HRP960533A2 - Novel macrocyclic compounds as metalloprotease inhibitors - Google Patents

Description

Reference to previously filed patent applications

This patent application is a continuation-in-part of Pending US Patent Application Serial No. 60/006,684 filed November 14, 1995. The disclosure of the prior filed patent application is hereby incorporated by reference.

The field of technology

This invention relates to macrocyclic molecules that inhibit metalloproteinases, including aggrecanases and the formation of tumor necrosis factor (TNF), pharmaceutical compositions containing them, and their use as pharmaceutical agents. In particular, these compounds are inhibitors of ethaloproteinases involved in tissue breakdown and inhibitors of the release of tumor necrosis factor.

State of the art

There is now considerable evidence that metalloproteinases (MPs) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. It is a feature of many pathological conditions such as rheumatoid and osteoarthritis, corneal, epidermal and gastric ulcerations; tumor metastasis or invasion; periodontal diseases and bone diseases. Normally, these catabolic enzymes are tightly regulated at the level of their synthesis as well as at the level of extracellular activity through the action of various inhibitors, such as alpha-2-macroglobulin and TIMP (tissue inhibitor of metalloproteinase), which create inactive complexes with MP.

Osteo- and rheumatoid arthritis (that is, OA and RA) are diseases that destroy joint cartilage, and are characterized by localized erosion of the cartilage surface. Tests have shown that in the articular cartilage of the head of the femur of patients suffering from OA, for example, the incorporation of radiologically labeled sulfates is reduced compared to the control ones, which indicates that in OA there must be an increased degradation of the cartilage (Mankin et al. J. Bone Joint Surg 52A, 1970, 424–434). In mammalian cells, there are four classes of enzymes that break down proteins: serine-, cysteine-, asparto- and metalloproteinases. Available evidence supports that metalloproteinases are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. In OA cartilage, increased activities of collagenase and stromelysin were detected and this activity correlates with the severity of damage (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 enzymatic activity of metalloproteinases) has been identified to yield a specific proteoglycan cleavage product found in patients with RA and OA (Lohmander L.S. et al. Arthritis Rheum. 36,1993, 1214-22).

Therefore, metalloproteinases (MPs) have been implicated as key enzymes in the destruction of cartilage and bone in mammals. It can be expected that the pathogenesis of such diseases can be favorably modified by the administration of MP inhibitors, and many compounds have been proposed for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175–184, AP, San Diego, 1990). .

This invention describes macrocyclic molecules that inhibit aggrecanases and other metalloproteinases. These new molecules are therapeutic agents for the protection of the scrotum. Inhibition of aggrecanase and other metalloproteinases by these new molecules prevents these enzymes from destroying cartilage and thus alleviates the pathological conditions of osteo- and rheumatoid arthritis.

Tumor necrosis factor (TNF) is a cell-bound cytokine that converts from a 26kd precursor form to a 17kd active form. In humans and animals, TNF has been shown to be a primary mediator of inflammation, fever, and acute phase responses similar to those observed during acute infection or shock. Excessive amounts of TNF have been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can have a beneficial effect in a variety of conditions including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes mellitus (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).

Therefore, compounds that inhibit the formation of TNF are of therapeutic importance in the treatment of inflammatory disorders. Recently, it was shown that matrix metalloproteinases or a family of metalloproteinases, hereinafter also called TNF-convertases (TNF-C), as well as other MPs can convert TNF from its inactive to active form (Gearing et al. Nature, 1994, 370, 555) . This invention describes macrocyclic molecules that inhibit this conversion and thus the secretion of active TNF-α from cells. These new molecules enable therapeutic intervention for diseases including, but not limited to, septic shock, hemodynamic shock, septic syndrome, post-ischemic reperfusion injury, malaria, Crohn's disease, inflammatory bowel disease, mycobacterial infection, cachexia, graft rejection, cancer, diseases that they include angiogenesis, autoimmune diseases, inflammatory skin diseases, rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, HIV, and non-insulin-dependent diabetes mellitus.

Since excessive production of TNF has been observed in several disease states characterized by MMP-mediated tissue degradation, compounds that inhibit both MMP and TNF formation may also be particularly useful for diseases in which both mechanisms are present. .

There are several patents disclosing hydromasmate and carboxylate-based MMP inhibitors.

PCT International Publication no. WO 92/213260 describes N-carboxyalkylpeptidyl compounds of the general formula:

[image]

characterized by the fact that AA is an amino acid, as disease inhibitors whose mediator is matrix metalloproteinase.

PCT International Publication no. WO 92/13831 describes collagenase inhibitors based on hydrosamic acid with the general formula:

[image]

PCT International Publication no. WO 92/13831 describes related hydroxamic acids active in inhibiting collagenase with the general formula:

[image]

PCT International Publication no. WO 94/02446 describes metalloproteinase inhibitors which are natural amino acid derivatives of the general formula:

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WO95/09841 describes compounds which are hydroxamic acid derivatives and inhibitors of cytokine production.

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European patent application publication no. 574, 758 A1, describes hydroxamic acid derivatives as collagen inhibitors of the general formula:

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Gb 2 268 934 A and WO 94/24140 claim that hydroxamate inhibitors of MMP are inhibitors of TNF production.

The compounds of this invention act as inhibitors of MMPs, specifically aggrecanase and TNF-C, thereby preventing cartilage loss and destruction and inflammatory disorders involving TNF. Hydroxamic and carboxylic acids and derivatives are cyclic, and therefore non-peptidic in nature, which represents a significant advantage compared to existing inhibitors because they have superior pharmacokinetic parameters. Some of these molecules are water soluble and suitable for oral administration.

Presentation of the essence of the invention

This invention provides new hydroxamic acids and carboxylic acids and their derivatives of Formula (I) (described below) which are used as inhibitors of metalloproteinases, such as aggrecanase and TNF-C. This invention also includes pharmaceutical compositions containing these compounds of Formula (I) and methods of using these compounds in the treatment of arthritis and other previously described inflammatory disorders in a patient.

Also included in this invention are pharmaceutical kits containing one or more containers with pharmaceutical dosage units containing a compound of Formula (I) for the treatment of arthritis and other previously described inflammatory disorders.

The present invention also encompasses 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 secondary therapeutic agents selected from other metalloproteinase inhibitors, such as aggrecanase and TNF-C and/or therapeutic agents for the treatment of arthritis and inflammation.

Detailed description of the invention

This invention provides new hydroxamic acids and carboxylic acids and their derivatives of Formula (I) (described below) which are used as inhibitors of metalloproteinases, such as aggrecanase and TNF-C. The present invention also encompasses pharmaceutical compositions containing such compounds of Formula (I) and methods of administering such compounds for the treatment of arthritis and other previously described inflammatory disorders in a patient.

This invention also covers pharmaceutical kits with one or more containers containing pharmaceutical unit doses with the compound of Formula (I) for the treatment of arthritis and other previously described inflammatory disorders.

This invention also encompasses 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 secondary therapeutic agents selected from other metalloproteinase inhibitors, such as aggrecanase and tumor necrosis factor alpha and/ or therapeutic agents for the treatment of arthritis and inflammation.

In the description that follows (–) symbolizes the attachment point.

Formula I

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or pharmaceutically acceptable salts or prodrug forms characterized in that

U is selected from: –CO2H, –CONHOH, –CONHOR11, –SH, –NH–

COR11, –N(OH)COR11, –SN2H2R6, –SONHR6, CH2CO2H, PO(OH)2,

PO(OH)NHR6, CH2SH, –C(O)NHOR12, –CO2R12 and common prodrug derivatives;

R1 is selected from:

H,

–(CO–C6)alkyl–S(O)p–(C1–C6)alkyl,

–(CO–C6)alkyl–O–(C1–C6)alkyl,

–(CO–C6)alkyl–S(O)p–(CO–C6)alkyl–aryl,

–(CO–C6)alkyl–O–(CO–C6)alkyl–aryl,

alkyl of 1 to 20 carbon atoms including branched, cyclic and unsaturated

alkyl groups, substituted alkyl

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio, (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido,

–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–substituted aryl,

–(CO–C8)aryl–(C1–C4)alkyl–aryl,

–(C1–C8)alkyl–biaryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl,

–(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[S(O)p–(CO–C8)alkyl],

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–alkyl–biaryl,

–(CO–C8)alkyl–O–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl,

–(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[O–(CO–C8)alkyl],

–(CO–C8)alkyl–O–(CO–C8)alkyl–biaryl,

–(CO–C8)alkyl–O–(CO–C8)alkyl–substituted aryl,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl;

R2 is selected from H, –CO2R5, –CONR6R5, –CONR6(OR5),

-alkyl, -alkylaryl, -alkylheteroaryl,

-alkylheterocyclic compound, -aryl, -heteroaryl or

– a heterocyclic compound that has been replaced by one or more substituents

selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy;

R3 is selected from:

–H, –OH, –OR6 –NH2, –NHR6, –N(R6)2, –(C1–C6)alkyl,

-(C1-C6)alkyl-aryl, SR6, halide or nitrile;

Likewise, R2 and R3 can form a 3- or 8-membered saturated, unsaturated, aryl, heteroaryl or heterocyclic ring;

R4 is selected from:

H, –OH, –OR6, –NH2, –NHR6, –N(R6)2, –(C1–C6)alkyl,

-(C1-C6)alkyl-aryl, -S(O)p-(C1-C6)alkyl, halide or nitrile;

R5 is selected from:

–(CHR1Y)n–R9, –C(R7R8)n–W–C(R7R8)m–R9

–C(R7R8)m–R9, –C(R7R8)m–aryl,

–C(R7R8)m–CONR7R8,

-C(R7R8)m-substituted heteroaryl,

–C(R7R8)m–substituted heterocyclic compound,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl;

R6 is selected from:

H, alkyl, –(C1–C6)alkyl–aryl,

–(C1–C6)alkyl–heteroaryl,

–(C1–C6)alkyl–heterocyclic compound,

-(C1-C6)alkyl-acyl;

Likewise, R5 and R6 can form a 3- to 8-membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from -O, -NR6, -S(O)p, or an acyl group, optionally attached to an aryl ring ;

R7 and R8 can be independently selected from:

H, R1 or from a 3- to 7-membered substitution ring with unsaturated bonds 0-3,

indicated that the substitute is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl,

optionally contains –O–, –S(O)p, –NR6, optionally fused with substituted

aryl ring,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl;

R9 is H, alkyl, cycloalkyl 5- to 6-membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with –OH, –O-(C1–C6)alkyl, – O-alkyl-alkyl, NHR10 or aryl;

R 10 is H or an optionally substituted alkyl group;

R11 is hydrogen, alkyl of 1 to 10 atoms including branched, cyclic and unsaturated alkyl groups, substituted alkyl characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide,

–(C1–C4)alkyl–aryl,

–(C1–C4)alkyl–(C1–C8)alkyl–aryl,

–(C1–C8)alkyl–biaryl,

substituted –(C1–C8)alkyl–aryl,

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide;

R11a is H, –SO2–C1–C6–alkyl, –SO2–C1–C6–alkyl, substituted aryl, –SO2–aryl, –SO2– substituted heteroaryl, –COR9, –CO2t–Bu, –CO2Bn, or –alkyl –substituted aryl

characterized in that the substituent is selected from:

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl;

R12 is selected from: H, aryl, (C1 to C10)alkyl–, aryl (C1 to C6)alkyl–,

C3 to C11 cycloalkyl,

C3 to C10 alkylcarbonyloxyalkyl,

C3 to C10 Alkoxycarbonyloxyalkyl,

C2 to C10 Alkoxycarbonyl,

C5 to C10 cycloalkylcarbonyloxyalkyl,

C5 to C10 cycloalkoxycarbonyloxyalkyl,

C5 to C10 cycloalkyloxycarbonyl,

aryloxycarbonyl, aryloxycarbonyloxy (C1 to C6 alkyl)–,

arylcarbonyloxy (C1 to C6 alkyl)–,

C5 to C12 Alkoxyalkylcarbonyloxyalkyl,

[5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-oneyl*] methyl,

(5-aryl-1,3-dioxa-cyclopenten-2-one*-yl)methyl,

(R17) (R17a)N–(C1–C10 alkyl)–, CH(R13)OC(=O)R14,

–CH(R 13 )OC(=O)OR 15 , or

[image] ;

indicated by that

R13 is H or C1-C4 linear alkyl;

R14 is selected from:

H,

C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from:

C1-C4 alkyl,

C3-C8 cycloalkyl,

C1-C5 Alkoxy,

aryl substituted with 0 to 2 groups independently selected from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1),

aryl substituted with 0-2 groups independently selected from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1);

R15 is selected from:

C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from:

C1-C4 alkyl,

C3-C8 cycloalkyl,

C1-C5 Alkoxy,

aryl substituted with 0 to 2 groups independently selected from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S (C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1),

aryl substituted with 0-2 groups independently selected from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S (C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1);

R16 is C1-C4 alkyl, benzyl or phenyl,

R17 and R17a are independently selected from: H, C1-C10 alkyl, C2-C6 alkenyl, C4-C11 cycloalkylalkyl and aryl (C1-C6 alkyl);

Combinations of A, B and D, and/or variables are permitted only if such combinations result in stable compounds (as defined herein).

A may be omitted, –(CHR6)m–, –O(CHR6)m–, –NR6(CHR6)m–, –S(O)p(CHR6)m–, or selected from alkyl of 1 to 10 carbon atoms which include branched cyclic and unsaturated alkyl groups or -(C1-C6 )alkyl-aryl;

B can be a bond or selected from –NH–, –NR11–, –NR11a–, –O–,

–S(O)p–(C1–C6 )alkyl–NH–(C1–C6)alkyl–,

(C1–C6)alkyl–NR11–(C1–C6)alky–, – C1–C6–NH–aryl–,

–O–(C1–C6 )alkyl–, –(C1–C6 )alkyl–O–aryl–,

–S–(C1–C6 )alkyl–, –(C1–C6)alkyl–S–aryl–,

–(C1–C6) alkyl–, –(C1–C6) alkenyl–, –(C1–C6) alkynyl–,

–CONH–, –CONR11, –NHCO–, –NR11CO–, –OCO–, –COO–, –OCO2–,

–R11NCONR11–, HNCONH–, –OCONR11–, –NR11COO–, –HNSO2–,

–SO2NH–, aryl, cycloalkyl, heterocycloalkyl,

–R11NCSNR11–, –HNCSNH–, –OCSNR11–, –NR11CSO–, –HNCNNH–,

and mimic peptide bond;

[image]

D may be omitted or alkyl of 1 to 10 carbon atoms optionally containing O, S or NR6, which includes branched cyclic and unsaturated alkyl groups and aryl C1-C6 alkyl-;

p can be 0, 1 or 2;

m is the integral from 0 to 5;

n is the integral from 1 to 5;

W is –O–, –S(O)p– or –NR10–;

Y is selected from: –CONR10–, –NR10CO–, –SO2NR10–, NR10SO2–, mimetic peptide bond, 5-membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N, O or S,

provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–C(U)(R4)–, is linked to no less than 11 atoms and no more than 22 atoms when forming a ring.

[2] The subject of this invention are the compounds of formula (II):

Formula II

[image]

or pharmaceutically acceptable salts or prodrug forms, characterized in that;

X is selected from CH2, NH, NR5, S(O)p or O;

U, Y, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R11a, R12, R13, R14, R15, R16, R17, R17a and p, m, n, A, B , D and W are previously determined in formula I and defined as stable compounds;

provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–X–C(U)(R4)–, is linked to not less than 11 atoms and no more than 22 atoms when forming a ring.

[3] The subject of this invention are the compounds of formula (III):

Formula III

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U is selected from: –CO2H, –CONHOH, –CONHOR11, –SH, –NH–

COR11, –N(OH)COR11, –SN2H2R6, –SONHR6, CH2CO2H, PO(OH)2, PO(OH)NHR6, CH2SH, and common derivatives of prodrugs –C(O)NHOR12 and –CO2R12;

Z is selected from: N or CH;

R1, R4, R6, R11, R11a, R12, R13, R14, R15, R16, R17, R17a, A, B, C are previously determined in formula I and defined as stable compounds;

[4] Preferred compounds of this invention are compounds of formula I where;

Formula I

[image]

or pharmaceutically acceptable salts or prodrug forms characterized in that

U is selected from: –CONHOH, –CONHOR11, –N(OH)COR11,

–SN2H2R6, –SONHR6, –CO2H, –CH2SH, –C(O)NHOR12 and common prodrug derivatives;

R1 is selected from:

H,

–(CO–C6)alkyl–S(O)p–(C1–C6)alkyl,

–(CO–C6)alkyl–O–(C1–C6)alkyl,

–(CO–C6)alkyl–S(O)p–(CO–C6)alkyl–aryl,

–(CO–C6)alkyl–O–(CO–C6)alkyl–aryl,

alkyl of 1 to 20 carbon atoms including branched, cyclic and unsaturated

alkyl groups, substituted alkyl

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio, (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido,

–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–substituted aryl,

–(CO–C8)aryl–(C1–C4)alkyl–aryl,

–(C1–C8)alkyl–biaryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl,

–(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[S(O)p–(CO–C8)alkyl],

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–alkyl–biaryl,

–(CO–C8)alkyl–O–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl,

–(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[O–(CO–C8)alkyl],

–(CO–C8)alkyl–O–(CO–C8)alkyl–biaryl,

–(CO–C8)alkyl–O–(CO–C8)alkyl–substituted aryl,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl;

R2 is selected from H, –CO2R5, –CONR6R5, –CONR6(OR5),

-alkyl, -alkylaryl, -alkylheteroaryl,

-alkylheterocyclic compound, -aryl, -heteroaryl or

-a heterocyclic compound that is substituted with one or more substituents selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy;

R3 is selected from:

–H, –OH, and –NH2;

Likewise, R2 and R3 can form a 3- or 6-membered saturated, unsaturated, aryl, heteroaryl or heterocyclic ring;

R4 is selected from:

H, –OH, and –NH2;

R5 is selected from:

–(CHR1Y)n–R9, –C(R7R8)n–W–C(R7R8)m–R9

–C(R7R8)m–R9, –C(R7R8)m–aryl,

–C(R7R8)m–CONR7R8,

-C(R7R8)m-substituted heteroaryl,

–C(R7R8)m–substituted heterocyclic compound,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl;

R6 is selected from:

H, alkyl, –(C1–C6)alkyl–aryl,

–(C1–C6)alkyl–heteroaryl,

–(C1–C6)alkyl–heterocyclic compound,

-(C1-C6)alkyl-acyl;

Likewise, R5 and R6 can form a 3- to 8-membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from -O, -NR6, -S(O)p, or an acyl group, optionally attached to an aryl ring ;

R7 and R8 can be independently selected from:

H, R1 or from a 3- to 7-membered substitution ring with unsaturated bonds 0-3,

indicated that the substitute is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl,

optionally contains –O–, –S(O)p, –NR6, optionally fused with a substituted aryl ring,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl;

R9 is H, alkyl, cycloalkyl 5- to 6-membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with –OH, –O–(C1–C6)alkyl, – O-alkyl-alkyl, NHR10 or aryl;

R 10 is H or an optionally substituted alkyl group;

R11 is hydrogen, alkyl of 1 to 10 atoms including branched, cyclic and unsaturated alkyl groups, substituted alkyl

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide,

–(C1–C4)alkyl–aryl,

–(C1–C4)alkyl–(C1–C8)alkyl–aryl,

–(C1–C8)alkyl–biaryl,

substituted –(C1–C8)alkyl–aryl,

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide;

R11a is H, –SO2–C1–C6–alkyl, –SO2–C1–C6–alkyl–substituted aryl, –SO2–aryl, –SO2– substituted heteroaryl, –COR9, –CO2t–Bu, –CO2Bn or –alkyl– substituted aryl

characterized in that the substituent is selected from:

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl;

R12 is selected from: H, aryl, (C1 to C10)alkyl–, aryl (C1 to C6)alkyl–,

C3 to C11 cycloalkyl,

C3 to C10 alkylcarbonyloxyalkyl,

C3 to C10 Alkoxycarbonyloxyalkyl,

C2 to C10 Alkoxycarbonyl,

C5 to C10 cycloalkylcarbonyloxyalkyl,

C5 to C10 cycloalkoxycarbonyloxyalkyl,

C5 to C10 cycloalkyloxycarbonyl,

aryloxycarbonyl, aryloxycarbonyloxy (C1 to C6 alkyl)–, arylcarbonyloxy (C1 to C6 alkyl)–,

C5 to C12 Alkoxyalkylcarbonyloxyalkyl,

[5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-oneyl*] methyl,

(5-aryl-1,3-dioxa-cyclopenten-2-one*-yl)methyl,

(R17) (R17a)N–(C1–C10 alkyl)–, CH(R13)OC(=O)R14,

–CH(R 13 )OC(=O)OR 15 , or

[image] ;

indicated by that

R13 is H or C1-C4 linear alkyl;

R14 is selected from:

H,

C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from:

C1-C4 alkyl,

C3-C8 cycloalkyl,

C1-C5 Alkoxy,

aryl substituted with 0 to 2 groups

independently chosen from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a), –CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1),

aryl substituted with 0–2 groups independently

selected from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a), –CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1);

R15 is selected from:

C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from:

C1-C4 alkyl,

C3-C8 cycloalkyl,

C1-C5 Alkoxy,

aryl substituted with 0 to 2 groups

independently chosen from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S(C1–C5 alkyl), –S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a), –CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1),

aryl substituted with 0-2 groups independently selected from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S(C1–C5 alkyl), –S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a), –CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1);

R16 is C1-C4 alkyl, benzyl or phenyl,

R17 and R17a are independently selected from: H, C1-C10 alkyl, C2-C6 alkenyl, C4-C11 cycloalkylalkyl and aryl (C1-C6 alkyl);

Combinations of A, B and D, and/or variables are permitted only if such combinations result in stable compounds (as defined herein).

A may be omitted, –(CHR6)m–, –O(CHR6)m–, –NR6(CHR6)m–, –S(O)p(CHR6)m–, or

Selected from alkyl of 1 to 10 carbon atoms including branched cyclic and unsaturated alkyl groups or -(C1-C6 )alkyl-aryl;

B can be a bond or selected from –NH–, –NR11–, –NR11a–, –O–,

–S(O)p–(C1–C6 )alkyl–NH–(C1–C6)alkyl–,

(C1–C6)alkyl–NR11–(C1–C6)alky–, – C1–C6–NH–aryl–,

–O–(C1–C6 )alkyl–, –(C1–C6 )alkyl–O–aryl–,

–S–(C1–C6 )alkyl–, –(C1–C6)alkyl–S–aryl–,

–(C1–C6) alkyl–, –(C1–C6) alkenyl–, –(C1–C6) alkynyl–,

–CONH–, –CONR11, –NHCO–, –NR11CO–, –OCO–, –COO–, –OCO2–,

–R11NCONR11–, HNCONH–, –OCONR11–, –NR11COO–, –HNSO2–,

–SO2NH–, aryl, cycloalkyl, heterocycloalkyl,

–R11NCSNR11–, –HNCSNH–, –OCSNR11–, –NR11CSO–, –HNCNNH–,

and mimic peptide bond;

[image]

D may be omitted or alkyl of 1 to 10 carbon atoms which are po

optionally terminated with O, S or NR6, which includes branched, cyclic and unsaturated alkyl groups and C1-C6-alkyl-aryl;

p can be 0, 1 or 2;

m is the integral from 0 to 5;

n is the integral from 1 to 5;

W is –O–, –S(O)p– or –NR10–;

Y is selected from: –CONR10–, –NR10CO–, –SO2NR10–, NR10SO2–, mimic peptide bond,

5-membered saturated, unsaturated or partially unsaturated heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O or S,

provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–C(U)(R4)–, is connected to no less than 11 atoms and no more than 22 atoms when forming a ring.

[5] Preferred compounds of this invention are compounds of formula II where;

Formula II

[image]

or pharmaceutically acceptable salts or prodrug forms characterized in that

X is selected from CH 2 , NH, S or O;

U, Y, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R11a, R12, R13, R14, R15, R16, R17, R17a and p, m, n, A, B , D and W are previously determined in formula I and defined as stable compounds;

provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–X–C(U)(R4)–, is linked to not less than 11 atoms and no more than 22 atoms when forming a ring.

[6] More preferred compounds of this invention are compounds of formula I where,

Formula I

[image]

or pharmaceutically acceptable salts or prodrug forms characterized in that

U is selected from: –CONHOH, –C(O)NHOR12, –CO2H and common prodrug derivatives;

R1 is selected from:

H,

–(CO–C6)alkyl–S(O)p–(C1–C6)alkyl,

–(CO–C6)alkyl–O–(C1–C6)alkyl,

–(CO–C6)alkyl–S(O)p–(CO–C6)alkyl–aryl,

–(CO–C6)alkyl–O–(CO–C6)alkyl–aryl,

alkyl of 1 to 20 carbon atoms including branched, cyclic and unsaturated

alkyl groups, substituted alkyl

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio, (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido,

–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–substituted aryl,

–(CO–C8)aryl–(C1–C4)alkyl–aryl,

–(C1–C8)alkyl–biaryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl,

–(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[S(O)p–(CO–C8)alkyl],

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–alkyl–biaryl,

–(CO–C8)alkyl–O–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl,

–(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[O–(CO–C8)alkyl],

–(CO–C8)alkyl–O–(CO–C8)alkyl–biaryl,

–(CO–C8)alkyl–O–(CO–C8)alkyl–substituted aryl,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl;

R2 is selected from H, –CO2R5, –CONR6R5, –CONR6(OR5),

-alkyl, -alkylaryl, -alkylheteroaryl,

-alkylheterocyclic compound, -aryl, -heteroaryl or

-a heterocyclic compound that is substituted with one or more substituents selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy;

R 3 and R 4 are H;

R5 is selected from:

–(CHR1Y)n–R9, –C(R7R8)n–W–C(R7R8)m–R9

–C(R7R8)m–R9, –C(R7R8)m–aryl,

–C(R7R8)m–CONR7R8,

-C(R7R8)m-substituted heteroaryl,

–C(R7R8)m–substituted heterocyclic compound,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl;

R6 is selected from:

H, alkyl, –(C1–C6)alkyl–aryl,

–(C1–C6)alkyl–heteroaryl,

–(C1–C6)alkyl–heterocyclic compound,

-(C1-C6)alkyl-acyl;

Likewise, R5 and R6 can form a 3- to 8-membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from -O, -NR6, -S(O)p, or an acyl group, optionally attached to an aryl ring ;

R7 and R8 can be independently selected from:

H, R1 or from a 3- to 7-membered substitution ring with unsaturated bonds 0-3,

indicated that the substitute is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl,

optionally contains –O–,–S(O)p, –NR6, optionally fused with a substituted aryl ring,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl;

R9 is H, alkyl, cycloalkyl 5- to 6-membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with –OH, –O–(C1–C6)alkyl, – O-alkyl-alkyl, NHR10 or aryl;

R 10 is H or an optionally substituted alkyl group;

R 11 is hydrogen, alkyl of 1 to 6 C atoms including branched, cyclic and unsaturated alkyl groups, substituted alkyl;

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio) carboxy , carboxamido, carbo-alkoxy, or sulfonamide,

–(C1–C4)alkyl–aryl,

-(C1-C8)alkyl-substituted aryl,

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio) carboxy , carboxamido, carbo-alkoxy, or sulfonamide;

R11a is H, –SO2–C1–C6–alkyl, –SO2–C1–C6–alkyl– substituted aryl, –SO2–aryl, – SO2–substituted heteroaryl, –COR9, –CO2t–Bu, –CO2Bn,

characterized in that the substituent is selected from:

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy,

amino, mono-alkylamino, di-alkylamino, acylamino,

thio, thioalkyl, carboxy, carboxamido or aryl;

R12 is selected from: H, aryl, (C1 to C10)alkyl–, aryl (C1 to C6)alkyl–,

C3 to C11 cycloalkyl,

C3 to C10 alkylcarbonyloxyalkyl,

C3 to C10 Alkoxycarbonyloxyalkyl,

C2 to C10 Alkoxycarbonyl,

C5 to C10 cycloalkylcarbonyloxyalkyl,

C5 to C10 cycloalkoxycarbonyloxyalkyl,

C5 to C10 cycloalkyloxycarbonyl,

aryloxycarbonyl, aryloxycarbonyloxy (C1 to C6 alkyl)–, arylcarbonyloxy (C1 to C6 alkyl)–,

C5 to C12 Alkoxyalkylcarbonyloxyalkyl,

[5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-oneyl*] methyl,

(5-aryl-1,3-dioxa-cyclopenten-2-one*-yl)methyl,

(R17) (R17a)N–(C1–C10 alkyl)–, CH(R13)OC(=O)R14,

–CH(R 13 )OC(=O)OR 15 , or

[image] ;

indicated by that

R13 is H or C1-C4 linear alkyl;

R14 is selected from:

H,

C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from:

C1-C4 alkyl,

C3-C8 cycloalkyl,

C1-C5 Alkoxy,

aryl substituted with 0 to 2 groups

independently chosen from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1),

aryl substituted with 0–2 groups independently

selected from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1);

R15 is selected from:

C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from:

C1-C4 alkyl,

C3-C8 cycloalkyl,

C1-C5 Alkoxy,

aryl substituted with 0 to 2 groups

independently chosen from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S (C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1),

aryl substituted with 0–2 groups independently

chosen from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S (C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1);

R16 is C1-C4 alkyl, benzyl or phenyl,

R17 and R17a are independently selected from: H, C1-C10 alkyl, C2-C6 alkenyl, C4-C11 cycloalkylalkyl and aryl (C1-C6 alkyl);

Combinations of A, B and D, and/or variables are permitted only if such combinations result in stable compounds (as defined herein).

A may be omitted, –(CHR6)m–, –O(CHR6)m–, –NR6(CHR6)m–, –S(O)p(CHR6)m–, or selected from alkyl of 1 to 10 carbon atoms which include branched cyclic and unsaturated alkyl groups or -(C1-C6 )alkyl-aryl;

B can be a bond or selected from –NH–, –NR11–, –NR11a–, –O–,

–S(O)p–C1–C6alkyl–NH–C1–C6alkyl–,

C1–C6alkyl–NR11–C1–C6alky–, – C1–C6–NH–aryl–,

–O–C1–C6alkyl–, C1–C6alkyl–O–aryl–,

–S–C1–C6alkyl–, C1–C6alkyl–S–aryl–,

–C1–C6alkyl–, C1–C6alkenyl–, C1–C6alkynyl–,

–CONH–, –CONR11, –NHCO–, –NR11CO–, –OCO–, –COO–, –OCO2–,

–R11NCONR11–, HNCONH–, –OCONR11–, –NR11COO–, –HNSO2–,

–SO2NH–, aryl, cycloalkyl, heterocycloalkyl,

–R11NCSNR11–, –HNCSNH–, –OCSNR11–, –NR11CSO–, –HNCNNH–,

and mimic peptide bond;

[image]

D may be omitted or an alkyl of 1 to 6 carbon atoms which includes branched cyclic and unsaturated alkyl groups or -(C1-C6)alkyl-aryl;

p can be 0, 1 or 2;

m is the integral from 0 to 3;

n is the integral from 1 to 4;

W is –O–, –S(O)p– or –NR10–;

Y is selected from: –CONR10–, –NR10CO–, –SO2NR10–, NR10SO2–, mimetic peptide bond, 5-membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N, O or S,

provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–C(U)(R4)–, is linked to no less than 11 atoms and no more than 22 atoms when forming a ring.

Only substituents which form stable compounds can be used for formula I.

[7] More preferred compounds of this invention are compounds of formula II where,

Formula II

[image]

or pharmaceutically acceptable salts or prodrug forms characterized in that

X is selected from CH 2 , NH, S or O;

U was selected from; –CO2H, –CO2R12 and common prodrug derivatives;

Y, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R17a and p, m, n, A, B, D and W are previously determined in formula I and defined as stable compounds;

provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–X–C(U)(R4)–, is linked to not less than 11 atoms and no more than 22 atoms when forming a ring.

[8] More preferred compounds of this invention are compounds of formula I where,

Formula I

[image]

or pharmaceutically acceptable salts or prodrug forms characterized in that

U is selected from: –CONHOH, –C(O)NHOR12, –CO2H and common prodrug derivatives;

R1 is selected from:

H,

–(CO–C6)alkyl–S(O)p–(C1–C6)alkyl,

–(CO–C6)alkyl–O–(C1–C6)alkyl,

–(CO–C6)alkyl–S(O)p–(CO–C6)alkyl–aryl,

–(CO–C6)alkyl–O–(CO–C6)alkyl–aryl,

alkyl of 1 to 20 carbon atoms including branched, cyclic and unsaturated

alkyl groups, substituted alkyl

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio, (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido,

–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–substituted aryl,

–(CO–C8)aryl–(C1–C4)alkyl–aryl,

–(C1–C8)alkyl–biaryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl,

–(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[S(O)p–(CO–C8)alkyl],

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–alkyl–biaryl,

–(CO–C8)alkyl–O–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl,

–(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[O–(CO–C8)alkyl],

–(CO–C8)alkyl–O–(CO–C8)alkyl–biaryl,

–(CO–C8)alkyl–O–(CO–C8)alkyl–substituted aryl,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl;

R2 is selected from H, –CO2R5, –CONR6R5, –CONR6(OR5),

-alkyl, -alkylaryl, -alkylheteroaryl,

-alkylheterocyclic compound, -aryl, -heteroaryl or

-a heterocyclic compound that is substituted with one or more substituents selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy;

R 3 and R 4 are H;

R5 is selected from:

–(CHR1Y)n–R9, –C(R7R8)n–W–C(R7R8)m–R9

–C(R7R8)m–R9, –C(R7R8)m–aryl,

–C(R7R8)m–heteroaryl,

–C(R7R8)m–heterocyclic compound,

R6 is selected from:

H, alkyl, –(C1–C6)alkyl–aryl,

–(C1–C6)alkyl–heteroaryl,

–(C1–C6)alkyl–heterocyclic compound,

-(C1-C6)alkyl-acyl;

Likewise, R5 and R6 can form a 3- to 8-membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from -O, -NR6, -S(O)p, or an acyl group, optionally attached to an aryl ring ;

R7 and R8 can be independently selected from:

H, R1 or from a 3- to 7-membered substitution ring with unsaturated bonds 0-3,

indicated that the substitute is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl, optionally containing –O–,–S(O)p, – NR6 is optionally fused to a substituted aryl ring,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl;

R9 is H, alkyl, cycloalkyl, 5- to 6-membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with -OH, -O-(C1-C6)alkyl, -O-alkyl-alkyl, NHR10 or aryl;

R 10 is H or an optionally substituted alkyl group;

R 11 is hydrogen, alkyl of 1 to 6 C atoms including branched, cyclic and unsaturated alkyl groups, substituted lower alkyl;

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio) carboxy , carboxamido, carbo-alkoxy, or sulfonamide,

–(C1–C4)alkyl–aryl,

-(C1-C8)alkyl-substituted aryl,

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio) carboxy , carboxamido, carbo-alkoxy, or sulfonamide;

R11a is H, –SO2–(C1–C6)–alkyl, –SO2–(C1–C6)–alkyl substituted aryl, –SO2–aryl, –SO2– substituted heteroaryl, –COR9, –CO2t–Bu, –CO2Bn,

characterized in that the substituent is selected from:

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl;

R12 is selected from: H, aryl, (C1 to C10)alkyl–, aryl (C1 to C6)alkyl–,

C3 to C11 cycloalkyl,

C3 to C10 alkylcarbonyloxyalkyl,

C3 to C10 Alkoxycarbonyloxyalkyl,

C2 to C10 Alkoxycarbonyl,

C5 to C10 cycloalkylcarbonyloxyalkyl,

C5 to C10 cycloalkoxycarbonyloxyalkyl,

C5 to C10 cycloalkyloxycarbonyl,

aryloxycarbonyl, aryloxycarbonyloxy (C1 to C6 alkyl),

arylcarbonyloxy (C1 to C6 alkyl),

C5 to C12 Alkoxyalkylcarbonyloxyalkyl,

[5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl*] methyl,

(5-aryl-1,3-dioxa-cyclopenten-2-one*-yl)methyl,

(R17) (R17a)N–(C1–C10 alkyl)–, CH(R13)OC(=O)R14,

–CH(R 13 )OC(=O)OR 15 , or

[image] ;

indicated by that

R13 is H or C1-C4 linear alkyl;

R14 is selected from:

H,

C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from:

C1-C4 alkyl,

C3-C8 cycloalkyl,

C1-C5 Alkoxy,

aryl substituted with 0 to 2 groups independently selected from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1),

aryl substituted with 0–2 groups independently

selected from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1);

R15 is selected from:

C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from:

C1-C4 alkyl,

C3-C8 cycloalkyl,

C1-C5 Alkoxy,

aryl substituted with 0 to 2 groups independently

selected from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S (C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1),

aryl substituted with 0–2 groups independently

selected from:

halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy,

NO2, –S (C1–C5 alkyl),–S(=O)(C1–C5 alkyl),

–SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a,

–C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1);

R16 is C1-C4 alkyl, benzyl or phenyl,

Combinations of A, B and D, and/or variables are permitted only if such combinations result in stable compounds (as defined herein).

And it can be; –(CH2)m–, –O–(CH2)m–, –S–(CH2)m–, NR6–(CH2)m–;

B can be a bond or selected from –NH–, –NR11–, –NR11a–, –O–,

–S(O)p–C1–C6alkyl–NH–C1–C6alkyl–,

C1–C6alkyl–NR11–C1–C6alky–, – C1–C6–NH–aryl–,

–O–C1–C6alkyl–, C1–C6alkyl–O–aryl–,

–S–C1–C6alkyl–, C1–C6alkyl–S–aryl–,

–C1–C6alkyl–, C1–C6alkenyl–, C1–C6alkynyl–,

–CONH–, –CONR11, –NHCO–, –NR11CO–, –OCO–, –COO–, –OCO2–,

–R11NCONR11–, HNCONH–, –OCONR11–, –NR11COO–, –HNSO2–,

–SO2NH–, aryl, cycloalkyl, heterocycloalkyl,

–R11NCSNR11–, –HNCSNH–, –OCSNR11–, –NR11CSO–, –HNCNNH–,

and mimic peptide bond;

[image]

D is –(CH2)m–;

p can be 0, 1 or 2;

m is the integral from 0 to 3;

n is the integral from 1 to 4;

W is –O–, –S(O)p– or –NR10–;

Y is selected from: –CONR10–, –NR10CO–, –SO2NR10–, NR10SO2–, mimic peptide bond,

5-membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N, O or S,

provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–C(U)(R4)–, is linked to no less than 11 atoms and no more than 22 atoms when forming a ring.

Only substituents which form stable compounds are required for formula I.

[9] The most preferred compounds for this invention are compounds of formulas Ia, Ib, Ic and Id where,

Formula IV

[image]

or pharmaceutically acceptable salts or prodrug forms characterized in that

R1 is selected from:

H,

–(CO–C6)alkyl–S(O)p–(C1–C6)alkyl,

–(CO–C6)alkyl–O–(C1–C6)alkyl,

–(CO–C6)alkyl–S(O)p–(CO–C6)alkyl–aryl,

–(CO–C6)alkyl–O–(CO–C6)alkyl–aryl,

alkyl of 1 to 20 carbon atoms including branched, cyclic and unsaturated

alkyl groups, substituted alkyl

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio, (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido,

–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–substituted aryl,

–(CO–C8)aryl–(C1–C4)alkyl–aryl,

–(C1–C8)alkyl–biaryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl,

–(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[S(O)p–(CO–C8)alkyl],

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–alkyl–biaryl,

–(CO–C8)alkyl–O–(CO–C8)alkyl–aryl,

–(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl,

–(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[O–(CO–C8)alkyl],

–(CO–C8)alkyl–O–(CO–C8)alkyl–biaryl,

–(CO–C8)alkyl–O–(CO–C8)alkyl–substituted aryl,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl;

R2 is selected from H, –CO2R5, –CONR6R5, –CONR6(OR5),

-alkyl, -alkylaryl, -alkylheteroaryl,

-alkylheterocyclic compound, -aryl, -heteroaryl or

-a heterocyclic compound that is substituted with one or more substituents selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy;

R5 is selected from:

–(CHR1Y)n–R9, –C(R7R8)n–W–C(R7R8)m–R9

–C(R7R8)m–R9, –C(R7R8)m–aryl,

–C(R7R8)m–CONR7R8,

–C(R7R8)m–heteroaryl,

–C(R7R8)m–heterocyclic compound,

R6 is selected from:

H, alkyl, –(C1–C6)alkyl–aryl,

–(C1–C6)alkyl–heteroaryl,

–(C1–C6)alkyl–heterocyclic compound,

-(C1-C6)alkyl-acyl;

Likewise, R5 and R6 can form a 3- to 8-membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from -O, -NR6, -S(O)p, or an acyl group, optionally attached to an aryl ring ;

R7 and R8 can be independently selected from:

H, R1 or from a 3- to 7-membered substitution ring with unsaturated bonds 0-3,

indicated that the substitute is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl,

optionally contains –O–, –S(O)p, –NR6, optionally fused with substituted

aryl ring,

characterized in that the substituent is selected from;

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl;

R9 is H, alkyl, cycloalkyl, 5- to 6-membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with -OH, -O-(C1-C6)alkyl, -O-alkyl-alkyl, NHR10 or aryl;

R 10 is H or an optionally substituted alkyl group;

R 11 is hydrogen, alkyl of 1 to 6 C atoms including branched, cyclic and unsaturated alkyl groups, substituted lower alkyl;

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio) carboxy , carboxamido, carbo-alkoxy, or sulfonamide,

–(C1–C4)alkyl–aryl,

-(C1-C8)alkyl-substituted aryl,

characterized in that the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide;

R11a is H, –SO2–(C1–C6)alkyl, –SO2–(C1–C6)alkyl– substituted aryl, –SO2–aryl, –SO2–substituted heteroaryl, –COR9, –CO2t–Bu, –CO2Bn,

characterized in that the substituent is selected from:

hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl;

m is the integral from 0 to 3;

n is the integral from 1 to 4;

p can be 0, 1 or 2;

W is –O–, –S(O)p– or –NR10–;

Z is CH 2 or 0

Y is selected from: –CONR10–, –NR10CO–, –SO2NR10–, NR10SO2–, mimetic peptide bond, 5-membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N, O or S,

Only substituents which form stable compounds can be used for formula Ia to Id.

[10] Most preferred compounds of this invention include compounds of formula I, or a pharmaceutically acceptable salt or prodrug form, selected from the following:

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-methylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(carboxymethyl)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-benzylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(hydrodidimethyl)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-alanine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[L(O-methyl)tyrosine-N-methylamide]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[L-(O-tert-butyl)serine-N-methylamide)-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-serine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(glycine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(D-alanine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(beta-alanine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[D-(O-tert-butyl)serine-N-methylamide)-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(D-serine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-lysine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-valine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(2-pyridyl)ethylcarboxamido]-[10]paracyclophane-6-N-hydroxycarboxamide trifluoroacetate;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(4-methyl)piperazinylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(2-benzimidazolyl)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(2-imidazolyl)carboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(2-benzimidazolyl)methylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(3-imidazolyl)propylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[2-(4-aminosulfomylphenyl)ethylcarboxamido)-[10]paracyclophane-6-

N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(glycine-N,N-dimethylamide)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(1-adamantylcarboxamido)-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(4-aminoindazolyl)carboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N,N-diethylcarboxamido)-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-isopropylcarboxamido)-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-cyclopropylcarboxamido)-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-tert-butylcarboxamido)-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-isopropyl)amide]-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-ethyl)amide]-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-cyclopropyl)amide]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-tertbutyl)amide]-[10]paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-cyclobutyl)amide]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-morpholino)amide]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-2-hydrodidimethylethyl)amide]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-ethylmethylpropyl)amide]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-dimethylpropyl)amide]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S–3–aza–4–oxo–10–oxa–5–isobutyl–2–[glycine-(N–(di–2 hydroxymethyl)ethylamide]–[10]paracyclophane–6–N–

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(4-hydroxypiperidine)amide]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(2-������������benzimidazolecarboxamido-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[S-(methyl)-2-phenylmethylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

4S, 7R, 8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-(carboxymethyl)-[12]paracyclophane-8-N-hydroxycarboxamide;

4S, 7R, 8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-(N-methylcarboxamido)-[12]paracyclophane-8-N-

hydroxycarboxamide;

4S, 7R, 8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-(glycine-N-methylamide)-[12]paracyclophane-8-N-hydroxycarboxamide;

2S, 3R, 6S-10-t-butoxycarbonyl-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamido)-1-oxa-4-oxo-3-(3-phenylprop-1 -yl)cyclotetradecane;

2S, 3R, 6S-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamido)-1-oxa-4-oxo-3-(3-phenylprop-1-yl)cyclotetradecane hydrochloride;

2S, 3R, 6S-10-acetylyl-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamido)-1-oxa-4-oxo-3-(3-phenylprop-1-yl )cyclotetradecane;

2S, 3R, 6S-10-benzenesulfonyl-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamido)-1-oxa-4-oxo-3-(3-phenylprop-1-yl )cyclotetradecane;

2S, 3R, 6S,12(R,S)-10-acetyl-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamido)-12-methyl-1-oxa-4-oxo -3-(3-phenylprop-1-yl)cyclotridecane;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(carboxymethyl)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(hydroxycarboxyl)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-methoxyloxy)carbonyl]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-phenylethyloxy)carboxy]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(1-(n-methylcarboximido)methylcarboxyl]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-(N-methylaminosulfonyl)ethylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(4-(N-methylaminosulfonyl)butylcarboxamido]-[10]paracyclophane-6-N-hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-(N-methylaminosulfonyl)hexylcarboxamido]-[10]paracyclophane-6-N-hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(carbomethoxy)ethylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(hydroxycarbonyl)ethylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(L-ornithine(4-t-butoxycarbonyl)carboxymethyl]-[10]paracyclophane-6-N-hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-ornithinecarboxymethyl�-[10]paracyclophane-6-N-hydroxycarboxamide hydrochloride;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(L-ornithine(4-t-butoxycarbonyl)-N-methylamide]-[10]paracyclophane-6-N -hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-ornithine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide

hydrochloride;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-lysinecarboxamide)-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(L-serine(O-tert-butyl)-N-methylamide]-[10]paracyclophane-6-N –

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-alanine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(D-alanine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(glycine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(benzylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(phenylethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-dephenylethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-(2-pyridyl)ethylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-(4-sulfonylaminophenyl)ethylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-(3,4-dimethoxyphenyl)ethylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-(4-morpholino)ethylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(3-(4-morpholino)propylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide hydrochloride;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(3-(1-imidazolyl)propylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(3-(1-imidazolyl)propylcarboxamido]-[10]paracyclophane-6-N-

hydroxycarboxamide trifluoroacetate;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-cyclohexylcarboxamido)-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(4-methylpiperazin-1-ylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide;

2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(dimethylcarboxamido)-[10]paracyclophane-6-N-

hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-�N-methylcarboxamido]-cyclopentadecane-13-N-

hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[N-(2-pyridyl)methylcarboxamido]-cyclopentadecane-13-N-hydroxycarboxamide trifluoroacetate;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[2-(5-methylthiazolyl)carboxamido]-cyclopentadecane-13-N-hydroxycarboxamide ;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[(2-pyridyl)carboxamido]-cyclopentadecane-13-N-hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[(3-pyridyl)carboxamido]-cyclopentadecane-13-N-hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[(4-pyridyl)carboxamido]-cyclopentadecane-13-N-hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[4-(N-ethoxycarbonyl)piperidinecarboxamido]-

cyclopentadecane-13-N-hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[4-hydroxycyclohexylcarboxamido]-cyclopentadecane-13-N-hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-(glycine-N-methylamide)-cyclopentadecane-13-N-

hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-(glycine-N,N-dimethylamide�-cyclopentadecane-13-N-hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-glycine-2-pyridylamide)-cyclopentadecane-13-N-

hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-2-(3,4,5,6-tetrahydropyridyl)amide] –

cyclopentadecane-13-N-hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-N-(4-hydroxy)piperidinamide]-cyclopentadecane-13-N -hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-N-pyrrolidinamide]-cyclopentadecane-13-N-hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-N-morpholinoamide]-cyclopentadecane-13-N-hydroxycarboxamide;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-(4-methyl)N-piperazinylamide]-cyclopentadecane-13-N -hydroxycarboxamide trifluoroacetate;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-2-(5-methyl)thiazolylamide]-cyclopentadecane-13-N -hydroxycarboxamide trifluoroacetate;

2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[glycine-N-morpholinoamide]-cyclopentadecane-13-N-

hydroxycarboxamide;

2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide);

2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(glycine-N-methylamide)-11-(N-hydroxycarboxamide);

2S,11S,12R–1,7–diaza–8,13–dioxo–12–isobutylcyclotridecane–2–(Nε–H–L–lycine–α–N–H–amide trifluoroacetate)–11–(N–

hydroxycarboxamide);

2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-alanine-α -N-methyl amide)-11-(N-hydroxycarboxamide);

2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(β-alanine-N-methyl amide)-11-(N-hydroxycarboxamide);

2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-mesitylenesulfonyl-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide);

2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-t-butyloxycarbonyl-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide);

2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide) hydrogen chloride;

5S,8R,9S-6-aza-2,7-dioxo-5-(N-methylcarboxamido)-1-oxa-8-isobutylcyclotridecane-9-(N-hydroxycarboxamide);

2S,11S,12R-7-N-benzenesulfonyl-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-12-isobutylcyclotridecane-11-(N-

hydroxycarboxamide);

2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-(p-amino-N-benzenesulfonyl)-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide);

2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-trifluoromethanesulfonyl-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide);

2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-(N-methyl-imidazolesulfon-4-yl)-12-

isobutylcyclotridecane-11-(N-hydroxycarboxamide);

2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-norleucine-α-N-methyl amide)-11-(N-

hydroxycarboxamide);

2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-serine-α-N-methyl amide)-11-(N-hydroxycarboxamide);

2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(glycine-N-dimethyl amide)-11-(N-hydroxycarboxamide);

2S,11S,12R–1,7–diaza–8,13–dioxo–12(R)–isobutylcyclotridecane–2(S)–(glycine N–1,2–ethylenediamine–N'N'–dimethyl amide)–11 (S)–(N–hydroxycarboxamide);

2S, 11S, 12R-1,7-diazo-8, 13-dioxo-12-isobutylcyclotridecane-2-(glycine N-morpholine amide)-11-(N-hydroxycarboxamide);

2S, 11S, 12R-1,7-diazo-8, 13-dioxo-12-isobutylcyclotridecane-2-(L-leucine-a-N-methyl amide)-11-(N-hydroxycarboxamide);

2S, 11S, 12R-1,7-diazo-8, 13-dioxo-12-isobutylcyclotridecane-2-(L-threonine-a-N-methyl amide)-11-(N-hydroxycarboxamide);

The present invention has discovered that the above compounds can be used as inhibitors of metalloproteinases, including aggrecanase and TNF-C, and are useful in the treatment of rheumatoid arthritis, osteoarthritis and related inflammatory disorders, as previously described. These compounds inhibit the production of TNF in animal models and are useful in the treatment of TNF-mediated diseases.

The present invention also provides methods for the treatment of osteo- and rheumatoid arthritis and related disorders as described above by administering to a host a pharmaceutically or therapeutically effective or acceptable amount of a compound of Formula (I to IV) as described above. By a therapeutically effective amount, is meant the amount of the compound of this invention that has the effect of inhibiting the target enzyme or treating the symptoms of osteo- or rheumatoid arthritis or similar diseases, in the host.

The compounds of the present invention may also be administered in combination with one or more additional therapeutic agents. Administering the compounds of Formulas I-IV of the invention in combination with such an additional therapeutic agent can provide an efficient advantage over the compounds and agents themselves, even by enabling the use of smaller doses of individual ingredients. A lower dose reduces the possibility of side effects, thereby ensuring a higher margin of safety.

By "therapeutically effective amount" is meant the amount of a compound of Formulas I-IV which, when administered alone or in combination with an additional therapeutic agent to a cell or mammal, has the effect of inhibiting the target enzyme, thereby preventing or improving the state of an inflammatory disease or the progression of the disease.

By "administration in combination" or "combination therapy" is meant that a compound of Formulas I-IV and one or more therapeutic agents are administered simultaneously to a treated mammal. When given in combination, each ingredient can be given at the same time or one after the other in any order and at any time. Thus, each ingredient can be given separately but in a sufficiently short time interval to ensure the desired therapeutic effect.

By "stable compound" or "stable structure" is meant here a compound that is stable enough to withstand isolation to the required degree of purity from the reaction mixture, and formulation into an effective therapeutic agent.

When any variant appears more than once in any ingredient or in Formulas I-IV (or in any other formula herein), then its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if it turns out that a group is substituted with 0–2 R5, then said group can be arbitrarily substituted with up to two R5, and R5 is chosen at each occurrence independently from the defined list of possible R5. Also, combinations of substituents and/or variants are allowed only if such combinations result in a stable compound.

The compounds shown here may have asymmetric centers. Unless otherwise indicated, then all chiral, diastereomeric and racemic forms are encompassed by this invention. Many geometric isomers of olefins, C=N double bonds, and the like may also be present in the compounds described herein, and any such stable isomer is considered part of the present invention. It will be appreciated that the compounds of this invention may contain asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. The method of preparing optically active forms, such as resolution of racemic forms or synthesis, from optically active starting substances is well known in the art. All chiral, diastereomeric, racemic forms and all geometrically isomeric forms of the structure are applicable, unless the specific stereochemistry or isomeric form is specifically indicated.

When a bond for a substituent crosses over a bond connecting two atoms in a ring, then such a substituent can bond to any atom in the ring.

When a substituent is specified without noting through which atom such a substituent is attached to the rest of the compound of Formula I-IV, then such a substituent may be attached through any atom in such a substituent. For example, if the substituent is piperazinyl, piperidinyl, or tetrazolyl, the tetrazolyl group may be attached to the remainder of the compound of Formula I via any atom in such piperazinyl, piperidinyl, tetrazolyl group.

Combinations or substitutions and/or variants are allowed only if such combinations result in stable compounds. By stable compound or stable structure is meant here a compound stable enough to withstand isolation to the required degree of purity from the reaction mixture, and formulation into an effective therapeutic agent.

The term "substituted", as used herein, means that any one or more hydrogens on an indicated atom are replaced by an atom selected from the indicated group, provided that the normal valency of the indicated atom is not exceeded, and that the substitution results in a stable compound. When the substituent is keto (that is, =O), then two hydrogens on the atom are replaced.

As used herein, "alkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having a number of carbon atoms (eg, "C1-C10" means alkyl having 1 to 10 carbon atoms); additionally, lower alkyl means a branched and/or unbranched alkyl chain with 1 to 8 C atoms; "haloalkyl" would include both branched and straight-chain saturated aliphatic hydrocarbon groups with a certain number of carbon atoms, substituted by 1 or more halogens (for example –CvFw, where v=1 to 3 and w=1 to (2v + 1)); "Alkoxy" represents an alkyl group of the indicated number of carbon atoms connected via an oxygen bridge; "cycloalkyl" would include saturated ring groups, including mono-, bi- or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl; and "bicycloalkyl" should include saturated bicyclic ring groups such as (3.3.0) bicyclooctane, (4.3.0) bicyclononane, (4.4.0) bicyclodecane (decalin), (2.2.2) bicyclooctane, and so on. "Alkenyl" would mean hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that may occur at any stable point along the chain, such as ethenyl, propenyl, and the like; and "alkynyl" would mean hydrocarbon chains either straight or branched configuration and with one or more carbon-carbon triple bonds that can occur at any stable point along the chain, such as ethynyl, propynyl, and the like.

"Alkylcarbonyl" would mean an alkyl group of the indicated number of carbon atoms attached via a carbonyl group to the rest of the compound at the indicated position. "Alkylcarbonylamino" would mean an alkyl group of a certain number of carbon atoms attached via a carbonyl group to a nitrogen bridge, where the bridge is attached to the rest of the compound at the designated position. "Alkylcarbonyloxy" would represent an alkyl group of a certain number of carbon atoms attached to a carbonyl group, which is attached via an oxygen atom to the rest of the compound at the indicated position.

The terms "alkylene", "alkenylene", "phenylene" and the like refer to alkyl, alkenyl and phenyl groups, which are attached by two bonds to the rest of the structure of Formulas I-III. Thus, "alkylene", "alkenylene", "phenylene" and the like, may be denoted here differently and equivalently as "–(alkyl)–", "–(alkenyl)–", and "–(phenyl)–", and the like .

"Halo" or "halogen" refers herein to fluoro, chloro, bromo and iodo; and oppositely charged ion is used to mean a small, negatively charged ion such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

As used herein, the terms "carbocyclic" or "carbocyclic residue" or "carbocyclic ring system" mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or up to 26-membered polycyclic carbon ring, from any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyclics include, but are not limited to, the following compounds: cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the terms "aryl" or "aromatic radical" mean phenyl or naphthyl and also generally refer to "heterocyclic" or "heteroaryl" or "heterocyclic" compounds; the term "arylalkyl" represents an aryl group attached via an alkyl bridge.

The terms "heterocyclic" or "heteroaryl" or "heterocyclic" herein mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic ring which may be partially unsaturated, or aromatic, and which consists of carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen may be optionally quaternized, and including any bicyclic group in which any of the above heterocyclic rings is attached to benzene ring. A heterocyclic ring can be attached to its dependent group on any heteroatom or carbon atom resulting in a stable structure. The aromatic rings described here may be substituted on the carbon or nitrogen atom if the resulting compound is stable. Examples of aryl groups, but not all, are pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiaziniol, 2H,6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, 2H–pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H–indolyl, indolyl, 1H–indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, 4aH-carbazole, carbazole, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phen arsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are closed ring and spiro compounds containing, for example, the above heterocycles.

As used herein, the term "aryl" means a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic ring which may be partially unsaturated, or aromatic, and which consists of carbon atoms and 1 to 4 heteroatoms independently selected from a group with N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen optionally quaternized, and includes any bicyclic group in which any of the above heterocyclic rings is closed to a benzene ring. A heterocyclic ring can be attached to its dependent group on any heteroatom or carbon atom resulting in a stable structure. The aromatic rings described here may be substituted on the carbon or nitrogen atom if the resulting compound is stable. Examples of aryl groups, but not all, are pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiaziniol, 2H,6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, 2H–pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H–indolyl, indolyl, 1H–indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, 4aH-carbazole, carbazole, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phen arsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are closed ring and spiro compounds containing, for example, the above heterocycles.

The term "amino acid" here means an organic compound that contains both a basic amino group and an acidic carboxyl group. This term includes natural amino acids, modified and unusual amino acids, as well as amino acids that are known to occur biologically in free or combined form, but mostly not in proteins. This term includes both modified and unusual amino acids, such as the amino acids shown in, for example, the cited reference Roberts and Vellaccio (1983) The peptides, 5:342-429. Some, but not all, of the modified or unusual amino acids that can be practically used in the invention are the following: D-amino acids, hydroxylysine, 4-hydroxyproline, N-Cbz-protected amino acid, ornithine, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, β-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 term "amino acid residue" is used herein to mean the portion of an amino acid (as defined herein) present in a peptide.

The term "peptide" means herein a compound consisting of two or more amino acids (as defined herein) linked by a peptide bond. The term "peptide" also includes compounds containing both peptide and non-peptide moieties, such as pseudopeptide residues or residues that mimic peptides, or other non-amino acid moieties. Such a compound containing both peptide and non-peptide constituents may also be referred to as a "peptide analog".

The term "peptide bond" means a covalent amide bond formed by the loss of a water molecule between the carboxyl group of one amino acid and the amino group of another amino acid.

"Prodrugs" are considered to be all covalently bound carriers that release the active parent drug according to Formulas I-III in vivo, when such prodrug is administered to a mammalian subject. Prodrugs of Formula I-III compounds are prepared by modifying the functional groups present in the compounds so that the modifications are cleaved either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of Formulas I–IV where hydroxyl, amino, sulfhydryl, or carboxyl groups are attached to a group, which, when the prodrug is administered to a mammal, is cleaved so that a free hydroxyl, amino, sulfhydryl, or carboxyl group is formed. Some, but not all, of the examples of prodrugs are: acetate, formate and benzoate derivatives of alcohol and amino functional groups in compounds of Formulas I-IV, phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters of alcohol and phenolic functional groups in compounds of formula (I) and the like.

The term "pharmaceutically acceptable salt" used herein refers to the derivatives in the invention of the described compounds in which the parent compound of Formula I-IV has been modified by obtaining acid or alkaline salts of the compound of Formula I-IV. Some examples of pharmaceutically acceptable salts are: mineral or organic acid salts of alkaline residues such as amines; alkaline or organic salts of acidic residues such as carboxylic acids and the like.

Pharmaceutically acceptable salts of compounds of Formulas I-IV include conventional non-toxic salts, or quaternary ammonium salts of compounds of Formulas I-IV formed, for example, from non-toxic inorganic or organic acids. For example, such accepted non-toxic salts include those formed from inorganic acids such as hydrochloric, bromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactate (lactic), malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic , 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic acid, and the like.

Pharmaceutically acceptable salts of this invention can be synthesized by conventional chemical methods from compounds of Formulas I-III containing a basic or acidic region. Generally, salts are prepared by reacting free bases or acids with stoichiometric amounts or excess amounts of inorganic or organic acids or bases that form salts in a suitable solvent or various combinations of solvents.

Pharmaceutically acceptable salts of acids Formulas I-IV (are prepared) with a certain amount of alkali, such as alkali or alkaline earth metal hydroxides, i.e. sodium, potassium, lithium, calcium, or magnesium, or organic bases such as amines, i.e. dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.

According to the above, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acidic or alkaline forms of these compounds with a stoichiometric amount of a suitable alkali or acid, in water or in an organic solvent, or in a mixture of the two; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are generally preferred. A list of suitable salts can be found in the reference herein Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418.

SYNTHESIS

The compounds of this invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. The compounds of this invention may be synthesized by the methods described below, together with synthetic methods known in synthetic organic chemistry, or by variations of these methods, as will be appreciated by those skilled in the art. Some, but not all, of the preferred methods are described below. The mentioned references are given in the text as a whole.

The novel compounds of this invention can be prepared using the reactions and techniques described in this chapter. The reactions are carried out in solvents that correspond to the reagents and substances used, and are suitable for the chemical changes performed. Also, in the synthesis methods described below, it should be clear that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of experiments and working procedures, are chosen as standard conditions for that reaction, which the expert should immediately recognize. Any expert in the field of organic synthesis knows that the functionality present on different parts of the molecule must be coordinated with the proposed reagents and reactions. Thus, the restrictions of the substituents compatible with the reaction conditions will be immediately obvious to the expert and then other methods must be applied.

A series of compounds of formula 21 are prepared by the methods shown in Schemes 1–5. Deprotected 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine or lysine (compound 1, Scheme 1) are converted to the corresponding amide 2 using a coupling agent such as BOP.

Coupling 1 with diaminobenzene, followed by reaction in acetic acid at 60°C, produces the benzimidazole analog 3. 1 can also be converted to the aldehyde 4, which reacts with ammonia and the glyoxal trimer to give the imidazole analog 5. Deprotection of the Nα–Boc group with 2 , 3 and 5 using an acid eg 4N HCl in dioxane gives compound 6. Deprotection of the side chain of 2, 3 and 5 by hydrogenation gives compound 7.

Scheme 1

[image]

The synthesis of the 2,3-disubstituted moiety of succinic acid is described below in Scheme 2. The acid halide (ie, X=Cl) is converted to its oxazolidinone derivative 8 using n-butyl lithium. Evan's aldol reaction with glyoxylate (JACS, 1982, 104, 1737) converts 8 to intermediate 9. The oxazolidinone group is removed with H2O2/LiOH and the resulting carboxylic acid is converted to benzyl ester 11. Alkylation of 11 with t-butyl bromoacetate affords compound 12. Benzyl The ester of compound 12 is removed by hydrogenation to give 13. Removal of the t-butyl group of compound 12 gives 14.

Scheme 2

[image]

The formation of the macrocyclic ring of this series of compounds can be achieved via two synthetic routes as shown in Schemes 3 and 4. Coupling of intermediates 6 and 13 gives intermediate compound 15. Hydrogenation followed by acid deprotection gives compound 16. Cyclization of compound 16 using a coupling agent such as BOP gives the macrocyclic intermediate 17. Alternatively, compound 17 can be synthesized by coupling 7 and 14 followed by deprotection and cyclization as shown in Scheme 4. Saponification of compound 17 followed by reverse HPLC (chromatographic) separation gives the two isomers 20a and 20b. The final two products 21a and 21b are obtained by coupling 20a or 20b with O-benzylhydroxylamine hydrochloride and then hydrogenation.

Scheme 3

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Scheme 4

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Scheme 5

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Another series of compounds of formula 30 is synthesized as shown in Schemes 6 and 7. Acids protected on the side chain with trifluoroacetyl – 2,3-diaminopropionic acid, 2,3-diaminobutyric acid, ornithine or lysine 22 – are attached with an alkylamine followed by alkylation which gives 23a. Amino acid derivative 22 can also be converted to a methyl ester that is alkylated to form 24. Removal of the TFA group from 24 and then protection of the resulting amine with benzyl chloroformate gives compound 25. 25 can be converted to benzimidazole derivative 23b or imidazole derivative 23c. Removal of the TFA group from 23a using LiOH or Cbz group from 23b or 23c by hydrogenation gives intermediate 26.

The target compound 30 is obtained using the procedures described in Scheme 7, which are similar to those used for the synthesis of the first series of compounds 21 (Schemes 4–5 above).

Scheme 6

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Scheme 7

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A second series of compounds of formula 43 is prepared by the methods described in Schemes 8–9. Nα–Cbz–serine or homoserine is converted to the corresponding amide which is alkylated with ethyl bromoacetate to give compound 31. Other starting materials Nα–Boc–serine or homoserine are converted to the benzyl ester which is also alkylated with ethyl bromoacetate to give 32. Benzyl the ester of compound 32 is removed by hydrogenation to give 33, which is converted to benzimidazole derivative 34 or imidazole derivative 35. Deprotection of the Cbz group of compound 31 by hydrogenation or the Boc group of compound 34 or 35 with acid produces intermediate 36.

Scheme 8

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Scheme 9

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The synthesis of disubstituted succinic acid derivative 39 is shown in Scheme 9 above. Alkylation of compound 8 with t-butyl bromoacetate produces intermediate 37. The auxiliary group of compound 37 is removed and alkylation of the resulting acid 38 with bromoacetonitrile gives a mixture of two isomers 39. Coupling of 39 and 36 followed by hydrogenation and saponification gives 41. Cyclization is performed using BOP to give the bicyclic compound 42. The t-butyl group is removed using acid and the two isomers are separated by reverse HPLC. The carboxylic acid of each isomer is converted to the corresponding O-benzylhydroxamide and then hydrogenated to give the target products 43a and 43b.

A second series of compounds of formula 51 is prepared as indicated in Schemes 10-11 below. The reaction of cysteine or homocysteine with halo-nitrobenzene followed by treatment of the resulting intermediate with di-t-butyl dicarbonate gives Nα-Boc-S-2-nitrophenyl-cysteine or -homocysteine 44. 44 is converted into amide 46 or benzimidazole derivative 45. Deprotection of compounds 45 and 46 with acid to give intermediate 47.

Coupling of 47 with the acidic component 8 gives intermediate 48. The nitro group is reduced with zinc in acetic acid/water and the t-butyl group is removed using 4N HCl in dioxane. Macrocyclization of compound 49 using BOP gave two isomers 50a and 50b which were separated on a silica gel column. Saponification of each isomer followed by coupling with hydroxylamine produces the target products 51a and 51b.

Scheme 10

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Scheme 11

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A second series of compounds of formula 61 is synthesized by the methods described in Schemes 12–13.

The carboxylic acid of the side chain of benzyl ester of Nα–Boc–aspartic acid or benzyl ester of Nα–Boc–glutamic acid is reduced to alcohol using borane and the alcohol is converted to bromide using carbon tetrabromide and triphenylphosphine. The reaction of compound 53 with acetoxyphenol gives the intermediate compound 54. The benzyl ester is deprotected by hydrogenation and the resulting carboxylic acid is converted into an amide, benzimidazole or imidazole. Saponification of 56a–56c to remove the acetyl group, followed by treatment with 4N HCl in dioxane to remove the t -butyl group, afforded compound 57 .

Reaction of intermediate 38 with the triflate produces 58. Coupling of the acidic component 58 with 57 gives 59. The benzyl group of compound 59 is removed by hydrogenation and the resulting alcohol is converted to bromide using carbon tetrabromide and triphenylphosphine. The macrocyclization of the resulting intermediate is carried out with potassium carbonate to give cyclic product 60. The t-butyl group is deprotected with TFA and the resulting carboxylic acid is converted to hydroxamic acid by binding hydroxylamine to give target product 61.

Scheme 12

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Scheme 13

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Another series of compounds of formula 67b is prepared as shown in Scheme 14 below. The side chain of the aspartic acid or glutamic acid derivative is reduced to an alcohol which is converted to bromide 62. Reaction of 62 with sodium acetylide gives 63 which is converted to an amide, benzimidazole or imidazole derivative. 64 according to the above description.

Alkylation of compound 11 with bromoacetal, followed by acid treatment and reaction with hydroxylamine gives intermediate 65. Reaction of compound 65 with compound 64 using an oxidant (sodium hypochlorite) gives isoxazole derivative 66. Deprotection of the Boc group using acid and the Bn group by hydrogenation followed by cyclization using BOP gives the cyclic compound 67a. Saponification followed by coupling with hydroxylamine produced the target compound 67b.

Scheme 14

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Another series of compounds of formula 71 is synthesized as indicated in Scheme 15 below. Alkylation of intermediate 11 with a dihaloalkane gives 68.

Reaction of 68 with a tryptophan derivative gives 69. The Boc and Bn groups are deprotected and macrocyclization is performed with BOP to give the bicyclic compound 70. Saponification followed by coupling with hydroxylamine gives the target compounds 71a and 71b.

Scheme 15

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Compounds of formula 75 can be prepared as described in Scheme 16 below. Succinate 61 can be coupled with a tyrosine derivative with the help of BOP reagent to give amide 72. Deprotection of the benzyl ether under hydrogenation conditions gives the alcohol which can be converted to bromide 73. Macrocyclization affords compound 74. The tert-butyl ester is deprotected to the acid, which is converted to the benzyl-protected hydroxamic acid. The desired compound 75 is obtained after deprotection by hydrogenation.

Scheme 16

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Compounds of formula 79, can be prepared as described in Scheme 17 below. The succinate 61 can be coupled with a histidine derivative using the BOP reagent to give the amide 76. Deprotection of the benzyl carbamate and benzyl ether under hydrogenation conditions would give the alcohol which can be converted into bromide 77. Macrocyclization would give compound 78. The tert-butyl ester is deprotected to the acid which is converted to the benzyl-protected hydroxamic acid. The desired product 79 is obtained after deprotection by hydrogenation.

Scheme 17

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Compounds of formula 84, can be prepared as described in Scheme 18 below. The succinate 38 can be coupled with the enolate with LDA and alkylated with the triflate to give 80. This material is coupled with the phenylalanine derivative using the BOP reagent to give the amide 81. Deprotection of the benzyl groups under hydrogenation conditions gives amino acid 82. Macrocyclization will give compound 83. The tert-butyl ester is deprotected to an acid that is converted to a benzyl-protected hydroxamic acid. The desired product 84 is obtained after deprotection by hydrogenation.

Scheme 18

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Compounds of formula 98 can be prepared as described in Scheme 21 below. Succinate 38 can be enolated with LDA and alkylated with triflate to give 95. This material is coupled with a lysine derivative using BOP reagent to give amide 96. Deprotection of benzyl carbamate under conditions of hydrogenation and saponification of ethyl ester gives an amino acid. Macrocyclization gives compound 96. The tert-butyl ester is deprotected to the acid, which is converted into the benzyl-protected hydroxamic acid. The desired product 98 is obtained after deprotection by hydrogenation.

Scheme 21

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Compounds of formula 102 can be prepared as described in Scheme 22 below. Succinate 58 can be coupled with tryptophan using the BOP reagent to give amide 99. Deprotection of the benzyl group and conversion to the tosylate gives 100. Macrocyclization will give compound 101. The tert-butyl ester is deprotected to the acid, which is converted to the benzyl-protected hydroxamic acid. The desired product 102 is obtained after deprotection by hydrogenation.

Scheme 22

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Compounds of formula 108, can be prepared as described in Scheme 23 below. The imide 8 can be enolated with LDA and alkylated with triflate to give 103. Then the chiral auxiliary group is saponified in acid 104. As shown above, this material can be converted to the enolate with LDA and alkylated with triflate. The resulting 105 can be coupled with the tyrosine derivative using the BOP reagent to give the amide 106. Deprotection of the benzyl ether under hydrogenation conditions affords the alcohol, which is converted to the bromide. Macrocyclization gives compound 107. The tert-butyl ester is then deprotected to give the desired acid 108.

Scheme 23

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Scheme 24

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A second series of compounds of formula 131 was prepared by the procedure outlined in Schemes 25–27 below. Methyl 3S-4-benzyloxy-3-hydroxybutyrate (119) was prepared according to a previously published procedure (Abood, N.A. Synth. Commun. 1993, 23, 811). Stereoselective allylation of 119 with allyl bromide 120 gives compound 121. After hydrolysis of the ester, the resulting acid 122 is coupled with an appropriately functionalized lysine (123, n=2), ornithine (123, n=1) or 1,4-diaminobutyric acid (123, n = 0).

Reaction of 124 with E-1,4-dibromo-2-butene gives bromide 125.

After removal of the BOP group, macrocyclization is carried out using a mild alkali such as diisopropylethylamine. The obtained cyclic amine was pretreated with di-t-butyl dicarbonate in one vessel. Treatment of 127 with Pd(OH)2 under hydrogen leads to reduction of both olefinic bonds as well as cleavage of the benzyl ether. Oxidation of alcohol 128 and subsequent coupling with O–benzyl hydroxylamine gives 130. In this step, the R4 group is introduced by acid hydrolysis of the BOC group and reaction with R4–C1. Finally, hydrogenolysis gives 131.

Scheme 25

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Scheme 26

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Scheme 27

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A second series of compounds of formula 133 is prepared by the procedure indicated in Schemes 28 below. Reaction of alcohol 124 with sodium hydride and 3-bromo-2-bromomethyl-1-propene gives 132. 132 is converted to 133 following the alanogonal sequence shown in Schemes 26 and 27.

Scheme 28

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The present invention also encompasses cyclic hydroxamates as described in Scheme 29. In the first step, succinate 134 is coupled with L–lysine (Nε–Cbz)–NHMe to give amide 135. The primary alcohol of 135 is oxidized to acid 136 with RuCl3 •H2O. After removal of the carbamate group, macrocyclization affords lactam 138. The t-butyl ester of 138 is then converted to acid 139. This acid is coupled with BnONH H2O to afford the protected hydroxamate 140. Hydrogenation of 140 affords the target hydroxamate 141.

Scheme 29

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The present invention also encompasses compounds obtained by the procedures described in Scheme 30, which allow for simple variations of R3 from common intermediate 145a. In the first step, succinate 134 is coupled with L–lysine (Nε–Cbz)–CO2Me to give amide 142. The primary alcohol of 142 is oxidized to acid 143 with RuCl3•H2O. After removal of the carbamate group, macrocyclization affords lactam 144. The t -butyl ester of 144 is then converted to the capped hydroxamate 145 , according to our standard protocol. The methyl ester from 145 is hydrolyzed with LiOH. The resulting acid 145a is introduced into the process to give the desired R3. Hydrogenation of 146 affords the target hydroxamate 147 .

Scheme 30

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The present invention also encompasses cyclic amino carboxylates of Formula II, wherein U = –CO2H, R4 = H, X = –NH, R1 = alkylaryl, Y = –C(O)NH–, R2 = H, R3 = –C(O )NHMe, C = alkyl, B = –C(O)NH, A = alkyl. Scheme 31 describes how a compound of this type can be prepared from D-glutamic-N-Fmoc t-butyl ester or D-aspartate-N-Fmoc t-butyl ester via standard peptide chemistry. Standard BOP coupling of this material with 7 gives amide 148. The Fmoc group can be deprotected to primary amine 149, followed by alkylation with triphate to give secondary amine 150 (Kogan, T.P.; Somers, T.C.; Venuti, M.C. Tetrahedron 1990, 46, 6623).

Dual deprotection via hydrogenation gives amino acid 151, which can be cyclized to give macrolactam 152. Simple deprotection with TFA gives the desired, cyclic amino carboxylate 153.

Scheme 31

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The present invention also encompasses cyclic amino carboxylates of Formula II, wherein U = –CO 2 H, R 4 = H, X = –NH, R 1 = alkylaryl, Y = –NHC(O)–, R 2 = H, R 3 = –C(O) NHMe, C = alkyl, B = –C(O)NH, A = alkyl. Scheme 32 describes how a compound of this type can be prepared from D-lysine-F-Fmoc t-butyl ester or D-ornithine-N-Fmoc t-butyl ester via standard peptide chemistry. Standard BOP coupling of this material with L–glutamic–Nα–Cbz methyl ester or L–aspartate–Nα gives amide 154. Deprotection of the Fmoc group leads to primary amine 155. The primary amine can be alkylated as shown above with triflate to give the secondary amine 156.

Dual deprotection via hydrogenation gives amino acid 157. Macrocyclization can be carried out with BOP to give lactam 158. Saponification of 158 followed by standard coupling with BOP and methylamine gives amide 159. Simple deprotection with TFA gives cyclic amino carboxylate 160.

Scheme 32

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The present invention also encompasses cyclic amino carboxylates of Formula II, wherein U = –CO2H, R4 = H, X = –NH, R1 = alkylaryl, Y = –C(O)NH–, R2 = H, R3 = –C(O )NHMe, C = alkyl, B = C6H4CO2, A = alkyl. Scheme 33 describes how a compound of this type can be prepared from D-aspartate-N-Boc-(α)-t-butyl ester or D-glutamate-N-Boc-(α)-t-butyl ester via standard peptide chemistry. The β-acid is converted to aldehyde 161 by Weinreb chemistry (Wernic, D.; DiMaio, J.; Adams, J.J. Org. Chem. 1989, 54, 4224).

This material can be converted to olefin 162 via a Wittig 2 reaction with 4-carbomethoxybenzyltriphenylphosphonium bromide (Lancaster). The serine amide is coupled with 163 to give the ester 164. The Boc-protected amine of 164 is deprotected with HCl to give the primary amine 165. The primary amine can be alkylated as shown above with the triflate to give the secondary amine 166. Dual deprotection via hydrogenation gives amino acid 167. Macrocyclization can be carried out to give lactam 168. Simple deprotection with TFA gives cyclic amino carboxylate 169.

Scheme 33

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The present invention also encompasses cyclic amino carboxylates of Formula II, wherein U = –CO2H, R4 = H, X = –NH, R1 = alkylaryl, Y = –C(O)NH–, R2 = H, R3 = –C(O )NHMe, C = alkyl, B = –C6H4O–, A = alkyl. Scheme 34 describes how a compound of this type can be prepared from D-homoserine-N-Fmoc-(α)-t-butyl ester via standard peptide chemistry. A primary alcohol derived from serine can be coupled with a phenol derived from tyrosine via the Mitsunobu reaction to give 170 (Hughes, D.1. Org. React. 1992, 42, 335).

Fmoc is deprotected with Et2NH to give primary amine 171. As above, this primary amine is alkylated with triflate to give secondary amine 172. Dual deprotection gives amino acid 173. Macrocyclization of 173 with BOP gives lactam 174. Simple deprotection with TFA gives the desired amino carboxylate 175.

Scheme 34

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The present invention also encompasses cyclic amino carboxylates of Formula II, wherein U = –CO2H, R4 = H, X = –NH, R1 = alkylaryl, Y = –C(O)NH–, R2 = H, R3 = –C(O )NHMe, C = alkylCO2, B = –C(O)NH–, A = alkyl. Scheme 35 describes how a compound of this type can be prepared from L-glutamic-N-Cbz-(α)-methyl ester or L-aspartate-N-Cbz-(α)-methyl ester via standard peptide chemistry. This material can be coupled to 2–N–Boc–aminoethanol with DCC and DMAP to give ester 176. Manipulation of the functional groups leads to the acid and then the amide 177 according to standard chemistry. The Boc group of 177 is then removed with TFA to give 178. This material can be attached to D-glutamate-N-Fmoc-(α)-t-butyl ester or D-aspartate-N-Fmoc-(α)- t -butyl ester to give amide 179. The Fmoc is removed with diethylamine to give the primary amine 180. As shown above, this primary amine can be alkylated with the triflate to give 181. Hydrogenation and macrocyclization of this amino acid with BOP gives lactam 182. Simple deprotection with TFA gives the desired amino carboxylate 183.

Scheme 35

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The present invention also encompasses cyclic amino carboxylates of Formula II, wherein U = –CO 2 H, R 4 = H, X = NH, R 1 = alkylaryl, Y = –C(O)NH–, R 2 = H, R 3 = –C(O) NHMe, C = –alkyl, B = –NR–, A = alkyl. Scheme 36 describes how a compound of this type can be prepared from L-aspartate-N-Fmoc-(α)-t-butyl ester or L-glutamate-N-Fmoc-(α)-t-butylmethyl ester via standard peptide chemistry. As shown above, this acid can be converted 2 to aldehyde 184 using Weinreb chemistry. This aldehyde can undergo reductive amination with a lysine derivative to give amine 185. After pretreatment with (Boc)2O, the Fmoc is removed with diethylamine to give primary amine 185. As shown above, primary amine 185 can be alkylated with a triphate to give the secondary amine 188. Dual protection of the material via hydrogenation gives amino acid 189. Macrocyclization of this amino acid with BOP gives lactam 188. Simple deprotection with TFA gives the desired amino carboxylate 189.

Scheme 36

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Another series of compounds is synthesized as shown in Scheme 37. Succinate 134 is coupled with L–lysine(Nε–Mts)–NHMe to give amide 190. This material is cyclized under Mitsunobu conditions to give macrocycle 191. T The –butyl ester of 191 is converted to acid 192. This acid is coupled to H2NOBn with BOP to give the capped hydroxamate 21193. Hydrogenation of the benzyl group affords the target hydroxamate 194.

Scheme 37

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Another series of compounds is synthesized as shown in Scheme 38. Mesitylenesulfonamide 191 from Scheme 37 is converted to amine 195 with HBr.

Amine 195 reacts with BoC2O to give carbamate 196. The acid from 196 is coupled to H2NOBn with BOP to give the capped hydroxamate 197. This material is hydrogenated to give hydroxamate 198. The carbamate is then converted to amine 199 with HCl.

Scheme 38

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A second series of compounds of formula 205 is synthesized as shown in Scheme 39. Succinate 134 is coupled with L–glutamate (γ–CO2Bn) N–methyl amide to give amide 200. After removal of the benzyl, the compound is cyclized under Mitsunobu conditions to give 202 was obtained. The t-butyl ester of 202 is converted to acid 203. This acid is coupled with BnONH2 to give the protected hydroxamate 204. Hydrogenation of 204 gives the target hydroxamate 205.

Scheme 39

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The compounds of this invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. The compounds of this invention may be synthesized by the methods described below, together with synthetic methods known in synthetic organic chemistry, or by variations of these methods, as will be appreciated by those skilled in the art. Some, but not all, of the preferred methods are described below. The mentioned references are given in the text as a whole.

The novel compounds of this invention can be prepared using the reactions and techniques described in this chapter. The reactions are carried out in solvents that correspond to the reagents and substances used, and are suitable for the chemical changes performed. Also, in the synthesis methods described below, it should be clear that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of experiments and working procedures, are chosen as standard conditions for that reaction, which the expert should immediately recognize. Any expert in the field of organic synthesis knows that the functionality present on different parts of the molecule must be coordinated with the proposed reagents and reactions. Thus, the restrictions of the substituents compatible with the reaction conditions will be immediately obvious to the expert and then other methods must be applied.

Examples

Abbreviations used in the examples indicate the following: "1x" once, "2x" twice, "3x" three times, "bs" broad singlet, "°C" degrees Celsius, "Cbz" benzyloxycarbonyl, "d" doublet, "dd" doublet of doublets, "eq" equivalent or equivalents, "g" gram or grams, "mg" milligram or milligrams, "ml" milliliter or milliliters, "H" hydrogen or hydrogens, "1H" proton, "hr" hour or hours, "m" multiple, "M" molar, "min" minutes or minutes, "mp" melting point range, "MHz" megahertz, "MS" mass spectroscopy, "nmr" or "NMR" nuclear magnetic resonance spectroscopy, "t" triple, "tlc" thin layer chromatography, "v/v" volume and volume fraction, "α", "β", "R" and "S" are stereochemical designations known to those skilled in the art.

1(a) 3R-Allyl-3-t-butoxycarbonyl-2-(R)-isobutyl propanoic acid:

In a stirred, cooled (–78°C) solution of 20 grams (87 mmol) of 3-t-butoxycarbonyl-2(R)-isobutylpropanoic acid (1.15 g, 5 mmol) (which was previously mixed with toluene into an azeotropic mixture) in 400 ml of anhydrous THF, 180 mmol of LDA is added via cannula over 30 minutes. After stirring for 1 hour, 8.3 ml (96 mmol) of allyl bromide was added dropwise. The reaction is allowed to slowly warm to room temperature with stirring overnight. The reaction is stopped with 10% aqueous solution of citric acid, and then the vapors are removed under reduced pressure. The remaining material is taken up in ethyl acetate and washed with H 2 O. The aqueous phase is then extracted 3 times with ethyl acetate, and the combined organic fractions are washed with 10% citric acid, saturated NaHCO3 (2x), H2O (2x), and brine and dried over MgSO4. The solvent was removed under reduced pressure to give 23.3 grams (99% yield) which was carried on without purification. MS (M+Na)+ = 293

1(b) 3S-Allyl-3-t-butoxycarbonyl-2-(R)-isobutyl propanoic acid:

In a stirred, cooled (–78°C) solution of 2 grams of the acid from 1 (a) (which was previously aziotropically 2 times with benzene) in 25 ml of anhydrous THF, 16.3 mmol of LDA was added via a cannula over 15 minutes. The reaction was stirred for 15 minutes at –78°C and then for 15 minutes in a water bath at room temperature (24°C). The reaction is then cooled to -78°C for 15 minutes, after which 15.6 ml of 1M diethylaluminum chloride (hexane) is added. The reaction is stirred for 10 minutes at –78°C, 15 minutes in a water bath at room temperature, then again for 15 minutes at –78°C, and then stopped by the rapid addition of methanol. The reaction mixture is concentrated under reduced pressure to ~1/4 of its initial volume, and the obtained material is dissolved in 200 ml of ethyl acetate and washed with a mixture of 70 ml of 1N HCl and 100 grams of ice. The aqueous fraction is extracted twice with ethyl acetate. The combined organic fractions are washed with a solution of 3.5 grams of KF dissolved in 100 ml of water and 15 ml of 1 N HCl (pH 3–4). The organic phase is washed with salt water, dried over MgSO4, filtered and the solvent is removed under reduced pressure with a mass recovery of 92%. 1H NMR in acetone d–6 shows a ~8:1 ratio of anti- and syn-isomers. MS (M+Na)+ = 293

1(c) Benzyl 3S-Allyl-3-t-butoxycarbonyl-2-(R)-isobutylpropanoate:

To a stirred, cooled (0°C) solution of 20.6 grams (76 mmol) of unpurified balanced acid 1 (b) (8:1 mixture) in 75 ml of benzene, 11.4 ml (76 mmol) of DBU is added, then 9.98 ml (84 mmol) of benzyl bromide. After 10 minutes, the reaction is refluxed for 4 hours. The reaction is then diluted with ethyl acetate to three times the initial volume and washed three times with a 10% aqueous solution of citric acid. The combined aqueous fraction is extracted 3 times with ethyl acetate. The combined organic fractions are then washed with brine, dried over MgSO4 and the vapors removed under reduced pressure. The obtained material was chromatographed over silica gel eluting with 2.2% ethyl acetate/hexane to give 16.9 grams of benzyl ester (62% yield). MS (M+NH4)+ = 378

1(d) Benzyl 3S - (3-hydroxypropyl) -3- t - butoxycarbonyl-2(R)-isobutylpropanoate:

To a stirred, cooled (0°C) solution of 5.2 grams of olefin from 1(c) in 100 ml of anhydrous THF, 72.2 ml of 0.5M 9–BBN in THF was added over 1 hour. The reaction is allowed to cool at room temperature for 12 hours with stirring. The reaction is cooled to 0°C, and then 2.9 ml of H2O is added dropwise over 5 minutes (caution, the mixture foams). After another 20 minutes of mixing, 8 ml of H2O with 3.21 grams of NaOAc are added simultaneously with 8 ml of 30% H2O2 for five minutes. The mixture is stirred for another 20 minutes, and then the vapors are removed under reduced pressure. The remaining material is dissolved in ethyl acetate and washed with brine. The aqueous phase is extracted twice with ethyl acetate. The combined organic fractions are then washed with brine, dried over MgSO4 and the vapors removed under reduced pressure. The resulting material was chromatographed on silica gel with an elution gradient ranging from 1:20 to 1:10 to 1:5 ethyl acetate/hexane to give 3.5 grams (64% yield). MS (M+H) + = 379

1(e) Benzyl 3S-(3-bromopropyl)-3-t-butoxycarbonyl-2(R)-isobutylpropanoate:

A solution of 8.0 grams of alcohol from 1 (d ) dissolved in 60 ml of anhydrous CH2Cl2. The reaction is stirred for 30 minutes at 0°C and then 1/2 of the initial amount of triphenylphosphine, imidazole and carbon tetrabromide in 30 ml of CH2Cl2 is added all at once. The reaction is stirred for another 2.5 hours at 0°C, 20 minutes at room temperature (24°C), and then it is diluted with 320 ml of hexane and filtered through a small volume of silica gel, washing it with 25% ethyl acetate/hexane. The vapors were removed under reduced pressure and the resulting material was chromatographed on silica gel eluting with a gradient of 1-10% ethyl acetate/hexane to give 6.1 grams (65% yield) of bromide. M+H = 442.

1(f) 3S - (3-bromopropyl)-3-t-butoxycarbonyl-2-(R)-isobutylpropanoic acid:

1 g of 10% Pd–C is added to 10.5 grams of benzyl ester from 1(e) in 250 ml of methanol. The mixture is stirred under H2 (balloon) for 3 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give 8.3 grams of material.

M+H = 352.

1 (g) 3S– (3–bromopropyl)–3–t–butoxycarbonyl–2R–isobutylpropanoyl – [tyrosine–methylester]

5.5 g of tyrosine-methyl ester of hydrochloric acid and 9.1 ml of NMM are added to 8.4 g of acid in 200 ml of DMF. 9.52 g of TBTU dissolved in 120 ml of DMF is added to this mixture over 30 minutes. The reaction was stirred for 2 hours at room temperature, and then the vapors were removed under reduced pressure. The resulting mass is dissolved in ethyl acetate and washed with cold 1N HCl. The aqueous phase is extracted three times with ethyl acetate. The combined organic fraction was washed successively with H 2 O, saturated NaHCO 3 , H 2 O, brine and dried over MgSO 4 . The solvent is removed under reduced pressure and the resulting material is chromatographed on silica gel eluting with 25 to 33% ethyl acetate/hexane to give 9.5 grams (75% yield) of material and 2.35 grams of HOBt byproduct. The HOBT adduct is dissolved in 25 ml of DMF, and then 0.57 ml of NMM and 1.2 grams of tyrosine-methyl ester of hydrochloric acid are added to it. The reaction is heated to 60°C for 30 minutes, during which time 1.4 ml of NMM and 2.4 grams of ester are added, and then heated to 60°C for another 30 minutes. This was carried out analogously to the initial reaction giving 2.6 grams of additional product. M+H = 329.

1(h) 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(carboxymethyl)-[10] paracyclophane-6-t-butoxycarbonyl:

In a stirred, heated (60°C) suspension of 5.2 g of Cs2CO3 in 130 ml of anhydrous DMF and 32.5 ml of anhydrous DMSO, a solution of 3.25 g of bromide 1(g) dissolved in 25 ml of DMF was added for 15 minutes. The reaction is then heated for an additional 30 minutes at 80°C. After that, it is cooled in an ice bath and stopped with 10% aqueous citric acid. The vapors are removed under reduced pressure, and the resulting material is partitioned into ethyl acetate/H2O. The aqueous fraction is extracted 4 times with ethyl acetate, and the 5 extracts obtained are washed 4 times with H2O, once with salt water, dried over MgSO4, and then the vapors are removed under reduced pressure. The resulting material was chromatographed on silica gel eluting with 1.5% MeOH/CH2Cl2 to give 2.0 grams (74% yield) of the macroring. M+H = 448.

1(i) 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(carboxymethyl)-[10] paracyclophane-6-carboxylic acid:

To 0.77 g of t-butyl ester from 1(h), 25 ml of TFA is added. The reaction was stirred at room temperature for 1 hour. The TFA is removed under reduced pressure to give 0.67 grams of the acid. M+H = 392.

1(j) 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(carboxymethyl)-[10] paracyclophane-6-[N-(O-benzyl) carboxamide]:

0.75 g of HOBt, 2 ml of NMM, 0.81 g of O-benzylhydroxylamine hydrochloric acid and 1.06 g of EDC are added to 1.8 g of acid in 150 ml of CH2Cl2. The reaction is stirred for 3 hours at room temperature. TLC in 10% MeOH/CHCl 3 indicated the presence of the starting acid, so 50 mg of TBTU was added and the reaction was stirred for an additional 30 minutes. When TLC shows that the acid is consumed, the solvent is removed under reduced pressure, and 50 ml of DMF and 4.3 g of O-benzylhydroxylamine free base are added to the remaining material. The reaction is heated to 80 °C for one hour. The vapors are removed under reduced pressure, and the obtained material is dissolved in ethyl acetate and washed with 1N HCl, H2O, saturated aqueous NaHCO2, H2O, brine and dried over MgSO4. The vapors are then removed under reduced pressure to give a material slightly contaminated with the HOBT adduct as shown by 1 H NMR. The yellow solid was triturated in boiling Et2O and then filtered to give 2.18 g (95%) of a white solid.

or alternatively the binding described above can be performed using HATU;

3.37 ml of NMM, 5.24 g of HATU and 3.77 grams of O-benzylhydroxylamine are added to a solution of 2.4 g of acid in 75 ml of anhydrous DMF. After stirring overnight at room temperature, the reaction mixture is heated to 60°C for 30 minutes. After cooling under reduced pressure, vapors are removed, and the obtained material is dissolved in ethyl acetate and washed with 10% aqueous solution of citric acid. The organic fraction is extracted three times with ethyl acetate. The four combined organic extracts are washed 3 times with H2O, once with salt water, dried over MgSO4, and the vapors are removed under reduced pressure. The obtained material is quenched 4 times with a mixture of 1:1:2 ethyl acetate:hexane:ether to obtain 1.4 g of product. The mother liquor was concentrated and the resulting material was chromatographed on silica gel eluting with a gradient of 25–90% ethyl/acetate/hexane to give another 1.05 grams of product for a combined yield of 81%.

1(k) 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(carboxy)-[10] paracyclophane-6-[N-(O-benzyl)carboxamide]:

2.23 ml of a saturated aqueous solution of LiOH is added to 0.7 g of the methyl ester from 1(j) in 65 ml of THF and 15 ml of H2O. The reaction is stirred for 2 hours at room temperature and stopped with 10 ml of 1N HCl. Most of the solvent is removed under reduced pressure, diluted with ethyl acetate and washed with H2O and 20 ml of 1N HCL. The aqueous fraction is extracted 4 times with ethyl acetate. The combined ethyl acetate fractions were washed with H 2 O, brine, dried over MgSO 4 and the solvent was removed under reduced pressure to give 0.67 g (99% yield) of a white solid. M+H = 483.

Example 15: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(hydroxy methyl)-[10] paracyclophane-6-N-hydroxycaroxamide:

To a stirred, cooled (0°C) solution of 0.031 grams (0.064 mmol) of the acid in 2 ml of anhydrous THF is added 0.19 ml of 1M B2H6 in THF, and after 2 hours another 0.19 ml of 1M B2H6 is added. The reaction is left overnight to slowly warm to room temperature with stirring. Excess boron was stopped by adding dropwise H2O. The material was partitioned into EtOAc and H2O, separated, then the aqueous fraction was extracted 3 more times with EtoAc. All four extracts are combined and washed with H2O, brine, dried over MgSO4 and the vapors removed under reduced pressure. The obtained material is purified by preparative chromatography analogously to the previously described procedure, yielding 19 mg of material.

25 mg of 5% Pd/BaSO4 is added to 18 mg of alcohol in 10 ml of MeOH. The product is exposed to the cherry under 50 psi H2 for 4 hours, filtered and the vapors removed under reduced pressure to give 15 mg of hydroxamic acid. M+H = 379.

Example 20: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-[(3-imidazolyl)propylcarboxamido]-[10] paracyclophane-6-N-hydroxycarboxamide:

To a solution of 0.035 grams of acid in 2 ml of DMF, 0.024 ml of NMM, 17 ml of aminopropylimidazole and 0.30 grams of TBTU are added, stirred overnight at room temperature, and then heated to 80°C for 30 minutes. The vapors were removed under reduced pressure and the resulting material was purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl 3 to give 0.042 grams of product.

LRMS found (M+H)+ = 590

HPLC reverse phase 70–5% H2O /CH3CN (0.1% TFA) 30 minutes

ramp: RT = 4.96 minutes

0.065 grams of 5% Pd/BaSO4 is added to 0.040 grams in 10 ml of MeOH. The reaction was shaken at 50 psi for 6 hours, filtered and the resulting material was purified by reverse phase HPLC (90% to 30% H2O/CH3CN with 0.1 TFA over 45 minutes) to give 0.025 grams of hydroxamic acid.

LRMS found (M+H)+= 500.

Example 23: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(2-pyridyl-2-ethylcarboxamido)-[10] paracyclophane-6-N-hydroxycaroxamide:

0.020 ml of NMM, 10 ml of aminoethyl pyridine and 0.032 grams of TBTU are added to the stirred mixture of 0.037 grams of acid in 2 ml of CH2Cl2. The reaction is carried out in a manner analogous to that described above, yielding after purification 20 mg.

35 mg of 5% Pd/BaSO4 is added to 20 mg in 10 ml of MeOH. Shake for 4 hours under 50 psi H 2 , filter and evaporate under reduced pressure to give the material purified by reverse phase HPLC (90% to 30% H 2 O/CH 3 CN with 0.1 TFA for 30 min) to give 15 mg of hydroxamic acid as the TFA salt. . M+H = 497.

Example 27: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(4-methylpiperazinylcaroxamido)-[10]paracyclophane-6-N-hydroxycarboxamide:

0.016 ml of NMM and 14 ml of N-methylpiperazine are added to 0.030 grams of acid in 2 ml of CH2Cl2. The reaction proceeds in a manner analogous to that described above, yielding after purification 25 mg.

45 mg of 5% Pd/BaSO4 is added to 25 mg in 10 ml of MeOH. Shake for 4 hours under 50 psi H 2 , filter and evaporate under reduced pressure to give 15 mg of hydroxamic acid. M+H = 475.

Example 41: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(2-imidazolyl)-[10] paracyclophane-6-N-hydroxycarboxamide:

0.096 ml of NMM, 0.33 grams of 2-aminoimidazole and 0.053 grams of TBTU are added to a solution of 0.061 grams of acid in 4 ml of DMF, and it is stirred overnight at room temperature and then heated to 80 °C for 30 minutes. The vapors are removed under reduced pressure and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl 3 to give 0.018 grams of bound product.

0.020 gram of 5% Pd/BaSO4 is added to 0.015 gram in 5 ml of MeOH. The reaction was shaken at 50 psi for 6 hours, filtered and the resulting material was purified by reverse phase HPLC (90% to 30% H 2 O/CH 3 CN with 0.1 TFA over 30 minutes) to give 0.007 grams of hydroxamic acid as the TFA salt. M+H = 457.

Example 50: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(N- methylcarboxamido) - [10] paracyclophane-6-N-hydroxycarboxamide:

The N-methyl amide of 1(k) is prepared as described above to give 50(a).

To 0.139 grams of 50(a) in 14 mL of MeOH is added 0.19 grams of 5% Pd/BaSO4. The mixture is shaken for 2 hours under 45 psi H2 in a Parr flask during. The mixture was then filtered through a 0.45 PTFE membrane filter and the vapors were removed under reduced pressure to give 0.12 grams of a white solid. Melting point 350–352° (decomposes). M+H = 406.

Example 55: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(2-benzimidazolyl)-[10]paracyclophane-6-N-hydroxycarboxamide:

To a mixture of 0.050 grams of acid in 3 ml of CH2Cl2, 0.028 ml of NMM, 0.022 grams of phenylamine diamine and 0.043 grams of TBTU are added and mixed overnight at room temperature. The vapors are removed under reduced pressure and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl 3 to give 0.025 grams of product.

3 ml of HOAc is added to a solution of 0.022 grams of the above compound in 3 ml of THF. The reaction was refluxed for 1 hour, then the vapors were removed under reduced pressure to give 0.021 gram of the benzamidazole product.

0.035 gram of 5% Pd/BaSO4 is added to 0.020 gram in 10 ml of MeOH. The reaction was shaken at 50 psi for 4 hours, filtered, and the vapors were removed under reduced pressure to give 0.012 grams of product. M+H = 465.

Example 61: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(glycine-N-methylamide)-[10] paracyclophane-6-N-hydroxycarboxamide:

To a solution of 0.030 grams of acid in 2 ml of DMF, 0.030 ml of NMM, 0.015 grams of glycine-N-methylamide hydrochloride, and 0.026 grams of TBTU are added, stirred for 18 hours at room temperature, and then heated at 80°C for 15 minutes. The vapors are removed under reduced pressure and the resulting material is purified by preparative thin layer chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl 3 to give 0.030 grams of product.

0.035 gram of 5% Pd/BaSO4 is added to 0.025 gram in 10 ml of MeOH. The reaction was shaken at 50 psi for 6 hours, filtered, and the vapors were removed under reduced pressure to give 0.020 grams of product. M+H = 463.

Example 63: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-alanine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide:

0.034 ml of NMM and 17 mg of L-alanine methylamide of hydrochloric acid and 26 mg of TBTU are added to a mixed solution of 0.030 grams (0.062 mmol) of acid in 2 ml of CH2Cl2. The reaction was stirred overnight at room temperature. It is poured into a 10% aqueous solution of citric acid and extracted 3 times with CHCl3. All the CHCl3 is combined and washed with H2O, saturated aqueous NaHCO3, H2O, brine and dried over MgSO4. The vapors are removed under reduced pressure and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl 3 . The main fraction is removed, pulverized and washed with 150 ml of 10% MeOH/CHCl 3 to give 20 mg of the desired product.

30 mg of 5% Pd/BaSO4 is added to a solution of 20 mg of the above-mentioned compound in 10 ml of MeOH. This is then shaken at 50 psi for 4 hours, filtered and the vapors removed under reduced pressure to give 15 mg of the desired hydroxamic acid. M+H = 477.

Example 65: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(D-alanine-N-methylamido)-[10] paracyclophane-6-N-hydroxycarboxamide:

To a solution of 0.036 grams of acid in 2 ml of DMF, 0.037 ml of NMM, 0.021 grams of D-alanine N-methylamide and 0.031 grams of TBTU are added, stirred overnight at room temperature, and then heated to 80°C for 15 minutes. The vapors are removed under reduced pressure, and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl 3 to give 0.050 grams of bound product.

0.050 gram of 5% Pd/BaSO4 is added to 0.040 gram in 10 ml of MeOH. The reaction was shaken at 50 psi for 4 hours, filtered and the vapors removed under reduced pressure to give 0.029 grams of product. M+H = 477

Example 67: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-valine-N-methylcarboxamido)-[10] paracyclophane-6-N-hydroxycarboxamide:

To a solution of 0.036 grams of acid in 2 ml of DMF, 0.039 ml of NMM, 0.022 grams of L-valine-N-methylamide and 0.030 grams of TBTU are added, stirred overnight at room temperature, and then heated to 80°C for 30 minutes. The vapors are removed under reduced pressure, and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl 3 to give 0.038 grams of bound product.

0.050 gram of 5% Pd/BaSO4 is added to 0.035 gram in 10 ml of MeOH. The reaction was shaken at 50 psi for 6 hours, filtered and the vapors were removed under reduced pressure to give 0.030 grams of product. M+H = 505.

Example 70: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-(0-methyl)tyrosine -N-methylamido) - [10] paracyclophane-6-N -hydroxycarboxamide:

0.030 ml of NMM and 0.029 grams of O-methyltyrosine N-methylamide and 0.026 grams of TBTU are added to 0.030 grams (0.062 moles) of acid in 3 ml of DMF. The reaction is heated to 80°C for 20 minutes. The DMF was removed under reduced pressure and the resulting material was taken up in EtOAc and washed with 10% aqueous citric acid. The water was extracted three times with EtOAc, combined and washed with H 2 O, saturated NaHCO 3 , H 2 O, brine and dried over MgSO 4 , and the solvent was removed under reduced pressure to give 0.33 grams of product which was carried on without purification.

To 0.30 grams of the above product in 10 ml of MeOH is added 0.040 grams of 5% Pd/BaSO4. The reaction was shaken at 50 psi for 6 hours, filtered and the resulting material was purified by reverse phase HPLC (90% to 30% H 2 O/CH 3 CN with 0.1 TFA over 30 min) to give 19 mg of hydroxamic acid. M+H = 583.

Example 71: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-serine -N-methylamido) - [10] paracyclophane-6-N-hydroxycarboxamide:

3 ml of TFA is added to 0.025 grams of the t-butyl ether 75 described above. The reaction is stirred for 2 hours at room temperature. The vapors are removed under reduced pressure to give 0.020 grams of product. M+H = 493.

Example 72: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(beta-alanine-N-methylcarboxamido)-[10] paracyclophane-6-N-hydroxycarboxamide:

To a solution of 0.035 grams of acid in 2 ml of DMF, 0.039 ml of NMM, 0.020 grams of β-alanine-N-methylamide and 0.030 grams of TBTU are added, stirred overnight at room temperature, then heated to 80°C for 15 minutes. The vapors are removed under reduced pressure, and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl 3 to give 0.043 grams of bound product.

To 0.040 of the above product in 10 ml of MeOH is added 0.050 gram of 5% Pd/BaSO4. The reaction was shaken at 50 psi for 6 hours, filtered and the vapors were removed under reduced pressure to give 0.030 grams of product. M+H = 499.

Example 73: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(D-serine-N-methylamido) - [10] paracyclophane-6-N-hydroxycarboxamide:

3 ml of TFA is added to 0.020 grams of ether. The reaction is stirred for 2 hours at room temperature. The vapors are removed under reduced pressure to give 0.015 grams of product.

LRMS found (M+H)+ = 493, (M+Na)+ = 515.

HPLC reverse phase 90–20% H20/CH3CN (0.1% TFA) 30 minutes

ramp: RT = 11.67 minutes

Example 75: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-0-tertbutyl) serine -N-methylamide) - [10] paracyclophane-6-N- hydroxycarboxamide:

To a solution of 0.062 grams of acid in 3 ml of DMF, 0.035 ml of NMM, 0.045 grams of O-t-butyl serine-N-methylamide, and 0.054 grams of TBTU are added overnight at room temperature, then heated at 80°C for 15 minutes. The vapors are removed under reduced pressure, and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl 3 to give 0.080 grams of bound product.

To 0.075 grams of the above product in 10 ml of MeOH is added 0.100 grams of 5% Pd/BaSO4. The reaction was shaken at 50 psi for 4 hours, filtered, and the vapors were removed under reduced pressure to give 0.050 grams of product. M+H = 549.

Example 77: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-[D-(0-tert-butyl)serine-N-methylamide) - [10] paracyclophane-6 -N-hydroxycarboxamide:

To a solution of 0.035 grams of acid in 2 ml of DMF, 0.024 ml of NMM, 0.033 grams of O-t-butyl-D-serine-N-methylamide and 0.030 grams of TBTU are added overnight at room temperature, then heated to 80°C for 30 minutes. The vapors are removed under reduced pressure, and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 3% MeOH/CHCl 3 to give 0.040 grams of product.

0.050 gram of 5% Pd/BaSO4 is added to 0.035 gram in 10 ml of MeOH. The reaction was shaken at 50 psi for 6 hours, filtered and the vapors removed under reduced pressure to give 0.030 grams of product. M+H = 549.

Example 90: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-lysine-N-methylamide) - [10] paracyclophane-6-N-hydroxycarboxamide:

To a solution of 0.035 grams of acid in 2 ml of DMF, 0.024 ml of NMM, 0.035 grams of L-lysine-N-methylamide and 0.030 grams of TBTU are added overnight at room temperature, then heated to 80°C for 15 minutes. The vapors are removed under reduced pressure, and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl 3 to give 0.035 grams of bound product.

LRMS found (M+H)+ = 744, (M+Na)+ = 766.

0.040 gram of 5% Pd/BaSO4 is added to 0.030 gram in 10 ml of MeOH. The reaction was shaken at 50 psi for 6 hours, filtered and the vapors removed under reduced pressure to give 0.026 grams of product.

LRMS found (M+H)+ = 520

Example 95: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-benzyl carboxamido) - [10] paracyclophane-6-N-hydroxycarboxamide:

0.015 ml of NMM and 24 mg of TBTU are added to a thick solution of 0.030 grams (0.06 mmol) of acid in 2 ml of CH2Cl2. The reaction is stirred for 30 minutes, during which time 10 ml of benzyl amine is added and the reaction is stirred for 1 hour. The mixture is diluted with CHCl3 and washed once with 1N HCl and once with H20.

Both aqueous phases are combined and extracted 3 times with CHCl3. All 4 CHCl3 are combined and washed with H2O, saturated aqueous NaHCO3, water, brine and dried over MgSO4. The solvent is removed under reduced pressure to give 30 mg (85% yield) of benzyl amide. M+H = 572; M+Na = 594.

35 mg of 5% Pd/BaSO4 is added to 25 mg of the above product in 10 ml of MeOH. The mixture is shaken at 50 psi H2 for 5 hours. The reaction was filtered through a 0.45 mM PTFE membrane filter and the gases were removed under reduced pressure to give 15 mg of hydroxamic acid. M + H = 482.

Example 106: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-[2-(4-aminosulfonylphenyl) ethylcarboxamido] - [10] paracyclophane-6-N-hydroxycarboxamide:

To a solution of 0.035 grams of acid in 2 ml of DMF, 0.024 ml of NMM, 0.029 grams of (4 aminosulfonylphenyl) ethylamine and 0.030 grams of TBTU are added overnight at room temperature, then heated to 80°C for 15 minutes. The vapors are removed under reduced pressure, and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl3 and once with 10% MeOH/CHCl3 to give 0.040 grams of bound product.

LRMS found (M+H)+ = 665, (M+Na)+ = 687

HPLC reverse phase 70–5% H20/ CH3CN (0.1% TFA) 30 minutes

ramp: RT = 11.39 minutes

0.050 gram of 5% Pd/BaSO4 is added to 0.035 gram in 10 ml of MeOH. The reaction was shaken at 50 psi for 6 hours, filtered and the vapors were removed under reduced pressure to give 0.030 grams of product.

LRMS found (M+H)+ = 575, (M+Na)+ = 597

Example 107: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-[(2-benzimidazolyl)methylcarboxamido] - [10] paracyclophane-6-N-hydroxycarboxamide:

To a solution of 0.035 grams of acid in 2 ml of DMF, 0.024 ml of NMM, 0.021 grams of aminomethylbenzamidizole and 0.030 grams of TBTU are added overnight at room temperature, then heated to 80°C for 15 minutes. The vapors are removed under reduced pressure, and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl 3 to give 0.030 grams of product.

LRMS found (M+H)+ = 612.

HPLC reverse phase 90–20% H20/ CH3CN (0.1% TFA) 30 minutes

ramp: RT = 13.01 minutes

0.035 gram of 5% Pd/BaSO4 is added to 0.025 gram in 10 ml of MeOH. The reaction was shaken at 50 psi for 6 hours, filtered and the resulting material was purified by reverse phase HPLC (90% to 30% H 2 O/CH 3 CN with 0.1 TFA over 45 minutes) to give 0.020 grams of hydroxamic acid.

LRMS found (M+H)+ = 522.

Example 108: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-(2-benzimidazolecarboxamido) - [10] paracyclophane-6-N-hydroxycarboxamide:

To a solution of 0.035 grams of acid in 2 ml of DMF, 24 ml of NMM, 0.019 grams of aminobenzamidazole and 0.030 grams of TBTU are added overnight at room temperature, then heated to 80°C for 15 minutes. The vapors are removed under reduced pressure, and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) eluting twice with 5% MeOH/CHCl 3 to give 0.036 grams of product.

0.045 gram of 5% Pd/BaSO4 is added to 0.030 gram in 10 ml of MeOH. The reaction was shaken at 50 psi for 6 hours, filtered and the resulting material was purified by reverse phase HPLC (90% to 30% H 2 O/CH 3 CN with 0.1% FA over 45 minutes) to give 0.020 grams of hydroxamic acid.

M+H+ = 508.

120(a): 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(carboxymethyl) - [10] paracyclophane-6-N-benzyloxycarboxamide:

After the previously applied synthesis sequence 120(a) is prepared as a white solid. ESI–MS (M+H)+:: calcd 525.3, found 525.6.

Example 120: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(carboxymethyl)- [10] paracyclophane-6-N-hydroxycarboxamide:

Following a procedure analogous to that previously employed, hydrogenolysis of 120(a) (122.1 mg, 0.233 mmol) afforded the hydroxamate (102 mg, 100%). ESI–MS (M+H)+: calcd 435.3, found 435.3.

Example 126: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-((2-methoxyethyloxy)carboxyl)-[10]paracyclophane-6-N-hydroxycarboxamide:

Following a procedure analogous to that used previously, hydrogenolysis of 126(a) (50.6 mg, 0.089 mmol) afforded the hydroxamate 126 (42.6 mg, 100%). ESI–MS (M+H)+: calcd 479.3, found 479.4.

Example 126 (a): 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-((2-methoxyethyloxy)carboxyl)-[10]paracyclophane-6-N-benzyloxycarboxamide:

A solution of N,N'–dicyclohexylcarbodiimide in 1.0 N dichloromethane (0.2 mL, 1 equiv.) was added to a solution of 212 (a) (100.6 mg, 0.197 mmol), 2-methoxyethanol (0.020 mL, 1, 3 equiv.), 1-hydroxybenzotriazole hydrate (0.0266 g, 1 equiv.) in tetrahydrofuran (6 ml) at room temperature. After 20 hours at room temperature and 4 hours of reflux, the reaction mixture is quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4) and concentrated. Silica gel chromatography (methanol–dichloromethane, 2:98 then 4:96 then 6:94) afforded 126 (a) (51.2 mg, 46%) as a white solid. ESI–MS (M+H)+: calcd 569.4, found 569.5.

Example 128: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-( (2-phenylethyloxy)carboxy)- [10] paracyclophane- 6 -N-hydroxycarboxamide:

Following a procedure analogous to that used previously, 212 (a) (32.3 mg, 0.063 mmol) was reacted with 2-phenylethanol (9.3 mg, 1.2 equiv.) to give the desired bound product (34.6 mg, 89%). Then hydrogenolysis of the bound product (34.6 mg, 0.0563 mmol) gives the hydroxamate (26.0 mg, 88%). ESI–MS (M+H)+: calcd 525.3, found 525.4.

Example 129: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(dimethylcarboxamido)- [10] paracyclophane-6-N-hydroxycarboxamide:

Following a procedure analogous to that used previously, 212 (a) (40.8 mg, 0.0800 mmol) was reacted with hydrochloric acid dimethylamine (16 mg, 2.45 equiv.) to give the desired bound product (36.0 mg, 84%).

Then hydrogenolysis of the bound product (31.7 mg, 0.0590 mmol) gives the hydroxamate (26.2 mg, 99%). ESI–MS (M+H)+: calcd 448.3, found 448.5.

Example 132: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(1-(n-methylcarboxamido) methylcarboxyl)-[10] paracyclophane-6-N-hydroxycarboxamide:

Following a procedure analogous to that used previously, 212 (a) (32.9 mg, 0.0644800 mmol) was reacted with 2-hydroxy-N-methylacetamide (8.6 mg, 1.5 equiv.) to give the desired bound product (25.3 mg, 68%).

Then hydrogenolysis of the bound product (25.1 mg, 0.0431 mmol) gives the hydroxamate (21.1 mg, 99%). ESI–MS (M+H)+: calcd 429.3, found 429.4.

Example 139: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(3-(1-imidazolyl)propylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that employed previously, 212 (a) (97.2 mg, 0.190 mmol) was reacted with 1-(3-aminopropyl)imidazole (0.0273 mL, 1.2 equiv.) to give the desired bound product (96.0 mg, 82%).

Then hydrogenolysis of the bound product (92.9 mg, 0.150 mmol) gives the hydroxamate (76.0 mg, 96%). ESI–MS (M+H)+: calcd 528.3, found 528.5.

Example 139. TFA: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2- (3-(1-imidazolyl) propylcarboxamido)-[10] paracyclophane-6-N-hydroxycarboxamide trifluoroacetate

Trifluoroacetic acid (1 drop) was added to a suspension of 139 (38.5 mg, 0.0730 mmol) in dichloromethane (6 mL). After stirring at room temperature for several minutes, the homogeneous solution was concentrated to give 34 (48 mg, 100%) as a white solid. ESI–MS (M+H)+: calcd 528.3, found 528.6.

Example 142: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2- (2-(2-pyridyl)ethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (35.2 mg, 0.0689 mmol) was reacted with 2-(2-aminoethyl)pyridine (10.9 mg, 1.3 equiv.) to give desired bound product (36.1 mg, 85%).

Then hydrogenolysis of the bound product (35.8 mg, 0.0582 mmol) gives the hydroxamate (31.3 mg, 100%). ESI–MS (M+H)+: calcd 525.4, found 525.5.

Example 146: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(4-methylpiperazin-1-yl) - [10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (43.5 mg, 0.0852 mmol) was reacted with 1-methylpiperazine (0.0142 mL, 1.5 equiv.) to give the desired bound product (43 .5 mg, 86%). Then hydrogenolysis of the bound product (43.5 mg, 0.0734) gave the hydroxamate (38.2 mg, 99%). ESI–MS (M+H) + : calcd 503.3, found 503.6.

Example 156: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(N-methylaminosulfonyl)ethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (34.9 mg, 0.0683 mmol) was reacted with ethylenediamine (0.050 mL, 11 equiv.) and then methanesulfonyl chloride (0.145 mL, 27.5 equiv.) as the desired bound product would be obtained (35.6 mg, 83%).

Hydrogenolysis of the bound product (46.9 mg, 0.0743 mmol) afforded the hydroxamate (40.3 mg, 100%). ESI–MS (M+H)+: calcd 541.3, found 541.5.

Example 157: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2- (4-(N-methylaminosulfonyl)butylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that previously applied, 212 (a) (35.2 mg, 0.0689 mmol) was reacted with 1,4-diaminobutane (84.6 mg, 14 equiv.) and then methanesulfonyl chloride (0.186 ml, 35 equiv.) to give the desired bound product (24.2 mg, 53%). Then hydrogenolysis of the bound product (24.0 mg, 0.0364 mmol) gave the hydroxamate (20.0 mg, 97%). ESI–MS (M+H)+: calcd 569.3, found 569.5.

Example 158: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(cyclohexylcarboxamido)-[10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (40.8 mg, 0.0689 mmol) was reacted with cyclohexylamine (0.012 mL, 1.3 equiv.) to give the desired bound product (41.7 mg, 88%). Then hydrogenolysis of the bound product (35.4 mg, 0.0598 mmol) gives the hydroxamate (30.5 mg, 100%). ESI–MS (M+H)+: calcd 502.4, found 502.5.

Example 159: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2- (2-(N-methylaminosulfonyl) hexylcarboxamido)-[10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that previously applied, 212 (a) (35.2 mg, 0.0689 mmol) was reacted with 1,6-diaminohexane (89.6 mg, 11 equiv.) and then methanesulfonyl chloride (0.150 ml, 28 equiv.) to give the desired bound product (28.1 mg, 59%). Hydrogenolysis of the bound product (28.1 mg, 0.0409 mmol) afforded the hydroxamate (25.0 mg, 100%). ESI–MS (M+H)+: calcd 597.3, found 597.6.

Example 165: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(L-ornithine-N-methylamide)-[10] paracyclophane-6-N-hydroxycarboxamide hydrochloric acid

Hydroxamate 205 (25 mg, 0.0386 mmol) was treated with 4 N HCl in dioxane (1 mL) for 40 min and then concentrated to give the desired product (18.2 mg, 81%) as a white solid. . ESI–MS (M+H)+: calcd 548.4, found 548.5.

Example 169: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(methylcarboxamido) - [10] paracyclophane-6-N-hydroxycarboxamide

Following a sequence analogous to that used previously in the preparation of 50, 169 was synthesized as a white solid. ESI–MS (M+H)+: calcd 434.3, found 434.4.

Example 180: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(glycine-N-methylamide)-[10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (40.8 mg, 0.080 mmol) was reacted with glycine-N-methylamide hydrochloric acid (15.0 mg, 1.5 equiv.) to give the desired bound product (42.2 mg, 91%). Then hydrogenolysis of the bound product (33.1 mg, 0.057 mmol) gives the hydroxamate (27.1 mg, 97%). ESI–MS (M+H) + : calcd 491.3, found 491.5.

Example 182: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(L-alanine-N- methylamide) - [10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (40.8 mg, 0.080 mmol) was reacted with glycine-N-methylamide hydrochloric acid (12.2 mg, 1.5 equiv.) to give the desired bound product (40.9 mg, 86%). Then hydrogenolysis of the bound product (33.0 mg, 0.555 mmol) gave the hydroxamate (28.0 mg, 100%). ESI–MS (M+H)+: calcd 505.4, found 505.6.

Example 184: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(D-alanine-N- methylamide) - [10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that previously employed, 212 (a) (40.8 mg, 0.080 mmol) was reacted with D-alanine-N-methylamide (12.2 mg, 1.5 equiv.) to give the desired bound product (39.0 mg, 82%). Then hydrogenolysis of the bound product (32.0 mg, 0.054 mmol) gives the hydroxamate (27.9 mg, 100%). ESI–MS (M+H)+: calcd 505.4, found 505.5.

Example 194: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2- (L-serine (O-tert-butyl) -N- methylamide) - [10] paracyclophane-6 –N-hydroxycarboxamide

Following a procedure analogous to that previously applied, 212 (a) (81.6 mg, 0.160 mmol) was reacted with O-tert-butyl-L-serine-N-methylamide (41.8 mg, 1.5 equiv.) as the desired bound product (82.8 mg, 77.6%) would be obtained. Then hydrogenolysis of the bound product (76.0 mg, 0.114 mmol) gives the hydroxamate (66.7 mg, 100%). ESI–MS (M+H)+: calcd 577.4, found 577.6.

Example 199: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2- (2-(carbomethoxy)ethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (35.2 mg, 0.689 mmol) was reacted with hydrochloric acid methyl 3-aminopropionate (12.4 mg, 1.3 equiv.) to give the desired bound product ( 36.9 mg, 90%). Then hydrogenolysis of the bound product (36.9 mg, 0.0620 mmol) gave the hydroxamate (31.0 mg, 100%). ESI–MS (M+H)+: calcd 506.3, found 506.4.

Example 201: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2- (2-(hydroxycarbonyl) ethylcarboxamido) - [10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (35.2 mg, 0.0689 mmol) was reacted with benzyl 3-aminopropionate (31.5 mg, 1.3 equiv.) to give the desired bound product ( 40.6 mg, 90%). Then hydrogenolysis of the bound product (40.6 mg, 0.0617 mmol) gave the hydroxamate (30.5 mg, 100%) as a white solid. ESI–MS (M+H)+: calcd 492.3, found 492.3.

Example 203: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(L-orthnithine (4-butoxycarbonyl) carboxylmethyl) - [10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (50.2 mg, 0.0983 mmol) was reacted with Nδ–BOC–ornithine methyl ester of hydrochloric acid (36.2 mg, 1.3 equiv.) to give obtained the desired bound product (58.2 mg, 80%). Then hydrogenolysis of the bound product (28.0 mg, 0.0379 mmol) gave the hydroxamate (24.6 mg, 100%). ESI–MS (M+H)+: calcd 649.4, found 649.5.

Example 205: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(L-orthnithine (4-t-butoxycarbonyl)-N-methylamide)-[10]paracyclophane-6 –N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (60 mg, 0.118 mmol) was reacted with Nδ–BOC–ornithine N-methylamide hydrochloric acid (42.9 mg, 1.3 equiv.) to give the desired bound product (52.2 mg, 60%). Then, hydrogenolysis of the bound product (21.0 mg, 0.0285 mmol) gave the hydroxamate (18.6 mg, 100%). ESI–MS (M+H)+: calcd 648.4, found 648.6.

Example 207: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(L-orthnithinecarboxymethyl)-[10] paracyclophane-6-N-hydroxycarboxamide hydrochloric acid

The amide coupling product (31.1 mg, 0.0421 mmol) to give 203 was treated for 1 hour with a solution of 4 N HCl in dioxane (1 mL) to remove the BOC group. Then hydrogenolysis of the crude material gives the hydroxamate (24.8 mg, 100%). ESI–MS (M+H)+: calcd 549.4, found 549.5.

Example 209: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(L-lysinecarboxamide)-[10]paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (105.6 mg, 0.207 mmol) was reacted with Nε–Cbz–L–lysine amide hydrochloric acid (85.0 mg, 1.3 equiv.) to give desired bound product (130 mg, 82%). Then hydrogenolysis of the bound product (113.2 mg, 0.147 mmol) gives the hydroxamate (74.5 mg, 93%). ESI–MS (M+H)+: calcd 548.4, found 548.5.

Example 211: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(phenylethylcarboxamido)-[10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (44.6 mg, 0.0873 mmol) was reacted with phenylethylamine (0.0219 mg, 2 equiv.) to give the desired bound product (46.5 mg, 87%). Then hydrogenolysis of the bound product (46.5 mg, 0.0758 mmol) gives the hydroxamate (39.2 mg, 99%). ESI–MS (M+H)+: calcd 524.4, found 524.5.

Example 212: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(hydroxycarboxyl)-[10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that previously employed, hydrogenolysis of 212(a) (205 mg, 0.401 mmol) afforded the hydroxamate (168 mg, 99%). ESI–MS (M+H) + : calcd 421.3, found 421.4.

Example 212 (a): 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(hydroxycarboxyl)-[10] paracyclophane-6-N-benzyloxycarboxamide

Aqueous 1 N lithium hydroxide (7.5 mL, 4.23 eq) was added to a solution of 120 (a) (930 mg, 1.77 mmol) in tetrahydrofuran (20 mL) at 0°C. After 25 minutes at room temperature, the mixture is neutralized with 1 N hydrochloric acid and extracted with ethyl acetate (3 x 40 ml). The combined extracts were washed with brine, dried (MgSO 4 ) and concentrated to give 212 (a) (840 mg, 93%) as a white solid. ESI–MS (M+H)+: calcd 511.3, found 511.4.

Example 213: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2- (2-(3,4-dimethoxyphenyl)ethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (29.2 mg, 0.0572 mmol) was reacted with 2-(3,4-dimethoxyphenyl)ethylamine (14.7 mg, 1.2 equiv.) to give the desired bound product was obtained (31.8 mg, 83%). Then hydrogenolysis of the bound product (31.6 mg, 0.0469 mmol) gives the hydroxamate (24.6 mg, 90%). ESI–MS (M+H)+: calcd 584.4, found 584.6.

Example 214: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(benzylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (40.8 mg, 0.080 mmol) was reacted with benzylamine (0.0114 mg, 1.3 equiv.) to give the desired bound product (43.0 mg, 90%). Then hydrogenolysis of the bound product (33.0 mg, 0.055 mmol) gives the hydroxamate (28.2 mg, 100%). ESI–MS (M+H)+: calcd 510.3, found 510.5.

Example 215: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2- (2-(4-morpholine) ethylcarboxamide) - [10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (41.2 mg, 0.0807 mmol) was reacted with 4-(2-aminoethyl)morpholine (0.015 mL, 1.4 equiv.) to give the desired bound product (40.0 mg, 80%). Then hydrogenolysis of the bound product (39 mg, 0.0626 mmol) gives the hydroxamate (30.4 mg, 91%). ESI–MS (M+H)+: calcd 533.4, found 533.5.

Example 217: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(3-(4-morpholino)propylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide hydrochloric acid

Following a procedure analogous to that used previously, 212 (a) (44.4 mg, 0.0870 mmol) was reacted with 4-(3-aminopropyl)pyridine (0.0254 mL, 2 equiv.) to give the desired bound product (40.0 mg, 72%). Then hydrogenolysis of the bound product (40.0 mg, 0.0628 mmol) in the presence of hydrochloric acid (1 equiv.) gives the hydroxamate (34.2 mg, 93%). ESI–MS (M+H)+: calcd 547.4, found 547.5.

Example 224: 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(diphenylethylcarboxamido)-[10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that used previously, 212 (a) (29.8 mg, 0.0584 mmol) was reacted with 2,2-diphenylethylamine (11.5 mg, 1.2 equiv.) to give the desired bound product (32.2 mg, 80%). Then hydrogenolysis of the bound product (32.0 mg, 0.0464 mmol) gives the hydroxamate (27.6 mg, 100%). ESI–MS (M+H)+: calcd 600.4, found 600.6.

Example 225 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(4-sulfonylaminophenyl)ethylcarboxamido)-[10] paracyclophane-6-N-hydroxycarboxamide

Following a procedure analogous to that employed previously, 212 (a) (70.0 mg, 0.137 mmol) was reacted with 4-(2-aminoethyl)benzenesulfonamide (33.0 mg, 1.2 equiv.) to give the desired bound product (80.7 mg, 85%). Then hydrogenolysis of the bound product (76.6 mg, 0.111 mmol) gives the hydroxamate (65.4 mg, 98%). ESI–MS (M+H) + : calcd 603.3, found 603.6.

Example 710: 4S, 7R, 8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-(carboxymethyl)-[12]paracyclophane-8-N-hydroxycarboxamide

Synthesis of homo-homo tyrosine:

710(a) In a stirred, cooled (0°C) solution of 5.0 grams of 3-(4-benzyloxyphenyl) propanol in 100 ml of anhydrous CH2Cl2, 4.3 ml of triethylamine is added, and after ten minutes, 1.76 ml of methanesulfonyl chloride . The reaction was stirred for one hour and then poured into a saturated aqueous NaHCO3 solution. The aqueous fraction is extracted twice with CH2Cl2. All three CH2Cl2 are combined, washed with H2O, 10% aqueous citric acid solution, H2O, brine, dried over MgSO4 and the solvent is removed under reduced pressure to give a quantitative yield of the mesylate as a white solid.

LRMS M+H = 338

710 (b) 3.9 grams of NaI are added to the mesylate obtained above in 100 ml of acetone. After stirring overnight at room temperature, another 3.9 grams of NaI was added and the reaction was refluxed for 1 hour. The reaction mixture is filtered and the vapors are removed under reduced pressure. The solid, which immediately turns yellow, is dissolved in hexane and washed with H 2 O, twice with aqueous sodium thiosulfate, H 2 O, brine, dried over MgSO 4 and the solvent removed under reduced pressure to give 6.79 grams of iodide as a white solids.

LRMS M+H = 370

710 (c) In a stirred, cooled (–78°C) thick solution of 1.15 grams of LiCl (flame-dried in a vacuum vial) and 0.99 grams of Meyers reagent (Meyers et al. JACS, 1995, 117, 8488) , in 30 ml of anhydrous THF is added 8.7 ml of 1M LDA in THF/hexane over 10 minutes. The mixture is stirred for 20 minutes at –78°C and 30 minutes at 0°C, then 1.57 grams of iodide in 10 ml of anhydrous THF are added dropwise over 10 minutes. The reaction was allowed to slowly warm to room temperature overnight with stirring. It is stopped with a 10% aqueous solution of citric acid, and the vapors are removed under reduced pressure. The remaining material is dissolved in EtoAc, washed with H2O, 5% aqueous sodium thiosulfate solution, H2O, saturated aqueous NaHCO3 solution, H2O, brine, dried over MgSO4 and the solvent is removed under reduced pressure. The obtained material is chromatographed on silica gel eluting with 4:100 MeOH/CHCl3 giving 0.9 grams of product 710 (c)

LRMS M+H = 447.

Hydrolysis of pseudoephedrine amide:

710(d) To 3.5 grams of the alkylation product 710(c) in 40 ml of H2O and 25 ml of MeOH is added 15.7 ml of an aqueous solution of 1N in NaOH. The reaction was refluxed for 1 hour during which time another 25 ml of MeOH was added. The reaction is refluxed for another 3 hours, then the vapors are removed under reduced pressure. The solid was triturated with CH2Cl2 and filtered to give 5.5 grams of sodium hydroxide and the sodium salt of the product. The CH2Cl2 from the filtrate is removed under reduced pressure, and the remaining solid is triturated with Et2O to give another 1.1 grams of product 710 (d).

LRMS sM+H = 298

Formation of methyl ester:

710 (e) 3 ml of concentrated HCl is added to the NaOH and sodium salt described above in 150 ml of MeOH. The reaction is refluxed overnight, during which time the vapors are removed under reduced pressure, and the obtained material is taken up in EtOAc and washed with saturated aqueous NaHCO3, brine and dried over MgSO4. The vapors were removed under reduced pressure to give 2.4 grams of the methyl ester.

LRMS found (M+H)+ = 314

Binding of homo-homo tyrosine to the succinate fragment:

710 (f) To a stirred, cooled (0°C) solution of 0.90 grams of the acid in 20 ml of anhydrous DMF is added 0.79 grams of the amino acid methyl ester from 710 (e), 1.14 ml of NMM and 0.884 grams of TBTU. The reaction was stirred for 20 minutes at 0°C and 2 hours at room temperature. The reaction is diluted with 300 ml EtOAc and washed 5 times with 10% aqueous citric acid solution. All aqueous fractions are combined and extracted 5 times with EtoAc. All 6 organic fractions are combined and washed 5 times with saturated aqueous NaHCO3 solution, once with salt water and dried over MgSO4. The vapors are removed under reduced pressure, and the resulting material is chromatographed on silica gel eluting with a gradient of 15-20% EtoAc in hexane, yielding 1.2 grams of bound product.

LRMS M+H = 674.

710 (g) To a stirred solution of 1.2 grams of benzyl ether in 50 ml of MeOH is added 5 ml of acetic acid and 0.15 grams of black palladium as an IPA thick solution. The mixture is stirred under 1 ATM H2 for 3 hours. The catalyst was removed by filtration and the vapors were removed under reduced pressure to give 0.76 grams of deprotected product.

LRMS M+H = 494

710 (h) 0.89 grams of carbon tetrabromide and 0.70 g of triphenyl phosphine are added to a mixed solution of 0.40 grams of alcohol 710 (i) in 20 ml of anhydrous CH2Cl2. The reaction is stirred for 1 hour, then poured into a 10% aqueous solution of citric acid, separated and the aqueous fraction is extracted 3 times with CH2Cl2. All 4 CH2Cl2 fractions are combined and washed with H2O, brine and dried over MgSO4. The solvent was removed under reduced pressure and the resulting material was chromatographed on silica gel eluting with a gradient of 25-50% EtoAc in hexane to give 0.32 grams of bromide from 710 (h).

LRMS found (M+H)+ = 558.

710 (j) To a stirred, cooled (0°C) solution of 0.29 grams of bromide in 60 ml of anhydrous DMF, 0.21 grams of Cs2CO3 is added in one portion. After 2 hours of stirring, the mixture is poured into EtOAc and washed twice with 10% citric acid solution and extracted 5 times with EtOAc. All 6 EtOAc fractions are combined, washed with H 2 O, twice with brine and dried over MgSO 4 . The solvent was removed under reduced pressure and the resulting material was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 0.08 g (32% yield) of the macroring.

LRMS found (M+H)+= 498.

710 (k) To 0.150 grams of 710 (j) is added 5 ml of TFA. After 2 hours of stirring, the vapors are removed under reduced pressure to give 0.125 grams of acid.

LRMS (M+H)+ = 420.

710 (l) To a mixed solution of 0.073 grams from 710 (k) in 8 ml of anhydrous CH2Cl2, 0.024 grams of HOBT, 0.077 ml of NMM, 0.033 grams of O-benzylhydroxylamine hydrochloric acid and 0.43 grams of DEC are added. The reaction is stirred for 2 hours, then the vapors are removed under reduced pressure. 3 ml of anhydrous DMF and 0.16 grams of O-benzylhydroxylamine are added to the remaining material. The reaction is heated to 80°C for 45 minutes, then poured into EtOAc and washed 5 times with 10% aqueous citric acid solution. The combined aqueous fractions are extracted 5 times with EtoAc, and the 6 combined extracts are washed 2 times with H20, twice with salt water and dried over MgSO4. The material obtained is chromatographed on silica gel eluting with 3% MeOH/CHCl3 to give 0.079 grams of O-benzylhydroxamate.

Example 710: 4S, 7R, 8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-(carboxymethyl)-[12]paracyclophane-8-N-hydroxycarboxamide

25 mg of 5% Pd/BaSO4 is added to 10 mg in 5 ml of MeOH. Shake for 2 hours at 50 psi H 2 , filter and evaporate under reduced pressure to give 7 mg of hydroxamic acid.

LRMS found (M+H)+ = 435

759 (a) To 0.035 grams of the methyl ester from 710 (1) in 3 ml of THF and 1 ml of H2O is added 0.13 ml of a saturated aqueous solution of LiOH. The reaction is stirred for 4 hours at room temperature and stopped with 2 ml of 1N HCl. The mixture was diluted with EtOAc and acidified with 1N HCl and extracted three times with EtOAc. All three EtOAc fractions were combined and washed with H 2 O, brine, dried over MgSO 4 and the solvent was removed under reduced pressure to give 0.025 grams of acid.

LRMS found (M+H)+ =511; (M+Na)+ = 533

Example 759: 4S, 7R, 8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-(N-methylcarboxamido)-[12]paracyclophane-8-N-hydroxycarboxamide:

To a solution of 0.023 grams of the acid from 759 (a) in 1 ml of DMF, 15 ml of NMM and 0.016 grams of TBTU are added. After 5 minutes of mixing, 16 ml of 40% aqueous solution of MMA is added and the reaction is stirred for 15 minutes at room temperature, diluted with EtoAc and washed 4 times with 10% aqueous solution of citric acid. All 5 EtoAc fractions are combined and washed with H 2 O, brine and dried over MgSO 4 . The vapors are removed under reduced pressure and the resulting material is purified by preparative chromatography (1 mm by 0.25 mm concentration zone) single elution with 3% MeOH/CHCl 3 to give 0.011 grams of product.

LRMS found (M+H)+ = 524; (M+Na)+ = 546

30 mg of 5% Pd/BaSO4 is added to 11 mg in 10 ml of MeOH. Shake at 45 psi H 2 for three hours, filter and evaporate under reduced pressure to give 7 mg of hydroxamic acid from Example 759.

LRMS found (M+H)+=434

Example 869: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-0xa-14-isobutyl-7-methyl-2-(N-methylcarboxamido)-cyclopentadecane-13-N-hydroxycarboxamide

Example 869 (a). N-methylmorpholine (4, 4 ml, 40 mmol) and the mixture is stirred overnight at room temperature. The solvent was removed in vacuo and the residue was taken up in 200 ml of EtOAc. The solution is washed 3 times with brine, dried (MgSO4) and concentrated. Purification on a silica gel column using 10% EtoAc/hexane afforded the desired product (15.0 g, 91%) as a pale yellow solid. DCI–MS: calculated (M+NH4)+= 561; found 561.

869 (b). Potassium carbonate ( 15 g, 109 mmol) and the mixture is heated for 1 hour at 50°C. The insoluble material was filtered off and EtOAc was added. The solution is washed with 10% citric acid, brine, NaHCO3 and brine, dried (MgSO4) and concentrated. Purification on a silica gel column using 15% EtoAc/hexane gave an oily product (17.0 g, 91%). ESI–MS: calculated M+1=713.5; found 713.7

869 (c).869 (b) (10.0 g, 14.02 mmol) was dissolved in 30 ml of MeOH and the solution was hydrogenated for 1 hour under atmospheric pressure using 10% Pd–C (1.0 g) as catalyst. The catalyst was filtered off and the solution was concentrated to give an oily product (6.8 g, 100%). ESI–MS: calculated M+1=489.4; found 489.6.

869(d). The solution from 869 (c) (6.8 g , 13.9 mmol) in 50 ml of CHCl3 and the mixture is stirred overnight at room temperature. The CHCl3 was removed in vacuo and EtOAc was added. The solution is washed with 5% acetic acid, brine, NaHCO3 and brine, dried (MgSO4) and concentrated. Purification on a silica gel column using 4% MeOH/CH2Cl2 gave the cyclic product (3.4g, 46%) as a powder. ESI–MS: calculated M+1 = 471.4; found 471.5.

869 (e). 869 (d) (2.6 g, 5.5 mmol) was treated with 20 mL of 50% TFA in CH 2 Cl 2 for 1 h and the solution was concentrated to give an oily product (2.3 g, 100%). ESI–MS: calcd. M+1 = 415.3; found 415.4.

869 (f). Diisopropylethylamine (4, 3 ml, 24.6 mmol) and then BOP (2.72 g, 6.15 mmol) and the solution is left to stir overnight. EtOAc was added and the solution was washed with 5% citric acid, brine, NaHCO 3 and brine, dried (MgSO 4 ) and concentrated to give the crude product as a pure solid (82.9 g, 90%). ESI–MS: calcd. M+1=520.5; found 520, 5.

869 (g). The product from 869(f) (0.5 g, 0.96 mmol) was treated for 1 hour with 5 ml of THF and 4 ml of 1N LiOH, and the solution was acidified with TFA and concentrated. EtOAc was added and the solution was washed with brine, dried (MgSO 4 ) and concentrated to give the acid as a solid (0.3 g, 63%). ESI–MS: calcd. M+1=506.5, ;found 506.5.

869 (h)). BOP (0.18 g, 0 .4 mmol) and then diisopropylethylamine (0.52 ml, 3 mmol). The solution is left to stir for 2 hours at room temperature. EtOAc was added and the product precipitated. The precipitate was filtered and washed with EtOAc and water to give the compound as a solid (0.15 g, 73%). ESI–MS: calcd. M+1=519.4; found 519, 5.

Example 869: 869(h) (120 mg, 0.23 mmol) in 5 ml MeOH was hydrogenated under atmospheric pressure for 30 min using 10% Pd–C (40 mg) as catalyst. The catalyst is filtered off and the solution is concentrated. Purification on reverse phase HPLC gives the final product as a powder (81 mg, 82%). ESI–ms: calculated M+1=429.3; found 429.4.

Example 871: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-(glycine-N,N-dimethylamide)-cyclopentadecane-13-N -hydroxycarboxamide

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=500.5; found 500.5.

Example 880: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-(glycine-N-methylamide)-cyclopentadecane-13-N-hydroxycarboxamide

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=486.3; found 486.5.

Example 904: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[(glycine-(4-methyl) N-piperazinylamide]-cyclopentadecane –13-N-hydroxycarboxamide trifluoroacetate

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=555.6; found 555.5.

Example 908: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-N-morpholinamide]-cyclopentadecane-13-N-hydroxycarboxamide

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=542.4; found 542.5.

Example 910: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[(2-pyridyl) carbocamido]-cyclopentadecane-13-N- hydroxycarboxamide

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: found 555.7.

Example 916: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[(2-pyridyl)carboxamido]-cyclopentadecane-13-N- hydroxycarboxamide

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=492.5; found 496.5.

Example 919: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-(glycine-2-pyridylamide)cyclopentadecane-13-N-hydroxycarboxamide

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=549.4; found 549.5.

Example 926: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[2-(5-methylthiazolyl)carboxamido]cyclopentadecane-13-N -hydroxycarboxamide

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=512.3; found 512.4.

Example 927: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-2-(3,4,5,6-tetrahydropyridyl ) amide]–cyclopentadecane–13–N–hydroxycarboxamide

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=553.6; found 553.6.

Example 928: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-2-(5-methyl)thiazolylamide]-cyclopentadecane- 13-N-hydroxycarboxamide trifluoroacetate

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=569.3; found 569.3.

Example 929: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[N-(2-pyridyl)methylcarboxamido]-cyclopentadecane-13- N-hydroxycarboxamide trifluoroacetate

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=506.3; found 506.5.

Example 1175: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-(3-phenyl propyl)-7-methyl-2-(N-morpholinecarboxamido)-cyclopenta-decane- 13-N-hydroxycarboxamide

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=547.4; found 547.4.

Example 1176: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-(3-phenyl propyl)-7-methyl-2-((4-methyl)N-piperazinylamide) -cyclopenta-decane-13-N-hydroxycarboxamide trifluoroacetate

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=560.4; found 560.6.

Example 1228: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-(3-phenyl propyl)-7-methyl-2-(N-methylcarboxamido)-cyclopenta-decane- 13-N-hydroxycarboxamide

This compound is obtained using procedures analogous to those of Example 869. ESI–MS: calculated. M+1=491.3; found 491.5.

Example 1442: 2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(glycine-N-methyl amide)-11-(N-hydroxycarboxamide).

1442(a): To a solution of succinate 1(c) (2.7g, 9.4 mmol) and Nε-benzyloxycarbonyl-L-lysine methyl ester (4.6 g, 14.0 mmol) in DMF (10 ml) is added diisopropylethylamine (4.1 ml, 23.4 mmol) and BOP (4.9 g, 11.2 mmol). After stirring overnight, ethyl acetate was added and the solution was washed with 10% citric acid, saturated NaHCO3 solution and brine. The ethyl acetate was dried (MgSO4) and concentrated. The resulting residue was purified by silica gel chromatography to give the amide yield (4.1 g, 77%) as a white foam: ES–MS (M+H)+565.5.

1442 (b): The compound from 1442 (a) (2.0 g, 3.5 mmol) was dissolved in a mixture of CH 3 CN (8.3 ml), CCl 4 (8.3 ml) and H 2 O (12.3 ml). H 5 IO 6 (3.7 g, 16.2 mmol) and RuCl 3 • H 2 O (16.4 mg, 0.08 mmol) were added at room temperature. After 1.5 hours, 10% citric acid is added and the fractions are separated. The organic layer is dried and concentrated. The resulting residue was purified by silica gel chromatography to yield the acid (1.1 g, 56%) as a white foam: ES.MS (M+H) 579.5.

1442 (c): The compound of Example 1442 (b) (500 mg, 0.8 mmol) was hydrogenated in MeOH (10 mL) with 5% Pd/C–Degussa 858 mg) under a hydrogen atmosphere (40 psi). After stirring overnight, the catalyst was filtered off and the solution was concentrated to yield the amino acid (370 mg, 97%) as a white foam: ES–MS (M+H) + 445.5.

1442 (d): To a solution of HBTU (375 mg, 1.0 mmol) and NMM (0.07 ml, 0.7 mmol) in DMF (5 ml) at 60°C was added the compound from 1442 (c) (100 .0 mg, 0.2 mmol) in DMF (5 ml). After the addition is complete, the mixture is stirred for another 30 minutes. The solution was concentrated and silica gel chromatography gave the lactam (60 mg, 63%) as a white solid: ES–MS (M+H)+427.5.

1442 (e): The compound from Example 1442 (d) (250 mg, 0.6 mmol) was dissolved in CH 2 Cl (2 ml). After stirring overnight, the solution was concentrated to give the crude acid (220 mg) which was dissolved in DMF. O-benzylhydroxylamine (157 mg, 1.3 mmol), diisopropylethylamine (0.2 ml, 1.1 mmol) and BOP (334 mg, 0.7 mmol) were added to DMF. After stirring overnight, the solid product was filtered from solution to give O-benzyl hydroxamate (165 mg, 60%): ES–MS (M+H)+476.4.

1442 (f): The compound from Example 1442 (e) (50 mg, 0.1 mmol) was dissolved in 1:1 THF/MeOH (8 ml) and 1M LiOH (0.5 ml, 0.5 mmol) was added. . The reaction was stirred for another 1.5 hours before removing the solvent. The remaining H2O is acidified with 1N HCl and extracted with CHCl3. The CHCl 3 was dried (MgSO 4 ) and concentrated to give the acid (52 mg, 86%) as a white foam: ES–MS (M+H)+371.4.

1442 (g): To a solution of compound 1442 (f) (70 mg, 0.15 mmol) and glycine N-methyl amide (29 mg, 0.25 mmol) in DMF was added diisopropylethylamine (0.06 ml, 0 37 mmol) and HBTU (85 mg, 0.25 mmol). After stirring overnight, the product solid was filtered from solution to give bound glycine (60 mg, 75%) as a white solid: ES–MS (M+H) + 532.4.

Example 1442: The compound from Example 1442 (g) (60 mg, 0.1 mmol) is hydrogenated in

of MeOH–CHCl3 (3:1, 15 mL) with 5% Pd/BaSO4 (120 mg) under hydrogen (40 psi). After stirring for 3.5 hours, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate yield (20 mg, 41%) as a white solid: ES–MS (M+H) + 442.4.

Example 1443: 2S, 11S, 12R -1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-alanine-α-N-methyl amide)-11-(N-hydroxycarboxamide).

Example 1443 (a): To a solution of the compound from Example 1442 (f) (80 mg, 0.17 mmol) and L-alanine N-methyl amide (23 mg, 0.22 mmol) in DMF was added NMM (0.06 ml, 0.52 mmol) and HBTU (256 mg, 0.69 mmol). After stirring overnight, the solid product was filtered from solution to give the bound material (66 mg) which was dissolved in MeOH–CHCl3 (3:1, 30 mL). This is hydrogenated with 5% Pd/BaSO4 (150 mg) under a hydrogen atmosphere (50 psi). After stirring for 3 h, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate yield (27 mg, 45%) as a yellow solid: ES–MS (M+H)+ 456.4.

Example 1447: 2S, 11S, 12R -1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-serine-α-N-methyl amide)-11-(N-hydroxycarboxamide).

Example 1447 (a): To a solution of the compound from Example 1442 (f) (700 mg, 1.5 mmol) in L-serine N-methyl amide 234 mg, 1.9 mmol) in DMF is added NMM (0.5 ml , 5.4 mmol) and HBTU (2.2 mg, 5.9 mmol). After stirring overnight, the solid product was filtered from solution to give the bound material (640 mg) which was dissolved in MeOH-CHCl3 (3:1, 300 ml). This is hydrogenated with 5% Pd/BaSO4 (1.6 g) under a hydrogen atmosphere (50 psi). After stirring for 3 h, the catalyst was filtered off and the solution was concentrated to yield the title hydroxamate (250 mg, 47%) as a yellow solid: ES–MS (M+H) + 472.4.

Example 1462: 2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide).

1462(a): In a solution of succinate 1(c) (170 mg, 0.6 mmol) and Nε-benzyloxycarbonyl-L-lysine N-methyl amide (224.6 mg, 0.8 mmol) in DMF (6 ml) add diisopropylethylamine (0.26 ml, 1.5 mmol) and BOP (286.9 g, 0.6 mmol). After stirring overnight, ethyl acetate was added and the solution was washed with 10% citric acid, saturated NaHCO3 solution and brine. The ethyl acetate was dried (MgSO4) and concentrated. The resulting residue was purified by silica gel chromatography to give the amide yield (255 mg, 77%) as a white foam: ES–MS (M+H)+564.4.

1462 (b): The compound from Example 1462 (a) (813 mg, 1.4 mmol) was dissolved in a mixture of CH 3 CN (3 ml), CCl 4 (3 ml) and H 2 O (4.5 ml). H 5 IO 6 (1.3 g, 5.9 mmol) and RuCl 3 • H 2 O (6 mg, 0.03 mmol) were added at room temperature. After 1.5 hours, 10% citric acid is added and the fractions are separated. The organic layer is dried and concentrated. The resulting residue was purified by silica gel chromatography to give the acid yield (504 mg, 60%) as a white foam: ES–MS (M+H)+ 578.5.

1462 (c): The compound of Example 1462 (b) (45 mg, 0.08 mmol) was hydrogenated in MeOH (5 mL) with 5% Pd/C–Degussa (15 mg) under hydrogen (50 psi). After stirring overnight, the catalyst was filtered off and the solution was concentrated to yield the amino acid (32 mg, 90%) as a white foam: ES–MS (M+H) + 444.4.

1462 (d): To a solution of HBTU (769 mg, 2.0 mmol) and NMM (0.15 ml, 6.0 mmol) in DMF (10 ml) at 60°C was added the compound from 1462 (c) (200 .0 mg, 0.4 mmol) in DMF (10 mL) dropwise. After the addition is complete, the mixture is stirred for another 30 minutes. The solution was concentrated and silica gel chromatography gave the lactam (135 mg, 70%) as a light yellow solid: ES–MS (M+H)+426.3.

1462 (e): The compound from Example 1462 (d) (85 mg, 0.2 mmol) was dissolved in CH 2 Cl 2 (2 ml) and TFA (2 ml). After stirring overnight, the solution was concentrated to give the acid (80 mg, quant.) as a white foam: ES–MS (M+H)+ 370.3.

1462 (f): To a solution of Example 1462 (e) (75.0 mg, 0.2 mmol) and O-benzylhydroxylamine (78.8 mg, 0.6 mmol) in DMF (1.5 ml) and added diisopropylethylamine (0.07 ml, 0.4 mmol) and BOP (97.3 mg 0.2 mmol). After stirring overnight, the solid product was filtered from solution to give O-benzyl hydroxamate (58 mg, 61%): ES–MS (M+H)+475, 3.

1462: The compound from Example 1462 (f) (50 mg, 0.1 mmol) is hydrogenated in a mixture of MeOH–CHCl3 (3:1, 40 ml) with 10% Pd/C (20 mg) under a hydrogen atmosphere (balloon). After stirring for 6 hours, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate yield (38 mg, 93%) as a white foam: ES–MS (M+H)+ 385.4.

Example 1473: 2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(β-alanine N-methyl amide)-11-(N-hydroxycarboxamide).

1473 (a): To a solution of the compound from Example 1442 (f) (100 mg, 0.22 mmol) and β-glycine N-methyl amide (29 mg, 0.28 mmol) in DMF was added NMM (0.07 ml , 0.66 mmol) and HBTU (320 mg, 0.84 mmol). After stirring overnight, the solid product was filtered from solution to give the bound material (80g), which was dissolved in MeOH–MeOH/CHCl3 (1:1, 30 ml). This is hydrogenated with 5% Pd/BaSO4 (180 mg) under a hydrogen atmosphere (balloon). After stirring for 3 hours, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate (70 mg, quant.) as a white solid: ES–MS (M+H)+ 456.4.

Example 1491: 2S,11S ,12R -1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(Nε-H-L-lycine-α-N-H-amide trifluoroacetate) -11-(N -hydroxycarboxamide).

1491 (a): Diisopropylethylamine (0.05 ml, 0.27 mmol) and BOP (57 mg, 0.13 mmol). After stirring overnight, the solid product was filtered from solution to give bound lysine (58 mg, 72%), as a white solid: ES–MS (M+H) + 723.4.

1491: The compound from Example 1491 (a) (60 mg, 0.1 mmol) is hydrogenated in a mixture of MeOH– MeOH/CHCl3 (3:1, 15 ml) with TFA (1 ml) including 5% Pd/BaSO4 (150 mg) under a hydrogen atmosphere (40 psi). After stirring for 5 hours, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate (21 mg, 45%), as a white solid: ES–MS (M+H)+ 499.5

Example 1930: 2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide) hydrogen chloride.

1930 (a): The compound from Example 7(c) (56 mg, 0.12 mmol) was dissolved at room temperature in 4 M HCl/dioxane (2 ml). After 3 h, the solvent was removed to give the amino salt (45 mg, quant.) as a pale-yellow solid: ES–MS (M+H)+ 471.4.

Example 2038: 2S,11S,12R-7-N-benzenesulfonyl-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide).

2038 (a): In a solution of succinate 1(c) (460.0 mg, 1.6 mmol) and Nε-benzenesulfonyl-L-lysine N-methyl amide (696.5 mg, 2.1 mmol) and diisopropylethylamine (0 .84 ml, 4.8 mmol) in DMF is added BOP (849.6 g, 1.9 mmol). After stirring overnight, ethyl acetate was added and the solution was washed with 10% citric acid, saturated NaHCO3 solution and brine. The ethyl acetate was dried (MgSO4) and concentrated. The resulting residue was purified by silica gel chromatography to give the amide (833 mg, 90%) as a white foam: ES–MS (M+H)+ 570.3.

2038 (b): The compound from Example 2038 (a) (875 mg, 1.5 mmol) and PPh 3a (1.21 g, 4.6 mmol) were dissolved in THF (137 ml). DIAD (0.88 mL, 4.5 mmol) in THF (27 mL) was added dropwise to the mixture. After stirring overnight, the solution was concentrated and the residue was purified by silica gel chromatography to give the cyclic material (470 mg, 55%) as a white solid: ES–MS (M+H)+ 552.3.

2038 (c): The compound from Example 2038 (b) (473.0 mg, 0.86 mmol) was dissolved in CH 2 Cl 2 (6 ml) and TFA (5 ml). After stirring overnight, the solution was concentrated to give the acid (500 mg, quant.) as a white solid: ES–MS (M+H) + 496.3.

2038 (d): To a solution of the compound from Example 2038(c) (260.0 mg, 0.52 mmol), O-benzylhydroxylamine (192.0 mg, 1.6 mmol), and diisopropyl-ethylamine (0.18 ml , 1.0 mmol) in DMF was added BOP (278.0 mg, 0.63 mmol). After stirring overnight, the solid product was filtered from solution to give O-benzyl hydroxamate (172 mg, 57%): ES–MS (M+H)+601.2.

2038: The compound from Example 2038 (d) (150.0 mg, 0.25 mmol) is hydrogenated in a mixture of MeOH– MeOH/CHCl3 (3:1, 50 ml) with 5% Pd/BaSO4 (300 mg) under a hydrogen atmosphere (50 psi). After stirring for 3 hours, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate (52 mg, 41%) as a white solid: ES–MS (M+H)+ 511.3.

Example 2135: 2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-trifluoromethanesulfonyl-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide).

2135 (a): In a solution of succinate 1(c) (608.0 mg, 2.1 mmol) and Nε-trifluoromethanesulfonyl L-lysine N-methyl amide (900.0 mg, 2.7 mmol) and diisopropylethylamine (1, 09 ml, 6.3 mmol) in DMF was added BOP (1.12 g, 2.5 mmol). After stirring overnight, DMF was removed and CH2Cl2 was added. Then CH2Cl2 is washed with 10% citric acid, saturated NaHCO3 solution and salt water. The CH2Cl2 is dried (MgSO4) and concentrated. The resulting residue was purified by silica gel chromatography to give the impure amide (1.30 g) which was dissolved in THF (100 ml). PPh 3 (1.84 g, 7.0 mmol) was added followed by DIAD (1.33 mL, 6.8 mmol) in THF (35 mL). After stirring overnight, the solution was concentrated and the residue was purified by silica gel chromatography to give the cyclic material (600 mg, 52%) as a white solid: ES–MS (M+H)+ 544.3.

2135 (b): The compound from Example 2135 8a) (300.0 mg, 0.55 mmol) was dissolved in CH 2 Cl 2 (4 ml) and TFA (4 ml). After stirring overnight, the solution was concentrated to the acid, which was dissolved in DMF (6 mL). To this solution was added O-benzylhydroxylamine (146.0 mg, 1.18 mmol) and diisopropylethylamine (0.19 ml, 1.0 mmol) followed by BOP (270.0 mg, 0.61 mmol). After stirring overnight, DMF was removed to give O-benzyl hydroxamate (190 mg, 58%): ES–MS (M+H) 593.4.

2135: The compound of Example 2135 (b) (180.0 mg, 0.3 mmol) was hydrogenated with MeOH (35 mL) with 5% Pd/BaSO 4 (210 mg) under hydrogen (50 psi). After stirring for 2.5 hours, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate (150 mg, 98%) as a solid: ES–MS (M+H)+ 503.3.

Example 2227: 2S,11S ,12R -1, 7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-(p-amino-N-benzenesulfonyl)-12-isobutylcyclotridecane-11-(N- hydroxycarboxamide).

2227 (a): Into a solution of succinate 1(c) (850.0 mg, 2.95 mmol), Nε-p-nitro-benzenesulfonyl- L-lysine N-methyl amide (1.45 g, 3.80 mmol) and diisopropylethylamine (1.54 ml, 8.80 mmol) in DMF was added BOP (1.56 g, 3.50 mmol). After stirring overnight, ethyl acetate was added and the solution was washed with 10% citric acid, saturated NaHCO 3 solution, and brine. The ethyl acetate was dried (MgSO4) and concentrated. The resulting residue was purified by silica gel chromatography to give the amide (1.37 g, 75%) as a white foam: ES–MS (M+H)+ **570.3.

2227 (b): The compound from Example 2227 (a) (547.0 mg, 0.89 mmol) and PPh 3 were dissolved in THF (30 ml). DIAD (0.50 mL, 2.5 mmol) in THF (6 mL) was added dropwise to the mixture. After stirring overnight, the solution was concentrated and the residue was purified by silica gel chromatography to give the cyclic material (0.14 g, 26%) as a white foam: ES–MS (M+H) 597.4.

2227 (c): The compound from Example 2227 (b) (24.0 mg, 0.04 mmol) was hydrogenated in a mixture of MeOH–CHCl3 (1:1, 2 ml) with 10% Pd/C (12 mg) under atmosphere of hydrogen (30 psi). After stirring overnight, the catalyst was filtered off and the solution was concentrated to give the amino compound (20 mg, 90%) as a white foam: ES–MS (M+H)+ 567.4.

2227 (d): The compound of Example 2227 (c) (226.0 mg, 0.40 mmol) was dissolved in CH 2 Cl 2 (2 ml) and TFA (2 ml). After stirring overnight, the solution was concentrated to give the acid as a solid which was dissolved in DMF (4 mL). To this DMF solution was added O-benzylhydroxylamine (108.0 mg, 0.88 mmol), diisopropyl-ethylamine (0.2 ml, 1.2 mmol) and BOP (230.0 mg 0.52 mmol). After stirring overnight, the solvent was removed to give O-benzyl hydroxamate (170 mg, 69%): ES–MS (M+H) + 616.4.

2227: A solution of the compound from Example 2227(d) (150.0 mg, 0.24 mmol) is hydrogenated in a mixture of MeOH–MeOH/CHCl3 (1.7:1, 19 ml) with 5% Pd/BaSO4 (200 mg ) under a hydrogen atmosphere (50 psi). After stirring for 4 hours, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate (107 mg, 84%) as a white solid: ES–MS (M+H)+ 526.3.

Example 2323: 2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-mesitylenesulfonyl-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide).

2323 (a): To a solution of succinate 1(c) (990 mg, 3.4 mmol) and Nε-mesitylenesulfonyl L-lysine N-methyl amide hydrogen chloride (1.7g, 4.5 mmol) in DMF is added diisopropylethylamine ( 1.8 ml, 10.2 mmol) and BOP (1.8 mg, 4.1 mmol). After stirring overnight, DMF was removed and CH2Cl2 was added. The solution is washed with 10% citric acid, saturated NaHCO3 solution and salt water. The CH2Cl2 is dried (MgSO4) and concentrated. The resulting residue was purified by silica gel chromatography to give the impure amide (2 g), which was dissolved in THF (158 ml). PPh 3 (2.8 g, 10.6 mmol) was added to THF followed by DIAD (2 ml, 10.1 mmol) in THF. After stirring overnight, the solution was concentrated and the residue was purified by silica gel chromatography to give the cyclic material (680 mg, 30%) as a yellow solid: ES–MS (M+H)+ 594.5.

2323 (b): The compound of Example 2323 (8a) (280 mg, 0.47 mmol) was dissolved in CH 2 Cl 2 (3.5 ml) and TFA (3.5 ml). After stirring overnight, the solution was concentrated to give the impure acid, which was dissolved in DMF. O-benzylhydroxylamine (118 mg, 0.9 mmol) and diisopropyl-ethylamine (0.15 ml, 0.8 mmol) and BOP (218 mg, 0.5 mmol) were added to this DMF solution. After stirring overnight, the solvent was removed to give O-benzyl hydroxamate (70 mg, 25%): ES–MS (M+H) 643.5.

2323: The compound from Example 2323 (b) (120 mg, 0.19 mmol) was hydrogenated with a mixture of MeOH–CHCl3 (3:1, 28 ml) with 5% Pd/BaSO4 (180 mg) under a hydrogen atmosphere (50 psi). . After stirring for 4 hours, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate (100 mg, 96%) as a white foam: ES–MS (M+H)+ 553.5.

Example 2413: 5S,8R,9S -6-aza-2,7-dioxo-5-(N-methylcarboxamido)-1-oxa-8-isobutylcyclotridecane-9-(N-hydroxycarboxamide).

2413 (a): To a solution of succinate 1(c) (200 mg, 0.69 mmol) and (L)-γ-benzyl ester glutamate-α-N-methyl amide (200 mg, 0.70 mmol) in DMF ( 6 ml) diisopropylethylamine (0.25 ml, 1.5 mmol) and BOP (305 mg, 0.69 mmol) were added. After stirring overnight, the DMF is removed. The resulting residue was purified by silica gel chromatography to give the amide (255 mg, 70%) as an oil: ES–MS (M+H)+ 521.3.

2413 (b): The compound of Example 2413 (8a) (240.0 mg, 0.46 mmol) was hydrogenated in MeOH (5 ml) with 10% Pd/C (25 mg) under a hydrogen atmosphere (balloon). After stirring overnight, the catalyst was filtered off and the solution was concentrated to give the acid, which was dissolved in THF (40 mL). PPh 3 (364.0 mg, 1.4 mmol) was added to THF followed by DIAD (0.27 mL, 1.4 mmol) in THF (9 mL). After stirring overnight, the solvent was concentrated and the residue was purified by silica gel chromatography to give the cyclic material (45 mg, 24%) as a white solid: ES–MS (M+H)+ 413.3.

2413 (c) The compound from Example 2413 (b) (200 mg, 0.49 mmol) was dissolved in CH 2 Cl 2 (5 ml) and THA (5 ml). After stirring overnight, the solution was concentrated to give the acid which was dissolved in DMF (50 mL). O-benzylhydroxylamine (122.0 mg, 0.93 mmol) and diisopropyl-ethylamine (0.16 ml, 0.92 mmol) and BOP (226.0 mg, 0.5 mmol) were added to this solution. After stirring overnight, the solid product was filtered from solution to give O-benzyl hydroxamate (110 mg, 48%): CIMS–NH3 (M+H) 462.

2413: The compound from Example 2413 (c) (105 mg, 0.23 mmol) was hydrogenated in a mixture of MeOH–CHCl3 (3:1, 40 ml) with 5% Pd/BaSO4 (150 mg) under a hydrogen atmosphere (50 psi). . After stirring for 2.5 hours, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate (100 mg) as a white solid: ES–MS (M+H)+372.3.

2518 (a). Nα-t-butyloxycarbonyl-Nε-benzyloxycarbonyl-L-lysine-N-methyl amide.

BOP (14.16 g, 32 mmol) and then diisopropylethylamine (25 ml, 128 mmol). The solution was allowed to stir overnight at room temperature. Ethyl acetate (150 ml) was added and the solution was washed with 10% citric acid, brine, saturated NaHCO3 and brine, dried (MgSO4) and concentrated. Purification on a silica gel column using 80% EtOAc/hexane afforded 12.92 g (95%) of product. ES–MS (M+H)+: caldc 394.3; found 394.4.

2518 (b). Nε-benzyloxycarbonyl-L-lysine-N-methyl amide hydrochloric acid.

The compound from Example 2518 (a) (6 g, 15.26 mmol) was dissolved in 25 ml of 4N HCl in dioxane. After stirring for 1 hour at room temperature, the solution is concentrated. The residue was triturated with ether to give 5.2 g (100%) of product. ES–MS (M+H)+: calcd. 294.2; found 294.3.

2518 (c). 4-methylpentanoic acid 4(S)-phenylmethyl-2-oxazolidinonamide.

To a solution of 4(s)-phenylmethyl-2-oxazolidinone (48.3 g, 272 mmol) in 500 ml of THF cooled to -78°C was added 131 ml of 2.5 M n-butyllithium (327 mmol) in hexane over 20 minutes and the solution is stirred for 45 minutes at –78°C. To this was added 4-methylpentane chloride (44 g, 327 mmol) and the solution was stirred at room temperature for 2.5 hours and quenched with ethyl acetate. Solvents are removed by concentration in small amounts and 500 ml of ethyl acetate are added. The solution is washed with 10% citric acid, water, NaHCO3 and brine, dried (MgSO4) and concentrated. Purification on a silica gel column using 10% ethyl acetate in hexane as eluent gives 68.53 g (91.5%) of the oily product. ES–MS (M+H)+: calcd 276.2; found 276.3.

2518 (d). 3-n-butoxycarbonyl-3 (R,S)-hydroxy-2-(isobutylpropionic acid 4(S)-phenylmethyl-2-oxazolidinonamide.

9.3 ml of 2.5 M n-butyllithium (23.25 mmol) in hexane was added to a solution of diisopropylethylamine (3.25 ml, 23.25 mmol) in 20 ml of THF cooled to -78°C and the solution was stirred for 30 minutes heats up to 0°C and then freezes at –78°C. The resulting solution is added to the solution from Example 2518 (c) (5.82 g, 21.13 mmol) in 50 ml of dry THF cooled to -78°C for 20 minutes and the mixture is stirred for 1 hour at -78°C. A solution of n-butyl glyoxalate (4.12 g, 31.69 mmol) in 10 ml of dry THF cooled to -78°C was added to it for 20 minutes and the mixture was stirred for 3 hours at -78°C. The reaction is stopped with ice water. Ethyl acetate is added, followed by 10% citric acid. The organic fraction is separated, washed with water, NaHCO3 and brine, dried (MgSO4), and concentrated. Purification on a silica gel column with the gradual use of 5% ethyl acetate, 10% ethyl acetate and 20% ethyl acetate in hexane as eluent gives 3.1 g (36%) of an oily product. ES–MS (M+H)+: calcd 406.3; found 406.2.

2518 (e). 3-n-butoxycarbonyl-3 (R,S)-hydroxy-2-(R)-isobutylpropionic acid.

Hydrogen peroxide (87.84 ml, 50.3 mmol) is added to a solution of the compound from Example 2518 (d) (5.1 g, 12.57 mmol) in 250 ml of THF/$ (4:1) cooled in an ice bath. and then a solution of LiOH (791 mg, 18.85 mmol) in 8 ml of water. After 1 hour, the reaction is stopped with Na2SO3 solution (6.33 g, 50.28 mmol). The THF is removed by concentration under reduced pressure and the solution is extracted twice with ethyl acetate. The aqueous fraction is acidified with cold concentrated HCl to pH3 and extracted 3x with CH2Cl2. The organic solution is washed with water and brine, dried (MgSO4) and concentrated. Purification on a silica gel column using CHCl3 5% MeOH/ CHCl3 and then 10% MeOH/ CHCl3 as eluents gave 2.29 g (74%) of an oily product. CI–MS (M+NH4)+: calcd 264.1; found 264.0.

2518 (f). Benzyl 3-n-butoxycarbonyl-3 (R,S)-hydroxy-2-(R)-isobutylpropionic acid.

A solution of Example 2518 (e) (8.33 g, 33.82 mmol), benzyl bromide (7.0 g, 37.2 mmol) and DBU (6.07 ml, 40.58 mmol) in 100 ml of benzene 3 hour is heated to 50°C and concentrated. Ethyl acetate is added and the solution is washed 3x with brine, dried (MgSO4), and concentrated. Purification on a silica gel column using 10% ethyl acetate/hexane as eluent gave 9 g (79%) of an oily product. ES–MS (M+H)+: calcd 337.3; found 337.3.

2518 (g). Benzyl-n-butoxycarbonyl-3 (R,S)-t-butoxycarbonylmethoxy-2(R)-isobutylpropionate.

A solution of Example 2518 (f) (8.95 g, 26.64 mmol) and t-butyl bromoacetate (4.33 ml, 29.3 mmol) in 50 ml of THF was cooled to 0°C and NaH (1 .5 g, 60% oil dispersion, 32 mmol). The mixture is stirred for 30 minutes at 0°C and 2 hours at room temperature. The THF is removed by concentration. Ethyl acetate was added and the solution was washed with 10% citric acid and brine, dried (MgSO4) and concentrated. Purification on a silica gel column gives 8.6 g (71%) of the product. ES–MS (M+H)+: calcd 451.3; found 451.4.

2518 (h). 3-n-butoxycarbonyl-3-(R,S)-t-butoxycarbonylmethoxy-2(R)-isobutylpropionic acid.

The compound of Example 2518 (5g, 11.11 mmol) was hydrogenated in 25 ml of isopropanol in the presence of 1.4 ml of 4N HCl/dioxane using 10% Pd/C as catalyst at atmospheric pressure for 3 hours. The catalyst was filtered off and the solution was concentrated to give 3.96 g (99%) of product. ES–MS (M+H)+: calcd 361.3; found 361.4.

2518 (i). 3-n-butoxycarbonyl-3-(R,S)-t-butoxycarbonylmethoxy-2(R)-isobutylpropionoyl-Nε-benzyloxycarbonyl-L-lysine N-methyl amide.

The compound from Example 2518(h) (1.76 g, 4.88 mmol) and the compound from Example 1(b) (1.61 g, 4.88 mmol) were dissolved in 10 ml of DMF and the solution was cooled in an ice bath . BOP (2.16 g, 4.88 mmol) was added, followed by diisopropylethylamine (3.42 ml, 10.58 mmol). After stirring for 4 hours at room temperature, ethyl acetate was added and the solution was washed with 10% citric acid, brine, NaHCO3 and brine, dried (MgSO4) and concentrated. Purification on a silica gel column

using 10% MeOH/CHCl3 as eluent gave 2.32 g (75%) of product. ES–MS (M+H)+: calcd 636.4, found 636.6.

2518 (j). 3-n-butoxycarbonyl-3-(R,S)-carboxymethoxy-2(R)-isobutylpropionoyl-L-lysine N-methyl amide.

The compound of Example 2518 (i) (2.21 g, 3.47 mmol) was hydrogenated for 2 hours in 15 ml of isopropanol in the presence of 4N HCl/dioxane (1 ml) using 10% Pd/C (0.35 g) as catalyst. The catalyst is filtered off and the solution is concentrated. The residue is taken up in 4N HCl/dioxane (30 ml). The solution was stirred for 2 hours and concentrated to give 1.78 g (99%) of product. ES–MS (M+H)+: calcd 446.3; found 446.4.

2518 (k) BOP (1.64 g, 3.7 mmol) was dissolved in 30 mL of CHCl 3 and the solution was cooled in an ice bath. The compound from Example 2518 (j) (1.78 g, 3.7 mmol) and diisopropylethylamine (2.6 ml, 14.6 mmol) in 50 ml of CHCl3 were added to it over 2 hours. The solution is left to stir overnight at room temperature and is concentrated. The residue was taken up in ethyl acetate and the solution was washed with 10% citric acid, brine, NaHCO3 and brine, dried (MgSO4), and concentrated. Purification on a silica gel column using 15% MeOH/CH 2 Cl 2 as eluent afforded 0.8 g (50%) of product. ES–MS (M+H)+ calculated 428.3; found 428.3.

2518 (l) The compound from Example 2518 (k) (0.77 g, 1.8 mmol) is treated for 2 hours with 4 ml of 1N LiOH in 20 ml of THF and the solution is acidified with 4N HCl/dioxane to pH 3. Add t-butanol and the solution was washed with brine 3x, dried (MgSO4) and concentrated to give 0.49 g (73%) of product. ES–MS (M+H)+: calcd 372.3; found 372.2.

2518 (m) To a solution of the compound from Example 2518 (l) (0.47 g, 1.27 mmol) and O-benzylhydrochylamine hydrochloric acid (0.2 g, 1.27 mmol) in 5 ml of DMF cooled in an ice bath is added to BOP (0.56 g, 1.27 mmol), then diisopropylethylamine (1.0 ml, 5.2 mmol). The solution is left to stir overnight at room temperature. Ethyl acetate was added and the solution was washed with 10% citric acid, NaHCO3 and brine, dried (MgSO4), and concentrated. Purification on a silica gel column using 5% MeOH/CH 2 Cl 2 gave 0.13 g (21%) of the first isomer and 80 mg (14%) of the second isomer. ES–MS (M+H)+ calculated 477.3; found 477.3. (both isomers)

Example 2518: The compound of Example 2518 (m), isomer 1 (100 mg, 0.21 mmol) was hydrogenated for 2 hours in 5 ml of MeOH at atmospheric pressure using 10% Pd/C (15 mg) as catalyst. The catalyst was filtered off and the solution was concentrated to give 50 mg (62%) of the product. ES–MS (M+H)+: calcd 387.3; found 387.3.

The compound of Example 2518 (m), isomer 2 (50 mg, 0.105 mmol) was hydrogenated in a similar manner to give 20 mg (50%) of product. ES–MS (M+H)+: calcd 387.3; found 387.3.

Example 2519

This compound is synthesized in a manner analogous to that described above. ES–MS (M+H)+: calcd 449.3; found 449.3.

Example 2708:

2708 (a). Na-t-butyloxycarbonyl-Ne-trifluoro-L-lysine N-methyl amide.

BOP (13 .27 g, 30 mmol), then diisopropylethylamine (23.5 ml, 135 mmol) and the mixture was stirred overnight at room temperature. Ethyl acetate was added and the solution was washed with citric acid, brine, NaHCO 3 and brine, dried (MgSO 4 ), and concentrated. Crystallization from ethyl acetate ether gives 10.1 g (94.8%) of the product. Melting point 95–98°C. ES–MS (M+H)+ calcd 356.2; found 356.3.

2708 (b) Nα-t-butyloxycarbonyl-Nε-methyl-Nε-trifluoro-L-lysine N-methyl amide.

A mixture of compound 2708 (a), iodomethane (14 ml, 223 mmol) and potassium carbonate (7.7 g, 56 mmol) in 50 ml DMF was stirred overnight at 100 °C and the insoluble material was filtered off. Ethyl acetate was added and the solution was washed with citric acid, brine, NaHCO3 and brine, dried with MgSO4, and concentrated. Purification on a silica gel column gives 4.45 g (43 %) of the product. ES–MS (M+H)+ calculated 370.2; found 370.3.

2708 (c). Nα-t-butyloxycarbonyl-Nε-methyl-L-lysine N-methyl amide.

Compound 2708 (b) (4.35 g, 11.78 mmol) was treated with 14.5 mL of 1N NaOH in 20 mL of MeOH for 30 min and the solution was concentrated. The residue is taken up in chloroform and the insoluble material is filtered off. The filtrate was concentrated to give 3.65 g (100%) of the product. ES–MS (M+H)+: calcd 274.3; found 274.5.

2708 (d) Nα-t-butyloxycarbonyl-Nε-methyl-Nε-{[(1(R,S)-n-butoxycarbonyl-2-(R)-benzyloxycarbonyl-3-methyl) pentyloxy] acetyl}-L-lysine N-methyl amide

Compound 2518 (g) (3.5 g, 7.77 mmol) was treated for 2 hours with 25 mL of 4N HCl in dioxane and the solution was concentrated. The residue is taken up in 15 ml of DMF and the solution is cooled in an ice bath. Compound 4(c) (2.4 g, 7.77 mmol) was added to it, followed by BOP (3.44 g, 7.77 mmol) and diisopropylethylamine (4.74 ml, 27 mmol). The mixture is stirred overnight at room temperature. EtOAc was added and the solution was washed with citric acid, brine, NaHCO 3 and brine, dried (MgSO 4 ), and concentrated. Purification on a silica gel column gives 4.46 g (93 %) of the product. ES–MS (M+H)+ calculated 650.7; found 650.7.

2708 (e). Nε-methyl-Nε-{[(1(R,S)-n-butoxycarbonyl-2-(R)-carboxy-3-methyl)pentyloxy] acetyl}-L-lysine N-methyl amide.

Compound 2708 (d) (4.31 g, 6.98 mmol) was treated with 50 mL of 4 N HCl in dioxane for 1 hour and the solution was concentrated. The residue is taken up in 60 ml of isopropanol and the solution is hydrogenated for 2 hours at atmospheric pressure using 10% Pd–C (0.5 g) as a catalyst. The catalyst was filtered off and the solution was concentrated to give 3.15 g (91%) of the product. ES–MS (M+H)+: calcd 460.4; found 460.5.

2708 (f). Compound 2708 (e) (3 g, 6.05 mmol) in 20 ml of chloroform and diisopropylethylamine were slowly and simultaneously added to a solution of BOP (2.68 g, 6.05 mmol) in 20 ml of chloroform cooled in an ice bath for 1 hour. (3.69 ml, 21.2 mmol) in 20 ml of chloroform. The mixture is stirred overnight at room temperature and concentrated. The residue was taken up in EtOAc and the solution was washed with citric acid, brine, NaHCO 3 and brine, dried (MgSO 4 ) and concentrated. Purification on a silica gel column yields 2 g (75 %) of the product. ES–MS (M+H)+ calculated 442.3; found 442.5.

2708 (g). Compound 2708 (f) (1.8 g, 4 mmol) was treated for 1 hour with 4.9 ml of 1N LiOH in 10 ml of THF and the solution was concentrated. Purification by HPLC gives 390 mg (25%) of the product. ES–MS (M+H)+: calcd 386.3; found 386.3.

Example 2708: BOP (254 mg, 0.576) was added to a solution of compound 4 (g) (0.17 g, 0.48 mmol) and hydrochloric acid O-benzylhydroxylamine (91 mg, 0.576 mmol) in 2 ml of DMSO cooled in an ice bath. mmol), then diisopropylethylamine (0.33 ml, 1.92 mmol) and the solution is stirred for 1 hour at room temperature. Purification on reverse phase HPLC afforded 30 mg of isomer 1 and 140 mg of isomer 2. ES–MS (M+H)+: calcd 491.5; found 491.6 (both isomers).

Example 2708: Compounds 2708 (h), isomer 1 and isomer 2 are hydrogenated in a manner analogous to that described in 1 (n). ES–MS (M+H)+: calcd 401.5; found 401.6.

Example 2809

2809 (a). Nα–Boc–S–(2–nitrophenyl)–L–cysteine.

2-chloro-nitrobenzene (7.88 g, 50 mmol), L-cysteine (6.66 g, 55 mmol) and potassium carbonate (7.6 g, 55 mmol) were dispersed in 30 ml of DMF and the solution was stirred for 4 hours stir at 80°C and cool to room temperature. Water (20 ml) is added and the solution is cooled in an ice bath. Di-t-butyl dicarbonate (10.9 g, 50 mmol) is added to it. After stirring for 2 hours, water is added and the solution is extracted 3x with ether. The water fraction is acidified with HCl at 0°C and the solution is extracted 3x with ethyl acetate. The combined extracts were washed with brine, dried (MgSO 4 ) and concentrated to give 8.21 g (48%) of product. ES–MS (M+H)+: calcd 343.3; found 343.2.

2809 (b) Nα–Boc–S–(2–nitrophenyl)–L–cysteine N–methyl amide.

Diisopropylethylamine (16.5 ml, 95 mmol) was added to a solution of compound 2518 (a) (8.1 g, 23.66 mmol) and hydrochloric acid methylamine (2.03 g, 30 mmol) cooled in an ice bath, then BOP (10.47 g, 23.66 mmol). After stirring for 2 hours at room temperature, ethyl acetate is added and the solution is washed with citric acid, brine, NaHCO3 and brine, dried (MgSO4) and concentrated. Purification on a silica gel column using 5% methanol in methylene chloride as eluent afforded 6.24 g (82%) of product. ES–MS (M+H)+: calcd 356.2; found 356.3.

2809 (c). S–2–nitrophenyl–L–cysteine N–methyl amide.

Compound 2518 (b) (6.0 g, 17 mmol) was treated with 4N HCl in dioxane for 1 hour and the solution was concentrated. The residue is triturated with ether to 3.88 g (71% product). ES–MS (M+H)+: calcd 256.1; found 256.1.

2809 (d). 3-n-butoxycarbonyl-3-(R,S)-t-butoxycarbonylmethoxy-2(R)-isobutylpropionoyl-S-(2-nitrophenyl)-L-cysteine N-methyl amide.

Diisopropylethylamine (4.53 mL, 26 mmol) was added to a solution of the compound from 2518 (h) (2.36 g, 6.5 mmol) and the compound from 3 (c) (1.91 g, 6.5 mmol) in 15 ml of chloroform cooled in an ice bath, then BOP ( 2.88 g, 6.5 mmol) and the solution was stirred overnight at room temperature and then concentrated. The residue was taken up in ethyl acetate and the solution was washed with citric acid, brine, NaHCO 3 , dried (MgSO 4 ), and concentrated. It is purified on a silica gel column using 3% MeOH–25% EtOAc–72% CH2 Cl2 as eluent to give the product 3.21 g (83%). ES–MS (M+H)+ calculated 598.3; found in 598.6

2809 (e). 3-n-Butoxycarbonyl-3(R,S)-carboxymethoxy-2(R)-isobutylpropionoyl-S-(2-aminophenyl)-L-cystine N-methyl amide.

The compound from 2809 (d) (3.05 g, 5.1 mmol) is treated for 30 minutes with 3 g of zinc in 15 ml of acetic acid and 0.5 ml of water. 30 ml of methanol is added and the solid is filtered off. The filtrate was concentrated and the residue was taken up in ethyl acetate. The solution is washed with NaHCO3 3X, dried (MgSO4), and concentrated. The residue is treated for 1 hour with 30 mL of 4N HCl in dioxane and 0.5 mL of water and the solution is concentrated to give the product 2.2 g, (84%). ES–MS (M+H)+ calculated 512.5; found 512.5.

2809 (f). BOP (1.36 g, 3.06 mmol) was dissolved in 10 ml DMF and the solution was cooled in an ice bath. The compound from 2809 (e) (1.4 g, 2.55 mmol) and diisopropylethylamine (1.78 ml, 10.2 mmol) were added there over 2 hours. The solution is left to stir overnight at room temperature. Ethyl acetate was added and the solution was washed with citric acid, brine, NaHCO 3 and brine, dried (MgSO 4 ), and concentrated. The crude product is purified on reverse phase HPLC to give 250 mg of isomer 1 and 620 mg of isomer 2 (69%). ES–MS (M+H) + : calculated 494.3; found 494.3 (both isomers).

2809 (g). Compound 2809 (f), isomer 1 (0.2 g, 0.4 mmol) or isomer 2 (0.55 g, 1.11 mmol) was treated for 1 hour with 1.1 equivalent of LiOH in THF and both products were purified by HPLC. Yield: isomer 1 0.15 g; isomer 2 0.41 g ES–MS (M+Na) +: calculated 460.2; found 460.3 (both isomers).

2809. Diisopropylethylamine (0.15 mL, 1 mmol) and BOP are added to a solution of the compound from Example 2809 (g), isomer 1 (100 mg, 0.228 mmol) and hydroxylamine hydrochloride (20 mg, 0.274 mmol) in 3 mL of DMF cooled in an ice bath. (0.12 g, 0.274 mmol) and the solution is stirred for 2 hours at room temperature. HPLC purification gives the product 85 mg (82%). ES–MS (M+H) +: calcd 453.2; found 453.3.

The compound from 2809 (g), isomer 2 was converted to the same product in the same way. ES–MS (M+Na) + : calculated 475.2; found in 475.3.

Example 2880: 2S, 11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-t-butyloxycarbonyl-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide).

2880 (a) : The compound from Example 2323 (a) (300 mg, 0.5 mmol) was dissolved in 33% HBr/AcOH (6.8 mL) containing phenol (63 mg, 0.67 mmol). After stirring for 5 hours, the solution was concentrated and the solid was filtered off with CH 2 Cl 2 /Et 2 O. This gives the crude amino acid salt (500 mg, quant.) ES–MS (M+H) +356.4.

2880 (b) The compound from Example 2880 (a) (140 mg, 0.32 mmol) was dissolved in THF (4 mL)/H 2 O (0.6 mL) and Et 3 N (0.38 mL, 2.6 mmol) was added. Next added at room temperature, (Boc)20 (452 mg, 206 mmol). After stirring overnight, the solution was removed and CH2Cl2 was added. The CH2Cl2 was washed with 10% HCl, dried (MgSO4) and concentrated. The resulting residue is purified by silica gel chromatography to give the crude carbamate, which is dissolved in DMF (5 ml). To this solution was added 0-benzylhydroxylamine (108 mg, 0.87 mmol), diisopropylethylamine (0.15 mL, 0.82 mmol) and BOP (214 mg, 0.48 mmol). After stirring overnight, the solid product was filtered from solution with CH 2 Cl 2 to give O-benzyl hydroxamate (120 mg, 67%) : ES–MS (M+H) + 561.5.

2880: The compound from Example 2880 (b) (160 mg, 0.29 mmol) was hydrogenated in MeOH (40 mL) with 5% Pd/BaSO4 (240 mg) under hydrogen atmosphere (50 psi). After stirring for 3 hours, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate (140 mg, quant.) as a pale yellow solid: ES–MS (M+H)+ 471.5.

Example 2890: 2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-(N-methyl-imidazolesulfon-4-yl)-12-isobutylcyclotridecane-11 –(N-hydroxycarboxamide).

2890 (a) : Solutions of succinate 1(c) (1.27 g, 4.39 mmol), N�-4-(N-methyl) imidazolesulfonyl-L-lysine N-methyl amide (1.73 g, 5.70 mmol), and diisopropylethylamine ( 3.19 mL, 17.6 mmol) in DMF was added BOP (2.34 g, 5.27 mmol). After stirring overnight, DMF is removed and CH2Cl2 is added. CH2Cl2 is washed with saturated NaHCO3 solution and brine. The CH2Cl2 is dried (MgSO4) and concentrated. The resulting residue was purified by silica gel chromatography to give the amide (1.73 g, 69%) as a white foam: ES–MS (M+H)+ 574.5.

2890 (b) The compound from Example 2890 (a) (200.0 mg, 0.35 mmol) and PPh 3 (274.0 g, 1.05 mmol) were dissolved in THF (15.5 mL). DIAD (0.20 mL, 1.05 mmol) in THF (5 mL) was added dropwise to the mixture. After stirring overnight, the solution was concentrated and the residue was purified by silica gel chromatography to give the cyclic material (100 mg, 52%) as a white foam: ES–MS (M+H)+556.5

2890 (c): The compound from Example 2890 (b) (400.0 mg, 0.72 mmol) was dissolved in CH2Cl2 (5.5 ml) and TFA (5.5 ml). After stirring overnight, the solution was concentrated in acid which was dissolved in DMF (6.4 ml). To this solution was added O-benzylhydroxylamine (172.0 mg, 1.40 mmol) and diisopropyl-ethylamine (0.24 ml, 1.38 mmol) followed by BOP (341.0 mg, 0.77 mmol). After stirring overnight, DMF was removed and silica gel chromatography gave O - benzyl hydroxamate (140 mg, 33%) : ES - MS (M+H)+ 605.5.

2890: Example compound 2890 (c) (135.0 mg, 0.22 mmol) was hydrogenated in MeOH (25 mL) with 5% Pd/BaSo 4 (202 mg) under a hydrogen atmosphere (50 psi). After stirring for 3 hours, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate (98 mg, 85%) as a solid: ES – MS (M+H)+ 515.4.

Example 2900: 2900 (a). 2R, 3S-methyl 4-benzyloxy-3-hydroxy-2-(2E-3-phenyl-2-propan-1-yl) butyrate

A 1.6 M hexane solution of n-butyllithium (140.4 ml, 2.1 equivalents) was added over 15 min to a solution of diisopropylamine (29.48 ml, 2.1 equivalents) in tetrahydrofuran (650 mL) at 0 ºC. The mixture is stirred for 15 minutes at 0 ºC and then cooled to -78 ºC. Methyl 4-benzyloxy-3S-hydroxybutyrate (24.00 g, 107 mmol) in tetrahydrofuran (40 mL) was added over 20 minutes via cannula and the residue was washed with tetrahydrofuran (2 x 20 mL). The resulting mixture is stirred for one hour at – 45 ºC, and 0.5 hours at – 20 ºC and cooled to – 78 ºC. A tetrahydrofuran (90 mL) solution of cinnamyl bromide (31.69 mL, 2.0 equivalents) and neat N,N,N'-tetramethylethylenediamine (32.33 mL, 2.0 equivalents) were gradually added. After 15 minutes at -40 ºC and 4 hours at -20 ºC, saturated ammonium chloride (500 mL) and hexane (400 mL) are added. After extracting the aqueous phase with ether (3 X 800 mL), the combined organic extracts were washed with water (50 mL), brine (50 mL), dried (MgSO4) and concentrated. Silica gel chromatography (ethyl acetate - hexane, 20 : 8, then 30 : 70, then 50 : 50) gives the product (28.78g, 73%, d.s. = 8:1) as a yellow oil. ESI – MS (M+H)+: calcd 341.2, found 341.2.

2900 (b). 2R, 3S-4-benzyloxy-3-hydroxy-(2E-phenyl-2-propan-1-yl) butyric acid

A 1.0 M aqueous solution of sodium hydroxide (450 mL) was added to a solution of 2900 (a) (28.08 g, 82.6 mmol) in methanol (450 mL) at 0 ºC and the resulting mixture was stirred for 2 hours at room temperature. After removal of methanol in vacuo, the aqueous residue was adjusted to pH 5 with 1 N sulfuric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and concentrated to give the product (27.06 g, 100%) as a solid. DCI – MS (M+NH4)+: calcd 344.2, found 340.

2900(c). 2R, 3S-4-benzyloxy-3-hydroxy-2-(2E-3-phenyl-2-propane-1-yl) butryl - N�- t-butoxycarbonyl -L-ornithine N-methyl amide

Diisopropylethylamine (12.18 mL, 4 equiv.) was added to a solution of 2900 (b) (5.70 g, 17.48 mmol), N�-t-butoxycarbonyl-L-ornithine N-methyl amide (7.49 g, 1.5 equiv., HCl salt) and benzotriazole- 1-yloxy-tri(dimethylamine)phosphonium hexafluorophosphate (7.97 g, 1.03 equivalents) in N,N-dimethylformamide (20mL) at 0 ºC. After 2 hours at 0 ºC, ethyl acetate (200 mL) is added. The mixture is washed with 10% citric acid (2 x 25 mL), brine (25 mL), saturated sodium bicarbonate (2 x 25 mL), brine (25 mL), dried (MgSO4) and concentrated. Silica gel chromatography (methanol - dichloromethane, 5:95 then 8:92) gives the product (7.16 g, 74%) as a solid. ESI – MS (M+H)+ calcd 554.4, found 554.4.

2900 (d).2R, 3S-4-benzyloxy-3-(2E-4-bromo-2-butan-1-yl)-2-(2E-3-phenyl-2-propan-1-yl) butyryl- N�- t - butoxycarbonyl-L-ornithine N-methyl amide

Sodium hydride (0.28 g, 1.8 equiv., 60% dispersion in mineral oil) was added to a solution of 2900 (c) (2.13 g, 3.85 mmol) and 2E - 1,4-dibromo-2-butane (8.00 g, 9.7 equiv.) in N,N – dimethylformamide (100ml) at 0 ºC. Additional amounts of 2E-1,4-dibromo-2-butane (4 g each) and sodium hydride (0.23 g each) were added every 20 minutes and the disappearance of starting materials was monitored by TLC analysis. After a total of 1.5 hours, the reaction seems complete. After addition of saturated ammonium chloride (40 ml) and ethyl acetate (120 ml), the aqueous phase is separated and extracted with ethyl acetate (6 x 60 ml). The combined extracts are dried (MgSO4) and concentrated. Silica gel chromatography (methanol - chloroform, 3:97 then 4:96) gives the desired product (1.86 g, 70%). ESI – MS (M + H)+: calcd 688.3, found 688.2.

2900 (e). 2S, 3R, 6S, 11E -2-benzyloxymethyl-10-t-butoxycarbonyl - 5, 10 -diaza-6-(N-methylcarboxamido)-1-oxa-4-oxo-3-(2E-3-phenyl-2 –propan–1–yl) cyclotetradecane

A 4 N solution of HCl in dioxane (20 mL) was added to 2900 (e) (1.86 g, 2.707 mmol). After 1.5 hours at room temperature, the solution is removed in vacuo. The remaining solid is washed with a small amount of ether, pumped to dryness to give the product (1.64 g). Diisopropylethylamine (2.33 mL, 5 equivalents) was added to a solution of this crude material in acetonitrile (1.3 L) at 0 ºC. The resulting mixture is stirred for 3 hours at room temperature. Di-t-butyl dicarbonate (2.33 g, 4 equivalents) was added. After 20 minutes at room temperature, the mixture is quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated. Silica gel chromatography twice (isopropanol - chloroform, 3:97 then 4:96 then 6:94 the first time, 5:95 the second time) gives the product (0.73 g, 45% for two steps). ESI – MS (M+H)+ :calculated 606.4, found 606.4.

2900 (f). 2S, 3R, 6S-10-t-butoxycarbonyl-5,10-diaza-2-hydroxymethyl-6-(N-methylcarboxamido)-1-oxa-4-oxo-3-(3-phenylprop-1-yl)cyclotetradecane

A suspension of 2900 (e) (0.73 g, 1.025 mmol) and Pearlman's catalyst (0.35 g) in methanol (200 mL) was stirred for 1 hour and 20 minutes under hydrogen pressure in a flask. The catalyst is removed by filtration. The filtrate is concentrated and purified by silica gel chromatography (methanol - chloroform, 3:97 then 5:95) to give the product (0.35 g, 56%). ESI – MS (M+H)+ : calculated 520.4, found 520.3.

2900 (g). 2S, 3R, 6S-10-t-Butoxycarbonyl-5,10-diaza-2-hydroxycarbonyl-6-(N-methylcarboxamido)-1-oxa-4-oxo-3-(3-phenylprop-1-yl)cyclotetradecane

Ruthenium (III) chloride (7.2 mg, 0.04 equivalents) and sodium periodate (0.74 g, 4 equivalents) were gradually added to a mixture of 2900 (f) (0.45 g, 0.866 mmol), acetonitrile (8 mL), carbon tetrachloride (8 mL ) and water (12 ml). After 2 hours at room temperature, chloroform (60 ml) is added. The aqueous fraction was separated and extracted with chloroform (5 x 30 ml). The combined organic phase is dried (MgSO4), and filtered through a pad of celite to give the desired carboxylic acid (0.43 g, 93%). ESI–MS (M+H)+: calcd 534.4, found 534.3.

2900 (h). 2S,3R,6S-2-(N-benzyloxycarboxamide)-10-t-butoxycarbonyl-5,10-diaza-6-(N-methylcarboxamido)-1-oxa-4-oxo-3-(3-phenylprop-1 -yl) cyclotetradecane

A 1.0 M solution of dicyclohexylcarbodiimide (0.038 mL, 1 equiv) in dichloromethane was added to a solution of 2900 (g) (20.1 mg, 0.0377 mmol), O-benzylhydroxyamine hydrochloride (7.2 mg, 1.2 equiv), 1-hydroxybenzotriazole hydrate (5.1 mg, 1.0 equiv) and diisopropylethylamine (0.0079 ml, 1.2 equiv) in tetrahydrofuran (2 ml). The mixture was stirred until the starting material disappeared, which was monitored by TLC and then quenched with saturated ammonium chloride. After extraction with ethyl acetate, the combined extracts were washed with brine, dried (MgSO4) and concentrated. Preparative thin-layer chromatography (methanol-chloroform, 5:95) afforded the desired product (12.8 mg, 53%) as a white solid. ESI–MS (M+H)+calcd 639.4, found 639.3.

2900: 2S,3R,6S-10-t-butoxycarbonyl-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamide)-1-oxa-4-oxo-3-(3-phenylprop –1–yl) cyclotetradecane

A mixture of 2900(h) (34.0 mg, 0.0532 mmol) and 5% Pd on BaSO4 (56.7 mg) and ethanol (4 ml) was stirred at room temperature under hydrogen pressure in a flask. Additional Pd on BaSO4 (115.3 mg) was added 1 hour later. After a total of 2 hours, the catalyst is removed by filtration. The filtrate was concentrated to give the desired hydroxamate (26.7 mg, 91%) as a white solid. ESI – MS (M+H)+ : calcd 549.3, found 549.3.

Example 2910:

2910(a). 2S, 3R, 6S-2-(N-benzyloxycarboxamide)-5,10-diaza-6-(N-methylcarboxamide)-1-oxa-4-oxo-3-(3-phenylprop-1-yl) cyclotetradecane hydrochloride

A mixture of 2900 (36.1 mg, 0.565 mmol) and a 4N solution of HCl in dioxane (1.0 mL) was stirred for 30 minutes at room temperature. Removal of the solution in vacuo gave the desired product as a white solid. The raw material is sent to the next stage of processing without purification. ESI–MS (M+H)+: calcd 539.3, found 539.3.

2910(b). 2S,3R,6S-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamide)-4-oxa-4-oxo-3-(3-phenylprop-1-yl) cyclotetradecane hydrochloride

Following a procedure analogous to the conversion of 2900 (h) to 2900 (i), 2900 (a) is converted to the desired product (26.3 mg, (95%, for two steps). ESI–MS (M+H)+ : calcd: 449.3 , found in 449.4.

Example 2920:

2920 (a). 2S, 3B, 6S-10-acetyl-2-(N-benzyloxycarboxamide)- 5,10-diaza-6-(N-methylcarboxamide)-1-oxa-4-oxo-3-(3-phenylprop-1-yl ) cyclotetradecane

The crude material from 2910 (a) derived from 2900 (h) (45.4 mg, 0.071 mmol) was treated with anhydrous acetate (1.5 mL) and diisopropylethylamine (0.040 mL, 3.2 equivalents). After 10 minutes, the reaction mixture is quenched with deionized ammonium chloride and extracted with ethyl acetate. The combined extracts are washed with saturated sodium bicarbonate and brine, dried (MgSO4) and concentrated. Silica gel chromatography (methanol-chloroform, 5:95 then 7.5:92.5) gives the desired product (32.9 mg, 80% for two phases). ESI–MS (M+H)+: calcd 581.4, found 581.4.

2920: 2S,3R,6S-10-acetyl-5, 10-diaza-2-(N-hydroxycarboxamide)-6-(N-methylcarboxamide)-1-oxa-4-oxo-3-(3-phenylprop-1 -yl) cyclotetradecane

After a procedure analogous to the conversion of 2900(h) to 2900(i), 2920(a) (31.8 mg, 0.0548 mmol) is converted to the desired product (24.0 mg, 89%). ESI–MS (M+H)+ : calcd 491.3, found 491.4.

Example 2930: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[glycine-N-hydroxypiperidine]-cyclopentadecane-13-N-hydroxycarboxamide

This compound is prepared using procedures analogous to those described above. ESI–MS: found 527.6.

Example 2931: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[glycine-N-(4-hydroxypiperidine)]-cyclopentadecane-13-N-hydroxycarboxamide

This compound is prepared using procedures analogous to those described above. ESI–MS: found 541.7.

Example 2940:

2940 (a) 2S,3R, 6S-2-(N-benzyloxycarboxamide)-10-benzenesulfonyl-5,10-diaza-6-(N-methylcarboxamide)-1-oxa-4-oxo-3-(3phenylprop-1 –yl)cyclotetradecane.

Benzenesulfonyl chloride (0.13 mL, 25 equiv) was added to 2910 (a) (23.2 mg, 0.043 mmol), and 4-(N,N-dimethylamine) pyridine (0.5 mg, 0.1 equiv) in pyridine (1 mL). After 30 minutes at room temperature, saturated ammonium chloride (2 ml) was added and the mixture was extracted with ethyl acetate. The combined extracts are washed with water, brine, dried (MgSO4) and concentrated. Preparative thin-layer chromatography (methanol-methylene chloride, 10:90) gives the desired product (11.1 mg, 41%). ESI–MS (M+H)+: calcd 679.4, found 679.3.

Example 2940: 2S,3R,6S-10-benzenesulfonyl-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamido)-1-oxa-4-oxo-3-(3-phenylprop- 1–yl) cyclotetradecane

Following a procedure analogous to the conversion of 2900 (h) to 2900(i), 2940 (a) (14 mg, 0.021 mmol) was converted to the desired product (12.7 mg, 100%) as a white solid. ESI–MS (M+H)+calcd 589.3, found 589.4.

Example 2950:

2950 (a). 2R, 3S-4-Benzyloxy-3-(2-bromomethyl-2-propan-1-yl)-2-(2E-3-phenyl-2-propan-1-yl) butyryl-Nδ-t-butoxycarbonyl-L -ornithine N-methyl amide

Following a procedure analogous to the conversion of 2900 (c) to 2900 (d), 2900 (c) (1.12 g, 2.03 mmol) was reacted with 3-bromo-2-bromomethylpropane to give the desired bromide (0.93 g, 67%) in the form white solid. ESI–MS (M+H)+ calcd 688.3, found 688.2.

2950 (b). 2R, 3S-4-Benzyloxy-3-(2-bromomethyl-2-propan-1-yl)-2-(2E-3-phenyl-2-propan-1-yl)butryl-L-ornithine N-methyl amide hydrochloride

Following a procedure analogous to the synthesis of 2900 (e), 2950 (a) (0.33 g, 0.48 mmol) was deprotected to give the desired product. The crude white solid is used without purification in the next step. ESI–MS (M+H)+: calcd 588.3, found 588.1.

2950 (c). 2S, 3R,6S-10-acetyl-2-benzyloxymethyl-5,10-diaza-6-(N-methylcarboxamido)-12-methylene-1-oxa-4-oxo-3-(2E-3-phenyl-2 –propan–1–yl) cyclotridecane

Following a procedure analogous to the conversion of 2900 (d) to 2900 (e), solid 2950 (b) was cyclized and reacted with anhydrous acetate to give the desired product (0.202 g, 76% over two steps) as a white solid. ESI–MS (M+H)+: calcd 548.3, found 548.4.

2950 (d). 2S, 3R, 6S, 12(R,S)-10-acetyl-5,10-diaza-2-hydroxymethyl-6-(N-methylcarboxamido)-12-methyl-1-oxa-4-oxo-3-( 3-phenylprop-1-yl) cyclotridecane

Following a procedure analogous to the conversion of 2900(e) to 2900(f), 2950(c) (0.20 g, 0.365 mmol) was reduced with hydrogen to give the desired product (0.14 g, 83%), an inseparable 1:1 mixture of the two diastereomers . ESI–MS (M+H)+: calcd 462.3, found 462.4

2950 (e) 2S,3R,6S,12 (R,S)-10-acetyl-5,10-diaza-2-hydroxycarbonyl-6-(N-methylcarboxamido)-12-methyl-1-oxa-4-oxo –3-(3-phenylprop-1-yl) cyclotridecane

Following a procedure analogous to the conversion of 2900 (f) to 2900 (g), 2950 (d) (0.14 g, 0.303 mmol) is oxidized to the desired acid (0.113 g, 78%). ESI–MS (M+H)+: calcd 476.3, found 476.3.

2950 (f). 2S, 3R, 6S, 12(R,S)-10-acetyl-2-(N-benzyloxycarboxamide)-5,10-diaza-6-(N-methylcarboxamido)-12-methyl-1-oxa-4-oxo –3-(3-phenylprop-1-yl) cyclotridecane

Following a procedure analogous to the conversion of 2900 (g) to 2900 (h), 2950 (e) (0.113 g, 0.237 mmol) was converted to the desired product (46 mg, 33%) as a white solid. ESI–MS (M+H)+ calcd 581.3, found 581.2.

2950 (g). 2S, 3R, 6S, 12(R,S)-10-acetyl-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamido)-12-methyl-1-oxa-4-oxo –3-(3-phenylprop-1-yl) cyclotridecane

Following a procedure analogous to the conversion of 2900 (h) to 2900 (i), 2950 (f) (51 mg, 0.088 mmol) is converted to the desired product (33 mg, 76%). ESI–MS (M+H)+ calcd 491.3, found 491.2.

Example 2960: 2S, 5S,12R-12-carboxy-3,10-dioxo-5-N-methylcarboxamide-2-phenethyl-1,4-9-triase - cyclotridecane trifluoroacetate

2960. 2S, 5S, 12R,-12-carboxy-3,10-dioxo-5-N-methylcarboxamido-2-phenethyl-1,4,9-triaza- cyclotridecane trifluoroacetate

Compound 2960 (d) (100 mg, 0.2 mmol) was dissolved in methylene chloride before the addition of TFA (1.7 mL). The reaction was stirred for 4 hours at RT. The solution is concentrated to give the title compound (80mg, 75%). MS (CI) m/e 419 (M+1) +

2960 (a). N-(9-fluorenylmethoxycarbonyl)-D-(β)-aspartic-t-butyl ester Nα-(benzyloxycarbonyl)-L-(ε)-lysine N-methylamide.

N-(9-Florenylmethoxycarbonyl)-D-aspartate-α-t-butyl ester (5 g, 12.1 mmol) is dissolved in methylene chloride and cooled to 0 ºC. HOBt (1.8 g, 13.3 mmol), 4-methylmorpholine (4.4 ml, 39.9 mmol), Nα-(benzyloxycarbonyl)-L-Lysine N-methylamide (4.8 g, 14.5 mmol), and EDC (3.0 g, 15.7 mmol) were then added. mmol). The reaction was warmed to RT and stirred for 15 h. The solution is washed with an aqueous solution of sodium bicarbonate, a 10% aqueous solution of citric acid, and a saline solution. The organic layer is dried and concentrated. The obtained material is purified by chromatography to give the desired amide (3.1 g, 47%). MS(CI) m/e 687 (M + 1)+

2960 (b). D-(β�-aspartic-t-butyl ester Nα-(benzyloxycarbonyl)-L-(ε)-lysine N-methylamide.

The compound from Example 2960 (a) (3.1 g, 4.6 mmol) was dissolved in DMF before the addition of diethylamine (7 ml). The reaction is stirred for 20 minutes. The solution was concentrated and purified by chromatography to give the desired amine (1.9 g, 86%). MS (CI) m/e 465 (M + 1)+

2960 (c). N–2'–(benzyl 4'–phenylbutanoate)–D–(β)–aspartic–t–butyl ester Nα–(benzyloxycarbonyl)–L–(ε)–lysine N–methylamide.

The compound of Example 2960 (b) (220 mg, 0.5 mmol) was dissolved in methylene chloride before the addition of Hunig's base (0.09 ml, 0.5 mmol) and (R)-benzyl 2-(trifluoromethyl)sulfonyloxy-4-phenylbutanoate (190 mg, 0.5 mmol) (Bennion, C.; Brown, R.C.; Cook, A.R.; Manners, C.N.; Payling, D.W.; Robinson, D.H. J. Med. Chem. 1991, 34, 439). After 15 hours, the solution was concentrated and purified by chromatography to give the desired secondary amine (290 mg, 86%). MS (Cl) m/e 717 (M + 1)+

2960 (d). 2S,5S,12R-12-t-butylcarboxy-3,10-dioxo-5-N-methylcarboxamido-2-phenethyl-1,4,9-triaza-cyclotridecane

The compound from Example 2960 (c) (270 mg, 0.4 mmol) is placed under a hydrogen atmosphere in methanol with 10% Pd/C (60 mg). After 5 hours, the solution is filtered and concentrated. The obtained material was dissolved in DMF and added to a solution of BOP (150 mg, 0.4 mmol) and Hunig's base (0.1 ml, 0.8 mmol) in DMF. This mixture is stirred for 24 hours. The solution was concentrated and purified by chromatography to give the desired triamide (55 mg, 30%). MS (Cl) m/e 475 (M + 1)+.

Example 2961: 2S,5S,13R-13-carboxy-3,10-dioxo-5-N-methylcarboxamido-2-phenethyl-1,4,9-triaza-cyclotetradecane trifluoroacetate

2961. 2S,5S,13R-13-carboxy-3,10-dioxo-5-N-methylcarboxamido-2-phenethyl-1,4,9-triaza-cyclotetradecane trifluoroacetate

The compound from Example 2961 (d) (60 mg, 0.1 mmol) was dissolved in methylene chloride before the addition of TFA (1 ml). The reaction was stirred for 4 hours at RT. The solution was concentrated to give the title compound (50 mg, 74%). MS (CI) m/e 433 (M + H) + .

2961 (a). N-(9-fluorenylmethoxycarbonyl)-D-(β)-glutamic-t-butyl ester Nα-(benzyloxycarbonyl)-L-(ε)-lysine N-methylamide.

N-Fmoc-D-glutamate-α-t-butyl ester (5g, 11.8 mmol) is dissolved in DMF and cooled to 0 ºC. HOBt (1.8 g, 13.3 mmol), 4-methylmorpholine (4.0 ml, 36.6 mmol), N–Cbz–L–LysineN-methylcarboxamide–HCl (5 g, 12.9 mmol), and BOP (6.8 g, 15.3 mmol) were then added. . The reaction was warmed to RT and stirred for 15 h. The solution is diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution, 10% aqueous citric acid solution, and saline solution. The organic layer is dried and concentrated. The resulting material was purified by chromatography to give the desired amide (8 g, quant). MS(CI) m/e 701 (M + 1)+

2961 (b) D-(β)-glutamic-t-butyl ester Nα�-(benzyloxycarbonyl)-L-(ε)-lysine N-methylamide

The compound from Example 2961 (a) (8 g, 11.8 mmol) was dissolved in DMF before the addition of diethylamine (36 ml). The reaction was stirred for 45 minutes. The solution was concentrated and purified by chromatography to give the desired amine (2.9 g, 49%). MS (CI) m/e 479 (M + 1)+

2961 (c). N-2'-(benzyl 4'-phenylbutanoate)-D-(β)-glutamic-t-butyl ester Nα��-(benzyloxycarbonyl)-L-(ε)-lysine N-methylamide

The compound of Example 2961 (b) (1 g, 2.1 mmol) was dissolved in methylene chloride before the addition of Hunig's base (0.4 mL, 2.1 mmol) and (R)-benzyl 2-(trifluoromethyl)sulfonyloxy-4-phenylbutanoate (0.6 mg, 2.1 mmol) (Bennion, C.; R.C.; Cook, A.R.; Manners, C.N.; Payling, D.W.; Robinson, D.H.J. Med. Chem. 1991, 34,439). After 15 hours, the solution was concentrated and purified by chromatography to give the desired secondary amine (2.3 g, 78%). MS (Cl) m/e 731 (M + 1)+

2961 (d). 2S,5S,13R-13-t-butylcarboxy-3,10-dioxo-5-N-methylcarboxamide-2-phenethyl-1,4,9-triaza-cyclotetradecane

The compound from Example 2961 (c) (2.1 g, 2.9 mmol) is placed under an atmosphere of hydrogen in methanol with 10% Pd/C (430 mg). After 4.5 hours, the solution is filtered and concentrated. An amount of the obtained material (400 mg, 0.8 mmol) was dissolved in DMF and added to a solution of BOP (454 mg, 1 mmol) and Hunig's base (0.3 ml, 1.6 mmol) in DMF. This mixture is stirred for 24 hours. The solution was concentrated and purified by chromatography to give the desired triamide (60 mg, 16%. MS (CI) m/e 489 (M + 1) + .

TABLE 1

For cyclophane:

[image]

[image] [image] TABLE 2

For cyclophane:

[image]

[image] [image] TABLE 3

For cyclophane:

[image]

[image] [image]

TABLE 4

For cyclophane:

[image]

[image] [image] TABLE 5

For cyclophane:

[image]

[image] [image] TABLE 6

For cyclophane:

[image]

[image] [image] TABLE 7

For cyclophane:

[image]

[image] [image] TABLE 8

For cyclophane:

[image]

[image] [image] TABLE 9

For a cyclic carbamate:

[image]

[image] [image]

TABLE 10

For a cyclic carbamate:

[image]

[image] [image] TABLE 11

For a cyclic carbamate:

[image]

[image] [image] TABLE 12

For a cyclic carbamate:

[image]

[image] [image] TABLE 13

For lactam:

[image]

[image] [image] TABLE 13

For cyclophane:

[image]

[image] [image] TABLE 14

For lactam:

[image]

[image] [image] TABLE 15

For lactam:

[image]

[image] [image] TABLE 16

For a cyclic amine:

[image]

[image] [image] TABLE 17

For cyclic sulphonamide:

[image]

[image] TABLE 18

For cyclic sulphonamide:

[image]

[image] TABLE 19

For cyclic sulphonamide:

[image]

[image] TABLE 20

For cyclic sulphonamide:

[image]

[image] TABLE 21

For cyclic sulphonamide:

[image]

[image] TABLE 22

For lactam:

[image]

[image] TABLE 23

For lactam:

[image]

[image] TABLE 24

For lactam:

[image]

[image] TABLE 25

For lactam:

[image]

[image] TABLE 26

For lactam:

[image]

[image]

TABLE 27

[image]

[image]

TABLE 28

[image]

[image]

TABLE 29

[image]

[image]

TABLE 30

[image]

[image]

TABLE 31

[image]

[image]

TABLE 32

[image]

[image]

TABLE 33

[image]

[image]

TABLE 34

[image]

[image]

APPLICATION

The compounds of Formula I show inhibitory activity against metalloproteinase, aggrecanase and TNF. The inhibitory activity of the ingredients of the present invention against MMP-3 was demonstrated by testing MMP-3 activity, for example, using the MMP-3 activity inhibitor assay described below. The compounds of this invention are available in vivo, as shown, for example, by the ex vivo assay described below. The ingredients of Formula I have the ability to suppress/inhibit the degradation of cartilage tissue in vivo, as shown, for example, by the animal model of acute cartilage degradation described below.

The compounds of this invention are also useful as standards and reagents for determining the ability of a potential pharmaceutical composition to inhibit MPs (metalloproteinases). These preparations would be found in commercially available kits that would contain the ingredient of this invention.

Metalloproteinases also participate in the degradation of basement membranes, which allows infiltration of tumor cells into the circulation and, as a result, penetration into other tissues and the formation of tumor metastases. (Stetler-Stevenson, Cancer and Metastasis Reviews, 9, 289-303, 1990) The compounds of this invention would be useful in the prevention and treatment of invasive tumors by inhibiting this aspect of metastasis.

The ingredients of this invention would also find application in the prevention and treatment of osteopenia associated with matrix metalloproteinase-mediated deterioration of cartilage and bone tissue that occurs in osteoporotic patients.

Compounds that inhibit the production or activity of TNF or aggrecanases and/or MPs are potentially useful in the treatment or prophylaxis of various inflammatory, infectious, immunological or malignant diseases. Some, but not all, of these diseases include inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, acute infection, septic shock, hemodynamic shock and septic syndrome, postischemic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, periodontitis, gingivitis, congestive heart failure, fibrotic disease, cachexia and anorexia, graft rejection, cancer, corneal ulceration or tumor invasion with secondary metastases, autoimmune diseases, skin inflammatory diseases, multiple osteo- and rheumatoid arthritis, multiple sclerosis, damage radiation, HIV, and hyperoxic alveolar injury.

Compounds of the invention have been shown to inhibit TNF production in lipopolysaccharide-stimulated mice, for example, using murine and human whole blood TNF induction assays as described below.

The compounds of the present invention show inhibition of aggrecanase, a key enzyme in the breakdown of cartilage, as determined by the aggrecanase assay described below.

As used herein, "g" means microgram, "mg" milligram, "g" gram, "L" microliter, "mL" milliliter, "L" liter, "nM" nanomolar, "M" micromolar, "mM" millimolar, " M" molar, "nm" nanometer. "Sigma" is the name of Sigma–Aldrich Corp. from St. Louis, Missouri.

A compound is considered active if it exhibits IC50 or Ki values of less than approximately 1 mM for MMP-3 inhibition.

Aggrecanase enzyme test

A new enzyme assay was developed to detect potential aggrecanase inhibitors. The test uses active aggrecanase accumulated in media from stimulated bovine nasal cartilage (BNC) or related cartilage sources and purified cartilage aggrecan monomer or its fragment as a substrate.

The concentration of the substrate, the duration of aggrecanase incubation and the amount of product required for Western analysis were optimized for the application of this test in finding potential aggrecanase inhibitors. Aggrecanase is produced by stimulation of cartilage slices with interleukin–1 (IL–1), tumor necrosis factor alpha (TNF), or other stimuli. Matrix metalloproteinases (MMPs) are secreted from cartilage in an inactive, zymogenic form after stimulation, although active enzymes are present within the matrix. We have shown that after depletion of the extracellular aggrecan matrix, active MMPs are released into the culture medium (Tortorella, M.D. et al. Trans. Ortho. Res. Soc. 20, 341, 1995). Therefore, in order to accumulate BNC aggrecanase in the culture medium, the cartilage is first released from endogenous aggrecan by stimulation with 500 mg/mL human recombinant IL– for 6 days and changing the medium every 2 days. The cartilage is then stimulated for an additional 8 days, without medium change, to allow accumulation of soluble, active aggrecanase in the culture medium. In order to reduce the amount of other matrix metalloproteinases released into the medium during aggrecanase accumulation, agents that inhibit the biosynthesis of MMP-1, -2, -3 and -9 are included during stimulation. This BNC conditioned medium, which contains aggrecanase activity, is then used as a source of aggrecanase in this assay. Enzymatic activity of aggrecanase is detected by monitoring the production of aggrecan fragments, which are formed exclusively by cleavage at the Glu373-Ala374 bond within the aggrecan core protein by Western analysis using the monoclonal antibody BC-3 (Hughes, C.E. et al., Biochem. J. 306:799-804, 1995). This antibody recognizes N-terminal aggrecan fragments, 374ARGSVIL.., created after cleavage by aggrecanase. The BC-3 antibody recognizes this neoepitope only when it is at the N-terminus and not when it is located within aggrecan fragments or within the core of the aggrecan protein. Other proteases produced in cartilage in response to IL–1 do not cleave aggrecan at the Glu373–Ala374 aggrecan site; therefore, the test detects only products formed by aggrecanase cleavage. Kinetic studies using this assay give a Km of 1.5+/– 0.35 µM for aggrecana.

To assess aggrecanase inhibition, compounds are prepared as 10 mM stock solutions in DMSO, water or other solvents and diluted to the appropriate concentration with water. The drug (50 L) is added to 50 L of medium containing aggrecanase and 50 L of 2 mg/mL aggrecan substrate and placed in a final volume of 200 L in 0.2 M Tris, pH 7.6 containing o.4 M NaCl and 40 mM CaCl2 . The test lasts 4 hours at a temperature of 37C, it is stopped with 20 mM EDTA and the products produced by aggrecanase are analyzed. The sample with enzyme and substrate without drug is taken as a positive control and the enzyme incubated without substrate serves as a blank test.

Removal of glycosaminoglycan side chains from aggrecan is necessary for the BC-3 antibody to recognize the ARGSVIL epitope on the protein core. Therefore, for the analysis of aggrecan fragments formed by cleavage at the Glu373–Ala374 site, proteoglycans and proteoglycan fragments are enzymatically deglycosylated with chondroitinase ABC (0.1 unit/10 g GAG) for 2 hours at 37C and then with keratanase (0.1 unit/10 g GAG) and keratanase II. (0.002 units/10 g GAG) for 2 hours at 37C in a buffer containing 50 mM Na-acetate, 0.1 M Tris HCl, pH 6.5. After digestion, aggrecan in the samples was precipitated with 5 volumes of acetone and resuspended in 30 L Tris–glycine–SDS sample buffer (Novex) containing 2.5% beta mercaptoethanol. Samples are loaded and then separated by SDS–PAGE under reducing conditions with 4–12% gradient gels, transferred to nitrocellulose and immunoblotted with 1:500 diluted BC-3 antibody. Membranes are then incubated with 1:5000 diluted alkaline phosphatase-labeled goat anti-mouse IgG secondary antibody and aggrecan catabolites are visualized by incubating with the appropriate substrate for 10–30 min to achieve optimal staining. Blots are quantified by scanning densitometry and aggrecanase inhibition is determined by comparing the amount of product formed in the presence or absence of the compound.

Bisacetylated substance P/MMP-3 fluorescence test

A high-throughput enzyme assay was developed to detect potential MMP-3 inhibitors. The test uses a derivative of the peptide substrate, substance P (Arg–Pro–Lys–Pro–Gln–Gln–Phe–Phe–Gly–Leu–Met), which is cleaved by the action of metalloproteinase exclusively at the glutamine-phenylalanine bond. To adapt this test to detailed "screening", we developed a fluorimetric product detection method. The formation of the hydrolysis product, substance P 7–11, is measured by reaction with fluorescamine, a fluorogenic compound that reacts with the primary amine of this fragment. The substance P substrate is biacetylated to block the primary amines of the intact substrate. The resulting fluorescence represents the formation of a product (7–11 peptide) formed after cleavage by MMP–3, and is quantified using a calibration curve with known concentrations of 7–11 peptide. Kinetic studies using a biacetylated substrate yield the following parameters for MMP–3: Km=769+/– 52 M; Vmax=0.090 +/- 0.003 nmoles 7–11 peptides/min.

To assess MMP–3 inhibition, compounds were prepared at a concentration of 10 mM in 100% methanol and then diluted to a 20X molar stock. Five microliters of stock of each preparation was added to the assay in the presence of 20 nM processed MMP-3 enzyme in 67.5 mM tricine (pH 7.5), 10 mM CaCl2, 40 mM NaCl, and 0.05% Brij 35 to a final volume of 100 microliters. Biacetylated substance P (1000 mM) was added and the test lasted for 1 hour at 25C. The reaction was stopped with EDTA (20 mM) and the product was detected fluorometrically after the addition of fluorescamine (0.075 mg/mL). The fluorescence of each sample is read as the amount of product formed from the calibration curve P 7–11. Under such conditions, the assay is linear for the amount of MMP-3 up to 10 pmol. Inhibition of MMP-3 was determined by comparing the amount of product formed in the presence and absence of the compound.

Selected compounds of this invention were tested and showed activity in the above assay.

Ex vivo assay for bioavailability of MMP–3 inhibitors

Blood was collected by cardiac puncture from rats at different time intervals after i.v., i.p. or p.o. compound dosing to determine the levels of inhibitor present. Plasma was extracted with 10% TCA in 95% methanol and placed on ice for 10 minutes. The plasma was then centrifuged for 15 minutes at 14,000 rpm in an Eppendorf microcentrifuge. The clear upper layer was removed, recentrifuged and the resulting supernatant diluted 1:10 in 50 mM tricine, pH 8.5. The pH of the sample was adjusted to 7.5, and then the sample was tested for MMP-3 substance P by fluorescent enzyme test. Plasma from control rats was extracted using the same method and was used as a negative control. This plasma was also used to prepare a wedge-type curve of the compound of interest in the plasma. Known concentrations of the compound were added to control plasma, the plasma was extracted using the same method, and then tested with the MMP-3 enzyme assay. A standard curve is prepared by relating the percent inhibition in the MMP-3 assay to the concentration of the compound added to the samples with a wedge-type curve. Based on the percent inhibition in the presence of plasma obtained from dosed rats, the concentration of the compound was determined using a standard curve.

Rat model of acute cartilage tissue degradation

A new in vivo model of acute cartilage degradation in rats is presented as a method for determining the content of proteoglycans in synovial fluid after the induction of cartilage degradation. The test groups show elevated levels of proteoglycan content in their synovial fluid compared to control rats. The criterion for proving the compound's activity in this model is the compound's ability to inhibit cartilage degradation, which is measured as increased proteoglycan content in the synovial fluid of rats after compound administration. Indomethacin, a nonsteroidal anti-inflammatory drug, is inactive in this model. Administration of indomethacin does not inhibit cartilage degradation in the tested rats. In contrast, administration of a compound of the present invention significantly inhibits the occurrence of cartilage degradation in this model.

TNF test on human whole blood

Blood is drawn from healthy donors in a tube with 143 USP units of heparin/10 mL. 225 L of blood is placed directly into sterile polypropylene tubes. The compounds are diluted in a medium without DMSO/serum and added to the blood samples in a final compound concentration of 50, 10, 5, 1, 0.5, 0.1 and 0.01 M. The final concentration of DMSO does not exceed 0.5%. Compounds are preincubated for 15 min before addition of 100 ng/mL LPS. The samples are incubated for 5 hours in an atmosphere of 5% CO2 in air. After 5 hours, 750 L of serum-free medium is added to each tube and the samples are spun at 1200 RPM for 10 minutes. The supernatant is collected from the top and tested for TNF- production using a standard sandwich ELISA test. The ability of compounds to inhibit TNF- production by 50% compared to DMSO-treated cultures is indicated as the IC50 value.

Induction of TNF in mice

Test compounds are administered to mice either i.p. or p.o. in zero time. Immediately after compound administration, mice receive an i.p. injection with 20 mg of D-galactosamine and 10 g of lipopolysaccharide. One hour later, the animals are anesthetized and exsanguinated by cardiac puncture. The levels of TNF in the blood plasma are assessed with an ELISA test specific for murine TNF. Administration of representative compounds of this invention to mice results in suppression of plasma TNF within one hour of administration of the compound in the experiment described above.

Dosage and formulation

The compounds of this invention may be administered orally using any pharmaceutically acceptable formulation known in the art for such drug administration. The active compound can be administered in solid drug forms such as dry powders, granules, tablets or capsules, or in liquid forms such as syrups or aqueous suspensions. The active compound can be given alone, but is generally taken with a pharmaceutical carrier. A valuable discussion of pharmaceutical drug formulation is Remington's Pharmaceutical Sciences, Mack Publishing.

The compounds of this invention may be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Similarly, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, always using formulations well known to those skilled in the pharmaceutical art. An effective but non-toxic amount of the desired compound can be used as an anti-inflammatory and anti-rheumatic agent.

The compounds of the present invention can be administered by any means that produces contact of the active agent with the site of action of the agent, MMP-3, in the body of a mammal. They can be administered by any conventional means available for pharmaceutical use, either as single medicinal agents or in combination of medicinal agents. They can be administered alone, but are generally administered with a pharmaceutical carrier chosen based on the chosen route of administration and standard pharmaceutical practice.

The prescribed method of dosing the compounds of this invention will vary, of course, depending on known factors such as the pharmacodynamic characteristics of the individual agent and its method and route of administration, species, age, sex, health, state of health, and weight of the recipient; nature and degree of symptoms; type of comparative therapy; frequency of therapy; the route of administration, the patient's renal and hepatic function, and the desired effect. An experienced physician or veterinarian can readily determine and prescribe the effective amount of medication needed to prevent, prevent, or halt the progression of a condition.

According to accepted regulations, the daily oral dosage of such an active ingredient, if used for the indicated effects, would be in the range of 0.001 to 1000 mg/kg of body weight, better between 0.01 to 100 mg/kg of body weight per day, and best about 1.0 to 20 mg/kg/day. For a healthy adult male weighing 70 kg, this would mean a dose of 70 to 1400 mg/day. The most appropriate intravenous doses would be in the range of 1 to 10 mg/kg/minute during a constant infusion rate. Advantageously, the compounds of this invention may be administered in a single daily dose, or the entire daily dose may be administered in divided doses two, three, or four times a day.

The compounds of this invention may be administered intranasally by topical application of a suitable intranasal vehicle, or by transdermal routes, using transdermal skin "patches" well known to the skilled artisan. To be administered as a transdermal delivery system, the prescribed dose will be administered continuously rather than intermittently.

According to the methods of the present invention, the compounds detailed herein may form an active compound, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (referred to herein collectively as carriers) selected as appropriate with respect to the intended route of administration, i.e. , as oral tablets, capsules, elixirs, syrups and as it is already similar and consistent with pharmaceutical practice.

For example, for oral administration in the form of a tablet or capsule, the active drug compound can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the ingredients of the oral drug can be combined with any oral, non-toxic, pharmaceutically suitable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may be included in the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, grain sweeteners, natural or synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these drug formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of this invention may also be administered in the form of liposomal carrier systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be constructed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

The compounds of this invention can also be bound to soluble polymers as drug target carriers. Such carriers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide polylysine substituted with palmitoyl residues. Furthermore, the compounds of this invention can be linked to a class of biodegradable polymers useful in achieving controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acids, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polyoxyacylates, and cross linked or amphipathic block-copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain about 1 milligram to about 100 milligrams of active ingredient per unit dose. In these pharmaceutical compositions, the active compound will generally be present in an amount of about 0.5–95% by weight with respect to the total weight of the composition. The active compound can be administered orally in solid dosage forms, such as capsules, tablets, or powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules can contain the active compound and powder carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be formulated as sustained-release products to provide continuous release of the medicinal agent over a period of several hours. Compressed tablets can be coated with sugar or film to mask the unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective degradation in the gastrointestinal tract.

The liquid formulation of the drug for oral administration may contain colors and additives to improve the patient's acceptance of the drug. In general, water, suitable oil, salt, aqueous dextrose (glucose), and related sugar and glycol solutions such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffering agents. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also in use are citric acid and its salts and sodium EDTA. Additionally, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in the art. Applications of pharmaceutical drug formulation for the administration of the compounds of this invention can be seen from the following:

Capsules

Capsules are prepared by conventional methods so that the unit dose is 500 milligrams of active ingredient, 100 milligrams of cellulose and 10 milligrams of magnesium stearate. A large number of unit capsules can also be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.

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The final volume is obtained by topping up to 100% with distilled water.

Aqueous suspension

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Xanthan gum is added slowly to distilled water before adding the active ingredient and other compounds of the recipe. The final suspension is passed through a homogenizer to ensure the appearance of the final product.

Resuspending powder

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Each ingredient is finely pulverized and then uniformly mixed together. Alternatively, the powder can be prepared as a suspension and then spray dried.

Semi-solid gel

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Gelatin is prepared in hot water. The finely pulverized active compound is suspended in the gelatin solution and then the remaining ingredients are mixed in. The suspension is filled into a suitable packaging container and cooled to form a gel.

Semi-solid paste

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Gelkarin® is dissolved in hot water (about 80°C) and then the finely powdered active compound is suspended in that solution. Sodium saccharin and other ingredients of the recipe are added to the suspension while it is still warm. The suspension is homogenized and filled into suitable containers.

Emulsion paste

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All ingredients are carefully mixed together to obtain a homogeneous paste.

Soft gelatin capsules

A mixture of the active ingredient in a digestible oil such as soybean oil, linseed oil, or olive oil is prepared and injected into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

Pills

Tablets can be prepared by usual (agreed) procedures so that the dosage unit is 500 milligrams of active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose and 10 milligrams of magnesium stearate.

A large number of tablets can also be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch, and 98.8 milligrams of lactose. Suitable coatings may be applied to improve taste or slow absorption.

Injections

A parenteral composition suitable for administration by injection is prepared by mixing the active ingredient (mass fraction 1.5%) in a mixture of water with 10% propylene glycol (v/v). Isotonicity of the solution is achieved with sodium chloride and the solution is sterilized.

Suspension

The aqueous suspension is prepared for oral administration so that each 5 mL contains 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.

The compounds of this invention may be administered in combination with other therapeutic agents, particularly non-steroidal anti-inflammatory drugs (NSAIDs). A compound of Formula I and such secondary therapeutic agent may be administered separately or in physical combination in a single dosage unit, in any dosage form and by various routes of administration, as described above.

A compound of Formula I may be formulated together with a secondary therapeutic agent in a single dosage unit (ie, combined together in a single capsule, tablet, powder, liquid form, etc.). If the compound of Formula I and the second therapeutic agent are not formulated together in a single dosage unit, then the compound of Formula I and the second therapeutic agent may be administered simultaneously, or in any order, for example the compound of Formula I may be administered first followed by the second agent . If not administered simultaneously, preferably the compound of Formula I and the other therapeutic agent are administered less than about one hour apart, more preferably less than about 5 to 30 minutes apart.

The preferred route of administration of the compound of Formula I is by oral route. Although it is preferred that the compound of Formula I and the secondary therapeutic agent are both administered in the same manner (ie, for example, both orally), if desired, it is possible to give each of them in a different manner and in different dosage forms (ie, for example, one ingredient of the combination the preparation can be given orally, and the other ingredient intravenously).

The dosage of a compound of Formula I when administered alone or in combination with a secondary therapeutic agent may vary depending on a variety of factors such as the pharmacodynamic characteristics of the individual agent and its method and route of administration, age, sex, health and weight of the recipient, nature and degree of symptoms, species comparative therapies, frequency of therapy, desired effect, as described above.

Especially when given as a single dosage unit, there is a possibility of chemical interaction between the combined active ingredients. Therefore, when a compound of Formula I and a secondary therapeutic agent are combined in a single dosage unit, they are formulated so that, although the active ingredients are combined in a single dosage unit, physical contact between the active ingredients is minimized. For example, one active ingredient can be enteric coated. By enteric coating of one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also to control the release of one of these ingredients in the digestive tract so that one of the ingredients is not released in the stomach but rather in the intestines. One of the active ingredients can also be coated with a sustained-release substance whose effect is sustained release through the digestive tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-release ingredient can be additionally enterically coated so that the ingredient is released only in the intestines. Another approach would involve formulating a combination composition in which one ingredient is coated with a sustained and/or enteric release polymer and the other ingredient is also coated with a polymer such as low viscosity hydroxypropyl methylcellulose (HPMC) or other suitable material known in the art, to separated the active ingredients even more. Coating with a polymer serves to create an additional barrier to interaction with another ingredient.

These and other ways of minimizing the contact between the ingredients of the combined preparations of this invention, whether they are administered in a single dosage form or in separate forms but simultaneously and in the same way, will be immediately clear to those skilled in the art, as soon as they become familiar with this discovery (invention). .

The present invention also includes pharmaceutical kits (kits) useful, for example, in the treatment or prevention of osteoarthritis or rheumatoid arthritis, which contain one or more containers with a pharmaceutical composition with a therapeutically effective amount of a compound of Formula I. Such kits may further contain, if necessary, one or more of a variety of conventional pharmaceutical kit components, such as for example containers with one or more pharmaceutically suitable carriers, additional containers, etc. as known to those skilled in the art. Instructions given either as inserts or as labels, which tell about the amounts of ingredients to be applied, the instructions for application and/or the instructions for mixing the ingredients, can also be found in the set.

It should be clear that the materials and conditions specified in this invention are significant in the implementation of the invention, but that unspecified materials and conditions are not excluded as long as they do not prevent the realization of the usefulness of the invention.

Although the present invention has been described with respect to specific (framework) conditions, the details of those conditions should not be considered limiting. Various equivalents, changes and modifications may be made without departing from the spirit and purpose of the present invention, and such equivalent terms are considered part of the present invention.

Claims (32)

1. Compound of Formula I: [image] Formula I or its pharmaceutically acceptable salts or prodrug forms, indicated that U is selected from: –CO2H, –CONHOH, –CONHOR11, –SH, –NH– COR11, –N(OH)COR11, –SN2H2R6, –SONHR6, CH2CO2H, PO(OH)2, PO(OH)NHR6, CH2SH, –C(O)NHOR12, –CO2R12 and common prodrug derivatives; R1 is selected from: H, –(CO–C6)alkyl–S(O)p–(C1–C6)alkyl, –(CO–C6)alkyl–O–(C1–C6)alkyl, –(CO–C6)alkyl–S(O)p–(CO–C6)alkyl–aryl, –(CO–C6)alkyl–O–(CO–C6)alkyl–aryl, alkyl of 1 to 20 carbon atoms including branched, cyclic and unsaturated alkyl groups, substituted alkyl characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio, (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido, –(CO–C8)alkyl–aryl, –(CO–C8)alkyl–substituted aryl, –(CO–C8)aryl–(C1–C4)alkyl–aryl, –(C1–C8)alkyl–biaryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–aryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl, –(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[S(O)p–(CO–C8)alkyl], –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–alkyl–biaryl, –(CO–C8)alkyl–O–(CO–C8)alkyl–aryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl, –(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[O–(CO–C8)alkyl], –(CO–C8)alkyl–O–(CO–C8)alkyl–biaryl, –(CO–C8)alkyl–O–(CO–C8)alkyl–substituted aryl, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl; R2 is selected from H, –CO2R5, –CONR6R5, –CONR6(OR5), -alkyl, -alkylaryl, -alkylheteroaryl, -alkylheterocyclic compound, -aryl, -heteroaryl or – a heterocyclic compound that has been replaced by one or more substituents selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy; R3 is selected from: –H, –OH, –OR6 –NH2, –NHR6, –N(R6)2, –(C1–C6)alkyl, -(C1-C6)alkyl-aryl, SR6, halide or nitrile; Likewise, R2 and R3 can form a 3- or 8-membered saturated, unsaturated, aryl, heteroaryl or heterocyclic ring; R4 is selected from: H, –OH, –OR6, –NH2, –NHR6, –N(R6)2, –(C1–C6)alkyl, -(C1-C6)alkyl-aryl, -S(O)p-(C1-C6)alkyl, halide or nitrile; R5 is selected from: –(CHR1Y)n–R9, –C(R7R8)n–W–C(R7R8)m–R9 –C(R7R8)m–R9, –C(R7R8)m–aryl, –C(R7R8)m–CONR7R8, -C(R7R8)m-substituted heteroaryl, –C(R7R8)m–substituted heterocyclic compound, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R6 is selected from: H, alkyl, –(C1–C6)alkyl–aryl, –(C1–C6)alkyl–heteroaryl, –(C1–C6)alkyl–heterocyclic compound, -(C1-C6)alkyl-acyl; Likewise, R5 and R6 can form a 3- to 8-membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from -O, -NR6, -S(O)p, or an acyl group, optionally attached to an aryl ring ; R7 and R8 can be independently selected from: H, R1 or from a 3- to 7-membered substitution ring with unsaturated bonds 0-3, indicated that the substitute is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl, optionally containing –O–,–S(O)p, – NR6 is optionally fused to a substituted aryl ring, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R9 is H, alkyl, cycloalkyl 5- to 6-membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with –OH, –O-(C1–C6)alkyl, – O-alkyl-alkyl, NHR10 or aryl; R 10 is H or an optionally substituted alkyl group; R11 is hydrogen, alkyl of 1 to 10 atoms including branched, cyclic and unsaturated alkyl groups, substituted alkyl characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide, –(C1–C4)alkyl–aryl, –(C1–C4)alkyl–(C1–C8)alkyl–aryl, –(C1–C8)alkyl–biaryl, substituted –(C1–C8)alkyl–aryl, characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide; R11a is H, –SO2–C1–C6–alkyl, –SO2–C1–C6–alkyl, substituted aryl, –SO2–aryl, –SO2– substituted heteroaryl, –COR9, –CO2t–Bu, –CO2Bn, or –alkyl –substituted aryl characterized in that the substituent is selected from: hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R12 is selected from: H, aryl, (C1 to C10)alkyl–, aryl (C1 to C6)alkyl–, C3 to C11 cycloalkyl, C3 to C10 alkylcarbonyloxyalkyl, C3 to C10 Alkoxycarbonyloxyalkyl, C2 to C10 Alkoxycarbonyl, C5 to C10 cycloalkylcarbonyloxyalkyl, C5 to C10 cycloalkoxycarbonyloxyalkyl, C5 to C10 cycloalkyloxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy (C1 to C6 alkyl)–, arylcarbonyloxy (C1 to C6 alkyl)–, C5 to C12 Alkoxyalkylcarbonyloxyalkyl, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-oneyl*] methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one*-yl)methyl, (R17) (R17a)N–(C1–C10 alkyl)–, CH(R13)OC(=O)R14, –CH(R 13 )OC(=O)OR 15 , or [image] ; indicated by that R13 is H or C1-C4 linear alkyl; R14 is selected from: H, C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 Alkoxy, aryl substituted with 0 to 2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1), aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1); R15 is selected from: C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 Alkoxy, aryl substituted with 0 to 2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S (C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1), aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S (C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1); R16 is C1-C4 alkyl, benzyl or phenyl, R17 and R17a are independently selected from: H, C1-C10 alkyl, C2-C6 alkenyl, C4-C11 cycloalkylalkyl and aryl (C1-C6 alkyl); Combinations of A, B and D, and/or variables are permitted only if such combinations result in stable compounds (as defined herein). A may be omitted, –(CHR6)m–, –O(CHR6)m–, –NR6(CHR6)m–, –S(O)p(CHR6)m–, or selected from alkyl of 1 to 10 carbon atoms which include branched cyclic and unsaturated alkyl groups or -(C1-C6 )alkyl-aryl; B can be a bond or selected from –NH–, –NR11–, –NR11a–, –O–, –S(O)p–(C1–C6 )alkyl–NH–(C1–C6)alkyl–, (C1–C6)alkyl–NR11–(C1–C6)alky–, – C1–C6–NH–aryl–, –O–(C1–C6 )alkyl–, –(C1–C6 )alkyl–O–aryl–, –S–(C1–C6 )alkyl–, –(C1–C6)alkyl–S–aryl–, –(C1–C6) alkyl–, –(C1–C6) alkenyl–, –(C1–C6) alkynyl–, –CONH–, –CONR11, –NHCO–, –NR11CO–, –OCO–, –COO–, –OCO2–, –R11NCONR11–, HNCONH–, –OCONR11–, –NR11COO–, –HNSO2–, –SO2NH–, aryl, cycloalkyl, heterocycloalkyl, –R11NCSNR11–, –HNCSNH–, –OCSNR11–, –NR11CSO–, –HNCNNH–, and mimic peptide bond; [image] D may be omitted or alkyl of 1 to 10 carbon atoms optionally containing O, S or NR6, which includes branched cyclic and unsaturated alkyl groups and aryl C1-C6 alkyl-; p can be 0, 1 or 2; m is the integral from 0 to 5; n is the integral from 1 to 5; W is –O–, –S(O)p– or –NR10–; Y is selected from: –CONR10–, –NR10CO–, –SO2NR10–, NR10SO2–, mimetic peptide bond, 5-membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N, O or S, provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–C(U)(R4)–, is linked to no less than 11 atoms and no more than 22 atoms when forming a ring. 2. Compound of Formula II [image] Formula II or its pharmaceutically acceptable salts or prodrug forms, characterized in that X is selected from CH2, NH, NR5, S(O)p or O; U, Y, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R11a, R12, R13, R14, R15, R16, R17, R17a and p, m, n, A, B , D and W are previously determined in formula I and defined as stable compounds; provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–X–C(U)(R4)–, is linked to not less than 11 atoms and no more than 22 atoms when forming a ring. 3. Compound of Formula III: [image] Formula III or its pharmaceutically acceptable salts or prodrug forms, characterized in that U is selected from: –CO2H, –CONHOH, –CONHOR11, –SH, –NH– COR11, –N(OH)COR11, –SN2H2R6, –SONHR6, CH2CO2H, PO(OH)2, PO(OH)NHR6, CH2SH, and common derivatives of prodrugs –C(O)NHOR12 and –CO2R12; Z is selected from: N or CH; R1, R4, R6, R11, R11a, R12, R13, R14, R15, R16, R17, R17a, A, B, C are previously determined in formula I and defined as stable compounds; 4. Compound from Claim 1, characterized in that U is selected from: –CONHOH, –CONHOR11, –N(OH)COR11, –SN2H2R6, –SONHR6, –CO2H, –CH2SH, –C(O)NHOR12 and common prodrug derivatives; R1 is selected from: H, –(CO–C6)alkyl–S(O)p–(C1–C6)alkyl, –(CO–C6)alkyl–O–(C1–C6)alkyl, –(CO–C6)alkyl–S(O)p–(CO–C6)alkyl–aryl, –(CO–C6)alkyl–O–(CO–C6)alkyl–aryl, alkyl of 1 to 20 carbon atoms including branched, cyclic and unsaturated alkyl groups, substituted alkyl characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio, (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido, –(CO–C8)alkyl–aryl, –(CO–C8)alkyl–substituted aryl, –(CO–C8)aryl–(C1–C4)alkyl–aryl, –(C1–C8)alkyl–biaryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–aryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl, –(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[S(O)p–(CO–C8)alkyl], –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–alkyl–biaryl, –(CO–C8)alkyl–O–(CO–C8)alkyl–aryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl, –(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[O–(CO–C8)alkyl], –(CO–C8)alkyl–O–(CO–C8)alkyl–biaryl, –(CO–C8)alkyl–O–(CO–C8)alkyl–substituted aryl, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl; R2 is selected from H, –CO2R5, –CONR6R5, –CONR6(OR5), -alkyl, -alkylaryl, -alkylheteroaryl, -alkylheterocyclic compound, -aryl, -heteroaryl or -a heterocyclic compound that is substituted with one or more substituents selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy; R3 is selected from: –H, –OH, and –NH2; Likewise, R2 and R3 can form a 3- or 6-membered saturated, unsaturated, aryl, heteroaryl or heterocyclic ring; R4 is selected from: H, –OH, and –NH2; R5 is selected from: –(CHR1Y)n–R9, –C(R7R8)n–W–C(R7R8)m–R9 –C(R7R8)m–R9, –C(R7R8)m–aryl, –C(R7R8)m–CONR7R8, -C(R7R8)m-substituted heteroaryl, –C(R7R8)m–substituted heterocyclic compound, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R6 is selected from: H, alkyl, –(C1–C6)alkyl–aryl, –(C1–C6)alkyl–heteroaryl, –(C1–C6)alkyl–heterocyclic compound, -(C1-C6)alkyl-acyl; Likewise, R5 and R6 can form a 3- to 8-membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from -O, -NR6, -S(O)p, or an acyl group, optionally attached to an aryl ring ; R7 and R8 can be independently selected from: H, R1 or from a 3- to 7-membered substitution ring with unsaturated bonds 0-3, indicated that the substitute is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl, optionally contains –O–,–S(O)p, –NR6, optionally fused with a substituted aryl ring, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R9 is H, alkyl, cycloalkyl 5- to 6-membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with –OH, –O-(C1–C6)alkyl, – O-alkyl-alkyl, NHR10 or aryl; R 10 is H or an optionally substituted alkyl group; R11 is hydrogen, alkyl of 1 to 10 atoms including branched, cyclic and unsaturated alkyl groups, substituted alkyl characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide, –(C1–C4)alkyl–aryl, –(C1–C4)alkyl–(C1–C8)alkyl–aryl, –(C1–C8)alkyl–biaryl, substituted –(C1–C8)alkyl–aryl, characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide; R11a is H, –SO2–C1–C6–alkyl, –SO2–C1–C6–alkyl–substituted aryl, –SO2–aryl, –SO2– substituted heteroaryl, –COR9, –CO2t–Bu, –CO2Bn or –alkyl– substituted aryl characterized in that the substituent is selected from: hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R12 is selected from: H, aryl, (C1 to C10)alkyl–, aryl (C1 to C6)alkyl–, C3 to C11 cycloalkyl, C3 to C10 alkylcarbonyloxyalkyl, C3 to C10 Alkoxycarbonyloxyalkyl, C2 to C10 Alkoxycarbonyl, C5 to C10 cycloalkylcarbonyloxyalkyl, C5 to C10 cycloalkoxycarbonyloxyalkyl, C5 to C10 cycloalkyloxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy (C1 to C6 alkyl)–, arylcarbonyloxy (C1 to C6 alkyl)–, C5 to C12 Alkoxyalkylcarbonyloxyalkyl, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-oneyl*] methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one*-yl)methyl, (R17) (R17a)N–(C1–C10 alkyl)–, CH(R13)OC(=O)R14, –CH(R 13 )OC(=O)OR 15 , or [image] ; indicated by that R13 is H or C1-C4 linear alkyl; R14 is selected from: H, C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 Alkoxy, aryl substituted with 0 to 2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a), –CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1), aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a), –CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1); R15 is selected from: C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 Alkoxy, aryl substituted with 0 to 2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S(C1–C5 alkyl), –S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a), –CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1), aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S(C1–C5 alkyl), –S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a), –CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1); R16 is C1-C4 alkyl, benzyl or phenyl, R17 and R17a are independently selected from: H, C1-C10 alkyl, C2-C6 alkenyl, C4-C11 cycloalkylalkyl and aryl (C1-C6 alkyl); Combinations of A, B and D, and/or variables are permitted only if such combinations result in stable compounds (as defined herein). A may be omitted, –(CHR6)m–, –O(CHR6)m–, –NR6(CHR6)m–, –S(O)p(CHR6)m–, or selected from alkyl of 1 to 10 carbon atoms which include branched cyclic and unsaturated alkyl groups or -(C1-C6 )alkyl-aryl; B can be a bond or selected from –NH–, –NR11–, –NR11a–, –O–, –S(O)p–(C1–C6 )alkyl–NH–(C1–C6)alkyl–, (C1–C6)alkyl–NR11–(C1–C6)alky–, – C1–C6–NH–aryl–, –O–(C1–C6 )alkyl–, –(C1–C6 )alkyl–O–aryl–, –S–(C1–C6 )alkyl–, –(C1–C6)alkyl–S–aryl–, –(C1–C6) alkyl–, –(C1–C6) alkenyl–, –(C1–C6) alkynyl–, –CONH–, –CONR11, –NHCO–, –NR11CO–, –OCO–, –COO–, –OCO2–, –R11NCONR11–, HNCONH–, –OCONR11–, –NR11COO–, –HNSO2–, –SO2NH–, aryl, cycloalkyl, heterocycloalkyl, –R11NCSNR11–, –HNCSNH–, –OCSNR11–, –NR11CSO–, –HNCNNH–, and mimic peptide bond; [image] D may be omitted or alkyl of 1 to 10 carbon atoms optionally terminated by O, S or NR6, which includes branched, cyclic and unsaturated alkyl groups and C1-C6-alkyl-aryl; p can be 0, 1 or 2; m is the integral from 0 to 5; n is the integral from 1 to 5; W is –O–, –S(O)p– or –NR10–; Y is selected from: –CONR10–, –NR10CO–, –SO2NR10–, NR10SO2–, mimetic peptide bond, 5-membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N, O or S, provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–C(U)(R4)–, is linked to no less than 11 atoms and no more than 22 atoms when forming a ring. 5. The compound of claim 2, characterized in that X is selected from CH 2 , NH, S or O; U, Y, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R11a, R12, R13, R14, R15, R16, R17, R17a and p, m, n, A, B , D and W are previously determined in formula I and defined as stable compounds; provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–X–C(U)(R4)–, is linked to not less than 11 atoms and no more than 22 atoms when forming a ring. 6. The compound of claim 1, characterized in that U is selected from: –CONHOH, –C(O)NHOR12, –CO2H and common prodrug derivatives; R1 is selected from: H, –(CO–C6)alkyl–S(O)p–(C1–C6)alkyl, –(CO–C6)alkyl–O–(C1–C6)alkyl, –(CO–C6)alkyl–S(O)p–(CO–C6)alkyl–aryl, –(CO–C6)alkyl–O–(CO–C6)alkyl–aryl, alkyl of 1 to 20 carbon atoms including branched, cyclic and unsaturated alkyl groups, substituted alkyl characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio, (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido, –(CO–C8)alkyl–aryl, –(CO–C8)alkyl–substituted aryl, –(CO–C8)aryl–(C1–C4)alkyl–aryl, –(C1–C8)alkyl–biaryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–aryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl, –(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[S(O)p–(CO–C8)alkyl], –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–alkyl–biaryl, –(CO–C8)alkyl–O–(CO–C8)alkyl–aryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl, –(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[O–(CO–C8)alkyl], –(CO–C8)alkyl–O–(CO–C8)alkyl–biaryl, –(CO–C8)alkyl–O–(CO–C8)alkyl–substituted aryl, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl; R2 is selected from H, –CO2R5, –CONR6R5, –CONR6(OR5), -alkyl, -alkylaryl, -alkylheteroaryl, -alkylheterocyclic compound, -aryl, -heteroaryl or -a heterocyclic compound that is substituted with one or more substituents selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy; R 3 and R 4 are H; R5 is selected from: –(CHR1Y)n–R9, –C(R7R8)n–W–C(R7R8)m–R9 –C(R7R8)m–R9, –C(R7R8)m–aryl, –C(R7R8)m–CONR7R8, -C(R7R8)m-substituted heteroaryl, –C(R7R8)m–substituted heterocyclic compound, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R6 is selected from: H, alkyl, –(C1–C6)alkyl–aryl, –(C1–C6)alkyl–heteroaryl, –(C1–C6)alkyl–heterocyclic compound, -(C1-C6)alkyl-acyl; Likewise, R5 and R6 can form a 3- to 8-membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from -O, -NR6, -S(O)p, or an acyl group, optionally attached to an aryl ring ; R7 and R8 can be independently selected from: H, R1 or from a 3- to 7-membered substitution ring with unsaturated bonds 0-3, indicated that the substitute is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl, optionally contains –O–,–S(O)p, –NR6, optionally fused with a substituted aryl ring, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R9 is H, alkyl, cycloalkyl 5- to 6-membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with –OH, –O-(C1–C6)alkyl, – O-alkyl-alkyl, NHR10 or aryl; R 10 is H or an optionally substituted alkyl group; R 11 is hydrogen, alkyl of 1 to 6 C atoms including branched, cyclic and unsaturated alkyl groups, substituted alkyl; characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio) carboxy , carboxamido, carbo-alkoxy, or sulfonamide, –(C1–C4)alkyl–aryl, -(C1-C8)alkyl-substituted aryl, characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio) carboxy , carboxamido, carbo-alkoxy, or sulfonamide; R11a is H, –SO2–C1–C6–alkyl, –SO2–C1–C6–alkyl– substituted aryl, –SO2–aryl, –SO2– substituted heteroaryl, –COR9, –CO2t–Bu, –CO2Bn, characterized in that the substituent is selected from: hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R12 is selected from: H, aryl, (C1 to C10)alkyl–, aryl (C1 to C6)alkyl–, C3 to C11 cycloalkyl, C3 to C10 alkylcarbonyloxyalkyl, C3 to C10 Alkoxycarbonyloxyalkyl, C2 to C10 Alkoxycarbonyl, C5 to C10 cycloalkylcarbonyloxyalkyl, C5 to C10 cycloalkoxycarbonyloxyalkyl, C5 to C10 cycloalkyloxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy (C1 to C6 alkyl)–, arylcarbonyloxy (C1 to C6 alkyl)–, C5 to C12 Alkoxyalkylcarbonyloxyalkyl, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-oneyl*] methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one*-yl)methyl, (R17) (R17a)N–(C1–C10 alkyl)–, CH(R13)OC(=O)R14, –CH(R 13 )OC(=O)OR 15 , or [image] ; indicated by that R13 is H or C1-C4 linear alkyl; R14 is selected from: H, C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 Alkoxy, aryl substituted with 0 to 2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1), aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1); R15 is selected from: C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 Alkoxy, aryl substituted with 0 to 2 groups independently chosen from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S (C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1), aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S (C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1); R16 is C1-C4 alkyl, benzyl or phenyl, R17 and R17a are independently selected from: H, C1-C10 alkyl, C2-C6 alkenyl, C4-C11 cycloalkylalkyl and aryl (C1-C6 alkyl); Combinations of A, B and D, and/or variables are permitted only if such combinations result in stable compounds (as defined herein). A may be omitted, –(CHR6)m–, –O(CHR6)m–, –NR6(CHR6)m–, –S(O)p(CHR6)m–, or selected from alkyl of 1 to 10 carbon atoms which include branched cyclic and unsaturated alkyl groups or -(C1-C6 )alkyl-aryl; B can be a bond or selected from –NH–, –NR11–, –NR11a–, –O–, –S(O)p–C1–C6alkyl–NH–C1–C6alkyl–, C1–C6alkyl–NR11–C1–C6alky–, – C1–C6–NH–aryl–, –O–C1–C6alkyl–, C1–C6alkyl–O–aryl–, –S–C1–C6alkyl–, C1–C6alkyl–S–aryl–, –C1–C6alkyl–, C1–C6alkenyl–, C1–C6alkynyl–, –CONH–, –CONR11, –NHCO–, –NR11CO–, –OCO–, –COO–, –OCO2–, –R11NCONR11–, HNCONH–, –OCONR11–, –NR11COO–, –HNSO2–, –SO2NH–, aryl, cycloalkyl, heterocycloalkyl, –R11NCSNR11–, –HNCSNH–, –OCSNR11–, –NR11CSO–, –HNCNNH–, and mimic peptide bond; [image] D may be omitted or an alkyl of 1 to 6 carbon atoms which includes branched cyclic and unsaturated alkyl groups or -(C1-C6)alkyl-aryl; p can be 0, 1 or 2; m is the integral from 0 to 3; n is the integral from 1 to 4; W is –O–, –S(O)p– or –NR10–; Y is selected from: –CONR10–, –NR10CO–, –SO2NR10–, NR10SO2–, mimetic peptide bond, 5-membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N, O or S, provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–C(U)(R4)–, is linked to no less than 11 atoms and no more than 22 atoms when forming a ring. Only substituents which form stable compounds can be used for formula I. 7. The compound of claim 2, characterized in that X is selected from CH 2 , NH, S or O; U was selected from; –CO2H, –CO2R12 and common prodrug derivatives; Y, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R17a and p, m, n, A, B, D and W are previously determined in formula I and defined as stable compounds; provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–X–C(U)(R4)–, is linked to not less than 11 atoms and no more than 22 atoms when forming a ring. 8. The compound of claim 1, characterized in that U is selected from: –CONHOH, –C(O)NHOR12, –CO2H and common prodrug derivatives; R1 is selected from: H, –(CO–C6)alkyl–S(O)p–(C1–C6)alkyl, –(CO–C6)alkyl–O–(C1–C6)alkyl, –(CO–C6)alkyl–S(O)p–(CO–C6)alkyl–aryl, –(CO–C6)alkyl–O–(CO–C6)alkyl–aryl, alkyl of 1 to 20 carbon atoms including branched, cyclic and unsaturated alkyl groups, substituted alkyl characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio, (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido, –(CO–C8)alkyl–aryl, –(CO–C8)alkyl–substituted aryl, –(CO–C8)aryl–(C1–C4)alkyl–aryl, –(C1–C8)alkyl–biaryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–aryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl, –(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[S(O)p–(CO–C8)alkyl], –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–alkyl–biaryl, –(CO–C8)alkyl–O–(CO–C8)alkyl–aryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl, –(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[O–(CO–C8)alkyl], –(CO–C8)alkyl–O–(CO–C8)alkyl–biaryl, –(CO–C8)alkyl–O–(CO–C8)alkyl–substituted aryl, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl; R2 is selected from H, –CO2R5, –CONR6R5, –CONR6(OR5), -alkyl, -alkylaryl, -alkylheteroaryl, -alkylheterocyclic compound, -aryl, -heteroaryl or -a heterocyclic compound that is substituted with one or more substituents selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy; R 3 and R 4 are H; R5 is selected from: –(CHR1Y)n–R9, –C(R7R8)n–W–C(R7R8)m–R9 –C(R7R8)m–R9, –C(R7R8)m–aryl, –C(R7R8)m–heteroaryl, –C(R7R8)m–heterocyclic compound, R6 is selected from: H, alkyl, –(C1–C6)alkyl–aryl, –(C1–C6)alkyl–heteroaryl, –(C1–C6)alkyl–heterocyclic compound, -(C1-C6)alkyl-acyl; Likewise, R5 and R6 can form a 3- to 8-membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from -O, -NR6, -S(O)p, or an acyl group, optionally attached to an aryl ring ; R7 and R8 can be independently selected from: H, R1 or from a 3- to 7-membered substitution ring with unsaturated bonds 0-3, indicated that the substitute is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl, optionally contains –O–, –S(O)p, –NR6, optionally fused with substituted aryl ring, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R9 is H, alkyl, cycloalkyl, a 5- to 6-membered ring optionally containing 1 to 2 N, O or S(O)p, optionally substituted with -OH, -O-(C1-C6)alkyl, -O-alkyl-alkyl, NHR10 or aryl; R 10 is H or an optionally substituted alkyl group; R 11 is hydrogen, alkyl of 1 to 6 C atoms including branched, cyclic and unsaturated alkyl groups, substituted lower alkyl; characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio) carboxy , carboxamido, carbo-alkoxy, or sulfonamide, –(C1–C4)alkyl–aryl, -(C1-C8)alkyl-substituted aryl, characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio) carboxy , carboxamido, carbo-alkoxy, or sulfonamide; R11a is H, –SO2–(C1–C6)–alkyl, –SO2–(C1–C6)–alkyl substituted aryl, –SO2–aryl, –SO2– substituted heteroaryl, –COR9, –CO2t–Bu, –CO2Bn, characterized in that the substituent is selected from: hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R12 is selected from: H, aryl, (C1 to C10)alkyl–, aryl (C1 to C6)alkyl–, C3 to C11 cycloalkyl, C3 to C10 alkylcarbonyloxyalkyl, C3 to C10 Alkoxycarbonyloxyalkyl, C2 to C10 Alkoxycarbonyl, C5 to C10 cycloalkylcarbonyloxyalkyl, C5 to C10 cycloalkoxycarbonyloxyalkyl, C5 to C10 cycloalkyloxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy (C1 to C6 alkyl), arylcarbonyloxy (C1 to C6 alkyl), C5 to C12 Alkoxyalkylcarbonyloxyalkyl, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl*] methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one*-yl)methyl, (R17) (R17a)N–(C1–C10 alkyl)–, CH(R13)OC(=O)R14, –CH(R 13 )OC(=O)OR 15 , or [image] ; indicated by that R13 is H or C1-C4 linear alkyl; R14 is selected from: H, C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 Alkoxy, aryl substituted with 0 to 2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1), aryl substituted with 0–2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S(C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1); R15 is selected from: C1-C8 alkyl or C3-C8 cycloalkyl, that is alkyl or cycloalkyl which is substituted with 1 to 2 groups independently selected from: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 Alkoxy, aryl substituted with 0 to 2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S (C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to (2v+1), aryl substituted with 0–2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, –S (C1–C5 alkyl),–S(=O)(C1–C5 alkyl), –SO2(C1–C5 alkyl), –OH, –N(R17)(R17a),–CO2R17a, –C(=O)N(R17)(R17a), or –CvFw where v=1 to 3 and w=1 to(2v+1); R16 is C1-C4 alkyl, benzyl or phenyl, Combinations of A, B and D, and/or variables are permitted only if such combinations result in stable compounds (as defined herein). And it can be; –(CH2)m–, –O–(CH2)m–, –S–(CH2)m–, NR6–(CH2)m–; B can be a bond or selected from –NH–, –NR11–, –NR11a–, –O–, –S(O)p–C1–C6alkyl–NH–C1–C6alkyl–, C1–C6alkyl–NR11–C1–C6alky–, – C1–C6–NH–aryl–, –O–C1–C6alkyl–, C1–C6alkyl–O–aryl–, –S–C1–C6alkyl–, C1–C6alkyl–S–aryl–, –C1–C6alkyl–, C1–C6alkenyl–, C1–C6alkynyl–, –CONH–, –CONR11, –NHCO–, –NR11CO–, –OCO–, –COO–, –OCO2–, –R11NCONR11–, HNCONH–, –OCONR11–, –NR11COO–, –HNSO2–, –SO2NH–, aryl, cycloalkyl, heterocycloalkyl, –R11NCSNR11–, –HNCSNH–, –OCSNR11–, –NR11CSO–, –HNCNNH–, and mimic peptide bond; [image] D is –(CH2)m–; p can be 0, 1 or 2; m is the integral from 0 to 3; n is the integral from 1 to 4; W is –O–, –S(O)p– or –NR10–; Y is selected from: –CONR10–, –NR10CO–, –SO2NR10–, NR10SO2–, mimetic peptide bond, 5-membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N, O or S, provided that the size of the macroring contained in formula I by –A–B–D–C(R2)(R3)–Y–C(R1)–C(U)(R4)–, is linked to no less than 11 atoms and no more than 22 atoms when forming a ring. 9. The compound of claim 1 or its pharmaceutically acceptable salt of formula IVa or formula IVb or formula IVc or formula IVd, characterized in that [image] or its pharmaceutically acceptable salts or prodrug forms, characterized in that R1 is selected from: H, –(CO–C6)alkyl–S(O)p–(C1–C6)alkyl, –(CO–C6)alkyl–O–(C1–C6)alkyl, –(CO–C6)alkyl–S(O)p–(CO–C6)alkyl–aryl, –(CO–C6)alkyl–O–(CO–C6)alkyl–aryl, alkyl of 1 to 20 carbon atoms including branched, cyclic and unsaturated alkyl groups, substituted alkyl characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio, (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido, –(CO–C8)alkyl–aryl, –(CO–C8)alkyl–substituted aryl, –(CO–C8)aryl–(C1–C4)alkyl–aryl, –(C1–C8)alkyl–biaryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–aryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl, –(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[S(O)p–(CO–C8)alkyl], –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–alkyl–biaryl, –(CO–C8)alkyl–O–(CO–C8)alkyl–aryl, –(CO–C8)alkyl–S(O)p–(CO–C8)alkyl–substituted aryl, –(C1–C4)alkyl–aryl–(CO–C8)alkyl–aryl–[O–(CO–C8)alkyl], –(CO–C8)alkyl–O–(CO–C8)alkyl–biaryl, –(CO–C8)alkyl–O–(CO–C8)alkyl–substituted aryl, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl; R2 is selected from H, –CO2R5, –CONR6R5, –CONR6(OR5), -alkyl, -alkylaryl, -alkylheteroaryl, -alkylheterocyclic compound, -aryl, -heteroaryl or -a heterocyclic compound that is substituted with one or more substituents selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy; R5 is selected from: –(CHR1Y)n–R9, –C(R7R8)n–W–C(R7R8)m–R9 –C(R7R8)m–R9, –C(R7R8)m–aryl, –C(R7R8)m–CONR7R8, –C(R7R8)m–heteroaryl, –C(R7R8)m–heterocyclic compound, R6 is selected from: H, alkyl, –(C1–C6)alkyl–aryl, –(C1–C6)alkyl–heteroaryl, –(C1–C6)alkyl–heterocyclic compound, -(C1-C6)alkyl-acyl; Likewise, R5 and R6 can form a 3- to 8-membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from -O, -NR6, -S(O)p, or an acyl group, optionally attached to an aryl ring ; R7 and R8 can be independently selected from: H, R1 or from a 3- to 7-membered substitution ring with unsaturated bonds 0-3, indicated that the substitute is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl, optionally contains –O–, –S(O)p, –NR6, optionally fused with substituted aryl ring, characterized in that the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R9 is H, alkyl, cycloalkyl, 5- to 6-membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with -OH, -O-(C1-C6)alkyl, -O-alkyl-alkyl, NHR10 or aryl; R 10 is H or an optionally substituted alkyl group; R 11 is hydrogen, alkyl of 1 to 6 C atoms including branched, cyclic and unsaturated alkyl groups, substituted lower alkyl; characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio) carboxy , carboxamido, carbo-alkoxy, or sulfonamide, –(C1–C4)alkyl–aryl, -(C1-C8)alkyl-substituted aryl, characterized in that the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide; R11a is H, –SO2–(C1–C6)alkyl, –SO2–(C1–C6)alkyl– substituted aryl, –SO2–aryl, –SO2–substituted heteroaryl, –COR9, –CO2t–Bu, –CO2Bn, characterized in that the substituent is selected from: hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; m is the integral from 0 to 3; n is the integral from 1 to 4; p can be 0, 1 or 2; W is –O–, –S(O)p– or –NR10–; Z is CH 2 or 0 Y is selected from: –CONR10–, –NR10CO–, –SO2NR10–, NR10SO2–, mimetic peptide bond, 5-membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N, O or S, Only substituents which form stable compounds can be used for formula Ia to Id. 10. The compound of Claim 1 selected from the group, characterized in that 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-methylcarboxamido)-[10]paracyclophane-6-N - hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(carboxymethyl)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-benzylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(hydrodidimethyl)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-alanine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[L(O-methyl)tyrosine-N-methylamide]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[L-(O-tert-butyl)serine-N-methylamide)-[10]paracyclophane-6-N- hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-serine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(glycine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(D-alanine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(beta-alanine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[D-(O-tert-butyl)serine-N-methylamide)-[10]paracyclophane-6-N- hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(D-serine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-lysine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-valine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(2-pyridyl)ethylcarboxamido]-[10]paracyclophane-6-N-hydroxycarboxamide trifluoroacetate; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(4-methyl)piperazinylcarboxamido]-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(2-benzimidazolyl)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(2-imidazolyl)carboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(2-benzimidazolyl)methylcarboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(3-imidazolyl)propylcarboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[2�(4-aminosulfomylphenyl)ethylcarboxamido)-[10]paracyclophane-6- N -hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(glycine-N,N-dimethylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(1-adamantylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(4-aminoindazolyl)carboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N,N-diethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-isopropylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-cyclopropylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-tert-butylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-isopropyl)amide]-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-ethyl)amide]-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-cyclopropyl)amide]-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-tert-butyl)amide]-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-cyclobutyl)amide]-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-morpholino)amide]-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-2-hydrodidimethylethyl)amide]-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-ethylmethylpropyl)amide]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-dimethylpropyl)amide]-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-(di-2hydroxymethyl)ethylamide]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S , 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(4-hydroxypiperidin)amide]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-isobutyl-2-�[-������������benzimidazolecarboxamide]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[S-(methyl)-2-phenylmethylcarboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide; 4S, 7R, 8S -5-aza-6-oxo-12-oxa-7-isobutyl-2-(carboxymethyl)-[12]paracyclophane-8-N-hydroxycarboxamide; 4S, 7R, 8S-5-aza-6-oxo-12- oxa-7-isobutyl-2-(N-methylcarboxamido)-[12]paracyclophane-8-N-hydroxycarboxamide; 4S, 7R, 8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-( glycine-N-methylamide)-[12]paracyclophane-8-N-hydroxycarboxamide; 2S, 3R, 6S-10-t-butoxycarbonyl-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamido )-1-oxa-4-oxo-3-(3-phenylprop-1-yl)cyclotetradecane; 2S, 3R, 6S-5,10-diaza-2-(N-hyd roxycarboxamido)-6-(N-methylcarboxamido)-1-oxa-4-oxo-3-(3-phenylprop-1-yl)cyclotetradecane hydrochloride; 2S, 3R, 6S-10-acetylyl-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamido)-1-oxa-4-oxo-3-(3-phenylprop-1-yl )cyclotetradecane; 2S, 3R, 6S-10-benzenesulfonyl-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamido)-1-oxa-4-oxo-3-(3-phenylprop-1-yl )cyclotetradecane; 2S, 3R, 6S,12(R,S)-10-acetyl-5,10-diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamido)-12-methyl-1-oxa-4-oxo -3-(3-phenylprop-1-yl)cyclotridecane; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(carboxymethyl)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(hydroxycarboxyl)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-methoxyloxy)carbonyl]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-phenylethyloxy)carboxy]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(1-(n-methylcarboximido)methylcarboxyl)-[10]paracyclophane-6-N- hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-(N-methylaminosulfonyl)ethylcarboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S,3R , 6S–3-aza-4-oxo-10-oxa-5-hexyl-2-[(4-(N-methylaminosulfonyl)butylcarboxamido]–[10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R, 6S– 3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-(N-methylaminosulfonyl)hexylcarboxamido]-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R, 6S-3-aza -4-oxo-10-oxa-5-hexyl-2-(2-(carbomethoxy)ethylcarboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10 -oxa-5-hexyl-2-(2-(hydroxycarbonyl)ethylcarboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl -2-[(L-ornithine(4-t-butoxycarbonyl)carboxymethyl)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl -2-(L-ornithinecarboxymethyl�-[10]paracyclophane-6-N-hydroxycarboxamide hydrochloride; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(L-ornithine (4-t-butoxycarbonyl)-N-methylamide)-[10]paracyclophane-6-N-hydroxy icarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-ornithine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide hydrochloride; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-lysinecarboxamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(L-serine(O-tert-butyl)-N-methylamide]-[10]paracyclophane-6-N - hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-alanine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(D-alanine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R, 6S-3 -aza-4-oxo-10-oxa-5-hexyl-2-(glycine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo- 10-oxa-5-hexyl-2-(benzylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-( phenylethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-dephenylethylcarboxamido)-[10]paracyclophane-6-N- hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-(2-pyridyl)ethylcarboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S,3R , 6S–3–aza–4–oxo–10–oxa–5–hexyl–2–[(2–(4–sulfonylaminophenyl)ethylcarboxamido]–[10]paracyclophane–6–N– hydroxycarboxamide; 2S,3R, 6S– 3-aza-4-oxo-10-oxa-5-hexyl-2-[(2-(3,4-dimethoxyphenyl)ethylcarboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S,3R, 6S-3 –aza-4-oxo-10-oxa-5-hexyl-2-[(2-(4-morpholino)ethylcarboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S,3R, 6S-3-aza- 4-oxo-10-oxa-5-hexyl-2-[(3-(4-morpholino)propylcarboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide hydrochloride; 2S,3R, 6S-3-aza-4- oxo-10-oxa-5-hexyl-2-[(3-(1-imidazolyl)propylcarboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10 -oxa-5-hexyl-2-[(3-(1-imidazolyl)propylcarboxamido]-[10]paracyclophane-6-N- hydroxycarboxamide trifluoroacetate; 2S,3R,6S-3-aza-4-oxo-10-oxa -5-hexyl-2-cyclohexylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S ,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(4-methylpiperazin-1-ylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(dimethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-�N-methylcarboxamido]-cyclopentadecane-13-N- hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[N-(2-pyridyl)methylcarboxamido]-cyclopentadecane-13-N-hydroxycarboxamide trifluoroacetate; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[2-(5-methylthiazolyl)carboxamido]-cyclopentadecane-13-N-hydroxycarboxamide ; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[(2-pyridyl)carboxamido]-cyclopentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[(3-pyridyl)carboxamido]-cyclopentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[(4-pyridyl)carboxamido]-cyclopentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[4-(N-ethoxycarbonyl)piperidinecarboxamido]-cyclopentadecane-13-N-hydroxycarboxamide ; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[4-hydroxycyclohexylcarboxamido]-cyclopentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-(glycine-N-methylamide)-cyclopentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-(glycine-N,N-dimethylamide�-cyclopentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-glycine-2-pyridylamide)-cyclopentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-2-(3,4,5,6-tetrahydropyridyl)amide] - cyclopentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-N-(4-hydroxy)piperidinamide]-cyclopentadecane-13-N -hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-N-pyrrolidinamide]-cyclopentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-N-morpholinoamide]-cyclopentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-(4-methyl)N-piperazinylamide]-cyclopentadecane-13-N -hydroxycarboxamide trifluoroacetate; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-2-(5-methyl)thiazolylamide]-cyclopentadecane-13-N -hydroxycarboxamide trifluoroacetate; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[glycine-N-morpholinoamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide); 2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(glycine-N-methylamide)-11-(N-hydroxycarboxamide); 2S,11S,12R–1,7–diaza–8,13–dioxo–12–isobutylcyclotridecane–2–(Nε–H–L–lycine–α–N–H–amide trifluoroacetate)–11–(N– hydroxycarboxamide) ; 2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-alanine-α-N-methyl amide)-11-(N-hydroxycarboxamide); 2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(β-alanine-N-methyl amide)-11-(N-hydroxycarboxamide); 2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-mesitylenesulfonyl-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide); 2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-t-butyloxycarbonyl-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide); 2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide) hydrogen chloride; 5S,8R,9S-6-aza-2,7-dioxo-5-(N-methylcarboxamido)-1-oxa-8--isobutylcyclotridecane-9-(N-hydroxycarboxamide); 2S,11S,12R-7-N-benzenesulfonyl-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide); 2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-(p-amino-N-benzenesulfonyl)-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide); 2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-trifluoromethanesulfonyl-12-isobutylcyclotridecane-11-(N-hydroxycarboxamide); 2S,11S,12R-1,7-diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-(N-methyl-imidazolesulfon-4-yl)-12- isobutylcyclotridecane-11-(N -hydroxycarboxamide); 2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-norleucine-α-N-methyl amide)-11-(N- hydroxycarboxamide); 2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-serine-α-N-methyl amide)-11-(N-hydroxycarboxamide); 2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(glycine-N-dimethyl amide)-11-(N-hydroxycarboxamide); 2S,11S,12R–1,7–diaza–8,13–dioxo–12(R)–isobutylcyclotridecane–2(S)–(glycine N–1,2–ethylenediamine– N',N'–dimethyl amide)– 11(S)-(N-hydroxycarboxamide); 2S,11S,12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(glycine-N-morpholino amide)-11-(N-hydroxycarboxamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-leucine-α-N-methyl amide)-11-(N-hydroxycarboxamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-threonine-α-N-methyl amide)-11-(N-hydroxycarboxamide); 11. Pharmaceutical mixture, characterized in that it is a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound from claim 1. 12. Pharmaceutical mixture, characterized in that it is a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound from claim 2. 13. Pharmaceutical mixture, characterized in that it is a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound from claim 3. 14. Pharmaceutical mixture, characterized in that it is a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound from claim 4. 15. Pharmaceutical mixture, characterized in that it is a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound from claim 5. 16. Pharmaceutical mixture, characterized in that it is a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound from Claim 6. 17. Pharmaceutical mixture, characterized in that it is a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound from claim 7. 18. Pharmaceutical mixture, characterized in that it is a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound from claim 8. 19. Pharmaceutical mixture, characterized in that it is a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound from claim 9. 20. Pharmaceutical mixture, characterized in that it is a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound from claim 10. 21. A method of treating an inflammatory disease in mammals, characterized in that a therapeutically effective amount of the compound from claim 1 is administered to a mammal in need of such treatment. 22. A method of treating an inflammatory disease in mammals, characterized in that the mammal in need of such treatment is given a therapeutically effective amount of the compound from claim 2. 23. A method of treating an inflammatory disease in mammals, characterized in that a therapeutically effective amount of the compound from claim 3 is administered to a mammal in need of such treatment. 24. A method of treating an inflammatory disease in mammals, characterized in that the mammal in need of such treatment is given a therapeutically effective amount of the compound from claim 4. 25. A method of treating an inflammatory disease in mammals, characterized in that the mammal in need of such treatment is given a therapeutically effective amount of the compound from claim 5. 26. A method of treating an inflammatory disease in mammals, characterized in that a therapeutically effective amount of the compound from claim 6 is administered to a mammal in need of such treatment. 27. A method of treating an inflammatory disease in mammals, characterized in that the mammal in need of such treatment is given a therapeutically effective amount of the compound from claim 7. 28. A method of treating an inflammatory disease in mammals, characterized in that the mammal in need of such treatment is given a therapeutically effective amount of the compound from claim 8. 29. A method of treating an inflammatory disease in mammals, characterized in that the mammal in need of such treatment is given a therapeutically effective amount of the compound from claim 9. 30. A method of treating an inflammatory disease in mammals, characterized in that a therapeutically effective amount of the compound from claim 10 is administered to a mammal in need of such treatment. 31. A method as in any one of claims 21-30, characterized in that it is taken orally. 32. A test for the detection of aggrecanase inhibitors, characterized in that it comprises: (a) generation of soluble aggrecanase by stimulation of cartilage slices; (b) detecting the enzymatic activity of aggrecanase using the soluble aggrecanase generated in (a) and monitoring the production of aggrecan fragments with an ARGSVIL end; (c) assessing aggrecanase inhibition by comparing the amount of product generated in the presence versus that generated in the absence of the compound.