CN1379762A - Beta substituted metalloprotease inhibitors - Google Patents

Abstract

Disclosed are compounds which are inhibitors of metalloproteases and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the compounds have a structure according to Formula (I), wherein R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, G and Z have the meanings described in the specification. This invention also includes optical isomers, diastereomers and enantiomers of Formula (I), and pharmaceutically-acceptable salts, biohydrolyzable amides, esters, and imides thereof. Also described are pharmaceutical compositions comprising these compounds, and methods of treating metalloprotease-related maladies using the compounds or the pharmaceutical compositions.

Description

β-disubstituted metalloproteinase inhibitors

technical field

The present invention relates to compounds useful in the treatment of diseases associated with the activity of metalloproteases, especially zinc-containing metalloproteases. The present invention also relates to a pharmaceutical composition comprising the compound, and a method for treating metalloprotease-related diseases with the compound or the pharmaceutical composition.

Background of the invention

There are many structurally related metalloproteases that destroy structural proteins. These metalloproteases normally act on the intercellular matrix, so they are involved in the destruction and remodeling of tissues. These proteins are called metalloproteases or MPs.

Several different families of MPs classified by sequence homology have been disclosed in the art. These MPs include matrix-metalloproteinases (MMPs), zinc-containing metalloproteases, various membrane-bound metalloproteases, TNF-converting enzymes, angiotensin-converting enzymes (ACE), lysins (disintegrins) (including ADAMs (see Wolfsberg et al., 131 J . Cell. Bio. 275-78, October 1995)) and enkephalinase. Examples of MPs include human skin fibroblast collagenase, human skin fibroblast gelatinase, human sputum collagenase, cartilage aggrecanse and gelatinase, and human stromelysin. Collagenase, stromelysin, aggrecanase and related enzymes are believed to be important in mediating various disease symptoms.

Potential therapeutic indications for MP inhibitors have been discussed in the literature. See, eg, U.S. Patent 5,506,242 (Ciba Geigy Corp.); U.S. Patent 5,403,952 (Merck &Co.); PCT Published Application WO 96/06074 (British Bio Tech Ltd); WO 96/00214 (Ciba Geigy); WO 95/35275 (British Bio Tech Ltd); WO 95/35276 (British Bio Tech Ltd); WO 95/33731 (Hoffman-LaRoche); WO 95/33709 (Hoffman-LaRoche); WO 95/32944 (British Bio Tech Ltd); 26989 (Merck); WO 9529892 (DuPont Merck); WO 95/24921 (Inst. Optithamology); WO 95/23790 (SmithKline Beecham); WO 95/22966 (Sanofi Winthrop); (British Bio Tech Ltd); WO 95/19957 (British BioTech Ltd); WO 95/19961 (British Bio Tech Ltd); WO 95/13289 (Chiroscience Ltd); WO 95/12603 (Syntex); WO 95/09633 ( Florida State Univ); WO 95/09620 (Florida State Univ.); WO 95/04033 (Celltech); WO 94/25434 (Celltech); WO 94/25435 (Celltech); WO93/14112 (Merck); (Glaxo); WO 93/21942 (Britich Bio Tech Ltd); WO92/22523 (Res. Corp. Tech. Inc.); WO 94/10990 (Britich Bio Tech Ltd); WO93/09090 (Yamanouchi) and British Patent GB 2282598 (Merck) and GB 2268934 (Britich BioTech Ltd); Published European Patent Application EP 95/684240 (Hoffman LaRoche); EP574758 (Hoffman LaRoche); EP 575844 (Hoffman LaRoche); Published Japanese Patent Application JP08053403 (Fujusowa Pharm. Co. Ltd.); JP 7304770 (Kanebo Ltd.); and Bird et al., J. Med. Chem Vol. 37, pp. 158-69 (1994).

Examples of potential therapeutic uses of MP inhibitors include: rheumatoid arthritis (D.E.Mullins et al., Biochim Biophys Acta (1983) 695:117-214); osteoarthritis (Henderson, B. et al., Drugs of the Future (1990) 15:495-508); Cancer (Yu, A.E. et al., "Matrix Metalloproteinases—New Targets for Targeted Cancer Therapy," Drugs & Aging, Vol. 11(3), pp. 229-244 (September 1997); Chamber , A.F. and Matrisian, L.M., Review: Changing perspective on the role of matrix metalloproteinases in metastasis, J. of the Nat'l Cancer Inst., Vol. 89(17), 1260-1270 (September 1997), Bramhall , S.R. Matrix Metalloproteinases and Their Inhibitors in Pancreatic Cancer, Internat'l J. of Pancreatology, Vol. 4, pp. 1101-1109 (May 1998), Nemunaitis, J. et al., Matrix Metalloproteinases A Combinatorial Analytical Study of the Effect of the Inhibitor Marimastat on Serum Tumor Markers in Progressive Carcinoma: Biological Activity and Tolerability Dose Selection for Long-Term Studies", Clin. Cancer Res. Vol. and Rasmussen, H.S. and McCann, P.P. Matrix Metalloproteinase Inhibitors as New Anticancer Strategies: A Review with Special Focus on Batimastat and Marimastat, Pharmacol. Ther., Vol. 75(1), pp. 69-75 (1997) ; tumor cell metastasis (supra, Broadhurst, M.J. et al., European Patent Application 276,436 (published 1987), Reich, R. et al., 48 CancerRes 3307-3312 (1988)); multiple sclerosis (Gijbels et al., J.Clin. Invest., Vol. 94, pp. 2177-2182 (1994)) and various tissue erosions or ulcerative diseases. For example, due to alkali burns or Pseudomonas aeruginosa, Acanthamoeba, herpes simplex and vaccinia virus infection, which can lead to ulcerative disease in the cornea. Other examples of diseases characterized by undesirable metalloprotease activity include periodontal disease, epidermolysis bullosa, fever, inflammation, and scleritis (Cf. DeCicco et al. , WO95 29892, published on November 9, 1995).

In view of the involvement of such metalloproteases in many pathologies, there have been various attempts to prepare inhibitors of these enzymes. A wide variety of such inhibitors are disclosed in the literature. Examples include US Patent No. 5,183,900 (issued to Galary on February 2, 1993); US Patent No. 4,996,358 (issued to Handa et al. on February 26, 1991); US Patent No. 4,771,038 (issued to Wolanin et al. ); U.S. Patent No. 4,743,587 (issued May 10, 1988 to Dickens et al); European Patent Application No. 575,844 issued December 29, 1993 to Broadhurst et al; International Patent issued May 13, 1993 to Isomura et al Application WO 93/09090; International Patent Application WO 92/17460 by Markwell et al., published October 15, 1992 and European Patent Application No. 498,665 by Beckett et al., published August 12, 1992.

Inhibition of these metalloproteases is beneficial in the treatment of diseases associated with undesired metalloprotease activity. Although various MP inhibitors have been prepared, there remains a need for potent inhibitors of matrix metalloproteinases for the treatment of such diseases associated with metalloprotease activity.

Brief description of the invention

The present invention provides compounds that are potent inhibitors of metalloproteases, which are effective in the treatment of diseases characterized by excessive activity of these enzymes. Specifically, the present invention relates to a compound of formula (I): in:

(A) R ^is selected from -OH and -NHOH;

(B) R ^is selected from hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl radicals, heteroaralkyls and halogens;

(C) ^R is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycloalkyl ;

(D) R ⁴ is -(CR ⁷ R ^7' ) _k -X-(CR ⁸ R ^8' ) _l -EA wherein:

(1) k is 0-4;

(2) l is 0-4;

(3) R ⁷ , R ^7′ , R ⁸ and R ^8′ , when present, are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, Heterocycloalkyl, halogen and haloalkyl;

(4) X is selected from -O-, -S-, -S(O)-, -S(O ₂ )-, -N(R ⁹ )-, -N(COR ⁹ )-, N(CO ₂ R ⁹ )-, -N(CONR ⁹ R ^9' )- and -N(SO ₂ R ⁹ )-, wherein (i) each R ⁹ and R ^9' , when present, are selected from hydrogen, alkyl, alkenes, respectively radical, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or (ii) ^R9 and R9 ^' and their The bonded nitrogen atoms are taken together to form optionally substituted heterocyclic rings containing 5-8 ring atoms, of which 1-3 are heteroatoms;

(5) E is selected from covalent bond, -O-, -S-, -S(O)-, -S(O ₂ )-, -N(R ¹⁰ )-, -N(COR ¹⁰ )-, - N(CO ₂ R ¹⁰ )-, -N(CONR ¹⁰ R ^10' )- and -N(SO ₂ R ¹⁰ )-, wherein (i) each R ¹⁰ and R ^10' , when present, is independently selected from hydrogen, Alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycloalkyl, or ( ⁱⁱ ) R and R ^10' are taken together with the nitrogen atoms to which they are bonded to form optionally substituted heterocyclic rings containing 5-8 ring atoms, of which 1-3 are heteroatoms; provided that when l=0, E is covalent key; and

(6) (a) A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycle Alkyl; or

(b) A and R ⁷ , R ^7' , R ⁸ , R ^8' , R ⁹ , R ^9' , R ¹⁰ or R ^10' are combined to form ring atoms containing 5-8 ring atoms, of which 1-3 are heterogeneous ring atoms. Atoms optionally substituted heterocyclic rings.

(E) R ^is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycloalkyl ;

(F) R ^is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl and hydroxy ; The condition is that when k>0, R ⁶ is -OH, and when k=0, R ⁶ is not -OH;

(G) G is selected from -S-, -O-, -N(R ¹¹ )-, -C(R ¹¹ )=C(R ^11′ )-, -N=C(R ¹¹ )- and N=N -, wherein each R ^{and R} , when present, are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

(H)Z is selected from:

(1) cycloalkyl and heterocycloalkyl;

(2)-L-(CR ¹² R ^12′ )aR ¹³ , wherein:

(a) a is 0-4;

(b) L is selected from -C≡C-, -CH=CH-, -N=N-, -O-, -S- and -SO ₂ -;

(c) each ^of R and ^R , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; and

(d) ^R is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl; if L is -C≡C- Or -CH=CH-, R ¹³ can also be selected from -CON(R ¹⁴ R ^14' ), wherein (i) R ¹⁴ and R ^14' are respectively selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl , heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or (ii) R ¹⁴ and R ^14' combined with the nitrogen atom to which they are bonded form a ring containing 5-8 ring atoms, Optionally substituted heterocyclic rings in which 1-3 are heteroatoms;

(3)-NR ¹⁵ R ^15′ , wherein:

(a) R and ^R are selected from hydrogen, ^alkyl , alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and -C(O )-Q-(CR ¹⁶ R ^16′ ) _b -R ¹⁷ , wherein:

(i) b is 0-4;

(ii) Q is selected from a covalent bond and -N(R ¹⁸ )-; and

(iii) each ^of R and ^R , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen , haloalkyl, hydroxy, and alkoxy; each R and ^R are independently selected from hydrogen, ^alkyl , alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and hetero Cycloalkyl, or R ¹⁷ and R ¹⁸ taken together with the atoms to which they are bonded form an optionally substituted heterocyclic ring containing 5-8 ring atoms, of which 1-3 are heteroatoms; or R ¹⁵ and R ¹⁸ and the nitrogen atoms to which they are bonded form an optionally substituted heterocyclic ring containing 5-8 ring atoms, of which 2-3 are heteroatoms; or

，其中(b) R ^{and R} taken together with the nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring containing 5-8 ring atoms, of which 1-3 are heteroatoms; and

,in

(a) E' and M' are independently selected from -CH- and -N-;

(b) L' is selected from -S-, -O-, -N(R ²⁰ )-, -C(R ²⁰ )=(R ^20' )-, -N=C(R ²⁰ )- and -N= N-, wherein R ²⁰ and R ^20′, if present, are selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, respectively;

(c) c is 0-4;

(d) R ^{and R} are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, Hydroxy and alkoxy;

(e) A' is selected from a covalent bond, -O-, -SO _d -, -C(O)-, -C(O)N(R ²¹ )-, -N(R ²¹ )-, and -N (R ²¹ )C(O)-; wherein d is 0-2; R ²¹ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkane radical, heterocycloalkyl and haloalkyl; and

(f) G' is -(CR ²² R ^22' ) _e -R ²³ , wherein e is 0-4; R ²² and R ^22' , if present, are independently selected from hydrogen, alkyl, alkenyl, alkynyl, Aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, and aryloxy; and ^R is selected from hydrogen, alkyl, alkenyl, alkyne group, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; or ^R21 and ^R23 combined with the atoms to which they are bonded form a ring containing 5-8 ring atoms , an optionally substituted heterocyclic ring in which 1-3 are heteroatoms; or ^R20 and ^R23 are joined together with the atoms to which they are bonded to form ring atoms containing 5-8 ring atoms, of which 1-3 are heteroatoms Optionally substituted heterocyclic rings of atoms;

Or an optical isomer, diastereomer or enantiomer of formula (I), or a pharmaceutically acceptable salt, biohydrolyzable amide, ester or imide thereof.

The present invention also includes the optical isomers, diastereomers and enantiomers of the above formula, their pharmaceutically acceptable salts, biohydrolyzable amides, esters or imides.

The compounds of the invention are useful in the treatment of diseases and conditions characterized by undesirable metalloprotease activity. Accordingly, the present invention also provides pharmaceutical compositions comprising these compounds. The present invention further provides methods for treating diseases associated with metalloproteases.

Detailed description of the invention

I. Terms and Definitions:

The following is a list of definitions of terms used herein.

"Acyl" or "carbonyl" refers to a group formed by removal of a hydroxyl group from a carboxylic acid (ie, R-C(=O)-). Preferable acyl groups include, for example, acetyl, formyl and propionyl.

"Alkyl" is a saturated hydrocarbon chain group having 1-15 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-4 carbon atoms. "Alkenyl" is a hydrocarbon chain having at least one (preferably only one) carbon-carbon double bond and 2-15 carbon atoms, preferably 2-10 carbon atoms, more preferably 2- 4 carbon atoms. "Alkyne" is a hydrocarbon chain having at least one (preferably only one) carbon-carbon triple bond and 2-15 carbon atoms, preferably 2-10 carbon atoms, more preferably 2-4 carbon atoms. Alkyl, alkene, and alkyne chains (collectively "hydrocarbon chains") may be straight or branched, and may be substituted or unsubstituted. Preferred branched alkyl, alkene and alkyne chains have one or two branches, preferably one branch. The preferred chain is alkyl. Each of the alkyl, alkene and alkyne chains may be substituted or unsubstituted with 1-4 substituents; when substituted, preferred chains are mono-, di- or tri-substituted. Alkyl, alkene and alkyne chains can each be replaced by halogen, hydroxy, aryloxy (e.g. phenoxy), heteroaryloxy, acyloxy (e.g. acetoxy), carboxyl, aryl (e.g. phenyl), heteroaryl Aryl, cycloalkyl, heterocycloalkyl, spiro, amino, amido, acylamino, keto, thioketo, cyano, or any combination thereof. Preferred hydrocarbon chain groups include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl and exomethylenyl.

Likewise, as used herein, a "lower" alkyl, alkene or alkyne moiety (such as "lower alkyl") is a chain of 1-6 carbon atoms (preferably 1-4 carbon atoms) (in in the case of alkyl groups), and chains having 2 to 6, preferably 2 to 4 carbon atoms (in the case of alkenes and alkynes).

"Alkoxy" is an oxy group having a hydrocarbon chain substituent wherein the hydrocarbon chain is alkyl or alkenyl (ie, -O-alkyl or -O-alkenyl). Preferred alkoxy groups include, for example, methoxy, ethoxy, propoxy and allyloxy.

"Aryl" is an aromatic hydrocarbon ring. The aromatic ring is a single ring or a fused bicyclic ring system. Monocyclic aromatic rings contain 6 carbon atoms in the ring. Monocyclic aromatic rings are also known as benzene rings. Bicyclic aromatic rings contain 8-17 carbon atoms, preferably 9-12 carbon atoms in the ring. Bicyclic aromatic rings include ring systems in which one ring is aryl and the other ring is aryl, cycloalkyl or heterocycloalkyl. Preferred bicyclic aromatic rings comprise 5-, 6- or 7-membered rings fused with 5-, 6- or 7-membered rings. The aromatic ring can be unsubstituted or substituted with 1-4 substituents on the ring. Aryl can be replaced by halogen, cyano, nitro, hydroxyl, carboxyl, amino, amido, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, alkoxy, heteroalkoxy, carbamoyl , haloalkyl, methylenedioxy, heteroaryloxy, or any combination thereof. Preferred aromatic rings include naphthyl, tolyl, xylyl and phenyl. The most preferred aromatic ring group is phenyl.

"Aryloxy" is an oxy group having an aryl substituent (ie -O-aryl). Preferred aryloxy groups include, for example, phenoxy, naphthoxy, methoxyphenoxy and methylenedioxyphenoxy.

"Cycloalkyl" is a saturated or unsaturated carbocyclic ring. Cycloalkyl rings are not aromatic. Cycloalkyl rings are monocyclic or fused, spiro or bridged bicyclic ring systems. The monocyclic cycloalkyl has about 3-9 carbon atoms, preferably 3-7 carbon atoms. The bicyclic cycloalkyl has 7-17 carbon atoms, preferably 7-12 carbon atoms. Preferred bicyclic cycloalkyls comprise a 4-, 5-, 6- or 7-membered ring fused to a 5-, 6- or 7-membered ring. Cycloalkyl rings can be unsubstituted, or substituted with 1-4 substituents on the ring. Cycloalkyl groups can be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, amido, aryloxy, heteroaryloxy, or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl and cyclohexyl.

"Halo" or "halogen" refers to fluorine. chlorine, bromine, or iodine. Preferred halo are fluoro, chloro and bromo; more preferred usually are chloro and fluoro.

"Haloalkyl" is a straight chain, branched chain or cyclic hydrocarbon substituted with one or more halo substituents. Preferred is C ₁ -C ₁₂ haloalkyl; more preferred is C ₁ -C ₆ haloalkyl; still more preferred is C ₁ -C ₃ haloalkyl. Preferred halogen substituents are fluoro and chloro.

A "heteroatom" is a nitrogen, sulfur or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.

A "heteroalkyl" is a saturated or unsaturated chain containing carbon and at least one heteroatom, no two of which are adjacent. There are 2-15 constituent atoms (carbon and heteroatoms) in the heteroalkyl chain, preferably 2-10, more preferably 2-5 constituent atoms. For example, alkoxy (ie, -O-alkyl or -O-heteroalkyl) is included within heteroalkyl. A heteroalkyl chain can be straight or branched. Preferred branched heteroalkyl groups have 1 or 2 branches, preferably one branch. Preferred heteroalkyl groups are saturated. Unsaturated heteroalkyl groups have one or more carbon-carbon double bonds and/or one or more carbon-carbon triple bonds. Preferred unsaturated heteroalkyl groups have one or two double bonds or one triple bond, more preferably one double bond. The heteroalkyl chain can be substituted or unsubstituted with 1-4 substituents. Preferred substituted heteroalkyl groups can be mono-, di- or tri-substituted. Heteroalkyl can be replaced by lower alkyl, haloalkyl, halogen, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxyl, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spiro Cyclic, amino, amido, amido, keto, thioketo, cyano, or any combination thereof.

1，2，3-噻二唑       1，2，4-噻二唑            苯并三唑                1，2，4-三唑               四唑

1，2，4-噁二唑       1，3，4-噁二唑         1，2，3，4-噁三唑        1，2，3，4-噻三唑       1，2，3，5-噻三唑

1，2，3，5-噁三唑    1，2，3-三嗪           1，2，4-三嗪             1，2，4，5-四嗪           二苯并呋喃

吡啶              哒嗪              嘧啶              吡嗪           1，3，5-三嗪      中氮茚             吲哚异吲哚               苯并呋喃               苯并噻吩           1H-吲唑                嘌呤                 喹啉

苯并咪唑             苯并噻唑               苯并噁唑              咔唑                 2，3-二氢-1H-异吲哚

"Heteroaryl" is an aromatic ring containing carbon atoms and 1-6 heteroatoms in the ring. Heteroaryl rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaromatic rings have about 5-9 constituent atoms (carbon and heteroatoms), preferably 5 or 6 constituent atoms. The bicyclic heteroaromatic ring has 8-17 constituent atoms, preferably 8-12 constituent atoms. Bicyclic heteroaryl rings include ring systems in which one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl or heterocycloalkyl. Preferred bicyclic heteroaromatic ring systems comprise a 5-, 6- or 7-membered ring fused to a 5-, 6- or 7-membered ring. The heteroaryl ring can be unsubstituted, or substituted with 1-4 substituents on the ring. Heteroaryl can be replaced by halogen, cyano, nitro, hydroxy, carboxy, amino, amido, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy, or Any combination can be substituted. Preferred heteroaromatic rings include but are not limited to the following: Furan Thiophene Pyrrole Pyrazole Imidazole Oxazole Isoxazole Isothiazole Thiazole 1,2,5-thiadiazole 1,2,3-triazole 1,3,4-thiadiazole Furazan

1,2,3-Thiadiazole 1,2,4-Thiadiazole Benzotriazole 1,2,4-Triazole Tetrazole

1,2,4-oxadiazole 1,3,4-oxadiazole 1,2,3,4-oxatriazole 1,2,3,4-thiatriazole 1,2,3,5-thiatriazole azole

1,2,3,5-oxatriazole 1,2,3-triazine 1,2,4-triazine 1,2,4,5-tetrazine dibenzofuran

Pyridine Pyridazine Pyrimidine Pyrazine 1,3,5-Triazine Indolizine Indole Isoindole Benzofuran Benzothiophene 1H-Indazeprine Quinoline

Benzimidazole Benzothiazole Benzoxazole Carbazole 2,3-Dihydro-1H-isoindole

Isoquinoline Cinnoline Phthalazine Quinazoline Quinoxaline 1,8-Naphthyridine

Pteridine                                                       

Thiazoline amines

Coumarin Indoline Phenoxazine 2H-Chromene 3H-Indole

Chromone chroman 4H-3,1-benzoxazine phenothiazine 1,3-dihydroisobenzofuran

"Heteroaryloxy" is oxy having one heteroaryl substituent (ie -O-heteroaryl). Preferred heteroaryloxy groups include, for example, pyridyloxy, furyloxy, (thiophene)oxy, (oxazole)oxy, (thiazole)oxy, (isoxazole)oxy, pyrimidinyloxy, Pyrazinyloxy and benzothiazolyloxy.

环氧乙烷         氮丙啶          氧杂环丁烷         吖丁啶         四氢呋喃            吡咯烷         1，4-氧硫"Heterocycloalkyl" is a saturated or unsaturated ring having carbon atoms and 1-4 (preferably 1-3) heteroatoms in the ring. Heterocycloalkyl rings are not aromatic. A heterocycloalkyl ring is a monocyclic ring, or a fused, bridged or spiro bicyclic ring system. The monocyclic heterocycloalkyl group contains 3-9 constituent atoms (carbon and heteroatoms), preferably 5-7 constituent atoms. The bicyclic heterocycloalkyl has 7-17 constituent atoms, preferably 7-12 constituent atoms. Bicyclic heterocycloalkyls contain 7-17 ring atoms, preferably 7-12 ring atoms. A bicyclic heterocycloalkyl can be a fused, spiro or bridged ring system. Preferred bicyclic heterocycloalkyls comprise a 5-, 6- or 7-membered ring fused to a 5-, 6- or 7-membered ring. A heterocycloalkyl ring can be unsubstituted, or substituted with 1-4 substituents on the ring. Heterocycloalkyl can be replaced by halogen, cyano, hydroxy, carboxyl, keto, thioketo, amino, amido, acyl, amido, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryl Oxygen, or any combination thereof. Preferred substituents on heterocycloalkyl include halo and haloalkyl. Preferred heterocycloalkyl rings include but are not limited to the following:

Ethylene oxide Aziridine Oxetane Azetidine Tetrahydrofuran Pyrrolidine 1,4-Oxysulfur

1，3-二氧戊环        1，2-二硫戊环          1，3-二硫戊环            4，5-二氢异噁唑         2，3-二氢异噁唑

六氢-哌嗪         4，5-二氢吡唑            咪唑烷            2H-吡咯           4H-喹嗪

吡唑烷                   2H-吡喃             3，4-二氢-2H-吡喃              四氢吡喃             1，3-二噁烷

5，6-二氢-        哌啶              吗啉           4H-1，3-噁嗪         6H-1，3-噁嗪4H-1，3-噁嗪

Cepham                哌嗪            六氢氮杂环庚稀       1，3-二噻烷         1，4-二噁烷  Penem

1，4-二硫杂         硫代吗啉      尿嘧啶             胸腺嘧啶            胞嘧啶             硫杂环戊烷(thiolane)环己烷Heterocyclohexane

1,3-Dioxolane 1,2-Dithiolane 1,3-Dithiolane 4,5-Dihydroisoxazole 2,3-Dihydroisoxazole

Hexahydro-Piperazine 4,5-Dihydropyrazole Imidazolidine 2H-Pyrrole 4H-Quinazine

Pyrazolidine 2H-pyran 3,4-dihydro-2H-pyran Tetrahydropyran 1,3-dioxane

5,6-Dihydro-piperidine Morpholine 4H-1,3-oxazine 6H-1,3-oxazine 4H-1,3-oxazine

Cepham Piperazine Hexahydroazepane 1,3-Dithiane 1,4-Dioxane Penem

1,4-Dithia Thiomorpholine Uracil Thymine Cytosine Thiolane (thiolane) cyclohexane

The term "mammalian metalloprotease" as used herein refers to the proteases disclosed in the "Background" section of this application. The compounds of the present invention are preferably active against "mammalian metalloproteases", which include any metal-containing enzymes found in animal (preferably mammalian) sources that catalyze the degradation of collagen, gelatin or proteoglycans under suitable assay conditions. (Preferably an enzyme containing zinc). Suitable assay conditions can be found, for example, in U.S. Patent No. 4,743,587, which refers to the steps of Cawston et al. in Anal. Biochem. (1979) 99: 340-345, and adopts Weingarten, H. et al. Synthetic substrates described in Res. Comm. (1984) 139: 1184-1187. See also, Knight, C.G. et al., "A Novel Coumarin-Labeled Peptide for the Continuous Sensitive Assay of Matrix Metalloproteases", FEBS Letters, Vol. 296, pp. 263-266 (1992). Of course, any standard method for analyzing the degradation of these structural proteins can be used. More preferred compounds of the invention are active against metalloproteases which are zinc-containing proteases structurally similar to, for example, human stromelysin or dermal fibroblast collagenase. Of course, the ability of candidate compounds to inhibit metalloprotease activity can be tested in the assays described above. The inhibitory activity of the compounds of the invention can be confirmed using isolated metalloproteases or crude extracts containing a range of tissue-degrading enzymes.

"Spiro ring" means an alkyl or heteroalkyl diradical substituent of an alkyl or heteroalkyl group, wherein the diradical substituents are geminally linked, wherein the diradical substituents form a ring, so The ring has 4-8 constituent atoms (carbon atoms or heteroatoms), preferably 5 or 6 constituent atoms.

Although, as stated above, alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl groups may be substituted with hydroxy, amino and amido groups, the following are not contemplated by the present invention:

1. Enols (OH attached to a carbon bearing a double bond).

2. The amino group is connected to the carbon carrying the double bond (except for the amides of alkenes).

3. Multiple hydroxy, amino, or amido groups attached to a single carbon (except that two nitrogen atoms are attached to one carbon and all three atoms are constituent atoms in a heterocycloalkyl ring).

4. A hydroxy, amino or amido group attached to a carbon to which another heteroatom is attached.

A "pharmaceutically acceptable salt" is a cationic salt formed on any acidic group, such as a hydroxamic acid or a carboxylic acid, or an anionic salt formed on any basic group, such as an amino group. Many of these salts are known in the art, such as those described in International Patent Publication 87/05297, Johnston et al., published September 11, 1987, which is incorporated herein by reference. Preferred cationic salts include alkali metal (such as sodium and potassium) and alkaline earth metal (such as magnesium and calcium) salts and organic salts. Preferred anionic salts include halides (eg, chlorides), sulfonates, carboxylates, phosphates, and the like.

These salts are well known to those skilled in the art, and those skilled in the art can prepare any salt according to the knowledge in the art. Additionally, those skilled in the art will recognize that one salt is preferred over the other for reasons of solubility, stability, ease of formulation, and the like. Determination and optimization of these salts are within the capabilities of those skilled in the art.

A "biohydrolyzable amide" is an amide of a metalloprotease inhibitor containing a hydroxamic acid (i.e., ^R in formula (I) is -NHOH), which does not interfere with the inhibitory activity of the compound, or is readily produced by animals (more Preferably a mammal, more preferably a human) is transformed in vivo to produce an active metalloproteinase inhibitor. These amide derivatives are, for example, alkoxyamides in which the hydroxyl hydrogen of the hydroxamic acid of formula (I) is replaced by an alkyl moiety, and acyloxyamides in which the hydroxyl hydrogen is replaced by an acyl moiety (i.e., RC(=O) -)replace.

"Biohydrolyzable hydroxyimides" are imides of metalloprotease inhibitors containing hydroxamic acids that do not interfere with the inhibitory activity of these compounds, or are readily produced by animals (preferably mammals, more preferably for humans) are converted in vivo to produce active metalloproteinase inhibitors. These imide derivatives are, for example, imide derivatives of hydroxamic acids of formula (I) in which the amino hydrogen is replaced by an acyl moiety (ie, R-C(=O)-).

"Biohydrolyzable esters" means esters of metalloprotease inhibitors containing carboxylic acids (i.e., where ^R in formula (I) is -OH) that do not interfere with the metalloprotease-inhibiting activity of these compounds, or are readily produced by animals. Transformation yields active metalloprotease inhibitors. These esters include lower alkyl esters, lower acyloxyalkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl), lactones (such as benzofuranone ester and thiobenzofuranone ester), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl ester, ethoxycarbonyloxyethyl ester and isopropoxycarbonyloxy ethyl esters), alkoxyalkyl esters, choline esters and alkylacylaminoalkyl esters (such as acetamidomethyl esters).

A "solvate" is a complex formed by combining a solute (eg, a metalloproteinase inhibitor) and a solvent (eg, water). See J. Honig et al., The Van Nostrand Chemist's Dictionary, p. 650 (1953). Pharmaceutically acceptable solvents employed in the present invention include those solvents that do not interfere with the biological activity of metalloproteinase inhibitors (for example, water, ethanol, acetic acid, N,N-dimethylformamide and those known to those skilled in the art or other solvents that are readily identifiable).

The terms "optical isomers", "stereoisomers", and "diastereomers" have standard art-recognized meanings (Cf., Hawley's Condensed Chemical Dictionary, 11th Ed.). There are no restrictions on the description of specific protection modes and other derivatives of the compounds of the present invention. The use of other suitable protecting groups, salt forms, etc. is within the ability of those skilled in the art.

II. Compounds:

The present invention relates to a compound of formula (I): wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , G and Z have the abovementioned meanings. Descriptions of particularly preferred groups are provided below, but are not intended to limit the scope of the claims.

^R1 is selected from -OH and -NHOH; preferably -OH.

^R is selected from hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, hetero Aralkyl and halogen; preferably hydrogen or alkyl, more preferably hydrogen.

^R is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycloalkyl; preferably hydrogen or alkyl, more preferably hydrogen.

R ⁴ is -(CR ⁷ R ^7' ) _k -X-(CR ⁸ R ^8' ) _l' -EA. Each k and 1 is selected from 0, 1, 2, 3 or 4, respectively; preferably k is 0, 1, 2 or 3; preferably 1 is 0, 1 or 2. ^R7 , ^R7' , ^R8 and ^R8' are selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen and Haloalkyl; preferably both are hydrogen.

X is selected from -O-, -S-, -S(O)-, -S(O ₂ )-, -N(R ⁹ )-, -N(COR ⁹ )-, N(CO ₂ R ⁹ )- , -N(CONR ⁹ R ^9' )- and -N(SO ₂ R ⁹ )-, wherein each R ⁹ and R ^9' are respectively selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkane radical, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycloalkyl (preferably ^R9 and R9 ^' are hydrogen respectively), or (ii) ^R9 and ^R9' with Taken together with the nitrogen atoms to which they are bound, optionally substituted heterocycles containing 5-8 ring atoms, 1-3 of which are heteroatoms. Preferably X is -O-, -S-, -N(SO ₂ R ⁹ )-, -N(COR ⁹ )-, N(CO ₂ R ⁹ )-, wherein R ⁹ is preferably lower alkyl or aryl.

E is selected from covalent bond, -O-, -S-, -S(O)-, -S(O ₂ )-, -N(R ¹⁰ )-, -N(COR ¹⁰ )-, -N(CO ₂ R ¹⁰ )-, -N(CONR ¹⁰ R ^10' )- and -N(SO ₂ R ¹⁰ )-, wherein (i) each of R ¹⁰ and R ^10' is selected from hydrogen, alkyl, alkenyl, Alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycloalkyl (preferably R ^{and R} are each hydrogen), or (ii ) R ¹⁰ and R ^10' together with the nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring containing 5-8 ring atoms, of which 1-3 are heteroatoms. Preferably E is a covalent bond, -O-, -S-, -N(SO ₂ R ¹⁰ )-, -N(COR ¹⁰ )- or -N(CO ₂ R ¹⁰ )-, wherein R ¹⁰ is lower alkyl or aryl. When l=0, E is a covalent bond.

A is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycloalkyl; preferably A is Alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.

^R is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycloalkyl; preferably hydrogen or lower alkyl; more preferably hydrogen.

R is selected from the group consisting of alkyl, alkenyl ^, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl and hydroxy; preferably aryl radical, heteroaryl or hydroxyl. When k>0, R ⁶ is -OH, and when k=0, R ⁶ is not -OH;

G is selected from -S-, -O-, -N(R ¹¹ )-, -C(R ¹¹ )=C(R ^11′ )-, -N=C(R ¹¹ )- and N=N-; In a preferred example, G is -S- or -C(R ¹¹ )=C(R ^11' )-. ^R11 and ^R11' are selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, respectively; preferably at least ^R11 and ^R11' One of is hydrogen, more preferably both are hydrogen.

Z is selected from cycloalkyl and heterocycloalkyl; -L-(CR ¹² R ^12' )aR ¹³ ; -NR ¹⁵ R ^15' ; and

When Z is cycloalkyl or heterocycloalkyl, it is preferred that Z is optionally substituted piperidine or piperazine.

When Z is -L-(CR ¹² R ^12' )aR ¹³ , a is 0, 1, 2, 3 or 4, preferably 0 or 1. L is selected from -C≡C-, -CH=CH-, -N=N-, -O-, -S- and -SO ₂ -; preferably L is -C≡C-, -CH=CH-, - N=N-, -O- or -S-; more preferably L is -C≡C-, -CH=CH- or -N=N-. R ¹² and R ^12' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy group; preferably R ¹² is hydrogen, R ^12' is hydrogen or lower alkyl. R is selected from aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl ^; preferably ^R is aryl, heteroaryl, heterocycle Alkyl or cycloalkyl. However, if L is -C≡C- or -CH=CH-, R ¹³ can also be selected from -CON(R ¹⁴ R ^14' ), wherein (i) R ¹⁴ and R ^14' are respectively selected from hydrogen, alkyl, Alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or (ii) ^R14 and ^R14' together with the nitrogen atom to which they are bonded Optionally substituted heterocyclic rings are formed containing 5-8, preferably 5 or 6 ring atoms, of which 1-3 (preferably 1 or 2) are heteroatoms.

When Z is -NR ¹⁵ R ^15' , R ¹⁵ and R ^15' are respectively selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, Heteroalkyl and -C(O)-Q-(CR ¹⁶ R ^16' ) _b -R ¹⁷ ; preferably R ¹⁵ and R ^15' are selected from hydrogen, alkyl, aryl and -C(O)-Q- (CR ¹⁶ R ^16' ) _b -R ¹⁷ . When R ¹⁵ and/or R ^15' is -C(O)-Q-(CR ¹⁶ R ^16' ) _b -R ¹⁷ , b is 0, 1, 2, 3 or 4; b is preferably 0 or 1. Q is selected from a covalent bond and -N(R ¹⁸ )-; Q is preferably a covalent bond. R and ^R are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen ^, haloalkyl, hydroxy and alkoxy group; preferably R ¹⁶ is hydrogen, and R ^16' is independently hydrogen or lower alkyl. R and ^R are independently selected from hydrogen, ^alkyl , alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl (preferably aryl); Or R ¹⁷ and R ¹⁸ combined with the nitrogen atom to which they are bonded form an optionally substituted ring containing 5-8 (preferably 5 or 6) ring atoms, of which 1-3 (preferably 1-2) are heteroatoms A heterocyclic ring; preferably R ¹⁷ is alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl. In addition, R ¹⁵ and R ¹⁸ together with the nitrogen atom bonded to them form an optional ring containing 5-8 (preferably 5 or 6) ring atoms, of which 1-3 (preferably 1 or 2) are heteroatoms. Substituted heterocycles. Most preferably R ¹⁵ is hydrogen or lower alkyl, and R ^15' is -C(O)-Q-(CR ¹⁶ R ^16' ) _b -R ¹⁷ , wherein Q is a covalent bond, b=0, and R ¹⁷ is aryl.

Alternatively, R ¹⁵ and R ^15' are combined with the nitrogen atom to which they are bonded to form an optional ring containing 5-8 (preferably 5 or 6) ring atoms, of which 1-3 (preferably 1 or 2) are heteroatoms. Optionally substituted heterocycles;

(在此称为式(A))时，E′和M′分别选自-CH-和-N-；优选是E′是-CH，M′是-CH。L′选自-S-，-O-，-N(R²⁰)-，-C(R²⁰)＝(R^20′)-，-N＝C(R²⁰)-和-N＝N-；优选L是-C(R²⁰)＝C(R^20′)-。R²⁰和R^20′分别选自氢、烷基、链烯基、炔基、杂烷基、芳基、杂芳基、环烷基和杂环烷基；优选氢或低级烷基。c是0、1、2、3或4，优选0或1。R¹⁹和R^19′各自独立选自氢、烷基、链烯基、炔基、芳基、杂烷基、杂芳基、环烷基、杂环烷基、卤素、卤代烷基、羟基和烷氧基；优选R¹⁹是氢，R^19′分别是氢或低级烷基。A′选自共价键、-O-、-SO_d-、-C(O)-、-C(O)N(R²¹)-、-N(R²¹)-、和-N(R²¹)C(O)-；优选A′是-O-或-S-。d是0、1或2。R²¹选自氢、烷基、链烯基、炔基、芳基、杂芳基、杂烷基、杂芳基、环烷基、杂环烷基和卤代烷基；R²¹优选是低级烷基或芳基。G′是-(CR²²R^22′)_e-R²³。e是0、1、2、3或4，优选0或1。R²²和R^22′分别选自氢、烷基、链烯基、炔基、芳基、杂烷基、杂芳基、环烷基、杂环烷基、卤素、卤代烷基、羟基、烷氧基和芳氧基；优选R²²是氢，R^22′分别是氢或低级烷基。R²³选自氢、烷基、链烯基、炔基、卤素、杂烷基、卤代烷基、芳基、杂芳基、环烷基和杂环烷基；优选R²³是低级烷基或芳基。另外，R²¹和R²³与和它们键合的原子合起来形成含有5-8(优选5或6)个环原子、其中有1-3(优选1或2)个是杂原子的任选取代的杂环。另外，R²⁰和R²³与和它们键合的原子一起连接形成含有5-8(优选5或6)个环原子、其中有1-3(优选1或2)个为杂原子的任选取代的杂环。when Z is

(herein referred to as formula (A)), E' and M' are respectively selected from -CH- and -N-; preferably E' is -CH and M' is -CH. L' is selected from -S-, -O-, -N(R ²⁰ )-, -C(R ²⁰ )=(R ^20' )-, -N=C(R ²⁰ )- and -N=N-; Preferably L is -C(R ²⁰ )=C(R ^20' )-. ^R20 and ^R20' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; preferably hydrogen or lower alkyl. c is 0, 1, 2, 3 or 4, preferably 0 or 1 . R and ^R are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen ^, haloalkyl, hydroxy and alkane Oxygen; preferably R ¹⁹ is hydrogen, and R ^19' is independently hydrogen or lower alkyl. A' is selected from covalent bonds, -O-, -SO _d -, -C(O)-, -C(O)N(R ²¹ )-, -N(R ²¹ )-, and -N(R ²¹ )C(O)-; preferably A' is -O- or -S-. d is 0, 1 or 2. R is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkyl; ^R is ^preferably lower alkyl or aryl. G' is -(CR ²² R ^22' ) _e -R ²³ . e is 0, 1, 2, 3 or 4, preferably 0 or 1 . R ²² and R ^22' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy; preferably R ²² is hydrogen and R ^22' is hydrogen or lower alkyl, respectively. ^R is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; preferably ^R is lower alkyl or aryl base. In addition, ^R21 and ^R23 are taken together with the atoms to which they are bonded to form optionally substituted ring atoms containing 5-8 (preferably 5 or 6) ring atoms, of which 1-3 (preferably 1 or 2) are heteroatoms of heterocycles. Additionally, ^R20 and ^R23 are joined together with the atoms to which they are bonded to form an optionally substituted of heterocycles.

Most preferred compounds are those where Z is -NR ¹⁵ R ^15' or A subgenus of preferred compounds are carboxylic acid-containing compounds, having the structure of formula (II) or formula (III): Wherein R ⁶ , X, k, I, E, A, G and Z are as described in formula (I).

III. Compound preparation:

The compounds of the present invention can be prepared in a variety of steps.

The starting materials used in the preparation of the compounds of the present invention are known, can be prepared by known methods, or are commercially available. Particularly preferred synthetic methods are described in the general reaction schemes below. (The R groups used to describe the reaction schemes need not be related to the respective R groups used to describe the various aspects of the compounds of formula I. That is, for example, R in formula (I) need not be represented as the same as _R herein. ⁾ Preparation of this Specific examples of inventive compounds are described in Section VIII below.

Process 1

In Scheme 1, aldehyde S1a is a commercially available material. Its synthetic utility is widely recognized and several conditions have been developed for its stereoselective reaction with affinity substances. In this way, various aryl or alkyl _R1 groups can be introduced to form alcohol S1b with controllable syn/trans stereochemistry depending on the reaction conditions. The newly formed hydroxyl group of S1b can be functionalized by various alkylating agents by methods well known to those skilled in the art to introduce a substituent R ₂ . The product S1c can then be converted to the target carboxylic acid using methods well documented in the chemical literature. In this way, the Boc and acetone protecting groups of S1c can be removed under acidic conditions to obtain aminoalcohol S1d. Selective derivatization of the amino group of this intermediate by the appropriate arylsulfonyl chloride using standard Schott and Bouman conditions affords the sulfonamide S1e. Further elaboration of aryl _R3 can be performed at this stage using, for example, Suzuki coupling methods. Finally, the alcohol functionality is converted to a carboxylic acid using standard oxidation methods, yielding the target molecule S1f.

If desired, the carboxylic acid functionality in compounds of type SIf can be converted to a hydroxamic acid by the mixed anhydride method or by coupling with hydroxylamine through the formation of an intermediate acid chloride.

Process 2

In scheme 2, commercially available epoxy alcohols S2a are converted into aziridine esters S2e by known methods (Zwanenburg et al., Rec. Trav. Chim. Pay. Bas 1992, 111, 1). First, the alcohol is oxidized and the resulting carboxylic acid S2b is esterified to give the epoxy ester S2c. The epoxide ring of S2c can then be opened by reaction with sodium azide in the presence of ammonium chloride to give the azidoalcohol S2d as a regioisomer. The aziridine S2e obtained after treatment of S2d with triphenylphosphine has been shown in the chemical literature to be a versatile electrophile capable of ring-opening reactions with various sulfur-, oxygen-, and nitrogen-based nucleophiles. For example, thiols react with S2e under the catalysis of boron trifluoride etherate to give functionalized amino acids S2f (X=S) in very good yields. Similarly, oxygen- or nitrogen-functionalized amino acids S2f (X=O or N) can be prepared by addition of acetic acid or azide, respectively (Legtersen, J. et al., Rec. Trav. Chim. Pay. Bas 1992, 111, 59) . The free amino group can then be derivatized with various sulfonyl chlorides to afford sulfonamide esters S2g. If desired, more complex arylsulfonyl groups can be introduced in a sequence of several synthetic steps. Finally, the ester function can be converted to the carboxylic acid using standard hydrolysis methods to obtain the target molecule S2h.

If desired, the ester functionality in compounds of type S2g can be converted to hydroxamic acid by reaction with hydroxylamine under basic conditions.

Process 3

In Scheme 3, the absolute and relative stereochemistry of the target aminoalcohol S3d chiral center was established using well-known Evans chemistry. Thus, oxazolidine bromoacetates S3a react with selected aldehydes to afford highly stereoselective bromoalcohols S3b. In the next step, the bromine atom was replaced with an azido group using standard conditions for _SN2 substitution to afford intermediate S3c. Hydrolysis of the oxazolidine group can be performed using conditions well described in the chemical literature to yield the key intermediate amino acid S3d. The free amino group of S3d can then be derivatized with various sulfonyl chlorides to give the target inhibitor S3e. If desired, a more complex arylsulfonyl group can be introduced in a series of synthetic steps. Solution requirements, the carboxyl functionality in compounds of type S3e can be converted to hydroxamic acids by coupling with hydroxylamine using the mixed anhydride method or forming an intermediate acid chloride.

These steps can be varied to increase the yield of the desired product. The skilled artisan will recognize that judicious choice of reactants, solvents and temperatures are important factors in any successful synthesis. Determining optimal conditions and the like is routine. Thus, the skilled artisan can prepare various compounds using the above schemes.

It will be recognized that standard manipulations of organic compounds can be readily performed by one skilled in the art of organic chemistry without additional instruction; ie, performing such manipulations is within the skillful range of practice. These operations include, but are not limited to: reduction of carbonyl compounds to their corresponding alcohols, oxidation of hydroxyl groups, etc., acylation, aromatic substitution (electrophilic and nucleophilic), etherification, esterification, and saponification, among others. Examples of these operations and others known to those skilled in the art are discussed in standard textbooks such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. II).

The skilled artisan will also readily appreciate that certain reactions proceed best when other potentially reactive functional groups on the molecule are shielded or protected, thereby avoiding any undesirable side reactions and/or improving reaction yields. Protecting groups are often utilized by the skilled artisan to achieve increased yields or to avoid adverse reactions. Such reactions are found in the literature and are within the purview of the skilled artisan. Many examples of these manipulations can be found in T. Greene, Protecting Groups in Organic Synthesis. Of course, amino acids with reactive side chains, used as starting materials, are preferably also blocked to prevent undesirable side reactions.

The compounds of the present invention possess one or more chiral centers. As a result, one optical isomer, including diastereomers and enantiomers, can be prepared selectively, for example, by chiral starting materials, catalysts, or solvents, or two stereoisomers or optical isomers can be prepared simultaneously. Isomers include diastereomers and enantiomers (racemates). Since the compound of the present invention may exist as a racemic mixture, optical isomers (including diastereoisomers and enantiomers) or Mixture of stereoisomers.

In addition, it is recognized that one optical isomer (including diastereomers and enantiomers) or stereoisomer may have more attractive properties than the other. Thus when the invention is disclosed and claimed, when a racemic mixture is disclosed, it should be clearly deemed to also disclose and claim two optical isomers (including diastereoisomers) substantially free of the other. and enantiomers) or stereoisomers.

IV. How to use

Metalloproteases (MPs) found in the body act in part by cleaving the extracellular matrix, including extracellular proteins and glycoproteins. Metalloprotease inhibitors are useful in the treatment of diseases at least in part caused by the cleavage of such proteins and glycoproteins. These proteins and glycoproteins play an important role in maintaining the volume, shape, structure and stability of body tissues. Therefore, MP is closely related to tissue remodeling.

As a result of this activity, MP is believed to be active in many diseases involving: (1) damage of tissues, including eye diseases; degenerative diseases, such as arthritis, multiple sclerosis, etc.; metastasis of tissues in vivo or migration; or (2) tissue reconstruction, including heart disease, fibrotic disease, scar formation, benign hyperplasia, etc.

The compounds of the invention prevent or treat disorders, diseases and/or undesired states characterized by unwanted or elevated activity of MPs. For example, these compounds can be used to inhibit MP, the protease

1. Destruction of structural proteins (that is, proteins that maintain tissue stability and structure);

2. Interference with intercellular/intracellular signaling, including signaling involving upregulation of cytokines, and/or cytokine processing and/or inflammation, tissue degeneration and other diseases [Mohler KM, et al., Nature 370(1994) 218 -220, Gearing AJH, et al., Nature 370 (1994) 555-557, McGeehan GM, et al., Nature 370 (1994) 558-561]; and

3. To promote processes that are not desired by the subject, such as sperm maturation, egg fertilization, etc.

As used herein, an "MP-associated disorder" or "MP-associated disease" is an undesired occurrence involved in the biological manifestations of a disease or disorder, in the biological cascade leading to a disease, or as a symptom of a disease. or diseases of elevated MP activity. MP's "involvement" include:

1. Undesirable or elevated MP activity as the "cause" of a disease or biological manifestation, whether the elevated activity is due to genetic, infectious, autoimmune, traumatic, biomechanical, lifestyle (eg, obesity ) or some other reasons;

2. MPs as part of an observable manifestation of a disease or disorder, ie, the disease or disorder is measurable in terms of elevated MP activity. From a clinical standpoint, undesired or elevated MP levels indicate disease. However, MP need not be a "marker" of a disease or disorder;

3. The unwanted or elevated MP activity is part of a biochemical or cellular cascade leading to or associated with the disease or disorder. In this regard, inhibition of MP activity blocks the cascade, thereby controlling the disease.

The term "treating" is used herein to mean that administration of a compound of the invention at least alleviates a disease associated with unwanted or elevated MP activity in a mammalian subject, preferably a human. Thus, the term "treating" includes: preventing MP-mediated disease in a mammal, especially when the mammal is predisposed to acquire the disease but has not been diagnosed with the disease; inhibiting the MP-mediated disease; and/or alleviating or Reversal of MP-mediated disease. Since the methods of the present invention relate to the prevention of a disease state associated with undesirable MP activity, it will be understood that the term "prevent" need not completely prevent the disease state. (See Webster's Ninth Collegiate Dictionary). In contrast, as used herein, the term "prevention" refers to the ability of the skilled person to identify a population predisposed to MP-associated disease so that a compound of the invention can be administered before the disease occurs. The term does not imply that the disease state can be avoided entirely. For example, osteoarthritis (OA) is the most common rheumatoid disease, with radiologically detectable joint changes in 80% of people over the age of 55. Fife, R.S., "A Brief History of Osteoarthritis", in Osteoarthritis: Diagnosis and Medical/Surgical Management, eds. R.W. Moskowitz, D.S. Howell, V.M. Goldberg and H.J. Mankin, pp. 11-14 (1992). A common risk factor that increases the incidence of OA is traumatic damage to the joints. Surgical removal of the meniscus following a knee injury increases the risk of radiologically detectable OA, and this risk increases over time. Roos, H, et al., "Osteoarthritis of the knee after meniscectomy: incidence of radiologic changes after 21 years compared with matched controls," Arthritis Rheum., Vol. 41, pp. 687-693; Roos, H, et al. "Osteoarthritis of the Knee Following Anterior Cruciate Ligament or Meniscus Injury: Effects of Time and Age" Osteoarthritis Cartilege. Vol. 3, pp. 261-267 (1995). Thus, such patient populations can be identified and the compounds of the invention can be administered prior to disease progression. Thus, it will be possible to "prevent" the progression of osteoarthritis in these individuals.

Advantageously, many MPs are not evenly distributed throughout the body. Thus, the distribution of MPs expressed in various tissues is often specific to those tissues. For example, the distribution of metalloproteases involved in joint tissue damage differs from that found in other tissues. Thus, it may be desirable, though not essential for activity or efficacy, to treat certain diseases, disorders and undesirable conditions with compounds that act on specific MPs in the affected tissue or region of the body. For example, compounds that exhibit high affinity and inhibition of MPs in joints (eg, chondrocytes) are better at treating diseases, disorders, or undesired conditions seen there than other compounds that are less specific.

In addition, certain inhibitors are more bioavailable to some tissues than others. Selection of MP inhibitors that are more bioavailable to a tissue and that act on specific MPs found in that tissue provides specific treatment of a disorder, disease, or undesirable condition. For example, the compounds of the invention vary in their ability to penetrate the central nervous system. Thus, compounds can be selected to produce effects mediated by MPs found specifically outside the central nervous system.

Determining the specificity of an MP inhibitor for a particular MP is within the skill of the art. Suitable test conditions can be found in the literature. Specifically, assay methods for stromelysin and collagenase are known. For example, US Patent No. 4,743,587 describes the method of Cawston et al., Anal Biochem (1979) 99:340-345. See also, Knight, C.G. et al., "A Novel Coumarin-Labeled Peptide for the Continuous Sensitive Assay of Matrix Metalloproteases", FEBS Letters, Vol. 296, pp. 263-266 (1992). Weingarten, H. et al., Biochem Biophy Res Comm (1984) 139: 1184-1187 describe the use of synthetic substrates in assays. Of course, any standard method for analyzing MP degraded structural proteins can be used. The ability of the compounds of the invention to inhibit the activity of metalloproteases can of course be tested using methods found in the literature or modifications thereof. The inhibitory activity of the compounds of the invention can be confirmed using isolated metalloproteases, or crude extracts containing a range of enzymes capable of lysing tissue can be used.

The compounds of the invention may also be used prophylactically or acutely. They may be administered in any manner desired by those skilled in the art of medicine or pharmacology. As will be readily apparent to the skilled artisan, the preferred route of administration will depend upon the disease state being treated and the dosage form chosen. Preferred routes of systemic administration include oral or parenteral administration.

However, the skilled artisan will readily appreciate that administering an MP inhibitor directly to the affected site is beneficial for many diseases, disorders or undesired conditions. For example, administering an MP inhibitor directly to an area of disease, disorder, or undesired condition (such as surgical trauma (such as angioplasty), scars or burns (such as localized skin) or affected areas for ocular and periodontal indications ) may be beneficial.

Since MP is involved in bone remodeling, the compounds of the invention can be used to prevent prosthetic loosening. It is well known in the art that, over time, prostheses loosen, causing pain and possibly further bone damage and requiring replacement. These prosthetic replacement needs include, for example, joint replacements (eg, hip, knee, and shoulder replacements), dentures, including dentures, bridges, and maxillary and/or mandibular resting dentures.

MP also plays a role in rebuilding the cardiovascular system (eg congestive heart failure). It has been suggested that one of the reasons for the higher than expected long-term failure rate (reclosure after a period) of angioplasty is that MP activity is undesirable in response to what the body recognizes as "damage" to the vascular basement membrane Or cause an increase in MP activity. Thus, modulation of MP activity may improve the long-term success of any other therapy, or as a therapy itself, in indications such as dilated cardiomyopathy, congestive heart failure, atherosclerosis , plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, angioplasty restenosis, and aortic aneurysm.

In skin care, MP is involved in the reconstruction or "renewal" of the skin. As a result, modulation of MP improves management of skin conditions, including (but not limited to) wrinkle repair, regulation, prevention and repair of UV-induced skin damage. Such treatment includes prophylactic treatment or treatment until physiological manifestations become evident. For example, MP can be applied as a pre-exposure treatment to prevent UV damage, and/or as an on-exposure or post-exposure treatment to prevent or reduce post-exposure damage. Additionally, MP has been implicated in abnormal tissue-related skin disorders and diseases such as epidermolysis bullosa, psoriasis, scleroderma, and atopic dermatitis due to abnormal turnover, including metalloprotease activity. The compounds of the invention are also useful for treating the consequences of "normal" damage to the skin, including tissue scarring or "shrinking," such as is seen after burns. MP inhibitors are also useful in surgical procedures involving the skin to prevent scarring and in promoting normal tissue growth, including procedures such as limb replacement and refractory surgery (whether laser or incision).

In addition, MP is associated with diseases involving irregular remodeling of other tissues such as bone, such as otosclerosis and/or osteoporosis, or with specific organs such as liver cirrhosis and pulmonary fibrotic diseases. Also, in diseases such as multiple sclerosis, MP may be associated with the irregular construction of the blood-brain barrier and/or the myelin sheath of nervous tissue. Therefore, modulation of MP activity can be used as a strategy for the treatment, prevention and management of these diseases.

MP is also thought to be associated with a number of infections, including cytomegalovirus [CMV]; retinitis; HIV and the resulting syndrome AIDS.

MP may also be associated with excessive blood vessel formation (when surrounding tissue needs to be destroyed to allow new blood vessels to form), such as angiofibromas and hemangiomas.

Since MPs damage the extracellular matrix, inhibitors of these enzymes are considered useful as family planning agents, eg, to prevent ovulation, prevent sperm from penetrating or passing through the extracellular environment of an egg, prevent implantation of a fertilized egg, and prevent sperm maturation.

Moreover, they are also considered for preventing or terminating premature labor and delivery.

Since MPs are involved in the inflammatory response and cytokine processing, these compounds are also used as anti-inflammatory agents for diseases where inflammation predominates, including inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatic inflammation, diverticulitis, asthma or related lung disease, rheumatoid arthritis, gout, and Reiter's syndrome.

When autoimmunity causes disease, the immune response often triggers MP and cytokine activity. In the treatment of these autoimmune diseases, modulation of MPs is a useful therapeutic strategy. Therefore, MP inhibitors can be used in the treatment of diseases including lupus erythematosus, ankylosing spondylitis and autoimmune keratitis. Sometimes, side effects of autoimmune therapy lead to exacerbation of other MP-mediated conditions where MP inhibitor therapy is also effective, eg, in autoimmune therapy-induced fibrosis.

In addition, other fibrotic diseases are likely to be treated with this type of treatment, including pulmonary disease, bronchitis, emphysema, cystic fibrosis and acute respiratory distress syndrome (especially acute phase reactions).

When MP is involved in unwanted tissue lysis caused by exogenous substances, treatment with MP inhibitors is available. For example, they are effective as rattlesnake bite antidotes, as anti-vessicants, in the treatment of allergic inflammation, sepsis and shock. Furthermore, they are useful as anti-parasitic (eg malaria) and anti-infective agents. For example, they are thought to be useful in the treatment or prevention of viral infections, including those that cause herpes, "colds" (such as rhinovirus infections), meningitis, hepatitis, HIV infection, and AIDS.

MP inhibitors are also considered useful in the treatment of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), muscular dystrophy, complications from diabetes (especially those involving loss of tissue viability), blood coagulation, graft resistance Host disease, leukemia, cachexia, anorexia, proteinuria, and perhaps regulation of hair growth.

For certain diseases, conditions or disorders, MP inhibition is considered a preferred treatment. These diseases, conditions or disorders include arthritis (including osteoarthritis and rheumatoid arthritis), cancer (especially to prevent or arrest tumor growth and metastasis), ophthalmic diseases (especially corneal ulcers, poor corneal healing, macular degeneration and pterygium) and gum disease (especially periodontal disease and gingivitis).

For, but not limited to, the treatment of arthritis, including osteoarthritis and rheumatoid arthritis, preferred compounds are those that are selective for metalloproteases and disintegrin metalloproteases. For, but not limited to, the treatment of cancer, particularly the prevention or arrest of tumor growth and metastasis, preferred compounds are compounds that preferentially inhibit gelatinase or type IV collagenase. For, but not limited to, the treatment of ophthalmic diseases, especially corneal ulcers, corneal malhealing, macular degeneration and pterygium, preferred compounds are those that broadly inhibit metalloproteases. These compounds are preferably administered topically, more preferably in the form of drops or gels. For the treatment of, but not limited to, gum disease, especially periodontal disease and gingivitis, preferred compounds are those that preferentially inhibit collagenase.

V. Composition

The composition of the present invention contains:

(a) a safe and effective amount of a compound of the invention; and

(b) A pharmaceutically acceptable carrier.

As discussed above, many diseases are known to be mediated by excess or unwanted activity of metalloproteases. They include tumor metastasis, osteoarthritis, rheumatoid arthritis, dermatitis and ulceration, especially of the cornea, reactions to infection, and periodontitis, among others. Accordingly, the compounds of the present invention are useful in the treatment of diseases associated with this undesirable activity.

The compounds of the invention can thus be formulated into pharmaceutical compositions for the treatment or prevention of these conditions. Standard pharmaceutical formulation techniques, such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., latest edition, can be used.

The "safe and effective amount" of the compound of formula (I) means that it can effectively inhibit the metalloprotease active site of an animal (preferably a mammal, more preferably a human) subject without excessive adverse side effects (such as toxicity, irritation or allergic reaction, etc.), and when used in the manner of the present invention, have a reasonable benefit/risk ratio. Obviously, the specific "safe and effective amount" will depend on the specific disease to be treated, the physical condition of the patient, the course of treatment and the nature of concurrent treatment (if any), the specific dosage form used, the carrier used, the formula (I) contained The solubility of the compound and the desired dosing regimen of the composition will vary, among other factors.

In addition to the subject compound, the compositions of the present invention comprise a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein refers to one or more compatible solid or liquid fillers, diluents or encapsulating substances suitable for administration to animals (preferably mammals, more preferably humans) . As used herein, the term "compatible" means that the components of the composition can be blended with the subject compound in a manner that does not interact with each other to substantially reduce the efficacy of the composition under normal use. Of course, the pharmaceutically acceptable carrier must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to a treated animal, preferably a treated mammal, and more preferably a treated human.

Substances that can be used as pharmaceutically acceptable carriers or their components are, for example: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose Sodium, ethylcellulose, and methylcellulose; powdered gum tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, Sesame oil, olive oil, corn oil, and cocoa bean oil; polyols, such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as Tween®; humectants, such as lauryl Sodium sulfate; coloring agent; flavoring agent; tableting agent; stabilizer; antioxidant; preservative; pyrogen-free water; isotonic saline; and phosphate buffer.

Pharmaceutically acceptable carriers for systemic administration include sugar, starch, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered saline, Emulsifiers, isotonic saline and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil. In compositions intended for parenteral administration, the pharmaceutically acceptable carrier will suitably comprise at least about 90% by weight of the total composition. The pharmaceutically acceptable carrier used in combination with the subject compound is basically selected according to the mode of administration of the compound. If the subject compound is to be administered by injection, a preferred pharmaceutically acceptable carrier is sterile physiological saline with a hemocompatible suspending agent, the pH of which is adjusted to about 7.4.

The compositions of the invention are preferably presented in unit dosage form. The term "unit dosage form" as used herein refers to a dosage form containing an amount of a compound of formula (I) suitable for administration in a single dose to an animal (preferably a mammalian subject, more preferably a human subject) in accordance with good medical practice. composition of the present invention. These compositions preferably contain about 5-1000 mg, more preferably about 10-500 mg, still more preferably about 10-300 mg of a compound of formula (I).

Compositions of the invention may be in various forms suitable for, for example, oral, rectal, topical, nasal, ophthalmic or parenteral administration. Depending on the particular route of administration desired, various pharmaceutically acceptable carriers well known in the art can be used. These include solid or liquid fillers, diluents, hydrotropes, surfactants and encapsulating materials. It may optionally include pharmaceutically active substances which do not substantially affect the inhibitory activity of the compound of formula (I). The amount of carrier used with a compound of formula (I) is sufficient to provide a practical amount of substance per unit dose of compound of formula (I) administered. Techniques and compositions for preparing dosage forms for use in the methods of the invention are described in the following documents, all of which are incorporated herein by reference: Modem Pharmaceuticals, Chapters 9 and 10 (Editors Banker & Rhodes, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

Various oral dosage forms are available, including solid dosage forms such as tablets, capsules, granules, and powders. These oral dosage forms contain a safe and effective amount, usually at least about 5%, preferably about 25-50%, of a compound of formula (I). Tablets may be compressed, triturated, enteric-coated, sugar-coated, film-coated or multi-layered. Tablets contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions prepared extemporaneously from non-effervescent granules and effervescent preparations extemporaneously formulated from effervescent granules, containing suitable solvents, Preservatives, emulsifiers, suspending agents, diluents, sweeteners, fluxes, coloring and flavoring agents.

Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets usually contain conventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders, such as starch, gelatin, and sucrose; disintegrants, such as starch , alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve the flow properties of the powder mixture. For aesthetic appearance, coloring agents such as FD&C dyes can be added. Sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors are useful adjuncts to chewable tablets. Capsules generally contain one or more of the above solid diluents. The carrier components are selected based on secondary considerations such as taste, cost and storage stability, which are not critical for the purposes of the present invention and can be readily selected by one skilled in the art.

Oral compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for preparing these compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, ^Avicel® RC-591, tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; Typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more sweetening, flavoring and coloring agents as described above.

These compositions may also be coated by conventional methods with pH or time dependent coating agents to release the subject compound within the gastrointestinal tract adjacent to the site of desired topical administration, or at different times to prolong the duration of the desired topical administration. required role. Such dosage forms typically contain, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethyl cellulose, Eudragit Coatings, waxes and shellac.

The compositions of the present invention may optionally contain other active drugs.

Other compositions for systemic administration of a subject compound include sublingual, buccal and nasal dosage forms. These compositions generally contain one or more water-soluble fillers, such as sucrose, sorbitol, and mannitol; binders, such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. The glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents mentioned above may also be included.

The compositions of the present invention may also be administered topically to a subject, that is, by placing or applying the composition directly on the epidermis or epithelial tissue of the subject, or by transdermally administering it via a "patch". Such compositions include, for example, lotions, ointments, solutions, gels and solids. These topical compositions preferably contain a safe and effective amount (usually at least about 0.1%, preferably about 1-5%) of the compound of formula (I). Carriers suitable for topical use preferably remain on the skin as a continuous film and are not removed by perspiration or immersion in water. The carrier is generally organic and may have the compound of formula (I) dispersed or dissolved therein. The carrier may include pharmaceutically acceptable softeners, emulsifiers, thickeners, solvents and the like.

VI. Administration method:

The present invention also provides a method of treating or preventing diseases associated with excess or undesirable metalloprotease activity in humans or other animals by administering to said patient a safe and effective amount of a compound of formula (I). The term "disease associated with excess or undesirable metalloprotease activity" as used herein is any disorder characterized by degradation of matrix proteins. The methods of the invention can be used to treat or prevent the disorders described above.

As indicated, the compositions of the invention can be administered topically or systemically. Systemic administration includes any method of introducing a compound of formula (I) into tissues in the body, such as intra-articular (especially in the treatment of rheumatoid arthritis), intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal , subcutaneous, sublingual, rectal and oral administration. The compounds of formula (I) according to the invention are preferably administered orally.

The specific dose of inhibitor given and the duration of treatment are interdependent between local and systemic treatment. Dosage and treatment regimen will also depend on such factors as the specific compound of formula (I) employed, the indications for treatment, the ability of the compound of formula (I) to achieve a minimal inhibitory concentration at the site of the metalloprotease to be inhibited, the individual attributes of the subject ( such as body weight), compliance with the treatment regimen, and the presence and severity of any treatment side effects.

Usually, for an adult (about 70 kg in body weight), systemic administration should give about 5-3000 mg of the compound of formula (I) per day, preferably 5-1000 mg, more preferably 10-100 mg mg. It should be understood that these dosages are by way of example only, and that the daily dosage may be adjusted according to the factors mentioned above.

The preferred method of administration for the treatment of rheumatoid arthritis is oral or parenteral by intra-articular injection. All preparations for parenteral administration must be sterile, as is known and practiced in the art. For mammals, especially humans (assuming a body weight of about 70 kg), the individual dose will suitably be between about 10-1000 mg.

A preferred method of systemic administration is oral. Individual doses will suitably be between about 10-1000 mg, preferably between 10-300 mg.

Topical administration may be used to administer compounds of formula (I) systemically, or to locally treat an individual. The amount of a compound of formula (I) to be administered topically will depend on such factors as the degree of skin sensitivity, the type and site of tissue to be treated, the composition and carrier (if any) to be administered, the The particular compound of formula (I), the particular disease to be treated and the degree of systemic (as opposed to local) effect desired.

By using targeting ligands, the inhibitors of the invention can be targeted to specific sites of metalloprotease accumulation. For example, to concentrate an inhibitor to a metalloprotease contained in a tumor, the inhibitor is coupled to an antibody or fragment thereof that is immunoreactive with a tumor marker, as is commonly known in the preparation of immunotoxins . The targeting ligand can also be a ligand for a receptor in the tumor. Any targeting ligand that specifically reacts with the desired target tissue marker can be used. Methods for conjugating the compounds of the present invention to targeting ligands are well known, and are similar to those described below for conjugation to carriers. Conjugates can be formulated and administered as described above.

For localized diseases, local administration should be adopted. For example, to treat an ulcerated cornea, formulations such as eye drops or aerosols may be applied directly to the affected eye. For the treatment of the cornea, the compounds of the invention may also be formulated as gels, drops or ointments, or may be incorporated into eye patches of collagen or hydrophilic polymers. The material may also be inserted as a contact lens or reservoir or subconjunctival formulation. For the treatment of skin inflammation, the compounds can be administered topically and topically in the form of gels, pastes, salves or ointments. For the treatment of oral disorders, the compounds can be applied topically in the form of gels, pastes, mouthwashes or implants. The mode of treatment will reflect the nature of the disease, and suitable formulations are known in the art for any chosen route.

Of course, in all the foregoing, the compound of the present invention can be administered alone or in the form of a mixture, and the composition also includes other drugs or excipients suitable for the indication.

Some compounds of the present invention also inhibit bacterial metalloproteases. Some bacterial metalloproteases may not have much to do with the stereochemistry of the inhibitor, but significant differences in the ability of the individual diastereomers to inactivate mammalian proteases have been found. Therefore, this mode of action can be used to distinguish mammalian enzymes from bacterial enzymes.

VII. Preparation and application of antibodies:

Targeting at particularly undesired locations (such as organs or certain types of cells) have active metalloproteases. Coupling methods are known in the art.

The present invention also relates to various other methods of exploiting the unique properties of these compounds. Accordingly, another aspect of the present invention relates to a compound of formula (I) coupled to a solid support. These conjugates can be used as affinity reagents for the purification of desired metalloproteases.

In another aspect, the present invention relates to a compound of formula (I) conjugated to a label. When a compound of the invention is coupled to at least one metalloprotease, the label can be used to detect the presence of relatively high levels of the metalloprotease in vivo or in vitro in cell culture.

In addition, the compounds of formula (I) may be coupled to carriers which allow these compounds to be used in immunization procedures for the preparation of antibodies specifically immunoreactive with the compounds of the invention. Typical coupling methods are known in the art. These antibodies can then be used in therapy and to monitor the dose of the inhibitor.

Compounds of the invention may also be conjugated to labels (eg scintigraphy labels such as technetium 99 or 1-131) using standard conjugation methods. The labeled compound is administered to the patient to determine the location in the body of the excess of one or more metalloproteases. In this way, the ability of inhibitors to selectively bind metalloproteases can be exploited to map the in situ distribution of these enzymes. This method can also be used in histological procedures, where labeled compounds of the invention can be used in competitive immunoassays.

The following non-limiting examples describe the compounds, compositions and uses of the invention.

VIII. EXAMPLES - PREPARATION OF COMPOUNDS

Tetrahydrofuran (THF) was usually distilled from sodium and benzophenone, diisopropylamine from calcium hydride, and all other solvents were commercially available in appropriate grades. Chromatography was performed on silica gel (70-230 mesh; Aldrich) or (230-400 mesh; Merk). Thin layer chromatography (TLC) was performed on silica gel plates (200-300 mesh; Baker) mounted on glass, visualized with UV or phosphomolybdic acid in 5% ethanol (EtOH).

The following abbreviations are used in this document:

MeOH: Methanol Et ₃ N: Triethylamine

EtOAc: ethyl acetate Et ₂ O: (di)ethyl ether

Ph: phenyl boc: tert-butoxycarbonyl

DMF: N,N-Dimethylformamide acac: Acetyl acetate

DME: dimethoxyethane dil: diluted

conc. condensed wrt.: about

DCC: 1,3-Dicyclohexylcarbodiimide HOBT: 1-Hydroxybenzotriazole

The R groups used to describe the compound examples are independent of the individual R groups used to describe the various moieties of formula (I). That is, for example, R ¹ , R ² and R ³ used to describe formula (I) in the Summary of the Invention and the Detailed Description Part II do not represent the same as R ₁ , R ₂ and R ₃ in this Part VIII.

Example 1-3

The following figures show the structures of the compounds prepared as described in Examples 1-3 below:

Example 1

(2R,3S)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propane acid

a) tert-butyl 4-(hydroxy-thiazol-2-yl-methyl)-2,2-dimethyl-oxazolidine-3-carboxylate.

A solution of (S)-tert-butyl 4-formyl-2,2-dimethyl-oxazolidine-3-carboxylate (4.86 g, 21.2 mol) in dichloromethane (100 ml) was stirred at room temperature, and then washed with 30 A solution of 2-(trimethylsilyl)thiazole (5.0 g, 31.8 mmol) in dichloromethane (30 mL) was added dropwise over 1 minute. The resulting mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and treated with 1N tetrabutylammonium fluoride in THF (31.8 mL, 31.8 mmol). The resulting mixture was stirred at room temperature for 1 hour, then the solvent was removed under reduced pressure. Sat _NaHCO3 was added and the resulting mixture was extracted with EtOAc. The organic extracts were dried over _Na2SO4 , then concentrated to an oil under reduced pressure _. The product was purified by chromatography on silica gel using 8/2 hexanes/EtOAc to afford the desired product as a white solid.

b) tert-butyl 2,2-dimethyl-4-[(4-methyl-benzyloxy)-thiazol-2-ylmethyl]-oxazolidine-3-carboxylate

4-(Hydroxy-thiazol-2-yl-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester 1a (3.95 g, 12.6 mol) in DME (100 mL) was stirred at room temperature solution, then sodium hydride (0.55 g, 13.9 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 15 minutes, then 4-methylbenzyl bromide (2.57 g, 13.9 mmol, 1.1 equiv) was added. The resulting mixture was stirred at room temperature overnight, then quenched by the addition of saturated _NaHCO3 solution (20 mL). The mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over _Na2SO4 , then concentrated to an oil under reduced pressure _. The oil was purified by chromatography on silica gel using 9/1 hexane/EtOAc as eluent to give the desired product as a colorless oil.

c) (2S, 3S)-2-amino-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propan-1-ol

2,2-Dimethyl-4-[(4-methyl-benzyloxy)-thiazol-2-ylmethyl]-oxazolidine-3-carboxylic acid tert-butyl ester 1b (5.05 g, 12.06 mol) in methanol (100 ml) solution, and then add Amberlyst 15 (10 g). The resulting heterogeneous mixture was stirred at room temperature for 24 hours. The mixture was treated with triethylamine (30 mL), then stirred at room temperature for 1 hour. The resulting mixture was filtered through celite with the help of methanol. The solvent was then removed to give the desired product as a brown oil.

d) (2S, 3S)-4-bromo-N-[1-hydroxymethyl-2-(4-methyl-benzyloxy)-2-thiazol-2-yl-ethyl]-benzenesulfonamide

Dioxin of (2S,3S)-2-amino-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propan-1-ol 1c (3.05 g, 10.9 mol) was stirred at room temperature Alkane (40 mL) and water (40 mL), then triethylamine (2.20 g, 21.8 mmol) was added, followed by 4-bromobenzenesulfonyl chloride (3.06 g, 11.9 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was diluted with 1N HCl and extracted with dichloromethane. The organic extracts were dried and concentrated to an oil under reduced pressure.

e) Methyl (2R, 3S)-2-(4-bromo-benzenesulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-ylpropionate

(2S, 3S)-4-bromo-N-[1-hydroxymethyl-2-(4-methyl-benzyloxy)-2-thiazol-2-yl-ethyl]-benzenesulfonamide with stirring at room temperature 1d (3.05 g, 6.13 mol) in acetone (50 mL) was then slowly added Jones reagent (8N, 30 mL excess). The resulting mixture was stirred at room temperature for 3 hours, then quenched by the addition of isopropanol. After stirring the mixture for 30 minutes a green precipitate formed. The solution was then filtered through celite with the help of acetone. The filtrate was concentrated to an oil under reduced pressure. The oil was dissolved in methanol and diazomethane in diethyl ether was added. The solution turned slightly yellow when excess diazomethane was added. The mixture was concentrated to a pale yellow solid. The solid was purified by chromatography on silica gel using 8/2 hexane/EtOAc as eluent to provide the product as a yellow solid.

f) (2R, 3S)-2-(4'-methoxy-biphenyl 4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-ylpropane methyl ester

Absorb (2R,3S)-2-(4- _bromo with 10 mL benzene, 1.5 mL EtOH and 1.5 mL water in the presence of Pd( _PPh3 ) ₄ (40 mg, 0.03 mmol) and 237 mg _Na2CO3 -Benzenesulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-ylpropanoic acid methyl ester 1e (590 mg, 1.12 mmol) and 4-methoxyphenylboronic acid (260 mg, 1.68 mmol), refluxed for 18 hours. The mixture was cooled to room temperature, poured into water, and extracted with dichloromethane. _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by silica gel chromatography using 6/4 hexanes/EtOAc to give the desired product as a colorless oil.

g) (2R, 3S)-2-(4'-methoxy-biphenyl 4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-ylpropane acid

(2R,3S)-2-(4′-methoxy-biphenyl 4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-ylpropionic acid Methyl ester 1f (550 mg, 1.00 mmol) was dissolved in water/methanol/THF (5 mL/5 mL/5 mL) and lithium hydroxide (1 g, excess) was added. The resulting mixture was stirred overnight at room temperature. The reaction was acidified with 1N HCl and the product precipitated out of solution as a white powder. The product was filtered to obtain the desired product as a white powder.

Example 2

(2R,3S)-3-(4-methyl-benzyloxy)-2-(4'-methylsulfanyl-biphenyl-4-sulfonylamino)-3-thiazol-2-yl propionic acid

a) (2R, 3S)-3-(4-methyl-benzyloxy)-2-(4′-methylsulfanyl-biphenyl-4-sulfonylamino)-3-thiazole-2 -methyl propionate

Absorb (2R,3S)-2-(4- _bromo with 10 mL benzene, 1.5 mL EtOH and 1.5 mL water in the presence of Pd( _PPh3 ) ₄ (44 mg, 0.03 mmol) and 267 mg _Na2CO3 -Benzenesulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-ylpropionic acid methyl ester 1e (660 mg, 1.26 mmol) and 4-thiomethoxybenzene Boronic acid (320 mg, 1.88 mmol), refluxed for 4 hours. The mixture was cooled to room temperature, poured into water, and extracted with dichloromethane. _The organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was purified by silica gel chromatography using 8/2 hexane/EtOAc to give the desired product as a colorless oil.

b) (2R, 3S)-3-(4-methyl-benzyloxy)-2-(4'-methylsulfanyl-biphenyl-4-sulfonylamino)-3-thiazole-2 -ylpropionic acid

(2R,3S)-3-(4-Methyl-benzyloxy)-2-(4′-methylsulfanyl-biphenyl-4-sulfonylamino)-3-thiazole-2- Methyl propionate 2a (500 mg, 0.88 mmol) was dissolved in water/methanol/THF (5 mL/5 mL/5 mL) and lithium hydroxide (1 g, excess) was added. The resulting mixture was stirred overnight at room temperature. The reaction was acidified with 1N HCl and the product crashed out of solution. The product was obtained as a white powder (345 mg).

Example 3

(2R,3S)-3-Benzothiazol-2-yl-3-methoxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-propionic acid

a) tert-butyl 4-(benzothiazol-2-yl-hydroxy-methyl)-2,2-dimethyl-oxazolidine-3-carboxylate

A solution of (S)-tert-butyl 4-formyl-2,2-dimethyl-oxazolidine-3-carboxylate (7.37 g, 32.1 mmol) in dichloromethane (150 mL) was stirred at room temperature, then washed with A solution of 2-(trimethylsilyl)benzothiazole (10.0 g, 48.2 mmol) in dichloromethane (30 mL) was added dropwise over 30 minutes. The resulting mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the mixture was treated with 1N tert-butylammonium fluoride in THF (48 mL, 48 mmol). The resulting mixture was stirred at room temperature for 1 hour, then the solvent was removed under reduced pressure. Sat _NaHCO3 was added and the mixture was extracted with EtOAc. The organic extracts _were dried ( _Na2SO4 ) and concentrated to an oil under reduced pressure. The product was purified by silica gel chromatography using 85/15 hexanes/EtOAc to give the desired product as a white solid.

b) tert-butyl 4-(benzothiazol-2-yl-methoxy-methyl)-2,2-dimethyl-oxazolidine-3-carboxylate

4-(Benzothiazol-2-yl-hydroxy-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester 3a (3.40 g, 9.30 mmol) in DME was stirred at room temperature ( 75 mL) solution, and then sodium hydride (60%, 0.45 g, 11.2 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 15 minutes, then iodomethane (1.45 g, 10.2 mmol, 1.1 equiv) was added. The resulting mixture was stirred at room temperature overnight, then quenched by the addition of saturated NaHCO ₃ solution (20 mL). The mixture was poured into water and extracted with dichloromethane. The organic extracts _were dried ( _Na2SO4 ) and concentrated to an oil under reduced pressure. The oil was purified by chromatography on silica gel using 8/2 hexane/EtOAc as eluent to give the desired product as a colorless oil.

c) (2S, 3S)-2-amino-3-benzothiazol-2-yl-3-methoxy-propan-1-ol

Stir at room temperature tert-butyl 4-(benzothiazol-2-yl-methoxy-methyl)-2,2-dimethyl-oxazolidine-3-carboxylate tert-butyl ester 3b (2.00 g, 5.28 mg mol) in methanol (100 ml) solution, was added Amberlystl5 (5 g). The resulting heterogeneous mixture was stirred at room temperature for 24 hours. The mixture was treated with triethylamine (25 mL) and stirred at room temperature for 1 hour. The resulting mixture was filtered through celite with the help of methanol. The solvent was then removed to give the desired product as a brown oil.

d) (2S, 3S)-N-(2-benzothiazol-2-yl-1-hydroxymethyl-2-methoxy-ethyl)-4-bromo-benzenesulfonamide

(2S,3S)-2-Amino-3-benzothiazol-2-yl-3-methoxy-propan-1-ol 3c (1.0 g, 4.20 mmol) in dioxane (20 mL) was stirred at room temperature and water (20 mL), then triethylamine (0.85 g, 8.40 mmol) was added, followed by 4-bromobenzenesulfonyl chloride (1.18 g, 46 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was diluted with 1N HCl and extracted with dichloromethane. The organic extracts were dried and concentrated to an oil under reduced pressure.

e) (2S, 3S) -4'-methoxy-biphenyl-4-sulfonic acid (2-benzothiazol-2-yl-1-hydroxymethyl-2-methoxy-ethyl)- Amide

( _2R , _3S )-N-( _{2 -} benzene Thiazol-2-yl-1-hydroxymethyl-2-methoxy-ethyl)-4-bromo-benzenesulfonamide 3d (505 mg, 1.10 mmol) and 4-methoxyphenylboronic acid (252 mg, 1.65 mmol), refluxed for 18 hours. The mixture was cooled to room _temperature and poured into water, extracted with dichloromethane, the organic layer was dried ( _Na2SO4 ), filtered and evaporated. The crude product was purified by silica gel chromatography using 6/4 hexanes/EtOAc to give the desired product as a colorless oil.

f) (2R, 3S)-3-benzothiazol-2-yl-3-methoxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-propionic acid

Stirring at room temperature (2S, 3S)-4'-methoxy-biphenyl-4-sulfonic acid (2-benzothiazol-2-yl-1-hydroxymethyl-2-methoxy-ethyl)- Amide 3e (400 mg) in acetone (50 mL) was then slowly added Jones reagent (8N, 15 mL excess). The resulting mixture was stirred at room temperature for 3 hours, then quenched by the addition of isopropanol. After stirring the mixture for 30 minutes a green precipitate formed. The solution was then filtered through celite with the help of acetone. The filtrate was concentrated to an oil under reduced pressure. The oil was dissolved in methanol and diazomethane in diethyl ether was added. The solution turned slightly yellow when excess diazomethane was added. The mixture was concentrated to a pale yellow solid. The solid was purified by chromatography on silica gel using 8/2 hexane/EtOAc as eluent to provide the product as a white solid.

Example 4-36

The figure below shows the structures of compounds prepared as described in Examples 4-36 below:

Example 4 (2S, 3R)-3-ethylsulfanyl-2-(4'-fluoro-biphenyl-4-sulfonylamino)-3-phenylpropionic acid

a) (2S,3R)-2-amino-3-ethylsulfanyl-3-phenyl-propionic acid methyl ester

In (2R,3S)-(+)-3-phenylaziridine-2-carboxylic acid methyl ester (302 mg, 1.70 mmol; as described in Letgers et al., in Recueil des Travaux Chimiques des PaysBas 111/1, p. 16-21, prepared as described in January 1992) and ethanethiol (0.260 ml, 3.51 mmol) in dichloromethane (14 ml) was added boron trifluoride diethyl etherate (0.220 ml, 1.74 Millimoles). The mixture was stirred overnight at room temperature. To the reaction was added saturated NaHCO ₃ . The layers were separated and the aqueous layer was extracted with additional dichloromethane. The combined organic layers were dried ( _Na2SO4 ), filtered and concentrated under reduced _pressure . The crude product was purified by column chromatography (silica gel, 10-20% EtOAc/ _CH2Cl2 ) to give the desired product as a light yellow oil _.

b) (2S,3R)-3-Ethylsulfanyl-2-(4′-fluoro-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid methyl ester

To a solution of (2S,3R)-2-amino-3-ethylsulfanyl-3-phenyl-propionic acid methyl ester 4a (49 mg, 0.20 mmol) in dichloromethane (2.0 mL) was added triethyl Amine (0.060 mL, 0.43 mmol) and 4'-fluoro-4-biphenylsulfonyl chloride (66 mg, 0.24 mmol). The mixture was stirred overnight at room temperature under argon. The reaction was diluted with dichloromethane and washed with 1.0N aqueous HCl. The aqueous layer was extracted with dichloromethane. _The combined organic layers were dried ( _Na2SO4 ) and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20% EtOAc/hexanes) to give the desired product.

c) (2S, 3R)-3-ethylsulfanyl-2-(4'-fluoro-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid

(2S,3R)-3-Ethylsulfanyl-2-(4′-fluoro-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid methyl ester 4b (28 mg, 0.059 mmol ) and lithium iodide (105 mg, 0.785 mmol) in pyridine (3 mL) was refluxed overnight under argon. The mixture was cooled to room temperature, partitioned between ethyl acetate and 1.0N aqueous HCl. The organic layer was dried ( _Na2SO4 ), filtered and concentrated _under reduced pressure. The crude product was purified by reverse phase preparative HPLC (gradient elution, 0.1% aqueous trifluoroacetic acid/acetonitrile) to give the desired crude product as a pale orange solid.

Example 5

(2S,3R)-3-Ethylthio-2-[(4'-methoxy[1,1'-biphenyl]-4-yl)sulfonyl]amino)-3-phenyl-propionic acid

a) Methyl (2S, 3R)-3-ethylthio-2-[(4-iodophenyl]sulfonyl]amino)-3-phenylpropionate

Triethylamine (0.290 mmol, 2.08 mmol). The mixture was cooled to 0°C and treated dropwise with p-iodobenzenesulfonyl chloride (378 mg, 1.25 mmol) in dichloromethane (1 mL). The mixture was stirred under argon while warming from 0°C to room temperature. The aqueous layer was extracted with dichloromethane and washed with 1.0N aqueous HCl. The aqueous phase was extracted with dichloromethane. The combined organic extracts were dried ( _Na2SO4 ), filtered and concentrated under reduced _pressure . The crude product was purified by column chromatography (silica gel, 15% EtOAc/hexanes) to give the desired product.

b) (2S, 3R)-3-ethylthio-2-[(4'-methoxy[1,1'-biphenyl]-4-yl)sulfonyl]amino)-3-phenylpropane methyl ester

(2S,3R)-3-Ethylthio-2-[(4-iodophenyl]sulfonyl]amino)-3-phenylpropanoic acid methyl ester 5a (376 mg, 0.744 mmol) in benzene ( 50 ml) solution was added sodium carbonate (158 mg, 1.49 mmol), water (0.75 ml), tetrakis(triphenylphosphine) palladium (0) (25 mg, 0.022 mmol), and finally 4-methoxybenzene A solution of boronic acid (166 mg, 1.09 mmol) in ethanol (0.75 mL). The mixture was refluxed under argon for 24 hours. The mixture was cooled to room temperature, treated with 35 wt% hydrogen peroxide (0.300 mL), and stirred for 0.25 hours. The reactant was diluted with water and extracted three times with diethyl ether. The combined organic extracts were dried ( _Na2SO4 ), filtered and concentrated under reduced _pressure . The crude product was purified by column chromatography (silica gel, 15-30% EtOAc/hexanes) to give the desired product as a pale yellow solid.

c) (2S, 3R)-3-ethylthio-2-[(4'-methoxy[1,1'-biphenyl]-4-yl)sulfonyl]amino)-3-phenylpropane acid

The title compound was prepared from 5b using similar ester hydrolysis conditions as in the preparation of Example 4.

Example 6-36

Examples 6-36 were prepared as described in Example 4 or 5 from the corresponding thiols and S2e.

Example 37

(2S,3R)-3-Ethylsulfanyl-2-[5-(4-methoxyphenyl)-thiophene-2-sulfonylamino]-3-phenyl-propionic acid

This compound was prepared according to the method described in Example 5, substituting 5-bromothienylsulfonyl chloride for p-iodobenzenesulfonyl chloride.

Example 38

(2S,3R)-3-Ethylsulfanyl-2-[4-(4-methoxyphenylethynyl)-benzenesulfonylamino]-3-phenyl-propionic acid

This compound was prepared according to the procedure described in Example 5, substituting 4-methoxyphenylethynylboronic acid for 4-methoxyphenylboronic acid.

Example 39

(2S,3R)-3-Ethylsulfanyl-2-[4-(4-methoxybenzamido)-benzenesulfonylamino]-3-phenyl-propionic acid

According to the procedure described in Example 5, substituting 4-nitrobenzenesulfonyl chloride for p-iodobenzenesulfonyl chloride, then 1) reducing the nitro group with tin(II) chloride, and 2) using 4-methoxybenzoyl chloride The amide was formed and the compound was prepared.

Examples 40-43

The diagram below shows the structures of compounds prepared as described in Examples 40-43 described below: Example R ₁ 40 -Me 41 -Et 42 -Ph 43 -CH ₂ Ph

Examples 40-43

Examples 40-43 were prepared as described in Example 4 or 5 from (2S,3R)-(-)-3-phenylaziridine-2-carboxylate methyl ester.

Examples 44-68

The diagram below shows the structures of the compounds prepared as described in Examples 44-68 described below:

Example 44

(2S,3R)-4-Benzyloxy-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butanoic acid

(a) 4(S)-Benzyl-3-[(2S,3R)-4-Benzyloxy-2-bromo-3-hydroxy-butyryl]-oxazolidin-2-one

4(S)-benzyl-3-(2-bromo-acetyl)-oxazolidin-2-one (1.621 grams, 5.43 mmol) in diethyl ether (25 ml) was cooled to -78°C, triethylamine (770 mg, 7.61 mmol) was added, followed by dibutylboron trifluoromethanesulfonate (1.84 g, 5.98 mmol ). The cooling bath was removed and the reaction mixture was stirred for 2.5 hours. The reaction mixture was cooled to -78°C, benzyloxyacetaldehyde (898 mg, 5.98 mmol) was added, and after stirring for 10 minutes, the mixture was warmed to 0°C and stirred for 3 hours. The reaction mixture was diluted with ether, washed with 1N aqueous _KHSO4 , and the solvent was removed in vacuo. The residue was dissolved in methanol (10 mL), cooled to 0°C, and 30% hydrogen peroxide (5 mL) was added. The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. Saturated aqueous NaHCO ₃ and dichloromethane were added to the reaction mixture. The layers were separated and the aqueous layer was washed with additional dichloromethane. The combined organic extracts _were dried ( _Na2SO4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 1% MeOH/ _CH2Cl2 ) to give the desired product as a pale yellow oil _.

(b) 4(S)-3-[(2R,3R)-2-azido-4-benzyloxy-3-hydroxy-butyryl]-4-benzyl-oxazolidin-2-one

In 4(S)-benzyl-3-[(2R,3S)-4-benzyloxy-2-bromo-3-hydroxy-butyryl]-oxazolidin-2-one (969 mg, 2.16 mL ) in dimethylformamide (9.0 mL) was added sodium azide (211 mg, 3.25 mmol), and the reaction mixture was stirred at 35°C for 4 hours. _The mixture was diluted with ethyl acetate and washed several times with water, brine, dried ( _Na2SO4 ). Filtration and removal of solvent in vacuo gave 4(S)-3-[(2R,3S)-2-azido-4-benzyloxy-3-hydroxy-butyryl]-4-benzyl-oxazolidine as an oil -2-one.

(c) (2R,3S)-2-azido-4-benzyloxy-3-hydroxybutanoic acid

4(S)-3-[(2S,3R)-2-azido-4-benzyloxy-3-hydroxy-butyryl]-4-benzyl-oxazolidine- A solution of lithium hydroxide hydrate (113 mg, 2.7 mmol) in water (1.5 ml) was added to a solution of 2-ketone in dioxane-water (3.5 ml, 6:1, v/v), and the reaction mixture was stirred at room temperature 2 Hour. 1N Hydrochloric acid (4 mL) was then added, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane, the organic phase was washed with water and brine, _dried ( _Na2SO4 ). Filtration and removal of solvent in vacuo afforded (2S,3R)-2-azido-4-benzyloxy-3-hydroxybutanoic acid as a thick oil.

(d) (2R,3S)-4-Benzyloxy-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butanoic acid

Add tin(II) chloride (60 mg) to a solution of (2R,3S)-2-azido-4-benzyloxy-3-hydroxybutyric acid (50 mg) in methanol (1 mL), room temperature The reaction mixture was stirred for 2 hours. The volatiles were removed in vacuo and the residue was dissolved in dioxane-water (1.6 mL, 1:1 v/v). Triethylamine (0.1 ml) and (4'-methoxy[1,1'-biphenyl]-4-yl)sulfonyl chloride (110 mg) were added to the mixture, and the mixture was stirred at room temperature for 10 hours. The volatiles were removed in vacuo and the residue was treated with methanol (3 mL) and acetic acid (1 mL). The precipitate was filtered off, the filtrate was concentrated and the crude product was purified by RF HPLC to give (2R,3S)-4-benzyloxy-3-hydroxy-2-(4′-methoxy-biphenyl-4- sulfonylamino)-butyric acid.

Examples 45-68

Examples 45-68 were prepared according to the method described in Example 44 using the corresponding aldehyde and S3a.

IX. Examples - Compositions and Methods of Use

The compounds of the invention are useful in the preparation of compositions for the treatment of diseases associated with undesirable MP activity. The following composition and method examples do not limit the invention, but provide guidance to the skilled artisan for making and using the compounds, compositions and methods of the invention. In each case, other compositions within the invention may be substituted for the example compounds shown below to provide substantially similar results. The skilled artisan will understand that the examples provide guidance and may vary with the condition and patient being treated.

The following abbreviations are used:

EDTA: ethylenediaminetetraacetic acid

SDA: synthetic denatured alcohol

USP: United States Pharmacopeia

Example A

According to the present invention, a tablet composition for oral administration is prepared, comprising: components quantity Compound of Example 1 15mg lactose 120 mg corn starch 70mg talc 4mg Magnesium Stuart 1 mg

A 60 kg (132 lbs) female patient with rheumatoid arthritis was treated with the method of the present invention. In particular, the patient was given oral administration of three tablets a day for 2 years.

At the end of the treatment period, patients were tested and found to have reduced inflammation and improved mobility without associated pain.

Example B

Prepared a kind of capsule for oral administration according to the present invention, containing: components Quantity (%w/w) Compound of Example 4 15% polyethylene glycol 85%

A 90 kg (198 lbs) male patient with osteoarthritis was treated with the method of the present invention. In particular, the patient was subjected to daily oral administration of the above-mentioned capsules containing 70 mg of the compound of Example 4 for 5 years.

At the end of the treatment period, no further erosion/fibrosis of the articular cartilage was found by X-ray, arthroscopy, and/or MRI examination of the patient.

Example C

A saline-based composition for topical administration is prepared in accordance with the present invention comprising: components Quantity (%w/w) Compound of Example 7 5% polyvinyl alcohol 15% brine 80%

One drop of the composition was applied twice daily to both eyes of patients with deep corneal abrasions. Healing is accelerated with no visual sequelae.

Example D

According to the present invention, a topical composition for topical administration is prepared, comprising: components Composition (%w/v) Compound of Example 9 0.20 benzalkonium chloride 0.02 Thimerosal 0.002 d-sorbitol 5.00 Glycine 0.35 Fragrance 0.075 pure water margin Total = 100.00

The composition was applied to patients with chemical burns at each dressing change (twice a day). The scars basically disappeared.

Example E

According to the present invention, an aerosol composition for inhalation is prepared, comprising: components Composition (%w/v) Compound of Example 13 5.0 Alcohol 33.0 ascorbic acid 0.1 Menthol 0.1 sodium saccharin 0.2 Propellant (F12, F114) margin Total = 100.00

0.01 ml of the composition is sprayed through the pump actuator into the mouth of the asthmatic patient during inhalation. Asthma symptoms disappeared.

Example F

According to the present invention, a kind of ophthalmia composition for external use is prepared, which contains: components Composition (%w/v) Compound of Example 16 0.10 benzalkonium chloride 0.01 EDTA 0.05 Hydroxyethyl Cellulose (NATROSOLM) 0.50 Sodium metabisulfite 0.10 Sodium chloride (0.9%) margin Total = 100.0

A 90 kg (198 lbs) male patient with a corneal ulcer was treated with the method of the present invention. Specifically, the above-mentioned saline solution containing 10 mg of the compound of Example 16 was administered twice daily for 2 months to the affected eye of the patient.

Example G

A composition for parenteral administration is prepared, comprising: components quantity Compound of Example 12 100 mg/ml vehicle Carrier: Sodium citrate buffer, containing (weight percent of carrier) Lecithin 0.48% carboxymethyl cellulose 0.53 Povidone 0.50 Methylparaben 0.11 Propyl paraben 0.011

The above ingredients are mixed to form a suspension. Patients with pre-metastatic tumors were administered about 2.0 ml of the suspension by injection. The injection site was juxtaposed with the tumor. Repeat the dose twice each time for about 30 days. After 30 days, the symptoms of the disease subsided, and the dose was gradually reduced to maintain the patient.

Example H

A mouthwash composition was prepared: components %w/v Compound of Example 14 3.0 SDA 40 Alcohol 8.0 flavoring agent 0.08 Emulsifier 0.08 sodium fluoride 0.05 glycerin 10.0 sweetener 0.02 benzoic acid 0.05 sodium hydroxide 0.20 dye 0.04 water Balance to 100%

Patients with gum disease use 1 ml of mouthwash three times a day to prevent further oral ulceration.

Example I

A lozenge composition was prepared: components %w/v Compound of Example 35 0.01 Sorbitol 17.50 Mannitol 17.50 starch 13.60 sweetener 1.20 flavoring agent 11.70 pigment 0.10 corn syrup Balance to 100%

The patient uses the lozenge to prevent loosening of the implant in the maxilla.

Example J

A chewing gum was prepared containing the following: components %w/v Compound of Example 55 0.03 Sorbitol crystals 38.44 Paloja-T Gum Base 20.0 Sorbitol (70% aqueous solution) 22.0 Mannitol 10.0 glycerin 7.56 flavoring agent 1.0

The patient chews the gum to prevent tooth decay.

Example K components %w/v Compound of Example 28 4.0 USP water 50.656 Methylparaben 0.05 Propyl paraben 0.01 xanthan gum 0.12 guar gum 0.09 calcium carbonate 12.38 Antifoam 1.27 sucrose 15.0 Sorbitol 11.0 glycerin 5.0 Benzyl alcohol 0.2 citric acid 0.15 coolant 0.00888 flavoring agent 0.0645 pigment 0.0014

The composition was prepared by first mixing 80 kg of glycerin and all benzyl alcohol, heating to 65° C., and then slowly adding and mixing methylparaben, propylparaben, water, xanthan gum and guar gum. The ingredients were mixed for about 12 minutes with a Silverson inline mixer. The following ingredients were then added in the following order: remaining glycerin, sorbitol, antifoam C, calcium carbonate, citric acid and sucrose. Mix the flavoring and cooling agent separately, then slowly add to the other ingredients. Blend the mixture for about 40 minutes. The patient takes the preparation to prevent colitis flare-ups.

Example L

The capsules described in Example B were administered to an obese female patient determined to be susceptible to osteoarthritis to prevent osteoarthritis symptoms. Specifically, the capsules are administered to the patient once daily.

Examination of the patient by X-ray, arthroscopy, and/or MRI revealed no significant erosion/fibrosis progression of the articular cartilage.

Example M

The capsules described in Example B were administered to a 90 kg (198 lb) male patient with a sports injury to prevent osteoarthritis symptoms. Specifically, the patient is administered the capsule once daily.

Examination of the patient by X-ray, arthroscopy, and/or MRI revealed no significant erosion/fibrosis progression of the articular cartilage.

All references mentioned herein are hereby incorporated by reference.

While specific embodiments of the present invention have been described, it will be apparent to those skilled in the art that various changes and modifications can be made in the present invention without departing from the spirit and scope of the invention. All such modifications within the scope of this invention are intended to be covered in the appended claims.

Claims (13)

1. A compound, characterized in that the compound has the structure of formula (I):

in: (A) R ^is selected from -OH and -NHOH; (B) R ^is selected from hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl radicals, heteroaralkyls and halogens; (C) ^R is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycloalkyl ; (D) R ⁴ is -(CR ⁷ R ^7' ) _k -X-(CR ⁸ R ^8' ) _l -EA wherein: (1) k is 0-4; (2) l is 0-4; (3) R ⁷ , R ^7′ , R ⁸ and R ^8′ , when present, are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, Heterocycloalkyl, halogen and haloalkyl; (4) X is selected from -O-, -S-, -S(O)-, -S(O ₂ )-, -N(R ⁹ )-, -N(COR ⁹ )-, N(CO ₂ R ⁹ )-, -N(CONR ⁹ R ^9' )- and -N(SO ₂ R ⁹ )-, wherein (i) each R ⁹ and R ^9' , when present, are selected from hydrogen, alkyl, alkenes, respectively radical, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or (ii) ^R9 and R9 ^' and their The bonded nitrogen atoms are taken together to form optionally substituted heterocyclic rings containing 5-8 ring atoms, of which 1-3 are heteroatoms; (5) E is selected from covalent bond, -O-, -S-, -S(O)-, -S(O2)-, -N(R ¹⁰ )-, -N(COR ¹⁰ )-, -N (CO ₂ R ¹⁰ )-, -N(CONR ¹⁰ R ^10' )- and -N(SO ₂ R ¹⁰ )-, wherein (i) each R ¹⁰ and R ^10' , when present, is selected from hydrogen, alkane, respectively radical, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycloalkyl, or ( ⁱⁱ ) R and ^{R '} together with the nitrogen atoms to which they are bonded form an optionally substituted heterocyclic ring containing 5-8 ring atoms, of which 1-3 are heteroatoms; provided that when l=0, E is a covalent bond ;and (6) (a) A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycle Alkyl; or (b) A and R ⁷ , R ^7' , R ⁸ , R ^8' , R ⁹ , R ^9' , R ¹⁰ or R ^10' are combined to form ring atoms containing 5-8 ring atoms, of which 1-3 are heterogeneous ring atoms. Atoms optionally substituted heterocyclic rings. (E) R ^is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and heterocycloalkyl ; (F) R ^is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl and hydroxy ; The condition is that when k>0, R ⁶ is -OH, and when k=0, R ⁶ is not -OH; (G) G is selected from -S-, -O-, -N(R ¹¹ )-, -C(R ¹¹ )=C(R ^11′ )-, -N=C(R ¹¹ )- and N=N -, wherein each R ^{and R} , when present, are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; (H)Z is selected from: (1) cycloalkyl and heterocycloalkyl; (2)-L-(CR ¹² R ^12′ )aR ¹³ , wherein: (a) a is 0-4; (b) L is selected from -C≡C-, -CH=CH-, -N=N-, -O-, -S- and -SO ₂ -; (c) each ^of R and ^R , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; and (d) ^R is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl; if L is -C≡C- Or -CH=CH-, R ¹³ can also be selected from -CON(R ¹⁴ R ^14' ), wherein (i) R ¹⁴ and R ^14' are respectively selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl , heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or (ii) R ¹⁴ and R ^14' combined with the nitrogen atom to which they are bonded form a ring containing 5-8 ring atoms, An optionally substituted heterocyclic ring in which 1 to 3 are heteroatoms. (3)-NR ¹⁵ R ^15′ , wherein: (a) R and ^R are selected from hydrogen, ^alkyl , alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and -C(O )-Q-(CR ¹⁶ R ^16′ ) _b -R ¹⁷ , wherein: (i) b is 0-4; (ii) Q is selected from a covalent bond and -N(R ¹⁸ )-; and (iii) each ^of R and ^R , when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen , haloalkyl, hydroxy, and alkoxy; each R and ^R are independently selected from hydrogen, ^alkyl , alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and hetero Cycloalkyl, or R ¹⁷ and R ¹⁸ taken together with the atoms to which they are bonded form an optionally substituted heterocyclic ring containing 5-8 ring atoms, of which 1-3 are heteroatoms; or R ¹⁵ and R ¹⁸ and the nitrogen atoms to which they are bonded form an optionally substituted heterocyclic ring containing 5-8 ring atoms, of which 2-3 are heteroatoms; or (b) R ^{and R} taken together with the nitrogen atom to which they are bonded form an optionally substituted heterocyclic ring containing 5-8 ring atoms, of which 1-3 are heteroatoms; and

,in (a) E' and M' are independently selected from -CH- and -N-; (b) L' is selected from -S-, -O-, -N(R ²⁰ )-, -C(R ²⁰ )=(R ^20' )-, -N=C(R ²⁰ )- and -N= N-, wherein R ²⁰ and R ^20′ , when present, are selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, respectively; (c) c is 0-4; (d) R ¹⁹ and R ^19′ , when present, are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen , haloalkyl, hydroxyl and alkoxy; (e) A' is selected from a covalent bond, -O-, -SO _d -, -C(O)-, -C(O)N(R ²¹ )-, -N(R ²¹ )-, and -N (R ²¹ )C(O)-; wherein d is 0-2; R ²¹ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkane radical, heterocycloalkyl and haloalkyl; and (f) G' is -(CR ²² R ^22' ) _e -R ²³ , wherein e is 0-4; R ²² and R ^22' , when present, are independently selected from hydrogen, alkyl, alkenyl, alkynyl , aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy; and ^R is selected from hydrogen, alkyl, alkenyl, Alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; or ^R21 and ^R23 combined with the atoms to which they are bonded form a ring containing 5-8 atoms, 1-3 of which are heteroatoms, optionally substituted heterocyclic rings; or ^R20 and ^R23 are joined together with the atoms to which they are bonded to form ring atoms containing 5-8 ring atoms, of which 1-3 are Optionally substituted heterocycles of heteroatoms; Or an optical isomer, diastereomer or enantiomer of formula (I), or a pharmaceutically acceptable salt, biohydrolyzable amide, ester or imide thereof. 2. The compound of claim 1, wherein R ¹ is -OH, and R ² , R ³ and R ⁵ are respectively selected from hydrogen, lower alkyl, aralkyl and heteroaralkyl. 3. The compound according to claim 1 or claim 2, wherein k=0; R ⁶ is aryl or lower alkyl; X is selected from O, S, -N(SO ₂ R ¹⁰ )-, -N(COR ¹⁰ )- and -N(CO ₂ R ¹⁰ )-, wherein R ¹⁰ is lower alkyl or aryl, preferably X is -S-; l=0, 1 or 2; E is selected from covalent bonds , -O- and -S-; and A are selected from lower alkyl, aryl and heteroaryl. 4. The compound according to claim 1 or claim 2, wherein k=1, 2 or 3; R ⁶ is -OH; X is selected from -O-, -S-, -N(SO ₂ R ⁹ )-, -N(COR ⁹ )- and -N(CO ₂ R ⁹ )-, wherein R ⁹ is lower alkyl or aryl, X is preferably -O- or -S-; l=0, 1 or 2; E is selected from covalent bond, -O-, -S-, -N(COR ¹⁰ )-, N(CO ₂ R ¹⁰ )-, -N(CONR ¹⁰ R ^10′ )- and -N(SO ₂ R ¹⁰ )-; and A is selected from lower alkyl, aryl and heteroaryl. 5. The compound according to any one of claims 1-4, wherein E is selected from covalent bonds, -O-, -S-. 6. The compound according to any one of claims 1-5, wherein G is selected from -S- and -CH=CH-, Z is selected from -L-(CR ¹² R ^12' )aR ¹³ , -NR ¹⁵ R ^15′ ; and 7. The compound according to any one of claims 1-6, wherein Z is -L-(CR ¹² R ^12' )aR ¹³ , wherein L is selected from -C≡C-, -CH=CH- and -N=N-; a is 0; and R ¹³ is selected from aryl, heteroaryl, heterocycloalkyl, and cycloalkyl. 8. The compound according to any one of claims 1-7, wherein Z is -NR ¹⁵ R ^15' , wherein R ¹⁵ is hydrogen, and R ^15' is -C(O)-Q-(CR ¹⁶ R ^16' ) _b -R ¹⁷ , wherein Q is a covalent bond, b is 0, and R ¹⁷ is selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl. 9. The compound of any one of claims 1-8, wherein Z is

wherein E' and M' are both -CH-; c is 0; and L' is -HC=CH-. 10. A compound characterized in that the compound is selected from the group consisting of: (2R,3S)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propane acid, (2R,3S)-3-(4'-methylsulfanyl-biphenyl-4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl propionic acid, (2R,3S)-3-Benzothiazol-2-yl-3-methoxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-propionic acid, (2S,3R)-3-Ethylsulfanyl-2-(4'-fluoro-biphenyl-4-sulfonylamino)-3-phenylpropionic acid, (2S,3R)-3-Ethylsulfanyl-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-phenylpropanoic acid, (2S,3R)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-methylsulfanyl-3-phenylpropionic acid, (2S,3R)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-3-phenylsulfanyl-propionic acid, (2S,3R)-2-(4′-Bromo-biphenyl-4-sulfonylamino)-3-phenyl-3-(pyridin-3-ylsulfanyl)-propionic acid, (2S,3R)-2-(4′-Bromo-biphenyl-4-sulfonylamino)-3-phenyl-3-(pyrimidin-2-ylsulfanyl)-propionic acid, (2S,3R)-3-(4-fluoro-phenylsulfanyl)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid, (2S,3R)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-3-(thiazol-2-ylsulfanyl)-propionic acid, (2S,3R)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-(1-methyl-1H-imidazol-2-ylsulfanyl)-3-benzene base-propionic acid, (2S,3R)-2-(4'-Chloro-biphenyl-4-sulfonylamino)-3-(oxazol-2-ylsulfanyl)-3-phenyl-propionic acid, (2S,3R)-2-(4′-Methylsulfanyl-biphenyl-4-sulfonylamino)-3-(1-methyl-1H-[1,2,4]triazole-3 -ylsulfanyl)-3-phenyl-propionic acid, (2S,3R)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-(1-methyl-1H-[1,2,4]triazol-3-yl Sulfanyl)-3-phenyl-propionic acid, (2S,3R)-2-[Benzyl-(4′-methoxy-biphenyl-4-sulfonyl)-amino]-3-phenyl-3-phenylsulfanylpropionic acid, (2S,3R)-3-Benzylsulfanyl-2-(biphenyl-4-sulfonylamino)-3-phenyl-propionic acid, (2S,3R)-3-Benzylsulfanyl-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid, (2S,3R)-2-(biphenyl-4-sulfonylamino)-3-phenethylsulfanyl-3-phenyl-propionic acid, (2S,3R)-3-(4-Methyl-benzylsulfanyl)-3-phenyl-2-(4′-trifluoromethyl-biphenyl-4-sulfonylamino)-propionic acid , (2S,3R)-3-(4-Methoxy-benzylsulfanyl)-2-(4′-methyl-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid, (2S,3R)-3-(4-fluoro-benzylsulfanyl)-2-(4′-methyl-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid, (2S,3R)-3-(2,4-Difluoro-benzylsulfanyl)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propane acid, (2S, 3R)-2-(4′-Methylsulfanyl-biphenyl-4-sulfonylamino)-3-phenyl-3-(pyridin-4-ylmethylsulfanyl)-propane acid, (2S,3R)-2-[(4′-methoxy-biphenyl-4-sulfonylamino)-methyl-amino]-3-phenyl-(pyridin-3-ylmethylsulfanyl )-propionic acid, (2S,3R)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-3-(pyridin-2-ylmethylsulfanyl)-propionic acid, (2S,3R)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-(5-methyl-oxazol-2-ylmethylsulfanyl)-3- Phenyl-lactate, (2S,3R)-3-(Benzothiazole-2-sulfanyl)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid, (2S,3R)-3-(2-tert-butoxycarbonylamino-ethylsulfanyl)-2-(4′-methoxy-biphenyl-4-sulfonylnitro)-3-benzene base-propionic acid, (2S,3R)-3-(2-Acetylamino-ethylsulfanyl)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid , (2S,3R)-3-[2-(Methanesulfonyl-pyridin-3-ylamino)-ethylsulfanyl]-2-(4'-methoxy-biphenyl-4-sulfonylamino )-3-phenyl-propionic acid, (2S,3R)-2-(4′-Bromo-biphenyl-4-sulfonylamino)-3-[2-(methylsulfonyl-pyridin-3-yl-amino)-ethylsulfanyl] -3-Phenyl-propionic acid, (2S,3R)-3-(2-Benzyloxy-ethylsulfanyl)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propane acid, (2S,3R)-2-(4′-Bromo-biphenyl-4-sulfonylamino)-3-(2-phenoxy-ethylsulfanyl)-3-phenyl-propionic acid, (2S,3R)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-(2-phenoxy-ethylsulfanyl)-3-phenyl-propionic acid , (2S, 3R)-3-[2-(4-fluoro-phenoxy)-ethylsulfanyl]-3-phenyl-2-(4'-trifluoromethyl-biphenyl-4- Sulfonylamino)-propionic acid, (2S,3R)-3-Ethylsulfanyl-2-[5-(4-methoxy-phenyl)-thiophene-2-sulfonylamino]-3-phenyl-propionic acid, (2S,3R)-3-Ethylsulfanyl-2-[4-(4-methoxy-phenylethynyl)-benzenesulfonylamino]-3-phenyl-propionic acid, (2S,3R)-3-Ethylsulfanyl-2-[4-(4-methoxy-benzamido)-benzenesulfonylamino]-3-phenyl-propionic acid, (2R,3S)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-methylsulfanyl-3-phenyl-propionic acid, (2R,3S)-3-Ethylsulfanyl-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid, (2R,3S)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-3-phenylsulfanyl-propionic acid, (2R,3S)-3-Benzylsulfanyl-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid, (2R,3S)-4-Benzyloxy-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butanoic acid, (2R,3S)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-4-phenoxy-butanoic acid, (2R,3S)-4-Benzyloxy-2-(biphenyl-4-sulfonylamino)-3-hydroxy-butanoic acid, (2R,3S)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-5-phenoxy-pentanoic acid, (2R,3S)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-5-(pyridine-3-oxyl)-pentanoic acid, (2R,3S)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-4-(thiazol-2-ylsulfanyl)-butanoic acid, (2R,3S)-4-(4-Fluoro-benzylsulfanyl)-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butanoic acid, (2R,3S)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-4-(1-methyl-1H-imidazol-2-ylsulfanyl) - butyric acid, (2R,3S)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-6-(1-methyl-1H-imidazol-2-ylsulfanyl) - caproic acid, (2R,3S)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-4-(1-methyl-1H-imidazol-2-ylsulfanyl) - butyric acid, (2R,3S)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-5-(1-methyl-1H-[1,2,4]triazole -3-ylsulfanyl)-pentanoic acid, (2R,3S)-4-(Benzoxazol-2-ylsulfanyl)-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfanylamino)-butanoic acid , (2R,3S)-5-(Benzoxazol-2-ylsulfanyl)-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfanylamino)-pentanoic acid , (2R,3S)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfanylamino)-6-phenoxy-hexanoic acid, (2R,3S)-4-(3,3-Dimethyl-butoxy)-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfanylamino)-butanoic acid , (2R,3S)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfanylamino)-4-(3-methyl-butoxy)-butanoic acid, (2R,3S)-3-Hydroxy-4-(2-isopropoxy-ethoxy)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butanoic acid, (2R,3S)-3-Hydroxy-4-(2-isopropoxy-ethoxy)-2-(4′-methylsulfanyl-biphenyl-4-sulfonylamino)-butanoic acid , (2R,3S)-5-tert-butoxycarbonylamino-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-pentanoic acid, (2R,3S)-6-tert-butoxycarbonylamino-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-hexanoic acid, (2R,3S)-5-tert-butoxycarbonylamino-3-hydroxy-2-(4'-methoxy-benzenesulfonylamino)-pentanoic acid, (2R,3S)-2-(4-Butoxy-benzenesulfonylamino)-5-tert-butoxycarbonylamino-3-hydroxy-pentanoic acid, (2R,3S)-3-Hydroxy-4-(methylsulfonyl-phenyl-amino)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-butanoic acid, (2R,3S)-3-Hydroxy-5-(methylsulfonyl-pyridin-3-yl-amino)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-pentanoic acid, and (2R,3S)-4-(2-tert-butoxycarbonylamino-ethoxy)-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butanoic acid . 11. A pharmaceutical composition, characterized in that the pharmaceutical composition contains: (a) a safe and effective amount of the compound of any one of claims 1-10; and (b) A pharmaceutically acceptable carrier. 12. A method of treating a disease regulated by metalloproteinases, wherein the disease is selected from arthritis, cancer, cardiovascular disease, skin disease, eye disease, inflammation and gum disease, the method comprising treating the disease in need of said A safe and effective amount of a metalloproteinase inhibitor according to claims 1-10 is administered to the treated mammal. 13. A method of treating a disease mediated by a metalloprotease, wherein the disease is (i) arthritis, selected from osteoarthritis and rheumatoid arthritis; (ii) cancer, the treatment prevents or stops tumor growth or metastasis; or (iii) cardiovascular disease selected from dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, angioplasty Restenosis and aortic aneurysm.