ZA200109006B - Aromatic sulfone hydroxamic acid metalloprotease inhibitor. - Google Patents
Aromatic sulfone hydroxamic acid metalloprotease inhibitor. Download PDFInfo
- Publication number
- ZA200109006B ZA200109006B ZA200109006A ZA200109006A ZA200109006B ZA 200109006 B ZA200109006 B ZA 200109006B ZA 200109006 A ZA200109006 A ZA 200109006A ZA 200109006 A ZA200109006 A ZA 200109006A ZA 200109006 B ZA200109006 B ZA 200109006B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- group
- aryl
- alkoxy
- cycloalkyl
- Prior art date
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- 208000027531 mycobacterial infectious disease Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000001209 o-nitrophenyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])[N+]([O-])=O 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- VMXUWOKSQNHOCA-UKTHLTGXSA-N ranitidine Chemical compound [O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-UKTHLTGXSA-N 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
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- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 230000008427 tissue turnover Effects 0.000 description 1
- 210000000515 tooth Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
AROMATIC SULFONE HYDROXAMIC ACID
METALLOPROTEASE INHIBITOR
:
This invention is directed to proteinase (protease) inhibitors, and more particularly to the use of aromatic sulfone hydroxamic acid compounds including hydroxamates that, inter alia, are selective inhibitors of . matrix metalloproteinases in a process for treating conditions associated with pathological matrix metalloproteinase activity, the selective inhibitors themselves, compositions of proteinase inhibitors, intermediates for the syntheses of proteinase : inhibitors, and processes for the preparation of. proteinase inhibitors. . 25 . oo Background of the Invention
Co 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
AMENDED SHEET 2004 -04- 2R
A biochemicals makeup, or are components of structures, - such as skin, bone, teeth, tendon, cartilage, basement membrane, blcod vessels, cornea and vitreous humor.
Under normal conditions, connective tissue turnover and/or repair processes are controlled and in equilibrium. The loss of this balance for ~~ whatever reason leads to a number of disease states.
Inhibition of the enzymes responsible loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for : these diseases.
Degradation of connective tissue or [ connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells. A major class of enzymes involved in this function are the zinc metalloproteinases (metalloproteases).
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, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane
MMP (MMP-14). MMP is 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,
S epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; Alzheimers Disease; coronary thrombosis and bone disease. Defective injury repair processes 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. :
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 oo shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal, and TNF can help control the growth of tumor cells.
J
. . | Ca
TNF-a convertase is a metalloprotease : involved in the formation of soluble TNF-a.
Inhibition of TNF-o convertase (TACE) inhibits production of active TNF-a. Compounds that inhibit : both MMPs activity and TNF-a production have been
C disclosed in WIPO International Publication Nos. WO © 94/24140, WO 94/02466 and WO 97/20824. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al. Nature 370, 555-557 (1994) , : McGeehan et al., Nature 370, 558-561 (1994)). There remains a need for effective MMP inhibitors. There also remains a need for effective TNF-a convertase inhibiting agents.
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 : 0 biochemical such as aj-PI supports the treatment and oo 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 oo 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, gelatinase A or B, or
AMENDED SHeey 2004 Dir 28 ]
collagenase III appear to be the relatively most important enzyme or enzymes to inhibit especially when compared with 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 of inflamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by . 10 administration of drugs one of whose modes of action
L is inhibition of MMP-13. See, for example, Mitchell ; et al., J. Clin. Invest., 973: 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 inhibitors of metalloproteinases (TIMPs), o2- : macroglobulin and their analogs or derivatives. . : These endogenous inhibitors are high molecular weight protein molecules that form inactive complexes with oo 20 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. os
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.
SE : oo Thiol group-containing amide or peptidyl El amide-based metalloprotease (MMP) inhibitors are known as is shown in, for example, W095/13289
W096/11209 and U.S. 4,595,700. Hydroxamic acid 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 hydroxamic acids that have a peptidyl back-
AMENDED SHEET + bones or peptidomimetic back-bones, as does the : article by Schwartz et al., Progr. Med. Chenm., 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: 175-185 (1997) .
One possible problem associated with known
CL MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each : of the MMP enzymes. For example, the peptidomimetic hydroxamic acids known as batimastat is reported to : exhibit IC5g 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 hydroxamic acids was reported to be another broad-spectrum.
MMP inhibitor with an enzyme inhibitory spectrum very similar to batimastat, except that marimastat exhibited an ICggp value against MMP-3 of 230 nM.
Rasmussen et al., Pharmacol . Ther., 75(1): 69-75 (1997). - : ’ ’ 20 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 _ _ 25 cancer-specific antigens used as surrogate markers . for biological activity. Although marimastat exhibited some measure of efficacy via these markers, toxic side effects were noted. The most common drug- related toxicity of marimastat in those clinical : trials was musculoskeletal pain and stiffness, often : commencing in the small joints in the hands, Co spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction
AMENDED SHEET ~~ 2004 04-28 permits treatment to continue. Rasmussen et al., oo Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect
I the MMPs may be the cause of that effect.
International application WO 98/38163, published on September 3, 1998 disclose a large group of hydroxamic acids inhibitors of MMPs and TACE. The compounds of WO 98/3B8163 contain one or two : + substituents adjacent to the hydroxamic acids : . 10 functionality and a substituent that can be an aromatic sulfonyl group adjacent to those one or two ; : substituents.
International application WO 98/37877, published on September 3, 1998 discloses compounds that contain a 5- to 7-membered heterocyclic ring : adjacent to the hydroxamate functionality and can contain an aromatic sulfonyl group adjacent to the heterocyclic ring.
Although many of the known MMP inhibitors : 20 such as batimastat, marimastat and the hydroxamic acid of WO 98/37877 and WO 98/38163 exhibit a broad spectrum of activity against MMPs, those compounds are not particularly selective in their inhibitory ) | activity. This lack of selectivity may be the cause
Co 25 of the musculoskeletal pain and stiffness observed - with their use. In addition, it can be therapeutically advantageous to utilize a medicament that is selective in its activity as compared to a generally active material so that treatment can be more closely tailored to the pathological condition presented by the host mammal. The disclosure that follows describes a process for treating a host mammal having a condition associated with
AMENDED SHEET or 28
") pathological matrix metalloprotease activity that utilizes a compound that selectively inhibits one or more MMPs, while exhibiting less activity against at least MMP-1.
Summary of the Inventjon
The present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid : metalloprotease inhibitor in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity. A contemplated molecule, inter alia, exhibits excellent J inhibitory activity of one or more matrix metalloprotease (MMP) enzymes, such as MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1. By "substantially less" it is meant that a contemplated compound exhibits an ICgqg value ratic against one or more of © 20 MMP-2, MMP-9 or MMP-13 as compared to its ICgg value against MMP-1, e.g., ICgp MMP-2:ICs5g MMP-1, that is less than about 1:10, preferably less than about 1:100, and most preferably less than about 1:1000 in the in vitro inhibition assay utilized hereinafter.
The invention also contemplates particular compounds that selectively inhibit the activity of one or more ® of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1, as well as a composition containing such a MMP inhibitor : 30 as active ingredient. Similarly contemplated are particular compounds such as those of Examples 16, 498, 667, 672 and 684 that selectively inhibit the activity of one or more of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-7, as well as a composition containing such a MMP inhibitor as active ingredient. The invention further contemplates intermediates in the preparation of a contemplated aromatic sulfone hydroxamic acid molecule and a process for preparing an aromatic sulfone hydroxamic acid molecule.
Briefly, one embodiment of the present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor that selectively inhibits matrix metalloprotease activity as above in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity. The ® administered enzyme inhibitor corresponds in structure to formula I, below, or a pharmaceutically acceptable salt thereof: 0
I rR
HONH—C~/\. 80,
R' R? 1 wherein
R! and R? are both hydrido or Rl and Rr? together with the atoms to which they are bonded form @ a 5- to 8-membered ring containing one, two or three hetercatoms in the ring that are oxygen, sulfur or nitrogen.
R3 in formula I is an optionally substituted aryl or optionally substituted heteroaryl radical. When R3 is a substituted aryl or heteroaryl radical, a contemplated substituent is selected from the group consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxy, arylthio, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl,
aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, an aralkylthioaryl radical, the sulfoxide or sulfone of any of the thio substituents, and a fused ring structure comprising two or more 5- or 6-membered rings selected from the group consisting of aryl, heteroaryl, carbocyclic and heterocyclic.
The substituent bonded to the aryl or heteroaryl radical of which the R3 radical is comprised itself can be substituted with one or more ® substituents; i.e., the substituting substituent is optionally substituted. When that aryl or heteroaryl radical is substituted, and the substituting moiety (group, substituent, or radical) is itself . substituted, the last-named substituent is independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, _ cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heterocaralkoxy, heterocaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl,
aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino, wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino
® nitrogen and two substituents attached thereto form a 5- to B8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heterocaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl,
aralkoxycarbonyl, hydroxycarbonyl,
@ aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo- alkylcarbonyl, and a cycloalkylcarbonyl group,
carbonylamino wherein the carbonylamino nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, © 35 cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, {
benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group, wherein the amino nitrogen is ® (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl ® group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8- membered heterocyclo or hetercaryl ring.
Preferably, the R3 substituent is Ph-Q-A-R-
E-Y wherein Ph is phenyl substituted at the 4- position relative to the depicted SO; group, and -Q-A-R-E-Y is a substituent in which Q is a 5- to 7- membered heterocyclic ring containing one or two : nitrogen atoms, one of which is bonded the depicted
Le ) RT . mh Eel Te el Co CL phenyl group, and whose remaining members are defined hereinafter for the substituent G-A-R-E-Y’.
A compound of formula I is a compound of more general formula A, wherein R3, rR! and R? are as defined before and R20is defined below.
I
R3
R®—C/\ S02"
R! R2
A
The substituent R20 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) -NH-0-R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p- methoxybenzyl (MOZ), carbonyl-C;-Cg-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C;-Cg- - alkyl, aryl, or ar-Cy-Cg-alkyl or a mixture thereof, (c) -NH-0-R}%4, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R23 where W ‘is 0 (oxo) or S (thioxo) and R29 is selected from the group consisting of an C,-Cg-alkyl, aryl, C;-Cg- alkoxy, heteroaryl-C;-Cg-alkyl, C3-Cg-cycloalkyl-Cj-~
Cg-alkyl, aryloxy, ar-C;-Cg-alkoxy, ar-C;-Cg-alkyl, heteroaryl and amino Cy-Cg-alkyl group wherein the
AMENDED SHEET ~~ 008 -04- 2° amino C1~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, 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) -NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C;-Cg-alkyl, amino C;- ®
Cg-alkyl, hydroxy C,-Cg-alkyl, aryl, ar-Cj-Cg-alkyl group, or R26 and R27 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. When used in a contemplated process or method, R20 jg -NH-0-R22, as defined above.
In preferred practice, R! and R? together with the atoms to which they are bonded form a 6-membered ring.
An R3 radical preferably has a length that ® is greater than that of a pentyl group [a -(CHy)4CH3 chain], more preferably greater than about that of a hexyl group [a -(CHp)s5CH3 chain}, and most preferably greater than an octyl group [a -(CHy)7CH3 chain]. An
R3 radical preferably has a length that is less than that of an icosyl group [a -(CHy)19CH3 chain], and more preferably a length that is less than that of a stearyl group [a -(CH3)17CH3 chain). A preferred R3 group contains two or more 5- or 6-membered rings. A contemplated R3 group, when rotated about an axis drawn through the SOj;-bonded l-position and the substituent-bonded 4-position of a 6-membered ring or the SO;-bonded l-position and substituent-bonded 3- or 4-position of a 5-membered ring, defines a three- dimensional volume whose widest dimension has the width in a direction transverse to that axis to rotation of about one furanyl ring to about two ® phenyl rings.
It is also preferred that a R3 radical be a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4- position when a 6-membered ring or at its own 3- or 4-position when a 5-membered ring with an optionally substituted substituent selected from the group consisting of one other single-ringed aryl or heteroaryl group, a C3-Cj4 alkyl group, a N-piperidyl group, a N-piperazyl group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group and a benzamido group. The substituent of the @® 5- or 6-membered aryl or hetercaryl group can itself be substituted as discussed before.
A preferred compound for use in a contemplated process has a structure that corresponds to formula
II, below, or a pharmaceutically acceptable salt thereof:
~16- :
VASE xX i
BE Cr, (CH),
R!“O—HN pd G—A—R—E—Y! hl so; 0 wherein r14 is hydrido, a pharmaceutically acceptable cation or c(wW)Rr1S where W is O or S and . . :
R15 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-Cj-Cg-alkyl, heteroaryl and amino C1-Cg-
N 10 alkyl group wherein the aminocalkyl 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-Cj-Cg-alkyl, c3-Cg-cycloalkyl-C;-Cg-alkyl, ar-C;-Cg- ~ alkoxycarbonyl, Cj-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; m is zero, 1 or 2; : n is zero, 1 or 2; p is zero, 1 or 2; } the sum of m+ n + p= 1, 2, 3 or 4; (a) one of X, Y and 2 is selected from the group consisting of C(0), NR®, 0, S, S(O), S(O), and.
AMENDED SHEET ~~ 2004 -04- 2° i
NS(0),R7, and the remaining two of X, Y and 2 are cr8R9, and cr1OR11, or (b) X and 2 or Z and Y together constitute a moiety that is selected from the group consisting of NRbc(0), NR®S(0), NROs(0),, NR®sS, NRO, ss, NRENRS oo and 0C(0), with the remaining one of X, Y and 2 being cr8RY, or (c) n is zero and X, Y and Z together constitute a moiety selected from the group ® 10 consisting of f i [o] jo}
RS J RRS s RS RS Pd R®'
Ny NGI NON
I. I I 12 il } rl? Rr?’ 1 0, 0 ' 6
YY , NPG INT [4 i % ¢ 1 R12 ri?’ Rr}? Rr?’
RS [3 6 >
R R
® oY oY YY {
fo) o o
PN AK PY PY i ? } CNT YN NF ’ [4 fd Pood 7 12° rR}? R rR}? gi?
Rré PY NE ~N RE . RS
CY
’ qld RD R13 gD
R12 pi2' Ne Ny
XX RS PY and PY r® ;
Poy ry wherein wavy lines are bonds to the atoms of the depicted ring;
R6 and R6' are independently selected from the group consisting of hydrido, formyl, sulfonic-C;-Cg- alkyl, Cy-Cg-alkoxycarbonyl-Cj-Cg-alkyl, hydroxycarbonyl-C;-Cg-alkyl, C,-Cg-alkylcarbonyl-C,-
Cg-alkyl, R8RY-aminocarbonyl-C;-Cg-alkyl, C1-Cg- alkoxycarbonyl-C4,-Cg-alkylcarbonyl, hydroxycarbonyl-
C;-Cg-alkylcarbonyl, C,-Cg-alkylcarbonyl-C;-Cg- alkylcarbonyl, C,-Cg-alkoxycarbonylcarbonyl, ® hydroxycarbonylcarbonyl, C,-Cg-alkylcarbonylcarbonyl,
R8RI-aminocarbonylcarbonyl, C,-Cg-alkanoyl, aryl-C;-
Cg-alkyl, aroyl, bis(C,-Cg-alkoxy-C,~Cg-alkyl)-C1-Cg- alkyl, C1-Cg-alkyl, C1-Cg-haloalkyl, C1-Cg- perfluoroalkyl, C;-Cg-trifluoromethylalkyl, C1-Cg- perfluoroalkoxy-Cj-Cg-alkyl, C;-Cg-alkoxy-C1-Cg- alkyl, C3-Cg-cycloalkyl, heteroarycarbonyl,
~19- heterocyclocarbonyl, C3-Cg-heterocycloalkyl, C3-Cg- heterocycloalkylcarbonyl, aryl, Cg-Cg-heterocyclo,
C5-Cg-heterocaryl, C3-Cg-cycloalkyl-C;-Cg-alkyl, ~aryloxy-C;-Cg-alkyl, heteroaryloxy-C;-Cg-alkyl, heteroaryl-Cj-Cg-alkoxy-C;-Cg-alkyl, heteroarylthio-
C,-Cg-alkyl, arylsulfonyl, C;-Cg-alkylsulfonyl, Cs-
Cg-heteroarylsulfonyl, carboxy-C,-Cg-alkyl, C;1-C4- alkoxycarbonyl-C;-Cg-alkyl, aminocarbonyl, C;-Cg- alkyl (R8BN)iminocarbonyl, aryl (R8N)iminocarbonyl, Cs- ® 10 Cg-heterocyclo(R8N)iminocarbonyl, arylthio-C;-Cg- alkyl, C,-Cg-alkylthio-C;-Cg-alkyl, arylthio-C3-Cg- alkenyl, C;-C4-alkylthio-C3-Cg-alkenyl, Cg-Cg- heteroaryl-Cy-Cg-alkyl, halo-C;-Cg-alkanoyl, hydroxy- : c,-Cg-alkanoyl, thiol-C;-Cg-alkanoyl, C3-Cg-alkenyl,
C3-Cg-alkynyl, C;-C4-alkoxy-C,-Cy-alkyl, C;-Cg- alkoxycarbonyl, aryloxycarbonyl, NRERI- (R8)iminomethyl, NR8RJ-c,-Cg-alkylcarbonyl, hydroxy-
C;-Cg-alkyl, R8R%-aminocarbonyl, R8RI-aminocarbonyl- @ ¢,-Cg-alkylcarbonyl, hydroxyaminocarbonyl, R8RI- aminosulfonyl, R8RI-aminosulfon-C,~-Cg-alkyl, R8RI- amino-C;-Cg-alkylsulfonyl and an R8RI-amino-Cy-Cg- alkyl group;
R’! is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C;-Cg- } alkyl, C3-Cg-alkynyl, C3-Cg-alkenyl, C,-Cg- carboxyalkyl and a C;-Cg-hydroxyalkyl group;
R8 and R? and R10 and R!! are independently selected from the group consisting of a hydrido, hydroxy, C;-Cg-alkyl, C,-Cg¢-alkanoyl, aroyl, aryl, ar-C;-Cg-alkyl, heteroaryl, heteroar-C,-Cg-alkyl, Ca-
Cg-alkynyl, Cy-Cg-alkenyl, thiol-C;-Cg-alkyl, C;-Cg- alkylthio-C;-Cg-alkyl, cycloalkyl, cycloalkyl-C;-Cg- alkyl, heterocycloalkyl-C;-Cg-alkyl, Cj-Cg-alkoxy-C;-
Cg-alkyl, aralkoxy-C;-Cg-alkyl, C;-Cg-alkoxy-C,-Cg- alkoxy-C,-Cg-alkyl, hydroxy-C;-Cg-alkyl, hydroxycarbonyl-C;-Cg-alkyl, hydroxycarbonylar-C,-Cg- 9 alkyl, aminocarbonyl-C,-Cg-alkyl, aryloxy-Cj;-Cg- alkyl, heteroaryloxy-C,-Cg-alkyl, arylthio-C;-Cg- alkyl, heteroarylthio-C;-Cg-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C,-
Cg-alkyl, trifluoromethyl-C;-Cg-alkyl, halo-C;-Cg- alkyl, alkoxycarbonylamino-C;-C¢-alkyl and an amino-
C,-Cg-alkyl group wherein the aminoalkyl nitrogen is (1) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of Cq-Cg-alkyl, ar-C;-Cg-alkyl, cycloalkyl and C;-Cg¢-alkanoyl, or wherein R® and RY or R10 and ®
R1! and the carbon to which they are bonded form a carbonyl group, or wherein R8 and RI or R10 and r11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen,
oxygen, or sulfur, with the proviso that only one of
R8 and R? or R10 and RI! is hydroxy; ) ’ R12 and r12' are independently selected from the group consisting of a hydrido, C1-Cg-alkyl, aryl, ar-C;-Cg-alkyl, heteroaryl, heteroaralkyl, Co-
Cg-alkynyl; C,-Cg—alkenyl, thiol-C;-Cg-alkyl, 4 cycloalkyl, cycloalkyl-C,-Cg-alkyl, heterocycloalkyl-
Cy-Cg-alkyl, C,-Cg-alkoxy-C;-Cg-alkyl, aryloxy-Cy-Cg- : alkyl, amino-C,-Cg-alkyl, C,-Cg-alkoxy-C;-Cg-alkoxy- “$10 C1-Cg-alkyl, hydroxy-C,-Cg-alkyl, hydroxycarbonyl-Cj- * Cg-alkyl, hydroxycarbonylar-C;-Cg-alkyl, aminocarbonyl-C;~Cg-alkyl, aryloxy-C;-Cg-alkyl, heteroaryloxy-C;-Cg-alkyl, Cy-Cg-alkylthio-C;-Cg- alkyl, arylthio-cj~Cg-alkyl, heteroarylthio-C)-Cg- Co alkyl, the sulfoxide or sulfone of any said thio . substituents, perfluoro-C;-Cg-alkyl, trifluoromethyl-
C,-Cg-alkyl, halo-Cj-Cg-alkyl, alkoxycarbonylamino-
C;-Cg-alkyl and an amino-C;-Cg-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C;-Cg-alkyl, ar-Cy-Cg-alkyl, cycloalkyl and C,-Cg-alkanoyl; | oo :
R13 is selected from the group consisting of a hydrido, benzyl, phenyl, Cj-Cg-alkyl, Cp-Cg- alkynyl, Cy-Cg-alkenyl and a C,-Cg-hydroxyalkyl : group; and : ~ G-A-R-E-Y' is a substituent that preferably has a length greater than that of a pentyl group, and more preferably has a length greater than that of a
AMENDED SHEET ~~ 2004 04-22
-22—~ hexyl group. The substituent G-A-R-E-Y' preferably has a length that is less than that of an icosyl group, and is more preferably less than that of a stearyl group. In this substituent:
G is an aryl or heteroaryl group;
A is selected from the group consisting of, (1) -0-; (2) =S5-; (3) —NRl7-; (4y —co-N(R17) or -N(R17)-co-, wherein R17 is hydrogen, C;-Cy-alkyl, or phenyl; (5) —CO0-0- or —0-CO-; : (6) —O-CO-O-; : (7) —HC=CH-; oo (8) —NH-CO-NH-; . : (9) —C=C-; (10) —NH-CO-O- or -0-CO-NH-; : (11) -N=N-; (12) —NH-NH-; and } (13) —cS-N(R18)- or —N(R18)-cs-, wherein
R18 is hydrogen C,-C4-~alkyl, or phenyl; or © (14) A is absent and G is bonded directly oo : © to R; Co SI )
R is a moiety selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, . cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, ' heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a
AMENDED sheer C0 or 2f 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 consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluorcalkylthio, : trifluoromethylalkyl, amino, alkoxycarbonylalkyl, ) alkoxy, Cj;-Cp-alkylene-dioxy, hydroxycarbonylalkyl, " hydroxycarbonylalkylamino, nitro, hydroxy, } 10 hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl "© group, and R is other than alkyl or alkoxyalkyl when
A is —0- or —S-;
E is selected from the group consisting of (1) —co(rl?)- or -(r1%)co-, wherein R19 is a heterocycloalkyl, or a cycloalkyl : group; (2) —CONB- or -HNCO-; and . (3), -cO-; | | oe (4) =-505-R19- or —R19-s0,-; (5) =-SO2~; (6) -NH-SOz- or -SO-NH-; (71) -S=3 ‘ (8) —-NH-CO-O- or -O-CO-NH-; or (9) E is absent and R.is bonded directly" to Y'; and . the moiety vy! is absent or is selected from oo the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, : hydroxy, aryloxy, aralkoxy, heteroaryloxy, ~ 30 heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a
AMENDED SHEET ~~ 2004 0-27
Claims (56)
1. A use of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to prepare a pharmaceutical composition for treating a condition associated with pathological matrix metalloprotease (MMP) activity in a subject having or susceptible to such a condition, wherein: the compound or salt inhibits the activity of one or more of MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibitory activity against MMP-1; the compound corresponds in structure to formula B: X \ : \ Q R y'
@. / ~Ne (CHm (CH), R20 S(O)¢ 0] B R20 is -NH-0-R'%; R14 is selected from the group consisting of hydrogen and C(W)R2>; W is selected from the group consisting of O and S; R25 is selected from the group consisting of C,-Cg-alkyl, aryl, C,-Cg-alkoxy, heteroaryl-C,-Cg-alkyl, Cy-Cg-cycloalkyl-Cy-Cg-alkyl, aryloxy, aryl-C;-Cg-alkoxy, aryl-C,-Cg-alkyl, heteroaryl, and amino C,-Cg-alkyl, wherein: the amino C;-Cg-alkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C;-Cg-alkyl, aryl, aryl-Cq-Cg-alkyl, C5-Cg-cycloalkyl-Cq-Cg-alkyl, aryl-C,-Cg-alkoxycarbonyl, C,-Cg-alkoxycarbonyl, and C,-Cg-alkanoyl, or the amino C;-Cg-alkyl nitrogen, together with the two substituents attached thereto, form a 5- to 8-membered heterocyclo or heteroaryl ring; AMENDED SHEET 28.11.2002
N g is 2; oe m is zero, 1, or 2; n is zero, 1, or 2; p is zero, 1, or 2; the sum of m+ n +p =1, 2 , 3, or 4; as to X, YY, and Z:
(a) one of X, Y, and Z is selected from the group consisting of C(O), NR®, 0, §, S(O), S(0),, and NS(0),R7, and the remaining two of X, Y, and Z are cr®R? , and CrIOR1 |, or
(b) X and 2, or Zz and Y together constitute a moiety selected from the group consisting of NrR6C (0), NR®S(0),
NRSS (0) ,, NR®s, NRPO, ss, NRENR®, and OC(0), with the remaining one of X and Y being cr8R?, or
(c) n is zero and X, Y, and Z together constitute a moiety selected from the group consisting of:
i I 0 [o)
RO PS R® 6 6' 6 \Y4 6 ~~ , R S R R S R N N Ny ~~ | Np TN fg SE SE 6 12 i Rr!Z ri’ R © $2 6 > 6 RS PY YY , AN re NT XY 0 [4 ¢ 8 $s 12 k R RY? Rr? R32 R12’ Jo NE we WON SE ' 0 Nn Sy ) § 3 SE SE AMENDED SHEET 28.11.2002
A 6 ® YY AY SE BE 0 ' EE 13 13 12 13 RY? RY? NY NY pe iy PY , and PY 6 1 Ploy ry wherein wavy lines are bonds to the atoms of the depicted ring; [ R® and R®' are independently selected from the group consisting of hydrogen, formyl, sulfonic-C,-Cg-alkyl, C1 -Cg-alkoxycarbonyl-C; -Cg-alkyl, hydroxycarbonyl-C,-Cg-alkyl, C,-Cg-alkylcarbonyl-C,-Cg-alkyl, R8R?-aminocarbonyl-Cq-Cg-alkyl, C,-Cg-alkoxycarbonyl-C,-Cg-alkylcarbonyl, hydroxycarbonyl-C,-Cg-alkylcarbonyl, C,-Cg-alkylcarbonyl-C,-Cg-alkylcarbonyl, C,-Cg-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C,-Cg-alkylcarbonylcarbonyl, R8R?-aminocarbonylcarbonyl, C,-Cg-alkanoyl, aryl-C,-Cg-alkyl, aroyl, bis (Cq-Cg-alkoxy-Cq-Cg-alkyl)-C,-Cg-alkyl, Cy-Cg-alkyl, Cq-Cg-haloalkyl, C,-Cg-perfluoroalkyl, C;-Cg-trifluoromethylalkyl, C,-Cg-perfluoroalkoxy-C,-Cg-alkyl, Cq-Cg-alkoxy-C,-Cg-alkyl, C3-Cg-cycloalkyl, heteroarylcarbonyl, heterocyclocarbonyl, 3- to 8- membered heterocycloalkyl, 3- to 8-membered heterocycloalkylcarbonyl, aryl, 5- to 6-membered heterocyclo, 5- to 6-membered heteroaryl, C3-Cg-cycloalkyl-C,-Cg-alkyl, aryloxy-C,-Cg-alkyl, heteroaryloxy-C,-Cg-alkyl, heteroaryl-C,-Cg-alkoxy-C;-Cg-alkyl, heteroarylthio-C,-Cg-alkyl, arylsulfonyl, C,-Cg-alkylsulfonyl, 5- to 6 -membered AMENDED SHEET 28.11.2002 heteroarylsulfonyl, carboxy-C,-Cg-alkyl,
C C,-C4-alkoxycarbonyl-C,-Cg- alkyl, aminocarbonyl, C,-Cg-alkyl (REN) iminocarbonyl, aryl (R8N) iminocarbonyl, 5- to 6- membered heterocyclo (R8N)iminocarbonyl, arylthio-C,-Cg-alkyl, C,-Cg-alkylthio-C,-Cg-alkyl, arylthio-Cy-Cg-alkenyl, C,-C4-alkylthio-Cy-Cg-alkenyl, 5- to 6 -membered heteroaryl-C,-Cg-alkyl, halo-C, -C¢-alkanoyl, hydroxy-C, -Cg-alkanoyl, thiol-C,-Cg-alkanoyl, C3-Cg-alkenyl, Cy-Cg-alkynyl, Cq-C4q-alkoxy-C,-Cy-alkyl, C,-Cg-alkoxycarbonyl, aryloxycarbonyl, NR8RP- (R8) iminomethyl, NR®RZ-C;-Cc-alkylcarbonyl,
( hydroxy-C,-Cg-alkyl, R8R?-aminocarbonyl , R8R7-aminocarbonyl-C,-Cg-alkylcarbonyl, hydroxyaminocarbonyl, R8R7-aminosulfonyl, R8R?-aminosulfon-C,-Cg-alkyl,
R®RZ-amino-C, -Cg-alkylsulfonyl, and R8R?-amino-C;-Cg-alkyl;
R’7 is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C,-Cg-alkyl, Cy-Cg-alkynyl, Cy-Cg-alkenyl, C,-Cg-carboxyalkyl, and C,-Cg-hydroxyalkyl;
as to R%:
R® is selected from the group consisting of hydrogen,
hydroxy, C;-Cg-alkyl, C,-Cg-alkanoyl, aroyl, aryl, .
aryl-C;-Cg-alkyl, heteroaryl, heteroaryl-C,-Cg-alkyl,
C,-Cg-alkynyl, C,-Cg-alkenyl, thiol-C,-Cg-alkyl,
C,~Cg-alkylthio-C,-Cg-alkyl, cycloalkyl,
cycloalkyl-Cq-Cc-alkyl, heterocyclo-Cq-Cg-alkyl,
C,-Cg-alkoxy-Cp-Cg-alkyl, arylalkoxy-Cq-Cg-alkyl,
Cq-Cg-alkoxy-Cq-Cg-alkoxy-Cy-Cg-alkyl, hydroxy-C;-Cg-alkyl,
hydroxycarbonyl-C;-Cg-alkyl, hydroxycarbonylaryl-C,-Cg-alkyl,
aminocarbonyl-C,-Cg-alkyl, aryloxy-C,-Cg-alkyl, heteroaryloxy-C,-Cg-alkyl, arylthio-C,-Cg-alkyl, AMENDED SHEET 28.11.2002 heteroarylthio-C,-Cc-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C,-Cg-alkyl, trifluoromethyl-C;-Cc-alkyl, halo-C;-Cg-alkyl, alkoxycarbonylamino-C; -Cg-alkyl, and amino-C, -Cg-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the i group consisting of Cq-Cg-alkyl, aryl-C,-Cg-alkyl, cycloalkyl, and Cq-Cg-alkanoyl, or rR8 and R?, together with the carbon to which they are bonded form a carbonyl group, or R® and R’ or R® and R', together with the atom(s) to which they are bonded, form a 5- to 8- membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R’:
RY is selected from the group consisting of hydrogen, hydroxy, Cq-Cg-alkyl, C4 -Cg-alkanoyl, aroyl, aryl, aryl-Cqy-Cg-alkyl, heteroaryl, heteroaryl-C,-Cg-alkyl, Cy-Cg-alkynyl, C,-Cg-alkenyl, thiol-C,-Cg-alkyl, C;-Cg-alkylthio-C,-Cg-alkyl, cycloalkyl, cycloalkyl-C,-Cg-alkyl, heterocyclo-Cq-Cg-alkyl,
Cq-Cg-alkoxy-C;-Cg-alkyl, arylalkoxy-C,-Cg-alkyl, : Cq-Cg-alkoxy-Cq-Cg-alkoxy-C;-Cg-alkyl, hydroxy-C, -Cg-alkyl, hydroxycarbonyl-Cq-Cg-alkyl, hydroxycarbonylaryl-Cq-Cg-alkyl, aminocarbonyl-Cq-Cg-alkyl, aryloxy-C;-Cg-alkyl, heteroaryloxy-C;-Cg-alkyl, arylthio-Cq-Cg-alkyl, heterocarylthio-C;-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C,-Cg-alkyl, trifluoromethyl-C;-Cg-alkyl, halo-C;-Cg-alkyl, alkoxycarbonylamino-Cq-Cg-alkyl, and amino-Cq-Cg-alkyl, wherein:
AMENDED SHEET 28.04.04 the aminoalkyl nitrogen is optionally substituted C with up to two substituents independently selected from the group consisting of C,-Cg-alkyl, aryl-Cq-Cg-alkyl, cycloalkyl, and Cq-Cg-alkanoyl, or r® and R?, together with the carbon to which they are bonded form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R*: R10 is selected from the group consisting of hydrogen, hydroxy, C,-Cg-alkyl, C,-Cg-alkanoyl, aroyl, aryl, ® aryl-Cq-Cg-alkyl, heteroaryl, heteroaryl-C,-Cg-alkyl, Cp-Cg-alkynyl, C,-Cg-alkenyl, thiol-C,-Cg-alkyl, Cq-Cg-alkylthio-C;-Cg-alkyl, cycloalkyl, cycloalkyl-C,-Cg-alkyl, heterocyclo-Cq,-Cg-alkyl, C,-Cg-alkoxy-C;-Cg-alkyl, arylalkoxy-Cq-Cg-alkyl, C,-Cg-alkoxy-C;-Cg-alkoxy-Cy-Cg-alkyl, hydroxy-C; -Cg-alkyl, hydroxycarbonyl-Cy -Cg-alkyl, hydroxycarbonylaryl-C,-Cg-alkyl, aminocarbonyl-C,-Cg-alkyl, aryloxy-C,-Cg-alkyl, heteroaryloxy-Cq-Cg-alkyl, arylthio-C,-C¢-alkyl, heteroarylthio-C,-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C,-Cg-alkyl, trifluoromethyl-C,-C¢-alkyl, halo-C,-Cg-alkyl, alkoxycarbonylamino-C;-Cg-alkyl, and amino-C,-Cg-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C,-Cg-alkyl, aryl-C,-Cg-alkyl, cycloalkyl, and C,-Cg-alkanoyl, R10 ang Rr1%, together with the carbon to which they are bonded form a carbonyl group, or AMENDED SHEET 28.11.2002
R10 and rR! or r® and RIO, together with the atom(s) to which they are bonded, form a 5- to 8 -membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to RY:
rll is selected from the group consisting of hydrogen, hydroxy, Cq-Cg-alkyl, C,-Cg-alkanoyl, aroyl, aryl, aryl-C;-Cg-alkyl, heteroaryl, heteroaryl-Cq-Cg-alkyl, Cy-Cg-alkynyl, C,-Cg-alkenyl, thiol-C,-Cg-alkyl, C,-Cg-alkylthio-C;-Cg-alkyl, cycloalkyl, cycloalkyl-Cq-Cg-alkyl, heterocyclo-C;-Cg-alkyl, C,-Cg-alkoxy-Cy-Cg-alkyl, arylalkoxy-C,-Cg-alkyl, Cc, -Cg-alkoxy-Cy-Cg-alkoxy-Cy-Cg-alkyl, hydroxy-C;-Cg-alkyl, hydroxycarbonyl-Cq-Cg-alkyl, hydroxycarbonylaryl-Cy -Cg-alkyl, aminocarbonyl-C;-Cg-alkyl, aryloxy-C,-Cg-alkyl, heteroaryloxy-Cq -Cg-alkyl, arylthio-Cq-Cg-alkyl, heterocarylthio-C;-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C;-Cg-alkyl, trifluoromethyl-Cy-Cg-alkyl, halo-Cy-Cg-alkyl, alkoxycarbonylamino-C,-Cg-alkyl, and amino-C;-C¢-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of Cq-Cg-alkyl, aryl-C;-Cg-alkyl, cycloalkyl, and C,-Cg-alkanoyl, or R10 and Rl, together with the carbon to which they are bonded form a carbonyl group, a 5- to 8 -membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; only one of R8 and R? or RO and r11 is hydroxy; AMENDED SHEET 28.04.04
R12 and R12' are independently selected from the group consisting of hydrogen, Cq-Cg-alkyl, aryl, aryl-C;-Cg-alkyl, heteroaryl, heteroarylalkyl, C,-Cg-alkynyl, C,-Cg-alkenyl, thiol-Cq-Cg-alkyl, cycloalkyl, cycloalkyl-Cq-Cg-alkyl, heterocyclo-C;-Cg-alkyl, Cq-Cg-alkoxy-Cy-Cg-alkyl, aryloxy-Cq-Cg-alkyl, amino-C,-Cg-alkyl,
) Cq-Cg-alkoxy-C; -Cg-alkoxy-Cp-Cg-alkyl, hydroxy-C,-Cg-alkyl, hydroxycarbonyl-C,-Cg-alkyl, hydroxycarbonylaryl-C; -Cg-alkyl, aminocarbonyl-C;-Cg-alkyl, aryloxy-C;-Cg-alkyl, heterocaryloxy-Cq-Cg-alkyl, Cy-Cg-alkylthio-Cy-Cg-alkyl, arylthio-C;-Cg-alkyl, heteroarylthio-C;-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C;-Cg-alkyl, trifluoromethyl-Cq-Cg-alkyl, halo-Cqy-Cg-alkyl, alkoxycarbonylamino-Cy-Cg-alkyl, and amino-C; -Cg-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of Cy -Cg-alkyl, aryl-C;-Cg-alkyl, cycloalkyl, and .
C,-Cg-alkanoyl;
R13 is selected from the group consisting of hydrogen, benzyl, phenyl, Cp-Cg-alkyl, Cp-Cg-alkynyl, Cp-Cg-alkenyl, and C,-Cg-hydroxyalkyl; Q is a 5- to 7-membered heterocyclo ring containing one or two nitrogen atoms one of which is bonded to the depicted phenyl group, wherein A-R-E-Y' is bonded at the 4-position relative to said phenyl-bonded nitrogen atom when Q is a 6- or 7-membered ring and at the 3- or 4-position relative to that nitrogen when Q is a 5-membered ring; . aA is selected from the group consisting of:
(1) -0-, (2) -5-, (3) -Nr17-, AMENDED SHEET 28.04.04
(a) -co-N(R'7),
(5) -N(R!7)-co-,
(6) -CO-0-, (7) -0-CO0-,
(8) -0-C0-0-,
(9) -HC=CH-,
(10) -NH-CO-NH-,
(11) -Cc=C-,
(12) -NH-CO-O-,
(13) -0-CO-NH-,
(14) -N=N-,
(15) -NH-NH-,
(16) -cs-N(rLS)-,
(17) -N(R18)-cs-, and
(18) a bond;
R17 is selected from the group consisting of hydrogen, Cq-C4q-alkyl, and phenyl;
R18 is selected from the group consisting of hydrogen, C;-C4 alkyl, and phenyl;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclo, arylalkyl, heterocarylalkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl,
cycloalkylthiocalkyl, and heterocyclothioalkyl, wherein: the aryl, heteroaryl, cycloalkyl, or heterocyclo 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,-Cy-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro,
hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl;
AMENDED SHEET 28.04.04
R is other than alkyl or alkoxyalkyl when A is -O- or - S-; E is selected from the group consisting of: (1) -co(r'?)-, (2) -(r%)co-, (3) -CONH-, (4) -HNCO-, (5) -CO-, (6) -S05-R12-, (7) -R9-s05-, (8) -S05-, (9) -NH-S05-, (10) -SO5-NH-, (11) -s-, (12) -NH-CO-O-, (13) -0-CO-NH-, and (14) a bond; R19 is selected from the group consisting of heterocycloalkyl and cycloalkyl; and v! is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heterocarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl AMENDED SHEET 28.04.04
2. The use according to claim 1, wherein the compound corresponds in structure to formula B-1l: TA X Y 3 ol Q ArP my (CHpm (CHa)p X 1 4 wo” TOA o OO © )
3. The use according to claim 1, wherein the compound corresponds in structure to formula B-2: (CH ~~ ! J aN AN AY X v Q \ / N (CH (CH), R20 S(O), bo} B-2
4. The use according to claim 1, wherein the sumof m + 1 + p = 1 or 2. ’ AMENDED SHEET 28.04.04
. ® 5. A use of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to prepare a pharmaceutical composition for treating a condition associated with pathological matrix metalloprotease (MMP) activity in a subject having or susceptible to such a condition, wherein:
the compound or salt inhibits the activity of one or more of MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibitory activity against MMP-1;
the compound corresponds in structure to formula B-3:
/ \ Ny X y Q \ / N lL] (CH, (CHa), R20 S(O) o B-3
R20 is -NH-0-R1%;
R14 jis selected from the group consisting of hydrogen and C(W)R?>;
W is selected from the group consisting of O and S;
R25 is selected from the group consisting of C,-Cg-alkyl, aryl, C,-Cg-alkoxy, heteroaryl-C;-Cg-alkyl, C3-Cg-cycloalkyl-C,-Cg-alkyl, aryloxy, aryl-C;-Cg-alkoxy, aryl-C;-Cg-alkyl, heteroaryl, and amino C,-Cg-alkyl, wherein:
the amino C,-Cg-alkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C;-Cg-alkyl, aryl, aryl-C,-Cg-alkyl,
C3-Cg-cycloalkyl-C,-Cg-alkyl, aryl-C,-Cg-alkoxycarbonyl,
C,-Cg-alkoxycarbonyl, and C,-Cg-alkanoyl, or the amino C,-Cg-alkyl nitrogen, together with the two substituents attached thereto, form a 5- to 8-membered heterocyclo or heteroaryl ring;
g is 2;
AMENDED SHEET 28.11.2002 m is zero, 1, or 2; n is zero, 1, or 2; p is zero, 1, or 2; the sum of m + n + p=1, 2 , 3, or 4; as to X, Y¥, and 2: (a) one of X, Y, and Z is selected from the group consisting of C(O), NR®, S, S(0), S(0),, and NS(O),R7, and the remaining two of X, Y, and Z are cr8Rr? and cr10r11 , Or (b) X and Z, or Z and Y together constitute a moiety selected from the group consisting of NRSC (0), NR®S (0), : NRs (0) 5, NR®S, NR®O, Ss, NRONR®, and OC(0), with the remaining one of X and Y being crR8R®, or (¢) n is zero and X, Y, and Z together constitute a moiety selected from the group consisting of: Q 0 0 0 6 6 I Ne R R 6 6 6 6 ~ PR _ R S R R S R N N rN TN Np NN $d SI SE I © 12 R , R rl? R12 PY 0 0 , 6 N 6 > ROR ’ RIN Nn Ny Xy ’ [4 $3 8 12
1 . Rl2 R12’ gl2 gl?’ R 6 6 . / pe R R > IE SL A SE Uh AMENDED SHEET 28.04.04
1 I JES WE ~~ \ rE @® 3 : , : : : 4 a 12° i’ J IN R12 R12’ ~ R pre 6 N
S R EEE g13 R13 R33 RrL3 R12 rl2' Ny Ny SE ed me Le YoY vo wherein wavy lines are bonds to the atoms of the depicted ring; ® R® and R®' are independently selected from the group consisting of hydrogen, formyl, sulfonic-C,-Cg-alkyl, C,-Cg-alkoxycarbonyl-C,-Cg-alkyl, hydroxycarbonyl-C,-Cg-alkyl, C,-Cg-alkylcarbonyl-C,-Cg-alkyl, r8RP-aminocarbonyl-C,-Cg-alkyl, C,-Cg-alkoxycarbonyl-Cy-Cg-alkylcarbonyl, hydroxycarbonyl-C,-Cg-alkylcarbonyl, C,-Cg-alkylcarbonyl-C;-Cg-alkylcarbonyl, C,-Cg-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C,-Cg-alkylcarbonylcarbonyl, R8RY-aminocarbonylcarbonyl, C,-Cg-alkanoyl, aryl-C,-Cg-alkyl, aroyl, bis (C,-Cg-alkoxy-Cq-Cg-alkyl) -C;-Cg-alkyl, C,-Cg-alkyl, C,-Cg-haloalkyl, C,-Cg-perfluoroalkyl, C,-Cg-trifluoromethylalkyl, C,-Cg-perfluorocalkoxy-C,-Cg-alkyl, Cy -Cg-alkoxy-C,-Cg-alkyl, C3-Cg-cycloalkyl, heteroarylcarbonyl, heterocyclocarbonyl, 3- to 8- membered heterocycloalkyl, 3- to 8-membered heterocycloalkylcarbonyl, aryl, 5- to 6-membered heterocyclo, 5- to 6-membered heteroaryl, C3-Cg-cycloalkyl-C,-Cg-alkyl, aryloxy-Cq-Cg-alkyl, heteroaryloxy-C,-Cg-alkyl, hetercaryl-C;-Cg-alkoxy-Cq-Cg-alkyl, hetercarylthio-Cq-Cg-alkyl, arylsulfonyl, C,-Cg-alkylsulfonyl, 5- to é6-membered AMENDED SHEET 28.11.2002 heteroarylsulfonyl, carboxy-C;-Cg-alkyl, ® C,-Cy -alkoxycarbonyl-C;-Cc-alkyl, aminocarbonyl, Cy-Cg-alkyl (R8N) iminocarbonyl, aryl (R8N) iminocarbonyl, 5- to 6- membered heterocyclo (RBN)iminocarbonyl, arylthio-C,-Cg-alkyl, C,-Cg-alkylthio-C,-Cg-alkyl, arylthio-C5-Cg-alkenyl, C,-C,-alkylthio-C3-Cg-alkenyl, 5- to 6 -membered heteroaryl-C,-Cg-alkyl , halo-C,-Cg-alkanoyl, hydroxy-C, -Cg-alkanoyl, thiol-C,-Cg-alkanoyl, Cy-Cg-alkenyl, C3-Cg-alkynyl, C,-C4-alkoxy-C,-Cy-alkyl, C,-Cg-alkoxycarbonyl, aryloxycarbonyl, NR8R?- (R8) iminomethyl, NR8RY-C, -Cg-alkylcarbonyl, ( 3D hydroxy-C,-Cg-alkyl, R8R?-aminocarbonyl, R8R?-aminocarbonyl-Cy-Cg-alkylcarbonyl, hydroxyaminocarbonyl, R8RY-aminosulfonyl, R8RI-aminosulfon-C, -Cg-alkyl, R8R%-amino-C,-Cg-alkylsulfonyl, and R8RI-amino-C; -Cg-alkyl;
R7 is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C,-Cg-alkyl, Cy-Cg-alkynyl, C3-Cg-alkenyl, C,-Cg-carboxyalkyl, and Cy -Cg-hydroxyalkyl;
as to R%:
R® is selected from the group consisting of hydrogen, hydroxy, C;-Cg-alkyl, C,-Cg-alkanoyl, aroyl, aryl, aryl-C,-Cg-alkyl, heteroaryl, heteroaryl-C,-Cg-alkyl, Co-Cg-alkynyl, Cy-Cg-alkenyl, thiol-C,-Cg-alkyl, C,-Cg-alkylthio-C,-Cg-alkyl, cycloalkyl, cycloalkyl-Cq-Cg-alkyl, heterocyclo-C,-Cg-alkyl, C,-Cg-alkoxy-C;-Cg-alkyl, arylalkoxy-Cq-Cg-alkyl, C,-Cg-alkoxy-C;-Cg-alkoxy-C;-Cg-alkyl, hydroxy-Cq-Cg-alkyl, hydroxycarbonyl-C,-Cg-alkyl, hydroxycarbonylaryl-C,-Cg-alkyl, aminocarbonyl-C;-Cg-alkyl, aryloxy-C,-Cg-alkyl, heteroaryloxy-C,-Cg-alkyl, arylthio-Cq-Cg-alkyl,
AMENDED SHEET 28.11.2002 heteroarylthio-C;-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C,-Cg-alkyl, trifluoromethyl-C;-Cg-alkyl, halo-C;-Cg-alkyl, alkoxycarbonylamino-C;-Cg-alkyl, and amino-C, -Cg-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C,-Cg-alkyl, aryl-Cq-Cg-alkyl,
cycloalkyl, and Cq-Cg-alkanoyl, or r8 and R?, together with the carbon to which they are bonded, form a carbonyl group, or R° and R® or R® and RY, together with the atom(s) to which they are bonded, form a 5- to 8 -membered carbocyclic ring, or a 5- to 8 -membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R’:
RY is selected from the group consisting of hydrogen, hydroxy, Cq-Cg-alkyl, C,-Cg-alkanoyl, aroyl, aryl, aryl-Cq-Cg-alkyl, heteroaryl, heteroaryl-C,-Cg-alkyl, Cy-Cg-alkynyl, C,-Cg-alkenyl, thiol-Cq-Cg-alkyl, C,-Cg-alkylthio-Cy-Cg-alkyl, cycloalkyl,
cycloalkyl-C;-Cg-alkyl, heterocyclo-C, -Cg-alkyl, Cy -Cg-alkoxy-Cqp-Cg-alkyl, arylalkoxy-C;-Cg-alkyl, : C,-Cg-alkoxy-Cy-Cg-alkoxy-Cy-Cg-alkyl, hydroxy-C, -Cg-alkyl, hydroxycarbonyl-C,-Cg-alkyl, hydroxycarbonylaryl-C;-Cg-alkyl, aminocarbonyl-C;-Cg-alkyl, aryloxy-Cq-Cg-alkyl, heteroaryloxy-C;-Cg-alkyl, arylthio-Cq-Cg-alkyl, heteroarylthio-C,-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-Cq-Cg-alkyl, trifluoromethyl-C;-Cg-alkyl, halo-Cq-Cg-alkyl, alkoxycarbonylamino-Cq-Cg-alkyl, and amino-Cq-Cg-alkyl, wherein:
AMENDED SHEET 28.04.04
R12 and rR1?' are independently selected from the group consisting of hydrogen, C;-Cg-alkyl, aryl, aryl-C;-Cg-alkyl, heteroaryl, heteroarylalkyl, C,-Cg-alkynyl, C,-Cg-alkenyl, thiol-C,-Cg-alkyl, cycloalkyl, cycloalkyl-C,-Cg-alkyl, heterocyclo-Cq-Cg-alkyl, C,-Cg-alkoxy-Cp-Cg-alkyl, aryloxy-C,-Cg-alkyl, amino-C; -Cg-alkyl, C,-Cg-alkoxy-C;-Cg-alkoxy-Cy-Cg-alkyl, hydroxy-C, -Cg-alkyl, hydroxycarbonyl-C;-Cg-alkyl, hydroxycarbonylaryl-C;-Cg-alkyl, aminocarbonyl-C, -Cg-alkyl, aryloxy-C; -Cg-alkyl, heteroaryloxy-C, -Cg-alkyl, C,-Cg-alkylthio-Cq-Cg-alkyl, arylthio-C,-Cg-alkyl, heteroarylthio-C,-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C,-Cg-alkyl, trifluoromethyl-C,-Cg-alkyl, halo-C;-Cg-alkyl, alkoxycarbonylamino-C; -Cg-alkyl, and amino-C;-Cg-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C;-Cg-alkyl, aryl-C,-Cg-alkyl, cycloalkyl, and
Cq-Cg-alkanoyl;
R13 is selected from the group consisting of hydrogen, benzyl, phenyl, C,-Cg-alkyl, C,-Cg-alkynyl, C,-Cg-alkenyl, and C,-Cg-hydroxyalkyl;
Q is a 5- to 7-membered heterocyclo ring containing one or two nitrogen atoms one of which is bonded to the depicted phenyl group, wherein E-Y' are bonded at the 4-position relative to said phenyl-bonded nitrogen atom when Q is a 6- or 7-membered ring and at the 3- or 4-position relative to that nitrogen when Q is a 5-membered ring;
E is selected from the group consisting of:
(1) -CO(RY?) -, (2) -(RrR%)co-, (3) -CONH-, AMENDED SHEET 28.04.04
(4) -HNCO-, (5) -CO-, (6) -SO5-R19-, (7) -R19-505-, (8) -S0,5-, (9) -NH-SO3-, (10) -SOy-NH-, (11) -s-, (12) -NH-CO-O-, (13) -0O-CO-NH-, and (14) a bond; R19 is selected from the group consisting of heterocycloalkyl and cycloalkyl; vy! is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocylo, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, aralkyl, heterocyclo or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
AMENDED SHEET 28.04.04
6. The use according to claim 5, wherein the compound corresponds in structure to formula VIC: J E Go A ~yi X Y \ N (CHy)m (CHa)p 1 NS SE o © ©O VIC
7. The use according to claim 5, wherein the sum of m + n + p =
1.
8. The use according to claim 5, wherein the compound corresponds in structure to formula IX: E Nyt Z N R20 or IN O oO © IX; and 7 is selected from the group consisting of S, NR®, SO, S0O,, and NSO,R’.
9. The use according to claim 8, wherein Z is NRE. AMENDED SHEET 28.04.04
10. The use according to claim 5, wherein the compound corresponds in structure to formula VIII: J \ N Y X Y \ n (CH)m (CH), R20 S(O) VIII
0 .
11. The use according to claim 5, wherein the compound corresponds in structure to formula X: E NY Z N SO, X 0 ; and 7 is selected from the group consisting of S, NR®, SO, SO,, and NSO,R’.
12. The use according to claim 11, wherein Z is NRC.
13. A use of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to prepare a pharmaceutical composition for treating a condition associated with pathological matrix metalloprotease (MMP) activity in a subject having or susceptible to such a condition, wherein: the compound or salt inhibits the activity of one or more of MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibitory activity against MMP-1; the compound corresponds in structure to formula VIC: AMENDED SHEET 28.04.04
\ / N
(CHpm (CH),
R2 S(O), ls) VIC ;
R20 ig -NH-0-R14;
R14 js selected from the group consisting of hydrogen and C(W) R25;
) W is selected from the group consisting of O and S;
R25 jig selected from the group consisting of C;-Cg-alkyl, aryl, C,-Cg-alkoxy, heteroaryl-C,-Cg-alkyl, C4-Cg-cycloalkyl-Cqy-Cg-alkyl, aryloxy, aryl-C,-Cg-alkoxy, aryl-C,-Cg-alkyl, heteroaryl, and amino C,-Cg-alkyl, wherein:
the amino C;-Cg-alkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C;-Cg-alkyl, aryl, aryl-C,-Cg-alkyl, C4-Cg-cycloalkyl-Cp-Cg-alkyl, aryl-C,-Cg-alkoxycarbonyl,
Cy -Cg-alkoxycarbonyl, and C,-Cg-alkanoyl, or the amino C;-Cg-alkyl nitrogen, together with the two substituents attached thereto, form a 5- to 8 -membered heterocyclo or hetercaryl ring;
g is 2;
m is zero, 1, or 2;
n is zero, 1, or 2;
p is zero, 1, or 2;
the sumof m +n +p =1, 2 , 3, or 4;
as to X, Y¥, and Z:
(a) one of X, Y, and Z is selected from the group consisting of C(0), NR®, S, S(O), S(0),, and NS(0),R7, and the remaining two of X, Y, and Z are cr8R? and CrIORI! |, or
AMENDED SHEET 28.04.04
(b) X and Z, or Z and Y together constitute a moiety selected from the group consisting of NRéC (0), NR®s5 (0), NRSS(0),, NRSS, NR®O, SS, NRONR®, and OC(0), with the remaining one of X and Y being cr8Rr?, or (c) n is zero and X, Y, and Z together constitute a moiety selected from the group consisting of: 0 0 I 0 0 RS RS’ 6 6 6 NZ 6" ~N PY ~~ ’ R S R R S R
N . Np NTN $d SE I A 12 i gl2 gl? R © 0 6 > 6 Rr PR N NT, $3 fs I glz p12’ giz gl2' R® 6 6 > , NEw a A SE Gh EE A * x J PY ~~ \ R® 0 * R® BY SNA R12 R12’ S we pe N S R SE R13 R13 R13 R13 RZ R12’ Ny Ny ON PN FY YY ry wherein wavy lines are bonds to the atoms of the depicted ring; R® and R®' are independently selected from the group consisting of hydrogen, formyl, sulfonic-Cq-Cg-alkyl, C1-Cg -alkoxycarbonyl-C;-Cg-alkyl, hydroxycarbonyl-Cq-Cg-alkyl, AMENDED SHEET 28.04.04
C,-Cg-alkylcarbonyl-C, -Cg-alkyl, R8R?-aminocarbonyl-Cy-Cg-alkyl, C, -C¢-alkoxycarbonyl-C,-Cg-alkylcarbonyl, hydroxycarbonyl-Cq -Cg-alkylcarbonyl, C;-Cg-alkylecarbonyl-C; -Cg-alkylcarbonyl, C, -C¢-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C,-Cg-alkylcarbonylcarbonyl, R8R?-aminocarbonylcarbonyl, C;,-Cg-alkanoyl, aryl-C;-Cg-alkyl, aroyl, bis (C;-Cg-alkoxy-Cq-Cg-alkyl)-Cy-Cg-alkyl, C,-Cg-alkyl, C,-Cg-haloalkyl, C,-Cg-perfluoroalkyl, C,-Cg-trifluoromethylalkyl, C,-Cg-perfluoroalkoxy-C;-Cg-alkyl, C,-Cg-alkoxy-C;-Cg-alkyl, C3-Cg-cycloalkyl, heterocarylcarbonyl, heterocyclocarbonyl, 3- to 8- membered heterocycloalkyl, 3- to 8-membered heterocycloalkylcarbonyl, aryl, 5- to 6-membered heterocyclo, 5- to 6-membered heteroaryl, C3-Cg-cycloalkyl-C;-Cg-alkyl, aryloxy-C;~Cg-alkyl, heteroaryloxy-C;-Cg-alkyl, heteroaryl-C;-Cg-alkoxy-Cq-Cg-alkyl, heteroarylthio-C; -Cg-alkyl, arylsulfonyl, C,-Cg-alkylsulfonyl, 5- to 6-membered heteroarylsulfonyl, carboxy-C; -Cg-alkyl, C,-C,4-alkoxycarbonyl-Cq-Cg-alkyl, aminocarbonyl, C,-Cg-alkyl (R8N) iminocarbonyl, aryl (R8N) iminocarbonyl, 5- to 6- membered heterocyclo (RBN)iminocarbonyl, arylthio-C,-Cg-alkyl, C,-Cg-alkylthio-Cy-Cg-alkyl, arylthio-C53-Cg-alkenyl, C,-C4-alkylthio-C3-Cg-alkenyl, 5- to 6-membered heteroaryl-C,-Cg-alkyl, halo-Cq-Cg-alkanoyl, hydroxy-C; -Cg-alkanoyl, thiol-Cq-Cg-alkanoyl, C3-Cg-alkenyl, C;-Cg-alkynyl, C,-C4-alkoxy-C;-Cy-alkyl, C, -Cg-alkoxycarbonyl, aryloxycarbonyl, NRSRY- (R8) iminomethyl, NRBR?-C; -C5-alkylcarbonyl, hydroxy-C;-Cg-alkyl, R8RY -aminocarbonyl, rR8R? -aminocarbonyl-Cq-Cg-alkylcarbonyl, hydroxyaminocarbonyl, AMENDED SHEET 28.04.04
R8R?-aminosulfonyl, R8R?-aminosulfon-C; -Cg-alkyl,
R®R?-amino-C; -Cg-alkylsulfonyl, and R8R%-amino-Cy-Cg-alkyl;
R7 is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C;-Cg-alkyl, C3-Cg-alkynyl, C3-Cg-alkenyl, C,-Cg-carboxyalkyl, and Cq-Cg-hydroxyalkyl;
as to R%:
RB is selected from the group consisting of hydrogen, hydroxy, Cq,-Cg-alkyl, C,-Cg-alkanoyl, aroyl, aryl, aryl-Cq,-Cg-alkyl, heteroaryl, heterocaryl-C;-Cg-alkyl,
Cp -Cg-alkynyl, C,-Cg-alkenyl, thiol-C,-Cg-alkyl,
C,-Cg-alkylthio-C,-Cg-alkyl, cycloalkyl, cycloalkyl-Cq-Cg-alkyl,
heterocyclo-C;-Cg-alkyl, C,-Cg-alkoxy-Cp-Cg-alkyl,
arylalkoxy-C,-Cg-alkyl, Cy -Cg-alkoxy-Cq-Cg-alkoxy-C; -Cg-alkyl, hydroxy-C; -Cg-alkyl, hydroxycarbonyl-C,-Cg-alkyl, hydroxycarbonylaryl-C; -Cg-alkyl, aminocarbonyl-Cq-Cg-alkyl, aryloxy-Cq -Cg-alkyl, heteroaryloxy-C; -Cg-alkyl, arylthio-C;-Cg-alkyl, heteroarylthio-C;-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C,-Cg-alkyl, trifluoromethyl-Cq-Cg-alkyl, halo-C;-Cg-alkyl, alkoxycarbonylamino-Cq-Cg-alkyl, and amino-Cq-Cg-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C;-Cg-alkyl, aryl-C,-Cg-alkyl, cycloalkyl, and Cq-Cg-alkanoyl, or
R8 and RP, together with the carbon to which they are bonded, form a carbonyl group, or RS and rR’ or RS and rT together with the atom(s) to which they are bonded, form a 5- to g-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
AMENDED SHEET 28.04.04 as to R°:
RY is selected from the group consisting of hydrogen, hydroxy, C;-Cg-alkyl, C,-Cg-alkanoyl, aroyl, aryl, aryl-C;-Cg-alkyl, heteroaryl, heteroaryl-C;-Cg-alkyl, Cy-Cg-alkynyl, C,-Cg-alkenyl, thiol-Cq-Cg-alkyl, C,-Cg-alkylthio-C;-Cg-alkyl, cycloalkyl, cycloalkyl-Cq-Cg-alkyl, heterocyclo-C;-Cg-alkyl, C,-Cg-alkoxy-Cy-Cg-alkyl, arylalkoxy-Cq-Cg-alkyl, Cy -Cg-alkoxy-Cy -Cg-alkoxy-Cy -Cg-alkyl, hydroxy-Cq -Cg-alkyl, hydroxycarbonyl-C;-Cg-alkyl, hydroxycarbonylaryl-C;-Cg-alkyl, aminocarbonyl-Cq-Cg-alkyl, aryloxy-C,-Cg-alkyl, heteroaryloxy-Cy-Cg-alkyl, arylthio-Cq-Cg-alkyl, heterocarylthio-C;-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C;-Cg-alkyl, trifluoromethyl-C,-Cg-alkyl, halo-C,-Cg-alkyl, alkoxycarbonylamino-C;-Cg-alkyl, and amino-C;-Cg-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C,-Cg-alkyl, aryl-C,-Cg-alkyl, cycloalkyl, and C,-Cg-alkanoyl, or
R8 and rR, together with the carbon to which they are bonded form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to RY: R10 jis selected from the group consisting of hydrogen, hydroxy, Cq-Cg-alkyl, Cq-Cg-alkanoyl, aroyl, aryl, aryl-C,-Cg-alkyl, heteroaryl, heteroaryl-C,-Cg-alkyl, Cy-Cg-alkynyl, C,-Cg-alkenyl, thiol-Cq-Cg-alkyl, C,-Cg-alkylthio-Cy-Cg-alkyl, cycloalkyl, AMENDED SHEET 28.04.04 cycloalkyl-Cq-Cg-alkyl, heterocyclo-Cq-Cg-alkyl, C1-Cg-alkoxy-C;-Cg-alkyl, arylalkoxy-C;-Cg-alkyl, C,-Cg-alkoxy-Cy-Cg-alkoxy-Cy-Cg-alkyl, hydroxy-C; -Cg-alkyl, hydroxycarbonyl-C,-C¢-alkyl, hydroxycarbonylaryl-Cy-Cg-alkyl, aminocarbonyl-Cy-Cg-alkyl, aryloxy-C,-Cg-alkyl, heteroaryloxy-C;-Cg-alkyl, arylthio-C,-Cg-alkyl, heterocarylthio-C,-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C;-Cg-alkyl, trifluoromethyl-C,-Cg-alkyl, halo-Cq-Cg-alkyl, alkoxycarbonylamino-C, -Cg-alkyl, and amino-C, -Cc-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C,-Cg-alkyl, aryl-C,-Cg-alkyl, cycloalkyl, and C,-Cg-alkanoyl, R10 ang rll, together with the carbon to which they are bonded form a carbonyl group, Or R10 and rR1l or r8 and r10, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to RY: rl is selected from the group consisting of hydrogen, hydroxy, C,-Cg-alkyl, Cy -Cg-alkanoyl, aroyl, aryl, aryl-Cq-Cg-alkyl, heteroaryl, heteroaryl-C;-Cg-alkyl, Cy-Cg-alkynyl, C,-Cg-alkenyl, thiol-C;-Cg-alkyl, Cy-Cg-alkylthio-Cp-Cg-alkyl, cycloalkyl, cycloalkyl-C, -Cg-alkyl, heterocyclo-C,-Cg-alkyl, C,-Cg-alkoxy-Cp-Cg-alkyl, arylalkoxy-C;-Cg-alkyl, C,-Cg-alkoxy-Cy-Cg-alkoxy-Cy-Cg-alkyl, hydroxy-C;-Cg-alkyl, hydroxycarbonyl-C;-Cg-alkyl, hydroxycarbonylaryl-C;-Cg-alkyl, AMENDED SHEET 28.04.04 aminocarbonyl-C;-Cg-alkyl, aryloxy-C,-Cg-alkyl,
heteroaryloxy-C;-Cg-alkyl, arylthio-Cq-Cg-alkyl,
heteroarylthio-Cq-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-Cq-Cg-alkyl, trifluoromethyl-C;-Cg-alkyl, halo-Cq-Cg-alkyl, alkoxycarbonylamino-C,; -Cg-alkyl, and amino-C,-Cg-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C;-Cg-alkyl, aryl-Cq-Cg-alkyl,
cycloalkyl, and C,-Cg-alkanoyl, or
R10 ana rll, together with the carbon to which they are bonded form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
only one of r8 and R? or RIC and rl is hydroxy;
R12 and rR12' are independently selected from the group consisting of hydrogen, Cq-Cg-alkyl, aryl, aryl-C,-Cg-alkyl, heteroaryl, heteroarylalkyl, C,-Cg-alkynyl, C,-Cg-alkenyl, thiol-Cq-Cg-alkyl, cycloalkyl, cycloalkyl-C;-Cg-alkyl, heterocyclo-C;-Cg-alkyl, C,-Cg-alkoxy-C; -Cg-alkyl, aryloxy-Cq-Cg-alkyl, amino-C, -Cg-alkyl,
Cy -Cg-alkoxy-Cq-Cg-alkoxy-C;-Cg-alkyl, hydroxy-C, -Cg-alkyl, hydroxycarbonyl-C; -Cg-alkyl, hydroxycarbonylaryl-C;-Cg-alkyl, aminocarbonyl-Cq-Cg-alkyl, aryloxy-Cp-Cg-alkyl, heteroaryloxy-C;-Cg-alkyl, C,-Cg-alkylthio-Cy-Cg-alkyl, arylthio-Cq-Cg-alkyl, heteroarylthio-C,-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C,-Cg-alkyl, trifluoromethyl-C,-Cg-alkyl,
AMENDED SHEET 28.04.04 halo-C;-Cg-alkyl, alkoxycarbonylamino-C,-Cg-alkyl, and amino-C, -Cc-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of Cy-Cg-alkyl, aryl-C,-Cg-alkyl, cycloalkyl, and
C,-Cg-alkanoyl;
R13 is selected from the group consisting of hydrogen, benzyl, phenyl, C,-Cg-alkyl, C,-Cg-alkynyl, C,-Cg-alkenyl, and C,-Cg-hydroxyalkyl;
E is selected from the group consisting of:
(1) -co®ld)-, (2) -(rY?)co-, (3) -CONH-, (4) -HNCO-, (5) -CO-, (6) -S0,-R1%-, (7) -R1%-50;-, (8) -S503-, (9) -NH-S053-, (10) -SO,-NH-, : (11) -S-, (12) -NH-CO-0O-, (13) -0-CO-NH-, and (14) a bond; R19 is selected from the group consisting of heterocycloalkyl and cycloalkyl; and vy! is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocyclo, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein:
AMENDED SHEET 28.04.04 the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
14. The use according to claim 13, wherein Z is selected from the group consisting of O, S, and NR®.
15. The use according to claim 13, wherein m = zero, n = 1, p= 1, and Z is NR°.
16. The use according to claim 13, wherein the compound ) corresponds in structure to formula VIC-1: E X Y \ / N (CH)m (CH), R20 S(O (© VIC-1
0 .
17. The use according to claim 13, wherein the compound corresponds in structure to formula VIC-2: X \, , \ / N A (CHam (CH), R20 S(O), VIC-2
0 . AMENDED SHEET 28.04.04
18. The use according to claim 13, wherein the compound corresponds in structure to formula IX-1: Ey z N HONH JO SO; 0 IX-1.
19. The use according to claim 13, wherein the compound corresponds in structure to formula IX-2: N ~~ HONH SO, 0 IX-2.
20. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound corresponds in structure to formula B: \ X Y Q R vl \ / yd Na pd Ng yd CH,) (CHm (CHyp), R20 S(O), Oo B ; R20 is selected from the group consisting of -0-r21, -NH-0-R22, -NH-0-R}%, and -NR26R27; R21 is selected from the group consisting of hydrogen, C,-Cg-alkyl, aryl, and aryl-C;-Cg-alkyl; R22 is a selectively removable protecting group; r1l%4 is selected from the group consisting of hydrogen, and c(W)R?>; W is selected from the group consisting of O and S; AMENDED SHEET 28.04.04
R25 js selected from the group consisting of Cq-Cg-alkyl, aryl, Cq-Cg-alkoxy, heteroaryl-Cq-Cg-alkyl, C,-Cg-cycloalkyl-Cq-Cg-alkyl, aryloxy, aryl-C,-Cg-alkoxy, aryl-Cq-Cg-alkyl, heteroaryl, and amino C,-Cg-alkyl, wherein:
the amino C;-Cg-alkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of Cq-Cg-alkyl, aryl, aryl-C,-Cg-alkyl, C3-Cg-cycloalkyl-Cq-Cg-alkyl, aryl-Cq-Cg-alkoxycarbonyl, C,-Cg-alkoxycarbonyl, and Cq-Cg-alkanoyl, or the amino C;-Cg-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring; as to R*® and R*":
R26 and R27 are independently selected from the group consisting of hydrogen, C;-Cg-alkyl, amino Cy -Cg-alkyl, hydroxy C,-Cg-alkyl, aryl, and aryl-C,-Cg-alkyl, or
R26 and R27, together with the depicted nitrogen atom, form a 5- to S8-membered ring containing zero or one additional heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur;
g is zero, 1, or 2;
m is zero, 1, or 2;
n is zero, 1, or 2;
p is zero, 1, or 2;
the sumof m + n+p =1, 2 , 3, or 4;
as to X, Y, and Z:
(a) one of X, YY, and Z is selected from the group consisting of C(0), NR®, S, §(0), S(0),, and NS(0),R’, and the remaining two of X, Y, and Z are CrRBR? , and cr1iOgll , or
(b) X and Z, or Zz and Y together constitute a moiety . selected from the group consisting of NRéC (0), NR®S (0),
NR6S (0),, NRSsS, NR®O, SS, NRONR®, and 0C(0), with the remaining one of X and Y being CR8R?, or
AMENDED SHEET 28.04.04
(¢) n is zero and X, Y, and Z together constitute a moiety selected from the group consisting of: Q 0 0 0 RS J RS’ 6 I 6 6 \ 4 6 NG RR s R R s R 12 i R12 gl?’ R ol 0 6 pe 6 RS YY FEN ve > ,
I . giz gl2’ plz gl?! R 6 ] / > wn 4 FY FY YY fo PN JE GE ~~ rE 0 2 Ae N s R pd RS AEE 4 R13 R13 R13 R13 r12 R12’ Ne NS > el oom Le FOOYY TY wherein wavy lines are bonds to the atoms of the depicted ring; R® and R®' are independently selected from the group consisting of hydrogen, formyl, sulfonic-C,-Cg-alkyl, C, -Cg-alkoxycarbonyl-Cq -Cg-alkyl, hydroxycarbonyl-C,-Cg-alkyl, C,-Cg-alkylcarbonyl-C,-Cg-alkyl, R8R?-aminocarbonyl-C; -Cg-alkyl, C,-Cg -alkoxycarbonyl-Cq -Cg -alkylcarbonyl, hydroxycarbonyl-Cq-Cg- alkylcarbonyl, C,-Cg -alkylcarbonyl-C;-Cg-alkyl carbonyl, C;-Cg -alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl + C1 -Cg-alkylcarbonylcarbonyl , AMENDED SHEET 28.04.04
R8R?-aminocarbonylcarbonyl, C,-Cg-alkanoyl, aryl-C,-Cg-alkyl, aroyl, bis (Cp -Cg-alkoxy-Cq-Cg-alkyl) -C;-Cg-alkyl, C,-Cg-alkyl, Cq-Cg-haloalkyl, C,-Cg-perfluoroalkyl, C,-Cg-trifluoromethylalkyl, C,-Cg-perfluorocalkoxy-C;-Cg-alkyl, Cq-Cg-alkoxy-Cj-Cg-alkyl, C3-Cg-cycloalkyl, heteroarylcarbonyl, heterocyclocarbonyl, 3- to 8- membered heterocycloalkyl, 3- to 8-membered heterocycloalkylcarbonyl, aryl, 5- to 6-membered heterocyclo, 5- to 6-membered heteroaryl, C3-Cg-cycloalkyl-Cq-Cg-alkyl, aryloxy-Cq-Cg-alkyl, . heteroaryloxy-C;-Cg-alkyl, heteroaryl-Cq-Cg-alkoxy-C;-Cg-alkyl, heteroarylthio-C;-Cg-alkyl, arylsulfonyl, C;-Cg-alkylsulfonyl, 5- to 6-membered heteroarylsulfonyl, carboxy-C, -Cg-alkyl, Cq,-C4-alkoxycarbonyl-C;-Cg-alkyl, aminocarbonyl, Cy -Cg-alkyl (R8N) iminocarbonyl, aryl (R8N) iminocarbonyl, 5- to 6- membered heterocyclo (RBN) iminocarbonyl, arylthio-C,-Cg-alkyl, C,-Cg-alkylthio-C;-Cg-alkyl, arylthio-C5-Cg-alkenyl, C,-C4-alkylthio-C3-Cg-alkenyl, 5- to 6-membered heterocaryl-C,-Cg-alkyl, halo-C, -Cg-alkanoyl, hydroxy-C, -Cg-alkanoyl, thiol-C,-Cg-alkanoyl, C;-Cg-alkenyl, C3-Cg-alkynyl, C1-C4-alkoxy-Cy-Cy-alkyl, C,-Cg-alkoxycarbonyl, aryloxycarbonyl, NR8R?- (R8) iminomethyl, NR8R?-C, -C-alkylcarbonyl, hydroxy-C, -Cg-alkyl, rR8R?-aminocarbonyl, rR8R?-aminocarbonyl-C;-Cg-alkylcarbonyl, hydroxyaminocarbonyl, R8R%-aminosul fonyl, R8RZ-aminosulfon-Cy-Cg-alkyl, R8RI-amino-C-Cg-alkylsulfonyl, and R8R?-amino-C; -Cg-alkyl;
R7 is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C,-Cg-alkyl, C3-Cg-alkynyl, C3-Cg-alkenyl, C;-Cg-carboxyalkyl, and C, -Cg-hydroxyalkyl;
as to R%:
R8 is selected from the group consisting of hydrogen, hydroxy, Cq-Cg-alkyl, Cq-Cg-alkanoyl, aroyl, aryl, AMENDED SHEET 28.04.04 aryl-C; -Cg-alkyl, heteroaryl, heteroaryl-C,-Cg-alkyl, Cy-Cg-alkynyl, C,-Cg-alkenyl, thiol-Cy-Cg-alkyl, C,-Cg-alkylthio-C;-Cg-alkyl, cycloalkyl, cycloalkyl-Cq-Cg-alkyl, heterocyclo-Cq-Cg-alkyl, C,-Cg-alkoxy-C;-Cg-alkyl, arylalkoxy-Cq-Cg-alkyl, Cy -Cg-alkoxy-Cp-Cg-alkoxy-C; -Cg-alkyl, hydroxy-Cq -Cg-alkyl, hydroxycarbonyl-C;-Cg-alkyl, hydroxycarbonylaryl-C,-Cg-alkyl, aminocarbonyl-Cq-Cg-alkyl, aryloxy-C,-Cg-alkyl, heterocaryloxy-C,-Cg-alkyl, arylthio-Cq-Cg-alkyl, heteroarylthio-C;-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C; -Cg-alkyl, trifluoromethyl-C,;-Cg-alkyl, halo-Cq-Cg-alkyl, alkoxycarbonylamino-Cq -Cg-alkyl, and amino-Cq-Cg-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C;-Cg-alkyl, aryl-Cq-Cg-alkyl,
cycloalkyl, and C,-Cg-alkanoyl, or .
R® and rR, together with the carbon to which they are bonded form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R%:
RY is selected from the group consisting of hydrogen, hydroxy, C,-Cg-alkyl, C,-Cg-alkanoyl, aroyl, aryl, aryl-Cq-Cg-alkyl, heteroaryl, heteroaryl-C;-Cg-alkyl, Cp-Cg-alkynyl, C,-Cg-alkenyl, thiol-C,-Cg-alkyl, : C,-Cg-alkylthio-C;-Cg-alkyl, cycloalkyl, cycloalkyl-C;-Cg-alkyl, heterocyclo-Cq-Cg-alkyl, C,-Cg-alkoxy-C;-Cg-alkyl, arylalkoxy-Cq-Cg-alkyl, C,-Cg-alkoxy-Cq-Cg-alkoxy-Cq-Cg-alkyl, hydroxy-C, -Cg-alkyl, hydroxycarbonyl-Cq-Cg-alkyl, hydroxycarbonylaryl-Cq-Cg-alkyl, aminocarbonyl-C,-Cg-alkyl,
AMENDED SHEET 28.04.04 aryloxy-Cq-Cg-alkyl, heteroaryloxy-C,-Cg-alkyl,
arylthio-C,-Cg-alkyl, heterocarylthio-C,-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C; -Cg-alkyl,
trifluoromethyl-C,-Cg-alkyl, halo-C,-Cg-alkyl,
alkoxycarbonylamino-C; -Cg-alkyl, and amino-C, -Cg-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C,-Cg-alkyl, aryl-C,-Cg-alkyl, cycloalkyl, and C,-Cg-alkanoyl, or
RE and r?, together with the carbon to which they are bonded, form a carbonyl group, or r® and R® or r® and RC, together with the atom(s) to which they are bonded, form a 5- to 8 -membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R*:
R10 is selected from the group consisting of hydrogen, hydroxy, C,-Cg-alkyl, Cy -Cg-alkanoyl, aroyl, aryl, aryl-C,-Cg-alkyl, heteroaryl, heteroaryl-C,-Cg-alkyl, Cp-Cg-alkynyl, C,-Cg-alkenyl, thiol-Cq-Cg-alkyl, C,-Cg-alkylthio-C;-Cg-alkyl, cycloalkyl, cycloalkyl-C,-C.-alkyl, heterocyclo-Cq-Cg-alkyl, Cy ~C-alkoxy-Cy~Cg-alkyl, arylalkoxy-C,-Cg-alkyl, C,-Cg-alkoxy-C;-Cg-alkoxy-Cy-Cg-alkyl, hydroxy-C, -Cg-alkyl, hydroxycarbonyl-C;-Cg-alkyl, hydroxycarbonylaryl-Cq-Cg-alkyl, aminocarbonyl-Cq -Cg-alkyl, aryloxy-Cq -Cg-alkyl, heteroaryloxy-C, -Cg-alkyl, arylthio-C;-Cg-alkyl, heteroarylthio-C;-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C,-Cc-alkyl,
AMENDED SHEET 28.04.04 trifluoromethyl-C;-Cg-alkyl, halo-C,-Cg-alkyl, alkoxycarbonylamino-C, -Cg-alkyl, and amino-C;-Cg-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C;-Cg-alkyl, aryl-Cq-Cg-alkyl, cycloalkyl, and C;-Cg-alkanoyl,
R10 and R1l, together with the carbon to which they are bonded form a carbonyl group, Or
R10 and rR! or R® and R10, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R':
R11 is selected from the group consisting of hydrogen, hydroxy, C;-Cg-alkyl, C,-Cg-alkanoyl, aroyl, aryl, aryl-C,-Cg-alkyl, heteroaryl, heteroaryl-C,-Cg-alkyl, Co-Cg-alkynyl, C,-Cg-alkenyl, thiol-C,-Cg-alkyl, C,-Cg-alkylthio-Cy-Cg-alkyl, cycloalkyl, cycloalkyl-Cq-Cg-alkyl, heterocyclo-C,-Cg-alkyl, C,-Cg-alkoxy-C;-Cg-alkyl, arylalkoxy-Cq-Cg-alkyl, C,-Cg-alkoxy-Cy -Cg-alkoxy-C; -Cg-alkyl, hydroxy-C; -Cg-alkyl, hydroxycarbonyl-Cq-Cg-alkyl, hydroxycarbonylaryl-C,-Cg-alkyl, aminocarbonyl-C,-Cgc-alkyl, aryloxy-Cy-Cg-alkyl, heteroaryloxy-Cq-Cg-alkyl, arylthio-C,-Cg-alkyl, heteroarylthio-Cy-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-Cq-Cg-alkyl, trifluoromethyl-Cq-Cg-alkyl, halo-Cq-Cg-alkyl, alkoxycarbonylamino-C, -Cg-alkyl, and amino-Cq-Cg-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C,;-Cg-alkyl, aryl-Cq-Cg-alkyl, AMENDED SHEET 28.04.04 cycloalkyl, and C;-Cg-alkanoyl, or
R10 and R11, together with the carbon to which they are bonded form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
only one of R® and R? or rR! and ri! is hydroxy;
RY2 and R1?' are independently selected from the group consisting of hydrogen, C;-Cg-alkyl, aryl, aryl-C,-Cg-alkyl, heteroaryl, heteroarylalkyl, C,-Cg-alkynyl, C,-Cg-alkenyl, thiol-C,-Cg-alkyl, cycloalkyl, cycloalkyl-C;-Cg-alkyl, heterocyclo-C,-Cg-alkyl, C,-Cg-alkoxy-Cq-Cg-alkyl, aryloxy-C;-Cg-alkyl, amino-C,-Cg-alkyl,
C,-Cg-alkoxy-C; -Cg-alkoxy-Cy-Cg-alkyl, hydroxy-C,-Cg-alkyl, hydroxycarbonyl-Cq-Cg-alkyl, hydroxycarbonylaryl-C,-Cg-alkyl, aminocarbonyl-Cq-Cg-alkyl, aryloxy-C;-Cg-alkyl, heteroaryloxy-C,-Cg-alkyl, C,-Cg-alkylthio-C,-Cg-alkyl, arylthio-Cq-Cg-alkyl, heteroarylthio-C;-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-Cq-Cg-alkyl, trifluoromethyl-C,-Cc-alkyl, halo-Cq-Cg-alkyl, alkoxycarbonylamino-C; -Cg-alkyl, and amino-C;-Cg-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C,-Cg-alkyl, aryl-C,-Cg-alkyl, cycloalkyl, and
R13 is selected from the group consisting of hydrogen, benzyl, phenyl, C,-Cg-alkyl, C,-Cg-alkynyl, C,-Cg-alkenyl, and C,-Cg-hydroxyalkyl;
Q is a 5- to 7-membered heterocyclo ring containing one or two nitrogen atoms one of which is bonded to the depicted phenyl group,
1 Co . . wherein A-R-E-Y is bonded at the 4-position relative to said phenyl-bonded nitrogen atom when Q is a 6- or 7-membered ring and at AMENDED SHEET 28.04.04 the 3- or 4-position relative to that nitrogen when Q is a 5 -membered ring; A is selected from the group consisting of:
(1) -0-,
(2) -S-,
(3) -Nrt7-,
(4) -co-N(rl7),
(5) -N(rR'7)-co-,
(6) -C0O-0-,
(7) -0-CO-,
(8) -0-C0-0-,
(9) -HC=CH-,
(10) -NH-CO-NH-,
(11) -c=C-,
(12) -NH-CO-O-,
(13) -O-CO-NH-,
(14) -N=N-,
(15) -NH-NH-,
(16) -CS-N(R®)-,
(17) -N(R'®)-cs-, and
(18) a bond;
R17 is selected from the group consisting of hydrogen, Cq-Cy-alkyl, and phenyl;
R18 is selected from the group consisting of hydrogen, C,-C4 alkyl, and phenyl;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heterocaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocyclothioalkyl, wherein:
the aryl, heteroaryl, cycloalkyl, or heterocyclo is optionally substituted with up to two substituents independently selected from the group consisting of halo, AMENDED SHEET 28.04.04 alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C,-Cy-alkylene-gdioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl; R is other than alkyl or alkoxyalkyl when A is -O- or -S-; E is selected from the group consisting of: (1) -co(rt?)-, (2) -(rRY®)co-, (3) -CONH-, (4) -HNCO-, (5) -CO-, (6) -SO,-R3-, (7) -r19-505-, (8) -S505-, (9) -NH-S05-, (10) -SO5-NH-, (11) -S-, (12) -NH-CO-0O-, (13) -0-CO-NH-, and (14) a bond; R1° is selected from the group consisting of heterocycloalkyl and cycloalkyl; and Y! is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted withup to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluorocalkoxy, and amino, wherein: AMENDED SHEET 28.04.04 the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
21. The compound or salt according to claim 20, wherein A is selected from the group consisting of -O- and -S-.
22. The compound or salt according to claim 20, wherein A is a bond.
23. The compound or salt according to claim 20, wherein R is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclo.
24. The compound or salt according to claim 20, wherein RM is hydrogen.
25. The compound or salt according to claim 20, wherein: W is O; and R* is selected from the group consisting of C,-Cs-alkyl, aryl, C,-C¢-alkoxy, heterocaryl-C,-C¢-alkyl, C,-Cy-cycloalkyl-C,-C¢-alkyl, and aryloxy.
26. The compound or salt according to claim 20, wherein the sum of m+n +p =1o0r 2.
27. The compound or salt according to claim 20, wherein the sum of m+n +p = 1.
28. The compound or salt according to claim 20, wherein Q is a 5-membered ring.
29. The compound or salt according to claim 20, wherein Q is a 7-membered ring.
30. The compound or salt according to claim 20, wherein Q is a 6-membered ring. AMENDED SHEET 28.04,04
31. The compound or salt according to claim 30, wherein: the compound corresponds in structure to formula B-A: z Q R Y! NT HONH SO, 0 B-A ; and Z is selected from the group consisting of S, NR®, SO, SO,, and NSO,R’.
32. The compound or salt according to claim 31, wherein Z is
NR®.
33. The compound or salt according to claim 20, wherein Q contains two nitrogen atoms.
34. The compound or salt according to claim 20, wherein R* is - NH-O-R*?.
35. The compound or salt according to claim 20, wherein R* is - NH-O-R™.
36. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound corresponds in structure to formula B-A: z Q R y! rd Na Ng” HONH SO, oO B-A ; 7 is selected from the group consisting of C(O), NR®, O, S, S(O), S(0),, and NS(O),R’; R® is selected from the group consisting of hydrogen, formyl, sulfonic-Cq-Cg-alkyl, C,-Cg-alkoxycarbonyl-Cy-Cg-alkyl, hydroxycarbonyl-Cq-Cg-alkyl, C,-Cg-alkylcarbonyl-C; -Cg-alkyl, AMENDED SHEET 28.04.04
R8R9 -aminocarbonyl-C;-Cg-alkyl, C,-Cg-alkoxycarbonyl-C, -Cc-alkylcarbonyl, hydroxycarbonyl-C; -Cg-alkylcarbonyl, C,-Cg-alkylcarbonyl-Cq-Cg-alkylcarbonyl, C,-Cg-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C;-Cg-alkylcarbonylcarbonyl, R8RY-aminocarbonylcarbonyl, C,-Cg-alkanoyl, aryl-C,-Cg-alkyl, aroyl, bis (C,-Cg-alkoxy-Cq-Cg-alkyl) -C;-Cg-alkyl, C;-Cg-alkyl, C,-Cg-haloalkyl, C,-Cg-perfluoroalkyl, Cq-Cg-trifluoromethylalkyl, C,-Cg-perfluoroalkoxy-C; -Cc-alkyl, Cq-Cg-alkoxy-C,-Cg-alkyl, C3-Cg-cycloalkyl, heteroarylcarbonyl, heterocyclocarbonyl, 3- to 8- membered heterocycloalkyl, 3- to 8-membered heterocycloalkylcarbonyl, aryl, 5- to 6-membered heterocyclo, 5- to 6-membered heteroaryl, C3-Cg-cycloalkyl-Cq-Cg-alkyl, aryloxy-Cq-Cg-alkyl, heteroaryloxy-C;-Cg-alkyl, heteroaryl-C,-Cg-alkoxy-Cq -Cg-alkyl, heteroarylthio-C;-Cg-alkyl, arylsulfonyl, C,-Cg-alkylsulfonyl, 5- to 6-membered heteroarylsulfonyl, carboxy-C;-Cg-alkyl, C;-C4-alkoxycarbonyl-C, -Cg-alkyl, aminocarbonyl, C, -Cg-alkyl (R8N) iminocarbonyl, aryl (R8N) iminocarbonyl, 5- to 6- membered heterocyclo (R8N) iminocarbonyl, arylthio-Cq-Cg-alkyl, C;-Cg-alkylthio-C,-Cg-alkyl, arylthio-C3-Cg-alkenyl, C,-C4-alkylthio-C3-Cg-alkenyl, 5- to 6 -membered heteroaryl-C, -Cg-alkyl, halo-C;-Cg-alkanoyl, hydroxy-C, -Cg-alkanoyl, . thiol-C;-Cg-alkanoyl, C;3-Cg-alkenyl, C3-Cg-alkynyl, C,-C4-alkoxy-C,-Cy-alkyl, C,-Cg-alkoxycarbonyl, aryloxycarbonyl, NR8R?- (R8) iminomethyl, NR8RZ-C; -Cg-alkylcarbonyl, hydroxy-C,-Cg-alkyl,
R8R?-aminocarbonyl, R8R?-aminocarbonyl-C, -Cg-alkylcarbonyl, hydroxyaminocarbonyl, rR8RP-aminosulfonyl, R8R?-aminosulfon-C, -C¢-alkyl, R8R?-amino-C, -Cg-alkylsulfonyl, and RER?-amino-Cq -Cg-alkyl; AMENDED SHEET 28.04.04
R’7 is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C;-Cg-alkyl, C5-Cg-alkynyl, C3-Cg-alkenyl, C,-Cg-carboxyalkyl, and C;-Cg-hydroxyalkyl;
as to R® and R’:
R® and R? are independently selected from the group consisting of hydrogen, hydroxy, C;-Cg-alkyl, C;-Cg-alkanoyl, aroyl, aryl, aryl-C;-Cg-alkyl, heteroaryl, heteroaryl-C;-Cg-alkyl, Cy-Cg-alkynyl, C,-Cg-alkenyl, thiol-C,-Cg-alkyl, Cq-Cg-alkylthio-Cq-Cg-alkyl, cycloalkyl, cycloalkyl-C,-Cg-alkyl, heterocyclo-C, -Cg-alkyl, C,-Cgz-alkoxy-Cq-Cg-alkyl, arylalkoxy-C,-Cg-alkyl, C,-Cg-alkoxy-Cq-Cg-alkoxy-C;-Cg-alkyl, hydroxy-C, -Cg-alkyl, hydroxycarbonyl-C,-Cg-alkyl, hydroxycarbonylaryl-Cq-Cg-alkyl, aminocarbonyl-C,-Cg-alkyl, aryloxy-C,-Cg-alkyl, heteroaryloxy-Cq-Cg-alkyl, arylthio-C,-Cg-alkyl, heteroarylthio-C;-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C,-Cg-alkyl, trifluoromethyl-C,-Cg-alkyl, halo-C,-Cg-alkyl, alkoxycarbonylamino-C,-Cg-alkyl, and amino-C, -Cg-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the : group consisting of C;-Cg-alkyl, aryl-C,-Cg-alkyl, : cycloalkyl, and Cq-Cg-alkanoyl, or rR® and RY, and the carbon to which they are bonded form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to g-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; only one of R8 and R® or RC and ri! is hydroxy;
Q is a 6-membered heterocyclo ring containing one or two nitrogen atoms one of which is bonded to the depicted phenyl group,
AMENDED SHEET 28.04.04 wherein A-R-E-Y' is bonded at the 4-position relative to said phenyl-bonded nitrogen; A is selected from the group consisting of: (1) -O-, (2) -8-, (3) -NR17-, (4) -co-N(r17), (5) -N(rl7)-co-, (6) -CO-0-, (7) -0-COo-, (8) -0-C0-0-, (9) -HC=CH-, (10) -NH-CO-NH-, (11) -C=C-, (12) -NH-CO-0O-, (13) -O-CO-NH-, (14) -N=N-, (15) -NH-NH-, (16) -CS-N(R8)-, (17) -N(R'®)-cs-, and (18) a bond; R17 is selected from the group consisting of hydrogen, C,-Cy-alkyl, and phenyl; R18 is selected from the group consisting of hydrogen, C1-Cy alkyl, and phenyl; R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, hetercarylthioalkyl, cycloalkylthioalkyl, and heterocyclothioalkyl, wherein: the aryl, heteroaryl, cycloalkyl, or heterocyclo is optionally substituted with up to two substituents independently selected from the group consisting of halo, AMENDED SHEET 28.04.04 alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C,-C,-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl; and R is other than alkyl or alkoxyalkyl when A is -O- or -S-; E is selected from the group consisting of: (1) -co(rl?)-, (2) -(R?)co-, (3) -CONH-, (4) -HNCO-, (5) -CO-, (6) -SO,-R1%-, (7) -r19-s0,-, (8) -SO,-, (9) -NH-S05-, (10) -SO,-NH-, (11) -S-, {12) -NH-CO-0O-, (13) -0-CO-NH-, and (14) a bond; R1% is selected from the group consisting of heterocycloalkyl and cycloalkyl; and vy! is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heterocaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminocalkyl, wherein: the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein: AMENDED SHEET 28.04.04 the amino nitrogen isoptionally substituted with up to two substituents independently selected from alkyl and arylalkyl.
37. The compound or salt according to claim 36, wherein Z is selected from the group consisting of S and NR.
38. The compound or salt according to claim 36, wherein: Z is NR®; and R® is selected from the group consisting of C,-C,-cycloalkyl, C,-Ce-alkyl, C,-C,-alkenyl, C,;-Cg-alkynyl, C,-Cgi-alkoxy-C,-Ce-alkyl, amino-C,-C,-alkyl, aminosulfonyl, heteroaryl-C,-C¢-alkyl, aryloxycarbonyl, and C,-C¢-alkoxycarbonyl.
39. The compound or salt according to claim 36, wherein A is a bond.
40. The compound or salt according to claim 39, wherein Q contains one nitrogen atom.
41. The compound or salt according to claim 40, wherein the compound corresponds in structure to the formula: O RPE HON S H N CN ON \ N Cry
42. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound corresponds in structure to formula B-3A: AMENDED SHEET 28.04.04 z E [gy N HONH S(O), B-3A O i
Z is selected from the group consisting of C(O), NR®, S, S(O), S(0),, and NS(O),R’;
R® is selected from the group consisting of hydrogen, formyl, sulfonic-Cq-Cg-alkyl, C,-Cg-alkoxycarbonyl-C,-Cg-alkyl, hydroxycarbonyl-C; -Cg-alkyl, Cq-Cg-alkylcarbonyl-Cq-Cg-alkyl, R®R?-aminocarbonyl-Cy-Cg-alkyl,
C,-Cg-alkoxycarbonyl-C; -Cg-alkylcarbonyl,
hydroxycarbonyl-C, -Cg-alkylcarbonyl,
C,-Cg-alkylcarbonyl-C;-Cg-alkylcarbonyl,
Cq-Cg-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl,
C,-Cg-alkylcarbonylcarbonyl, R8R?-aminocarbonylcarbonyl,
C,-Cg-alkanoyl, aryl-Cq-Cg-alkyl, aroyl,
bis (Cq-Cg-alkoxy-Cy-Cg-alkyl) -Cq-Cg-alkyl, C;-Cg-alkyl,
Cy -Cg-haloalkyl, C,-Cg-perfluoroalkyl, C,-Cg-trifluoromethylalkyl,
Cy -Cg-perfluoroalkoxy-Cq-Cg-alkyl, Cy -Cg-alkoxy-Cq,-Cg-alkyl,
C3-Cg-cycloalkyl, heteroarylcarbonyl, heterocyclocarbonyl, 3- to 8-
membered heterocycloalkyl, 3- to 8-membered heterocycloalkylcarbonyl,
aryl, 5- to 6-membered heterocyclo, 5- to é-membered heteroaryl,
C3-Cg-cycloalkyl-Cy-Cg-alkyl, aryloxy-C;-Cg-alkyl,
heteroaryloxy-C,-Cg-alkyl, heteroaryl-Cq-Cg-alkoxy-Cq-Cg-alkyl,
heteroarylthio-C;-Cg-alkyl, arylsulfonyl, C,-Cg-alkylsulfonyl, 5- to
6 -membered heteroarylsulfonyl, carboxy-C,-Cg-alkyl,
C,-C4-alkoxycarbonyl-Cy -Cg-alkyl, aminocarbonyl,
Cc, -Cg-alkyl (REN) iminocarbonyl, aryl (R8N) iminocarbonyl, 5- to 6-
membered heterocyclo (R8N)iminocarbonyl, arylthio-C,-Cg-alkyl, AMENDED SHEET 28.04.04
C,-Cg-alkylthio-C;-Cg-alkyl, arylthio-C5-Cg-alkenyl, C,-C4-alkylthio-C5-Cg-alkenyl, 5- to 6-membered heteroaryl-C,-Cg-alkyl, halo-C;-Cg-alkanoyl, hydroxy-C, -Cg-alkanoyl, thiol-C,-Cc-alkanoyl, C53-Cg-alkenyl, C4y-Cg-alkynyl, C,-C4-alkoxy-Cq-Cy4-alkyl, Cy -Cg-alkoxycarbonyl, aryloxycarbonyl, NRBR?- (R®) iminomethyl, NR®RI-C,-Cg-alkylcarbonyl, hydroxy-Cj-Cg-alkyl, R8R?-aminocarbonyl, R®R?-aminocarbonyl-C; -C¢-alkylcarbonyl, hydroxyaminocarbonyl, R8RY -aminosulfonyl, R®R®-aminosulfon-C,-Cg-alkyl, R8R?-amino-C; -Cg-alkylsulfonyl, and R8R?-amino-Cq-Cg-alkyl; 1"%6 yi
R’ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, Cq-Cg-alkyl, Cy-Cg-alkynyl, C3-Cg-alkenyl, C, -Cg-carboxyalkyl, and C, -Cg-hydroxyalkyl;
as to R® and R’:
R8® and R? are independently selected from the group consisting of hydrogen, hydroxy, Cp-Cg-alkyl, C;-Cg-alkanoyl, aroyl, aryl, aryl-Cq-Cg-alkyl, heteroaryl, heteroaryl-C,-Cg4-alkyl, Cp-Cg-alkynyl, C,-Cg-alkenyl, thiol-C,-Cg-alkyl, C,-Cg-alkylthio-Cq-Cg-alkyl, cycloalkyl, cycloalkyl-C;-Cg-alkyl, heterocyclo-C, -Cg-alkyl,
Cy -Cg-alkoxy-C;-Cg-alkyl, arylalkoxy-Cq-Cg-alkyl, © Cp-Cg-alkoxy-C;-Cg-alkoxy-C;-Cg-alkyl, hydroxy-C; -Cg-alkyl, hydroxycarbonyl-C;-Cg-alkyl, hydroxycarbonylaryl-C,-Cg-alkyl, aminocarbonyl-Cq-C¢-alkyl, aryloxy-Cq-Cg-alkyl, heteroaryloxy-Cq-Cg-alkyl, arylthio-Cyq-Cg-alkyl, heteroarylthio-C;-Cg-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, perfluoro-C,-Cg-alkyl, trifluoromethyl-Cq-Cg-alkyl, halo-Cq-Cg-alkyl, alkoxycarbonylamino-C,-Cg-alkyl, and amino-Cq-Cg-alkyl, wherein: AMENDED SHEET 28.04.04 the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C;-Cg-alkyl, aryl-C;-Cg-alkyl, cycloalkyl, and C;-Cg-alkanoyl, or R8® and RY, and the carbon to which they are bonded form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocycle or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; only one of R8 and R? or RO and rR! is hydroxy; Q is a 6-membered heterocyclo ring containing one or two nitrogen atoms, one of which is bonded to the depicted phenyl group; E is selected from the group consisting of: (1) -co(r'?)-, (2) -(rRY9)co-, (3) -CONH-, (4) -HNCO-, (5) -CO-, (6) -SO,-R19-, (7) -R19-50,-, (8) -505-, (9) -NH-SO5-, (10) -SO,-NH-, (11) -S-, (12) -NH-CO-0O-, (13) -0-CO-NH-, and (14) a bond; R1® is selected from the group consisting of heterocycloalkyl and cycloalkyl; and vy! is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocyclo, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: AMENDED SHEET 28.04.04 the aryl, heteroaryl, aralkyl, heterocyclo or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from alkyl and arylalkyl.
43. The compound or salt according to claim 42, wherein Q contains two nitrogen atoms.
44. The compound or salt according to claim 48, wherein the compound corresponds in structure to formula X: E NY! Zz N HONH ir SO,
45. The compound or salt according to claim 42, wherein Q contains one nitrogen atom.
46. The compound or salt according to claim 42, wherein the compound corresponds in structure to formula IX-1: E Syl Z N HONH Ir SO, 0 IX-1. AMENDED SHEET 28.04.04
47. The compound or salt according to claim 42, wherein the compound corresponds in structure to formula IX-2: N ~~ A E HONH SO, 0 IX-2.
48. The compound or salt according to claim 42, wherein Z is selected from the group consisting of S and NR®.
49. The compound or salt according to claim 48, wherein: Z is NR®; and R® is selected from the group consisting of C,-Cs-cycloalkyl, C,-Ce-alkyl, C,-Cs-alkenyl, C,;-Cs-alkynyl, C,-C¢-alkoxy-C,-Cs-alkyl, amino-C,-C¢-alkyl, aminosulfonyl, heteroaryl-C,;-Cs-alkyl, aryloxycarbonyl, and C,-C,-alkoxycarbonyl.
50. The compound or salt according to claim 49, wherein said compound corresponds in structure to the formula: O SVs HO S N H N N CH, OCF;
51. The compound or salt according to claim 50, wherein said compound corresponds in structure to the formula: 0 o © \7/ HO S N H OCH; N A
O . AMENDED SHEET 28.04.04
52. A pharmaceutical composition that comprises a compound or salt according to claim 20 dissolved or dispersed in a pharmaceutically acceptable carrier.
53. A pharmaceutical composition that comprises a compound or salt according to claim 36 dissolved or dispersed in a pharmaceutically acceptable carrier.
54. A pharmaceutical composition that comprises a compound or salt according to claim 39 dissolved or dispersed in a pharmaceutically acceptable carrier.
55. A pharmaceutical composition that comprises a compound or salt according to claim 42 dissolved or dispersed in a pharmaceutically acceptable carrier.
56. A pharmaceutical composition that comprises a compound or salt according to claim 48 dissolved or dispersed in a pharmaceutically acceptable carrier. AMENDED SHEET 28.04.04
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US31183799A | 1999-05-14 | 1999-05-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200109006B true ZA200109006B (en) | 2002-12-02 |
Family
ID=27757522
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200109006A ZA200109006B (en) | 1999-05-14 | 2001-10-31 | Aromatic sulfone hydroxamic acid metalloprotease inhibitor. |
Country Status (5)
| Country | Link |
|---|---|
| AR (1) | AR035547A1 (en) |
| CO (1) | CO5251417A1 (en) |
| PE (1) | PE20010202A1 (en) |
| UY (1) | UY26145A1 (en) |
| ZA (1) | ZA200109006B (en) |
-
2000
- 2000-05-15 UY UY26145A patent/UY26145A1/en not_active Application Discontinuation
- 2000-05-15 PE PE2000000455A patent/PE20010202A1/en not_active Application Discontinuation
- 2000-05-15 AR ARP000102342 patent/AR035547A1/en not_active Application Discontinuation
- 2000-05-15 CO CO00035030A patent/CO5251417A1/en not_active Application Discontinuation
-
2001
- 2001-10-31 ZA ZA200109006A patent/ZA200109006B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CO5251417A1 (en) | 2003-02-28 |
| AR035547A1 (en) | 2004-06-16 |
| UY26145A1 (en) | 2000-12-29 |
| PE20010202A1 (en) | 2001-02-19 |
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