This invention relates to molecules which inhibit metalloproteinases, including aggrecanase, and the production of tumor necrosis factor (TNF). In particular, the compounds are inhibitors of metalloproteinases involved in tissue degradation and inhibitors of the release of tumor necrosis factor. The present invention also relates to pharmaceutical compositions comprising such compounds and to methods of using these compounds for the treatment of inflammatory diseases.

The present invention relates to novel molecules which inhibit metalloproteinases, including aggrecanase, and the production of tumor necrosis factor (TNF), pharmaceutical preparations containing them and to their use as pharmaceutical agents. In particular the compounds are inhibitors of metalloproteinases involved in tissue degradation and inhibitors of the release of tumor necrosis factor.
There is now a body of evidence that metalloproteinases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with the MP""s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteinases. The available evidence supports that it is the metalloproteinases which are responsible for the degradation of the extracellular matrix of articullar cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly identified metalloproteinase enzymatic activity) has been identified that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Therefore metalloproteinases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).
This invention describes novel molecules that inhibit aggrecanase and other metalloproteinases. These novel molecules are provided as cartilage protecting therapeutics. The inhibition of aggrecanase and other metalloproteinases by these novel molecules prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of osteo- and rheumatoid arthritis.
Tumor necrosis factor (TNF) is a cell associated cytokine that is processed from a 26 kD precursor form to a 17 kD active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L.S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn""s disease (Macdonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP""s are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes novel molecules that inhibit this conversion and hence the secretion of active TNF-xcex1 from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may also have a particular advantage in diseases where both mechanisms are involved.
There are several patents which disclose hydroxamate and carboxylate based MMP inhibitors.
PCT International Publication No. WO 92/213260 describes N-carboxyalkylpeptidyl compounds of general formula:
wherein AA is an amino acid, as inhibitors of matrix metallproteinase mediated diseases.
PCT International Publication No. WO 90/05716 discloses hydroxamic acid based collagenase inhibitors having the general formula:
PCT International Publication No. WO 92/13831 describes related hydroxamic acids having collagenase inhibiting activity with the general formula:
PCT International Publication No. WO 94/02446 discloses metalloproteinase inhibitors which are natural amino acid derivatives of general formula:
WO95/09841 describes compounds that are hydroxamic acid derivatives and are inhibitors of cytokine production.
European Patent Application Publication No. 574,758 A1, discloses hydroxamic acid derivatives as collagenase inhibitors having the general formula:
GB 2 268 934 A and WO 94/24140 claim hydroxamate inhibitors of MMPs as inhibitors of TNF production.
The compounds of the current invention act as inhibitors of MPs, in particular aggrecanase and TNF-C, thereby preventing cartilage loss and destruction and inflammatory disorders involving TNF. The hydroxamic and carboxylic acids and derivatives contain a cyclic peptide mimic attached to a succinate peptide mimic, and thus the inhibitors are non-peptide in nature. A selection of these molecules are water soluble and are orally bioavailable.
This invention provides novel hydroxamic acids and carboxylic acids and derivatives thereof of formula (I) (described below) which are useful as inhibitors of metalloproteinases, such as aggrecanase and TNF-C. The present invention also includes pharmaceutical compositions comprising such compounds of formula (I) and methods of using such compounds for the treatment of arthritis and other inflammatory disorders as described previously, in a patient.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of formula (I), for the treatment of arthritis and other inflammatory disorders as described previously.
The present invention also includes methods of inhibiting metalloproteinases, such as aggrecanase and TNF-C, and for the treatment of arthritis by administering a compound of formula (I) in combination with one or more second therapeutic agents selected from other inhibitors of metalloproteinases, such as aggrecanase and TNF-C and/or therapeutic agents for the treatment of arthritis and inflammation.
This invention provides novel hydroxamic acids and carboxylic acids and derivatives thereof of formula (I) (described below) which are useful as inhibitors of metalloproteinases, such as aggrecanase and TNF-C. The present invention also includes pharmaceutical compositions comprising such compounds of formula (I) and methods of using such compounds for the treatment of arthritis and other inflammatory disorders as described previously, in a patient.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of formula (I), for the treatment of arthritis and other inflammatory disorders as described previously.
The present invention also includes methods of inhibiting metalloproteinases, such as aggrecanase and tumor necrosis factor alpha, and for the treatment of arthritis by administering a compound of formula (I) in combination with one or more second therapeutic agents selected from other inhibitors of metalloproteinases, such as aggrecanase and tumor necrosis factor alpha and/or therapeutic agents for the treatment of arthritis and inflammation.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cHxe2x80x9d is intended to include substitutions with deuterium or tritium. Where xe2x80x9cHxe2x80x9d is not indicated but is part of a bond then substitutions with deuterium or tritium are also intentded.
As used herein, xe2x80x9cC1-10 alkylxe2x80x9d or xe2x80x9cC1-10 alkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl;
xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like.
As used herein, xe2x80x9carylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d is intended to include phenyl or naphthyl as well as commonly referred to xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheteroarylxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d compounds.
As used herein the term xe2x80x9calkylarylxe2x80x9d represents an aryl group attached through an alkyl bridge.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d,or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The term xe2x80x9camino acidxe2x80x9d as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids (e.g., L-amino acids), modified and unusual amino acids (e.g., D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which is hereby incorporated by reference. Natural protein occurring amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine. Natural non-protein amino acids include, but are not limited to arginosuccinic acid, citrulline, cysteine sulfinic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine, 3-monoiodotyrosine, 3,5-diiodotryosine, 3,5,5xe2x80x2-triiodothyronine, and 3,3xe2x80x2,5,5xe2x80x2-tetraiodothyronine. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, xcex2-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent. compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d and xe2x80x9cprodrug derivativesxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
[1] There is provided by this invention a compound of the formula (I):
or a pharmaceutically acceptable salt form or a steroisomer thereof, wherein:
R1 is selected from:
xe2x80x94CO2H, xe2x80x94C(O)NHOH, xe2x80x94C(O)NHOR7, xe2x80x94SH, xe2x80x94CH2CO2R7, xe2x80x94COR7, xe2x80x94N(OH)COR7, xe2x80x94SN2H2R7, xe2x80x94SONHR7, xe2x80x94CH2CO2H, xe2x80x94PO(OH)2, xe2x80x94PO(OH)NHR7, xe2x80x94CH2SH, xe2x80x94C(O)NHOR7, xe2x80x94CO2R7, and common prodrug derivatives;
R2 is selected from the formula:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R3 is selected from the formula:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R4 is selected from:
hydrogen, (C1-C5)alkyl, (C1-C5)alkyl-aryl,
R5 and R6 are independently selected from:
xe2x80x83Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R7 is selected from: C1-C10 alkyl, alkylaryl, and common prodrug derivatives
A is selected from:
SO2, SO, CHOH;
E is (CR8R9)mxe2x80x94Wxe2x80x94(CR8R9)n,
wherein W can be absent or selected from:
CH2, CO, O, S(O)m and NR10,
m is 0-2,
n is 0-2;
with the proviso that when W is O, S or NR10 then m must not be 0;
R8 and R9 is independently selected from:
H,
C1-C8 alkyl substituted with 0-5 Rb,
C1-C8 alkenyl,
C1-C8 alkylaryl substituted with 0-5 Rb,
C3-13 carbocyclic residue substituted with 0-5 Rb,
5-14 membered heterocyclic system containing from
1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
amino,
C1-C8 alkyl-NR10
hydroxyl,
R8 and R9 can also form a ring interrupted by NR10, O, S(O)m.
R10 is selected from:
hydrogen,
C1-C8 alkyl
C1-C8 alkylaryl
J1, J2, J3, J4 are independently selected from:
CH, or N.
with no more than two N in the cycle.
[2] The present invention includes compounds of formula (I) wherein:
R1 is selected from: xe2x80x94CO2H, xe2x80x94C(O)NHOH, xe2x80x94C(O)NHOR7, xe2x80x94SH, xe2x80x94CH2CO2R7, xe2x80x94COR7, xe2x80x94N(OH)COR7, xe2x80x94SN2H2R7, xe2x80x94SONHR7, xe2x80x94CH2CO2H, xe2x80x94PO(OH)2, xe2x80x94PO(OH)NHR7, xe2x80x94CH2SH, xe2x80x94C(O)NHOR7, xe2x80x94CO2R7, and common prodrug derivatives;
R2 is selected from the formula:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R3 is selected from the formula:
xe2x80x83Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R4 is selected from:
hydrogen,
R5 and R6 are independently selected from:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R7 is selected from: C1-C10 alkyl, alkylaryl, and common prodrug derivatives
A is selected from:
SO2, SO, CHOH;
E is (CR8R9)mxe2x80x94Wxe2x80x94(CR8R9)n,
wherein W can be absent or selected from:
CH2, CO, O, S(O)m and NR10,
m is 0-2,
n is 0-2;
with the proviso that when w is O, S or NR10 then
m must not be 0;
R8 and R9 is independently selected from:
H,
C1-C8 alkyl substituted with 0-5 Rb,
C1-C8 alkenyl,
C1-C8 alkylaryl substituted with 0-5 Rb,
C3-13 carbocyclic residue substituted with 0-5 Rb,
5-14 membered heterocyclic system containing from
1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
amino,
C1-C8 alkyl-NR10
hydroxyl,
R8 and R9 can also form a ring interrupted by NR10, O, S(O)m.
R10 is selected from:
hydrogen,
C1-C8 alkyl
C1-C8 alkylaryl
J1, J2, J3, J4 are independently selected from:
CH, or N.
with no more than two N in the cycle.
[3] The present invention includes preferred compounds of formula (I) wherein:
R1 is selected from:
xe2x80x94CO2H, xe2x80x94C(O)NHOH, xe2x80x94C(O)NHOR7, xe2x80x94SH, xe2x80x94CH2CO2R7,
and common prodrug derivatives;
R2 is selected from the formula:
xe2x80x83Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Ra, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R3 is selected from the formula:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRa, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R4 is selected from:
hydrogen,
R5 and R6 are independently selected from:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R7 is selected from: C1-C10 alkyl, alkylaryl, and common prodrug derivatives
A is selected from:
SO2, SO, CHOH;
E is (CR8R9)mxe2x80x94Wxe2x80x94(CR8R9)n,
wherein W can be absent or selected from:
CH2, CO, O, S(O)m and NR10,
m is 0-2,
n is 0-2;
with the proviso that when W is O, S or NR10 then
m must not be 0;
R8 and R9 is independently selected from:
H,
C1-C8 alkyl substituted with 0-5 Rb,
C1-C8 alkenyl,
C1-C8 alkylaryl substituted with 0-5 Rb;
C3-13 carbocyclic residue substituted with 0-5 Rb,
5-14 membered heterocyclic system containing from
1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
amino,
C1-C8 alkyl-NR10
hydroxyl,
R8 and R9 can also form a ring interrupted by NR10, O, S(O)m.
R10 is selected from:
hydrogen,
C1-C8 alkyl
C1-C8 alkylaryl
J1, J2, J3, J4 are independently selected from:
CH,or N.
with no more than two N in the cycle.
[4] There is provided by this invention preferred compounds of the formula (II):
or a pharmaceutically acceptable salt form or a steroisomer thereof, wherein:
R1 is selected from:
xe2x80x94CO2H, xe2x80x94C(O)NHOH, xe2x80x94C(O)NHOR7, xe2x80x94SH, xe2x80x94CH2CO2R7,
and common prodrug derivatives;
R2 is selected from the formula:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R3 is selected from the formula:
xe2x80x83Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(OO, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRa, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R5 is selected from:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R7 is selected from: C1-C10 alkyl, alkylaryl, and common prodrug derivatives
E is (CR8R9)mxe2x80x94Wxe2x80x94(CR8R9)n,
wherein W can be absent or selected from:
CH2, CO, O, S(O)m and NR10,
m is 0-2,
n is 0-2;
with the proviso that when W is O, S or NR10 then
m must not be 0;
R8 and R9 is independently selected from:
H,
C1-C8 alkyl substituted with 0-5 Rb,
C1-C8 alkenyl,
C1-C8 alkylaryl substituted with 0-5 Rb,
C3-13 carbocyclic residue substituted with 0-5 Rb,
5-14 membered heterocyclic system containing from
1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
amino,
C1-C8 alkyl-NR10
hydroxyl,
R8 and R9 can also form a ring interrupted by NR10, O, S(O)m.
R10 is selected from:
hydrogen,
C1-C8 alkyl
C1-C8 alkylaryl
J1, J2, J3, J4 are independently selected from:
CH, or N.
with no more than two N in the cycle.
[5] Preferred compounds of the present invention include compounds of formula (II) wherein:
R1 is selected from:
xe2x80x94C(O)NHOH,
and common prodrug derivatives;
R2 is selected from the formula:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRa, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R3 is selected from the formula:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, C1, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R5 is selected from:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R7 is selected from: C1-C10 alkyl, alkylaryl, and common prodrug derivatives
E is (CR8R9)mxe2x80x94Wxe2x80x94(CR8R9)n,
wherein W can be absent or selected from:
CH2, CO, O, S(O)m and NR10,
m is 0-2,
n is 0-2;
with the proviso that when W is O, S or NR10 then
m must not be 0;
R8 and R9 is independently selected from:
H,
C1-C8 alkyl substituted with 0-5 Rb,
C1-C8 alkenyl,
C1-C8 alkylaryl substituted with 0-5 Rb,
C3-13 carbocyclic residue substituted with 0-5 Rb,
5-14 membered heterocyclic system containing from
1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
amino,
C1-C8 alkyl-NR10
hydroxyl,
R8 and R9 can also form a ring interrupted by NR10, O, S(O)m.
R10 is selected from:
hydrogen,
C1-C8 alkyl
C1-C8 alkylaryl
J1, J2, J3, J4 are independently selected from:
CH, or N.
with no more than two N in the cycle.
[6] More preferred compounds of the present invention are compounds of the formula (III):
or a pharmaceutically acceptable salt form or a steroisomer thereof, wherein:
R1 is selected from:
xe2x80x94C(O)NHOH
and common prodrug derivatives;
R2 is selected from the formula:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R3 is selected from the formula:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H; a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R5 is selected from:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa,
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-1 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R8 and R9 is independently selected from:
H,
C1-C8 alkyl substituted with 0-5 Rb,
C1-C8 alkenyl,
C1-C8 alkylaryl substituted with 0-5 Rb,
C3-13 carbocyclic residue substituted with 0-5 Rb,
5-14 membered heterocyclic system containing from
1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
amino, C1-C8 alkyl-NR10
hydroxyl,
R8 and R9 can also form a ring interrupted by NR10, O, S(O)m.
R10 is selected from:
hydrogen,
C1-C8 alkyl
C1-C8 alkylaryl
J1, J2, J3, J4 are independently selected from:
CH, or N.
with no more than two N in the cycle.
[7] The more preferred compounds provided by this invention are compounds of the formula (IV):
or a pharmaceutically acceptable salt form or a steroisomer therof, wherein:
R2 is selected from the formula:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, 01-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRa, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R3 is selected from the formula:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R5 is selected from:
Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za
wherein:
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Y is absent or selected from H, O, NRa, S(O)p, and C(O);
Z is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
Ua is absent or is selected from: H, O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from H, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from H, O, NRa, S(O)p, and C(O);
Za is absent or selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rc;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaS(O)2Raxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R8 and R9 is independently selected from:
H,
C1-C8 alkyl substituted with 0-5 Rb,
C1-C8 alkenyl,
C1-C8 alkylaryl substituted with 0-5 Rb,
C3-13 carbocyclic residue substituted with 0-5 Rb,
5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-5 Rb;
amino, C1-C8 alkyl-NR10
hydroxyl,
R8 and R9 can also form a ring interrupted by NR10, O, S(O)m.
R10 is selected from:
hydrogen,
C1-C8 alkyl
C1-C8 alkylaryl
[8] Most preferred compounds of the present invention include compounds selected from the group consisting of:
N1-(2(R)-hydroxy-1(S)-indanyl)-N4-hydroxy-2(R)-isobutyl-butanediamide;
N1-(2(R)-hydroxy-1(S)-indanyl)-N4-hydroxy-2(R)-isobutyl-3(S)-(5-hydroxycarbonyl)-pentanamide;
N1-(2(R)-hydroxy-1(S)-indanyl)-N4-hydroxy-2(R)-isobutyl-3(S)-methyl-butanediamide;
N1-(2(R)-hydroxy-1(S)-indanyl)-N4-hydroxy-2(R)-isobutyl-3(S)-propyl-butanediamide;
N1-(2(R)-hydroxy-1(S)-indanyl)-N4-hydroxy-2(R)-hexyl-3(S)-propyl-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[4-hydroxy-phenyl)methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[4-methoxy-phenyl)methyl]butanediamide;
N1-[1(S)-indanyl]-N4-hydroxy-2(R)-[4-(hydroxy-phenyl)methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-phenyl-propyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(benzyloxy)-phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[3-(benzyloxy)-phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[4-(fluoro-phenyl)methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3,4-(methylenedioxy-phenyl)methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(methoxy-phenyl)methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(3-trifluoromethyl-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(2-tert-butylaminosulfonyl-phenyl)phenyl]methyl]-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(2-methoxy-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[(3-hydroxy-4-methoxy-phenyl)methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[3-(3-thiophene)isoxazoline]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(2-chloro-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(2-benzofuran)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(2-methyl-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[3,4-(methylenedioxy-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(2-tetrazole-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[3-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[3-methyl-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[4-(amino-phenyl)methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(benzyloxy-carbonyl)amino]phenyl)methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(2-hydroxymethlene)phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(3,4,5-trimethoxy-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(2,4-di-methoxy-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(3,5-di-chloro-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(2-trifluoromethyl-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(3-isopropyl-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(2,4-dichloro-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(3-chloro-4-fluoro-phenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(p-toluenesulfonyl-amino)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-phenylmethyl-3(S)-(tert-butyloxy-carbonyl-amino)-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(3,4-methylenedioxyphenyl)phenyl]methyl]-3(S)-(tert-butyloxy-carbonyl-amino)-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(3-methoxyphenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(3-fluorophenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(fluoro-phenyl)methyl]-3(S)-(tert-butyloxy-carbonyl-amino)-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(tert-butyloxy-carbonyl-amino)-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(3-nitrophenyl)phenyl]methyl]butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[[4-(3-(methylsulfonyl-amino)-phenyl)phenyl]methyl]-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(3-trimethylsilyl-propyl)-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2,2-dimethyl-propionamido)-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(ethyloxy-carbonyl-amino)-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(iso-butyloxy-carbonyl-amino)-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(propionamido)-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-methyl-cyclopropane carboxamido-1-yl)-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2,2-dimethylpropyl-amino)-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(methylsulfonyl-amino)-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-amino-butanediamide;
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[4-(methylsulfonylamino)-phenyl)methyl]-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(cyclobutane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-hydroxymethyl-isobutanamide)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-hydroxyl-cyclopropane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-phenyl-cyclopropane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(bezene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-cyano-cyclopropane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-phenyl-cyclopentane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-methyl-cyclohexane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-indole carboxamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-furan carboxamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-quinoline carboxamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(3,4,5-trimethoxy benzene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-methyl-3-amino-benzene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-methyl-6-amino-benzene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(3-pyridine carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-(2,4-dichloro-phenyl)-cyclopropane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-(4-chloro-phenyl)-cyclopropane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(3-methylsulfonyl)-benzene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-methylsulfonyl-benzene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(3-cyano-benzene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[(3-hydroxy-phenyl)methyl]-3(S)-(6-quinoline carboxamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[(3-hydroxy-phenyl)methyl]-3(S)-(1-ethyl, 3-methyl-pyrazole 5-carboxamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[(3-hydroxy-phenyl)methyl]-3-(4-morpholino-benzene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[(3-hydroxy-phenyl)methyl]-3(S)-(2-chloro-4-methylsulfonyl-benzene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[(3-hydroxy-phenyl)methyl]-3(S)-(4-(imidazol-1-yl)benzene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[(3-hydroxy-phenyl)methyl]-3(S)-(2-thiophene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[(3-hydroxy-phenyl)methyl]-3(S)-(1-tert-butyl, 3-methyl-pyrazole 5-carboxamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[(3-hydroxy-phenyl)methyl]-3(S)-(4-aminomethyl benzene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[(3-hydroxy-phenyl)methyl]-3(S)-(2-hydroxyl-isobutanamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(cyclopropane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(cyclopentane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-(3-(hydroxy-phenyl)methyl-3(S)-(2cyclopentyl acetamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(cyclohexane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(4-(4-N-Boc-piperazinyl-1-yl)benzene carboxamido-1-yl)butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(4-(piperazinyl-1-yl)benzene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-Fluoro-6-chloro-benzene carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-amino-cyclohexane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-methylthio-acetamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-methoxy-acetamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-allyl-cyclopentane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-n-propyl-cyclopentane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-allyl-cyclopropane carboxamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(8-quinoline-sulfonamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(4-nitro-benzene sulfonamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1,4-di-methyl-2-chloro-pyrazole-3-sulfonamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl-3(S)-(1,5-dimethyl-isooxazole-3-sulfonamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1-methyl-imidazole 3-sulfonamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(benzene sulfonamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(1,4-dimethyl pyrazole 3-sulfonamido)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-methylsulfonyl benzene sulfonamido-1-yl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(cyclohexylamino)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(iso-propylamino)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[4(2-trifluoromethylphenyl)-phenylmethyl]-3(S)-(2,2-dimethylpropyl-amino)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(cyclopentylamino)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(cyclopropylmethyl)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(benzylamino)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-furanmethylamino)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-4-methylphenyl)methyl]-3(S)-(3-cyanophenylmethylamino)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2,2-dimethylpropyl-amino)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-pentylamino)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(bis-cyclopropylmethyamino)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-thiophenemethylamino)-butanediamide
N1-[2(R)-hydroxy-1(S)-indanyl]-N4-hydroxy-2(R)-[3-(hydroxy-phenyl)methyl]-3(S)-(2-methyl-propylamino)-butanediamide
The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) as described herein.
The present invention also provides for treating an inflammatory disease in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) as described herein.
The present invention also provides a method for treating a condition or disease mediated by MMPs and/or TNF and/or aggrecanase in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) as described herein.
The present invention alsoprovides a method for treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, multiple sclerosis, or psoriasis in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) as described herein.
The present invention also provides a method for treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) as described herein.
In the following description a (xe2x88x92) symbolizes the point of attachment.
The novel compounds of the present invention may be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformation being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvents, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A series of compounds of formula 5 are prepared by the methods outlined in scheme 1. Coupling of carboxylic acid 1 with cis-(1S,2R-(xe2x88x92)-1-amino-2-indanol provided amide 2. The hydroxyl group of 2 was protected as the acetonide 3, followed by alkylation with tert-butyl 2-bromo-acetate to afford the desired diastereomer 4. Removal of the tert-butyl group of 4 with TFA in methylene chloride, followed by coupling with O-benzyl hydroxy amine, and hydrogenation afforded the target molecule 5.
Compounds of formula 5 can also be prepared by the methods outlined in scheme 2. The 2-substituted succinic acid 10 can be prepared using standard Evans chemistry. An acid 6 (X=OH) is converted to its oxazolidinone derivative 8 using the standard chemistry. Asymmetric alkylation, followed by hydrolysis using H2O2/LiOH afforded the desired acid 10. The mono-protected succinic acid was coupled to (1S, 2R)-(xe2x88x92) cis-1-amino-2-indanol using standard BOP, or other peptide coupling reagents such as DCC, EDAC, TBTU. The intermediate 11 can then be readily converted into the target compounds 5 using the similar procedures to that used for the synthesis of target 5 as described in scheme 1.
Compounds of formula 12 are prepared by the methods outlined in scheme 3. Dianion reaction of the intermidate 10 with an organic halides or triflates produces the 2,3-disubstituted succinate 13. The acid 13 was coupled with cis-(1S, 2R)-(xe2x88x92)-1-amino-2-indanol. Following similar procedures to that used for the synthesis of target 5 as described in scheme 1, compounds of formula 12 can be readily prepared.
Compounds of formula 19 are prepared as shown in scheme 4. The intermediate 15 prepared using the method described in scheme 3, was hydrogenated to produce 16. Compound 16 was then converted to the triflate 17. The Pd catalyzed Suzuki or stille cross coupling of triflate 17 with either a boronic acid or organostanane afford the coupling product 18. Using the standard chemistry as described in scheme 3, 18 can be easily converted to the compounds of formula 19.
Compounds of formula 20 are prepared as shown in scheme 5. Compound 21 prepared as described in scheme 2 can be hydrogenated to give the free amine 22. The free amino group can then be protected as sulfonamides, carbamates, and amides 23. Following similar chemistry to that described in scheme 1, compound 23 can be readily converted to the target of formula 20.
Compounds of formula 24 are prepared as shown in scheme 6. Starting from 22 prepared in scheme 5, the free amino group can be further functionalized to afford compound 28 by either palladium catalyzed aryl amination (Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron, 1996, 52, 7525-7546, Hartwig, J. F. Synlett, 1996, 329), or displacement with a substituted aryl fluoride. As described in the previous scheme 5, 28 can be easily converted to the final compound 24.
Compounds of formula 29 are prepared as shown in schemes 7-9.
The synthesis of substituted cis-1-amino-2-indanol (36) was followed by the route developed by Ghosh et al Ghosh, A. K.; Kincaid, J. F.; Haske, M. G. Synthesis, 1997, 541-544) The substituted indene (30) is converted to the epoxide 31 with MCPBA, or to the optically pure epoxide of 31 with Jacobsen""s highly enantioselective epoxidation catalysts (Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113, 7063-7064.). The epoxide 31 is converted to the alcohol 32 by treating it with NaN3. The racemic alcohol of 32 is resolved by Lipase P Sas described by Ghosh et al (Ghosh, A. K.; Kincaid, J. F.; Haske, M. G. Synthesis, 1997, 541-544). The azide of 33 was hydrogenated in the presence of O(CO2Et)2 to give 34. The compound 34 was then converted to final substituted cis-1-amino-2-indanol 36 first by mixing with SOCl2, followed by hydrolysis.
Alternatively, the substituted cis-1-amino-2-indanol 36 is directly prepared from substituted indene (30) following a method recently developed by Sharpless, K. B. et al as shown in scheme 8 (Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1996, 35, 2813). The cbz group of 38 was removed by hydrogenation to give the free amine 36.
Following a similar sequence, the compound 36 can then be readily converted to the final compound 29 as shown in scheme 9.
Compounds of formula 39 can be synthesized as shown in scheme 10. Following the method developed by Sudo and Saigo (Sudo, A.; Saigo, K. Tetrahedron Asymetry, 1996, 7, 2939-2956), the racemic cis-2-amino-1-indanol can be readily synthesized from substituted indanone 40 as outlined in scheme 9. The indanone can be readily converted into oxime 41 with butyl nitrile under acidic conditions. Reduction of 41 with NaBH4 in methanol could provide the hydroxy oxime, which was then treated with acetic anhydride and pyridine to give diacetate 42. Borane reduction of 42 then gives the racemic 43, which can then be directly used or resolved by co-crystalization with tartaric acid or others to provide the desired enantiomerically pure amine 43. Using similar chemistry to that used for the synthesis of target 5 as described in scheme 1, compound 44 can be readily converted to the target 39.
Compounds of formula 45 are synthesized as shown in scheme 11. The carboxylic group of commercially available aspartic acid was protected as methyl ester 47. Compound 47 was then treated with LiHMDS in THF at xe2x88x9278xc2x0 C. to form the enolate, which was reacted with benzyl bromide to afford 48. The benzyl group of 48 was removed by hydrogenation. The resulting acid was then coupled with cis-2-amino indanol to give 49. Hydrolysis of compound 49, followed by coupling with hydroxy amine to furnish the desired target 45.
Compounds of formula 50 are synthesized as shown in scheme 12. Compound 51 was prepared using the similar procedure to that used for the synthesis of compound 49 (see scheme 11). The amino protecting group of 51 was removed by TFA in methylene chloride. The free amino group was converted to its corresponding amide, carbamate and sulfonamide 53 using the standard chemistry. Hydrolysis of compound 53, followed by coupling with hydroxy amine to furnish the desired target 50.
Compounds of formula 56 are synthesized as shown in scheme 13. The amino TFA salt 54 can be prepared as described in scheme 11 and scheme 12. The reductive amination of 54 with either ketone or aldehyde under the reducing agent of NaBH(OAc)3 provided the desired alkyl amine 55. The, benzyl or methyl group of 55 was removed by either hydrogenation or hydrolysis. The resulting acid was then coupled with hydroxy amine to furnish the desired target 56.

Inhibitors of aggrecanase and matrix metalloproteinases for the treatment of arthritis