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AU781339B2 - Hydroxamic acid derivatives as matrix metalloprotease inhibitors - Google Patents
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AU781339B2 - Hydroxamic acid derivatives as matrix metalloprotease inhibitors - Google Patents

Hydroxamic acid derivatives as matrix metalloprotease inhibitors Download PDF

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AU781339B2
AU781339B2 AU49718/00A AU4971800A AU781339B2 AU 781339 B2 AU781339 B2 AU 781339B2 AU 49718/00 A AU49718/00 A AU 49718/00A AU 4971800 A AU4971800 A AU 4971800A AU 781339 B2 AU781339 B2 AU 781339B2
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AU4971800A (en
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Thomas E. Barta
Daniel P. Becker
Louis J. Bedell
John N. Freskos
Daniel P. Getman
Joseph J. Mcdonald
Brent V. Mischke
Shashidhar N. Rao
Clara I Villamil
Gary A. De Crescenzo
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GD Searle LLC
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    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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Description

WO 00/69819 PCT/US00/06713 -1- HYDROXAMIC ACID DERIVATIVES AS MATRIX METALLOPROTEASE INHIBITORS Description Technical Field This invention is directed to proteinase (protease) inhibitors, and more particularly to sulfonyl aryl or heteroaryl hydroxamic acid compounds that, inter alia, inhibit the activity of matrix metalloproteinases, compositions of those inhibitors, intermediates for the syntheses of those compounds, processes for the preparation of the compounds and processes for treating pathological conditions associated with pathological matrix metalloproteinase activity.
Background of the Invention Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. .These biochemicals make up, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.
Under normal conditions, connective tissue turnover and/or repair processes are WO 00/69819 PCT/US00/06713 -2controlled and in equilibrium. The loss of this balance for whatever reason leads to a number of disease states. Inhibition of the enzymes responsible for the loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for these diseases.
Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells. A major class of enzymes involved in this function are the zinc metalloproteinases (metalloproteases, or MMPs).
The metalloprotease enzymes are divided into classes with some members having several different names in common use. Examples are: 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, matrilysin (MMP-7), gelatinase A (MMP-2, 72kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane MMP (MMP-14).
MMP is an abbreviation or acronym representing the term Matrix Metalloprotease with the attached numerals providing differentiation between specific members of the MMP group.
The uncontrolled breakdown of connective tissue by metalloproteases is a feature of many WO 00/69819 PCT/US00/06713 -3pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; Alzheimer's Disease; coronary thrombosis and bone disease. Defective injury repair processes can also occur. This can produce improper wound healing leading to weak repairs, adhesions and scarring. These latter defects can lead to disfigurement and/or permanent disabilities as with post-surgical adhesions.
Matrix metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF) and inhibition of the production or action of TNF and related compounds is an important clinical disease treatment mechanism. TNF-a, for example, is a cytokine that at present is thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. For example, TNF can cause and/or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects such as post-ischemic reperfusion injury, congestive heart failure, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage and acute phase responses like those seen with infections and sepsis and.during shock such as WO 00/69819 PCT/US00/06713 -4septic shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal.
TNF-a convertase is a metalloproteinase involved in the formation of active TNF-a.
Inhibition of TNF-a convertase inhibits production of active TNF-a. Compounds that inhibit both MMPs activity have been disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466 and WO 97/20824. There remains a need for effective MMP and TNF-a convertase inhibiting agents. Compounds that inhibit MMPs 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 involved in other biochemical processes in mammals as well. Included is the control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (P-Amyloid Precursor Protein) to the amyloid plaque and inactivation of al-protease inhibitor (ac-PI) Inhibition of these metalloproteases permits the control of fertility and the treatment or prevention of Alzheimers Disease. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor drug or biochemical such as ao-PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.
WO 00/69819 PCT/US00/06713 Inhibition of selected MMPs can also be desirable in other instances. Treatment of cancer and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of approaches to the treatment of diseases wherein the selective inhibition of stromelysin (MMP-3), gelatinase (MMPgelatinase B (MMP-9) or collagenase III (MMP- 13) may be relatively more important than inhibition of collagenase I (MMP-1). A drug that does not inhibit collagenase I can have a superior therapeutic profile. Osteoarthritis, another prevalent disease wherein it is believed that cartilage degradation in inflamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by administration of drugs one of whose modes of action is inhibition of MMP-13. See, for example, Mitchell et al., J. Clin. Invest., 97:761- 768 (1996) and Reboul et al., J. Clin. Invest., 97:2011-2019 (1996).
Inhibitors of metalloproteases are known.
Examples include natural biochemicals such as tissue inhibitor of metalloproteinase (TIMP), a 2 macroglobulin and their analogs or derivatives.
These are high molecular weight protein molecules that form inactive complexes with metalloproteases.
A number of smaller peptide-like compounds that inhibit metalloproteases have been described.
Mercaptoamide peptidyl derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) aids in the production of angiotensin II, a potent pressor substance in WO 00/69819 PCT/US00/06713 -6mammals and inhibition of this enzyme leads to the lowering of blood pressure.
Thiol group-containing amide or peptidyl amide-based metalloprotease (MMP) inhibitors are known as is shown in, for example, WO95/12389, W096/11209 and U.S. 4,595,700. Hydroxamate groupcontaining MMP inhibitors are disclosed in a number of published patent applications such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 that disclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO 95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidyl back-bones or peptidomimetic back-bones, as does the article by Schwartz et al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. New Drugs, 15(3): 175-185 (1997).
One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes. For example, the peptidomimetic hydroxamate known as batimastat is reported to exhibit IC 50 values of about 1 to about nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat, another peptidomimetic hydroxamate was reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum very similar to batimastat, except that marimastat exhibited an IC 50 value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
Meta analysis of data from Phase I/II studies using marimastat in patients with advanced, WO 00/69819 PCT/US00/06713 -7rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although marimastat exhibited some measure of efficacy via these markers, toxic side effects were noted. The most common drug-related toxicity of marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction permits treatment to continue.
Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.
In view of the importance of hydroxamate MMP inhibitor compounds in the treatment of several diseases and the lack of enzyme specificity exhibited by two of the more potent drugs in clinical trials, it would be a great benefit if hydroxamates of greater enzyme specificity could be found. This would be particularly the case if the hydroxamate inhibitors exhibited strong inhibitory activity against one or more of MMP-2, MMP-9 or MMP-13 that are associated with several pathological conditions, while at the same time exhibiting limited inhibition of MMP-1, an enzyme that is relatively ubiquitous and as yet not associated with any pathological condition. The disclosure that follows describes one family of WO 00/69819 PCT/US00/06713 -8hydroxamate MMP inhibitors that exhibit those desirable activities Brief Summary of the Invention The present invention is directed to a family of molecules that among other properties inhibit matrix metalloprotease (MMP) activity and particularly inhibit the activity of one or more of MMP-2, MMP-9, or MMP-13, while generally exhibiting little activity against MMP-1. The present invention is also directed to intermediates useful in the synthesis of inhibitors, processes for preparing a contemplated compound and for treating a mammal having a condition associated with pathological matrix metalloprotease activity.
Briefly, one embodiment of the present invention is directed to a sulfonyl aryl or heteroaryl hydroxamic acid compound, or a pharmaceutically acceptable salt of such a compound that can act as a matrix metalloprotease enzyme inhibitor, a precursor to such a compound or a prodrug form of such a compound. A contemplated compound corresponds in structure to Formula C.
o0 R2O S 'R 1
C
W
R
wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring; WO 00/69819 PCT/US00/06713 -9-
R
1 is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted S0 2 -group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R 1 defining a three-dimensional volume, when rotated about an axis drawn through the S0 2 -bonded 1-position and the 4-position of a 6membered ring radical or drawn through the S0 2 -bonded 1-position and the center of 3,4-bond of a ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings.
Alternatively, R1 is an -NR 7
R
8 group in which R 7 and
R
8 are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted arylhydrocarbyl. More preferably, R 7 and R 8 are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, Raoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and a heterocyclo substituent, each of which substituent groups is optionally substituted with an -A-R-E-Y substituent; in such an -A-R-E-Y substituent, A is selected from the group consisting of
-NR
k -CO-N(Rk) or WO 00/69819 WO 0069819PCTIUSOO/06713 -co-a- or -O-CO-;
-O-CO-O-;
-HC=CH-;
-NH-CO-NH-;
C= (11) -NH-NH-; (12) -CS-N(Rk)_ or -N(Rk)-CS-; (13) -CH 2 (14) -O-CH 2 or
-S-CH
2 or (16) and (17) -S02-; or (18) A is absent and R is directly bonded to R7or R 8 or both R 7 and R 8 the moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1
-C
2 -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, WO 00/69819 PCT[USOO/06713 -11hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group; the group E is selected from the group consisting of -CORg- or -RgCO-; -CON(Rk)- or -(Rk)NCO-;
-CO-;
-SO
2 Rg- or -RgS02-;
-SO
2 -N(Rk)-SO2 or -SO2-N(Rk)-; or E is absent and R is bonded directly to Y; and the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Raoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and an amino group wherein the amino nitrogen is unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group; or WO 00/69819 PCT/US00/06713 -12-
R
7 and R 8 taken together with the nitrogen atom to which they are bonded form a group -G-A-R-E-Y wherein G is a N-heterocyclo group; the substituent A is selected from the group consisting of
-NR
k -CO-N(Rk) or -N(Rk)-CO-; -CO-O- or -O-CO-;
-O-CO-O-;
-HC=CH-;
-NH-CO-NH-;
(11) -NH-NH-; (12) -CS-N(Rk)- or -N(Rk)-CS-; (13) -CH 2 (14) -O-CH 2 or -CH 2
-S-CH
2 or -CH2-S-; (16) and (17) -S02-; or (18) A is absent and R is directly bonded to the N-heterocyclo group, G; the moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a WO 00/69819 PCT[USOO/06713 -13heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1
-C
2 -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group; the moiety E is selected from the group consisting of -CQRg- or -RgCO-; -CON(Rk)- or -(Rk)NCO
-CO-;
-SO
2 -Rg- or -Rg-S02-;
-SO
2 -N(Rk)-S02- or -S02-N(Rk)-; or E is absent and R is bonded directly to Y; and the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Raoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two WO 00/69819 PCT/US00/06713 -14radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and an amino group wherein the amino nitrogen is unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.
Alternatively, and still more preferably, R 7 and R 8 taken together with the nitrogen atom to which they are bonded; a -NR 7
R
8 group, form a group -G-A-R-E-Y wherein G is a N-heterocyclo group; the substituent A is selected from the group consisting of
-NR
k -CO-N(Rk) or -N(Rk)-CO-; -CO-O- or -O-CO-;
-O-CO-O-;
-HC=CH-;
-NH-CO-NH-;
(11) -NH-NH-; (12) -CS-N(Rk)- or -N(Rk)-CS-; (13) -CH 2 (14) -O-CH 2 or -CH2-O-;
-S-CH
2 or -CH 2 (16) and (17) -S02-; or WO 00/69819 PCTIUSO0/06713 (18) A is absent and R is directly bonded to the N-heterocyclo group, G; the moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1
-C
2 -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group; the moiety E is selected from the group consisting of -CORg- or -RgCO-; -CON(Rk)- or -(Rk)NCO-;
-CO-;
-SO
2
-R
g or -R9-SO2-;
-SO
2 -N(Rk)-SO2 or -SO2-N(Rk)-; or E is absent and R is bonded directly to Y; and the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, WO 00/69819 PCTIUS00/06713 -16haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Raoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and an amino group wherein the amino nitrogen is unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.
Substituents R 5 and R 6 are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, a RbRCaminoalkyl substituent, thiol alkylthio, arylthio, cycloalkylthio, cycloalkkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and a RbRcaminoalkyloxy substituent; or R 5 and R 6 together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having to 7-members.
A R 20 group is -O-R 21 where R 21 is selected from the group consisting of a hydrido, C 1
-C
6 -alkyl, aryl, ar-C 1
-C
6 -alkyl group and a pharmaceutically acceptable cation, -NR13-O-R 22 wherein R 22 is a WO 00/69819 PCT/US00/06713 -17selectively removable protecting group such as a 2tetrahydropyranyl, benzyl, p-methoxybenzyl, C 1
-C
6 alkoxycarbonyl, trisubstituted silyl group or onitrophenyl group, peptide systhesis resin and the like, wherein the trisubstituted silyl group is substituted with C 1 -Cg-alkyl, aryl, or ar-C 1
-C
6 -alkyl or a mixture thereof, and R 13 is a hydrido, C 1
-C
6 alkyl or benzyl group, -NR13-O-R 14 where R 13 is as before and R 14 is hydrido, a pharmaceutically acceptable cation or C(V)R 15 where V is 0 (oxo) or S (thioxo) and R 15 is selected from the group consisting of an C 1
-C
6 -alkyl, aryl, C 1 -Cg-alkoxy, heteroaryl-C 1
-C
6 -alkyl, C 3 -Cg-cycloalkyl-C 1
-C
6 -alkyl, aryloxy, ar-C 1
-C
6 -alkoxy, ar-C 1
-C
6 -alkyl, heteroaryl and amino C 1
-C
6 -alkyl group wherein the amino C1-Cgalkyl nitrogen is unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C 1
-C
6 -alkyl, aryl, ar-C 1
-C
6 -alkyl, C 3 -Cgcycloalkyl-C 1
-C
6 -alkyl, ar-C 1
-C
6 -alkoxycarbonyl, C 1
C
6 -alkoxycarbonyl, and C 1
-C
6 -alkanoyl radical, or (iii) wherein the amino C 1 -Cg-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or -NR 23
R
24 where R 23 and R 24 are independently selected from the group consisting of a hydrido, C 1
-C
6 -alkyl, amino C 1
C
6 -alkyl, hydroxy C 1
-C
6 -alkyl, aryl, and an ar-C 1 -Cgalkyl group, or R 23 and R 24 together with the depicted nitrogen atom form a 5- to 8-membered ring WO 00/69819 PCT[USOO/06713 -18containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur.
In the formula above, Ra is selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRcaminoalkanoyl, haloalkanoyl, RbRcaminoalkyl, alkoxyalkyl, haloalkyl and an arylalkyloxy group; Rb and Rc are independently selected from the group consisting of a hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with one or two Rd radicals, or'the substituents on the amino group taken together with the amino nitrogen form a saturated or partially unsaturated heterocyclo group optionally substituted with one, two or three WO 00/69819 PCT/USOO/06713 -19groups independently selected from Rd substituents or a heteroaryl group optionally substituted with one, two or three groups independently selected from Rf substituents; Rd and Re are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl or arylalkyloxycarbonyl group; Rf is selected from the group consisting of a nitro, hydroxy, alkyl, halogen (halo; F, Cl, Br, I), aryl, alkoxy, cyano, and RdReamino group; Rg is selected from the group consisting of a hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen Cl, Br, cyano, aldehydo (CHO, formyl), hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RhRi-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RhRi-aminocarbonyloxy, RhRi-aminocarbonyl, RhRi-aminoalkanoyl, hydroxyaminocarbonyl, RhRiaminosulfonyl, RhRi-aminocarbony1(Rh)amino, trifluoromethylsulfonyl(Rh)amino, heteroarylsulfonyl- (Rh)amino, arylsulfonyl(Rh)amino, arylsulfonyl(Rh)aminocarbonyl, alkylsulfonyl (Rh)amino, arylcarbonyl- WO 00/69819 PCT/US00/06713 (Rh)aminosulfonyl, and an alkylsulfonyl(Rh)aminocarbonyl substituent; Rh is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups is optionally substituted by one or two groups independently selected from RJ substituents as are the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups;
R
i is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups are optionally substituted by one or two RJ substituents; RJ is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl WO 00/69819 PCT/US00/06713 -21groups are selected from the group consisting of an alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl and an alkyloxycarbonyl group; and Rk is selected from hydrido, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RcRdamino carbonyl, RCRdaminosulfonyl, RcRdaminoalkanoyl and RcRdaminoalkysulfonyl.
In some preferred embodiments, R 5 and R 6 are independently selected from the group consisting of hydrido, hydrocarbyl, preferably C 1
-C
4 hydrocarbyl, hydroxylhydrocarbyl, hydroxyl, amino, dihydrocarbylamino, heterocyclo, heterocyclohydrocarbyl, heterocyclooxy, and heterocyclothio.
In preferred embodiments, the 5- or 6membered aromatic or heteroaromatic ring W is a 1,2phenylene, 2,3-pyridinylene, 3,4-pyridinylene, pyridinylene, 2,3-pyrazinylene, or 5,6-pyrimidinylene group.
In some preferred embodiments, R 20 is -NR13-O-R 14 whereas in other preferred embodiments,
R
20 is -NR13-O-R 22 In particularly preferred embodiements, R 20 is -NHOH so that a compound of Formula C corresponds in structure to Formula C1 R Cl _1 C1 WO 00/69819 PCT/US00/06713 -22wherein W, R 1
R
5
R
6
R
13 and R 14 are as defined before.
In one preferred embodiment, a contemplated compound corresponds in structure to Formula C2, O S'PhR4 C2
R
14 ONH 4 C2
W
R
5
R
6 wherein W, R 5
R
6 and R 14 are as defined above and Ph is a phenyl group substituted at the 4position with substituent R 4 A R 4 substituent can be a single-ringed cyclohydrocarbyl, heterocyclo, aryl such as phenyl or heteroaryl group or another substituent having a chain length of 3 to about 14 carbon atoms such as a hydrocarbyl or hydrocarbyloxy group C 3
-C
14 hydrocarbyl or O-C2-C14 hydrocarbyl], a phenoxy group [-OCgH 5 a thiophenoxy group [phenylsulfanyl; -SC 6
H
5 an anilino group
[-NHC
6
H
5 a phenylazo group [-N 2
C
6
H
5 a phenylureido group [aniline carbonylamino; -NHC(O)NH-
C
6
H
5 a benzamido group [-NHC(O)C 6
H
5 a nicotinamido group [3-NHC(0)C 5
H
4 an isonicotinamido group [4-NHC(0)C 5
H
4 or a picolinamido group [2-NHC(O)C 5
H
4 A R 4 substituent is further defined hereinafter.
In another aspect of the invention, a contemplated compound corresponds in structure to Formula VI-1 WO 00/69819 PCT[USOO/06713 -23- O O 0 S N A, D R 8 C R6 wherein each of R 5
R
6
R
7
R
8 and R 2 0 is as defined before and each of A, B, C and D is carbon, nitrogen, sulfur or oxygen and is present or absent so that the depicted ring has 5- or 6-members.
When R 20 is NH-OH, compound of one of the above formulas such as Formula C or C1 is a hydroxamate that is a selective inhibitor of MMP-2 over MMP-1 and usually also over MMP-13. That is, a hydroxamate compound of one of the formulas such as Formula C or C1 exhibits greater activity in inhibiting MMP-2 than in inhibiting MMP-1 and usually also MMP-13. When
R
20 is other than NH-OH, a compound of Formula VI-1 can be a precursor, pro-drug or active carboxylate as is the compound of Example 13.
A particularly preferred embodiment of this aspect is a compound that corresponds in structure to Formulas VIA or VIA-1 o o o oo R 20 S N R 20 S
N
R 5\ R4 R5
R
4 R6 R6 VIA-1 VIA
VIA-
wherein R 20
R
4
R
5 and R 6 are as defined before and ring structure W 2 including the depicted nitrogen atom is a heterocylic ring that contains or 6-members, and R 4 is bonded at the 4-position WO 00/69819 PCT/US00/06713 -24relative to that depicted nitrogen atom when W 2 is a 6-membered ring and at the 3- or 4-position relative to that depicted nitrogen when W 2 is a ring.
Another particularly preferred embodiment of this aspect is a compound that corresponds in structure to Formulas VIB, VIB-1, VIB-2 or VIB-3
,R
7 VIB VIB-1 0 0/0 O OO HONH
N
R
5 s
R
8
R
6 0 0 0 R7 HONH N
R
5 s
R
8
R
6 VIB-2 VIB-3 wherein R 20
R
5
R
6
R
7 and R 8 are as defined before.
A particularly preferred group of compounds of this class are the compounds whose structure corresponds to Formula D
D
R-E.Y
Y
WO 00/69819 PCT/US00/06713 wherein the substituent groups or moieties A, R, E, Y, R 20
R
5 and R 6 are as before described.
A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity is also contemplated. That process comprises administering to a mammalian host having such a condition a compound corresponding in structure to Formula C, such as a conpound corresponding in styructure to Formula C1, below, or a salt of such a compound, that selectively inhibits one or more MMPs, while exhibiting less activity against at least MMP-1 in an MMP enzyme-inhibiting effective amount. A contemplated compound also does not substantially inhibit the production of TNF.
S 0 0 R14ONR"S R1 C1
W
R R 6 wherein W, R 1
R
5
R
6
R
13 and R 14 are as defined before.
Among the several benefits and advantages of the present invention are the provision of compounds and compositions that are effective for the inhibition of metalloproteinases implicated in diseases and disorders involving uncontrolled breakdown of connective tissue.
More particularly, a benefit of this invention is the provision of a compound and composition effective for inhibiting metalloproteinases, particularly MMP-13 and/or MMP-2, associated with pathological conditions such as, for WO 00/69819 PCT/US00/06713 -26example, rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's Disease, coronary thrombosis, plaque formation and bone disease.
An advantage of the invention is the provision of a method for preparing such compounds and compositions. Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.
Another advantage of the invention is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase such as MMP-13 and MMP-2 associated with such conditions with minimal side effects resulting from inhibition of other proteinases such as MMP-1, whose activity is necessary or desirable for normal body function.
Still further benefits and advantages of the invention will be apparent to the skilled worker from the disclosure that follows.
Detailed Description of Preferred Embodiments In accordance with the present invention, it has been found that certain sulfonyl aryl or heteroaryl hydroxamic acids (hydroxamates) are effective, inter alia, for inhibition of matrix metalloproteinases ("MMPs") believed to be associated with uncontrolled or otherwise pathological breakdown of connective tissue. In particular, it has been found that these certain sulfonyl aryl or heteroaryl WO 00/69819 PCT/US00/06713 -27hydroxamic acid compounds are effective for inhibition of collagenase III (MMP-13) and also gelatinase A (MMP-2), which can be particularly destructive to tissue if present or generated in abnormal quantities or concentrations, and thus exhibit a pathological activity.
Moreover, it has been discovered that many of these aromatic sulfonyl alpha-cycloamino hydroxamic acids are selective in the inhibition of MMPs associated with diseased conditions without excessive inhibition of other collagenases essential to normal bodily function such as tissue turnover and repair. More particularly, it has been found that particularly preferred sulfonyl aryl or heteroaryl hydroxamic acid compounds or salts of such compounds are particularly active in inhibiting of MMP-13 and/or MMP-2, while having a limited or minimal effect on MMP-1, and some compounds such as that of Example 8, also exhibit minimal inhibition of MMP-7.
This point is discussed in detail hereinafter and is illustrated in the Inhibition Table hereinafter.
One embodiment of the present invention is directed to a sulfonyl aryl or heteroaryl hydroxamic acid compound, a pharmaceutically acceptable salt of such a compound that can act as a matrix metalloprotease enzyme inhibitor, a precursor to such a compound or a pro-drug form of such a compound. A contemplated compound corresponds in structure to Formula C.
WO 00/69819 PCTUSOO/06713 -28- 0 0 0 S R 1
C
R
2 R
W
R6 R s R6 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 cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted S0 2 -group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, the R 1 group defining a threedimensional volume, when rotated about an axis drawn through the S0 2 -bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the S0 2 -bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is.about that of one furanyl ring to about that of two phenyl rings. Alternatively, a R 1 group is (ii) an -NR 7
R
8 group in which R 7 and R 8 are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted arylhydrocarbyl. More preferably, a R 1 group is an -NR 7
R
8 group in which R 7 and R 8 are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, Raoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and a WO 00/69819 PCT/US00/06713 -29heterocyclo substituent, each of which substituent groups is optionally substituted with an -A-R-E-Y substituent; in such an -A-R-E-Y substituent, A is selected from the group consisting of
-NR
k -CO-N(Rk) or -N(Rk)-CO-; -CO-O- or -O-CO-;
-O-CO-O-;
-HC=CH-;
-NH-CO-NH-;
(10) (11) -NH-NH-; (12) -CS-N(Rk)- or -N(R k (13) -CH 2 (14) -O-CH 2 or (15) -S-CH 2 or -CH2-S-; (16) and (17) -S02-; or (18) A is absent and R is directly bonded to R 7 or R 8 or both R 7 and R 8 the moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl, WO 00/69819 PCT/US00/06713 heteroaryl, cycloalkyl or heterocycloalkyl substituent is unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1
-C
2 -alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group; the group E is selected from the group consisting of -CORg- or -RgCO-; -CON(Rk)- or -(Rk)NCO-;
-CO-;
-S0 2 or -(Rg)SO2-;
-SO
2 -N(Rk)-S02- or -S02-N(Rk)-; or E is absent and R is bonded directly to Y; and the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Raoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group WO 00/69819 PCT/US00/06713 -31consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and an amino group wherein the amino nitrogen is unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group; or
R
7 and R 8 taken together with the nitrogen atom to which they are bonded (-NR 7
R
8 form a group -G-A-R-E-Y wherein G is a N-heterocyclo group; the substituent A is selected from the group consisting of
-NR
k -CO-N(Rk) or -N(Rk)-CO-; -CO-O- or -O-CO-;
-O-CO-O-;
-HC=CH-;
-NH-CO-NH-;
(11) -NH-NH-; (12) -CS-N(R k or -N(Rk CS-; (13) -CH 2 (14) -O-CH 2 or
-S-CH
2 or -CH2-S-; (16) and (17) -S02-; or (18) A is absent and R is directly bonded to the N-heterocyclo group, G.
WO 00/69819 PCTUSOO/06713 -32- The moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aryithicalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1
-C
2 -alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group.
The moiety E is selected from the group consisting of -CQRg- or -RgCO-; -CON(Rk)- or -(Rk)NCO-;
-CO-;
-S0 2 or -(Rg)S0 2 -S0 2 -N(Rk)-S02- or -S02-N(Rk)-; or E is absent and R is bonded directly to Y; and the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Raoxyalkyl, WO 00/69819 PCT/US00/06713 -33perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and an amino group wherein the amino nitrogen is unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group;
R
5 and R 6 are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, and a RbRcaminoalkyl substituent; or
R
5 and R 6 together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having 5- to 7members.
In an above formula, R a is selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRcaminoalkanoyl, haloalkanoyl, RbRcaminoalkyl, alkoxyalkyl, haloalkyl and an arylalkyloxy group; Rb and Rc are independently selected from the group consisting of a hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, WO 00/69819 PCTUSOO/06713 -34perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, a'kyliminocarbonyl, aryliminocarboyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with one or two Rd radicals, or the substituents on the amino group taken together with the amino nitrogen form a saturated or partially unsaturated heterocyclo group optionally substituted with one, two or three groups independently selected from Rd substituents or a heteroaryl group optionally substituted with one, two or three groups independently selected from Rf substituents; Rd and Re are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl or arylalkyloxycarbonyl group; WO 00/69819 PCT[USOO/06713 Rf is selected from the group consisting of a nitro, hydroxy, alkyl, halogen (halo; F, Cl, Br, aryl, alkoxy, cyano, and RdReamino; Rg is selected from the group consisting of a hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen Cl, Br, cyano, aldehydo (CHO, formyl), hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RhRi-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RhRi-aminocarbonyloxy, RhRi-aminocarbonyl, RhRi-aminoalkanoyl, hydroxyaminocarbonyl, RhRiaminosulfonyl, RhRi-aminocarbonyl(Rh)amino, trifluoromethylsulfonyl(Rh)amino, heteroarylsulfonyl- (Rh) amino, arylsulfonyl(Rh) amino, arylsulfonyl (Rh)aminocarbonyl, alkylsulfonyl(Rh)amino, arylcarbonyl- (Rh)aminosulfonyl, and an alkylsulfonyl(Rh)aminocarbonyl substituent; Rh is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups is optionally substituted by one or two groups.
WO 00/69819 PCT/US00/06713 -36independently selected from RJ substituents as are the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups;
R
i is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups are optionally substituted by one or two Ri substituents; RJ is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are selected from the group consisting of an alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl and an alkyloxycarbonyl group; and Rk is selected from hydrido, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RCRdamino carbonyl, RcRdaminosulfonyl, RcRdaminoalkanoyl and RcRdaminoalkysulfonyl.
R
20 is -O-R 21 where R 21 is selected from the group consisting of a hydrido, C 1
-C
6 -alkyl, aryl, WO 00/69819 PCT/USOO/06713 -37ar-C 1
-C
6 -alkyl group and a pharmaceutically acceptable cation, -NR13-O-R 22 wherein R 22 is a selectively removable protecting group such as a 2tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), C 1
C
6 -alkoxycarbonyl, trisubstituted silyl group or onitrophenyl group, peptide systhesis resin and the like, wherein the trisubstituted silyl group is substituted with C 1
-C
6 -alkyl, aryl, or ar-C 1
-C
6 -alkyl or a mixture thereof, and R 13 is a hydrido, C 1 -Cgalkyl or benzyl group, -NR13-O-R 14 where R 13 is as before and R 14 is hydrido, a pharmaceutically acceptable cation or C(V)R 15 where V is 0 (oxo) or S (thioxo) and R 15 is selected from the group consisting of an C 1
-C
6 -alkyl, aryl, C 1
-C
6 -alkoxy, heteroaryl-C 1
-C
6 -alkyl, C 3
-C
8 -cycloalkyl-Ci-C 6 -alkyl, aryloxy, ar-C 1
-C
6 -alkoxy, ar-C 1
-C
6 -alkyl, heteroaryl and amino C 1 -Cg-alkyl group wherein the amino C1-C 6 alkyl nitrogen is unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C 1
-C
6 -alkyl, aryl, ar-C 1
-C
6 -alkyl,. C 3 -Cgcycloalkyl-C 1 -Cg-alkyl, ar-C 1
-C
6 -alkoxycarbonyl, C 1
C
6 -alkoxycarbonyl, and C 1 -Cg-alkanoyl radical, or (iii) wherein the amino C 1
-C
6 -alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or -NR 23
R
24 where R 23 and R 24 are independently selected from the group consisting of a hydrido, C 1 -Cg-alkyl, amino C 1
C
6 -alkyl, hydroxy C 1 -Cg-alkyl, aryl, and an ar-C 1 -Cg- WO 00/69819 PCT/US00/06713 -38alkyl group, or R 23 and R 24 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur.
A compound of Formula C embraces a useful precursor compound, a pro-drug form of a hydroxamate and the hydroxamate itself, as well as amide compounds that can be used as intermediates and also as MMP inhibitor compounds. Thus, for example, where
R
20 is -O-R 21 in which R 21 is selected from the group consisting of a hydrido, C 1 -Cg-alkyl, aryl, ar-
C
1
-C
6 -alkyl group and a pharmaceutically acceptable cation, a precursor carboxylic acid or ester is defined that can be readily transformed into a hydroxamic acid, as is illustrated in several Examples hereinafter. Such a carboxyl compound that is a precursor to a hydroxamate can also have activity as an inhibitor of MMP enzymes as is seen from the Inhibition Table of those Examples.
Another useful precursor compound is defined when R 20 is -NR 13
-O-R
22 wherein R 22 is a selectively removable protecting group and R 13 is a hydrido or benzyl group, preferably a hydrido group.
A selectively removable protecting group is exemplified as a 2-tetrahydropyranyl, benzyl, pmethoxybenzyloxycarbonyl (MOZ), benzyloxycarbonyl (BOC), C 1
-C
6 -alkoxycarbonyl, C 1 -Cg-alkoxy-CH 2
C
1
C
6 -alkoxy-C 1
-C
6 -alkoxy-CH 2 trisubstituted silyl group, an o-nitrophenyl group, peptide synthesis resin and the like. A trisubstituted silyl group is WO 00/69819 PCT/US00/06713 -39a silyl group substituted with C 1
-C
6 -alkyl, aryl, or ar-C 1
-C
6 -alkyl substituent groups or a mixture thereof such as a trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, triphenylsilyl, tbutyldiphenylsilyl, diphenylmethylsilyl, a tribenzylsilyl group, and the like. Exemplary trisubstituted silyl protecting groups and their uses are discussed at several places in Greene et al., Protective Groups In Organic Synthesis, 2nd ed., John Wiley Sons, Inc., New York (1991).
A contemplated peptide synthesis resin is solid phase support also known as a so-called Merrifield's Peptide Resin that is adapted for synthesis and selective release of hydroxamic acid derivatives as is commercially available from Sigma Chemical Co., St. Louis MO. An exemplary peptide synthesis resin so adapted and its use in the synthesis of hydroxamic acid derivatives is discussed in Floyd et al., Tetrahedron Let., 37(44):8048- 8048(1996).
A 2-tetrahydropyranyl (THP) protecting group is a particularly preferred selectively removable protecting group and is often used when R 13 is a hydrido group. A contemplated THP-protected hydroxamate compound of Formula A can be prepared by reacting the carboxylic acid precursor compound of Formula A [where R 20 is -O-R 21 and R 21 is a hydrido group] in water with O-(tetrahydro-2H-pyran-2yl)hydroxylamine in the presence of Nmethylmorpholine, N-hydroxybenzotriazole hydrate and a water-soluble carbodiimide such as 1-(3dimethylaminopropyl)-3-ethylcarbodiimide WO 00/69819 PCT/US00/06713 hydrochloride. The resulting THP-protected hydroxamate corresponds in structure to Formula C3, below, where W, R 1
R
5 and R 6 are as defined previously and more fully hereinafter. The THP protecting group is readily removable in an aqueous acid solution such as an aqueous mixture of ptoluenesulfonic acid or HC1 and acetonitrile or methanol.
C O
-NH"'R
1 C3 O-NH" SR R6 Another aspect of the invention contemplates a compound that corresponds in structure to Formula VI-1, below, 0 0,0
R
20 VI-1 A D R8 R6 wherein each of R 5
R
6
R
7
R
8 and R 20 is as defined before, and in greater detail hereinafter, and each of A, B, C and D is carbon, nitrogen, sulfur or oxygen and is present or absent so that the depicted ring has 5- or 6-members. A hydroxamate compound of Formula VI-1 is a selective inhibitor of MMP-2 over both of MMP-1 and MMP-13. That is, a hydroxamate compound of Formula VI exhibits greater WO 00/69819 PCT/US00/06713 -41activity in inhibiting MMP-2 than in inhibiting either MMP-1 and usuallya also MMP-13.
A particularly preferred embodiment of this aspect of the invention is a compound that corresponds in structure to Formulas VIA or VIA-1 0 0 0 0 00 Rs 5
R
4
R
R4
R
20 /\Nw2 R 0
/\S
R I R 6 VIA-1
VIA
wherein R 20
R
5
R
6 and R 4 are as defined before, ring structure W 2 including the depicted nitrogen atom is a heterocylic ring that contains or 6-members, and R 4 is bonded at the 4-position relative to that depicted nitrogen atom when W 2 is a 6-membered ring and at the 3- or 4-position relative to that depicted nitrogen when W 2 is a ring. The ring structure W 2 is preferably a Npiperidinyl group that is itself preferably substituted as is discussed hereinafter.
Another particularly preferred embodiment of this aspect is a compound that corresponds in structure to Formula VIB 0 O SI R
R
20 5 VIB
R
6
R
6 WO 00/69819 PCT[USOO/06713 -42wherein R 20
R
5
R
6
R
7 and R 8 are as defined before.
A further embodiment of the present invention is directed to a sulfonyl aryl or heteroaryl hydroxamic acid compound that can act as a matrix metalloprotease enzyme inhibitor. That compound corresponds in structure to Formula C4 O 0 S" ^R 1 C4 HONH RC4
W
R
5
R
6 wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring;
R
1 is-a substituent containing a 5- or 6membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted S0 2 -group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R 1 defining a three-dimensional volume, when rotated about an axis drawn through the S0 2 -bonded 1-position and the 4-position of a 6membered ring radical or drawn through the S0 2 -bonded 1-position and the center of 3,4-bond of a ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings; and WO 00/69819 PCT/US00/06713 -43-
R
5 and R 6 are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, a RbRcaminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and a RbRCaminoalkyloxy substituent; or R 5 and R 6 together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having to 7-members.
Again, in some preferred embodiments, R 1 is an -NR 7
R
8 group in which R 7 and R 8 are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and subsituted arylhydrocarbyl.
More preferably still, R 7 and R 8 are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, Raoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and a heterocyclo substituent, each of which substituent groups is optionally substituted with an -A-R-E-Y substituent; in such an -A-R-E-Y substituent, A is selected from the group consisting of
-NR
k -CO-N(Rk) or -N(Rk)-CO-; -CO-O- or -O-CO-; WO 00/69819 PCT[USOO/06713 -44-
-O-CO-O-;
-HC=CH-;
-NH-CO-NH-;
(10) (11) -NH-NH-; (12) -CS-N(Rk)- or -N(Rk)-CS-; (13)
-CH
2 (14) -O-CH 2 or (15) -S-CH 2 or -CH2-S-; (16) and (17) -S02-; or (18) A is absent and R is directly bonded to R 7 or R 8 or both R 7 and R8; the moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1
-C
2 -alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group; WO 00/69819 PCT/US00/06713 the group E is selected from the group consisting of -CORg- or -RgCO-; -CON(Rk)- or -(Rk)NCO-;
-CO-;
-S0 2 or -(R9)S02-;
-SO
2 -N(Rk)-S02- or -SO2-N(Rk)-; or E is absent and R is bonded directly to Y; and the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Raoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and an amino group wherein the amino nitrogen is unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.
More preferably yet, R 7 and R 8 taken together with the nitrogen atom to which they are bonded
NR
7
R
8 )form a group -G-A-R-E-Y wherein G is a N-heterocyclo group; WO 00/69819 PCTUSOO/06713 -46the substituent A is selected from the group consisting of -Nk- -CO-N(Rk) or -N(Rk)-CO-; -CO-O- or -0-CO-;
-O-CO-O-;
-HC=CH-;
-NH-CO-NH-;
(11) -NH-NH-; (12) -CS-N(Rk)_ or -N(Rk)_CS_; (13) -CH 2 (14) -O-CH 2 or
-S-CH
2 or -CH2-S-; (16) and (17) -S02-; or (18) A is absent and R is directly bonded to the N-heterocyclo group, G; the moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a WO 00/69819 PCT/US00/06713 -47halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1
-C
2 -alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group; the moiety E is selected from the group consisting of -CORg- or -RgCO-;
-CONR
k or -RkNCO-;
-CO-;
-S0 2 or -(Rg)S0 2
-SO
2 -N(Rk)-SO2 or -S02-N(Rk)-; or E is absent and R is bonded directly to Y; and the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Raoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and an amino group wherein the amino nitrogen is unsubstituted or WO 00/69819 PCT/US00/06713 -48- (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.
The superscripted groups, Ra, Rb and the like above and hereinafter are as defined before.
In one preferred embodiment, R 5 and R 6 are independently selected from the group consisting of a hydrido, hydrocarbyl, preferably C 1
-C
4 hydrocarbyl, hydroxylhydrocarbyl, hydroxyl, amino, RbRCaminohydrocarbyl, halo, nitro, cyano, hydrocarbyloxy, halohydrocarbyl, halohydrocarbyloxy, hydroxyhydrocarbyl, dihydrocarbylamino, heterocyclo, heterocyclohydrocarbyl, heterocyclooxy, and a heterocyclothio group. More preferably, R 5 and R 6 are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, and a RbRCaminoalkyl substituent.
Contemplated aromatic or heteroaromatic rings include 1,2-phenylene, 2,3-pyridinylene, 3,4pyridinylene, 4,5-pyridinylene, 2,3-pyrazinylene, and 5,6-pyrimidinylene groups.
1,2-Phenylene a 1,2-disubstituted phenyl ring) is a particularly preferred aromatic or heteroaromatic ring, and is used illustratively herein as W.
As noted above, an R 1 substituent contains a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted S0 2 -group. An R 1 substituent also has length, width and substitution requirements that are discussed in detail below. It is noted here, however, that a single- ringed or fused ring WO 00/69819 PCT/US00/06713 -49cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is not itself long enough to fulfill the length requirement for a preferred compound, particularly where R 1 is NR 7
R
8 As such, that cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical should itself be substituted.
Exemplary 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radicals that can constitute a portion of a R 1 substituent and are themselves substituted as discussed herein include phenyl, or 4pyridyl, 2-naththyl, 2-pyrazinyl, 2- or pyrimidinyl, 2- or 3-benzo(b)thienyl, 8-purinyl, 2or 3-furyl, 2- or 3-pyrrolyl, 2-imidazolyl, cyclopentyl, cyclohexyl, 2- or 3-piperidinyl, 2- or 3-morpholinyl, 2- or 3-tetrahydropyranyl, 2imidazolidinyl, 2- or 3-pyrazolidinyl and the like.
A phenyl radical is particularly preferred and is used illustratively herein.
When examined along its longest chain of atoms, an R 1 substituent (including NR 7
R
8 as an R 1 substituent), including its own substituent when present, has a total length equivalent to a length that is greater than that of a fully extended saturated chain of six carbon atoms (a hexyl group); a length of a heptyl chain in staggered conformation or longer, and a length that is less than that of a fully extended saturated chain of about 20 carbons (an eicosyl group). Preferably, that length is about 8 to about 18 carbon atoms, even though many more atoms may be present in ring structures or substituents. This length requirement is discussed further below.
WO 00/69819 PCT/US00/06713 Looked at more generally, and aside from specific moieties from which it is constructed, an R 1 substituent (radical, group or moiety) has a length of a heptyl group or greater. Such an R 1 substituent also has a length that is less than that of an eicosyl group. That is to say that a R 1 is a substituent having a length greater than that of a fully extended saturated six carbon chain and shorter than that of a fully extended saturated twenty carbon chain, and more preferably, a length greater than that of a octyl group and less than that of a palmityl group. The radical chain lengths are measured along the longest linear atom chain in the radical, following the skeletal atoms of a ring where necessary. Each atom in the chain, e.g. carbon, oxygen or nitrogen, is presumed to be carbon for ease in calculation.
Such lengths can be readily determined by using published bond angles, bond lengths and atomic radii, as needed, to draw and measure a chain, or by building models using commercially available kits whose bond angles, lengths and atomic radii are in accord with accepted, published values. Radical (substituent) lengths can also be determined somewhat less exactly by presuming, as is done here, that all atoms have bond lengths of saturated carbon, that unsaturated and aromatic bonds have the same lengths as saturated bonds and that bond angles for unsaturated bonds are the same as those for saturated bonds, although the above-mentioned modes of measurement are preferred. For example, a 4-phenyl or 4-pyridyl group has a length of a four carbon chain, as does a propoxy group, whereas a biphenyl WO 00/69819 PCT/US00/06713 -51group has a length of about an eight carbon chain using a contemplated measurement mode.
In addition, an R 1 substituent, when rotated about an axis drawn through the SO 2 -bonded 1-position and the 4-position of a 6-membered ring radical or the SO 2 -bonded 1-position and through the 3,4 bond of a 5-membered ring radical defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about the width of two phenyl rings in a direction transverse to that axis to rotation.
When utilizing this width or volume criterion, a fused ring system such as a naphthyl or purinyl radical is considered to be a 6- or membered ring that is substituted at appropriate positions numbered from the S0 2 -linkage that is deemed to be at the 1-position as discussed before.
Thus, a 2-naphthyl substituent or an 8-purinyl substituent is an appropriately sized R 1 radical as to width when examined using the above rotational width criterion. On the other hand, a l-naphthyl group or a 7- or 9-purinyl group is too large upon rotation and is excluded.
As a consequence of these length and width requirements, R 1 substituents such as 4-(phenyl)phenyl [biphenyl], 4-(4'-methoxyphenyl)phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4- (phenylthio)phenyl], 4-(phenylazo)phenyl 4- (phenylureido)phenyl, 4-(anilino)phenyl, 4- (nicotinamido)phenyl, 4-(isonicotinamido)phenyl, 4-(picolinamido)phenyl and 4-(benzamido)phenyl are among particularly preferred R 1 substituents, with WO 00/69819 PCTIUS00/06713 -52- 4-(phenoxy)phenyl and 4-(thiophenyl)phenyl being most preferred.
An S0 2 -linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is a 5- or 6-membered single-ring that is itself substituted with one other substituent, R 4 The S0 2 -linked single-ringed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is R 4 -substituted at its own 4-position when a 6-membered ring and at its own 3or 4-position when a 5-membered ring. The cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical to which R 4 is bonded in some embodiments is preferably a phenyl group, so that R 1 is preferably PhR 4 in which R 4 is bonded at the 4-position of the S0 2 -linked phenyl (Ph) radical, and in which R 4 can itself be optionally substituted as is discussed hereinafter. In other embodiments, a heterocyclo or heteroaryl radical is preferred over a phenyl radical, with the R 4 substituent being linked at the 4-position relative to the bond between the ring and the SO 2 group.
A contemplated R 4 substituent can be a single-ringed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group or another substituent having a chain length of 3 to about 14 carbon atoms such as a hydrocarbyl or hydrocarbyloxy group C 3
-C
14 hydrocarbyl or O-C 2
-C
14 hydrocarbyl], a phenyl group, a phenoxy group [-OC 6
H
5 a thiophenoxy group [phenylsulfanyl; -SC 6
H
5 an anilino group [-NHC 6
H
5 a phenylazo group [-N 2
C
6
H
5 a phenylureido group [aniline carbonylamino; -NHC(O)NH-C 6
H
5 a benzamido WO 00/69819 PCT[USOO/06713 -53group I-NHC(O)C 6
H
5 a nicotinamido group [3-NHC(O)C 5
H
4 an isonicotinamido group [4-NHC(O)C 5
H
4 or a picolinamido group [2-NHC(O)C 5
H
4 Additionally contemplated R 4 substituent groups include a heterocyclo, heterocyclohydrocarbyl, arylhydrocarbyl, arylheterocyclohydrocarbyl, heteroarylhydrocarbyl, heteroaryiheterocyclo-hydrocarbyl, aryihydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbyl-thiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbyl thiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, or a heteroarylthio group.
A contemplated R 4 substituent can itself also be substituted with one or more substituent radicals at the meta- or para-position or both of a six-membered ring with a single atom or a substituent containing a longest chain of up to ten atoms, excluding hydrogen. Exemplary substituent radicals include a halo, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarhydrocarbyl, hydrocarbyloxycarbonyl hydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, WO 00/69819 WO 0069819PCT[USOO/06713 -54cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbyl amino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryl hydrocarbylamino, aryihydrocarbyloxy, aryihydrocarbyl thio, aryihydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, aryihydrocarbyloyl, hydrocarboyloxy, aryihydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbyithia, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonyihydrocarbyl, hydrocarbylhydroxycarbolyl hydrocarbylthio, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamilo, heterocyc lohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, hete roaryl carbonylamino, heteroarylhydrocarbylcarbonylamilo, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryihydrocarbyl sul fonyl amino, cyclohydrocarbylsul fonylami no, heterocyclohydrocarbylsulfonylamilo and Nmonosubstituted or N, N-disubstituted aminohydrocarbyl group wherein the substituent(s) on the nitrogen are selected from the group consisting of hydrocarbyl, aryl, aryihydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group.
WO 00/69819 PCTUSOO/06713 Thus, initial studies indicate that so long as the length, substitution and width (volume upon rotation) requirements of an S0 2 -linked R 1 substituent discussed herein are met, an R 1 substituent can be extremely varied.
A particularly preferred R 4 substituent of an S0 2 -linked Ph group is a single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo, phenylureido, nicotinamido, isonicotinamido, picolinamido, anilino or benzamido group that is unsubstituted or is itself substituted (optionally substituted) at the para-position when a 6-membered ring or the 3- or 4-position when a 5-membered ring.
Here, single atoms such as halogen moieties or substituents that contain one to a chain of about ten atoms other than hydrogen such as C 1
-C
10 hydrocarbyl,
C
1
-C
9 hydrocarbyloxy or carboxyethyl groups can be used.
Exemplary particularly preferred PhR 4 (particularly preferred R 1 substituents include biphenyl, 4-phenoxyphenyl, 4-thiophenoxyphenyl, 4benzamidophenyl, 4-phenylureido, 4-anilinophenyl, 4nicotinamido, 4-isonicotinamido, and 4-picolinamido.
Exemplary particularly preferred R 4 groups contain a 6-membered aromatic ring and include a phenyl group, a phenoxy group, a thiophenoxy group, a phenylazo group, a phenylureido group, an anilino group, a nicotinamido group, an isonicotinamido group, a picolinamido group and a benzamido group.
More specifically, a particularly preferred sulfonyl butanhydroxamate compounds has an R 4 substituent that is a phenyl group, a phenoxy group, WO 00/69819 PCT/US00/06713 -56a thiophenoxy group, a phenylazo group, a phenylureido group, an anilino group, a nicotinamido group, an isonicotinamido group, a picolinamido group or a benzamido group that is itself optionally substituted at its own meta or para-position or both with a moiety that is selected from the group consisting of a halogen, a halohydrocarbyl group, a halo C 1
-C
9 hydrocarbyloxy group, a perfluoro C 1
-C
9 hydrocarbyl group, a C 1
-C
9 hydrocarbyloxy (-O-C 1
-C
9 hydrocarbyl) group, a C 1
-C
10 hydrocarbyl group, a di-
C
1
-C
9 hydrocarbylamino [-N(C 1
-C
9 hydrocarbyl)(C 1
-C
9 hydrocarbyl)] group, a carboxyl C 1 -Cg hydrocarbyl
(C
1
-C
8 hydrocarbyl-CO 2 H) group, a C1-C4 hydrocarbyloxy carbonyl C 1
-C
4 hydrocarbyl [C 1
-C
4 hydrocarbyl-O-(CO)-C 1
-C
4 hydrocarbyl] group, a C1-C 4 hydrocarbyloxycarbonyl C 1
-C
4 hydrocarbyl [C 1
-C
4 hydrocarbyl(CO)-O-C 1
-C
4 hydrocarbyl] group and a C 1
C
8 hydrocarbyl carboxamido [-NH(CO)-C 1
-C
8 hydrocarbyl] group, or is substituted at the metaand para-positions by two methyl groups or by a C1-C 2 alkylenedioxy group such as a methylenedioxy group.
Inasmuch as a contemplated S0 2 -linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is itself preferably substituted with a 6membered aromatic ring, two nomenclature systems are used together herein for ease in understanding substituent positions. The first system uses position numbers for the ring directly bonded to the S0 2 -group, whereas the second system uses ortho, meta or para for the position of one or more substituents of a 6-membered ring bonded to a S0 2 -linked WO 00/69819 PCTUSOO/06713 -57cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical. When a R 4 substituent is other than a 6membered ring, substituent positions are numbered from the position of linkage to the aromatic or heteroaromatic ring. Formal chemical nomenclature is used in naming particular compounds.
Thus, the 1-position of an above-discussed
SO
2 -linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is the position at which the SO 2 group is bonded to the ring. The 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding from the S0 2 -linkage as compared to formalized ring numbering positions used in heteroaryl nomenclature.
0 0 0 "'PhR4 C2
R
14 ONH PhR C2
W
R
5
R
6 In some preferred embodiments, a contemplated compound corresponds in structure to Formula C2, wherein W, R 5
R
6 and R 14 are as defined above, Ph is phenyl substituted at the 4-position with substituent R 4 that is defined hereinabove.
The length of a R 1 substituent bonded to the SO2 group is believed to play a role in the overall activity of a contemplated inhibitor compound against MMP enzymes generally. Thus, a compound having an R 1 substituent that is shorter in length WO 00/69819 PCT/USOO/06713 -58than a heptyl group, a 4-methoxyphenyl group, typically exhibits moderate to poor inhibitory activity against all of the MMP enzymes, whereas compounds whose R 1 substituents have a length of about an heptyl chain or longer, a 4phenoxyphenyl group that has a length of about a nine-carbon chain, typically exhibit good to excellent potencies against MMP-13 or MMP-2 and also selectivity against MMP-1. Exemplary data are provided in the Inhibition Tables hereinafter in which the activities of the above two compounds can be compared.
In view of the above-discussed preferences, compounds corresponding in structure to particular formulas constitute particularly preferred embodiments.
In one of those embodiments, a contemplated compound corresponds in structure to Formula C4, below, 0 //0 HONH R C4
W
R
s R6 wherein W, R 1
R
5 and R 6 are as defined above, and
R
1 is preferably PhR 4 as is also defined above.
Again taking into account the before-stated preference that W be a 1,2-phenylene radical and the preference for R 1 being PhR 4 particularly preferred compounds correspond in structure to Formulas VIB, WO 00/69819 WO 0069819PCTIUSOO/06713 -59- VIB-1, VIB-2 VIB-3, VII, VII-B, VIIC, VIID, VIIE, VIII and, VIIIB, below, wherein the above definitions for
W
2
R
1
R
5
R
6
R
7
R
8 and
R
20 also apply, and wherein the substituent -A-R-E-Y is bonded to ring structure W2or a depicted ring structure.
0 0 0 0 00 7 7 20 N~.
R
R
R VIB R VIB-1 0o C 7
SNR
HONH R 5 Q-
R
VIB-2 HONH SI~R1 R VITA HONH
(WA-R-E-Y
k'~ VI~c HONH
/N
R
6 VIB-3 HONH S- G-A-R-E-Y R6
VIIB
o 00
VIID
WO 00/69819 PCT/US00/06713
VIIE
N
"A-R-E-Y
VIII VIII-B The compounds that correspond in structure to Formulas D, D1, D2 ,D3 and D4, below, wherein the above definitions for R 4
R
5
R
6 and R 2 0 also apply and wherein each of A, B, C and D of the ring structure is carbon, nitrogen, sulfur or oxygen that is present or absent so that the depicted ring has 5- or 6-members, are also among the particularly preferred compounds contemplated herein and can be viewed as subsets of compounds of Formula VIB.
0 0 0
D
A, D a A, R5/B=CR6
R
o 0p S'N
H
6 'R Dl 'Ey o 0op ONH S'
R
5 6 R D2 "y WO 00/69819 PCT/US00/06713 -61o qp o op SN HONH S N 4S 4 k R6 R4 R5 R6 R 4 D3 D4 The compound of Example 24 has a structure that corresponds to that of Formula D2. In that compound, R 5 and R 6 are both methoxy, the A moiety is a sulfur atom, R is 1,4-phenylene, E is absent and the moiety Y is hydrido. The compound of Example also corresponds in structure to Formula D2.
There, R 5 and R 6 are again both methoxy, the A moiety is an oxygen atom, R is 1,4-phenylene, E is absent and the moiety Y is a dialkoxy-substituted phenyl (aryl) group.
Particularly preferred compounds contemplated herein are illustrated hereinbelow, along with the number of the specific Example in which each is prepared.
WO 00/69819 PTUO/61 PCTfUSOO/06713 -62- 0 0 0 H N HOHN 0~ 0 H Cr~CH 3 HOHN0 7 0
NH
0 o~s
HOHN
NH-OH
0 0 9 HN0
H
HNH
HCH
0 11 WO 00/69819 PTUO/61 PCTfUSOO/06713 -63-
HNI-'OH
0 13CF
,OH
HN
0
S-I
."OH"
HN
CH
3 0
NH-OH
CH
3 0 00 s 16 WO 00/69819 WO 0069819PCT[USOO/06713 -64- Nf.OH Z0H ci
NH
0
HCI
WO 00/69819 PTUO/61 PCT[USOO/06713 0 0
HN
4 0 HN dH N Oj 0
NH-
0 0 0 9 0 H N 0
H
4 S~N7$ 0
\OCH
3 0 0 HN 00 0 N a-O C F 3 12 WO 00/69819 PTUO/61 PCT[USOO/06713 66:- 0 HN 0 13 CF 0
HN
CF
3 14 0 HN'
CH
3 0 0H0
N
00 16 I0 0 9
CF
3 WO 00/69819 PTUO/61 PCT[USOO/06713 -67- 0 ,~0-0 F
NH
0 19CF 0 0 0 0a \/CF 3 0 HN 0 0 0 1 21 OMe 0 MeO NHOH MeO 6 "z'6 J 22 0 0 ~jANHH -0 -aCF 3 00c0 0~&Lj 23 MeO 0 Me0 NHOH S- N aS
-Q
0 WO 00/69819 PTUO/61 PCTfUSOO/06713 -68- MeO 0 MeO~b fNO OMe o' u- MeO 0 MeO
NHOH
CF
3 00 \J26 MeO 0 MeO NHOH
CF
3 o' 0 27 MeO 0 MeO
NO
Q 0 A N H0 28 0 -ANHOH0 ciO~~ 29 00
-,,,.ANHOH
0' 0I 0
NNHOH
CI 31'~ '3 WO 00/69819 WO 0069819PCT[USOO/06713 -69- MeO 0 MeO N
NHOH
OCF
3 o 33 MeC 0 Meo NHOH MeC 0 6 34 CH 3 0O N NHOH
CH
3 O
CF
3 f- o 0
NHOH
o"-N 0/ CF 3 6- 636 OMe 0 Me0 NH0H MeO OMe 37 OMeO0 MeG NHOH F 3
C
6 38 MeG NHOHMe 0 39 OMe 0 MeG NHOH EtO K -LS -b 6 6 WO 00/698 19 PTUO/61 PCT[USOO/06713 Me0 0 M e0 NHOH UL S-N e 0 0 NHOH 0 42 ON
NHOH
S:.N D-(n -hepty 1) "zo 44 OMeO0 MeO
NHOH
N OMeO 00 4600- 4 OO~eO Mee, ,b
NHOH
6- 0 47 MeO
NHOH
WO 00/69819 WO 0069819PCT[USOO/06713 -71co 0 NHOH 0 4 ~J NHOH MeO 0 *S-Nf N -0 0 MO0 MeO ~NHOH 0- 0 /OF MeO 0 MeO ~.ANHOH 54 MeO0 KMebAl:
NHOH
MeO 0 MeO
NHOH
N -0 O(n-Bu) 000- 00 WO 00/69819 PCT/US00/06713 -72- MeO O MeO ANHOH O M e 0 O S0 57 The word "hydrocarbyl" is used herein as a S short hand term to include straight and branched chain aliphatic as well as alicyclic groups or radicals that contain only carbon and hydrogen.
Thus, alkyl, alkenyl and alkynyl groups are contemplated, whereas aromatic hydrocarbons such as phenyl and naphthyl groups, which strictly speaking are also hydrocarbyl groups, are referred to herein as aryl groups or radicals, as discussed hereinafter.
Where a specific aliphatic hydrocarbyl substituent group is intended, that group is recited; C 1
-C
4 alkyl, methyl or dodecenyl. Exemplary hydrocarbyl groups contain a chain of 1 to about 12 carbon atoms, and preferably one to about 10 carbon atoms.
A particularly preferred hydrocarbyl group is an alkyl group. As a consequence, a generalized, but more preferred substituent can be recited by replacing the descriptor "hydrocarbyl" with "alkyl" in any of the substituent groups enumerated herein.
Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Examples of suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3butenyl, decenyl and the like. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, WO 00/69819 PCT[USO0/06713 -73decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
Usual chemical suffix nomenclature is followed when using the word "hydrocarbyl" except that the usual practice of removing the terminal "yl" and adding an appropriate suffix is not always followed because of the possible similarity of a resulting name to one or more substituents. Thus, a hydrocarbyl ether is referred to as a "hydrocarbyloxy" group rather than a "hydrocarboxy" group as may possibly be more proper when following the usual rules of chemical nomenclature. On the other hand, a hydrocarbyl group containing a -C(O)Ofunctionality is referred to as a hydrocarboyl group inasmuch as there is no ambiguity in using that suffix. As a skilled worker will understand, a substituent that cannot exist such as a C 1 alkenyl group is not intended to be encompassed by the word "hydrocarbyl".
The term "carbonyl", alone or in combination, means a group wherein the remaining two bonds (valences) are independently substituted. The term "thiol" or "sulfhydryl", alone or in combination, means a -SH group. The term "thio" or "thia", alone or in combination, means a thiaether group; an ether group wherein the ether oxygen is replaced by a sulfur atom, as in a thiophenoxy group (C 6
H
5 The term "amino", alone or in combination, means an amine or -NH2 group, whereas the term monosubstituted amino, alone or in combination, means a substituted amine -N(H)(substituent) group wherein one hydrogen atom is replaced with a substituent, and WO 00/69819 PCT/US00/06713 -74disubstituted amine means a -N(substituent)2 wherein two hydrogen atoms of the amino group are replaced with independently selected substituent groups.
Amines, amino groups and amides are classes that can be designated as primary secondary (II) or tertiary (III) or unsubstituted, mono-substituted or di-substituted depending on the degree of substitution of the amino nitrogen. Quaternary amine (IVo) means a nitrogen with four substituents [-N+(substituent)4] that is positively charged and accompanied by a counter ion or N-oxide means one substituent is oxygen and the group is represented as [-N+(substituent)3-O-]; the charges are internally compensated.
The term "cyano", alone or in combination, means a -C-triple bond-N group. The term "azido", alone or in combination, means an -N-double bond-N-double bond-N- The term "hydroxyl", alone or in combination, means a -OH group. The term "nitro", alone or in combination, means a -N02 group.
The term "azo", alone or in combination, means a group wherein the bonds at the terminal positions are independently substituted. The term "hydrazino", alone or in combination, means a -NH-NHgroup wherein the remaining two bonds (valences) are independently substituted. The hydrogen atoms of the hydrazino group can be replaced, independently, with substituents and the nitrogen atoms can form acid addition salts or be quaternized.
The term "sulfonyl", alone or in combination, means a group wherein the remaining two bonds (valences) can be independently WO 00/69819 PCTUSOO/06713 substituted. The term "sulfoxido", alone or in combination, means a group wherein the remaining two bonds (valences) can be independently substituted. The term "sulfonylamide", alone or in combination, means a 2 group wherein the remaining three bonds (valences) are independently substituted. The term "sulfinamido", alone or in combination, means a group wherein the remaining three bonds (valences) are independently substituted. The term "sulfenamide", alone or in combination, means a group wherein the remaining three bonds (valences) are independently substituted.
The term "hydrocarbyloxy", alone or in combination, means an 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, tertbutoxy and the like. The term "cyclohydrocarbyl", alone or in combination, means a hydrocarbyl radical that contains 3 to about 8 carbon atoms, preferably from about 3 to about 6 carbon atoms, and is cyclic.
The term "cyclohydrocarbylhydrocarbyl" means an hydrocarbyl radical as defined above which is substituted by a cyclohydrocarbyl as also defined above. Examples of such cyclohydrocarbylhydrocarbyl radicals include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl cyclooctynyl and the like.
The term "aryl", alone or in combination, means a phenyl or naphthyl radical that optionally carries one or more substituents selected from hydrocarbyl, hydrocarbyloxy, halogen, hydroxy, amino, WO 00/69819 PCTIUS00/06713 -76nitro and the like, such as phenyl, p-tolyl, 4methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, and the like. The term "arylhydrocarbyl", alone or in combination, means an hydrocarbyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2phenylethyl and the like. The term "arylhydrocarbyloxycarbonyl", alone or in combination, means a radical of the formula arylhydrocarbyl in which the term "arylhydrocarbyl" has the significance given above. An example of an arylhydrocarbyloxycarbonyl radical is benzyloxycarbonyl. The term "aryloxy" means a radical of the formula aryl-O- in which the term aryl has the significance given above. The term "aromatic ring" in combinations such as substituted-aromatic ring sulfonamide, substituted-aromatic ring sulfinamide or substituted-aromatic ring sulfenamide means aryl or heteroaryl as defined above.
The terms "hydrocarbyloyl" or "hydrocarbylcarbonyl", alone or in combination, mean an acyl radical derived from an 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 cyclohydrocarbylcarboxylic acid such as cyclopropanecarbonyl, cyclohexenecarbonyl, adamantanecarbonyl, and the like, or from a benzfused monocyclic cyclohydrocarbylcarboxylic acid that is optionally substituted by, for example, a hydrocarbyloylamino group, such as 1,2,3,4- WO 00/69819 PCT/US00/06713 -77tetrahydro-2-naphthoyl, 2-acetamido-l,2,3,4tetrahydro-2-naphthoyl. The terms "arylhydrocarbyloyl" or "arylhydrocarbylcarbonyl" mean an acyl radical derived from an aryl-substituted hydrocarbylcarboxylic acid such as phenylacetyl, 3phenylpropenyl (cinnamoyl), 4-phenylbutyryl, (2naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4aminocinnamoyl, 4-methoxycinnamoyl and the like.
The terms "aroyl" or "arylcarbonyl" means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 2naphthoyl, 6-carboxy-2 naphthoyl, 6- (benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2naphthoyl, 3-hydroxy-2-naphthoyl, 3- (benzyloxyformamido)-2-naphthoyl, and the like.
The heterocyclyl (heterocyclo) or heterocyclohydrocarbyl portion of a heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylhydrocarbyloxycarbonyl, or heterocyclohydrocarbyl group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle that contains one to four hetero atoms selected from nitrogen, oxygen and sulphur, which is optionally substituted on one or more carbon atoms by a halogen, alkyl, alkoxy, oxo group, and the like, and/or on a secondary nitrogen atom by an hydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloyl, aryl or arylhydrocarbyl or on a tertiary nitrogen atom (i.e.
by oxido and that is attached via a carbon atom.
WO 00/69819 PCTUSOO/06713 -78- The tertiary nitrogen atom with three substituents can also form a N-oxide group. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, and the like.
The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, or a heteroarylhydrocarbyloyl (heteroarylhydrocarbyl carbonyl) group or the like is an aromatic monocyclic, bicyclic, or tricyclic heterocycle that contains the hetero atoms and is optionally substituted as defined above with respect to the definition of heterocyclyl. A "heteroaryl" group is an aromatic heterocyclic ring substituent that preferably contains one, or two, up to three or four, atoms in the ring other than carbon. Those heteroatoms can be nitrogen, sulfur or oxygen. A heteroaryl group can contain a single 5- or 6membered ring or a fused ring system having two 6membered rings or a 5- and a 6-membered ring.
Exemplary heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,2,4- or 1,2,3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or 1,3,4oxadiazolyl and isothiazolyl groups; fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranilyl groups; and 6-/6-membered fused rings such as 2,3- and 2,1benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl groups.
WO 00/69819 PCT/US00/06713 -79- The term "cyclohydrocarbylhydrocarbyloxycarbonyl" means an acyl group derived from a cyclohydrocarbylhydrocarbyloxycarboxylic acid of the formula cyclohydrocarbylhydrocarbyl-O-COOH wherein cyclohydrocarbylhydrocarbylhas the significance given above. The term "aryloxyhydrocarbyloyl" means an acyl radical of the formula aryl-O-hydrocarbyloyl wherein aryl and hydrocarbyloyl have the significance given above. The term "heterocyclyloxycarbonyl" means an acyl group derived from heterocyclyl-O-COOH wherein heterocyclyl is as defined above. The term "heterocyclylhydrocarbyloyl" is an acyl radical derived from a heterocyclyl-substituted hydrocarbylcarboxylic acid wherein heterocyclyl has the significance given above. The term "heterocyclylhydrocarbyloxycarbonyl" means an acyl radical derived from a heterocyclyl-substituted hydrocarbyl-O-COOH wherein heterocyclyl has the significance given above. The term "heteroaryloxycarbonyl" means an acyl radical derived from a carboxylic acid represented by heteroaryl-O- COOH wherein heteroaryl has the significance given above.
The term "aminocarbonyl" alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amino-substituted carboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents selected from hydrogen, hydrocarbyl, aryl, aralkyl, cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl radicals and the like.
The term "aminohydrocarbyloyl" means an acyl group derived from an amino-substituted hydrocarbyl- WO 00/69819 PCT/US00/06713 carboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents independently selected from hydrogen, alkyl, aryl, aralkyl, cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl radicals and the like.
The term "halogen" means fluorine, chlorine, bromine or iodine. The term "halohydrocarbyl" means a hydrocarbyl radical having the significance as defined above wherein one or more hydrogens are replaced with a 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 wherein each hydrogen has been replaced by a fluorine atom. Examples of such perfluorohydrocarbyl groups, in addition to trifluoromethyl above, are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.
Table 1 through Table 88, below, show several contemplated sulfonyl aryl or heteroaryl hydroxamic acid compounds as structural formulas that illustrate substituent groups. Each group of compounds of Tables 1 through 70 is illustrated by a generic formula, followed by a series of preferred moieties or groups that constitute various substituents that can be attached at the position clearly shown in the generic structure. The substituent symbols, R 1
R
2 X, are as shown in each Table, and are often different from those shown elsewhere herein in structural formulas bearing Roman numerals of capital letters. One or two bonds (straight lines) are shown with those substituents to WO 00/69819 PCT/USOO/06713 -81indicate the respective positions of attachment in the illustrated compound. This system is well known in the chemical communication arts and is widely used in scientific papers and presentations. Tables 71 through 88 illustrate specific compounds of the previous tables as well as other contemplated compounds using complete molecular formulas.
WO 00/69819 WO 0069819PCT[USOO/06713 -82- Table I Ph S ~-~CH 3 )rN CH3 P hii Ph--
H
0 Ph S C H 0",S .Ph s~ Ph
N
WO 00/69819 PTUO/61 PCTfUSOO/06713 -83- Table 2
HO,,
Z.
N.
H
N.N,
H
"c 0 OCH 3
N.
H
N.N.
H
HN
0 0 H 0D HN N~N? N N O 0 0
CH
3 H I N. y
-H
ZI
zx zx z: 0 o 0 4 0 0 0 0 0 x m 0 /z 0
ZI
ZI
0
ZI
ZI zx 0 0 x x W4 WO 00/69819 WO 0069819PCT[USOO/06713 Table 4 111R4
CH
3
N
N
N
N N
N
CH
3 ci CF 3 S CH 3 CI F
OCH
3
N'O
N
O
WO 00/69819 PCTUSOO/06713 -86- Table HO,
N
H
CH
3
CH
3
CH
3 N
N
CH3 CH3
"I
N s N%
N
H
Ss KSo s~r 0 TI, )",CH 3
CH
3 H 0 0 0 00 00 000 0 0 z/ z
CC
z zz zI WO 00/69819 WO 0069819PCTJUSOO/06713 -88- Table 7
H
NN
0 H 3 C
H
'CCH,
NY[ON&CH3
CH
3 0 H H
H
KY z N0 N ja 0 0 2 0 O, H 3
H
N 1 a
NH
2 0 H
F
H
N
F
F
H C 3 H H N N. NY H o H
HH
N Oa H 3 0 -0 WO 00/69819 WO 0069819PCTUSOO/06713 -89- Table 8
HO,
04 N NJN
CH
3 13 0 1 OC H 3 H H yN 0
H
,o H H
N
N N, o CH31 y 0
H
-0 NNy r~ 00
H
NNH
2 0fN K>CH3 0-
H
N N O 0 CH3 H H yjg.0
H,
H
N N, CH 3 >N,~J0 WO 00/69819 PCTUSOO/06713 Table 9
HO,
H
yN.
HL;M H H H
N
01 -CH3 H H
H
H NyNa, CH3 Nj, X
.,O
0 CH H N~ N)
N
CH
3 CH 3 N
N
CH3 CH3 H H H N N N N y~KU~
H
H a~ryCH Nya NV H2 0 CH3~ F~Q N H0 HII N N 0 0
H
N C F 0~r H H N y NC 0 P CH3 02 N N N' CH3 ~~0 WO 00/69819 WO 0069819PCTJUSOO/06713 -91- Table
HO,
Example 1 HN- 2 N/O
HN~~H
H
H
CH
3
H
CH
3
N;-
6H 3
CH
3
H
Example
R
-N
HN-/HN
-N
12 1-1N/ H
-N
13 1- 3 C -N 14 N
CH
3 HN
IH
16 a
QH
HN
I
H
H
'NI-a H
H
WO 00/69819 PTUO/61 PCT[USOO/06713 -92- Table I11 Example X A 1 0
N
N
2 0
I\A
Example X A 9 N.
10 S,,N 3 0 -a N 11 4 0 12 0 N N-CH 3 13 6 0 N-Ph 14 7 0 Ph 15 8 0 NJ 16 S ND S
N-OH
3 S \N N-Ph S -a/NO-Ph S -aNj) WO 00/69819 WO 0069819PCTUSOO/067 13 -93- Table 12 0,
NR
H
R4 I P1 O-01CH 0 I ~S,,,CH3 1J JSI%CH 3
N
Ph N~SI j.yS Ph 0 Ph
J
CF
3 N 1
N
P h
N
s
I
WO 00/69819 WO 0069819PCT[USOOIO6713 -94- Table 13
H
N,
H
N.
0
CH
3 H I N6
H
0 00 o x 0 x 0 x 0 xz 0 0 0 x -n -n 0 0/0 I 01 W x 00 0 0 C z 0 0 Z I 0 0 wIZ 0/ 0.
QI 0- /\C 0 00 2 0 0x 0 X 0 W t WO 00/69819 WO 0069819PCTIUSOO/06713 -96- Table
HOI-
111R4
N
I-
CH
3
N
C
3
~N
WO 00/69819 WO 0069819PCTUSOO/06713 -97- Table 16 N z~tt N
N
CH
3 CH 3 N s
N
X;I
N
IH
::Sy
N/
N~ Cos~ 0 N- N! NH 3
H
I "r/N 0 CH 3 s~ N/ WO 00/69819 PTUO/61 PCT[USOO/06713 -98- Ho H NTable 17 0 KzS.()XAr Example X Ar 1 0 2 0 \C I 3 0 4 0 \/0 0CH3
CH
3 6 0 6
CH
3 7 0
H
-N
8 0 9 0 0\/ 11 0 Example X Ar 12 S 13 S
C
14 s 15 S c 16 SCH3
CH
3 17 S 18 S
CH
3
-N
19 s 20 s C\ 21 S F 22 N N, WO 00/69819 WO 0069819PCT[USOO/06713 -99- HN Table 18 Cl 0=SI Ar -Example
X
H
1 -Na N \-CH 3 0 2 -N NH, CH3 0 0 QrN 0 H 0 4 N _f N O H 0
CH
3 6 _N 0
\_N
7
N
rCF 3 0 Example 8 9 WO 00/69819 WO 0069819PCTUSOO/067 13 -100- HO -r Table 19 61 Ar Example Example
HN-/
2 >4 H H
,,H
H
CH
3
-H
CH
3 6H 3
CH
3 HN \,N N
H
-N
11 HN-/
-N
12 N/4 H
-N
13
H
3 C -N 14 4 C 3 HN-a 16 ~N/
H
HN \/C 18 ~N/aCI
H
19 HN--a
H
>4 -CH
H
WO 00/69819 WO 0069819PCT[USOO/06713 -101- Table H0 Example -No-: 2
-N
H 3 3 -Na OHo 4 -NC -o CH 3 0 6
-N(
tNH 2 0 0 7 -NC<D 0 Example x
CH
3 9 -N
CH
3 10 -N
/\NH
11 -N N 12 -P CH3 0 13-N
CF
3 14 -N 15 -N N N0 2 16 IN-~ -N 0 WO 00/69819 WO 0069819PCT[USOO/06713 102- Tabl 21 HO YTbe2 o zs",- 01,"0-XA Example X Ar 1 0
N
pN 3 0 o-/ 4 0 0 a N \-/N-Cl 6 0N
N-PR
7 0 \/Na Ph 8 0 Example X A 9 N, 10 S I1I S N§1 12 S -13 13 S -a N-CH- 3 14 S N-Ph 15 ND -Ph 16
ND
WO 00/69819 WO 0069819PCTIUSOO/06713 -103-
H
HO Table 22 N R4 N Ph 0 Ph O4 0-CH 3 01II-J.' Ph O I ,P h NzN
N
N:S CH 3 S Ph -O "Ph JsN 0,_OCF 3 s,%L~
N
WO 00/69819 WO 0069819PCTIUSOO/06713 -104- Table 23 R 4
H
N,
H
N 'r 0 H CH 3 N yN- CH3 WO 00/69819 WO 0069819PCT[USOO/06713 -105- Table 24
HO~
4
N.
N
CH
3 N
CH
3 N B
K-
N.F
N.0
H
N. CH 3 N. CH 3
'NCH
3
HH
NOH H N CHCF3j 0 0 s 0\
H
NC0 2 HI N N fCH3 0
H
\S .N Y-N. CH 3 0 H0 N CH 0CH 3
N
0
H
3
C
-iz: NH N~ CH 3 N Ph 0 0 0 0 H 0 0 0 0NIN CH 3 0NN'P H H S 0~ WO 00/69819 WO 00/98 19PCTUSOO/06713 -106- Table R 4 N N N
N"'I
CH
3
CH
3
-~N
N N
CI
N
N N
CF
3 0 CF 3 oCH 3 N CH 3 WO 00/69819PCIS/671 PCT[USOO/06713 -107- Table 26
HO
'I-
N
OH
3
OH
3
'I
N
N
H
"N
0
S<
"CN/\
q Syo
N/
'N-
s II-I 0s
N
H
N
OH I 'N~a H "a s Nki N /I
OH
3 H WO 00/69819 WO 0069819PCT(USOO/06713 -108- Table 27
H
HO i 0 It R 4 0. C,
D
0 0 N s N. NN
CH
3 I~ >CF I WO 00/69819 WO 00/98 19PCTJUSOO/06713 -109- Table 28
H
R
4 0,CH3 H H
CH
3 O01--CH 3
HH
N Y- N N CH 3
H
N
H
N
NH
2
F
N ya
F
H
N
F
0 <CH 3
H
N Na
NO
2 H I"c NN yN 1- 0 H H N y N 0 CH3 H H N y N 0 CH3
H
0 WO 00/69819 WO 0069819PCT[USOO/06713 -110- Table 29
H
0O~ 0= Ar 11 0 2 0 2 0
'CH,
3
S
F
4 s
H
s 6 s WO 00/69819 WO 0069819PCT[USOO/06713 111- Table Example 6 6 R 2 x Ar
\N
-N
\/CI
-a CH 3 WO 00/69819 WO 0069819PCTUSOOIO6713 -112- 0 Table 31 HO,
N
H oz~s 6 l.Ar Example X Ar 0 0,~ 2 0 -0
'"CH
3 3 S 4 s 0 -0 CH 3 S o WO 00/69819 WO 0069819PCTJUSOO/067 13 -113- Table 32 Example X Ar 1 0 2 0
\CI
3 0 4 0
CI
0 H
OH
3 6 0
H
3 7 0 H
-N
8 0 9 0 CN 0\/ 11 0 Example X Ar 12 s o 13 s C I 14 S C 15 S c 16 s
H
CH
3 17 S 18 S /C CH 3
N
19 s 20 s 21
F
22 S WO 00/69819 PTUO/61 PCT[USOO/06713 -114- Table 33 7 Example -NR 7 R 8
H
1 -NC N,_CH 3 0 2 -N QrNH, CH 0 3 -N
N
0
H
0 OH0 0 -N
OH
3 0 6 _NQ o
N
7
N
CF
3 0 Example -NR 7R8 8 -No-0 9 -No-O-0-
-N
I -No-,_o WO 00/69819 WO 0069819PCTJIJSOO/06713 -115- Table 34 HO N
H
Exampic -NR 7 R 8 2N
H
H
4 N"--CH 3
H
CH
3 6N
CH
3 7
CH
6H 3 8 N NCH
OH
3 HN
N
H
Example -NR 7 R 8
-N
11 HN-
-N
12 N H
-N
13
H
3 C -N 14 CH3 16 N~ /O
H
17 HN \C
N-
18
N/\/CI
H
19 HN-/ 20 N
H
3
H
WO 00/69819 PTUO/61 PCT[USOO/06713 -116- Table Example X Ar
/N
2 0N" 3 0 4 0 0 \/aNNNCI 6 0 N N-PI 7 0 ND Pl 8 0 ND -Example X Ar pN S 10 N\S 12 S o
H
3 1 3 s __Aa N N-CH 3 14 NP 15 S N Ph 16 s Nj WO 00/69819 WO 0069819PCT[USOO/06713 -117- Table 36 Na '1 R4 Ph
S
Ph SONCH3_ICPh 117zrOIS-CH3 S S Ph Ph) NJ 0- CS &1s
N
S--Ph S
N
WO 00/69819 PCTUSOO/06713 -118- Table 37 HO N
H
Ozs 0R4 N~4 op, H
H
H
N
N IfNT
CH
3 0 ci H H H
N
0 0D
CH
3 H KH N
N
H N
NN
0 CF 3 0 OCH 3 H Hy Nr: a,"rN N j
CF
3 Nk
CF
3 H H H NoNy a N N N 000
CH
3 H
H
f y N K Q N N O N c H WO 00/69819 WO 0069819PCTJUSOO/06713 -119- Table 38
HO,.
NCF
N. CH 3 I D <rCI yF 0 2N.~ H
H
H NyCH3 CH3 IRk- OH N YCF3 0 k I 1 0 IN
CH
3 ~rCH3
S
rC02H5 y CH 3
NH
H
7N, CH 0 CH3
H
N.t Nh
H
3
C
H H0 2N~
,CH
3 N Ph
I
~i~~r142 0 0 0o 2 NH 3 0 N. N ,CH3.
S
N_
WO 00/69819 PTUO/61 PCTIUSOO/06713 -120- Table 39 111R4 N N
NA
JN
CH
3
-CH
3
-N
C
3 0 WO 00/69819 PTUO/61 PCTfUSOO/06713 -121- Table HO,
N'
H
0
OH
3 H 3 N N s~ I
N
(N
H
C(N
0 ySs As 0>O Ocs cr SyS 0 ,s
OH
3
H
mC)U
C)
0
C)
I
U
0 0
C)
C)
I
U
0 0
U
0 0 cn 0 0 0 Cl) dcnI 0 0
C)
6 m 0 mz 6 WO 00/69819 PTUO/61 PCT[USOO/06713 -123- Table 42 HO,
N.
H
,R
4 i, CH3 H OH 3 H H H I Hy lN :N N N N rN 0 C0& H3
CH
3 op O1--CH 3 H H HH N N CH 3 N 0N~N AoiII- 0 0C H H
OH
3
H
H N N 'N yr OH3 H 0
OH
3 H H CH CV N N 'NI N MW CH 3
HOHH
H H 11 2 0 H
F
H
N a 0
H
N 'N
NO
2
H
H
N 'N
OH
3 PCTIUSOO/10671 3 WO 00/698 19 -124- Table 43 Example X Ar Example X
A
1 0 12
S
Cl 2 0cl 13 s 3 0 14 S C 4 0 CI 15 Cl 0 16
S
CH
3
CH
3 6 0 17 s 5 3
C
3 7 0
CH
3 18 S.
CH
3 -N
-N
8 0 19 9 0 -N 20
-C/
0 F 21 s /-pN -S4 11 0 22 WO 00/69819 PTUO/61 PCTfUSOO/06713 -125- Tabe 4
~R
Example -NR 7 R 8 _N
H
1 -N
NCH
3 0 2 NH'CH3 0 3 -N
N
0 H0 OH0 0 -N
CH
3 N -CH3 0 6 _NQ
N
7
N
rCF 3 0 Example -NR 7 R 8 8 -Na 9 -Na -Na 11 -Na WO 00/69819 PCTUSOO/06713 -126- Table Example -NR 7R8 N-0 2 N/O
H
3 N H 3
H
4 N--"H
H
N-X
CH
3 6 N
CH
3 7 NN-X,_,CH3 6H3 8 NN NNC H 3
CH
3 HN \,N "N \,NC
H
Example -NR 7R8
-N
11 HN-/
-N
12 N H
-N
13
H
3 C -N 14 H N CH3 HN
CH
3 16
IH
HCH
17
-C
HN- \/C 18 N/
\/CI
H
19 HN CH 20 INN/\ /CH 3
H
WO 00/69819 WO 0069819PCTIUSOO/06713 -127- Table 46 HO,
N
H It X ,Ar Example X Ar 1
N
-N
2 0 4 0 /N7 0 a N \/N-Cl 6 0 \/&NNP1 7 0 -Pt 8 0 N\ Example X Ar 9
SN
S
11 s 12 S NQ
H
3 13 S &N 3 114 s aN \/N-Ph 15 s Ph 16 s -N WO 00/69819 PTUO/61 PCTfUSOO/06713 -128- Table 47 0, S, 3 .00 0 C 3 Rz P h
CH
11- 01 CH3
N
0~ Ph0 Phr Sl CH 3 S1%-IPh SN-Ph 0= 0=<z 0 0
I
tZm 0= 0 0 tI 0x 0
ZI
0= 0
ZI
0 WO 00/69819 PTUO/61 PCT[USOO/06713 -130- Table 49 0
N
HO,
N
H 0:=s N. CH 3 li
H
H
H. NH CHN )f CH 3 OH/ N F
H
JyN CH 0 ,H
H
Ph
H
3
C
H H0 K rNH2 N SH N PhI 0 0 00 0 0 0 A CH3 N )Ph _X N~
S
PCTUSOOIO6713 WO 00/69819 -131- Table HO,
N
H
R4 N N
NN
H
3
OCH
3
N
N N
N
CF
3 ro WO 00/69819 PTUOI61 PCT[USOO/06713 -132- Table 51
CH
3
CH
3
I
N )j NN
N
N
H
J~s< 0 ifQ~w ~~s
NYN~O
ys~j:y:o N
-N
H
3 CH3
N
3 H b o d o-nu b o d o-nu 0 0
I'I
0 0 0
I
U
0 0o 0 cno 0o 0 0o 0 0 6 cn Ki 0o 0
U,
I
0 Iz pCT[USOO/0671 3 WO 00/69819 -134- Table 53 HO,
N'
H
0,CH 3 H H
CH
3 H N H N H H 00
H
N
H
0
H
N
H
N a
F
0 H
N
WO 00/69819 WO 0069819PCTfUSOO/06713 -135- Table 54 HO N
H
Example X Ar 1 0 2 0 C /IC 3 0 4 0 \/C
CH
3 6 0
CH
3 7 0 -H
-N
8 0 9 0N 0\/ 11/-0 Example X Ar 1 2 S 13 s \/CI Cl 14 S S c 16 S
H
CH
3 17
S
CH
3 18 s O CH
-N
19 s 20 s 21 s 22 S
N
WO 00/69819 PTU0161 PCT[USOO/06713 -136- Table 0 s HON 1
OSR
7 Example -NR 7 R 8
H
1 -NC N,,,CH 3 0 2
-N
NH'CH3 0 3 -N 0
N
0 H 0 4 -N _f N O H -N
CH
3 0 6 _NQ 0o
N_,
7
N:
rCF 3 0 Example -NR 7 R 8 8 Na- 9 -Nao, C 11 WO 00/69819 PTUOI61 PCTfUSOO/06713 -137- Table 56 0 s HO R Nu
H~
Example -NR 7 R 8
HN--
2 N
H
3 N 3
H
4 N~--CH 3
H
CH
3 6
OH
3 7 N -,,CH3 6H 3 8 ~N'--CH 3
OH
3
N/
H
Example -N7R8
-N
11 HN-
-N
12 N H
-N
13
H
3 C -N
OH
3 16 N
H
17 HN C 18
\/CI
H
'9 HN-/
CH
3 20 ~N/a
H
H
WO 00/69819 PTOOI61 PCT[USOO/06713 -138- Table 57 0 s HON 1
H
aAr .Example X Ar /-pN 1 0 2 0 3 0 4 0 0 N-C 6 0 N NP 7 0 \/Na Pg.
8 0 Example X
A
9 s 10
N
11 I s 12 S -N
H
3 13 s N N-CH 3 h 14 s -N N-Ph 15 S -Ph 16 s -N\ PCT[USOO/06713 WO 00/69819 PTUO/61 -139- Table 58 0 s
H
0/I Na R0 0 CH 3 Nz: Ph I P
N-*CH
3
IN
S
CH
3 -cr SICH 3 ON-ciPh S Ph Ph
N
.oof) F yP WO 00/69819 PCTUSOOIO67 13 -140- Table 59 0 s
H
0s
HH
H N 11:z N N J:>0 0 CF13 0F H H H IN ~N N~
CH
3 N31jyf CA N CH 3 c H NHHP
I
HH H yN NON
HH
H J 0c r CF 3 N0 OCH 3 00
HH
",NNyNCH 3 0 WO 00/69819 PCTIUSOO/06713 -141- Table 1-1R4
CH
3
H
CH
3 hofl (Tfl CH3 CHs N CH 3 Ozk0 0CH 3 N y CH3 yY3H
H
H
3
C
H H0
NH
2 N -s-CH 3 N Ph V, S N H3 0 0 0,A NCH 3 0rO.NA.Ph
N,
WO 00/69819 WO 0069819PCT[USOO/06713 -142- Table 61
HO,
H
op
I
N
N
CF
3
CH
3
CI
CH
3 N. N pCT[USOOIO6 7 13 WO 00/69819 -143- Table 62 HO,)LN
H
CH
3 1CH 3 117: z s N) N y
N
N
H
I*Z
S
N
S 0 c )y >0 00 SCI C H3
N.
s N'i
N
CM N
NH
00 0 00 0'0 '-A0n pCrUSof06713 WO 00/69819 -145- Table 64 o s H O N I
H
0 it 0
R
13 H H CH3
CH
3 H H N y NCH3
H
N.
H Ht N Ya NH2 "0 H H H ca N yHH H CHKIK3
.H
00 N OfO H
IN
H N H CH 3 N Ya CH3 WO 00/69819 PCTIUSOO/06713 -146- Table HO,
N'
H
4
H
H
yN, CH3 CH Y H H N N 3~ 0 A
H
~N.
H N Y-JOCH 3 N NH0 0NHH H H H H
N
<N N0 2
H
N ra
F
HI)If N N CH 3 "0 WO 00/69819 PTUOI61 PCTfUSOO/06713 -147- Table 66 HO,
N
H
o v-N R4 0 RH H H 3
CH
3 H 0, CH 3 H H H H N N.yN N )r1 0 HH H CHH3 I OH~H~ I 0 NyCH 3
C
3 H-C N N N. H H ~Ji1~~N N.NN CH3. H >LH3 L)N.CH N. NHN 01!
H
-H F N
N.NO
H N N.faN N N.
H 0 Nya~~ N.2 OH 3 N0 0 H WO 00/698 19 PTUO/61 PCT[USOO/06713 -148- Table 67
CH
3 Exampic
R
HN-/
2 N'-O
H
H
4 N'-'-CH 3
H
CH
3 6 ~N
CH
3 7 ~N -,_CH3 6H3
CH
3 N \,N
H
Example
-N
11 HN-
-N
12 "1.N O H
-N
13
H
3 C -N 14 N4
CH
3 HN-
'CH
3 16 a
CH
H
'9 HN CH >4-a
H
PCT[USOO/06713 WO 00/69819 -149- Table 68 HO-1,
CH
3 Example X Ar Example X Ar N, 1 9
N,
/N 2 0 \NN 10 SN 3 0 4 0 0 N N-CH 3 6 0 -0 N \-N-Ph 7 0 N -Ph 8 0 0N 11 S 12 S -O N 13 S N N-CH 3 14 S N\N-Ph 15 S \/ND -Ph 16 s -N: -00 2 00 0 0 0 0 00 0o 0 0 z
C)
WI
zI WO 00169819 PCT[USO/06713 -151- Table
HO
N
H
,R4N
H
N0"
H
N"
H
H
N."
13 H H -aCH3
CH
3 H H NN N H H CH31 Y 'oo N
NH
NH
2 0
HF
lkczr F 0 Ii" lC, H H NYO N
H
H 0y"!0CCH N~ NO 0 CH3 H I N aN2 N" t x "~0
H
N Na
OH
3 AN~0 WO 00/69819 WO 0069819PCTIUSOO/06713 -152- Table 71 0
NHOH
0
CF
3 0 HO
NHOH
0
H
3 C NHOH ClH 0,0 OCF 3 N- NHOH
.OCF
3 -S- 0 0
H
3 0
NHOH
0
H
3 C NH0H 0- \/&OCF 3 0
H
3 C
NHOH
O -N
SCF
3 0
NHOH
0
OCF
3
CH
3 0.
,NHOH
H
3 C 0U 3C NHOH 00 0
NHOH
I NY- 0, \ci SCF 3 WO 00/69819 WO 0069819PCTJIJSOO/06713 -153- Table 72 0 NH0K 7 9 0 0Oi 0
~S-N~\--CJOCF
3 4 hi"-N-OH O NHO -0 %S-Nj-O O 0NHO-o 0 NHO: 00 00 O 1 Nl- 12 1'11\ 0 PCTIUSOOIO6713 WO 00/69819 -154- Table 73 0 N
NHOH
F
3 C N ND
O
H 0
HOH
N
S-ND OoK
F
3 0 0 0 HO NH0H' 0.S-ND 0 0-NHOH 0
CH
3
O
NH0H 0- -S-ND 0.Oo
CH
3 0 0 NHOH 0
NHOH
0
S
11 -0,0 0 06- WO 00/69819 C[SO/61 PCTfUSOO/06713 -155- Table 74 0 HO NHOSi(CH 3 3
NCH
0f' O CF 3 0 _HO NHOSi(CH 3 3 Sr ~S-ND7O'- 3 0 0 HO ,NHOSi(CH 3 3 0 N0 NNHOSi(CH 3 3 4 S-ND-0-aCF3 0 0 O0-,OCF3 0 HO LNHOSi(CH 3 3
NCH
2 SNjj- N3D-aOCF 3 HC0
H
3 NHOSi(CH 3 3 Do 1
,OCF,
H
3 C 0NHOSi(CH 3 3 I 1200'7
H
3 C 0NHOSi(CH 3 3 S-SI- ,J&SCF3 14 0 N NHOSi(CH 3 k ND''& 8 j NHosi(CH 3 3 NHOSi(CH 3 3
H
3 C 0
H
3 C vINHOSi(CH 3 3 (I )N5 150 WO 00/69819PC/SO071 PCT[USOO/06713 -156- Table
NHOH
H
3 C 0 NO N H O6 H 0NHOH 6~s- N N -(ajCF, o NHOH 0 0 6,k HOH F 0,11
F
9 0~y- 0NHOH li CH 3 0 NHOH Q SNN N1\ 13 0'
N-NHOH
F
3 C 0 0 iOCF 3 0 NHOH
HCH
H3 N 0
NHOH
10 1 0 HNI>--jNHOH MeO 0
NH
Me0 0 C; 14 0
;NHOH
1800Ss
D-OC
i~d 0" 0 WO 00/69819 PTUO/61 PCT[USOO/06713 -157- Table 76
NHOH
,NHOH
0
NHOH
CSO
NHOH
9 0 NHOH
SN
0 NHOH
O,
4 ND-SCo 0 N0NHOH
F
3
C--
N S-~j0~f
HO-O
11 WO 00/69819 PTUOI6I PCT[USOO/06713 -158- Table 77 N*H 0F 3 C NH0 jLNHOH N~)j
NHOH
S 0 N§--aCF 3 2 0- "ND -0vcCF rlNH0
F
3 C N H0 N NHOHN j: jLNHOH N HOsNHOH <N
H
0WjCF3
C
3
O
r'HS 0 ~fNHH OSs-N-i-0N&jF3 86
CH
3
NHO
0 '6-N -O-CFF ~fL HOH N~ H0 -6 N.J 0
J-CF
3 10 0J3% WO 00/69819 PTUOI61 PCTfUSOO/06713 -159- Table 78
CH
3 9 I I ND 0"I CF 3 0) IN 0
NHOH
CI 0 3 0 CF
CH
3 0 NHOH 0 -0
CH
3 0. WO 00/69819 PTUO/61 PCTIUSOO/06713 -160- Table 79
CH
3 0
NHOH
0' 0 MeO 0
NHOH
NH0 2 0 N NHOH 0 OH 3
CH
3
CH
3
CH
3
CH
3 0 0 CH3
NHOH
0 -S-N NHOH 40 QSNDj-
CH
3 0 0 0a
SCF
3
NHOH
3 0O 0 6
NHOH
7
H
AcN 0
NHOH
8 0 WO 00/69819 WO 0069819PCT1JSOO/06713 -161- Table Ho NHO O 0' -NDo 2 6- N NHO -0- 3F N C0
HO
og NQ NDJ&OCF 3
H
3 C 0 NH 0 H3 0NHO--0O -aOCF 3
H
3 C 0NHO.LI- I 00 0C-*CS ND§-OOOCF3 130 eN(N0 N NHO 0 606
H
3 9C 0 ,C-N LNHO'00
ND--OF
0 NHOJ-0I
H
3 C 0 C NHI 0 N3D--,
CF
12 00 14 ,0N I
OF
WO 00/69819 WO 0069819PCTUSOOIO6713 -162- Table 81 /00 NH0 4 7 N NHO ~0 i: 0 1 0 0-01 2 CH 3
H
3 0 N NHO_J -NH0 NI /0 00 0,0~/ 0 NHO 0 NHO Q 0_ N 0 0 -a/OCF 3 0NHO-() 0 NHOVN N 0
N
7 6OH Os a 7 0 8 01- 0 NHH3C. NCH3 N0 '0J F 0NHO-G 0ON F N 0O N H 0 0D
,CH
3 0 N NHO4 C S--N HN' 0 0 S-ND- -0 12 0 NHO4
CH
3 O0 NO0 N 3 0' I- cH 3 0 0 14
H
0 0 SNH O
S
3
NH
r, 0 0
F
3 C 0 0 16 WO 00169819PCJIO/61 PCT[USOO/06713 -163- Table 82
CH
3 9 9
NHOH
CH
2 tO 0
,NHOH
CH
3 9
NHOH
L S-ND 0 11 0CH 3 WO 00/69819 WO 0069819PCTUSOOIO6713 -164- Table 83 CH3 'N..H3
HSN
-NHOH
CH
3
-N-CH
3 HN CH3-N-CH 3
NHOH
3 0 DOC CH3 -N CH3 So0 HN 0 CH3'N..CH 3 4 0
NHOH
0~ WO 00169819 WO 0069819PCTIUSOO/06713 -165- Table 84
NHOH
NHOH
2 0
NHOH
S-N a -3 0a
H
3 CO 0 WO 00/69819 PTUOI6I PCTIUSOO/06713 -166- Table
NHOH
NHOH
N HOH WO 00/69819 PTUO/61 PCTfUSOO/06713 -167- Table 86 F 0
NHOH
N S-N 0 1 0 C F 3
NHOH
F 0
NHOH
00C/ 3 F 0
NHOH
0 WO 00/69819 PTUO/61 PCT[USOO/06713 -168- Table 87 0 -D 0,1
F
1 0 0 CFa OH 0 NH0H 2 0
NHOH
OHO0
NHOH
4 0 0 -j DHO0
-NHOH
S 0o- I
OCH
3 PCT[USOOIO6713 WO 00/69819 -169- Table 88 0
NHOH
C 0o 0- CF 3
H
2
N
NHOH
H
2
N
NHOH
H
2
N
,NHOH
H
2
N
NHOH
WO 00/69819 PCT/US00/06713 -170- Treatment Process A process (method) for treating a host mammal having a condition associated with pathological matrix metalloprotease activity is also contemplated. That process comprises administering a compound described hereinbefore in an MMP enzymeinhibiting effective amount to a mammalian host having such a condition. The use of administration repeated a plurality of times is particularly contemplated.
A contemplated compound is used for treating a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee or human that has a condition associated with pathological matrix metalloprotease activity.
Also contemplated is the similar use of a contemplated compound in the treatment of a disease state that can be affected by the activity of metalloproteases such as TNF-a convertase. Exemplary of such disease states are the acute phase responses of shock and sepsis, coagulation responses, hemorrhage and cardiovascular effects, fever and inflammation, anorexia and cachexia.
In treating a disease condition associated with pathological matrix metalloproteinase activity, a contemplated MMP inhibitor compound can be used, where appropriate, in the form of an amine salt derived from an inorganic or organic acid. Exemplary acid salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, WO 00/69819 PCTUSOO/06713 -171butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.
Also, a basic nitrogen-containing group can be quaternized with such agents as lower alkyl (C l
C
6 halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, long chain (C 8
-C
20 halides such as decyl, lauryl, myristyl and dodecyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others to provide enhanced water-solubility.
Water or oil-soluble or dispersible products are thereby obtained as desired. The salts are formed by combining the basic compounds with the desired acid.
Other compounds useful in this invention that are acids can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts.
In some cases, the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.
Total daily dose administered to a host mammal in single or divided doses of an MMP enzyme- WO 00/69819 PCTUSOO/06713 -172inhibiting effective amount can be in amounts, for example, of about 0.001 to about 100 mg/kg body weight daily, preferably about 0.001 to about mg/kg body weight daily and more usually about 0.01 to about 10 mg. Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. A suitable dose can be administered, in multiple sub-doses per day. Multiple doses per day can also increase the total daily dose, should such dosing be desired by the person prescribing the drug.
The dosage regimen for treating a disease condition with a compound and/or composition of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as Part of a drug combination. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the preferred dosage regimen set forth above.
A compound useful in the present invention can be formulated as a pharmaceutical composition.
Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
Topical administration can also involve the use of transdermal administration such as transdermal WO 00/69819 PCT/US00/06713 -173patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania; 1975 and Liberman, H.A.
and Lachman, Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, 1980.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic monoor diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa WO 00/69819 PCTUSOO/06713 -174butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered p p, the compounds can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.
For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or WO 00/69819 PCT/IUS00/06713 -175diluents mentioned for use in the formulations for oral administration. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.
Preparation of Useful Compounds Procedures are provided in the discussion and schemes that follow of exemplary chemical transformations that can be useful for the preparation of compounds of this invention. These syntheses, as with all of the reactions discussed herein, can be carried out under a dry inert atmosphere such a nitrogen or argon if desired.
Selected reactions known to those skilled in the art, can be carried out under a dry atmosphere such as dry air whereas other synthetic steps, for example, WO 00/69819 PCT/US00/06713 -176aqueous acid or base ester or amide hydrolyses, can be carried out under laboratory air.
Aryl and heteroaryl aryl compounds of this invention as define above by W can be prepared in a similar manner as is known to those skilled in the art. It should be understood that the discussion below refers to both aromatic systems, i. e., heteroaromatics and carbon aromatics, even though only one may be specifically mentioned.
In general, the choices of starting material and reaction conditions can vary as is well know to those skilled in the art. Usually, no single set of conditions is limiting because variations can be applied as required and selected by one skilled in the art. Conditions will also will be selected as desired to suit a specific purpose such as small scale preparations or large scale preparations. In either case, the use of less safe or less environmentally sound materials or reagents will usually be minimized. Examples of such less desirable materials are diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, some halogenated solvents, benzene and the like. In addition, many starting materials can be obtained from commericial sources from catalogs or through other arrangements.
An aromatic compound of this invention where y is 1 can be prepared as illustrated by converting a carbonyl group bonded to an aromatic (e.g.,benzene) ring ortho-substituted with a sulfide.
The sulfide can be prepared via a nucleophilic displacement reaction of the ortho fluoride.
The nucleophile can be a thiol or thiolate anion prepared from a aryl thiol discussed below. A WO 00/69819 PCT[USOO/06713 -177preferred thiol is 4-phenoxybenzenethiol converted in situ into its anion (thiolate) using potassium carbonate in iso-propyl alcohol at reflux temperature.
The carbonyl group can be a aldehyde, ketone or carboxylic acid derivative, i.e, a protected carboxylic acid or hydroxamate. A preferred carbonyl group is an aldehyde and a preferred aldehyde is 2-flourobenzaldehyde (orthofluorobenzaldehyde). A ketone can be converted by oxidation into an acid and/or an acid derivative using reagents such as those discussed below for oxidation of a sulfide or other methods well known in the art. It is noted that this oxidation can accomplish the oxidation of a sulfide intermediate into the corresponding sulfone in the same reaction system; in the same pot, if desired.
The carbonyl group can then be homologated if desired by reaction with an anion to form an addition compound. An example of a homologation reagent is a tri-substituted methane compound such as tetraethyl dimethylammoniummethylenediphosphonate or trimethylorthoformate. Tetraethyl dimethylammoniummethylenediphosphonate is preferred. Hydrolysis of the reaction product can provide a phenylacetic substituted on the aromatic ring with a sulfide of this invention. Acid hydrolysis is preferred. Acids and bases are discussed below and hydrochloric acid is preferred.
The sulfide can then be oxidized to form a sulfone in one or two steps as discused below. A preferred oxidizing agent is hydrogen peroxide in acetic acid. The carboxylic acid product or WO 00/69819 PCT/US00/06713 -178intermediate of this invention can then be converted into a protected derivative such as an ester or converted into an activated carboxyl group for reaction with hydroxylamine or and protected hydroxylamine; i.e, a hydroxamate. The conversion of an acid into a hydroxamate is discussed below as is the coupling process and removal of a protecting group if required.
The preferred protected hydroxamic acid derivative is the O-tetrahydropyranyl compound and the preferred coupling procedure utilizes a diimide (EDC), hydroxybenzotriazol and DMF solvent for the coupling reaction to form the intermediate.
hydroxybenzotriazol activated ester. A preferred reagent for removal of the THP protecting group is hydrochloric acid.
Alkylation of the acid at the carbon alpha to the carbonyl group to form the compounds of this invention can be carried out by first forming an anion using a base. Bases are discussed below. The preferred bases are strong bases that are either hindered and/or non-nucleophilic such as lithium amides, metal hydrides or lithium alkyls.
Following or during formation of the anion, an alkylating agent (an electrophile) is added that undergoes a nucleophilic substitution reaction. Nonlimiting examples of such alkylating agents are haloalkanes, dihaloalkanes, haloalkanes also substituted by an activated ester group or activated esters and alkanes substitued with sulfate esters.
Activated ester groups are well known in the art and can include, for example, an activated ester of an alcohol or a halo compound, an ester of a WO 00/69819 PCTUSOO0/06713 -179haloalcohol such as a bromo-, iodo- or chloroderivative of a tosylate, triflate or mesylate activated ester. Compounds wherein, for example, R 2 and R 3 are taken together as defined above, can be prepared using disubstituted alkylating agent; i.e., alkylating agents with two leaving groups in the same molecule. For example, 1,5-dihalo-diethylether or analogous reagents containing one or more sulfate ester leaving groups replacing one or more halogens can be used to form a pyran ring. A similar sulfur, nitrogen or protected nitrogen alkylating agent can be used to form a thiapyran or piperidine ring. A thiapyran can be oxidized to form a sulfoxide or a sulfone using methods discussed herein. A leaving group in an electrophilic reagent, as is well known in the art, can be a halogen such as chlorine, bromine or iodine or an active ester such as a sulfonate ester, toluenesulfonate (tosylate), triflate, mesylate and the like as discussed above.
The conversion of a cyclic amino acid, heterocycle or alpha-amino acid defined by R 2 and R 3 that can include an amino acid (nitrogen heterocycle), which can be protected or unprotected, into a compound of this invention can be accomplished by alkylation or acylation. The carboxylic acid group can be protected with a group such as an alkyl ester such as methyl, ethyl, tert-butyl and the like or a tetrahydropyranyl ester or an arylalkyl ester such as benzyl or it can remain as a carboxylic acid.
A protected amino acid such as an ethyl ester is preferred. The substituent on the heterocycle group is as defined above and can include hydrogen, tertbutoxycarbonyl (BOC or tBOC), benzyloxycarbonyl
(Z)
WO 00/69819 PCT/US00/06713 -180and iso-butyloxycarbonyl groups. In addition, the amine can be considered as being a protected intermediate as well as being a product of this invention when the N-substituent is not hydrogen.
The nitrogen substituent on the amino acid portion of the compounds of this invention can be varied. In addition, that variation can be accomplished at different stages in the synthetic sequence based on the needs and objectives of the skilled person preparing the compounds of this invention. The nitrogen side chain variations can include replacing the hydrogen substituent with a alkyl, arylalkyl, alkene or alkyne.
This can be accomplished by methods well known in the art such as alkylation of the amine with an electrophile such as halo- or sulfate ester (activated ester) derivative of the desired sidechain. An alkylation reaction is typically carried out in the presence of a base such as those discussed above and in a pure or mixed solvent as discussed above. A preferred base is postassium carbonate and a preferred solvent is DMF.
The alkenes, arylalkenes, arylalkynes and alkynes so formed can be reduced, for example, by hydrogenation with a metal catalyst and hydrogen, to an alkyl or arylalkyl compound of this invention and a alkyne or arylalkyne can be reduced to a alkene, arylalkene, arylakane or alkane with under catalytic hydrogenation conditions as discussed herein or with an deactivated metal catalyst. Catalysts can include, for example, Pd, Pd on Carbon, Pt, Pt02 and the like. Less robust catalysts (deactivated) WO 00/69819 PCTJSO/06713 -181include such thing as Pd on BaCO3 or Pd with quinoline or/and sulfur.
An alternative method for alkylation of the amine nitrogen is reductive alkylation. This process, well known in the art, allows treatment of 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, reductive alkylation can be carried out under hydrogenation conditions in the presence of a metal catalyst. Catalysts, hydrogen pressures and temperatures are discussed and are well known in the art. A preferred reductive alkylation catalyst is borane:pyridine complex.
In the case where an intermediate is a carboxylic acid, standard coupling reactions well known in the art can be used to form the compounds of this invention including protected intermediates.
For example, the acid can be converted into an acid chloride, mixed anhydride or activated ester and reacted with an alcohol, amine, hydroxylamine or a protected hydroxylamine in the presence of base to form the amide, ester, hydroxamic acid, protected hydroxamic acid. This is the same product as discussed above. Bases are discussed above and include N-methyl-morpholine, triethylamine and the like.
Coupling reactions of this nature are well known in the art and especially the art related to peptide and amino acid chemistry. Removal of the protecting group can be accomplished, if desired, using standard hydrolysis conditions such as base WO 00/69819 PCT/US0O/06713 -182hydrolysis or exchange or acid exchange or hydrolysis as discussed.
The Schemes and/or dicussion also illustrate conversion of a carboxylic acid protected as an ester or amide into an hydroxamic acid derivative such as a O-arylalkylether or Ocycloalkoxyalkylether group such as the THP group.
Methods of treating an acid or acid derivative with hydroxylamine or a hydroxylamine derivative to form a hydroxamic acid or hydroxamate derivative are discussed above. Hydroxylamine can be used in an exchange reaction by treatment of a precursor compound where the carboxyl is protected as an ester or amide with one or more equivalents of hydroxylamine hydrochloride or hydroxylamine at room temperature or above to provide a hydroxamic acid directly. The solvent or solvents, usually protic or protic solvent mixtures such as those listed herein.
This exchange process can be further catalyzed by the addition of additional acid.
Alternatively, a base such as a salt of an alcohol used as a solvent, for example, sodium methoxide in methanol, can be used to form hydroxylamine from hydroxylamine hydrochloride in situ which can exchange with an ester or amide. As mentioned above, exchange can be carried out with a protected hydroxyl amine such as tetrahydropyranyl-hydroxyamine (THPONH2), benzylhydroxylamine (BnONH2), 0- (trimethylsilyl)hydroxylamine and the like, in which case the compounds formed are tetrahydropyranyl (THP), benzyl (Bn) or TMS hydroxamic acid derivatives. Removal of the protecting groups when desired, for example, following further WO 00/69819 PCT[USOOIO6713 -183transformations in another Part of the molecule or following storage, can be accomplished by standard methods well known in the art such as acid hydrolysis of the THP group as discussed above or reductive removal of the benzyl group with hydrogen and a metal catalyst such as palladium, platinum, palladium on carbon or nickel.
alpha-Amino acids or alpha-hydroxy carboxylic acids or protected carboxylic acids, hydroxamates or hydroxamic acid derivatives or intermediates (precursors) of this invention can be prepared by displacing, for example, a halogen, sulfate ester or other electrophile, from the alpha carbon of an acid or a derivative as listed. Methods for the halogenation of acids, esters, acid chlorides and like are well known in the art and include, for example, the HVZ reaction, treatment with CuC12, Nbromo- or N-chloro-succinimide, 12, carbon tetraiodide or bromide and the like. The halogen can be displaced with a nucleophile in an SN2 reaction.
Nucleophiles can include hydroxide, ammonia or amines.
The aryl or heteroaryl carboxylic acids of this invention where Y is 0 and z is 1 can be prepared from heteroaryl or aryl fused lactones. An example of a fused lactone is phthalide. A preferred starting material is phthalide. This compound can be treated with an thiol, thiolate or metal -SH in order to undergo a SN2 displacement at the methylene carbon to provide a sulfide or thiol compound of this invention or intermediate to a compound of this invention. A preferred thiol is 4-phenoxybenzenethiol that is used in the presence of WO 00/69819 PCT/1S00106713 -184potassium carbonate as a preferred base. The sulfide can be oxidized, before or after conversion of the acid to a hydroxamate or hydroxamic acid, to a sulfone of this invention. A preferred oxidizing agent is meta-chloroperbenzoic acid.
A preferred acid activating group is the chloride prepared by reaction of an acid with oxalyl chloride as a preferred reagent. A phthalide or a heteroaryl analog of a phthalide can be treated with a Lewis acid such as zinc chloride or zinc bromide along with a halogenating reagent such as phosphorus trichloride or thionyl bromide or the like to form a ortho-(haloalkyl)-aryl acid or ortho-(haloalkyl)heteroaryl acid derivative. Examples include bromomethyl acid bromides and chloromethyl acid chlorides. These carboxylic acids can be derivatized with protecting groups, hydroxamic acids or hydroxamic acid precursors (hydroxamates) or hydrolyzed to the acid as required. A preferred hydroxamate forming reagent is 0- (trimethylsilyl)hydroxylamine (TMS-hydroxylamine) and removal of the TMS protecting group is preferably accomplished by acid hydrolysis using hydrochloric acid.
Displacement
(SN
2 of the halogen in this example by a thiol in the presence of base or a preformed thiolate can be accomplished as discussed and/or shown and as is well known in the art. Again, oxidation of the sulfide can be carried out before or after derivatization of the carboxylic acid as discussed to prepare the hydroxamic acids of this invention. Removal of the protecting groups can be WO 00/69819 PCT/US00/06713 -185carried out using acid hydrolysis or reduction as discussed elsewhere in this document.
The alcohols of this invention can be protected or deprotected as required or desired.
Protecting groups can include THP ethers, acylated compounds and various silyl derivatives. These groups, including there 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 those of sodium, potassium, lithium, calcium or magnesium, metal carbonates such as those of sodium, potassium, lithium, calcium or magnesium, metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, primary secondary (II) or tertiary (III0) organic amines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary ammonium hydroxides. As non-limiting examples, such amines can include triethyl amine, trimethyl amine, diisopropyl amine, methyldiisopropyl amine, diazabicyclononane, tribenzyl amine, dimethylbenzyl amine, morpholine, Nmethylmorpholine, N,N'-dimethylpiperazine,
N-
ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine and the like.
Non-limiting examples of ammonium hydroxides, usually made from amines and water, can include ammonium hydroxide, triethyl ammonium hydroxide, trimethyl ammonium hydroxide, methyldiiospropyl ammonium hydroxide, tribenzyl WO 00/69819 PCT[USOOI6713 -186ammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholinium hydroxide, Nmethylmorpholinium hydroxide, N,N'dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limiting examples, quaternary ammonium hydroxides can include tetraethyl ammonium hydroxide, tetramethyl ammonium hydroxide, dimethyldiiospropyl ammonium hydroxide, benzymethyldiisopropyl ammonium hydroxide, methyldiazabicyclononyl ammonium hydroxide, methyltribenzyl ammonium hydroxide, N,Ndimethylmorpholinium hydroxide, tetramethylpiperazenium hydroxide, and N-ethyl-N'hexylpiperidinium hydroxide and the like. Metal hydrides, amide or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like can also be suitable reagents. Organometallic deprotonating agents such as alkyl or aryl lithium reagents such as methyl, phenyl, butyl, iso-butyl, sec-butyl or tertbutyl lithium, nodium or potassium salts of dimethylsulfoxide, Grignard reagents such as methylmagnesium bromide or methymagnesium chloride, organocadium reagents such as dimethylcadium and the like can also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents. Preferred base for use in the alkylation reaction is lithium diisopropyl amide as mentioned above.
WO 00/69819 PCT/US00/06713 -187- Reaction media in general can be comprised of a single solvent, mixed solvents of the same or different classes or serve as a reagent in a single or mixed solvent system. The solvents can be protic, non-protic or dipolar aprotic. Non-limiting examples of protic solvents include water, methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanol and the like.
Typical non-protic solvents include acetone, tetrahydrofurane (THF), dioxane, diethylether, tert-butylmethyl ether (TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane and the like. Dipolar 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 solvents or as Part of a mixed solvent system include organic or inorganic mono- or multiprotic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines for making esters or amides or thiols for making the products of this invention and the like. Room temperature or less or moderate warming (-100C to 600C) are the preferred temperatures of the reaction. If desired, the reaction temperature might be about WO 00/69819 PCT[US00106713 -188- -780C to the reflux point of the reaction solvent or solvents. The preferred solvent for an alkylation reaction is tetrahydrofurane (THF).
Acids are used in many reactions during various synthesis. The Schemes as well as this discussion preparative methods illustrate acid use for the removal of the THP protecting group to produce a hydroxamic acid, removal of a tert-butoxy carbonyl group, hydroxylamine/ester exchange and the like. Acid hydrolysis of carboxylic acid protecting groups or derivatives is well known in the art.
These methods, as is well known in the art, can use acid or acidic catalysts. The acid can be mono-, dior tri-protic organic or inorganic acids. Examples of acids include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, hydrobromic acid, hydrofluoric acid, carbonic acid, phosphorus acid, p-toluene sulfonic acid, trifluoromethane sulfonic acid, trifluoroacetic acid, difluoroacetic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid, 2,6dimethylbenzene sulfonic acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid, and the like. They can also be Lewis acids such as aluminum chloride, borontrifluoride, antimony pentafluoride and the like.
Contemplated compounds can include compounds wherein a nitrogen of an amine is acylated to provide, for example, amino acid carbamates. Nonlimiting examples of these carbamates are the carbobenzoxycarbonyl CBZ, benzyloxycarbonyl), iso-butoxycarbonyl and tert-butoxycarbonyl (BOC, t- WO 00/69819 PCT/USOO/06713 -189- BOC) compounds. The materials can be made, as discussed above, at various stages in the synthesis based on the needs and decisions made by a person skilled in the art using methods well know in the art.
Useful synthetic techniques and reagents include those used in protein, peptide and amino acid synthesis, coupling and transformation chemistry.
The use of the tert-butoxycarbonyl (BOC) and benzyloxycarbonyl as will as their synthesis and removal are examples of such protection or synthesis schemes. Transformations of amino acids, amino esters, amino acid hydroxamates, amino acid hydroxamate derivatives and amino acid amides of this invention or compounds used in this invention is discussed herein or/and shown in the schemes. This includes, for example, active ester or mixed anhydride couplings wherein preferred bases, if required, are tertiary amines such as Nmethylmorpholine. Reagents for protection of the amine group of the protected amino acids include carbobenzoxy chloride, iso-butylchloroformate, tertbutoxycarbonyl chloride, di-tert-butyl dicarbonate and the like which are reacted with the amine in nonprotic or dipolar aprotic solvents such as DMF or THF or mixtures of solvents.
Removal of protecting groups such as carbamates, silyl groups and benzyl, p-methoxybenzyl, or other substituted benzyl groups or diphenylmethyl (benzhydryl) or triphenylmethyl (trityl) can be carried out at different stages in the synthesis of the compounds of this invention as required by methods selected by one skilled in the art. These WO 00/69819 PCTIUS00/06713 -190methods are well known in the art including the amino acid, amino acid coupling, peptide synthesis, peptide mimetic synthesis art. Removal methods can include catalytic hydrogenation, base hydrolysis, carbonyl addition reactions, acid hydrolysis and the like.
Both the preparation and removal of protecting groups, for example, carbamates, benzyl groups and/or substitued arylalkyl groups is discussed in Green, Protecting Groups in Organic Chemistry, Second ed., John Wiley Sons, New York (1991). A preferred method of removal of a BOC group is HC1 gas in methylene chloride which, following normal workup, provides directly an HC1 salt of an aminoacid of this invention.
Sulfone compounds such as those where R 1 is nitrobenzene can be prepared as compounds of this invention by synthesis of a thiol, displacement of an electrophile by the nucleophilic thiol or thiolate and oxidation of the product thiol ether to the sulfone. For example, displacement of the electrophilic group with a nitro-benzene thiol can yield a compound where R 1 is nitrobenzene, whose nitro group can be reduced to provide a useful amino compound wherein R 1 is an aniline. It should be noted that nitrobenzenethiol is an example and not to be considered as limiting or required. Oxidation of the thioether product can be carried out as discussed below when desired.
The reduction of nitro groups to amines is well known in the art with a preferred method.being hydrogenation. There is usually a metal catalyst such as Rh, Pd, Pt, Ni or the like with or without an additional support such as carbon, barium carbonate WO 00/69819 PCT[USOO/06713 -191and the like. Solvents can be protic or non-protic pure solvents or mixed solvents as required. The reductions can be carried out at atmospheric pressure to a pressure of multiple atmospheres with atmospheric pressure to about 40 pounds per square inch (psi) preferred.
The resulting amino group can be alkylated if desired. It can also be acylated with, for example, an aroyl chloride, heteroaryl chloride or other amine carbonyl forming agent to form an R 1 amide of this innvention. The amino sulfone or thioether can also be reacted with a carbonic acid ester chloride, a sulfonyl chloride, a carbamoyl chloride or an isocyanate to produce the corresponding carbamate, sulfonamides, or ureas of this invention. Acylation of amines of this type are well known in the art and the reagents are also well known.
Usually these reactions are carried out in aprotic solvents under an inert or/and dry atmosphere at about 450C to about -10°C. An equivalent of a non-competitive base is usually used with sulfonyl chloride, acid chloride or carbonyl chloride reagents. Following or before this acylation step, synthesis of the hydroxamic acid products of this invention can proceed as discussed.
Other thiol reagents can also be used in the preparation of compounds of this invention.
Examples are fluoroaryl, fluoroheteroaryl, azidoaryl or azidoheteroaryl or heteroaryl thiol reagents.
These thiols can be used a nucleophiles to as discussed above. Oxidation to the corresponding sulfone can then be carried out.
WO 00/69819 PCT/US00/06713 -192- The sulfones, if substituted by a hydrazine or substituted hydrazine, can be oxidized to a hydrazone of this invention. The fluoro substituted sulfone can be treated with a nucleophile such as ammonia, a primary amine, a quaternary ammonium or metal azide salt or a hydrazine under pressure if desired, to provide an azido, amino, substituted amino or hydrazino group. Azides can be reduced to an amino group using, for example, hydrogen with a metal catalyst or metal chelate catalyst or by an activated hydride transfer reagent. The amines can be acylated as discussed above.
Methods of preparing useful aminethiol intermediates include protection of an aromatic or heteroaromatic thiol with trityl chloride to form the trityl thiol derivative, treatment of the amine with as reagent such as an aromatic or heteraromatic acid chloride to form the amide, removal of the trityl group, with acid to form the thiol. Acylating agents include benzoyl chloride and trityl removing reagents include triflouroacetic acid and trisiopropylsilane.
The fluorine on the fluorosulfones of this invention can also be displaced with other aryl or heteroaryl nucleophiles for form compounds of this invention. Examples of such nucleophiles include salts of phenols, thiophenols, -OH group containing aromatic heterocyclic compounds or -SH containing heteroaryl compounds. Tautomers of such groups azo, hydrazo, -OH or -SH are specifically included as useful isomers.
A preferred method of preparing intermediates in the synthesis of the substituted sulfones is by oxidation of an appropriate WO 00/69819 PCTUSOO/06713 -193acetophenone, prepared from a flouroacetophenone, with for example, peroxymonosulfate, to form the corresponding phenol-ether. The phenol-ether is converted into its dimethylthiocarbamoyl derivative using dimethylthiocarbamoyl chloride, rearranged into the dimethylthiocarbamoyl derivative with heat to provide the thiol required for preparation of the thioether intermediate discussed and/or shown in the schemes.
The compounds of this invention including protected compounds or intermediates can be oxidized to the sulfones as shown in the schemes and/or discussed above. The selection of the stage of the alternative synthesis to implement this conversion of sulfides into the sulfones or sulfoxides can be carried out by one skilled in the art.
Reagents for this oxidation process may, in a non-limiting example, include peroxymonosulfate (OXONE®), hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlactic acid, tert-butyl peroxide, tert-butyl hydroperoxide, tert-butyl hypochlorite, sodium hypochlorite, hypochlorus acid, sodium meta-peroiodate, periodic acid, ozone and the like. Protic, non-protic, dipolar aprotic solvents, either pure or mixed, can be chosen, for example, methanol/water. The oxidation can be carried out at temperature of about -780 to about 500 degrees centigrade and normally selected from a range -10°C to about 40 0
C.
Preparation of the sulfones can also be carried out in two steps by the oxidation of a sulfide to a sulfoxide followed by oxidation of the sulfoxide to the sulfone. This can occur in one pot WO 00/69819 PCTfUSOO/06713 -194or by isolation of the sulfoxide. This latter oxidation can be carried out in a manner similar to the oxidation directly to the sulfone except that about one equivalent of oxidizing agent can be used preferably at a lower temperature such as about zero degrees C. Preferred oxidizing agents include peroxymonosulfate and meta-chloroperbenzoic acid.
A sulfonamide of this invention can be prepared in a similar manner using methods and procedures discussed hereinbefore. Aryl, substituted aryl, heteroaryl or substituted heteroaryl dicarboxylic anhydrides, imides phthalic anhydrides or imides), their sulfonyl analogs or mixed carboxylic-sulfonic acid amides, imides 1,2-benzenethiazole-3(2H)-one 1,1-dioxides) or anhydrides are useful starting material substrates.
Reactions utilizing such substrates can be carried out before or after changes in the substitution patterns of the aryl or heteroaryl rings are made.
The sulfonamides can also be prepared from heterocyclic compounds such as saccharine, saccharine analogs and saccharine homologs. Such compounds and methods are well known in the literature. For example, alkylation of sodium saccharine followed by ring opening or ring opening followed by alkylation permits coupling toto form a protected hydroxamic acid derivative such as a THP (tetrahydropyranyl) or TMS (trimethylsilyl) derivative. Hydrolysis of the protecting group provides the hydroxamic acid. The sulfonamide nitrogen can be further alkylated, acylated or otherwise treated to form various compounds of, for example, Formula VI at this stage of prior to coupling and deprotection.
WO 00/69819 PCT/US00/06713 -195- As a non-limiting example, treatment of a mixed sulfonic/carboxylic anhydride (2-sulfobenzoic acid cyclic anhydride) with an alcohol or the salt of an alcohol or a protected hydroxamic acid provides a ring opened carboxylic acid derivative (ester or anhydride, respectively) as a sulfonic acid or salt.
The carboxylic acid derivative so prepared is a product of this invention, and can be converted by standard procedures with reagents such as thionyl chloride, phosphorus pentachloride or the like into a sulfonylhalide.
Reaction of the sulfonylhalide with a primary amine, secondary amine or ammonia with or without added base provides a sulfonamide or sulfonimide of this invention, a sulfonamide that can be alkylated to produce a sulfonamide of this invention or an intermediate to a sulfonamide of this invention. These imides or amides of sulfonamides can be alkylated as desired before or after opening to a benzoic acid substituted sulfonamide or phenylacetic acid substituted sulfonamide.
Compounds prepared as above with protected carboxyl groups are readily converted by exchange, combination exchange/hydrolysis or hydrolysiscoupling processes into the hydroxamic acids of this invention. The exchange/conversion of esters, amides and protected hydroxylamines (protected hydroxamic acids) into hydroxamic acids is discussed herein.
For example, a sulfonamide-ester can be hydrolyzed to a carboxylic acid that is coupled via a benzotriazole active ester with a THP-hydroxylamine reagent and then deprotected. Phenylacetic acid analogs of the above sulfo benzoic acid compounds can also be used WO 00/69819 PCT/USOO/06713 -196in processes similar to those above to prepare the corresponding phenylacetic-derived compounds of this invention.
Aryl or heteraryl 5- or 6-membered ring thiolactones or dithiolactones are also desirable starting materials for the preparation of compounds of this invention. Such thiolactones can be opened to form protected carboxylic acid derivatives such as esters, amides or hydroxylamides before or after changes in the substitution patterns of the aryl or heteroaryl rings are made. Oxidation of the thiol function can be achieved prior to or following substitution changes depending upon the needs and wishes of the skilled chemist. Sulfur compounds can also be oxidized directly to sulfonyl chloride compounds using oxidizing agents whose mechanism involved putative positive chlorine species.
Oxidizing agents and methods are discussed hereinabove. The sulfonic acid derivatives so obtained are then converted into the sulfonamides of this invention as previously discussed.
Changes in substitution patterns on the rings of the compounds of this invention can be carried out by processes well known in the art. Nonlimiting examples of such processes include diazonium chemistry, aromatic ring substitution reactions or addition-elimination sequences, metallation reactions and halogen metal exchange reactions.
A substituted or unsubstituted aryl or heteroaryl sulfonic acid, sulfonic acid derivative or sulfonamide of this invention can be prepared starting with a halo-sulfonic acid or a sulfonic acid substituted in such a manner that the corresponding WO 00/69819 PCT/US00/06713 -197anion can be reacted with carbon dioxide, a carbonyl.
compound, isocyanate, a halogenating reagent, alkylating reagent, acylating reagent,a protected hydroxylamine isocyanate or isothiocyanate derivative to form a compound of this invention or an intermediate to a compound of this invention. An anion can be formed via, for example, direct metallation or metal-halogen exchange. The substituted or unsubstituted aryl or heteroaryl sulfonic acid, sulfonic acid derivative or sulfonamide can be prepared by sulfonation or chlorosulfonation of the substituted or unsubstituted aryl or heteroaryl compound. Metallation reactions as well as halogen-metal exchange reactions to form the salts of the corresponding anions or complexed anions can be carried out by direct treatment with a metal such as lithium, sodium, potassium, palladium, platinum or their compleses, and the like or treatment with a strong base such as tert-butyl lithium, sec-butyl lithium, and the like as discussed above. These intermediates are then quenched with a reagent such as is discussed elsewhere. The resulting carboxylic acids or carboxylic acid derivatives are converted into the sulfonamides of this invention by methods and processes known in the art and discussed herein.
Salts of the compounds or intermediates of this invention are prepared in the normal manner wherein acidic compounds are reacted with bases such as those discussed above to produce metal or nitrogen containing cation salts. Basic compounds such as amines can be treated with an acid to form an amine salt.
WO 00/69819 PCTUS00/06713 -198- It is noted that some compounds of this invention can be synthesized by biochemical processes, including mammalian metabolic processes.
For example, methoxy groups can be converted by the liver in situ into alcohols and/or phenols. Where more than one methoxy group is present, either or both groups can be independently metabolized to hydroxy compounds.
Compounds of the present can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes well known in the art, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base.
Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
Still another available method involves synthesis of covalent diastereoisomeric molecules, esters, amides, acetals, ketals, and the like, by reacting compounds of Formula I with an optically active acid in an activated form, a optically active diol or an optically active isocyanate. The synthesized diastereoisomers can be separated by WO 00/69819 PCTfUSOO/06713 -199conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomericaly pure compound. In some cases hydrolysis to the parent optically active drug is not necessary prior to dosing the patient since the compound can behave as a prodrug. The optically active compounds of Formula I can likewise be obtained by utilizing optically active starting materials.
In addition to the optical isomers or potentially optical isomers discussed above, other types of isomers are specifically intended to be included in this discussion and in this 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 substitution isomers are also included as isomers. Solvates or solvent addition compounds such as hydrates or alcoholates are also specifically included both as chemicals of this invention and in, for example, formulations or pharmaceutical compositions for drug delivery.
Where a substituent is designated as, or can be, a hydrogen, the exact chemical nature of a substituent which is other than hydrogen at that position, a hydrocarbyl radical or a halogen, hydroxy, amino and the like functional group, is not critical so long as it does not adversely affect the overall activity and/or synthesis procedure. For example, two hydroxyl groups, two amino groups, two thiol groups or a mixture of two hydrogen-heteroatom WO 00/69819 PCT/USOO/06713 -200groups on the same carbon are known not to be stable without protection or as a derivative.
The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions can not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials.
Other compounds of this invention that are acids can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts.
In some cases, the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.
WO 00/69819 WO 0069819PCTfUS00106713 -201- Scheme 1 0 F HSPhOPh
K
2 C0 3 /i-PrOH reflux 0 11 P-(OEt) 2 M e 2
N-
NaHITI-F 2) HCI/l00 degrees
H
2 0 2 /HOAc H0 2
C
100 degrees 'Ph0Ph 11 Ph0Ph 0 0 HO,
JN
H
1) THPONH 2
EDC/HOBT/DMF
2) HCI Example I WO 00/69819 PTUO/61 PCT[USOO/06713 -202- Scheme 2 0
HS
(COG 1)2 2. TMSONH 2 Example 2 WO 00/69819 PTOOI61 PCT[US00106713 -203- Scheme 3 SOC1 2 MeOH 1PhOPh 0
O(CH
2
CH
2 Br) 2 Na1H/DMF 01 PhOPh 0 1) NaOH 2) THPONH 2
EDC/HOBT/DMF
3) HCI
HON'
H
PlOPh WO 00/69819 WO 0069819PCTfIJSOO/06713 -204- Scheme 4 0 .HOQalkyL O -alkyl CC 'I thionyl -chlorde or PCI base HNR 7
R
saponify 0
OH
SNRR
6 O 0 O -alkyl 0NHO..n NR78R couple to
THPONH
2 acid 0
NHOH
7 IN
R~
R 7and R8 are as in Formula VI WO 00/69819 WO 00/98 19PCTJIJSOO/06713 -205- Scheme R 5 Br NHR 7R8 Br s6c 0 :N7R8 R
N
Metal Base Carbonyl Compound Metal 0 R?HO O Exchange
NH
2 0THP Hydrolysis N 7\ R 2 5 6 7 8 R R R R and R are as discussed for Formula VI, and P =is a selectively removable protecting group as discussed for R2 Pcr/USOO/06713 WO 00/69819 -206scheme 6 B\A :1 RI 6
CI.
acid R 5 R 6 0 O1 jbase
HNR
7
R
8 R R 6 I chl orosulfonate [0] Cl+
B\A
S H 1.base 2. carbony/ 1. base 2.0C02\ 1. base saponify ITHPONH2 Sacid 0 B\A O /0 S-NR 7R8 6 couple to 4THPONH 2 I acid R 5 0
A:NHOTHP
.R 6 sN /acid
IHOH
0
NHOH
A, B, C, and D 2 5 6 7 8 R R R R R, are as discussed for Formula VI WO 00/69819 WO 0069819PCTfUSOO/06713 -207- Scheme 7
OH
(N
B0C Base IMBC-N\ 0 acid Heat Br sul fonyl chloride MeO organometallic coupling MeO- 2. C0 2 0 HOHN 0%1 MeO ~eSa Meo
R
WO 00/69819 WO 0069819PCTUSOO/06713 -208- Scheme 8 ozs NQ7D Nucleophile -(Nu) F- base N 0sQ3- 1. butytlithium 2. C0 2 0- 0 4Z S .N -OH MeO -o MeO 1. butyllithium I2. C0 2 Meo-- MesvlaW, 0 O'S-N3o-Ms MeO -o MeO Displace with HSR' 0
HOHN
MeO MeO
SR'
WO 00/69819 PCT/US00/06713 -209- 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. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limiting of the remainder of the disclosure in any way whatsoever.
Example 1: N-hydroxy-2-[[(4-phenoxyphenyl)sulfonyllmethyllbenzamide 0 0 HOHN O 0 Part A: To a solution of phthalide (6.30 g, 47.0 mmol) in DMF (100 mL) was added K 2
CO
3 (10.0 g, 49.4 mmol) and 4-(phenoxy)benzenethiol (9.59 g, 49.4 mmol) and the solution was heated to one hundred degrees Celsius for 2 hours. The solution was diluted with H 2 0 and acidified with IN HC1 to pH 1.
The resulting tan solid was collected and washed with
H
2 0. The solid was dissolved into ethyl ether and dried over MgSO 4 Concentration in vacuo followed by recrystallization (ethyl ether/hexane) provided the sulfide as a white solid (9.12 g, 58 MS(CI) MH calculated for C 20
H
16 0 3 S: 337, found 337. Analytical calculation for C 20
H
16 0 3 S: C, 71.41; H, 4.79; S, 9.53.
Found: C, 71.28; H, 4.67; S, 9.19.
Part B: To a solution of the sulfide of Part A (3.00 g, 8.92 mmol) in dichloromethane (28 mL) and WO 00/69819 PCT/US00/06713 -210- DMF (1 drop) was added oxalyl chloride (1.08 mL, 12.4 mmol) and the solution was stirred for one hour.
After concentration in vacuo, the residue was dissolved into dichloromethane (16 mL) and the solution was cooled to zero degrees Celsius.
Tetramethylsilyl hydroxylamine (2.55 mL, 20.8 mmol) was added and the solution was stirred for 1.5 hours.
The solution was diluted with dichloromethane and washed with 1 N HC1, H 2 0 and saturated NaCl and dried over MgSO 4 Chromatography (on silica, ethyl acetate/hexane/ toluene) provide the hydroxylamine as a clear paste (970 mg, 31%).
Part C: To a solution of the hydroxylamine of Part B (970 mg, 2.76 mmol) in dichloromethane (25 mL) cooled to zero degrees Celsius was added 3chloroperbenzoic acid 2.14 g, 7.45 mmol) and the solution was stirred for 3 hours at ambient temperature. 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 (on silica, provided the title compound as a white solid (345 mg, MS(CI) MH calculated for
C
20
H
17 NOsS: 384, found 384. Analytical calculation for
C
20 Hi 7 N0 5 S0.3H 2 0: C, 61.70; H, 4.56; N, 3.60; S, 8.25.
Found: C, 61.74; H, 4.42; N, 3.61; S, 8.31.
Example 2: N-hydroxy-2-[(4-phenoxyphenyl)sulfonyllbenzeneacetamide WO 00/69819 PCT/US00/06713 -211- 0
HOHN
0= S Part A: To a solution of 4-(phenoxy)benzenethiol (6.06 g, 30.0 mmol) and K 2 CO3 (4.55 g, 33.0 mmol) in isopropanol (30 mL) was added 2fluorobenzaldehyde (3.2 mL, 30.0 mmol). The solution was refluxed for 20 hours. The reaction was quenched by the addition of ice-H 2 0 and was extracted with CHC13. The organic layer was dried over MgSO 4 Filtration through a pad of silica gel provided the sulfide as a yellow solid (7.43 g, 81 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 zero degrees Celsius and tetraethyl dimethylammoniummethylene diphosphonate (1.99 g, 6.0 mmol) was added. The solution was warmed to ambient temperature and the sulfide of Part A (1.84 g, 6.0 mmol) was added. The solution was stirred for 4 hours at ambient temperature. The solution was extracted with ethyl acetate and washed with H 2 0 and dried over MgSO 4 Concentration in vacuo provided a brown oil which was dissolved in 6M HCl mL) and the solution was heated to one hundred degrees Celsius for 1 hour. The solution was extracted with CHCl 3 and the organic layer was dried over MgSO 4 Concentration in vacuo provided the acid as an oil (918 mg, 48 Part C: To a solution of the acid of Part B (918 mg, 3 mmol) in acetic acid (30 mL) was added WO 00/69819 PCT/US00106713 -212hydrogen peroxide (1.2 mL, 12 mmol) and the solution was heated to one hundred degrees Celsius for minutes. The solution was lyophilized and chromatography (hexane/ethyl acetate) provided the sulfone as a foam (697 mg, 63 Part D: To a solution of the sulfone of Part C (695 mg, 1.89 mmol) in acetonitrile (2 mL) was added O-tetrahydropyranyl hydroxylamine (270 mg, 2.3 mmol).
After 5 minutes EDC (442 mg, 2.3 mmol) was added and the solution was stirred for 3 hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H 2 0. The organic layer was dried over MgSO 4 Chromatography (on silica gel, ethyl acetate/hexane) provided the THP-ether as a white foam (688 mg, 77 Part E: To a solution of the THP-ether of Part D (565 mg, 1.2 mmol) in methanol (10 mL) was added ptoluenesulfonic acid (25 mg) and the solution was stirred at ambient temperature for 2 hours. The solution was concentrated in vacuo and chromatography (chloroform/methanol) provided the title compound as a white solid (339 mg, 74 Example 3: N-hydroxy-2-[[4-(phenylmethyl)-1piperidinyllsulfonyllbenzamide WO 00/69819 PCT/US00/06713 -213- Part A: To a solution of 2-chlorosulfonylbenzoic acid ethyl ester, prepared per Nagasawa, et.
al. J. Med. Chem. 1995, 38, 1865-1871, (5.80 g, 23.0 mmol) in acetonitrile (50 mL) was added 4benzylpiperidine (4.38 mL, 25 mmol), triethylamine (3.78 mL, 27 mmol) and 4-dimethylaminopyridine mg). The solution was stirred for 4 hours at ambient temperature and concentrated in vacuo. The residue was dissolved into 1N HC1 and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and filtered through a pad of silica gel to provide the sulfonamide as an oil (7.45 g, 84 Part B: To a solution of the sulfonamide of Part A (1.08 g, 2.80 mmol) in methanol (50 mL) and H 2 0 (20 mL) was added KOH (2 g) and the solution was stirred for 3 hours at ambient temperature. The solution was concentrated in vacuo and the remaining aqueous solution was acidified with 1N HC1. The solution was extracted with chloroform and the organic layer was dried over MgS0 4 and filtered through a pad of silica gel. Concentration in vacuo provided the acid as a white foam (996 mg, quantitative yield).
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).
After the solution was stirred for 5 minutes EDC (325 mg, 1.7 mmol) was added and the solution was stirred for 3 hours at ambient temperature. The solution was concentrated in vacuo and the residue was dissolved into H 2 0 and extracted with ethyl acetate. The organic layer was dried over MgS0 4 Chromatography WO 00/69819 PCT/US00/06713 -214- (on silica, ethyl acetate/hexane) provided the THPether as a white solid (437 mg, 82 Part D: To a solution of the THP-ether of Part C (437 mg, 0.98 mmol) in methanol (5 mL) was added ptoluenesulfonic acid (40 mg) and the solution was stirred for 1 hour at ambient temperature. The solution was concentrated in vacuo. Chromatography (ethyl acetate,1% NH40H) provided the title compound as an oil (122 mg, 34 Example 4: 2-[([1,1'-biphenyl]-4-ylmethyl)sulfonyll-N-hydroxybenzamide 0
HOHN
Part A: To a solution of thiosalicylic acid (5.00 g, 32.4 mmol) and 4-phenylbenzyl chloride (6.57 g, 32.4 mmol) in ethanol (81 mL) and H 2 0 (40 mL) was added K 2
CO
3 (4.48 g, 32.4 mmol) and the solution was heated to reflux for 2 hours. Upon cooling to ambient temperature a white solid formed. To this mixture is added 1N HC1 (200 mL) and vacuum filtration provided the sulfide as a white solid (7.32 g, 70 Part B: To a solution of the sulfide of Part A (1.00 g, 3.12 mmol) in formic acid (17 mL) heated to fifty degrees Celsius was added 30% hydrogen peroxide (1.16 mL). The solution was stirred at fifty-five degrees Celsius for 3 hours followed by 40 hours at ambient temperature. The solution was concentrated WO 00/69819 PCT/US00/06713 -215and reverse phase chromatography provided the sulfone as a white solid (500 mg, 45 Part C: To a solution of the sulfone of Part B (500 mg, 1.42 mmol) in DMF (2.8 mL) was added Otetrahydropyranyl hydroxylamine (173 mg, 1.48 mmol), N-hydroxybenzotriazole (211 mg, 1.56 mmol) and EDC (299 mg, 1.56 mmol) and the solution was stirred for 18 hours at ambient temperature. The solution was concentrated in vacuo and the residue was dissolved into H 2 0. The solution was extracted with ethyl acetate and the organic layer was washed with 1 N HC1, saturated NaHCO 3
H
2 0 and saturated NaCl and dried over MgSO 4 Concentrated in vacuo provided the ester as a white solid (571 mg, 89 MS(CI) MH calculated for C 25
H
25
NO
5 S: 452, found 452.
Part D: To a solution of the ester of Part C (570 mg, 1.26 mmol) in methanol (10 mL) was added ptoluenesulfonic acid (15 mg) and the solution was stirred at ambient temperature for 1.5 hours. The solution was concentrated in vacuo and reverse phase chromatography (acetonitrile/H2 0) provided the title compound as a white solid (244 mg, 53 MS(EI) M' calculated for C 20
H
1
,NO
4 S: 367, found 367. Analytical calculation for C 20 Hi 7
NO
4 S: C, 65.38; H, 4.66; N, 3.81.
Found: C, 65.01; H, 4.64; N, 4.04.
Example 5: N-hydroxy-2-[[(4-phenoxyphenyl)sulfonyllaminolbenzamide WO 00/69819 PCTUJSOO/06713 -216- Part A: To a solution.of isatoic anhydride (1.00 g, 6.13 mmol) in acetonitrile (3 mL) was added O-tetrahydropyranyl hydroxylamine (1.56 g, 6.74 mmol) and the solution was heated to reflux for 2 hours.
The solution was concentrated in vacuo and recrystallization of the residue (ethyl acetate/hexane) provided the THP-ether as a white solid (760 mg, 52 MS(CI) MH calculated for
C
12
H
16
N
2 0 3 237, found 237. Analytical calculation for
C
1 2
H
1 6
N
2 0 3 C, 61.00; H, 6.83; N, 11.86. Found: C, 60.82; H, 6.95; N, 11.76.
Part B: To a solution of 4-(phenoxy)benzene sulfonyl chloride, prepared per J. Am. Chem. Soc., 1931, 93, 1112-1115) (341 mg, 1.27 mmoL) in pyridine (2 mL) cooled to zero degrees Celsius was added the THP-ether of Part B (300 mg, 1.27 mmol) and the solution was stirred at zero degrees Celsius for 3 hours. The solution was concentrated in vacuo and the residue was dissolved in 1 N HC1 and was extracted with ethyl acetate. The organic layer was washed with 1 N HC1, H 2 0 and saturated NaCl and dried over MgSO 4 Chromatography (on silica gel, ethyl acetate/hexane) provided the sulfone as a white solid (321 mg, MS(CI) MH+ calculated for C 24
H
24
N
2 0 6
S:
469, found 469. Analytical calculation for C 2 24
N
2 0 6
S:
C, 61.53; H, 5.16; N, 5.98; S, 6.84. Found: C, 61.10; H, 4.93; N, 5.86; S, 6.41.
Part C: Into a solution of the sulfone of Part B (320 mg, 0.68 mmol) in methanol (3 mL) cooled to zero degrees Celsius was bubbled HC1 gas for minutes. The solution was concentrated in vacuo and the residue was triturated with ethyl ether.
WO 00/69819 PCT/US00/06713 -217- Collection by vacuum filtration provided the title compound as a pink solid (163 mg, 62 MS(CI) MH calculated for Cl 9
H
6 iN 2 OdS: 385, found 385. Analytical calculation for C 19
H
1 6
N
2 0 6 S*0.2H 2 0: C, 58.81; H, 4.26; N, 7.22; S, 8.26. Found: C, 58.88; H, 4.37; N, 6.98; S, 7.83.
Example 6 N-hydroxy-2-[[(4-methoxyphenyl)sulfonyllmethyllbenzamide 0i S CH3 HOHN 1 3 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 g (10.9 mM) methyl (2-bromomethyl)benzoate in acetone (100 mL). The solution was treated with 1.8 g (13.1 mM) potassium carbonate and heated at 55 0 C in an oil bath. The reaction mixture was stirred at 55 0 C for 17 hours, then concentrated in vacuo. The residue was partitioned between EtOAc and H 2 0, the layers were separated and the aqueous layer was extracted with EtOAc the organic phases were combined, washed with 5% citric acid solution, saturated sodium bicarbonate solution and brine, dried (Na 2
SO
4 and concentrated in vacuo to yield 3.3 g of product 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 WO 00/69819 PCT[USOO/06713 -218- 3.1 g (10.8 mM) of product from Part A in 90 mL MeOH.
The solution was then treated with 15 mL water and 13.9 g (22.6 mM) Oxone®. The reaction mixture was stirred 17 hours, 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 0, the layers were separated and the aqueous layer was extracted with EtOAc The organic phases were combined, washed with saturated sodium bicarbonate solution and brine, dried (MgSO 4 and concentrated in vacuo to yield the 3.3 g of crude product. This was chromatographed on silica gel using 25-45% ethyl acetate/hexane to yield 2.1 g of pure product, m/z= 321 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 acetic acid mL) and conc. HC1 solution (25 mL) and the solution was heated to reflux for a total of 24 hours. The reaction mixture was concentrated in vacuo, then two aliquots of toluene were added and stripped, then dried under high vacuum to yield 2.0 g of product suitable for the next reaction.
Part D A 2-necked 50 mL round bottom flask equipped with addition funnel, thermometer, magnetic stir bar and N 2 inlet was charged with 1.0 mL of DMF in 10 mL CH 2 C12. The solution was cooled in an ice bath, then treated with 3.5 mL (0.9 g, 6.9 mM) of a M oxalyl chloride solution in CH 2 C1 2 then with a solution of 1.0 g (3.3 mM) of product from Part C in mL DMF. The bath was removed and the reaction was stirred for 1 hour. That reaction mixture was added to a 2-necked 100 mL round-bottomed flask equipped WO 00/69819 PCT[US00/06713 -219with addition funnel, thermometer, magnetic stir bar and N 2 inlet and containing a cooled solution of 2.1 mL (1.1 g, 37.7 mM) of 50% aqueous hydroxylamine in THF (25 mL). 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 the organic phases were combined and washed with water and brine, dried (Na 2
SO
4 and concentrated in vacuo to yield 1.3 g ofcrude product. That material was chromatographed on silica gel using 80% ethyl acetate/hexane to yield g of pure product, m/z= 328 (M+Li).
Example 7 N-hydroxy-2-[(4-methoxyanilino)sulfonyllbenzamide 0
H
HOHN oC Part A A 3-necked 100 mL round bottom flask equipped with addition funnel, thermometer, magnetic stir bar and N 2 inlet was charged with 0.5 g (4.3 mM) of p-anisidine and 1.8 mL (1.3 g, 12.8 mM) triethylamine in CH 2 C12 (20 mL). The solution was cooled in an ice bath, then treated with a solution of 1.0 g (4.3 mM) methyl (2-chlorosulfonyl)benzoate in CH 2 C1 2 (10 mL). The reaction mixture was stirred for 17 hours, then concentrated in vacuo. The residue was partitioned between EtOAc and H 2 0, the WO 00/69819 PCT/US00/06713 -220layers 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 crude product. This was chromatographed on silica gel using 20-30% ethyl acetate/hexane to yield 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 (2.1 mM) of the product from Part A and 0.7 g (10.2 mM) of hydroxylamine hydrochloride in 10 mL MeOH. The reaction was cooled to zero degrees C and charged with 0.4 g (16.4 mM) of sodium metal. After stirring for 17 hours, the reaction was concentrated in vacuo, the residue was slurried in 20 mL of water, then acidified using 2 N HC1 solution. The aqueous slurry was extracted with EtOAc The organic layers were combined and washed with brine, dried (Na 2 SO4), and concentrated in vacuo to yield 0.6 g of crude product. The addition of methylene chloride to the crude product precipitated an off-white solid.
Filtration gave 0.2 g of pure product, m/z= 323 (M+Li).
Example 8 N-hydroxy-2-[(benzylamino)sulfonvllbenzamide WO 00/69819 PCT/US00/06713 -221- Part A A 3-necked 100 mL round bottom flask equipped with addition funnel, thermometer, magnetic stir bar and N 2 inlet was charged with 0.5 mL (0.5 g, 4.3 mM) of benzylamine and 1.8 mL (1.3 g, 12.8 mM) triethylamine in CH 2 C1 2 (20 mL). The solution was cooled in an ice bath, then treated with a solution of 1.0 g (4.3 mM) methyl (2-chlorosulfonyl)benzoate in CH 2 C1 2 (10 mL). The reaction mixture was stirred for 2 hours, then concentrated in vacuo. The residue was partitioned between EtOAc and H 2 0, the layers were separated and the organic phase was washed with citric acid solution, saturated sodium bicarbonate solution and brine, dried (Na 2
SO
4 and concentrated in vacuo to yield 0.9 g of crude product. This was chromatographed on silica gel using 20% ethyl acetate/hexane to yield 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 (2.1 mM) of the product from Part A and 0.7 g (10.6 mM) of hydroxylamine hydrochloride in 10 mL MeOH. The reaction was cooled to zero degrees C and charged with 0.4 g (17.0 mM) of sodium metal. After stirring for 17 hours, the reaction was concentrated in vacuo, the residue was slurried in 20 mL of water, then acidified using 2 N HC1 solution. The aqueous slurry was extracted with EtOAc The organic layers were combined and washed with brine, dried (Na 2
SO
4 and concentrated in vacuo to yield 0.3 g of crude product. The addition of methylene chloride to the crude product precipitated a white solid.
Filtration gave 0.1 g of pure product, m/z= 307 WO 00/69819 PCTUSOO/06713 -222- Example 9: Preparation of N-Hydroxy-2-[[4-(phenyl)- 1-piperidinyllsulfonyl benzamide
~OH
NH
0 Ob Part A: 2-Carboethoxybenzenesulfonyl chloride (3.72 g, 15 mmol) was dissolved in methylene chloride 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 hours, the mixture was diluted with 10 percent aqueous HC1 (100 mL). The organic layer was separated and dried over magnesium sulfate. The solution was filtered through a silica pad and concentrated affording the ester sulfonamide as an oil (3.27 g, 63%).
Part B: The ester sulfonamide from Part A (938 mg, 2.51 mmol) was stirred for 20 hours at ambient temperature 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 using concentrated HC1 to approximately pH 4. The product was extracted using chloroform (2 X 100 mL), and the combined organic layers were dried using anhydrous magnesium sulfate. Concentration afforded carboxylic acid (768 mg, which was carried on to the next step.
Part C: To a solution of the acid from Part B (764 mg, 2.2 mmol) dissolved in acetonitrile (15 mL) WO 00/69819 PCT/US00/06713 -223was added O-tetrahydropyranyl hydroxylamine (351 mg, mmol) and N-hydroxybenzotriazole (405 mg, mmol), followed by 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (600 mg, 3 mmol).
The reaction was stirred for 16 hours and then concentrated. The residue was diluted with halfsaturated 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 affording, on concentration, the desired THP-protected hydroxamate as a white foam (833 mg, 82%).
Part D: The THP-protected hydroxamate from Part C (833 mg, 1.8 mmol) was dissolved in absolute methanol (3 mL). Acetyl chloride (0.28 mL, 4 mmol) was added drop-wise. After 3 hours, the reaction was concentrated, and the residue was subjected to purification by chromatography, affording the title compound (430 mg, 66 as a white foam. Anal.
calculated for C 18
H
20
N
2 0 4
S(H
2 C, 57.08; H, 5.81; N, 7.40. Found: C, 57.02; H, 5.61; N, 6.90.
Example 10: Preparation of N,2-Dihydroxy-2methyl-2-[(4-phenyl-l-piperidinyl)sulfonyllbenzeneacetamide o
HNOH
CH
3
OH
S--N
Part A: 2-Bromobenzenesulfonyl chloride (2.56 g, 10 mmol) was added to a solution of 4- WO 00/69819 PCTfUSOO/06713 -224phenylpiperidine (1.61 g, 10 mmol), triethylamine 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 afford the bromo sulfonamide as a white solid (3.47 g, 96%).
Part B: The bromo sulfonamide (359 mg, 1 mmol) was dissolved in dry tetrahydrofuran (2 mL) and cooled to minus seventy-eight degrees, t- Butyllithium (0.68 mL, 1.7 M in pentane) was added drop-wise and the anion was permitted to form over minutes. Ethyl pyruvate (0.11 mL, 1.15 mmol) was added. The cooling bath was removed. When the reaction reached ambient 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 afford the desired hydroxy ester as a glass (163 mg 40 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 hours the mixture was heated at 50 degrees Celsius for one hour, then cooled, neutralized with dilute hydrochloric acid, concentrated, and azeotroped to dryness with acetonitrile to afford the crude hydroxy acid, which was used directly as is. The hydroxy acid was diluted with acetonitrile (1 mL). 0- Tetrahydropyranylhydroxylamine (117 mg, 1.0 mmol) and N-hydroxybenzotriazole (135 mg, 1.0 mmol) were added, WO 00/69819 PCT/US00/06713 -225followed by 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (191 mg, 1 mmol).
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 over ethyl acetate, concentrated and chromatographed to afford the THP-protected hydroxamate as a glass mg, 48%).
Part D: The THP-protected hydroxamate from Part C (80 mg) was diluted with absolute methanol (4 mL), and toluenesulfonic acid (6 mg) was added. After 3 hours, the reaction mixture was concentrated, and the residue was chromatographed using 1:1 hexane:ethyl acetate 1% NH40H. The title compound was isolated as a white foam (40 mg, Analysis calculated for
C
20
H
24
N
2 0 5 S(1.33 H 2 C, 53.75; H, 5.90; N, 6.27.
Found: C, 53.80; H, 5.65; N, 5.84.
Example 11: Preparation of N-Hydroxy-2-[[3-[(4methoxybenzoyl)amino]-1-pyrrolidinyl]sulfonyllbenzamide
OH
HN
0
H
N- 0
OCH
3 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 chilled to zero degrees Celsius. 4-Methoxybenzoyl chloride (0.54 mL, 4 mmol) was added, drop-wise.
WO 00/69819 PCT/US00/06713 -226- After 30 minutes, 2-carboethoxybenzenesulfonyl chloride (0.996 g, 4.0 mmol) was introduced, dropwise, by syringe. The mixture was stirred at zero Celsius for 1 hour, then at ambient temperature for 2 hours. Water was added (50 mL). The mixture was extracted using 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 using 1:1 ethyl acetate:hexane to ethyl acetate as eluant. The desired amide sulfonamide was isolated as a foam (282 mg,16%).
Part B: The amide sulfonamide 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 was brought to reflux. After 40 minutes, the reaction was permitted to cool. Acetic acid (0.1 mL) and absolute ethanol (20 mL) were added.
Concentration followed by chromatography (9:1 ethyl acetate:methanol to methanol; 20 g silica gel) afforded the desired acid as a crystalline solid (229 mg, The acid (229 mg, 0.57 mmol) was dissolved in acetonitrile (1 mL). O-Tetrahydropyranyl hydroxylamine (117 mg, 1.0 mmol) and Nhydroxybenzotriazole (135 mg, 1.0 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (191 mg, 1 mmol).
The mixture was stirred at ambient temperature overnight (about 18 hours), then concentrated and chromatographed (ethyl acetate to 9:1 ethyl acetate: methanol), affording the THP-protected hydroxamate as a white crystalline solid (98 mg, 33%).
WO 00/69819 PCT[USOO/06713 -227- Part C: The THP-protected hydroxamate (76 mg,0.15mmol) was dissolved in methanol (2 mL).
Acetyl chloride (0.01 mL, 1 mmol) was added. After minutes, the solution was concentrated, and then azeotroped with chloroform/acetonitrile affording the title compound as a solid (65 mg, quantitative.). MS (EI) MH+: calculated for C 19
H
21
N
3 0 6 S: 420, found 420.
Example 12: Preparation of N-Hydroxy-2-[[4-[4- (trifluoromethoxy)phenoxy]-1piperidinyllsulfonyllbenzamide
OH
HN
S-N
OCF
3 Part A: Diethyl azodicarboxylate (4.11 g, 23.6 mmol) was added at ambient temperature under an atmosphere of nitrogen to a mixture of N-(tertbutyloxycarbonyl)-4-piperidinol (4.31 g,21.4 mmol) (Wells, Kenneth et al; Tetrahedron Lett., 1996, 37, 6439-6442), 4-trifluoromethoxyphenol (4.20 g, 23.6 mmol) and triphenylphosphine (6.19 g, 23.6 mmol) in THF (200 mL). After 1.5 hours, the reaction mixture was concentrated. The residue was diluted with ethyl ether, filtered, and purified by chromatography (on silica, methyl tert-butyl ether/hexane) to afford the impure BOC-amine as an off-white solid (5.23 To the off-white solid cooled to zero degrees Celsius under an atmosphere of nitrogen was added a solution of 4 N HC1 in dioxane WO 00/69819 PCT/US00/06713 -228- (36.1 mL, 145 mmol). After two hours, the reaction mixture was concentrated and diluted with ethyl ether to give a white solid. The white solid was diluted with H 2 0 (15 mL) and a solution of NaHCO 3 (1.68 g, 20.0 mmol) in water (10 mL) was added. The precipitate was extracted into ethyl ether. The organic layer was washed with brine, dried over MgSO 4 and concentrated to give the amine as a white solid (1.93 g, MS MH calculated for C 12 Hi 4
NO
2
F
3 :262, found 262.
Part B: A solution of the amine of Part A (1.90 g, 7.28 mmol), ethyl 2-chlorosulfonylbenzoate (1.70, 6.85 mmol), triethylamine (1.15 mL, 8.22 mmol), and 4-dimethylaminopyridine (10 mg) in acetonitrile mL) was stirred under an atmosphere of nitrogen at ambient temperature for 18 hours. After concentrating the solution, the residue was diluted with H 2 0 and extracted into ethyl acetate. The organic layer was washed with 1.0 N KHSO 4 saturated NaHCO 3
H
2 0, and brine; and then dried over MgSO 4 and concentrated to a yellow oil. Chromatography (on silica, ethyl acetate/hexane) provided the sulfonamide as a white solid (1.59 g, MS MH calculated for C 21
H
22
NO
6
F
3 S:474, found 474.
Part C: A solution of the sulfonamide of Part B (1.45 g, 3.17 mmol) and potassium hydroxide (1.77 g, 31.7 mmol) in a mixture of MeOH (30 mL), H 2 0 (10 mL), and THF (10 mL) was heated at reflux for 1.5 hours.
After the solution was concentrated in vacuo, the residue was triturated with ethyl ether, dissolved into H 2 0, acidified with concentrated HC1, and extracted into ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 and concentrated WO 00/69819 PCTUSOO0i6713 -229in vacuo to provide the acid as a clear oil (1.04 g, Anal. calculated for C 19
H
1 N0 6
OF
3 S: C, 51.23;
H,
4.07; N, 3.14; S, 7.20. Found: C, 51.34; H, 3.78; N, 3.15; S, 7.30.
Part D: A solution of the acid of Part C (0.97 g, 2.18 mmol), N-hydroxybenzotriazole (0.89 g, 6.50 mmol), 4-methylmorpholine (0.71 mL, 6.50 mmol), 0tetrahydro-2H-pyran-2-yl-hydroxylamine (0.51 g, 4.36 mmol), and 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (1.25 g, 6.50 mmol) in DMF (19 mL) was stirred at ambient 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 0, and brine; and then dried over MgS04 and concentrated in vacuo to afford the THP-protected hydroxamate as a white solid (1.05 g, Anal.
calculated. for C 24
H
27
N
2 0 7
F
3 S: C, 52.94; H, 5.00; N, 5.14; S, 5.89. Found: C, 52.80; H, 4.84; N, 5.23; S, 6.14.
Part E: The THP-protected hydroxamate of Part D (1.01 g,1.86 mmol) was dissolved in methanol (10 mL).
Acetyl chloride (0.36 mL, 5.0 mmol) was added. After 1 hour, the solution was concentrated, and the residue was subjected to chromatography (1:1 hexane:ethyl acetate; 1% NH 4 OH to ethyl acetate; 1%
NH
4 0H) affording the title compound as foam (643 Anal. calculated for CI 9
H
19
F
3
N
2 0 6 S: C, 49.56; H, 4.13; N, 6.09. Found: C, 49.27; H, 3.72; N, 5.87.
WO 00/69819 PCTUSOOI/06713 -230- Example 13: Preparation of N-hydroxy-2-[[4- [4-(trifluoromethyl)phenoxy]-1piperidinyllsulfonyl benzamide
/OH
HN
0 S N OC SCF 3 Part A: A solution of N-(tert-butyloxycarbonyl)-4-piperidinol (5.00 g, 2.48 mmol), 4fluorobenzo-trifluoride (3.46 mL, 2.73 mmol), and cesium carbonate (12.1 g, 3.72 mmol) in DMF (60 mL) was heated at 120 degrees Celsius under an atmosphere of nitrogen for 2 days. The mixture was concentrated, diluted with H 2 0, and extracted with ethyl acetate. The organic layer was washed with and brine, dried with MgSO 4 and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexane) provided the BOC-aminoether as a white solid (6.97 g, Anal. calculated. for
C
17
H
22 N0 3
F
3 C, 59.12; H, 6.42; N, 4.06. Found: C, 59.29; H, 6.47; N, 3.99.
Part B: A solution of the BOC-aminoether of Part A (4.00 g, 11.6 mmol) and p-toluenesulfonic acid (6.61 g, 34.7 mmol) in CH 2 C12 (30 mL) at ambient temperature under an atmosphere of nitrogen was stirred for 3 hours and then concentrated in vacuo.
The residue was partitioned between aqueous NaHC03 and ethyl acetate. The organic layer was dried over MgSO 4 and concentrated to provide the free amine as a clear, yellow oil (1.57 g, MS MH+ calculated.
for C 12 Hi4NOF 3 246, found 246.
WO 00/69819 PCTUSOO/06713 -231- Part C: A solution of the amine of Part B (1.57 g, 6.40 mmol), ethyl 2-chlorosulfonylbenzoate (1.57 g, 6.03 mmol), triethylamine (1.00 mL, 7.24 mmol), and 4-dimethylaminopyridine (10 mg) in acetonitrile (20 mL) was stirred under an atmosphere of nitrogen at ambient temperature for around 1.5 hours. After concentrating the solution, the residue was diluted with H20 and extracted into ethyl acetate. The organic layer was washed with 1.0 N KHS0 4 saturated NaHC03, H 2 0, and brine; and then dried over MgSO 4 and concentrated to provided the sulfonamide as a clear, yellow oil (2.52 g, MS MH+ calculated for
C
21
H
22 NOsF 3 S: 458, found 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 0 (24 mL) was heated at reflux for 4 hours. After the solution was concentrated in vacuo, the residue was triturated with ethyl ether, dissolved into H 2 0, acidified with concentrated HC1, and extracted into ethyl acetate. The organic layer was washed with N KHSO 4
H
2 0, and brine, dried over MgSO 4 and concentrated in vacuo to provide the acid as an oil (2.17 g, MS MH' calculated for C 19 HisNOsF 3 S: 430, found 430.
Part E: A solution of the acid of Part D (2.10 g, 4.89 mmol), N-hydroxybenzotriazole (1.97 g, 14.6 mmol), 4-methylmorpholine (1.61 mL, 14.6 mmol), 0tetrahydro-2H-pyran-2-yl-hydroxylamine (1.15 g, 9.79 mmol), and 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (2.80 g, 14.6 mmol) in DMF (43 mL) was stirred at ambient temperature under a nitrogen atmosphere for about 18 hours. The WO 00/69819 PCT(US00106713 -232mixture was concentrated in vacuo, diluted with water, and extracted into ethyl acetate. The organic layer was washed with 1.0 .N KHSO 4
H
2 0, and brine, and then dried over MgSO 4 and concentrated in vacuo.
Chromatography (on silica, ethanol/CHC13) provided the THP-protected hydroxamate as a white solid (2.09 g, 81%) MS MH+ calculated for C 24
H
2 7
N
2 0 6
F
3 S: 529, found 529.
Part F: To a solution of the THP-protected hydroxamate of Part C (1.80 g, 3.41 mmol) in methanol (24 mL) was added acetyl chloride (0.73 mL, 10.2 mmol) and the solution was stirred at ambient temperature under a nitrogen atmosphere for hours. The solution was concentrated in vacuo and chromatography (on silica, MeOH/CHC13) provided the title compound as an off white solid (1.18 g, 78%): Anal. calculated. for C 19
H
19
N
2 0sF 3 S'0.2%H 2 0: C, 50.94; H, 4.36; N, 6.25; S, 7.16. Found: C, 50.88; H, 4.31; N, 6.20; S, 7.43. MS MH+ calculated. for C 19
H
1 9
N
2 0 5
F
3
S:
445, found 445.
Example 14: Preparation of N-hydroxy-2-[[4-[[4- (trifluoromethyl)phenyl]methoxy]-1piperidinyllsulfonyllbenzamide H OH
HN
Part A: A solution of 4-(trifluoromethyl)benzyl bromide (2.00 mL, 12.9 mmol) in THF (6 mL) was added drop-wise under an atmosphere of nitrogen to a -52 WO 00/69819 PCT/US00/06713 -233degrees Celsius mixture of N-(tert-butyloxycarbonyl)- 4-piperidinol (2.85, 14.9 mmol) and 60% sodium hydride (0.600 g, 14.9 mmol) in THF (15 mL) and then stirred at ambient temperature for about 20 hours.
The reaction mixture was quenched with a saturated
NH
4 C1 solution, concentrated in vacuo, diluted with
H
2 0, and extracted with ethyl acetate. The organic layer was washed with 1.0 N HC1, a saturated NaHC03 solution, H 2 0, and brine; and then dried over MgSO 4 and concentrated in vacuo to provide the BOCaminoether as an off white solid (3.35 g, MS MH calculated for C 18
H
24 NO3F 3 360, found 360.
Part B: A zero degrees Celsius solution of the BOC-aminoether of Part A (3.35 g, 9.32 mmol) in ethyl acetate (40 mL) was saturated with HC1 (gas) and the stirred at ambient temperature for 1 hour. After concentrating in vacuo and triturating with ethyl ether, the crude free base was partitioned between aqueous NaHCO 3 and ethyl ether. The organic layer was washed with H 2 0 and brine, dried over MgSO 4 and concentrated in vacuo to provide the amine as a clear, yellow oil (2.11 g, which had a proton NMR spectrum consistent for the desired product.
Part C: A solution of the amine of Part B (2.11 g, 8.14 mmol), ethyl 2-chlorosulfonylbenzoate (2.65 g, 10.7 mmol), triethylamine (1.75 mL, 12.6 mmol), and 4-dimethylaminopyridine (50 mg) in acetonitrile mL) was stirred under an atmosphere of nitrogen at ambient temperature for about 18 hours. After concentrating the solution, the residue was diluted with 1.0 N KHSO 4 and extracted into ethyl acetate.
The organic layer was washed with 1.0 N KHSO 4 saturated NaHC0 3
H
2 0, and brine, and then dried over WO 00/69819 PCT/US00/06713 -234- MgSO 4 and concentrated to a yellow oil.
Chromatography (on silica, ethyl acetate/hexane) provided the sulfonamide as a clear oil (2.48 g, MS MH calculated for C 22
H
24 NOsF 3 S: 472, found 472.
Part D: A solution of the sulfonamide of Part C (2.10 g, 4.45 mmol) and potassium hydroxide (2.49 g, 44.5 mmol) in a mixture of MeOH (40 mL), H 2 0 (20 mL), and THF (4 mL) was heated at reflux for 1.5 hours.
After the solution was concentrated in vacuo, the residue was triturated with ethyl ether, dissolved into H 2 0, acidified with concentrated HC1, and extracted into ethyl acetate. The organic layer was washed with 1.0 N KHSO 4 H20, and brine, dried over MgSO 4 and concentrated in vacuo to provide the acid as a white solid (2.08 g, Anal. Calculated for C 20
H
2 0NOsF 3 S: C, 54.17; H, 4.55; N, 3.16; S, 7.23.
Found: C, 54.29; H, 4.68; N, 3.11; S, 7.19.
Part E: A solution of the acid of Part D (2.00 g, 4.51 mmol), N-hydroxybenzotriazole (1.83 g, 13.5 mmol), 4-methylmorpholine (1.48 mL, 13.5 mmol), 0tetrahydro-2H-pyran-2-yl-hydroxylamine (1.06 g, 9.02 mmol), and 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (2.59 g, 13.5 mmol) in DMF (40 mL) was stirred at ambient temperature under a nitrogen atmosphere for about 20 hours. The mixture was concentrated in vacuo, diluted with water, and extracted into ethyl acetate. The organic layer was washed with saturated NaHCO 3
H
2 0, and brine, and then dried over MgSO 4 and concentrated in vacuo to provide the THP-protected hydroxamate as a white solid (2.01 g, Anal. calculated, for WO 00/69819 PCT[USOO/06713 -235-
C
2 sH 29
N
2 0 6
F
3 S: C, 55.34; H, 5.39; N, 5.16; S, 5.91.
Found: C, 55.36; H, 5.63; N, 5.20; S, 6.12.
Part F: To a solution of the THP-protected hydroxamate of Part E (2.00 g, 3.69 mmol) in methanol (25.9 mL) was added acetyl chloride (0.78 mL, 11.1 mmol), and the solution was stirred at ambient temperature under a nitrogen atmosphere for hours. The solution was concentrated in vacuo and chromatography (on silica, MeOH/CHC13) provided the title compound as an off-white solid (1.07 g, 63%): Anal. calculated. for C 20
H
21
N
2 0sF 3 S: C, 52.40; H, 4.62; N, 6.11; S, 6.99. Found: C, 52.53; H, 4.74; N, 6.25; S, 7.16. MS MH+ calculated. for C 20
H
21
N
2 0 5
SF
3 459, found 459.
Example 15: Preparation of N-Hydroxy-2-[[(4phenoxyphenyl)aminolsulfonyllbenzamide
/OH
HN
o\ o Part A: A solution 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 4-dimethylaminopyridine (50 mg) in acetonitrile mL) was stirred under an atmosphere of nitrogen at ambient temperature for about 18 hours. After concentrating the solution, the residue was diluted with 1.0 N KHSO 4 and extracted into ethyl acetate.
The organic layer was washed with 1.0 N KHSO 4
H
2 0, and brine, and then dried over MgSO 4 and concentrated WO 00/69819 PCT[USOO/06713 -236in vacuo. Chromatography (on silica, ethyl acetate/hexane) provided the sulfonamide as a tan solid (4.94 g, Anal. calculated. for C 21 Hi 9
NO
5
S:
C, 63.46; H, 4.82; N, 3.52; S, 8.07. Found: C, 63.36; H, 4.78; N, 3.45; S, 8.31. MS M' calculated for C 21 Hi 9 NOsS: 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), THF (8 mL), and H 2 0 (33 mL) was heated at reflux for 2 hours.
After the solution was concentrated in vacuo, the residue was triturated with ethyl ether, dissolved into H 2 0, acidified with concentrated HC1, and extracted into ethyl acetate. The organic layer was washed with 1.0 N HC1, H 2 0, and brine, dried over MgSO 4 and concentrated in vacuo to provide the acid as a tan solid (2.31 g, Anal. calculated. for
C
1 9 Hs 1 NOsS: C, 61.78; H, 4.09; N, 3.79; S, 8.68.
Found: C, 61.66; H, 4.22; N, 3.73; S, 8.70. MS M calculated for C 19
H
15 sN
O
s: 369, found 369.
Part C: A 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), 0tetrahydro-2H-pyran-2-yl-hydroxylamine (1.46 g, 12.5 mmol), and 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (3.57 g, 18.6 mmol) in DMF (55 mL) was stirred at ambient temperature under a nitrogen atmosphere for about 18 hours. The mixture was diluted with water, and extracted into ethyl acetate. The organic layer was washed with saturated NaHC03, H 2 0, and brine, and then dried over MgS04 and concentrated in vacuo to provide the saccharin compound as a white solid (2.13 g, 97%): WO 00/69819 PCTIUS00/06713 -237- Anal. calculated. for C 1 9
H
1 3 N0 4 S: C, 64.95; H, 3.73; N, 3.99; S, 9.13. Found: C, 64.98; H, 3.82; N, 4.17; S, 9.07. MS MH+ calculated for C 19
H
13 N0 4 S: 352, found 352.
Part D: A solution of the saccharin of Part C (0.500 g, 1.42 mmol) and O-tetrahydro-2H-pyran-2-ylhydroxylamine (0.183 g, 1.56 mmol) in dioxane (2 mL) under an atmosphere of nitrogen was stirred for 6 days at ambient temperature and 1 day at 50 degrees Celsius. The solution was concentrated and chromatography provided the THP-protected hydroxamate as a white solid (0.285 g, MS MH calculated for
C
24
H
24
N
2 0 6 S: 469, found 469.
Part E: To a solution of the THP-protected hydroxamate of Part D (0.275 g, 0.587 mmol) in methanol (5 mL) was added acetyl chloride (0.150 mL, 2.13 mmol) and the solution was stirred at ambient temperature under a nitrogen atmosphere for 2 hours.
The solution was concentrated in vacuo and chromatography (on silica, MeOH/CHC1 3 provided the title compound as an off-white solid (1.18 g, 78%).
The proton NMR was consistent for the desired product.
Example 16: Preparation of N-Hydroxy-2,3-dimethoxy- 6-[[4-[4-(trifluoromethyl)phenoxy] 1-piperidinyl)sulfonyllbenzamide
NH-OH
WO 00/69819 PCT[USOO/06713 -238- Part A: The piperidine from Example 13, Part B (as the hydrochloride) (1.12 g, 4.0 mmol) was dissolved in a mixture of acetonitrile (6 ml), triethylamine (1.3 mL, 9.0 mmol), and N,Ndimethylaminopyridine (80 mg). 3,4- Dimethoxybenzenesulfonyl chloride (947 mg, 4.0 mmol) was added, and the mixture was stirred at ambient temperature for 6 hours. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate (100, then 25 mL). The combined organic layers were dried over magnesium sulfate, filtered through silica, and concentrated to afford the desired sulfonamide as a white solid (1.05 g, 59%) Part B: The sulfonamide from Part A (1.05 g, 2.38 mmol) was dissolved in tetrahydrofuran (20 mL) and was cooled to zero degrees Celsius. t- Butyllithium (1.7 M in pentane, 2.8 mL) was added drop-wise. Fifteen minutes after complete addition of the base, the solution was rapidly saturated with dry carbon dioxide gas. After an additional 15 minutes, the solution was acidified with a minimum of concentrated hydrogen chloride. The reaction mixture was concentrated, azeotroped with absolute ethanol, and the residue was subjected to silica gel chromatography, using 8:1 ethyl acetate:methanol, affording the desired acid as a glass (279 mg, 24%).
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 for 1.5 hours at ambient temperature, during which time gas was evolved. The reaction WO 00/69819 PCTIUS00/06713 -239mixture was concentrated, and dried in vacuo, affording crude acid chloride, which was used as is.
To the acid chloride was added a solution of Otetrahydropyranylhydroxylamine (234 mg, 2.0 mmol) and pyridine (0.5 mL, 6.0 mmol) in acetonitrile (2-3 mL).
The reaction was stirred at ambient temperature for 16 hours, then was 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 silica pad, and concentrated, affording 376 mg of crude THPprotected hydroxamate. The THP-protected hydroxamate was used directly without purification and was diluted with absolute methanol (10 mL). Acetyl chloride (0.36 mL, 5.0 mmol) was added, drop-wise.
After 2.5 hours, the mixture was concentrated and the residue was chromatographed (ethyl acetate:1% The desired hydroxamate was obtained as a glass (121 mg, 51% from acid). MS MH' calculated for C 21
H
23
F
3
N
2 0 7 S: 505, found 505.
Example 17: Preparation of N-Hydroxy-2-[[3- [4- (trifluoromethyl)phenoxy]-1pyrrolidinvllsulfonyllbenzamide 0
CF
3
N,OH
H
0 e i x -N 0 Part A: Diethyl azodicarboxylate (2.03 mL, 12.9 mmol) was added under an atmosphere of nitrogen to a WO 00/69819 PCT/US00/06713 -240solution of 1-(tert-butoxycarbonyl)-3hydroxypyrrlidine (2.31 g, 12.3 mmol), ptrifluoromethylphenol (2.09 g, 12.9 mmol), and triphenylphosphine (3.38 g, 12.9 mmol) in anhydrous THF (40 mL) at ambient temperature. After stirring for 2 hours, the reaction was concentrated in vacuo.
The residue was diluted with ether, filtered through a silica gel bed, concentrated, and purified by flash chromatography (on silica, ethyl acetate/hexane) to afford the BOC-protected amine as a white solid (1.85 g, Anal. Calculated for C 16
H
20 N0 3
F
3 C, 58.00; H, 6.08; N, 4.23. Found: C, 57.86; H, 6.17; N, 3.92.
Part B: To the BOC-protected amine of Part A (1.75 g, 5.28 mmol) was added a solution of 4 N HC1 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 saturated NaHCO 3 solution was added until the pH value was 8. The mixture was extracted with ethyl acetate. The organic layer was washed with H 2 0 and brine, dried over MgSO 4 and concentrated in vacuo to give the amine as a clear, yellow oil (0.75 g, MS MH+ calculated for
C
11 HI2NOF3:231, found 232.
Part C: A solution of the amine of Part B (0.680 g, 2.94 mmol), ethyl 2-chlorosulfonylbenzoate (0.688, 2.77 mmol), triethylamine (0.46 mL, 3.3 mmol), and 4-dimethylaminopyridine (10 mg) in acetonitrile (10 mL) was stirred under an atmosphere of nitrogen at ambient temperature for 18 hours.
After concentrating in vacuo, the residue was diluted with H 2 0 and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO 4 saturated WO 00/69819 PCTIUS00/06713 -241- NaHC03, H 2 0, and brine, dried over MgSO 4 and concentrated to a yellow oil. Chromatography (on silica, ethyl acetate/hexane) provided the sulfonamide as a clear, colorless oil (0.95 g, 76%); MS MH+ calculated for C 2 0
H
20 NOsF 3 S:443, found 444. Anal.
Calculated for C 20
H
20 NOsF 3 S: C, 54.17; H, 4.55; N, 3.16; S, 7.23. Found: 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 0 (8 mL) was heated at reflux for 4 hours. After the solution was concentrated in vacuo, the residue was dissolved into H 2 0, acidified with concentrated HC1, and extracted into ethyl acetate. The organic layer was washed with H 2 0 and brine, dried over MgSO 4 and concentrated in vacuo to provide the acid as a clear, colorless wax (0.74 g, MS MH calculated for CisH 16 NOsF 3 S: 415, found 416.
Part E: A solution of the acid of Part D (0.690 g, 1.56 mmol), N-hydroxybenzotriazole (0.629 g, 4.65 mmol), 4-methylmorpholine (0.51 mL, 4.7 mmol), 0tetrahydro-2H-pyran-2-yl-hydroxylamine (0.340 g, 2.90 mmol), and 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (0.891 g, 4.65 mmol) in DMF (13 mL) was stirred at ambient temperature under a nitrogen atmosphere for 3 days. The mixture was concentrated in vacuo, diluted with 1.0 N KHSO 4 and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO 4 saturated NaHCO 3
H
2 0, and brine, dried over MgSO 4 and concentrated in vacuo. Chromatography on silica, with ethyl acetate/hexane as eluant afford the THP-protected hydroxamate as a white foam (0.575 g, Anal.
WO 00/69819 PCT/US00/06713 -242calculated. for C 23
H
2 sN 2 0 6
F
3 S: C, 53.69; H, 4.90; N, 5.44; S, 6.23. Found: C, 53.48; H, 4.95; N, 5.37; S, 6.35.
Part F: To a solution of the THP-protected hydroxamate of Part E (0.500 g, 0.972 mmol) in methanol (6 mL) was added acetyl chloride (0.24 mL, mmol) and the solution was stirred at ambient temperature under a nitrogen atmosphere for hours. The solution was concentrated in vacuo and chromatography (on silica, MeOH/CHCl 3 provided the title compound as a white solid (0.325 g, MS MH+ calculated. for C 18
H
1 7
N
2 0 5
SF
3 430, found 431.
Example 18: Preparation of N-alpha-Dihydroxy-2- [[4-[4-(trifluoromethyl)phenoxy]-1piperidinyllsulfonyllbenzeneacetamide 0
HNOH
OH
O N O C
F
0 Part A: A mixture of 4-[(4-trifluoromethyl)phenoxy]piperidine hydrochloride (the hydrochloride from the product of Example 13, Part B (2.50 g, 8.87 mmol), 2-bromobenenesulfonyl chloride (2.16 g, 8.45 mmol), triethylamine (2.51 mL, 18.0 mmol), and 4- (dimethylamino)pyridine (20 mg) in acetonitrile mL) was stirred at ambient temperature under an atmosphere of nitrogen for 18 hours, concentrated in vacuo, and partitioned between H 2 0 and ethyl acetate.
The organic layer was washed with 1.0 N KHSO 4 saturated NaHC03, H 2 0, and brine, dried over MgSO 4 WO 00/69819 PCT/US00/06713 -243and concentrated in vacuo. The oil was.purified by chromatography (on silica, ethyl acetate/hexane) to provide the bromide as a clear oil (3.38 g, 82.8%): MS+ calculated. for C 8
H
17
NO
3
SF
3 Br 464, found 464.
Part B: To a -78 degree Celsius solution of the sulfonamide from Part A (3.68 g, 7.93 mmol) in anhydrous THF (40 mL) under an atmosphere of nitrogen was added 1.7 M tert-butyl lithium (9.35 mL, 15.9 mmol). The reaction was maintained at -78 degrees Celsius for 1 hour, warmed up to -30 degrees Celsius, and then cooled down to -78 degrees Celsius. A ethyl glyoxalate solution in toluene was added dropwise while maintaining the reaction mixture at a temperature below -50 degrees Celsius. The solution was warmed up slowly to ambient temperature, stirred 2 days at ambient temperature, poured into a saturated NH 4 C1 solution, diluted with H 2 0, and extracted with ethyl acetate. The organic layer was washed with H 2 0 and brine, dried over MgSO 4 and concentrated in vacuo. Chromatography on silica, with ethyl acetate/hexane as eluant provided the ester as a yellow oil (1.55 g, Anal.
calculated. for C 22
H
24 N0 6
F
3 S: C, 54.20; H, 4.96; N, 2.87. Found: C, 54.18; H, 4.72; N, 2.77. MS MH+ calculated for C 22
H
24
NO
6
F
3 S: 487, found 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 0 (14.7 mL) was stirred at ambient temperature for 1 hour. The solution was concentrated in vacuo, dissolved into a mixture of H 2 0 and acetonitrile, acidified with concentrated HC1, and extracted with ethyl acetate.
The organic layer was washed with 1.0 N KHSO 4
H
2 0, WO 00/69819 PCT/US0006713 -244and brine, dried over MgS04, and concentrated in vacuo to provide the acid as a wax (1.09 g, Anal.
calculated, for C 20
H
20
NO
6
F
3 S: C, 52.29; H, 4.39; N, 3.05; S, 6.98. Found: C, 52.06; H, 4.41; N, 2.90; S, 7.11.
Part D: A solution of the acid of Part C (1.00 g, 2.18 mmol), N-hydroxybenzotriazole (0.876 g, 6.48 mmol), 4-methylmorpholine (0.712 mL, 6.48 mmol), 0tetrahydro-2H-pyran-2-yl-hydroxylamine (0.474 g, 4.05 mmol), and 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (1.24 g, 6.48 mmol) in DMF (15 mL) was stirred at ambient temperature under a nitrogen atmosphere for 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 saturated NaHCO 3
H
2 0, and brine, dried over MgS04 and concentrated in vacuo. Chromatography on silica with ethyl acetate/hexane as eluant provided the THP-protected hydroxamate as a white solid (0.81 g, Anal.
calculated. for C 25
H
29 N20 7
F
3 S: C, 53.76; H, 5.23; N, 5.02; S, 5.74. Found: C, 53.73; H, 5.39; N, 4.85; S, 5.72.
Part E: A solution of the THP-protected hydroxamate of Part D (0.800 g, 1.43 mmol) and acetyl chloride (0.36 mL, 5.2 mmol) in methanol (15 mL) was stirred at ambient temperature under a nitrogen atmosphere for 1.5 hours. The solution was concentrated in vacuo and purified by preparatory HPLC (CH 3
CN/H
2 0) to provide the title compound as a white solid (0.310 g, Anal. calculated. for
C
20
H
21
N
2 0 6
SF
3 -0.2%H20: C, 50.25; H, 4.51; N, 5.86; S, 6.71. Found: C, 50.18; H, 4.52; N, 5.82; S, 6.58 WO 00/69819 PCT/US00/06713 -245- Example 19: Preparation of 2-Flouro-N-hydroxy-6- [[4-[4-(trifluoromethyl)phenoxyl]-1piperidinyllsulfonyllbenzamide
,OH
F
NH
O C O 0 O/N
OCF
3 Part A: A solution of the piperidine from Example 13, Part B (as the hydrochloride) (2.0 g, 6.72 mmol), 3-flourobenzenesulphonyl chloride (1.19 g, 6.11 mmol), triethylamine (2.13 mL, 15.3 mmol), and 4-dimethylaminopyridine (10 mg) in acetonitrile mL) was stirred under an atmosphere of argon at ambient temperature for 18 hours. After concentrating the solution, the residue was diluted with H 2 0 and extracted into ethyl acetate. The organic layer was washed with saturated NaHSO 4
H
2 0, and brine; and dried over MgSO 4 and concentrated to an oil. Chromatography (on silica, 20% ethyl acetate/hexane) provided the sulfonamide as a viscous oil (2.35 g, MS H+ calculated for
C
18
H
17
NSO
3
F
4 :404, found 404.
Part B: t-Butyl lithium (3.5 mL, 5.96 mmol) was added to a solution of the sulfonamide of Part A (1.2 g, 2.98 mmol) 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 for 7 minutes at 0°C, and the mixture was stirred for hours. Water was added to the solution, the WO 00/69819 PCT/US00/06713 -246mixture was acidified to pH 1.0 with 1 N HC1, and concentrated in vacuo to give an oil. Chromatography (on silica, 1% acetic acid/5% methanol/ethyl acetate) provided the acid as a white powder (0.970 mg, 73%).
MS H+ calculated for C 19
H
16 NSOsF 4 :448, found 448.
Part C: A solution of the acid of Part B (88-0 mg, 1.97 mmol), N-hydroxybenzotriazole (319 mg, 2.36 mmol), 4-methylmorpholine (0.649 mL, 5.91 mmol), 0tetrahydro-2H-pyran-2-yl-hydroxylamine (346 mg, 2.95 mmol), and 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (528 mg, 2.76 mmol) in DMF (10 mL) was stirred at ambient temperature under an argon atmosphere for 18 hours, followed by stirring at 60 0 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 on a C-18 reverse phase column, eluting with acetonitrile/water afforded the THP-protected hydroxamate as a white solid (240 mg, Part D: To a solution of the THP-protected hydroxamate of Part C (230 mg, 0.422 mmol), in dioxane (5 mL) was added 4 N HCl (1 mL), and the solution was stirred at ambient temperature under argon atmosphere for 1 hour. The solution was concentrated in vacuo to give an oil. Chromatography on a C-18 reverse phase column, eluting with acetonitrile/water afforded the titled hydroxamate as a white foam (180 mg, 92%).
Example 20: Preparation of 2-Chloro-N-hydroxy-6- [[4-[4-(triflouromethyl)phenoxyl]-1- DiDeridinyllsulfonyllbenzamide WO 00/69819 PCTUSOO/06713 -247-
,OH
CI
NH
S-N 0 0
CF
3 Part A: A solution of the amine of piperidine from Example 13, Part B (as the hydrochloride) (2.00 g, 6.72 mmol), 3-chlorobenzenesulphonyl chloride (1.29 g, 6.11 mmol), triethylamine (2.2 mL, 15.3 mmol), and 4-dimethylaminopyridine (10 mg) in acetonitrile (10 mL) was stirred under an atmosphere of argon at ambient temperature for 18 hours. After concentrating the solution, the residue was diluted with H 2 0 and extracted into ethyl acetate. The organic layer was washed with saturated NaHSO 4
H
2 0, and brine, and dried over MgSO 4 and concentrated to an oil. Chromatography (on silica, 20% ethyl acetate/hexane) provided the sulfonamide as a viscous oil (2.44 g, MS H+ calculated for
C
18
H
17 NS0 3
F
3 Cl:419, found 419.
Part B: t-Butyl lithium (3.4 mL, 5.7 mmol) was added to a solution of the sulfonamide of Part A (1.2 g, 2.9 mmol) 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 for 7 minutes at 0°C, then the reaction was stirred for 1.5 hours. Water was added to the solution, which was then acidified to pH 1.0 with 1 N HC1, and then concentrated in vacuo to give an oil.
Chromatography (on silica, 1% acetic WO 00/69819 PCT[USOO/06713 -248methanol/ethyl acetate) provided 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 ambient temperature and the solution was stirred under argon atmosphere for 1 hour. The solution was concentrated in vacuo to give the acid chloride. To the acid chloride in DMF mL) was added 4-methylmorpholine (0.200 mL, 1.77 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (155 mg, 1.30 mmol) and the reaction was stirred at ambient 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 on a C-18 reverse phase column, eluting with acetonitrile/water afforded the THP-protected hydroxamate as a white foam (260 mg, 52%).
Part D: To a solution of the THP-protected hydroxamate of Part C in dioxane was added 4 N HCl and the was solution stirred at ambient temperature under argon atmosphere for 1 hour. The solution was concentrated in vacuo to give a semi-solid.
Chromatography (on silica, 60% ethyl acetate/hexane) provided the title compound.
Example 21: Preparation of N-Hydroxy-2-[[4-(4pyridinyloxy)-1-piperidinyl]sulfonyl]benzamide. monohvdrochloride WO 00/69819 PCTiUS00/06713 -249- H OH
HN
-N HCI
S-N
Part A: To a solution of N-BOC-4hydroxypiperidine (3.00 g, 14.9 mmol) in dimethylsulfoxide (10 mL) are sequentially added 4chloropyridine hydrochloride (2.35 g, 15.6 mmol) and potassium-t-butoxide (30.5 mL of a 1.0 M solution in tetrahydrofuran, 30.5 mmol). After 16 hours at ambient temperature, the reaction mixture is diluted with diethyl ether (100 mL) and washed with water (3X) and brine, and then dried over sodium sulfate.
Concentration of the organic solution gives the desired 4-pyridyloxypiperidine (4.24 g, 100%) as a white solid. Analytical calculation for C 15
H
22
N
2 0 3
C,
64.73; H, 7.97; N, 10.06. Found: C, 64.48; H, 8.14; N, 9.82.
Part B: A solution of hydrogen chloride in 1,4dioxane (20 mL of a 4 N solution, 80 mmol) is added to a solution of pyridyloxypiperidine of Part A (3.81 g, 13.7 mmol) in 1,4-dioxane (28 mL) at ambient temperature. After one hour, the suspension is concentrated and the residue triturated with hot isopropanol. The resulting solid is dried at 50 degrees Celsius under vacuum to afford the desired piperidine hydrochloride salt as a white powder (3.03 g, 88%).
Analytical calculation for CioHi 4
N
2 0.2HCl: C, 47.82; H, 6.42; N, 11.15. Found: C, 47.40; H, 6.64; N, 11.04.
WO 00/69819 PCT/US00/06713 -250- Part C: The solid piperidine hydrochloride from Part B (450 mg, 1.79 mmol) is added to a solution of 2-carboxyethoxy-benzenesulfonyl chloride (580 mg, 2.33 mmol) in acetonitrile (5 mL), followed by the addition of neat triethylamine (0.95 mL, 7.16 mmol) and dimethylaminopyridine (10 mg, 0.08 mmol).
Additional acetonitrile (10 mL) is added, along with methylene chloride (3 mL) to aid in dissolution.
After 16 hours at ambient temperature, water (100 mL) is added and the mixture is extracted twice with ethyl acetate. The combined organic extracts are washed successively with water (3X) and brine, and then dried over sodium sulfate. Concentration gives a residue (0.49 g) that is chromatographed on silica gel eluting with ethanol/ethyl acetate (4/96) to afford the desired aryl sulfonamide (462 mg, 66%) as a pale yellow foam. Analytical calculation for
C
19
H
22
N
2 0sS. %H 2 0: C, 56.49; H, 5.86; N, 6.93. Found: C, 56.36; H, 5.88; N, 6.68.
Part D: Sodium hydroxide (10 equivalents) is added to a solution of the aryl sulfonamide of Part C in ethanol, water and tetrahydrofuran, and the solution is heated to 60 degrees Celsius for 24 hours. The solution is cooled and then diluted with water followed by 10% aqueous hydrochloric acid to bring the pH value to 3. The resulting solution is extracted with ethyl acetate. The organic extracts are combined and washed with water and brine, and dried over sodium sulfate to afford the desired carboxylic acid.
Part E: To a solution of the carboxylic acid of Part D in N,N-dimethylformamide are added 4methylmorpholine (6.0 equivalents), N- WO 00/69819 PCT/US00/06713 -251hydroxybenzotriazole (1.2 equivalents), and 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.3 equivalents), followed by O- (tetrahydro-2H-pyran-2-yl)hydroxylamine (1.3 equivalents). After stirring for 2 days at ambient temperature the solution is concentrated. Water is added and the mixture is extracted with ethyl acetate. The organic extracts are washed with water and brine, and dried over sodium sulfate.
Concentration affords a residue that is chromatographed on silica gel eluting with ethyl acetate/hexane (20/80 to 90/10) as eluate to afford the THP-protected hydroxamate derivative.
Part F: To a solution of the THP-protected hydroxamate of Part E in 1,4-dioxane is added 4 N HC1 in 1,4-dioxane (10 equivalents), and the solution is permitted to stir at ambient temperature for 3 hours.
Concentration gives a residue that is then triturated with diethyl ether to afford the title compound.
Example 22: Preparation of N-Hydroxy-2,3-dimethoxy- 6-[[4-[(2'-methoxy[l,1'-biphenyl]-4-yl)oxy-l-piperidinyllsulfonyllbenzamide OMeO MeO0) NHOH MeO 6'N j Part A: To a solution of N-BOC-4hydroxypiperidine (25 mmol, 5.0 g) in 1 methyl-2pyrrolidinone (20 mL) was added hexane-washed sodium hydride (26 mmol, 1.01 The reaction mixture was stirred at ambient temperature for 15 minutes, then heated to 65 degrees Celsius for 30 minutes. Bromo- WO 00/69819 PCT/US00/06713 -252- 4-fluorobenzene (25 mmol, 4.38 g) was added, and the solution was heated at 120 degrees Celsius for 24 hours. The reaction mixture was permitted to cool to ambient temperature, was diluted with water (100 mL), and was extracted with ethyl acetate (150 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo to afford an oil, which was further purified by passage through silica pad, eluting with ethyl acetate. 7.28 g were obtained. MS calculated for C 16
H
22
NO
3 Br: 356, found 356.
Part B: To a solution of the bromide of part A (20 mmol, 7.2 g) in dioxane (20 mL) was added 4N HC1 (50 mL). The solution was stirred at ambient temperature for two hours, then concentrated to give a solid. The solid was triturated with diethyl ether, affording the desired piperidine hydrochloride (5.8 g 99%).
Part C: To a solution of 3,4dimethoxybenzenesulfonyl chloride (18 mmol, 4.26 g) in acetonitrile (75 mL) was added the hydrochloride from part B (20 mmol, 5.8 followed by triethylamine (36 mmol, 7.5 mL) and N,Ndimethylaminopyridine (100 mg). The solution was stirred at ambient 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 (1:1 hexane:ethyl acetate) provided the desired sulfonamide as a solid (5.45 g, MS calculated for C 19
H
22 BrNSOs 456, found 456.
WO 00/69819 PCTfUSOO/06713 -253- Part D: To a solution of the compound of Part C (2.96 g, 6.49 mmol) in ethylene glycol dimethyl ether (30 mL) at ambient temperature under an atmosphere of nitrogen was added tetrakis(triphenylphosphine)palladium(0) (0.375 g, 0.325 mmol). After stirring for 5 minutes, 2methoxyphenylboronic 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 overnight (about 18 hours) at ambient temperature. 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 a black solid. Chromatography (on silica, acetone/hexane) provided the biphenyl as a white solid (2.69 g, 86% yield); Anal. calcd for C 26
H
29
NO
6
S:
C, 64.58; H, 6.04; N, 2.90; S, 6.63. Found: C, 64.30; H, 6.16; N, 2.86; S, 6.90. MS (EI) MH+ calcd.
for C 26
H
29
NO
6 S 484, found 484.
Part E: To a solution of the biphenyl of Part D (2.85 g, 5.89 mmol) in THF (80 mL) at degrees Celsius under a nitrogen atmosphere was added a solution of 1.6 M n-butyllithium in hexane (5.17 mL, 8.27 mmol). After stirring at ambient temperature for 30 minutes, the solution was cooled to -80 degrees Celsius and carbon dioxide was bubbled into the solution for 7 minutes. The solution was diluted with lN HC1 (50 mL) and extracted with ethyl acetate (3x50 mL). The organic layer was washed with water (2x50 mL) and brine (50 mL), dried with MgS0 4 and concentrated in vacuo to provide the carboxylic acid as a tan solid (3.00 g, 96% yield) Anal.
WO 00/69819 PCT/US0/06713 -254calcd for C 27
H
29 NOS: C, 61.47; H, 5.54; N, 2.65; S, 6.08. Found: C, 61.46; H, 5.94; N, 2.48; S, 5.70. MS (EI) MH+ calcd. for C 27
H
29 NOsS 528, found 528.
Part F: To a solution of the carboxylic acid of Part E (2.92 g, 5.53 mmol) and DMF (2 drops, catalytic amount) in 1,2-dichloroethane(50 mL) was added oxalyl chloride(4.07 mL, 46.7 mmol). After stirring for 1.5 hours at ambient temperature under a nitrogen atmosphere, the solution was concentrated in vacuo to a yellow oil. To the oil were added Nmethylmorpholine (1.57 mL, 14.2 mmol), O-(tetrahydro- 2H-pyran-2-yl)hyroxylamine (1.66 g, 14.2 mmol), and 1,2-dichloroethane (19 mL). After stirring for about hours at ambient temperature under an atmosphere of nitrogen, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (3x50 mL). The organic layer was washed with lN HC1 (50 mL), saturated NaHCO 3 (50 mL), water (50 mL), and brine mL), dried with MgSO 4 and concentrated in vacuo to a tan solid. Chromatography (on silica, ethyl acetate/hexane) provided the O-protected hydroxamate as a white solid (2.41 g, 69% yield);MS (EI) MH+ calcd. for C 32 H38N 2 0 9 S 627, found 627.
Part G: To a solution of acetyl chloride (2.61 mL, 38.1 mmol) in MeOH (39 mL) was added the 0protected hydroxamate of Part F (2.39 g, 3.81 mmol) and stirred at ambient temperature under a nitrogen atmosphere for 1.5 hours. The solution was concentrated, triturated with ether, concentrated, and dried to give a white solid. Chromatography (on silica, MeOH/CHC1 3 provided the title compound as a white solid(1.36 g, 66% yield); Anal. calcd for
C
27
H
30
N
2 0 8 S: C, 59.77; H, 5.57; N, 5.16; S, 5.91.
WO 00/69819 PCT[USOO/06713 -255- Found: C, 57.60; H, 5.17; N, 5.04; S, 5.67. MS (EI) MH+ calcd. for C 27
H
30
N
2 0 8 S 543 Example 23: Preparation of N-Hydroxy-2-(2-methoxyethoxy)-6-[[4-[4-(trifluoromethyl)phenoxyl-1-piperidinyllsulfonyllbenzamide 0 0
SNHOH
OS-N -0 a CF 3 Part A: A solution of 1-[(3-fluorophenyl)sulfonyl]-4-[4 (trifluoromethyl)phenoxy]piperidine (7.00 g, 17.4 mmol), 60% sodium hydride(l.13 g, 28.2 mmol) and 2-methoxy-l-ethanol (2.19 mL, 27.7 mmol) in l-methyl-2-pyrrolidinone (10 mL) was heated at 120 degrees Celsius for 5 hours. The solution was diluted with water (300 mL) and extracted with ethyl acetate (3x100 mL). The organic layer was washed with water (2x100 mL) and brine (100 mL), dried with MgSO4, and concentrated in vacuo to a brown paste.
Recrystallization from methyl tert-butyl ether/hexane provided the ether as a white solid (6.59 g, 83% yield). The proton NMR spectrum was consistent for the desired ether.
Part B: To a solution of the ether of Part A (6.59 g, 14.3 mmol) in THF (120 mL) at -10 degrees Celsius under a nitrogen atmosphere was added a solution of 1.7 M t-butyllithium in pentane (16.8 mL, 26.8 mmol). After stirring at -60 degrees Celsius for 30 minutes, carbon dioxide was bubbled into the solution for 7 minutes, the resulting solution was WO 00/69819 PCT/US00/06713 -256poured into a solution of 1N HC1 (100 mL) and water (500 mL), and extracted with ethyl acetate (3x100 mL). The organic layer was washed with 1N HC1 (100 mL), water (2x100 mL) and brine (100 mL), dried with MgSO 4 and concentrated in vacuo. Chromatography (acetic acid/ MeOH/CHC13) provided the carboxylic acid as a yellow oil (4.67 g, 64% yield) Anal. calcd for C 22
H
24 N0 7
F
3 S: C, 52.48; H, 4.80; N, 2.78; S, 6.37.
Found: C, 52.49; H, 4.70; N, 2.69; S, 6.31.MS (EI) MH+ calcd. for C 22
H
24 N0 7
F
3 S 504, found 504.
Part C: To a solution of the carboxylic acid of Part B (5.45 g, 10.8 mmol) and DMF (4 drops, catalytic amount) in dichloromethane (99 mL) was added oxalyl chloride (8.03 mL, 92.0 mmol). After stirring for 2 hours at ambient temperature, the solution was concentrated in vacuo to a dark brown mixture. To the mixture were added Nmethylmorpholine (4.76 mL, 43.3 mmol), O-(tetrahydro- 2H-pyran-2-yl)hyroxylamine (5.07 g, 43.3 mmol), and dichloromethane (77 mL). After stirring for about 4 hours at ambient temperature, the solution was washed with water,1.0 N HC1, saturated NaHCO 3 water, and brine, dried with MgSO 4 and concentrated in vacuo to a paste. Chromatography (on silica, MeOH/ethyl acetate) provided the O-protected hydroxamate as a pink solid (5.23 g, 80% yield); Anal. calcd for
C
27
H
33
N
2 0 8
F
3 S: C, 53.81; H, 5.52; N, 4.65; S, 5.32.
Found: C, 53.67; H, 5.43; N, 4.77; S, 5.17. MS (EI) MH+ calcd. C 27
H
33
N
2 0 8
F
3 S for 603, found 603.
Part D: A solution of acetyl chloride (5.90 mL, 86.3 mmol) in MeOH (89 mL) was added to the 0protected hydroxamate of Part C (5.20 g, 8.63 mmol) and stirred at ambient temperature for 3 hours. The WO 00/69819 PCT/US00/06713 -257solution was concentrated, triturated with ether, and concentrated to give an off white solid.
Chromatography (on silica, MeOH/methylene chloride) provided the title compound as a white solid (2.25 g, 50% yield); Anal. calcd for C 22
H
25
N
2 07S: C, 50.96; H, 4.86; N, 5.40; S, 6.18. Found: C, 50.57; H, 4.91; N, 5.37; S, 6.08.MS (EI) MH+ calcd. for C 22
H
2 sN 2 0 7 S 519, found 519.
Example 24: Preparation of N-Hydroxy-2,3-dimethoxy- 6-[[4-(phenylthio)-1-piperidinyl]sulfonyllbenzamide MeO O MeO
NHOH
O SO-N- S 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 (500 mg). 3,4-dimethoxy-benzenesulfonyl chloride (50 mmol, 11.84 g) was added. The mixture was stirred overnight (about 18 hours), then concentrated by rotary evaporation. The residue was diluted with water (100 mL) and extracted with dichloromethane (2 X 150 mL). The combined organic phases were dried using magnesium sulfate, filtered through a silica plug, and concentrated to afford the desired alcohol as a foam (7.31 g, 51%).
Part B: The alcohol from Part A (6.39 g, 22.4 mmol) was combined with methylene chloride mL) and triethylamine (3.46 mL, 25 mmol). The solution was chilled to zero degrees Celsius.
Methanesulfonyl chloride (1.79 mL, 23 mmol) was added. The reaction was stirred at ambient WO 00/69819 PCT[USOO/06713 -258temperature for 4 hours, then diluted to 150 ml with additional methylene chloride, and washed with water (2 X 25 mL). The organic phase was dried over magnesium sulfate, filtered through silica, and concentrated to provide the mesylate as a white solid (3.51 g, 41%).
Part C: 60% Sodium hydride in mineral oil (324 mg, 8.1 mmol) was washed with hexanes. The washed hydride was covered with N,N-dimethylformamide (12 mL) and chilled to zero degrees Celsius.
Thiophenol (0.83 mL, 8.1 mmol) was added, and the mixture was stirred for 20 minutes. Solid mesylate from Part B, above, (3.0 g, 7.9 mmol) was added.
Mesylate displacement was slow at ambient temperature; the reaction was warmed at 55 degrees Celsius for 3 hours. Work-up comprised of azeotropic removal of the DMF assisted by toluene, followed by chromatography of the residue, affording 1.45 g (44%) of the sulfide as a white foam.
Part D: The sulfide was dissolved in tetrahydrofuran (24 mL) and cooled to zero degrees Celsius. T-BuLi (1.7 M in pentane, 4.1 mL) was added over 1 minute. After 15 minutes, the reaction was quenched with carbon dioxide gas. After 10 minutes, the mixture was acidified using concentrated HC1, concentrated, and chromatographed to give the desired acid as a foam (1.067 g, Part E: The acid from Part C was diluted with methylene chloride (15 mL). Three drops of N,Ndimethylformamide were added, followed by oxalyl chloride (0.35, 4 mmol). The reaction was stirred at ambient temperature for 2 hours, then concentrated.
The crude acid chloride was added using about 3 mL of WO 00/69819 PCT/US00/06713 -259methylene chloride to a mixture of tetrahydropyranhydroxylamine (0.47 g, 4 mmol), pyridine (0.47 ml, 6 mmol) and acetonitrile (3 mL). The mixture was stirred overnight (about 18 hours), then subjected to aqueous extraction (50 mL methylene chloride/50 mL water). The organic phase was dried over magnesium sulfate, concentrated, and chromatographed to afford the O-THP hydroxamate as a foam (619 mg).
The O-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, affording the desired hydroxamate as a foam (428 mg, MS (EI) MH+ calculated for C 20
H
24
N
2 0 6
S
2 453, found 453.
The following analogs were made in good yield using similar procedures: Example 25: 6-[[4-[(3'-Dimethoxy[l,l'-biphenyl]-4yl)-1-piperidinyl]sulfonyl]-N hydroxy- 2.3-dimethoxybenzamide MeO 0 MeO NHOH OMe ON OMe MS (EI) MH+ calculated for C 28
H
32
N
2 0 9 S: 573, found 573.
Example 26: N-Hydroxy-2,3-dimethoxy-6-[[4- [4-(trifluoromethyl)phenyl]-1piperazinyllsulfonyllbenzamide WO 00/69819 WO 0069819PCTUSOOIO6713 -260- MeO M e NHOH vs s-N N-(f CF 3 MS (El) calculated for C 2 0
H
2 2
F
3
N
3 0 6 S: 490, found 490.
Example 27: N-Hydroxyl-2,3-dimethoxy-6-[[4- (trifluoromethyl) 11,1' -biphenyl] -4yll oxyl -l-piperidinyll sulfonyll benzamide MeO 0 MeO '.ANHOH CF 3 0' MS (El) calculated for C 27
H
2 7
F
3
N
2 0 7 S: 581, found 581.
Example 28: 6-[[4-(1,1'-Biphenyll-4-yloxy)- 1-piperidinyl] sulfonyl] -N-hydroxy- 2.3-dime thoxybenzamide MeO 0 Me0 ANHOH 6- 0 Example 29: 2-[[4-(2,3-Dihydro-2-oxo-lHbenzimidazol-l-yl) -1-piperidinyl] sul fonvll1-N-hydroxvbenzamide 0 QANHOH NHNH MS (El) calculated for C 1 9H 2 oN 4 OsS: 417, found 417.
Example 30: 2,3-Dihydro-N-hydroxy-6- [(4-methoxy- WO 00/69819 WO 0069819PCTJUSOOIO6713 -261- 1-piperidinyl) sulfonyll -1,4-benzodioxilcarboxamide 0- 0
SNHOH
0 U- MS (El) calculated for C 1 5
H
2 0
N
2 0 7 S: 372, found 373.
Example 31: 2,3-Dihydro-N-hydroxy-6- (trifluoromethyl)phenoxy-lpiperidinyl] sulfonyl -1,4benzodioxin- 0 NHOH 100 MS (El) calculated for C 2 lH 2 lF 3
N
2 0' 7 S: 502, found 503.
Example 32: 2,5-Dichloro-N-hydroxy-4- (trifluoromethyl)pheloxyl -1piperidinyl] sulfonyll -3thi onhenecarboxami de Ci 0
NHOH
~S~NQ-0-&(-CF3 Example 33: N-Hydroxy-2,3-dimethoxy-6- (trifluoromethoxy)phenoxy] 1 -piperinyll sulfonylbenzamide MeO 0 Me0 NHOH SS-:Na oO 0 WO 00/69819 WO 0069819PCT[USOOIO6713 -262- Example 34: N-Hydroxy-2,3-dimethoxy-6- (2-methoxyphenoxy) -l-piperidinyl] sul fonyll1benzamide MeO 0 MeO IN NHOH MeO c; 6\-J Anal. Calc.'d for C 2 1
H,
6
N
2 0 8 S: C, 50.07; H, 5.62; N, 6.00. Found: C, 53.77; H, 5.64; N, 5.79.
Example 35: N-Hydroxy-3, 6-dimethoxy-2- (trifluoromethyl)phenoxy] -1pineridinyll sulfonyll benzamide CH3 0O
NHOH
CH
3 0 0 \0I:L
F
Example 36: N-Hydroxyl-5- (trifluoromethyl) phenoxy-l1-piperidinyl] sulfonyl -1,3benzodioxole-4 -carboxamide 0 ,-,JNHOH b"11S-d \-CF 3 6 6 \-J MS (El) calculated for C 2 0 HjqF 3
N
2 0 7 S: 489, found 489.
Example 37: 6-[[4-[(2',5'-Dimethoxy[1,l'-biphenyl)- 4-yl)oxy] -1-piperidinyllsulfonyll -Nhydroxv-2. 3-dimethoxybenzamide OMeO0 MeG N14:k 1 A NHOH MeG OMe WO 00/69819 WO 0069819PCTLJSOOIO6713 -263- Anal. Calc.'d for C 2 8
H
3 2
N
2 0 9 S: C, 58.73; H, 5.63; N, 4.89. Found: C, 58.55; H, 5.82; N, 4.81.
Example 38: N-Hydroxy-2,3-dimethoxy-6- [14- (trifluoromethyl) [l,1'-biphenyl] -4yll oxyl -l-piloeridinyll sulfonyll benzamide OMeO0 M eO,~ J N HOH
F
3 67)- Anal. Calc.'d for C 2 7H 2 7
F
3
N
2 0 7 S: C, 55.86; H, 4.69; N, 4.83. Found: C, 55.77; H, 4.75; N, 4.77.
Example 39: N-Hydroxy-2,3-dimethoxy-6- [[4-1111'- (trifluoromethyl) [1,1'-biphenyl] -4vlloxyl -1-piperidinyll sulfonyllbenzamide OMeO0 MeO NHOH MeO Anal. Calc.'Id for C 3 0
H
3 6
N
2 0 8 S: C, 61.63; H, 6.21; N, 4.79. Found: C, 61.36; H, 6.29; N, 4.64.
Example 40: 6-[[4-[(2'-Ethoxy[1,1-biphenyl]-4yl) oxy-1-piperidinyl] sulfonyl] -Nhydroxyl-2. 3-dimethoxvbenzamide OMe 0 NHOH EtO Anal. Calc.'d for C 2 8
H
3 2
N
2 0 8 S: C,60.42; H,5.79; N, 5.03. Found: C,60.30; H, 5.94; N, 4.88.
Example 41: N-Hydroxy-2,3-dimethoxy-6-[[4-( 4 WO 00/69819 PTU0I61 PCTfUSOO/06713 -264methoxyphenyl) -piperazinyl] sulfonyl] benzamide. monohydrochioride MeO 0 MeO-,)z
NHOH
SZ-N'- OMe MS (El) MH-+ calculated for C 2 0
H
2 5
N
3 0 7 S (free base) 452, found 452.
Example 42: N-hydroxyl-2- [14- (2-pyridinyloxy) -1piperidinyl] sulfonyll benzamide, monohydrochloride 0
NHOH
o MS (El) MH+ calculated for C 1 7
H
19
N
3 0 7 S (free base) 378, found 378.
Example 43: 5- [(4-Butoxy-1-piperidinyl) sulfonyl] N-hydroxy- 1.3 -benzodioxole-4 -carboxamide 0
,,,)INHOH
Anal. Calc.'d for C 17
H
24
N
2 0 7 S: C, 50.99; H, 6.04; N, 7.00. Found: C,50.97; H, 6.27; N, 6.88.
Example 44: 5- [(4-Heptyloxy-l-piperidinyl)sulfonyl] N-hydroxy- 1.3 -benzodioxole-4 -carboxamide 0 z 0 k,4YtS-NQ-- 0(n-heptyl) WO 00/69819 PTLSO071 PCTIUSOO/06713 -265- Anal. Calc.'Id for C 2 0
H
3 0
N
2 0 7 S: C, 54.28; H, 6.33; N, 6.33. Found: C,53.91; H, 7.10; N, 6.25.
Example 45: N-Hydroxy-2,3-dimethoxy-6- (4methoxyphenoxy-l-piperidinyl] sulfonyll1benzamide OMeO0 Me0
NHOH
I S-NQ)-0-C OMe 100 Example 46: 6- (4-Chlorophenoxy) -1-piperidinyl] sulfonyll -N-hydroxy-2, 3dimethoxybenzamide OMeO0 MeO "flNHOH 6' 0 Anal. Calc.'Id f or C 2 0
H
2 3 ClN 2 0 8 S: C, 51. 01; H, 4. 92; N, 5.95. Found: C,50.62; H, 4.93; N, 5.92.
Example 47: N-Hydroxy-2,3-dimethoxy-6- [(4-phenoxy- 1-piperidinyl) sulfonyll benzamide OMeO0 MeO -~NHOH 00O MS (EI) calculated for C 2 0
H
2 4
N
2 0 7 S: 436, found 437.
Example 48: N-Hydroxy-2- [(tetrahydro-2H-pyran-4yl)oxy] (trifluormethyl)phenoxy) 1-Diperidinyll sulfonvll benzamide WO 00/69819 WO 00/98 19PCTIUSOO/06713 -266- 021 0 kl: -I--Nf -O-e CF 3 C; 6 Anal. Calc.'d for C 2 4
H
2 7
F
3
N
2 0 7 S: C,52.94; H,5.00; N, 5.14. Found: C,52.64; H, 4.92; N, 5.02.
Example 49: 5-[[4-((l,3-Beflzodioxol]-5-yloxy)- 1-piperidinyl] sulfonyll -N-hydroxy- 1. 3-benzodioxole-4 -carboxamide 0" NHOH K o-Q- 0- Example 50: 6- (1,3-Benzodioxole-5-yloxy) 1-piperinyl] sulfonyl] -N-hydroxy- 2. 3-dimethoxvbenzamide MeO 0 MeO
NHOH
0 MS (El) calculated for C 2 1
H
2 4
N
2 0 9 S: 481, found 481.
Example 51: 2-[(4-Benzoyl-1-piperazilyl) sulfonyll1-N-hydroxybenzamide 0
NHOH
-S-N N-< MS (El) MH+ calculated for C3 1 8 HjqN 3 0 5 S: 390, found 390.
Example 52: N-Hydroxy-2,3-dimethoxy-6- (phenylmethyl) -1-piperazinyl] sulfonyl] WO 00/69819 WO 0069819PCf/USOO/06713 -267benzamide. monohydrochloride MeO 0 MeO N NHOH MS (El) MH+ calculated f or C 2 0
H
2 5
N
3 0 6 S (free base) 436, found 436.
Example 53: N-Hydroxy-2,3-dimethoxy-6- (trifluoromethoxy) phenyl] methyl] -l piperazinyl] sulfonyl] benzamide, monohydrochioride MeO 0 MeO 1: NHOH 6 S N N
OF
MS (El) MH+ calculated for C 2 lH 2 4
F
3
N
3 0 7 S: 520, found 520.
Example 54: 6- (4-Butoxyphenoxy) -1-piperidinyl] sulfonyll -N-hydroxy-2. 3-dimethoxvbeflzamide MeO 0 MeO A1 NHOH S,7N -00(n-Bu) MS (EI) MH+ calculated for C 24
H
32
N
2 0 8 S: 509, found 509.
Example 55: N-Hydroxy-2- (4-pyridinyloxy) -1piperidinyl] sulfonyllbenzamide, monohydrochl oride MeO 0 MeO 'A NH0H Q-S7O-
-GJN
WO 00/69819 WO 0069819PCT[USOO/06713 -268- MS (El) MH+ calculated for C 17
H
19
N
3 0 5 S (free base) 378, found 378.
Example 56: 6- (4-Butoxy-3-methylphenyl) -1piperazinyllsulfolyl] -N-hydroxy-2,3dimethoxybenzamide. monohydrochioride MeO 0 Me
NHOH
ti-N j3-0 0(n-Bu) MS (El) MH+ calculated for C 24
H
3 3
N
3 0 7 S (free base): 508, found 508.
Example 57: N-Hydroxy-2,3-dimethoxy-6- (3-methoxyphenoxy-lipiperidinyll sulfonyll benzamide MeO 0 MeO I N NHOH OMe SS-N' Anal. Calc.'d for C 21
H
26
N
2 0 8 S: C,54.07; H,5.62; N, 6.00. Found: C,53.77; H, 5.64; N, 5.79.
Example 58: In Vitro Metalloprotease Inhibition The compounds prepared in the manner described in the Examples above were assayed for activity by an in vitro assay. Following the procedures of Knight et al., FEBS Lett. 296i(3)I:263 (1992). Briefly, 4-aminophenylmercuric acetate (APMA) or trypsin-activated MMPs were incubated with various concentrations of the inhibitor compound at room temperature for 5 minutes.
More specifically, recombinant human MM'P-13, MMP-l and MMP-2 enzymes were prepared in WO 00/69819 PCT/US00/06713 -269laboratories of the assignee following usual laboratory procedures. MMP-13 from a full length cDNA clone was expressed as a proenzyme using a baculovirus as discussed in V.A. Luckow, Insect Cell Expression Technology, pages 183-218, in Protein Engineering: Principles and Practice, J.L.Cleland et al eds., Wiley-Liss, Inc., (1996). See, also, Luckow et al., J. Virol., 67:4566-4579 (1993); O'Reilly et al., Baculovirus Expression Vectors: A Laboratory Manual, W.H. Freeman and Company, New York, (1992); and King et al., The Baculovirus Expression System: A Laboratory Guide, Chapman Hall, London (1992) for further details on use of baculovirus expression systems. The expressed enzyme was purified first over a heparin agarose column and then over a chelating zinc chloride column. The proenzyme was activated by APMA for use in the assay.
MMP-1 expressed in transfected HT-1080 cells was provided by Dr. Harold Welgus of Washington University, St. Louis, MO. The enzyme was also activated using APMA and was then purified over a hydroxamic acid column. Dr. Welgus also provided transfected HT-1080 cells that expressed MMP-9.
Transfected cells that expressed MMP-2 were provided by Dr. Gregory Goldberg, also of Washington University. Studies carried out using MMP-2 in the presence of 0.02% 2-mercaptoethanol are shown in the table below with an asterisk. Further specifics for preparation and use of these enzymes can be found in the scientific literature describing these enzymes.
See, for example, Enzyme Nomenclature, Academic Press, San Diego, Ca (1992) and the citations WO 00/69819 PCT/US00/06713 -270therein, and Frije et al., J. Biol. Chem., 26(24): 16766-16773 (1994).
The enzyme substrate is a methoxycoumarincontaining polypeptide having the following sequence: MCA-ProLeuGlyLeuDpaAlaArgNH2, wherein MCA is methoxycoumarin and Dpa is 3-(2,4-dinitrophenyl)- L-2,3-diaminopropionyl alanine. This substrate is commercially available from Baychem as product M-1895.
The buffer used for assays contained 100 mM Tris-HCl, 100 mM NaCl, 10 mM CaC1 2 and 0.05 percent polyethyleneglycol (23) lauryl ether at a pH value of Assays were carried out at room temperature, and dimethyl sulfoxide (DMSO) at a final concentration of 1 percent was used to dissolve inhibitor compound.
The assayed inhibitor compound in DMSO/buffer solution was compared to an equal amount of DMSO/buffer with no inhibitor as control using MicrofluorTM White Plates (Dynatech). The inhibitor or control solution was maintained in the plate for minutes and the substrate was added to provide a final concentration of 4 pM.
In the absence of inhibitor activity, a fluorogenic peptide was cleaved at the gly-leu peptide bond, separating the highly fluorogenic peptide from a 2,4-dinitrophenyl quencher, resulting in an increase of fluorescence intensity (excitation at 328 nm/emission at 415 nm). Inhibition was measured as a reduction in fluorescent intensity as a function of inhibitor concentration, using a Perkin Elmer L550 plate reader. The IC 50 values were calculated from those values. The results are set WO 00/69819 PCT/US00/06713 -271forth in the Inhibition Tables A and B below, reported in terms of IC 5 0 to three significant figures, where appropriate.
Inhibition Table A values in nM) Example MMP-1 MMP-2 MMP-13 1 >10,000 10 2 900 0.3 2 3 >10,000 148 1000 4 >10,000 >10,000 >10,000 >10,000 3500 >10,000 6 >10,000 4000 7 >10,000 >10,000 8 >10,000 >10,000 9 >10,000 45.0 1500 >10,000 70.0 520 11 >10,000 2,300 2,200 12 >10,000 2.2 33.0 13D >10,000 3300 3800 13 >10,000 1.3 28.5 14 >10,000 35 900 >10,000 3,500 9,000 16 >10,000 2.4 2.7 17 >10,000 1,800 2,000 18 19 >10,000 5.0 12.3 >10,000 1.8 14.8 21 >10,000 5.9 63 WO 00/69819 PCT/USOO/06713 -272- Inhibition Table B values in nM) Example MT1- Niumber MMP-1 MMP-2 MMP-3 MMP-8 MMP-9 MMP-13 MMP 22 >10,000 15.5 170 800 300 5.5 2500 23 >10,000 1.0 4.3 24 >10,000 0.9 400 10.7 10.0 3.0 25.4 >10,000 3.3 100 115 370 2.6 1700 26 >10,000 6.5 1750 37.2 970 40 1920 27 >10,000 3.3 300 210 520 3.0 690 28 >10,000 0.4 1.8 29 >10,000 370 2000 >10,000 >10,000 >10,000 31 >10,000 1.4 7.7 32 >10,000 110 730 33 >10,000 0.9 100 1.5 5.0 360 34 >10,000 330 2500 >10,000 21 110 36 >10,000 3.0 600 12.2 8.0 18.0 300 37 38 20 1700 82 39 120 400 100 80 4400 41 >10,000 6.0 8000 120 470 100 4000 442 >10,000 42 1200 43 >10,000 200 3700 44 >10,000 206 330 >10,000 1.8 900 1.1.4 3.0 13.9 300 46 >10,000 0.3 47 >10,000 1.1 6.7 48 >10,000 1.0 2.2 49 >10,000 1.1 19 >10,000 1.1 1300 12.2 9.0 18.6 270 51 >10,000 1000 6700 52 1500 >10,000 4000 53 >10,000 240 1900 54 >10,000 0.8 31.6 70.0 2.0 1.6 200 >10,000 5.9 63 56 >10,000 9.0 20.0 57 >10,000 12.1 250 Example 59: In Vivo Angiogenesis Assay The study of angiogenesis depends on a reliable and reproducible model for the stimulation and inhibition of a neovascular response. The corneal micropocket assay provides such a model of angiogenesis in the cornea of a mouse. See, A Model WO 00/69819 PCT/US00/06713 -273of Angiogenesis in the Mouse Cornea; Kenyon,BM, et al., Investigative Ophthalmology Visual Science, July 1996, Vol. 37, No. 8.
In this assay, uniformly sized Hydron
TM
pellets containing bFGF and sucralfate are prepared and surgically implanted into the stroma mouse cornea adjacent to the temporal limbus. The pellets are formed by making a suspension of 20 iL sterile saline containing 10 lg recombinant bFGF, 10 mg of sucralfate and 10 pL of 12 percent Hydron TM in ethanol. The slurry is then deposited on a 10 x 10 mm piece of sterile nylon mesh. After drying, the nylon fibers of the mesh are separated to release the pellets.
The corneal pocket is made by anesthetizing a 7 week old C57B1/6 female mouse, then proptosing the eye with a jeweler's forceps. Using a dissecting microscope, a central, intrastromal linear keratotomy of approximately 0.6 mm in length is performed with a #15 surgical blade, parallel to the insertion of the lateral rectus muscle. Using a modified cataract knife, a lamellar micropocket is dissected toward the temporal limbus. The pocket is extended to within mm of the temporal limbus. A single pellet is placed on the corneal surface at the base of the pocket with a jeweler's forceps. The pellet is then advanced to the temporal end of the pocket. Antibiotic ointment is then applied to the eye.
Mice are dosed on a daily basis for the duration of the assay. Dosing of the animals is based on bioavailability and overall potency of the compound. an exemplary dose is 50 mg/kg bid, po.
Neovascularization of the corneal stroma begins at WO 00/69819 PCT/USOO/06713 -274about day three and is permitted to continue under the influence of the assayed compound until day five.
At day five, the degree of angiogenic inhibition is scored by viewing the neovascular progression with a slit lamp microscope.
The mice are anesthetized and the studied eye is once again proptosed. The maximum vessel length of neovascularization, extending from the limbal vascular plexus toward the pellet is measured.
In addition, the contiguous circumferential zone of neovascularization is measured as clock hours, where degrees of arc equals one clock hour. The area of angiogenesis is calculated as follows.
(0.4 x clock hours x 3.14 x vessel length (in mm)) area 2 The studied mice are thereafter compared to control mice and the difference in the area.of neovascularization is recorded. A contemplated compound typically exhibits about 25 to about percent inhibition, whereas the vehicle control exhibits zero percent inhibition.
It will be observed that numerous modifications and variations can be effectuated without departing from the spirit and scope of the novel concepts of the present invention. No limitation with respect to the specific examples presented is intended or should be inferred. The disclosure is intended to encompass such modifications as fall within the scope of the claims.
275 With reference to the use of the word(s) "comprise" or "comprises" or "comprising" in the foregoing description and/or in the following claims, unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that each of those words is to be so interpreted in construing the foregoing description and/or the following claims.
o o *o o o* *o o *ooo* o*

Claims (13)

1. A compound or a pharmaceutically acceptable.salt thereof, wherein: the compound corresponds in structure to Formula C: o O O R I w R 5 R C W is phenyl; as to R': R' is a substituted 5- or 6-membered cyclohydrocarbyl, substituted 5- or
6-membered heterocyclo, substituted phenyl, or substituted 5- or 6-membered heteroaryl; R' has a length greater than about that of a hexyl group and less than about that of an eicosyl group; R' defines a three-dimensional volume, when rotated about an axis drawn through the S0 2 -bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the S0 2 -bonded 1-position and the center of 3,4-bond of a Sring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings; as to R 5 and R6: R 5 and R 6 are independently selected from the group consisting ofhydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RbRCaminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RbRaminoalkyloxy, or R 5 and R 6 together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 ring members; R 20 is selected from the group consisting of-O-R 21 -NR' 3 -O-R 22 -NR3-O-R' 4 and -NR23R24 R 21 is selected from the group consisting ofhydrido, Ci-C 6 -alkyl, aryl, and aryl-Cl-C 6 -alkyl; R 2 2 is a selectively removable protecting group; 277 R 3 is selected from the group consisting of hydrido, C 1 -C 6 -alkyl, and benzyl; R' 4 is selected from the group consisting of hydrido and C(V)R'i; V is selected from the group consisting of 0 and S; R' 5 is selected from the group consisting of CI-C 6 -alkyl, aryl, C 1 -C 6 -alkoxy, heteroaryl-C-C 6 -alkyl, C 3 -Cs-cycloalkyl-C 1 -C 6 -alkyl, aryloxy, aryl-C 1 -C 6 -alkoxy, aryl-C 1 -C 6 -alkyl, heteroaryl, and amino C 1 -C 6 -alkyl, wherein the amino CI-C 6 -alkyl nitrogen is optionally substituted with: up to two substituents independently selected from the group consisting of CI-C 6 -alkyl, aryl, aryl-CI-C 6 -allcyl, C 3 -Cs-cycloalkyl-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkoxycarbonyl, CI -C 6 -alkoxycarbonyl, and CI-C 6 -alkanoyl, or two substituents such that the amino C 1 -Cs-alkyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl; as to R 2 3 and R 2 4 R 23 and R 24 are independently selected from the group consisting of hydrido, C 1 -C 6 -alcyl, amino C 1 -C 6 -alkyl, hydroxy C 1 -C 6 -alkyl, aryl, and aryl-C 1 -C 6 -alkyl, or R 23 and R 2 4 together with the nitrogen atom to which they are both bonded, form a 5- to 8-membered ring containing zero or one additional heteroatom that is selected from the group consisting of oxygen, nitrogen, and sulfur; each Rb or RC is independently selected from the group consisting of hydrido, alkanoyl, Sarylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, Sperfluoroalkoxyalkyl, alkoxyalkyl, cycloallcyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, and aminosulfonyl, wherein any amino nitrogen in such S substituents is optionally substituted with: d up to two independently selected non-hydrido R substituents, or two substituents such that the substituents, together with the amino nitrogen, form: a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido Rd substituents, or 278 a heteroaryl optionally substituted with up to three independently selected R' substituents; each Rd or Re is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl; each R' is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and RdReamino; and the compound is other than: H 0 0 0 *o oo* o °°Co* 2. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound corresponds in structure to Formula C: R20 R R' W is phenyl; as to R 5 and R 6 R 5 and R 6 are independently selected from the group consisting of hydrido, 279 alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalcyl, haloallcyloxy, hydroxyalcyl, R6Rcaminoalcyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyallcoxy, perfluoroalkyl, haloalcyl, heterocyclooxy, and RbRcaminoalkyloxy, or R 5 and R together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 ring members; R 20 is selected from the group consisting of -0-R 2 _NRI 3 -O-R 22 -NIR'-O-R' 4 and -NR 23 R 24 R 2 1 is selected from the group consisting of hydrido, CI-C 6 -allcyl, aryl, and aryl-C 1 -C 6 -alkyl; R 2 is a selectively removable protecting group; *R1 3 is selected from the group consisting of hydrido, C 1 -C 6 -alkyl, and benzyl; *R1 4 is selected from the group consisting of hydrido and C(V)R' 5 is selected from the group consisting of 0 and S; *R1 5 is selected from the group consisting Of CI-C 6 -alcyl, aryl, CI-C 6 -alkoxy, heteroaryl-C 1 -C 6 -alkyl, C 3 -C8-cycloalcyl-C 1 -C 6 -allcyl, aryloxy, aryl-C 1 -C 6 -alkoxy, aryl-C 1 -C 6 -alkyl, heteroaryl, and amino CI-C 6 -alkyl, wherein the amino CI-C 6 -alkyl nitrogen is optionally substituted with: up to two substituents independently selected from the group consisting of CI-C 6 -alkyl, aryl, aryl-C 1 -C 6 -alkyl, C 3 -C8-cycloalkyl-Cl-C 6 -alcyl, aryl-C 1 -C6-alkoxycarbonyl, C 1 -C 6 -alkoxycarbonyl, and C 1 -C 6 -alkanoyl, or two substituents such that the amino C 1 -C 6 -allcyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl; as toR 13and R14 *23 24 R and R are independently selected from the group consisting of hydrido, C 1-C 6 -alkyl, amino C I-C 6 -alkyl, hydroxy C I-C 6 -alkyl, aryl, and aryl-C 1-C 6 -alkyl, or 23 24 R and R together with the nitrogen atom to which they are both bonded, form a 5- to 8-membered ring containing zero or one additional heteroatom that is selected from the group consisting of oxygen, nitrogen, and sulfur; R' is -NR 7 R 8 as to R 7 and R 8 R 7 and R 8 are independently selected from -the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted aryihydrocarbyl, or 280 R 7 and R 8 are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R aoXyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclo, wherein each substitutable substituent is optionally substituted with or R 7 and R together with the nitrogen atom to which they are bonded, form -G-A-R-E-Y; is N-heterocyclo; A is selected from the group consisting of: -NRk~ -N(R ki-GO-, -CO-O-, -0-CO-, -O-CO-O-, -HC=CH-, -NEl-CO-NH-, -CE=C-, (12) (13) -NHl-NH-, (14) -CS-N(Rk)-, -N(R (16) -CH 2 -O-CH 2 (18) -CH 2 -S-CH 2 -CH 2 (21) -SO-, (22) -SO 2 and (23) a bond; R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloal kyl, heterocycloalkyl, arylal kyl, heteroarylalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl, wherein: the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C -C 2 -alkylenedioxy, hydroxycarbonylalcyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyallcyl, alkanoylamino, and alkoxycarbonyl; E is selected from the group consisting of: -COR 5 -R9CO-, -CON(Rk)-, -N(Rk)CO-, -CO-, -S0 2 R-, -RgSO2-, -SO 2 -N(Rk)-S02-, -SO 2 and (11) abond; is selected from the group consisting of a bond, hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, Raoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, arylalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, arylalkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl; each Ra is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbR aminoalkanoyl, haloalkanoyl, RbR aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy; each Rb or RC is independently selected from the group consisting of hydrido, alkanoyl, 282 arylalkyl, aroyl, bisalkoxyalcyl, alkyl, haloalkyl, perfluoroalkyl, trifluoroniethylalkyl, perfluoroalcoxyalcyl, alkoxyalkyl, cycloalcyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalcyl, aryloxyalkyl, heteroaryloxyalcyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylailcanoyl, ailcylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloimninocarbonyl, arylthioalcyl, alkylthioalcyl, arylthioalkenyl, allcylthioallcenyl, heteroarylalkyl, haloallcanoyl, hydroxyalkanoyl, thiolailcanoyl, alkenyl, alkynyl, alkoxyalcyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, amninoalcyl, aminoalkylsulfonyl, and aminosulfonyl, wherein any amino nitrogen in such substituents is optionally substituted with: up to two independently selected non-hydrido R dsubstituents, or two substituents such that the substituents, together with the amino nitrogen, form: a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido R d substituents, or a heteroaryl optionally substituted with up to three independently selected Rf substituents; each Rd or Rei independently selected from the group consisting of hydrido, ailkyl, alkenyl, arylailcyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, ailcoxycarbonyl, and arylailkyloxycarbonyl; and each Rf is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and RdR eamino; R9 is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, *hi alkoxyaryl, alkoxyheteroaryl, R R -amino, alkoxyalkyl, aikylenedioxy, aryloxyalkyl, perfi uoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R hR -amninocarbonyloxy, R hR -aminocarbonyl, R hR -aminoalkanoyl, hydroxyaminocarbonyl, R hR -aminosulfonyl, R hR -aminocarbonyl(R h)amnino, tri fluoromethylsulfonyl(R h)amnino, heteroarylsulfonyl(R h).-amino, arylsulfonyl(R h)amino, arylsulfonyl(R h)aminocarbonyl, alkylsulfonyl(R h)amino, arylcarbonyl(R h)aminosulfonyl, and alkylsulfonyl(R h)aminocarbonyl; 283 R h is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, ailkenyl, alkoxyallcyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalicyl, alkanoyl, aroyl, arninoalkanoyl, halo ailcanoyl, and hydroxyalcyl, wherein: any such substituent is optionally substituted by up to two independently selected Ri substituents; R' is selected from the group consisting of arylailcyl, aryl, heteroaryl, heterocyclo, alkyl, alcynyl, alcenyl, allcoxyallcyl, alkoxyalkylalkyl, aminoalcyl, ailcyloxycarbonyl, arylailcyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo ailcanoyl, and hydroxyalkyl, wherein: any such substituent is optionally substituted by up to two independently selected Ri substituents; each R' is independently selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, ailcynyl, alkenyl, alkoxyalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalcyl, haloalcyl, ailcanoyl, aroyl, aniinoallcanoyl, halo alkanoyl, and hydroxyalkyl, wherein: the aminoalkyl and aminoallcanoyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alcyloxycarbonyl; each R~ is independently selected from the group consisting of hydrido, ailkyl, alkenyl, ayarylailcyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RcRd amino carbonyl, RcR daminosulfonyl, RcR daminoalkanoyl, and RcR daminoalkysulfonyl; and the compound is other than: 0 0 0 HO, S N N 0 0 S- HO N 0 0 0 284 0 00 HO or Ho, 0 3. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound corresponds in structure to Formula C: 0 0 R 5 R6 C W is phenyl; as to R' R' is a substituted 5- or 6-membered cyclohydrocarbyl, substituted 5- or 6-membered heterocyclo, substituted phenyl, or substituted 5- or 6-membered heteroaryl; R has a length greater than about that of a hexyl group and less than about that of an eicosyl group; R' defines a three-dimensional volume, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SOz-bonded 1-position and the center of 3,4-bond of a ring radical, whose widest dimension in a directiorr transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings; 285 R 5 and R 6 are independently selected from the group consisting of hydrido, hydrocarbyl, hydroxyhydrocarbyl, hydroxy, amino, dihydrocarbylamino, heterocyclo, heterocyclohydrocarbyl, heterocyclooxy, and heterocyclothio; 2 21 R is selected from the group consisting of R 1 -NR' 3 -O-R 2 2 -NR' 3 -O-R' 4 and -NR 23 R 24 R 2 1 is selected from the group consisting of hydrido, CI-C 6 -allcyl, aryl, and aryl-C 1 -C 6 -alkyl; R 22is a selectively removable protecting group; R 1 3 is selected from the group consisting of hydrido, C 1-C 6 -alkyl, and benzyl; R 1 4 is selected from the group consisting of hydrido and C(V)R' 5 V is selected from the group consisting of 0 and S; R 1 5 is selected from the group consisting Of CI-C 6 -alcyl, aryl, CI-C 6 -alkoxy, heteroaryl-C 1 -C 6 -alkyl, C 3 -C8-cycloalkyl-C 1 -C 6 -alkyl, aryloxy, arYI-C 1 -C 6 -alkoxy, aryl-Cl-C 6 -allcyl, heteroaryl, and amino CI-C 6 -alkyl, wherein the amino CI-C 6 -alkyl nitrogen is optionally substituted with: up to two substituents independently selected from the group consisting of CI-C 6 -allcyl, aryl, aryl-Cl-C 6 -alkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, aryl-C! -C 6 -alkoxycarbonyl, C 1 -C 6 -allcoxycarbonyl, and C! -C 6 -alkanoyl, or two substituents such that the amino C I-C 6 -atkyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl; as toR 23and R24 R 2R and R 24are independently selected from the group consisting of hydrido, CI-C 6 -alkyl, amino CI-C 6 -alkyl, hydroxy CI-C 6 -alkyl, aryl, and aryl-C 1 -C 6 -alkyl, or 23 and R together with the nitrogen atom to which they are both bonded, formn a 5- to 8-membered ring containing zero or one additional heteroatom that is selected from the group consisting of oxygen, nitrogen, and sulfur; each Rb or RC is independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, 286 alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, and aminosulfonyl, wherein any amino nitrogen in such substituents is optionally substituted with: up to two independently selected non-hydrido Rd substituents, or two substituents such that the substituents, together with the amino nitrogen, form: a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido Rd substituents, or a heteroaryl optionally substituted with up to three independently selected R f substituents; each R d or R e is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl; each R f is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and RdReamino; and the compound is other than: 0 0 0 H a a a 4. The compound or salt according to claim 1, wherein R 20 is -NR'-O-R 14 The compound or salt according to claim 1, wherein R 2 0 is -NR 3 -O-R 22 287 6. The compound or salt according to claim 1, wherein the compound corresponds in structure to Formula Cl: R 5 6 C I
7. The compound or salt according to claim 1, wherein the compound corresponds in structure to Formula C2: 0 0 0 14 N PhR 4 C2 PhR 4 is phenyl substituted at its 4-position with R 4 and R 4 has a chain length of 3 to about 14 carbon atoms.
8. The compound or salt according to claim 7, wherein R 4 is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, aryiheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, aryihydrazinoaryl, hydrocarbyithiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroaryithiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, aryihydrocarbylamino, heteroaryihydrocarbyl amino, and heteroarylthio. 4 The compound or salt according to claim 7, wherein R is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, pico linarnido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, aryihydrocarbyl, heteroarylhydrocarbyl, 288 heteroaryiheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, aryihydrazinoaryl, hydrocarbyithiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroaryithiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, aryihydrocarbyithiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroaryihydrocarbylamino, and heteroarylthio, wherein: any such substituent is substituted by one or more substituents independently selected from the group consisting of halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethyihydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, aryihydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaryihydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylami~no, heteroaryihydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, aryihydrocarbylamino, heterocyclo, heteroaryl, hydroxycarbonyihydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arythydrocarbyloyl, hydrocarboyloxy, aryihydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonyihydrocarbyloxy, V hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonyihydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, aryihydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, aryihydrocarbylsulfonylamnino, heteroarylsulfonylamino, heteroaryihydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and axrinohydrocarbyl, wherein the aminohydrocarbyl nitrogen is substituted with: one or two substituent(s) that is/are independently selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or two substituents such that the aminohydrocarbyl nitrogen, together 289 with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl. The compound or salt according to claim 1, wherein: the compound corresponds in structure to Formula D3: 0 0 0 R 0R R= R 6 ".N D3 ;and R 4 has a chain length of 3 to about 14 carbon atoms.
11. The compound or salt according to claim 10, wherein R 4 is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, aryiheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroaryiheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonyihydrocarbyl, arylazoaryl, aryihydrazinoaryl, hydrocarbyithiohydrocarbyl, hydrocarbylthioaryl, aryithiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, aryihydrocarbyithiohydrocarbyl, arylhydrocarbylthioaryl, aryihydrocarbylamnino, ***heteroaryihydrocarbylamino, and heteroarylthio.
12. The compound or salt according to claim 10, wherein R 4 is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzarnido, nicotinamido, isonicotinarnido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, aryihydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbyithiohydrocarbyl, hydrocarbylthioaryl, aryithiohydrocarbyl, heteroaryithiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroaryihydrocarbylamino, and heteroarylthio, wherein:.- any such substituent is substituted by one or more substituents independently selected from the group consisting of halogen, hydrocarbyl, hydrocarbyloxy, nitro, 290 cyano, perfluorohydrocarbyl, trifluoromethyihydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, aryihydrocarbyl, aryl, heteroaryloxy, heteroaryltbio, heteroarylamino, heteroaryihydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonyihydrocarbyl, heterocyclothio, heterocycloarnino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroaryihydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryihydrocarbylamino, aryihydrocarbyloxy, arylhydrocarbylthio, aryihydrocarbylamino, heterocyclo, heteroaryl, hydroxycarbonyihydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, aryihydrocarbyloyl, hydrocarboyloxy, aryihydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonyihydrocarbyloxy, hydrocarbyloxycarbonyihydrocarbyl, hydrocarbyliiydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonyihydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroaryihydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, aryflhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryihydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and aminohydrocarbyl, wherein the aminohydrocarbyl nitrogen is substituted with: one or two substituent(s) that is/are independently selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or ::E.two substituents such that the aminohydrocarbyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl. 291
13. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-1; the compound corresponds in structure to Formula C4: HO I N N 7 R l H w R 5 S R 6 C4 W is phenyl; as to R': R' is a substituted 5- or 6-membered cyclohydrocarbyl, substituted 5- or 6-membered heterocyclo, substituted phenyl, or substituted 5- or 6-membered heteroaryl; R' has a length greater than about that of a hexyl group and less than about that of an eicosyl group; R' defines a three-dimensional volume, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the S0 2 -bonded 1-position and the center of 3,4-bond of a ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings; S: as to R 5 and R 6 R 5 and R 6 are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RbRCaminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RbR'aminoalkyloxy, or R 5 and R 6 together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 ring members; each R b or Rc is independently selected from the group consisting of hydrido, alkanoyl, S arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, 292 heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioallkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, and aminosulfonyl, wherein any amino nitrogen in such substituents is optionally substituted with: up to two independently selected non-hydrido Rd substituents, or two substituents such that the substituents, together with the amino nitrogen, form: a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido Rd substituents, or a heteroaryl optionally substituted with up to three independently selected R' substituents; each Rd Or Re is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl; each R' is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and RdR amino; and the compound is other than: 0 0 0 OOP HO N N 0 00 r .HON 00 S., or *0 0 0 H* 0 N 'N 293
14. The compound according to claim 13, wherein: the 5- or 6-membered cyclohydrocarbyl, 5- or 6-membered heterocyclo, phenyl, or or 6-membered heteroaryl of R' is substituted with R 4 and R 4 has a chain length of 3 to about 14 carbon atoms. The compound or salt according to claim 14, wherein R 4 is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, aryihydrocarbyl, heteroaryihydrocarbyl, heteroarylheterocyclohydrocarbyl, aryihydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboythydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, aryihydrazinoaryl, hydrocarbyithiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroaryithiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arythydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio.
16. The compound or salt according to claim 14, wherein RW is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinainido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, aryiheterocyclohydrocarbyl, arylhydrocarbyl, heteroaryihydrocarbyl, heteroarylheterocyclohydrocarbyl, aryihydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, aryhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, aryithiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylbydrocarbylamino, and heteroarylthio, wherein: any such substituent is substituted by one or more substituents independently selected from the group consisting of halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroaryl amino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocycloo-xy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamnino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryihydrocarbylamnino, arylhydrocarbyloxy, arylhydrocarbylthio, aryihydrocarbylamino, heterocyclo, heteroaryl, hydroxycarbonyihydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, aryihydrocarbyloyl, hydrocarboyloxy, aryihydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonyihydrocarbyloxy, hydrocarbyloxycarbonyihydrocarbyl, hydrocarbylhydroxycarbonylhyclrocarbylthio, hydrocarbyloxycarbonyihydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, aryihydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroaryihydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, aryihydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryihydrocarbylsulfonylamnino, cyc lohydrocarbylsulfonylamnino, heterocyclohydrocarbylsulfonylamino, and aminohydrocarbyl, wherein the aminohycirocarbyl nitrogen is substituted with: one or two substituent(s) that is/are independently selected from the group consisting of hydrocarbyl, aryl, aryihydrocarbyl, cyclohydrocarbyl, aryihydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or two substituents such that the amninohydrocarbyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl.
17. The compound or salt according to claim 14, wherein R 4 is selected from the group consisting of single-ringed cyclohydrocarbyl, single-ringed heterocyclo, phenyl, single-ringed heteroaryl, C 3 -Cl 4 hydrocarbyl, C 2 -Cl 4 hydrocarbyloxy, phenoxy, thiophenoxy, 4-thiopyridyl, phenylazo, phenylureido, nicotinamido, isonicotinamido, picolinamido, anilino, and benzamido.
18. The compound or salt according to claim 13, wherein: R is phR 4 *0PhR 4is phenyl substituted with R 4at the 4-position; R4 is selected from the group consisting of phenyi phenoxy, thiophenoxy, phenylazo, benzamido, anilino, nicotinamido, isonicotinamido, picolinamido, and phenylureido, wherein: 295 the phenyl, phenoxy, thiophenoxy, phenylazo, benzamido, anilino, nicotinamido, isonicotinamido, picolinamido, and phenylureido is optionally substituted: at the meta- or para- position, or both with substituent(s) independently selected from the group consisting of halogen, CI-C 9 hydrocarbyloxy, C 1 -Clo hydrocarbyl, di- C 1 -C 9 hydrocarbylamino, carboxyl C-Cs hydrocarbyl, C 1 -C 4 hydrocarbyloxy carbonyl C 1 -C 4 hydrocarbyl, C 1 -C 4 hydrocarbyloxycarbonyl C 1 -C 4 hydrocarbyl, and carboxamido C 1 -Cs hydrocarbyl, or at the meta- and para- positions by two methyl groups or by a methylenedioxy group.
19. The compound or salt according to claim 13, wherein R' has a length greater than the length of an octyl group and less than the length of a stearyl group. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound corresponds in structure to the following formula: 0 0 0 R 20 R R6 E as to R and R6: R and R6 are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RbRCaminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RbRcaminoalkyloxy, or R 5 and R 6 together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 ring members; A is selected from the group consisting of: -NRk -CO-N(Rk)_, -N(Rk)-CO-, 296 -CO-C-, -0-CO-, -0-co-c-, -RC=CH-, -NH-cc-NH-, (11) (12) (13) (14) -cS-N(Rk)-, -N(R (16) -CR 2 (17) -O-CH 2 (18) -CH 2 (19) -S-CR 2 -CH 2 (21) -SO-, (22) -SO 2 and (23) a bond; R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalKyl, neterocycloalkyl, arylalkyl, neteroarylalkyl, cycloalk~ylaIkyl, cycloalkyloxyalkyl, heterocycloalkoxyal kyl, aryloxyalkyl, heteroaryloxyal kyl, arylthioalkyl, heteroarylthioal kyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl, wherein: the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of halo, o* al kyl, peril uoroal kyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethyl alkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1 -C 2 -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonyl al kyl amino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl; E is selected from the group consisting of: -CR- -RgCO-, -CON(R k)- -Cc-, -S0 2 Rg-, -RgSO 2 -So 2 -SO 2 and (11) a bond; Y is selected from the group consisting of a bond, hydrido, ailkyl, ailcoxy, haloalkyl, aryl, arylailcyl, cycloallcyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylaikoxy, heteroaryloxy, heteroarylalkyl, Raoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, ailcenyl, heterocycloalcyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalcyl, wherein: the aryl, heteroaryl, arylailcyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, nitrile, haloalkcyl, alkyl, arylalkyl, aryl, alkoxy, perfluoroatkyl, perfluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of ailkyl and arylailcyl; each R' is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkcyl, aryl, alcanoyl, aroyl, arylalkycarbonyl, RbRcaminoallcanoyl, haloalkanoyl, 0000 R~Raminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy; each Rb or Rc is independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalcyl, ailcyl, haloalkcyl, perfluoroalkyl, trifluoromethylalkyl, se perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalcyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalicoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, see: heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, ease
404.000 aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, and aminosulfonyl, wherein any amino nitrogen in such S sub stituents is optionally substituted with: up to two independently selected non-hydrido R d substituents, or two substituents such that the substituents, together with the amino nitrogen, form: 298 a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido Rd substituents, or a heteroaryl optionally substituted with up to three independently selected Rf substituents; each R d or Re is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylailcyl, aryl, ailcanoyl, aroyl, arylallcylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl; each Rf is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and RdReanino; R9 is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkcynyl, cycloalkyl, cycloatkenyl, ailcoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, ailcoxyaryl, alkoxyheteroaryl, RhRi-amino, alkoxyalkyl, ailcylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alcyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylailcyloxycarbonyl, arylallcyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R hR -aminocarbonyloxy, R hR -aminocarbonyl, R hR -aminoalkanoyl, hydroxyaminocarbonyl, R hR -aminosulfonyl, R hR -aminocarbonyl(R h)amino, trifluoromethylsulfonyl(R h)amino, heteroarylsulfonyl(R h) amino, arylsulfonyl(R"h)amino, arylsulfonyl(Rh)aminocarbonyl, alkylsulfonyl(Rh)amino, arylcarbonyl(Rh aminosulfonyl, and alkylsulfonyl(R )aminocarbonyl; Rh is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, ailkyl, alkynyl, ailcenyl, alcoxyalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: any such substituent is optionally substituted by up to two independently selected Ri substituents; R' is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: any such substituent is optionally substituted by up to two independently selected Ri substituents; each Ri is independently selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, aminoalkyl, alkyloxycarbonyl, 299 arylailkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoallcanoyl, halo alkanoyl, and hydroxyalcyl, wherein: the aminoalcyl and aminoalkanoyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, ailcenyl, aryl, arylailcyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl; each R k is independently selected from the group consisting of hydrido, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalcyl, aryloxycarbonyl, alkyloxycarbonyl, RcRdamino carbonyl, RcRdaminosulfonyl, RCRd aminoalkanoyl, and RCR daminoalkysulfonyl; R 20 is selected from the group consisting of -0-R 21 -NR' 3 -O-R 22 -NR' 3 -O-R 1 4 and -N4R 2 R 24 R 21 is selected from the group consisting of hydrido, CI-C 6 -alcyl, aryl, and aryl-Ci -C 6 -allcyl; R 2 is a selectively removable protecting group; *R 13 is selected from the group consisting of hydrido, C 1 -C 6 -alkyl, and benzyl; *1 4 is selected from the group consisting of hydrido and C(V)R 1 5 V is selected from the group consisting of 0 and S; *R1 5 is selected from the group consisting Of C 1 -C 6 -alkyl, aryl C 1-C 6 -atkoxy, heteroaryl-C 1 -C 6 -alkyl, C 3 -C8-cycloalcyl-C 1 -C 6 -alkyl, aryloxy, aryl-C 1 -C 6 -allcoxy, aryl-Cl-C 6 -alcyl, heteroaryl, and amino C 1 -C 6 -alkyl, wherein the amino C 1 -C 6 -alkyl nitrogen is optionally substituted with: up to two substituents independently selected from the group consisting of C 1 -C 6 -alkcyl, aryl, aryl-C 1 -C 6 -alcyl, C 3 -C 8 -cycloalkyl-Cl-C 6 -alkyl, aryl-Cj -C 6 -alkoxycarbonyl, C 1 -C 6 -alkoxycarbonyl, and C 1 -C 6 -alkanoyl, or two substituents such that the amino CI-C 6 -alkyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl; and as to R and R 24 R 23and R 24 are independently selected firom 'the group consisting of hydrido, Cl-C 6 -alkyl, amino C 1 -C 6 -alkyl, hydroxy C 1 -C 6 -alkyl, aryl, and aryl-Ci-C 6 -alkyl, or R 23 and R 24 together with the nitrogen atom to which they are both bonded, form a 5- to 8-membered ring containing zero or one additional heteroatom that is selected from the group consisting of oxygen, nitrogen, and sulfur; and the compound is other than: 300 v o0 00 HO, S, N 0 0,0 HO N or o osp 21. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound corresponds in structure to Formula VIA: R N S R R 6 VIA W 2 is a heterocyclic ring containing 5 or 6 ring members (including the depicted nitrogen atom); as toR 4 R 4 has a chain length of 3 to about 14 carbon atoms; .i R 4 is bonded at the 4-position relative to the depicted nitrogen atom when W 2 is a 6-membered ring, and at the 3- or 4-position relative to the depicted nitrogen 2 when W is a 5-membered ring; 5 6 as to R and R6: R 5 and R 6 are independently selected from the group consisting ofhydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RbRCaminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RbRCaminoalkyloxy, or R s and R 6 together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 ring members; R 20 is selected from the group consisting of-O-R 2 1 -NR 3 -O-R 2 2 -NR 3 -O-R' 4 and -NR 23 R 24 301 R 21is selected from the group consisting of hydrido, C 1 -C 6 -alkyl, aryl, and aryl-Ci -C 6 -allcyl; *R 22 is a selectively removable protecting group; *R1 3 is selected from the group consisting of hydrido, G 1 -C 6 -allcyl, and benzyl; R'1 4 is selected from the group consisting of hydrido and C(V)R1 5 V is selected from the group consisting of 0 and S; *R1 5 is selected from the group consisting Of C 1 -C 6 -allcyl, aryl, Cl-G 6 -alkoxy, heteroaryl-C 1 -C 6 -allcyl, C 3 -Cg-cycloalcyl-C 1 -C 6 -alkyl, aryloxy, aryl-Ci -C 6 -alkoxy, aryl-Ci-C 6 -alkyl, heteroaryl, and amino C 1 -C 6 -allcyl, wherein the amino C 1 -C 6 -alkyl nitrogen is optionally substituted with: up to two substituents independently selected from the group consisting of Cl-C 6 -alkyl, aryl, aryl-C 1 -C 6 -alkyl, C 3 -C 8 -cycloallcyl-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkoxycarbonyl, and CI-C 6 -alkanoyl, or two substituents such that the amino C I-C 6 -alkyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl; as toR 23and R24 R 23 and R 2 4 are independently selected from the group consisting of hydrido, C 1 -C 6 -allcyl, amino C 1 -C 6 -allcyl, hydroxy CI-C 6 -alkyl, aryl, and aryl-Ci-C 6 -alcyl, or R 2 and R 24 together with the nitrogen atom to which they are both bonded, form a 5- to 8-membered ring containing zero or one additional heteroatom that is selected from the group consisting of oxygen, nitrogen, and sulfur; each Rb or Rc is independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalcyl, :::heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, amino alkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, and aminosulfonyl, wherein any amino nitrogen in such substituents is optionally substituted with: up to two independently selected non-hydrido Rd substituents, or two substituents such that the substituents, together with the amino nitrogen, 302 form: a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido Rd substituents, or a heteroaryl optionally substituted with up to three independently selected Rf substituents; each Rd or R' is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylailcyloxycarbonyl; each Rf is independently selected fr~om the group consisting of nitro, hydroxy, ailkyl, halogen, aryl, alkoxy, cyano, and R dReamino; and the compound is other than: 0 0 0 H N N 0 0 HO0 N O- *0 0 0 coy or :0 00 H 3 C, 0 N NN N 0 22. The compound or salt according to claim 2 1, wherein R~ is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, aryiheterocyclohydrocarbyl, arylhydrocarbyl, heteroaryihydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonyihydrocarbyl, arylazoaryl, aryihydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, aryithiohydrocarbyl, heteroaryithiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, 303 aryihydrocarbyithiohydrocarbyl, arylhydrocarbylthioaryl, aryihydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio. 23. The compound or salt according to claim 2 1, wherein R 4 is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilmno, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, aryiheterocyclohydrocarbyl, aryihydrocarbyl, heteroaryihydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonyihydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbyithiohydrocarbyl, hydrocarbylthioaryl, aryithiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, aryihydrocarbyith-iohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylbydrocarbylamino, and heteroarylthio, wherein: any such substituent is substituted by one or more substituents independently selected from the group consisting of halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethyihydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, aryihydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaryihydrocarbyl, hydrocarbyloxycarbonyihydrocarbyl, heterocyclooxy, hydroxycarbonyihydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryihydrocarbylamnino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamnino, heterocyclo, heteroaryl, hydroxycarbonyihydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arythydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonyihydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamnino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamnino, hetero arylhydrocarbylcarbonyl amino, heterocyclohydrocarbyloxy, hydrocarbylsul fonylamino, aryisulfonylamino, arylhydrocarbylsulfonylamino, 304 heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and aminohydrocarbyl, wherein the aminohydrocarbyl nitrogen is substituted with: one or two substituent(s) that is/are independently selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or two substituents such that the aminohydrocarbyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl. 24. The compound or salt according to claim 21, wherein R2O is -NR' R14 The compound or salt according to claim 24, wherein R' is hydrido. 20 26. The compound or salt according to claim 21, wherein R2 is -NR' 3 -O-R 2 2 27. The compound or salt according to claim 26, wherein: R1 3 is hydrido; and R22 is selected from the group consisting of 2-tetrahydropyranyl, benzyl, p-methoxybenzyl, Ci-C 6 -alkoxycarbonyl, trisubstituted silyl, o-nitrophenyl, peptide synthesis resin, and a mixture thereof, wherein: the trisubstituted silyl is substituted with three substituents independently selected from the group consisting of CI-C 6 -alkyl, aryl, and aryl-Ci-C 6 -alkyl. 28. The compound or salt according to claim 21, wherein the compound corresponds in structure to Formula VIA-I: 0 0 0\/ '.o N 62 I R ww R5 4 R6 VIA-I 305 29. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-1; the compound corresponds in structure to Formula VIIC: HO 'S H W 2 IR6 A E VIIC as to R 5 and R 6 R 5 and R 6 are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RbRCaminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RbRCaminoalkyloxy, or R s and R 6 together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 ring members; W 2 is a heterocyclic ring containing 5 or 6 ring members (including the depicted S nitrogen atom); -A-R-E-Y is bonded at the 4-position relative to the depicted nitrogen atom when W 2 S* is a 6-membered ring, and at the 3- or 4- position relative to the depicted nitrogen atom when 2 W is a 5-membered ring; A is selected from the group consisting of: -NRk, -CO-N(Rk)-, -N(Rk)-CO-, -CO-O-, -O-CO-, -O-CO-O-, -HC=CH-, -NH-CO-NH-, 306 (11) (12) (13) -NH-NH-, (14) -CS-N(R -N(R k)_CS_, (16) -CH 2 (17) -O-CH 2 (18) -CH 2 (19) -S-CH 2 -CH 2 (21) -SO-, (22) -SO 2 and (23) a bond; R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloalkoxyal kyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioal kyl, heteroarylthioalkyl, cycloal kylthioal kyl, and heterocyc loalkylthioal kyl, wherein: the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, tri fiuoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1 -C 2 -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl; E is selected from the group consisting of: -CR- -RC- boo,(3) -C O N (R -CO-, -S0 2 R9, -SO 2 -S0 2 -N(R and 307 (11) a bond; Y is selected from the group consisting of a bond, hydrido, alkyl, alkoxy, haloallcyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalyl, Raoxyalkyl, perfluoroaloxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, arylalkyl, or heterocycloallcyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, nitrile, haloalkyl, ailcyl, arylalkyl, aryl, alkoxy, perfluoroallcyl, perfluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl; Ra is selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRCaminoalkanoyl, haloalkanoyl, RbRcaminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy; each Rb or RC is independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalyl, cycloalkyl, heterocycloallcyl, heterocycloalylcarbonyl, go. ::aryl, heterocyclo, heteroaryl, cycloallcylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, 'o aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, and aminosulfonyl, wherein any amino nitrogen in such substituents is optionally substituted with: up to two independently selected non-hydrido Rd substituents, or V.0% two substituents such that the substituents, together with the amino nitrogen, form: a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido Rd substituents, or a heteroaryl optionally substituted with up to three independently selected Rr substituents; each Rd or R' is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylailcylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl; each Rf is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alcoxy, cyano, and RdR eamino; R9 is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alcanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, ailkyl, ailcenyl, alkynyl, cycloallcyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R hR'-amino, alkoxyalkyl, alkylenedioxy, aryloxyalcyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonyl amino, aryloxycarbonyloxy, carboxy, R h R'aminocarbonyloxy, R hR -aminocarbonyl, R h Riarninoalkanoyl, hydroxyaminocarbonyl, R hR -aminosulfonyl, R R -aminocarbonyl(R h)amnino, trifluoromethylsulfonyl(R h)amino, heteroarylsulfonyl(R h) amino, arylsulfonyl(R h)amino, arylsulfonyl(R h)aminocarbonyl, alkylsulfonyl(R h)amino, arylcarbonyl(R h)aminosulfonyl, and alkylsulfonyl(R h)alminocarbonyl; R his selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, aikenyl, alkoxyalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, 000. carboxyalkyl, haloalcyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: any such substituent is optionally substituted by up to two independently selected R' substituents; R' is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, *4:606 and hydroxyalkyl, wherein: to. any such substituent is optionally substituted by up to two independently 4000 selected Ri substituents; each Ri is independently selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, aminoalkyl, alkyloxy carbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: the aminoalkyl and aminoalkanoyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, aryl, 309 arylalkyl, heteroaryl, heteroarylalcyl, aryloxycarbonyl, and alkyloxycarbonyl; each R kis independently selected from the group consisting of hydrido, ailkyl, alkenyl, aryl, arylallcyl, heteroaryl, heteroarylalcyl, aryloxycarbonyl, alkyloxycarbonyl, RcR damino carbonyl, RcR daminosulfonyl, RcRdaminoallcanoyl, and RcR d aminoalkysulfonyl; and the compound is other than: 0 0 0 HO 0 0 0 HO N or 0 A compound or a pharmaceutically acceptable salt thereof, wherein: the compound or salt inhibits the activity of Mi~iP-2 and/or MiMP- 13, while exhibiting substantially less inhibitory activity against MMLP-1; the compound corresponds in structure to Formula VIIB: 00 0 HO* S A E N G R Y H 400 :as to R 5 and R 6 6O R 5 and R 6 are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RbRcaminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, arid RbRcarninoalkyloxy, or R 5 and R together with the atoms to whichi they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 ring members; G is N-heterocyclo; 310 A is selected from the group consisting of: -R- -CO-N(R -CO-0-, -0-CO-, -0-CO-O-, -HC=CH-, -NHl-CO-NH-, (11) (12) (13) -NB-NH-, (14) -CS-N(Rk)-, -N(R k)-CS-, (16) -CR 2 -0-CR 2 (18) -CH 2 (19) -S-CR 2 -CR 2 (21) -S0-, -SO 2 and (23) a bond; R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, ~heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl, wherein: the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylal kyl, amino, alkoxycarbonylal kyl, alkoxy, C 1 -C 2 -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl; E is selected from the group consisting of- -COR 8 -RgCO-, -CO-, -SO 2 R9-, -RgSO 2 -So 2 -SO 2 and (11) a bond; Y is selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, R aoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: 0% 0the aryl, heteroaryl, arylailcyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, arylalkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and amino, wherein: :the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl; R a is selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, bc bc alkanoyl, aroyl, arylalkycarbonyl, R Rcaminoalkanoyl, haloalkanoyl, R R aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy; :each R b or R' is independently selected from the gro up consisting of hydnido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalcyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloallcylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, heteroarylsul fonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, 312 ailcynyl, alkoxyalkyl, alcoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoallcylsulfonyl, and amninosulfonyl, wherein any amino nitrogen in such substituents is optionally substituted with: up to two independently selected non-hydrido Rd substituents, or two substituents such that the substituents, together with the amino nitrogen, form: a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido Rd substituents, or a heteroaryl optionally substituted with up to three independently selected Rf substituents; each Rd or R' is independently selected from the group consisting of hydrido, alkyl, ailcenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl; each R f is independently selected from the group consisting of itro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R dR eamino; R9 is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aikoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, ailcoxyaryl, alkoxyheteroaryl, R Ri-amino, alkoxyalcyl, alkylenedioxy, aryloxyalcyl, perfluoroaikyl, trifluoroalkyl, allcylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, Shi hi carboxy, R R -aminocarbonyloxy, R R -aminocarbonyl, RhRi-aminoalkanoyl, hydroxyaminocarbonyl, RhR -aminosulfonyl, R hR -aminocarbonyl(R h)amino, 0:0 trifluoromethylsulfonyl(R h)amino, heteroarylsulfonyl(R h) amino, arylsulfonyl(R h)amino, arylsulfonyl(R h)aminocarbonyl, alkylsulfonyl(R h)amino, arlcarbonyl(R h)wminosulfonyl, and 0 0 alkylsulfonyl(R h)aminocarbonyl; R his selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, :o *o carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: any such group is optionally substituted by up to two independently selected Ri substituents; R is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, aminoalkyl, alkyloxycarbonyl, 313 arylalkyloxycarbonyl, carboxyallkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: any such substituent is optionally substituted by up to two independently selected Ri substituents; each Ri is independently selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyallcyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyallcyl, wherein: the aminoalkyl and aminoalkanoyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl; each Rk is independently selected from the group consisting of hydrido, alkyl, alkenyl, aryl, arylalcyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RCRdamino carbonyl, RCRdaminosulfonyl, RcRdaminoalkanoyl, and RCRdaminoalkysulfonyl; and the compound is other than: 0 0 0 HO S HON N 0 0 0 or or or 0 0 0 3 1. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: /OH VHN 0I 0 32. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: O0 0 OCH 3 HO N S-N N o 33. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: HNOH 0 -N O OCF 3 34. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: /OH HN /.CF 3 in structure to the following formula: OH 315 36. The compound or salt according to claim 2, wherein the compound corresponds in structure to the following formula: o 00 7° HO"N O0 N H H 37. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OCH 3 ,OH HN CH 3 S -N CF 3 0 38. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: 0 0 0 HO H CF 3 CF 39. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: HOH SF HNOH 0 11 O I CF 3 •i c 316 The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: 41. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: 42. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OH C C C C C. C C 43. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: 317 44. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: CH 3 INHOH S-N -0 CF 3 The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: C C C. C 46. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OCH3, 47. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OCH 3 O CH 3 0 SNHOH S-N N CF 3 S 0 318 48. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OCH 3 0 CH 3 0" NHOH CF 3 S-N O 49. A compound or pharmaceutically acceptable salt thereof, wherein the compound corresponds in structure to the following formula: 0 NHOH S-N N NH The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: o NH NHOH S"S- N OCH3 51. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: 0 0 NHOH OS- N -0 -CF 3 0//0-y 0 319 52. A compound or a pharmaceutically acceptable salt thereof, wherein the compound corresponds in structure to the following formula: o ci NHOH S N -0 CF 3 53. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OCH 3 NHOH SNHOH S-N 0 OCF 3 54. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OCH 3 0 *CH 3 NHOH *H30 CH0 9o The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: CH30 O s- NHOH 320 56. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: r-0 0 NHOH 0S-N 0 CF 3 57. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OCH 3 O "NHOH 58. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: *000 C r .t *4 4 0 0 0 4 0 6@OS 0440 4 4 0 4I 4 59. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OCH 3 0 CH30 NHOH QCH 3 Ir NHOH 3 321 The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OCH 3 0 CH 3 NHOH 0 7 CH 3 61. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OCH 3 0 CH 3 NHOH S-N N- OCH 3 62. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: 0 NHOH :o S-N O 63. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: .:NHOH %0 64. The compound or salt according to claim 30, wherein the compound corresponds S in structure to the following formula: 322 The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: IHOH 66. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: 67. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: NHOH 68. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: 00 oo NHOH S-N 0- CF 3 0 0 323 69. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: 0 /O '-NHOH i S-N //0 The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: CH 3 0 CH3 C H NHOH S-N -O 0 0 71. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: o O HOHN N O in structure to the following formula: "72. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: HOHN U CH 3 324 73. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: 0 0o S OCF 3 HOHN N CH 3 0 OCH 3 74. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OCH 3 0 CH 3 0 NHOH S-N 0 O CH 3 The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: CH 3 0 CH CH NHOH S-N N 0 0 /N 76. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: OCH 3 SH 3 NHOH CH 3 S-N 0 OCH3 o o a a g* *o o o. a .a a o• a ao a a* a a ao.. a ft 325 77. The compound or salt according to claim 30, wherein the compound corresponds in structure to the following formula: H 3 O CH3 ,.i H 3 NHOH OCH 3 S3-N O 00 78. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound corresponds in structure to Formula VIIE: 0 0 0 N G-A-R-E-Y oHo R 6 VIIE as to R s and R6: R 5 and R 6 are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RbRCaminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RbRCaminoalkyloxy, or R 5 and R 6 together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 ring members; .G is N-heterocyclo; A is selected from the group consisting of: -NRk -CO-N(Rk)-, -N(Rk)-CO-, -CO-O-, -0-CO-, -0-CO-O-, -HC=CH-, -NH-CO-NH-, 326 (11) (12) (13) -NH-NI--, (14) -CS-N(Rk)-, -N(Rk)-CS-, (16) -CH 2 (17) -O-CH 2 (18) -CH 2 (19) -S-CH 2 -CH 2 (21) -SO-, (22) -SO 2 and (23) a bond; R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloal koxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl, wherein: the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1 -C 2 -alkylenedioxy, hydroxycarbonylalkyl, hydrox ycarbonyl al kyl amino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl; E is selected from the group consisting of: -CR- -RC- (3 k)_ -CO-, -S2R- -SO 2 -(R')S02k -S0 2 -N(R and 327 (11) a bond; Y is selected from the group consisting of a bond, hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, Raoxyalkyl, perfluoroalkoxy, perfluoroalylthio, trifluoromethylalcyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalyl, wherein: the aryl, heteroaryl, arylalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, arylalkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of ailcyl and arylalkyl; each Ra is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRcaminoalkanoyl, haloalkanoyl, RbRCaminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy; each Rb or RC is independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalyl, alkyl, haloalcyl, perfluoroalcyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalyl, heterocycloalkylcarbonyl, 0% a aryl, heterocyclo, heteroaryl, cycloalylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, *:heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, and aminosulfonyl, wherein any amino nitrogen in such substituents is optionally substituted with: up to two independently selected non-hydrido Rd substituents, or two substituents such that the substituents, together with the amino nitrogen, form: a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido Rd substituents, or a heteroaryl optionally substituted with up to three independently selected Rf substituents; each Rd or R' is independently selected from the group consisting of hydrido, alkyl, ailkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylailcyloxycarbonyl; each Rf is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R d eanino; R9 is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, ailcynyl, cycloallcyl., cycloalkenyl, alcoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RhRi-amino, alkoxyalcyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, allcylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalcyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RhR -aminocarbonyloxy, R hR -aminocarbonyl, R hR -aminoalkanoyl, hydroxyaminocarbonyl, RhR -amino sulfonyl, RhR -aminocarbonyl(R h)amino, trifluoromethylsulfonyl(R h)amino, heteroarylsulfonyl(R h) amino, arylsulfonyl(R h)amino, arylsulfonyl(R h)aminocarbonyl, alkylsulfonyl(R h)amino, arylcarbonyl(R h)aminosulfonyl, and alkylsulfonyl(R h)aminocarbonyl; Rh is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkcyl, alkynyl, alcenyl, alkoxyalkyl, aminoalcyl, alcyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoallcanoyl, halo alkanoyl, and hydroxyalkyl, wherein: any such sub stituent is optionally substituted by up to two independently selected R' substituents; R' is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, aikenyl, alkoxyalkyl, alkoxyalkylalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, amninoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: any such substituent is optionally substituted by up to two independently selected Ri substituents; each 89 is independently selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, aininoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: the aminoalkyl and amninoalkanoyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl; 329 each R k is independently selected from the group consisting of hydrido, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RCRdamino carbonyl, RcRdaminosulfonyl, RcRdaminoalkanoyl, and RCRdaminoalkysulfonyl; and the compound is other than: 0 0 0 YO SN Z 79. The compound or salt according to claim 78, wherein the compound corresponds in structure to the following formula: 0 HN' 00 The compound or salt according to claim 78, wherein the compound corresponds in structure to the following formula: 0.i" o o OCH 3 *0 S H N N N o *oHo 81. The compound or salt according to claim 78, wherein the compound corresponds in structure to the following formula: HN o•-Nl 330 82. The compound or salt according to claim 78, wherein the compound corresponds in structure to the following formula: 0 HN\ o 0 S-N0 83. The compound or salt according to claim 78, wherein the compound corresponds in structure to the following formula: 0- HN O- o- 0 0 84. The compound or salt according to claim 2, wherein the compound corresponds in structure to the following formula: H H 85. The compound or salt according to claim 78, wherein the compound corresponds S in structure to the following formula: 0 "'.CH 3 HN o o iI 331 86. The compound or salt according to claim 78, wherein the compound corresponds in structure to the following formula: o 00 0 O. N S.. NH N O CF 3 87. The compound or salt according to claim 78, wherein the compound corresponds in structure to the following formula: 0 F HN'-0 S-N 0 0 CF 3 88. The compound or salt according to claim 78, wherein the compound corresponds in structure to the following formula: CI HN- (I N S-N 0 'CF 3 89. The compound or salt according to claim 78, wherein the compound corresponds in structure to the following formula: HN0 SHNC O ON SON 332 A process for treating a mammal having a condition associated with pathological matrix metalloprotease (MMP) activity, wherein: the process comprises administering to the mammal having such a condition an MMP enzyme-inhibiting effective amount of a compound or a pharmaceutically acceptable salt thereof; the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-1; the compound corresponds in structure to Formula C: R 20 RI w R 5 R 6 C W is phenyl; as to R': R' is a substituted 5- or 6-membered cyclohydrocarbyl, substituted 5- or 6-membered heterocyclo, substituted phenyl, or substituted 5- or 6-membered heteroaryl; R' has a length greater than about that of a hexyl group and less than about that of an eicosyl group; R' defines a three-dimensional volume, when rotated about an axis drawn through the S0 2 -bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO 2 -bonded 1-position and the center of 3,4-bond of a S: ring radical, whose widest dimension in a direction transverse to the axis of rotation is 0* about that of one furanyl ring to about that of two phenyl rings; o" as to R 5 and R6: R 5 and R 6 are independently selected from the group consisting of hydrido, *j alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RbRcaminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RbRcaminoalkyloxy, or R 5 and R 6 together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 ring members; 333 R 20is selected from the group consisting of -0-R 2, -NR -O-R 2 1 2 -NR' 3 -O-R1 4 and NR23 R24 R 21is selected from the group consisting of hydrido, CI-C 6 -alkyl, aryl, and aryl-CI-C 6 -alkyl; R 22is a selectively removable protecting group; R 1 3 is selected from the group consisting of hydrido, CI-C 6 -alkyl, and benzyl; R'1 4 is selected from the group consisting of hydrido and C(V)R 1 5 V is selected from the group consisting of 0 and S; R1 5 is selected from the group consisting Of C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alkoxy, heteroaryl-Ci -C 6 -alkyl, C 3 -C8-cycloalkyl-C 1 -C 6 -alkyl, aryloxy, aryl-C 1 -C 6 -alkoxy, aryl-C 1 -C 6 -alkyl, heteroaryl, and amino CI-C 6 -alkyl, wherein the amino CI-C 6 -alkyl nitrogen is optionally substituted with: up to two substituents independently selected from the group consisting of C 1 -C 6 -alkyl, aryl, aryl-C, -C 6 -alkyl, C 3 -C8-cycloalkyl-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkoxycarbonyl, and C -C 6 -alkanoyl, or two substituents such that the amino CI-C 6 -alkyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl; 23 24 R 2 and R 24are independently selected from the group consisting of hydrido, e...CI-C 6 -alkyl, amino C 1 -C 6 -alkyl, hydroxy CI-C 6 -alkyl, aryl, and aryl-C 1 -C 6 -alkyl, or see* goR 2 and R 24 together with the nitrogen atom to which they are both bonded, form a 5- to 8-membered ring containing zero or one additional heteroatom that is selected from the group consisting of oxygen, nitrogen, and sulfur; each R b or Rc is independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, .:perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heteroc yclIoal kyl carbon yl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyal kyl, alkoxycarbonylalkyl, aminocarbonyl, al kyliminocarbonyl, aryli minocarbonyl, heterocycloi minocarbonyl, arylthioalkyl, al kylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thialkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, and aminosulfonyl, wherein any amino nitrogen in such substituents is optionally substituted with: up to two independently selected non-hydrido Rd substituents, or two substituents such that the substituents, together with the amino nitrogen, form: a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido R d substituents, or a heteroaryl optionally substituted with up to three independently selected R' substituents; each Rd or R e is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl; each R' is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and RdReamino; and the compound is other than: 0 o ,.O or 0 00 °0 N N 91. A process for treating a mammal having a condition associated with pathological matrix metalloprotease (MMP) activity, wherein: 335 the process comprises administering to the mammal having such a condition an MMP enzyme-inhibiting effective amount of a compound or a pharmaceutically acceptable salt thereof; the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-1; the compound corresponds in structure to Formula C: R 4 RI R 5 R C W is phenyl; as to R 5 and R6: R 5 and R 6 are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RbRCaminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RbRaminoalkyloxy, or R 5 and R together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 ring members; R 20 is selected from the group consisting of -O-R 2 1 -NR3-O-R22, -NR1-O-RI4, and _NR23R24 SR 2 1 is selected from the group consisting of hydrido, CI-C6-alkyl, aryl, and aryl-Ci-C 6 -alkyl; R 22 is a selectively removable protecting group; S 1 3 R is selected from the group consisting of hydrido, Ci-C 6 -alkyl, and benzyl; S* R 14 is selected from the group consisting of hydrido and C(V)Rs 5 V is selected from the group consisting of O and S; R' 5 is selected from the group consisting of Ci-C 6 -alkyl, aryl, CI-C 6 -alkoxy, heteroaryl-Ci-C 6 -alkyl, C 3 -C8-cycloalkyl-Ci-C 6 -alkyl, aryloxy, aryl-Cl-C 6 -alkoxy, aryl-Ci-C 6 -alkyl, heteroaryl, and amino Ci-C 6 -alkyl, wherein the amino Ci-C 6 -alkyl nitrogen is optionally substituted with: up to two substituents independently selected from the group consisting of 336 Ci-C 6 -alkyl, aryl, aryl-Ci-C 6 -alkyl, C 3 -Cs-cycloalkyl-CI-C 6 -alkyl, aryl-Ci-C 6 -alkoxycarbonyl, C 1 -C 6 -alkoxycarbonyl, and CI-C 6 -alkanoyl, or two substituents such that the amino CI-C 6 -alkyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl; as to R 23 and R24 R 2 3 and R 2 4 are independently selected from the group consisting of hydrido, Ci-C 6 -alkyl, amino Ci-C 6 -alkyl, hydroxy Ci-C 6 -alkyl, aryl, and aryl-Ci-C 6 -alkyl, or R 2 3 and R 24 together with the nitrogen atom to which they are both bonded, form a 5- to 8-membered ring containing zero or one additional heteroatom that is selected from the group consisting of oxygen, nitrogen, and sulfur; R' is-NR 7 R 8 as to R 7 and R 8 R 7 and R 8 are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted arylhydrocarbyl, or R 7 and R 8 are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, Raoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclo, wherein each substitutable substituent is optionally substituted with or R 7 and R 8 together with the nitrogen atom to which they are bonded, form -G-A-R-E-Y; G is N-heterocyclo; A is selected from the group consisting of: -NR k -CO-N(Rk)-, -N(Rk)-CO-, -CO-O-, -O-CO-, -O-CO-O-, -HC=CH-, -NH-CO-NH-, (11) 337 (12) (13) -NH-NH-, -N(Rk)-CS-, (16) -CR 2 (17) -0-CR 2 (18) -CR 2 (19) -S-CR 2 -CR 2 (21) -SO-, (22) -SO 2 and (23) a bond; R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloal koxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioal kyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl, wherein: the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, Cl-C 2 -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl; E is selected from the group consisting of: -R9CO-, -CO-, -S2R- -SO 2 -SO 2 -N(R and (11) a bond; 338 Y is selected from the group consisting of a bond, hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, Raoxyalkyl, perfiuoroalkoxy, perfiuoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, arylalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, arylalkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl; each Ra is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRcaminoalkanoyl, haloalkanoyl, R bRaminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy; each Rb or RC is independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, i aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, and aminosulfonyl, wherein any amino nitrogen in such substituents is optionally substituted with: up to two independently selected non-hydrido Rd substituents, or two substituents such that the substituents, together with the amino nitrogen, form: a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido Rd substituents, or a heteroaryl optionally substituted with up to three independently selected Rf substituents; each Rd or Re is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and 339 arylalkyloxycarbonyl; and each R is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and RdReamino; R9 is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RhR'-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylal kyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RhR'-aminocarbonyloxy, RhR'-aminocarbonyl, R hR-aminoalkanoyl, hydroxyaminocarbonyl, R R'-aminosulfonyl, R R'-aminocarbonyl(R )amino, trifluoromethylsulfonyl(R )amino, heteroarylsulfonyl(Rh) amino, arylsulfonyl(Rh)amino, arylsulfonyl(R )aminocarbonyl, alkylsulfonyl(Rh)amino, arylcarbonyl(Rh)aminosulfonyl, and alkylsulfonyl(R )aminocarbonyl; Rh is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, ::wherein: o ooo any such substituent is optionally substituted by up to two independently :selected Ri substituents; 0. R' is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: 0 :any such substituent is optionally substituted by up to two independently selected Ri substituents; each RJ is independently selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: the aminoalkyl and aminoalkanoyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl; each Rk is independently selected from the group consisting of hydrido, alkyl, alkenyl, 340 aryl, arylalkyl, heteroaryl, heteroarylal kyl, aryloxycarbonyl, al kylox ycarbonyl, RcR dami no carbonyl, RcR daminosulfonyl, RcR daminoalkanoyl, and RcR daminoalkysulfonyl; and the compound is other than: 0 0 0 HO, S H HO,N H 9 9 9 *9* 9* .9 9*9* 9* 9 9.9 9**9 9. 90 9 9 0 0 9* 0 90 90 or 1-3C IN Ni 5 01 3 4 92. The process according to claim 90, wherein the compound corresponds in structure to Formula ClI: N R 13 0 0 \S" 341 93. The process according to claim 90, wherein the compound corresponds in structure to Formula C2: R PhR 4 H w C2 PhR 4 is phenyl substituted at its 4-position with R 4 and R 4 has a chain length of 3 to about 14 carbon atoms. 94. The process according to claim 93, wherein R 4 is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, aryiheterocyclohydrocarbyl, aryihydrocarbyl, heteroaryl hydrocarbyl, heteroaryiheterocyclohydrocarbyl, aryihydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonyihydrocarbyl, arylazoaryl, aryihydrazinoaryl, hydrocarbyithiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroaryithiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, aryihydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, aryihydrocarbylami no, 7: heteroaryihydrocarbylamino, and heteroarylthio. The process according to claim 93, wherein R 4 is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroaryl hydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, aryl hydrocarboylh ydrocarbyl, arylcarbonylhydrocarbyl, aryl azoaryl, aryl hydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthi ohydrocarbyl, hydrocarbylthioaryl hydrocarbyl, aryihydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroaryihydrocarbylamino, and heteroarylthio, wherein: any such substituent is substituted by one or more substituents independently selected from the group consisting of halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, tifluoromethylhydrocarbyl, hydroxy, mercapto, 342 hydroxycarbonyl, aryloxy, arylthio, arylamino, aryihydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamnino, heteroaryihydrocarbyl, hydrocarbyloxycarbonyihydrocarbyl, heterocyclooxy, hydroxycarbonyihydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylami no, heteroaryihydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryihydrocarbylamino, aryihydrocarbyloxy, arylhydrocarbylthio, aryihydrocarbylamino, heterocyclo, heteroaryl, hydroxycarbonyihydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, aryihydrocarbyloyl, hydrocarboyloxy, aryihydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonyihydrocarbyl, hydrocarbyl hydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonyihydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonyl amino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonyl amino, aryihydrocarbylcarbonyl amino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, aryihydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroaryihydrocarbylsul fon yl amino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and ami nohydrocarbyl, wherein the aminohydrocarbyl nitrogen is substituted with: one or two substituent(s) that is/are independently selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or two substituents such that the aminohydrocarbyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl. 96. The process according to claim 90, wherein the compound corresponds in structure to Formula D4: 0 0 0 HO -'-NN H ;and R 4 has a chain length of 3 to about 14 carbon atoms. 97. The process according to claim 96, wherein R 4 is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, aryiheterocyclohydrocarbyl, aryihydrocarbyl, heteroaryihydrocarbyl, heteroaryl heterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, aryihydrazinoaryl, hydrocarbyithiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroaryl hydrocarbylamino, and heteroarylthio. 98. The process according to claim 96, wherein R 4 is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arleeoylhdoabl arlyrcryl e.or~hdoabl arylheterocyc lohydrocarbyl, aryhydrocarbyl eeoayryl ry rlxhydrocarbyl, heterocarbyl eeolhydrocarbyl, arylhydrocarb loxhydrocarbyl, aryl oy hydrocarbyl, hrydroarbyl ahydrabylarylhydrocarbyltihydrocyarylcayronaylhoarbyl, aryithi ohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, aryihydrocarbyithiohydrocarbyl, arylhydrocarbylthioaryl, ary h ydrocarbylamino, heteroaryihydrocarbylamino, and heteroarylthio, wherein: any such substituent is substituted by one or more substituents independently selected from the group consisting of halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifl uoromethylhydrocarbyl, hydroxy, mercapto, aryloxy, arylthio, arylamino, aryihydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaryihydrocarbyl, hydrocarbylox ycarbonylhydrocarbyl, heterocyci oox y, hydroxycarbonyihydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyc lohydrocarbylami no, heteroaryihydrocarbylox y, heteroaryl hydrocarbylthi o, heteroaryihydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, aryihydrocarbylamino, heterocyclo, heteroaryl, h ydroxycarbonyl hydrocarbyloxy, alkox ycarbonyl alkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and aminohydrocarbyl, wherein the aminohydrocarbyl nitrogen is substituted with: one or two substituent(s) that is/are independently selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, *a arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or two substituents such that the aminohydrocarbyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl. 99. The process according to claim 90, wherein R' has a length greater than the length of an octyl group and less than the length of a stearyl group. *S 'del 100. The process according to claim 90, wherein the compound or salt is S administered a plurality of times. S SO V& a6 a0 P. 101. A process for treating a mammal having a condition associated with pathological matrix metalloprotease (MMP) activity, wherein: the process comprises administering to the mammal having such a condition an MMP enzyme-inhibiting effective amount of a compound or a pharmaceutically acceptable salt thereof; the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-1; the compound corresponds in structure to Formula VIB3-2: 345 o o HO N NR R VIB-2; as to R 5 and R 6 R 5 and R 6 are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RbRcaminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RbRCaminoalkyloxy, or R and R 6 together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 ring members; as to R 7 and R8: R 7 and R 8 are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, Raoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclo, wherein each substitutable substituent is optionally substituted with or R 7 and R 8 together with the nitrogen atom to which they are bonded, form -G-A-R-E-Y; G is N-heterocyclo; A is selected from the group consisting of: k o o 2 -NR-, -CO-N(R -N(Rk)-CO-, o• -CO-O-, -O-CO-, -O-CO-O-, -HC=CH-, -NH-CO-NH-, (11) (12) 346 (13) -NH-NH-, (14) -CS-N(Rk)-, -N(Rk)-CS-, (16) -CH 2 (17) -O-CH 2 (18) -CH 2 (19) -S-CH 2 -CH 2 (21) -SO-, (22) -SO 2 and (23) a bond; R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyal kyl, arylthioal kyl, heteroarylthioal kyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl, wherein: the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1 -C 2 -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamno, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl; E is selected from the group consisting of: -CR- -RgCO-, -CON(Rk)_, -N(Rk)CO,' -CO-, -SO 2 -N(R k)-S0 2 -S0 2 -N(R and (11) a bond; Y is selected from the group consisting of a bond, hydrido, alkyl, alkoxy, haloalkyl, 347 aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, Raoxyalkyl, perfiuoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, arylalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, arylalkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl; each Ra is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRCaminoalkanoyl, haloalkanoyl, RbRCaminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy; each Rb or Rc is independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyal kyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloal kylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, and aminosulfonyl, wherein any amino nitrogen in such substituents is optionally substituted with: d up to two independently selected non-hydrido R substituents, or two substituents such that the substituents, together with the amino nitrogen, form: a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido Rd substituents, or a heteroaryl optionally substituted with up to three independently selected Rr substituents; each Rd or Re is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl; 348 each R is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and Rd Ramino; R9 is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RhR'-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RhR'-aminocarbonyloxy, R R'-aminocarbonyl, R R'-aminoalkanoyl, hydroxyaminocarbonyl, RhR'-aminosulfonyl, R R'-aminocarbonyl(Rh)amino, trifluoromethylsulfonyl(R )amino, heteroarylsulfonyl(R amino, arylsulfonyl(Rh)amino, arylsulfonyl(Rh)aminocarbonyl, alkylsulfonyl(R )amino, arylcarbonyl(Rh)aminosulfonyl, and alkylsulfonyl(R )aminocarbonyl; Rh is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: any such substituent is optionally substituted by up to two independently selected Ri substituents; R' is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: any such substituent is optionally substituted by up to two independently selected RJ substituents; each RJ is independently selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: the aminoalkyl and aminoalkanoyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl; each Rk is independently selected from the group consisting of hydrido, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RcRdamino 349 carbonyl, RCRdaminosulfonyl, RCRdaminoalkanoyl, and RcRdaminoalkysulfonyl; and the compound is other than: o 0 0 HO, N 'N or o oo CH "0 3 HO, N S, N H H 102. The process according to claim 101, wherein the compound corresponds in structure to Formula VIB-3: O O O HON S N R H 8 RR 6 VIB-3 R 103. The process according to claim 101, wherein the compound corresponds in structure to Formula VIII or VUI-B: 0 00 0 00 R 104. The process according to claim 101, wherein -NRR has a length greater than the length of an octyl group and less than the length of a stearyl group. 105. The process according to claim 104, wherein -NR 7 R is -G-A-R-E-Y. 106. The process according to claim 101, wherein the compound or salt is administered a plurality of times. 350 107. A process for treating a mammal having a condition associated with pathological matrix metalloprotease (MMP) activity, wherein: the process comprises administering to the mammal having such a condition an MMP enzyme-inhibiting effective amount of a compound or a pharmaceutically acceptable salt thereof; the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-1; the compound corresponds in structure to Formula VIB-2: O O HONG A RE, E H R R VIIB as to R 5 and R6: R 5 and R 6 are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RbRCaminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RbRaminoalkyloxy, or R 5 and R 6 together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 ring members; G is N-heterocyclo; A is selected from the group consisting of: -NR-, -CO-N(Rk)-, -N(Rk)-CO-, -CO-O-, -0-CO-, -0-CO-0-, -HC=CH-, -NH-CO-NH-, (11) (12) (13) -NE-NI--, (14) -CS-N(Rk)-, -N(Rk)-CS-, (16) -CH 2 (17) -O-CH 2 (18) -CH 2 (19) -S-CH 2 -CH 2 (21) -SO-, (22) -SO 2 and (23) a bond; R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, ::::cycloalkylthioalkyl, and heterocycloalkylthioalkyl, wherein: th aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of halo, al kyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, tri fiuoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1 -C 2 -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl; E is selected from the group consisting of: -RC- -N(Rk)C0_, -GO-, -S2R- -SO 2 -N(R )-S02-, -SO 2 -N(R and (11) a bond; I 352 Y is selected from the group consisting of a bond, hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, Raoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, arylalkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, arylalkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl; each Ra is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRcaminoalkanoyl, haloalkanoyl, R R aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy; each Rb or RC is independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, and aminosulfonyl, wherein any amino nitrogen in such substituents is optionally substituted with: up to two independently selected non-hydrido Rd substituents, or two substituents such that the substituents, together with the amino nitrogen, form: a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido Rd substituents, or a heteroaryl optionally substituted with up to three independently selected R' substituents; each Rd or Re is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and 353 arylalkyloxycarbonyl; each Rf is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and RdR'amino; R9 is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen, cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RhR'-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R R'-aminocarbonyloxy, R R'-aminocarbonyl, R R'-aminoalkanoyl, hydroxyaminocarbonyl, R R'-aminosulfonyl, R R'-aminocarbonyl(Rh)amino, trifluoromethylsulfonyl(Rh)amino, heteroarylsulfonyl(R amino, arylsulfonyl(R )amino, arylsulfonyl(Rh)aminocarbonyl, alkylsulfonyl(Rh)amino, arylcarbonyl(Rh)aminosulfonyl, and alkylsulfonyl(Rh)aminocarbonyl; Rh is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: any such substituent is optionally substituted by up to two independently selected R substituents; R' is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: any such substituent is optionally substituted by up to two independently selected RJ substituents; each RJ is independently selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, aminoalkanoyl, halo alkanoyl, and hydroxyalkyl, wherein: the aminoalkyl and aminoalkanoyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl; each Rk is independently selected from the group consisting of hydrido, alkyl, alkenyl, 354 aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RCRdamino carbonyl, RCRdaminosulfonyl, RCR d aminoalkanoyl, and RcRdaminoalkysulfonyl; and the compound is other than: 0 0 0 HO, N SN H 108. The process according to claim 107, wherein the compound or salt is administered a plurality of times. 109. A pharmaceutical composition that comprises a compound or salt according to any one of claims 1-89 dissolved or dispersed in a pharmaceutically acceptable carrier. 110. A pharmaceutical composition that comprises a compound or salt according to any one of claims 1 or 4-12 dissolved or dispersed in a pharmaceutically acceptable carrier. 111. A pharmaceutical composition that comprises a compound or salt according to 1 any one of claims 2 or 36 dissolved or dispersed in a pharmaceutically acceptable carrier. 112. A pharmaceutical composition that comprises a compound or salt according to claim 3 dissolved or dispersed in a pharmaceutically acceptable carrier. A pharmaceutical composition that comprises a compound or salt according to any one of claims 13-19 dissolved or dispersed in a pharmaceutically acceptable carrier. 114. A pharmaceutical composition that comprises a compound or salt according to claim 20 dissolved or dispersed in a pharmaceutically acceptable carrier. S** 115. A pharmaceutical composition that comprises a compound or salt according to any one of claims 21-28 dissolved or dispersed in a pharmaceutically acceptable carrier. 116. A pharmaceutical composition that comprises a compound or salt according to claim 29 dissolved or dispersed in a pharmaceutically acceptable carrier. 355 117. A pharmaceutical composition that comprises a compound or salt according to any one of claims 30-35, 37-48, 50-5 1, or 53-77 dissolved or dispersed in a pharmaceutically acceptable carrier. 118. A pharmaceutical composition that comprises a compound or salt according to claim 49 dissolved or dispersed in a pharmaceutically acceptable carrier. 119. A pharmaceutical composition that comprises a compound or salt according to claim 52 dissolved or dispersed in a pharmaceutically acceptable carrier. 120. A pharmaceutical composition that comprises a compound or salt according to any one of claims 78-89 dissolved or dispersed in a pharmaceutically acceptable carrier. 121. A process for treating a mammal having a condition associated with pathological matrix metalloprotease (MMP) activity, wherein the process comprises administering to the mammal an effective amount of a compound or salt according to any one of claims 1-89, or a pharmaceutical composition according to any one of claims 109-120. 122. The process of claims 121 wherein the compound or salt is as defined in any one of claims I or 4-11, or the pharmaceutical composition is as defined in claim 110. 123. The process of claims 121 wherein the compound or salt is as defined in any one of claims 2 or 36, or the pharmaceutical composition is as defined in claim 111. 124. The process of claims 121 wherein the compound or salt is as defined in claim 3, or the pharmaceutical composition is as defined in claim 112. 125. The process of claims 121 wherein the compound or salt is as defined in any one of claims 13-19, or the pharmaceutical composition is as defined in claim 113. 126. The process of claims 121 wherein the compound or salt is as defined in claim or the pharmaceutical composition is as defined in claim 114. e 356 127. The process of claims 121 wherein the compound or salt is as defined in any one of claims 21-28, or the pharmaceutical composition is as defined in claim 115. 128. The process of claims 121 wherein the compound or salt is as defined in claim 29, or the pharmaceutical composition is as defined in claim 116. 129. The process of claims 121 wherein the compound or salt is as defined in any one of claims 30-35, 37-48, 50-51 or 53-77, or the pharmaceutical composition is as defined in claim 117. 130. The process of claims 121 wherein the compound or salt is as defined in claim 49, or the pharmaceutical composition is as defined in claim 118. 131. The process of claims 121 wherein the compound or salt is as defined in claim 52, or the pharmaceutical composition is as defined in claim 119. 132. The process of claims 121 wherein the compound or salt is as defined in any one of claims 78-89, or the pharmaceutical composition is as defined in claim 120. 133. The process according to any one of claims 121-132, wherein the compound or salt composition is administered a plurality of times. 134. A compound or salt according to claim 1, wherein: the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while oooo exhibiting substantially less inhibitory activity against MMP-I. 135. A compound or salt according to claim 2, wherein: o:i the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-I. 136. A compound or salt according to claim 3, wherein: the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-l. 1 I 357 137. A compound or salt according to claim 6, wherein: the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-1. 138. A compound or salt according to claim 7, wherein: the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-1. 139. A compound or salt according to claim 10, wherein: the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-1. 140. A compound or salt according to claim 20, wherein: the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-1. 141. A compound or salt according to claim 21, wherein: S.the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-1. 142. A compound or salt according to claim 78, wherein: the compound or salt inhibits the activity of MMP-2 and/or MMP-13, while exhibiting substantially less inhibitory activity against MMP-1. DATED this 23 day of March 2005 D. SEARLE CO., By its Patent Attorneys, E. F. WELLINGTON CO., By: 4 (Bruce Wellington) BW 5247
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