WO2008147764A1

WO2008147764A1 - Mmp inhibitors and methods of use thereof

Info

Publication number: WO2008147764A1
Application number: PCT/US2008/064211
Authority: WO
Inventors: Andrew M. Fryer
Original assignee: Array Biopharma, Inc.
Priority date: 2007-05-23
Filing date: 2008-05-20
Publication date: 2008-12-04

Abstract

Provided are MMP inhibitors having the Formula (I): wherein R1, R2 and Y are as defined herein, which are useful in the treatment and/or prevention of MMP-mediated diseases and disorders.

Description

MMP INHIBITORS AND METHODS OF USE THEREOF BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

[0001] The present invention relates to alkylsulfamide-substituted triazole compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly it relates to certain alkylsulfamide-substituted triazole compounds useful in the treatment and prevention of diseases alleviated by the inhibition of matrix metalloproteases DESCRIPTION OF THE STATE OF THE ART

[0002] Matrix metalloproteases ("MMPs") are naturally-occurring proteases

(enzymes) found in most mammals. MMPs are a family of endopeptidases that are part of a larger group of proteases called metzincins. MMPs are involved in the degradation and remodeling of connective tissues, and are present in various cell types that reside in or are associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells, and invasive or metastatic tumor cells.

[0003] The MMP family shares a number of properties, including zinc and calcium dependence. MMPs also share a common domain structure. The minimum common domains are the pro-peptide and the catalytic zinc domain, and commonly there is an additional hemopexin-like C-terminal domain, which is linked to the catalytic domain by a flexible hinge region. The MMPs can be classified into several families based on their domain structure: matrilysin (minimal domain, MMP-7 and MMP-27), collagenase (hemopexin domain, MMP-I, MMP-8, MMP-13 and MMP-18), gelatinase (fibronectin domain, MMP-2, MMP-9), stromelysin (hemopexin domain, MMP-3, MMP-10, MMP-I l), metalloelastase (MMP- 12). In addition, the transmembrane domain family (MT-MMPs) has been discovered and includes MMP- 14 through MMP- 17.

[0004] The catalytic zinc domain in MMPs is typically the focal point for inhibitor design. Modification of substrates by introducing a zinc binding group (ZBG) has generated MMP inhibitors. Zinc binding groups in known MMP inhibitors include carboxylate, hydroxamate, pyrimidine trione, hydantoin, thiol and phosphinyl groups. [0005] Inhibition of matrix metalloproteases may be useful in the treatment of inflammatory diseases such as, arthritis (rheumatoid arthritis and osteoarthritis), bone resorptive diseases, such as osteoporosis, diseases characterized by abnormal blood vessel growth and remodeling, such as macular degeneration, diabetic retinopathy and restenosis, hyperproliferative diseases such as cancer, periodontitis, multiple sclerosis, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal and gastric ulceration, ulceration of skin, and aneurysmal disease. Inhibition of the activity of one or more MMPs may be of benefit in these diseases or conditions.

[0006] MMP inhibitors are known, see for example, International Publication WO

2008/024784 and International Publication WO 02/064552.

[0007] The need remains to find new low molecular weight compounds that are potent and selective MMP inhibitors, and that have an acceptable therapeutic index of toxicity/potency to make them amenable for use clinically in the prevention and treatment of the associated disease states.

SUMMARY OF THE INVENTION

[0008] The present invention relates to novel compounds that are inhibitors of MMPs.

In one aspect of the present invention, the compounds are inhibitors of MMP-2, MMP-9, MMP-12 and/or MMP-13.

[0009] More specifically, one aspect of the invention provides compounds of Formula

I

I

[0010] and pharmaceutically acceptable salts thereof.

[0011] It will be appreciated that certain compounds according to the invention may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form, and accordingly that any such enantiomeric pure form is included within the scope of the present invention.

[0012] It will further be appreciated that the compounds of Formula I or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention.

[0013] The compounds of Formula I include pharmaceutically acceptable salts thereof. The compounds of Formula I also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating enantiomers of compounds of Formula I.

[0014] According to another aspect, the present invention provides a pharmaceutical composition, which comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, as defined hereinabove. In a further aspect, the pharmaceutical composition includes the compound of Formula I together with a pharmaceutically acceptable diluent or carrier.

[0015] The compounds of the present invention can be used as prophylactics or therapeutic agents for treating diseases or disorders including, but not limited to, diseases and disorders mediated by MMP-2, MMP-9, MMP- 12 or MMP-13. The compounds and compositions containing them are therefore useful in the treatment of diseases associated with the MMP-2, MMP-9, MMP- 12 or MMP- 13 -induced excessive degradation of matrix and connective tissue within the mammal, such as arthritis (rheumatoid arthritis and osteoarthritis), bone resorptive diseases (such as osteoporosis), diseases characterized by abnormal blood vessel growth and remodeling such as macular degeneration, diabetic retinopathy and restenosis, hyperproliferative diseases such as cancer, periodontitis, multiple sclerosis, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal and gastric ulceration, ulceration of skin, and aneurysmal disease. Inhibition of the activity of one or more MMPs may be of benefit in these diseases or conditions. [0016] Accordingly, another aspect of the invention provides methods of treating or preventing diseases or conditions described herein by administering to a mammal, such as a human, a therapeutically effective amount of a compound of Formula I. [0017] An additional aspect of the invention is the use of a compound of Formula I in the preparation of a medicament for treating MMP2, MMP-9, MMP- 12 or MMP- 13 -mediated diseases and conditions.

[0018] According to another aspect, the present invention provides a compound of

Formula I or a pharmaceutically acceptable salt thereof, for use in therapy. [0019] According to a further aspect, the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament to treat an immunologic disorder. DETAILED DESCRIPTION OF THE INVENTION

[0020] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, tem usage, described techniques, or the like, this application controls. DEFINITIONS

[0021] The term "alkyl" includes linear or branched-chain radicals of carbon atoms.

[0022] Some alkyl moieties have been abbreviated, for example, methyl ("Me"), ethyl

("Et"), propyl ("Pr") and butyl ("Bu"), and further abbreviations are used to designate specific isomers of compounds, for example, 1 -propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-l -propyl or isobutyl ("i-Bu"), 1- methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu") and the like. The abbreviations are sometimes used in conjunction with elemental abbreviations and chemical structures, for example, methanol ("MeOH") or ethanol ("EtOH"). Additional abbreviations that may be used throughout the application include, for example, benzyl ("Bn"), phenyl ("Ph") and acetate ("Ac").

[0023] The terms "treat" or "treatment" refer to therapeutic, prophylactic, palliative or preventative measures. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. [0024] The phrases "therapeutically effective amount" or "effective amount" mean an amount of a compound of the present invention that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.

[0025] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.

[0026] The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith. [0027] The phrase "pharmaceutically acceptable salt," as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. [0028] The compounds of this invention also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of this invention and/or for separating enantiomers of compounds of this invention. [0029] The term "mammal" means a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.

[0030] The term "a" as used herein means one or more.

MMP INHIBITOR COMPOUNDS

[0031] In one embodiment of the present invention, a compound of Formula I is provided:

I

[0032] and pharmaceutically acceptable salts thereof, wherein:

[0033] R¹ and R² are independently H, C₁-C₆ alkyl, aryl, or a 5-6 membered heteroaryl ring, wherein the alkyl, aryl or heteroaryl are optionally substituted; [0034] Y is a five or six membered aryl or heteroaryl ring, optionally substituted by one or more Z¹ groups; and

[0035] Z¹ is independently selected from H, F, Cl, Br, I, CN, CF₃, C₁-C₆ alkyl, 0-(C₁-

C₆ alkyl), or (C₁-C₆ alkyl)-OH. [0036] In certain embodiments, R¹ is H.

[0037] In certain embodiment, R¹ is C₁-C₆ alkyl. hi certain embodiments, R¹ is methyl.

[0038] In certain embodiments, R² is H.

[0039] In certain embodiment, R² is C₁-C₆ alkyl. In certain embodiments, R² is methyl.

I O 1

[0040] In certain embodiments, R and R may be aryl. In a further embodiment, R and R² may be Cs-C₆ aryl.

I O 1

[0041] In certain embodiments, R and R may be aryl. In a further embodiment, R and R² may be C₆ aryl. In a further embodiment, R¹ and R² may be phenyl.

[0042] In certain embodiments, Y is independently selected from the structures:

wherein the aryl and heteroaryl groups are optionally substituted by one or more Z¹ groups independently selected from H, F, Cl₅ Br, I₅ CN, CF₃, C₁-C₆ alkyl, 0-(C₁-C₆ alkyl), or (C₁-C₆ alkyl)-OH.

[0043] In certain embodiments, Y is a six membered aryl ring. In a further embodiment, Y is a six membered aryl ring having the structure:

[0044] In another embodiment, Y is a six membered aryl ring having the structure:

[0045] In certain embodiments, Y is a five or six membered heteroaryl ring optionally substituted with one or more Z¹ groups. In certain embodiments, Y is a five or six membered heteroaryl ring containing one or two nitrogen heteroatoms and optionally substituted with one or more Z¹ groups. In certain embodiments, Y is a five or six membered heteroaryl ring containing one nitrogen heteroatom and optionally substituted with one or more Z¹ groups.

In certain embodiments, Y is a six membered heteroaryl ring containing one nitrogen heteroatom and optionally substituted with one or more Z¹ groups. In certain embodiments,

Y is pyridinyl optionally substituted with one or more Z¹ groups. In certain embodiments, Y is pyridin-2-yl optionally substituted with one or more Z¹ groups.

[0046] In certain embodiments, each Z¹ is independently a halogen selected from the group consisting of F, Cl or Br. In certain embodiments, Z¹ is Cl. In certain embodiments, both Z¹ groups are Cl.

[0047] In certain embodiments, Z¹ is CF₃.

[0048] It will be appreciated that certain compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.

[0049] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. [0050] It will be further be appreciated that the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.

[0051] It will also be appreciated that certain compounds of Formula I may be used as intermediates for further compounds of Formula I. SYNTHESIS OF COMPOUNDS

[0052] Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma- Aldrich (St. Louis, MO), Alfa Aesar (Ward Hill, MA), or TCI (Portland, OR), or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N. Y. (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database).

[0053] For illustrative purposes, Schemes 1-4 show a general method for preparing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0054] In preparing compounds of Formula I, protection of remote functionalities

(e.g., primary or secondary amines, etc.) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

Scheme 1

II . *Ψ V % »>*O<-

[0055] Scheme 1 shows a method of preparing compound (6) of Formula I, wherein

Y, R¹ and R² are as defined herein. According to Scheme 1, amines (1) can be treated with chlorosulfonic acid in the presence of a base such as triethylamine to give sulfamic acids (2). These sulfamic acids can be chlorinated with chlorinating agents such as PCl₅ to give sulfamoyl chlorides (3). Treatment of (3) with appropriately substituted propargylamines (4) yields propargyl sulfamides (5). Alkynes (5) can be converted to the triazole sulfamides (6) by heating in the presence of copper (I) iodide, and azidotrimethylsilane.

Scheme 2

[0056] Scheme 2 shows a method of preparing compound (6) of Formula I, wherein

Y, R¹ and R² are as defined herein. According to Scheme 2, appropriately substituted propargylamines (4) are converted into sulfamoyl oxazoladinones (7) by reacting with chlorosulfonyl isocycanate and 2-chloroethanol in the presence of a base such as N- methylmorpholine. Coupling of sulfamoyl oxazolidinones (7) with amines (1) with heating gives propargyl sulfamides (5). Alkynes (5) can be converted to the triazole sulfamides (6) by heating in the presence of copper (I) iodide, and azidotrimethylsilane. Scheme 3

[0057] Scheme 3 shows a method of preparing compound (6) of Formula I₅ wherein

Y, R¹ and R² are as defined herein. According to Scheme 3, appropriately substituted propargylamines (4) are converted into their Boc-protected derivatives (8) with Boc anhydride. The protected aminomethyl triazoles (9) are then prepared by a cycloaddition reaction with heating in the presence of copper (I) iodide, and azidotrimethylsilane. After removal of the Boc-protecting group with an acid (e.g., TFA), the liberated aminomethyl triazoles (10) are reacted with chlorosulfonyl isocycanate and 2-chloroethanol in the presence of a base such as N-methylmorpholine to give the triazole sulfamoyl oxazolidinones (11). Displacement of the oxazolidinone by heating with amines (1) gives the triazole sulfamides (6).

Scheme 4

[0058] Scheme 4 shows a method of preparing compound (6) of Formula I, wherein

Y, R¹ and R² are as defined herein. According to Scheme 4, sulfamoyl chlorides (3) can be heated with aminotriazoles (10) in the presence of a base to give the triazole sulfamides (6). [0059] Accordingly, another aspect of the present invention provides a process for preparing compounds of Formula I, comprising: a) reacting a compound of Formula 1 :

wherein Y is a five or six membered aryl or heteroaryl ring, optionally substituted by one or more Z¹ groups; Z¹ is independently selected from H, F, Cl, Br₅ 1, CN, CF₃, C₁-C₆ alkyl, O- (C₁-C₆ alkyl), or (C₁-C₆ alkyl)-OH; and X is a halogen or suitable leaving group, with a compound of Formula 2:

wherein R and R are independently H, C₁-C₆ alkyl, aryl, or a 5-6 membered heteroaryl ring, wherein the alkyl, aryl or heteroaryl are optionally substituted; or a salt thereof, to form a compound of Formula I; or b) heating a compound of Formula 3 :

wherein R¹, R² are independently H, C₁-C₆ alkyl, aryl, or a 5-6 membered heteroaryl ring, wherein the alkyl, aryl or heteroaryl are optionally substituted; Y is a five or six membered aryl or heteroaryl ring, optionally substituted by one or more Z¹ groups; and Z¹ is independently selected from H, F, Cl, Br, I, CN, CF₃, C₁-C₆ alkyl, 0-(C₁-C₆ alkyl), or (C₁-C₆ alkyl)-OH; with copper (I) iodide and azidotrimethylsilane to form a compound of Formula I; or c) reacting a compound of Formula 4 :

wherein R¹ and R² are independently H, C₁-C₆ alkyl, aryl, or a 5-6 membered heteroaryl ring, wherein the alkyl, aryl or heteroaryl are optionally substituted; with a compound of Formula 5:

wherein Y is a five or six membered aryl or heteroaryl ring, optionally substituted by one or more Z¹ groups; and Z¹ is independently selected from H, F, Cl₅ Br, I, CN, CF₃, C₁-C₆ alkyl, 0-(C₁-C₆ alkyl), or (C₁-C₆ alkyl)-OH to form a compound of Formula I. [0060] In step a) of the above process, the process is preferably performed in a suitable solvent, such as acetonitrile, 1,4-dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, preferably acetonitrile. The reaction is preferably performed in the presence of a base, such as triethylamine, diisopropylethylamine (Hunig's base), or N- methylmorpholine, preferably triethylamine. The reaction may be performed at a temperature ranging from about 6O⁰C to about 100⁰C, preferably at a temperature of about 8O⁰C. X may be a halogen or other suitable leaving group. Preferably X is a halogen, and most preferably X is chlorine. The compound of Formula 2 may be in salt form. The preferred salt of Formula 2 is the hydrochloride salt.

[0061] In step b) of the above process, the process is preferably performed in a suitable solvent such as DMF, methanol ("MeOH"), or a mixture thereof. Other alcohol solvents can also be used in combination with DMF such as ethanol, isopropanol, n-butanol and t-butanol. The preferred solvent is a 1:1 mixture of DMF and MeOH. The reaction may be performed at an external temperature ranging from about 8O⁰C to about 120⁰C, preferably at an external temperature ranging from about 90°C to about 110⁰C, and most preferably at an external temperature of about 100⁰C. The reaction is preferably performed in a sealed vessel.

[0062] In step c) of the above process, the process is preferably performed in a suitable solvent, such as acetonitrile, 1,4-dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, preferably acetonitrile. The reaction is preferably performed in the presence of a base, such as triethylamine, diisopropylethylamine (Hunig's base), or N- methylmorpholine, preferably triethylamine. The reaction may be performed at a temperature ranging from about 6O⁰C to about 100⁰C, preferably at a temperature ranging from about 7O⁰C to about 9O⁰C, and most preferably at a temperature of about 8O⁰C. METHODS OF SEPARATION

[0063] It may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art will apply techniques most likely to achieve the desired separation.

[0064] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[0065] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: "Drug Stereochemistry, Analytical Methods and Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993). [0066] Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl- β-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.

[0067] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, α-methoxy-α- (trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem., (1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111).

[0068] By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. of Chromatogr., (1990) 513:375- 378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

BIOLOGICAL EVALUATION

[0069] The ability of the compounds of Formula I to inhibit matrix metalloprotease activity may be demonstrated by a variety of in vitro assays known to those of ordinary skill in the art, such as the MMP Enzymatic Assay described in FEBS, 296, 263, (1992) or modifications thereof as described in more detail in Example A. ADMINISTRATION AND PHARAMCEUTICAL FORMULATIONS [0070] The compounds of the invention may be administered by any convenient route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.

[0071] The compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.

[0072] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (8^th Ed. 2004); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20^th Ed. 2000); and Raymond C. Rowe, Handbook of Pharmaceutical Excipients, (5^th Ed. 2005). The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifϊers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0073] One embodiment of the present invention includes a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

METHODS OF TREATMENT WITH COMPOUNDS OF THE INVENTION [0074] The compounds of the present invention can be used as prophylactics or therapeutic agents for treating diseases or disorders including, but not limited to, diseases and disorders mediated by MMP-2, MMP-9, MMP- 12 or MMP-13. The compounds and compositions containing them are therefore useful in the treatment of diseases associated with the MMP-2, MMP-9, MMP-12 or MMP- 13 -induced excessive degradation of matrix and connective tissue within the mammal, such as arthritis (rheumatoid arthritis and osteoarthritis), bone resorptive diseases (such as osteoporosis), destruction of articular cartilage, periodontitis, multiple sclerosis, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal and gastric ulceration, ulceration of skin, aneurysmal disease, and in complications of diabetes. Inhibition of the activity of one or more MMPs may be of benefit in these diseases or conditions.

[0075] In one embodiment of the present invention, a method of treating or preventing diseases or conditions described herein by administering to a mammal, such as a human, a therapeutically effective amount of a compound of Formula I is provided. [0076] In another embodiment of the present invention, the use of a compound of

Formula I in the preparation of a medicament for treating MMP2, MMP-9, MMP- 12 or MMP- 13 -mediated diseases and conditions is provided.

[0077] Another embodiment of the present invention provides a compound of

Formula I or a pharmaceutically acceptable salt thereof, for use in therapy. [0078] A further embodiment of the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament to treat an immunologic disorder. COMBINATION THERAPY

[0079] The compounds of this invention and stereoisomers and pharmaceutically acceptable salts thereof may be employed alone or in combination with other therapeutic agents for treatment. The compounds of the present invention can be used in combination with one or more additional drugs, for example an anti-inflammatory compound that works by a different mechanism of action. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of this invention such that they do not adversely affect each other. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. The compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time. EXAMPLES

[0080] In order to illustrate the invention, the following Examples are included.

However, it is to be understood that these Examples do not limit the invention and are only meant to suggest a method of practicing the invention. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.

[0081] In the Examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise indicated.

[0082] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. [0083] Column chromatography was done on a Biotage system (Manufacturer: Dyax

Corporation) having a silica gel column or on a silica SepPak cartridge (Waters) (unless otherwise stated). ¹H NMR spectra were recorded on a Varian instrument operating at 400 MHz. ¹H-NMR spectra were obtained as CDCI₃, d_δ-DMSO, CH₃OD or d₆-acetone solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm). When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplex), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

Example A MMP- 13 Assay

[0084] The MMP- 13 assay (C. Graham Knight, Frances Willenbrock, and Gillian

Murphy (1992) FEBS Letters 296 (3), 263-266) is based on intramolecular fluorescence resonance energy transfer for detection of the activity of Matrix Metalloproteinase 13 (MMP- 13) using a quenched-fluorogenic substrate. The cleavage reaction is detected continuously by the elevation of the fluorescence due to release from quenching. The fluorescence of the product increases in proportion to progress of the cleavage reaction.

[0085] MMP- 13 (baculo virus expressed full-length protein) and inhibitor in assay buffer (50 mM HEPES, pH 7.4, 100 mM NaCl, 5 mM CaCl₂, 0.005% Brij-35, final DMSO concentration 1% (v/v)) are pre-incubated for 10 minutes at ambient temperature. MMP- 2/MMP-7 Substrate, Mca-PLGL-Dap(Dnp)-AR-NH₂ (AnaSpec, Inc.), is added and the plates are monitored over the length of the assay (20 minutes) for change in fluorescence (excitation 325, emission 395). When tested in this assay, compounds of Examples 1-4 had an IC_5O of <10 μM. Inhibitors are also tested in the same buffer with 0.5% HSA (Human Serum Albumin, Sigma) to assess shift in activity in the presence of serum albumin.

Example 1 JV-(^'(^'lH-1.2.3-triazol-5-yl^>)methylV4-(^'4-chlorophenoxy)piperidine-l-sulfonamide

[0086] Step A: Preparation of 4-(4-chlorophenoxy)piperidine-l-sulfonyl chloride: 4-

(4-chlorophenoxy)piperidine (1.63 g, 7.70 mmol) was dissolved in DCM (38.5 mL, 0.2 M) and cooled to a temperature of 0°C. Triethylamine (2.15 mL, 15.4 mmol) and sulfurochloridic acid (0.512 mL, 7.70 mmol) were added dropwise. After warming up to room temperature and stirring for 15 hours, the reaction mixture was concentrated, washed with Et₂O and dried in vacuo. The crude residue was then suspended in benzene (20 mL), and PCl₅ (1.60 g, 7.70 mmol) was added. The reaction mixture heated under reflux for 2 hours. After cooling, the mixture was diluted in EtOAc and washed with 5% citric acid, saturated bicarbonate, and brine. After drying with MgSO₄, the crude material was concentrated down to an oil, which solidified in vacuo to afford 0.23 g of 4-(4- chlorophenoxy)piperidine-l-sulfonyl chloride (2.30 g, 96%). ¹H NMR (400 MHz. CDCl₃) δ 7.26 (d, 2H, J = 8.98 Hz), 6.86 (d, 2H, J = 8.98 Hz), 4.52 (m, IH), 3.34-3.58 (m, 4H), 2.00- 2.20 (m, 4H).

[0087] Step B: Preparation of tert-butyl prop-2-ynylcarbamate: A solution of propargylamine (5.00 g, 90.8 mmol) and BoC₂O (18.8 g, 86.2 mmol) in DCM (200 mL) was stirred for 12 hours. The mixture was washed with dilute aqueous HCl, and the organic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo. The resulting oil crystallized upon standing to give 12.0 g (90%) of the title compound. ¹H NMR (400 MHz, CDCl₃) δ 4.78 (br s, IH), 3.92 (s, 2H), 2.22 (s, IH)₅ 1.46 (s, 9H).

[0088] Step C: Preparation of tert-butyl (lH-l,2,3-triazol-5-yl)methylcarbamate: A solution of tert-butyl prop-2-ynylcarbamate (2.00 g, 12.9 mmol), azidotrimethylsilane (2.60 mL, 19.3 mmol), and CuI (123 mg, 0.65 mmol) in 9:1 DMF/MeOH (25 mL) was heated at a temperature of 95⁰C in a sealed vessel for 12 hours. The mixture was concentrated in vacuo, the resulting oil was diluted with DCM, and the undissolved solids were filtered off. The filtrate was concentrated in vacuo to give 1.80 g of the title compound. MS APCI (+) m/z 199 detected. ¹H NMR (400 MHz, CDCl₃) δ 7.65 (s, IH), 5.37 (br s, IH), 4.44 (d, J = 5.9 Hz, 2H), 1.45 (s, 9H).

[0089] Step D: Preparation of (IH- 1,2,3 -triazol-5-yl)methanamine hydrochloride: A solution of tert-butyl (lH-l,2,3-triazol-5-yl)methylcarbamate (1.80 g, 9.1 mmol) in 4.0 M HCl in dioxane (40 mL) was stirred for 2 hours resulting in the formation of a precipitate. The mixture was concentrated in vacuo to 1/4 volume, diluted with acetonitrile, and filtered to give 1.3 g (100%) of the title compound as a solid. ¹HNMR (400 MHz, DMSOd₆) δ 8.60 (br s, 4H), 7.94 (s, IH), 4.04 (m, 2H).

[0090] Step E: Preparation of N-((3H-l,2,3-triazol-4-yl)methyl)-4-(4- chlorophenoxy)piperidine- 1 -sulfonamide: 4-(4-chlorophenoxy)piperidine- 1 -sulfonyl chloride (115 mg, 0.371 mmol) and ( IH-1, 2,3 -triazol-4-yl)methanamine hydrochloride (50.0 mg, 0.372 mmol) were dissolved in acetonitrile (0.2 M). Triethylamine (0.155 mL, 1.11 mmol) was added, and the reaction mixture was heated to a temperature of 8O⁰C. After stirring for 16 hours, the reaction mixture was concentrated in vacuo and purified by chromatography (SiO2, 33-100% ethyl acetate/hexanes) to afford N-((3H- 1,2,3 -triazol-4-yl)methyl)-4-(4- chlorophenoxy)piperidine-l -sulfonamide as a solid (47 mg, 34%). MS APCI (+) m/z 372 detected. ¹H NMR (400 MHz. CDC13) δ 7.70 (s, IH), 7.22 (d, 2H), 6.81 (d, 2H), 5.97 (s, IH), 4.38 (m, 3H), 3.37 (m, 2H), 3.22 (m, 2H), 1.87 (m, 4H).

Example 2 N-(I-(I H- 1 ,2,3 -triazol-4-yl)propan-2-yl)-4-f 4-chlorophenoxy)piperidine- 1 -sulfonamide

[0091] Step A: Preparation of Ν-(2-methylbut-3-yn-2-yl)-2-oxooxazolidine-3- sulfonamide: A solution was prepared using a 0.2 M solution of chlorosulfonyl isocyanate (4.19 mL, 48.1 mmol) in acetonitrile and then cooled in an ice bath. Chloroethanol (3.23 mL, 48.1 mmol) was added to the solution. After stirring at a temperature of 0°C for 30 minutes, the reaction mixture was warmed to room temperature for 1 hour. Then N-methyl morpholine (21.2 mL, 192.5 mmol) was added in one portion, followed by 2-methylbut-3-yn- 2-amine (4.0Og, 48.1 mmol). After heating to a temperature of 50°C for 5 hours, the reaction mixture was cooled to room temperature and stirred for 15 hours. The acetonitrile was removed in vacuo and the residue diluted in ethyl acetate ("EtOAc"). The N-methyl morpholine ("NMM") salt formed and was filtered out. The filtrate was washed with saturated NaHCO₃ (2X) and brine (2X). After drying with MgSO₄ and concentrating in vacuo, the N-(2-methylbut-3-yn-2-yl)-2-oxooxazolidine-3 -sulfonamide (9.4g, 84%) was isolated as a solid. MS APCI (-) m/z 231.0 detected. ¹H NMR (400 MHz. CDCl₃) δ 5.69 (br s, IH)₅ 4.43 (m₅ 2H), 4.16 (m, 2H)₅ 2.49 (s, IH)₅ 1.65 (s, 6H).

[0092] Step B: Preparation of 4-(4-chlorophenoxy)-N-(2-methylbut-3-yn-2- yl)piperidine-l-sulfonamide: Triethylamine (0.126 mL, 0.904 mmol) and 4-(4- chlorophenoxy)piperidine (63.8 mg, 0.301 mmol) were added to a solution of N-(2- methylbut-3-yn-2-yl)-2-oxooxazolidine-3-sulfonamide (70.0 mg, 0.301 mmol) in acetonitrile (2.0 mL). After the reaction mixture was heated to a temperature of 8O⁰C overnight, it was diluted in EtOAc and washed with IN HCl (2X)₅ saturated aqueous NaHCO₃ (2X) and brine. The organic layer was dried with MgSO₄ and concentrated in vacuo to afford 4-(4- chlorophenoxy)-N-(2-methylbut-3-yn-2-yl)piperidine-l-sulfonamide (86.4 mg, 80.3 %). MS APCI (+) m/z 356.9 detected.

[0093] Step C: Preparation of N-(2-(lH-l,2,3-triazol-4-yl)ρropan-2-yl)-4-(4- chlorophenoxy) piperidine-1 -sulfonamide: CuI (2.31 mg, 0.0120 mmol) and azidotrimethylsilane ("TMSN₃", 0.0643 mL, 0.484 mmol) were added to a solution of 4-(4- chlorophenoxy)-N-(2-methylbut-3-yn-2-yl)piperidine-l -sulfonamide (86.4 mg, 0.242 mmol) in 1:1 dimethylformamide/methanol (2 mL). After heating to a temperature of 100⁰C for 15 hours, the reaction was incomplete and subjected to the above conditions again. After heating an additional 15 hours, the reaction mixture was concentrated in vacuo and purified by silica chromatography using a gradient of 33%-100% EtOAc/hexanes to afford N-(2-(lH- 1, 2,3 -triazol-4-yl)propan-2-yl)-4-(4-chlorophenoxy)piperidine-l -sulfonamide (26.8 mg, 27.7 %). MS APCI (+) m/z 399.9 detected. ¹H NMR (400 MHz. CD₃OD) δ 7.78 (s, IH), 7.23 (d, 2H, J = 8.98 Hz), 6.90 (d, 2H₅ J = 8.98 Hz), 4.40 (m, IH), 3.21-3.30 (m, 2H), 3.96-3.04 (m, 2H)₅ 1.82-1.90 (m, 2H)₅ 1.72 (s, 6H)₅ 1.61-1.70 (m, 2H). Example 3

N-(2-dH-l,2,3-triazol-4-yl^')propan-2-ylV4-r3.,4-dichlorophenoxy^')piτ)eridine- 1 -sulfonamide

[0094] Step A: Preparation of tert-butyl 2-methylbut-3-yn-2-ylcarbamate: A solution of dimethylpropargylamine (3.0 g, 36 mmol) and Boc anhydride (7.5 g, 34 mmol) in DCM (73 rnL) was stirred at room temperature for 15 hours. The reaction mixture was washed with dilute aqueous HCl, and the organic layer was dried with MgSO₄ and concentrated in vacuo to afford tert-butyl 2-methylbut-3-yn-2-ylcarbamate (6.0 g, 91%) as a solid. ¹H NMR (400 MHz. CDCl₃) δ 2.30 (s, IH), 1.55 (s, 3H)₅ 1.53 (s, 3H)₅ 1.46 (s₅ 9H). [0095] Step B: Preparation of tert-butyl 2-(3H-l₅2,3-triazol-4-yl)propan-2- ylcarbamate: In a 150 mL pressure vessel, tert-butyl 2-methylbut-3-yn-2-ylcarbamate (6.00 g₅ 32.7 mmol) was dissolved in 9:1 DMF/MeOH (65 mL). CuI (0.312 g, 1.64 mmol) and azidotrimethylsilane (5.22 mL, 39.3 mmol) were added. After heating to a temperature of 100⁰C for 15 hours, the reaction mixture was concentrated in vacuo and the residue diluted in DCM. After extracting with IN NaOH (3 times), the aqueous layer was neutralized with 2N HCl and extracted with DCM (3X). The combined organic layers were dried with MgSO₄ and concentrated in vacuo to afford tert-butyl 2-(3H-l,2,3-triazol-4-yl)propan-2-ylcarbamate (5.49g, 74%) as a solid. MS APCI (+) m/z 226.8 detected. ¹H NMR (400 MHz. CDCl₃) δ 7.56 (s, IH), 5.10 (br s, IH), 1.70 (s, 6H), 1.41 (s, 9H).

[0096] Step C: Preparation of 2-( IH- 1,2,3 -triazol-4-yl)propan-2-amine: Tert-butyl 2-

(3H-l₅2,3-triazol-4-yl)propan-2-ylcarbamate (0.500 g, 2.21 mmol) was dissolved in 1:1 (v/v) DCM/TFA (10 mL). After 90 minutes, the reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and free-based using polystyrene supported diisopropylethylamine ("PS-DIEA") overnight (3 equiv). After stirring for 15 hours, the resin was filtered, washed with MeOH and concentrated in vacuo to afford 2-(1H-1, 2,3- triazol-4-yl)propan-2-amine. MS APCI (+) m/z 126.9 detected.

[0097] Step D: Preparation of N-(2-(lH-l,2,3-triazol-4-yl)propan-2-yl)-2- oxooxazolidine-3-sulfonamide: Chloroethanol (0.148 mL, 2.21 mmol) was added to a 0.2 M solution of chlorosulfonyl isocyanate (0.192 mL, 2.21 mmol) in acetonitrile cooled in an ice bath. After stirring at a temperature of O⁰C for 30 minutes, the reaction mixture was warmed to room temperature for 1 hour. Then iV-methyl morpholine (0.972 mL, 8.84 mmol) was added in one portion, followed by 2-(lH-l,2,3-triazol-4-yl)propan-2-arnine. After heating to a temperature of 5O⁰C for 5 hours, the reaction mixture was cooled to room temperature and stirred for 15 hours. The reaction mixture was concentrated in vacuo, and the residue diluted with EtOAc. The NMM salt was filtered out, and the filtrate washed with saturated NaHCO₃ (aq.) (2X) and brine (2X). After drying with MgSO₄, the crude material was concentrated in vacuo to afford N-(2-(lH-l,2,3-triazol-4-yl)propan-2-yl)-2-oxooxazolidine-3-sulfonamide (0.18g, 30 %).

[0098] Step E: N-(2-(lH-l,2,3-triazol-4-yl)propan-2-yl)-4-(3,4- dichlorophenoxy)piperidine-l -sulfonamide: 4-(3,4-dichlorophenoxy)piperidine hydrochloride was free-based by dissolving in IN NaOH and DCM, separating the layers and extracting the aqueous layer with DCM (2X). The combined organic layers were dried with MgSO₄ and concentrated in vacuo to afford 4-(3,4-dichlorophenoxy)piperidine as an oil (93%). 4-(3,4-Dichlorophenoxy) piperidine (98.4 mg, 0.400mmol) and JV-(2-(lH-l,2,3- triazol-4-yl) propan-2-yl)-2-oxooxazolidine-3-sulfonamide (110 mg, 0.400 mmol) were dissolved in acetonitrile (2.6 mL). Triethylamine (0.111 mL, 0.799 mmol) was added, and the reaction mixture was heated to a temperature of 8O⁰C for 15 hours. After purification by silica gel chromatography using a gradient of 25%-50% EtOAc/hexanes, N-(2-( IH- 1,2,3 - triazol-4-yl)propan-2-yl)-4-(3,4-dichlorophenoxy)piperidine-l -sulfonamide (70 mg, 40%) was isolated as an oil. MS APCI (-) m/z 434.0 detected. ¹H NMR (400 MHz. CDCl₃) δ 7.67 (s, IH), 7.31 (d, IH, J = 8.59 Hz), 6.98 (d, IH, J = 2.73 Hz), 6.72-6.75 (m, IH), 5.30 (s, IH), 4.35 (m, IH), 3.26-3.34 (m, 2H), 3.10-3.18 (m, 2H), 1.83-1.94 (m, 2H)₅ 1.73-1.82 (m, 8H).

Example 4

N-(2-(lH-1.2.3-triazol-4-yl)propan-2-ylV4-(^'4-(trifluoromethvπphenoxy)piperidine-l- sulfonamide

[0099] Same procedure as Example 3 (Steps A to D), except for last step: N-(2-(lH-

1 ,2,3-triazol-4-yl)propan-2-yl)-4-(4-(trifluoromethyl)phenoxy) piperidine- 1 -sulfonamide: 4- (4-(trifluoromethyl)phenoxy)piperidine hydrochloride was free-based by dissolving in IN NaOH and DCM, separating the two layers and extracting the aqueous phase with DCM (2X). The combined organic layers were dried with MgSO₄ and concentrated in vacuo to afford 4-(4-(trifluoromethyl)phenoxy)piperidine as an oil (94%). 4-(4-

(Trifluoromethyl)phenoxy)piperidine (113 mg, 0.400mmol) and N-(2-( IH- 1,2,3 -triazol-4- yl)propan-2-yl)-2-oxooxazolidine-3-sulfonamide (110 mg, 0.400 mmol) were dissolved in acetonitrile (2.6 mL). Triethylamine (0.111 mL, 0.799 mmol) was added, and the reaction mixture was heated to a temperature of 8O⁰C for 15 hours. After purification by silica chromatography using a gradient of 25%-50% EtOAc/hexanes, N-(2-(lH-l,2,3-triazol-4- yl)propan-2-yl)-4-(4-(trifluoromethyl)phenoxy) piperidine-1 -sulfonamide (71 mg, 41%) was isolated as a film. MS APCI (-) m/z 432.0 detected. ¹H NMR (400 MHz. CDCl₃) δ 7.67 (s, IH), 7.53 (d, IH, J = 8.59 Hz), 6.93 (d, IH, J = 8.59 Hz), 5.34 (s, IH)₅ 4.48 (m, IH), 3.28- 3.36 (m, 2H), 3.12-3.20 (m, 2H), 1.68-1.96 (m, 10H).

[00100] The foregoing description is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown as described above. Accordingly, all suitable modifications and equivalents may be considered to fall within the scope of the invention as defined by the claims that follow.

[00101] The words "comprise," "comprising," "include," "including," and "includes" when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

Claims

What is claimed is:

1. A compound selected from Formula I:

I and pharmaceutically acceptable salts thereof, wherein:

R¹ and R are H₅ C₁-C₆ alkyl, aryl and 5 or 6 membered heteroaryl ring, wherein the alkyl, aryl or heteroaryl are optionally substituted;

Y is a five or six membered aryl or heteroaryl ring, optionally substituted by one or more Z¹ groups; and Z¹ is independently selected from H, F, Cl, Br, I, CN, CF₃, C₁-C₆ alkyl, 0-(C₁-C₆ alkyl), or (Ci-C₆ alkyl)-OH.

2. The compound of Claim 1 , wherein R¹ is H.

3. The compound of Claim 1, wherein R¹ is C₁-C₆ alkyl.

4. The compound of Claim 3, wherein R¹ is methyl.

5. The compound of Claims 1-4, wherein R² is H.

6. The compound of Claims 1-4, wherein R² is C₁-C₆ alkyl.

7. The compound of Claim 6, wherein R² is methyl.

8. The compound of Claims 1-7, wherein Y is independently selected from the structures:

wherein the aryl and heteroaryl groups are optionally substituted by one or more Z¹ groups.

9. The compound of Claims 1-7, wherein Y is a six membered aryl ring.

10. The compound of Claim 9, wherein Y is a six membered aryl ring having the structure:

11. The compound of Claim 10, wherein Z¹ is a halogen selected from the group consisting of F, Cl₅ Br or I.

12. The compound of Claim 11 , wherein Z¹ is Cl.

13. The compound of Claim 10, wherein Z¹ is CF₃.

14. The compound of Claim 9, wherein Y is a six membered aryl ring having the structure:

15. The compound of Claim 14, wherein each Z is independently a halogen selected from the group consisting of F, Cl, Br or I.

16. The compound of Claim 15, wherein both Z¹ groups are CL

17. The compounds of Claim 1, selected from the structures:

18. A compound selected from the group consisting of: N-((lH-l,2,3-triazol-5- yl)methyl)-4-(4-chlorophenoxy)piperidine- 1 -sulfonamide, N-(2-( 1 H- 1 ,2,3 -triazol-4- yl)propan-2-yl)-4-(4-chlorophenoxy)piperidine- 1 -sulfonamide, N-(2-( 1 H- 1 ,2,3 -triazol-4- yl)propan-2-yl)-4-(3,4-dichlorophenoxy)piperidine- 1 -sulfonamide and N-(2-(l H- 1 ,2,3- triazol-4-yl)propan-2-yl)-4-(4-(trifluoromethyl)phenoxy)piperidine-l-sulfonamide.

19. A pharmaceutical composition comprising a compound according to any of claims 1-19 and a pharmaceutically acceptable excipient, diluent or carrier.

20. A method of treating or preventing MMP-mediated diseases and conditions by administering to a mammal a therapeutically effective amount of a compound according to any of claims 1-19.

21. The use of a compound of claims 1-19 in the manufacture of a medicament to treat an immunological disorder.

22. A process for preparing compounds of Formula I, comprising: a) reacting a compound of Formula 1 :

with a compound of Formula 2:

or a salt thereof, to form a compound of Formula I; or b) heating a compound of Formula 3 :

with copper (I) iodide and azidotrimethylsilane to form a compound of Formula I; or c) reacting a compound of Formula 4:

with a compound of Formula 5 :

to form a compound of Formula I; wherein R¹ and R² are H, C₁-C₆ alkyl, aryl and 5 or 6 membered heteroaryl ring, wherein the alkyl, aryl or heteroaryl are optionally substituted; Y is a five or six membered aryl or heteroaryl ring, optionally substituted by one or more Z¹ groups;

Z¹ is independently selected from H, F, Cl, Br, I, CN, CF₃, C₁-C₆ alkyl, 0-(C₁-C₆ alkyl), or (C₁-C₆ alkyl)-OH; and X is a halogen.