GB2348198A - Formamide derivatives as metalloprotease inhibitors - Google Patents

Abstract

A family of compounds having the general structural formula <EMI ID=1.1 HE=27 WI=54 LX=718 LY=769 TI=CF> <PC>where W is a reverse hydroxamic acid group, and R<SB>1</SB>, R<SB>2</SB>, R<SB>3</SB>, R<SB>4</SB>, R<SB>5</SB> and R<SB>6</SB> are as described in the specification, or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof. Also described are methods for their preparation, pharmaceutical compositions including such compounds and their use in medicine.

Description

FORMAMIDE COMPOUNDS AS THERAPEUTIC AGENTS FIELD OF THE INVENTION The present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, such compounds generally pharmacologically useful as agents in those disease states alleviated by the inhibition or antagonism of matrix metalloproteases, metalloproteases, and/or tumor necrosis factor-alpha (TNF), which pathologically involve aberrant extracellular matrix degradation, shedding of cell surface protein ectodomains, and/or TNF synthesis, such disease states including arthritis, tumor metastasis and diabetes. The aforementioned pharmacologic activities are useful in the treatment of mammals.

More specifically, the compounds of the present invention can be used in the treatment of rheumatoid arthritis, osteoarthritis, inflammatory bowel syndromes, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal ulceration and the complications of diabetes. At the present time, there is a need in the areas of rheumatology, oncology, dentistry, opththalmology, gastroenterology, cardiology, neurology, nephrology, infectious disease and endocrinology therapy for such agents.

BACKGROUND OF THE INVENTION The matrix metalloprotease (MMP) family of zinc endoproteases includes fibroblast collagenase (MMP-1, collagenase-1), neutrophil collagenase (MMP-8, collagenase-2), chondrocyte collagenase (MMP-13, collagenase-3), gelatinases A and B (MMP's 2 and 9), and members of the stromelysin family such as stromelysin-1 (MMP-3), stromelysin-3 (MMP-11), and matrilysin (MMP-7).

These enzymes accelerate breakdown of connective tissue by catalyzed resorption of the extracellular matrix. This is a feature of diverse pathologies ; therefore, inhibitors of one or more of the matrix metalloproteases would have utility in a wide range of disease states such as in abrogating the initiation of tumor metastasis and angiogenesis and in halting the pathogenesis of demyelinating diseases of the nervous system, multiple sclerosis being one example. MMP inhibitors would also find utility in diseases involving connective tissue degradation in the joint, as occurs in osteoarthritis and rheumatoid arthritis. MMP's-1 and-3 have been found in elevated levels in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis.

Collagenase-3 (MMP-13) is a member of the family of MMP's which preferentially digest collagen. Collagenase-3 is one of the more newly characterized MMP's ; biochemical studies on the recombinant protein have demonstrated that it cleaves type 11 collagen, the predominant matrix component of articular cartilage, more efficiently than either MMP-1 or MMP-2 and that it is expressed by chondrocytes in osteoarthritic cartilage. These data would implicate collagenase-3 as a significant target in rheumatoid arthritis and osteoarthritis for inhibition by MMP inhibitors.

Compounds which inhibit the activities of one or more of the matrix metalloproteases are recognized as having therapeutic benefit in one or more pathologies where MMP activity is upregulated, such as; i) inflammatory/autoimmune diseases, including but not limited to rheumatoid arthritis, osteoarthritis, Crohn's disease and other inflammatory bowel diseases, periodontal disease, gingivitis, and corneal ulceration ; ii) cardiovascular diseases, including but not limited to atherosclerosis and restenosis ; iii) metabolic diseases, including but not limited to complications of diabetes, osteoporosis, and other disorders involving resorption of bone; iv) neurologic diseases, including but not limited to multiple sclerosis and other demyelination ailments; v) diseases of cancer and malignancy, including but not limited to cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, colon, breast, cervix uteri, corpus endometrium, ovary, prostate, testis, bladder, kidney and other urinary tissues, eye, brain and central nervous system, thyroid and other endocrine gland, leukemias (lymphocytic, granulocytic, monocytic), Hodgkin's disease, non Hodgkin's lymphomas, multiple myeloma, tumor invasion, and metastatic and angiogenic events thereof ; vi) renal diseases, including but not limited to nephrotic syndromes and glomerulonephritis ; vii) infectious diseases, including but not limited to those mediated by viruses, bacteria, and fungi : and viii) respiratory diseases, including but not limited to emphysema and COPD.

Many inhibitors of matrix metalloproteases have been disclosed, including some structure activity relationships for a series of carboxylalkylamine These molecules are exemplary for MMP inhibitors in general. They generally embody a functional group capable of tightly binding the zinc cofactor at the enzyme active site, which is contained within a peptidic or pseudopeptide structure. Zinc binding groups among the MMP inhibitor art have included hydroxamic acid, reverse hydroxamic acid, thiol, carboxylate, and phosphinate.

Hydroxamate metalloprotease inhibitors disclosed in the art usually have the following general structure (I) :

where W is a zinc-chelating acyl derivative group of the formula-C (O) NHOH (which by convention and in this application are referred to as"forward hydroxamates") or a zinc-chelating substituted amine group of the formula NH (OH) C (O) R (which by convention and in this application are referred to as "reverse hydroxamates"), where R is usually hydrogen or alkyl. The other substituents vary according to specifications expressed by the art disclosure. It is understood and demonstrated that variations in these substituents can have dramatic effects on potency and selectivities between the matrix metalloproteases.

Suppression of MMP activity in conditions characterized by its overproduction would be of benefit, and compounds which inhibit MMP's would act in this manner at a specific target and be useful and of benefit. The present invention fulfills this need by providing potent, specific, orally active inhibitors of matrix metalloproteases.

Tumor necrosis factor-a (TNFa), hereinafter called"TNF", is a mammalian protein capable of inducing cellular effects by virtue of its interaction with specific cellular receptors. It was initially characterized and so named due to its ability to cause death of cancerous cells. It is produced primarily by activated monocytes and macrophages. Human TNF is produced as a larger pro-form of 26 kD which is processed to a secreted 17 kD mature form by proteolytic processing of the alanine-76-valine-77 peptide bond.

Recently, certain compounds having matrix metalloprotease-inhibiting activity have been found to inhibit the release of mature 17 kD TNF from cells. Further, these inhibitors also protect mice from a lethal dose of endotoxin indicating that the compounds can inhibit TNF secretion in vivo. These compounds inhibit the cell-associated proteolytic processing of the 26 kD pro-TNF to the mature 17 kD form. The proteolytic activity is thought to reside in an intracellular or cell- associated specific enzyme or family of enzymes, which by convention is called a"TNF convertase", distinct from the matrix metalloproteases but related in that both contain a zinc cation at the active site. TNF convertase enzymatic activity can be detected in monocyte membrane fractions, and the enzyme activity can be inhibited by certain matrix metalloprotease-inhibiting compounds. v A metalloprotease is thought to mediate the proteolysis of the cell-surface IgE receptor CD23. Certain of the CD23-derived peptides possess proinflammatory biological activities mimicking those of cytokines, including TNFa.

Metalloprotease-like activity is also thought to contribute to the shedding of certain cell surface protein ectodomains such as L-selectin, fibronectin, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density lipoprotein receptor, beta amyloid precursor protein, interleukin-6 receptor alpha subunit, Fas ligand, CD40 ligand, epidermal growth factor receptor, macrophage colony stimulating factor, interleukin-1 receptor type II, CD30, and tumor necrosis factor receptors type I and 11.

TNF is known to mediate many biological responses in vivo. Preclinical and clinical studies in animals and humans with specific TNF neutralizing antibodies, soluble TNF receptor constructs, and TNF detection techniques have implicated TNF as a mediator in numerous pathologies. The compounds of the present invention by virtue of their activity in inhibiting TNF production and/or their activity in preventing cell surface protein ectodomain shedding should show utility in the treatment of diverse pathologies such as; i) inflammatory/autoimmune diseases, including but not limited to rheumatoid arthritis, osteoarthritis, Crohn's disease and other inflammatory bowel diseases and inflammatory gastrointestinal diseases, and systemic lupus erythematosis; ii) reperfusion injuries, such as those caused by an initial ischemic event; iii) systemic inflammatory response syndromes, including but not limited to sepsis, burn injury, pancreatitis, and adult respiratory distress syndrome; iv) allergic and dermatologic diseases, including but not limited to delayed type hypersensitivity, psoriasis, asthma, eczema, allergic rhinitis, and allergic conjunctivitis; v) cardiovascular diseases, including but not limited to hyperlipidemia, myocardial infarction, atherosclerosis, chronic obstructive pulmonary disease, and restenosis; vi) metabolic diseases, including but not limited to osteoporosis, obesity, and diabetes; vii) neurologic diseases, including but not limited to Alzheimer's disease, Parkinson's disease, multiple sclerosis, aneurism, and stroke; viii) transplant rejection, including but not limited to organ transplant rejection and graft versus host disease; ix) diseases of cancer and malignancy, including but not limited to cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, colon, breast, cervix uteri, corpus endometrium, ovary, prostate, testis, bladder, kidney and other urinary tissues, eye, brain and central nervous system, thyroid and other endocrine gland, < . leukemias (lymphocytic, granulocytic, monocytic), Hodgkin's disease, non Hodgkin's lymphomas, multiple myeloma, tumor invasion, and metastatic and angiogenic events thereof; x) renal diseases, including but not limited to nephrotic syndromes and glomerulonephritis ; xi) cachexia and related wasting syndromes; xii) infectious diseases, including but not limited to HIV infection and neuropathy, Epstein-Barr viral infection, herpes viral infection, malaria, meningitis, schistosomiasis, leprosy, hepatitis (which includes hepatitis A, hepatitis B, and hepatitis C), infectious arthritis, leishmaniasis, tuberculosis, Lyme disease, and viral encephalitis; xiii) effects of disease therapy, including but not limited to cytokine therapy, chemotherapy, radiation therapy and therapies using anti-T-cell antibodies or cytotoxin-antibody conjugates; and xiv) ocular diseases, including but not limited to diabetic retinopathy and macular degeneration.

Suppression of TNF activity in conditions characterized by its overproduction would be of benefit, and compounds which inhibit TNF convertase would act in this manner at a specific target and be useful and of benefit. The present invention fulfills this need by providing potent, specific, orally active inhibitors of TNF-alpha release from monocyte cells acting via inhibition of TNF-alpha converting enzyme (TNFc).

Suppression of shedding of cell surface protein ectodomains in conditions characterized by an overactivity of such a shedding enzyme or enzymes would be of benefit, and compounds which inhibit this cell surface protein ectodomain shedding would be useful and of benefit. The present invention fulfills this need by providing potent, orally active inhibitors of shedding of cell surface protein ectodomains acting via inhibition of one or more specific enzymes which mediate this proteolytic event.

Suppression of CD23 proteolysis in conditions characterized by an overabundance of CD23 proteolytic fragments would be of benefit, and compounds which inhibit CD23 proteolysis would be useful and of benefit. The present invention fulfills this need by providing potent, orally or parenterally active inhibitor sof CD23 proteolysis acting via inhibition of one or more specific enzymes which mediate this proteolytic event.

SUMMARY OF THE INVENTION Accordingly it is an object of the present invention to provide a potent, specific, orally active inhibitor of MMP's.

It is another object of the present invention to provide a potent, specific, orally active inhibitor of TNF-alpha release from monocyte cells acting via inhibition of < .

TNF-alpha converting enzyme (TNFc).

Yet another object of the present invention is to provide a potent, orally active inhibitor of shedding of cell surface protein ectodomains acting via inhibition of one or more specific enzymes which mediate this proteolytic event.

It is another object of the present invention to provide a potent orally or parenterally active inhibitor of CD23 proteolysis acting via inhibition of one or more specific enzymes which mediate this proteolytic event. It is an object of the present invention, therefore, to provide a compound of the formula

where R, is alkyl ; R2 is

where D is alkyl ; R3 is hydrogen or lower alkyl ; R4 is

where E, is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, C (O) NR7, NR7C (O), C (O), C (O) O, OC (O), or a direct bond, where R7 is as defined below ; E2 z alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR8, S, SO, SO2, O, C (O), C (O) O, OC (O), or a direct bond, where R8 is as defined below ; E3 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR9, S, SO, SO2, O, C (O), C (O) O, OC (O),

or a direct bond, where R9, R10 and Ru are as defined below ; E4 iS alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR12, S, SO, S02, O, C (O), C (O) O, OC (O),

or a direct bond, where R12, R12 and R14 are as defined below ; E5 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NRr5, S, SO, S02, O, C (O), C (O) O, OC (O),

or a direct bond, where R15, Ri6 and Ri7 are as defined below ; E6 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR18, S, SO, SO2, O, C (O), C (O) O, OC (O), or a direct bond, where R, 8 is as defined below ; E7 is hydrogen, NR19R20, Orra, 9, SR, g, SOR19, S02Rg, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, where Rig and R2o are as defined below ; R5 is hydrogen or lower alkyl ; R6 is heteroaryl; and R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, are, independently, hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or t heteroaryl ; or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a family of compounds having the general structural formula :

or a pharmaceutically acceptable salt, solvate, biohydrolyzable esters, biohydrolyzable amides, affinity reagents, or prodrugs thereof, wherein W is a reverse hydroxamic acid group; R, is a substituent other than hydrogen; R4 is a lipophilic substituent preferably with steric bulk proximal to the peptide backbone, and; R6 is a heteroaryl substituent.

Such compounds are novel and are unknown in the art and, given the appropriate choice of Ri, R2, R3, R4, R5, and R6 as described herein show potent inhibition of MMP's, cell-free TNF convertase enzyme and TNF release from cells, and in some cases inhibit TNF convertase and TNF release from cells in preference to matrix metalloproteases. The heteroaryl nature of R6 in combination with an appropriate choice of Ri, Rs, Rs, R4, and R5 as described herein is beneficial in achieving increased potency against TNF release from cells relative to inhibition of MMP's. Such molecules can be selective for TNF inhibition over MMP's and can possess an improved therapeutic profile where inhibition of one or more of the matrix metalloproteases is associated with an adverse biological response or anormal pathology. The heteroaryl nature of R6 in combination with an appropriate choice of RI, R2, R3, R4, and R5 as descril herein is also beneficial in achieving selective inhibition of one or more of the matrix metalloproteases (for example, collagenase-3) in preference to TNF convertase inhibition and inhibition of TNF release from whole cells.

A more preferred group of compounds of the present invention include those the formula (11) :

where R, is alkyl ; R2 is

where D, is alkyl ; R3 is hydrogen or lower alkyl ;

where E, is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, C (O) NR7, NR7C (O), C (O), C (O) O, OC (O), or a direct bond, where R7 is as defined below ; E2 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR8, S, SO, S02, O, C (O), C (O) O, OC (O), or a direct bond, where R8 is as defined below ; E3 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR9, S, SO, S02, 0, C (O), C (O) O, OC (O),

or a direct bond, where Rs, R10 and Rll are as defined below ; E4 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR, 2, S, SO, So2, O, C (O), C (O) 0, OC (O),

or a direct bond, whereR12, Rn3 and Ri4 are as defined below ; E5 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR15, S, SO, SO2, O, C (O), C (O) O, OC (O),

or a direct bond, where R15, R16 and R17 are as defined below ; E6 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR18, S, SO, S02, O, C (O), C (O) 0, OC (O), or a direct bond, where Rie is as defined below ; E7 is hydrogen, NR19R20, OR19, SR19, SOR19, SO2R19, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, where Rrs and R2o are as defined below ; R5 is hydrogen or lower alkyl ; R6 is heteroaryl ; and R7, R8, Rg, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, are, independently, hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl ; or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.

Compounds of the present invention which are currently preferred for their high biological activity are listed below in Tables 1A and 1B ; variables below are with reference to the generic structure (I).

Table IA

Example W R, RZ R3 R4 RS Rs ~ OH < ~ ~ N % HNs S H p H 2 H H N F O) -OH S" OH vh e C w. S) H I I N H H OH H ~"c N 0 CF3 4 1 H H N o "Y r"r C OH 0 -N' 0

Example R, Rz ~ 6 O H-M'F F'"" w Nez Y H N H liz-s 0 OH F IWYI^ 7 1 F N, O 8, OH w F F-w-N) nu Oh F OH w H NU F H H S O UN O Oh 9 F z 10 OH vv Hy N F H H s HN set If OH. H H s HN oÓ . ~ ~ O) H N HN z t j HNO

Example W Ri R2 R3 R4 Rs 12 H vvW-~~ y F H H-N 0 HN 0 OH 13 OH wh ~~ ~ N) Hb, Ny ~ L H ~ H XS 13 OH wh ~. N) ? H N , FI, H H oh 14 N 0 N-0 ou O 15 V H -nr HN H OH H 16 H N y H---OH H s 0 H 17 V H NEZ H N H H s 0 HN O NEZ I

Example W R, R2 R3 R4 Rs Re OH H N H,, rNy H I zou 19 i N H II N H I H, S "vu r w/o N) oh in NEZ H N y H H Y HN O N H CN/PJ H SN o H XS 21 NY S H II N Fi H O NH "T r "r H s 0! NH" a -- NI PO 22 Ny H H HNy A tJ H N, CNXHNH H XS O NHTNH ouzo O=S=O 0 PO

Example W R, R2 R3 R4 R5 Rs OH 24 N H I I N H O~ r H y N 25 CT'N" H y N H H, -S O HN O\ O -N Oh HN o) -N \ 0 Ii H FI., --S 26? '-ir r'T N 0 HAN., P PO N 27 1 i N H y Ny H H HN HN-IP 6 N,/ 28 H NH' ~ N' ! O ? H H F y % t 0 NH

Example w R, R2 R3 R4 R5 R6 29 OH w < ~ H o-I Fi N'I H y N H H O 0 00 114 OH "31 ?"-rT"TN H N s s y H-T H OH H-H,/ OH 32 "' NEZ H I I N, H ZOU H ~". S OH 31 OH < ~ w H NY H H x s 0-H'T 34 in '. O w OH 33 OH ~ N % 0 35 u 'cv'~'r'-"r w NEZ 'S 0 OH H) (NS A X H T SX H XS 35 OH w C S N A H) S N > , (IPJ H T H XS

Example W R, R2 R, Ra Rs R6 OH'Vt. ^A 36 1 N 1f O N (N) 37 H N H N' ! H H., ~ S O 0"il 0 OH 37 1 N HN H H N' ! p "S N nu ZON 'LN H y N H H \-S 0 ) 39 -N \ 0- NH" ..,, Oh 40 N O NU NON

Example W R, R2 R3 R4 R5 R6 OH han 0-HN 0\ un han s 0 NEZ z O HAN Han 43 OH-"''"w-M^r H N N S H H 43 N N,/ 44 OH-wv."", ,, ~. N'1 HNS (vJ H) H XS 0 HN 0 N OH H N r N N , ~ -S 0 0 H H 0 j- o H"

Example W R, R2 R3 l Rs R6 OH N H N . H o H.,,, S p So (N -oh 47 y N H H "N NH NN : < - < rS OH H H S HYNY H H s HN. O HN0, 49 H w^^n, ~ ~ Oh H H-, ' HAN,/ 0 H H HN0, 0 OH 0 Hy NY H H 0 nui O NU Hy N H H "vuzoo

Example w R, R2 R3 R4 R5 R6 52 OH NEZ H H S 0 c NH /NJ 52 N H H s 0 HN 0 114 H II N H I H S p HN O O 54eX 4-1 N N O nu OH OO\ 55 O H-... Nw HO s II H H" S N C) OU 56 OH-. ' NEZ vs OUZO CND 0 5 S.

O 57 y N H H-S 0 HNy0 ~- ( N 57? T? S""NT 0

Example W R, NU 58 1 N Q nu N 59 OH N H 'N S H NH 0 OH O H nu 0 nu so O 1 61 H N H- ! HI "' N'I o H S 0 S, o N) N < ' I-I I I N !-I Fi S H y N 1"v H 0 N N OH S 61 OH < N) HNy tJ H g H XS 63 1

Example R2 R3 R4 Rs R6 OH--%" / H., S O I, J'''11 66 IOH w w N % H II N Fi OH H S OU "Y H OHH S 66''PSNT 67 N -H S H S H H 67 OH -N ! nr N ~I OH O 68 OH w S N% HNS ~ tJ H O-S H XS zon 0 OH 68 AAAM HYN,/H H vs 70 H - NH XS 0 0 HNH ICI

Example W R, R2 R3 R4 R5 Rs H N-N 0 h HNS H-1--OHH O H 72 ? S" Fi H-N H H H -pu-.

HuN, c H H H ~ O CF3 OH H H H N JAZZ H-+C H N -pH-.. wv z ci HYNS H N /\ R OH ~* OU ce 3 77 oh HYNY H I H N

Example w R, R2 R. I R4 R5 R6 78 S", H II N I H H ~N 0 CF 3 3 Table 1B

Example W R, R2 R3 R4 R5 Re 79 O H-w -N II CF 3 Compounds of the present invention which are currently preferred for their biological activity are listed by name below in Tables 2A and 2B.

Table 2A

Example Chemical Name 1 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcydohexyimethyl)-4- methylpentanoicAcid [ (1S, 2R)-2-Methoxy-1- (1, 3-thiazol-2 ylcarbamoyl)-1-propyl] amide 2 (2R, 3S)-3-(Fromyl-hydroxyamino)-2-(4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-5-Ethoxycarbonylamino- 1-(1,3-thiazol-2-ylcarbamoyl)-1-pentyl)amide

Example Chemical Name 3 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl) 6,6,6-trifluorohexanoicAcid [ (1S, 2R)-2-Hydroxy-1- (1, 3-thiazol-2 ylcarbamoyl)-1-propyl] amide 4 (2R, 3S)3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-2,2-Dimethyl-1- (1, 3, thiazol-2-ylcarbamoyl)-1-propyll~mide 5 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-5 Ethoxywarbonylamino-1-(2-pyridylcarbamoyl > 1-pentyl] amide 6 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 trifluoromethylcyclohexylmethyl)-4-methylpentanoic Acid [ (1 S)-2, 2 Dimethyl-1- (1, 3, thiazol-2-ylcarbamoyl)-1-propyl] amide 7 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 trifluoromethylcyclohexylmethyl) hexanoic Acid [ (1 S)-2,2-Dimethyl 1- (1, 3, thiazol-2-ylcarbamoyl)-1-propyl] amide 8 (2R, 3S)-3-Formyl-hydroxyamino)-2-(4 trifluoromethylcyclohexyfmethyl) hexanoic Acid [ (I S, 2R)-2-Hydroxy 1- (1, 3-thiazol-2-ylcarbamoyl)-1-propyl) amide 9 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 trifluoromethylcy ohexylmethyl) 4-methylpentanoic Acid [ (1 S)-5 (2-Pyridinecarbonylamino)-l- (1, 3-thiazol-2-ylcarbamoyl)-l pentyqamide 10 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 trifluoromethylcyclohexylmethyl) hexanoic Acid [ (l S, 2RY2-Methoxy 1-(1, 3-thiazol-2-ylcarbamoyl > 1-propyl] amide 11 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 trifluoromethylcyclohexylmethyl) hexanoic Acid [ (1 S)-5 Ethoxywarbonylamino-1-(1, 3-thiazol-2-ylcarbamoyl > 1-pentyl] amide 12 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 trifluoromethylcyclohexylmethyl) hexanoic Acid [ (1 S)-5 Ethoxycarbonylamino-1- (pyridine-2-ylcarbamoyl)1-pentyl] amide

Example Chemical Name 13 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [(1S)-2, 2-Dimethyl-1-(1, 3, thiazol-2 ylcarbamoyl)-1-propyl] amide 14 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [ (1 S)-3- (4-Morpholinecarbonyl)-1- (1, 3 thiazol-2-ylcarbamoyl)-1-propyl] amide 15 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcydohexylmethyl) hexanoicAcid 1 (1S)-2-Hydroxy-1-(1, 3 thiazol-2-ylcarbamoyl)-1-ethyqamide 16 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoicAcid [ (1S, 2R)-2-Hydroxy-1- (1, 3 thiazol-2-ylcarbamoyl)-1-propyqamide 17 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcydohexylmethyl) hexanoicA d [(1S > 5-(2 Pyridinecarbonylamino)-1- (1, 3-thiazol-2-ylcarbamoyl)-1 pentyl] amide 18 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-3-Methanesulfonyl-1 (1, 3-thiazol-2-ylcarbamoyl)-1-propyl] amide 19 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (l S)-2- (3-Pyridyl)- 1- (1, 3 thiazol-2-ylcarbamoyl)-1-ethyqamide 20 (2R ; 3S3- (Formyl-hydroxyamino-2- (4-methylcyclohexylmethyl4 methylpentanoicAcid 1 (1S)-5-(2-pyridylcarbonylamino)-1-(1, 3 thiazol-2-ylcarbamoyl)l-pentyamide 21 (2R, 3S)-3-(Formyl-hydroxyamino > 2-(4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-4- (Imino- (2, 3,6 trimethyl-4-methoxybenzenesulfonylamino)) methylamino-l- (1, 3 thiazol-2-ylcarbamoyl)-1-butyliamide

Example Chemical Name 22 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [ (1 S)-4- (Imino- (2, 3, 6-trimethyl-4 methoxybenzenesulfonylamino)) methylamino-1- (1, 3-thiazol-2 yicarbamoyl1-butyl] amide 23 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-3 Dimethylaminosulfonyl-1-(1, 3-thiazol-2-ylcarbamoyl)-1 propyl]amide 24 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [ (1S)-5-Ethoxycarbonylamino-1- (1, 3-thiazol 2-ylcarbamoyl)-1-pentyi] amide 25 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methyfcyclohexylmethyl) hexanoic Acid [ (1 S)-5- (2-Dimethylamino 1-ethoxycarbonylamino)-1- (1, 3-thiazol-2-ylcarbamoyl)-1 pentyl] amide 26 (2R, 3S)-3- (Formyl-hydr6xyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [ (1S)-5- (2-Pyridinesulfonylamino)-1- (1, 3 thiazol-2-ylcarbamoyl)-1-pentyllamide 27 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-5- (2 Pyridinesulfonylamino)-1-(1, 3-thiazol-2-ylcarbamoyl > 1 pentyqamide 28 (2R, 3S)-3- (Formyl-hydroxyamino2- (4 methylcyclohexylmethyl) hexanoic Acid [ S) 4-Carbamoylamino-1 (1,3-thiazol-2-ylcarbamoyl)-1-butyl] amide 29 (2R, 3S-3-(Forrnyl-hydroxyamino)-2-(4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-3- (4 Morpholinesulfonyl)-1-(1, 3-thiazol-2-ylcarbamoyl)-1-propyl] amide 30 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [(1R)-2-Methyl-2-methanesulfanyl-1-(1, 3 thiazol-2-ylcarbamoyl)-1-propyamide

Example Chemical Name 31 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [(1 S)-2-Hydroxy-1-(1, 3-thiazol-2 ylcarbamoyl)-1-ethyliamide 32 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexyylmethyl)-4 methylpentanoic Acid [ (1 S, 2R)-2-Hydroxy-1- (1, 3-thiazol-2 ylcarbamoyl)-1-propyliamide 33 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-2-Methoxy-1- (1, 3 ~ thiazol-2-ylcarbamoyl)-1-ethyl] amide 34 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [ (1R)-2-Methyl-2-methanesulfenyl-1- (1, 3 thiazol-2-ylcarbamoyl)-1-propyliamide 35 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-2-Hydroxy-2-methyl 1-(1, 3-thiazol-2-ylcarbamoyl > 1-propyl] amide 36 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-3- (4 Ethoxycarbonylpiperazine-1-sulfonyl)-1- (1, 3-thiazol-2 ylcarbamoyl)-1-propyl] amide 37 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-5- (1, 3-pyrimidin-2 ylamino)-1-(1, 3-thiazol-2-ylcarbamoyl)-1-pentyl] amide 38 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [(1 S)-5-(1, 3-pyrimidin-2-ylamino)-1-(1, 3 thiazol-2-ylcarbamoyl)-1-pentyl] amide 39 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [(1 S)-5-(2-Dimethylamino-1 ethoxycarbonylamino)-1- (1, 3-thiazol-2-ylcarbamoyl)-1-pentyl] amide 40 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1S)-4- (1, 3-pyrimidin-2 ylamino)-1- (1, 3-thiazol-2-ylcarbamoyl)-1-butyljamide

Example Chemical Name 41 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-4- (2 Thiophenesulfonylamino)-l- (1, 3-thiazol-2-ylcarbamoyl)-i butyl] amide 42 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (I S)-4 Ethoxycarbonylamino-1- (1, 3-thiazol-2-ylcarbamoyl)-1-butyl] amide 43 (2R, 3S > 3-(Fonmyl-hydroxyamino)-2-(4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-3- (2 Pyridinecarbonylamino)-1- (1, 3-thiazol-2-ylcarbamoyl)-1 propyl] amide 44 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [ (1S)-3- (2-Pyridinecarbonylamino)-1- (1, 3 thiazol-2-ylcarbamoyl)-1-propyliamide 45 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-3- (1,3-thiazol-2 ylaminosulfonyl)-1-(1, 3-thiazol-2-ylcarbamoyl)-1-propyqamide 46 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [(1 S)-3-(4-Morpholinesulfonyl)-1-(1, 3-thiazol 2-ylcarbamoyl)-1-propyl] amide 47 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoicAcid [ (1S4- (1, 3-Pymidin-2-ylamino)-1- (1, 3 thiazol-2-ylcarbamoyl)-1-butyqamide 48 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-5 Methoxycarbonylamino-1- (1, 3-thiazol-2-ylcarbamoyl)-1 pentyl] amide 49 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [ (I SY5-Methoxycarbonylamino-I- (1, 3 thiazol-2-ylcarbamoyl)-1-pentyl] amide 50 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-4- (2 Pyridinesulfonylamino)-1- (1, 3-thiazol-2-ylcarbamoyl)-1-butyl]I

Example Chemical Name 51 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-4- (3, 5 Dimethylisoxazol-4-sulfonylamino)-i- (1, 34hiazol-2-ylcarbamoyl)-l butvl] amide f 52 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-4- (2 Pyridinecarbonylamino)-1- (1, 3-thiazol-2-ylcarbamoyl)-1-, butyl] amide 53 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoicAcid [(1S)-3 (Ethoxycarbonylamino)-1- (1, 3-thiazol-2-ylcarbamoyl)-1 propyqamide 54 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexyimethyl) hexanoic A d [(1 S)-4 Methanesulfonylamino-1- (1, 3-thiazol-2-ylcarbamoyl)-1-butyl] amide 55 (2R, 3S)-3- (Formyl-hydr6xyamino)-2- (4-methylcyclohexylmethyl) 4 methylpentanoicA d [(1S)-3-(1-Piperidinecarbonyl)-1-(1, 3-thiazol 2-ytcarbamoyl)-1-propyl] amide 56 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [ (l S)-3- (4-Methanesulfonylpiperazine-I carbonyl)-l- (1, 3-thiazol-2-ylcarbamoyl)-1-propyl] amide 57 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Ad [ (1 S)-S (Ethoxywarbonylaminot1-(1, 3 thiazol-2-ylcarbamoyl)-1-propyl] amide 58 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-4- (3 Pyridylcarbonylaminot1-(1, 3-thiazol-2-yrlcarbamoylt1-butyqamide 59 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl) 4 methylpentanoic Acid [ (1 S)-4- (Amino methanesulfonylimino) methylamino-1- (1, 3-thiazol-2-ylcarbamoyl) 1-butyi] amide

Example Chemical Name 60 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [ ( S)-3- (4-Ethoxycarbonylpiperazine-1 sulfonyl)-1-(1, 3-thiazol-2-ylcarbamoyl)-1-propyl] amide 61 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexyimethyl) hexanoicAcid [(1S)-3-(4-(2 Furancarbonyl) piperazine-1-carbony))-1- (1, 3-thiazo)-2 ylcarbamoyl)-1-propyl] amide 62 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S)-2- (4 Ethoxycarbonylpiperazine-1-carbonyl)-l- (1, 3-thiazol-2 ylcarbamoyl)-1-ethyl] amide 63 (2R, 3S)-3- (Formy)-hydroxyamino)-2- (4 methylcyclohexylmethyl) butanoic Acid [ (1S)-2, 2-Dimethyl-1- (1, 3, thiazol-2-ylcarbamoyl)-1-propyqamide 64 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) butanoic Acid [ (1 S, 2S)-2-Methyl-1- (1, 3 thiazol-2-ylcarbamoyl)-1-butyl] amide 65 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [ (1 S)-2-Hydroxy-2-methyl-1- (1, 3-thiazol-2 ylcarbamoyl)-1-propyl] amide 66 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcydohexylmethyl) butanoic Acid [ (1 R)-2-Methyl-2 methanesulfanyl-1-(1, 3-thiazol-2-ylcarbamoyl > 1-propyl] amide 67 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) butanoic Acid [ (1S, 2R)-2-Methoxy-1- (1, 3 thiazol-2-ylcarbamoyl)-1-propyl] amide 68 (2R, 3S > 3-(Formyl-hydroxyamino)-2-(4 methylcydohexylmethyl) butanoic Acid [ (1 S)-3- (4 Morpholinesulfonyl)-1-(1, 3-thiazol-2-ylcarbamoyl)-1-propyqamide

Example Chemical Name 69 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcyclohexylmethyl) hexanoic Acid [ (1 S, 2R)-2-Methyl-3- (2 pyridylcarbonylamino)-1-(1, 3-thiazol-2-ylcarbamoyl > 1-propyqamide 70 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 methylcydohexylmethyl) butanoic Acid [ ( R)-2-Methyl-2 methanesulfenyl-1- (1, 3-thiazol-2-ylcarbamoyl)-1-propyl] amide 71 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4 s methylcyclohexylmethyl) butanoic Acid [ (I S, 2R)-2-Hydroxy-l- (1, 3 thiazol-2-ylcarbamoyl)-1-prop] amide 72 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [ (1 S, 2R)-2-Methyl-3- (2 pyridylcarbonylamino)-1-(1, 3-thiazol-2-ylcarbamoyl > 1-propyqamide 73 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl) 6, 6, 6-trifluorohexanoic Acid [ (1 S, 2S)-2-methyl-1-(2 pyridylcarbamoyl)-1-butyqamide 74 (2R, 3S)-3- (Formyl-hydrbxyamino)-2- (4-methylcyclohexylmethyl)-4 methylpentanoic Acid [ (1S, 2R)-2- (4-Chlorobenzyloxy)-1- (2 pyridylcarbamoyl)-1-propyqamide 75 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl) 6,6,6-trifluorohexanoic Acid [ (1 S, 2R)-2-Methoxy-1- (1, 3-thiazol-2 ylcarbamoyl > 1-propyl] amide 76 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcydohexylmethyl 6, 6, 6-trifluorohexanoicAcid [(1S)-2, 2-Dimethyl-1-(2 pyridylcarbamoyl)-1-propyl] amide 77 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcydohexylmethyl) 6, 6, 6-trifluorohexanoic Acid j (1$)-2, 2-Dimethyf-1- (1,3-thiazol-2 ylcarbamoyl)-1-propyl] amide 78 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl) 6, 6,6-trifluorohexanoic Acid [ (1 S)-2-Methyl-1- (1, 3-thiazol-2 ylcarbamoyl > 1-propyl]amide Preferred embodiments of the invention include compounds of general formula (II) where R, is methyl, ethyl, tert-butyl, isopropyl, n-propyl, or 3, 3,3-trifluoro-1-propyl; R2 is 4-methylcyclohexylmethyl, 4-ethylcyclohexylmethyl, 4-isobutylcyclohexylmethyl, 4- (3, 3,3-trifluoropropyl) cyclohexylmethyl, or 4-trifluoromethylcyclohexylmethyl; R3 is hydrogen, isobutyl, or methyl ; R4 is tert-butyl, sec-butyl, 1-methoxy-1-ethyl, 1-propoxy-1-ethyl, 4 ethoxycarbonylamino-1-butyl, 4-isobutoxycarbonylamino-1-butyl, 1-hydroxy-1-ethyl, hydroxymethyl, methoxymethyl, 4- (2-pyridylcarbonylamino)-1-butyl, 4- (2 pyridylcarbonylamino)-2-methyl-2-butyl, 2- (4-morpholinecarbonyl)-1-ethyl, 1methanesulfanyl-1-ethyl, 2-methanesulfonyl-1-ethyl, 3-pyridylmethyl, 2- (4- (2 furyl) carbonylpiperazine-1-ylcarbonyl)-1-ethyl, 4- (4-pyridylcarbonylamino)-2-methyl-2- butyl, 3-(pyrimidin-2-ylamino)-1-propyl, 4-(pyrimidin-2-ylamino)-1-butyl, 1methanesulfenyl-1-ethyl, 3- (imino- (1, 2,6-trimethyl-4-methoxybenzenesulfonylamino)) methylamino-1-propyl, 3-(imino-benzenesulfonylamino)-methylamino-1-propyl, 2 dimethylaminosulfonyl-1-ethyl,, 4- (2-dimethylamino-1-ethoxycarbonylamino)-1-butyl, 4 (2-pyridinesulfonylamino)-1-butyl, 3-methylcarbamoylamino-1-propyl, 3 carbamoylamino-1-propyl, 3-phenylcarbamoylamino-1-propyl, 2- (4-morpholinesulfonyl)- 1-ethyl, 2-methanesulfanyl-2-propyl, 4-ethoxycarbonylamino-1-butyl, 2 Table 2B

Example Chemical Name 79 (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)- 6,6, 6-trifluorothexanoic Acid [(1S)-Cyclohexyl-(1,3-thiazol-2 ylcarbamoyl) methyl] amide methanesulfenyl-2-propyl, 2-hydroxy-2-propyl, 2- (4-ethoxycarbonylpiperazine-1 ylsulfonyl)-1-ethyl, 3- (2-thiophenesulfonylamino)-1-propyl, 4-propoxycarbonylamino-1- butyl, 3- (ethoxycarbonylamino)-1-propyl, 2- (2-pyridylcarbonylamino)-1-ethyl, 2- (3- pyridylcarbonylamino)-1-ethyl, 1,1-dimethyl-1-propyl, 2-(2-thiazolaminosulfonyl)-1-ethyl, 2-(2-(1,3,4-thiadiazol)ylaminosulfonyl)-1-ethyl, 2-(2-thiophene)-1-ethyl, 4 methoxycarbonylamino-1-butyl, 3- (2-thiophenecarbonylamino)-2-propyl, 4 methoxycarbonylamino-1-butyl, 4-propoxycarbonylamino-2-butyl, 3- (2- pyridinesulfonylamino)-1-propyl, 1-ethoxycarbonylamino-1-ethyl, 3- (3, 5 dimethylisoxazol-4-ylsulfonylamino)-1-propyl, 3- (3-pyridinecarbonylamino)-1-propyl, 3 (2-thiophenecarbonylamino)-2-methyl-2-propyl, 2-ethoxycarbonylamino-1-ethyl, 2 ethoxycarbonylamino-1-propyl, 3-methanesulfonylamino-1-propyl, 1- (tetrahydrofuran-3- yloxy)-1-ethyl, 2- (1-piperazinecarbonyl)-1-ethyl, 2- (4-methanesulfonyl-1- piperazinecarbonyl)-1-ethyl, 2- (4-morpholinesulfonyl)-l-ethyl, 3- (2- pyridylcarbonylamino)-2-propyl, 3- (2-pyridylcarbonylamino)-2-methyl-2-propyl, 1- (4- chlorobenzyloxy)-1-ethyl, orisopropyl ; R5 is hydrogen, methyl, ethyl, or propyl ; and R6 is 2-thiazolyl, 3-pyridyl, 4-pyridyl, 2-(1, 3,4-thiadiazolyl), or 2-pyridyl; or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.

Other preferred embodiments of the invention include compounds of general formula (II) where where R1, R2, R3, R5 and R6 are as defined above and R4 is cyclohexyl ; or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.

Particularly preferred embodiments of the invention include compounds of general formula (II) where R, is methyl, isopropyl, n-propyl, or 3, 3,3-trifluoro-1-propyl; R2 is 4-methylcyclohexylmethyl or 4-trifluoromethylcyclohexylmethyl ; R3 is hydrogen; R4 is tert-butyl, sec-butyl, 1-methoxy-1-ethyl, 4-ethoxycarbonylamino-1-butyl, 1hydroxy-1-ethyl, hydroxymethyl, methoxymethyl, 4-(2-pyridylcarbonylamino)-1-butyl, 2 (4-morpholinecarbonyl)-1-ethyl, 2-methanesulfonyl-1-ethyl, 3-pyridylmethyl, 2-(4-(2- furyl) carbonylpiperazine-1-ylcarbonyl)-1-ethyl, 3-(pyrimidin-2-ylamino)-1-propyl, 4 (pyrimidin-2-ylamino)-l-butyl, 3- (imino- (1, 2,6-trimethyl-4 methoxybenzenesulfonylamino))-methylamino-1-propyl, 2-dimethylaminosulfonyl-1- ethyl,, 4-(2-dimethylamino-1-ethoxycarbonylamino)-1-butyl, 4-(2 pyridinesulfonylamino)-1-butyl, 3-carbamoylamino-1-propyl, 2- (4-morpholinesulfonyl)-1- ethyl, 2-methanesulfanyl-2-propyl, 2-methanesulfenyl-2-propyl, 2-hydroxy-2-propyl, 2 (4-ethoxycarbonylpiperazine-1-ylsulfonyl)-1-ethyl, 3- (2-thiophenesulfonylamino)-1- propyl, 3-(ethoxycarbonylamino)-1-propyl, 2-(2-pyridylcarbonylamino)-1-ethyl, 2-(2 thiazolaminosulfonyl)-1-ethyl, 4-methoxycarbonylamino-1-butyl, 3- (2- pyridinesulfonylamino)-1-propyl, 3- (3, 5-dimethylisoxazol-4-ylsulfonylamino)-1-propyl, 3 (3-pyridinecarbonylamino)-1-propyl, 2-ethoxycarbonylamino-1-ethyl, 3 methanesulfonylamino-1-propyl, 2- (1-piperazinecarbonyl)-1-ethyl, 2- (4- methanesulfonyl-1-piperazinecarbonyl)-1-ethyl, 2- (4-morpholinesulfonyl)-1-ethyl, 3- (2- pyridylcarbonylamino)-2-propyl, 1- (4-chlorobenzyloxy)-1-ethyl, or isopropyl ; Rs is hydrogen ; and R6 is 2-thiazolyl or 2-pyridyl ; or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.

More particularly preferred embodiments of the invention include compounds of general formula (II) where R, is isopropyl or 3,3,3-trifluoro-1-propyl; R2 is 4-methylcyclohexylmethyl ; R3 is hydrogen ; R4 is tert-butyl, sec-butyl, 1-methoxy-1-ethyl, 4-ethoxycarbonylamino-1-butyl, 1 hydroxy-1-ethyl, 2-methanesulfanyl-2-propyl, 2-methanesulfenyl-2-propyl, 3-(2- pyridylcarbonylamino)-2-propyl, or isopropyl ; Rs is hydrogen; and R6 is 2-thiazolyl ; '. or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.

The compounds of the present invention are inhibitors of matrix metalloproteases, TNF converting enzyme, and TNF activity from whole cells. The compounds of the present invention may also inhibit shedding of pathologically significant cell surface protein ectodomains. The compounds of the present invention may also inhibit proteolysis of CD23. The invention described herein is addition directed to pharmaceutical compositions and methods of inhibiting matrix metalloprotease and/or TNF activity and/or CD23 proteolytic fragment activity in a mammal, which methods comprise administering to a mammal in need of a therapeutically defined amount of a compound of formula (I) or (II), defined above, as a single or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers, a single diastereoisomer, a mixture of diastereomers, a solvate, a pharmaceutically acceptable salt, a solvate, a prodrug, a biohydrolyzable ester, or a biohydrolyzable amide thereof.

According to a further aspect of the present invention there is provided a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof for use in therapy.

Thus, the present invention provides a method of inhibiting a matrix metalloprotease, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention. The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit a matrix metalloprotease. A matrix metalloprotease-inhibiting amount can be an amount that reduces or inhibits a matrix metalloprotease activity in the subject.

According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for inhibiting a matrix metatbprotease.

The present invention further provides a method of inhibiting the intracellular release of tumor necrosis factor alpha, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention.

The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit cellular release of mature tumor necrosis factor. An amount sufficient to inhibit cellular release of mature tumor necrosis factor can be an amount that reduces or inhibits cellular release of mature tumor necrosis factor in the subject.

According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for inhibiting the intracellular release of tumor necrosis factor alpha.

Also provided is a method of inhibition of shedding of cell surface protein ectodomains, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention. The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit shedding of cell surface protein ectodomains. An amount sufficient to inhibit shedding of cell surface protein ectodomains can be an amount that reduces or inhibits shedding of one or more cell surface protein ectodomains, such as L-selectin, fibronectin, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density lipoprotein receptor, beta amyloid precursor protein, intedeukin-6 receptor alpha subunit, Fas ligand, CD40 ligand, epidermal growth factor receptor, macrophage colony stimulating factor, interleukin-1 receptor type 11, CD30, and tumor necrosis factor receptors type I and 11, in the subject.

According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for inhibiting the shedding of cell surface protein ectodomains.

Also provided is a method of inhibiting CD23 proteolysis, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention. The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit CD23 proteolysis. An amount sufficient to inhibit CD23 proteolysis can be an amount that reduces or inhibits CD23 proteolysis in the subject.

According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for inhibiting CD23 proteolysis.

Additionally provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to decrease, or inhibit, a alignant growth.

According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for inhibiting the growth of tumor metastases.

.

Further, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat arthritis. Such an amount can be an amount that relieves, i. e., reduces or eliminates, one or more physiologic characteristic of arthritis.

According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for treating arthritis.

Also provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat diabetes. Such an amount can be an amount that reduces or eliminates one or more of the complications associated with diabetes.

According to a further aspect of the present invention there is also provided the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for treating diabetes.

Additionally, the present invention contemplates treating any of these diseases/conditions in a subject by administering to the subject the recited pharmaceutical composition.

The compounds of the present invention can be administered to any mammal in need of inhibition of matrix metalloprotease activity, CD23 proteolysis, shedding of cell surface protein ectodomains and/or TNF activity. Such mammals can include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and, most preferably humans.

Certain examples of the invention also are orally bioavailable in animals and possess oral activity in animal models of disease.

Salts encompassed within the term"pharmaceutically acceptable salts"refer to nontoxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. Representative salts include the following salts :, Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrocloride, Hydroxynaphthoate, lodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate, N methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and Valerate.

Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of formula (I) or (II) and these form a further aspect of the invention.

Also included within the scope of the invention are the individual enantiomers of the compounds represented by formula (I) or (II) above as well as any wholly or partially racemic mixtures thereof. The present invention also covers the individual enantiomers of the compounds represented by formula above as mixtures with diastereoisomers thereof in which one or more of the three stereocenters are inverted.

As used herein, the term"lower"refers to a group having between one and six carbons.

As used herein, the term"alkyl"refers to a straight or branched chain hydrocarbon having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of"alkyl"as used herein include, but are not limited to, n-butyl, n-pentyl, isobutyl, and isopropyl, and the like.

As used herein, the term"alkylene"refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyi, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of"alkylene"as used herein include, but are not limited to, methylene, ethylene, and the like.

As used herein, the term"alkenyl"refers to a hydrocarbon radical having from two to ten carbons and at least one carbon-carbon double bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.

As used herein, the term"alkenylene"refers to an straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carboncarbon double bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of"alkenylene"as used herein include, but are not limited to, ethene-1,2-diyl, propene-1,3-diyl, methylene-1, 1-diyl, and the like.

As used herein, the term"alkynyl"refers to a hydrocarbon radical having from two to ten carbons and at least one carbon-carbon triple bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.

As used herein, the term"alkynylene"refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carboncarbon triple bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of"alkynylene"as used herein include, but are not limited to, ethyne-1,2-diyl, propyne-1, 3-diyl, and the like.

As used herein,"cycloalkyl"refers to a alicyclic hydrocarbon group with one or more degrees of unsaturation, having from three to twelve carton atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower afkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed."Cycloalkyl" includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the like.

As used herein, the term cycloalkylene"refers to an non-aromatic alicyclic divalent hydrocarbon radical having from three to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of "cycloalkylene"as used herein include, but are not limited to, cyclopropyl-1, 1-diyl, cyclopropyl-1, 2-diyl, cyclobutyl-1, 2-diyl, cyclopentyl-1, 3-diyl, cyclohexyl-1, 4-diyl, cycloheptyl-1, 4-diyl, or cyclooctyl-1, 5-diyl, and the like.

As used herein, the term"cycloalkenyl"refers to a substituted alicyclic hydrocarbon radical having from three to twelve carbon atoms and at least one carbon-carbon double bond in the ring system, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of"cycloalkenylene"as used herein include, but are not limited to, 1-cyclopentene-3-yl, 1-cyclohexene-3-yl, 1-cycloheptene4-yl, and the like.

As used herein, the term"cycloalkenylene"refers to a substituted alicyclic divalent hydrocarbon radical having from three to twelve carbon atoms and at least one carboncarbon double bond in the ring system, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of"cycloalkenylene"as used herein include, but are not limited to, 4,5-cyclopentene-1, 3-diyl, 3,4-cyclohexene-1,1-diyl, and the like. i As used herein, the term"heterocyclic"or the term"heterocyclyl"refers to a three to twelve-membered heterocyclic ring having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, SO2, O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more of another gheterocyclic"ring (s) or cycloalkyl ring (s).

Examples of"heterocyclic"include, but are not limited to, tetrahydrofuran, pyran, 1,4 dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.

As used herein, the term"heterocyclylene"refers to a three to twelve-membered heterocyclic ring radical having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO2, O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more of another"heterocyclic"rings or cydoalkyl rings.

Examples of"heterocyclylene"include, but are not limited to, tetrahydrofuran-2, 5-diyl, morpholine-2, 3-diyl, pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2, 4-diyl, piperidine-1,4-diyl, pyrrolidine-1, 3-diyl, morpholine-2, 4-diyl, and the like.

As used herein, the tenm aarylV refers to a benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of aryl include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, and the like.

As used herein, the term"aryiene"refers to a benzene ring radical or to a benzene ring system radical fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of "arylene"include, but are not limited to, benzene-1,4-diyl, naphthalene-1, 8-diyl, anthracene-1, 4-diyl, and the like.

< .

As used herein, the term"heteroaryl"refers to a five-to seven-membered aromatic ring, or to a polycyclic heterocyclic aromatic ring, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. For polycyclic aromatic ring systems, one or more of the rings may contain one or more heteroatoms. Examples of "heteroaryl"used herein are furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, and indazole, and the like.

As used herein, the term"heteroarylene"refers to a five-to seven-membered aromatic ring radical, or to a polycyclic heterocyclic aromatic ring radical, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. For polycyclic aromatic ring system diradicals, one or more of the rings may contain one or more heteroatoms. Examples of"heteroaryiene"used herein are furan-2,5-diyl, thiophene 2, 4-diyl, 1, 3, 4-oxadiazole-2, 5-diyl, 1,3,4-thiadiazole-2, 5-diyl, 1,3-thiazole-2, 4-diyl, 1,3thiazole-2, 5-diyl, pyridine-2, 4-diyl, pyridine-2, 3-diyl, pyridine-2,5-diyl, pyrimidine-2, 4-diyl, quinoline-2, 3-diyl, and the like.

As used herein, the term"direct bond", where part of a structural variable specification, refers to the direct joining of the substituents flanking (preceding and succeeding) the variable taken as a"direct bond". Where two or more consecutive variables are specified each as a"direct bond", those substituents flanking (preceding and succeeding) those two or more consecutive specified"direct bonds"are directly joined.

As used herein, the term"alkoxy"refers to the group RaO-, where Ra is alkyl.

As used herein, the term"alkenyloxy"refers to the group Raz-, where Ra is alkenyl.

As used herein, the term"alkynyloxy"refers to the group Rua0-, where Ra is alkynyl.

As used herein, the term galkylsulfanylb refers to the group RaS-, where Ra is alkyl.

As used herein, the term"alkenylsulfanyl"refers to the group RaS-, where Ra is alkenyl As used herein, the term"alkynylsulfanyl"refers to the group RaS-, where Ra is alkynyl.

As used herein, the term"alkylsulfenyl"refers to the group RaS (O)-, where Ra is alkyl.

As used herein, the term"alkenylsulfenyl"refers to the group RaS (O)-, where Ra is alkenyl.

As used herein, the term"alkynylsulfenyl"refers to the group RaS (O)-, where Ra is alkynyl.

As used herein, the term "alkylsulfonyl" refers to the group RaSO2-, where Ra is alkyl.

As used herein, the term aalkenylsulfonyl"refers to the group RaSO2-, where Ra is alkenyl.

As used herein, the term"alkynylsulfonyl"refers to the group RaSO2-, where Rais alkynyl.

As used herein, the term"acyl"refers to the group RaC (O)-, where Ra is alkyl, alkenyl alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.

As used herein, the term"aroyl"refers to the group RaC (O)-, where Ra is aryl.

As used herein, the term"heteroaroyl"refers to the group RaC (O)-, where Ra is heteroaryl.

As used herein, the term"alkoxycarbonyl"refers to the group RaOC (O)-, where Ra is alkyl.

As used herein, the term"acyloxy"refers to the group RaC (O) O-, where Ra is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.

As used herein, the term"aroyloxy"refers to the group RaC (O) O-, where Ra is aryl.

As used herein, the term"heteroaroyloxy"refers to the group RaC (O) O-, where Ra is heteroaryl.

As used herein, the term"optionally"means that the subsequently described event (s) may or may not occur, and includes both event (s) which occur and events that do not occur.

As used herein, the term"substituted"refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.

As used herein, the terms"contain"or ucontaining"can refer to in-line substitutions at any position along the above-defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one or more of any of O, S, SO, SO2, N, or N-alkyl, including, for example,-CH2-O- CH2-,-CH2-SO2-CH2-,-CH2-NH-CH3 and so forth.

As used herein, the term"solvate"is a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or (II)) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol, or acetic acid.

As used herein, the term"biohydrolyzable ester"is an ester of a drug substance (in this invention, a compound of general formula (I) or (II)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principe. The advantage is that, for example, the biohydrolyzable ester is orally absorbed from the gut and is transformed to (I) or (II) in plasma. Many examples of such are known in the art and include by way of example lower alkyl esters, lower acyloxy-alkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. An example of such a biohydrolyzable ester applied to the general formula (II) is illustrated below in general formula (ici).

As used herein, the term Ubiohydrolyzable amideV is an amide of a drug substance (in this invention, a compound of general formula (I) or (II)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable amide is orally absorbed from the gut and is transformed to (I) or (II) in plasma. Many examples of such are known in the art and include by way of example lower alkyl amides, a-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

As used herein, the term"prodrug"includes biohydrolyzable amides and biohydrolyzable esters and also encompasses a) compounds in which the biohydrolyzable functionality in such a prodrug is encompassed in the compound of formula (I) or (ll) : for example, the lactam formed by a carboxylic group in R2 and an amine in R4, and b) compounds which may be oxidized or reduced biologically at a given functional group to yield drug substances of formula (I) or (II). Examples of these functional groups are, but are not limited to, 1,4-dihydropyridine, N-alkylcarbonyl-1, 4 dihydropyridine, 1,4-cyclohexadiene, tert-butyl, and the like.

As used herein, the term"affinity reagent"is a group attached to the compound of formula (I) or (II) which does not affect its in vitro biological activity, allowing the compound to bind to a target, yet such a group binds strongly to a third component allowing a) characterization of the target as to localization within a cell or other organism component, perhaps by visualization by fluorescence or radiography, or b) facile separation of the target from an unknown mixture of targets, whether proteinaceous or not proteinaceous. An example of an affinity reagent according to b) would be biotin either directly attached to (I) or (II) or linked with a spacer of one to 50 atoms selected < . from the group consisting of C, H, O, N, S, or P in any combination. An example of an affinity reagent according to a) above would be fluorescein, either directly attached to (I) or (II) or linked with a spacer of one to 50 atoms selected from the group consisting of C, H, O, N, S, or P in any combination.

The term"pharmacologically effective amount"shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician. This amount can be a therapeutically effective amount.

Whenever the terms"alkyl"or"aryl"or either of their prefix roots appear in a name of a substituent (e. g. arylalkoxyaryloxy) they shall be interpreted as including those limitations given above for"alkyl"and"aryl". Alkyl or cycloalkyl substituents shall be recognized as being functionally equivalent to those having one or more degrees of unsaturation. Designated numbers of carbon atoms (e. g. C1 10) shall refer independently to the number of carbon atoms in an alkyl, alkenyl or aikynyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which the term"alkyl" appears as its prefix root.

As used herein, the term"oxo"shall refer to the substituent =O.

As used herein, the term"halogen"or"halo"shall include iodine, bromine, chlorine and fluorine.

As used herein, the term"mercapto"shall refer to the substituent-SH.

As used herein, the term"carboxy"shall refer to the substituent-COOH.

As used herein, the term"cyano"shall refer to the substituent-CN.

As used herein, the term"aminosulfonyl"shall refer to the substituent-SO2NH2.

As used herein, the term"carbamoyl"shall refer to the substituent-C (O) NH2.

As used herein, the term"sulfanyl"shall refer to the substituent-S-.

As used herein, the term"sulfenyl"shall refer to the substituent-S (O)-.

As used herein, the term"sulfonyl"shall refer to the substituent-S (O) 2- The compounds of formulae (I) and (II) can be prepared readily according to the following reaction Schemes (in which all variables are as defined before) and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.

The most preferred compounds of the invention are any or ail of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the \ compounds or their moieties may itself form a genus. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless noted otherwise.

Abbreviations used in the Examples are as follows : g = grams mg = milligrams L = liters mL = milliliters psi = pounds per square inch M = molar N = normal mM = millimolar i. v. = intravenous p. o. = per oral s. c. = subcutaneous Hz = hertz mol = moles mmol = millimoles mbar = millibar rt = room temperature min = minutes h = hours d = days mp = melting point TLC = thin layer chromatography Rf = relative TLC mobility MS = mass spectrometry NMR = nuclear magnetic resonance spectroscopy APCI = atmospheric pressure chemical ionization ESI = electrospray ionization m/z = mass to charge ratio = retention time ether = diethyl ether MeOH = methanol EtOAc = ethyl acetate TEA = triethylamine DIEA = diisopropylethylamine DMAP = 4-dimethylaminopyridine BOP = (1-benzotriazolyloxy) tris (dimethylamino) phosphonium hexafluorophosphate THF = tetrahydrofuran DMF = N, N-dimethylformamide DMSO = dimethylsulfoxide LAH = lithium aluminum hydride TFA = trifluoroacetic acid EDC =1-ethyl-3- (3-dimethylaminopropyl)-carbodiimide hydrochloride HOBt =1-hydroxybenzotriazole LDA = lithium diisopropylamide THP = tetrahydropyranyl NMM = N-methylmorpholine, 4-methylmorpholine HMPA = hexamethylphosphoric triamide DMPU = 1,3-dimethypropylene urea ppm = parts per million kD = kiloDalton LPS = lipopolysaccharide PMA = phorbol myristate acetate SPA = scintillation proximity assay EDTA = ethylenediamine tetraacetic acid FBS = fetal bovine serum PBS = phosphate buffered saline solution ELISA = enzyme-linked immunosorbent assay Several of the following examples represent pairs of stereoisomers which were separated as diastereoisomers but were not identified therein. Determination and/or preparation of the R and S isomers can advantageously be approached by stereoselective chemical methods, see"Advanced Organic Chemistry", Carey and Sundberg, 3rd edition, Plenum Press, 1990,596, by analytical methods such as X-ray crystallography, or by determination of biological activity and subsequent correlation to biologically active compounds of known stereochemistry.

GENERAL REACTION SCHEMES Compounds of the invention may be prepared by methods known in the art, where such a method is shown in reaction Scheme 1.

Fraction Sci 1

Ri, R2, R3, R4, R5, and Re are defined as for formula (II).

RPG, is a protecting group suitable for the hydroxylamine oxygen, such as benzyl or 2 tetrahydropyranyl.

R2, is chosen from the group consisting of hydroxyl, O-C6F5, or halogen.

When R2, is hydroxyl, the conversion of (V) to (VII) involves methods known in peptide chemistry; for example, the reaction may be conducted using HOBt in combination with a dehydrating agent such as dicyclohexylcarbodiimide in a suitable solvent, such as .

DMF. When R2, is O-C6F5, the conversion of (IV) to (V) is conducted by treating (IV) in a suitable solvent such as dichloromethane with pentafluorophenyl trifluoroacetate in the presence of pyridine, or with EDC and pentafluorophenol in a suitable solvent such as dichloromethane. The displacement reaction to produce (Vil) is carried out in the presence of a suitable solvent such as dioxane, THF, dichloromethane, or DMF, at a temperature of 0 C to 140 C. The reaction is effected in the presence of an organic base such as NMM or triethylamine. The removal of the RPG, group where RPG, is benzyl may be achieved by hydrogenation of (Vil) with palladium on barium sulfate in a suitable solvent such as ethanol or THF, or, where RPG, is 2-tetrahydropyranyl, by hydrolysis with aqueous acetic acid at a temperature of 20 C to 100 C.

Reaction Scheme 2 depicts the synthesis of a compound of formula (IV).

Reaction Scheme2

R, and R2 are as defined for formula (II).

R220 is a nucleofugal group such as methanesulfonate or p-toluenesulfonate.

RPG, is as defined for reaction Scheme 1.

The acid of formula (Vlil) may be converted to the alcohol of formula (IX) by treatment with HOBt, O-benzylhydroxylamine hydrochloride or 0- (2- tetrahydropyranyl) hydroxylamine, NMM, and a carbodiimide reagent such as EDC in a suitable solvent such as DMF. The alcohol of formula (IX) may be converted to (X) by treatment with methanesulfonyl chloride or p-toluenesulfonyl chloride and pyridine in a suitable solvent such as dichloromethane. The conversion of (X) to (XI) may be conducted by treatment with potassium carbonate in a suitable solvent such as acetone or 2-butanone, at temperature of 20 C to 90 C. Alternatively, (IX) may be converted directly to (XI) by treatment with triphenylphosphine and diethyl azodicarboxylate or another azodicarbonyl diester or diamide in a suitable solvent such as THF at a temperature of-78 C to 50 C. The compound of formula (XI) may be converted to (XII) by treatment with an inorganic base such as sodium hydroxide in water or water in combination with a water-soluble organic cosolvent such as MeOH or THF, followed by acidification with an acidic solution such as aqueous citric acid or aqueous sodium bisulfate. The compound of formula (XII) may be converted to (IV) by treatment with acetic anhydride and formic acid or by treatment with formic acetic anhydride in pyridine in the presence or absence of a suitable cosolvent such as dichloromethane.

An alternative route of preparation of compounds of formula (IX) is depicted in reaction Scheme 3.

!.

Reaction Scheme 3

RPG, is as defined for reaction Scheme 1.

R, and R2 are as defined as for formula (II).

R23 is lower alkoxy or 1-oxazolidinyl, where such an oxazolidinyl group may optionally be substituted at the 4-and 5-positions with alkyl, aryl, or aklylaryl substituents.

A carbonyl compound of formula (XIII), where R23 is an alkoxy group such as methoxy or tert-butoxy, may be treated with a strong base such as LDA in a solvent such as THF at a temperature of from-78 C to 0 C, followed by treatment with the aldehyde (XIV) to provide (XV). Where R23 is a oxazolidinon-1-yl substituent, treatment of (XIII) with a Lewis acid such as di (n-butyl) boron trifluoromethanesulfonate in the presence of N, N-diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature of 0 C, followed by addition of the aldehyde (XIV) provides (XV).

Treatment of (XV) with aqueous base in the presence or absence of hydrogen peroxide affords (VIII) upon acidification. The acid (VIII) may be converted directly to (IX) as in reaction Scheme 2, or may be treated with a dehydrating agent such a p-toluenesulfonyl chloride in pyridine or with triphenylphosphine and diethyl azodicarboxylate in a suitable solvent such as THF, to afford the lactone (XVI). Treatment of the lactone (XVI) with H2NORPG, in the presence of a Lewis acid such as trimethylaluminum in a suitable solvent such as toluene affords the alcohol (IX).

Reaction scheme 4 describes the preparation of an intermediate of formula (VIII).

Réaction Scheme 4

R, and R2, are as defined for formula (II).

R24 is lower alkyl.

R25 is

D, is as defined for formula (11).

L is bromide, iodide, or trifluoromethanesulfonyloxy.

The ketoester of general formula (XIX), if not commercially available, may be prepared by reaction of ester (XVI I) with a strong base such as LDA followed by treatment with the aldehyde (XIV). The resulting hydroxyester (XVIII) may be used directly or converted to the ketoester (XIX) by oxidation with, for example, pyridinium dichromate in a solvent such as dichloromethane. The ketoester of general formula (XIX) may also be prepared by treating the acid chloride (XX) with 2,2-dimethyl-4,6-dioxo-1,3-dioxane in the presence of pyridine in a suitable solvent such as dichloromethane to afford the adduct (XXI), which is then treated with excess R24-OH to provide (XIX). The ketoester of general formula (XIX) may be reduced with a reducing agent such as sodium borohydride to afford the hydroxyester (XVIII). Alternately, a chiral catalyst or chiral ligand in the presence of a reducing agent such as hydrogen or a metal hydride such as borane or LAH may be employed to afford (XVIII) with chiral induction at the newiy formed asymmetric center. The alcohol (XVIII) may be converted to (XXII) by treatment with a strong base such as LDA in a suitable solvent such as THF, followed by the addition of R25-L in the presence or absence of a cosolvent such as DMPU.

Where R2s contains an aromatic substituent, the adduct (XXII) may be treated with rhodium on either carbon or alumina in the presence of hydrogen at a pressure of 20 to 100 psi to provide (XXII) where R25 contains a saturated cyclohexane ring. Removal of the ester group by hydrolysis with aqueous hydroxide ion or, in the case where R24 is tert-butyl, by treatment with a strong acid such as TFA, affords (vil).

The preparation of compounds of general formula (VI) is shown in reaction Scheme 5.

Fraction Sdqem, e 5

R3, R4, R5, and R6 are as defined for general formula (II).

RPG2 is a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl.

R26 is hydroxyl or halogen.

The acid of formula (XXIII) may be converted in situ to (XXIV), where R26 is bromide, by treatment with bromo-tris (pyrrolidino) phosphonium hexafluorophosphate in a suitable solvent such as DMF in the presence of an organic base such as DIEA. Addition of the amine (XXV) in the displacement step in the presence of a suitable solvent such as DMF and an organic base such as DIEA affords the amide (XXVI). Alternatively, the intermediate of formula (XXIV) where R26 is hydroxyl may be treated with carbonyidiimidazole in a solvent such as dichloromethane, followed by treatment with the amine (XXV) to afford (XXVI). Altematively, the intermediate of formula (XXIII) may be treated with HOBt, the amine (XXV), an organic base such as NMM, and a carbodiimide reagent such as EDC in a suitable solvent such as DMF, at a temperature of 0 C to 80 C to provide (XXVI). The compound of formula (XXVI) may be converted to (VI) by deprotection, conditions being particular to the nature of RPG2. For example, where RPG2 is tert-butoxycarbonyl, conversion of (XXVI) to (VI) may be accomplished by treatment of (XXVI) with a strong acid such as hydrogen chloride or trifluoroacetic acid in the presence or absence of a suitable solvent such as dichloromethane, at a temperature of 0 C to 50 C.

A preparation of compounds of general formula (XXIII) is shown in reaction Scheme 6.

Reaction Sobre6

R3 and R4 are as defined for general formula (11).

RPG2 is defined as for reaction scheme 5.

R27 is lower alkyl or hydrogen.

R28 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or SOz substituents.

R29 is lower alkyl or hydrogen.

R30 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, O, NH, N-alkyl, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or SO2 substituents.

*R3, is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO2 substituents.

R32 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or S02 substituents.

The compound (XXVII) may be treated with the reagent R3,-R30-COCI in a solvent such as dichloromethane in the presence of tertiary base such as TEA to afford (XXVIII).

Altemately, (XXVII) may be treated with R3,-R30-COOH (where R30 is not O, N, or Nalkyl) and a dehydrating agent such as EDC in a solvent such as DMF to afford (XXVIII). The compound (XXVIII) where R30 is NH may be prepared by treating (XXVII) with R3,-NCO in a solvent such as dichloromethane. (XXIX) may be prepared by treating (XXVII) with R32-SO2CI in the presence of a tertiary amine base such as NMM in a solvent such as dichloromethane. Removal of the alkyl group R27 by saponification with aqueous base (or, if appropriate and where R27 is tert-butyl, by treatment with trifluoroacetic acid) provides (XXIII).

Reaction scheme 7 depicts an alternate preparation of an intermediate of general formula (XXIII).

Reaction Scheme 7

R3 and R4 are as defined for general formula (II).

RPG2 is defined as for reaction scheme 5.

R27, R28, R29, and R32 are as defined for reaction scheme 6.

R33 and R34 are, independently, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl substituents may contain one or more O, S, SO, or SO2 substituents.

R33 and R34 may be taken together to constitute three-to ten-membered ring.

The amine compound (XXVII) is treated with (XXX) in the presence of a tertiary base such as triethylamine or NMM to afford (XXXI). Treatment of (XXXI) with silver nitrate and an amine HNR33R34 provides (XXXII). Removal of the alkyl group R27 by saponification with aqueous base (or, if appropriate and where R27 is tert-butyl, by treatment with trifluoroacetic acid) provides (XXIII).

Reaction scheme 8 depicts an alternate preparation of an intermediate of general formula (XXIII).

Reaction SchemsS

R3 and R4 are as defined for general formula (II).

RPG2 is defined as for reaction scheme 5.

R28, R27, R30. and R3, are as defined as for reaction scheme 6.

R35 is alkylene or heteroarylene.

The hydroxy compound (XXXIII) may be treated with the reagent R31-R30-COCI in a solvent such as dichloromethane in the presence of tertiary base such as triethylamine to afford (XXXIV). Altemately, (XXXIII) may be treated with R3,-R30-COOH (where R30 is not O, N, or N-alkyl) and a dehydrating agent such as EDC and a catalyst such as DMAP in a solvent such as DMF or dichloromethane to afford (XXXIV). The compound (XXXIV) where R3o is NH may be prepared by treating (XXXIII) with R3,-NCO in a solvent such as dichloromethane. The ether (XXXV) may be prepared by treating (XXXIII) with R31R35Br or R3, R351 in the presence of a base such as potassium carbonate or sodium hydride in a solvent such as DMF. Removal of the aiky) group R27 by saponification with aqueous base (or, if appropriate and where R27 is tert-butyl, by treatment with trifluoroacetic acid) provides the acid (XXIII).

Reaction scheme 9 depicts an alternate preparation of an intermediate of general formula (XXIII).

Reaction Scheme9

R3 and R4 are as defined for general formula (II).

RPG2 is defined as for reaction scheme 5.

R28, R27, Rao. and R3, are as defined for reaction scheme 6.

R35 is as defined for reaction scheme 8. n is 1 to 2.

The thioether (XXXVII) may be prepared by treating (XXXVI) with R31R35Br or R31R351 and a base such as potassium carbonate or sodium hydride in a solvent such as DMF.

The sulfur atom may be oxidized with a reagent such as m-chloroperoxybenzoic acid.

Use of one molar equivalent of oxidant may be employed to provide (XXXVIII) where n is 1. Use of two molar equivalents of oxidant may be employed to provide (XXXVIII) where n is 2. Removal of the alkyl group R27 in either (XXXVIII) or (XXXVII) by saponification with aqueous base (or, if appropriate and where R27 is tert-butyl, by treatment with trifluoroacetic acid) provides the acid (XXIII).

Reaction scheme 10 depicts an alternate preparation of an intermediate of general formula (XXIII).

Reaction Scheme 10

R3 and R4 are as defined for general formula (II).

RPG2 is defined as for reaction scheme 5.

R28 and R27 are as defined for reaction scheme 6.

R36 and R37 are, independently, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO2 substituents.

Rse and R37 may be taken together to constitute a three-to ten-membered ring.

The thiol (XXXVI) may be oxidized to the disulfide (XXXIX) by treatment with a mild base such as TEA and oxygen or air. Either the thiol (XXXVI) or the disulfide (XXXIX) may be converted to the sulfonyl chloride (XL) by treatment with chlorine gas in tetrachloromethane. Treatment of the sulfonyl chloride (XL) with an amine R36R37NH in the presence of a tertiary amine base such as TEA or NMM affords (XLI). Removal of the alkyl group R27 in (XLI) by saponification with aqueous base (or, if appropriate and where R27 is tert-butyl, by treatment with trifluoroacetic acid) provides the acid (XXIII).

Reaction scheme 11 depicts an alternate preparation of an intermediate of general formula (XXIII).

Reaction Sdlar. 11

R3 and R4 are as defined for general formula (II).

RPG2 is defined as for reaction scheme 5.

R28 and R27 are as defined for reaction scheme 6.

R36 and R37 are as defined for reaction scheme 10.

R36 and R37 may be taken together to constitute a three-to ten-membered ring. The acid (XLII) may be converted to the amide (XLIII) by treatment of (XLIII) and the amine R36R37NH with a dehydrating agent such as EDC or BOP in the presence of HOBt. Removal of the alkyl group R27 in (XLIII) by saponification with aqueous base (or, if appropriate and where R27 is tert-butyl, by treatment with trifluoroacetic acid) provides the acid (XXIII).

Reaction Scheme 12 depicts an alternate preparation of an intermediate of general formula (XXIII).

Reaction Scheme 12

R3 and R4 are as defined for general formula (II).

RPG2 is defined as for reaction scheme 5.

Rsa is hydrogen or lower alkyl.

Rss, R40, and R4, are, independently, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, hydrogen, or heteroaryl.

R40 and R4, may be taken together to constitute a five-to ten-membered ring.

R39 and R4, may be taken together to constitute a five-to ten-membered ring.

R42 is methyl, ethyl or tert-butyl.

R43 is S, NH, or 0.

The acid (XLIV) is treated with trifluoroacetic anhydride and TFA to afford the trifluoroacetamide, which is then treated with the bromide (XLV) and a base such as potassium carbonate in a solvent such as DMF to provide the ester (XLVI). (XLVI) is treated with LDA and aluminum triisopropoxide in the presence of quinidine or quinine in a solvent such as THF at a temperature of from-78 C to 0 C, to afford (XLVII) with a high degree of asymmetric induction. (XLVII) is subjected to hydrolysis with aqueous base and the resulting amine is protected with RPG2-CI (where RPG2 is benzyloxycarbonyl) or (RPG2) 20 (where RPG2 is tert-butoxycarbonyl) and aqueous base. (XLVIII) is then esterified with the R42 group (where R42 is methyl or ethyl) by treatment with R42-Br and potassium carbonate in a solvent such as DMF, or by treatment with dimethylformamide di-tert-butyl acetal (where R42 is tert-butyl). (XLIX) may be treated with ozone in dichloromethane or dichloromethane/MeOH, followed by reduction with, for example, dimethyl sulfide, to afford the carbonyl compound (L). (L) may be reduced with sodium borohydride to afford the alcohol (LI) (where R43 is 0), which may be treated with methanesulfonyl chloride in pyridine to afford the mesylate.

The methanesulfonate may be then treated with sodium azide in a solvent such as DMF at a temperature of from 25 C to 120 C to afford the azide, which may be reduced with hydrogen gas and palladium, fully active or partially poisoned, on a solid support such as carbon, to provide (LI) where R43 is NH. The olefin in (XLIX) may be hydroborated with, for example, tert-hexylborane and the intermediate oxidized with alkaline hydrogen peroxide to afford (Lll) where R28 is 0. R28 in (LII) may be converted to NH as described above. (LI) and (Lll) where R43 is O may be treated with diisopropyl azodicarboxylate, CH3C (O) SH, and triphenylphosphine in a solvent such as THF at a temperature of-50 C to 40 C, followed by treatment with K2CO3 in MeOH in the presence or absence of water, to give (LI) and (Lll) where R43 is S. R43 (where R43 is O or S) in (LI) and (vil) may be alkylated according to the procedure in reaction schemes 8 and 9. R43 (where R43 is 0) in (LI) and (LII) may be acylated according to the procedure in reaction scheme 8. R43 (where R43 is NH) in (LI) and (LII) may be acylated, guanidinylated, or sulfonylated according to the procedure in reaction schemes 6 and 7. R43 (where R43 is S) in (II) and (LII) may be oxidized to the sulfonyl chloride according to the procedure in reaction scheme 10 and processed accordingly. These products of the modification of (LI) and (Lll) may be further manipulated by treatment with sodium hydroxide in aqueous THF (where R42 is ethyl or methyl), or by treatment of with TFA or anhydrous HCI (where R42 is tert-butyl), to produce (XXIIl). Selection of R42 as tert-butyl and RPG2 as benzyloxycarbonyl is optimal for the preparation of (XXIII) according to reaction scheme 12.

Reaction scheme 13 depicts an alternate preparation of an intermediate of general formula (VI).

Rection Sdere 13

R3, R4, R5, and R6 are as defined for general formula (II).

R4o and R4, are as defined for reaction scheme 12.

R44 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, aryiene, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or SO2 substituents.

The amino alcohol (LIIl) is treated with phthalic anhydride in a solvent such as toluene at a temperature of from 25 C to 120 C, or with N-ethoxycarbonylphthalimide and sodium bicarbonate at a temperature of from-20 C to 45 C, followed by oxidation of the resulting phthalimido alcohol with an oxidizing agent such as pyridinium chlorochromate to provide the aldehyde (LIV). Treatment of (LIV) with phenylglycinol in a solvent mixture such as chloroform-MeOH followed by addition of trimethylsilyl cyanide affords (LV). Use of nonracemic phenylgycinol in this step may induce chirality in the product (LV) which may be preserved in further transformations in reaction scheme 13. Treatment of (LV) with 12 N HCI at a temperature of 25 C to 70 C is followed by treatment with hydrazine and acidification with 1 N HCI. The product is treated in a solvent such as MeOH with palladium hydroxide on carbon under 60 psi of hydrogen pressure at a temperature of from 25 C to 80 C, followed by treatment with di-tert-butyl dicarbonate and aqueous sodium hydroxide to afford (LVI) after acidification. Treatment of (LVI) with the amine (XXVII) and a dehydrating agent such as EDC in the presence of HOBt in a solvent such as DMF at a temperature of 0 C to 25 C, followed by treatment with HCI in a solvent such as dichloromethane or dioxane affords (LVII). Treatment of (LVII) with N-ethoxycarbonylphthalimide in a solvent such as DMF with TEA at a temperature of-20 C, followed by treatment of the product with di-tert-butyl dicarbonate and DMAP in a solvent such as dichloromethane affords (LVIII). (LVIII) may be treated with hydrazine in a solvent such as MeOH or ethanol to provide (LIX). (LIX) may be transformed to an intermediate of formula (VI) according to procedures noted in previous reaction schemes.

Reaction scheme 14 describes an alternate preparation of an intermediate of formula (XXIII).

Reaction Scheme 14

R3 and R4 are as specified for formula (II).

RPG2 is as specified for reaction scheme 5.

R40, R4,, and R42 are as specified for reaction scheme 12.

The intermediate of formula (LX) may be treated with osmium tetraoxide or an osmium (IV) derivative in the presence of an oxidizing agent such as an iron (III) salt in aqueous tert-butanol to afford (LXI). Asymmetric induction may be achieved in the reaction via use of a chiral ligand, such as hydroquinine 1,4-phthalazinediyl diether.

(LXI) may be treated with thionyl chloride in the presence of a tertiary amine base such as TEA, and the sulfite may be oxidized with Ru04, or RuCl3 and NalO, , in aqueous acetonitrile/CCl4 to afford the sulfate (LXII). Treatment of the sulfate with sodium azide in aqueous acetone affords (LXIII). Reduction of the azide with hydrogen gas and palladium, fully active or partially poisoned, on a solid support such as carbon, gives the amine (LXIV). The amine may be alkylated with R3-Br and a tertiary amine base such as TEA, if desired, then protected with RPG2-CI (where RPG2 is benzyloxycarbonyl) or (RPG2) 20 (where RPG2 istert-butoxycarbonyl) and aqueous base. The R42 ester group may be removed as generally described previously to provide (XXIII). Selection of R42 as benzyl and RPG2 as tert-butoxycarbonyl are desirable for the sequence of reactions in reaction scheme 14.

PHARMACEUTICAL FORMULATION AND DOSES The compounds of the present invention can be administered in such oral (including buccal and sublingual) dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and mulsions. Likewise, they may also be administered in nasal, ophthalmic, otic, rectal, topical, intravenous (both bolus and infusion), intraperitoneal, intraarticular, subcutaneous or intramuscular inhalation or insufflation form, all using forms well known to those of ordinary skill in the pharmaceutical arts.

The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration ; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicated effects, will range between about 0.1 to 300 mg/kg of body weight per day, and particularly 1 to 100 mg/kg of body weight per day. Oral dosage units will generally be administered in the range of from 1 to about 250 mg and more preferably from about 25 to 250 mg. The daily dosage for a 70 kg mammal will generally be in the range of about 10 mg to 5 grams of a compound of formula I or 11.

' < While the dosage to be administered is based on the usual conditions such as the physical condition of the patient, age, body weight, past medical history, route of administrations, severity of the conditions and the like, it is generally preferred for oral administration to administer to a human. In some cases, a lower dose is sufficient and, in some cases, a higher dose or more doses may be necessary. Topical application similarly may be once or more than once per day depending upon the usual medical < . considerations. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as"carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.

Capsules are made by preparing a powder mixture as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quatemary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to < . prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compresse into tablets.

The compounds of the present invention can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcools and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

The present invention includes pharmaceutical compositions containing 0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula (II) in combination with a pharmaceutically acceptable carrier.

Parenteral administration can be effected by utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound in a non-toxic liquid vehicle suitable for injection such as aqueous oleaginous medium and sterilizing the suspension or solution. k Alternatively, a measured amount of the compound is placed in a vial and the via and its contents are sterilized and sealed. An accompanying vial or vehicle can be provided for mixing prior to administration. Non-toxic salts and salt solutions can be added to render the injection isotonic. Stabilizers, preservations and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in which the compound is admixed with low-melting water-soluble or insoluble solids such as polyethylene glycol, cocoa butter, higher ester as for example flavored aqueous solution, while elixirs are prepared through myristyl paimitate or mixtures thereof.

Topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.

For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e. g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e. g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.

The preferred pharmaceutical compositions are those in a form suitable for oral administration, such as tablets and liquids and the like and topical formulations.

EXAMPLES The following examples are illustrative embodiments of the invention, not limiting the scope of the invention in any way. Reagents are commercially available or are prepared according to procedures in the literature.

Example 1; (2R, 3S)-3-(Formyl-hydroxyamino)-2-(4-methylcyclohexylmethyl)-4methylpentanoic Acid [ (1 S, 2R)-2-Methoxy-1- (1, 3-thiazol-2-ylcarbamoyl)-1- propyl] amide

Example 1 a ; Methyl (3S)-3-Hydroxy-4-methylpentanoate Methyl isobutyrylacetate (135 g, 0.935 mol) in 135 mL of degassed MeOH is treated with 564 mg of [ (RuC6) (Ph H) (R- (+YBI NAP)]. The solution is purged with nitrogen and stirred under 62 psi of hydrogen while heating at 100 C for 72 h. The reaction mixture is cooled to 25 C and degassed followed by purging with nitrogen. The reaction mixture is concentrated to dryness and the residue is distille (39 C, 0.52 mm Hg) to afford 106 g of methyl (3S)-3-hydroxy-4-methylpentanoate as an oil.

'H NMR (400 MHz, CDCI3) 8 3.80 (m, 1 H), 3.70 (s, 3H), 2.82 (s, 1 H), 2.52-2.40 (m, 2H), 1.70 (m, 1 H), 0.97 (dd, 6H) ppm.

ESI-MS m/z 147 (M+H) +.

Example 1b ; Methyl (2R, 3R)-3-Hydroxy-2- (4-methylbenzyl)-4-methylpentanoate A solution of diisopropylamine (35 mL, 270 mmol) in 50 mL anhydrous THF is cooled to -78 C. n-Butyllithium (108 mL, 2.5 M in hexanes, 270 mmol) is added and the mixture is stirred at-78 C for 30 min. Methyl (3S)-3-hydroxy-4-methylpentanoate (19.17 g, 0.135 mmol) is added and the solution is warmed to 0 C and kept at 0 C for 1 h. The mixture is again cooled to-78 C and 4-methylbenzyl bromide (25.0 g, 135 mmol) is added. After 45 min at-78 C, the reaction is kept at 4 C for 2 d, then quenched with 50 mL of saturated ammonium chloride and extracted with EtOAc. The organic layers are washed with 1 N HCI, water, and saturated aqueous sodium chloride, dried over sodium sulfate and the solvent evaporated to give a yellow oil. Flash chromatography on silica gel with hexane-EtOAc (85: 15) gives 13.04 g (39%) of methyl (2R, 3R)-3 hydroxy-2- (4-methylbenzyl)-4-methylpentanoate as a yellow oil.

'H NMR (300 MHz, CDCI3) 8 0.95 (d, 3H), 1.0 (d, 3H), 1.7 (m, 1 H), 2.3 (s, 3H), 2.7 (d, 1 H), 3.0 (m, 3H), 3.3 (m, 1 H), 3.65 (s, 3H), 7.1 (m, 4H) ppm.

ESI-MS m/z 273 (M+Na) + Example 1c ; Methyl (2R, 3R)-3-Hydroxy-2- (4-methylcyclohexylmethyl)-4 methylpentanoate A solution of methyl (2R, 3R)-3-hydroxy-2-(4-methylbenzyl) 4-methylpentanoate (13.03 g, 52.1 mmol) is added to 1.6 g of rhodium on alumina in a pressure bottle. The mixture is evacuated, flushed with nitrogen and filled with 60 psi of hydrogen. After 20 h, the mixture is filtered and the solvent is evaporated to give 13.0 g of methyl (2R, 3R) 3-hydroxy-2- (4-methylcyclohexylmethyl)-4-methylpentanoate as an oil.

'H NMR (300 MHz, CDCb) 8 0. 9 (m, 10H), 1.2-1.8 (m, 12H), 2.8 (m, 1H), 3.3 (m, 1 H), 3.7 (s, 3H) ppm.

ESI-MS m/z 279 (M+Na) * Example 1d ; (2R, 3R)-3-Hydroxy-2- (4-methyicyclohexylmethyl)-4-methylpentanoic Acid Methyl (2R, 3R)-3-hydroxy-2- (4-methylcyclohexylmethyl)-4-methylpentanoate (13. 0 g, 52 mmol) is dissolved in 40 mL THF. Lithium hydroxide (1.4 g, 57 mmol), 40 mL of water, and 120 mL of methanol is added. After stirring at 25 C for 18 h, the mixture is acidified with concentrated HCI, concentrated under vacuum, extracted with EtOAc, the organic layers washed with water and saturated aqueous sodium chloride, and dried over sodium sulfate. The solvent is evaporated to give 12 g of (2R, 3R)-3-hydroxy-2- (4- methylcyclohexylmethyl)-4-methylpentanoic acid as a yellow oil.

'H NMR (300 MHz, CDCI3) 8 1. 0 (m, 10H), 1.2-1.8 (m, 12H), 2.75 (m, 1 H), 3.35 (m, 1H) ppm.

ESI-MS m/z 241 (M-H)- Example 1e ; (2R, 3R)-3-Hydroxy-2- (4-methylcyclohexylmethyl)-4-methylpentanoic Acid 2-Tetrahydropyranyloxyamide 2-Tetrahydropyranyloxyamine (12.2 g, 104 mmol) and EDC (13. 0g, 67.6 mmol) are added to a solution of (2R, 3R)-3-hydroxy-4-methyl-2- (4- methylcyclohexylmethyf) pentanoic acid (12 g, 52 mmol) in 150 mL of dichloromethane.

After stirring at 25 C for 2.5 h, the mixture is diluted with dichloromethane, washed with aqueous sodium bisulfate, saturated aqueous sodium bicarbonate, and dried over sodium sulfate. The solvent is removed under vacuum to give a yellow oil which is purified by chromatography on silica gel to give 9.4 g of (2R, 3R)-3-hydroxy-2- (4- methylcyclohexylmethyl)-4-methylpentanoic Acid 2-tetrahydropyranyloxyamide as an oil.

'H NMR (300 MHz, CDCI3) 8 1. 0 (m, 10H), 1.2-2.0 (m, 20H), 2.4 (m, 1H), 3.3 (m, 1H), 3.65 (m, 1H), 4.0 (m, 1H), 5.0 (m, 1H), 8.8 (m, 1H) ppm.

ESI-MS m/z 364 (M+Na) + Example 1f ; (3R, 4S)-1-(2-Tetrahydropyranyloxy)-3-(4-methylcycloheXylmethyl) 4- isopropylazetidin-2-one A solution of (2R, 3R)-3-hydroxy-4-methyl-2- (4-methylcyclohexylmethyl) pentanoic acid 2-tetrahydropyranyloxyamide (9.3 g, 27 mmol) in 50 mL of anhydrous pyridine is cooled to 0 C under nitrogen. Methanesulfonyl chloride (2.3 mL, 30 mmol) is added and the mixture is stirred at 25 C for 18 h. Pyridine is evaporated under vacuum. The residue is partitioned between 1 N HCI and EtOAc. The EtOAc layer is washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and the solvent removed under vacuum. The residue is dissolved in 30 mL of acetone and added to potassium carbonate (11.2 g, 81 mmol) in 80 mL of refluxing acetone, under nitrogen. The mixture is heated at reflux for 18 h. After cooling to 25 C, solids are filtered off and the filtrate is evaporated under vacuum to give a yellow oil. Flash chromatography on silica gel with hexane: EtOAc (4: 1) gives 6.55 g (74%) of (3R, 4S)-I- (2-tetrahydropyranyloxy)-3- (4- methylcydohexylmethyl)-4-isopropylazetidin-2-one as a white solid.

ESI-MS m/z 346 (M+Na) + Example 1g ; (2R, 3S)-3- (2-Tetrahydropyranyloxyamino)-2- (4-methylcyclohexylmethyl)-4- methylpentanoic Acid To a solution of (3R, 4S)-1- (2-tetrahydropyranyloxy)-3- (4-methylcyclohexylmethyl)-4- isopropylazetidin-2-one in 100 mL of dioxane is added 100 mi of 3 M aqueous sodium hydroxide. After stirring at 25 C for 20 h, the mixture is acidified with saturated sodium bisulfate and extracted with EtOAc. The organic layer is washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, and the solvent evaporated under vacuum to give 7.1 g of (2R, 3S)-3- (2-tetrahydropyranyloxyamino)-2- (4-methylcyclohexylmethyl)-4-methylpentanoic acid as a foam.

'H NMR (300 MHz, CDCI3) 8 0. 9 (m, 9H), 1.2-2.0 (m, 16H), 2.8-3.1 (m, 2H), 3.6 (m, 1H), 3.95 (m, 1 H), 4.8 (m, 1 H) ppm.

ESI-MS m/z 342 (M+H)' Example 1h ; (2R, 3S)-3- (Formyl-2-tetrahydropyranyloxyamino)-2- (4- methylcyclohexylmethyl)-4-methylpentanoic Acid A solution of (2R, 3S)-3- (2-tetrahydropyranyloxyamino)-2- (4-methylcyclohexylmethyl)-4- methylpentanoic acid in pyridine is cooled to 0 C. Formic acetic anhydride (5.0 mL) is added. After 2.5 h the pyridine is evaporated under vacuum. The residue is taken up in EtOAc, washed with aqueous 1 N HCI, water, and saturated aqueous sodium chloride, and dried over sodium sulfate. The solvent is evaporated to give a yellow oil which is purified by flash chromatography on silica gel with hexane-EtOAc (1: 1) to give 5.35 g of (2R, 3S)-3- (formyl-2-tetrahydropyranyloxyamino)-2- (4-methylcyclohexylmethyl)-4- methylpentanoic acid as a foam.

'H NMR (300 MHz, CDCI3) 81. 0 (m, 10H), 1.1-2.0 (m, 20H), 2.8-3.2 (m, 1H), 3.6 (m, 1 H), 3.95 (m, 1 H), 4.2-4.4 (m, 1H), 4.9 and 5.05 (two m, 1 H), 8.0 and 8.5 (two m, 1H) ppm.

ESI-MS m/z 370 (M+H) + Example 1i ; (2S, 3R)-2-tert-Butoxycarbonylamino-3-methoxybutanoic Acid 1, 3-Thiazol-2- ylamide To a solution of (2S, 3R)-2-tert-butoxycarbonylamino-3-methoxybutanoic acid (0.20 g, 0.86 mmol) and 2-aminothiazole (0.095 g, 0.95 mmol) in anhydrous DMF (2. 0 mL) at 25 C is added anhydrous DIEA (0.30 mL, 1.7 mmol) and 1- [bis (dimethylamino) methylene] 1H-1, 2, 3-triazolo-3-oxo [4,5-b] pyridinium hexafluorophosphate (HATU) (0.33 g, 0.86 mmol). The mixture is stirred at 25 C for 18 h and then is diluted with 30 mL of dichloromethane and 50 mL of water. The aqueous phase is extracted with dichloromethane and the dichloromethane extracts are washed with 10% aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and dried over magnesium sulfate. Concentration and purification by chromatography on silica gel (elution with 2: 1 EtOAc-hexanes) gives 0.23 g of (2S, 3R)-2-tert-butoxycarbonylamino3-methoxybutanoic acid 1,3-thiazol-2-ylamide as a solid.

'H NMR (300 MHz, CDCI3) 8 9.93 (s, 1H), 7.51 (d, 1 H), 7.04 (d, 1 H), 5.51 (d, 1H), 4.52 (d, 1 H), 4.09 (m, 1H), 3.45 (s, 3H), 1.65 (s, 9H), 1.22 (d, 3H) ppm.

Example 1j ; (2S, 3R)-2-Amino-3-methoxybutanoic Acid 1, 3-Thiazol-2-ylamide Hydrochloride To a solution of (2S, 3R)-2-tert-butoxycarbonylamino-3-methoxybutanoic acid 1,3thiazol-2-ylamide (0.22 g, 0.70 mmol) in 2.5 mL dichloromethane at 25 C is added 1.5 mL (6 mmol) of 4 N hydrogen chloride in dioxane. The reaction mixture is stirred for 2 h and the resulting white precipitate is isolated by filtration to give 0.20 g of (2S, 3R)-2amino-3-methoxybutanoic acid 1,3-thiazol-2-ylamide hydrochloride as a white solid.

'H NMR (300 MHz, CD3OD) 8 7.57 (d, 1 H), 7.33 (d, 1 H), 4.13 (d, 1 H), 3.93 (m, 1 H), 3.44 (s, 3H), 1.37 (d, 3H) ppm.

Example 1k ; (2R, 3S)-3- (Formyl-2-tetrahydropyranyloxyamino)-2- (4- methylcyclohexylmethyl)-4-methylpentanoic Acid [ (1S, 2R)-2-Methoxy-1- (1, 3-thiazol-2- ylcarbamoyl)-1-propyl] amide To a solution of (2S, 3R)-2-amino-3-methoxybutanoic acid 1,3-thiazol-2-ylamide hydrochloride (0.10 g, 0.40 mmol) and (2R, 3S)-3-(formyl-2-tetrahydropyranyloxyamino)- 2- (4-methylcyclohexylmethyl)-4-methylpentanoic acid (0.16 g, 0.44 mmol) in anhydrous DMF (3.0 mL) at 25 C is added DIEA (0.28 mL, 1.6 mmol) and1- [bis (dimethylamino) methylene]-1 H-1, 2, 3-triazolo-3-oxo [4,5-b] pyridinium hexafluorophosphate (HATU) (0.15 g, 0.40 mmol). The mixture is stirred for 21 h and then is diluted with 30 mL of dichloromethane and 50 mL of water. The aqueous phase is extracted with dichloromethane and the dichloromethane extracts are washed with 10% aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and dried over magnesium sulfate. The solvent is removed under vacuum to afford 0.23 g of (2R, 3S)-3- (formyl-2-tetrahydropyranyloxyamino)-2- (4-methylcyclohexylmethyl)-4- methylpentanoic acid [ ( S, 2R)-2-methoxy-1- (1, 3-thiazol-2-ylcarbamoyl)-1-propyl] amide which is used without further purification.

Example 1; (2R, 3S)-3- (Formyl-hydroxyamino)-2- (4-methylcyclohexylmethyl)-4- methylpentanoic Acid [ (1 S, 2R)-2-Methoxy-1- (1, 3-thiazol-2-ylcarbamoyl-1-propyl] amide (2R, 3S)-3- (Formyl-2-tetrahydropyranyloxyamino)-2- (4-methylcyclohexylmethyl)-4- methylpentanoic acid [ (1S, 2R)-2-methoxy-1- (1, 3-thiazol-2-ylcarbamoyl)-1-propyl] amide (0.23 g) is dissolved in a solution of acetic acid (4 mL) and water (1 mL) and is stirred at 25 C for 18 h. The mixture is filtered, and the collecte solid is washed with water and hexane to give 0.074 g of (2R, 3S)-3- (formyl-hydroxyamino)-2- (4- methylcyclohexylmethyl)-4-methylpentanoic acid [(1S,2R)-2-methoxyl-1-(1,3-thiazol-2ylcarbamoyl)-1-propyl] amide as a solid.

1H NMR (300 MHz, DMSO-d6) 8 0.78 (d, 1H), 0.90 (d, 6H), 1.05 (d, 3H), 1.15 (d, 3H), 1.50 (m, 12H), 3.10 (m, 1 H), 3.39 (d, 3H), 3.50 (m, 1H), 3.79 (m, 1 H), 4.80 (m, 1 H), 7.22 (m, 1 H), 7.50 (d, 1H), 7.92 (d, 1H), 8.60 (m, 1 H), 9.41 (m, 1H) ppm.

ESI-MS m/z 483 (M+H) + 505 (M+Na) + 481 (M-H) PHARMACOLOGY The efficacy of compounds of the present invention as inhibitors of matrix metalloproteases, TNFa converting enzyme and TNFa cellular release can be evaluated and measured using pharmacological methods known in the art or as described in detail below based on similarly established methodologies.

Pharmacological Example 9 A. Matrix Metalloprotease Inhibition Protocol The potency of compounds of the invention as inhibitors of 19 kD truncated collagenase-1 (MMP-1), 20 kD truncated collagenase-3 (MMP-13), stromelysin-1 (MMP-3), and 50 kD truncated gelatinase B (MMP-9) is determined according to the general procedure of Bickett et. al. (Anal. Biochem. 1993,212,58-64) using the fluorogenic substrate, DNP-Pro-Cha-Gly-Cys (Me)-His-Ala-Lys (NMA)-NH2 (DNP = 2,4dinitrophenyl, NMA = N-methylanthranilic acid). Assays are conducted in a total volume of 0.180 mL assay buffer (200 mM NaCI, 50 mM Tris, 5 mM Cal2, 10M ZnSO4, 0.005% Brij 35, pH 7.6) in each well of a black 96-well microtiter plate. 19 kD collagenase-1, 20 kD collagenase-3, stromelysin-1, and 50 kD gelatinase B concentrations are adjusted to 500 pM, 30 pM, 5 nM, and 100 pM, respectively. A dose response is generated using an eleven-point, 3-fold serial dilution with initial starting test compound concentrations of 100,10, or 1 p. M. Inhibitor and enzyme reactions are incubated for 30 min at ambient temperature and then initiated with 10 M fluorogenic substrate (above). The product formation is measured at Excitation343/Emission450 nm after 45-180 min using a Fluostar SLT fluorescence analyzer. Percent inhibition is calculated at each inhibitor concentration and the data are plotted using standard curve fitting programs. I values are determined from these curves. Assays are run at low substrate concentration ( [S] K, r) such that the calculated IC50 values are equivalent to K ; within experimental error.

B. TNFa Converting Enzyme Inhibition Protocol The potency of compounds of the invention as inhibitors of cell-free tumor necrosis factor a converting enzyme is determined as follows ; Membrane preparation from MonoMac 6 cells (subfractionated extract from equivalent of 6x106 cells per 60 Ll assay) is incubated for 1 hr with 200 nM radiolabeled substrate (Biotin-SPLAQAVRSSSRT (3H) P-S-NH2, 4.1 Ci/mmol, ref &num; 0935 from Zeneca) in 10 mM hepes buffer, 250 mM sucrose, pH 7.5. The reaction is quenched by addition of streptavidin SPA beads (Amersham RPNQ0006), with excess binding capacity relative to substrate, suspended in 250 mM EDTA, pH 8.0. Binding is complete within 15 min and plates are counted in a Wallac 1450 Microbeta liquid scintillation counter. Percent inhibition is calculated at each inhibitor concentration and the data are plotted using standard curve fitting programs. IC50 values are determined from these curves. Assays are run at low substrate concentration ([S] ,) such that the calculated IC50 values are equivalent to K. within experimental error.

C. Cell-Based TNFa Release Inhibition Protocol The potency of compounds of the invention as inhibitors of release of soluble tumor necrosis factor a from stimulated monocytes in vitro is determined as follows ; LPS/PMA solution for assay consisting of a) 4 pL of 5 mg/mL LPS stock and b) 6 pL of 10 mg/mL PMA stock are added to 500 iL of medium (RPMI + 10% FBS + penicillin/streptomycin + I-glutamine). This solution is then diluted 1: 1000 (40 ng/mL and 120 ng/mL) for use later in the assay. Compounds (10 mM) are serially diluted 1: 3 in DMSO. Compound dilutions (20 pL) are added to a sterile round bottom 96 well plate (20 pL : 200 pL total volume = 1 : 10 for final concentrations of 50 IlM for test compounds). MonoMac 6 cell suspension (130 L, 1.5 x106 cells/mL) is then added to each well resulting in 2 x 105 cells/well. LPS/PMA (50 IlL) solution is then added to each well (final concentrations of 10 ng/mL and 30 ng/mL respectively). The plate is incubated at 37 C for 2 h then spun at 1,500 rpm for 3 min to pellet cells. The supernatant (120 RUwell) is removed to a new round bottom 96 well plate and diluted 1: 10 in PBS. Then, 20 L of the supernatant is transferred to a Cistron TNFa ELISA plate and processed according to the manufacturer's instructions to quantitate levels of TNFa. Percent inhibition of TNFa release is calculated at each inhibitor concentration and the data are plotted using standard curve fitting programs. IC50 values are determined from these curves.

Results are listed in Table 3.

Table 3

Example TNFa Collagenase Collagenase Gelatinas Stromelysin-TNFa Converting-1 K1 -3 K1 e B K1 1 K1 Release Enzyme K ; Inhibition 'Co + ++ + ++ +++ 2 +++ ++ ++ 3 + ++ + ++ ++ nd 75 + ++ + ++ ++ ++ 78 + ++++ ++ ++++ ++++ nd Key; + < 100 nM ++ 100 nM-500 nM +++ 500 nM-1 M ++++ I PM nd not done Pharmacological Example 2 Murine LPS-Stimulated Serum TNF Inhibition Protocol The potency of compounds of the invention as inhibitors of serum TNFa elevation in mice treated with lipopolysaccharide (LPS) is determined as follows ; a) for subcutaneous (s. c.) administration, test compound is dissolved in DMSO and added to a mixture of 0.9% sodium chloride solution and 30% Trappsol HPB-20 (Cyclodextrin Technology Development Inc., Gainesville, Florida USA) for a final DMSO concentration of 1 %. The dosing solution is sonicated briefly and 0.2 mL is injected subcutaneously 10 min prior to LPS injection, b) for per oral (p. o.) administration, test compounds are formulated in 0.2 mL of PBS and 0.1% Tween 80 and given orally via gavage 10 min prior to LPS administration.

C3/hen female mice are injected intraperitoneally with 200 fig/kg LPS (Escherichia coli, Serotype 0111 : B4, Sigma Chemical Co, St. Louis, MO) in PBS and sacrificed 90 min later by COz asphyxiation. Blood is immediately taken from the caudal vena cava and plasma prepared and frozen at-80 C. Plasma concentrations of TNF are measured by ELISA (Genzyme Co., Cambridge MA).

Results are listed in Table 4.

Table 4

Compound Route of Administration Dose Percentage Inhibition of Serum TNFa Example 1 s. c. 40 mg/kg +++ Example 2 s. c. 40 mg/kg ++ Example 2 p. o. 40 mglkg + Example 75. o. 40 mglkg ++ Key ; + 25%-50% ++ 50%-75% +++ > 75% Throughout this application, various references have been cited. These references are hereby incorporated by reference in their entirety.

While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for inflammatory conditions, or for other indications for the compounds of the invention indicated above.

Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims (30)

1. WHAT IS CLAIMED IS : 1. A compound of the formula

   where R, is alkyl ; R2 is

   where D, is alkyl ; R3 is hydrogen or lower alkyl ; R4 is

   where E1 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, C (O) NR7, NR7C (O), C (O), C (O) O, OC (O), or a direct bond, where R7 is as defined below ; E2 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR8, S, SO, SO2, O, C (O), C (O) O, OC (O), or a direct bond, where R8 is as defined below ; E3 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR9, S, SO, SO2, O, C (O), C (O) O, OC (O),

   or a direct bond, where R9, Rio and R"are as defined below ; E4 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR12, S, SO, SO2, O, C (O), C (O) 0. OC (O),

   or a direct bond, where R12, R13 and R14 are as defined below; E5 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR,5, S, SO, SO2, O, C (O), C (O) O, OC (O),

   or a direct bond, where R15, R16 and R17 are as defined below ; E6 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR16, S, SO, SO2, O, C (O), C (O) O, OC (O), or a direct bond, where Rie is as defined below ; E7 is hydrogen, NR19R20, OR19, SR19, SOR19, SO2R19 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, where R, g and R2o are as defined below ; R5 is hydrogen or lower alkyl ; R6 is heteroaryl ; and R7, R8 R9 R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, are, independently, hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl ; or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
2. 2. A compound of the formula :

   where R, is methyl, ethyl, tert-butyl, isopropyl, n-propyl, or 3,3,3-trifluoro-1-propyl; R2 is 4-methylcyclohexylmethyl, 4-ethylcyclohexylmethyl, 4-isobutylcyclohexylmethyl, 4 (3,3,3-trifluoropropyl) cyclohexylmethyl, or 4-trifluoromethylcyclohexylmethyl ; R3 is hydrogen, isobutyl, or methyl ; R4 is tert-butyl, sec-butyl, 1-methoxy-1-ethyl, 1-propoxy-1-ethyl, 4-ethoxycarbonylamino-1- butyl, 4-isobutoxycarbonylamino-1-butyl, 1-hydroxy-1-ethyl, hydroxymethyl, methoxymethyl, 4-(2-pyridylcarbonylamino)-1-butyl, 4-(2-pyridylcarbonylamino)-2- methyl-2-butyl, 2-(4-morpholinecarbonyl)-1-ethyl, 1-methanesulfanyl-1-ethyl, 2 methanesulfonyl-1-ethyl, 3-pyridylmethyl, 2- (4- (2-furyl) carbonylpiperazine-1- ylcarbonyl)-1-ethyl, 4- (4-pyridylcarbonylamino)-2-methyl-2-butyl, 3- (pyrimidin-2- ylamino)-1-propyl, 4-(pyrimidin-2-ylamino)-1-butyl, 1-methanesulfenyl-1ethyl, 3-(imino- (1,2,6-trimethyl-4-methoxybenzenesulfonylamino))-methylamino-1-propyl,

   3-(imino benzenesulfonylamino)-methylamino-1-propyl, 2-dimethylaminosulfonyl-1-ethyl,, 4- (2- dimethylamino-1-ethoxycarbonylamino)-1-butyl, 4-(2-pyridinesulfonylamino)-1-butyl, 3 methylcarbamoylamino-1-propyl, 3-carbamoylamino-1-propyl, 3 phenylcarbamoylamino-1-propyl, 2- (4-morpholinesulfonyl)-1-ethyl, 2-methanesulfanyl- 2-propyl, 4-ethoxycarbonylamino-1-butyl, 2-methanesulfenyl-2-propyl, 2-hydroxy-2propyl, 2- (4-ethoxycarbonylpiperazine-1-ylsulfonyl)-1-ethyl, 3- (2- thiophenesulfonylamino)-1-propyl, 4-propoxycarbonylamino-1-butyl, 3 (ethoxycarbonylamino)-1-propyl, 2-(2-pyridylcarbonylamino)-1-ethyl, 2-(3- pyridylcarbonylamino)-1-ethyl, 1,1-dimethyl-1-propyl, 2-(2-thiazolaminosulfonyl)-1-ethyl, 2- (2- (1, 3, 4-thiadiazol) ylaminosulfonyl)-1-ethyl, 2- (2-thiophene)-1-ethyl, 4methoxycarbonylamino-1-butyl, 3-(2-thiophenecarbonylamino)-2-propyl, 4 methoxycarbonylamino-l-butyl, 4-propoxycarbonylamino-2-butyl, 3- (2- pyridinesulfonylamino)-1-propyl, 1-ethoxycarbonylamino-1-ethyl, 3- (3, 5 dimethylisoxazol-4-ylsulfonylamino)-1-propyl, 3- (3-pyridinecarbonylamino)-1-propyl, 3 (2-thiophenecarbonylamino)-2-methyl-2-propyl, 2-ethoxycarbonylamino-1-ethyl, 2 ethoxycarbonylamino-1-propyl, 3-methanesulfonylamino-1-propyl, 1- (tetrahydrofuran-3yloxy)-1-ethyl, 2- (1-piperazinecarbonyl)-1-ethyl, 2- (4-methanesulfonyl-1- piperazinecarbonyl)-1-ethyl, 2- (4-morpholinesulfonyl)-l-ethyl,

   3- (2- pyridylcarbonylamino)-2-propyl, 3- (2-pyridylcarbonylamino)-2-methyl-2-propyl, 1- (4- chlorobenzyloxy)-1-ethyl, or isopropyl ; R5 is hydrogen, methyl, ethyl, or propyl ; and R6 is 2-thiazolyl, 3-pyridyl, 4-pyridyl, 2- (1, 3,4-thiadiazolyl), or 2-pyridyl; or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
3. 3. A compound of the formula :

   where Rl, R2, R3, R5 and R6 are as defined above in claim 2 and where R4 is cyclohexyl ; or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
4. 4. A compound of the formula :

   where R, is methyl, isopropyl, n-propyl, or 3, 3, 3-trifluoro-1-propyl ; R2 is 4-methylcyclohexylmethyl or 4-trifluoromethylcyclohexylmethyl ; R3 is hydrogen; R4 is tert-butyl, sec-butyl, 1-methoxy-1-ethyl, 4-ethoxycarbonylamino-1-butyl, 1-hydroxy-1- ethyl, hydroxymethyl, methoxymethyl, 4- (2-pyridylcarbonylamino)-1-butyl, 2- (4- morpholinecarbonyl)-1-ethyl, 2-methanesulfonyi-1-ethyl, 3-pyridylmethyl, 2- (4- (2- furyl) carbonylpiperazine-1-ylcarbonyl)-1-ethyl, 3-(pyrimidin-2-ylamino)-1-propyl, 4 (pyrimidin-2-ylamino)-1-butyl,, 3- (imino- (1, 2,6-trimethyl-4 methoxybenzenesulfonylamino))-methylamino-1-propyl, 2-dimethylaminosulfonyl-1- ethyl,, 4-(2-dimethylamino-1-ethoxycarbonylamino)-1-butyl, 4-(2 pyridinesulfonylamino)-1-butyl, 3-carbamoylamino-1-propyl, 2- (4-morpholinesulfonyl)-1- ethyl, 2-methanesulfanyl-2-propyl, 2-methanesulfenyl-2-propyl, 2-hydroxy-2-propyl, 2 (4-ethoxycarbonylpiperazine-1-ylsulfonyl)-1-ethyl, 3-(2-thiophenesulfonylamino)-1- propyl, 3-(ethoxycarbonylamino)-1-propyl, 2-(2-pyridylcarbonylamino)-1-ethyl, 2-(2thiazolaminosulfonyl)-1-ethyl, 4-methoxycarbonylamino-1-butyl, 3-(2 pyridinesulfonylamino)-1-propyl, 3- (3, 5-dimethylisoxazol4-ylsulfonylamino)-1-propyl, 3 (3-pyridinecarbonylamino)-1-propyl, 2-ethoxycarbonylamino-1-ethyl, 3 methanesulfonylamino-1-propyl, 2- (1-piperazinecarbonyl)-1-ethyl, 2- (4- methanesulfonyl-1-piperazinecarbonyl)-1-ethyl, 2- (4-morpholinesulfonyl)-1-ethyl, 3-(2- pyridylcarbonylamino)-2-propyl, 1- (4-chlorobenzyloxy)-1-ethyl, or isopropyl ; R5 is hydrogen; and R6 is 2-thiazolyl or 2-pyridyl ; or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
5. 5. A compound of the formula :

   where R, is isopropyl or 3, 3,3-trifluoro-1-propyl; R2 is 4-methylcyclohexylmethyl ; R3 is hydrogen; R4 is tert-butyl, sec-butyl, 1-methoxy-1-ethyl, 4-ethoxycarbonylamino-1-butyl, 1-hydroxy-1 ethyl, 2-methanesulfanyl-2-propyl, 2-methanesulfenyl-2-propyl, 3- (2- pyridylcarbonylamino)-2-propyl, or isopropyl ; R5 is hydrogen; and R6 is 2-thiazolyl ; or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
6. 6. A compound of claim 1, wherein the compound is selected from the compounds listed in Table 2A.
7. 7. A compound of claim 1, wherein the compound is selected from the compounds listed in Table 2B.
8. 8. A compound of claim 1, wherein the compound is selected from the compounds listed in Table 3.
9. 9. A compound of formula (II) as claimed in any one of claims 1 to 8 for use in therapy.
10. 10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound as claimed in any one of claims 1 to 8.
11. 11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in any one of claims 1 to 8 sufficient to inhibit the cellular release of mature tumor necrosis factor alpha.
12. 12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in any one of claims 1 to 8 sufficient to inhibit a matrix metalloprotease.
13. 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in any one of claims 1 to 8 sufficient to inhibit the shedding of cell surface protein ectodomains.
14. 14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in any one of claims 1 to 8 sufficient to inhibit CD23 proteolysis.
15. 15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in any one of claims 1 to 8, sufficient to inhibit the growth of tumor metastases.
16. 16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in any one of claims 1 to 8, sufficient to treat arthritis.
17. 17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in any one of claims 1 to 8, sufficient to treat diabetes.
18. 18. A method of inhibiting a matrix metalloprotease, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound as claimed in any one of claims 1 to 8.
19. 19. A method of inhibiting the intracellular release of tumor necrosis factor alpha, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound as claimed in any one of claims 1 to 8.
20. 20. A method of inhibition of shedding of cell surface protein ectodomains, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound as claimed in any one of claims 1 to 8.
21. 21. A method of inhibition of CD23 proteolysis, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound as claimed in any one of claims 1 to 8.
22. 22. A method of treating periodontal disease comprising of administering to a mammal in need thereof a pharmacologically effective amount of a compound as claimed in any one of claims 1 to 8.
23. 23. Use of a compound as claimed in any one of claims 1 to 8 in the preparation of a medicament for inhibiting the intracelluiar release of mature tumor necrosis factor alpha.
24. 24. Use of a compound as claimed in any one of claims 1 to 8 in the preparation of a medicament for inhibiting a matrix metalloprotease.
25. 25. Use of a compound as claimed in any one of claims 1 to 8 in the preparation of a medicament for inhibiting the shedding of cell surface protein ectodomains.
26. 26. Use of a compound as claimed in any one of claims 1 to 8 in the preparation of a medicament for inhibiting CD23 proteolysis.
27. 27. Use of a compound as claimed in any one of claims 1 to 8 in the preparation of a medicament for inhibiting the growth of tumor metastases.
28. 28. Use of a compound as claimed in any one of claims 1 to 8 in the preparation of a medicament for treating arthritis.
29. 29. Use of a compound as claimed in any one of claims 1 to 8 in the preparation of a medicament for treating diabetes.
30. 30. Use of a compound as claimed in any one of claims 1 to 8 in the preparation of a I medicament for treating periodontal disease.