KR20020009610A - Hydroxamic acid derivatives as matrix metalloprotease inhibitors - Google Patents

Abstract

The present invention is particularly directed to sulfonyl aromatic or heteroaromatic hydroxamic acid compounds that inhibit matrix metalloproteinase activity, such as those disclosed herein, in which the known sulfonyl aromatic or heteroaromatic hydroxamic acid compounds are administered in an MMP enzyme- Lt; RTI ID = 0.0 > metalloprotease < / RTI > activity comprising administration to a recipient having a condition associated with matrix metalloprotease activity. The known compounds correspond to the following formula a:

(A)

Wherein the W and R groups are as defined above.

Description

HYDROXAMIC ACID DERIVATIVES AS MATRIX METALLOPROTEASE INHIBITORS AS MATRIX METALLOPROTEASE INHIBITORS Field of the Invention < RTI ID = 0.0 >

Connective tissue, extracellular matrix components, and basement membrane are essential components of all mammals. The components are biological materials that provide rigidity, differentiation, attachment and, in some cases, elasticity, to the biological system, including humans and other mammals. The connective tissue components include, for example, collagen, elastin, proteoglycan, fibronectin and laminin. The biochemical material constitutes or is a component of the structure such as skin, bone, tooth, tendon, cartilage, basement membrane, blood vessel, cornea, and glass liquid.

Under normal conditions, the connective tissue replacement and / or repair process is controlled and in equilibrium. Regardless of the reason, the loss of balance results in a number of disease states. Inhibition of the enzyme, which is the cause of loss of equilibrium, provides a control mechanism for the tissue degradation, and thus treatment of the disease.

The degradation of connective tissue or connective tissue components is carried out by the action of protease enzymes, which are released from the zygote tissue cells and / or which are targeted to inflammation or tumor cells. A major class of enzymes involved in this function is zinc metalloproteinase (metalloprotease or MMP).

Metalloprotease enzymes are classified into classes having several members with several different names in common use. For example, collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); Collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10, EC 3.4.24.22), proteoglycanase, martrilin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24) , Gelatinease B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) And membrane MMP (MMP-14). MMP is the abbreviation or acronym for the term matrix metalloprotease, numbered according to the difference between the specific membranes of the MMP group.

The uncontrolled disorder of connective tissue by metalloprotease is a hallmark of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; Cornea, epithelium or stomach ulcer; Tumor metastasis, invasion or angiogenesis; Periodontal disease; Proteinuria; Alzheimer's disease; Coronary artery thrombosis and bone disease. A deficit recovery process may also occur. This can provide inadequate healing that causes weak recovery, adhesion, and scarring. These latter defects can cause deformities such as postoperative adhesions and / or permanent disability.

Matrix metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF) and are a clinical disease treatment mechanism in which inhibition of the production or action of TNF and related compounds is important. For example, TNF- [alpha] is a cytokine currently believed to be produced as a 28 kD cell-associated molecule. It is released as an active 17 kD form, which can mediate many in vitro and in vivo harmful effects. For example, TNF can be used in the treatment of inflammation, rheumatoid arthritis, autoimmune diseases, multiple sclerosis, graft rejection, fibrotic diseases, cancer, infectious diseases, malaria, mycobacterial infections, meningitis, Cause and / or prevent acute phase reactions such as those occurring during cardiovascular / pulmonary functions such as cardiovascular / pulmonary function, such as cardiac vascular / pulmonary damage, as well as during seizures such as septic shock and hemodynamic shock with infection and septicemia, Or cause the reaction. Chronic release of active TNF can cause cachexia and anorexia. TNF can be fatal.

TNF-a converting enzyme is a metalloproteinase associated with the formation of active TNF-a. Inhibition of TNF-a converting enzyme inhibits the production of active TNF-a. Compounds that inhibit both MMP activity (and TNF-a production) are disclosed in WIPO International Application Nos. WO 94/24140, WO 94/02466 and WO 97/20824. There is a need for effective MMP and TNF- [alpha] converting enzyme inhibitors. Compounds that inhibit MMP such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al., Nature 376 , 555-557 (1994), McGeehan et al., Nature 376 , 558-561 (1994)).

MMPs are also involved in other biochemical processes in mammals. Include inactivation of protease inhibitor (α ₁ -PI) - control of ovulation, postpartum uterine atrophy, possible implantation, cleavage of APP (β- Amyloid Precursor Protein) to the amyloid plaque, and α _1. The inhibition of this metalloprotease makes it possible to control fertility and to treat or prevent Alzheimer's disease. In addition, the increase and maintenance of the levels of endogenous or administered serine protease inhibitor drugs or biochemicals such as alpha ₁ -PI may be beneficial in the treatment of a variety of diseases, such as, Thereby enabling treatment and prevention of diseases.

Inhibition of selected MMPs may also be preferred in other examples. The inhibition of cancer therapy and / or metastasis and / or the inhibition of angiogenesis are examples of approaches to the treatment of diseases, including but not limited to stromelysin (MMP-3), gelatinase (MMP-2), gelatinase Selective inhibition of collagenase B (MMP-9), or collagenase III (MMP-13) may be relatively more important than inhibition of collagenase I (MMP-1). Drugs that do not inhibit collagenase I may have an excellent therapeutic profile. Osteoarthritis, another dominant disease that cartilage degradation of inflammatory arthritis is thought to be caused, at least in part, by MMP-13 released from cells such as stimulated chondrocytes, is that one of the modes of action is inhibition of MMP-13 Lt; RTI ID = 0.0 > administration. ≪ / RTI > Reference example: Mitchell et al., J. Clin. Invest., 97 : 761-768 (1996) and Reboul et al., J. Clin. Invest., 97 : 2011-2019 (1996).

Inhibitors of metalloprotease are known. Examples include natural biochemicals such as metalloproteinase tissue inhibitors (TIMP),? ₂ -macroglobulin and analogs or derivatives thereof. These are high molecular weight protein molecules that form inactive complexes with metalloprotease. Many smaller peptide-like compounds have been described that inhibit metalloprotease. The mercaptoamide peptide derivatives showed in vitro and in vivo ACE inhibition. Angiotensin - converting enzyme (ACE) aids in the production of angiotensin II, a potent blood pressure enhancer in mammals, and inhibition of this enzyme induces a drop in blood pressure.

Thiol group-containing amides or peptidic amide-based metalloprotease (MMP) inhibitors are known, for example, as shown in WO 95/12389, WO 96/11209 and US 4,595,700. Hydroxamate group-containing MMP inhibitors are described in Schwartz et al., Progr. Med. Chem., 29: 271-334 (1992) and Rasmussen et al., Pharmacol. Ther., 75 (1): 69-75 (1997) and Denis et al., Invest. WO 95/29892, WO 97/24117, WO 97/49679, and EP 0 780 386, which disclose many open patent applications such as carbon skeletal compounds, such as, for example, the New Drugs, 15 (3): 175-185 And WO 90/05719, WO 93/20047, WO 95/09841, and WO 96/06074, which disclose hydroxamates having a peptide backbone or peptide backbone backbone.

One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory action on each of the MMP enzymes. For example, peptide analogs known as batimastat Hydroxamate has been reported to exhibit IC ₅₀ values of about 1 to about 20 nanomoles (nM) for MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9, respectively. Another peptidomimetic hydroxamate, marimastat, is another broad spectrum with an enzyme inhibition spectrum very similar to batimastat, except that it exhibits an IC ₅₀ value of 230 nM for MMP-3 MMP inhibitors. Rasmussen et al., Pharmacol. Ther., 75 (1): 69-75 (1997).

Advanced Progressive Therapy - Meta-analysis of data from period I / II studies using marimastat in patients with refractory fidelity tumors (colon, oesophageal, ovarian, prostate) can be used as a surrogate marker for biological activity - dose-related reduction in the increase of specificity antigens. While marimastat shows a constant value of efficiency through these markers, toxic side effects have been noted. The most common drug-related toxicity of marimastat in the clinical trials was musculoskeletal pain and stiffness, which spread to the arms and shoulders, often starting from the small joints of the hands. Short dosing breaks of 1 to 3 weeks, and subsequent dosing reductions make it possible to continue to be treated. Rasmussen et al., Pharmacol. Ther., 75 (1): 69-75 (1997). It is believed that the lack of specificity of inhibitory action in MMP may be the cause of such action.

In view of the importance of hydroxamate MMP inhibitory compounds in the treatment of serious diseases and the lack of enzyme specificity exhibited by more potent drugs in clinical trials, it would be highly beneficial if hydroxamates of greater enzyme specificity could be found. This suggests that hydroxamate inhibitors exhibit potent inhibitory activity against one or more of MMP-2, MMP-9 or MMP-13 associated with several pathological conditions, while being relatively ubiquitous and not yet associated with any pathological condition Lt; RTI ID = 0.0 > MMP-1 < / RTI > enzyme. The following describes a family of hydroxamate MMP inhibitors that exhibit this desirable activity.

Summary of the Invention

The present invention contemplates the inhibition of matrix metalloproteinase (MMP) activity among other properties, particularly inhibiting one or more activities of MMP-2, MMP-9 or MMP-13, Lt; / RTI > relates to a family of molecules that are rarely represented. The present invention also relates to intermediates useful in the synthesis of inhibitors, methods of making the known compounds, and methods of treating mammals having conditions associated with pathological matrix metalloprotease activity.

Briefly, one embodiment of the present invention provides a pharmaceutical composition comprising a sulfonylaryl or heteroarylhydroxamic acid compound, or a pharmaceutically acceptable salt of such a compound that can act as a matrix metalloproteinase enzyme inhibitor, a precursor of such a compound, ≪ / RTI > The known compounds correspond to the structure of formula (C)

Wherein ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring.

R ¹ is (i) a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl radical that is directly attached to the depicted SO ₂ - group and is shorter in length than the approximately hexyl group and shorter than the approximately eicosyl group and containing substituent, wherein R ¹ is SO ₂ in the 6-membered ring radical - the combined first position and connecting the center of 3,4-bond axis-SO ₂ of the coupling 1 and the axial position or 5-membered ring radical linking the 4-position And the largest volume in the transverse direction of the rotation axis is the volume of approximately one furyl ring to the volume of two phenyl rings.

Alternatively, R ¹ is a group -NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, aryl hydrocarbyl, and substituted aryl hydrocarbyl Lt; / RTI > More preferably, R ⁷ and R ⁸ are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R ^a oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, Aryl, alkyl, and heterocyclo substituents, each substituent being optionally substituted with -AR < 110 >substituents;

[In the above-A-R-E-Y substituent, A is selected from the group consisting of:

(1) -O-;

(2) -S-;

(3) -NR < ^k >-;

(4) -CO-N (R ^k ) or -N (R ^k ) -CO-;

(5) -CO-O- or -O-CO-;

(6) -O-CO-O-;

(7) -HC = CH-;

(8) -NH-CO-NH-;

(9) -C C-;

(10) -N = N-;

(11) -NH-NH-;

(12) -CS-N (R ^k ) - or -N (R ^k ) -CS-;

(13) -CH ₂ -;

(14) -0-CH ₂ - or -CH ₂ -0-;

(15) -S-CH ₂ - or -CH ₂ -S-;

(16) -SO-; And

(17) -SO ₂ -;

or

(18) A is a member, R is directly bonded to R ⁷ or R ⁸ , or both R ⁷ and R ⁸ ;

R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituents are either (i) unsubstituted or (ii) halo Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, Substituted by one or two radicals selected from the group consisting of halogen, cyano, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl groups. Lt; / RTI >

E group is selected from the group consisting of:

(1) -COR ^g - or - R ^g CO-;

(2) -CON (R ^k ) - or - (R ^k ) NCO-;

(3) -CO-;

(4) -SO ₂ R ^g - or -R ^g SO ₂ -;

(5) -SO ₂ -;

(6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -;

or

(7) E is a member and R is directly bonded to Y;

The Y moiety is either absent or substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, (Wherein R &^lt; 1 > is a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkyl group, a cycloalkyl group, a cycloalkyl group, The heteroaryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted by one or more of (i) unsubstituted or (ii) alkanoyl, halo, nitro, An amino group wherein the amino nitrogen is substituted with one or two groups independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) Selected from the group consisting of substituted) radical; or

R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a -GAREY group;

Wherein G is an N-heterocyclo group;

Substituent A is selected from the group consisting of:

(1) -O-;

(2) -S-;

(3) -NR < ^k >-;

(4) -CO-N (R ^k ) or -N (R ^k ) -CO-;

(5) -CO-O- or -O-CO-;

(6) -O-CO-O-;

(7) -HC = CH-;

(8) -NH-CO-NH-;

(9) -C C-;

(10) -N = N-;

(11) -NH-NH-;

(12) -CS-N (R ^k ) - or -N (R ^k ) -CS-;

(13) -CH ₂ -;

(14) -0-CH ₂ - or -CH ₂ -0-;

(15) -S-CH ₂ - or -CH ₂ -S-;

(16) -SO-; And

(17) -SO ₂ -;

or

(18) A is a member and R is directly bonded to an N-heterocyclo group, G;

R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is selected from the group consisting of (i) unsubstituted or (ii) halo (lower) alkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, 1 < / RTI > or 2 radicals selected from the group consisting of < RTI ID = 0.0 > Selected from the group consisting of substituted) as being;

Part E is selected from the group consisting of:

(1) -COR ^g - or - R ^g CO-;

(2) -CON (R ^k ) - or - (R ^k ) NCO-;

(3) -CO-;

(4) -SO ₂ -R ^g - or -R ^g -SO ₂ -;

(5) -SO ₂ -;

(6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -;

or

(7) E is a member and R is directly bonded to Y;

Y section member or Hi give also, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a Alkyl, aryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, cycloalkyl, , Aralkyl or heterocycloalkyl groups may be unsubstituted or substituted with (i) unsubstituted or (ii) alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and amino groups Wherein the amino nitrogen is optionally substituted with one or two groups independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) Is selected from the group consisting of a knife substituted)].

Alternatively, even more preferably, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, that is -NR ⁷ R ⁸ , form a -GAREY group;

Wherein G is an N-heterocyclo group;

Substituent A is selected from the group consisting of:

(1) -O-;

(2) -S-;

(3) -NR < ^k >-;

(4) -CO-N (R ^k ) or -N (R ^k ) -CO-;

(5) -CO-O- or -O-CO-;

(6) -O-CO-O-;

(7) -HC = CH-;

(8) -NH-CO-NH-;

(9) -C C-;

(10) -N = N-;

(11) -NH-NH-;

(12) -CS-N (R ^k ) - or -N (R ^k ) -CS-;

(13) -CH ₂ -;

(14) -0-CH ₂ - or -CH ₂ -0-;

(15) -S-CH ₂ - or -CH ₂ -S-;

(16) -SO-; And

(17) -SO ₂ -;

or

(18) A is a member and R is directly bonded to an N-heterocyclo group, G;

R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is selected from the group consisting of (i) unsubstituted or (ii) halo (lower) alkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, 1 < / RTI > or 2 radicals selected from the group consisting of < RTI ID = 0.0 > Selected from the group consisting of substituted) as being;

Part E is selected from the group consisting of:

(1) -COR ^g - or - R ^g CO-;

(2) -CON (R ^k ) - or - (R ^k ) NCO-;

(3) -CO-;

(4) -SO ₂ -R ^g - or -R ^g -SO ₂ -;

(5) -SO ₂ -;

(6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -;

or

(7) E is a member and R is directly bonded to Y;

Y section member or Hi give also, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a Alkyl, aryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, cycloalkyl, , Aralkyl or heterocycloalkyl groups may be unsubstituted or substituted with (i) unsubstituted or (ii) alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and amino groups Wherein the amino nitrogen is optionally substituted with one or two radicals independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) Substituted with a carboxyl group.

The substituents R ⁵ and R ⁶ is Hi give also, alkyl, cycloalkyl, acyl alkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, halo, alkyloxy, hydroxy-alkyl, R ^b R ^c aminoalkyl substituents, thiol (-SH), alkylthio, arylthio, cyclo alkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl independently selected from alkyl, haloalkyl, heterocycloalkyl and R ^b R ^c oxy amino group consisting of alkyloxy substituents Or;

Or R < ⁵ > and R < ⁶ > together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring.

R ²⁰ is selected from the group consisting of: (a) -O-R ^{21 wherein} R ²¹ is selected from hydrido, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl groups and pharmaceutically acceptable cations (B) -NR ¹³ -0-R ^{22 wherein} R ²² is an optionally removable protecting group such as, for example, 2-tetrahydropyranyl, benzyl, p-methoxybenzyl, C ₁ -C ₆ alkoxycarbonyl, trisubstituted silyl or o-nitrophenyl groups, peptide synthetic resins, etc. wherein the trisubstituted silyl groups are C ₁ -C ₆ -alkyl or aryl or ar-C ₁ -C ₆ -alkyl Or a mixture thereof), R ¹³ is a hydrido, C ₁ -C ₆ -alkyl or benzyl group), (c) -NR ¹³ -0-R ¹⁴ wherein R ¹³ is R ¹⁴ is a hydrido, a pharmaceutically acceptable cation or C (V) R ^{15 wherein} V is O (oxo) or S (thioxo) and R ¹⁵ is C ₁ -C ₆ -alkyl , aryl, C _l -C ₆ - alkoxy, heteroaryl, -C _l -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - Kiel, aryloxy, aralkyl, -C _l -C ₆ - alkoxy, aralkyl, -C _l -C ₆ - alkyl, heteroaryl and amino-C _l -C ₆ - alkyl group (wherein, an amino C _l -C ₆ - alkyl nitrogen is (i) unsubstituted or (ii) C _l -C ₆ - alkyl, aryl, aralkyl, -C _l -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aralkyl, -C _l -C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxycarbonyl, and C ₁ -C ₆ - alkynyl or substituted from the group consisting of alkanoyl radicals in the selected one or two substituents independently, or (iii) amino C ₁ -C ₆ alkyl nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring), or (d) -NR ²³ R ²⁴ (wherein, R ²³ and R ²⁴ have Hi laundry Figure, C _l -C ₆ - alkyl, amino, C _l -C ₆ - alkyl, hydroxy C _l -C ₆ - alkyl, aryl, and aralkyl -C _l - C ₆ - independently selected from the group consisting of an alkyl group, or R ²³ and R ²⁴ are the above-mentioned Together with the nitrogen atom, form a 5- to 8-membered ring containing 0, or one additional heteroatom which is oxygen, nitrogen or sulfur.

Wherein R ^a is selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, R ^b R ^c aminoalkanoyl, haloalkanoyl, R ^b R ^c Aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy groups;

R ^b and R ^c are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl Heteroarylthioalkyl, arylsulfonyl, aralkanoyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, Alkylthioalkyl, arylthioalkyl, alkylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, Alkenyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, amino, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, Amino nitrogen is (i) unsubstituted or (ii) is independently substituted with one or two R ^d radicals, or is amino (meth) acryloyloxy, A saturated or partially unsaturated heterocyclyl group in which the substituent on the amino group taken together with the nitrogen is optionally substituted by 1, 2, or 3 groups independently selected from R ^d substituents, or by 1, 2, or 3 groups independently selected from R ^f substituents Lt; / RTI > independently from each other are selected from the group consisting of hydrogen;

R ^d and R ^e are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl or arylalkyloxycarbonyl groups Being;

R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen (halo; F, Cl, Br, I), aryl, alkoxy, cyano, and R ^d R ^e amino groups;

R ^g is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F, Cl, Br, I), cyano, aldehydo (CHO, formyl) Amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ - amino, alkoxy Alkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyl oxy carbonyl amino, aryloxy carbonyloxy, carboxy, R ^h R ⁱ - aminocarbonyl-oxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - amino alkanoyl, hydroxy-aminocarbonyl, R ^h R ⁱ aminosulfonyl, R ^h R ⁱ -aminocarbonyl (R ^h ) amino, trifluoromethylsulfonyl (R ^h) amino, heteroaryl sulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) aminocarbonyl, alkylsulfonyl (R ^h) amino, arylcarbonyl (R ^h) Aminosulfonyl, and alkylsulfonyl (R ^h ) aminocarbonyl substituents;

R ^h is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with a substituent of a substituted aminoalkanoyl group, such as R ^j Lt; RTI ID = 0.0 > 1 < / RTI >

R ⁱ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with one or two R < ^j > substituents;

R ^j is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Alkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl are alkyl, alkenyl, alkenyl, aryl, arylalkyl , Heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl groups); < RTI ID = 0.0 >

R ^k is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d amino Sulfonyl, R ^c R ^d aminoalkanoyl and R ^c R ^d aminoalkylsulfonyl.

In some preferred embodiments, R ⁵ and R ⁶ are selected from the group consisting of hydrido, hydrocarbyl, preferably C ₁ -C ₄ hydrocarbyl, hydroxylhydrocarbyl, hydroxyl, amino, dihydrocarbylamino, Gt; is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclohydrocarbyl, heterocyclooxy, and heterocyclothio.

In a preferred embodiment, the 5- or 6-membered aromatic or heteroaromatic ring W is selected from the group consisting of 1,2-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 4,5- , 3-pyrazinylene, 4,5-pyrimidinylene, or 5,6-pyrimidinylene group.

In some preferred embodiments, R ²⁰ is -NR ¹³ -OR ¹⁴ , while in another preferred embodiment, R ²⁰ is -NR ¹³ -OR ²² . In a particularly preferred embodiment, R < ²⁰ > is -NHOH such that the compound of formula (C) corresponds to the structure of formula (C1)

Wherein W, R ¹ , R ⁵ , R ⁶ , R ¹³ and R ¹⁴ are as defined above.

In one preferred embodiment, the known compound corresponds to the structure of formula C2:

Wherein W, R ⁵ , R ⁶ and R ¹⁴ are as defined above and Ph is a phenyl group substituted at the 4-position with the substituent R ⁴ . The R ⁴ substituent may be a single cyclic hydrocarbyl, heterocyclo, aryl such as a phenyl or heteroaryl group or another substituent having a chain length of 3 to about 14 carbon atoms, such as hydrocarbyl or hydrocarbylox A period [e.g., C ₃ -C ₁₄ hydrocarbyl or OC ₂ -C _{l 4} hydrocarbyl], a phenoxy group [-OC ₆ H ₅ ], a thiophenoxy group [phenylsulfanyl] -SC ₆ H ₅ ], anilino group [-NHC ₆ H ₅ ], phenyl azo group [-N ₂ C ₆ H ₅ ], phenylureido group [anilincarbonylamino; -NHC (O) NH-C ₆ H ₅ ], benzamido [-NHC (O) C ₆ H ₅ ], nicotinamido [3-NHC (O) C ₅ H ₄ N], isonicotinoamido [ 4-NHC (O) C ₅ H ₄ N], or picolinamido [2-NHC (O) C ₅ H ₄ N]. R ⁴ substituents are also defined below.

In another aspect of the present invention, the known compounds correspond to the structure of formula (VI-1): < EMI ID =

Wherein each of R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ²⁰ is as defined above and A, B, C and D are each carbon, nitrogen, sulfur or oxygen, - or 6-membered). When R < ²⁰ > is NH-OH, the compound of one of the above formulas, such as formula C or Cl, is a selective inhibitor of MMP-2 rather than MMP-1 and is generally also a selective inhibitor of MMP- It is a rosemate. That is, a hydroxamate compound of one of the formulas such as formula C or Cl exhibits greater activity on MMP-1 inhibition and generally also inhibition of MMP-2 than inhibition of MMP-13. When R < ²⁰ > is other than NH-OH, the compound of formula VI-1 may be the same active carboxylate, precursor, or prodrug as the compound of example 13.

A particularly preferred embodiment of this aspect is a compound corresponding to the structure of formula VIA or VIA-1:

Wherein R ²⁰ , R ⁴ , R ⁵ and R ⁶ are as defined above, and the ring structure W ² containing the above-mentioned nitrogen atom is a heterocyclic ring containing a 5- or 6-membered ring, R ⁴ is bonded at the 4-position to the above-mentioned nitrogen atom when W ² is a 6-membered ring and is bonded at the 3- or 4-position to the above-mentioned nitrogen atom when W ² is a 5-membered ring.

Another particularly preferred embodiment of this aspect is a compound corresponding to the structure of formula VIB, VIB-1, VIB-2 or VIB-3:

Wherein R ²⁰ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are as defined above.

A particularly preferred group of compounds of this series is a compound of structure < RTI ID = 0.0 >

Wherein A, R, E, Y, R ²⁰ , R ⁵ and R ⁶ substituents or moieties are as defined above.

Methods of treating recipient mammals with conditions associated with pathological matrix metalloprotease activity are also known. This method selectively inhibits one or more MMPs, while at least a compound corresponding to the structure of formula C, which exhibits less activity against MMP-1, for example, a salt of formula Cl, is reacted with an MMP enzyme- Into a mammalian recipient having conditions associated with pathological matrix metalloprotease activity. The known compounds also do not substantially inhibit the production of TNF:

(C1)

Wherein W, R ¹ , R ⁵ , R ⁶ , R ¹³ and R ¹⁴ are as defined above.

Among the several advantages and advantages of the present invention are the supply of compounds and compositions effective for the inhibition of metalloproteinases associated with disorders and diseases, including uncontrolled destruction of connective tissue.

More particularly, the advantages of the present invention include, for example, the treatment of rheumatoid arthritis, osteoarthritis, septic arthritis, cornea, epithelium or gastric ulcer, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's disease, Particularly effective for the inhibition of metalloproteinases, particularly MMP-13 and / or MMP-2, associated with pathological conditions such as inflammatory bowel disease, bone formation and bone disease.

An advantage of the present invention is the provision of such compounds and methods of making the compositions. Another advantage is the provision of a method of treating pathological conditions associated with abnormal matrix metalloproteinase activity.

Another advantage of the present invention is the selective inhibition of metalloproteinases, such as MMP-13 and MMP-2, associated with such conditions with minimal adverse side effects, other proteins that are necessary or desirable for normal somatic action For example, the delivery of effective methods and compounds, compositions for the treatment of such pathological conditions that inhibit MMP-1.

Further advantages and advantages of the present invention will become apparent to those skilled in the art from the following description.

The present invention relates to sulfonylaryl or heteroarylhydroxamic acid compounds which inhibit the activity of protease (protease) inhibitors, more particularly matrix metalloproteinases, compositions of said inhibitors, intermediates for the synthesis of said compounds, And to methods of treating pathological conditions associated with pathological matrix metalloproteinase activity.

In accordance with the present invention, certain sulfonylaryl or heteroarylhydroxamic acids (hydroxamates) are particularly useful in the treatment of matrix metalloproteinases (" MMPs ") which are believed to be associated with uncontrolled or other pathological destruction of connective tissue Lt; / RTI > In particular, these particular sulfonylaryl or heteroarylhydroxamic acid compounds are capable of inhibiting collagenase III (MMP-13) and also gelatinase A (MMP-13), which may be particularly destructive to tissue if present or occurring in abnormal amounts or concentrations, 2), and thus has been shown to exhibit pathological activity.

In addition, many of these aromatic sulfonyl alpha-cycloaminohydroxamic acids have been found to be selective for the inhibition of MMP associated with disease states without excessive inhibition of other collagenases essential for normal bioactivity, such as tissue repair and replacement. More particularly, especially preferred sulfonylaryl or heteroarylhydroxamic acid compounds or salts of such compounds are particularly active in the inhibition of MMP-13 and / or MMP-2 and at the same time have limited or minimal effect on MMP-1 , And some compounds, such as Example 8, were also found to exhibit minimal inhibition of MMP-7. This will be discussed in detail later and is shown in the inhibition table below.

One embodiment of the present invention is directed to a sulfonylaryl or heteroarylhydroxamic acid compound that may act as a matrix metalloprotease enzyme inhibitor, a pharmaceutically acceptable salt of such a compound, a precursor of such a compound, or a prodrug form of such a compound . The known compounds correspond to the structure of formula (C)

≪ RTI ID = 0.0 &

Wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring;

R ¹ is selected from the group consisting of (i) a 5- or 6-membered cyclic hydrocarbyl, heterocyclo, aryl, or heteroaryl radical directly bonded to the SO ₂ - group described above and having a longer length than the approximately hexyl group, Is a short substituent, and R ¹ is an axial connecting the 1-position of the SO ₂ -bond of the 6-membered ring to the 4-position or an axis connecting the 1-position of the SO ₂ - bond and the center of the 3,4- , And the largest volume in the transverse direction of the rotation axis is the volume of approximately one furyl ring to the volume of approximately two phenyl rings.

Alternatively, R ¹ is (ii) R ⁷ and R ⁸ are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted aryl hydrocarbyl. NR ⁷ R ⁸ group. More preferably, R ¹ group is R ⁷ and R ⁸ are Hi give also, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R ^a oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, Aryl, heteroarylalkyl, and heterocyclo substituents, each substituent being an -NR <^7> R <^8> group optionally substituted with a -AREY substituent;

In the above-A-R-E-Y substituents, A is selected from the group consisting of:

(1) -O-;

(2) -S-;

(3) -NR ^k -

(4) -CO-N (R ^k ) or -N (R ^k ) -CO-;

(5) -CO-O- or -O-CO-;

(6) -O-CO-O-;

(7) -HC = CH-;

(8) -NH-CO-NH-;

(9) -C C-;

(10) -N = N-;

(11) -NH-NH-;

(12) -CS-N (R ^k ) - or -N (R ^k ) -CS-;

(13) -CH ₂ -;

(14) -0-CH ₂ - or -CH ₂ -0-;

(15) -S-CH ₂ - or -CH ₂ -S-;

(16) -SO-; And

(17) -SO ₂ -;

or

(18) A is a member, R is directly bonded to R ⁷ or R ⁸ , or both R ⁷ and R ⁸ ;

R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituents are either (i) unsubstituted or (ii) halo Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkylene-dioxy, hydroxycarbonyl 1 or 2 radicals selected from the group consisting of alkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl groups. It is selected from the group consisting of a search);

E group is selected from the group consisting of:

(1) -COR ^g - or - R ^g CO-;

(2) -CON (R ^k ) - or - (R ^k ) NCO-;

(3) -CO-;

(4) -SO ₂ (R ^g ) - or - (R ^g ) SO ₂ -;

(5) -SO ₂ -;

(6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -;

or

(7) E is a member and R is directly bonded to Y;

The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more groups selected from (i) unsubstituted or (ii) alkanoyl, halo, nitro, (Wherein the amino nitrogen is independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) A is selected from the group consisting of substituted) with one or two radicals; or

R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a (-NR ⁷ R ⁸ ) -GAREY group;

Wherein G is an N-heterocyclo group;

Substituent A is selected from the group consisting of:

(1) -O-;

(2) -S-;

(3) -NR &lt; ^k &gt;-;

(4) -CO-N (R ^k ) or -N (R ^k ) -CO-;

(5) -CO-O- or -O-CO-;

(6) -O-CO-O-;

(7) -HC = CH-;

(8) -NH-CO-NH-;

(9) -C C-;

(10) -N = N-;

(11) -NH-NH-;

(12) -CS-N (R ^k ) - or -N (R ^k ) -CS-;

(13) -CH ₂ -;

(14) -0-CH ₂ - or -CH ₂ -0-;

(15) -S-CH ₂ - or -CH ₂ -S-;

(16) -SO-; And

(17) -SO ₂ -;

or

(18) A is a member and R is directly bonded to the N-heterocyclo group, G.

R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is selected from the group consisting of (i) unsubstituted or (ii) halo (lower) alkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkylene-dioxy, hydroxycarbonyl 1 or 2 radicals selected from the group consisting of alkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl groups. Substituted with a carboxyl group.

Part E is selected from the group consisting of:

(1) -COR ^g - or - R ^g CO-;

(2) -CON (R ^k ) - or - (R ^k ) NCO-;

(3) -CO-;

(4) -SO ₂ (R ^g ) - or - (R ^g ) SO ₂ -;

(5) -SO ₂ -;

(6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -;

or

(7) E is a member and R is directly bonded to Y;

Y section member or Hi give also, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a Alkyl, aryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, cycloalkyl, , Aralkyl or heterocycloalkyl groups may be unsubstituted or substituted with (i) unsubstituted or (ii) alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and amino groups Wherein the amino nitrogen is optionally substituted with one or two radicals independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) &Lt; / RTI &gt;

R ⁵ and R ⁶ is Hi give too, consists of an alkyl, cycloalkyl, acyl alkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, halo, alkyloxy, hydroxy-alkyl, R ^b R ^c aminoalkyl substituent &Lt; / RTI &gt;

Or R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring.

Wherein R ^a is selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, R ^b R ^c aminoalkanoyl, haloalkanoyl, R ^b R ^c Aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy groups;

R ^b and R ^c are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl Heteroarylthioalkyl, arylsulfonyl, aralkanoyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, Alkylthioalkyl, arylthioalkyl, alkylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, Alkenyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, amino, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, Amino nitrogen is (i) unsubstituted or (ii) is independently substituted with one or two R ^d radicals, or is amino (meth) acryloyloxy, A saturated or partially unsaturated heterocyclyl group in which the substituent on the amino group taken together with the nitrogen is optionally substituted by 1, 2, or 3 groups independently selected from R ^d substituents, or by 1, 2, or 3 groups independently selected from R ^f substituents Lt; / RTI &gt; independently from each other are selected from the group consisting of hydrogen;

R ^d and R ^e are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl or arylalkyloxycarbonyl groups Being;

R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen (halo; F, Cl, Br, I), aryl, alkoxy, cyano, and R ^d R ^e amino groups;

R ^g is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F, Cl, Br, I), cyano, aldehydo (CHO, formyl) Amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ - amino, alkoxy Alkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyl oxy carbonyl amino, aryloxy carbonyloxy, carboxy, R ^h R ⁱ - aminocarbonyl-oxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - amino alkanoyl, hydroxy-aminocarbonyl, R ^h R ⁱ aminosulfonyl, R ^h R ⁱ -aminocarbonyl (R ^h ) amino, trifluoromethylsulfonyl (R ^h ) Amino, heteroaryl sulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) aminocarbonyl, alkylsulfonyl (R ^h) amino, arylcarbonyl (R ^h) amino Sulfonyl, and alkylsulfonyl (R ^h ) aminocarbonyl substituents;

R ^h is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with a substituent of a substituted aminoalkanoyl group, such as R ^j Lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &gt;

R ⁱ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with one or two R &lt; ^j &gt; substituents;

R ^j is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Alkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are alkyl, alkenyl, alkenyl, aryl, aryl Alkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl groups;

R ^k is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d amino Sulfonyl, R ^c R ^d aminoalkanoyl and R ^c R ^d aminoalkylsulfonyl.

R ²⁰ is selected from: (a) -O-R ^{21 wherein} R ²¹ is selected from: hydrido, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl and a pharmaceutically acceptable cation (B) -NR ¹³ -0-R ^{22 wherein} R ^{22 is an} optionally removable protecting group such as 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ) , C ₁ -C ₆ alkoxycarbonyl, trisubstituted silyl or o-nitrophenyl groups, peptide synthetic resins, etc. wherein the trisubstituted silyl group is C ₁ -C ₆ alkyl, aryl or ar-C ₁ -C ₆ alkyl or are substituted) in a mixture thereof, R ¹³ is Hi laundry Figure, c _l -C ₆ - alkyl or benzyl ^{giim), (c) -NR 13 -0} -R l4 ( wherein, R ¹³ is the same as above, R ¹⁴ is hydrido, a pharmacologically acceptable cation or C (V) R ^{15 wherein} V is O (oxo) or S (thioxo) and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, heteroaryl-C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, aryloxy, C ₁ -C ₆ -alkoxy, ar-C ₁ -C ₆ -alkyl, heteroaryl and amino C ₁ -C ₆ -alkyl groups, wherein the amino C ₁ -C ₆ -alkyl nitrogen is (i) (ii) C ₁ -C ₆ -alkyl, aryl, ar -C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, ar -C ₁ -C ₆ -alkoxycar C ₁ -C ₆ -alkoxycarbonyl, and C ₁ -C ₆ -alkanoyl radical, or (iii) an amino C ₁ -C ₆ -alkyl substituted with one or two substituents independently selected from the group consisting of Nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring), or (d) -NR ²³ R ²⁴ , wherein R is selected from the group consisting of R ²³ and R ²⁴ are independently selected from the group consisting of hydrido, C ₁ -C ₆ -alkyl, aminoC ₁ -C ₆ -alkyl, hydroxyC ₁ -C ₆ -alkyl, aryl, and ar-C ₁ -C ₆ -alkyl independently selected from the group, or R ²³ and R ²⁴ is 0 with the above-mentioned nitrogen atoms, Is to form a 5- to 8-membered ring containing a further heteroatom oxygen, nitrogen or sulfur a).

The compounds of formula (C) include useful precursor compounds, the prodrugs of hydroxamates and the hydroxamates themselves, as well as the intermediates and amide compounds which can also be used as MMP inhibiting compounds. Thus, for example, compounds of formula I wherein R ²⁰ is -OR ²¹ wherein R ²¹ is selected from hydrido, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl and pharmaceutically acceptable cations , The precursor carboxylic acid or ester is defined as being easily convertible to hydroxamic acid, as shown in the following examples. Such carboxyl compounds which are precursors to hydroxamates may also be active as inhibitors of MMP enzymes as seen from the inhibition table in the Examples below.

Another useful precursor compound is the compound wherein R ²⁰ is -NR ¹³ -OR ²² wherein R ²² is an optionally removable protecting group and R ¹³ is a hydrido or benzyl group, preferably a hydrido group Is defined. Group can selectively remove the 2-tetrahydropyranyl, benzyl, p- methoxybenzyl oxycarbonyl (MOZ), benzyloxycarbonyl _{(BOC), C 1 -C 6} - alkoxycarbonyl, C ₁ -C ₆ - Alkoxy-CH ₂ -, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy-CH ₂ -, trisubstituted silyl group, o-nitrophenyl group, and peptide synthetic resin. The trisubstituted silyl group is a silyl group substituted with C ₁ -C ₆ -alkyl, aryl, or ar-C ₁ -C ₆ -alkyl substituents or mixtures thereof, such as trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, Triphenylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl, tribenzylsilyl and the like. Exemplary trisubstituted silyl protecting groups and their use have been discussed in several places (Greene et al., Protective Groups In Organic Synthesis , 2nd ed., John Wiley & Sons, Inc., New York (1991)].

Known peptide synthetic resins are solid phase supports, also known as Merrifield's Peptide Resins, which are suitable for the synthesis and selective release of hydroxy acid derivatives, such as those commercially available from Sigma Chemical Co. (St. Louis, Mo.). An example of such a suitable peptide synthetic resin, and examples of its use in the synthesis of hydroxamic acid derivatives, are discussed in Tetrahedron Let., Floyd et al., 37 (44): 8048-8048 (1996).

The 2-tetrahydropyranyl (THP) protecting group is particularly preferably a selectively removable protecting group, and is often used when R ¹³ is a hydrido group. The known THP-protected hydroxamate compounds of formula A are prepared by reacting N-methylmorpholine, N-hydroxybenzotriazole hydrate and a water-soluble carbodiimide such as 1- (3-dimethylaminopropyl) -3 -Ethylcarbodiimide hydrochloride is reacted with a carboxylic acid precursor compound of formula A (wherein R ²⁰ is -OR ²¹ and R ²¹ is a hydrido group) in the presence of O- (tetrahydro-2H-pyran-2 -Yl) hydroxylamine. &Lt; / RTI &gt; The resulting THP-protected hydroxamates correspond to the structure of formula C3, wherein W, R ¹ , R ⁵ and R ⁶ are as defined above and are defined in more detail hereinafter. The THP-protecting group is readily removable from an aqueous acid solution, for example p-toluenesulfonic acid or an aqueous mixture of HCl and acetonitrile or methanol.

Another aspect of the present invention is that of compounds corresponding to the structure of formula (VI-1): &lt; EMI ID =

[Formula VI-1]

[Wherein, R ^5, R ^6, R ^7, R ⁸ and R ²⁰ each, and in further detail defined below the same as defined above, A, B, C, and D each is a carbon, nitrogen, sulfur or oxygen, , And the ring is present or absent such that it is a 5- or 6-membered ring. The hydroxamate compound of formula VI-1 is a selective inhibitor of MMP-2 rather than both MMP-1 and MMP-13. That is, the hydroxamate compound of formula VI exhibits greater activity in inhibiting MMP-2 than MMP-1 and generally also MMP-13.

A particularly preferred embodiment from the point of view of the present invention is a compound corresponding to the structure of formula VIA or VIA-1:

(VIA)

[Chemical Formula VIA-1]

Wherein R ²⁰ , R ⁵ , R ⁶ and R ⁴ are the same as defined above, and the ring structure W ² containing the above-mentioned nitrogen atom is a heterocyclic ring containing a 5- or 6-membered ring, R ⁴ is bonded at the 4-position to the above-mentioned nitrogen atom when W ² is a 6-membered ring and is bonded at the 3- or 4-position to the above-mentioned nitrogen atom when W ² is a 5-membered ring. The ring structure W ² is preferably a preferably substituted N-piperidinyl group as discussed below.

Another particularly preferred embodiment of this aspect is a compound corresponding to the structure of formula VIB:

[Chemical Formula VIB]

Wherein R ²⁰ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are as defined above.

A further embodiment of the present invention relates to a sulfonylaryl or heteroarylhydroxynaphthoic acid compound which may act as a matrix metalloprotease enzyme inhibitor. The compound corresponds to the structure of formula C4:

Wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring;

R ¹ contains a 5-membered or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical directly bonded to the SO ₂ - group described above and is longer in length than the hexyl group and shorter in length than the eicosyl group substituents, and wherein R ¹ is SO ₂ in the 6-membered ring radical-rotated in the coupled position and the first axis connecting the center of 3,4-bond coupling first position and a 5-membered ring radical or the SO of the axis connecting the 4-position ₂ , And the largest volume in the transverse direction of the rotation axis is the volume of approximately one furyl ring to the volume of approximately two phenyl rings;

R ⁵ and R ⁶ is Hi give also, alkyl, cycloalkyl, acyl alkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, halo, alkyloxy, hydroxy-alkyl, R ^b R ^c aminoalkyl substituent, a thiol , alkylthio, arylthio, cyclo alkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclo-oxy, and R ^b R ^c amino independently selected from the group consisting of alkyloxy substituents;

Or R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring.

Also, in some preferred embodiments, (ii) R ¹ is selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted aryl hydrocarbyl, wherein R ⁷ and R ⁸ are independently selected by a -NR ⁷ R ⁸ group. More preferably, R ⁷ and R ⁸ are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R ^a oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, Arylalkyl, and heterocyclo-substituents, each substituent being optionally substituted with -AREY substituents;

In the above-A-R-E-Y substituents, A is selected from the group consisting of:

(1) -O-;

(2) -S-;

(3) -NR ^k -

(4) -CO-N (R ^k ) or -N (R ^k ) -CO-;

(5) -CO-O- or -O-CO-;

(6) -O-CO-O-;

(7) -HC = CH-;

(8) -NH-CO-NH-;

(9) -C C-;

(10) -N = N-;

(11) -NH-NH-;

(12) -CS-N (R ^k ) - or -N (R ^k ) -CS-;

(13) -CH ₂ -;

(14) -0-CH ₂ - or -CH ₂ -0-;

(15) -S-CH ₂ - or -CH ₂ -S-;

(16) -SO-; And

(17) -SO ₂ -;

or

(18) A is a member, R is directly bonded to R ⁷ or R ⁸ , or both R ⁷ and R ⁸ ;

R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituents are either (i) unsubstituted or (ii) halo Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkylene-dioxy, hydroxycarbonyl 1 or 2 radicals selected from the group consisting of alkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl groups. It is selected from the group consisting of a search);

E group is selected from the group consisting of:

(1) -COR ^g - or - R ^g CO-;

(2) -CON (R ^k ) - or - (R ^k ) NCO-;

(3) -CO-;

(4) -SO ₂ (R ^g ) - or - (R ^g ) SO ₂ -;

(5) -SO ₂ -;

(6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -;

or

(7) E is a member and R is directly bonded to Y;

The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more groups selected from (i) unsubstituted or (ii) alkanoyl, halo, nitro, Wherein the amino nitrogen is substituted with one or two groups independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) Lt; / RTI &gt; is substituted with a radical.

More preferably, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a (-NR ⁷ R ⁸ ) -GAREY group;

Wherein G is an N-heterocyclo group;

Substituent A is selected from the group consisting of:

(1) -O-;

(2) -S-;

(3) -NR &lt; ^k &gt;-;

(4) -CO-N (R ^k ) or -N (R ^k ) -CO-;

(5) -CO-O- or -O-CO-;

(6) -O-CO-O-;

(7) -HC = CH-;

(8) -NH-CO-NH-;

(9) -C C-;

(10) -N = N-;

(11) -NH-NH-;

(12) -CS-N (R ^k ) - or -N (R ^k ) -CS-;

(13) -CH ₂ -;

(14) -0-CH ₂ - or -CH ₂ -0-;

(15) -S-CH ₂ - or -CH ₂ -S-;

(16) -SO-; And

(17) -SO ₂ -;

or

(18) A is a member and R is directly bonded to an N-heterocyclo group, G;

R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is selected from the group consisting of (i) unsubstituted or (ii) halo (lower) alkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkylene-dioxy, hydroxycarbonyl 1 or 2 radicals selected from the group consisting of alkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl groups. &Lt; / RTI &gt;

Part E is selected from the group consisting of:

(1) -COR ^g - or - R ^g CO-;

(2) -CONR ^k - or -R ^k NCO-;

(3) -CO-;

(4) -SO ₂ (R ^g ) - or - (R ^g ) SO ₂ -;

(5) -SO ₂ -;

(6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -;

or

(7) E is a member and R is directly bonded to Y;

The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more groups selected from (i) unsubstituted or (ii) alkanoyl, halo, nitro, Wherein the amino nitrogen is substituted with one or two groups independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) Lt; / RTI &gt; is substituted with a radical.

The superscripts of the " R " group, i. E., R ^a , R ^b , and the like, are as defined above.

In one preferred embodiment, R ⁵ and R ⁶ are independently selected from the group consisting of hydrido, hydrocarbyl, preferably C ₁ -C ₄ hydrocarbyl, hydroxylhydrocarbyl, hydroxyl, amino, R ^b R ^c amino hydro Substituted or unsubstituted heterocycloalkyl, carbocycle, halo, nitro, cyano, hydrocarbyloxy, halohydrocarbyl, halohydrocarbyloxy, hydroxyhydrocarbyl, dihydrocarbylamino, heterocyclo, heterocyclohydrocarbyl, heterocycloxy , And a heterocyclothio group. More preferably, R ⁵ and R ⁶ is Hi give also, alkyl, cycloalkyl, acyl alkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, halo, alkyloxy, hydroxy-alkyl, and R ^b R ^c &Lt; / RTI &gt; aminoalkyl substituents.

Known aromatic or heteroaromatic rings include, but are not limited to, 1,2-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 4,5-pyridinylene, 2,3- Methylene, and 5,6-pyrimidinylene groups. The 1,2-phenylene (1,2-disubstituted phenyl ring) is a particularly preferred aromatic or heteroaromatic ring, and is used herein as W.

As mentioned above, the R &lt; ¹ &gt; substituent contains a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl radical that is directly attached to the SO ₂ - group described above. The R ¹ substituents also have the length, width and substitution requirements discussed in detail below. However, it is mentioned that a single or fused ring cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is not long enough to satisfy the desired length requirement of the compound, especially when R ¹ is NR ⁷ R ⁸ . For that reason, the cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical must itself be substituted.

An exemplary 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl radical, which may constitute part of an R ¹ substituent and is itself substituted as discussed herein, is phenyl, 2-, 3- , Or 4-pyridyl, 2-naphthyl, 2- pyrazinyl, 2- or 5-pyrimidinyl, 2- or 3-benzo (b) thienyl, 2- or 3-piperidinyl, 2- or 3-morpholinyl, 2- or 3-tetrahydropyranyl, 2- or 3-pyrrolyl, 2- Imidazolidinyl, 2- or 3-pyrazolinyl, and the like. Phenyl radicals are particularly preferred and are used as exemplified herein.

When tested along the longest chain of atoms, the R ¹ substituent, when present, including its own substituent, has an overall length equal to the length of the fully extended saturated chain of six carbon atoms (hexyl group); That is, the length of the heptyl chain in twisted form or longer, and shorter than the length of the fully extended saturated chain of about 20 carbons (eicosyl group). Preferably, the length is in the range of from about 8 to about 18 carbon atoms, although more atoms are present in the ring structure or substituent. The length requirements are discussed further below.

More generally, and in addition to the specific moieties constructed, the R ¹ substituent (radical, group or moiety) has a length of greater than or equal to the heptyl group. Such R ¹ substituents also have a shorter length than the eicosyl group. That is, R ¹ is a substituent that is longer than the length of the fully extended saturated six carbon atom chain and shorter than the length of the fully extended saturated 20 carbon atom chain, more preferably longer than the octyl group, It is a short length. The radical chain length is measured along the longest atomic chain in the radical and, if necessary, along the skeletal atom of the ring. Each atom in the chain, carbon, oxygen or nitrogen, is assumed to be carbon for ease of calculation.

If necessary, such lengths can be easily determined by making the model using a commercially available kit in which the published coupling angle, coupling length and atomic radius or coupling angle, length and atomic radius match the allowed published values . The radical (substituent) length is, as here, assumed that all atoms have the length of the bond of saturated carbon, the unsaturation and aromatic bonds have the same length as the saturated bond, and the bonding angle to the unsaturated bond is the same as that of the saturated bond (Although the above-mentioned measurement mode is preferred). For example, a 4-phenyl or 4-pyridyl group has a length of four carbon chains such as a propoxy group, while a biphenyl group has a length of about 8 carbon chains using a known measurement mode.

In addition, R ¹ substituent is 6-membered ring - when rotated in the coupled position and the first axis connecting the center of 3,4-bond of the radical SO ₂ - bond first position and the 4-position the connecting axis or five-membered ring-SO ₂ of the radicals , And the largest volume in the transverse direction of the rotation axis is the volume of approximately one furyl ring to the volume of approximately two phenyl rings.

When using the above width or volume criteria, a fused ring system such as a naphthyl or furunyl radical may be substituted with a 6- or 5-position substituted at a suitable position, counting from the SO &lt; ₂ &gt; - It is regarded as a circle. Thus, a 2-naphthyl substituent or an 8-furyl substituent is an R &lt; ¹ &gt; radical of a suitable size for the width when tested using the above rotation rate reference. On the other hand, the 1-naphthyl group or the 7- or 9-prunyl group is too large to be excluded during rotation.

As a result of these length and width requirements, R ¹ substituents such as 4- (phenyl) phenyl [biphenyl], 4- (4'-methoxyphenyl) -phenyl, 4- Phenyl, 4- (phenylthio) phenyl, 4- (phenylthio) phenyl, 4- (phenylthio) Phenyl, 4- (picolinamido) phenyl and 4- (benzamido) phenyl are particularly preferred among the R ¹ substituents, and 4- (phenoxy) phenyl and 4- Phenyl) phenyl are most preferred.

SO ₂ -bonded cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl radical is a 5- or 6-membered monocyclic ring that is itself substituted with another substituent R ⁴ . When the SO ₂ -bonded monocyclic cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is a 6-membered ring at its 4-position, and when it is a 5- ⁴ -substituted. In a preferred embodiment, the C ⁴ hydrocarbyl, heterocyclo, aryl or heteroaryl radical to which R ⁴ is attached is preferably a phenyl group, and therefore R ¹ is preferably PhR ⁴ , wherein R ⁴ is SO ₂ -bonded phenyl (Ph) radical, and R &lt; ⁴ &gt; may itself be optionally substituted as discussed below. In another embodiment, a heterocyclo or heteroaryl radical is preferred for a phenyl radical wherein the R ⁴ substituent is attached at the 4-position to the bond between the ring and the SO ₂ group.

Known R &lt; ⁴ &gt; substituents include monocyclic cyclohydrocarbyl, heterocyclo, aryl or heteroaryl groups or another substituent having a chain length of 3 to about 14 carbon atoms, such as a hydrocarbyl or hydrocarbyloxy group [ For example, C ₃ -C ₁₄ hydrocarbyl or OC ₂ -C ₁₄ hydrocarbyl], a phenyl group, a phenoxy group [-OC ₆ H ₅ ], a thiophenoxy group [phenylsulfanyl] -SC ₆ H ₅ ], anilino group [-NHC ₆ H ₅ ], phenyl azo group [-N ₂ C ₆ H ₅ ], phenylureido group [anilincarbonylamino; -NHC (O) NH-C ₆ H ₅ ], benzamido [-NHC (O) C ₆ H ₅ ], nicotinamido [3-NHC (O) C ₅ H ₄ N], isonicotinoamido [ 4-NHC (O) C ₅ H ₄ N], or picolinamido [2-NHC (O) C ₅ H ₄ N]. Additionally known R ⁴ substituents include, but are not limited to, heterocyclo, heterocyclohydrocarbyl, arylhydrocarbyl, arylheterocyclohydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclo-hydrocarbyl, arylhydrocarbyloxyhydrocarbyl The present invention relates to the use of a compound selected from the group consisting of benzyloxycarbonyl, benzyloxycarbonyl, benzyloxycarbonyl, benzyloxycarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, Arylthiocarbylthioaryl, arylhydrocarbylthioaryl, arylhydrocarbylthioaryl, arylhydrocarbylthioaryl, arylhydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbyl-thiohydrocarbyl, Arylhydrocarbylamino, or heteroarylthio group.

Known R &lt; ⁴ &gt; substituents may also be substituted with one or more substituent radicals containing up to 10 of the longest chain except for a single atom or hydrogen at the meta- or para-position of the 6-membered ring or both . Exemplary substituent radicals are selected from the group consisting of halo, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethyl-hydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy Heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocycloxy, hydroxycarbamoyl, heteroarylthio, arylthio, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, Heteroaryl hydrocarbyloxy, heteroaryl hydrocarbyloxy, heteroaryl hydrocarbyloxy, heteroaryl hydrocarbyloxy, heteroaryl hydrocarbyloxy, heteroaryl hydrocarbyloxy, heteroaryl hydrocarbyloxy, heteroaryl hydrocarbyloxy, heteroaryl hydrocarbyloxy, heteroaryl hydrocarbyloxy, Aminocarbonyloxy, aminocarbonyloxy, aminocarbonyloxy, aminocarbonyloxy, aminocarbonyloxy, aminocarbonyloxy, aminocarbonyloxy, Alkoxycarbonyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyl, Hydrocarbyloxycarbonyloxycarbonyl, hydrocarbyl-hydrocarbyloxy, hydrocarbyloxy-carbonylhydrocarbyl, hydrocarbylhydroxycarbyl, hydrocarbyloxycarbonyloxy, Hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino , Heterocyclo-hydrocarbylcarbonylamino, arylhydrocarbyl-carbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbyl Arylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl-sulfonylamino, cyclohydrocarbylsulfonylamino, arylsulfonylamino, arylsulfonylamino, Amino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted amino hydrocarbyl groups wherein the substituent (s) on the nitrogen is selected from the group consisting of hydrocarbyl, aryl, aryl hydrocarbyl, cyclohydrocarbyl , Aryl hydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl, or nitrogen and the two substituents attached thereto are selected from the group consisting of 5- to 8-membered heterocyclic or hetero To form an aryl ring.

Thus, early studies of SO ₂ is discussed here - one that meets the combined R length, substitution and width of the ^substituents (volume upon rotation) requirements, the R ¹ substituent can be extremely changed.

Particularly preferred R ⁴ substituents of SO ₂ -bonded Ph groups are unsubstituted or monosubstituted (optionally substituted) mono-substituted aryl at the 3- or 4-position in the para position when the 6- Or a heteroaryl, phenoxy, thiophenoxy, phenylazo, phenylureido, nicotinamido, isonicotinoamido, picolinamido, anilino or benzamido group. Here, a substituent containing a single atom such as a halogen moiety or a chain of 1 to about 10 atoms other than hydrogen, for example a C ₁ -C ₁₀ hydrocarbyl, a C ₁ -C ₉ hydrocarbyloxy or a carboxyethyl group, have.

Exemplary more preferred PhR ⁴ (particularly preferred R ¹ ) substituents are biphenyl, 4-phenoxyphenyl, 4-thiophenoxyphenyl, 4-benzamidophenyl, 4-phenylureido, 4-anilinophenyl, 4-nicotinamido, 4-isonicotinamido, and 4-picolinamido. Particularly preferred examples of R &lt; ⁴ &gt; groups include 6-membered aromatic rings and include phenyl, phenoxy, thiophenoxy, phenyl azo, phenylureido, anilino, nicotinamido, isonicotinoamido, And benzamido groups.

More specifically, a particularly preferred sulfonyl butane hydroxide roksa formate compound itself in the meta or para-position or in both halogen, halo-hydrocarbyl group, a halo-C ₁ -C ₉ hydrocarbyl bilok group, a perfluoro C ₁ -C ₉ hydrocarbyl groups, C ₁ -C ₉ hydrocarbyl oxy (-OC ₁ -C ₉ hydrocarbyl) group, C ₁ -C ₁₀ hydrocarbyl group, di -C ₁ -C ₉ hydrocarbyl-amino [-N (C ₁ -C ₉ hydrocarbyl) (C ₁ -C ₉ hydrocarbyl)] group, a carboxyl C ₁ -C ₈ hydrocarbyl (C ₁ -C ₈ hydrocarbyl-CO ₂ H) group, a C ₁ -C ₄ hydrocarbyl oxycarbonyl C ₁ -C ₄ hydrocarbyl [C ₁ -C ₄ hydrocarbyl -O- (CO) -C ₁ -C ₄ hydrocarbyl] group, C ₁ -C ₄ Hydrocarbyloxycarbonyl C ₁ -C ₄ hydrocarbyl [C ₁ -C ₄ hydrocarbyl (CO) -OC ₁ -C ₄ hydrocarbyl] group and C ₁ -C ₈ hydrocarbylcarboxamido [ -NH (CO) -C ₁ -C ₈ hydrocarbyl] group, Optionally substituted, or meta or para-position or a methyl group in C ₁ -C ₂ alkylenedioxy group, for example substituted with methylenedioxy group, phenyl group, phenoxy group, thiophenoxy group, a phenyl azo group, a phenyl ureido group, anilino group, an amido nicotine, nicotine has a iso-amido group, an amido group-picoline, or benz amido group of R ⁴ substituents.

As long as the known SO ₂ -bonded cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radicals themselves are preferably substituted by 6-membered aromatic rings, here two nomenclature Is used. The first nomenclature uses the number of positions for the ring to which the SO ₂ group is directly attached while the second method uses one or more of the six-membered rings attached to the SO ₂ -bonded cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl radicals Meta or para to the position of the substituent. When the R ⁴ substituent is other than a 6-membered ring, the substitution position counts from the bonded position to the aromatic or heteroaromatic ring. Formal chemical nomenclature is used to order specific compounds.

Accordingly, the above discussion SO ₂ - cycloalkyl bonded hydrocarbyl, heterocycloalkyl, aryl or 1-position of the heteroaryl radical is the position SO ₂ group is bonded to the ring. The 3- and 4-positions of the rings discussed herein count the number from the sites of the substitution bonds from the SO ₂ - bond, as compared to the position counting the number of regular rings used in the heteroaryl nomenclature.

(C2)

In some preferred embodiments, were known compounds, such as the one (wherein the formula C2, W, R ^5, R ⁶ and R ¹⁴ are as defined above, Ph is substituted at the 4-position with a substituent R ⁴ defined above Lt; / RTI &gt; phenyl).

The length of the R ¹ substituent attached to the SO ₂ group is generally believed to play a role in the overall activity of the known inhibitor compounds on the MMP enzyme. Therefore, a compound having an R ¹ substituent having a shorter length than a heptyl group, for example, a 4-methoxyphenyl group exhibits a moderate or poor inhibitory activity against all MMP enzymes, while R ¹ Substituted compounds, for example, 4-phenoxyphenyl groups having a length of about 9 carbon chains, typically exhibit a good or superior ability to MMP-13 or MMP-2 and also have good or superior ability to MMP-1 see. Exemplary data are provided in subsequent inhibition tables in which the activity of the two compounds can be compared.

In view of the above-discussed preferred aspects, the compounds corresponding to the structures of particular formulas constitute particularly preferred embodiments.

In one of their embodiments, the known compound corresponds to a structure of formula C4:

(C4)

Wherein W, R ¹ , R ⁵ , and R ⁶ are as defined above and R ¹ is also preferably PhR ⁴ as defined above.

W is a 1,2-phenylene radical, R ¹ is PhR ⁴ called again considering the above-described preferred that, particularly preferred compounds are the formula VIB, VIB-1, 2-VIB, VIB-3, VII, VIIB, VIIC, VIID, VIII, VIII and VIIIB wherein the definition above for -AREY, -GAREY, W ² , R ¹ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ²⁰ is also applied and substituent- Cyclic structure W &lt; ² &gt; or the ring structure described above)

[Formula VIB] [Formula VIB-1]

[Formula VIB-2] [Formula VIB-3]

[Formula VIIA] [Formula VIIB]

[Formula VIIC] [Formula VIID]

(VIIE)

[Formula VIII] [VIII-B]

To the formula D, D1, D2, D3 and D4 (expression, -AREY, R ^4, R ^5, R ⁶ and R ²⁰ are defined above also apply to the, the ring structure A, B, C, and D, respectively Is a carbon, nitrogen, sulfur or oxygen and the ring described above may be present or absent with a 5- or 6-membered ring is also one of the particularly preferred compounds noted herein and is a compound of formula VIB Can be regarded as a subgroup of:

[Chemical Formula D]

[Chemical formula D1] [Chemical formula D2]

[Chemical formula D3] [Chemical formula D4]

The compound of Example 24 has a structure corresponding to the structure of formula (D2). In this compound, R ⁵ and R ⁶ are all methoxy, the A moiety is a sulfur atom, -S-, R is 1,4-phenylene, E is absent and the Y moiety is hydrido. Further, the compound of Example 25 corresponds to the structure of the formula D2. Wherein R ⁵ and R ⁶ are all again methoxy, the A moiety is an oxygen atom, -O-, R is 1,4-phenylene, E is absent and the Y moiety is a dialkoxy- ).

Particularly preferred compounds which are noteworthy herein are illustrated below, each with the number of the particular embodiment in which it is made:

The term " hydrocarbyl " is used herein as an acronym including acyclic and cyclic aliphatic as well as radicals containing only carbon and hydrogen, as well as straight and branched aliphatic groups. Thus, alkyl, alkenyl and alkynyl groups are noted, while aromatic hydrocarbons, such as phenyl and naphthyl groups, which are strictly also hydrocarbyl groups, are mentioned herein as the aryl groups or radicals discussed hereinafter. The group is incorporated, where a specific aliphatic hydrocarbyl substituent group is intended: that is, C ₁ -C ₄ alkyl, methyl or dodecenyl. Exemplary hydrocarbyl groups contain a chain of from 1 to about 12 carbon atoms, preferably from 1 to about 10 carbon atoms.

A particularly preferred hydrocarbyl group is an alkyl group. As a consequence, although generalized, more preferred substituents can be recited by replacing the descriptor " hydrocarbyl " with " alkyl " in numerous substituents herein.

Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, Examples of suitable alkenyl radicals include, but are not limited to, ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, -Butenyl, decenyl, and the like. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl and the like.

The general use of removing the terminal " work " and adding suitable suffixes when using the word " hydrocarbyl " does not always follow because of the likelihood that the resulting names of one or more substituents may be similar. Follow suffix naming. Thus, hydrocarbyl ethers are referred to as " hydrocarbyloxy " rather than " hydrocarbyloxy &quot;, which may possibly be more suitable when followed according to the general chemical nomenclature. On the other hand, hydrocarbyl groups containing -C (O) O- functional groups are referred to as hydrocarbyl groups unless there is ambiguity in the use of suffixes. As will be appreciated by those skilled in the art, substituents that may not be present, such as a C ₁ alkenyl group, are not intended to be encompassed by the word " hydrocarbyl &quot;.

The term " carbonyl &quot;, alone or in combination, signifies a -C (= O) - group in which the remaining two bonds (valences) may be independently substituted. The term " thiol " or " sulfhydryl &quot;, alone or in combination, signifies a -SH group. The term " thio " or " thia &quot;, alone or in combination, means a thioether group, i.e. an ether group in which the ether oxygen is replaced by a sulfur atom, such as in the thiophenoxy group (C ₆ H ₅ -S-).

The term "amino", alone or in combination, signifies an amine or -NH ₂ group, while the term "monosubstituted amino", alone or in combination, signifies a substituted amine -N (H) One hydrogen atom is substituted with a substituent), and the disubstituted amine means -N (substituent) ₂ (wherein two hydrogen atoms of the amino group are independently substituted with a selected substituent). Amines, amino groups, and amides are groups that can be represented by primary (I ⁰ ), secondary (II ⁰ ), or tertiary (III ⁰ ) or unsubstituted, monosubstituted or disubstituted rings depending on the degree of substitution of amino nitrogen. The quaternary amine (IV ⁰ ) means nitrogen with four substituents [-N ⁺ (substituent) ₄ ] which are positively charged and are accompanied by counter ions, or N-oxides, in which one substituent is oxygen and the It is displayed ^as-charge has to be compensated internally [-N ⁺ (substituent) ₃ -O].

The term " cyano &quot;, alone or in combination, signifies a C-triple bond -N- (- C N) group. The term " azido &quot;, alone or in combination, signifies an N-double bond -N-double bond -N- (-N = N = N-).

The term " hydroxyl &quot;, alone or in combination, signifies a -OH group. The term " nitro &quot;, alone or in combination, signifies a -NO ₂ group.

The term " azo ", alone or in combination, means an -N = N- group wherein the bond at the terminal position is independently substituted. The term " hydrazino ", alone or in combination, signifies an -NH-NH- group in which the remaining two bonds (valences) are independently substituted. The hydrogen atom of the hydrazino group may be independently substituted with a substituent, and the nitrogen atom may form an acid addition salt or be quaternized.

The term " sulfonyl &quot;, alone or in combination, means a -S (O) ₂ - group in which the remaining two bonds (valences) may be independently substituted. The term " sulfoxido &quot;, alone or in combination, signifies a -S (= O) - group in which the remaining two bonds (valences) may be independently substituted. The term " sulfonylamide &quot;, alone or in combination, signifies a -S (= O) ₂ -N = group in which the remaining three bonds (valences) are independently substituted. The term " sulfinamido &quot;, alone or in combination, signifies a -S (= O) ₁ N = group in which the remaining three bonds (valences) are independently substituted. The term " sulfenamide &quot;, alone or in combination, means -SN = group in which the remaining three bonds (valences) are independently substituted.

The term " hydrocarbyloxy ", alone or in combination, means a hydrocarbyl ether radical, wherein the term hydrocarbyl is as defined above. Examples of suitable hydrocarbyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy, tert- . The term " cyclohydrocarbyl ", alone or in combination, refers to a cyclic hydrocarbyl radical containing from 3 to about 8 carbon atoms, preferably from 3 to about 6 carbon atoms. The term " cyclohydrocarbyl hydrocarbyl " means a hydrocarbyl radical, as defined above, substituted by a cyclohydrocarbyl as defined above. Examples of such cyclohydrocarbyl hydrocarbyl radicals include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctynyl, and the like.

The term " aryl ", alone or in combination, signifies a phenyl or naphthyl radical optionally accompanied by one or more substituents selected from hydrocarbyl, hydrocarbyloxy, halogen, hydroxy, amino, , p-tolyl, 4-methoxyphenyl, 4- (tert-butoxy) phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl and the like. The term " arylhydrocarbyl ", alone or in combination, signifies a hydrocarbyl radical as defined above, e.g., benzyl, 2-phenylethyl, etc., wherein one hydrogen atom is replaced by an aryl radical as defined above . The term " aryl hydrocarbyloxycarbonyl ", alone or in combination, signifies a group of formula -C (O) -O-arylhydrocarbyl, wherein the term " arylhydrocarbyl " Radical. &Lt; / RTI &gt; An example of an aryl hydrocarbyloxycarbonyl radical is benzyloxycarbonyl. The term " aryloxy " means a radical of the formula aryl-O-, wherein the term aryl has the meaning given above. The combined term "aromatic ring", for example, substituted-aromatic ring sulfonamide, substituted-aromatic ring sulfamide or substituted aromatic ring sulfenamide, means an aryl or heteroaryl as defined above.

The term " hydrocarbyloyl " or " hydrocarbylcarbonyl ", alone or in combination, signifies an acyl radical derived from a hydrocarbylcarboxylic acid, examples of which include acetyl, propionyl, acryloyl, Butyryl, valeryl, 4-methylvaleryl, and the like. The term " cyclohydrocarbylcarbonyl " means an acyl group derived from a monocyclic or bridged cyclic hydrocarbylcarboxylic acid, for example, cyclopropanecarbonyl, cyclohexenecarbonyl, adamantanecarbonyl, etc. Or an acyl group derived from a benz-fused monocyclic cyclohydrocarbylcarboxylic acid optionally substituted, for example, by a hydrocarbylamino group, for example, 1,2,3,4-tetrahydro 2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term " arylhydrocarbyloyl " or " arylhydrocarbylcarbonyl " refers to an acyl radical derived from an aryl-substituted hydrocarbylcarboxylic acid such as phenylacetyl, 3-phenylpropenyl (cinnamoyl) 4-phenylbutyryl, (2-naphthyl) acetyl, 4-chlorohydrocinnamoyl, 4-aminocinnamoyl, 4-methoxycinnamoyl and the like.

The term " aroyl " or " arylcarbonyl " means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals are aromatic carboxylic acids, optionally substituted benzoic acids or naphthoic acids such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4- (benzyloxycarbonyl) benzoyl, 2- 2-naphthoyl, 3-hydroxy-2-naphthoyl, 3- (benzyloxyformamido) - 2-naphthoyl, and the like.

The heterocyclyl (heterocyclo) or heterocyclohydrocarbyl moiety, such as heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclyl hydrocarbyloxycarbonyl or heterocyclohydrocarbyl group, may be substituted with nitrogen, oxygen and sulfur Saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle containing one to four heteroatoms selected from halogen, alkyl, alkoxy, oxo group or the like on one or more carbon atoms Or optionally substituted on the secondary nitrogen atom (i.e., -NH-) by hydrocarbyl, aryl hydrocarbyloxycarbonyl, hydrocarbyloyl, aryl or aryl hydrocarbyl, or tertiary nitrogen atoms I. E., = N-), and is attached via a carbon atom. The tertiary nitrogen atom with three substituents can also form an N-oxide [= N ⁺ (O) ^- ] group. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl and the like.

The heteroaryl moiety, such as a heteroaroyl, heteroaryloxycarbonyl, or heteroarylhydrocarbyloyl (heteroarylhydrocarbylcarbonyl) group, contains a heteroatom and is as defined above for the definition of heterocyclyl Optionally substituted aromatic monocyclic, bicyclic, or tricyclic heterocycle. The " heteroaryl " group is preferably an aromatic heterocyclic ring substituent containing 1, 2, 3 or 4 atoms other than carbon in the ring. Such a heteroatom may be nitrogen, sulfur or oxygen. The heteroaryl group may contain a fused ring system having a single 5- or 6-membered ring or two 6-membered rings or 5- and 6-membered rings. Exemplary heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4-, or 1,2,3-triazinyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl , Thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl groups; 6- / 5-membered fused ring substituents such as benzothiopyranyl, isobenzothiopyranyl, benzisoxazolyl, benzoxazolyl, pyridinyl and anthranyl groups; And 6- / 6-membered fused rings such as 1,2-, 1,4-, 2,3- and 2,1-benzopyranyl, quinolyl, isoquinolinyl, Benzyloxycarbonyl, benzyloxycarbonyl, zolinyl, and 1,4-benzoxazinyl groups.

The term " cyclohydrocarbylhydrocarbyloxy-carbonyl " refers to an acyl group derived from a cyclohydrocarbyl hydrocarbyloxycarboxylic acid of the formula cyclic hydrocarbyl hydrocarbyl-O-COOH, Carbylhydrocarbyl have the meanings given above. The term " aryloxyhydrocarbyloyl " means an acyl radical of formula aryl-O-hydrocarbyloyl, wherein aryl and hydrocarbyloyl have the meanings given above. The term " heterocyclyloxycarbonyl " means an acyl group derived from heterocyclyl-O-COOH, wherein heterocyclyl is as defined above. The term " heterocyclyl hydrocarbyloyl " means an acyl radical derived from a heterocyclyl-substituted hydrocarbylcarboxylic acid (wherein the heterocyclyl has the meaning given above). The term " heterocyclyl hydrocarbyloxycarbonyl " means an acyl radical derived from a heterocyclyl-substituted hydrocarbyl-O-COOH, wherein heterocyclyl has the meaning given above. The term " heteroaryloxycarbonyl " means an acyl radical derived from a carboxylic acid represented by heteroaryl-O-COOH, wherein heteroaryl has the meaning given above.

The term " aminocarbonyl ", alone or in combination, refers to an amino-substituted carboxylic acid, wherein the amino group is hydrogen, hydrocarbyl, aryl, aralkyl, cyclohydrocarbyl, cyclohydrocarbyl hydrocarbyl radical, (Which may be a primary, secondary or tertiary amino group containing a substituent selected from the group consisting of: The term " aminohydrocarbyloyl " refers to an amino-substituted hydrocarbyl-carboxylic acid, wherein the amino group is selected from hydrogen, alkyl, aryl, aralkyl, cyclohydrocarbyl, cyclohydrocarbyl hydrocarbyl radical, Which may be a primary, secondary or tertiary amino group containing an independently selected substituent).

The term " halogen " means fluorine, chlorine, bromine, or iodine. The term " halohydrocarbyl " means a hydrocarbyl radical having the meaning defined above wherein one or more of the hydrogens is replaced by halogen. Examples of such halohydrocarbyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like. The term perfluorohydrocarbyl means a hydrocarbyl group in which each hydrogen atom is replaced by a fluorine atom. Examples of such perfluorohydrocarbyl groups include perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl in addition to the above trifluoromethyl.

Tables 1 to 88 below show some known sulfonylaryl or heteroarylhydroxynthio compounds as substituents. Each of the groups of the compounds of Tables 1 to 70 is represented by the general formula and is followed by a series of preferred moieties or groups which constitute the various substituents which may be attached at the positions clearly shown in the general structure. The substituent symbols, such as R ¹ , R ² , and X, are as shown in the respective tables, and are often different from those shown here in the structural formulas that include uppercase Roman letters. One or two bonds (straight lines) are shown with each substituent to indicate the individual positions of attachment in the indicated compounds. This system is well known in the field of chemical communication and is widely used in scientific papers and presentations. Tables 71 to 88 show not only the specific compounds in the previous table but also other known compounds using the complete molecular formula.

Treatment method

Methods of treating recipient mammals with conditions associated with pathological matrix metalloprotease activity are also known. The method comprises administering to a mammalian host in such a condition a compound as described above in an MMP-enzyme inhibiting effective amount. The use of repeated administrations is particularly noted.

Known compounds are used in the treatment of recipient mammals, such as mice, rats, rabbits, dogs, horses, primates, such as monkeys, chimpanzees or humans, with conditions associated with pathological matrix metalloprotease activity.

In addition, similar uses of compounds known in the treatment of diseases which may be affected by the activity of metalloproteases, such as TNF-a converting enzyme, are also known. Examples of such diseases are acute reactions of shock and sepsis, clotting reactions, bleeding and cardiovascular effects, fever and inflammation, anorexia and cachexia.

In the treatment of diseases associated with pathological matrix metalloprotease activity, the known MMP inhibitory compounds can be used where appropriate in the form of the amine salts derived from inorganic or organic acids. Exemplary acid salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, nisulfate, butyrate, camphorate, camphorsulfonate, digluconate , Cyclopentane propionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, heptate artphette, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, polycarboxylate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, Pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and Decanoate.

Also, basic nitrogen containing groups include lower alkyl (C ₁ -C ₆ ) halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; Dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain (C ₈ -C ₂₀ ) halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides Alkyl halides, such as benzyl and phenethyl bromide, and the like, to improve water solubility. A water soluble or oil soluble or dispersible product is thus obtained as desired. Salts are formed by combining basic compounds with the desired acid.

Other compounds useful in the present invention which are also acids can form salts. Examples thereof are: alkali metal or alkaline earth metals, for example salts with sodium, potassium, calcium or magnesium, salts with organic bases or basic quaternary ammonium salts.

In addition, in some cases, salts may be used as adjuvants in the separation, purification or degradation of the compounds of the present invention.

The total daily dose to be administered to the recipient mammal in one cycle or in divided doses of the MMP-enzyme inhibiting effective amount is, for example, from about 0.001 to about 100 mg / kg body weight per day, preferably from about 0.001 to about 30 mg / kg body weight per day, More usually from 0.01 to about 10 mg per day. Dosage unit compositions may contain the above amounts, or about several times thereof, to fill a daily dose. Appropriate doses can be administered at multiple sub-doses per day. In addition, the total dose can be increased in multiple daily doses if needed by the person receiving the drug.

The dosage regimen for treating a disease state with the compounds and / or compositions of the present invention may vary depending on the type of patient, age, weight, sex, diet and medical condition, the severity of the disease, the route of administration, Pharmacokinetic considerations such as pharmacokinetic and toxicological profiles, whether a drug delivery system is used, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually used can vary considerably and can deviate from the indicated preferred dosage regimen.

The compounds useful in the present invention may be formulated into pharmaceutical compositions. The composition can then be administered orally, parenterally, spray-in, rectally or topically, in dosage unit formulations containing the usual non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles, if desired. Topical administration may also employ skin permeation administration, such as a skin permeation patch or iontophoresis device. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal injection or drip technique. Formulation of the drug is described, for example, in Hoover, John E., Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania; 1975] and in Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms , Marcel Decker, New York, NY,

Injectables, such as sterile injectable solutions or oily suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Aseptic injections can also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as, for example, solutions in 1,3-butanediol. Examples of acceptable vehicles and solvents that may be employed include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are also commonly used as a solvent or suspending medium. For this purpose, any mixed fixed oil, including synthetic mono- or diglycerides, may be used. Fatty acids such as oleic acid can also be used for the preparation of injectables. Dimethylacetamide, surfactants including ionic and nonionic detergents, and polyethylene glycol can also be used. Mixtures of solvents and wettable agents as discussed above are also useful.

Suppositories for rectal administration of the drug are solid at normal temperatures but liquid at the rectal temperature and are therefore suitable for the administration of suitable noninflammatory agents such as cocoa butter, synthetic mono-, di- or triglycerides, fatty acids and polyethylene glycols which dissolve in the rectum and release the drug Can be prepared by mixing the excipient and the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of the invention are usually combined with one or more adjuvants appropriate to the administration route being presented. When administered orally, the compound can be administered orally or parenterally such as lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acid, , Sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. The capsule or tablet may contain a sustained release formulation which may be provided as a dispersion of the active compound in hydroxypropylmethylcellulose. For capsules, tablets and pills, the dosage form may also contain buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can also be additionally prepared as enteric coatings.

For therapeutic purposes, formulations for parenteral administration may be in the form of an aqueous or non-aqueous isotonic sterile injection or suspension. The solutions and suspensions may be prepared from sterile powders or granules having one or more carriers or diluents mentioned for use in formulations for oral administration. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cotton seed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffer solutions. Other adjuvants and methods of administration are well known and widely known in the pharmacology arts.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water. The compositions may also contain adjuvants and sweeteners such as wetting agents, emulsifying and suspending agents, wind deflecting agents and retarding agents.

The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the mammalian recipient being treated and the particular mode of administration.

Preparation of useful compounds

Procedures are provided in the discussion and in the reaction schemes of the exemplary chemical modification procedures that may be useful in the preparation of the compounds of the invention below. This synthesis may be carried out under a dry inert atmosphere such as nitrogen or argon, if desired, as in all reactions discussed herein. Other synthetic steps, such as aqueous acid or base ester or amide hydrolysis can be carried out under laboratory air, while the selected reactions known to those skilled in the art can be carried out under a dry atmosphere such as dry air.

The aryl and heteroaryl aryl compounds of the present invention as defined by W above may be prepared in a manner analogous to those known to those skilled in the art. The following discussion should be understood to refer to both aromatic systems, both heteroaromatic and carbonaromatic, although only one is specifically mentioned.

In general, the choice of starting materials and reaction conditions can be varied as is well known to those skilled in the art. In general, any single set of conditions is not limited, as the degree of change may be applied as needed and by the choice of those skilled in the art. In addition, the conditions will be selected as appropriate for specific purposes, such as small scale manufacturing or large scale manufacturing, as desired. In either case, the use of less safe or less environmentally sound substances or reagents will generally be minimized. Examples of such less preferred materials are diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, some halogenated solvents, benzene, and the like. Additionally, many starting materials can be obtained from commercial sources through catalogs or other arrangements.

An aromatic compound of the present invention wherein y is 1 can be prepared as shown by converting a carbonyl group attached to a sulfide ortho-substituted aromatic (e.g., benzene) ring. The sulfide feed can be prepared through the nucleophilic displacement reaction of orthofluoride.

The nucleophile may be a thiol or thiolate anion prepared from an aryl thiol as discussed below. The preferred thiol is 4-phenoxybenzenethiol converted at that position to an anion (thiolate) using potassium carbonate in isopropyl alcohol at reflux temperature.

The carbonyl group may be an aldehyde, ketone or carboxylic acid derivative, i.e. a protected carboxylic acid or hydroxamate. A preferred carbonyl group is aldehyde, and the preferred aldehyde is 2-fluorobenzaldehyde (ortho-fluorobenzaldehyde). The ketone may be converted to an acid and / or an acid derivative by oxidation, using reagents such as those described below for oxidation of the sulfide, or by other methods known in the art. It is mentioned that such oxidation can achieve oxidation of the sulfide intermediate to the corresponding sulfone in the same reaction system, i. E., If desired, in the same pot.

The carbonyl group can then be homologated, if desired, by reaction with an anion to produce an additive compound. Examples of monocomponent reagents include trisubstituted methane compounds such as tetraethyldimethylammonium methylene diphosphonate or trimethylorthoformate. Tetraethyldimethylammonium methylene diphosphonate is preferable. Hydrolysis of the reaction product may provide phenylacetic acid substituted on the aromatic ring with the sulfide of the present invention. Acid hydrolysis is preferred. Acids and bases are discussed below, with hydrochloric acid being preferred.

The sulfide can then be oxidized to produce the sulfone in one or two steps as discussed below. The preferred oxidizing agent is hydrogen peroxide in acetic acid. The carboxylic acid products or intermediates of the present invention can then be converted into protected derivatives such as esters or converted to the activated carboxyl groups, i. E. Hydroxamate, during the reaction with hydroxylamine and / or protected hydroxylamine . Conversion of the acid to the hydroxamate is discussed below, as necessary, such as coupling methods and removal of the protecting group.

A preferred protected hydroxamic acid derivative is an O-tetrahydropyranyl compound, and the preferred coupling method is the coupling reaction using an intermediate of hydroxybenzotriazole activation using diimide (EDC), hydroxybenzotriazole and DMF solvent Lt; / RTI &gt; ester. A preferred reagent for the removal of the THP protecting group is hydrochloric acid.

Alkylation of an acid to a carbonyl group in carbon alpha to produce a compound of the present invention can be carried out by first generating an anion using a base. The bases are discussed below. Preferred bases are strong bases which are hindered and / or nucleophilic such as lithium amide, metal hydride or lithium alkyl.

During or after anion formation, an alkylating agent (electrophile) is added to effect a nucleophilic substitution reaction. Non-limiting examples of such alkylating agents include haloalkanes, dihaloalkanes, haloalkanes substituted by activated ester groups or activated esters, and alkanes substituted with sulfate esters.

Activated ester groups are known in the art and include, for example, the activated esters of alcohol or halo compounds, the bromo, iodo or chloro-derivatives of the tosylate, triflate or mesylate activated ester and And esters of the same halo alcohols. In the formula, as an example, a compound in which R ² and R ³ are taken together as defined above can be prepared using a disubstituted alkylating agent, ie, an alkylating agent having two leaving groups in the same molecule. As an example, 1,5-dihalo-diethyl ether or similar reagents containing one or more sulfate ester leaving groups replacing one or more halogens may be used to generate the pyran ring. A similar sulfur, nitrogen or protected nitrogen alkylating agent may be used to generate the thiapyrane or piperidine ring. Thiapyranes can be oxidized using the methods discussed herein to produce sulfoxides or sulfones. The leaving group in the electrophilic reagent is as known in the art and includes halogen or sulfonate esters such as chlorine, bromine or iodine, such as toluene sulfonate (tosylate), triflate, mesylate, etc., May be the same active ester.

Conversion of the cyclic amino acid, heterocycle or alpha amino acid defined by R &lt; ² &gt; and R &lt; ³ &gt;, which may contain a protected or unprotected amino acid (nitrogen heterocycle) Can be achieved by misfiring. The carboxylic acid group may be protected with a group such as an alkyl ester such as methyl, ethyl, tert-butyl or the like or an arylalkyl ester such as tetrahydropyranyl ester or benzyl, or may be left as a carboxylic acid. Protected amino acids, such as ethyl esters, are preferred. The substituents on the heterocycle group are the same as defined above and may include hydrogen, tert-butoxycarbonyl (BOC or tBOC), benzyloxycarbonyl (Z) and iso-butyloxycarbonyl groups. Additionally, if the N-substituent is not hydrogen, the amine can be considered as the protected intermediate of the invention as well as the product of the present invention.

The nitrogen substituents on the amino acid portion of the compounds of the present invention may be varied. Additionally, the changes may be accomplished in other steps within the synthetic sequence based on the needs and objectives of the skilled artisan to prepare the compounds of the present invention. Nitrogen side chain changes can include replacing hydrogen substituents with alkyl, arylalkyl, alkenes or alkynes.

This can be accomplished by methods known in the art, such as alkylation of amines with electrophiles such as halo or sulfate ester (activated ester) derivatives of preferred side chains. The alkylation reaction is typically carried out in the presence of a base as discussed above, in a pure or mixed solvent such as those discussed above. The preferred base is potassium carbonate, and the preferred solvent is DMF.

The alkenes, arylalkenes, arylalkenes and alkyls thus formed may be reduced to the alkyl or arylalkyl compounds of the present invention by hydrogenation, for example, with a metal catalyst and hydrogen, and the alkyne or arylalkyne may be catalytically hydrogenated Arylalkane, arylalkane, or alkane under conditions or using a deactivated metal catalyst. The catalyst may include by way of example, Pd, on carbon, Pd, Pt, PtO ₂ and the like. Less effective (deactivated) catalysts include such as Pd on BaCO ₃ or Pd with quinoline and / or sulfur.

An alternative method for the alkylation of amine nitrogen is reductive alkylation. This method known in the art makes it possible to treat the secondary amine with an aldehyde or ketone in the presence of a reducing agent such as borane, borane: THF, borane: pyridine, lithium aluminum hydride. Alternatively, the reductive alkylation may be carried out under hydrogenation conditions in the presence of a metal catalyst. Catalysts, hydrogen pressures and temperatures have been discussed and are known in the art. A preferred reductive alkylation catalyst is a borane: pyridine complex.

When the intermediate is a carboxylic acid, standard coupling reactions known in the art can be used to produce the compounds of the present invention, including protected intermediates. For example, the acid is converted to an acid chloride, mixed anhydride or activated ester and reacted with an alcohol, amine, hydroxylamine or protected hydroxylamine in the presence of a base to form an amide, ester, hydroxamic acid, protected hydroxamic acid Can be generated. This is the same product as discussed above. The bases are mentioned above, including N-methyl-morpholine, triethylamine, and the like.

This type of coupling reaction is well known in the art, particularly in the peptide and amino acid chemistry. Removal of the protecting group can be achieved if desired using standard hydrolysis conditions such as base hydrolysis or exchange, or acid exchange or hydrolysis, as discussed.

The reaction schemes and / or discussion also show the conversion of the protected carboxylic acids as esters or amides to hydroxamic acid derivatives such as O-arylalkyl ethers or O-cycloalkoxyalkyl ether groups such as THP groups. A method for producing a hydroxamic acid or a hydroxamate derivative by treating an acid or an acid derivative with a hydroxylamine or a hydroxylamine derivative has been discussed above. If the hydroxylamine is protected as a carboxyl ester or amide, the precursor compound may be used in an exchange reaction by treating the precursor compound with at least one equivalent of hydroxylamine hydrochloride or hydroxylamine at room temperature to provide the hydroxamic acid directly have. The solvent (s) are generally protic or protic solvent mixtures such as those listed herein.

This exchange method can be further catalyzed by addition of an additional acid. Alternatively, a base such as a salt of an alcohol used as a solvent, for example, sodium methoxide in methanol, may be used to generate hydroxylamine from hydroxylamine hydrochloride, which can exchange with an ester or amide at that position. As mentioned above, the exchange is carried out using protected hydroxylamines such as tetrahydropyranyl-hydroxyamine (THPONH ₂ ), benzylhydroxylamine (BnONH ₂ ), O- (trimethylsilyl) hydroxylamine and the like. In which case the resulting compound is tetrahydropyranyl (THP), benzyl (Bn) or TMS hydroxamic acid derivative. In a preferred case, as an example, the removal of the protecting group after further modification or after storage in another part of the molecule may be carried out by acid hydrolysis of the THP groups discussed above or by hydrogenation and benzylation using a metal catalyst such as palladium, platinum, palladium on carbon or nickel Can be accomplished by standard methods known in the art, such as the reductive elimination of &lt; RTI ID = 0.0 &gt;

The alpha amino acid or alpha hydroxycarboxylic acid or protected carboxylic acid, hydroxamate or hydroxamic acid derivative or intermediate (precursor) of the present invention may be obtained, for example, from the alpha carbon of the listed acids or derivatives by halogen, Or other electrophiles themselves. Halogenation methods such as acids, esters, acid chlorides and the like are well known in the art and include, for example, HVZ reaction, CuCl ₂ , N-bromo-, N-chloro-succinimide, I ₂ , carbon tetraiodide or bromide Lt; / RTI &gt; Halogen can be transferred from the SN ₂ reaction to the nucleophile. The nucleophile may comprise a hydroxide, ammonia or an amine.

The aryl or heteroaryl carboxylic acid of the present invention wherein Y is 0 and z is 1 may be prepared from a heteroaryl or aryl fused lactone. An example of a fused lactone is phtalide. A preferred starting material is phthalide. This compound may be treated with a thiol, thiolate or metal-SH to provide a sulfide or thiol compound of the present invention or an intermediate of the present invention to effect SN ₂ transition at the methylene carbon. Preferred thiols are 4-phenoxy-benzenethiol which is used in the presence of potassium carbonate as the preferred base. The sulfide can be oxidized with the sulfone of the present invention before or after conversion of the acid to the hydroxamic acid or hydroxamic acid. A preferred oxidizing agent is meta-chloroperbenzoic acid.

A preferred acid activating group is the chloride prepared by reaction of oxalyl chloride with an acid as the preferred reagent. The heteroaryl analog of phthalide or phthalide is treated with a Lewis acid such as zinc chloride or zinc bromide with a halogenating reagent such as phosphorus trichloride or thionyl bromide to form ortho (haloalkyl) -aryl acid or ortho- (haloalkyl) -Heteroarylic acid derivatives. Examples include bromomethyl acid bromide and chloromethyl acid chloride. Such a carboxylic acid can be derivatized with an acid or hydrolyzed if necessary using a protecting group, a hydroxamic acid or a hydroxamic acid precursor (hydroxamate). The preferred hydroxamate producing reagent is O- (trimethylsilyl) hydroxylamine (TMS-hydroxylamine) and removal of the TMS protecting group is preferably achieved by acid hydrolysis with hydrochloric acid.

In this example, the transfer reaction (SN ₂ ) of a halogen with a thiol or with a preformed thiolate in the presence of a base can be achieved as discussed and / or shown and is known in the art. The oxidation of the sulfide can also be carried out before or after derivatization of the carboxylic acid as discussed, to produce the hydroxamic acid of the present invention. Removal of the protecting group may be carried out using acid hydrolysis or reduction as discussed elsewhere herein.

The alcohols of the present invention can be protected or deprotected if desired or desired. The protecting group may include THP ethers, acylating compounds and various silyl derivatives. These groups, including protection and removal, are well known in the art.

Examples of bases that can be used include, for example, metal hydroxides such as sodium, potassium, lithium or magnesium hydroxide, oxides such as sodium, potassium, lithium, calcium or magnesium oxides, sodium, potassium, lithium, calcium or A metal carbonate such as magnesium carbonate, a metal bicarbonate such as sodium bicarbonate or potassium bicarbonate, an alkylamine, arylalkylamine, alkylarylalkylamine, heterocyclic amine or heteroaryl (II), or tertiary (III) organic amine, such as amine, ammonium hydroxide or quaternary ammonium hydroxide. By way of non-limiting example, the amine is selected from the group consisting of triethylamine, trimethylamine, diisopropylamine, methyldiisopropylamine, diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine, N-methylmorpholine, N , N'-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine and the like.

Non-limiting examples of ammonium hydroxides, which are usually prepared from amines and water, include ammonium hydroxide, triethylammonium hydroxide, trimethylammonium hydroxide, methyldiisopropylammonium hydroxide, tribenzylammonium hydroxide Dimethylpiperidinium hydroxide, N, N'-dimethylpiperidinium hydroxide, N-methylpiperidinium hydroxide, and the like can be used. . As a non-limiting example, the quaternary ammonium hydroxide may be selected from the group consisting of tetraethylammonium hydroxide, tetramethylammonium hydroxide, dimethyldiisopropylammonium hydroxide, benzylmethyldiisopropylammonium hydroxide, methyldiazabicyclonylammonium N, N ', N'-tetramethylpiperazinium hydroxide, and N-ethyl-N', N'-dimethylmorpholinium hydroxide, - hexylpiperidinium hydroxide, and the like. A metal hydride such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropylamide, The alcoholate may also be an appropriate reagent. Alkyl or aryl lithium reagents such as methyl, phenyl, butyl, iso-butyl, sec-butyl or tert-butyl lithium, sodium or potassium salts of dimethylsulfoxide, Grignard reagents such as methylmagnesium bromide or methylmagnesium chloride, Can also act as bases for causing salt formation or for catalysing the reaction. &Lt; RTI ID = 0.0 &gt; [0040] &lt; / RTI &gt; Quaternary ammonium hydroxides or mixed salts are also useful for assisting transfer coupling or being provided as phase transfer reagents. The preferred base to be used in the alkylation reaction is lithium diisopropylamide as mentioned above.

The reaction medium may generally consist of a single solvent, a mixed solvent of the same or a different class, or may be provided as a reagent in a single or mixed solvent system. The solvent may be protic, non-protic or bipolar aprotic. Non-limiting examples of protic solvents include water, methanol (MeOH), denatured or 95% pure or pure ethanol, isopropanol, and the like.

Typical anionic solvents include aromatic, such as acetone, tetrahydrofuran (THF), dioxane, diethyl ether, tert-butyl methyl ether (TBME), xylene, toluene or benzene, ethyl acetate, methyl acetate, butyl acetate, Trichloroethane, methylene chloride, ethylene dichloride (EDC), hexane, heptane, isooctane, cyclohexane and the like. Bipolar aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, nitromethane, tetramethylurea, N-methylpyrrolidone and the like.

Non-limiting examples of reagents that can be used as a solvent or as part of a mixed solvent system include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N- methylmorpholine, Alcohols or amines for the preparation of organic or inorganic mono-or multi-protonic acids or bases, esters or amides such as pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide or the products of the invention And the like. Room temperature or less or slightly warm (-10 캜 to 60 캜) is the preferred temperature for the reaction. If desired, the reaction temperature may be from about -78 占 폚 to the reflux point of the reaction solvent (s). A preferred solvent for the alkylation reaction is tetrahydrofuran (THF).

Acids are used in many reactions during various syntheses. Reaction formulas and discussion of the preparation process illustrate the use of acids for the removal of THP protecting groups for the preparation of hydroxamic acids, the removal of the tert-butoxycarbonyl group, the hydroxylamine / ester exchange, and the like. Acid hydrolysis of carboxylic acid protecting groups or derivatives is well known in the art. These processes, which are known in the art, can use acidic or acidic catalysts. The acid may be a mono-, di-, or tri-protic organic or inorganic acid. Examples of acids include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, hydrobromic acid, hydrofluoric acid, carbonic acid, phosphorous acid, p- toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, difluoroacetic acid , Benzoic acid, methanesulfonic acid, benzenesulfonic acid, 2,6-dimethylbenzenesulfonic acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid and the like. They may also be Lewis acids such as aluminum chloride, boron trifluoride, antimony pentafluoride, and the like.

Known compounds may include compounds wherein the nitrogen of the amine is acylated to provide, for example, an amino acid carbamate. Non-limiting examples of these carbamates are carbobenzoxycarbonyl (Z, CBZ, benzyloxycarbonyl), iso-butoxycarbonyl and tert-butoxycarbonyl (BOC, t-BOC) compounds. The materials may be prepared using methods known in the art at various stages during the synthesis, based on the needs and decisions of those skilled in the art, as discussed above.

Useful synthetic techniques and reagents include those used in protein, peptide and amino acid synthesis, coupling and modification chemistry. The use of tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (Z) and their synthesis and removal are examples of such protecting or synthetic reaction schemes. Modifications of the amino acids, amino esters, amino acid hydroxamates, amino acid hydroxamate derivatives and amino acid amides of the present invention, or the compounds used in the present invention, are discussed herein and / or shown in the reaction schemes. This includes, by way of example, an activated ester or mixed anhydride coupling, where the preferred base is a tertiary amine such as N-methyl morpholine. Reagents for protecting the amine groups of the protected amino acids include carbobenzoxychloride, iso-butyl chloroformate, tert-butoxycarbonyl chloride, di-tert-butyl dicarbonate, and the like, Lt; RTI ID = 0.0 &gt; amphoteric &lt; / RTI &gt; aprotic solvent, such as a solvent mixture.

Removal of carbamates, silyl groups and benzyl, p-methoxybenzyl, or other substituted benzyl groups or protecting groups such as diphenylmethyl (benzhydryl) or triphenylmethyl (trityl) can be carried out by methods selected by those skilled in the art And may be carried out in other steps during the synthesis of the compounds of the present invention as necessary. Such methods are well known in the art and include amino acid, amino acid coupling, peptide synthesis, and peptide mimetic synthesis. Catalytic hydrogenation, base hydrolysis, carbonyl addition, acid hydrolysis, . &Lt; / RTI &gt; The preparation and removal of protecting groups such as carbamate, benzyl and / or substituted arylalkyl groups are all discussed in [Green, T., Protecting Groups in Organic Chemistry , 2nd Ed., John Wiley & Sons, New York (1991) . A preferred method of removal of the BOC group is to provide the HCl salt of the amino acid of the present invention directly after normal operation with HCl gas in methylene chloride.

Sulfone compounds such as those wherein R &lt; ^{1 &gt;} is nitrobenzene may be prepared as compounds of the present invention by synthesis of thiols, transfer of electrophiles by nucleophilic thiols or thiolates, and oxidation of thiol ether products to sulfones. For example, the transition of the nitro-benzenethiol and the electrophilic group can yield a compound wherein R ¹ is nitrobenzene, and the nitro group is reduced to provide a useful amino compound wherein R ¹ is aniline. It should be noted that the nitrobenzenethiol is illustrative and is not considered to be limiting or necessary. Oxidation of the thioether product can be carried out as discussed below if desired.

Reduction of the nitro group to an amine is well known in the art and there is a preferred method of hydrogenation. Generally, there are metal catalysts such as Rh, Pd, Pt, Ni and the like with or without additional support such as carbon, barium carbonate and the like. The solvent may be a protic or an amphoteric pure solvent or a mixture of solvents, if necessary. The reduction may be carried out at multiple atmospheric pressures with atmospheric pressure, preferably about 40 pounds per square inch (psi).

The resulting amino group may be alkylated, if desired. It may also be acylated using, for example, aroyl chloride, heteroaryl chloride or other amine carbonyl generators to produce the R &lt; ¹ &gt; amide of the invention. Aminosulfone or thioether can also be reacted with carbonic ester chloride, sulfonyl chloride, carbamoyl chloride or isocyanate to produce the corresponding carbamates, sulfonamides, or ureas of the present invention. Acylation of these types of amines is well known in the art, and reagents are also known.

Generally, these reactions are carried out in an aprotic solvent at about 45 &lt; 0 &gt; C to about -10 &lt; 0 &gt; C, under inert and / or dry conditions. Noncompetitive base equivalents are generally used with sulfonyl chlorides, acid chlorides or carbonyl chloride reagents. In this or subsequent acylation step, the synthesis of the hydroxamic acid product of the present invention can proceed as described.

Other thiol reagents may also be used in the preparation of the compounds of the present invention. Examples include fluoroaryl, fluoroheteroaryl, azidoaryl or azidoheteroaryl or heteroarylthiol reagents. Such thiols may be used as nucleophiles as described above. Oxidation to the corresponding sulfone can then be carried out.

When substituted by hydrazine or substituted hydrazine, the sulfone may be oxidized to the hydrazone of the present invention. The fluorosubstituted sulfone can, if desired, be treated with a nucleophile such as ammonia, primary amine, quaternary ammonium or metal azide salt or hydrazine under pressure to provide an azido, amino, substituted amino or hydrazino group. Azide can be reduced to amino groups, for example, using a metal catalyst or a metal chelate catalyst and hydrogen, or by an activated hydride reagent. Amines can be acylated as discussed above.

Methods for the preparation of useful amine thiol intermediates include the protection of aromatic or heteroaromatic thiols with trityl chloride to produce trityl thiol derivatives, the treatment of amines with reagents such as aromatic or heteroaromatic acid chlorides to produce amides, To remove the trityl group using an acid. The acylating agent includes benzoyl chloride, and the trityl removal reagent includes trifluoroacetic acid and triisopropylsilane.

The fluorine on the fluorosulfone of the present invention may also be converted to other aryl or heteroaryl nucleophiles to produce the compounds of the present invention. Examples of such nucleophiles include phenol, thiophenol, an aromatic heterocyclic compound containing an -OH group or a salt of a -SH containing heteroaryl compound. Tautomers of such groups as azo, hydrazo, -OH or -SH are included as particularly useful isomers.

A preferred method for preparing the intermediate in the synthesis of the substituted sulfone is to oxidize the appropriate acetophenone prepared from the fluoroacetophenone using, for example, peroxymonosulfate to produce the corresponding phenol-ether. The phenol-ether is converted to its dimethylthiocarbamoyl derivative by using dimethylthiocarbamoyl chloride and the dimethylthiocarbamoyl derivative is rearranged by heating to give the thioether intermediate of the formula &lt; RTI ID = 0.0 &gt; To provide the thiol required for manufacture.

Compounds of the invention, including protected compounds or intermediates, may be represented by and / or oxidized to sulfones as described above. The choice of an alternative synthesis step to fulfill this conversion to the sulfone or sulfoxide of the sulfide can be carried out by those skilled in the art.

Reagents for this oxidation method include, but are not limited to, peroxymonosulfates (OXONE ), Hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlactic acid, tert-butyl peroxide, tert-butyl hydroperoxide, tert-butyl hypochlorite, sodium hypochlorite, hypochlorous acid, Meta-peroiodate, peroiodic acid, ozone, and the like. Pure or mixed, protic, amphoteric, bipolar aprotic solvents may be selected, for example methanol / water. The oxidation may be carried out at a temperature of from about -78 째 C to about 50 째 C, generally in the range of from -10 째 C to about 40 째 C.

The preparation of the sulfone can also be carried out in two steps: oxidation of the sulfide to sulfoxide and subsequent oxidation of the sulfoxide to the sulfone. This can occur either in one port or by isolation of the sulfoxide. The latter oxidation can be carried out in a manner analogous to direct oxidation to sulfone, except that about one equivalent of oxidizing agent can be used, preferably at a low temperature, such as about 0 占 폚. Preferred oxidizing agents include peroxymonosulfate and meta-chloroperbenzoic acid.

The sulfonamides of the present invention can be prepared in a similar manner using the methods and procedures described above. Aryl, substituted aryl, heteroaryl or substituted heteroaryl dicarboxylic anhydrides, imides (e.g., phthalic anhydride or imide), sulfonyl analogs or mixed carboxyl-sulfonic acid amides thereof, Benzothiazol-3 (2H) -one 1,1-dioxide) or an anhydride is a useful starting material substrate. The reaction using such a substrate can be carried out before or after the change in the substitution pattern of the aryl or heteroaryl ring occurs.

Sulfonamides may also be prepared from heterocyclic compounds such as saccharin, saccharin analogs and saccharin analogs. Such compounds and methods are known in the literature. For example, ring opening or ring opening alkylation after alkylation of sodium saccharin allows the coupling to generate protected hydroxy acid derivatives such as THP (tetrahydropyranyl) or TMS (trimethylsilyl) derivatives. Hydrolysis of the protecting group provides hydroxamic acid. The sulfonamide nitrogen may be further alkylated, acylated or otherwise treated to produce various compounds of formula VI, for example, at this stage prior to coupling and deprotection.

As a non-limiting example, the treatment of the mixed sulfonic acid / carboxylic acid anhydride (2-sulfobenzoic acid cyclic anhydride) with an alcohol or alcohol salt or protected hydroxamic acid may be carried out in the presence of a sulfonic acid or a ring opening carboxylic acid derivative Anhydride). The carboxylic acid derivative thus prepared can be converted into the sulfonyl halide by standard procedures using reagents such as thionyl chloride, phosphorus pentachloride and the like as the product of the present invention.

The reaction of a sulfonyl halide with an added base or without a base provides the sulfonamide or sulfonimide of the present invention and the sulfonamide is alkylated to form the sulfonamide of the present invention or the sulfone of the present invention Lt; RTI ID = 0.0 &gt; amides. &Lt; / RTI &gt; Such imides or amides of the sulfonamides can be alkylated before or after opening to the benzoic acid substituted sulfonamides or phenylacetic acid substituted sulfonamines, if desired.

Compounds prepared using protected carboxyl groups as described above are readily converted to the hydroxamic acids of the present invention by exchange, exchange / hydrolysis combination, or hydrolysis-coupling methods. The exchange / conversion of esters, amides and protected hydroxylamines (protected hydroxamic acids) to hydroxamic acids has been discussed herein. For example, a sulfonamide-ester can be hydrolyzed to a carboxylic acid that is coupled with a THP-hydroxylamine reagent via a benzotriazole active ester and then deprotected. The phenylacetic acid analog of the sulfobenzoic acid compound may also be used in a manner analogous to that described above for preparing the corresponding phenylacet-derived compound of the present invention.

Aryl or heteroaryl 5- or 6-membered thiolactones or dithiolakones are also preferred starting materials for the preparation of the compounds of the present invention. The thiolactone may be opened before or after a change in the substitution pattern of the aryl or heteroaryl ring to give a protected carboxylic acid derivative such as an ester, amide or hydroxylamide. Oxidation of thiol functionalities can be accomplished before or after the substitution change, depending on the needs and desires of the skilled chemist. Sulfur compounds can also be directly oxidized to sulfonyl chloride compounds using an oxidant that is implicated in the mechanism of putative positive chlorine species. Oxidants and methods are discussed above. The thus obtained sulfonic acid derivative is then converted into the sulfonamide of the present invention as described above.

Changes in the substitution pattern on the ring of the compounds of the present invention can be carried out by methods known in the art. Non-limiting examples of such processes include diazonium chemistry, aromatic ring substitution reactions or addition-elimination sequences, metallization reactions and halogen metal exchange reactions.

The substituted or unsubstituted aryl or heteroarylsulfonic acid, sulfonic acid derivative or sulfonamide of the present invention is a compound wherein the corresponding anion is carbon dioxide. Or a protected hydroxylamine isocyanate or an isothiocyanate derivative to produce a compound of the present invention or an intermediate of the compound of the present invention in the presence of a carbonyl compound, an isocyanate, a halogenating reagent, an alkylating reagent, an acylating reagent, , Halo-sulfonic acid or sulfonic acid. Anions can be produced, for example, through direct metallization or metal-halogen exchange. Substituted or unsubstituted aryl or heteroaryl sulfonic acids, sulfonic acid derivatives or sulfonamides can be prepared by sulfonation or chlorosulfonation of substituted or unsubstituted aryl or heteroaryl compounds. The metallization and halogen-metal exchange reactions to produce the corresponding anion or complex anion salt may be carried out by treatment directly with a metal such as lithium, sodium, potassium, palladium, platinum or their complexes, or by treatment with tert- Lithium, sec-butyllithium, and the like. These intermediates are quenched with the reagents discussed elsewhere herein. The resulting carboxylic or carboxylic acid derivatives are converted into the sulfonamides of the invention by methods and processes known in the art and discussed herein.

Salts of compounds or intermediates of the invention are prepared in a conventional manner in which an acidic compound is reacted with bases such as those discussed above to produce a metal or nitrogen containing cation salt. Basic compounds such as amines can be treated with an acid to form amine salts.

It is recognized that some of the compounds of the present invention may be synthesized by biochemical processes involving mammalian metabolic processes. For example, the methoxy group can be converted to an alcohol and / or phenol at that position by the liver. When more than one methoxy group is present, one or both groups may be independently metabolized to a hydroxy compound.

The compounds of the present invention may possess one or more asymmetric carbon atoms and thus may exist in the form of optical isomers and racemic mixtures thereof or in the form of a mixture of vicacies. The optical isomers can be obtained according to conventional processes known in the art, for example by decomposition of the racemic mixture by the formation of diastereoisomeric salts by treatment with an optically active acid or base.

Examples of suitable acids include tartar, diacetyltartar, dibenzoyltartar, ditoluoyltartar and camphorsulfonic acid, after freeze of the optically active base from these salts after separation by crystallization of the diastereomeric mixture. Other processes for the resolution of optical isomers include the use of optimally selected chiral chromatography columns to maximize the separation of the enantiomers.

Another useful method involves the synthesis of covalent diastereomeric molecules, such as esters, amides, acetals, ketals, etc., by reacting a compound of formula I with an optically active acid, an optically active diol or an optically active isocyanate in the activated form. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver enantiomerically pure compounds. In some cases, hydrolysis of the optically active parent drug is not required prior to administration to the patient, since the compound may act as a prodrug. The optically active compounds of formula I can likewise be obtained using optically active starting materials.

In addition to the optical isomers or potential optical isomers discussed above, other types of isomers are specifically intended to be included in this discussion and the present invention. Examples include cis isomers, trans isomers, E isomers, Z isomers, syn-isomers, anti-isomers, tautomers and the like. Aryl, heterocyclo or heteroaryl tautomers, heteroatom isomers and ortho, meta or para substituted isomers are also included as isomers. Solvates or solvated compounds, such as hydrates or alcoholates, are also specifically included as chemicals in both the present invention and, for example, pharmaceutical formulations or pharmaceutical compositions for drug delivery.

The precise chemical nature of functional groups, such as hydrocarbyl radicals or halogens, hydroxy, amino, etc., which are outside of the hydrogen at that position, when the substituent is hydrogen or can be hydrogen, It is not important unless it has adverse effects. For example, a mixture of two hydroxyl groups, two amino groups, two thiol groups, or two hydrogen-heteroatom groups on the same carbon is known to be unstable or not stable as a derivative.

The chemical reactions described above are generally disclosed for their broadest application for the preparation of these compounds of the invention. Sometimes, the reactions are not applicable as described for each compound contained within the disclosed range. Compounds in which this occurs will be readily recognized by those skilled in the art. In all these cases, the reaction can be successfully performed by conventional modifications known to those skilled in the art, such as appropriate protection of interferents, changes to alternative conventional reagents, routine modification of reaction conditions, Or other conventional reactions may be applied to the preparation of the corresponding compounds of the present invention. In all preparation methods, all starting materials are known or readily producible from known starting materials.

Acids Other compounds of the present invention may also produce salts. Examples include salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium or magnesium, or salts with organic bases or basic quaternary ammonium salts.

In some cases, salts may be used as an aid in the isolation, purification or separation of the compounds of the present invention.

Best Mode for Carrying Out the Invention

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, certain preferred embodiments below are merely illustrative and should not be construed as limiting the remainder of the description in any way.

Example 1: Synthesis of N-hydroxy-2 - [[(4-phenoxyphenyl) -sulfonyl] methyl]

Part A: K ₂ CO ₃ (10.0 g, 49.4 mmol) and 4- (phenoxy) benzenethiol (9.59 g, 49.4 mmol) were added to a solution of phthalide (6.30 g, 47.0 mmol) in DMF And the solution was heated to 100 &lt; 0 &gt; C for 2 hours. The solution was diluted with H ₂ O and acidified with 1N HCl to pH = 1. It collects produced a tan solid that was washed with H ₂ O. The solid was dissolved in ethyl ether and dried over MgSO _4. Concentration in vacuo followed by recrystallization (ethyl ether / hexane) provided sulfide (9.12 g, 58%) as a white solid.

_{C 20 H 16 O 3 S MS} (CI) MH + calculated for: 337, measurements: 337.

Analysis calculated for _{C 20 H 16 O 3 S:} C, 71.41; H, 4.79; S, 9.53.

Measured: C, 71.28; H, 4.67; S, 9.19.

Part B: Oxalyl chloride (1.08 mL, 12.4 mmol) was added to a solution of Part A sulfide (3.00 g, 8.92 mmol) and DMF (1 drop) in dichloromethane (28 mL) . After concentration in vacuo, the residue was dissolved in dichloromethane (16 mL) and the solution was cooled to 0 &lt; 0 &gt; C. Tetramethylsilylhydroxylamine (2.55 mL, 20.8 mmol) was added and the solution was stirred for 1.5 h. The solution was diluted with dichloromethane, washed with 1N HCl, H ₂ O and saturated NaCl and dried over MgSO ₄ . Chromatography (silica phase, ethyl acetate / hexane / toluene) gives the hydroxylamine (970 mg, 31%) as a clear paste.

Part C: 3- Chloroperbenzoic acid (60%, 2.14 g, 7.45 mmol) was added to a solution of the hydroxylamine of Part B (970 mg, 2.76 mmol) in dichloromethane (25 mL) Was stirred at room temperature for 3 hours. The solution was diluted with ethyl ether and washed with saturated Na ₂ SO ₃ , saturated NaHCO ₃ and saturated NaCl and dried over MgSO ₄ . Reverse phase chromatography to give (345 mg, 33%) (silica phase, acetonitrile / H ₂ O) as a white solid.

_{^{MS (CI) MH + C 20}} H 17 NO 5 S Calcd for analysis: 384, measurements: 384.

Analysis for C ₂₀ H ₁₇ NO ₅ S · 0.3H ₂ O

Calculated: C, 61.70; H, 4.56; N, 3.60; S, 8.25.

Measured: C, 61.74; H, 4.42; N, 3.61; S, 8.31.

Example 2: Synthesis of N-hydroxy-2 - [(4-phenoxyphenyl) -sulfonyl] benzeneacetamide

Part A: To a solution of K ₂ CO ₃ (4.55 g, 33.0 mmol) and 4- (phenoxy) -benzenethiol (6.06 g, 30.0 mmol) in isopropanol (30 mL) was added 2-fluorobenzaldehyde mmol). The solution was refluxed for 20 hours. The reaction was quenched by the addition of ice-H ₂ O and extracted with CHCl ₃ . The organic layer was dried with MgSO _4. Filtration through a pad of silica gel provided the sulfide (7.43 g, 81%) as a yellow solid.

Part B: A solution of NaH (60% dispersion in mineral oil, washed with hexane, 264 mg, 6.6 mmol) in THF (12 mL) was cooled to 0 C and tetraethyldimethylammonium methylene diphosphonate (1.99 g, 6.0 mmol) Lt; / RTI &gt; The solution was allowed to warm to room temperature and the sulfide (1.84 g, 6.0 mmol) of Part A was added. The solution was stirred at room temperature for 4 hours. The solution was extracted with ethyl acetate, washed with H ₂ O and dried over MgSO ₄ . Concentration in vacuo provided a brown oil dissolved in 6M HCl (10 mL) and the solution was heated to 100 &lt; 0 &gt; C for 1 hour. The solution was extracted with CHCl ₃ and the organic layer was dried with MgSO _4. Concentration in vacuo provided the acid (918 mg, 48%) as an oil.

Part C: 30% hydrogen peroxide (1.2 mL, 12 mmol) was added to a solution of the acid of Part B (918 mg, 3 mmol) in acetic acid (30 mL) and the solution was heated to 100 <0> C for 40 min. The solution was lyophilized and chromatography (hexane / ethyl acetate) provided the sulfone (697 mg, 63%) as a foam.

Part D: To a solution of Part C sulfone (695 mg, 1.89 mmol) in acetonitrile (2 mL) was added O-tetrahydropyranyl hydroxylamine (270 mg, 2.3 mmol). After 5 min, EDC (442 mg, 2.3 mmol) was added and the solution was stirred for 3 h. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. The organic layer was dried with MgSO _4. Chromatography (silica phase, ethyl acetate / hexane) provided THP-ether (688 mg, 77%) as a white foam.

Part E: To a solution of THP-ether (565 mg, 1.2 mmol) in Part D in methanol (10 mL) was added p-toluenesulfonic acid (25 mg) and the solution was stirred at room temperature for 2 hours. The solution was concentrated in vacuo and chromatography (chloroform / methanol) provided the title compound (339 mg, 74%) as a white solid.

Example 3: Synthesis of N-hydroxy-2 - [[4- (phenylmethyl) -1-piperidinyl] sulfonyl] benzamide

Part A: A solution of 2-chlorosulfonylbenzoic acid ethyl ester (5.80 g, 23.0 mmol) (prepared according to Nagasawa et al., J. Med. Chem. 1995, 38, 1865-1871) in acetonitrile 4-benzylpiperidine (4.38 mL, 25 mmol), triethylamine (3.78 mL, 27 mmol) and 4-dimethylaminopyridine (50 mg) were added. The solution was stirred at room temperature for 4 hours and concentrated in vacuo. The residue was dissolved in 1N HCl and extracted with ethyl acetate. The organic layer is dried over MgSO ₄ and filtered through a pad of silica gel to give the sulfonamide (7.45 g, 84%) as an oil.

Part B: KOH (2 g) was added to a solution of the sulfonamide of Part A (1.08 g, 2.80 mmol) in H ₂ O (20 mL) and methanol (50 mL) and the solution was stirred at room temperature for 3 h. The solution was concentrated in vacuo and the residual aqueous solution was acidified with 1N HCl. The solution was extracted with chloroform and the organic layer was dried with MgSO ₄ and filtered through a pad of silica gel. Concentration in vacuo afforded the acid (996 mg, quantitative yield) as a white foam.

Part C: To a solution of the acid of Part B (415 mg, 1.2 mmol) in acetonitrile (2 mL) was added O-tetrahydropyranyl hydroxylamine (200 mg, 1.7 mmol). The solution was stirred for 5 minutes then EDC (325 mg, 1.7 mmol) was added and the solution was stirred at room temperature for 3 hours. The solution was concentrated in vacuo and the residue was dissolved in H ₂ O and was extracted with ethyl acetate. The organic layer was dried with MgSO _4. Chromatography (silica phase, ethyl acetate / hexanes) provided THP-ether (437 mg, 82%) as a white solid.

Part D: p-Toluenesulfonic acid (40 mg) was added to a solution of Part C THP-ether (437 mg, 0.98 mmol) in methanol (5 mL) and the solution was stirred at room temperature for 1 h. The solution was concentrated in vacuo. By chromatography (ethyl acetate, 1% NH ₄ OH) to provide the title compound (122 mg, 34%) as an oil.

Example 4: Synthesis of 2 - [([1,1'-biphenyl] -4-ylmethyl) -sulfonyl] -N-hydroxybenzamide

Part A: ethanol (81 mL) and H ₂ O (40 mL) of 4-phenyl-benzyl chloride (6.57 g, 32.4 mmol) and a solution of thiosalicylic acid (5.00 g, 32.4 mmol) K 2 CO 3 (4.48 g, 32.4 mmol) and the solution was heated to reflux for 2 hours. Upon cooling to room temperature, a white solid was formed. To the mixture was added IN HCl (200 mL) and vacuum filtration provided sulfide (7.32 g, 70%) as a white solid.

Part B: To a solution of the sulfide of Part A (1.00 g, 3.12 mmol) in formic acid (17 mL) heated to 50 <0> C was added 30% hydrogen peroxide (1.16 mL). The solution was stirred at 55 &lt; 0 &gt; C for 3 h and then at room temperature for 40 h. The solution was concentrated and subjected to reverse phase chromatography (acetonitrile / H ₂ O) to provide the sulfone (500 mg, 45%) as a white solid.

Part C: O-tetrahydropyranylhydroxylamine (173 mg, 1.48 mmol) and N-hydroxybenzotriazole (211 mg, 1.48 mmol) were added to a solution of the sulfone of Part B (500 mg, 1.42 mmol) in DMF , 1.56 mmol) and EDC (299 mg, 1.56 mmol) and the solution was stirred at room temperature for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in H ₂ O. The solution was washed with ethyl acetate and the organic layer was washed with 1N HCl, saturated NaHCO ₃ , H ₂ O and saturated NaCl and dried over MgSO ₄ . Concentration in vacuo provided the ester (571 mg, 89%) as a white solid.

_{C 25 H 25 NO 5 S MS} (CI) MH + calculated for: 452, measurements: 452.

Part D: p-Toluenesulfonic acid (15 mg) was added to a solution of the ester of Part C (570 mg, 1.26 mmol) in methanol (10 mL) and the solution was stirred at room temperature for 1.5 hours. The solution was concentrated in vacuo and reverse phase chromatography to give (244 mg, 53%) as (acetonitrile / H ₂ O) as a white solid.

_{C 20 H 17 NO 4 MS (} EI) for S M ⁺ Calculated: 367, 367 measurements.

Analysis for C ₂₀ H ₁₇ NO ₄ S

Calculated: C, 65.38; H, 4.66; N, 3.81.

Measured: C, 65.01; H, 4.64; N, 4.04.

Example 5: Synthesis of N-hydroxy-2 - [[(4-phenoxyphenyl) -sulfonyl] amino]

Part A: O-tetrahydropyranyl hydroxylamine (1.56 g, 6.74 mmol) was added to a solution of isatoic anhydride (1.00 g, 6.13 mmol) in acetonitrile (3 mL) And the mixture was heated to reflux. The solution was concentrated in vacuo and recrystallization of the residue (ethyl acetate / hexane) gave THP-ether (760 mg, 52%) as a white solid.

_{C 12 H 16 N MS (CI} ) for the ₂ O ₃ MH ⁺ calculated: 237, measurements: 237.

Analysis for C ₁₂ H ₁₆ N ₂ O ₃

Calculated: C, 61.00; H, 6.83; N, 11.86.

Measured: C, 60.82; H, 6.95; N, 11.76.

Part B: J. Am. Chem. To a solution of 4- (phenoxy) benzenesulfonyl chloride (341 mg, 1.27 mmol) in pyridine (2 mL) cooled to 0 C prepared by Soc., (1931, 93, 1112-1115) THP-ether (300 mg, 1.27 mmol) was added and the solution was stirred at 0 &lt; 0 &gt; C for 3 hours. The solution was concentrated in vacuo and the residue was dissolved in 1N HCl and extracted with ethyl acetate. The organic layer was washed with 1N HCl, H ₂ O and saturated NaCl and dried over MgSO ₄ . Chromatography (silica phase, ethyl acetate / hexane) provided the sulfone (321 mg, 54%) as a white solid.

C ₂₄ H ₂₄ N ₂ O MS for ₆ S (CI) MH ⁺ calculated: 469, measured value: 469.

Analysis for C ₂₄ H ₂₄ N ₂ O ₆ S

Calculated: C, 61.53; H, 5.16; N, 5.98; S, 6.84.

Measured: C, 61.10; H, 4.93; N, 5.86; S, 6.41.

Part C: HCl gas was bubbled in a solution of Part B sulfone (320 mg, 0.68 mmol) in methanol (3 mL) cooled to 0 ° C for 5 minutes. The solution was concentrated in vacuo and the residue was triturated with ethyl ether. Collection by vacuum filtration gave the title compound (163 mg, 62%) as a pink solid.

_{C 19 H 16 N MS (CI} ) for _{2 d} O S MH ⁺ calculated: 385, measurements: 385.

Analysis for C ₁₉ H ₁₆ N ₂ O ₆ S · 0.2 H ₂ O

Calculated: C, 58.81; H, 4.26; N, 7.22; S, 8.26.

Measured: C, 58.88; H, 4.37; N, 6.98; S, 7.83.

Example 6: Synthesis of N-hydroxy-2 - [[(4-methoxyphenyl) -sulfonyl] methyl]

Part A: A 500 mL round bottom flask equipped with magnetic stir bar and N ₂ inlet was charged with 1.5 mL (1.7 g, 12.0 mM) 4-methoxybenzenethiol and 2.5 g (10.9 mM) methyl (2- Bromomethyl) benzoate was added thereto. The solution was treated with 1.8 g (13.1 mM) of potassium carbonate and heated in an oil bath at 55 [deg.] C. The reaction mixture was stirred at 55 &lt; 0 &gt; C for 17 h and then concentrated in vacuo. The residue was partitioned between EtOAc and H ₂ O, the layers separated and the aqueous layer extracted with EtOAc (1 ×), the organic phases combined and washed with 5% citric acid solution, saturated sodium bicarbonate solution and brine, dried Na ₂ SO ₄ ) and concentrated in vacuo to give 3.3 g of product which is suitable for the next reaction.

Part B: A 500 mL round bottom flask equipped with magnetic stir bar and N ₂ inlet was charged with 3.1 g (10.8 mM) of product from Part A in 90 mL MeOH. The solution was then washed with 15 mL water and 13.9 g (22.6 mM) oxone (Oxone ). The reaction mixture was stirred for 17 hours and then filtered. The filter cake was washed with MeOH and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and H ₂ O, the layers were separated and the aqueous layer was extracted with EtOAc (2 ×). Combining the organic phases were washed with saturated sodium bicarbonate solution and brine, and dried to give a crude product of (MgSO _4), concentrated in vacuo to 3.3 g. This was chromatographed on silica gel using 25-45% ethyl acetate / hexanes to give 2.1 g of pure product, m / z = 321 (M + H).

Part C: A 250 mL round bottom flask equipped with magnetic stir bar and N ₂ inlet was charged with 2.1 g (6.6 mM) of product from Part B in concentrated HCl solution (25 mL) and acetic acid (25 mL) And heated to reflux for 24 hours. The reaction mixture was concentrated in vacuo, then two portions of toluene were added, distilled and volatilized, and then dried under high vacuum to yield 2.0 g of product which was suitable for the next reaction.

Part D: A 2 necked 50 mL round bottom flask equipped with an addition funnel, thermometer, magnetic stirring bar and N ₂ inlet was charged with 1.0 mL of DMF in 10 mL CH ₂ Cl ₂ . The solution was cooled in an ice bath and then a solution of 3.5 mL (0.9 g, 6.9 mmol) in 2.0 M oxalyl chloride in CH ₂ Cl ₂ and then 1.0 g (3.3 mmol) of the product solution from Part C in 5 mL DMF Lt; / RTI &gt; The bath was removed and the reaction was stirred for 1 hour. The reaction mixture was poured into a two necked 100 mL rounded flask containing a cold solution of 50% aqueous hydroxylamine in 2.1 mL (1.1 g, 37.7 mmol) in THF (25 mL) equipped with addition funnel, thermometer, magnetic stir bar and N ₂ inlet Bottom flask. The bath was then removed and the reaction mixture was stirred for 2 hours. The reaction was filtered, the filtrate was concentrated in vacuo, the residue was partitioned between EtOAc / water, the layers were separated, the aqueous layer was extracted with EtOAc (1X), the organic phases were combined, washed with water and brine, dried (Na ₂ SO ₄₎ to give the crude product was concentrated in vacuo to 1.3 g. The material was chromatographed on silica gel using 80% ethyl acetate / hexanes to give 0.5 g of pure product, m / z = 328 (M + Li).

Example 7: Synthesis of N-hydroxy-2 - [(4-methoxyanilino) -sulfonyl]

Part A: an addition funnel, thermometer, magnetic stir bar and N ₂ in a three neck 100 mL round bottom flask equipped with an inlet _{CH 2 Cl 2 (20 mL)} 1.8 mL of triethylamine and 0.5 g of (1.3 g, 12.8 mM) (4.3 mM) of p-anisidine. The solution was cooled in an ice bath and then treated with a solution of 1.0 g (4.3 mM) methyl (2-chlorosulfonyl) benzoate in CH ₂ Cl ₂ (10 mL). The reaction mixture was stirred for 17 hours and then concentrated in vacuo. The residue was partitioned between EtOAc and H ₂ O, the layers were separated and the organic phase was washed with 5% citric acid solution, saturated sodium bicarbonate solution and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to yield 0.9 g of A crude product was obtained. This was chromatographed on silica gel using 20-30% ethyl acetate / hexanes to give 0.7 g of pure product, m / z = 328 (M + Li).

Part B: A 100 mL round bottom flask equipped with magnetic stir bar and N ₂ inlet was charged with 0.7 g (10.2 mM) of hydroxylamine hydrochloride in 10 mL of MeOH and 0.7 g (2.1 mM) of product from Part A. The reaction was cooled to 0 &lt; 0 &gt; C and 0.4 g (16.4 mM) sodium metal was added. After stirring for 17 hours, the reaction was concentrated in vacuo and the residue was slurried in 20 mL water and then acidified with 2N HCl solution. The aqueous slurry was extracted with EtOAc (3X). The organic layers were combined, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 0.6 g of crude product. Off-white solids were precipitated by the addition of methylene chloride to the crude product. Filtration gave 0.2 g of pure product, m / z = 323 (M + Li).

Example 8: Synthesis of N-hydroxy-2 - [(benzylamino) -sulfonyl] benzamide

Part A: an addition funnel, thermometer, magnetic stir bar and N ₂ triethylaluminum in 1.8 mL (1.3 g, 12.8 mM ) of with an inlet to a three neck 100 mL round bottom flask was added CH ₂ Cl ₂ (20 mL) amine and 0.5 mL (0.5 g, 4.3 mM) of benzylamine. The solution was cooled in an ice bath and then treated with a solution of 1.0 g (4.3 mM) methyl (2-chlorosulfonyl) benzoate in CH ₂ Cl ₂ (10 mL). The reaction mixture was stirred for 2 hours and then concentrated in vacuo. The residue was partitioned between EtOAc and H ₂ O, the layers were separated and the organic phase was washed with 5% citric acid solution, saturated sodium bicarbonate solution and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to yield 0.9 g of A crude product was obtained. This was chromatographed on silica gel using 20% ethyl acetate / hexanes to give 0.7 g of pure product, m / z = 312 (M + Li).

Part B: A 100 mL round bottom flask equipped with magnetic stir bar and N ₂ inlet was charged with 0.7 g (10.6 mM) of hydroxylamine hydrochloride in 10 mL of MeOH and 0.7 g (2.1 mM) of product from Part A. The reaction was cooled to 0 &lt; 0 &gt; C and 0.4 g (17.0 mM) of sodium metal was added. After stirring for 17 hours, the reaction was concentrated in vacuo and the residue was slurried in 20 mL of water and then acidified with 2N HCl solution. The aqueous slurry was extracted with EtOAc (3X). The organic layers were combined, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 0.3 g of crude product. White solids were precipitated by the addition of methylene chloride to the crude product. Filtration gave 0.1 g of pure product, m / z = 307 (M + H).

Example 9: Preparation of N-hydroxy-2 - [[4- (phenyl) -1-piperidinyl] sulfonyl] benzamide

Part A: 2-Carbethoxybenzenesulfonyl chloride (3.72 g, 15 mmol) was dissolved in methylene chloride (60 mL). 4-phenylpiperidine (2.89 g, 18 mmol) was added followed by triethylamine (2.5 mL, 18 mmol) and 4- (dimethylamino) piperidine (100 mg). After 5 h, the mixture was diluted with 10% aqueous HCl (100 mL). The organic layer was separated and dried over magnesium sulfate. The solution was filtered through a pad of silica and concentrated to give the ester sulfonamide (3.27 g, 63%) as an oil.

Part B: The ester sulfonamide from Part A (938 mg, 2.51 mmol) was stirred at room temperature for 20 hours in the presence of potassium hydroxide (940 mg, 17 mmol), ethanol (15 mL), and water (5 mL) . The mixture was diluted with water (20 mL) and acidified to about pH 4 using concentrated HCl. The product was extracted with chloroform (2 X 100 mL) and the combined organic layers were dried using anhydrous magnesium sulfate. Concentration gave the carboxylic acid (768 mg, 89%), which was transferred to the next step.

Part C: To a solution of the acid (764 mg, 2.2 mmol) from Part B in acetonitrile (15 mL) was added O-tetrahydropyranyl hydroxylamine (351 mg, 3.0 mmol) and N-hydroxybenzotriazole (405 mg, 3.0 mmol) followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (600 mg, 3 mmol). The reaction was stirred for 16 hours and then concentrated. The residue was diluted with half-saturated brine (15 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried using magnesium sulfate, concentrated and the residue was purified by silica gel chromatography to give the desired THP-protected hydroxamate (833 mg, 82%) as a white foam upon concentration.

Part D: THP-protected hydroxamate (833 mg, 1.8 mmol) from Part C was dissolved in pure methanol (3 mL). Acetyl chloride (0.28 mL, 4 mmol) was added dropwise. After 3 h, the reaction was concentrated and the residue was purified by chromatography to give the title compound (430 mg, 66%) as a white foam.

Analysis for C ₁₈ H ₂₀ N ₂ O ₄ S (H ₂ O)

Calculated: C, 57.08; H, 5.81; N, 7.40.

Measured: C, 57.02; H, 5.61; N, 6.90.

Example 10: Preparation of N, 2-dihydroxy-2-methyl-2 - [(4-phenyl-1-piperidinyl) -sulfonyl] benzeneacetamide

Part A: 2-Bromobenzenesulfonyl chloride (2.56 g, 10 mmol) was added to a solution of 4-phenylpiperidine (1.61 g, 10 mmol), triethylamine (2.0 mL, 14 mmol), 4- dimethylaminopyridine 75 mg), and acetonitrile (20 mL). After 24 hours, water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL, then 50 mL). The combined organic layers were dried over magnesium sulfate, filtered through silica and concentrated to give bromosulfonamide (3.47 g, 96%) as a white solid.

Part B: Bromosulfonamide (359 mg, 1 mmol) was dissolved in dry tetrahydrofuran (2 mL) and cooled to -78 &lt; 0 &gt; C. t-Butyl lithium (0.68 mL, 1.7 M in pentane) is added dropwise and anion is allowed to form over 15 minutes. Ethyl pyruvate (0.11 mL, 1.15 mmol) was added. The cooling bath was removed. When the reaction reached room temperature, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate, filtered through silica, concentrated and chromatographed to give the desired hydroxy ester (163 mg, 40%) as an ice (ice).

Part C: The hydroxy ester from part B (134 mg, 0.33 mmol) was stirred in the presence of potassium hydroxide (134 mg, 2.4 mmol) in ethanol (1 mL) and water (1 mL). After 4 h, the mixture was heated at 50 &lt; 0 &gt; C for 1 h, then cooled, neutralized with dilute hydrochloric acid, concentrated and azeotropically dried with acetonitrile to give the crude hydroxy acid, which was used directly. The hydroxy acid was diluted with acetonitrile (1 mL). (135 mg, 1.0 mmol) and then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide Hydrochloride (191 mg, 1 mmol) was added. The reaction was stirred overnight (about 18 hours) then diluted with water (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried with ethyl acetate, concentrated and chromatographed to afford THP-protected hydroxamate (80 mg, 48%) as an ice-cream.

Part D: THP-protected hydroxamate (80 mg) from Part C was diluted with pure methanol (4 mL) and toluenesulfonic acid (6 mg) was added. After 3 hours, concentrate the reaction mixture, 1: 1 hexane: was The residue was purified by chromatography using ethyl acetate to 1% NH ₄ OH. The title compound was isolated as a white foam (40 mg, 60%). Analysis for C ₂₀ H ₂₄ N ₂ O ₅ S (1.33 H ₂ O)

Calculated: C, 53.75; H, 5.90; N, 6.27.

Measured: C, 53.80; H, 5.65; N, 5.84.

Example 11: Preparation of N-hydroxy-2 - [[3 - [(4-methoxybenzoyl) amino] -1-pyrrolidinyl] -sulfonyl] benzamide

Part A: 3-Aminopyrrolidine (636 mg, 4 mmol), triethylamine (2.7 mL, 20 mmol) and 4- (dimethylamino) pyridine (75 mg) were suspended in acetonitrile. After 10 minutes, the reaction was cooled to 0 &lt; 0 &gt; C. 4-Methoxybenzoyl chloride (0.54 mL, 4 mmol) was added dropwise. After 30 minutes, 2-carboethoxybenzenesulfonyl chloride (0.996 g, 4.0 mmol) was added dropwise via syringe. The mixture was stirred at 0 &lt; 0 &gt; C for 1 hour, then at room temperature for 2 hours. Water (50 mL) was added. The mixture was extracted with ethyl acetate (2 X 50 mL). The organic layer was dried over magnesium sulfate, filtered through silica and concentrated. The residue was purified using silica gel chromatography with ethyl acetate in 1: 1 ethyl acetate: hexane as the eluent. The desired amide sulfonamide was isolated as a foam (282 mg, 16%).

Part B: Amidesulfonamide from Part A (272 mg, 0.63 mmol) was combined with potassium hydroxide (156 mg, 2.8 mmol), ethanol (3 mL), and water (2 mL) and refluxed. After 40 minutes, the reaction was allowed to cool. Acetic acid (0.1 mL) and pure ethanol (20 mL) were added. Concentration followed by chromatography (9: 1 ethyl acetate: methanol in methanol; 20 g silica gel) gave the desired acid (229 mg, 96%) as a crystalline solid. Acid (229 mg, 0.57 mmol) was dissolved in acetonitrile (1 mL). (135 mg, 1.0 mmol) and then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide Hydrochloride (191 mg, 1 mmol) was added. The mixture was stirred at room temperature overnight (about 18 hours), then concentrated and chromatographed (ethyl acetate to 9: 1 ethyl acetate: methanol) to give THP-protected hydroxamate (98 mg, 33 %).

Part C: THP-protected hydroxamate (76 mg, 0.15 mmol) was dissolved in methanol (2 mL). Acetyl chloride (0.01 mL, 1 mmol) was added. After 30 minutes, the solution was concentrated and then azeotroped with chloroform / acetonitrile to give the title compound (65 mg, quant.) As a solid.

^{MS (EI) MH +: C} 19 H 21 N 3 O 6 S Calcd: 420, measured value: 420.

Example 12: Preparation of N-hydroxy-2 - [[4- [4- (trifluoromethoxy) phenoxy] -1-piperidinyl] sulfonyl] benzamide

Part A: Diethyl azodicarboxylate (4.11 g, 23.6 mmol) was added at room temperature under a nitrogen atmosphere to a solution of N- (tert-butyloxycarbonyl) -4-piperidinol (4.31 g, 21.4 (4.20 g, 23.6 mmol) and triphenylphosphine (6.19 g, 23.6 mmol) were added to a solution of 2-amino-2-pyrrolidone (Wells, Kenneth M. et al; Tetrahedron Lett. , 1996, 37, 6439-6442) Was added to the mixture. After 1.5 h, the reaction mixture was concentrated. The residue was diluted with ethyl ether, filtered and purified by chromatography (silica phase, methyl tert-butyl ether / hexane) to give impure BOC-amine (5.23 g) as an off-white solid. To the off-white solid cooled to 0 &lt; 0 &gt; C under a nitrogen atmosphere was added a solution of 4N HCl in dioxane (36.1 mL, 145 mmol). After 2 h, the reaction mixture was concentrated and diluted with ethyl ether to give a white solid. The white solid was diluted with H ₂ O (15 mL) and a solution of NaHCO ₃ (1.68 g, 20.0 mmol) in water (10 mL) was added. The precipitate was extracted with ethyl ether. The organic layer was washed with brine, dried over MgSO ₄ and concentrated to give the amine (1.93 g, 34%) as a white solid.

MS MH ⁺ calculated for C _{12 H 14 NO 2 F 3: 262} , 262 measurements.

Part B: To a solution of 4-dimethylaminopyridine (10 mg), the amine of Part A (1.90 g, 7.28 mmol), ethyl 2-chlorosulfonylbenzoate (1.70, 6.85 mmol) Amine (1.15 mL, 8.22 mmol) in dichloromethane was stirred at room temperature under a nitrogen atmosphere for 18 hours. After concentration of the solution, the residue was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , saturated NaHCO ₃ , H ₂ O, and brine; Then dried over MgSO ₄ and concentrated to a yellow oil. Chromatography (silica phase, ethyl acetate / hexanes) provided the sulfonamide (1.59 g, 51%) as a white solid.

MS MH ⁺ C ₂₁ H ₂₂ NO ₆ F ₃ S: 474, found 474.

Solution of _{MeOH (30 mL), H 2} O (10 mL), and THF (10 mL) sulfonamide (1.45 g, 3.17 mmol) and potassium hydroxide (1.77 g, 31.7 mmol) of Part B in a mixture of Part C Was heated to reflux for 1.5 hours. After concentrating the solution in vacuo, the residue was triturated with ethyl ether, dissolved in H ₂ O, acidified with concentrated HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ and, provided the acid (1.04 g, 74%) as a clean oil and concentrated in vacuo.

Analysis for C ₁₉ H ₁₈ NO ₆ F ₃ S

Calculated: C, 51.23; H, 4.07; N, 3.14; S, 7.20.

Measured: C, 51.34; H, 3.78; N, 3.15; S, 7.30.

Part D: To a solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.25 g, 6.50 mmol), Part C acid (0.97 g, 2.18 mmol), N- (0.81 g, 6.50 mmol), 4-methylmorpholine (0.71 mL, 6.50 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxyamine (0.51 g, 4.36 mmol) The solution was stirred at room temperature under a nitrogen atmosphere for 20 hours. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , saturated NaHCO ₃ , H ₂ O, and brine; It was then dried over MgSO ₄ and concentrated in vacuo to give THP-protected hydroxamate (1.05 g, 88%) as a white solid.

Analysis for C ₂₄ H ₂₇ N ₂ O ₇ F ₃ S

Calculated: C, 52.94; H, 5.00; N, 5.14; S, 5.89.

Measured: C, 52.80; H, 4.84; N, 5.23; S, 6.14.

Part E: THP-protected hydroxamate (1.01 g, 1.86 mmol) in Part D was dissolved in methanol (10 mL). Acetyl chloride (0.36 mL, 5.0 mmol) was added. After 1 hour, the solution is concentrated and the residue chromatography (1: 1 hexane: ethyl acetate; in 1% NH ₄ OH in ethyl acetate; 1% NH ₄ OH) to the title compound (643 mg, 75 as a foam %).

Analysis for C ₁₉ H ₁₉ F ₃ N ₂ O ₆ S

Calculated: C, 49.56; H, 4.13; N, 6.09.

Measured: C, 49.27; H, 3.72; N, 5.87.

Example 13: Preparation of N-hydroxy-2 - [[4- [4- (trifluoromethyl) phenoxy] -1-piperidinyl] sulfonyl] benzamide

Part A: Cesium carbonate (12.1 g, 3.72 mmol), N- (tert-butyloxycarbonyl) -4-piperidinol (5.00 g, 2.48 mmol) and 4- fluorobenzo- A solution of triflouroide (3.46 mL, 2.73 mmol) was heated at 120 &lt; 0 &gt; C under a nitrogen atmosphere for 2 days. The mixture was concentrated, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexanes) provided BOC-amino ether (6.97 g, 81%) as a white solid.

Analysis for C ₁₇ H ₂₂ NO ₃ F ₃

Calculated: C, 59.12; H, 6.42; N, 4.06.

Measured: C, 59.29; H, 6.47; N, 3.99.

Part B: A solution of p-toluenesulfonic acid (6.61 g, 34.7 mmol) and BOC-amino ether (4.00 g, 11.6 mmol) in Part A in CH ₂ Cl ₂ (30 mL) at room temperature under nitrogen atmosphere was stirred for 3 h &Lt; / RTI &gt; and concentrated in vacuo. The residue was partitioned between NaHCO ₃ and ethyl acetate. The organic layer was dried over MgSO ₄ and concentrated to give the free amine as a clear yellow oil (1.57 g, 55%).

_{C 12 H 14 NOF 3 MS MH} + calculated for: 246, measurements: 246.

Part C: To a solution of 4-dimethylaminopyridine (10 mg), the amine of Part B (1.57 g, 6.40 mmol), ethyl 2-chlorosulfonylbenzoate (1.57 g, 6.03 mmol) A solution of ethylamine (1.00 mL, 7.24 mmol) was stirred at room temperature under a nitrogen atmosphere for about 1.5 hours. After concentration of the solution, the residue was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , saturated NaHCO ₃ , H ₂ O, and brine; It was then dried over MgSO ₄ and concentrated to provide the sulfonamide (2.52 g, 92%) as a clear yellow oil.

C ₂₁ H ₂₂ NO MS MH ⁺ calculated for ₅ F ₃ S: 458, measured value: 458.

Part D: A solution of the sulfonamide of Part C (2.50 g, 5.46 mmol) and potassium hydroxide (3.06 g, 54.6 mmol) in a mixture of MeOH (49 mL) and H ₂ O (24 mL) . After concentrating the solution in vacuo, the residue was triturated with ethyl ether, dissolved in H ₂ O, acidified with concentrated HCl and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , H ₂ O, and brine, dried over MgSO ₄ and concentrated in vacuo to give the acid as an oil (2.17 g, 93%).

MS MH ⁺ calculated for C _{19 H 18 NO 5 F 3 S:} 430, 430 measurements.

Part E: To a solution of l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.80 g, 14.6 mmol), Part D acid (2.10 g, 4.89 mmol), N- (1.97 g, 14.6 mmol), 4-methylmorpholine (1.61 mL, 14.6 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.15 g, 9.79 mmol) The solution was stirred at room temperature under a nitrogen atmosphere for about 18 hours. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , H ₂ O, and brine, then dried over MgSO ₄ and concentrated in vacuo. Chromatography (silica phase, ethanol / CHCl ₃₎ has provided THP- protected hydroxy roksa formate (2.09 g, 81%) as a white solid.

_{C 24 H 27 N 2 O 6} F 3 MS MH + calculated for S: 529, 529 measurements.

Part F: To a solution of THP-protected hydroxamate (1.80 g, 3.41 mmol) in Part C in methanol (24 mL) was added acetyl chloride (0.73 mL, 10.2 mmol) and the solution was stirred at room temperature under a nitrogen atmosphere for 1.5 h Lt; / RTI &gt; The solution was concentrated to provide the vacuum and purification by chromatography the title compound (1.18 g, 78%) as an off-white solid (phase silica, MeOH / CHCl _3).

Analysis for C ₁₉ H ₁₉ N ₂ O ₅ F ₃ S · 0.2% H ₂ O

Calculated: C, 50.94; H, 4.36; N, 6.25; S, 7.16.

Measured: C, 50.88; H, 4.31; N, 6.20; S, 7.43.

_{C 19 H 19 N 2 O 5} F 3 S MS MH + calculated for: 445, measurements: 445.

Example 14: Preparation of N-hydroxy-2 - [[4- [[4- (trifluoromethyl) phenyl] methoxy] -1-piperidinyl] sulfonyl] benzamide

Part A: A solution of 4- (trifluoromethyl) benzyl bromide (2.00 ml, 12.9 mmol) in THF (6 ml) was added to a solution of N- (tert- butyloxycarbonyl) (2.85 g, 14.9 mmol) and 60% sodium hydride (0.600 g, 14.9 mmol) was added dropwise to the mixture at -52 째 C, followed by stirring at room temperature for about 20 hours. The reaction mixture was quenched with saturated NH ₄ Cl solution, concentrated in vacuo, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with 1.0 N HCl, saturated NaHCO ₃ solution, H ₂ O and brine, then dried over MgSO ₄ and concentrated in vacuo to give BOC-amino ether (3.35 g, 72%) as an off-white solid.

MS MH ⁺ calculated for C _{18 H 24 NO 3 F 3: 360} , measurements: 360.

Part B: A 0 ° C solution of BOC-amino ether (3.35 g, 9.32 mmol) in Part A in ethyl acetate (40 ml) was saturated with HCl (gas) and stirred at room temperature for 1 hour. After concentrating in vacuo and trituration with ethyl ether, the crude free base was partitioned between aqueous NaHCO ₃ and ethyl ether. The organic layer was washed with H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo to give the amine (2.11 g, 87%) as a clear yellow oil, which has a proton NMR spectrum consistent with the desired product.

Part C: To a solution of the amine of part B (2.11 g, 8.14 mmol), ethyl 2-chlorosulfonyl benzoate (2.65 g, 10.7 mmol), triethylamine (1.75 ml, 12.6 mmol) and 4 -Dimethylaminopyridine (50 mg) was stirred at room temperature in a nitrogen atmosphere for 18 hours. After concentrating the solution, the residue was diluted with KHSO ₄ of 1.0N and extracted with ethyl acetate. The organic layer was washed with KHSO _4, saturated NaHCO _3, H ₂ O, and brine, and then 1.0N, dried over MgSO ₄ and concentrated to give a yellow oil. Chromatography (silica phase, ethyl acetate / hexanes) provided the sulfonamide (2.48 g, 65%) as a clear oil.

MS MH ⁺ calculated for C _{22 H 24 NO 5 F 3 S:} 472, measured value: 472.

Part D: MeOH (40ml), H 2 O (20ml) for 1.5 hours and a solution of sulfonamide (2.1Og, 4.45mmol) and potassium hydroxide (2.49g, 44.5mmol) in a mixture of THF (4ml) Part C And heated under reflux. After concentrating the solution in vacuo, the residue was triturated with ethyl acetate, dissolved in H ₂ O, acidified with concentrated HCl and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo to give the acid as a white solid (2.08 g, 1.06%).

Analysis for C ₂₀ H ₂₀ NO ₅ F ₃ S

Calculated: C, 54.17; H, 4.55; N, 3.16; S, 7.23.

Measured: C, 54.29; H, 4.68; N, 3.11; S, 7.19.

Part E: To a stirred solution of Part D acid (2.00 g, 4.51 mmol), N-hydroxybenzotriazole (1.83 g, 13.5 mmol), 4-methylmorpholine (1.48 ml, 13.5 mmol) A solution of tetrahydro-2H-pyran-yl-hydroxylamine (1.06 g, 9.02 mmol) and 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (2.59 g, 13.5 mmol) Lt; / RTI &gt; at room temperature under a nitrogen atmosphere. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , H ₂ O, and brine, then dried over MgSO ₄ and concentrated in vacuo to give THP protected hydroxamate (2.01 g, 82%) as a white solid.

Analysis for C ₂₅ H ₂₉ N ₂ O ₆ F ₃ S

Calculated: C, 55.34; H, 5.39; N, 5.16; S, 5.91.

Measured: C, 55.36; H, 5.63; N, 5.20; S, 6.12.

Part F: To a solution of THP protected hydroxamate (2.00 g, 3.69 mmol) in Part E in methanol (25.9 ml) was added acetyl chloride (0.78 ml, 11.1 mmol) and the solution was stirred at room temperature Lt; / RTI &gt; The solution was concentrated under vacuum and purified by chromatography (silica phase, MeOH / CHCl ₃₎ to give the title compound (1.07g, 63%) as an off-white solid.

Analysis for C ₂₀ H ₂₁ N ₂ O ₅ F ₃ S

Calculated: C, 52.40; H, 4.62; N, 6.11; S, 6.99.

Measured: C, 52.53; H, 4.74; N, 6.25; S, 7.16.

C ₂₀ H ₂₁ MS MH ⁺ calculated for _{N 2 O 5 SF 3: 459} , measurements: 459.

Example 15: Preparation of N-hydroxy-2 - [[(4-phenoxyphenyl) amino] sulfonyl]

Part A: A mixture of 4-phenoxyaniline (3.43 g, 18.5 mmol), ethyl 2-chlorosulfonylbenzoate (4.25 g, 17.1 mmol), triethylamine (2.81 ml, 20.1 mmol) and A solution of 4-dimethylaminopyridine (50 mg) was stirred at room temperature in a nitrogen atmosphere for 18 hours. After concentrating the solution, the residue was diluted with KHSO ₄ of 1.0N and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , H ₂ O, and brine, then dried over MgSO ₄ and concentrated in vacuo. Chromatography (silica phase, ethyl acetate / hexane) gave the sulfonamide (4.94 g, 73%) as a tan solid.

Analysis for C ₂₁ H ₁₉ NO ₅ S

Calculated: C, 63.46; H, 4.82; N, 3.52; S, 8.07.

Measured: C, 63.36; H, 4.78; N, 3.45; S, 8.31.

MS M ^&lt; ^{+ &} gt ^; calculated for C ₂₁ H ₁₉ NO ₅ S: 397, found: 397.

Part B: A solution of the sulfonamide of Part A (3.00 g, 7.55 mmol) and potassium hydroxide (4.23 g, 75.5 mmol) in a mixture of MeOH (68 ml), H ₂ O (33 ml) and THF And heated under reflux. After concentrating the solution in vacuo, the residue was triturated with ethyl acetate, dissolved in H ₂ O, acidified with concentrated HCl and extracted with ethyl acetate. The organic layer was washed with 1.0 N HCl, H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo to give the acid as a tan solid (2.31 g, 83%).

Analysis for C ₁₉ H ₁₅ NO ₅ S

Calculated: C, 61.78; H, 4.09; N, 3.79; S, 8.68.

Measured: C, 61.66; H, 4.22; N, 3.73; S, 8.70.

MS M ⁺ calcd for C ₁₉ H ₁₅ NO ₅ S: 369, found: 369.

Part C: To a stirred solution of the acid of Part B (2.30 g, 6.23 mmol), N-hydroxybenzotriazole (2.52 g, 18.6 mmol), 4-methylmorpholine (2.04 ml, 18.6 mmol) A solution of tetrahydro-2H-pyran-2-yl-hydroxylamine (1.46 g, 12.5 mmol) and 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (3.57 g, 18.6 mmol) And stirred in a nitrogen atmosphere at room temperature for about 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , H ₂ O and brine, then dried over MgSO ₄ and concentrated in vacuo to give a saccharin compound (2.13 g, 97%) as a white solid.

Analysis for C ₁₉ H ₁₃ NO ₄ S

Calculated: C, 64.95; H, 3.73; N, 3.99; S, 9.13.

Measured: C, 64.98; H, 3.82; N, 4.17; S, 9.07.

MS MH ⁺ calculated for C ₁₉ H ₁₃ NO ₄ S: 352, measured value: 352.

Part D: A solution of Part C of saccharin (0.500 g, 1.42 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.183 g, 1.56 mmol) in dioxane (2 ml) The mixture was stirred at room temperature for 6 days and at 50 ° C for 1 day. The solution was concentrated and chromatographed to give THP protected hydroxamate (0.285 g, 43%) as a white solid.

_{C 24 H 24 N 2 O 6} S MS MH + calculated for: 469, measurements: 469.

Part E: Acetyl chloride (0.150 ml, 2.13 mmol) was added to a solution of THP protected hydroxamate (0.275 g, 0.587 mmol) in Part D in methanol (5 ml) and the solution was stirred at room temperature for 2 hours in a nitrogen atmosphere . The solution was concentrated under vacuum and purified by chromatography (silica phase, MeOH / CHCl ₃₎ to give the title compound (1.18g, 78%) as an off-white solid. The proton NMR was consistent with the desired product.

Example 16: Preparation of N-hydroxy-2,3-dimethoxy-6 [[4- [4- (trifluoromethyl) phenoxy] -1-piperidinyl) sulfonyl] benzamide

Part A: As the hydrochloride, piperidine (1.12 g, 4.0 mmol) from Part B of Example 13 was dissolved in acetonitrile (6 ml), triethylamine (1.3 ml, 9.0 mmol) and N, N-dimethylaminopyridine (80 mg). 3,4-Dimethoxybenzenesulfonyl chloride (947 mg, 4.0 mmol) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and the residue was extracted with ethyl acetate (100 ml, then 25 ml). The combined organic layers were dried over magnesium sulfate, filtered through silica and concentrated to give the desired sulfonamide (1.05 g, 59%) as a white solid.

Part B: The sulfonamide from Part A (1.05 g, 2.38 mmol) was dissolved in tetrahydrofuran (20 ml) and cooled to 0 &lt; 0 &gt; C. t-Butyllithium (1.7 M in pentane, 2.8 ml) was added dropwise. After 15 minutes of complete addition of the base, the solution was rapidly saturated with dry carbon dioxide gas. The reaction mixture was concentrated, azeotroped with pure ethanol, and the residue was subjected to a preparative car- gel chromatography (using ethyl acetate: methanol = 8: 1) to give the title compound as a white solid The objective acid (279 mg, 24%) was obtained as an ice bath.

Part C: The acid from Part B (231 mg, 0.47 mmol) was dissolved in methylene chloride (4 ml). N, N-Dimethylformamide (2 drops) was added followed by oxalyl chloride (0.35 ml, 4 mmol). The reaction was stirred at room temperature for 1.5 hours, during which time gas evolution occurred. The reaction mixture was concentrated and dried in vacuo to give the crude acid chloride which was used as such. A solution of O-tetrahydropyranyl hydroxylamine (234 mg, 2.0 mmol) and pyridine (0.5 ml, 6.0 mmol) in acetonitrile (2.3 ml) was added to the acid chloride. The reaction was stirred at room temperature for 16 h and then diluted with water (3 ml). The mixture was extracted with ethyl acetate (100 ml, then 50 ml). The combined organic layers were dried over magnesium sulfate, filtered through a pad of silica and concentrated to give 376 mg of crude THP protected hydroxamate. The THP protected hydroxamate was used directly without purification and was diluted with pure methanol (10 ml). Acetyl chloride (0.36 ml, 5.0 mmol) was added dropwise. After 2.5 h, the mixture was concentrated and the residue was purified by chromatography: performed the (ethyl acetate 1% NH ₄ OH). The objective hydroxamate (121 mg, 51% from the acid) was obtained as ice.

_{C 21 H 23 F 3 N MS} MH + calculated for ₂ O ₇ S: 505, measured value: 505.

Example 17: Preparation of N-hydroxy-2 - [[3- [4- (trifluoromethyl) phenoxy] -1-pyrrolidinyl] sulfonyl] benzamide

Part A: Diethyl azodicarboxylate (2.03 ml, 12.9 mmol) was added to a solution of l- (tert-butoxycarbonyl) -3-hydroxypyrrolidine (2.31 g, , 12.3 mmol), p-trifluoromethylphenol (2.09 g, 12.9 mmol) and triphenylphosphine (3.38 g, 12.9 mmol). After stirring for 2 hours, the reaction was concentrated in vacuo. The residue was diluted with ether, filtered through a pad of silica gel, concentrated and purified by flash chromatography (silica phase, ethyl acetate / hexanes) to give BOC protected amine (1.85 g, 45%) as a white solid.

Analysis for C ₁₆ H ₂ ONO ₃ F ₃

Calculated: C, 58.00; H, 6.08; N, 4.23

Measured: C, 57.86; H, 6.17; N, 3.92

Part B: To a BOC protected amine (1.75 g, 5.28 mmol) in Part A was added a solution of 4N HCl in dioxane (13.2 ml, 52.8 mmol). After 1 hour, the reaction mixture was concentrated, diluted with ethyl ether and concentrated to give an oil. The oil was dissolved in water and a saturated solution of NaHCO ₃ was added until the pH was 8. The mixture was extracted with ethyl acetate. The organic layer was washed with H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo to afford the amine as a clear yellow oil (0.75 g, 61%).

MS MH ^{&lt; + &} gt ^; calculated for C ₁₁ H ₁₂ NOF ₃ : 231, found: 232.

Part C: To a solution of the amine of Part B (0.680 g, 2.94 mmol), ethyl 2-chlorosulfonylbenzoate (0.688 g, 2.77 mmol), triethylamine (0.46 ml, 3.3 mmol), and 4 -Dimethylaminopyridine (10 mg) in dichloromethane was stirred at room temperature for 18 hours under a nitrogen atmosphere. After concentration in vacuo, the residue was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with 0.1 N KHSO ₄ , saturated NaHCO ₃ , H ₂ O and brine, dried over MgSO ₄ and concentrated to give a yellow oil. Chromatography (silica phase, ethyl acetate / hexane) gave the sulfonamide (0.95 g, 76%) as a clear, colorless oil.

C ₂₀ H ₂₀ NO MS MH ⁺ calculated for ₅ F ₃ S: 443, measured value: 444.

Analysis for C ₂₀ H ₂₀ NO ₅ F ₃ S

Calculated: C, 54.17; H, 4.55; N, 3.16; S, 7.23.

Measured: C, 53.82; H, 4.35; N, 3.13.

Part D: A solution of the sulfonamide of Part C (0.85 g, 1.9 mmol) and potassium hydroxide (1.07 g, 19.2 mmol) in a mixture of MeOH (17 ml) and H ₂ O (8 ml) was heated to reflux for 4 hours. After the solution was concentrated in vacuo, the residue was dissolved in H ₂ O, acidified with concentrated HCl and extracted with ethyl acetate. The organic layer was washed with H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo to give the acid as a clear, colorless wax (0.74 g, 93%).

MS MH ⁺ calculated for C _{18 H 16 NO 5 F 3 S:} 415, measured value: 416.

Part E: To a stirred solution of Part D acid (0.690 g, 1.56 mmol), N-hydroxybenzotriazole (0.629 g, 4.65 mmol), 4-methylmorpholine (0.51 ml, 4.7 mmol) A solution of tetrahydro-2H-pyran-2-yl-hydroxylamine (0.340 g, 2.90 mmol) and 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (0.891 g, 4.65 mmol) And stirred at room temperature under a nitrogen atmosphere for 3 days. The mixture was concentrated in vacuo, diluted with 1.0N KHSO ₄ and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , saturated NaHCO ₃ , H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo. Chromatography on silica (ethyl acetate / hexane as eluent) gave THP protected hydroxamate (0.575 g, 71.6%) as a white foam.

Analysis for C ₂₃ H ₂₅ N ₂ O ₆ F ₃ S

Calculated: C, 53.69; H, 4.90; N, 5.44; S, 6.23.

Measured: C, 53.48; H, 4.95; N, 5.37; S, 6.35.

Part F: To a solution of THP protected hydroxamate (0.500 g, 0.972 mmol) in Part E in methanol (6 ml) was added acetyl chloride (0.24 ml, 3.5 mmol) and the solution was stirred at room temperature under a nitrogen atmosphere for 4.5 h . The solution was concentrated under vacuum and purified by chromatography (silica phase, MeOH / CHCl ₃₎ to give the title compound (0.325g, 77.8%) as a white solid.

C ₁₈ H ₁₇ N MS MH ⁺ calculated for ₂ O ₅ SF _3: 430, measurements: 431.

Example 18: Preparation of N-alpha-dihydroxy-2 - [[4- [4- (trifluoromethyl) phenoxy] -1-piperidinyl] sulfonyl] benzeneacetamide

Part A: To a solution of 4 - [(4-trifluoromethyl) -phenoxy] piperidine hydrochloride (2.50 g, 8.87 mmol) from the product of Part B of Example 13 in acetonitrile (25 ml) A mixture of 2-bromobenzenesulfonyl chloride (2.16 g, 8.45 mmol), triethylamine (2.51 ml, 18.0 mmol) and 4- (dimethylamino) pyridine (20 mg) was stirred at room temperature under a nitrogen atmosphere for 18 hours , Concentrated in vacuo and partitioned between H ₂ O and ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , saturated NaHCO ₃ , H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo. The oil was purified by chromatography (silica phase, ethyl acetate / hexane) to give the bromide as a clear oil (3.38 g, 82.8%).

C ₁₈ MS + calcd for _{H 17 NO 3 SF 3 Br:} 464, measured value: 464.

Part B: To a -78 ° C solution of the sulfonamide (3.68 g, 7.93 mmol) from Part A in anhydrous THF (40 ml) was added 1.7 M tert-butyllithium (9.35 ml, 15.9 mmol) in a nitrogen atmosphere. The reaction was maintained at -78 [deg.] C for 1 h, warmed to -30 [deg.] C and then cooled to -78 [deg.] C. A solution of 50% ethyl glyoxalate in toluene was added dropwise while maintaining the reaction mixture below -50 &lt; 0 &gt; C. The solution was slowly warmed to room temperature, stirred at room temperature for 2 days, poured into saturated NH ₄ Cl solution, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo. Chromatography (silica, ethyl acetate / hexane as eluent) gave the ester as a yellow oil (1.55 g, 40%).

Analysis for C ₂₂ H ₂₄ NO ₆ F ₃ S

Calculated: C, 54.20; H, 4.96; N, 2.87.

Measured: C, 54.18; H, 4.72; N, 2.77.

C ₂₂ H ₂₄ NO MS MH ⁺ calculated for ₆ F ₃ S: 487, measured value: 488.

Part C: A solution of the ester of Part B (1.35 g, 2.77 mmol) and potassium hydroxide (1.55 g, 27.7 mmol) in a mixture of MeOH (24.5 ml) and H ₂ O (14.7 ml) was stirred at room temperature for 1 hour . The solution was concentrated in vacuo, dissolved in a mixture of H ₂ O and acetonitrile, acidified with concentrated HCl and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , H ₂ O and brine and concentrated in vacuo over MgSO ₄ to give the acid as a wax (1.09 g, 85.8%).

Analysis for C ₂₀ H ₂₀ NO ₆ F ₃ S

Calculated: C, 52.29; H, 4.39; N, 3.05; S, 6.98.

Measured: C, 52.06; H, 4.41; N, 2.90; S, 7.11.

Part D: To a stirred solution of the acid from Part C (1.00 g, 2.18 mmol), N-hydroxybenzotriazole (0.876 g, 6.48 mmol), 4-methylmorpholine (0.712 ml, 6.48 mmol) A solution of tetrahydro-2H-pyran-2-yl hydroxylamine (0.474 g, 4.05 mmol) and 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (1.24 g, 6.48 mmol) Lt; / RTI &gt; at room temperature under a nitrogen atmosphere. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , saturated NaHCO ₃ , H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo. Chromatography (silica, ethyl acetate / hexanes as eluent) gave THP protected hydroxamate (0.81 g, 66%) as a white solid.

Analysis for C ₂₅ H ₂₉ N ₂ O ₇ F ₃ S

Calculated: C, 53.76; H, 5.23; N, 5.02; S, 5.74.

Measured: C, 53.73; H, 5.39; N, 4.85; S, 5.72.

Part E: A solution of THP protected hydroxamate (0.800 g, 1.43 mmol) and acetyl chloride (0.36 ml, 5.2 mmol) in Part D in methanol (15 ml) was stirred at room temperature under a nitrogen atmosphere for 1.5 h. The solution was concentrated under vacuum and purified by preparative _{HPLC (CH 3 CN / H 2} O) to give the title compound as a white solid (0.310g, 45%).

Analysis for C ₂₀ H ₂₁ N ₂ O ₆ SF ₃揃 0.2% H ₂ O

Calculated: C, 50.25; H, 4.51; N, 5.86; S, 6.71.

Measured: C, 50.18; H, 4.52; N, 5.82; S, 6.58.

Example 19: Preparation of 2-fluoro-N-hydroxy-6 - [[4- [4- (trifluoromethyl) phenoxy] -1-piperidinyl] sulfonyl]

Part A: To a solution of the piperidine (2.0 g, 6.72 mmol), 3-fluorobenzenesulfonyl chloride (1.19 g, 6.11 mmol), triethylamine (2.13 ml, 15.3 mmol) and 4-dimethylaminopyridine (10 mg) was stirred at room temperature under an argon atmosphere for 18 hours. After concentrating the solution, the residue was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with saturated NaHSO ₄ , H ₂ O, and brine, then dried over MgSO ₄ and concentrated to give an oil. Chromatography (silica phase, 20% ethyl acetate / hexanes) gave the sulfonamide (2.35 g, 95%) as a viscous oil.

_{C 18 H 17 NSO 3 F 4} MS H + Calcd: 404, measurements: 404.

Part B: t-Butyl lithium (3.5 ml, 5.96 mmol) was added to a solution of the sulfonamide (1.2 g, 2.98 mmol) of Part A in dry THF (10 ml) at 0 ° C. The solution was stirred at this temperature for 15 minutes. Carbon dioxide was bubbled into the reaction mixture at 0 &lt; 0 &gt; C for 7 min and the mixture was stirred for 0.5 h. Water was added to the solution, the mixture was acidified to pH = 1.0 with 1N HCl and concentrated in vacuo to give an oil. Chromatography (silica phase, 1% acetic acid / 5% methanol / ethyl acetate) gave the acid as a white powder (0.970 mg, 73%).

MS H ⁺ calculated for C ₁₉ H ₁₆ NSO ₅ F ₄ : 448, found: 448.

Part C: To a solution of the acid of Part B (880 mg, 1.97 mmol), N-hydroxybenzotriazole (319 mg, 2.36 mmol), 4-methylmorpholine (0.649 ml, 5.91 mmol), O- -2H-pyran-2-yl-hydroxylamine (346 mg, 2.95 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (528 mg, 2.76 mmol) Was stirred at room temperature under an argon atmosphere and then at 60 DEG C for 24 hours. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo to give a solid. Chromatography (C-18 reverse phase column phase, acetonitrile / water as eluent) THP protected as a white solid hydroxide roksa formate (240mg, 30 %).

Part D: To a solution of THP protected hydroxamate (230 mg, 0.422 mmol) in Part C in dioxane (5 ml) was added 4 N HCl (1 ml) and the solution was stirred at room temperature under an argon atmosphere for 1 hour. The solution was concentrated in vacuo to give an oil. Chromatography (C-18 reversed phase column, acetonitrile / water as eluent) gave the title compound hydroxamate (180 mg, 92%) as a white foam.

Example 20: Preparation of 2-chloro-N-hydroxy-6 - [[4- [4- (trifluoromethyl) phenoxyl-1-piperidinyl] sulfonyl] benzamide

Part A: Amine (2.00 g, 6.72 mmol), piperidine (2.00 g, 6.72 mmol), 3-chlorobenzenesulfonyl chloride (1.29 g, 6.11 mmol) in Example 13, Part B in acetonitrile A solution of ethylamine (2.2 ml, 15.3 mmol) and 4-dimethylaminopyridine (10 mg) was stirred in an argon atmosphere at room temperature for 18 hours. After concentrating the solution, the residue was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with saturated NaHSO ₄ , H ₂ O and brine, then dried over MgSO ₄ and concentrated to give an oil. Chromatography (silica phase, 20% ethyl acetate / hexanes) gave the descriptive phonamide (2.44 g, 95%) as a viscous oil.

_{C 18 H 17 NSO 3 F 3} MS H + calculated for Cl: 419, measured value: 419.

Part B: t-Butyl lithium (3.4 ml, 5.7 mmol) was added to a solution of the sulfonamide (1.2 g, 2.9 mmol) of Part A in dry THF (10 ml) at 0 ° C. The solution was stirred at this temperature for 15 minutes. Carbon dioxide was bubbled through the reaction mixture at 0 DEG C for 7 minutes and then the reaction was stirred for 1.5 hours. Water was added to the solution, the mixture was acidified to pH = 1.0 with 1N HCl, and then concentrated under vacuum to give an oil. Chromatography (silica phase, 1% acetic acid / 5% methanol / ethyl acetate) gave the acid as a white powder (320 mg, 24%).

Part C: Oxalyl chloride (0.154 ml) was added to a solution of the acid of Part B (410 mg, 0.88 mmol) in methylene chloride (4 ml) at room temperature and the solution was stirred in an argon atmosphere for 1 hour. The solution was concentrated in vacuo to give the acid chloride. To the acid chloride in DMF (5ml) was added 4-methylmorpholine (0.200ml, 1.77mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (155mg, 1.30mmol) Was stirred at room temperature under an argon atmosphere for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo to give an oil. Chromatography (C-18 reverse phase column, acetonitrile / water as eluent) gave THP protected hydroxamate (260 mg, 52%) as a white foam.

Part D: To a solution of the THP protected hydroxamate of Part C in dioxane was added 4N HCl and the solution was stirred at room temperature under an argon atmosphere for 1 hour. The solution was concentrated in vacuo to give a semisolid. Chromatography (silica phase, 60% ethyl acetate / hexanes) gave the title compound.

Example 21: Preparation of N-hydroxy-2 - [[4- [4- (pyridyloxy) -1-piperidinyl] sulfonyl] benzamide, monohydrochloride

To a solution of N-BOC-4-hydroxypiperidine (3.00 g, 14.9 mmol) in dimethylsulfoxide (10 ml) was added 4-chloropyridine hydrochloride (2.35 g, 15.6 mmol) and potassium- The seed (30.5 ml of a 1.0 M solution in tetrahydrofuran, 30.5 mmol) was continuously added. After 16 h at room temperature, the reaction mixture was diluted with diethyl ether (100 ml), washed with water (3x) and brine, and then dried over sodium sulfate. The organic solution was concentrated to give the objective 4-pyridyloxypiperidine (4.24 g, 100%) as a white solid.

Analysis for C ₁₅ H ₂₂ N ₂ O ₃

Calculated: C, 64.73; H, 7.97; N, 10.06.

Measured: C, 64.48; H, 8.14; N, 9.82.

Part B: A solution of hydrogen chloride in 1,4-dioxane (20 ml of a 4N solution, 80 mmol) was added to a solution of Part A of pyridyloxypiperidine (3.81 g, 13.7 mmol) in 1,4-dioxane (28 ml) Was added at room temperature. After 1 hour, the suspension was concentrated and the residue was triturated with hot isopropanol. The obtained solid was dried under vacuum at 50 캜 to obtain the desired piperidine hydrochloride (3.03 g, 88%) as a white powder.

Analysis for C ₁₀ H ₁₄ N ₂ O.2HCl

Calculated: C, 47.82; H, 6.42; N, 11.15.

Measured: C, 47.40; H, 6.64; N, 11.04.

Part C: Solid piperidine hydrochloride (450 mg, 1.79 mmol) from Part B was added to a solution of 2-carboxyethoxy-benzenesulfonyl chloride (580 mg, 2.33 mmol) in acetonitrile (5 ml) Triethylamine (0.95 ml, 7.16 mmol) and dimethylaminopyridine (10 mg, 0.08 mmol) were added. Additional acetonitrile (10 ml) was added with methylene chloride (3 ml) to aid dissolution. After 16 hours at room temperature, water (100 ml) was added and the mixture was extracted twice with ethyl acetate. The combined organic extracts were washed successively with water (3x) and brine, then dried over sodium sulfate. The residue was concentrated to give a residue (0.49 g) which was chromatographed (silica gel, using ethanol / ethyl acetate (4/96) as an eluent) to give the desired arylsulfonamide (462 mg, 66%) as a pale yellow foam.

Analysis for C ₁₉ H ₂₂ N ₂ O ₅ S 3 / 4H ₂ O

Calculated: C, 56.49; H, 5.86; N, 6.93.

Measured: C, 56.36; H, 5.88; N, 6.68.

Part D: Sodium hydroxide (10 eq.) Was added to the arylsulfonamide solution of Part C in ethanol, water and tetrahydrofuran and the solution was heated to 60 C for 24 hours. The solution was cooled, diluted with water and diluted with 10% aqueous hydrochloric acid to a pH of 3. The resulting solution was extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, and dried over magnesium sulfate to yield the desired carboxylic acid.

Part E: To a solution of the carboxylic acid of Part D in N, N-dimethylformamide was added 4-methylmorpholine (6.0 equivalents), N-hydroxybenzotriazole (1.2 equivalents) and 1- [3- ) Propyl] -3-ethylcarbodiimide hydrochloride (1.3 eq.) Was added followed by O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (1.3 eq.). After stirring for 2 days at room temperature, the solution was concentrated. Water was added and the mixture was extracted with ethyl acetate. The organic extracts were washed with water and brine, and dried over sodium sulfate. Concentrated to give a residue which was chromatographed (silica, ethyl acetate / hexane (20/80 to 90/10) as an eluent) to give the THP protected hydroxamate derivative.

Part F: To a solution of THP protected hydroxamate of Part E in 1,4-dioxane was added 4N HCl in 1,4-dioxane (10 eq) and the solution was stirred at room temperature for 3 h. Concentration to give a residue which was triturated with diethyl ether to give the title compound.

Example 22: Synthesis of N-hydroxy-2,3-dimethoxy-6- [[4 - [(2'-methoxy [1,1'-biphenyl] -4- &Lt; / RTI &gt; yl] sulfonyl] benzamide

Part A: To a solution of N-BOC-4-hydroxypiperidine (25 mmol, 5.0 g) in 1-methyl-2-pyrrolidinone (20 ml) was added sodium hydride (26 mmol, 1.01 g) Was added. The reaction mixture was stirred at room temperature for 15 minutes and then heated to 65 &lt; 0 &gt; C for 30 minutes. Bromo-4-fluorobenzene (25 mmol, 4.38 g) was added and the solution was heated at 120 &lt; 0 &gt; C for 24 hours. The reaction mixture was cooled to room temperature, diluted with water (100 ml) and extracted with ethyl acetate (150 ml). The organic layer was washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo to an oil which was purified by passing through a pad of silica and eluted with ethyl acetate. 7.28 g (82%) was obtained.

MS calculated for C ₁₆ H ₂₂ NO ₃ Br: 356, found: 356.

Part B: To a solution of Part A bromide (20 mmol, 7.2 g) in dioxane (20 ml) was added 4N HCl (50 ml). The solution was stirred for 2 hours at room temperature and then concentrated to give a solid. The solid was triturated with diethyl ether to give the desired piperidine hydrochloride (5.8 g, 99%).

Part C: To a solution of 3,4-dimethoxybenzenesulfonyl chloride (18mmol, 4.26g) in acetonitrile (75ml) was added the hydrochloride of Part B (20mmol, 5.8g) followed by triethylamine (36mmol, 7.5 ml) and N, N-dimethylaminopyridine (100 mg) were added. The solution was stirred at room temperature for 75 hours. The mixture was diluted with water (200 ml) and extracted with ethyl acetate (300 ml). The ethyl acetate layer was washed with brine (100 ml) and dried over magnesium sulfate. Concentration followed by chromatography (hexane: ethyl acetate = 1: 1) gave the desired sulfonamide (5.45 g, 66%) as a solid.

C ₁₉ H ₂₂ BrNSO ₅ MS Calcd: 456, measurements: 456.

Part D: Tetrakis (triphenylphosphine) palladium (0) (0.375 g, 0.325 mmol) was added to a solution of Part C compound (2.96 g, 6.49 mmol) in ethylene glycol dimethyl ether (30 ml) Was added. After stirring for 5 minutes, 2-methoxyphenylboronic acid (1.18 g, 7.79 mmol) was added followed by a solution of sodium carbonate (0.954 g, 9.00 mmol) in water (18 ml). The mixture was refluxed for 1.5 hours and then stirred at room temperature overnight (about 18 hours). The mixture was diluted with water (50 ml) and extracted with methylene chloride (50 ml). The solution was filtered through a silica bed and concentrated in vacuo to give a black solid. Chromatography (silica phase, acetone / hexane) gave biphenyl (2.69 g, yield: 86%) as a white solid.

Analysis for C ₂₆ H ₂₉ NO ₆ S

Calculated: C, 64.58; H, 6.04; N, 2.90; S, 6.63.

Measured: C, 64.30; H, 6.16; N, 2.86; S, 6.90.

C ₂₂ H ₂₉ NO MS for ₆ S (EI) MH ⁺ calculated: 484, measurements: 484.

Part E: To a solution of biphenyl (2.85 g, 5.89 mmol) in Part D in THF (80 ml) was added a solution of 1.6 M n-butyllithium in hexane (5.17 ml, 8.27 mmol) under nitrogen atmosphere at -80 < . After stirring for 30 minutes at room temperature, the solution was cooled to -80 &lt; 0 &gt; C and carbon dioxide was bubbled into the solution for 7 minutes. The solution was diluted with 1N HCl (50 ml) and extracted with ethyl acetate (3 x 50 ml). The organic layer was washed with water (2 × 50ml) and brine (50ml), dried over MgSO ₄ and concentrated under vacuum to a tan solid carboxylic acid (3.00g, yield: 96%) was obtained.

Analysis for C ₂₇ H ₂₉ NO ₈ S

Calculated: C, 61.47; H, 5.54; N, 2.65; S, 6.08.

Measured: C, 61.46; H, 5.94; N, 2.48; S, 5.70.

MS (EI) MH &lt; ⁺ & gt ^; calculated for C ₂₇ H ₂₉ NO ₈ S: 528, found: 528.

Part F: Oxalyl chloride (4.07 ml, 46.7 mmol) was added to a solution of the carboxylic acid of Part E (2.92 g, 5.53 mmol) and DMF (2 drops, catalytic) in 1,2-dichloroethane . After stirring at room temperature under a nitrogen atmosphere for 1.5 hours, the solution was concentrated in vacuo to give a yellow oil. To this oil was added N-methylmorpholine (1.57 ml, 14.2 mmol), O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (1.66 g, 14.2 mmol) and 1,2- Was added. After stirring at room temperature under a nitrogen atmosphere for about 20 hours, the mixture was diluted with water (150 ml) and extracted with ethyl acetate (3 x 50 ml). The organic layer was washed with 1N HCl (50 ml), saturated NaHCO ₃ (50 ml), water (50 ml) and brine (50 ml), dried over MgSO ₄ and concentrated in vacuo to give a tan solid. Chromatography (silica phase, ethyl acetate / hexane) gave O-protected hydroxamate (2.41 g, yield 69%) as a white solid.

_{C 32 H 38 N 2 MS (} EI) for O ₉ S MH ⁺ calculated: 627, measurements: 627.

Part G: O-protected hydroxamate (2.39 g, 3.81 mmol) of Part F was added to a solution of acetyl chloride (2.61 ml, 38.1 mmol) in MeOH (39 ml) and stirred at room temperature under a nitrogen atmosphere for 1.5 h . The solution was concentrated, triturated with ether, concentrated and dried to give a white solid. To give the: Chromatography (silica phase, MeOH / CHCl ₃₎ to the title compound (1.36g 66%, yield) as a white solid.

Analysis for C ₂₇ H ₃₀ N ₂ O ₈ S

Calculated: C, 59.77; H, 5.57; N, 5.16; S, 5.91.

Measured: C, 57.60; H, 5.17; N, 5.04; S, 5.67.

MS (EI) MH &lt; ⁺ & gt ^; calculated for C ₂₇ H ₃₀ N ₂ O ₈ S: 543.

Example 23: N-Hydroxy-2- (2-methoxy-ethoxy) -6 - [[4- [4- (trifluoromethyl) -phenoxy] -1- piperidinyl] sulfonyl] Preparation of benzamide

To a solution of 1 - [(3-fluorophenyl) -sulfonyl] -4- [4 (trifluoromethyl) phenoxy] piperidine (7.00 g, 17.4 mmol), 60% sodium hydride (1.13 g, 28.2 mmol) and 2-methoxy-1-ethanol (2.19 mL, 27.7 mmol) was heated at 120 <0> C for 5 h. The solution was diluted with water (300 mL) and extracted with ethyl acetate (3 x 100 mL). After drying the organic layer was washed with water and MgSO ₄ (2 x lOOml) and brine (100 mL), and concentrated in vacuo to give a brown paste. Recrystallization from methyl tert-butyl ether / hexane gave the ether (6.59 g, 83% yield) as a white solid. The proton NMR spectrum was consistent with the target ether.

Part B: To a solution of the ether of Part A (6.59 g, 14.3 mmol) in THF (120 mL) at -10 <0> C was added a 1.7 M solution of t-butyllithium in pentane (16.8 mL, 26.8 mmol) under a nitrogen atmosphere. After stirring for 30 min at-60 C the carbon dioxide was bubbled through the solution for 7 min and then the resulting solution was poured into a solution of 1 N HCl (100 mL) and water (500 mL), then ethyl acetate (3 x 100 mL). The organic layer was dried with MgSO ₄ and washed with 1N HCl (100 mL), water (2 x lOO mL) and brine (100 mL), and concentrated under vacuum. By this chromatography (ethyl / MeOH / CHC1 ₃₎ to give the carboxylic acid (4.67g, 64% yield) as a yellow oil;

Analysis for C ₂₂ H ₂₄ NO ₇ F ₃ S

Calculated: C, 52.48; H, 4.80; N, 2.78; S, 6.37.

Measured: C, 52.49; H, 4.70; N, 2.69; S, 6.31.

_{C 22 H 24 NO 7 F 3} MS (EI) MH + calculated for the S 504, the measurements 504.

Part C: Oxalyl chloride (8.03 mL, 92.0 mmol) was added to a solution of the carboxylic acid of Part B (5.45 g, 10.8 mmol) and DMF (4 drops, catalytic) in dichloromethane (99 mL). After stirring at room temperature for 2 hours, the solution was concentrated in vacuo to give a dark brown mixture. To this mixture was added N methyl morpholine (4.76 mL, 43.3 mmol), O- (tetrahydro 2H-pyran-2-yl) hydroxylamine (5.07 g, 43.3 mmol) and dichloromethane (77 mL). After stirring for about 4 hours at room temperature, the solution was obtained with water, 1.0 N HC1, saturated NaHCO _3, dried over MgSO ₄ and washed with water and brine, and concentrated to a paste under vacuum. This was chromatographed (silica phase, MeOH / ethyl acetate) to give 0-protected hydroxamate (5.23 g, 80% yield) as a pink solid.

Analysis for C ₂₇ H ₃₃ N ₂ O ₈ F ₃ S

Calculated: C, 53.81; H, 5.52; N, 4.65; S, 5.32.

Measured: C, 53.67; H, 5.43; N, 4.77; S, 5.17.

MS (EI) MH &lt; + &gt; calculated for C ₂₇ H ₃₃ N ₂ O ₈ F ₃ S 603, found 603.

Part D: A solution of acetyl chloride (5.90 mL, 86.3 mmol) in MEOH (89 mL) was added to the O-protected hydroxamate of Part C (5.20 g, 8.63 mmol) and stirred at room temperature for 3 hours. The resulting solution was concentrated and triturated with ether and then concentrated to give an off-white solid. This was chromatographed (silica phase, MeOH / methylene chloride) to give the title compound (2.25 g, 50% yield) as a white solid.

Analysis for C ₂₂ H ₂₅ N ₂ O ₇ S

Calculated: C, 50. 96; 4.86; N, 5.40; S, 6.18.

Measured: C, 50.57; H, 4.91; N, 5.37; S, 6. 08.

_{C 22 H 25 N 2 0 7} S of MS (El) MH + calculated 519, 519 measurements.

Example 24: Preparation of N-hydroxy-2,3-dimethoxy-6 - [[4- (phenylthio) -1-piperidinyl] -sulfonyl] benzamide

Part A: 4- Hydroxypiperidine (55 mmol, 5.56 g) was diluted with acetonitrile (100 mL), triethylamine (55 mmol, 7.7 mL) and N, N-dimethylaminopyridine . 3,4-dimethoxy-benzenesulfonyl chloride (50 mmol, 11.84 g) was added. The mixture was stirred overnight (about 18 hours) and then concentrated by rotary evaporation. The residue was diluted with water (100 mL) and extracted with dichloromethane (2 X 15 mL). The combined organic phases were dried using magnesium sulfate, filtered through a silica plug, and concentrated to give the desired alcohol (7.31 g, 51%) as a foam.

Part B: Alcohol from Part A (6.39 g, 22.4 mmol) was combined with methylene chloride (65 mL) and triethylamine (3.46 mL, 25 mmol). The solution was cooled to 0 &lt; 0 &gt; C. Methanesulfonyl chloride (1.79 mL, 23 mmol) was added. The reaction was stirred at room temperature for 4 hours, then further diluted with methylene chloride to 150 ml and washed with water (2 X 25 mL). The organic phase was dried over magnesium sulfate and filtered through silica and concentrated to give mesylate (3.51 g, 41%) as a white solid.

Part C: A 60% sodium hydroxide solution in mineral oil (324 mg, 8.1 mmol) was washed with hexane. The washed hydride was immersed in N, N-dimethylformamide (12 mL) and cooled to 0 占 폚. Thiophenol (0.83 mL, 8.1 mmol) was added and the resulting mixture was stirred for 20 min. The solid mesylate from Part B (3.0 g, 7.9 mmol) was added. Mesylate transitions were performed slowly at room temperature; The reaction was allowed to warm to 55 &lt; 0 &gt; C for 3 hours. Separation purification work involves azeotropic removal of DMF with toluene followed by chromatography of the residue to give 1.45 g (44%) of sulfide as a white foam.

Part D: The sulfide was dissolved in tetrahydrofuran (24 mL) and cooled to 0 &lt; 0 &gt; C. t-BuLi (1.7 M in pentane, 4.1 mL) was added over 1 minute. After 15 minutes, the reaction was cooled with carbon dioxide gas. After 10 min, the mixture was acidified with concentrated HCl, then concentrated and chromatographed to give the desired acid (1.067 g, 70%) as a foam.

Part E: The acid from Part C was diluted with methylene chloride (15 mL). After 3 drops of N, N-dimethylformamide was added, oxalyl chloride (0.35 ml, 4 mmol) was added. The reaction was stirred at room temperature for 2 hours and then concentrated. The crude acid chloride was added to a mixture of tetrahydropyranylhydroxylamine (0.47 g, 4 mmol), pyridine (0.47 ml, 6 mmol) and acetonitrile (3 mL) using about 3 mL of methylene chloride. The mixture was stirred overnight (about 18 hours) and then aqueous extracted (50 mL methylene chloride / 50 mL water). The organic phase was dried and concentrated with magnesium sulfate and then chromatographed to give 0-THP hydroxamate (619 mg) as a foam.

0-THP hydroxamate (614 mg) was diluted with dry methanol (20 mL). Acetyl chloride (0.6 mL, 8 mmol) was added. After 1 hour, the mixture was concentrated and chromatographed to give the desired hydroxamate (428 mg, 31%) as a foam. _{C 2O H 24 N 2 0 6} MS (EI) MH + calculated for S _2: 453, 453 measurements.

The following analogs were prepared in good yield using a similar procedure.

Example 25: 6 - [[4 - [(3'-Dimethoxy [1,1'-biphenyl] -4-yl) -1- piperidinyl] sulfonyl] -N- Dimethoxybenzamide

_{C 28 H 32 N 2 0 9} S MS (El) MH + calculated 573, the measurements 573 for the.

Example 26: Synthesis of N-hydroxy-2,3-dimethoxy-6- [[4- [4- (trifluoromethyl) phenyl] -1- piperazinyl] sulfonyl] benzamide

_{C 20 H 22 F 3 N 3} MS (EI) calculated for 0 ₆ S: 490, 490 measurements.

Example 27: Synthesis of N-hydroxy-2,3-dimethoxy-6 - [[4 - [[3 '- (trifluoromethyl) [1,1'- 1-piperidinyl] sulfonyl] benzamide

MS (El) calculated for C ₂₇ H ₂₇ F ₃ N ₂ O ₇ S: 581, found 581.

Example 28: Synthesis of 6 - [[4- (1,1'-biphenyl) -4-yloxy) -1-piperidinyl] sulfonyl] -N-hydroxy-2,3-dimethoxybenzamide

Example 29: Preparation of 2 - [[4- (2,3-dihydro-2-oxo-1H-benzimidazol- 1 -yl) -1-piperidinyl] -sulfonyl] -N-

_{C l9 H 20 N 4 0 5} MS (El) calculated for S: 417, 417 measurements.

Example 30: Synthesis of 2,3-dihydro-N-hydroxy-6 - [(4-methoxy- 1 -piperidinyl) sulfonyl] -1,4-benzodioxine-

_{C 15 H 20 N 2 MS (} EI) calculated for 0 ₇ S: 372, 373 measurements.

Example 31: 2,3-Dihydro-N-hydroxy-6 - [[4- [4- (trifluoromethyl) phenoxy- 1 -piperidinyl] sulfonyl-1,4-benzodioxine -5-carboxamide

_{2l 2l} F ₃ N ₂ H C MS (EI) calculated for 0 ₇ S: 502, 503 measurements.

Example 32: 2,5-Dichloro-N-hydroxy-4 - [[4- {4- (trifluoromethyl) phenoxy] -1-piperidinyl] sulfonyl] mid

Example 33: Synthesis of N-hydroxy-2,3-dimethoxy-6- [[4- (4- (trifluoromethoxy) phenoxy] -1-piperidinyl] sulfonylbenzamide

Example 34: Synthesis of N-hydroxy-2,3-dimethoxy-6- [[4- (2-methoxyphenoxy) -1-piperidinyl] -sulfonyl]

Analysis for C _2l H ₁₆ N ₂ O ₈ S

Calculated: C, 50.07; H, 5.62; N, 6.00.

Measured: C, 53.77; H, 5.64; N, 5.79.

Example 35: N-Hydroxy-3,6-dimethoxy-2 - [[4- (trifluoromethyl) phenoxy] -1-piperidinyl] sulfonyl] benzamide

Example 36: Synthesis of N-Hydroxyl-5 - [[4- [4- (trifluoromethyl) -phenoxy-1-piperidinyl] sulfonyl-1,3-benzodioxole-

_L9 H ₂₀ F ₃ N ₂ C MS (EI) calculated for 0 ₇ S: 489, 489 measurements.

Example 37: 6 - [[4 - [(2 ', 5'-Dimethoxy [1,1'-biphenyl] -4-yl) oxy] -1- piperidinyl] sulfonyl] Hydroxy-2,3-dimethoxybenzamide

Analysis for C ₂₈ H ₃₂ N ₂ 0 ₉ S

Calculated: C, 58.73; H, 5.63; N, 4.89.

Measured: C, 58.55; H, 5.82; N, 4.81.

Example 38: N-Hydroxy-2,3-dimethoxy-6 - [[4 - [[2 '- (trifluoromethyl) [1,1'- 1-piperidinyl] sulfonyl] benzamide.

Analysis for C ₂₇ H ₂₇ F ₃ N ₂ O ₇ S

Calculated. C, 55.86; H, 4.69; N, 4.83.

Measured: C, 55.77; H, 4.75; N, 4.77.

Example 39: N-Hydroxy-2,3-dimethoxy-6 - [[4 - [[2 '- (trifluoromethyl) [1,1'- 1-piperidinyl] sulfonyl] benzamide.

Analysis for Circular C ₃₀ H ₃₆ N ₂ 0 ₈ S

Calculated: C, 61.63; H, 6.21; N, 4.79.

Measured: C, 61.36; H, 6.29; N, 4.64.

Example 40: Synthesis of 6 - [[4 - [(2'-ethoxy [1,1-biphenyll-4- yl) oxy- 1 -piperidinyl] sulfonyl] -N- - dimethoxybenzamide

Analysis for C ₂₈ H ₃₂ N ₂ O ₈ S

Calculated: C, 60.42; H, 5.79; N, 5.03.

Measured: C, 60.30; H, 5.94; N, 4.88.

Example 41: N-Hydroxy-2,3-dimethoxy-6- [[4- (4-methoxyphenyl) -1-piperazinyl] sulfonyl] -benzamide, monohydrochloride

_{C 20 H 25 N 3 0 7} S MS (EI) for (free base) MH + calculated 452, 452 measurements.

Example 42: N-Hydroxyl-2 - [[4- (2-pyridinyloxy) -1-piperidinyl] sulfonyl] benzamide, monohydrochloride

_{C 17 H 19 N 3 0 7} S MS (EI) for (free base) MH + calculated 378, 378 measurements.

Example 43: 5 - [(4-Butoxy-1-piperidinyl) sulfonyl] -N-hydroxy-1,3-benzodioxole-4-carboxamide

Analysis for C ₁₇ H ₂₄ N ₂ O ₇ S

Calculated: C, 50.99; H, 6.04; N, 7.00.

Measured: C, 50.97; H, 6.27; N, 6.88.

Example 44: 5 - [(4-heptyloxy-1-piperidinyl) sulfonyl] -N-hydroxy-1,3-benzodioxole-4-carboxamide

Analysis for C ₂₀ H ₃₀ N ₂ O ₇ S

Calculated: C, 54.28; H, 6.33; N, 6.33.

Measured: C, 53.91; H, 7.10; N, 6.25.

Example 45: N-Hydroxy-2,3-dimethoxy-6 - [[4- (4-methoxyphenoxy- 1 -piperidinyl] -sulfonyl]

Analysis for C ₂₁ H ₂₆ N ₂ O ₈ S

Calculated: C, 54.07; H, 5.62; N, 6.00.

Measured: C, 53.69; H, 5.87; N, 5.79.

Example 46: 6 - [[4- (4-Chlorophenoxy) -1-piperidinyl] -sulfonyl] -N-hydroxy-2,3-dimethoxybenzamide

Analysis for C ₂₀ H ₂₃ ClN ₂ O ₈ S

Calculated: C, 51.01; H, 4.92; N, 5.95.

Measured: C, 50.62; H, 4.93; N, 5.92.

Example 47: N-Hydroxy-2,3-dimethoxy-6 - [(4-phenoxy-1-piperidinyl) sulfonyl] benzamide

₂₀ H ₂₄ N ₂ C MS (El) calculated for 0 ₇ S: 436, 437 measurements.

Example 48: Synthesis of N-hydroxy-2 - [(tetrahydro-2H-pyran-4-yl) oxy] -6 - [[4- (trifluoromethyl) phenoxy] Phenyl] benzamide

Analysis for C ₂₄ H ₂₇ F ₃ N ₂ O ₇ S

Calculated: C, 52.94; H, 5.00; N, 5.14.

Measured: C, 52.64; H, 4.92; N, 5.02.

Example 49: Synthesis of 5 - [[4 - ((1,3-benzodioxol-5-yloxy) -1-piperidinyl] sulfonyl] -N- 4-carboxamide

Example 50: Synthesis of 6 - [[4- (1,3-benzodioxol-5-yloxy) -1-piperidinyl] sulfonyl] -N-hydroxy-2,3-dimethoxybenzamide

_2l H ₂₄ N ₂ C MS (EI) calculated for 0 ₉ S: 481, 481 measurements.

Example 51: Synthesis of 2 - [(4-benzoyl-1-piperazinyl) sulfonyl] -N-hydroxybenzamide

_{C 18 H 19 N 3 MS (} EI) for 0 ₅ S MH + calculated: 390, 390 measurements.

Example 52: Synthesis of N-hydroxy-2,3-dimethoxy-6- [[4- (phenylmethyl) -1-piperazinyl] sulfonyl] -benzamide, monohydrochloride

_{C 20 H 25 N 3 0 6} S MS (El) MH + calculated 436, the measurements 436 for the (free base).

Example 53: Synthesis of N-hydroxy-2,3-dimethoxy-6- [[4- [[4- (trifluoromethoxy) phenyl] methyl] -1- piperazinyl] sulfonyl] Hydrochloride

_{C 21 H 24 F 3 N 3} 0 7 MS (El) for S MH + calculated: 520, 520 measurements.

Example 54: 6 - [[4- (4-Butoxyphenoxy) -1-piperidinyl] -sulfonyl] -N-hydroxy-2,3-dimethoxybenzamide

₂₄ H ₃₂ N ₂ C MS (El) for 0 ₈ S MH + calculated: 509, 509 measurements.

Example 55: Synthesis of N-hydroxy-2 - [[4- (4-pyridinyloxy) -1-piperidinyl] sulfonyl] benzamide, monohydrochloride

_{C 17 H l9 N 3 0 5} S MS (EI) for (free base) MH + calculated 378, 378 measurements.

Example 56: Synthesis of 6 - [[4- (4-butoxy-3-methylphenyl) -1-piperazinyl] sulfonyl] -N-hydroxy-2,3-dimethoxybenzamide, monohydrochloride

_{C 24 H 33 N 3 0 7} S MS (EI) for (free base) MH + calculated 508, 508 measurements.

Example 57: Synthesis of N-hydroxy-2,3-dimethoxy-6- [[4- (3-methoxyphenoxy- 1 -piperidinyl] sulfonyl] benzamide

Analysis for C ₂₁ H ₂₆ N ₂ O ₈ S

Calculated: C, 54.07; H, 5.62; N, 6.00.

Measured: C, 53.77; H, 5.64; N, 5.79.

Example 58: In vitro metalloprotease inhibition

The activity of the compounds prepared in the manner described in the above examples was analyzed by in vitro analysis. Knight et al. , FEBS Lett. 296 (3) : 263 (1992). Briefly, 4-aminophenylmercylacetate (APMA) or trypsin-activated MMP was incubated with various concentrations of inhibitor compounds for 5 minutes at room temperature.

More specifically, recombinant human MMP-13, MMP-1 and MMP-2 enzymes were prepared in transfection laboratories according to conventional laboratory methods. MMP-13 from a CDNA clone of full length was prepared as described in VA Luckow, Insect Cell Expression Technology, p. 183-218, Protein Engineering: Principles and Practice , JLCleland et al., Wiley-Liss, And expressed with pro-enzyme using baculovirus as discussed. For more information on the use of the baculovirus expression system, see Luckow et al., J. Virol., 67: 4566-4579 (1993); O'Reilly et al., Baculovirus Expression Vectors: A Laboratory Manual , WH Freeman and Company, New York, (1992); and King et al., The Baculovirus Expression System: A Laboratory Guide , Chapman & Hall, London (1992). The expressed enzyme was first purified on a heparin agarose column and then purified on a chelated zinc chloride column. Pro-enzymes were activated by APMA and used for analysis.

MMP-1 expressed in transfected HT-1080 cells was provided by Dr. Harold Welgus of the University of Washington (St. Louis, Mo.). The enzyme was also activated using APMA and then purified on a hydroxamic acid column. Dr. Wells also provided transfected HT-1080 cells expressing MMP-9. Transfected cells expressing MMP-2 were also provided by Dr. Gregory Goldberg of the University of Washington. Studies conducted using MMP-2 in the presence of 0.02% 2-mercaptoethanol are marked with an asterisk in the table below. Further features of the preparation and use of such enzymes can be found in the scientific literature in which such enzymes are described. See, for example, Enzyme Nomenclature , Academic Press, San Diego, Ca (1992) and the citations contained therein, and Frije et al., J. Biol. Chem., 26 (24) : 16766-16773 (1994).

The enzyme substrate is a polypeptide of the following sequence containing methoxy coumarin: MCA-ProLeuGlyLeuDpaAlaArgNH ₂ , wherein MCA is methoxy coumarin and Dpa is 3- (2,4-dinitrophenyl) -L-2,3- Diaminopropionyl alanine. This substrate is commercially available as M-1895 from Baychem.

The buffer used for the analysis are contained lauryl ether La 100mM Tris-HCl, 100 mM NaCl , 10 mM CaCl 2 and 0.05 percent polyethyleneglycol (23) to pH 7.5. Analysis was performed at room temperature and dimethylsulfoxide (DMSO) was used at a final concentration of 1% to dissolve the inhibitor compound.

The inhibitor compounds analyzed in DMSO / buffer solution were compared using an equal volume of DMSO / buffer without inhibitor and Microfluor ^TM White Plates (Dynatech) as controls. The inhibitor or control solution was kept on the plate for 10 minutes, and the substrate was added to give a final concentration of 4 [mu] M.

In the absence of inhibitor activity, the fluorescence-generating peptide was cleaved at the gly-leu peptide bond to separate the high-fluorescent peptide from the 2,4-dinitrophenyl quenched to increase the fluorescence intensity (excitation at 328 nm / 415 nm). Inhibition ratios were measured using a Perkin Elmer L55O plate reader as a decrease in fluorescence intensity as a function of inhibitor concentration. An IC _5O values were calculated from the above values. The results are shown in the following inhibition ratios Tables A and B, where appropriate, expressed as IC ₅₀ for three important characteristics.

[Inhibition rate table A]

[Inhibition Ratio Table B]

Example 59: Angiogenesis analysis

Angiogenesis studies are dependent on a reliable and reproducible model for stimulation and inhibition of angiogenic responses. Corneal micropocket analysis provides such an angiogenic model in the cornea of mice. Reference: A Model of Angiogenesis in the Mouse Cornea ; Kenyon, BM, et al., Investigative Ophthalmology & Visual Science, July 1996, Vol. 37, No. 8.

In this assay, uniform sized Hydron ^TM pellets containing bFGF and sucralate were prepared and surgically implanted into the stromal mouse cornea near the temporal limbus. The pellet was formed by making a suspension of 20 μL of sterile saline containing 10 μg of recombinant bFGF in ethanol, 10 mg of sucralfate and 10 μL of 12% Hydron ^™ . The slurry was then attached to a 10 x 10 mm piece of sterile nylon body. After drying, the nylon fibers of the sieve were separated to release the pellets.

Corneal pockets were obtained by anesthetizing 7 week old C57BI / 6 female mice and then projecting the eyeball with a Jewler forceps. Using a dissecting microscope, a 15-mm surgical knife was used to insert a linear corneal incision of about 0.6 mm in length into the lateral rectus muscle parallel to the lateral rectus muscle. Using a modified cataract knife, laminated micropockets were cut in the direction of the temporal limbus. The pocket extends within 1.0 mm of the temporal limbus. The single pellet was placed on the corneal surface of the pocket bottom with a glazing forceps. Then, the pellet was pulled up to the terminal end of the pocket. Antibiotic ointment was then applied to the eye.

Until the end of the analysis, daily doses were administered daily to the mice. The dose of animal can be determined based on bioavailability and the overall effectiveness of the compound, for example, when the dose is 50 mg / kg bid, po. Respectively. The angiogenesis of ocular stroma began approximately 3 days and continued until the 5th day under the influence of analytical compounds. On the fifth day, the extent of angiogenesis inhibition was evaluated by observing the progress of angiogenesis with a slit lamp microscope.

The mice were anesthetized and the studied eyeballs were once again projected. The maximum blood vessel length of angiogenesis from the limbus blood gun to the pellet was measured. In addition, the proximal periphery zone of angiogenesis was measured as time, in which the arc 30 degrees was expressed in 1 hour. The neovascularization zone was calculated as follows:

The mice studied later recorded differences in angiogenic regions compared to control mice. The known compounds typically exhibited inhibition of about 25% to about 75%, while the control group showed 0% inhibition.

It will be appreciated that many modifications and variations can be made without departing from the spirit and scope of the novel concept of the invention. It is not intended that the scope be limited or intended to the specific embodiments shown. The disclosure is intended to include such modifications as fall within the scope of the claims.

Claims (118)

A compound corresponding to formula C or a pharmaceutically acceptable salt thereof: &Lt; RTI ID = 0.0 & Wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring; R ¹ is selected from the group consisting of (i) a 5-membered or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical directly bonded to the SO ₂ - group described above and having a longer length than the approximately hexyl group, Is a short substituent, and R ¹ is an axial chain connecting the 1-position of SO ₂ - bond and the 4-position of the 6-membered ring radical or an axis connecting the 1-position of SO ₂ - , Wherein the widest volume in the transverse direction of the axis of rotation is the volume of about one furyl ring to about the volume of two phenyl rings; R ⁵ and R ⁶ is Hi give also, alkyl, cycloalkyl, acyl alkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, halo, alkyloxy, hydroxy-alkyl, R ^b R ^c aminoalkyl substituent, a thiol , alkylthio, arylthio, cyclo alkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclo-oxy, and R ^b R ^c aminoalkyl is independently selected from the group consisting of aryloxy substituents; Or R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring; R ²⁰ is selected from the group consisting of: (a) -O-R ^{21 wherein} R ²¹ is selected from hydrido, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl groups and pharmaceutically acceptable cations (B) -NR ¹³ -0-R ²² , wherein R ^{22 is an} optionally removable protecting group, R ¹³ is a hydrido, C ₁ -C ₆ -alkyl or benzyl group, ( c) -NR ¹³ -0-R ¹⁴ wherein R ¹³ is as defined above and R ¹⁴ is hydrido, a pharmaceutically acceptable cation or C (V) R ¹⁵ , wherein V is 0 or S And R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, heteroaryl-C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl , aryloxy, aralkyl, -C _l -C ₆ - alkoxy, aralkyl, -C _l -C ₆ - alkyl, heteroaryl and amino-C _l -C ₆ - alkyl group (wherein, an amino C _l -C ₆ - alkyl nitrogen is ( i) unsubstituted or (ii) C _l -C ₆ - alkyl, aryl, aralkyl, -C _l -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aralkyl, -C _l - C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkoxycar Carbonyl, and C ₁ -C ₆ - or substituted from the group consisting of alkanoyl radical with one or two substituents independently selected, or (iii) amino-C _l -C ₆ - alkyl nitrogen and two substituents attached to it a Membered heterocycle or heteroaryl ring), or (d) -NR ²³ R ^{24 wherein} R ²³ and R ²⁴ are independently selected from the group consisting of hydrido, C ₁ -C ₆ -alkyl, amino C ₁ -C ₆ -alkyl, hydroxy C ₁ -C ₆ -alkyl, aryl and ar-C ₁ -C ₆ -alkyl groups, or R &lt; ²³ &gt; and R &lt; ²⁴ &gt; together with the above-mentioned nitrogen atom are 0, or a 5- to 8-membered ring containing one additional heteroatom which is oxygen, nitrogen or sulfur; Wherein R ^b and R ^c are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl Heteroarylthioalkyl, arylsulfonyl, aryl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, Alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, , Arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, Wherein the amino nitrogen is independently selected from the group consisting of (i) unsubstituted or (ii) one or two R ^d radicals independently selected from the group consisting of hydrogen, the substituents on the amino group taken together with the amino nitrogen, R ^d substituents independently selected from one, two, or three groups optionally substituted saturated or partially unsaturated heterocycloalkyl group or R ^f substituents independently of the selected one, two, or three from from Lt; / RTI &gt; independently of one another, form a heteroaryl group optionally substituted by a group; R ^d and R ^e are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl and arylalkyloxycarbonyl groups ; R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano and R ^d R ^e amino groups. The compound of claim 1, wherein R ¹ is selected from the group consisting of (i) R ⁷ and R ⁸ are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted aryl hydrocarbyl -NR ⁷ R ⁸ group, or (ii) R ⁷ and R ⁸ are Hi give also, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R ^a oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, Alkyl, heteroaryl, heteroarylalkyl, and heterocyclo substituents, wherein each substituent is an -NR <^7> R <^8> group optionally substituted with a -AREY substituent; In the above-A-R-E-Y substituents, A is selected from the group consisting of: (1) -O-; (2) -S-; (3) -NR &lt; ^k &gt;-; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k ) - or -N (R ^k ) -CS-; (13) -CH ₂ -; (14) -0-CH ₂ - or -CH ₂ -0-; (15) -S-CH ₂ - or -CH ₂ -S-; (16) -SO-; And (17) -SO ₂ -; or (18) A is a member, R is directly bonded to R ⁷ or R ⁸ , or both R ⁷ and R ⁸ ; R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituents are either (i) unsubstituted or (ii) halo Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, Substituted by one or two radicals selected from the group consisting of halogen, cyano, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl groups. Lt; / RTI &gt; E group is selected from the group consisting of: (1) -COR ^g - or - R ^g CO-; (2) -CON (R ^k ) - or - (R ^k ) NCO-; (3) -CO-; (4) -SO ₂ R ^g - or -R ^g SO ₂ -; (5) -SO ₂ -; And (6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -; or (7) E is a member, R is directly bonded to Y; The Y moiety is either absent or substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, (Wherein R &^lt; 1 &gt; is a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkyl group, a cycloalkyl group, a cycloalkyl group, The heteroaryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted by one or more of (i) unsubstituted or (ii) alkanoyl, halo, nitro, An amino group wherein the amino nitrogen is substituted with one or two groups independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) Selected from the group consisting of substituted) is a radical; or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a -GAREY group; Wherein G is an N-heterocyclo group; Substituent A is selected from the group consisting of: (1) -O-; (2) -S-; (3) -NR &lt; ^k &gt;-; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH; (9) -C C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k ) - or -N (R ^k ) -CS-; (13) -CH ₂ -; (14) -0-CH ₂ - or -CH ₂ -0-; (15) -S-CH ₂ - or -CH ₂ -S-; (16) -SO-; And (17) -SO ₂ -; or (18) A is a member, R is directly bonded to G, which is an N-heterocyclo group; R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is selected from the group consisting of (i) unsubstituted or (ii) halo (lower) alkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, 1 &lt; / RTI &gt; or 2 radicals selected from the group consisting of &lt; RTI ID = 0.0 &gt; Selected from the group consisting of substituted) to be; Part E is selected from the group consisting of: (1) -COR ^g - or - R ^g CO-; (2) -CON (R ^k ) - or - (R ^k ) NCO-; (3) -CO-; (4) -SO ₂ -R ^g - or -R ^g -SO ₂ -; (5) -SO ₂ -; And (6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -; or (7) E is a member and R is directly bonded to Y; The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more groups selected from (i) unsubstituted or (ii) alkanoyl, halo, nitro, (Wherein the amino nitrogen is substituted with one or two radicals independently selected from (i) unsubstituted or (ii) one or two groups independently selected from hydrido, alkyl, and aralkyl groups) &Lt; / RTI &gt; Wherein R ^a is selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, R ^b R ^c aminoalkanoyl, haloalkanoyl, R ^b R ^c Aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy groups; R ^g is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, Alkoxy, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ - amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, Alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R &lt; ^{h &} R ⁱ - aminocarbonyl-oxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - amino alkanoyl, hydroxy-aminocarbonyl, R ^h R ⁱ aminosulfonyl, R ^h R ⁱ - aminocarbonyl (R ^h ) amino, trifluoromethyl-sulfonyl (R ^h ) amino, heteroaryl Sulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) aminocarbonyl, alkylsulfonyl (R ^h) amino, arylcarbonyl (R ^h) aminosulfonyl, and an alkyl Sulfonyl (R ^h ) aminocarbonyl substituent; R ^h is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with a substituent of a substituted aminoalkanoyl group such as R ^j &Lt; / RTI &gt; wherein the substituent is optionally substituted with one or two groups independently selected from &lt; RTI ID = 0.0 &gt; R ⁱ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with one or two R &lt; ^j &gt; substituents; R ^j is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Alkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are alkyl, alkenyl, alkenyl, aryl, aryl Alkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl groups; R ^k is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d amino Sulfonyl, R ^c R ^d aminoalkanoyl and R ^c R ^d aminoalkylsulfonyl, or a salt thereof. The compound of claim 1, wherein R ⁵ and R ⁶ are selected from the group consisting of hydrido, hydrocarbyl, hydroxylhydrocarbyl, hydroxyl, amino, dihydrocarbylamino, heterocyclo, heterocyclohydrocarbyl, heterocycloxy , And a heterocyclothio group, or a salt thereof. 2. A compound according to claim 1, wherein said 5- or 6-membered aromatic or heteroaromatic ring W is selected from the group consisting of 1,2-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 4,5- , 2,3-pyrazinylene, 4,5-pyrimidinylene, and 5,6-pyrimidinylene group, or a salt thereof. A compound or a salt thereof according to claim 1, wherein R ²⁰ is -NR ¹³ -OR ¹⁴ . The compound or a salt thereof according to claim 1, wherein R ²⁰ is -NR ¹³ -OR ²² . A compound or a salt thereof according to claim 1, wherein said compound corresponds to the structure of formula Cl: (C1) Wherein W, R ¹ , R ⁵ , R ⁶ , R ¹³ and R ¹⁴ are as defined above. A compound or a salt thereof according to claim 1, wherein said compound corresponds to the structure of formula (C2): (C2) Wherein W, R ⁵ , R ⁶ and R ¹⁴ are as defined above and Ph is a substituent R ⁴ at its 4-position, wherein R ⁴ is a chain of 3 to about 14 carbon atoms &Lt; / RTI &gt; substituted phenyl). 9. The compound according to claim 8, wherein the R ⁴ substituent is selected from the group consisting of a phenyl group, a phenoxy group, a thiophenoxy group, an anilino group, a phenyl azo group, a phenylureido, a benzamido, a nicotinoamido, an isonicotinoamido group, The present invention also relates to the use of a compound selected from the group consisting of a heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxihydrocarbyl, But are not limited to, hydrocarbyl hydrocarbyl, hydrocarbyl hydrocarbyl, aryl hydrocarbyl hydrocarbyl, arylcarbonyl hydrocarbyl, aryl azo aryl, aryl hydrazino aryl, hydrocarbyl thio hydrocarbyl, hydrocarbyl thioaryl, aryl thio hydrocarbyl , Heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylheldocarbylthioaryl, aryl Draw hydrocarbyl amino, heteroaryl, hydrocarbyl amino, and a compound or a salt thereof, wherein is selected from the heteroaryl group consisting of thiophenyl group. 10. The compound of claim 9, wherein said R &lt; ⁴ &gt; substituent is selected from the group consisting of halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethyl-hydrocarbyl, Aryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, arylthio, arylthio, arylthio, arylthio, arylthio, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, Heterocycloalkylthio, heterocycloalkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, Heterocyclylthio, heteroaryl hydrocarbyl-amino, aryl hydrocarbyloxy, aryl hydrocarbylthio, aryl hydrocarbylamino, heterocyclic, Alkoxycarbonyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxycarboyloxy, hydroxyhydrocarbyloxy, Hydrocarbyloxy-carbonylhydrocarbyl, hydrocarbyl-hydrocarbyloxy, hydrocarbyl-hydrocarbyloxy, hydrocarbyloxy-hydrocarbyloxy, hydrocarbyloxy- Hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohexylcarbyloxycarbonylhydrocarbyloxy, Heterocyclylcarbonylamino, hydrocarbylcarbonylamino, heterocyclo-hydrocarbylcarbonylamino, arylhydrocarbyl-carbonylamino, heteroarylcarbonylamino, Arylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl-sulfonylamino, heteroarylsulfonylamino, heteroarylsulfonylamino, heteroarylaminocarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, Heterocyclohexylcarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted amino hydrocarbyl groups wherein the substituent (s) on the nitrogen is selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl Wherein the nitrogen and the two substituents attached thereto are selected from the group consisting of 5- to 8-membered carbocyclic rings, Lt; / RTI &gt; is optionally substituted by one or more substituents selected from the group consisting of halogen, Or a salt thereof. A compound or a salt thereof according to claim 1, wherein said compound corresponds to the structure of formula (D3) [Chemical formula D3] Wherein R ⁵ , R ⁶ and R ²⁰ are as defined above and R ⁴ is a substituent having a chain length of from 3 to about 14 carbon atoms. 12. The compound according to claim 11, wherein the R ⁴ substituent is selected from the group consisting of a phenyl group, a phenoxy group, a thiophenoxy group, an anilino group, a phenyl azo group, a phenylureido, a benzamido, a nicotinoamido, isonicotinoamido, Substituted or unsubstituted heterocycloalkyl groups, such as, for example, alkyl, alkenyl, cycloalkyl, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclo-hydrocarbyl, arylhydrocarbyloxyhydrocarbyl, , Hydrocarbylhydrocarbyl, hydrocarbylthiocarbyl, arylthiocarbylhydrocarbyl, arylcarbonylhydrocarbyl, arylzodoaryl, arylhydrazinoaryl, hydrocarbylthio-hydrocarbyl, hydrocarbylthioaryl, arylthio- Hydrocarbyl, hydrocarbyl, hydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbyl-thioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, Reel hydrocarbyl amino, heteroaryl, and hydrocarbyl-amino compound or a salt thereof, wherein is selected from the heteroaryl group consisting of thiophenyl group. 13. The compound of claim 12, wherein the R &lt; ⁴ &gt; substituent is itself halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethyl-hydrocarbyl, Aryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, arylthio, arylthio, arylthio, arylthio, arylthio, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, Heterocycloalkylthio, heterocycloalkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, Substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, Alkoxycarbonyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxycarboyloxy, hydroxyhydrocarbyloxy, Hydrocarbyloxy-carbonylhydrocarbyl, hydrocarbyl-hydrocarbyloxy, hydrocarbyl-hydrocarbyloxy, hydrocarbyloxy-hydrocarbyloxy, hydrocarbyloxy- Hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohexylcarbyloxycarbonylhydrocarbyloxy, Heterocyclylcarbonylamino, hydrocarbylcarbonylamino, heterocyclo-hydrocarbylcarbonylamino, arylhydrocarbyl-carbonylamino, heteroarylcarbonylamino, Arylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl-sulfonylamino, heteroarylhydrocarbylsulfonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, Heterocyclohexylcarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted amino hydrocarbyl groups wherein the substituent (s) on the nitrogen is selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl , Cyclohydrocarbyl, aryl hydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl, or nitrogen or two substituents attached thereto are selected from the group consisting of 5- to 8- Lt; / RTI &gt; is substituted by one or more substituents selected from the group consisting of hydrogen, Or a salt thereof. The compound or a salt thereof according to claim 1, wherein said compound corresponds to the structure of formula (VI-1): [Formula VI-1] Wherein each of R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ²⁰ is as defined above and A, B, C and D are each carbon, nitrogen, sulfur or oxygen, - or 6-membered). A compound corresponding to formula C4: or a pharmaceutically acceptable salt thereof: (C4) Wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring; R ¹ is a substituent containing a 5- or 6-membered cyclic hydrocarbyl, heterocyclo, aryl or heteroaryl radical directly bonded to the SO ₂ - group described above and having a length longer than the approximately hexyl group and shorter than the approximately eicosyl group and, wherein R ¹ is SO ₂ in the 6-membered ring radical - have rotated shaft coupling connecting the first position and the center of 3,4-bond coupling first position and connecting the 4-position of the shaft or a 5-membered ring radical SO ₂ , The largest volume in the transverse direction of the axis of rotation being the volume of approximately one furyl ring to the volume of approximately two phenyl rings; R ⁵ and R ⁶ is Hi give also, alkyl, cycloalkyl, acyl alkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituent, a thiol, alkylthio, arylthio, cyclo alkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclo-oxy, and R ^b R ^c aminoalkyl is independently selected from the group consisting of aryloxy substituents; Or R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring; R ^b and R ^c are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl Heteroarylthioalkyl, arylsulfonyl, aralkanoyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, Alkylthioalkyl, arylthioalkyl, alkylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, Alkenyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, amino, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, Amino nitrogen is (i) unsubstituted or (ii) is independently substituted with one or two R ^d radicals, or is amino (meth) acryloyloxy, 2, or 3 substituents independently selected from R ^f substituents, wherein the substituents on the amino group taken together with the nitrogen are selected from saturated or partially unsaturated heterocyclyl groups optionally substituted with 1, 2, or 3 groups independently selected from R ^d substituents, Lt; / RTI &gt; independently selected from the group consisting of hydrogen; R ^d and R ^e are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl and arylalkyloxycarbonyl groups Being; R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino groups. Of claim 15, wherein that the method, wherein R ¹ is substituted by a 5- or 6-membered cycloalkyl hydrocarbyl, heterocycloalkyl, aryl or heteroaryl radical having 3 to about 14 carbon atom chain length of the substituent, R ⁴ a Or a salt thereof. 17. The compound according to claim 16, wherein the R ⁴ substituent is selected from the group consisting of a phenyl group, a phenoxy group, a thiophenoxy group, an anilino group, a phenyl azo group, a phenylureido, a benzamido, a nicotinoamido, an isonicotinoamido group, The present invention also relates to the use of a compound selected from the group consisting of a heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxihydrocarbyl, The present invention relates to a process for the preparation of a compound of formula (I), wherein the compound is selected from the group consisting of hydrocarbyl hydrocarbyl, aryl hydrocarbyl hydrocarbyl, arylcarbonyl hydrocarbyl, aryl azoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, , Heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, aryl Wherein the compound is selected from the group consisting of dihydrocarbylamino, dihydrocarbylamino, dihydrohalocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio groups. 18. The compound of claim 17 wherein said R &lt; ⁴ &gt; substituent is selected from the group consisting of halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethyl-hydrocarbyl, Aryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, arylthio, arylthio, arylthio, arylthio, arylthio, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, Heterocycloalkylthio, heterocycloalkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, Heterocyclyl, carbocyclyl, hydrocarbylthio, heteroaryl hydrocarbylamino, aryl hydrocarbyloxy, aryl hydrocarbylthio, aryl hydrocarbylamino, heterocyclic, Alkoxycarbonyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxycarboyloxy, hydroxyhydrocarbyloxy, Hydrocarbyloxy-carbonylhydrocarbyl, hydrocarbyl-hydrocarbyloxy, hydrocarbyl-hydrocarbyloxy, hydrocarbyloxy-hydrocarbyloxy, hydrocarbyloxy- Hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohexylcarbyloxycarbonylhydrocarbyloxy, Heterocyclylcarbonylamino, hydrocarbylcarbonylamino, heterocyclo-hydrocarbylcarbonylamino, arylhydrocarbyl-carbonylamino, heteroarylcarbonylamino, Arylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl-sulfonylamino, heteroarylsulfonylamino, heteroarylsulfonylamino, heteroarylaminocarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, Heterocyclohexylcarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted amino hydrocarbyl groups wherein the substituent (s) on the nitrogen is selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl , Cyclohydrocarbyl, aryl hydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl, or nitrogen or two substituents attached thereto are selected from the group consisting of 5- to 8- Substituted with one or more substituents selected from the group consisting of a halogen atom, a halogen atom, a cyano group, a heterocyclic group or a heteroaryl ring group) Water or its salt. 19. The method of claim 18, wherein the R ¹ substituent is itself a group different monocyclic cycloalkyl hydrocarbyl, heterocycloalkyl, aryl or heteroaryl, C ₃ -C ₁₄ hydrocarbyl group, C ₂ -C ₁₄ hydrocarbyl group bilok A substituent selected from the group consisting of a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenyl azo group, a phenylureido group, a nicotinamido group, an isonicotinoamido group, a picolinamido group, R &lt; ^{4 &} gt ;, or a salt thereof. 20. The method of claim 19, of the R ¹ substituent is PhR ⁴ (formula, Ph is a phenyl substituted at the 4-position with R ^4, wherein R ⁴ is meta- or para-position or both halogens at the location, C ₁ -C ₉ hydrocarbyl bilok group, C ₁ -C ₁₀ hydrocarbyl group, di -C ₁ -C ₉ hydrocarbyl group, a carboxyl C ₁ -C ₈ hydrocarbyl, C ₁ -C ₄ hydrocarbyl oxycarboxylic C ₁ -C ₄ hydrocarbyl groups, C ₁ -C ₄ hydrocarbyloxycarbonyl C ₁ -C ₄ hydrocarbyl groups, and carboxamido C ₁ -C ₈ hydrocarbyl groups. Phenyl substituted with two methyl or methylenedioxy groups in the meta-or para-position, phenoxy, thiophenoxy, phenylazo, benzamido, anilino, nicotinamido, isonicotinoamido, Lt; / RTI &gt; is selected from the group consisting of pyrrolidino, The compound or a salt thereof 16. The compound or a salt thereof according to claim 15, wherein the R ¹ substituent is longer than the octyl group and shorter than the stearyl group. Claims 1. A compound corresponding to the formula (D) or a pharmaceutically acceptable salt thereof: [Chemical Formula D] Wherein each of A, B, C, and D is carbon, nitrogen, sulfur, or oxygen and the above-mentioned ring is present or absent to have a 5- or 6-membered ring; R ⁵ and R ⁶ is Hi give also, alkyl, cycloalkyl, acyl alkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituent, a thiol, alkylthio, arylthio, cyclo alkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclo-oxy, and R ^b R ^c is independently selected from the aminoalkyl consists of oxy substituted doeneungun; Or R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring; In the above-A-R-E-Y substituents, A is selected from the group consisting of: (1) -O-; (2) -S-; (3) -NR &lt; ^k &gt;-; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k ) - or -N (R ^k ) -CS-; (13) -CH ₂ -; (14) -0-CH ₂ - or -CH ₂ -0-; (15) -S-CH ₂ - or -CH ₂ -S-; (16) -SO-; And (17) -SO ₂ -; or (18) A is a member, and R is directly bonded to both rings; R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituents are either (i) unsubstituted or (ii) halo Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, Substituted with one or two radicals selected from the group consisting of halogen, cyano, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl groups) It is selected from; E group is selected from the group consisting of: (1) -COR ^g - or - R ^g CO-; (2) -CON (R ^k ) - or - (R ^k ) NCO-; (3) -CO-; (4) -SO ₂ R ^g - or -R ^g SO ₂ -; (5) -SO ₂ -; And (6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -; or (7) E is a member and R is directly bonded to Y; The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more groups selected from (i) unsubstituted or (ii) alkanoyl, halo, nitro, Wherein the amino nitrogen is substituted with one or two groups independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) Lt; / RTI &gt; is substituted with a radical; or R ^a is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, R ^b R ^c aminoalkanoyl, haloalkanoyl, R ^b R ^c aminoalkyl, Alkoxyalkyl, haloalkyl, and arylalkyloxy groups; R ^b and R ^c are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl Heteroarylthioalkyl, arylsulfonyl, aralkanoyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, Alkylthioalkyl, arylthioalkyl, alkylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, Alkenyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, amino, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, Amino nitrogen is (i) unsubstituted or (ii) is independently substituted with one or two R ^d radicals, or is amino (meth) acryloyloxy, A saturated or partially unsaturated heterocyclyl group in which the substituent on the amino group taken together with the nitrogen is optionally substituted by 1, 2, or 3 groups independently selected from R ^d substituents, or by 1, 2, or 3 groups independently selected from R ^f substituents Lt; / RTI &gt; independently of each other, form an optionally substituted heteroaryl group; R ^d and R ^e are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl and arylalkyloxycarbonyl groups Being; R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino groups; R ^g is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, Alkoxy, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ - amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, Alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R &lt; ^{h &} R ⁱ - aminocarbonyl-oxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - amino alkanoyl, hydroxy-aminocarbonyl, R ^h R ⁱ aminosulfonyl, R ^h R ⁱ - aminocarbonyl (R ^h ) amino, trifluoromethyl-sulfonyl (R ^h ) amino, heteroaryl Sulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) aminocarbonyl, alkylsulfonyl (R ^h) amino, arylcarbonyl (R ^h) aminosulfonyl, and an alkyl Sulfonyl (R ^h ) aminocarbonyl substituent; R ^h is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with a substituent of a substituted aminoalkanoyl group, such as R ^j Lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &gt; R ⁱ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with one or two R &lt; ^j &gt; substituents; R ^j is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Alkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl are alkyl, alkenyl, alkenyl, aryl, arylalkyl , Heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl groups); &lt; RTI ID = 0.0 &gt; R ^k is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d amino Sulfonyl, R ^c R ^d aminoalkanoyl and R ^c R ^d aminoalkylsulfonyl. A compound corresponding to formula VIA, or a pharmaceutically acceptable salt thereof: (VIA) Wherein R &lt; ⁴ &gt; is a substituent having a chain length of from 3 to about 14 carbon atoms; The ring structure W ² containing the above-mentioned nitrogen atom is a heterocyclic ring containing a 5- or 6-membered ring, and R ⁴ is a 4-position to the above-mentioned nitrogen atom when W ² is a 6- When W &lt; ^{2 &gt;} is a 5-membered ring, it is a substituent bonded at the 3- or 4-position to the above-mentioned nitrogen atom; R ⁵ and R ⁶ is Hi give also, alkyl, cycloalkyl, acyl alkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, halo, alkyloxy, hydroxy-alkyl, R ^b R ^c aminoalkyl substituent, a thiol , alkylthio, arylthio, cyclo alkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclo-oxy, and R ^b R ^c aminoalkyl are independently selected from the group consisting of aryloxy substituents; Or R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring; R ²⁰ is selected from the group consisting of: (a) -O-R ^{21 wherein} R ²¹ is selected from hydrido, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl groups and pharmaceutically acceptable cations (B) -NR ¹³ -0-R ²² , wherein R ²² is an optionally removable protecting group, R ¹³ is a hydrido, C ₁ -C ₆ -alkyl or benzyl group, (c) -NR ¹³ -O-R ¹⁴ wherein R ¹³ is as defined above and R ¹⁴ is hydrido, a pharmaceutically acceptable cation or C (V) R ¹⁵ , wherein V is 0 or S and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, heteroaryl-C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, Alkyl, aryloxy, ar-C ₁ -C ₆ -alkoxy, ar -C ₁ -C ₆ -alkyl, heteroaryl and amino C ₁ -C ₆ -alkyl groups wherein the amino C ₁ -C ₆ -alkyl nitrogen is i) unsubstituted or (ii) C _l -C ₆ - alkyl, aryl, aralkyl, -C _l -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aralkyl, -C _l - C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkoxycar Viterbo carbonyl, and C ₁ -C ₆ - or substituted from the group consisting of alkanoyl radical with one or two substituents independently selected, or (iii) amino-C _l -C ₆ - alkyl nitrogen and two attached to it Wherein the substituent is selected from the group consisting of a 5- to 8-membered heterocyclo or heteroaryl ring), or (d) -NR ²³ R ^{24 wherein} R ²³ and R ²⁴ are selected from the group consisting of hydrido C ₁ -C ₆ -alkyl, amino C ₁ -C ₆ -alkyl, hydroxy C ₁ -C ₆ -alkyl, aryl, and ar-C ₁ -C ₆ -alkyl groups, Or R &lt; ²³ &gt; and R &lt; ²⁴ &gt; together with the abovementioned nitrogen atoms are zero, or a 5- to 8-membered ring containing one additional heteroatom which is oxygen, nitrogen or sulfur; Wherein R ^b and R ^c are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl Heteroarylthioalkyl, arylsulfonyl, aryl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, Alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, , Arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, Of the diamino-alkyl-carbonyl, hydroxyalkyl, aminoalkyl, amino, alkylsulfonyl, aminosulfonyl (wherein the amino nitrogen is (i) unsubstituted or (ii) 1 or disubstituted independently of the other, is a single R ^d radical, or the substituents on the amino group taken together with the amino nitrogen, R ^d substituents independently selected from one, two, or three groups optionally substituted saturated or partially unsaturated heterocycloalkyl group or R ^f substituents independently of the selected one, two, or three from from Lt; / RTI &gt; independently of one another, form a heteroaryl group optionally substituted by a group; R ^d and R ^e are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl and arylalkyloxycarbonyl groups ; R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino groups. 24. The compound of claim 23, wherein the R ⁴ substituent is selected from the group consisting of a phenyl group, a phenoxy group, a thiophenoxy group, an anilino group, a phenyl azo group, a phenylureido, a benzamido, a nicotinoamido, an isonicotinoamido, The present invention also relates to the use of a compound selected from the group consisting of a heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxihydrocarbyl, The present invention relates to a process for the preparation of a compound of formula (I), wherein the compound is selected from the group consisting of hydrocarbyl hydrocarbyl, aryl hydrocarbyl hydrocarbyl, arylcarbonyl hydrocarbyl, aryl azoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, , Heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylheldocarbylthioaryl, aryl Lt; / RTI &gt; is selected from the group consisting of hydrocarbylamino, hydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio groups. 25. The compound of claim 24, wherein the R &lt; ⁴ &gt; substituent is itself halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethyl-hydrocarbyl, Aryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, arylthio, arylthio, arylthio, arylthio, arylthio, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, Heterocycloalkylthio, heterocycloalkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, Substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, Alkoxycarbonyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxycarboyloxy, hydroxyhydrocarbyloxy, Hydrocarbyloxy-carbonylhydrocarbyl, hydrocarbyl-hydrocarbyloxy, hydrocarbyl-hydrocarbyloxy, hydrocarbyloxy-hydrocarbyloxy, hydrocarbyloxy- Hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohexylcarbyloxycarbonylhydrocarbyloxy, Heterocyclylcarbonylamino, hydrocarbylcarbonylamino, heterocyclo-hydrocarbylcarbonylamino, arylhydrocarbyl-carbonylamino, heteroarylcarbonylamino, Arylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl-sulfonylamino, heteroarylsulfonylamino, heteroarylsulfonylamino, heteroarylaminocarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, Heterocyclohexylcarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted amino hydrocarbyl groups wherein the substituent (s) on the nitrogen is selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl , Cyclohydrocarbyl, aryl hydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl, or nitrogen or two substituents attached thereto are selected from the group consisting of 5- to 8- Lt; RTI ID = 0.0 &gt; R &lt; / RTI &gt; is substituted by at least one substituent selected from the group consisting of Compound or a salt thereof. 24. The method of claim 23, wherein R ²⁰ is -NR ¹³ -OR compound or a salt thereof, characterized in that ^14. 27. The compound of claim 26, wherein R &lt; ¹³ &gt; is hydrido or a salt thereof. 24. The method of claim 23 wherein the compound or salt thereof according to the above R ²⁰ is characterized in that -NR ¹³ -OR ^22. A compound according to claim 28, wherein R ¹³ is hydrido, R ²² is 2-tetrahydropyranyl, benzyl, p-methoxybenzyl, C ₁ -C ₆ -alkoxycarbonyl, A nitrophenyl group, and a peptide synthetic resin wherein said trisubstituted silyl group is substituted by C ₁ -C ₆ -alkyl, aryl, or ar-C ₁ -C ₆ -alkyl groups or mixtures thereof. Or a salt thereof. 24. A compound or a salt thereof according to claim 23, wherein said compound corresponds to the structure of formula VIA-1: [Chemical Formula VIA-1] Or a pharmaceutically acceptable salt thereof, wherein R &lt; 1 &gt; [Formula VIIC] [Wherein, R ⁵ and R ⁶ is Hi give also, alkyl, cycloalkyl, acyl alkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, R ^b R ^c aminoalkyl Wherein R is selected from the group consisting of alkyl, alkoxy, alkoxy, perfluoroalkyl, haloalkyl, heterocycloxy and R ^b R ^c aminoalkyloxy substituents; Or R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring; The ring structure W ² containing the above-mentioned nitrogen atom is a heterocyclic ring containing a 5- or 6-membered ring, and the substituent AREY is, when W ² is a 6-membered ring, at the 4-position to the above- And when W &lt; ² &gt; is a 5-membered ring at the 3- or 4-position to the above-mentioned nitrogen atom; In the above-A-R-E-Y substituents, A is selected from the group consisting of: (1) -O-; (2) -S-; (3) -NR &lt; ^k &gt;-; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k ) - or -N (R ^k ) -CS-; (13) -CH ₂ -; (14) -0-CH ₂ - or -CH ₂ -0-; (15) -S-CH ₂ - or -CH ₂ -S-; (16) -SO-; And (17) -SO ₂ -; or (18) A is a member, R is directly bonded to ring structure W ² ; R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituents are either (i) unsubstituted or (ii) halo Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, Substituted by one or two radicals selected from the group consisting of halogen, cyano, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl groups. Lt; / RTI &gt; E group is selected from the group consisting of: (1) -COR ^g - or - R ^g CO-; (2) -CON (R ^k ) - or - (R ^k ) NCO-; (3) -CO-; (4) -SO ₂ R ^g - or -R ^g SO ₂ -; (5) -SO ₂ -; And (6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -; or (7) E is a member and R is directly bonded to Y; The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more groups selected from (i) unsubstituted or (ii) alkanoyl, halo, nitro, Wherein the amino nitrogen is substituted with one or two groups independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) Lt; / RTI &gt; is substituted with a radical; R ^a is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, R ^b R ^c aminoalkanoyl, haloalkanoyl, R ^b R ^c aminoalkyl, Alkoxyalkyl, haloalkyl, and arylalkyloxy groups; R ^b and R ^c are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl Heteroarylthioalkyl, arylsulfonyl, aralkanoyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, Alkylthioalkyl, arylthioalkyl, alkylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, Alkenyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, amino, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, Amino nitrogen is (i) unsubstituted or (ii) is independently substituted with one or two R ^d radicals, or is amino (meth) acryloyloxy, A saturated or partially unsaturated heterocyclyl group in which the substituent on the amino group taken together with the nitrogen is optionally substituted by 1, 2, or 3 groups independently selected from R ^d substituents, or by 1, 2, or 3 groups independently selected from R ^f substituents Lt; / RTI &gt; independently of each other, form an optionally substituted heteroaryl group; R ^d and R ^e are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl and arylalkyloxycarbonyl groups ; R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino groups; R ^g is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, Alkoxy, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ - amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, Alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R &lt; ^{h &} R ⁱ - aminocarbonyl-oxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - amino alkanoyl, hydroxy-aminocarbonyl, R ^h R ⁱ aminosulfonyl, R ^h R ⁱ - aminocarbonyl (R ^h ) amino, trifluoromethyl-sulfonyl (R ^h ) amino, heteroaryl Sulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) aminocarbonyl, alkylsulfonyl (R ^h) amino, arylcarbonyl (R ^h) aminosulfonyl, and an alkyl Sulfonyl (R ^h ) aminocarbonyl substituent; R ^h is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with a substituent of a substituted aminoalkanoyl group, such as R ^j Lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &gt; R ⁱ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with one or two R &lt; ^j &gt; substituents; R ^j is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Alkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl are alkyl, alkenyl, alkenyl, aryl, arylalkyl , Heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl groups); &lt; RTI ID = 0.0 &gt; R ^k is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d amino Sulfonyl, R ^c R ^d aminoalkanoyl and R ^c R ^d aminoalkylsulfonyl. A compound corresponding to formula (VIIB): or a pharmaceutically acceptable salt thereof: [Formula VIIB] Wherein R ⁵ and R ⁶ are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c amino alkyl substituent, thiol, alkylthio, arylthio, cyclo alkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclo-oxy, and R ^b R ^c aminoalkyl is independently selected from the group consisting of aryloxy substituents ; Or R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring; G is an N-heterocyclo group; Substituent A is selected from the group consisting of: (1) -O-; (2) -S-; (3) -NR &lt; ^k &gt;-; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k ) - or -N (R ^k ) -CS-; (13) -CH ₂ -; (14) -0-CH ₂ - or -CH ₂ -0-; (15) -S-CH ₂ - or -CH ₂ -S-; (16) -SO-; And (17) -SO ₂ -; or (18) A is a member, R is an N-heterocyclo group, directly bonded to G; R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is selected from the group consisting of (i) unsubstituted or (ii) halo (lower) alkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, 1 &lt; / RTI &gt; or 2 radicals selected from the group consisting of &lt; RTI ID = 0.0 &gt; Selected from the group consisting of substituted) as being; Part E is selected from the group consisting of: (1) -COR ^g - or - R ^g CO-; (2) -CON (R ^k ) - or - (R ^k ) NCO-; (3) -CO-; (4) -SO ₂ -R ^g - or -R ^g -SO ₂ -; (5) -SO ₂ -; And (6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -; or (7) E is a member, R is directly bonded to Y; And The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more groups selected from (i) unsubstituted or (ii) alkanoyl, halo, nitro, (Wherein the amino nitrogen is substituted with one or two radicals independently selected from (i) unsubstituted or (ii) one or two groups independently selected from hydrido, alkyl, and aralkyl groups) &Lt; / RTI &gt; Wherein R ^a is selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, R ^b R ^c aminoalkanoyl, haloalkanoyl, R ^b R ^c Aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy groups; R ^b and R ^c are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl Heteroarylthioalkyl, arylsulfonyl, aralkanoyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, Alkylthioalkyl, arylthioalkyl, alkylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, Alkenyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, amino, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, Amino nitrogen is (i) unsubstituted or (ii) is independently substituted with one or two R ^d radicals, or is amino (meth) acryloyloxy, A saturated or partially unsaturated heterocyclyl group in which the substituent on the amino group taken together with the nitrogen is optionally substituted by 1, 2, or 3 groups independently selected from R ^d substituents, or by 1, 2, or 3 groups independently selected from R ^f substituents Lt; / RTI &gt; independently from each other are selected from the group consisting of hydrogen; R ^d and R ^e are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl and arylalkyloxycarbonyl groups Being; R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino groups; R ^g is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, Alkoxy, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ - amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, Alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R &lt; ^{h &} R ⁱ - aminocarbonyl-oxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - amino alkanoyl, hydroxy-aminocarbonyl, R ^h R ⁱ aminosulfonyl, R ^h R ⁱ - aminocarbonyl (R ^h ) amino, trifluoromethyl-sulfonyl (R ^h ) amino, heteroaryl Sulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) aminocarbonyl, alkylsulfonyl (R ^h) amino, arylcarbonyl (R ^h) aminosulfonyl, and an alkyl Sulfonyl (R ^h ) aminocarbonyl substituent; R ^h is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with a substituent of a substituted aminoalkanoyl group, such as R ^j &Lt; / RTI &gt; wherein the substituent is optionally substituted with one or two groups independently selected from &lt; RTI ID = 0.0 &gt; R ⁱ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with one or two R &lt; ^j &gt; substituents; R ^j is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Alkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl are alkyl, alkenyl, alkenyl, aryl, arylalkyl , Heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl groups); &lt; RTI ID = 0.0 &gt; R ^k is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d amino Sulfonyl, R ^c R ^d aminoalkanoyl and R ^c R ^d aminoalkylsulfonyl. 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound is of the formula &Lt; / RTI &gt; or a salt thereof: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound is of the formula &Lt; / RTI &gt; or a salt thereof: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: &lt; EMI ID = 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: 33. The compound of claim 32, wherein said compound corresponds to the formula: A compound corresponding to formula VIIE, or a pharmaceutically acceptable salt thereof: (VIIE) Wherein R ⁵ and R ⁶ are selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c amino alkyl substituent, thiol, alkylthio, arylthio, cyclo alkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclo-oxy, and R ^b R ^c aminoalkyl is independently selected from the group consisting of aryloxy substituents ; Or R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring; G is an N-heterocyclo group; Substituent A is selected from the group consisting of: (1) -O-; (2) -S-; (3) -NR &lt; ^k &gt;-; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k ) - or -N (R ^k ) -CS-; (13) -CH ₂ -; (14) -0-CH ₂ - or -CH ₂ -0-; (15) -S-CH ₂ - or -CH ₂ -S-; (16) -SO-; And (17) -SO ₂ -; or (18) A is a member, R is an N-heterocyclo group, directly bonded to G; R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is selected from the group consisting of (i) unsubstituted or (ii) halo (lower) alkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, 1 &lt; / RTI &gt; or 2 radicals selected from the group consisting of &lt; RTI ID = 0.0 &gt; Selected from the group consisting of substituted) as being; Part E is selected from the group consisting of: (1) -COR ^g - or - R ^g CO-; (2) -CON (R ^k ) - or - (R ^k ) NCO-; (3) -CO-; (4) -SO ₂ -R ^g - or -R ^g -SO ₂ -; (5) -SO ₂ -; (6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -; or (7) E is a member, R is directly bonded to Y; And The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more groups selected from (i) unsubstituted or (ii) alkanoyl, halo, nitro, (Wherein the amino nitrogen is substituted with one or two groups independently selected from the group consisting of (i) unsubstituted or (ii) hydrido, alkyl, and aralkyl groups) Lt; / RTI &gt; is substituted with a radical; Wherein R ^a is selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, R ^b R ^c aminoalkanoyl, haloalkanoyl, R ^b R ^c Aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy groups; R ^b and R ^c are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl Heteroarylthioalkyl, arylsulfonyl, aralkanoyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, Alkylthioalkyl, arylthioalkyl, alkylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, Alkenyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, amino, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, Amino nitrogen is (i) unsubstituted or (ii) is independently substituted with one or two R ^d radicals, or is amino (meth) acryloyloxy, A saturated or partially unsaturated heterocyclyl group in which the substituent on the amino group taken together with the nitrogen is optionally substituted by 1, 2, or 3 groups independently selected from R ^d substituents, or by 1, 2, or 3 groups independently selected from R ^f substituents Lt; / RTI &gt; independently of each other, form an optionally substituted heteroaryl group; R ^d and R ^e are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl and arylalkyloxycarbonyl groups ; R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino groups; R ^g is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, Alkoxy, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ - amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, Alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R &lt; ^{h &} R ⁱ - aminocarbonyl-oxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - amino alkanoyl, hydroxy-aminocarbonyl, R ^h R ⁱ aminosulfonyl, R ^h R ⁱ - aminocarbonyl (R ^h ) amino, trifluoromethyl-sulfonyl (R ^h ) amino, heteroaryl Sulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) aminocarbonyl, alkylsulfonyl (R ^h) amino, arylcarbonyl (R ^h) aminosulfonyl, and an alkyl Sulfonyl (R ^h ) aminocarbonyl substituent; R ^h is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with a substituent of a substituted aminoalkanoyl group, such as R ^j Lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &gt; R ⁱ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with one or two R &lt; ^j &gt; substituents; R ^j is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Alkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are alkyl, alkenyl, alkenyl, aryl, aryl Alkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl groups; R ^k is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d amino Sulfonyl, R ^c R ^d aminoalkanoyl and R ^c R ^d aminoalkylsulfonyl. 87. The compound of claim 86, wherein said compound is of the formula: 87. The compound of claim 86, wherein said compound is of the formula: 87. The compound of claim 86, wherein said compound is of the formula: 87. The compound of claim 86, wherein said compound is of the formula: 87. The compound of claim 86, wherein said compound is of the formula: 87. The compound of claim 86, wherein said compound is of the formula: 87. The compound of claim 86, wherein said compound is of the formula: 87. The compound of claim 86, wherein said compound is of the formula: 87. The compound of claim 86, wherein said compound is of the formula: 87. The compound of claim 86, wherein said compound is of the formula: 87. The compound of claim 86, wherein said compound is of the formula: 87. The compound of claim 86, wherein said compound is of the formula: 87. The compound of claim 86, wherein said compound is of the formula: Comprising administering to a mammalian recipient a compound corresponding to the structure of formula &lt; RTI ID = 0.0 &gt; (C) &lt; / RTI &gt; or a pharmaceutically acceptable salt thereof as a mammalian recipient having a condition associated with pathological matrix metalloprotease activity in an MMP enzyme- Methods of treating recipient mammals with conditions associated with activity: &Lt; RTI ID = 0.0 & Wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring; R ¹ is selected from the group consisting of (i) a 5- or 6-membered cyclic hydrocarbyl, heterocyclo, aryl, or heteroaryl radical directly bonded to the SO ₂ - group described above and having a longer length than the approximately hexyl group, Is a short substituent, and R ¹ is an axial connecting the 1-position of the SO ₂ -bond of the 6-membered ring to the 4-position or an axis connecting the 1-position of the SO ₂ - bond and the center of the 3,4- , Wherein the widest volume in the transverse direction of the axis of rotation is the volume of about one furyl ring to about the volume of two phenyl rings; R ⁵ and R ⁶ is Hi give also, alkyl, cycloalkyl, acyl alkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, halo, alkyloxy, hydroxy-alkyl, R ^b R ^c aminoalkyl substituent, a thiol , alkylthio, arylthio, cyclo alkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclo-oxy, and R ^b R ^c aminoalkyl is independently selected from the group consisting of aryloxy substituents; Or R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring; R ²⁰ is selected from: (a) -O-R ^{21 wherein} R ²¹ is selected from: hydrido, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl and a pharmaceutically acceptable cation (B) -NR ¹³ -0-R ²² , wherein R ²² is an optionally removable protecting group, R ¹³ is a hydrido, C ₁ -C ₆ -alkyl or benzyl group, (c) -NR ¹³ -O-R ¹⁴ wherein R ¹³ is as defined above and R ¹⁴ is hydrido, a pharmaceutically acceptable cation or C (V) R ¹⁵ , wherein V is 0 or S and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, heteroaryl-C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, Alkyl, aryloxy, ar-C ₁ -C ₆ -alkoxy, ar -C ₁ -C ₆ -alkyl, heteroaryl and amino C ₁ -C ₆ -alkyl groups wherein the amino C ₁ -C ₆ -alkyl nitrogen is (i) unsubstituted or (ii) C _l -C ₆ - alkyl, aryl, aralkyl, -C _l -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl, -C ₁ -C ₆ - alkyl, aralkyl, -C _l -C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkoxy car Carbonyl, and C ₁ -C ₆ - alkynyl or substituted from the group consisting of alkanoyl radical with 1 or 2 substituents independently selected, or (iii) amino-C _l -C ₆ - alkyl nitrogen and two substituents attached there to the 5- to 8-membered heterocyclo or heteroaryl ring), or (d) -NR ²³ R ^{24 wherein} R ²³ and R ²⁴ are selected from the group consisting of hydrido, C _l -C ₆ - alkyl, amino, C _l -C ₆ - alkyl, hydroxy C _l -C ₆ - alkyl, aryl, and aralkyl -C _l -C ₆ - independently selected from the group consisting of an alkyl group, or R ²³ and R &lt; ²⁴ &gt; together with the nitrogen atom described above form 0- or a 5- to 8-membered ring containing one additional heteroatom which is oxygen, nitrogen or sulfur; Wherein R ^b and R ^c are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl Heteroarylthioalkyl, arylsulfonyl, aryl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, Alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, alkylthioalkyl, , Arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, Of the diamino-alkyl-carbonyl, hydroxyalkyl, aminoalkyl, amino, alkylsulfonyl, aminosulfonyl (wherein the amino nitrogen is (i) unsubstituted or (ii) 1 or disubstituted independently of the other, is a single R ^d radical, or the substituents on the amino group taken together with the amino nitrogen, R ^d substituents independently selected from one, two, or three groups optionally substituted saturated or partially unsaturated heterocycloalkyl group or R ^f substituents independently of the selected one, two, or three from from Lt; / RTI &gt; independently of one another, form a heteroaryl group optionally substituted by a group; R ^d and R ^e are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl and arylalkyloxycarbonyl groups ; R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino groups. Wherein R ¹ is selected from the group consisting of (i) R ⁷ and R ⁸ independently of the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted aryl hydrocarbyl selected -NR ⁷ R ⁸ group, or (ii) R ⁷ and R ⁸ are Hi give also, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R ^a oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl , Arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclo substituents, wherein each substituent is an -NR <^7> R <^8> group optionally substituted with a -AREY substituent; In the above-A-R-E-Y substituents, A is selected from the group consisting of: (1) -O-; (2) -S-; (3) -NR &lt; ^k &gt;-; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k ) - or -N (R ^k ) -CS-; (13) -CH ₂ -; (14) -0-CH ₂ - or -CH ₂ -0-; (15) -S-CH ₂ - or -CH ₂ -S-; (16) -SO-; And (17) -SO ₂ -; or (18) A is a member, R is directly bonded to R ⁷ or R ⁸ , or both R ⁷ and R ⁸ ; R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituents are either (i) unsubstituted or (ii) halo Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, Substituted by one or two radicals selected from the group consisting of halogen, cyano, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl groups. Lt; / RTI &gt; E group is selected from the group consisting of: (1) -COR ^g - or - R ^g CO-; (2) -CON (R ^k ) - or - (R ^k ) NCO-; (3) -CO-; (4) -SO ₂ R ^g - or -R ^g SO ₂ -; (5) -SO ₂ -; And (6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -; or (7) E is a member, R is directly bonded to Y; The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more groups selected from (i) unsubstituted or (ii) alkanoyl, halo, nitro, Wherein the amino nitrogen is substituted with one or two groups independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) Lt; / RTI &gt; is substituted with a radical; or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a -GAREY group; Wherein G is an N-heterocyclo group; Substituent A is selected from the group consisting of: (1) -O-; (2) -S-; (3) -NR &lt; ^k &gt;-; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k ) - or -N (R ^k ) -CS-; (13) -CH ₂ -; (14) -0-CH ₂ - or -CH ₂ -0-; (15) -S-CH ₂ - or -CH ₂ -S-; (16) -SO-; And (17) -SO ₂ -; or (18) A is a member, R is directly bonded to G, which is an N-heterocyclo group; R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is selected from the group consisting of (i) unsubstituted or (ii) halo (lower) alkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, 1 &lt; / RTI &gt; or 2 radicals selected from the group consisting of &lt; RTI ID = 0.0 &gt; Selected from the group consisting of substituted) as being; Part E is selected from the group consisting of: (1) -COR ^g - or - R ^g CO-; (2) -CON (R ^k ) - or - (R ^k ) NCO-; (3) -CO-; (4) -SO ₂ -R ^g - or -R ^g -SO ₂ -; (5) -SO ₂ -; (6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -; or (7) E is a member, R is directly bonded to Y; The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more groups selected from (i) unsubstituted or (ii) alkanoyl, halo, nitro, (Wherein the amino nitrogen is substituted with one or two radicals independently selected from (i) unsubstituted or (ii) one or two groups independently selected from hydrido, alkyl, and aralkyl groups) &Lt; / RTI &gt; R ^a is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, R ^b R ^c aminoalkanoyl, haloalkanoyl, R ^b R ^c aminoalkyl, Alkoxyalkyl, haloalkyl, and arylalkyloxy groups; R ^g is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, Alkoxy, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ - amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, Alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R &lt; ^{h &} R ⁱ - aminocarbonyl-oxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - amino alkanoyl, hydroxy-aminocarbonyl, R ^h R ⁱ aminosulfonyl, R ^h R ⁱ - aminocarbonyl (R ^h ) amino, trifluoromethyl-sulfonyl (R ^h ) amino, heteroaryl Sulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) aminocarbonyl, alkylsulfonyl (R ^h) amino, arylcarbonyl (R ^h) aminosulfonyl, and an alkyl Sulfonyl (R ^h ) aminocarbonyl substituent; R ^h is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with a substituent of a substituted aminoalkanoyl group, such as R ^j Lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &gt; R ⁱ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, Substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups, each of which is optionally substituted with one or two R &lt; ^j &gt; substituents; R ^j is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Alkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl are alkyl, alkenyl, alkenyl, aryl, arylalkyl , Heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl groups); &lt; RTI ID = 0.0 &gt; R ^k is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d amino Sulfonyl, R ^c R ^d aminoalkanoyl and R ^c R ^d aminoalkylsulfonyl. 104. The method of claim 100, wherein said compound corresponds to the structure of formula Cl: (C1) Wherein W, R ¹ , R ⁵ , R ⁶ , R ¹³ and R ¹⁴ are as defined above. 102. The method of claim 100, wherein said compound corresponds to the structure of formula C2: (C2) [Wherein, W, R ^5, R ⁶ and R ¹⁴ are the same as defined above, Ph is a substituent of R ⁴ (formula in their 4-position, R ⁴ is a chain of 3 to about 14 carbon atoms &Lt; / RTI &gt; substituted phenyl). Wherein said R ⁴ substituent is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenyl azo, phenylureido, The present invention also relates to the use of a compound selected from the group consisting of a heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxihydrocarbyl, The present invention relates to a process for the preparation of a compound of formula (I), wherein the compound is selected from the group consisting of hydrocarbyl hydrocarbyl, aryl hydrocarbyl hydrocarbyl, arylcarbonyl hydrocarbyl, aryl azoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, , Heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhyrdocarbylthioaryl, Reel hydrocarbyl amino, heteroaryl, hydrocarbyl amino, and wherein is selected from the heteroaryl group consisting of thiophenyl group. The method of claim 104, wherein the R ⁴ substituent is itself a halogen, hydrocarbyl, hydrocarbyl oxy, nitro, cyano, perfluoro hydrocarbyl, trifluoromethyl-hydrocarbyl, hydroxy, MER Aryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, aryloxy, arylthio, arylamino, arylheterocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, , Heterocycloalkoxy, heteroarylhydrocarbyloxy, heteroarylhydrocarbyloxy, heteroarylhydrocarbyloxy, heteroarylhydrocarbyloxy, heteroarylhydrocarbyloxy, heteroarylhydrocarbyloxy, heteroarylhydrocarbyloxy, Alkylthio groups, alkylthio groups, alkylthio groups, alkylthio groups, alkylthio groups, alkylthio groups, alkylthio groups, alkylthio groups, alkylthio groups, Alkylcarbonyloxy, arylcarbonyloxy, arylhydrocarbyloxy, hydroxycarbonyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, Hydrocarbyloxy-carbonylhydrocarbyl, hydrocarbyl-hydrocarbyloxy, hydrocarbyl-hydrocarbyloxy, hydrocarbyloxy-hydrocarbyloxy, hydrocarbyloxy- Hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohexylcarbyloxycarbonylhydrocarbyloxy, Heterocyclylcarbonylamino, heterocyclyl-hydrocarbylcarbonylamino, arylhydrocarbyl-carbonylamino, heteroarylcarbonylamino, he Arylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl-sulfonylamino, heteroarylsulfonylamino, heteroarylsulfonylamino, heteroarylaminocarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, Heterocyclohexylcarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted amino hydrocarbyl groups wherein the substituent (s) on the nitrogen is selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl Wherein the nitrogen and the two substituents attached thereto are selected from the group consisting of 5- to 8-membered carbocyclic rings, Lt; / RTI &gt; is substituted by at least one substituent selected from the group consisting of a heterocyclic or heteroaryl ring group) . 104. The method of claim 100, wherein said compound corresponds to the structure of formula &lt; RTI ID = 0.0 &gt; D4: [Chemical formula D4] Wherein R ⁵ and R ⁶ are as defined above and R ⁴ is a substituent having a chain length of from 3 to about 14 carbon atoms. The method of claim 106, wherein the R ⁴ substituent is selected from the group consisting of a phenyl group, a phenoxy group, a thiophenoxy group, an anilino group, a phenyl azo group, a phenylureido, a benzamido, a nicotinoamido, an isonicotinoamido group, The present invention also relates to the use of a compound selected from the group consisting of a heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxihydrocarbyl, The present invention relates to a process for the preparation of a compound of formula (I), wherein the compound is selected from the group consisting of hydrocarbyl hydrocarbyl, aryl hydrocarbyl hydrocarbyl, arylcarbonyl hydrocarbyl, aryl azoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, , Heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhyrdocarbylthioaryl, Reel hydrocarbyl amino, heteroaryl, hydrocarbyl amino, and wherein is selected from the heteroaryl group consisting of thiophenyl group. The method of claim 107, wherein the R ⁴ substituent is itself a halogen, hydrocarbyl, hydrocarbyl oxy, nitro, cyano, perfluoro hydrocarbyl, trifluoromethyl-hydrocarbyl, hydroxy, MER Aryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, arylthio, arylthio, arylthio, arylthio, arylthio, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, Heterocycloalkylthio, heterocycloalkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, Substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, Alkoxycarbonyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxycarboyloxy, hydroxyhydrocarbyloxy, Hydrocarbyloxy-carbonylhydrocarbyl, hydrocarbyl-hydrocarbyloxy, hydrocarbyl-hydrocarbyloxy, hydrocarbyloxy-hydrocarbyloxy, hydrocarbyloxy- Hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohexylcarbyloxycarbonylhydrocarbyloxy, Heterocyclylcarbonylamino, hydrocarbylcarbonylamino, heterocyclo-hydrocarbylcarbonylamino, arylhydrocarbyl-carbonylamino, heteroarylcarbonylamino, Arylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl-sulfonylamino, heteroarylhydrocarbylsulfonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, Heterocyclohexylcarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted amino hydrocarbyl groups wherein the substituent (s) on the nitrogen is selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl , Cyclohydrocarbyl, aryl hydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl, or nitrogen or two substituents attached thereto are selected from the group consisting of 5- to 8- Lt; / RTI &gt; is substituted by one or more substituents selected from the group consisting of hydrogen, How to. 104. The method of claim 100, wherein the R &lt; ¹ &gt; substituent is longer than the octyl group and shorter than the stearyl group. 104. The method of claim 100, wherein the compound or salt thereof is administered in multiple doses. A compound corresponding to the structure of formula VIB-2 or a pharmaceutically acceptable salt thereof is administered to a mammalian recipient having a condition associated with pathological matrix metalloprotease activity in an MMP enzyme-inhibiting effective amount. Methods of treating recipient mammals with conditions associated with protease activity: [Formula VIB-2] Wherein R ⁵ and R ⁶ are selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c amino alkyl substituent, thiol, alkylthio, arylthio, cyclo alkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclo-oxy, and R ^b R ^c aminoalkyl is independently selected from the group consisting of aryloxy substituents ; Or R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring; Wherein R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R ^a oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Heterocyclic substituents, each substituent being optionally substituted with -AR &lt; 110 &gt;substituents; In the above-A-R-E-Y substituents, A is selected from the group consisting of: (1) -O-; (2) -S-; (3) -NR &lt; ^k &gt;-; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k ) - or -N (R ^k ) -CS-; (13) -CH ₂ -; (14) -0-CH ₂ - or -CH ₂ -0-; (15) -S-CH ₂ - or -CH ₂ -S-; (16) -SO-; And (17) -SO ₂ -; or (18) A is a member, R is directly bonded to R ⁷ or R ⁸ , or both R ⁷ and R ⁸ ; R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Cycloalkyl, thioalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituents are either (i) unsubstituted or (ii) halo Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, Substituted by one or two radicals selected from the group consisting of halogen, cyano, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl groups. ) It is selected from the group consisting of; E group is selected from the group consisting of: (1) -COR ^g - or - R ^g CO-; (2) -CON (R ^k ) - or - (R ^k ) NCO-; (3) -CO-; (4) -SO ₂ R ^g - or -R ^g SO ₂ -; (5) -SO ₂ -; And (6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -; or (7) E is a member and R is directly bonded to Y; The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with at least one substituent selected from the group consisting of (i) unsubstituted or (ii) alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, Nitrogen is substituted with one or two radicals independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) It is selected from the group that are generated; or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a -GAREY group; G is an N-heterocyclo group; Substituent A is selected from the group consisting of: (1) -O-; (2) -S-; (3) -NR &lt; ^k &gt;-; (4) -CO-N (R ^k ) or -N (R ^k ) -C-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k ) - or -N (R ^k ) -CS-; (13) -CH ₂ -; (14) -0-CH ₂ - or -CH ₂ -0-; (15) -S-CH ₂ - or -CH ₂ -S-; (16) -SO-; And (17) -SO ₂ -; or (18) A is a member, R is directly bonded to G, which is an N-heterocyclo group; R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is selected from the group consisting of (i) unsubstituted or (ii) halo (lower) alkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, 1 &lt; / RTI &gt; or 2 radicals selected from the group consisting of &lt; RTI ID = 0.0 &gt; Selected from the group consisting of substituted) as being; Part E is selected from the group consisting of: (1) -COR ^g - or - R ^g CO-; (2) -CON (R ^k ) - or - (R ^k ) NCO-; (3) -CO-; (4) -SO ₂ -R ^g - or -R ^g -SO ₂ -; (5) -SO ₂ -; And (6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -; or (7) E is a member and R is directly bonded to Y; The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more groups selected from (i) unsubstituted or (ii) alkanoyl, halo, nitro, (Wherein the amino nitrogen is substituted with one or two radicals independently selected from (i) unsubstituted or (ii) one or two groups independently selected from hydrido, alkyl, and aralkyl groups) ), &Lt; / RTI &gt; R ^a is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, R ^b R ^c aminoalkanoyl, haloalkanoyl, R ^b R ^c aminoalkyl, Alkoxyalkyl, haloalkyl, and arylalkyloxy groups; R ^b and R ^c are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl Heteroarylthioalkyl, arylsulfonyl, aralkanoyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, Alkylthioalkyl, arylthioalkyl, alkylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, Alkenyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, amino, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, Amino nitrogen is (i) unsubstituted or (ii) is independently substituted with one or two R ^d radicals, or is amino (meth) acryloyloxy, 2, or 3 substituents independently selected from R ^f substituents, wherein the substituents on the amino group taken together with the nitrogen are selected from saturated or partially unsaturated heterocyclyl groups optionally substituted with 1, 2, or 3 groups independently selected from R ^d substituents, Lt; / RTI &gt; independently selected from the group consisting of hydrogen; R ^d and R ^e are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl and arylalkyloxycarbonyl groups Being; R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino groups; R ^g is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, Alkoxy, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ - amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, Alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R &lt; ^{h &} R ⁱ - aminocarbonyl-oxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - amino alkanoyl, hydroxy-aminocarbonyl, R ^h R ⁱ aminosulfonyl, R ^h R ⁱ - aminocarbonyl (R ^h) amino, trifluoromethyl sulfonyl (R ^h) amino, heteroaryl Sulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) aminocarbonyl, alkylsulfonyl (R ^h) amino, arylcarbonyl (R ^h) aminosulfonyl, and alkylsulfonyl (R &lt; ^h &gt;) aminocarbonyl substituent; R ^h is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with a substituent of a substituted aminoalkanoyl group, such as R ^j Lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &gt; R ⁱ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with one or two R &lt; ^j &gt; substituents; R ^j is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Alkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl are alkyl, alkenyl, alkenyl, aryl, arylalkyl , Heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl groups); &lt; RTI ID = 0.0 &gt; R ^k is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d amino Sulfonyl, R ^c R ^d aminoalkanoyl and R ^c R ^d aminoalkylsulfonyl. 111. The method of claim 111, wherein said compound corresponds to the structure of formula VIB-3. [Formula VIB-3] 111. The method of claim 111, wherein said compound corresponds to the structure of formula VIII or VIII-B. (VIII) [Formula VIII-B] The method of claim 111, wherein NR ⁷ R ⁸ substituents of length longer than octyl, characterized in that the length is shorter than the stearyl group. The method of claim 114, wherein the method is characterized in that the NR ⁷ R ⁸ is a substituent -GAREY. 111. The method of claim 111, wherein said compound or salt thereof is administered in multiple doses. A pathological matrix metalloprotease activity comprising administration of a compound corresponding to the structure of formula (VIIB) or a pharmaceutically acceptable salt thereof to a mammalian recipient having a condition associated with pathological matrix metalloprotease activity at an MMP enzyme-inhibiting effective amount A method of treating a recipient mammal having a condition associated with: [Formula VIIB] Wherein R ⁵ and R ⁶ are selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c amino alkyl substituent, thiol, alkylthio, arylthio, cyclo alkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclo-oxy, and R ^b R ^c aminoalkyl is independently selected from the group consisting of aryloxy substituents ; Or R &lt; ⁵ &gt; and R &lt; ⁶ &gt; together with the atoms to which they are attached form an additional 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic ring; In the substituent -G-A-R-E-Y, G is an N-heterocyclo group; Substituent A is selected from the group consisting of: (1) -O-; (2) -S-; (3) -NR &lt; ^k &gt;-; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k ) - or -N (R ^k ) -CS-; (13) -CH ₂ -; (14) -0-CH ₂ - or -CH ₂ -0-; (15) -S-CH ₂ - or -CH ₂ -S-; (16) -SO-; And (17) -SO ₂ -; or (18) A is a member, R is directly bonded to G, which is an N-heterocyclo group; R moiety is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is selected from the group consisting of (i) unsubstituted or (ii) halo (lower) alkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkenedioxy, hydroxycarbonylalkyl, 1 &lt; / RTI &gt; or 2 radicals selected from the group consisting of &lt; RTI ID = 0.0 &gt; Selected from the group consisting of substituted) as being; E group is selected from the group consisting of: (1) -COR ^g - or - R ^g CO-; (2) -CON (R ^k ) - or - (R ^k ) NCO-; (3) -CO-; (4) -SO ₂ R ^g - or -R ^g SO ₂ -; (5) -SO ₂ -; (6) -N (R ^k ) -SO ₂ - or -SO ₂ -N (R ^k ) -; or (7) E is a member, R is directly bonded to Y; The Y moiety is either absent or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkylene, perfluoro alkoxy, perfluoro alkylthio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group (wherein the aryl, heteroaryl, The aryl, aralkyl or heterocycloalkyl group may be unsubstituted or substituted with one or more groups selected from (i) unsubstituted or (ii) alkanoyl, halo, nitro, Wherein the amino nitrogen is substituted with one or two groups independently selected from the group consisting of (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and aralkyl groups) Lt; / RTI &gt; is substituted with a radical; Wherein R ^a is selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, R ^b R ^c aminoalkanoyl, haloalkanoyl, R ^b R ^c Aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy groups; R ^b and R ^c are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl Heteroarylthioalkyl, arylsulfonyl, aralkanoyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heteroarylthioalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, Alkylthioalkyl, arylthioalkyl, alkylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, alkylthioalkyl, arylthioalkyl, arylthioalkyl, arylthioalkyl, Alkenyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, amino, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, Kill-carbonyl, hydroxyalkyl, aminoalkyl, amino, alkylsulfonyl, aminosulfonyl (wherein the amino nitrogen is (i) unsubstituted or (ii) 1 or disubstituted independently of the other, is a single R ^d radical, or an amino A saturated or partially unsaturated heterocyclyl group in which the substituent on the amino group taken together with the nitrogen is optionally substituted by 1, 2, or 3 groups independently selected from R ^d substituents, or by 1, 2, or 3 groups independently selected from R ^f substituents Lt; / RTI &gt; independently of each other, form an optionally substituted heteroaryl group; R ^d and R ^e are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl and arylalkyloxycarbonyl groups ; R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino groups; R ^g is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, Alkoxy, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ - amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, Alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R &lt; ^{h &} R ⁱ - aminocarbonyl-oxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - amino alkanoyl, hydroxy-aminocarbonyl, R ^h R ⁱ aminosulfonyl, R ^h R ⁱ - aminocarbonyl (R ^h ) amino, trifluoromethyl-sulfonyl (R ^h ) amino, heteroaryl Sulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) aminocarbonyl, alkylsulfonyl (R ^h) amino, arylcarbonyl (R ^h) aminosulfonyl, and an alkyl Sulfonyl (R ^h ) aminocarbonyl substituent; R ^h is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with a substituent of a substituted aminoalkanoyl group, such as R ^j Lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &gt; R ⁱ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, Substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each of which is optionally substituted with one or two R &lt; ^j &gt; substituents; R ^j is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, halo Alkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl are alkyl, alkenyl, alkenyl, aryl, arylalkyl , Heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl groups); &lt; RTI ID = 0.0 &gt; R ^k is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d amino Sulfonyl, R ^c R ^d aminoalkanoyl and R ^c R ^d aminoalkylsulfonyl. 118. The method of claim 117, wherein said compound or salt thereof is administered in multiple doses.