucose homeostasis. More preferably, the cathepsin B inhibitor is given in a dosage sufficient to restore insulin sensitivity or decrease insulin resistance. [020] In yet another aspect, this invention is directed to a method of treating an animal with hyperglycemia, comprising administering to said animal a cathepsin B inhibitor in combination with another antidiabetic therapy to said animal. [021] Preferably, the cathepsin B inhibitor is a compound of Formula I:

wherein:

[022] R¹ and R² are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, or aralkyl; or

[023] R¹ and R² together with the carbon atom to which they are attached form cycloalkylene or heterocycloalkylene;

[024] R³ is alkyl or halo;

[025] R⁴ is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl wherein the aromatic or alicyclic ring in R⁴ is optionally substituted with one, two or three R^a wherein:

[026] each R^a is independently selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl, carboxy, and alkoxycarbonyl wherein wherein the aromatic or alicyclic ring in each R^a is optionally substituted with one, two or three R^b wherein:

[027] each R is independently selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl, carboxy, and alkoxycarbonyl wherein the aromatic or alicyclic ring in each R is optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cyano, and nitro;

[028] R⁵ and R are independently hydrogen or alkyl; and

[029] R⁷ is halo;

[030] or a pharmaceutically acceptable salt thereof.

[031] In another aspect, this invention is directed to a pharmaceutical composition comprising a compound of Formula I, individual isomer, mixture of isomers or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically suitable excipients.

[032] More preferably, the cathepsin B inhibitor is a compound of Formula la:

la wherein:

[033] R¹ and R² are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, or aralkyl; or

[034] R¹ and R² together with the carbon atom to which they are attached form cycloalkylene or heterocycloalkylene; [035] R³ is alkyl or iodo;

[036] R⁴ is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl wherein the aromatic or alicyclic ring in R⁴ is optionally substituted with one, two or three R^a wherein:

[037] each R^a is independently selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl, carboxy, and alkoxycarbonyl wherein the aromatic or alicyclic ring in each R^a is optionally substituted with one, two or three R^b wherein: [038] each R is independently selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl, carboxy, and alkoxycarbonyl wherein the aromatic or alicyclic ring in each R^b is optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cyano, and nitro; and [039] R⁵ and R⁶ are independently hydrogen or alkyl; [040] or a pharmaceutically acceptable salt thereof.

[041] In another aspect, this invention is directed to a pharmaceutical composition comprising a compound of Formula la, individual isomer, mixture of isomers or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically suitable excipients.

[042] In another aspect, the compounds generically and specifically disclosed in U.S. Patents US 6,387,908, US 5,843,992, US 5,550,138, US 5,374,623, US 5,158,936, US 6,576,630, US 6,287,840, US 5,976,858, US 5,238,964, US 5,691,368, and US 5,055,451; PCT applications publication Nos. WO 2004/026851, WO 99/24460, WO 96/21655, WO 99/24460, WO 00/27418, WO 00/21509, WO 00/66175, WO 01/34153, WO 01/34154, WO 01/34155, WO 01/34156/WO 01/34157, WO 01/34158, WO 01/34159, WO 01/34160, WO 01/34565, WO 01/34566, WO 01/34599, WO 01/34600, WO 03/097664, WO 98/13059, WO 98/46559, WO 01/68645, WO 99/48522, WO 99/44624, WO 02/34252, WO 01/41757, WO 01/26648, and WO 98/56425; and US applications publication Nos. US 2002094958, 20030166574, 20030166573, 20030162964, 20030153508, 20030031658, 20020150961, and 20020091131; Japanese applications publication Nos. JP 08073352, JP 07115985, JP 08034792, JP 2002241304, and JP 08119983; European Union applications publication Nos. EP 624377, EP 655447, EP 655447, EP 272671, EP 229370, EP 0771565, and EP 450232 can also be used to practice the present invention. The compounds disclosed in the above patents and patent applications are incorporated herein by reference in their entirety. [043] In another aspect, the Invention is directed to the use of a cathepsin B inhibitor for the manufacture of a medicament for monotherapy or combination therapy with standard treatment, wherein the cathepsin B inhibitor treats Type II diabetes, hyperinsulinemia, Metabolic Syndrome, or hyperglycemia.

BRIEF DESCRIPTION OF THE FIGURES [044] Table 1. depicts the tissue weight in cathepsin B knockout (ctsb^~'^~) mice, TNFR1 knockout (TNFRT^1') mice, and wild type mice littermates after 16 weeks on either high carbohydrate or control diet.

[045] Figure 1. depicts the effect on leptin, insulin, glucose, free fatty acid, and TNF-α of inhibition of cathepsin B in obese ctsb^+/+ mice treated with a cathepsin B inhibitor as compared to untreated obese ctsb^'1' mice, untreated obese TNFRT^1' mice, and untreated obese ctsb^{+ +} mice.

[046] Figure 2. depicts the protein sequence of GLP-1 in its acid form. [047] Figure 3. depicts the degradation of the acid form of GLP-1 in the presence of cathepsin B.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[048] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meanings.

[049] "Acyl" means a -C(O)R radical where R is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl as defined herein, e.g., formyl, acetyl, trifluoroacetyl, benzoyl, or piperazin-1-ylcarbonyl, and the like.

[050] "Acyloxy" means a -OC(O)R radical where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl as defined herein, e.g., acetyloxy, trifluoroacetyloxy, benzoyloxy, piperazin-1-ylcarbonyloxy, and the like.

[051] "Alicyclic" means a moiety characterized by arrangement of the carbon atoms in closed non-aromatic ring structures e.g., cycloalkyl and heterocycloalkyl rings as defined herein.

[052] "Alkoxy" means an -OR radical where R is alkyl, as defined herein, as defined herein, e.g., methoxy, or ethoxy, and the like. [053] "Alkoxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, alkoxy group(s), as defined herein, e.g., 2-methoxyethyl, 1-,

2-, or 3-methoxypropyl, 2-ethoxyethyl, or 3,4-dimethoxybutyl, and the like.

[054] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or pentyl (including all isomeric forms), and the like.

[055] "Alkoxycarbonyl" means a -C(O)OR radical where R is alkyl as defined herein, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, or 2-propoxycarbonyl, n-, iso-, or tert-butoxycarbonyl, and the like.

[056] "Alkylamino" or "dialkylamino" means an -NHR and -NRR' radical respectively, where R and R' are independently alkyl, as defined herein, e.g., methylamino, dimethylamino, and the like.

[057] "Alkylaminocarbonyl" or "dialkylaminocarbonyl" means a -CONHR and

-CONRR' radical respectively, where R and R' are independently alkyl, as defined herein, e.g., methylaminocarbonyl, and the like.

[058] "Alkylaminosulfonyl" or "dialkylaminosulfonyl" refers to a -SO₂NHR and

-SO₂NRR' radical respectively, where R and R' are independently alkyl, as defined herein, e.g., methylaminosulfonyl, and the like.

[059] "Alkylthio" means a -SR radical where R is alkyl as defined herein, e.g., methylthio, ethylthio, propylthio (including all isomeric forms), butylthio (including all isomeric forms), and the like.

[060] "Amino" means the radical -NH₂.

[061] "Aminocarbonyl" means a -CONH₂ radical .

[062] "Aminosulfonyl" refers to a -SO₂NH2 radical.

[063] "Animal" includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like). Preferably, the animal is human.

[064] "Aralkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, aryl group(s) as defined herein, e.g., benzyl or phenethyl, and the like. [065] "Aromatic" means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp² hybridized and the total number of π electrons is equal to 4n+2.

[066] "Aryl" means a monocyclic or fused bicyclic ring assembly containing 6 to 10 ring carbon atoms unless otherwise indicated, wherein each ring is aromatic e.g., phenyl or naphthyl.

[067] "Arylamino" means a -NRR' radical where R is hydrogen or alkyl, as defined herein, and R' is aryl, as defined herein, e.g., phenylamino, napthylamino, and the like.

[068] "Aryloxy" means an -OR radical where R is aryl as defined herein.

[069] "Arylthio" means a -SR radical where R is aryl as defined herein, e.g., phenylthio, napthylthio, and the like.

[070] "Carboxy" means the radical -C(O)OH.

[071] "Cycloalkyl" means a monovalent saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing three to eight ring carbon atoms e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,

2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, and the like.

[072] "Cycloalkylalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two cycloalkyl group(s), as defined herein, e.g., cyclopropylmethyl, cyclobutylethyl, cyclobutylmethyl, and the like.

[073] "Cycloalkylene" means a divalent saturated or partially unsaturated monocyclic ring or bridged polycyclic ring assembly containing three to eight ring carbon atoms. For example, the instance wherein "R¹ and R² together with the carbon atom to which both R¹ and R² are attached form cycloalkylene" includes, but is not limited to, the following:

[074] "Disease" specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy. [075] "Halo" means fluoro, chloro, bromo or iodo.

[076] "Haloalkoxy" refers to an -OR radical where R is haloalkyl group as defined herein e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, and the like.

[077] "Haloalkyl" means an alkyl radical, as defined herein, substituted by one or more, preferably one to five, "halo" atoms, as such terms are defined herein, e.g. chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, or

2,2,2-trifluoro-l,l-dichloroethyl, and the like.

[078] "Heteroaralkyl" means an alkyl radical substituted with at least one, preferably one or two heteroaryl group(s) as defined herein e.g., pyridinylmethyl, 1- or

2-furanylethyl, or imidazolylmethyl, and the like.

[079] "Heteroaryl" means an aromatic monocyclic or multicyclic ring of 5 to 10 ring atoms in which one or more, preferably one, two, or three, of the ring atoms are selected from nitrogen, oxygen or sulfur, the remaining ring atoms being carbon. Representative heteroaryl rings include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, or pyrazolyl, and the like.

[080] "Heteroarylamino" means a -NRR' radical where R is hydrogen or alkyl, as defined herein, and R' is heteroaryl as defined herein, e.g., pyridylamino, thienylamino, or indolylamino, and the like.

[081] "Heteroaryloxy" means an -OR radical where R is heteroaryl as defined herein, e.g., pyridyloxy, thienyloxy, or furanyloxy, and the like.

[082] "Heteroarylthio" means an -SR radical where R is heteroaryl as defined herein, e.g., pyridylthio, isoquinolinylthio, or imidazolylthio and the like.

[083] "Heterocycloalkyl" means cycloalkyl, as defined herein, provided that one or more, preferably one, two, or three of the ring carbon atoms indicated are replaced by a heteroatom selected from -N-, -O-, -S-, -SO-, or -S(O)₂- and additionally one or two carbon atoms are optionally replaced by -C(O)-. Representative examples include, but are not limited to, imidazolidinyl, morpholinyl, thiomorpholinyl, thiomorpholino-1 -oxide, thiomorpholino- 1,1 -dioxide, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxo- tetrahydrothiopyranyl, 1,1-dioxotetrathiopyranyl, indolinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl, and quinuclidinyl, and the like.

[084] "Heterocycloalkylamino" means an -NRR' radical where R is hydrogen or alkyl, as defined herein and R' is heterocycloalkyl as defined herein, e.g., tetrahydrofuranylamino, or pyrrolidinylamino, and the like.

[085] "Heterocycloalkylene" means cycloalkylene, as defined herein, provided that one or more, preferably one or two, of the ring member carbon atoms is replaced by a heteroatom selected from -N-, -O-, -S- or -S(O)₂- and optionally one or two ring member carbon atoms are replaced with -C(O)~. For example, the instance wherein "R¹ and R² together with the carbon atom to which they are attached form heterocycloalkylene" includes, but is not limited to, the following:

[086] "Heterocycloalkyloxy" means a radical -OR where R is heterocycloalkyl as defined above, e.g., piperidinyloxy, piperazinyloxy, pyrrolidinyloxy, or tetrahydrofuranyloxy, and the like.

[087] "Heterocycloalkylthio" means an -SR radical where R is heterocycloalkyl as defined herein, e.g., morpholinylthio or piperidinylthio, and the like.

[088] "Hydroxy" means the radical -OH.

[089] "Hydroxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two hydroxy group(s), provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3 -hydroxypropyl, 1-

(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3- dihydroxypropyl, l-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4- dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3- dihydroxypropyl, and l-(hydroxymethyl)-2-hydroxyethyl.

[090] "Isomers" mean compounds useful in the practice of the present invention having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers" or sometimes "optical isomers". A carbon atom bonded to four nonidentical substituents is termed a "chiral center". A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture". A compound that has more than one chiral center has 2"^"1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomers or as a mixture of diastereomers, termed a "diastereomeric mixture". When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see "Advanced Organic Chemistry," 4th edition, March, Jerry, John Wiley & Sons, New York, 1992). It is understood that the names and illustration used in this Application to describe compounds of Formula (I) or (la) are meant to be encompassed all possible stereoisomers.

[091] "Cathepsin B inhibitor" is any molecular species which inhibits the transcription of a cathepsin B gene, the processing or translation of a cathepsin B mRNA, or the processing, trafficking or activity of a cathepsin B protein, when administered in vivo or in vitro to a mammalian cell which is otherwise competent to express active cathepsin B. Thus, for example, the term "inhibitor of cathepsin B" embraces a repressor which inhibits induction and/or transcription of the cathepsin B gene, or an antisense sequence which selectively binds to cathepsin B DNA or mRNA sequences and which inhibits the transcription or translation of the cathepsin B sequences. Similarly, the term "inhibitor of cathepsin B" includes competitive, uncompetitive and non-competitive inhibitors of the activity of the cathepsin B protein, such as small molecules which structurally mimic the natural substrates of cathepsin B but which are resistant to the proteolytic activity of the enzyme. Although an inhibitor of cathepsin B may have some degree of inhibitory activity for other genes or proteins which are structurally or functionally related, the term

"inhibitor of cathepsin B" is not intended to embrace non-selective suppressors of all gene expression or protein synthesis, or general toxins (e.g., transcription blockers such as actinomycin D, and alpha.-amanitin, protein synthesis inhibitors such as puromycin, cycloheximide, and diptheria toxin).

[092] "Oxo" means the radical (=O).

[093] "Nitro" means the radical -NO₂.

[094] "Optional" or "optionally" or "may be" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase "wherein the aromatic ring R^a is optionally substituted with one or two substituents independently selected from alkyl" means that the aromatic ring may or may not be substituted with alkyl in order to fall within the scope of the invention.

[095] The present invention also includes N-oxide derivatives of the compounds of this invention. N-oxide derivatives means derivatives of compounds of the present invention in which nitrogens are in an oxidized state (i.e., N- O) e.g., pyridine N-oxide, and which possess the desired pharmacological activity.

[096] "Pathology" of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.

[097] "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.

[098] "Pharmaceutically acceptable salts" means salts of compounds useful in the practice of the present invention which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methylsulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, ^-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, /p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like. [099] Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

[0100] The present invention also includes prodrugs of a compound useful in the practice of the present invention. Prodrug means a compound that is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of the present invention. For example an ester of a compound useful in the practice of the present invention containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene- bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methylsulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. Suitable esters of compounds containing a carboxy group, are for example those described by Leinweber, F.J. Drug Metab. Res., 1987, 18, pg. 379. An especially useful class of esters of compounds of the present invention containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)-benzoates, for example, dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (moφholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiρerazin-l-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-l-yl)benzoates. [0101] "Protected derivatives" means derivatives of compounds useful in the practice of the present invention in which a reactive site or sites are blocked with protecting groups. Protected derivatives of compounds are useful in the preparation of compounds or in themselves may be active cathepsin B inhibitors. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

[0102] "Therapeutically effective amount" means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease. [0103] "Treatment" or "treating" means any administration of a cathepsin B inhibitor of the present invention and includes:

(1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of Type II diabetes;

(2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting further development of the pathology and/or symptomatology); or

(3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of Type II diabetes (i.e., reducing in degree or severity, or extent or duration, the overt manifestations of the disease or reversing the pathology and/or symptomatology e.g., glucose homeostasis, etc..

Preferred Embodiments

[0104] Preferably, the cathepsin B inhibitors shown below in Tables 1, 2, and 3 can be used to practice the Invention.

and are named as: [0105] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4-

(2-pyridin-4-ylamino-thiazol-4-yl)benzamide; [0106] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- morpholin-4-ylbenzamide; [0107] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dibromophenyl)ethyl]-

4-mo holin-4-ylbenzamide; [0108] (S)-Ν-[l-((cyanomethyl)aminocarbonyl)-2-(4-methoxy-3,5-diiodophenyl)ethyl]-

4-morpholin-4-ylbenzamide; [0109] (S)-N-[ 1 -((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4-

[2-(4-methylpiperazin- 1 -yl)-thiazol-4-yl]benzamide;

[0110] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3-iodo-5- methylphenyl)ethyl]-4-morpholin-4-ylbenzamide;

[0111] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3-iodo-5- ethylphenyl)ethyl]-4-morpholin-4-ylbenzamide;

[0112] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- iodobenzamide;

[0113] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- bromobenzamide ;

[0114] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- methylbenzamide;

[0115] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- tert-butylbenzamide;

[0116] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- trifluoromethoxybenzamide;

[0117] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- trifluoromethylbenzamide;

[0118] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- methylthiobenzamide;

[0119] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- methylsulfonylbenzamide;

[0120] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]-

4-chlorobenzamide;

[0121] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]-

4-bromobenzamide ;

[0122] (S)-N- [ 1 -((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3 ,5-dichlorophenyl)ethyl] -

4-phen- 1 -ylbenzamide;

[0123] (S)-N-[l-((cyanocyclopropyl)aminocarbonyl)-2-(4-hydroxy-3,5- dichlorophenyl)ethyl]-4-bromobenzamide;

[0124] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-(4-methylpiperazinyl)benzamide; and

[0125] (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]-

4-(4-morpholin-4-yl-piperidin- 1 -yl)benzamide;

[0126] or a pharmaceutically acceptable salt thereof.

Table 3.

and are named as

[0127] { [2-(phenylsulfonyl)vin- 1 -ylcarbonyl] amino-(isobutylmethyl) } - carbonylpyrrolidine-2-carboxylic acid;

[0128] l-{[(S)-carboxy-(phenylmethyl)methyl]aminocarbonyl}-(2-(phenylsulfonyl)vin- l-yl)carbonyl-(S)-N-(isobutylmethyl)amine;

[0129] 1 - { [(S)-carboxy-(phenylmethyl)methyl] aminocarbonyl} -(2-(phenylsulfonyl)vin- l-yl)carbonyl-(S)-N-[(2-methylbut-l-yl)]amine;

[0130] l-{[{-c/_.-[2-(phenylsulfonyl)vinyl]-(3-phenyl)prop-l-yl}aminocarbonyl-

(phenylmethyl)methyl] aminocarbonyl } -4-methylpiperazine ;

[0131] l-{[{[S-ethyl-(benzoxazol-2-ylcarbonyl)methyl]}aminocarbonyl-(2-(lH-

[l,2,4]triazol-3-yl)eth-l-yl)]aminocarbonyl}-4-bromobenzene; [0132] l-{[{[S-ethyl-(benzoxazol-2-ylcarbonyl)methyl]}aminocarbonyl-(3S- propynylmethyl)]aminocarbonyl}-4-bromobenzene;

[0133] l-{[{l-[2-(methylsulfonyl)vinyl]-S-[(5-phenylmethyloxycarbonylamino)pent-l- yl]}aminocarbonyl-S-2-(phenylaminocarbonyl)ethylmethyl]aminocarbonyl}-4- bromobenzene; and

[0134] l-{[{l-[2-(methylsulfonyl)vinyl]-S-[(5-phenylmethyloxycarbonylamino)pent-l- yl]}aminocarbonyl-(2-(lH-[l,2,4]triazol-3-yl)eth-l-yl)]aminocarbonyl}-4- bromobenzene;

[0135] or a pharmaceutically acceptable salt thereof.

GENERAL SYNTHETIC SCHEME [0136] Compounds useful in the practice of this invention can be made by the methods known to one of ordinary skill in the art. In particular, Compound Example No. 1 may be prepared as described in JP 07115985. Compound Example No. 2 may be prepared as described in US 5,691,368. Compound Example No. 3 and 9 may be prepared as described in EP 655,447. Compound Example No. 4 may be prepared as described in JP 08119983. Compound Example No. 5 is commercially available from Sigma or Bachem. Compound Example No. 6 may be prepared as described in WO 9924460. Compound Example No. 7 is commercially available from Chem-Impex Tools For Peptide and Solid Phase Synthesis. Compound Example No. 8 is commercially available form Bachem. Compound Example Nos. 10-15 may be prepared as described in Ahmed, N.; Martin, L.; Watts, L.; Palmer, J.; Thornburg, L.; Prior, J.; Esser, R. Biochem Pharmacol 44, 1201-7. Compound Example No. 16 may be obtained as described in Isshiki, K.; Nishio, M.; Sakurai, N.; Uchida, T.; Okuda, T.; Komatsubara, S. Biochem Pharmacol, 44, 1201-7 which is hereby incorporated by reference. Compound Example No. 17 may be prepared as described in Schirmeister, T. J. Med. Chem.,1999, 42(4), 560- 572 which is hereby incorporated by reference. Compounds 18-38 may be prepared as described in 60/412,368. Methods to prepare Compound Example No. 39-42 are well known to a person of ordinary sill in the art. Compound Example No. 43-44 may be prepared as described in US 6,576,630. Compound Example No. 45-46 may be prepared as described in US 6,287,840. [0137] A compound useful in the practice of the present invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of such a compound can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of such compounds are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of the present invention can be prepared using salts of the starting materials or intermediates. [0138] The free acid or free base forms of the compounds useful in the practice of the present invention can be prepared from the corresponding base addition salt or acid addition salt form. For example, such a compound in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). Such a compound in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).

[0139] The N-oxides of the compounds useful in the practice of the present invention can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of a compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, metα-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0°C. Alternatively, the N-oxides of compounds can be prepared from the N-oxide of an appropriate starting material.

[0140] Compounds useful in the practice of the present invention in unoxidized form can be prepared from N-oxides of compounds by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 °C. [0141] Prodrug derivatives of the compounds useful in the practice of the present invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et -./.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of the present invention with a suitable carbamylating agent (e.g., l,l-acyloxyalkylcarbonochloridate, -flrα-nitrophenyl carbonate, or the like). [0142] Protected derivatives of the compounds useful in the practice of the present invention can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3^rd edition, John Wiley & Sons, Inc. 1999.

[0143] Compounds useful in the practice of the present invention may be conveniently prepared as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol. [0144] Compounds useful in the practice of this Invention may exist as tautomers. It will be recognized by a person skilled in the art that the amount of tautomers will vary based on certain conditions such as steric interactions, electronic effects of substituents, solvent polarity, hydrogen bonding capability, temperature, pH, and the like. [0145] Compounds useful in the practice of the present invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferably, by separation resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, Enantiomers, Racemates, and Resolutions, Krieger Publishing Co. (1994).

TESTING [0146] The cysteine protease inhibitory activity, in particular, the cathepsin B inhibitory activities of the compounds useful in the practice of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Typically, the assay measures protease-induced hydrolysis of a peptide-based substrate. Details of an assay for measuring cathepsin B inhibitory activity is set forth in Biological Examples 1, infra. Details of assays for measuring plasma glucose, TNF-α, serum insulin, free fatty acid, leptin, and glycated hemoglobin are described in Biological Example 2-7, infra. Details of the db/db and ob/ob mouse models are set forth in Example 8-9, infra. Biological Examples Example 1 Cathepsin B Assay [0147] Solutions of test compounds in varying concentrations were prepared in 10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising: NN- bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 50 mM (pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2.5 mM). Human cathepsin B (0.025 pMoles in 25 μL of assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature. Z-FR-AMC (20 nMoles in 25 μL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at (λ 460 nm) for 5 minutes. Apparent inhibition constants (Kj) were calculated from the enzyme progress curves using standard mathematical models. [0148] Compounds in Table 2 and 3 were tested by the herein-described assay and observed to exhibit cathepsin B inhibitory activity. Example 2 Plasma Glucose Assay [0149] Fasting blood glucose concentrations is measured using gluco-analyser blood glucose strips (Roche Diagnostics, Indianapolis, IN).

Example 3 Serum TNF-α Assay [0150] Blood is collected from treated mice and serum is prepared by standard methodology. TNF-alpha concentration present in serum is measured by ELISA, using a kit available from a variety of commercial suppliers - R&D Systems, Minneapolis, MN or Assay Designs, Inc, Ann Arbor, MI, per the manufacturer's instructions.

Example 4 Serum insulin [0151] Blood is collected from treated mice and serum is prepared by standard methodology. Insulin concentration present in serum is measured by ELISA, using a kit available from CRYSTAL CHEM INC, USA, 1536 Brook Drive, Suite A, Downers Grove, II 60515, USA, per the manufacturer's instructions.

Example 5 Free fatty acid assay [0152] Free fatty acids are determined on a Hitachi 912 automated analyzer using reagents from WACO Chemicals (Richmond, NA). Briefly, Serum free fatty acids react with CoA in the presence of ATP, Mg++ and acyl-CoA synthetase to form thiol esters of CoA. The esters are oxidized by acyl-CoA oxidase to produce hydrogen peroxide which reacts with a signal compound to produce purple adduct. The free fatty acid concentration is proportional to the absorbance at 550 nm. Ascorbate oxidase is included as a reagent to completely remove any ascorbic acid in the specimen which would interfere with the oxidative reactions. Example 6 Serum leptin assay [0153] Blood is collected from treated mice and serum is prepared by standard methodology. Leptin concentration present in serum is measured by ELISA, using a kit available from CRYSTAL CHEM INC, USA, 1536 Brook Drive, Suite A, Downers Grove, II 60515, USA, per the manufacturer's instructions.

Example 7 [0154] An assay to measure glycated hemoglobin would be known to one of ordinary skill in the art.

Example 8 [0155] One of ordinary skill in the art would know how to practice this invention using a standard model, the db/db mouse. Example 9 [0156] One of ordinary skill in the art would know how to practice this invention using a standard model, the ob/ob mouse.

ADMINISTRATION AND PHARMACEUTICAL COMPOSITIONS [0157] In general, a compound useful in the practice of the present invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. When used in combination with one or more therapeutic agents, a compound useful in the practice of the present invention may be given before, simultaneously with, or after administration of the therapeutic agent. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound may range from about 10 micrograms per kilogram body weight (μg/kg) per day to about 20 milligram per kilogram body weight (mg/kg) per day, typically from about 100 μg/kg/day to about 10 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from about 1 mg/day to about 1.6 g/day, typically from about 1 mg/day to about 100 mg/day. In general, one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this Application, will be able to ascertain a therapeutically effective amount of a compound of the present invention.

[0158] The compounds useful in the practice of the present invention can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of the present invention in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0159] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols. [0160] The amount of a compound useful in the practice of the present invention in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences. In general, a composition of a compound of the present invention will comprise from 0.0 l%w to 10%w, preferably 0.3%w to l%w, of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required. Representative pharmaceutical formulations containing a compound of the present invention are described in the tables below.

Pharmaceutical Composition Examples [0161] The following are representative pharmaceutical formulations containing a compound of Formula I or la. Tablet Formulation [0162] The following ingredients are mixed intimately and pressed into single scored tablets. Ingredient Quantity per tablet, mg inhibitor 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Capsule Formulation [0163] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Ingredient Quantity per tablet, mg inhibitor 200 lactose, spray-dried 148 magnesium stearate 2

Suspension Formulation [0164] The following ingredients are mixed to form a suspension for oral administration. Ingredient Amount inhibitor 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g Neegum K (Nanderbilt Co.) 1.0 g flavoring 0.035 mL colorings 0.5 mg distilled water q.s. to 100 mL

Injectable Formulation [0165] The following ingredients are mixed to form an injectable formulation. Ingredient Amount inhibitor 1.2 g sodium acetate buffer solution 0.4 M 2.0 mL HCl (1 Ν) or ΝaOH (1 M) q.s. to suitable pH water (distilled, sterile) q.s.to 20 mL

[0166] All of the above ingredients, except water, are combined and heated to 60- 70.degree. C. with stirring. A sufficient quantity of water at 60.degree. C. is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. to 100 g.

Suppository Formulation [0167] A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol.RTM. H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: Ingredient Quantity per tablet, mg inhibitor 500 Witepsol^®H-15 balance

[0168] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

Table 1. Tissue weight in ctsb^''^', TNFRT'^' and wild type littermates after 16 weeks on either high carbohydrate or control diet.

Nalues are mean ± SD. (n = 5-7/group)

Claims

WHAT IS CLAIMED

1. A method of treating an animal with Type II diabetes, comprising administering to the animal a cathepsin B inhibitor.

2. The method of Claim 1 wherein the cathepsin B inhibitor is given in combination with another anti-diabetic therapy to said animal.

3. A method of treating an animal with Metabolic Syndrome, comprising administering to the animal a cathepsin B inhibitor.

4. The method of Claim 3 wherein the cathepsin B inhibitor is given in combination with another anti-diabetic therapy to said animal.

5. A method of treating an animal with hyperinsulinemia, comprising administering to the animal a cathepsin B inhibitor.

6. A method of treating an animal with hyperglycemia, comprising administering to the animal a cathepsin B inhibitor.

7. The method of Claim 1 wherein the cathepsin B inhibitor is a compound of Formula I:

wherein: R¹ and R² are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, or aralkyl; or R¹ and R² together with the carbon atom to which they are attached form cycloalkylene or heterocycloalkylene; R³ is alkyl or halo; R⁴ is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl wherein the aromatic or alicyclic ring in R⁴ is optionally substituted with one, two or three R^a wherein: each R^a is independently selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl, carboxy, and alkoxycarbonyl wherein wherein the aromatic or alicyclic ring in each R^a is optionally substituted with one, two or three R^b wherein: each R^b is independently selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl, carboxy, and alkoxycarbonyl wherein the aromatic or alicyclic ring in each R^b is optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cyano, and nitro; R⁵ and R⁶ are independently hydrogen or alkyl; and R is halo; or a pharmaceutically acceptable salt thereof.

8. The method of Claim 3 wherein the cathepsin B inhibitor is a compound of formula I:

wherein: R¹ and R² are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, or aralkyl; or R¹ and R² together with the carbon atom to which they are attached form cycloalkylene or heterocycloalkylene; R³ is alkyl or halo; R⁴ is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl wherein the aromatic or alicyclic ring in R⁴ is optionally substituted with one, two or three R^a wherein: each R^a is independently selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl, carboxy, and alkoxycarbonyl wherein wherein the aromatic or alicyclic ring in each R^a is optionally substituted with one, two or three R^b wherein: each R^b is independently selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl, carboxy, and alkoxycarbonyl wherein the aromatic or alicyclic ring in each R^b is optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cyano, and nitro; R⁵ and R⁶ are independently hydrogen or alkyl; and R⁷ is halo; or a pharmaceutically acceptable salt thereof.

9. The method of Claim 5 wherein the cathepsin B inhibitor is a compound of formula I:

I wherein: R¹ and R² are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, or aralkyl; or R and R together with the carbon atom to which they are attached form cycloalkylene or heterocycloalkylene; R is alkyl or halo; R⁴ is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl wherein the aromatic or alicyclic ring in R⁴ is optionally substituted with one, two or three R^a wherein: each R^a is independently selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl, carboxy, and alkoxycarbonyl wherein wherein the aromatic or alicyclic ring in each R is optionally substituted with one, two or three R^b wherein: each R^b is independently selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl, carboxy, and alkoxycarbonyl wherein the aromatic or alicyclic ring in each R^b is optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cyano, and nitro; R⁵ and R⁶ are independently hydrogen or alkyl; and R is halo; or a pharmaceutically acceptable salt thereof.

10. The method of Claim 6 wherein the cathepsin B inhibitor is a compound of formula I:

I wherein: R¹ and R² are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, or aralkyl; or R¹ and R² together with the carbon atom to which they are attached form cycloalkylene or heterocycloalkylene; R³ is alkyl or halo; R⁴ is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl wherein the aromatic or alicyclic ring in R⁴ is optionally substituted with one, two or three R^a wherein: each R^a is independently selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl, carboxy, and alkoxycarbonyl wherein wherein the aromatic or alicyclic ring in each R is optionally substituted with one, two or three R^b wherein: each R^b is independently selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl, heteroaryl, heterocycloalkyl, arylamino, heteroarylamino, heterocycloalkylamino, aryloxy, heteroaryloxy, heterocycloalkyloxy, arylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heteroarylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, heterocycloalkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, cyano, acyl, carboxy, and alkoxycarbonyl wherein the aromatic or alicyclic ring in each R^b is optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, hydroxy, alkylthio wherein the sulfur may be oxidized to sulfoxide or sulfone, halo, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cyano, and nitro; R⁵ and R⁶ are independently hydrogen or alkyl; and R⁷ is halo; or a pharmaceutically acceptable salt thereof.

11. The method of Claim 1 wherein the cathepsin B inhibitor is a compound selected from: (5)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- (2-pyridin-4-ylamino-thiazol-4-yl)benzamide; (S)-N- [ 1 -((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3 ,5-diiodophenyl)ethyl] -4- morpholin-4-ylbenzamide; (5)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dibromophenyl)ethyl]- 4-morpholin-4-ylbenzamide ; (S)-Ν- [ 1 -((cyanomethyl)aminocarbonyl)-2-(4-methoxy-3 ,5 -diiodophenyl)ethyl] - 4-morpholin-4-ylbenzamide ; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- [2-(4-methylpiperazin- 1 -yl)-thiazol-4-yl]benzamide; (S)-N-[ 1 -((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3-iodo-5- methylphenyl)ethyl] -4-morpholin-4-ylbenzamide ; (S)-N-[ 1 -((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3-iodo-5- ethylphenyl)ethyl]-4-morpholin-4-ylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- iodobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- bromobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- methylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- tert-butylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- trifluoromethoxybenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- trifluoromethylbenzamide; (S)-N- [ 1 -((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3 , 5-diiodophenyl)ethyl] -4- methylthiobenzamide; (S)-N- [ 1 -((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3 ,5 -diiodophenyl)ethyl] -4- methylsulfonylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-chlorobenzamide ; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-bromobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-phen- 1 -ylbenzamide; (S)-N-[l-((cyanocyclopropyl)aminocarbonyl)-2-(4-hydroxy-3,5- dichlorophenyl)ethyl]-4-bromobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-(4-methylpiperazinyl)benzamide; and (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-(4-morpholin-4-yl-piperidin- 1 -yl)benzamide; or a pharmaceutically acceptable salt thereof.

12. The method of Claim 3 wherein the cathepsin B inhibitor is a compound selected from: (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- (2-pyridin-4-ylamino-thiazol-4-yl)benzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- morpholin-4-ylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dibromophenyl)ethyl]- 4-morpholin-4-ylbenzamide; (5)-Ν-[l-((cyanomethyl)aminocarbonyl)-2-(4-methoxy-3,5-diiodophenyl)ethyl]- 4-morpholin-4-ylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- [2-(4-methylpiperazin- 1 -yl)-thiazol-4-yl]benzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3-iodo-5- methylphenyl)ethyl]-4-morpholin-4-ylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3-iodo-5- ethylphenyl)ethyl]-4-morpholin-4-ylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- iodobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- bromobenzamide ; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- methylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- tert-butylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- trifluoromethoxybenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- trifluoromethylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- methylthiobenzamide ; (S)-N- [ 1 -((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3 ,5-diiodophenyl)ethyl] -4- methylsulfonylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-chlorobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-bromobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-phen- 1 -ylbenzamide; (S)-N-[ 1 -((cyanocyclopropyl)aminocarbonyl)-2-(4-hydroxy-3,5- dichlorophenyl)ethyl]-4-bromobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-(4-methylpiperazinyl)benzamide; and (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-(4-morpholin-4-yl-piperidin- 1 -yl)benzamide; or a pharmaceutically acceptable salt thereof.

13. The method of Claim 5 wherein the cathepsin B inhibitor is a compound selected from: (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- (2-pyridin-4-ylamino-thiazol-4-yl)benzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- morpholin-4-ylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dibromophenyl)ethyl]- 4-morpholin-4-ylbenzamide ; (S)-Ν-[l-((cyanomethyl)aminocarbonyl)-2-(4-methoxy-3,5-diiodophenyl)ethyl]- 4-morpholin-4-ylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- [2-(4-methylpiperazin- 1 -yl)-thiazol-4-yl]benzamide; (S)-N-[ 1 -((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3-iodo-5- methylphenyl)ethyl]-4-morpholin-4-ylbenzamide; (S)-N-[ 1 -((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3-iodo-5- ethylphenyl)ethyl]-4-morpholin-4-ylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- iodobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- bromobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- methylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- tert-butylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- trifluoromethoxybenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- trifluoromethylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- methylthiobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- methylsulfonylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-chlorobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-bromobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-phen- 1 -ylbenzamide; (S)-N-[l-((cyanocyclopropyl)aminocarbonyl)-2-(4-hydroxy-3,5- dichlorophenyl)ethyl]-4-bromobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-(4-methylpiperazinyl)benzamide ; and (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-(4-morpholin-4-yl-piperidin- 1 -yl)benzamide; or a pharmaceutically acceptable salt thereof.

14. The method of Claim 6 wherein the cathepsin B inhibitor is a compound selected from: (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- (2-pyridin-4-ylamino-thiazol-4-yl)benzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- mo holin-4-ylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dibromophenyl)ethyl]- 4-morpholin-4-ylbenzamide; (S)-Ν-[l-((cyanomethyl)aminocarbonyl)-2-(4-methoxy-3,5-diiodophenyl)ethyl]- 4-morpholin-4-ylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- [2-(4-methylpiperazin- 1 -yl)-thiazol-4-yl]benzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3-iodo-5- methylphenyl)ethyl]-4-morpholin-4-ylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3-iodo-5- ethylphenyl)ethyl]-4-morpholin-4-ylbenzamide; (S)-N- [ 1 -((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3 , 5 -diiodophenyl)ethyl] -4- iodobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- bromobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- methylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- tert-butylbenzamide ; (5)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- trifluoromethoxybenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- trifluoromethylbenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- methylthiobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-diiodophenyl)ethyl]-4- methylsulfonylbenzamide; (S)-N- [ 1 -((cy anomethyl)aminocarbonyl)-2-(4-hydroxy-3 , 5 -dichlorophenyl)ethyl] - 4-chlorobenzamide ; (5)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-bromobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-phen- 1 -ylbenzamide; (S)-N-[l-((cyanocyclopropyl)aminocarbonyl)-2-(4-hydroxy-3,5- dichlorophenyl)ethyl]-4-bromobenzamide; (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-(4-methylpiperazinyl)benzamide; and (S)-N-[l-((cyanomethyl)aminocarbonyl)-2-(4-hydroxy-3,5-dichlorophenyl)ethyl]- 4-(4-morpholin-4-yl-piperidin- 1 -yl)benzamide; or a pharmaceutically acceptable salt thereof.

15. The method of Claim 1 wherein the cathepsin B inhibitor is a compound selected from: { [2-(phenylsulfonyl)vin- 1 -ylcarbonyl] amino-(isobutylmethyl) } - carbonylpyrrolidine-2-carboxylic acid; 1 - { [(S)-carboxy-(phenylmethyl)methyl] aminocarbonyl } -(2-(phenylsulfonyl)vin- l-yl)carbonyl-(S)-N-(isobutylmethyl)amine; l-{[(S)-carboxy- henylme1_ayl)methyl]aminocarbonyl}-(2-(phenylsulfonyl)vin- 1 -yl)carbonyl-(S)-N- [(2-methylbut- 1 -yl)] amine; 1 - { [ { -cis- [2-(phenylsulfonyl)vinyl] -(3 -phenyl)prop- 1 -yl } aminocarbonyl- (phenylmethyl)methyl]aminocarbonyl}-4-methylpiperazine; 1 - { [ { [S-ethyl-(benzoxazol-2-ylcarbonyl)methyl] } aminocarbonyl-(2-( 1 H- [ 1 ,2,4]triazol-3 -yl)eth- 1 -yl)] aminocarbonyl} -4-bromobenzene; 1 - { [ { [S-ethyl-(benzoxazol-2-ylcarbonyl)methyl] } aminocarbonyl-(3 S - propynylmethyl)] aminocarbonyl} -4-bromobenzene; 1 - { [ { 1 - [2-(methylsulfonyl) vinyl] -S- [(5 -phenylmethyloxycarbonylamino)pent- 1 - yl]}aminocarbonyl-S-2-(phenylaminocarbonyl)ethylmethyl]aminocarbonyl}-4- bromobenzene; and 1 - { [ { 1 - [2-(methylsulfonyl) vinyl] -S- [(5-phenylmethyloxycarbonylamino)pent- 1 - yl] } aminocarbonyl-(2-( 1 H- [ 1 ,2,4] triazol-3 -yl)eth- 1 -yl)] aminocarbonyl } -4- bromobenzene; or a pharmaceutically acceptable salt thereof.

16. The method of Claim 3 wherein the cathepsin B inhibitor is a compound selected from: { [2-(phenylsulfonyl)vin- 1 -ylcarbonyl] amino-(isobutylmethyl) } - carbonylpyrrolidine-2-carboxylic acid; 1 - { [(S)-carboxy-(phenylmethyl)methyl]aminocarbonyl} -(2-(phenylsulfonyl)vin- l-yl)carbonyl-(S)-N-(isobutylmethyl)amine; l-{[(S)-carboxy-(phenylmethyl)methyl]aminocarbonyl}-(2-(phenylsulfonyl)vin- l-yl)carbonyl-(S)-N-[(2-methylbut-l-yl)]amine; 1 - { [ { -c is- [2-(phenylsulfonyl)vinyl] -(3 -phenyl)prop- 1 -yl} aminocarbonyl- (phenylmethyl)methyl]aminocarbonyl}-4-methylpiperazine; 1 - { [ { [S-ethyl-(benzoxazol-2-ylcarbonyl)methyl] } aminocarbonyl-(2-( 1 H- [l,2,4]triazol-3-yl)eth-l-yl)]aminocarbonyl}-4-bromobenzene; 1 - { [ { [S-ethyl-(benzoxazol-2-ylcarbonyl)methyl] } aminocarbonyl-(3 S- propynylmethyl)] aminocarbonyl} -4-bromobenzene; 1 - { [ { 1 - [2-(methylsulfonyl)vinyl] -S- [(5-phenylmethyloxycarbonylamino)pent- 1 - yl]}aminocarbonyl-S-2-(phenylaminocarbonyl)ethylmethyl]aminocarbonyl}-4- bromobenzene; and 1 - { [ { 1 -[2-(methylsulfonyl)vinyl] -S-[(5-phenylmethyloxycarbonylamino)pent- 1 - yl] } aminocarbonyl-(2-( 1 H- [ 1 ,2,4] triazol-3 -yl)eth- 1 -yl)] aminocarbonyl } -4- bromobenzene; or a pharmaceutically acceptable salt thereof.

17. The method of Claim 5 wherein the cathepsin B inhibitor is a compound selected

{ [2-(phenylsulfonyl)vin- 1 -ylcarbonyl] amino-(isobutylmethyl) } - carbonylpyrrolidine-2-carboxylic acid; 1 - { [(S)-carboxy-(phenylmethyl)methyl] aminocarbonyl } -(2-(phenylsulfonyl)vin- l-yl)carbonyl-(S)-N-(isobutylmethyl)amine; 1 - { [(S)-carboxy-(phenylmethyl)methyl] aminocarbonyl} -(2-(phenylsulfonyl)vin- 1 -yl)carbonyl-(S)-N- [(2-methylbut- 1 -yl)] amine; 1 - { [ { -cis- [2-(phenylsulfonyl)vinyl] -(3 -phenyl)prop- 1 -yl} aminocarbonyl- (phenylmethyl)methyl]aminocarbonyl}-4-methylpiperazine; l-{[{[S-ethyl-(benzoxazol-2-ylcarbonyl)methyl]}aminocarbonyl-(2-(lH- [ 1 ,2,4]triazol-3 -yl)eth- 1 -yl)] aminocarbonyl } -4-bromobenzene; 1 - { [ { [S-ethyl-(benzoxazol-2-ylcarbonyl)methyl] } aminocarbonyl-(3 S- propynylmethyl)]aminocarbonyl}-4-bromobenzene; l-{[{l-[2-(methylsulfonyl)vinyl]-S-[(5-phenylmethyloxycarbonylamino)pent-l- yl]}aminocarbonyl-S-2-(phenylaminocarbonyl)ethylmethyl]aminocarbonyl}-4- bromobenzene; and 1 - { [ { 1 - [2-(methylsulfonyl)vinyl] -S- [(5 -phenylmethyloxycarbonylamino)pent- 1 - yl]}aminocarbonyl-(2-(lH-[l,2,4]triazol-3-yl)eth-l-yl)]aminocarbonyl}-4- bromobenzene; or a pharmaceutically acceptable salt thereof.

18. The method of Claim 6 wherein cathepsin B inhibitor is a compound selected

{ [2-(phenylsulfonyl) vin- 1 -ylcarbonyl] amino-(isobutylmethyl) } - carbonylpyrrolidine-2-carboxylic acid; l-{[(iS)-carboxy-(phenylmethyl)methyl]aminocarbonyl}-(2-(phenylsulfonyl)vin- l-yl)carbonyl-(S)-N-(isobutylmethyl)amine; 1 - { [(S)-carboxy-(phenylmethyl)methyl] aminocarbonyl} -(2-(phenylsulfonyl)vin- 1 -yl)carbonyl-(S)-N- [(2-methylbut- 1 -yl)]amine; l-{[{-cis- [2-(phenylsulfonyl) vinyl] -(3 -phenyl)prop- 1 -yl} aminocarbonyl- (phenylmethyl)methyl]aminocarbonyl}-4-methylpiperazine; 1 - { [ { [S-ethyl-(benzoxazol-2-ylcarbonyl)methyl] } aminocarbonyl-(2-( 1 H- [l,2,4]triazol-3-yl)eth-l-yl)]aminocarbonyl}-4-bromobenzene; 1 - { [ { [S-ethyl-(benzoxazol-2-ylcarbonyl)methyl] } aminocarbonyl-(3 S- propynylmethyl)]aminocarbonyl}-4-bromobenzene; l-{[{l-[2-(methylsulfonyl)vinyl]-S-[(5-phenylmethyloxycarbonylamino)pent-l- yl]}aminocarbonyl-S-2-(phenylaminocarbonyl)ethylmethyl]aminocarbonyl}-4- bromobenzene; and l-{[{l-[2-(metlιylsulfonyl)vinyl]-S-[(5-phenylmethyloxycarbonylamino)pent-l- yl]}aminocarbonyl-(2-(lH-[l,2,4]triazol-3-yl)eth-l-yl)]aminocarbonyl}-4- bromobenzene; or a pharmaceutically acceptable salt thereof.

19. The use of a cathepsin B inhibitor for the manufacture of a medicament for monotherapy or combination therapy with standard antidiabetic therapy, wherein the cathepsin B inhibitor treats Type II diabetes, hyperinsulinemia, Metabolic Syndrome, or hyperglycemia.