ZA200109007B - Hydroxamic acid derivatives as matrix metalloprotease inhibitors. - Google Patents

Hydroxamic acid derivatives as matrix metalloprotease inhibitors. Download PDF

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ZA200109007B
ZA200109007B ZA200109007A ZA200109007A ZA200109007B ZA 200109007 B ZA200109007 B ZA 200109007B ZA 200109007 A ZA200109007 A ZA 200109007A ZA 200109007 A ZA200109007 A ZA 200109007A ZA 200109007 B ZA200109007 B ZA 200109007B
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South Africa
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group
alkyl
aryl
independently selected
heteroaryl
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ZA200109007A
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Louis J Bedell
Joseph J Mcdonald
Thomas E Barta
Daniel P Becker
Shashidhar N Rao
John N Freskos
Brent V Meschke
Daniel P Getman
Gary A Decrescenzo
Clara I Villamil
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Searle & Co
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Publication of ZA200109007B publication Critical patent/ZA200109007B/en

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Description

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HYDROXAMIC ACID DERIVATIVES AS MATRIX
METALLOPROTEASE INHIBITORS
—_— :
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
\ -2- controlled 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 5S 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 pathological 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 septic shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal.
TNF-a convertase is a metalloproteinase
S 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 (B-Amyloid Precursor Protein) to the amyloid plaque and inactivation of aj-protease inhibitor (a -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 oj-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.
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 (MMP- 2), gelatinase 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), ap- 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 mammals and inhibition of this enzyme leads to the lowering of blood pressure.
Thiol group-containing amide or peptidyl amide-based metalloprotease (MMP) inhibitors are 5S known as is shown in, for example, W095/12389,
WO096/11209 and U.S. 4,595,700. Hydroxamate group- containing 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 ICgg values of about 1 to about 20 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 ICgg 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,
rapidly 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 5S 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 hydroxamate 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 pro- drug form of such a compound. A contemplated compound corresponds in structure to Formula C. 0 0] EN /
R20 S— R! C
Ww
R® R°® wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring;
Rl is (i) a substituent containing a S5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or hetercaryl radical bonded directly to the depicted
SO,-group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R! defining a three-dimensional volume, when rotated about an axis drawn through the
SO3-bonded 1-position and the 4-position of a 6- membered ring radical or drawn through the SO;-bonded l-position and the center of 3,4-bond of a S5-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, Rl is an -NR7R8 group in which R’7 and
R8 are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted arylhydrocarbyl. More preferably, R’7 and R8 are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R2oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocaryl, 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 (1) -0-; (2) -5-; (3) -Nrk-; (4) -CO-N(RK) or -N(RK)-cO-;
(5) -CO-0- or -0-CO-; (6) -0-C0-0-; (7) ~-HC=CH-; (8) -NH-CO-NH-; (9) -C=C-; (10) -N=N-; (11) -NH-NH-; (12) -CS-N(R¥)- or -N(RK)-cs-; : (13) -CHp-; (14) -0O-CHy- or -CHy-0O-; (15) -S-CHp- or -CH»-S-; (16) -S0-; and (17) -502-; or (18) A is absent and R is directly bonded to R7 or R8, or both R7 and RS; the moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthiocalkyl, heteroarylthiocalkyl, cycloalkylthiocalkyl, and a heterocycloalkylthioalkyl group wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluorocalkyl, perfluorocalkoxy, perfluorocalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, Cy-Cy-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy,
hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group; the group E is selected from the group consisting of (1) -COR9- or -RICO-; (2) -CON(RK)- or -(rRK)NCO-; (3) -CoO-; (4) -SO3RY- or -RISO,-; (5) -SOy-; (6) -N(RK)-s05- or -50,-N(RK)-; or (7) 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, R3%oxyalkyl, perfluoroalkoxy, perfluorocalkylthio, 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 congisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluorocalkoxy and an amino group wherein the amino nitrogen is (i) unsubstituted or (11) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group; or
R7 and R8 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;
S the substituent A is selected from the group consisting of (1) -0-; (2) -5-; (3) -NRK-; (4) -co-N(RK) or -N(RK)-co-; (5) -CO-0- or -0-CO-; (6) -0-C0O-0-; (7) -HC=CH-; (8) -NH-CO-NH-; (9) -C=C-; (10) -N=N-; (11) -NH-NH-; (12) -Cs-N(RK)- or -N(RK)-Cs-; (13) -CHz-; (14) -0-CHp- or -CHp-O-; (15) -S-CHy- or -CHp-S-; (16) -SO-; and (17) -802-; 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, arylthicalkyl, heterocarylthicalkyl, cycloalkylthiocalkyl, and a heterocycloalkylthiocalkyl 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
S consisting of a halo, alkyl, perfluorocalkyl, perfluoroalkoxy, perfluorocalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C;-Cy-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group; the moiety E is selected from the group consisting of (1) -CORY9- or -RYICO-; (2) -CON(RK)- or -(RK)NCO-; (3) -co-; (4) -SO5-RI- or -RI-S0,-; (5) -S05-; (6) -N(RK)-50,- or -50,-N(RK)-; or (7) 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, R%oxyalkyl, 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, perfluorcalkyl, perfluorocalkoxy and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.
Alternatively, and still more preferably, R7 and R8 taken together with the nitrogen atom to which they are bonded; i.e., a -NR7R8 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 (1) -0-; (2) -8-; (3) -NRK-; (4) -co-N(RK) or -N(RK)-co-; (5) -CO-0- or -0-CO-; (6) -0-CO0-0-; (7) -HC=CH-; (8) ~-NH-CO-NH-; - (9) -C=C-; (10) -N=N-; (11) -NH-NH-; (12) -Cs-N(RK)- or -N(rRK)-cs-; (13) -CHp-; (14) -O-CHy- or -CHy-0-; (15) -S-CHy- or -CH,-S-; (16) -SO-; and (17) -802-; 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, heterocaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthiocalkyl, cycloalkylthiocalkyl, 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 halo, alkyl, perfluoroalkyl,
perfluorocalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C;-Cy-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group;
the moiety E is selected from the group consisting of (1) -CORS- or -RYCO-; (2) -CON{(RK)- or -(RK)NCO-; (3) -co-; (4) -SO2-RY9- or -RY-SOy-; (5) -SO3-; (6) -N(RK)-S05- or -S0,-N(RK)-; or (7) 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, RZ%oxyalkyl, perfluoroalkoxy, perfluoroalkylthio, 5) 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 (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.
Substituents R5 and R® are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, a RPRCaminocalkyl substituent, thiol (-SH), alkylthio, arylthio, cycloalkylthio, cycloalkkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and a
RPRCaminoalkyloxy substituent; or R® and R® together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having 5- to 7-members. a R20 group is (a) -0-R?1, where R21 is selected from the group consisting of a hydrido, C;-Cg-alkyl, aryl, ar-C;-Cg-alkyl group and a pharmaceutically acceptable cation, (b) -NR13-0-R22 wherein R22 is a selectively removable protecting group such as a 2- tetrahydropyranyl, benzyl, p-methoxybenzyl, C,-Cg- alkoxycarbonyl, trisubstituted silyl group or o- nitrophenyl group, peptide systhesis resin and the like, wherein the trisubstituted silyl group is substituted with C;-Cg-alkyl, aryl, or ar-Cj-Cg-alkyl or a mixture thereof, and R13 is a hydrido, C;-Cg- alkyl or benzyl group, (c) -NR13-0-R14, where R13 is as before and R14 is hydrido, a pharmaceutically acceptable cation or C(V)R1® where Vv is © (oxo) or Ss (thioxo) and R!® is selected from the group consisting of an C;-Cg-alkyl, aryl, C;-Cg-alkoxy, heterocaryl-C,-Cg-alkyl, C3-Cg-cycloalkyl-C;-Cg-alkyl, aryloxy, ar-C;-Cg-alkoxy, ar-C;-Cg-alkyl, heteroaryl and amino C;-Cg-alkyl group wherein the amino C;-Cg- alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C;-Cg-alkyl, aryl, ar-C,-Cg-alkyl, C3-Cg- cycloalkyl-C;-Cg-alkyl, ar-C,-Cg-alkoxycarbonyl, Cq-
Cg-alkoxycarbonyl, and C;-Cg-alkanoyl radical, or (iii) wherein the amino C;-Cg-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) -NR23R24, where R23 and R24 are independently selected from the group consisting of a hydrido, C,-Cg-alkyl, amino Cq-
Cg-alkyl, hydroxy C1-Cg-alkyl, aryl, and an ar-C;-Cg- alkyl group, or R23 and R24 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.
In the formula above, R2 is selected from the group consisting of a hydrido, alkyl, alkenyl,
S alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RPRCaminoalkanoyl, haloalkanoyl,
RPRCaminoalkyl, alkoxyalkyl, haloalkyl and an arylalkyloxy group;
RP and RC are independently selected from the group consisting of a hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluorocalkyl, trifluoromethylalkyl, perfluorocalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heterocarylthioalkyl, arylsulfonyl, aralkanoyl, alkylsulfonyl, heterocarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthiocalkyl, alkylthioalkyl, arylthiocalkenyl, alkylthioalkenyl, hetercarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosul fonyl wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with one or two RA 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 RA substituents or a heteroaryl group optionally substituted with one, two or three groups independently selected from RE substituents; :
RA and R® 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 RARC®amino group;
RY is selected from the group consisting of a hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F, Cl, Br, I), cyano, aldehydo (CHO, formyl), hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RhR1-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluorocalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RPR1.aminocarbonyloxy, RARi-aminocarbonyl,
RPRi-aminoalkanoyl, hydroxyaminocarbonyl, RDRi- aminosul fonyl, RBRi-aminocarbonyl (Rh) amino, trifluoromethylsulfonyl (Rh) amino, heteroarylsulfonyl- (RP) amino, arylsulfonyl (RD) amino, arylsulfonyl (Rh) - aminocarbonyl, alkylsulfonyl (RP)amino, arylcarbonyl -
(Rh) aminosulfonyl, and an alkylsulfonyl (Rh) - aminocarbonyl substituent;
RP 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 aminocalkyl and substituted aminoalkanoyl groups;
Ri 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;
R] 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 aminocalkanoyl 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,
RCRAamino carbonyl, RCRYaminosul fonyl,
RCRYaminoalkanoyl and RCRYaminoalkysulfonyl.
In some preferred embodiments, RS and Rr® are independently selected from the group consisting of hydrido, hydrocarbyl, preferably C;-C4 hydrocarbyl, hydroxylhydrocarbyl, hydroxyl, amino, dihydrocarbylamino, heterocyclo, heterocyclohydrocarbyl, heterocyclooxy, and heterocyclothio.
In preferred embodiments, the 5- or 6- membered aromatic or heteroaromatic ring W is a 1,2- phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 4,5- pyridinylene, 2,3-pyrazinylene, 4,5-pyrimidinylene, or 5,6-pyrimidinylene group.
In some preferred embodiments, R20 is -NR13-0-R1%4, whereas in other preferred embodiments,
R20 is -NR13-0-R22., In particularly preferred embodiements, R20 is -NHOH so that a compound of
Formula C corresponds in structure to Formula C1 0 o. °
NJ
R"“ONR™ “R “
Ww
R® RS wherein Ww, RL, RS, R®, R13 and R!? are as defined before.
In one preferred embodiment, a contemplated compound corresponds in structure to Formula C2, 0) EN ya
Sach PhR* C2
Ww
R® R® wherein W, RO, R® and R14 are as defined above and Ph is a phenyl group substituted at the 4- position with substituent R4. A R? 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 [e.g., C3-Cy14 hydrocarbyl or 0-C5-Cjiq4 hydrocarbyl], a phenoxy group [-OCgHgl, a thiophenoxy group [phenylsulfanyl; -SCgHgl, an anilino group [-NHCgHg] , a phenylazo group [-N;CgHgl, a phenylureido group [aniline carbonylamino; -NHC(O)NH-
CgHgl, a benzamido group [-NHC(O)CgHgl, a nicotinamido group [3-NHC(O)CgH4N]l, an isonicotinamido group [4-NHC(O)CgH4N], or a picolinamido group [2-NHC(O)CgH4N]. A R% substituent is further defined hereinafter.
In another aspect of the invention, a contemplated compound corresponds in structure to
Formula VI-1
, A x 7
Ere rs NY ee VE \ /
RS” B=C 6 wherein each of R53, R®, R7, R8 and R20 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 R40 is NH-OH, compound of one of the above formulas such as Formula C or Cl 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
Cl exhibits greater activity in inhibiting MMP-2 than in inhibiting MMP-1 and usually also MMP-13. When
R20 js 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 6) AL Oo AL
S< S< oA (9) R20 )
RS |= R* R® R* i. RUA RS VIA-1 wherein R20, R4, RS and R® are as defined before and ring structure W2 including the depicted nitrogen atom is a heterocylic ring that contains 5- or 6-members, and R% is bonded at the 4-position relative to that depicted nitrogen atom when W2 is a 6-membered ring and at the 3- or 4-position relative to that depicted nitrogen when W2 is a 5-membered ring.
S Another particularly preferred embodiment of this aspect is a compound that corresponds in structure to Formulas VIB, VIB-1, VIB-2 or VIB-3 0) Oo Oo O
RV. RV
S\y-R S yh
R20 7 \ \ go R? \ o
R 5 R
R Va R 6 6
R® vis R™ viB-1
O 0 0 o} 0 \/~ RY
Ss So _R
HONH J \ \ HONH N
RCL, R RS R®
RS RG
ViB-2 ViB-3 wherein R20, RS, R®, R7, and R8 are as defined before.
A particularly preferred group of compounds of this class are the compounds whose structure corresponds to Formula D 0) 0 NY
AN ~N 7 \ D
A. D A
RS” B=C “pe Re
El
Y wherein the substituent groups or moieties
A, R, E, Y, R20, R5 and R® 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 Cl, 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. 0 o.
Ng
R™ONR'3 Sp Cl
Ww
R® R® wherein W, Rl, RS, R®, R13 and R!? 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 example, 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 hydroxamic 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.
(0) NS
S—Rg? C
R20 go
R® RS wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring;
Rl is (i) a substituent containing a 5- or 6 -membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted
SO5-group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, the Rl group defining a three- dimensional volume, when rotated about an axis drawn through the SO;-bonded 1l-position and the 4-position of a 6-membered ring radical or drawn through the
SO5-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! group is (ii) an -NR7R8 group in which R7 and R8 are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted arylhydrocarbyl. More preferably, a R1 group is an -NR7R8 group in which R7 and R8® are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R3oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heterocarylalkyl, 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
S selected from the group consisting of (1) -0-; (2) -5-; (3) -NrRK-; (4) -Co-N(RK) or -N(r¥)-co-; (5) ~C0-0- or -0-CO-; (6) -0-CO-0-; (7) -HC=CH-; (8) ~NH-CO-NH-; (9) ~C=C-; (10) -N=N-; (11) -NH-NH-; (12) -Cs-N(RK)- or -N(RK)-cs-; (13) -CHp-; (14) -O-CHy- or -CHy-0O-; (15) -S-CHy- or -CHp-S-; (16) -SO-; and (17) -802-; or (18) A is absent and R is directly bonded to R7 or R8, or both R7 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, arylthiocalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl,
heteroaryl, cycloalkyl or heterocycloalkyl substituent is (i) 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, Cq-Cgp-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group;
the group E is selected from the group consisting of ’ (1) -CorY9- or -RYICO-; (2) -CON(RK)- or -(RK)NCO-; (3) -co-; (4) -50,5(RY)- or -(RY)SO5-; (5) -S05-; (6) -N(RK)-S0,- or -S05-N(RK)-; or (7) 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, RZ%oxyalkyl, perfluoroalkoxy, perfluorocalkylthio, 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 (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group; or
R7 and R8® taken together with the nitrogen atom to which they are bonded (-NR7R8) 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 (1) -0-; (2) -S-; (3) -NRK-; (4) -CO-N(RK) or -N(RK)-co-; (5) -CO-0- or -0-CO-; (6) -0-CO0-0-; (7) -HC=CH-; (8) ~NH-CO-NH-; (9) -C=C-; (10) -N=N-; (11) -NH-NH-; (12) -CS-N(RK)- or -N(rRK)-cs-; (13) -CHy-; (14) -0-CHz- or -CHp-O-; (15) -S-CHy- or -CHp-S-; (16) -SO-; and (17) -5802-; 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, heterocaryl- oxyalkyl, 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 halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C;-Cp-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group.
The moiety E is selected from the group consisting of (1) -CoRY- or -RYCO-; (2) -CON(RK)- or - (RK)NCO-; (3) -co-; (4) -SO02(RYI)- or -(RY)S0y-; (5) -805-; (6) -N(RK)-S05- or -S0,-N(RK)-; or (7) 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, R%oxyalkyl,
perfluoroalkoxy, perfluorocalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl,
S 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, perfluorocalkoxy and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group;
RS and R® are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, and a
RPRCaminoalkyl substituent; or
R® and R® together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having 5- to 7- members. .
In an above formula, R2 is selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RPRCaminoalkanoyl, haloalkanoyl,
RPRCaminoalkyl, alkoxyalkyl, haloalkyl and an arylalkyloxy group; :
RP 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, heterocaryloxyalkyl,
S heterocarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthiocalkyl, arylthioalkenyl, alkylthioalkenyl, heterocarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminocalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with one or two RA 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 RA substituents or a heteroaryl group optionally substituted with one, two or three groups independently selected from RE substituents;
RQ and R® 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 RAR€amino; .
RY is selected from the group consisting of a hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heterocaroyl, halogen (F, Cl, Br, I), cyano, aldehydo (CHO, formyl), hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RPRi-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RBR1i-aminocarbonyloxy, RORi-aminocarbonyl,
RhR1-aminocalkanoyl, hydroxyaminocarbonyl RhRi- aminosulfonyl, RDOR1-aminocarbonyl (RD) amino, trifluoromethylsul fonyl (RP) amino, heteroarylsulfonyl- (Rh) amino, arylsul fonyl (RB) amino, arylsul fonyl (Rh) - aminocarbonyl, alkylsul fonyl (RD) amino, arylcarbonyl - (Rh) aminosulfonyl, and an alkylsulfonyl (Rh) - aminocarbonyl substituent;
Rh ig 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 amincalkanoyl, 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 amincalkyl and substituted aminocalkanoyl groups;
Ri 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 aminocalkanoyl, 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, heterocarylalkyl, aryloxycarbonyl and an alkyloxycarbonyl group; and
RK is selected from hydrido, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl,
RCRdamino carbonyl, RCRYaminosulfonyl,
RCRAaminoalkanoyl and RCRYdaminoalkysulfonyl.
R20 is (a) -0-R?l, where R?l is selected from the group consisting of a hydrido, C,-Cg-alkyl, aryl,
ar-C,-Cg-alkyl group and a pharmaceutically acceptable cation, (b) -NR13-0-R22 wherein R?? is a selectively removable protecting group such as a 2- tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), Cq-
Cg-alkoxycarbonyl, trisubstituted silyl group or o- nitrophenyl group, peptide systhesis resin and the like, wherein the trisubstituted silyl group is substituted with C;-Cg-alkyl, aryl, or ar-Cj-Cg-alkyl ‘or a mixture thereof, and R13 is a hydrido, Cj-Cg- alkyl or benzyl group, (c) -NR13-0-R14, where R13 is as before and Rl? js hydrido, a pharmaceutically acceptable cation or C(V)RLS where V is O (oxo) or S (thioxo) and R1® is selected from the group consisting of an C;-Cg-alkyl, aryl, C;-Cg-alkoxy, heteroaryl-C;-Cg-alkyl, C3-Cg-cycloalkyl-C,-Cg-alkyl, aryloxy, ar-C;-Cg-alkoxy, ar-C;-Cg-alkyl, heteroaryl and amino C;-Cg-alkyl group wherein the amino Cq1-Cg- alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an Cp-Cg-alkyl, aryl, ar-C;-Cg-alkyl, C53-Cg- cycloalkyl-C,-Cg-alkyl, ar-C;-Cg-alkoxycarbonyl, C;-
Cg-alkoxycarbonyl, and C,-Cg-alkanoyl radical, or (iii) wherein the amino C;-Cg-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) -NR23Rr24, where R23 and R24 are independently selected from the group consisting of a hydrido, C;-Cg-alkyl, amino Cq-
Cg-alkyl, hydroxy C;-Cg-alkyl, aryl, and an ar-C,;-Cg-
alkyl group, or R23 and R24 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
R20 js -0-R2l, in which R21 is selected from the group consisting of a hydrido, C,-Cg-alkyl, aryl, ar-
C,-Cg-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 R20 is -NR13-0-Rr22, wherein R22 is a selectively removable protecting group and R13 is a hydrido or benzyl group, preferably a hydrido group.
A selectively removable protecting group is exemplified as a 2-tetrahydropyranyl, benzyl, p- methoxybenzyloxycarbonyl (MOZ), benzyloxycarbonyl (BOC), Cp-Cg-alkoxycarbonyl, C;-Cg-alkoxy-CHp-, Cj-
Cg-alkoxy-C,-Cg-alkoxy-CHp-, trisubstituted silyl group, an o-nitrophenyl group, peptide synthesis resin and the like. A trisubstituted silyl group is a silyl group substituted with Cj-Cg-alkyl, aryl, or ar-Cj-Cg-alkyl substituent groups or a mixture thereof such as a trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, triphenylsilyl, t- butyldiphenylsilyl, 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 R13 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 R20 js -0-R?1 and Rr?! is a hydrido group] in water with O- (tetrahydro-2H-pyran-2- yl) hydroxylamine in the presence of N- methylmorpholine, N-hydroxybenzotriazole hydrate and a water-soluble carbodiimide such as 1-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The resulting THP-protected hydroxamate corresponds in structure to Formula C3, below, where W, RI, R> and R® 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 p- toluenesulfonic acid or HCl and acetonitrile or methanol. 0 oP
VY
NI rR! C3
O—NH
Td
R® R®
Another aspect of the invention contemplates a compound that corresponds in structure to Formula VI-1, below, 9 Ar 7 rn 5 N~ R
Ie p Ase VI \ /
RS “B=C “ge wherein each of R53, R®, R7, R® and R20 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 activity 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) Ar 0) AL
S< SN “7 9) R20 7 \ 9)
RS == R* R \— RY
RY VIA R® VIA-1 wherein R20, R5, R6 and R? are as defined before, ring structure W2 including the depicted nitrogen atom is a heterocylic ring that contains 5- or 6-members, and R4 is bonded at the 4-position relative to that depicted nitrogen atom when W2 is a 6-membered ring and at the 3- or 4-position relative to that depicted nitrogen when W2 is a 5-membered ring. The ring structure WZ is preferably a N- piperidinyl 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
Oo A py ,
Ss... R “7S N VIB
RS R®
RS wherein R20, R53, R6, R7, and R8 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 0) EN Va
S—ng! C4
HONH go!
R® RS wherein the ring structure W is a 5- or 6-membered aromatic or hetercaromatic ring;
Rl is a substituent containing a 5- or 6- membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted
SO -group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R! defining a three-dimensional volume, when rotated about an axis drawn through the
SO5-bonded 1-position and the 4-position of a 6- membered ring radical or drawn through the SO;-bonded l-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; and
RS and R® are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, a
RPRCaminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and a
RPRCaminoalkyloxy substituent; or R® and R® together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having 5- to 7-members.
Again, in some preferred embodiments, (ii), R1 is an -NR7R8 group in which R7 and R® are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and subsituted arylhydrocarbyl.
More preferably still, R7 and R® are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl,
R2oxyalkyl, 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 (1) -0-; (2) -S-; (3) -NrK-; (4) -CO-N(RX) or -N(RK)-cO-; (5) -CO0-0- or -0O-CO-;
(6) -0~-CO-0-; (7) ~-HC=CH-; (8) -NH-CO-NH-; (9) -C=C-; (10) -N=N-; (11) -NH-NH-; (12) -cs-N(RK)- or -N(RK)-cs-; (13) -CHy-; (14) -0-CHy- or -CH3-0-; (15) -S-CHp- or -CHp-S-; (16) -SO-; and (17) -S02-; or (18) A is absent and R is directly bonded to R7? or R8, or both R7 and RS;
the moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl,
heterocaryloxyalkyl, arylthioalkyl, hetercarylthiocalkyl, cycloalkylthioalkyl, and a heterocycloalkylthicalkyl group wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is (i) 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;-C,-alkylene-dioxy, hydroxycarbonylalkyl,
hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group;
the group E is selected from the group consisting of (1) -CORY- or -RYCO-; (2) -CoN(RK)- or -(rR¥)NcO-; (3) -CO-; (4) -S05(RY)- or -(RY)SO,-; (5) -S05-; (6) -N(RXK)-50,- or -50,-N(RX)-; or (7) E is absent and R is bonded directly to ¥; 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, R2oxyalkyl, perfluorcalkoxy, 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 (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.
More preferably yet, R7 and R8 taken together with the nitrogen atom to which they are bonded (-
NR7R8 ) 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 (1) -0-; (2) -S-; (3) -NRK-; (4) -co-N(RK) or -N(rRK)-co-; (5) -CO-0- or -0-CO-; (6) -0-C0-0-; (7) -HC=CH- ; (8) -NH-CO-NH-; (9) -C=C-; (10) -N=N-; (11) -NH-NH-; (12) -cs-N(rRK)- or -N(RK)-Cs-; (13) -CHz-; (14) -O-CHy- or -CH,-0-; (15) -S-CHz- or -CHp-S-; (16) -S0-; and (17) -802-; 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, heterocaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroaryl- . thiocalkyl, cycloalkylthioalkyl, and a heterocyclo- alkylthioalkyl 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 halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C;-C,-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group; the moiety E is selected from the group consisting of (1) -CORY- or -RYCO-; (2) -CONRK- or -rRKNCO-; (3) -CO-; (4). -S02(RY)- or -(RI)SO05-; (5) -SO3-; (6) -N(RK)-S0,- or -S0,-N(RK)-; or (7) 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, R2oxyalkyl, perfluorocalkoxy, perfluorocalkylthio, 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 (i) unsubstituted or
(ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.
The superscripted "R" groups, R32, RP and the like above and hereinafter are as defined before.
In one preferred embodiment, R® and R® are independently selected from the group consisting of a hydrido, hydrocarbyl, preferably C;-C4 hydrocarbyl, hydroxylhydrocarbyl, hydroxyl, amino, : RPRCaminohydrocarbyl, halo, nitro, cyano, hydrocarbyloxy, halohydrocarbyl, halohydrocarbyloxy, hydroxyhydrocarbyl, dihydrocarbylamino, heterocyclo, heterocyclohydrocarbyl, heterocyclooxy, and a heterocyclothio group. More preferably, RS and R® are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, and a RPRCaminoalkyl substituent.
Contemplated aromatic or heteroaromatic rings include 1,2-phenylene, 2,3-pyridinylene, 3,4- pyridinylene, 4,5-pyridinylene, 2,3-pyrazinylene, 4,5-pyrimidinylene, 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 Rl substituent contains a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO,-group. An Rl 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 cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is not itself long enough to fulfill the length requirement for a preferred compound, particularly where Rl is NR7R8. 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 RI substituent and are themselves substituted as discussed herein include phenyl, 2-, 3-, or 4- pyridyl, 2-naththyl, 2-pyrazinyl, 2- or 5- pyrimidinyl, 2- or 3-benzo(b)thienyl, 8-purinyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-imidazolyl, cyclopentyl, cyclohexyl, 2- or 3-piperidinyl, 2- or 3-morpholinyl, 2- or 3-tetrahydropyranyl, 2- imidazolidinyl, 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 Rl substituent (including NR7R8 as an Rl 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); i.e., 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.
Looked at more generally, and aside from specific moieties from which it is constructed, an Rl substituent (radical, group or moiety) has a length of a heptyl group or greater. Such an Rl substituent also has a length that is less than that of an eicosyl group. That is to say that a Rl 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 group has a length of about an eight carbon chain using a contemplated measurement mode.
In addition, an Rl substituent, when rotated about an axis drawn through the SO;-bonded . 5 1-position and the 4-position of a 6-membered ring radical or the SO;-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 S5- membered ring that is substituted at appropriate positions numbered from the SO;-linkage that is deemed to be at the l-position as discussed before.
Thus, a 2-naphthyl substituent or an 8-purinyl substituent is an appropriately sized Rl radical as to width when examined using the above rotational width criterion. On the other hand, a 1l-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, Rl 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! substituents, with
4 - (phenoxy) phenyl and 4- (thiophenyl) phenyl being most preferred.
An SOj-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is a 5- or 6-membered single-ring that is itself substituted with one other substituent, R%. The S0,-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 3- or 4-position when a 5-membered ring. The cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical to which R%? is bonded in some embodiments is preferably a phenyl group, so that Rl is preferably
PhR% in which R%? is bonded at the 4-position of the
SOj3-linked phenyl (Ph) radical, and in which R% 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%? substituent being linked at the 4-position relative to the bond between the ring and the SO, group.
A contemplated R% 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 [e.g., C3-Cjga hydrocarbyl or 0-C3-C34 hydrocarbyl}, a phenyl group, a phenoxy group [-OCgHgl], a thiophenoxy group [phenylsulfanyl; -SCgHgl, an anilino group [-NHCgHg], a phenylazo group [-N3CgHgl, a phenylureido group [aniline carbonylamino; -NHC(O)NH-CgHg], a benzamido
~53- group [-NHC(O)CgHgl, a nicotinamido group [3-NHC(O)CgHy4N], an isonicotinamido group [4-NHC (O)CgHyN], or a picolinamido group [2-NHC(0O)CsH4N] . Additionally contemplated R4 substituent groups include a heterocyclo, heterocyclohydrocarbyl, arylhydrocarbyl, arylheterocyclohydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclo-hydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbyl-thiohydrocarbyl, hydrocarbylthiocaryl, arylthiohydrocarbyl, hetercarylthiohydrocarbyl, hydrocarbylthiocarylhydrocarbyl, arylhydrocarbyl- thiohydrocarbyl, arylhydrocarbylthiocaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, or a heterocarylthio group.
A contemplated R4 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, trifluoromethyl- hydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarhydrocarbyl, hydrocarbyloxycarbonyl - hydrocarbyl, heterocyclooxy, hydroxycarbonyl- hydrocarbyl, heterocyclothio, heterocycloamino,
cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, hetercaryl- hydrocarbylamino, arylhydrocarbyloxy,
arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl- hydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxy-
hydrocarbyloxy, hydrocarbylthio, hydrocarbyloxy- hydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxy- carbonylhydrocarbyl, hydrocarbylhydroxycarbonyl- hydrocarbylthio, hydrocarbyloxycarbonyl -
hydrocarbyloxy, hydrocarbyloxycarbonyl- hydrocarbylthio, amino, hydrocarbylcarbonylamino,
. arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heterocaryl-
carbonylamino, heterocarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl- sulfonylamino, cyclohydrocarbylsulfonylamino,
heterocyclohydrocarbylsulfonylamino and N- monosubstituted or N,N-disubstituted aminohydrocarbyl group wherein the substituent (s) on the nitrogen are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, 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.
Thus, initial studies indicate that so long as the length, substitution and width (volume upon rotation) requirements of an SO,-linked R1 substituent discussed herein are met, an R1 substituent can be extremely varied.
A particularly preferred R4 substituent of an SOp-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;-C;o hydrocarbyl,
C1-Cg hydrocarbyloxy or carboxyethyl groups can be used.
Exemplary particularly preferred PhR% (particularly preferred Rl) substituents include biphenyl, 4-phenoxyphenyl, 4-thiophenoxyphenyl, 4- benzamidophenyl, 4-phenylureido, 4-anilinophenyl, 4- nicotinamido, 4-isonicotinamido, and 4-picolinamido.
Exemplary particularly preferred R4 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 R4 substituent that is a phenyl group, a phenoxy group,
-5 6 - a 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;-Cg hydrocarbyloxy group, a perfluoro C;-Cg hydrocarbyl group, a C;-Cg hydrocarbyloxy (-0-C;-Cg hydrocarbyl) group, a Cj-Cjg hydrocarbyl group, a di-
C1 -Cg9 hydrocarbylamino [-N(Cj-Cg hydrocarbyl) (Cy-Cg hydrocarbyl)] group, a carboxyl C;-Cg hydrocarbyl (C1-Cg hydrocarbyl-COsH) group, a C1-Cy hydrocarbyloxy carbonyl C;-C4 hydrocarbyl [C;-C4 hydrocarbyl-O- (CO) -C;-C4 hydrocarbyl] group, a C;-C4 " hydrocarbyloxycarbonyl C,-C4 hydrocarbyl [C;-C4 hydrocarbyl (CO) -0-C1-C4 hydrocarbyl] group and a C;-
Cg hydrocarbyl carboxamido [-NH(CO)-C;-Cg hydrocarbyl] group, or is substituted at the meta- and para-positions by two methyl groups or by a C;-Cj alkylenedioxy group such as a methylenedioxy group.
Inasmuch as a contemplated SOj-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is itself preferably substituted with a 6- membered 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
SO -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 SO3-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical. When a R% substituent is other than a 6- membered ring, substituent positions are numbered from the position of linkage to the aromatic or
S heteroaromatic ring. Formal chemical nomenclature is used in naming particular compounds.
Thus, the l-position of an above-discussed
SO5-1linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is the position at which the SOj- 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 SO;-linkage as compared to formalized ring numbering positions used ) in heteroaryl nomenclature. 0 0) EN Vi
R™ONH > phR! ©
Ww
R® R®
In some preferred embodiments, a contemplated compound corresponds in structure to
Formula C2, wherein W, R®, R® and R14 are as defined above, Ph is phenyl substituted at the 4-position with substituent R? that is defined hereinabove.
The length of a Rl substituent bonded to the SO; 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 Rl substituent that is shorter in length than a heptyl group, e.g., a 4-methoxyphenyl group, typically exhibits moderate to poor inhibitory activity against all of the MMP enzymes, whereas compounds whose Rl substituents have a length of : about an heptyl chain or longer, e.g., a 4- phenoxyphenyl 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 ya
NC C4
HONH
Ww
R® RS wherein W, Rl, RS, and R® are as defined above, and
Rl 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! being PhR%, particularly preferred compounds correspond in structure to Formulas VIB,
viB-1, VIB-2 VIB-3, VII, VII-B, VIIC, VIID, VIIE,
VIII and, VIIIB, below, wherein the above definitions for -A-R-E-Y, -G-A-R-E-Y, W2, Rl, R35, R6, R7, R8 and
R20 also apply, and wherein the substituent -A-R-E-Y is bonded to ring structure W2 or a depicted ring structure. o) oO 0] o 0 \V/3 \V74
SiR EPL
R® 7 \ es R% "
R R
RA R® 6 6
R™ vis R™ viB-1 0 oOo 0
V2 QL
ENT S. _R
HONH 7 \ \ . HONH™ N
REL R RS R®
RS 6
R
ViB-2 VIB-3 0 0 O oO
RY \ — 1 Se.
HONH — R HONH — G-ARE-Y \, / wo /
R® via VIB 0) oO Oo 0 \Y/j 0 QF
S~N ~ S—~Rt
HONH = w? @ NH —
R—% RS—L \ A-R-E-Y N
REN J REE /
VIIC VIID
0] 0 0 QF ~ S~G-A-R-E —Y
NH —
R ———
AS
3 /
VIIE
O oO 0] oO
Yj NY
S< S<
HONH — N 4 HONH = N
RS— rey RL S
X_/ YX J S
REX REX A-R-EY
VII VII-B
The compounds that correspond in structure to Formulas D, D1, D2 ,D3 and D4, below, wherein the above definitions for -A-R-E-Y, R%, RS, R6, and R20 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) - 20 ~N
RET 7X D
A. ND A
Ex
Y
9 °F 0 2
R® RE R.. R57 RE R.c
Dl ha D2 Ys
O Q, hy O Q 2 “Ts OL oy)
RS 0, R* RS LX, Rr
D3 D4
The compound of Example 24 has a structure that corresponds to that of Formula D2. In that compound, R5 and Ré are both methoxy, the A moiety is a sulfur atom, -S-, R is 1,4-phenylene, E is absent and the moiety Y is hydrido. The compound of Example 25 also corresponds in structure to Formula D2.
There, RS and R® are again both methoxy, the A moiety is an oxygen atom, -O-, 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.
ORS o =" ow 3 0] 0 o=$ ® o=
WI Thy
-62-~ % Pe ag fo) le) H \__N
CH,
Se 0” 7
HOHN
8 nH- CH
Cr 0 9
OH
HN
Cr NT)
OCH,
S— g X ‘Sl (o} 5 11
OH iN
Cr °
FH
OH
HN
Cr
V,
AO
13 CFs
OH
HN
(o] —~ )~CF
S—N 0
Oo 14
OH
HN"
Ce 0 oH lo fi'e) 15
CH;0 nH OH
CHO o iO
Oo 16
Q CFs (7) a |!
N
H
0)
S—N 0 Cr fo)
_OH
F NH
Ph
SN) o) 19 _OH cl NH
Cr
SoN_-e
Oo
CF, 20 _OH
HN
0
CC SRY
_ HCI
AN
O o 21
OH
Cre ar Ho 00 13C CF 0
Oo 3 0 [J lo} \ . 0 o=S ® ~ 0 4 : O°
O HN~ oO. 7) HN lo} [o} wee)
Cr
S—N ’ 0” g fo) 0)
HN” o N dT Oren
SN (o)
W\ °% 11 fo) o~_)
HN"
Cr °
Or (0 Js) 5 12 OCF,
o} ~_)
HN
Cr °
Oo 13 CF, [o}
HN
0} ~~ )—CFs
S—N oO
Oo 14 [o) wo)
O: ° . gn oo 15 : CH30 NH™
CH,0. 0 0)
Se
CF, 16 0] J CF, n°
H
0
S—N oo Cr (0) .
fo) ~~)
FE NA
Cr
SN )-o 0] 0
CF, 19 fo) o~_)
Cl NH
Cr
EAA o) er, 20 o O (0)
S—N
Vi 0% 21
OMe O
Heo Aron MeO
CrilD-0-0 "SN fo) fo} o\/ \_/ 22
Oo Oo od pa sa ol on oO 23
MeO O
CL
2-0 o© 24
~68-
MeO O
Ye OMe
PD — ee “0 \ / -
MeO O
Ra:
ZF ScN NL )-0Fs fo} oO \— 26
MeO O
Oe CF3 oo \ / a.
MeO O
RSA oO 28 0) ofa hi # ~s-N nN NH hinly 5 29 [9 0 : Oe ~ScN Y—0— oO 30 9 0 re oO 31 ca O
J” ~NHOH
S —— gag c 00 32
MeO O
Rea sa -o-O-omn oO 33
MeO O
Le MeO
LO o © 34
CHO 9
NHOH lo) s” TL 29% cH0 © Yo CFs 9 0 a o © 36
OMe O
Ye MeO,
Go \_4
OMe 37
OMe O
MeO AA hon F3C 0-0-0 50 N / \ / I.
OMe
MeO XX ~ NHOH MeO :
PD — 5-0 o 0 \ / ~— 39
OMe O eo Aon EtO
Ee: O--0-0
Ss \ 4 fe) o\/ 40
MeO O neo Awan /\ = ovr 7 o a1 fo)
Cre N 2 sof yo) go _/ \ 42
Rp
CN
Ls \— O(n-Bu) 0 0 43 9 Oo
Le
Z sen -otnnesty oO 44
OMe O "Oe toon o © 45
OMe O oe soo 00 46
OMe O
Nea:
Lele o 0 a7 1
O Oo olive
Ash 0 Y-cF so / \7/ 7° 48
/Q (0) ae NHOH
Ls Vo” oO Ne) \ / \ / J 0 49
MeO O wo AN NHOH
Ls ,—0 o o\__/ J
Oo 50 lo)
NHOH
SoN N 'e) Oo 51
MeO ©
MeO NHOH
SN N oO Orv 52
MeO O
MeO NHOH
S-N N oO 0\— ~~) OCF3 53
MeO O ea
SSN ~~ )-omeu o © 54 wo “0 NHOH
Lao v fe} /,
Oo 55
MeO O
Ne o 0 56
MeO O
MeO AA NHOH OMe 6 o\/ 57
The word "hydrocarbyl" is used herein as a 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; i.e., C1-C4 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, 1,4- pentadienyl, 1,4-butadienyl, 1l-butenyl, 2-butenyl, 3- butenyl, decenyl and the like. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl,
decynyl, 1l-butynyl, 2-butynyl, 3-butynyl, and the like.
Usual chemical suffix nomenclature is followed when using the word "hydrocarbyl" except
S 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(0)O- functionality 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 Cj; alkenyl group is not intended to be encompassed by the word "hydrocarbyl".
The term “carbonyl", alone or in combination, means a -C(=0)- 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; i.e., an ether group wherein the ether oxygen is replaced by a sulfur atom, as in a thiophenoxy group (CgHg-S-).
The term "amino", alone or in combination, means an amine or -NH2 group, whereas the term mono- substituted amino, alone or in combination, means a substituted amine -N(H) (substituent) group wherein one hydrogen atom is replaced with a substituent, and disubstituted 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 (I°), secondary (II°) or tertiary (III°) or unsubstituted, mono-substituted or di-substituted depending on the degree of substitution of the amino nitrogen. Quaternary amine (IV°) 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) 3-0~]; i.e., the charges are internally compensated.
The term "cyano", alone or in combination, means a -C-triple bond-N (-CN) group. The term "azido", alone or in combination, means an -N-double bond-N-double bond-N- (-N=N=N-).
The term "hydroxyl", alone or in combination, means a -OH group. The term "nitro", alone or in combination, means a -NO3 group.
The term "azo", alone or in combination, means a -N=N- group wherein the bonds at the terminal positions are independently substituted. The term "hydrazino”", alone or in combination, means a -NH-NH- group 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 -S(0)2- group wherein the remaining two bonds (valences) can be independently substituted. The term "sulfoxido", alone or in combination, means a -S5(=0)- group wherein the remaining two bonds (valences) can be independently substituted. The term "sulfonylamide", alone or in combination, means a -S(=0)32-N= group wherein the remaining three bonds (valences) are independently substituted. The term "sulfinamido", alone or in combination, means a -S(=0)]1N= group wherein the remaining three bonds (valences) are independently substituted. The term "sulfenamide", alone or in combination, means a -S-N= 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, tert- butoxy 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,
nitro and the like, such as phenyl, p-tolyl, 4- methoxyphenyl, 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, 2- phenylethyl and the like. The term "arylhydrocarbyloxycarbonyl", alone or in combination, means a radical of the formula -C(O)-0- 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 benz- fused monocyclic cyclohydrocarbylcarboxylic acid that is optionally substituted by, for example, a hydrocarbyloylamino group, such as 1,2,3,4-
tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4- tetrahydro-2-naphthoyl. The terms "arylhydrocarbyloyl" or "arylhydrocarbylcarbonyl" mean an acyl radical derived from an aryl-substituted hydrocarbylcarboxylic acid such as phenylacetyl, 3- phenylpropenyl (cinnamoyl), 4-phenylbutyryl, (2- naphthyl) acetyl, 4-chlorohydrocinnamoyl, 4- aminocinnamoyl, 4-methoxycinnamoyl and the like.
The 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, 2- naphthoyl, 6-carboxy-2 naphthoyl, 6- (benzyloxycarbonyl) -2-naphthoyl, 3-benzyloxy-2- naphthoyl, 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 (i.e., -NH-) by an hydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloyl, aryl or arylhydrocarbyl or on a tertiary nitrogen atom (i.e. =N-) by oxido and that is attached via a carbon atom.
The tertiary nitrogen atom with three substituents can also form a N-oxide [=N*(0)"-] group. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, and the like.
The heteroaryl portion of a heteroaroyl, heterocaryloxycarbonyl, or a heteroarylhydrocarbyloyl (heterocarylhydrocarbyl 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 6- membered ring or a fused ring system having two 6- membered 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 1,3,5-, 1,2,4- or 1,2,3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4- oxadiazolyl and isothiazolyl groups; 6-/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranilyl groups; and 6-/6-membered fused rings such as 1,2-, 1,4-, 2,3- and 2,1- benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl groups.
The term "cyclohydrocarbylhydrocarbyloxy- carbonyl" means an acyl group derived from a cyclohydrocarbylhydrocarbyloxycarboxylic acid of the formula cyclohydrocarbylhydrocarbyl-0-COOH wherein
S 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-0O-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 "heterocaryloxycarbonyl" 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 -
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, l-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluorocethyl 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, e.g., Rl, R2, 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 indicate 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.
Table 1 fo)
HO. : H
Oxg_
J R* ~ N,
R* | CH,
ORO oye 0
TT TTT ye
N= oJ) _N
Shad o JJ : S_Ph
Ll
NZ ZN
Jonaifo nad the
N o-M
Table 2 0] "on
Og
V/4 NTS ge 0]
J
CH,
R* ry I 0 cm 6 G
NZ H
+30 pty he i qr 0 ° ©
CH, cl
N 4 H qr o ° ©
Or ye
N x qr yo ° ©” iy O OCH, o)
H H
Ore othe oOo oh 0
CF, OCH; wD - x JT
Jol 0 ° ©
H CH,
Neo Ppuy in
N_ _N ~CH;, ory YT OY
Table 3 0
HO.
N
H (8) =s. / NH 4 le} R — : _R* CH, o.
CH H CH, H H
J ’ 1 JT Jona! ® 0 IC 0 CH,
CHa Suits HM CH
TT A oro 0 or 0 yo 0 o_~
OP TO or 0 JO 0
CH, Och; 4 un Sts
H H N__N
Fo} 0 o
CH, OCs
H H
IG I 1 LT H H
JON ICRA sa as
H fo} CHa
Seats!
NH, oy fo) 0 o-CHs
F H ot
DOUGH Oi Gi
N 0 of is - ISS \ No ASN ry I
ISR NN i FS) fo} cl
PY Jo 0
CHa ry 0
Table 4
O
HO. © N : 0; n g V7 (J > > I x ov B re }
OCH,
C) OCH, O._ _CHy
TI. 9 3 or or
Table 5
O vo, LL
H o={ “CH, _R* 00 OD oo RD ooge G- Oy otc oC
Cry. orn Sok oD OD § o CH, g J Ty ol or JOR “
Or 0
JORIS SA®
OO go, ot fonciPoaviions fonsaioasiBens fonsWeasiPonca jenoalioncsiPeae
Table 7 0
HO. :
H Oo =S. _N—N
R4 HaC o “CH
CH H 3 H H
LT 3 1 ST Joh ae! o} Je o © CH,
CH; OCH, H H oy 1 © > ’ 4 o._ ~~ on EO or 0 Jo 0 y CHa, Och, PR
H N N__N
Joi Joi Joaas 0 lo] Y
CH, O CHa
H H
Jo Y oy 0 4° JO 0 Ul en
OY HK
N O CH, hil
NH, 0) CH 0 H oe
H F N NO, HN SO : N c lo) [o]
JO 0 1 JF N or
H fo} ) | wr ci i LL, 0 lo)
Table 8 0)
HO. © N : 0) a 0) rR?
R*
Och
CH H 3 H
OT AY To o) 0° 0 CH,
CH, 0_-CHa H H
WT NY oo o or lo} Jo °
NR o_~
OT 1 LY on OF T 1® uy 0 JO 0
TO
Jo 0 Jl ° pos °
CH, Oo CHs
H H
J 1 LF H H
SOA ERP CRAIC 408
H o! CH,
N CH, yo Ce JT oy 0 H © oe
N . o) jon 0 iQ
H hd Jol 0 = A oY
H
1 LL, °c )
Table 9
Oo
HO.
N
: 0) =
ZN
0 rR
R4 oO.
CH, H CH, H H
Sea Shad JOR AS! 0 © © CH,
CH, O._-CHsy i H c
OT A or oy of © o ° dH 0
Oe OTTO
JO 0 pos °
H CH O"cn H oH J
Jo Jo: Jeans o lo} o
CHa oO _~_-CHs
H H
TG JOT H H
JY ISRAE saa ol
H 0 CH,
R O CH, he
NH 0 CH ol H 0°? } F N NO, ENGNG
N c 0 a
JO o (SK N
H " he Jol 0 gy i Se la Jo °
-9]1-
Table 10
O
HO.
N
O=g
I
R?
Example R* Example R* 0 »
I HN n wa. =N 2 Ww) 12 av
H H N
3 SN-CHs 3 J
H HaC —N 4 TNTCH, 14 =) 0) * sy wo 0
CH, 15 HN CH, — 0 6 Ww 16 ON CH;
CH, H ~~ CH ~~) 7 N 7 AN
CH, — > 8 SNTTCH, 8 ~N C
CH, _ H 9 wat. 19 wats
WN 20 NN 4 ) CH,
H H
Table 11 0 "On
O=g
J ON
O
R4
Example X Ar Example X Ar /=N /~=N 1 0 — 9 S —~ )N B
N° N° 2 © /~N /=N — NN 0S — NA 3 1 = o {NJ 1s CN)
Co OND rs XO) 5s O —~ A N-CH; 13 S — N—CH, __/ ___/ /\ /\ 6 O —~ N-Ph 14 S — A N-Ph ro Om ss Om es SEs
Table 12
O
HO.
N
H
Ox
S< oN
AN
R
Jonsson Jonas
GT ops 23
OTT
_N yO o JJ ond
ZN jonales x Jonas
N? ZN
Jonas anil sae _N oH
Table 13
Oo
HOS
H
Ox
IN
NGL
~R*
H H
N or 5 O CH o a
NZ H H
1A ry g Ee ol ° ° ©
CHj Cl
N EN
OY AITT O o
N SN or 0 Cf or O OCH,
[0] .
Ho ] H
N
0 oy Jol nL, 0
JON :
CFs OCH;
H H wD ory 8 i LF
Jol ° ° ° i A os
N OD y er fopapeg
Table 14
HO
~N
H
Og ~ 70)
ON
_R o.
CH
CH, H a H H
H JS H AT or N
LG
JO Y AT © © CHy
O.__CH
CHa H ~~ N__N CHa ~H oY OTTO o} ° ik oO
Te a OTTO
H N
N or lo} oy o
CH, Oem, Hon fe
TO ry lo} 0 lo] Jl 0
JT TT
H N H H ro fy
No H y i LL O CH, he oy hs © o th 0 Ho ]
H F N NO, HN SO
N 0 ofr ME
N x N nO, or
N F 0 N o) ” or cl
N o)
CH, lo}
Table 15
HO
IY
H
~ 770
NGL
~N rR
LQ v ® or
I — ~ or ~
OCH,
C] OCH; ony os ® CHa ) 3 ot oot
Table 16 (0)
HOS 1
H ~L
N
208 _R* 00D Ow ooo oY ogg Uy
JORGEN CRS
Co on L-
Joa sIP ORV IIR
OCD or
HN Table 17
HO
0) SL 0) Ar
Example X Ar Example X Ar
Te nO 2 © —_)—c 13 8 —_)-c
Cl cl 30 5 14 S ne
Cl Cl 4 0 {Sa 15 S (Sa
CH3 CH3 6 O 5 17 S oe!
CH CH, —N =N 8 © —) 19 S —) 0 © — ans — )-F /~=N /~N 11 Oo NS 22 S — ND
HN Table 18
HO
O Og
SL x AT
Example X Example X
H
~~ CH Nome oO : x > goon
NH ch, (0)
NJ 0 o I 11 —~ ro 4 N —N
Or “Aon 0] —N CH;
NCH, 0] 6
Fs 7 —N
CF, 0]
HN
HO™ ve Table 19
O O=s 20
Ar
Example X Example X =N ! HN— @ In Wat, =N : 2 a 12 a
H H —N 3 SCH 0" “N ~)
H HaC —N 4 CNTYTeH 14 =) oO
Cy Ee
CH, 15 ~~ p 0] 6 “N 16 ON { ) \
CH, H 7 SNCF 17 Wats
CHa — )—Cl 8 SN CH, 5 SN
CH, _ H 9 SN 19 waa 10 EN 20 NN < )—CHy
H H
Table 20
HN
HO
Oo O-s 20W"
Example X Example X
CH;
Sw
CH, 2 —N 10 \ —N NH
CHj ——/
Go I
OH 11 —N N 4 NOt /\
Te AN) oO _/ —N NH © 2 / \ _/ 6 —N CF,
NH» /\ 0) 14 —N NF 0)
Nd ® ~— 8 —N 0) 16 —N O) n_/ \__/
HN
O Os
SCL x Ar
Example X Ar Example X Ar /=N /=N 1 oO —~ 9 s—_)N
B » /=N /~N
A) 2 © — NON 10 s—_ NN
Co OM0 n On0 4 © —~ ) 12 3 ~~ \ /\ /\ 0 — N-CHs 13S — _ 3 N N-CH,
N N—-Ph _ 6 (0) —~ ) 14 s—_)-N N—-Ph so SOs Om co OO we sO

Claims (108)

WHAT IS CLAIM IS:
1. 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 C: R20 gl R® R® C 5 W is phenyl or 5- or 6-membered heteroaryl; 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 SO-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO;-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; as to R’ and R®: R® and R°® are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R°R‘aminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RPR‘aminoalkyloxy, or R® 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? is selected from the group consisting of -O-R?!, -NR'3-0-R??, -NR'*-0-R", and _NR®R?*: AMENDED SHEET 24.01.2003
R?' is selected from the group consisting of hydrido, C,-Ce-alkyl, aryl, and aryl-C,-Cg¢-alkyl;
R?isa selectively removable protecting group;
R"3 is selected from the group consisting of hydrido, C,-C¢-alkyl, and benzyl,
R'is selected from the group consisting of hydrido and C(V)R';
V is selected from the group consisting of O and S;
R'is selected from the group consisting of C,-Ce-alkyl, aryl, C,-Cs-alkoxy, heteroaryl-C,-C¢-alkyl, C3-Cg-cycloalkyl-C,-Cs-alkyl, aryloxy, aryl-C,-Cs-alkoxy, aryl-C,-Ce-alkyl, heteroaryl, and amino C;-Ce-alkyl, wherein the amino C,-Ce-alkyl nitrogen is optionally substituted with:
up to two substituents independently selected from the group consisting of C,-Ce-alkyl, aryl, aryl-C,-Ce-alkyl, C3-Cs-cycloalkyl-C-Cg-alkyl, aryl-C,-C¢-alkoxycarbonyl, C,-Cs-alkoxycarbonyl, and C,-Ce-alkanoyl, or two substituents such that the amino C,-Cs-alkyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl;
as to R* and R*:
R* and R* are independently selected from the group consisting of hydrido,
C,-C¢-alkyl, amino C,-Cs-alkyl, hydroxy C,-Ce-alkyl, aryl, and aryl-C,-C¢-alkyl, or
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;
each R® or R® 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:
AMENDED SHEET 24.01.2003 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 RY substituents, or a heteroaryl optionally substituted with up to three independently selected Rf substituents; each RY or R® 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 R%R°amino; and the compound is other than: i AP
HO. gas OL H 0 0 0 “Se, HO J} N N N H it 0 0 0
HO. | Ye N H or 0 ZN Ase “No "N NT ON Sve
Oo .
2. 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; AMENDED SHEET 24.01.2003 the compound corresponds in structure to Formula C: R20 Ng! R3 RC C >
W is phenyl or 5- or 6-membered heteroaryl;
as to R® and R®:
R® and R® are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R’R°aminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and R°R‘aminoalkyloxy, or
R® 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% is selected from the group consisting of -O-R?', -NR"-0-R%, -NR'*-0-R"*, and .NR®R?,
R?! is selected from the group consisting of hydrido, C,-Ce-alkyl, aryl, and aryl-C;-C¢-alkyl;
R*? is a selectively removable protecting group;
R" is selected from the group consisting of hydrido.
C,-Ce-alkyl, and benzyl,
R' is selected from the group consisting of hydrido and C(V)R";
V is selected from the group consisting of O and S;
R'is selected from the group consisting of C,-Cq-alkyl, aryl, C,-Cs-alkoxy, heteroaryl-C,-Ce-alkyl, C3-Cs-cycloalkyl-C,-Ce-alkyl, aryloxy, aryl-C,-C¢-alkoxy, aryl-C,-Ce-alkyl, heteroaryl, and amino C,-C¢-alkyl, wherein the amino C,-Ce-alkyl nitrogen is optionally substituted with:
up to two substituents independently selected from the group consisting of C,-Ce-alkyl, aryl, aryl-C,-Cs-alkyl.
C3-Cg-cycloalkyl-C,-Ce-alkyl, aryl-C,-Ce-alkoxycarbonyl, C,-Ce-alkoxycarbonyl, and C,-Ce-alkanoyl, or two substituents such that the amino C;-Cg-alkyl nitrogen, together with the two substituents. form a 5- to 8-membered heterocyclo or heteroaryl;
AMENDED SHEET 24.01.2003 as to R” and R*: R* and R?** are independently selected from the group consisting of hydrido, C;-Ce-alkyl, amino C,-Cs-alkyl, hydroxy C,-Ce-alkyl, aryl, and aryl-C,-C¢-alkyl, or 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'R®; as to R” and R®: R’ and R® are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted arythydrocarbyl, or R’ and R® are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R*oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclo, wherein each substitutable substituent is optionally substituted with -A-R-E-Y, or R’ and R®, 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: 1-0 (2) -S-, (3) -NR, (4) -CO-N(R¥)-. (5) -NRY-CO-. (6) -CO-0O-, (7 -0-CO-, (8) -0-CO-O-, 9) -HC=CH-, (10) -NH-CO-NH-, (1 -C=C-, (12) -N=N-, (13) -NH-NH-. (14) -CS-N(RY)-, AMENDED SHEET 24.01.2003
(15) -N(RY)-CS-, (16) -CHa-, (17) -O-CHa-, (18) -CH;-O-, (19) -S-CH,-, (20) -CH,-S-, 21) -SO-, (22) -S0O,-, and (23) abond;
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 heterocycloalky! 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,-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl;
E is selected from the group consisting of:
(1) -COR:, (2) -RE&CO-. (3) -CONRY, 4) -NRHCO-, S) -CO-, (6) -SO;RE-, (7) -R®SO»-, (8) -SO»-, 9) -N(RY-SOr, (10) -SO2-N(R%)-, and (11) abond; Y is selected from the group consisting of a hydrido. alkyl. alkoxy, haloalkyl, aryl, AMENDED SHEET 24.01.2003 arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, R%xyalkyl, 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 R” is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RPR‘aminoalkanoyl, haloalkanoyl, RR°aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy; each R® or R® 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 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 R? substituents, or a heteroaryl optionally substituted with up to three independently selected Rf substituents: each RY or R® is independently selected from the group consisting of hydrido, alkyl. alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl. alkoxycarbonyl, and AMENDED SHEET 24.01.2003 arylalkyloxycarbonyl; and each R'is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R*R°amino;
RE 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, R"R-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R"R'-aminocarbonyloxy, R"R'-aminocarbonyl, R"R'-aminoalkanoyl, hydroxyaminocarbony], R"R'-aminosulfonyl, R"R'-aminocarbonyl(R")amino, trifluoromethylsulfonyl(R")amino, heteroarylsulfonyl(R") amino, arylsulfonyl(R"amino, arylsulfonyl(R")aminocarbonyl, alkylsulfonyl(R")amino, arylcarbonyl(R™aminosulfonyl, and alkylsulfonyl(R™)aminocarbonyl;
R" 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
R’ substituents;
each R’ 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 aminoalkanoy! are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl. and alkyloxycarbonyl; AMENDED SHEET 24.01.2003 each R is independently selected from the group consisting of hydrido, alkyl, alkenyl. aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R°R%mino carbonyl, R°R%minosulfonyl, R°R%aminoalkanoyl, and R°R%aminoalkysulfonyl; and the compound is other than:
o 0. 0
HO. N N N Ra3OVS ON 0] 0 0 CH; -_- Lr N N H H o 0. 0 wo. 4 N N or lo] ZN HC 4 ™ je J ~o “N NT ON Sve
0 .
3. 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 C:
0 o. 0 \/ R% Ng! R® R® C W is phenyl or 5- or 6-membered heteroaryl; asto R": R' is a substituted 5- or 6-membered cyclohydrocarbyl, substituted 5- or AMENDED SHEET 24.01.2003
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 SO,-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO,-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;
R’ and R® are independently selected from the group consisting of hydrido, hydrocarbyl, hydroxyhydrocarbyl, hydroxy, amino, dihydrocarbylamino, heterocyclo, heterocyclohydrocarbyl, heterocyclooxy, and heterocyclothio;
R? is selected from the group consisting of -0-R*', -NR"*-0-R%, -NR">-0-R"*, and _NRZR¥:
R?! is selected from the group consisting of hydrido, C,-Ce-alkyl, aryl, and aryl-C,-Cg¢-alkyl;
R? is a selectively removable protecting group;
R" is selected from the group consisting of hydrido, C,-C¢-alkyl, and benzyl;
R'is selected from the group consisting of hydrido and C(V)R'?;
V is selected from the group consisting of O and S;
R" is selected from the group consisting of C,-Ce-alkyl. aryl, C,-Ce-alkoxy, heteroaryl-C,-Cg¢-alkyl, C3-Cg-cycloalkyl-C,-C¢-alkyl, aryloxy. aryl-C,-Cs-alkoxy, aryl-C,-Ce-alkyl, heteroaryl, and amino C,-C¢-alkyl, wherein the amino C,-C¢-alkyl nitrogen is optionally substituted with:
up to two substituents independently selected from the group consisting of
C,-Ce-alkyl, aryl, aryl-C-Ce-alkyl, C;-Cg-cycloalkyl-C;-Ce-alkyl,
aryl-C,-Cs-alkoxycarbonyl, C,-C¢-alkoxycarbonyl, and C,-Ce-alkanoyl, or two substituents such that the amino C,-Ce-alkyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl;
as to R? and R**:
R* and R* are independently selected from the group consisting of hydrido,
C,-Ce-alkyl, amino C,-Ce-alkyl, hydroxy C,-Ce-alkyl, aryl, and aryl-C,-C¢-alkyl, or
R* and R*, together with the nitrogen atom to which they are both bonded. form
AMENDED SHEET 24.01.2003 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® 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 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 RY substituents, or a heteroaryl optionally substituted with up to three independently selected R substituents; each RY or R® 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 R‘R*amino; and the compound is other than: HO I A 2a300e AMENDED SHEET 24.01.2003
0 0 0 Sen, HO J NY N N H H 0 0 0 N’ 7S H or 0 ZN NEN ~o °N N” ON Sve
0 .
4. The compound or salt according to claim 1, wherein W is selected from the group consisting of 1,2-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 4,5-pyridinylene, 2,3-pyrazinylene, 4,5-pyrimidinylene, and 5,6-pyrimidinylene.
S. The compound or salt according to claim 1, wherein R¥ is -NR"3-O0-R™.
6. The compound or salt according to claim 1, wherein R? is -NR'3-0-R%.
7. The compound or salt according to claim 1, wherein the compound corresponds in structure to Formula C1:
0 0. 0 4 \Y/ R™0__ Se N rR rR rR’ R® Cl AMENDED SHEET 24.01.2003
8. The compound or salt according to claim 1, wherein the compound corresponds in structure to Formula C2:
0 0. 0 R"“0__ ' \ 4 ) N PhR R® R® C2 : PhR* is phenyl substituted at its 4-position with R*; and R? has a chain length of 3 to about 14 carbon atoms.
9. The compound or salt according to claim 8, wherein R* is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arythydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio.
10. The compound or salt according to claim 8, wherein R* is selected from the group consisting of phenyl, phenoxy, thiophenoxy. anilino. phenylazo. phenylureido, benzamido. nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl. arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbyithioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, 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, AMENDED SHEET 24.01.2003 perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arythydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclo, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, 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, 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.
AMENDED SHEET 24.01.2003
11. The compound or salt according to claim 1, wherein: the compound corresponds in structure to Formula D3: YA R20 ARO! rR? A ee RE R* D3 : and R* has a chain length of 3 to about 14 carbon atoms.
12. The compound or salt according to claim 11, wherein R* is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio.
13. The compound or salt according to claim 11, wherein R* is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido. nicotinamido, isonicotinamido, picolinamido. heterocyclo. heterocyclohydrocarbyl. arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arythydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, 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. AMENDED SHEET 24.01.2003 aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arythydrocarbylthio, arylhydrocarbylamino, heterocyclo, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, 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. 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.
AMENDED SHEET 24.01.2003
14. The compound or salt according to claim 2, wherein the compound corresponds in structure to the following formula:
0 0. 0 " AS 2 3 A rR? N z \ 0 Sam VI-1; and X!, X2, x3, and X* are independently selected from the group consisting of a bond, carbon, nitrogen, sulfur, and oxygen so that the depicted ring has 5 or 6 ring members.
15. 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: 0 0 0 HO ' \ 4 : N R R® R® C4 W is phenyl or 5- or 6-membered heteroaryl; astoR": R'is a substituted 5- or 6-membered cyclohydrocarbyl, substituted S- 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 SO,-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO;-bonded 1-position and the center of 3,4-bond of a S-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; as to R® and R®: R’ and R® are independently selected from the group consisting of hydrido, alkyl, AMENDED SHEET 24.01.2003 cycloalkyl, acylalkyl, halo, nitro, hydroxy. cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R°Raminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RPR‘aminoalkyloxy, or R’ and RS, 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® or R® 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 RY 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 RY substituents, or a heteroaryl optionally substituted with up to three independently selected R' substituents; each RY or R® 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 R°Ramino; and the compound is other than: 0 0 0 HOS J§ NX LO) H AMENDED SHEET 24.01.2003
0 0 0 en, HO J he N N H H o 0,0 HO Ye a N’ a H or 0 ZN H3C p% ™ Je J No “ON NT ON Sve
0 .
16. The compound according to claim 15, wherein: the 5- or 6-membered cyclohydrocarbyl, 5- or 6-membered heterocyclo, phenyl, or 5- or 6-membered heteroaryl of R! is substituted with R*: and R* has a chain length of 3 to about 14 carbon atoms.
17. The compound or salt according to claim 16, wherein R” is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarby], heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio.
18. The compound or salt according to claim 16, wherein R* is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, AMENDED SHEET 24.01.2003 arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl. arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, 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, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclo, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, 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, AMENDED SHEET 24.01.2003 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.
19. The compound or salt according to claim 16, wherein R* is selected from the group consisting of single-ringed cyclohydrocarbyl, single-ringed heterocyclo, phenyl, single-ringed heteroaryl, C3-Cy4 hydrocarbyl, C,-C,4 hydrocarbyloxy, phenoxy, thiophenoxy, 4-thiopyridyl, phenylazo, phenylureido, nicotinamido, isonicotinamido, picolinamido, anilino, and benzamido.
20. The compound or salt according to claim 15, wherein: R'is PhR*; PhR* is phenyl substituted with R* at the 4-position; R* is selected from the group consisting of phenyl, phenoxy, thiophenoxy, phenylazo. benzamido, anilino, nicotinamido, isonicotinamido, picolinamido, and phenylureido, wherein: 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, C,-Co hydrocarbyloxy, C-C) hydrocarbyl, di- C,-Cq hydrocarbylamino, carboxyl C;-Cg hydrocarbyl, C,-C,4 hydrocarbyloxy carbonyl C,-C4 hydrocarbyl. C,-C4 hydrocarbyloxycarbonyl C,- C4 hydrocarbyl, and carboxamido C;-Cg hydrocarbyl, or at the meta- and para- positions by two methyl groups or by a methylenedioxy group.
21. The compound or salt according to claim 15, wherein R' has a length greater than the length of an octyl group and less than the length of a stearyl group. AMENDED SHEET 24.01.2003
22. 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 the following formula:
0 0. O R% SN a Ne CL R Y RS Sm RE A” SNe : X!, X%, X3, and X* are independently selected from the group consisting of a bond, carbon, nitrogen, sulfur, and oxygen so that the depicted ring has 5 or 6 ring members; as to R® and R®: R’ and R® are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RR‘aminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and R°R‘aminoalkyloxy, or R’ 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; A is selected from the group consisting of: (1 -0- (2) -S-, (3) -NRX- (4) -CO-NRY-, (5) -NRY-CO-, (6) -CO-0O-, (7) -0-CO-, (8) -0-CO-0O-, 9) -HC=CH-, (10) -NH-CO-NH-, (11) -C=C-, (12) -N=N-, (13) -NH-NH-, AMENDED SHEET 24.01.2003
(14) -CS-N(R)-, (15) -N(RH-CS-, (16) -CHy, (17) -O-CH;-, (18) -CHy-O-, (19) -S-CHj-, (20) -CHj-S-, 21) -SO-, (22) -SO,-, and (23) abond,
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, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C,-C;-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl;
E is selected from the group consisting of:
(1) -CORE&-,
(2) -RCO-,
(3) -CONRY-,
4) -NRHCO-,
(5) -CO-,
(6) -SO;RE-,
(7) -R*SO»-,
(8) -SOy-,
9) -NR"-SO-,
(10) -SO,-N(RY)-. and
(11) abond; AMENDED SHEET 24.01.2003
Y is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, R%xyalkyl, 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 R* is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, R’R aminoalkanoyl, haloalkanoyl, RPR°aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy:; each R® 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 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 RY substituents, or a heteroaryl optionally substituted with up to three independently selected R substituents; each R% or R® is independently selected from the group consisting of hydrido, alkyl, AMENDED SHEET 24.01.2003 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 R*R*amino;
R® 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, R"R'-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(R")amino, trifluoromethylsulfonyl(R")amino, heteroarylsulfonyl(R") amino, arylsulfonyl(R")amino, arylsulfonyl(R"aminocarbonyl, alkylsulfonyl(R")amino, arylcarbonyl(R")aminosulfonyl, and alkylsulfonyl(R")aminocarbonyl;
R" 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
R substituents;
each R’ 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, AMENDED SHEET 24.01.2003 arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl;
each R* is independently selected from the group consisting of hydrido, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R°R%amino carbonyl, R°R%minosulfonyl, R°R%minoalkanoyl, and R°R%minoalkysulfonyl;
R? is selected from the group consisting of -0-R?', -NR"-0-R%, -NR"*-0-R'*, and NRZR?:
R?! is selected from the group consisting of hydrido, C;-Ce-alkyl, aryl, and aryl-C,-Cg¢-alkyl;
R*? is a selectively removable protecting group;
R" is selected from the group consisting of hydrido, C,-Ce-alkyl, and benzyl;
R'* is selected from the group consisting of hydrido and C(V)R';
V is selected from the group consisting of O and S;
R'? is selected from the group consisting of C,-Ce-alkyl, aryl, C,-Ce-alkoxy, heteroaryl-C,-C¢-alkyl, C3-Cs-cycloalkyl-C,-Ce-alkyl, aryloxy, aryl-C,-Ce¢-alkoxy, aryl-C,-Ce-alkyl, heteroaryl, and amino C,-Cq-alkyl, wherein the amino C;-Cs-alkyl nitrogen is optionally substituted with:
up to two substituents independently selected from the group consisting of C,-Ce-alkyl, aryl, aryl-C,-C¢-alkyl, C3-Cg-cycloalkyl-C,-Ce-alkyl, aryl-C;-Cg-alkoxycarbonyl, C;-C¢-alkoxycarbonyl, and C,-C¢-alkanoyl, or two substituents such that the amino C,-Ce-alkyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl; and as to R* and R*:
R? and R* are independently selected from the group consisting of hydrido,
C,-Ce-alkyl, amino C,-Cg-alkyl, hydroxy C,-Ce-alkyl, aryl, and aryl-C,-Cg¢-alkyl, or
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; and the compound is other than:
O 0 0 H AMENDED SHEET 24.01.2003
23. 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 VIA:
YA RZ Sy ARE R6 VIA :
Wlisa heterocyclic ring containing 5 or 6 ring members (including the depicted nitrogen atom);
as to R*:
R* has a chain length of 3 to about 14 carbon atoms;
R* is bonded at the 4-position relative to the depicted nitrogen atom when Wis a 6-membered ring, and at the 3- or 4-position relative to the depicted nitrogen when W? is a S-membered ring; as to R® and R®:
R® and R® are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R°Raminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and R°Raminoalkyloxy, or
R> 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% is selected from the group consisting of -O-R?', -NR'3-0-R*?, -NR'*-0-R". and NRZPR®.
R?! is selected from the group consisting of hydrido, C,-Ce-alkyl. aryl, and aryl-C,-Ce-alkyl;
R? is a selectively removable protecting group;
R" is selected from the group consisting of hydrido, C,-Ce-alkyl, and benzyl;
R'is selected from the group consisting of hydrido and C(V)R'?;
V is selected from the group consisting of O and S;
R'is selected from the group consisting of C,-Ce-alkyl. aryl, C,-Ce-alkoxy. heteroaryl-C;-Cs-alkyl, C3-Cg-cycloalkyl-C,-Cg-alkyl, aryloxy, aryl-C,-Ce-alkoxy,
AMENDED SHEET 24.01.2003 aryl-C,-Ce-alkyl, heteroaryl, and amino C;-C¢-alkyl, wherein the amino C,;-C¢-alkyl nitrogen is optionally substituted with: up to two substituents independently selected from the group consisting of C,-Ce-alkyl, aryl, aryl-C,-C¢-alkyl, C3-Cg-cycloalkyl-C;-Ce-alkyl, aryl-C,-Ce-alkoxycarbonyl, C-Cs-alkoxycarbonyl, and C,-C¢-alkanoyl, or two substituents such that the amino C,-C¢-alkyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl; as to R* and R*: R* and R* are independently selected from the group consisting of hydrido, C,-Ce-alkyl, amino C,-C¢-alkyl, hydroxy C,-Cs-alkyl, aryl, and aryl-C,-C¢-alkyl, or 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; each R® or R® 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, heteroaryloxyaikyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, arylalkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, aryithioalkyl. 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 RY 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? substituents, or a heteroaryl optionally substituted with up to three independently selected R' substituents; each RY or R® is independently selected from the group consisting of hydrido, alkyl, AMENDED SHEET 24.01.2003 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 RYR¢amino; and the compound is other than: o 0 0 Hi or 7 fCsg I by pe J gages
0 .
24. The compound or salt according to claim 23, wherein R? is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl. arylhydrocarbylthiohydrocarbyi. arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio.
25. The compound or salt according to claim 23, wherein R® is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl. arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl. arylazoaryl. arylhydrazinoaryl, hydrocarbylthiohydrocarbyl. hydrocarbylthioaryl, arylthiohydrocarbyl. heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl. arylhydrocarbylthiohydrocarbyl, AMENDED SHEET 24.01.2003 arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, 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, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy; hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclo, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbyithio, 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. 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.
26. The compound or salt according to claim 23, wherein R* is -NR'"*-O-R'*. AMENDED SHEET 24.01.2003
27. The compound or salt according to claim 26, wherein Ris hydrido.
28. The compound or salt according to claim 23, wherein R* is -NR"}-0-R*2.
29. The compound or salt according to claim 28, wherein: R" is hydrido; and R? is selected from the group consisting of 2-tetrahydropyranyl, benzyl, p-methoxybenzyl, C,-Cs-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 C,-Ce-alkyl, aryl, and aryl-C,-C¢-alkyl.
30. The compound or salt according to claim 23, wherein the compound corresponds in structure to Formula VIA-1: 0 0, 0 \/ R% SN w2 R® od R® VIA-1
31. 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:
O 0. 0 \v4 AN RNY Hod w R Y RS Nee RE A” Ng” VIIC : as to R’ and R®: AMENDED SHEET 24.01.2003
R’ and R® are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R°R aminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RPR‘aminoalkyloxy, or R’ 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;
W? is a heterocyclic ring containing 5 or 6 ring members (including the depicted nitrogen atom);
-A-R-E-Y is bonded at the 4-position relative to the depicted nitrogen atom when W? is a 6-membered ring, and at the 3- or 4- position relative to the depicted nitrogen atom when W? is a 5S-membered ring;
A is selected from the group consisting of: 1-0 2 -S4 (3) -NR%, 4) -CO-NRY-, (5) -N(RM-CO-, (6) -CO-0O-, @)) -0-CO-, (8) -0-CO-O-, 9) -HC=CH-, (10) -NH-CO-NH-, (11) -C=C-, (12) -N=N- (13) -NH-NH-, (14) -CS-N(RY)-, (15) -N(RH-CS-, (16) -CH,-. (17) -O-CH,-, (18) -CH,-O-, (19) -S-CH,-, (20) -CH,-S-,
AMENDED SHEET 24.01.2003
(21) -SO-, (22) -SO;-, and (23) abond;
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, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C;-C,-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl;
E is selected from the group consisting of:
(1) -CORé&-, (2) -RECO-, (3) -CON(RY-, 4) -NRHCO-, 65) -CO-, (6) -SO;RE., (7) -R®SOy-, (8) -SO,-. 9) -N(RY-SOr, (10) -SO,-N(R¥)-, and (11) abond;
Y is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, R%xyalkyl, 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 AMENDED SHEET 24.01.2003 amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl,
R® is selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RPR°aminoalkanoyl, haloalkanoyl, RPR‘aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy;
each R® or R® 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 RY 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? substituents, or a heteroaryl optionally substituted with up to three independently selected Rf substituents;
each R% or R® 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 RYRamino;
R® 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,
AMENDED SHEET 24.01.2003 alkoxyheteroaryl, R"R'-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(R")amino, trifluoromethylsulfonyl(R")amino, heteroarylsulfonyl(R") amino, arylsulfonyl(R"amino, arylsulfonyl(R")aminocarbonyl, alkylsulfonyl(R")amino, arylcarbonyl(R")aminosulfonyl, and alkylsulfonyl(R")aminocarbonyl;
R" 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
RI substituents;
each R! 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 R¥ is independently selected from the group consisting of hydrido, alkyl, alkenyl. aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R‘R%amino carbonyl, R°R%aminosulfonyl, R°R%aminoalkanoyl, and R°R%aminoalkysulfonyl; and the compound is other than:
AMENDED SHEET 24.01.2003
0 UY
HO. XL N N COL or 0] ZY HC ~0 N ™ N LL] owe
0 .
32. 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 VIIB:
0 0. 0 \¥ : HO S.A EN N G R Y He RZ N—"R® VIB : as to R’ and R®: R® and R® are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RPR‘aminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RPR‘aminoalkyloxy, or R’ 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; G 1s N-heterocyclo; A is selected from the group consisting of: (1) -O-, 2) -S-, (3) -NR%, 4) -CO-NRY-, (5) -NRY-CO-, AMENDED SHEET 24.01.2003
(6) -CO-O-, @)) -0-CO-, (8) -0-CO-0O-, ) -HC=CH-, (10) -NH-CO-NH-, (11) -C=C-, (12) -N=N-, (13) -NH-NH-, (14) -CS-N(RY-, (15) -N(R%-CS-, (16) -CH-, (17) -O-CHy-, (18) -CH,-O-, (19) -S-CHa-, (20) -CH,-S-, 21) -SO-, (22) -SO;-, and (23) abond;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl. arylthioalkyl, heteroaryithioalkyl, 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;-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl;
E is selected from the group consisting of:
(1) -CORE&-, (2) -RECO-, (3) -CONRY):-, AMENDED SHEET 24.01.2003
4) -N(R"CO-, 6) -CO-, (6) -SO3RE-, (7) -R®SO., (8) -SO.-, (9) -N(RY-SO-, (10) -SO,-N(R")-, and (11) abond;
Y is selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, R%xyalkyl, perfluoroalkoxy, perfluoroalkylthio, triftuoromethylalkyl, 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;
R® is selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, R°R°aminoalkanoyl, haloalkanoyl, R°R‘aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy;
each R® or R® 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:
AMENDED SHEET 24.01.2003 up to two independently selected non-hydrido RY 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® substituents, or a heteroaryl optionally substituted with up to three independently selected Rf substituents;
each RY or R® is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl;
each R'is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R‘R°amino;
RE 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, R"R'-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(R")amino, trifluoromethylsulfonyl(R"amino, heteroarylsulfonyl(R") amino. arylsulfonyl(R")amino, arylsulfonyl(R")aminocarbonyl, alkylsulfonyl(R™)amino. arylcarbonyl(R")aminosulfonyl, and alkylsulfonyl(R™aminocarbonyl;
R" 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 group 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:
AMENDED SHEET 24.01.2003 any such substituent is optionally substituted by up to two independently selected R) substituents; each R! 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 R* is independently selected from the group consisting of hydrido, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R°R%amino carbonyl, R°R%aminosulfonyl, R°R%aminoalkanoyl, and R°R%aminoalkysulfonyl; and the compound is other than: i AF HO X N N Ra30ve or 0 ZN H;C 4 ™ eg J So ON NT ON Sue
0 .
33. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: oN UH Cr §—N Ho AMENDED SHEET 24.01.2003
34. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: O 0,0 AA OCH; HO S< H N N N H
0 .
35. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OH HN" Cr S—N 0 ol - 0 OCF;
36. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OH HN Cre S—N 0 ol 5 0 CF3
37. The compound or salt according to claim 32. wherein the compound corresponds in structure to the following formula: OH HN 0 CF; S—N 0 J 95
0 . AMENDED SHEET 24.01.2003
38. The compound or salt according to claim 2, wherein the compound corresponds in structure to the following formula: 0) O 0, O HO N H H
39. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH OH 3 uNT CH3 0 S—N CF; dl ( { ) oO 0
40. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: O AL
HO. SL H Bs TL CF;
41. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: _OH F HN S—N O 4 95 CF; . AMENDED SHEET 24.01.2003
42. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: _OH Cl HN oC S—N ef “ny CFy
43. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OH HN o 0) N CC ye S—N of
44. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OH or S—-N O, S| 9s 0 O CFy
45. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH; O NO OCH; NHOH dN AMENDED SHEET 24.01.2003
46. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: y CH, ™ 0 0 (ye (OIG) .
47. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH3 Noe NHOH 0 0 .
48. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH3 CH 0 0 .
49. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH; CH30 NHOH AN — 0 0 / i AMENDED SHEET 24.01.2003
50. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH; CH30 - ro CFs S—N 0 na J YN
51. A compound or pharmaceutically acceptable salt thereof, wherein the compound corresponds in structure to the following formula:
[0] NHOH Py { NH J Y, 3
52. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: To 0 NHOH so oe do i
53. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: To 0 0 100 S—N 0— )—CFs 0 0 . AMENDED SHEET 24.01.2003
54. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: Cl Q ~ NHOH S Pr a oy,
55. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH3 CH;0 NHOH S—N 0 OCF; IN 4 )
56. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH3 ee CH50 NHOH IN
57. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: CH;0 o NHOH +O (0- AN CF; CHy0 0 0 AMENDED SHEET 24.01.2003
58. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: /—Q 0 0} NHOH S—N 0— )—CF 0 0
59. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH; O "OC CH3Q NHOH Oo 0 OCH;
60. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH; O CH30 Fs NHOH S—N 0 IN 5 () CC) 0 0 .
61. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH; O CH Nr CH; NHOH AY a () ®, 0 0 CH; H;C } AMENDED SHEET 24.01.2003
62. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH3 O CH; Schl Roly: 1) CH; S—N 0 J 0 }
63. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH3 O CHj NHOH /N\ SN N— OCHs 0 0 \__/ .
64. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: O NHOH N= SOS #N\ FAN \_/
65. The compound or salt according to claim 32. wherein the compound corresponds in structure to the following formula: /—Q 0 0 NHOH so moan, ZA 0 0 . AMENDED SHEET 24.01.2003
66. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: JQ 0 O NHOH ’ )- FAV aL S—N 0 AY 0 0
67. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH; O Cll; NHOH 0 0
68. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH; O CH;0 NHOH IN
69. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH; 0 CH; NHOH IN, AMENDED SHEET 24.01.2003
70. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: QL oO 0 CY IN 0 0
71. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: JQ 0 0 NHOH OC AN EAN J oO .
72. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: CH; NHOH so 0 5 Va do P
0”.
73. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: 0 0 HOHN "SN ™ (nw
0 . AMENDED SHEET 24.01.2003
74. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: 0 0 NE CH;0O CH3
75. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: 0 04 he S< OCF HOHN NT ’ NR CH30 OCH;
76. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH3 8 NHOH A 0 0 .
77. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH3 (y CH NHOH IN A \_/ AMENDED SHEET 24.01.2003
78. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: OCH; CH30 . } Le CH3 Oo ZN 00
79. The compound or salt according to claim 32, wherein the compound corresponds in structure to the following formula: CH3 ( CH oy OCH3 0 O .
80. 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 VIIE:
0 0.0 o WY SN NG-A-R-E-Y 0 Hs AN R® A= VIE . as to R® and R®: R’ and R® are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RPRCaminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl. haloalkyl, heterocyclooxy. and R’R‘aminoalkyloxy. or R* and RS, together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5S to 7 ring members; G is N-heterocyclo; A is selected from the group consisting of: AMENDED SHEET 24.01.2003
1 -O-, 2 -S, 3) -NR, (4) -CO-NRY-, (5) -N(R"-CO-, (6) -CO-0O-, 7 -0-CO-, (8) -0-CO-0O-, ¢)) -HC=CH-, (10) -NH-CO-NH-, (11) -C=C-, (12) -N=N-, (13) -NH-NH-, (14) -CS-NRY-, (15) -N(RY-CS-, (16) -CHy-, (17) -O-CH,-, (18) -CH,-O-, (19) -S-CH,-, (20) -CH,-S-, (21) -SO-, (22) -SO;-, and (23) abond;
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, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy.
C,-C;-alkylenedioxy. hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro. hydroxy. hydroxyalkyl, alkanoylamino, and AMENDED SHEET 24.01.2003 alkoxycarbonyl;
E is selected from the group consisting of:
(1) -CORE&-,
(2) -RECO-,
(3) -CON(RY-, 4) -NR"CO-, 5) -CO-
(6) -SORE,
(7) -R®SOy,
8) -SO,-,
(9) -N(R%-SO,-, (10) -SO;-N(RY)-, and (11) abond;
Y is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, R%xyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein:
the aryl, heteroaryl, arylalkyl, or heterocycloalky! 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 R* is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, R°R‘aminoalkanoyl, haloalkanoyl, RPR°aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy;
each R® 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, AMENDED SHEET 24.01.2003 aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkyithioalkyl, 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 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 R? substituents, or a heteroaryl optionally substituted with up to three independently selected R" substituents;
each R% or R® 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 RYR¢amino:
RE 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, R"R'-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbony]. arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R'R'-aminocarbonyloxy, R"R'-aminocarbonyl, R"R'-aminoalkanoyl, hydroxyaminocarbonyl, R"R'-aminosulfonyl, R"R'-aminocarbonyl(R"amino, trifluoromethylsulfonyl(R")amino, heteroarylsulfonyl(R") amino, arylsulfonyl(R"amino, arylsulfonyl(R")aminocarbonyl, alkylsulfonyl(R"amino, arylcarbonyl(R")aminosulfonyl, and alkylsulfonyl(R"yaminocarbonyl:
R" 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 AMENDED SHEET 24.01.2003
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
R} substituents;
each R’ 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 R¥ is independently selected from the group consisting of hydrido, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R°R%mino carbonyl, R°R%minosulfonyl, R°R‘aminoalkanoyl, and R°R%aminoalkysulfonyl; and the compound is other than:
Oo % pe HOS J{ JS.
OL 0) H or " 0 9, 4 |S Ji gejevey 0 AMENDED SHEET 24.01.2003
81. The compound or salt according to claim 80, wherein the compound corresponds in structure to the following formula: 0 [o) oy 4 0) OL S N
82. The compound or salt according to claim 80, wherein the compound corresponds in structure to the following formula: O HN Sa AY FAS
83. The compound or salt according to claim 80, wherein the compound corresponds in structure to the following formula: O 0 0 OCH \ / 3
0. _O, NT H N N N SRPal Ps 0
84. The compound or salt according to claim 80, wherein the compound corresponds in structure to the following formula: 0 _0 6 0 0 OCF; AMENDED SHEET 24.01.2003
85. The compound or salt according to claim 80, wherein the compound corresponds in structure to the following formula: 0 0] Cr (OI 6) CF3
86. The compound or salt according to claim 80, wherein the compound corresponds in structure to the following formula: 0 a, oO Os ~~) S—N 0) AN 0 0 }
87. The compound or salt according to claim 80, wherein the compound corresponds in structure to the following formula: oO AY O_ _O. So N N
88. The compound or salt according to claim 80, wherein the compound corresponds in structure to the following formula: 0 CIO yy 0X) CH 3 0
00 . AMENDED SHEET 24.01.2003
89. The compound or salt according to claim 80, wherein the compound corresponds in structure to the following formula: o 0 0 10] (6) \ 0 ~N * N H CF;
90. The compound or salt according to claim 80, wherein the compound corresponds in structure to the following formula: 0 F HN 0X) CC A ON CF3
91. The compound or salt according to claim 80, wherein the compound corresponds in structure to the following formula: 0 Cl HN 0~_) oC CFy
92. The compound or salt according to claim 80, wherein the compound corresponds in structure to the following formula: 0 _0 0 0 N CC yr RN 0 0 : AMENDED SHEET 24.01.2003
93. A use of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to prepare a pharmaceutical composition for treating a mammal having a condition associated with pathological matrix metalloprotease activity, 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 C: R20 TNR! R® R® C W is phenyl or 5- or 6-membered heteroaryl; astoR":
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 SO,-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO,-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; as to R® and R®:
R’ and R® are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy,
hydroxyalkyl, R°Raminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RPR‘aminoalkyloxy, or
R® 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? is selected from the group consisting of -O-R?', -NR'}.0-R??, -NR"3-0-R", and _NRZR: AMENDED SHEET 24.01.2003
R?! is selected from the group consisting of hydrido, C,-Cg-alkyl, aryl, and aryl-C;-Ce-alkyl;
R* isa selectively removable protecting group;
R"} is selected from the group consisting of hydrido, C,-C¢-alkyl, and benzyl;
R" is selected from the group consisting of hydrido and C(V)R';
V is selected from the group consisting of O and S;
R" is selected from the group consisting of C;-Cg-alkyl. aryl, C,-C¢-alkoxy, heteroaryl-C,-Ce-alkyl, C3-Cs-cycloalkyl-C,-Ce-alkyl, aryloxy, aryl-C,-C¢-alkoxy, aryl-C,-C¢-alkyl, heteroaryl, and amino C,-Ce-alkyl, wherein the amino C,-C¢-alkyl nitrogen is optionally substituted with:
up to two substituents independently selected from the group consisting of C,-Ces-alkyl, aryl, aryl-C,-C¢-alkyl, C3-Cg-cycloalkyl-C,-C¢-alkyl, aryl-C,-C¢-alkoxycarbonyl, C,-Cg-alkoxycarbonyl, and C,-C¢-alkanoyl, or two substituents such that the amino C,-C¢-alkyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl;
as to R* and R**:
R* and R* are independently selected from the group consisting of hydrido,
C,-Ce-alkyl, amino C,-Ce-alkyl, hydroxy C;-Ces-alkyl, aryl, and aryl-C,-Cg¢-alkyl, or
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;
each R® or R 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:
AMENDED SHEET 24.01.2003 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 R? substituents, or a heteroaryl optionally substituted with up to three independently selected R' substituents; each RY or R® 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 R‘Ramino; and the compound is other than: o 0 0 \Y/4 HO S.
N N ) 0 00 “Sew, HO JI{ NW N N H H Q 0 0 od or N H or 0 ZN "Co N, ™ N Li Sve 0 AMENDED SHEET 24.01.2003
94. A use of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to prepare a pharmaceutical composition for treating a mammal having a condition associated with pathological matrix metalloprotease activity, 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 C:
R20 Ng! R3 R® C s
W is phenyl or 5- or 6-membered heteroaryl;
as to R® and R®:
R® and R® are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RPR‘aminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RPR‘aminoalkyloxy, or
R’ 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? is selected from the group consisting of -O-R?', -NR"*-0-R*, -NR"*-0-R"*, and _NR®R?:
R?! is selected from the group consisting of hydrido, C,-Ce-alkyl, aryl, and aryl-C,-C¢-alkyl;
R*? is a selectively removable protecting group;
R"? is selected from the group consisting of hydrido.
C,-Ce-alkyl. and benzyl;
R'is selected from the group consisting of hydrido and C(V)R'?;
V is selected from the group consisting of O and S:
R'’ is selected from the group consisting of C;-Ce-alkyl, aryl, C,-Ce-alkoxy. heteroaryl-C,-Ce-alkyl, C3-Cs-cycloalkyl-C,-Ce-alkyl, aryloxy, aryl-C-Cs-alkoxy, aryl-C,-Ce-alkyl, heteroaryl, and amino C,-Cs-alkyl. wherein the amino C,-Ce-alkyl nitrogen is optionally substituted with:
AMENDED SHEET 24.01.2003 up to two substituents independently selected from the group consisting of C,-Ce-alkyl, aryl, aryl-C,-Ce-alkyl, C3-Cg-cycloalkyl-C,-C¢-alkyl, aryl-C,-Cg-alkoxycarbonyl, C,-Cs-alkoxycarbonyl, and C,-Cs-alkanoyl, or two substituents such that the amino C;-C¢-alkyl nitrogen, together with the two substituents, form a 5- to 8-membered heterocyclo or heteroaryl; as to R* and R**: R* and R* are independently selected from the group consisting of hydrido, C,-C¢-alkyl, amino C;-Cs-alkyl, hydroxy C,-Cs-alkyl, aryl, and aryl-C,-Cs-alkyl, or 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'R%; as to R” and R®: R’ and R® are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted arylhydrocarbyl, or R’ and R® are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R°0xyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclo, wherein each substitutable substituent is optionally substituted with -A-R-E-Y, or R’ and R®, 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: ( 0 (2) -S-, (3) -NR*., (4) -CO-N(RY-, (5) -NRY-CO-, (6) -CO-0O-, N -0-CO-, (8) -0-CO-0-, 9) -HC=CH-, AMENDED SHEET 24.01.2003
(10) -NH-CO-NH-, (1 -C=C-, (12) -N=N-, (13) -NH-NH-, (14) -CS-N(RY)-, (15) -N(R5-CS-, (16) -CH»-, (17) -O-CHa-, (18) -CH,-O-, (19) -S-CH,-, (20) -CH;-S-, 21) -SO-, (22) -SO;-,and (23) abond,
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, trifluoromethylalkyl, amino, alkoxycarbonylalkyl. alkoxy, C,-C,-alkylenedioxy. hydroxycarbonylalkyl. hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl;
E is selected from the group consisting of:
(1) -COR®-,
(2) -R:CO-,
(3) -CON(RY)-, 4) -NRHCO-, (5) -CO-,
(6) -SO;RE-
(7) -RESOy-,
AMENDED SHEET 24.01.2003
(8) -SOo-, (9) -N(R")-SOr-, (10) -SO;-N(RY)-, and (11) abond;
Y is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, R%xyalkyl, 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 R? is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, R°R°aminoalkanoyl, haloalkanoyl, RPR°aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy;
each R® or R® 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 R? substituents, or two substituents such that the substituents, together with the amino nitrogen, form: a saturated or partially unsaturated heterocyclo optionally substituted with AMENDED SHEET 24.01.2003
: up to three independently selected non-hydrido RY substituents, or a heteroaryl optionally substituted with up to three independently selected Rf substituents;
each R? or R® is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl; and each R'is independently selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and RYR°amino;
R8 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, R"R'-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(R")amino, trifluoromethylsulfonyl(R")amino, heteroarylsulfonyl(R") amino, arylsulfonyl(R™amino, arylsulfonyl(R")aminocarbonyl, alkylsulfony!(R")amino, arylcarbonyl(R"aminosulfonyl, and alkylsulfonyl(R")aminocarbonyl;
R" 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
RJ 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
R’ substituents;
each R is independently selected from the group consisting of arylalkyl, aryl. heteroaryl. heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, aminoalkyl, alkyloxycarbonyl,
AMENDED SHEET 24.01.2003 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 R* is independently selected from the group consisting of hydrido, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R°R%mino carbonyl, R°R%aminosulfonyl, R°R“aminoalkanoyl, and R°R®aminoalkysulfonyl; and the compound is other than: 0 0 0
HO. NY N N COL 0 0 0 O~en, HO J 4 N N H H 7 A pa
HO. J{ x N N H C0) or 0 ZN HC, N ~ N x J N ye 0 )
95. The use according to claim 93, wherein the compound corresponds in structure to Formula C1:
0 0. 0 / R"“0__ b 4 N R' R!3 R® R® Cl AMENDED SHEET 24.01.2003
96. The use according to claim 93, wherein the compound corresponds in structure to Formula C2: O R'0__ V \ N PhR R® RC C2 : PhR* is phenyl substituted at its 4-position with R*; and R* has a chain length of 3 to about 14 carbon atoms.
97. The use according to claim 96, wherein R* is selected from the group consisting of phenyl, phenoxy, thiophenoxy. anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylthydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio.
98. The use according to claim 96, wherein R* is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, 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. AMENDED SHEET 24.01.2003 perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl. aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino. heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclo, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, 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 aminohydrocarby! 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 S- to 8-membered heterocyclo or heteroaryl.
AMENDED SHEET 24.01.2003
99. The use according to claim 93, wherein the compound corresponds in structure to Formula D4: HO I 4 E2ANO! RS —=/"R¢ R* D4 : and R? has a chain length of 3 to about 14 carbon atoms.
100. The use according to claim 99, wherein R* is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio.
101. The use according to claim 99, wherein R* is selected from the group consisting of phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylithiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, 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, AMENDED SHEET 24.01.2003
Co heteroarylamino. heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclo, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, 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, 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.
102. The use according to claim 93. wherein R' has a length greater than the length of an octyl group and less than the length of a stearyl group.
103. A use of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to prepare a pharmaceutical composition for treating a mammal having a condition associated with pathological matrix metalloprotease activity. wherein: AMENDED SHEET 24.01.2003 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:
0 0 HO at _R’ Ho J \ \ 8 R® = VIB-2.
as to R’ and R®:
R’ and R° are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R°R‘aminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RR‘aminoalkyloxy, or
R and RS, 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” and R®:
R’ and R? are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R*oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclo, wherein each substitutable substituent is optionally substituted with -A-R-E-Y, or
R’ and R®, 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:
(1 0
2 -S
(3) -NRM,
4) -CO-NRY-,
(5) -N(RM-CO-,
(6) -CO-0O-, :
(7) -0-CO-,
(8) -0-CO-O-,
AMENDED SHEET 24.01.2003
9) -HC=CH-, (10) -NH-CO-NH-, 11 -C=C-, (12) -N=N-, (13) -NH-NH-, (14) -CS-NRY-, (15) -N(R"-CS-, (16) -CH,-, (17) -O-CH-, (18) -CH,-O-, (19) -S-CH-, (20) -CH»-S-, 21) -SO-, (22) -SO;-, and (23) abond;
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, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C;-C;-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl;
E is selected from the group consisting of:
(1) -CORE&-, (2) -R:CO-, (3) -CONRY)-, 4) -N(RMHCO-, 5) -CO-, (6) -SO;R%., AMENDED SHEET 24.01.2003
(7) -R®SO»-, (8) -SOy-, (9) -NR")-S0-, (10) -SO,-N(RY)-, and (11) abond,
Y is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, R%xyalkyl, 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 R” is independently selected from the group consisting of hydrido, alkyl, alkenyl. arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, R"Raminoalkanoyl, haloalkanoy], RPR°aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy;
each R® or R® 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 R substituents, or two substituents such that the substituents. together with the amino nitrogen.
form: AMENDED SHEET 24.01.2003 a saturated or partially unsaturated heterocyclo optionally substituted with up to three independently selected non-hydrido R? substituents, or a heteroaryl optionally substituted with up to three independently selected R substituents;
each R® or R® 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 R°R®amino;
RE 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, R"R'-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(R")amino, trifluoromethylsulfonyl(R")amino, heteroarylsulfonyl(R") amino, arylsulfonyl(R")amino, arylsulfonyl(R")aminocarbonyl, alkylsulfonyl(R™amino, arylcarbonyl(R"aminosulfonyl, and alkylsulfonyl(R™)aminocarbonyl;
R" 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 R’ substituents: each R! is independently selected from the group consisting of arylalkyl, aryl, heteroaryl, AMENDED SHEET 24.01.2003 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 alkyloxycarbony], each R¥ is independently selected from the group consisting of hydrido, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R°R%mino carbonyl, R°R%aminosulfonyl, R°R%minoalkanoyl, and R°R%aminoalkysulfonyl; and the compound is other than: 0 OP
HO. x zagele H 0 0 0 O~en, HO Je NY N N H H 0 CY
HO. Ji{ NX N N i C0) or 0 ZN HC 4 ™ ge J ~o “ON NT ON See 0 -
104. The use according to claim 103, wherein the compound corresponds in structure to Formula VIB-3: 0 0 oO A HO Sy _R’ H \ R RS R® VIB-3 AMENDED SHEET 24.01.2003
ST
105. The use according to claim 103, wherein the compound corresponds in structure to Formula VIII or VIII-B: 0 0,0 0 0,0 HO NA HO NY Yr ete or AERIS NS RSX lz RSX els VIII VIII-B .
106. The use according to claim 103, wherein -NR'R® has a length greater than the length of an octyl group and less than the length of a stearyl group.
107. The use according to claim 103, wherein -NR'R? is -G-A-R-E-Y.
108. A use of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to prepare a pharmaceutical composition for treating a mammal having a condition associated with pathological matrix metalloprotease activity, 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 VIIB: Oo HOSS ea ry Hf \ RX VIIB . as to R® and R®: R’ and R° are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxy. cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, RR aminoalkyl, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkyloxy. alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and RPR‘aminoalkyloxy, or R® 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; G is N-heterocyclo; AMENDED SHEET 24.01.2003
A is selected from the group consisting of:
a1 0,
2 -S,
(3) -NR%,
(4) -CO-N(RY-,
(5) -N(R¥-CO-,
(6) -CO-0O-,
(7) -0-CO-,
(8) -0-CO-O-,
9) -HC=CH-,
(10) -NH-CO-NH-,
11 -C=C-,
(12) -N=N-,
(13) -NH-NH-,
(14) -CS-N(RY)-,
(15) -N(R5-CS-,
(16) -CH,-,
(17) -O-CHa-,
(18) -CH;-O-,
(19) -S-CH,-,
(20) -CH»-S-,
21) -SO-.
(22) -SO;-,and
(23) abond;
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. trifluoromethylalkyl. amino, alkoxycarbonylalkyl, alkoxy, C,-C;-alkylenedioxy, hydroxycarbonylalkyl, AMENDED SHEET 24.01.2003 hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl;
E is selected from the group consisting of:
(1) -CORE&-,
(2) -R:CO-,
(3) -CON(RY)-. (4) -N(R4CO-, (5) -CO-,
(6) -SOzRE.,
(7) -R®SO,
(8) -SO»-,
(9) -N(R%-S0:-, (10) -SO,-N(R¥)-, and (11) abond;
Y is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, R%oxyalkyl, 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 R” is independently selected from the group consisting of hydrido, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl.
R°R°aminoalkanoyl, haloalkanoyl, RR‘aminoalkyl, alkoxyalkyl, haloalkyl, and arylalkyloxy:
each R® or R® 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, AMENDED SHEET 24.01.2003 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 RY 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 RY substituents, or a heteroaryl optionally substituted with up to three independently selected R substituents;
each RY or R® 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 R%Ramino;
RE 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, R"R'-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(R")amino. trifluoromethylsulfonyl( R"amino. heteroarylsulfonyl(R") amino, arylsulfonyl(R™amino, arylsulfonyl(R"aminocarbonyl, alkylsulfonyl(R")amino, arylcarbonyl(R")aminosulfonyl. and alkylsulfonyl(R™)aminocarbony!;
R" 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:
AMENDED SHEET 24.01.2003 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 alkanoy], and hydroxyalkyl, wherein:
any such substituent is optionally substituted by up to two independently selected
RJ substituents;
each R 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 alkanoy], 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 R* is independently selected from the group consisting of hydrido, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R°R%mino carbonyl, R°R%minosulfonyl, R°R%minoalkanoyl, and R°R%minoalkysulfonyl; and the compound is other than:
0 0 0 H or = so I NM pe J gages 0 } AMENDED SHEET 24.01.2003
ZA200109007A 1999-05-12 2001-10-31 Hydroxamic acid derivatives as matrix metalloprotease inhibitors. ZA200109007B (en)

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