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US20040209914A1 - Aromatic sulfone hydroxamic acids and their use as protease inhibitors - Google Patents

Aromatic sulfone hydroxamic acids and their use as protease inhibitors Download PDF

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Publication number
US20040209914A1
US20040209914A1 US10/730,403 US73040303A US2004209914A1 US 20040209914 A1 US20040209914 A1 US 20040209914A1 US 73040303 A US73040303 A US 73040303A US 2004209914 A1 US2004209914 A1 US 2004209914A1
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United States
Prior art keywords
alkyl
group
alkoxy
amino
substituted
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US10/730,403
Inventor
Thomas Barta
Daniel Becker
Louis Bedell
Terri Boehm
Jeffery Carroll
Gary DeCrescenzo
Yvette Fobian
John Freskos
Daniel Getman
Susan Hockerman
Carol Howard
Darren Kassab
Stephen Kolodziej
Madeleine Li
Joseph McDonald
Deborah Mischke
Joseph Rico
Nathan Stehle
Michael Tollefson
William Vernier
Clara Villamil
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Pharmacia LLC
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Pharmacia LLC
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Priority claimed from US09/570,731 external-priority patent/US6750228B1/en
Application filed by Pharmacia LLC filed Critical Pharmacia LLC
Priority to US10/730,403 priority Critical patent/US20040209914A1/en
Assigned to PHARMACIA CORPORATION reassignment PHARMACIA CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BARTA, THOMAS E., Bedell, Louis J., VERNIER, WILLIAM F., LI, MADELEINE H., HOWARD, CAROL P., KASSAB, DARREN J., Carroll, Jeffery N., Fobian, Yvette M., FRESKOS, JOHN N., HOCKRMAN, SUSAN L., KOLODZIEJ, STEPHEN A., RICO, JOSEPH G., BOEHM, TERRI L., DECRESCENZO, GARY A., MCDONALD, JOSEPH J., STEHLE, NATHAN W., TOLLEFSON, MICHAEL B., VILLAMIL, CLARA I., GETMAN, DANIEL P., BECKER, DANIEL P., MISCHKE, DEBORAH A.
Publication of US20040209914A1 publication Critical patent/US20040209914A1/en
Abandoned legal-status Critical Current

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Definitions

  • This invention is directed generally to proteinase (also known as “protease”) inhibitors, and, more particularly, to aromatic sulfone hydroxamate compounds (also known as “aromatic sulfone hydroxamic acid compounds”) and salts thereof (particularly pharmaceutically acceptable salts) that, inter alia, inhibit matrix metalloproteinase (also known as “matrix metalloprotease” or “MMP”) and/or aggrecanase activity.
  • MMP matrix metalloprotease
  • This invention also is directed to pharmaceutical compositions of such compounds and salts, and methods of using such compounds and salts to prevent or treat conditions associated with MMP and/or aggrecanase activity, particularly pathological conditions.
  • Connective tissue is a required component of all mammals. It provides rigidity, differentiation, attachments, and, in some cases, elasticity. Connective tissue components include, for example, collagen, elastin, proteoglycans, fibronectin, and laminin. These biochemicals make up (or are components of) structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea, and vitreous humor.
  • connective tissue turnover and/or repair processes are in equilibrium with connective tissue production.
  • Degradation of connective tissue is carried out by the action of proteinases released from resident tissue cells and/or invading inflammatory or tumor cells.
  • Matrix metalloproteinases a family of zinc-dependent proteinases, make up a major class of enzymes involved in degrading connective tissue. Matrix metalloproteinases are divided into classes, with some members having several different names in common use.
  • MMP-1 also known as collagenase 1, fibroblast collagenase, or EC 3.4.24.3
  • MMP-2 also known as gelatinase A, 72 kDa gelatinase, basement membrane collagenase, or EC 3.4.24.2
  • MMP-3 also known as stromelysin 1 or EC 3.4.24.17
  • proteoglycanase MMP-7 (also known as matrilysin)
  • MMP-8 also known as collagenase II, neutrophil collagenase, or EC 3.4.24.34
  • MMP-9 also known as gelatinase B, 92 kDa gelatinase, or EC 3.4.24.35
  • MMP-10 also known as stromelysin 2 or EC 3.4.24.22
  • MMP-1 I also known as stromelysin 3
  • MMP-12 also known as metalloelastase, human macrophage elastase or HME
  • MMP-13 also known as
  • MMPs Excessive breakdown of connective tissue by MMPs is a feature of many pathological conditions. Inhibition of MMPs therefore provides a control mechanism for tissue decomposition to prevent and/or treat these pathological conditions.
  • pathological conditions generally include, for example, tissue destruction, fibrotic diseases, pathological matrix weakening, defective injury repair, cardiovascular diseases, pulmonary diseases, kidney diseases, liver diseases, and diseases of the central nervous system.
  • Such conditions include, for example, rheumatoid arthritis, osteoarthritis, septic arthritis, multiple sclerosis, a decubitis ulcer, corneal ulceration, epidermal ulceration, gastric ulceration, tumor metastasis, tumor invasion, tumor angiogenesis, periodontal disease, liver cirrhosis, fibrotic lung disease, emphysema, otosclerosis, atherosclerosis, proteinuria, coronary thrombosis, dilated cardiomyopathy, congestive heart failure, aortic aneurysm, epidermolysis bullosa, bone disease, Alzheimer's disease, and defective injury repair (e.g., weak repairs, adhesions such as post-surgical adhesions, and scarring).
  • defective injury repair e.g., weak repairs, adhesions such as post-surgical adhesions, and scarring.
  • TNFs tumor necrosis factors
  • TNF- ⁇ is a cytokine that is presently 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. TNF- ⁇ can cause and/or contribute to the effects of inflammation (e.g.
  • TNF- ⁇ chronic release of active TNF- ⁇ can cause cachexia and anorexia. TNF- ⁇ also can be lethal.
  • MMP matrix metalloproteinase inhibitors
  • TNF- ⁇ release e.g., Gearing et al. Nature 376, 555-557 (1994).
  • McGeehan et al. See also, Nature 376, 558-561 (1994).
  • MMP inhibitors also have been reported to inhibit TNF- ⁇ convertase, a metalloproteinase involved in forming active TNF- ⁇ .
  • Matrix metalloproteinases also are involved in other biochemical processes in mammals. These include control of ovulation, postpartum uterine involution, possibly implantation, cleavage of APP ( ⁇ -amyloid precursor protein) to the ainyloid plaque, and inactivation of ( ⁇ 1 -protease inhibitor ( ⁇ 1 -PI). Inhibiting MMPs therefore may be a mechanism that may be used to control of fertility.
  • an endogenous or administered serine protease inhibitor (e.g., ⁇ 1 -PI) supports the treatment and prevention of pathological conditions such as emphysema, pulmonary diseases, inflammatory diseases, and diseases of aging (e.g., loss of skin or organ stretch and resiliency).
  • Metalloproteinase inhibitors include, for example, natural biochemicals, such as tissue inhibitor of metalloproteinase (TIMP), ⁇ 2-macroglobulin, and their analogs and derivatives. These are high-molecular-weight protein molecules that form inactive complexes with metalloproteinases.
  • TIMP tissue inhibitor of metalloproteinase
  • ⁇ 2-macroglobulin ⁇ 2-macroglobulin
  • a number of smaller peptide-like compounds also have been reported to inhibit metalloproteinases.
  • Mercaptoamide peptidyl derivatives for example, have been reported to inhibit angiotensin coniierting enzyme (also known as ACE) in vitro and in vivo.
  • ACE aids in the production of angiotensin II, a potent pressor substance in mammals. Inhibiting ACE leads to lowering of blood pressure.
  • hydroxamate compounds also have been reported to inhibit MMPs.
  • Such compounds reportedly include hydroxamates having a carbon backbone. See, e.g., WIPO Int'l Pub. No. WO 95/29892. See also, WIPO Int'l Pub. No. WO 97/24117. See also, WIPO Int'l Pub. No. WO 97/49679. See also, European Patent No. EP 0 780 386.
  • Such compounds also reportedly include hydroxamates having peptidyl backbones or peptidomimetic backbones. See, e.g, WIPO Int'l Pub. No. WO 90/05719. See also, WIPO Int'l Pub. No.
  • WO 93/20047 See also, WIPO Int'l Pub. No. WO 95/09841. See also, WIPO Int'l Pub. No. WO 96/06074. See also, Schwartz et al., Progr. Med. Chem., 29:271-334(1992). See also, Rasmussen et al., PharmacoL Ther., 75(1): 69-75 (1997). See also, Denis et al., Invest New Drugs, 15(3): 175-185 (1997). Sulfamato hydroxamates have additionally been reported to inhibit MMPs. See, WIPO Int'l Pub. No. WO 00/46221.
  • an MMP inhibitor drug it is often advantageous for an MMP inhibitor drug to target a certain MMP(s) over another MMP(s). For example, it is typically preferred to inhibit MMP-2, MMP-3, MMP-9, and/or MMP-13 (particularly MMP-13) when treating and/or preventing cancer, inhibiting of metastasis, and inhibiting angiogenesis. It also is typically preferred to inhibit MMP-13 when preventing and/or treating osteoarthritis. See, e.g., Mitchell et al., J Clin. Invest., 97:761-768 (1996). See also, Reboul et al., J Clin. Invest., 97:2011-2019 (1996).
  • MMP-1 and MMP-14 are involved in several homeostatic processes, and inhibition of MMP-1 and/or MMP-14 consequently tends to interfere with such processes.
  • MMP inhibitors exhibit the same or similar inhibitory effects against each of the MMPs.
  • batimastat a peptidomimetic hydroxamate
  • Marimastat another peptidomimetic hydroxamate
  • Marimastat has been reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum similar to batimastat, except that Marimastat reportedly exhibited an IC 50 value against MMP-3 of 230 nM. See Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
  • Marimastat 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, and prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although Marimastat exhibited some measure of efficacy via these markers, toxic side effects reportedly were observed. 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, and then spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction reportedly permits treatment to continue. See Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.
  • aggrecanase-1 also known as ADAMTS-4
  • articular cartilage contains large amounts of the proteoglycan aggrecan.
  • Proteoglycan aggrecan provides mechanical properties that help articular cartilage in withstanding compressive deformation during joint articulation.
  • the loss of aggrecan fragments and their release into synovial fluid caused by proteolytic cleavages is a central pathophysiological event in osteoarthritis and rheumatoid arthritis. It has been reported that two major cleavage sites exist in the proteolytically sensitive interglobular domains at the N-terminal region of the aggrecan core protein.
  • hydroxamate compounds have been reported to inhibit aggrecanase-1. Such compounds include, for example, those described in European Patent Application Publ. No. EP 1 081 137 A1. Such compounds also include, for example, those described in WIPO PCT Int'l Publ. No. WO 00/09000. Such compounds further include, for example, those described in WIPO PCT Int'l Publ. No. WO 00/59874.
  • hydroxamate compounds and salts thereof In view of the importance of hydroxamate compounds and salts thereof in the prevention or treatment of several NMP- and/or aggrecanase-related pathological conditions and the lack of enzyme specificity exhibited by at least some of the hydroxamates that have been in clinical trials, there continues to be a need for hydroxamates having greater enzyme inhibition specificity (preferably toward MMP-2, MMP-9, MMP-13, and/or aggrecanase, and particularly toward MMP-13 and/or aggrecanase), while exhibiting little or no inhibition of MMP activity essential to normal bodily function (e.g., tissue turnover and repair).
  • the following disclosure describes hydroxamate compounds and salts thereof that tend to exhibit such desirable activities.
  • This invention is directed to compounds that inhibit MMP (particularly MMP-2, MMP-9, and/or MMP-13) and/or aggrecanase activity, while generally exhibiting relatively little or no inhibition against MMP activity essential to normal bodily function (particularly MMP-1 and MMP-14 activity).
  • This invention also is directed to a method for inhibiting MMP and/or aggrecanase activity, particularly pathological activity. Such a method is particularly suitable to be used with mammals, such as humans, other primates (e.g., monkeys, chimpanzees. etc.), companion animals (e.g., dogs, cats, horses.
  • farm animals e.g., goats, sheep, pigs, cattle, etc.
  • laboratory animals e.g., mice, rats, etc.
  • wild and zoo animals e.g., wolves, bears, deer, etc.
  • the invention is directed in part to a compound or salt thereof.
  • the compound has a structure corresponding to Formula X:
  • the present invention also is directed to treatment methods that comprise administering a compound described above (or pharmaceutically-acceptable salt thereof) in an effective amount to a host mammal having a condition associated with pathological metalloprotease and/or aggrecanase activity.
  • a contemplated compound or salt thereof tends to exhibit, for example, inhibitory activity of one or more matrix metalloprotease (MMP) enzymes (e.g., MMP-2, MMP-9 and MMP-13), while exhibiting substantially less inhibition of MMP-1 and/or MMP-14.
  • MMP matrix metalloprotease
  • a contemplated compound exhibits an IC 50 value ratio against one or more of MMP-2, MMP-9, or MMP-13 as compared to its IC 50 value against MMP-1 and/or MMp-14 (e.g., IC 50 MMP-13:IC 50 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 described in the Example section below.
  • the process comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to prevent or treat the condition.
  • a condition may be, for example, tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, and a central nervous system disease.
  • Such conditions include osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermolysis bullosa, aortic aneurysm, weak injury repair, an adhesion, scarring, congestive heart failure, coronary thrombosis, emphysema, proteinuria, and Alzheimer's disease.
  • the prevention or treatment method comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to inhibit matrix metalloprotease-2, matrix metalloprotease-9, and/or matrix metalloprotease-13 activity.
  • the prevention or treatment method comprises administering an above-described compound or pharmaceutically acceptable salt, thereof to the host animal in an amount effective to prevent or treat a condition associated with TNF- ⁇ convertase activity.
  • a condition associated with TNF- ⁇ convertase activity examples include inflammation, a pulmonary disease, a cardiovascular disease, an autoimmune disease, graft rejection, a fibrotic disease, cancer, an infectious disease, fever, psoriasis, hemorrhage, coagulation, radiation damage, acute-phase responses of shock and sepsis, anorexia, and cachexia.
  • the prevention or treatment method comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to prevent or treat a condition associated with aggrecanase activity.
  • a condition may be, for example, an inflammatory disease or cancer.
  • This invention additionally is directed, in part, to pharmaceutical compositions comprising the above-described compounds or pharmaceutically acceptable salts thereof, and the use of those compositions in the above-described prevention or treatment processes.
  • This invention further is directed, in part, to the use of an above-described compound or pharmaceutically acceptable salt thereof for production of a medicament for use in the treatment of a condition related to MMP activity.
  • a condition may be, for example, tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, and a central nervous system disease.
  • Applicants have found that certain aromatic sulfone hydroxamates tend to be effective toward inhibiting MMPs, particularly those associated with excessive (or otherwise pathological) breakdown of connective tissue. Specifically, Applicants have found that these hydroxamates tend to be effective for inhibiting MMP-2 MMP-9, and/or MMP-13, which can be particularly destructive to tissue if present or generated in abnormally excessive quantities or concentrations. Applicants also have discovered that many of these hydroxamates tend to be effective toward inhibiting pathological aggrecanase activity.
  • hydroxamates tend to be selective toward inhibiting aggrecanase and/or MMPs associated with pathological condition conditions, and tend to avoid excessive inhibition of MMPs (particularly MMP-1 and MMP-14) essential to normal bodily function (e.g., tissue turnover and repair).
  • these hydroxamates tend to be particularly active toward inhibiting MMP-2, MMP-9, MMP-13, and/or aggrecanase activity in in vitro assays that are generally predictive of in vivo activity, while exhibiting minimal inhibition toward MMP-1 and/or MMP-14 in such assays. Examples of such in vitro assays are discussed in the example section below.
  • Compounds (or salts) that are particularly useful as selective MMP inhibitors exhibit, for example, an in vitro IC 50 value against one or more of MMP-2, MMP-9, and MMP-13 that is no greater than about 0.1 times the IC 50 value against MMP-1 and/or MMP-14, more preferably no greater than about 0.01 times the IC 50 value against MMP-1 and/or MMP-14, and even more preferably 0.001 times the IC 50 value against MMP-1 and/or MMP-14.
  • MMP-1 is believed to be undesirable due to the role of MMP-1 as a housekeeping enzyme (i.e., helping to maintain normal connective tissue turnover and repair). Inhibition of MMP-1 can lead to toxicities or side effects such as such as joint or connective tissue deterioration and pain.
  • MMP-13 is believed to be intimately involved in the destruction of joint components in diseases such as osteoarthritis.
  • potent and selective inhibition of MMP-13 is typically highly desirable because such inhibition can have a positive effect on disease progression in a patient (in addition to having an anti-inflammatory effect).
  • Another advantage of the compounds and salts of this invention is their tendency to be selective with respect to tumor necrosis factor release and/or tumor necrosis factor receptor release. This provides the physician with another factor to help select the best drug for a particular patient. Without being bound by theory, it is believed that there are multiple factors to this type of selectivity to be considered. The first is that presence of tumor necrosis factor can be desirable for the control of cancer in the organism, so long as TNF is not present in a toxic excess. Thus, uncontrolled inhibition of release of TNF can be counterproductive and actually can be considered an adverse side effect even in cancer patients. In addition, selectivity with respect to inhibition of the release of the tumor necrosis factor receptor can also be desirable. The presence of that receptor can be desirable for maintaining a controlled tumor necrosis level in the mammal by binding excess TNF.
  • this invention is directed, in part, to a compound or salt thereof (particularly a pharmaceutically acceptable salt thereof).
  • the compound has a structure corresponding to Formula X:
  • Z is —C(O)—, —N(R 6 )—, —O—, —S—, —S(O)—, —S(O) 2 —, or —N(S(O) 2 R 7 )—.
  • Z is —O—.
  • Z is —N(R 6 )—.
  • R 6 is hydrogen, formyl, sulfonic-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkyl, carboxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl-C 1 -C 6 -alkyl, R 8 R 9 -aminocarbonyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkylcarbonyl, carboxy-C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylcarbonyl-C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, carboxy, C 1 -C 6 -alkylcarbonyl, R 8 R 9 -aminocarbonyl, aryl-C 1
  • R 6 is C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylsulfonyl, C 3 -C 6 -alkenyl, or C 3 -C 6 -alkynyl.
  • R 7 is aryl-C 1 -C 6 -alkyl, aryl, heteroaryl, heterocyclyl, C 1 -C 6 -alkyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkenyl, carboxy-C 1 -C 6 -alkyl, or hydroxy-C 1 -C 6 -alkyl.
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, arylcarbonyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heteroaryl-C 1 -C 6 -alkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, thiol-C 1 -C 6 -alkyl, C 1 -C 6 -alkylthio-C 1 -C 6 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, heterocyclyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkoxy-C 1 -C 6 -
  • amino-C 1 -C 6 -alkyl nitrogen optionally is substituted with up to 2 substituents independently selected from the group consisting of C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkyl, cycloalkyl, and C 1 -C 6 -alkylcarbonyl.
  • substituents independently selected from the group consisting of C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkyl, cycloalkyl, and C 1 -C 6 -alkylcarbonyl.
  • no greater than one of R 8 and R 9 is hydroxy.
  • R 8 and R 9 together with the atom to which they are bonded, form a 5- to 8-membered heterocyclic or heteroaryl ring containing up to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • R 10 is hydrogen, hydroxy, C 1 -C 6 -alkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heteroaryl-C 1 -C 6 -alkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, thiol-C 1 -C 6 -alkyl, C 1 -C 6 -alkylthio-C 1 -C 6 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, heterocyclyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-C 1 -C
  • amino-C 1 -C 6 -alkyl nitrogen optionally is substituted with up to 2 substituents independently selected from the group consisting of C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkyl, cycloalkyl, and C 1 -C 6 -alkylcarbonyl.
  • E is a bond, —C(O)—, or —S—.
  • Y is hydrogen, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocyclyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, or aminoalkyl.
  • the aryl, heteroaryl, arylalkyl, or heterocyclyl optionally is substituted with up to 2 substituents independently selected from the group consisting of alkylcarbonyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino.
  • the amino optionally is substituted with up to 2 substituents independently selected from the group consisting of alkyl and arylalkyl.
  • Y comprises a cyclic structure, i.e., Y is optionally substituted aryl, arylalkyl, cycloalkyl, heteroaryl, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, heterocyclyl, or cycloalkyl.
  • Y is optionally substituted phenyl.
  • Y is optionally substituted phenylmethyl.
  • Y is optionally substituted heteraryl.
  • Y is optionally substituted heteroarylmethyl.
  • R is hydrogen, cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, arylalkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, arylalkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroarylalkyl, cycloalkyl, heterocylyloxy, heterocylylthio, heterocylylamino, cycloalkyloxy, cycloalkylthio, heteroarylalkoxy, heteroarylalkylthio, arylalkoxy, arylalkylthio, arylalkylamino, heterocylyl, heteroaryl, arylazo, hydroxycarbonyl, ary
  • the nitrogen of an R amino may be unsubstituted.
  • the amino nitrogen may be substituted with up two substituents that are independently selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, arylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, and alkylcarbonyl.
  • the amino nitrogen optionally may be substituted with two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that: (i) contains from zero to two additional heteroatoms that are independently selected from the group consisting of nitrogen, oxygen, and sulfur; and (ii) optionally is substituted with up to two substituents independently selected from the group consisting of aryl, alkyl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, alkylcarbonyl, cycloalkyl, heterocylylalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocylylalkyl, hydroxyalkoxyalkyl, arylalkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocylylalkoxy, benzofused cycloalkylcarbonyl, heterocycl
  • the nitrogen of an R aminocarbonyl is may be unsubstituted.
  • the aminocarbonyl nitrogen may be the reacted amine of an amino acid.
  • the aminocarbonyl nitrogen may be substituted with up to two substituents independently selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroarylalkyl, cycloalkyl, arylalkyl, trifluoromethylalkyl, heterocylylalkyl, benzofused heterocylylalkyl, benzofused cycloalkyl, and N,N-dialkylsubstituted alkylamino-alkyl.
  • the aminocarbonyl nitrogen may be substituted with two substituents such that the two substituents, together with the aminocarbonyl nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that optionally is substituted with up to two substituents independently selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocyclylalkyl, hydroxy, hydroxycarbonyl, aryl, arylalkyl, heteroaralkyl, and amino.
  • amino nitrogen in turn, optionally is substituted with: (i) two substituents independently selected from the group consisting of alkyl, aryl, and heteroaryl; or (ii) two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring.
  • the nitrogen of an R aminoalkyl may be unsubstituted.
  • the aminoalkyl nitrogen may be substituted with up to two substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, and alkylcarbonyl.
  • the aminoalkyl nitrogen may be substituted with two substituents such that the two substituents, together with the aminoalkyl nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring.
  • R is halogen (preferably chloro or fluoro, and even more preferably chloro).
  • R is hydrogen so that the compound corresponds in structure to Formula XA:
  • Z is —C(O)—, —N(R 6 )—, —O—, —S—, or —S(O) 2 —. In one particularly preferred embodiment, Z is —N(R 6 )—. In another particularly preferred embodiment, Z is —O—.
  • R 6 is hydrogen, arylalkoxycarbonyl, alkylcarbonyl, alkyl, alkoxyalkyl, cycloalkyl, heteroarylcarbonyl, heteroaryl, cycloalkylalkyl, alkylsulfonyl, haloalkylcarbonyl, alkenyl, alkynyl, and R 8 R 9 -aminoalkylcarbonyl.
  • R 6 is hydrogen, aryl-C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkyl (preferably isopropyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, heteroaryl, heteroarylcarbonyl, halo-C 1 -C 6 -alkylcarbonyl, or R 8 R 9 -amino-C 1 -C 6 -alkylcarbonyl.
  • R 6 is C 1 -C 6 -alkyl (preferably ethyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (preferably methoxyethyl), C 3 -C 6 -cycloalkyl (preferably cyclopropyl), C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl (preferably cyclopropylmethyl), C 3 -C 6 -alkenyl (preferably C 3 -alkenyl), C 3 -C 6 -alkynyl (preferably C 3 -alkynyl), or C 1 -C 6 -alkylsulfonyl (preferably methylsulfonyl).
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylcarbonyl, haloalkyl, and aminoalkyl.
  • the aminoalkyl nitrogen optionally is substituted with up to two substituents independently selected from the group consisting of alkyl.
  • R 8 and R 9 together with the atom to which they are bonded, form a 5- to 8-membered heterocyclyl or heteroaryl containing up to 3 (in many instances, no greater than 2) heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • any such heterocyclyl or heteroaryl (particularly heterocyclyl) optionally is substituted with one or more substituents independently selected from the group consisting of hydroxy, keto, carboxy, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxyalkyl, alkoxycarbonylalkyl, heterocyclylalkyl, alkoxycarbonyl, and aminoalkyl.
  • the aminoalkyl nitrogen in turn, optionally is substituted with up to two substituents independently selected from the group consisting of alkyl.
  • E is a bond, —C(O)—, or —S—.
  • Y is cycloalkyl, 2,3-dihydroindolyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl.
  • the cycloalkyl, 2,3-dihydroindolyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, keto, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkoxy, alkylcarbonyl, haloalkoxy, alkylthio, alkoxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkoxy, cycloalkylalkoxyalkyl, aryl, arylalkyl
  • substituents optionally are substituted with one or more substituents independently selected from the group consisting of halogen, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylcarbonyl. Additionally, the nitrogen of the amino, aminoalkyl, or aminocarbonyl optionally is substituted with up to two substituents independently selected from the group consisting of alkyl and cycloalkylalkyl.
  • E is —C(O)—
  • Y is heterocyclyl, aryl (particularly phenyl), heteroaryl, or arylmethyl (particularly phenylmethyl).
  • the heterocyclyl, aryl, heteroaryl, or arylmethyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylcarbonyl, halo-C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl
  • optional substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, nitro, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -alkylcarbonyl.
  • the nitrogen of the amino or amino-C 1 -C 6 -alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C 1 -C 6 -alkyl and C 3 -C 6 -cycloalkyl-C 1 -C 6 -alkyl.
  • E is —C(O)—
  • Y is aryl (particularly phenyl), heteroaryl, arylmethyl (particularly phenylmethyl), or heteroarylmethyl.
  • the aryl, heteroaryl, arylmethyl, or heteroarylmethyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl-C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyloxy, C 3 -C 6 -cycloalkyl-C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl-cycloalkyl-
  • nitrogen of the amino or amino-C 1 -C 6 -alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C 1 -C 6 -alkyl.
  • Y is optionally substituted phenyl.
  • Such compounds include, for example:
  • Y is optionally substituted heteroaryl.
  • Such compounds include, for example, compounds wherein Y is optionally substituted thienyl:
  • E is a bond
  • Y is aryl (particularly phenyl), 2,3-dihydroindolyl, heterocyclyl, or heteroaryl.
  • the aryl, 2,3-dihydroindolyl, heterocyclyl, or heteroaryl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, keto, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, aryl, aminocarbonyl, and C 1 -C 6 -alkylsulfonyl.
  • optional substituents also are optionally substituted with one or more substituents independently selected from the group consisting of halogen, halo-C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkoxy.
  • the nitrogen of the aminocarbonyl optionally is substituted with up to 2 substituents independently selected from the group consisting of C 1 -C 6 -alkyl.
  • E is a bond
  • Y is heteroaryl, aryl (particularly phenyl), or heterocyclyl.
  • the heteroaryl, aryl, or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and aryl.
  • E is —S—
  • Y is cycloalkyl, aryl, arylmethyl, or heteroaryl.
  • the cycloalkyl, aryl (particularly phenyl), arylmethyl (particularly phenylmethyl), or heteroaryl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, halo-C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkoxy.
  • E is —S—
  • Y is heteraryl
  • R preferably is halogen (preferably chloro or fluoro, and even more preferably chloro).
  • R preferably is hydrogen so that the compound corresponds in structure to Formula XA (shown above).
  • the compounds of this invention can be used in the form of salts derived from inorganic or organic acids.
  • a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
  • salts are intended to be administered to a patient (as opposed to, for example, being used in an in vitro context)
  • the salt preferably is pharmaceutically acceptable.
  • Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means with a compound of this invention by reacting, for example, the appropriate acid or base with the compound.
  • Pharmaceutically-acceptable acid addition salts of the compounds of this invention may be prepared from an inorganic or organic acid.
  • suitable inorganic acids include hydrochloric, hydrobromic acid, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid.
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, buty
  • Pharmaceutically-acceptable base addition salts of the compounds of this invention include, for example, metallic salts and organic salts.
  • Preferred metallic salts include alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts, and other physiological acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • Preferred organic salts can be made from tertiary amines and quaternary amine salts, such as tromethamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl (C 1 -C 6 ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • C 1 -C 6 halides
  • dialkyl sulfates e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates
  • long chain halides e.g., decyl, lauryl
  • Particularly preferred salts of the compounds of this invention include hydrochloric acid (HCl) salts and trifluoroacetate (CF 3 COOH or TFA) salts.
  • One embodiment of this invention is directed to a process for preventing or treating a pathological condition associated with MMP activity in a mammal (e.g., a human, companion animal, farm animal, laboratory animal, zoo animal, or wild animal) having or disposed to having such a condition.
  • a pathological condition associated with MMP activity e.g., a human, companion animal, farm animal, laboratory animal, zoo animal, or wild animal
  • a condition may be, for example, tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, and a central nervous system disease.
  • Such conditions include osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermolysis bullosa, aortic aneurysm, weak injury repair, an adhesion, scarring, congestive heart failure, coronary thrombosis, emphysema, proteinuria, and Alzheimer's disease.
  • the condition may alternatively (or additionally) be associated with TNF- ⁇ convertase activity.
  • a condition include inflammation (e.g., rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, a fibrotic disease, cancer, an infectious disease (e.g., malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, a cardiovascular disease (e.g., post-ischemic reperfusion injury and congestive heart failure), a pulmonary disease, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage, acute phase responses like those seen with infections and sepsis and during shock (e.g., septic shock, hemodynamic shock, etc.), cachexia, and anorexia.
  • inflammation e.g., rheumatoid arthritis
  • autoimmune disease e.g., rheumatoid arthritis
  • graft rejection e.g., multiple sclerosis
  • the condition may alternatively (or additionally) be associated with aggrecanase activity.
  • inflammation diseases e.g., osteoarthritis, rheumatoid arthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, and psoriatic arthritis
  • cancer e.g., obstructive pulmonary disease
  • the phrase “preventing a condition” means reducing the risk of (or delaying) the onset of the condition in a mammal that does not have the condition, but is predisposed to having the condition.
  • the phrase “treating a condition” means ameliorating, suppressing, or eradicating an existing condition.
  • the pathological condition may be, for example: (a) the result of pathological MMP and/or aggrecanase activity itself, (b) affected by MMP activity (e.g., diseases associated with TNF- ⁇ ), and/or (c) affected by aggrecanase activity.
  • hydroxamates and salt thereof may be administered orally, parenterally, by inhalation spray, rectally, or topically.
  • Oral administration can be advantageous if, for example, the patient is ambulatory, not hospitalized, and physically able and sufficiently responsible to take drug at the required intervals. This may be true even if the person is being treated with more than one drug for one or more diseases.
  • IV drug administration can be advantageous in, for example, a hospital setting where the dose (and thus the blood levels) can be well controlled.
  • a compound or salt of this invention also can be formulated for IM administration if desired. This route of administration may be desirable for administering prodrugs or regular drug delivery to patients that are either physically weak or have a poor compliance record or require constant drug blood levels.
  • a compound (or pharmaceutically acceptable salt thereof) described in this patent is administered in an amount effective to inhibit a target MMP(s).
  • the target MMP is/are typically MMP-2, MMP-9, and/or MMP-13, with MMP-13 often being a particularly preferred target.
  • the preferred total daily dose of the hydroxamate or salt thereof is typically from about 0.001 to about 100 mg/kg, more preferably from about 0.001 to about 30 mg/kg, and even more preferably from about 0.01 to about 10 mg/kg (i.e., mg hydroxamate or salt thereof per kg body weight).
  • Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the administration of the compound or salt will be repeated a plurality of times. Multiple doses per day typically may be used to increase the total daily dose, if desired.
  • Factors affecting the preferred dosage regimen include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; the route of administration; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular hydroxamate or salt thereof employed; whether a drug delivery system is utilized; and whether the hydroxamate or salt thereof is administered as part of a drug combination.
  • the dosage regimen actually employed can vary widely, and, therefore, can deviate from the preferred dosage regimen set forth above.
  • This invention also is directed to pharmaceutical compositions comprising a hydroxamate or salt thereof described above, and to methods for making pharmacetucal compositions (or medicaments) comprising a hydroxamate or salt thereof described above.
  • the preferred composition depends on the method of administration, and typically comprises one or more conventional pharmaceutically acceptable carriers, adjuvants, and/or vehicles.
  • Formulation of drugs is generally discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.: 1975). See also, Liberman, H. A. See also, Lachman, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N.Y., 1980).
  • Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules.
  • the hydroxamates or salts thereof are ordinarily combined with one or more adjuvants. If administered per os, the hydroxamates or salts thereof can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets can contain a controlled-release formulation, as can be provided in a dispersion of the hydroxamate or salt thereof in hydroxypropylmethyl cellulose.
  • the dosage forms also can comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally can be prepared with enteric coatings.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • adjuvants such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • Parenter administration includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and infusion.
  • injectable preparations e.g., sterile injectable aqueous or oleaginous suspensions
  • suitable dispersing, wetting agents, and/or suspending agents can be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
  • Acceptable vehicles and solvents include, for example, water, 1,3-butanediol, Ringer's solution, isotonic sodium chloride solution, bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids (e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic and non-ionic detergents), and/or polyethylene glycols.
  • Formulations for parenteral administration may, for example, be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • the hydroxamates or salts thereof can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Suppositories for rectal administration can be prepared by, for example, mixing the drug with a suitable nonirritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, such as cocoa butter; synthetic mono-, di-, or triglycerides; fatty acids; and/or polyethylene glycols
  • Topical administration includes the use of transdermal administration, such as transdermal patches or iontophoresis devices.
  • alkyl (alone or in combination with another term(s)) means a straight-or branched-chain saturated hydrocarbyl group typically containing from 1 to about 20 carbon atoms, more typically from about 1 to about 8 carbon atoms, and even more typically from about 1 to about 6 carbon atoms.
  • Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, and the like.
  • alkenyl (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl group containing one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms.
  • Examples of such groups include ethenyl (vinyl); 2-propenyl; 3-propenyl; 1,4-pentadienyl; 1,4-butadienyl; 1-butenyl; 2-butenyl; 3-butenyl; decenyl; and the like.
  • alkynyl (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl group containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms.
  • Examples of such groups include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
  • carbocyclyl (alone or in combination with another term(s)) means a saturated cyclic, partially saturated cyclic, or aryl hydrocarbyl group containing from 3 to 14 carbon ring atoms (“ring atoms” are the atoms bound together to form the ring or rings of a cyclic group).
  • a carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms.
  • Examples of such single-ring carbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.
  • a carbocyclyl alternatively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl”), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl”), fluoreneyl, decalinyl, and norpinanyl.
  • cycloalkyl (alone or in combination with another term(s)) means a saturated cyclic hydrocarbyl group containing from 3 to 14 carbon ring atoms.
  • a cycloalkyl may be a single carbon ring, which typically contains from 3 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropanyl, cyclobutanyl, cyclopentyl, and cyclohexyl.
  • a cycloalkyl alternatively may be 2 or 3 carbon rings fused together, such as, decalinyl or norpinanyl.
  • aryl (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl.
  • the number of carbon atoms in a hydrocarbyl group is indicated by the prefix “C x -C y -”, wherein x is the minimum and y is the maximum number of carbon atoms in the group.
  • C 1 -C 6 -alkyl refers to an alkyl group containing from 1 to 6 carbon atoms.
  • C 3 -C 6 -cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
  • hydrogen (alone or in combination with another term(s)) means a hydrogen radical, and may be depicted as —H.
  • nitro (alone or in combination with another term(s)) means —NO 2 .
  • cyano (alone or in combination with another term(s)) means —CN, which also may be depicted as or —COOH:
  • keto (alone or in combination with another term(s)) means an oxo radical, and may be depicted as ⁇ O.
  • amino (alone or in combination with another term(s)) means —NH 2 .
  • monosubstituted amino (alone or in combination with another term(s)) means an amino group wherein one of the hydrogen radicals is replaced by a non-hydrogen substituent.
  • disubstituted amino (alone or in combination with another term(s)) means an amino group wherein both of the hydrogen atoms are replaced by non-hydrogen substituents, which may be identical or different.
  • halogen (alone or in combination with another term(s)) means a fluorine radical (which may be depicted as —F), chlorine radical (which may be depicted as —Cl), bromine radical (which may be depicted as —Br), or iodine radical (which may be depicted as —I).
  • a fluorine radical or chlorine radical is preferred.
  • a substituted alkyl group is an alkyl group wherein at least one hydrogen on the alkyl group is replaced with a non-hydrogen substituent. It should be recognized that if there are more than one substitutions on a group, each non-hydrogen substituent may be identical or different.
  • haloalkyl means an alkyl group wherein at least one hydrogen radical is replaced with a halogen radical.
  • haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.
  • haloalkoxy means an alkoxy group wherein at least one hydrogen radical is replaced by a halogen radical.
  • haloalkoxy groups include chlormethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as “perfluoromethyoxy”), 1,1,1,-trifluoroethoxy, and the like. It should be recognized that if a group is substituted by more than one halogen radical, those halogen radicals may be identical or different.
  • the prefix “perhalo” indicates that every hydrogen radical on the group to which the prefix is attached is replaced with independently selected halogen radicals, i.e., each hydrogen radical on the group is replaced with a halogen radical. If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the term “perfluoro” means that every hydrogen radical on the group to which the prefix is attached is substituted with a fluorine radical. To illustrate, the term “prefluoroalkyl” means an alkyl group wherein each hydrogen radical is replaced with a fluorine radical.
  • perfluoroalkyl groups examples include trifluoromethyl (—CF 3 ), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, perfluorodecyl, and the like.
  • perfluoroalkoxy means an alkoxy group wherein each hydrogen radical is replaced with a fluorine radical.
  • perfluoroalkoxy groups include trifluoromethoxy (—O—CF 3 ), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, perfluorodecoxy, and the like.
  • carbonyl (alone or in combination with another term(s)) means —C(O)—, which also may be depicted as:
  • This term also is intended to encompass a hydrated carbonyl group, i.e., —C(OH) 2 —.
  • aminocarbonyl (alone or in combination with another term(s)) means —C(O)—NH 2 , which also may be depicted as:
  • oxy (alone or in combination with another term(s)) means an ether group, and may be depicted as —O—.
  • alkoxy (alone or in combination with another term(s)) means an alkylether group, i.e., —O-alkyl. Examples of such a group include methoxy (—O—CH 3 ), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
  • alkylcarbonyl (alone or in combination with another term(s)) means —C(O)-alkyl.
  • ethylcarbonyl may be depicted as:
  • aminoalkylcarbonyl (alone or in combination with another term(s)) means —C(O)-alkyl-NH 2 .
  • aminomethylcarbonyl may be depicted as:
  • alkoxycarbonyl (alone or in combination with another term(s)) means —C(O)—O-alkyl.
  • ethoxycarbonyl may be depicted as:
  • Carbocyclylcarbonyl (alone or in combination with another term(s)) means —C(O)-carbocyclyl.
  • phenylcarbonyl may be depicted as:
  • heterocyclylcarbonyl (alone or in combination with another term(s)) means —C(O)-heterocyclyl.
  • Carbocyclylalkylcarbonyl (alone or in combination with another term(s)) means —C(O)-alkyl-carbocyclyl.
  • phenylethylcarbonyl may be depicted as:
  • heterocyclylalkylcarbonyl (alone or in combination with another term(s)) means —C(O)-alkyl-heterocyclyl.
  • Carbocyclyloxycarbonyl (alone or in combination with another term(s)) means —C(O)—O-carbocyclyl.
  • phenyloxycarbonyl may be depicted as:
  • Carbocyclylalkoxycarbonyl (alone or in combination with another term(s)) means —C(O)—O-alkyl-carbocyclyl.
  • phenylethoxycarbonyl may be depicted as:
  • thio or “thia” (alone or in combination with another term(s)) means a thiaether group, i.e., an ether group wherein the ether oxygen atom is replaced by a sulfur atom. Such a group may be depicted as —S—.
  • alkyl-thio-alkyl means alkyl-S-alkyl.
  • thiol or “sulfhydryl” (alone or in combination with another term(s)) means a sulfhydryl group, and may be depicted as —SH.
  • (thiocarbonyl) (alone or in combination with another term(s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a group may be depicted as —C(S)—, and also may be depicted as:
  • alkyl(thiocarbonyl) (alone or in combination with another term(s)) means —C(S)-alkyl.
  • ethyl(thiocarbonyl) may be depicted as:
  • alkoxy(thiocarbonyl) (alone or in combination with another term(s)) means —C(S)—O-alkyl.
  • ethoxy(thiocarbonyl) may be depicted as:
  • Carbocyclyl(thiocarbonyl) (alone or in combination with another term(s)) means —C(S)-carbocyclyl.
  • phenyl(thiocarbonyl) may be depicted as:
  • heterocyclyl(thiocarbonyl) (alone or in combination with another term(s)) means —C(S)-heterocyclyl.
  • Carbocyclylalkyl(thiocarbonyl) (alone or in combination with another term(s)) means —C(S)-alkyl-carbocyclyl.
  • phenylethyl(thiocarbonyl) may be depicted as:
  • heterocyclylalkyl(thiocarbonyl) (alone or in combination with another term(s)) means —C(S)-alkyl-heterocyclyl.
  • Carbocyclyloxy(thiocarbonyl) (alone or in combination with another term(s)) means —C(S)—O-carbocyclyl.
  • phenyloxy(thiocarbonyl) may be depicted as:
  • Carbocyclylalkoxy(thiocarbonyl) (alone or in combination with another term(s)) means —C(S)—O-alkyl-carbocyclyl.
  • phenylethoxy(thiocarbonyl) may be depicted as:
  • sulfonyl (alone or in combination with another term(s)) means —S(O) 2 —, which also may be depicted as:
  • alkyl-sulfonyl-alkyl means alkyl-S(O) 2 -alkyl.
  • aminosulfonyl (alone or in combination with another term(s)) means —S(O) 2 —NH 2 , which also may be depicted as:
  • sulfoxido (alone or in combination with another term(s)) means —S(O)—, which also may be depicted as:
  • alkyl-sulfoxido-alkyl means alkyl-S(O)-alkyl.
  • heterocyclyl (alone or in combination with another term(s)) means a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • a heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.
  • a heterocyclyl alternatively may be 2 or 3 rings fused together.
  • heteroaryl (alone or in combination with another term(s)) means an aromatic ring containing from 5 to 14 ring atoms. At least one of the ring atoms is a heteroatom, with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • a heteroaryl may be a single ring, which typically contains from 5 to 7 ring atoms, and more typically from 5 to 6 ring atoms.
  • a heteroaryl alternatively may be 2 or 3 rings fused together.
  • heterocyclyls and heteroaryls examples include furanyl, dihydrofurnayl, tetradydrofurnayl, thiophenyl (also known as “thiofuranyl”), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, isothiazolidin
  • heterocyclyl and heteroaryl rings having 2 or 3 rings fused together include, for example, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.
  • fused-ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (also known as “isobenzazolyl” or “pseudoisoindolyl”), indoleninyl (also known as “pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl”), benzazinyl (including quinolinyl (also known as “1-benzazinyl”) or isoquinolinyl (also known as “2-benzazinyl”)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as “1,2-benzodiazinyl”) or quinazolinyl (also known as “1,3-benzodiazinyl”)), benzopyranyl (including “chromanyl” or “isochromanyl”), benzothiochro
  • heteroaryl includes 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1,2,3-tiiazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as 1,2-, 1,4-
  • a carbocyclyl, heterocyclyl, or heteroaryl optionally can be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as “alkanoyl”), aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, and cycloalkylalkoxycarbonyl.
  • substituents independently selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as “alkanoyl”), aryl, arylalkyl, arylalkoxy,
  • a carbocyclyl or heterocyclyl may optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, —OH, —C(O)—OH, keto, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, aryl, aryl-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkoxy, aryl-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkoxycarbonyl, cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, cycloalkyl-C 1 -C 6 -alkoxy, cycloalkyl,
  • alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl, aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, or arylalkoxycarbonyl substituent(s) may further be substituted with, for example, one or more halogen.
  • the aryls or cycloalkyls are typically single-ring groups containing from 3 to 6 ring atoms, and more typically from 5 to 6 ring atoms.
  • An aryl or heteroaryl optionally can be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , —SH, —C(O)—OH, amino, aminocarbonyl, aminoalkyl, alkyl, alkylthio, carboxyalkylthio, alkylcarbonyl, alkylcarbonyloxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxyalkylthio, alkoxycarbonylalkylthio, carboxyalkoxy, alkoxycarbonylalkoxy, carbocyclyl, carbocyclylalkyl, carbocyclyloxy, carbocyclylthio, carbocyclylalkylthio, carbocyclylamino, carbocyclylalkylamino, carbocyclylcarbonylamino, carbocyclylcarbonylamin
  • an aryl or heteroaryl may, for example, optionally be substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , —SH, —C(O)—OH, amino, aminocarbonyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkylthio, carboxy-C 1 -C 6 -alkylthio, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C
  • one or more hydrogens bound to a carbon in any such group may, for example, optionally be replaced with halogen.
  • the cycloalkyl, aryl, and heteroaryl are typically single-ring groups containing 3 to 6 ring atoms, and more typically 5 or 6 ring atoms.
  • an aryl or heteroaryl optionally is substituted with one or more substituents independently selected from the group consisting of cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocylyloxy, heterocylylthio, heterocylylamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkylamino
  • (a) contains from zero to two additional heteroatoms that are independently selected from the group consisting of nitrogen, oxygen, and sulfur;
  • (b) optionally is substituted with up to two substituents independently selected from the group consisting of aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocylylalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocylylalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocylylalkoxy, benzofused cycloalkylcarbonyl, heterocyclylalkylcarbonyl, and cycloalkylcarbonyl.
  • substituents independently selected from the group consisting of aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocylylalkyl
  • aminocarbonyl nitrogen is:
  • aminoalkyl nitrogen optionally is substituted with:
  • a prefix attached to a multi-component group only applies to the first component.
  • alkylcycloalkyl contains two components: alkyl and cycloalkyl.
  • the C 1 -C 6 - prefix on C 1 -C 6 -alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the C 1 -C 6 -prefix does not describe the cycloalkyl component.
  • the prefix “halo” on haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl group is substituted with one or more halogen radicals.
  • halogen substitution may alternatively or additionally occur on the alkyl component, the group would instead be described as “halogen-substituted alkoxyalkyl” rather than “haloalkoxyalkyl.” And finally, if the halogen substitution may only occur on the alkyl component, the group would instead be described as “alkoxyhaloalkyl.”
  • benzene substituted with cyclohexanylthiobutoxy has the following structure:
  • the rightmost-described component of the substituent is the component that is bound to the left element in the depicted structure.
  • the chemical structure is X-L-Y and L is described as methylcyclohexanylethyl, the chemical would be X-ethyl-cyclohexanyl-methyl-Y.
  • the leftmost dash of the substituent indicates the portion of the substituent that is bound to the left element in the depicted structure.
  • the rightmost dash indicates the portion of the substituent that is bound to the right element in the depicted structure.
  • DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
  • EDC 1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride
  • NMM N-methyl morpholine
  • TsCl toluenesulfonyl chloride
  • THP-O-hydroxylamine O-tetrahydropyran-hydroxylamine and O-tetrahydro-2H-pyran-2-yl-hydroxylamine
  • Part A A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (DMSO; 20 mL) was heated to 65° C. for 5 hr. The solution remained at ambient temperature for 18 hr. The solution was extracted with ethyl acetate and the combined organic layers were washed with H 2 O and saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).
  • Part B To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) drop-wise over 20 min. The solution was stirred overnight (about 18° C.) at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (7:3 ethyl acetate/hexanes) and concentrated in vacuo to give the BOC-piperidine compound (26.2 g, quantitative yield) as a clear, colorless oil.
  • Part C To a solution of diisopropylamine (2.8 mL, 20 mmoL) in THF (30 mL), cooled to ⁇ 78° C., was added n-butyl lithium (12.5 mL, 20 mmol) drop-wise. After 15 min, the BOC-piperidine compound of part B (2.6 g, 10 mmol) in THF (10 mL) was added drop-wise. After 1.5 hr, the solution was cooled to ⁇ 60° C. and the disulfide of part A (2.0 g, 10 mmol) in THF (7 mL). The solution was stirred at ambient temperature for 2 hr. The solution was diluted with H 2 O and extracted with ethyl acetate.
  • Part D To a solution of the sulfide of part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to 0° C., was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hr followed by dilution with H 2 O and extraction with dichloromethane. The organic layer was washed with 10 percent Na 2 SO 4 , H 2 O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15 g, 59%).
  • Part E To a solution of the sulfone of part D (800 mg, 1.63 mmol) in THF (9 mL) and ethanol (9 mL) was added NaOH (654 mg, 16.3 mmol) in H 2 O (3 mL). The solution was heated at 65° C. for 18 hr. The solution was concentrated in vacuo and the residue was dissolved in H 2 O. Following acidification with 2N HCl to pH 4, the solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the acid as a white foam (790 mg, quantitative yield). Analytical calculated for C 23 H 27 NO 7 S: C, 59.86; H, 5.90; N, 3.04; S, 6.95. Found: C, 59.49; H, 6.37; N, 2.81; S, 6.59.
  • Part F To a solution of the acid of part G (730 mg, 1.58 mmol) in DMF (9 mL) was added HOBT (256 mg, 1.90 mmol) followed by EDC (424 mg, 2.21 mmol), 4-methylmorpholine (0.521 mL, 4.7 mmol) and 50 percent aqueous hydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for 20 hr and additional N-hydroxybenzotriazole.H 2 O (256 mg), EDC (424 mg) and 50 percent aqueous hydroxylamine (1.04 mL) were added.
  • Part A To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) drop-wise over 20 min. The solution was stirred overnight (about 18 hr) at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (ethyl acetate/hexanes) and concentrated in vacuo to give the BOC-piperidine compound as a clear, colorless oil (26.2 g, quantitative yield).
  • Part B A solution of 4-fluorothiophenol (50.29 g, 390 mmol) in DMSO (500 mL) was heated to 65° C. for 6 hr. The reaction was quenched into wet ice and the resulting solid was collected by vacuum filtration to provide the disulfide as a white solid (34.4 g, 68.9%).
  • Part C To a solution of the BOC-piperdine compound of part A (16 g, 62 mmol) in THF (300 mL) cooled to minus 50° C. was added lithium diisopropylamide (41.33 mL, 74 mmol) and the solution was stirred for 1.5 hr at 0° C. To this solution was added the disulfide of part B (15.77 g, 62 mmol), and the resulting solution was stirred at ambient temperature for 20 hr. The reaction was quenched with the addition of H 2 O and the solution was concentrated in vacuo.
  • Part D To a solution of the sulfide of part C (16.5 g, 43 mmol) in dichloromethane (500 mL) cooled to 0° C. was added 3-chloroperbenzoic acid (18.0 g, 86 mmol) and the solution was stirred for 20 hr. The solution was diluted with H 2 O and extracted with dichloromethane. The organic layer was washed with 10 percent Na 2 SO 3 , H 2 O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (10.7 g, 60%).
  • Part E Into a solution of the sulfone of part D (10 g, 24.0 mmol) in ethyl acetate (250 mL) was bubbled HCl gas for 10 min followed by stirring at ambient temperature for 4 hr. Concentration in vacuo provided the amine hydrochloride salt as a white solid (7.27 g, 86%).
  • Part F To a solution of the amine hydrochloride salt of part E (5.98 g, 17.0 mmol) in DMF (120 mL) was added potassium carbonate (4.7 g, 34.0 mmol) followed by propargyl bromide (2.02 g, 17.0 mmol) and the solution was stirred for 4 hr at ambient temperature. The solution was partitioned between ethyl acetate and H 2 O, and the organic layer was washed with H 2 O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the propargyl amine as a yellow oil (5.2 g, 86%).
  • Part G To a solution of the propargyl amine of part F in DMF (15 mL) was added thiophenol (0.80 mL, 7.78 mmol) and CsCO 3 (2.79 g, 8.56 mmol) and the solution was heated to 70° C. for 6 hr. The solution was partitioned between ethyl ether and H 2 O. The organic layer was washed with H 2 O and saturated NaCl, and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the S-phenoxyphenyl compound as an oil (1.95 g, 56%).
  • Part H To a solution of the S-phenoxyphenyl of part G (1.81 g, 4.06 mmol) in ethanol (21 mL) and H 2 O (3.5 mL) was added KOH (1.37 g, 24.5 mmol) and the solution was heated to 105° C. for 4.5 hr. The solution was acidified to a pH value of 1 with concentrated HCl solution and then concentrated to provide the acid as a yellow residue that was used without additional purification (1.82 g).
  • Part I To a solution of the acid of part H (1.82 g, 4.06 mmol) in acetonitrile (20 mL) was added O-tetrahydro-2H-pyran-2-yl-hydroxylamine (723 mg, 6.17 mmol) and triethylamine (0.67 mL, 4.86 mmol). To this stirring solution was added EDC (1.18 g, 6.17 mmol) and the solution was stirred for 18 hr. The solution was partitioned between H 2 O and ethyl acetate. The organic layer was washed with H 2 O, saturated NaHCO 3 and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as a white solid (1.32 g, 63%).
  • Part J To a solution of the protected hydroxamate of part 1 (9.65 g, 18.7 mmol) in methanol (148 mL) cooled to 0° C. was added acetyl chloride (4.0 mL, 56.2 mmol), and the solution was stirred for 45 min at ambient temperature. Concentration in vacuo followed by trituration with ethyl ether provided the title compound as a white solid (8.10 g, 94%). MS(CI) MH + calculated for C 21 H 22 N 2 O 4 S 2 : 431, found 431.
  • Part A A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (20 mL) was heated to 65° C. for 5 hr. The solution remained at ambient temperature for 18 hr. The solution was extracted with ethyl acetate and the combined organic layers were washed with H 2 O and saturated NaCl, and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).
  • Part B To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) dropwise over 20 min. The solution was stirred overnight at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (ethyl acetate/hexane) and concentrated in vacuo to give the BOC-piperidine compound as a clear, colorless oil (26.2 g, quantitative yield).
  • Part C To a solution of diisopropylamine (2.8 mL, 20 mmoL) in THF (30 mL), cooled to ⁇ 78° C., was added n-butyl lithium (12.5 mL, 20 mmol) dropwise. After 15 min, the BOC-piperidine compound of Part B (2.6 g, 10 mmol) in THF (10 mL) was added dropwise. After 1.5 hr, the solution was cooled to ⁇ 60° C. and the disulfide of Part A (2.0 g, 10 mmol) in THF (7 mL) was added. The solution was stirred at ambient temperature for 2 hr.
  • Part D To a solution of the sulfide of Part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to 0° C., was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hr followed by dilution with H 2 O and extraction with dichloromethane. The organic layer was washed with 10 percent Na 2 SO 4 , H 2 O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15 g, 59%).
  • Part E Into a solution of the sulfone of Part D (3.56 g, 7.0 mmol) in ethyl acetate (100 mL) cooled to 0° C. was bubbled HCl gas for 5 min. Concentration in vacuo followed by trituration with ethyl ether provided the amine hydrochloride salt as a white solid (3.5 g, quantitative yield). MS(CI) MH + calculated for C 20 H 23 NO 5 S: 390, found 390.
  • Part F To a solution of the amine hydrochloride salt of part E (2.6 g, 6 mmol) and K 2 CO 3 (1.66 g, 12 mmol) in DMF (50 mL) was added propargyl bromide (892 mg, 6 mmol) and the solution was stirred at ambient temperature for 4 hr. The solution was diluted with H 2 O and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the propargyl amine as a white solid (2.15 g, 82%).
  • Part G To a solution of the propargyl amine of part F (2.15 g, 5 mmol) in THF (30 mL) and ethanol (30 mL) was added NaOH (2.0 g, 50 mmol) and the solution was heated at 65° C. for 48 hr. The solution was concentrated in vacuo and the aqueous residue was acidified to a pH value of 5. Vacuum filtration of the resulting precipitate provided the acid as a white solid (2.04 g, quantitative yield).
  • Part H To a solution of the acid of part G (559 mg, 1.4 mmol) in dichloromethane (5 mL) was added triethylamine (0.585 mL, 4.2 mmol) and 50 percent aqueous hydroxylamine (0.925 mL, 14.0 mmol) followed by bromotris(pyrrolidino)phosphonium hexafluourphosphate (PyBroP®; 718 mg, 1.54 mmol). The solution was stirred at ambient temperature for 4 hr. The solution was diluted with H 2 O and extracted with dichloromethane. The organic layer was washed with saturated NaCl and dried over magnesium sulfate.
  • Part I To a solution of the hydroxamate of part H (121 mg, 0.292 mmol) in methanol (2 mL) cooled to 0° C. was added acetyl chloride (0.228 mL, 0.321 mmol) in methanol (1 mL). After stirring at ambient temperature for 30 min, the solution was concentrated under a stream of N 2 . Trituration with ethyl ether provided the title compound as a white solid (107 mg, 81%). Analytical calculation for C 21 H 22 N 2 O 5 S.HCl.0.3H 2 O: C, 55.27; H, 5.21; N, 6.14. Found: C, 54.90; H, 5.37; N, 6.07.
  • Part A In dry equipment under nitrogen, sodium metal (8.97 g, 0.39 mol) was added to methanol (1000 mL) at 2° C. The reaction was stirred at ambient temperature for 45 min, at which time the sodium had dissolved. The solution was chilled to 5° C. and p-fluorothiophenol (41.55 mL, 0.39 mmol) was added, followed by methyl 2-chloroacetate (34.2 mL, 0.39 mol). The reaction was stirred at ambient temperature for 4 hr, filtered, and concentrated in vacuo to give the sulfide as a clear colorless oil (75.85 g, 97%).
  • Part B To a solution of the sulfide from part A (75.85 g, 0.38 mol) in methanol (1000 mL) were added water (100 mL) and Oxone® (720 g, 1.17 mol) at 20° C. An exotherm to 67° C. was noted. After 2 hr, the reaction was filtered and the cake was washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with brine, dried over MgSO 4 , filtered, and concentrated in vacuo to give the sulfone as a crystalline solid (82.74 g, 94%).
  • Part C To a solution of the sulfone from part B (28.5 g, 0.123 mol) in N,N-dimethylacetamide (200 mL) were added potassium carbonate (37.3 g, 0.27 mol), bis-(2-bromoethyl)ether (19.3 mL, 0.147 mol), 4-dimethylaminopyridine (0.75 g, 6 mmol), and tetrabutylammonium bromide (1.98 g, 6 mmol). The reaction was stirred overnight (about 18 hr) at ambient temperature. The reaction was slowly poured into 1N HCl (300 mL), the resultant solid filtered and the cake washed well with hexanes.
  • potassium carbonate 37.3 g, 0.27 mol
  • bis-(2-bromoethyl)ether (19.3 mL, 0.147 mol)
  • 4-dimethylaminopyridine (0.75 g, 6 mmol
  • Part D In dry equipment under nitrogen, the pyran compound from part C (8.0 g, 26.5 mmol) was dissolved in dry tetrahydrofuran (250 mL) and a solution of potassium trimethylsilonate (10.2 g, 79.5 mmol) in dry tetrahydrofuran (15 mL) was added at ambient temperature. After 90 min, water (100 mL) was added and the solution concentrated in vacuo. The residue was taken up in water and extracted with ethyl acetate to remove unreacted starting material. The aqueous solution was treated with 6N HCl until pH ⁇ I.
  • Part E In dry equipment under nitrogen, the carboxylic acid from part D (9.1 g, 31.6 mmol) was dissolved in dry N,N-dimethylformamide (70 mL) and the remaining reagents were added to the solution in the following order: N-hydroxybenzotriazole hydrate (5.1 g, 37.9 mmol), N-methylmorpholine (10.4 mL, 94.8 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (11.5 g, 98 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.48 g, 44.2 mmol).
  • Part A To a solution of the title compound of Preparative Example TV (3.1 g, 8 mmol) in N,N-dimethylacetamide (20 mL) were added cesium carbonate (8.8 g, 27 mmol) and p-(trifluoromethoxy)phenol (2.1 mL, 16 mmol). The slurry was stirred at 95° C. for 19 hr. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Part B To a slurry of the THP-protected hydroxamate from part A (4.0 g, 7.3 mmol) in dioxane (20 mL) were added a 4N HCl dioxane solution (20 mL) and methanol (20 mL). After 15 min, at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The product was recrystallized (acetone/hexanes) to give the title compound as a white solid (2.2 g, 65%).
  • Part A To a solution of the product of Preparative Example II, part E, (14.36 g, 40 mmol) in methanol (50 mL) was added acetic acid (24.5 g, 400 mmol), a portion (about 2 g) of 4-Angstrom molecular sieves, (1-ethoxycyclopropyl)-oxytrimethyl silane (25.8 mL, 148 mmol) and sodium cyanoborohydride (7.05 g, 112 mmol). The solution was heated at reflux for 8 hr. The precipitated solids were removed by filtration and the filtrate was concentrated in vacuo.
  • Part B A solution of the cyclopropyl amine of Part A (2.0 g, 5.6 mmol), ethylene glycol phenyl ether (2.8 mL, 23 mmol), and cesium carbonate (7.3 g, 23 mmol) in DMAC (10 mL) was heat at 125-135° C. for 18 hr under an atmosphere of nitrogen. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried over magnesium sulfate, concentrated in vacuo, dissolved in diethyl ether, precipitated as the hydrochloride salt, and dried at 40° C.
  • Part C A mixture of the ether of part B (1.8 g, 3.7 mmol) and a 50% NaOH aqueous solution (3.0 g, 37 mmol) in THF (32 mL), EtOH (32 mL), and H 2 O (16 mL) was heated at 60° C. under a N 2 atmosphere for 24 hr. The material was concentrated in vacuo and triturated with diethyl ether to give a solid. The tan solid was dissolved into a mixture of water, ethanol, and THF, precipitated by adjusting the pH to 3 with concentrated hydrochloric acid, concentrated in vacuo, triturated with water, and dried at 50° C. in a vacuum oven to give a crude white solid acid (2.3 g).
  • Part D To an ambient temperature solution of acetyl chloride (0.31 mL, 4.4 mmol) in methanol (11 mL) under a nitrogen atmosphere was added the protected hydroxamate of part C (0.80 g, 1.5 mmol). After stirring for 2.5 hr, the precipitate was collected by filtration, washed with diethyl ether, and dried at 45° C. in a vacuum oven to afford the title compound as a white solid (0.58 g, 79%): MS MH+ calcd. for C 23 H 28 N 2 O 6 S 461, found 461. Anal. calcd. for C 23 H 28 N 2 O 6 S.1.5HCl: C, 53.62; H, 5.77; N, 5.44; S, 6.22. Found: C, 53.47; H, 5.79; N, 5.41; S, 6.16.
  • Part A To a solution of the product of Preparative Example II, Part D (30 g, 161 mmol) in dichloromethane (50 mL) cooled to 0° C. was added trifluroacetic acid (25 mL) and the solution was stirred at ambient temperature for 1 hr. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the trifluoroacetate salt and K 2 CO 3 (3.6 g, 26 mmol) in N,N-dimethylformamide (50 mL) cooled to 0° C.
  • Part B To a solution of methoxyethyl amine (6.0 g, 16.0 mmol) of Part A and powdered K 2 CO 3 (4.44 g, 32 mmol) in N,N-dimethylformamide (30 mL) was added 4-(trifluoromethoxy)phenol (5.72 g, 32 mmol) at ambient temperature and the solution was heated to 90° C. for 25 hr. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H 2 O and dried over MgSO 4 . Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (7.81 g, 91.5%).
  • Part D To a solution of the acid of Part C (5.64 g, 10.8 mmol), N-methyl morpholine (4.8 mL, 43.1 mmol), 1-hydroxybenzotriazole (4.38 g, 32.4 mmol) and O-tetrahydropyranyl hydroxylamine (2.5 g, 21.6 mmol) in N,N-dimethylformamide (50 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.2 g, 32.4 mmol), and the solution was stirred at ambient temperature for 24 hr. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate.
  • Part E To a solution of 4N HCl in dioxane (28 mL, 110 mmol) was added a solution of the tetrahydropyranyl-protected hydroxamate of Part D (6.65 g, 11.03 mmol) in methanol (3 mL) and dioxane (9 mL) and was stirred at ambient temperature for 3 hr. Concentration in vacuo and trituration with diethyl ether provided the title compound as a white solid (4.79 g, 78.2%). Analytical calculation for C 22 H 25 N 2 O 7 SF 3 .HCl.0.5H 2 O: C, 46.85; H, 4.83; N, 4.97; S, 5.69. Found: C, 46.73; H, 4.57; N, 4.82; S, 5.77.
  • Part A To a suspension of 4-bromopiperidine hydrobromide (107.0 g, 0.436 mol) in tetrahydrofuran (1 L) was slowly added triethylamine (122 mL, 0.872 mol) followed by di-tert-butyl dicarbonate (100 g, 0.458 mol), which was added in several portions. The resulting mixture was stirred at ambient temperature for 22 hr then filtered and concentrated in vacuo. The solids were washed with hexanes and then collected by filtration to give the Boc-piperidine compound as an amber oil (124 g, >100%).
  • Part B To a solution of 4-fluorophenol (50.0 g, 0.390 mol) in acetone (400 mL), degassed with N 2 , was added Cs 2 CO 3 (159 g, 0.488 mol). After degassing the resulting mixture with N 2 for 5 min, the Boc-piperidine compound of Part A (85.9 g, 0.325 mol) was added. The resulting mixture was stirred at ambient temperature for 18 hr and then filtered through a pad of Celite®, washing with acetone. The filtrate was concentrated in vacuo to provide the sulfide as a tan residue (98.5 g, 97%).
  • Part C To a solution of the sulfide of Part B (8.00 g, 25.7 mmol) in dichloromethane (90 mL) and methanol (15 mL) was added monoperoxyphthalic acid magnesium salt hexahydrate (19.1 g, 38.6 mmol) in two portions. The resulting mixture was stirred at ambient temperature for 1.5 hr and then filtered. The filtrate was washed with saturated NaHCO 3 and then with saturated NaCl. The combined aqueous layers were extracted with dichloromethane (100 mL). The combined organic layers were dried over Na 2 SO 4 and then concentrated in vacuo.
  • Part D To a solution of sulfone of Part C (7.00 g, 20.4 mmol) in N,N-dimethylformamide (40 mL) was added Cs 2 CO 3 (19.9 g, 61.2 mmol) and ⁇ , ⁇ , ⁇ -trifluoro-p-cresol (3.97 g, 24.5 mmol). The resulting mixture was heated at 80° C. for 16 hr. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The resulting residue was treated with H 2 O and the solids were collected by filtration. The solids were then washed with hexanes then methanol to provide the biaryl ether as a tan solid (8.60 g, 87%).
  • Part E To a solution of the biaryl ether of Part D (8.59 g, 17.7 mmol) in tetrahydrofuran (100 mL), cooled to 0° C., was slowly added lithium bis(trimethylsilyl)amide (22.0 mL, 11.0M in tetrahydrofuran, 22.0 mmol), at such a rate that the temperature of the reaction never exceeded 1° C. The resulting mixture was stirred at 0° C. for 1 hr then a solution of methyl chloroformate (2.05 mL, 26.6 mmol) in tetrahydrofuran (5.0 mL) was slowly added, at such a rate that the temperature of the reaction mixture never exceeded 4° C.
  • Part F To a solution of the methyl ester of Part E (7.66 g, 14.1 mmol) in dioxane (30 mL) and methanol (10 mL) was added a solution of 4N HCl in dioxane (10 mL, 40 mmol). After stirring at ambient temperature for 2 hr, additional 4N HCl in dioxane (10 mL, 40 mmol) was added. After stirring at ambient temperature for 2.5 hr, the reaction mixture was concentrated in vacuo to provide the amine as an off-white solid (6.80 g, >100%).
  • Part G To a suspension of the amine of Part F (3.00 g, 6.25 mmol) in acetonitrile (20 mL) was added K 2 CO 3 (3.46 g, 25.0 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.22 g, 6.56 mmol) and a catalytic amount of NaI. The resulting mixture was heated at reflux for 22 hr. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo to provide the morpholinyl ethyl amine as a tan solid (3.45 g, >100%).
  • Part H To a solution of the morpholinyl ethyl amine of Part G (3.45 g, 6.25 mmol) in tetrahydrofuran (60 mL) was added potassium trimethylsilanolate (1.60 g, 12.50 mmol). After stirring at ambient temperature for 25 hr, H 2 O was added. The reaction mixture was then neutralized (pH 7) with 1N HCl. The tetrahydrofuran was removed in vacuo and the resulting precipitate was collected by filtration and washed with diethyl ether to provide the amino acid as an off-white solid (2.87 g, 85%).
  • Part I To a suspension of the amino acid of Part H (2.87 g, 5.29 mmol) in dichloromethane (25 mL) was added N-methylmorpholine (1.74 mL, 15.9 mmol), O-(tetrahydropuranyl)hydroxylamine (0.682 g, 5.82 mmol) and PyBroP® (2.96 g, 6.35 mmol). After stirring at ambient temperature for 19 hr, additional N-methylmorpholine (0.872 mL, 7.94 mmol), O-(tetrahydropuranyl) hydroxylamine (0.310 g, 2.65 mmol) and PyBroP® (1.48 g, 3.17 mmol) were added.
  • Part J To a solution of the protected hydroxamate of Part I (2.62 g, 4.08 mmol) in dioxane (9 mL) and methanol (3 mL) was added a solution of 4N HCl in dioxane (10 mL, 40.0 mmol). The resulting mixture was stirred at ambient temperature for 2 hr and then diethyl ether (20 mL) was added. The resulting solids were collected by filtration to give the title compound as an off-white solid (2.31 g, 90%). MS MH + calculated for C 25 H 31 O 6 N 3 SF 3 : 558, found 558.
  • Part A To a solution of the product of Preparative Example VI, Part A, (6.97 g, 19.6 mmol) in DMF (500 mL) was added K 2 CO 3 (3.42 g, 18.0 mmol) and 4-(triflouromethoxy)phenol (3.7 g, 24.8 mmol). The solution was stirred at 90° C. for 40 hr. The solution was diluted with H 2 O (600 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO 4 , filtered and concentrated in vacuo to afford the desired diaryl ether as an oil (8.5 g, quantitative). HRMS MH + calculated for C 24 H 26 NSO 6 F 3 : 514.1511. Found 514.1524.
  • Part C To a solution of the hydrochloride salt of Part B (5.0 g, 10.3 mmol) in DMF (80 mL) were added 1-hydroxybenzotriazole (1.65 g, 12.3 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranyl hydroxylamine hydrochloride (1.8 g, 15.4 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.60 g, 12.3 mmol). The solution was stirred at ambient temperature for 42 hr.
  • Part D To a solution of tetrahydropyranyl-protected hydroxamate of Part C (5.4 g, 9.2 mmol) in dioxane (80 mL) and methanol (20 mL) was added 4 N HCl/dioxane (50 mL). The reaction was stirred at ambient temperature for 2.5 hr, the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (4.02 g, 81%).
  • Part A To a solution of the product of Preparative Example VI, Part A, (5.96 g, 15.0 mmol) in DMF (100 mL) was added K 2 CO 3 (12.34 g, 38.0 mmol) and ⁇ -trifluoromethyl phenol (3.65 g, 22.5 mmol). The solution was stirred 90° C. for 28 hr. The solution was diluted with H 2 O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO 4 , filtered and concentrated in vacuo to afford desired aryl ether as an oil (7.54 g, quantitative)
  • Part C To a solution of the hydrochloride salt of Part B (7.60 g, 15.0 mmol) in DMF (100 mL) were added 1-hydroxybenzotriazole (2.44 g, 18.0 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranyl hydroxylamine hydrochloride (2.63 g, 22.5 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.02 g, 21.0 mmol). The solution was stirred at ambient temperature for 96 hr.
  • Part D To a solution of tetrahydropyranyl-protected hydroxamate of Part C (3.8 g, 6.7 mmol) in dioxane (100 mL) was added 4 N HCl/dioxane (30 mL). The reaction was stirred at ambient temperature for 2 hr, then the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (3.33 g, 96%). MS MH + calculated for C 22 H 23 N 2 SO 5 F 3 : 485, found 485.
  • Step 1 Attachment of Compound of Preparative Example IV to Resin I.
  • Resin II 50 mg, 0.046 mmol was weighed into an 8 mL glass vial, and a 0.5 M solution of a nucleophile in 1-methyl-2-pyrrolidinone (1 mL) was added to the vessel.
  • a nucleophile in 1-methyl-2-pyrrolidinone 1 mL was added to the vessel.
  • cesium carbonate 148 mg, 0.46 mmol was added, and in the case of substituted piperazine nucleophiles, potassium carbonate (64 mg, 0.46 mmol) was added.
  • the vial was capped and heated to 70 to 155° C. for 24-48 hr, then cooled to room temperature.
  • the resin was drained and washed with 1-methyl-2-pyrrolidinone, 1-methyl-2-pyrrolidinone/water (1:1), water, 10% acetic acid/water, methanol, and methylene chloride (3 ⁇ 3 mL each solvent).
  • Resin II (5 g, 0.91 mmol) was weighed into an oven-dried three-necked round bottom flask fitted with a temperature probe, an overhead stirring paddle, and a nitrogen inlet.
  • Anhydrous 1-methyl-2-pyrrolidinone 35 mL was added to the flask followed by ethyl isonipecotate (7.0 mL, 45.5 mmol).
  • the resin slurry was stirred slowly with the overhead stirrer, and the mixture was heated to 80° C. with a heating mantle for 65 hr. The flask was thereafter cooled to room temperature.
  • Step 3 Cleavage of Hydroxamic Acids from the Polymer-Support
  • Resin III was treated with a trifluoroacetic acid/water mixture (19:1, 1 mL) for 1 hr at room temperature. During that time, the resin became a deep red color. The resin was then drained and washed with trifluoroacetic acid/water (19:1) and methylene chloride (2 ⁇ 1 mL each solvent), collecting the combined filtrates in a tared vial. The volatiles were removed in vacuo, then a toluene/methylene chloride mixture (2 mL each) was added to the residue. The mixture was again concentrated in vacuo. The product was characterized by electrospray mass spectroscopy.
  • Step 4 Hydrolysis of Polymer-Bound Ester: Preparation of Resin IVa
  • Resin IIIa (5.8 g, 4.5 mmol) was weighed into a three-necked round bottomed flask fitted with an overhead stirring paddle. 1,4-Dioxane was added to the flask, and the resin slurry was stirred for 15 min. Then, a 4 M solution of KOH (5 mL, 20 mmol) was added, and the mixture was stirred for 44 hr. The resin was thereafter collected in a sintered-disk glass funnel and washed with dioxane/water (9:1), water, 10% acetic acid/water, methanol and methylene chloride (3 ⁇ 30 mL each solvent).
  • the resin was dried in vacuo to yield 5.64 g of resin IVa as off-white polymer beads.
  • FTIR microscopy showed bands at 1732 and 1704 cm ⁇ 1 and a broad band from 2500-3500 cm ⁇ 1 .
  • the theoretical loading of the polymer-bound acid was 0.84 mmol/g.
  • Step 1 Hydrolysis of methyl 4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxylate.
  • methyl 4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxylate dissolved in tetrahydrofuran (150 mL) was added potassium trimethylsilanolate (12.1 g) and stirred 2 hr. Water was added to the reaction mixture and extracted with ethyl acetate (2 ⁇ 100 mL).
  • the pH value of the aqueous layer was adjusted to 2 with 2M hydrochloric acid and extracted with ethyl acetate (2 ⁇ 100 mL). The latter organics were washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow solid (8.20 g).
  • Step 2 Loading on resin.
  • the compound obtained in step 1 (4.0 g, 13.1 mmol) was dissolved in 1-methyl-2-pyrrolidinone (15 mL) and added to a suspension of resin I (6.0 g, 6.6 mmol; Preparative Example XI) in 1-methyl-2-pyrrolidinone (40 mL).
  • pyBOP (6.85 g) and N-methylmorpholine (2.9 mL)
  • the resin was filtered and washed with dimethylformamide (3 ⁇ 50 mL), methanol (3 ⁇ 50 mL), dichloromethane (3 ⁇ 50 mL) and ether (3 ⁇ 50 mL).
  • the resin was dried in vacuo to provide resin MT-III (6.79 g).
  • Step 3 Aryl fluoride displacement of resin MT-III.
  • a suspension of resin MT-III (200 mg, 0.17 mmol), 1-methyl-2-pyrrolidinone (2 mL), cesium carbonate (560 mg) and 4-methoxyphenyl (306 mg) were stirred at 105° C. for 16 hr.
  • the reaction mixture was cooled and the resin filtered.
  • the resin was washed with dimethylformamide (3 ⁇ 5 mL), methanol (3 ⁇ 5 mL), 10% aqueous acetic acid (3 ⁇ 5 mL), methanol (3 ⁇ 5 mL) and dichloromethane (3 ⁇ 5 mL).
  • Step 1 Oxidation of Resin MT-III.
  • a suspension of resin MT-III (2.0 g, 1.72 mmol), m-chloroperbenzoic acid (4.37 g) and dichloromethane (25 mL) was stirred at room temperature for 20 hr.
  • the resin was filtered and washed with dichloromethane (3 ⁇ 25 mL), dimethylformamide (3 ⁇ 25 mL), methanol (3 ⁇ 25 mL), 1M aqueous sodium bicarbonate (2 ⁇ 25 mL), methanol (3 ⁇ 25 mL), dichloromethane (3 ⁇ 25 mL) and ether (3 ⁇ 25 mL).
  • the resin was dried in vacuo to afford resin MT-IV (2.16 g).
  • Step 2 Aryl fluoride displacement of resin MT-IV. N-hydroxy-4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxamide 1,1-dioxide was prepared by the method of Example 48 using resin MT-IV in the place of resin MT-III. ES (MS) m/z 473 (M+NH 4 ) + .
  • Step 1 Aryl fluoride displacement of Resin MT-III.
  • resin MT-III (4.06 g, 3.4 mmol) in 1-methyl-2-pyrrolidinone (40 mL)
  • ethyl isonipecotate (5.25 mL)
  • the cooled reaction mixture was filtered and the resin was washed with methanol (3 ⁇ 25 mL), dichloromethane (1 ⁇ 10 mL) and ether (3 ⁇ 25 mL).
  • the resin was dried in vacuo to afford resin MT-V (4.21 g).
  • Step 2 Hydrolysis of resin MT-V.
  • resin MT-V 4M aqueous potassium hydroxide (10 mL) and stirred at room temperature for 5 days.
  • the resin was filtered and washed with methanol (3 ⁇ 25 mL), dichloromethane (3 ⁇ 25 mL) and ether (3 ⁇ 25 mL). The resin was dried in vacuo to afford resin MT-VI.
  • Step 3 Conversion to amide.
  • Part A An oven-dried 1.0 liter flask fitted with a thermometer and nitrogen inlet was charged with 55 mL of a 2 M solution of lithium diisopropoylamide in tetrahydrofuran and 50 mL of tetrahydrofuran. The flask was immersed in a dry ice/acetone bath. When the temperature of the solution was less than ⁇ 70° C., a solution of N-t-butoxycarbonylpiperidinone (20.0 g, 0.1 mole) in 100 mL tetrahydrofuran was added dropwise, maintaining the temperature less than ⁇ 65° C. After complete addition, the flask was stirred with cooling for 20 min.
  • Part B A three-necked 15 mL round-bottom flask was charged with the product from Part A (6 g, 18.1 mmol), o-trifluorobenzeneboronic acid (4.94 g, 26 mmol), lithium chloride (2.34 g, 55 mmol), 2 M sodium carbonate (26 mL, 52 mmol) and ethylene glycol dimethyl ether (60 mL). Nitrogen was bubbled through the solution for 10 min, then palladium tetrakistriphenylphosphine (1.06 g, 0.92 mmol) was added. The mixture was heated to reflux for 1.5 hr, then cooled to room temperature.
  • Example 54 The title compound of Example 54 (300 mg, 0.92 mmol) was dissolved in methylene chloride (5 mL) in a 15 mL round-bottom flask, and 5 mL of trifluoroacetic acid was added dropwise. After 15 min, the solvent was removed in vacuo, and the residue partitioned between 20 mL of ethyl acetate and 20 mL of 2 M sodium carbonate. The organic layer was washed with additional 2 M sodium carbonate, dried over magnesium carbonate and concentrated in vacuo to yield 195 mg of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 228 (M+H).
  • Part A A solution of the title compound of Example 54 (2.3 g, 7 mmol) in 20 mL ethanol was added to a hydrogenation flask containing 1 g of 4% palladium on carbon (0.38 mmol). The mixture was placed under 100 PSI hydrogen and heated to 50° C. for 5 hr. Then the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo to give 2.27 g of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 330 (M+H).
  • Part B The product from Part A above (2.24 g, 6.8 mmol) was dissolved in 100 mL methylene chloride, and 100 mL of trifluoroacetic acid was added dropwise. After 15 min, the solvent was removed in vacuo, and the residue partitioned between 100 mL of ethyl acetate and 100 mL of 2 M sodium carbonate. The organic layer was washed with additional 2 M sodium carbonate, dried over magnesium carbonate and concentrated in vacuo to yield 1.12 g of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 230 (M+H).
  • Part A A 2 dram vial was charged with aryl fluoro compound of Preparative Example IV (170 mg, 0.44 mmol), 1 ml of 2-methylpyrrolidinone, cesium carbonate (360 mg, 1.1 mmol) and 0.66 mmol of an amine. A small magnetic stirring bar was added, then the vial was capped and placed in a Pierce Reacti-thermTM at 115° C. The reaction progress was followed by analytical HPLC. When the reaction was greater than 90% complete, the vial was cooled to room temperature. The reaction mixture was diluted with 5 mL of water, then 1.2 mL of 5% hydrogen chloride/water was added dropwise. Then, the entire mixture was poured onto a column of Celite. The column was washed exhaustively with ethyl acetate (30-40 mL) and the filtrate was collected and concentrated to give the crude products.
  • Part B The product from above was dissolved in 2 mL 1,4-dioxane and 2 mL of methanol in a 4 dram vial with a small magnetic stirring bar. A solution of 4 N hydrogen chloride in 1,4-dioxane was carefully added to the reaction, and the mixture was stirred for 2 hr. Then the solvent was removed in vacuo and the residue purified by preparative reversed-phase HPLC.
  • Part B To a solution of the N-Boc-isonipecotic acid of part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hr. The solution was concentrated in vacuo.
  • Part C To a solution of the amide of part B (1.20 g, 3.84 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 1 hr. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (956 mg, 2.56 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.92 g, 8.96 mmol) was added and the solution was heated to 100° C. for 18 hr.
  • Part E To a solution of the acid of part D (492 mg, 0.84 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (136 mg, 1.01 mmol), 4-methylmorpholine (0.46 mL, 4.20 mmol), and O-tetrahydropyranyl hydroxylamine (147 mg, 1.26 mmol). After 1 hr, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (225 mg, 1.18 mmol) was added and the solution was stirred for 72 hr at ambient temperature. The solution was partitioned between ethyl acetate and water.
  • Part F To a solution of the protected hydroxamate of part E (514 mg, 0.79 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hr. The solution was concentrated in vacuo and trituration (ethyl ether) provided the title compound as a white solid (360 mg, 76%). MS(CI) MH + calculated for C 28 H 44 N 4 O 6 S: 565, found 565. HRMS calculated for C 28 H 44 N 4 O 6 S: 565.3060, found 565.3070.
  • Part A To a solution of the N-Boc-isonipecotic acid of Example 70, Part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hr. The solution was concentrated in vacuo.
  • Part B To a solution of the amide of part A (1.4 g, 4.49 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hr. Concentration in vacuo provided a solid that was added directly to a solution of the compound of Preparative Example II, Part D, (1.24 mg, 2.99 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.42 g, 10.5 mmol) was added and the solution was heated to 100° C. for 20 hr.
  • Part D To a solution of the acid of part C (1.87 g, 3.00 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (486 mg, 3.6 mmol), 4-methylmorpholine (1.65 mL, 15 mmol), and O-tetrahydropyranyl hydroxylamine (526 mg, 4.5 mmol). After 1 hr, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (805 mg, 4.2 mmol) was added and the solution was stirred for 18 hr at ambient temperature. The solution was partitioned between ethyl acetate and water.
  • Part E To a solution of the protected hydroxamate of part D (1.61 g, 2.33 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 45 min. The solution was concentrated in vacuo and trituration (ethyl ether) a white solid. Reverse phase chromatography (on silica, acetonitrile/water (hydrochloric acid)) produced fractions A, B, C and D. Concentration in vacuo of fraction A provided the title compound as a white solid (59 mg). MS(CI) MH + calculated for C 25 H 38 N 4 O 5 S: 507, found 507.
  • Part A To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B (750 mg, 3.27 mmol) in dichloromethane (3 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (564 mg, 3.21 mmol). The solution was cooled to 0° C. and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After 2 hr, indoline (0.36 mL, 3.21 mmol) was added and the solution was stirred for 22 hr at ambient temperature. The solution was concentrated in vacuo.
  • Part B To a solution of the amide of part A (935 g, 2.83 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hr. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A, (705 mg, 1.89 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.15 g, 6.61 mmol) was added and the solution was heated to 110° C. for 18 hr.
  • Part D To a solution of the acid of part C (465 g, 0.79 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (128 mg, 0.95 mmol), 4-methylmorpholine (0.43 mL, 3.95 mmol), and O-tetrahydropyranyl hydroxylamine (139 mg, 1.18 mmol). After 1 hr, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (212 mg, 1.10 mmol) was added and the solution was stirred for 18 hr at ambient temperature. The solution was partitioned between ethyl acetate and water.
  • Part E To a solution of the protected hydroxamate of part D (300 mg, 0.46 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (5 mL) and the solution was stirred for 2 hr. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (260 mg, 94%). MS(CD) MH + calculated for C 29 H 34 N 4 O 6 S: 571, found 571.
  • Part B Aryl fluoride displacement.
  • a solution of the aryl fluoride from Part A (0.45 mmol), Cs 2 CO 3 (1.35 mmol, 3 eq), and 4-(4-chlorobenzoyle)piperidine (Maybridge Chemical Co., England, 0.67 mmol, 1.5 eq) in DMSO (1 mL) was heated to 110° C. for 18-48 hr.
  • the mixture was then cooled, dissolved in saturated aq. NH 4 + Cl ⁇ (5 mL), and extracted with dichloromethane (3 ⁇ 3 mL).
  • the combined organic layer was blown down.
  • the crude product was purified by RPHPLC (eluting with 10% to 90% acetonitrile/water), and the pure fractions were combined and concentrated.
  • Part C Conversion of the THP hydroxamic acid of Part B to the hydroxamic acid.
  • Part B Aryl fluoride displacement.
  • a solution of the aryl fluoride (0.45 mmol., as prepared in Part A of the preceding example), Cs 2 CO 3 (1.35 mmol, 3 eq), and the 4-(4-n-propylbenzoyl)piperidine prepared in Part A above (0.65 mmol, 1.5 eq) in DMSO (1 mL) was heated to 110° C. for 18-48 hr. The mixture was cooled, dissolved in saturated aqueous NH 4 + Cl ⁇ (5 mL), and extracted with dichloromethane (3 ⁇ 3 mL). The combined organic layer was blown down.
  • the crude product was purified by RPHPLC (eluting with 10% to 90% acetonitrile/water), and the pure fractions were combined and concentrated.
  • Part C Conversion of the THP hydroxamic acid of Part B to the hydroxamic acid.
  • Part B Aryl fluoride displacement.
  • a solution of the aryl fluoride from Part A (0.45 mmol), Cs 2 CO 3 (1.35 mmol, 3 eq), and 4-(4-chlorobenzoyle)piperidine (Maybridge, England, 0.67 mmol, 1.5 eq) in DMSO (1 mL) was heated to 1110° C. for 18-48 h.
  • the mixture was cooled, dissolved in saturated aqueous NH 4 + Cl ⁇ (5 mL), and extracted with dichloromethane (3 ⁇ 3 mL).
  • the combined organic layer was blown down, and the crude product was purified by crystallization using ethanol and ether.
  • Part A Preparation of 4-(4-metholcyclopropylbenzoyl)piperidine.
  • 4-bromophenylcyclopropyl ketone (Acros, 20 g, 89 mmol) in THF (75 mL) was added sodium borohydride (2.25 g, 60 mmol) and aluminum trichloride (3.95 g, 30 mmol) in small portions at ⁇ 5° C.
  • the mixture was allowed to warm to room temperature for 18 hr, and then stirred an additional 3 hr at 40° C.
  • the mixture was then cooled, quenched with saturated NH 4 + Cl ⁇ , and extracted with CH 2 Cl 2 three times.
  • the weinreb amide described in Example 120 (5 g, 18.4 mmol) was added at 0° C., and the mixture was stirred at room temperature for 48 hr. The mixture was then quenched with saturated NH 4 + Cl ⁇ , and extracted with CH 2 Cl 2 three times. The combined organic layer was dried and concentrated in vacuo. The mixture was chromatographed over 70 g of SiO 2 eluting with EtOAc/Hexane (0:100 to 30:70) to give 5.54 g (16 mmol) of the desired BOC-protected piperidine. The BOC-protected piperidine was then dissolved in 20 mL of CH 2 Cl 2 and 20 mL of TFA, and stirred at room temperature for 1 hr.
  • Part B Aryl fluoride displacement.
  • a solution of ethyl 4-[(4-fluorophenyl)sulfonyl]-1-(2-methoxyethyl)-4-piperidinecarboxylate (0.45 mmol), Cs 2 CO 3 (1.35 mmol, 3 eq), and 4-(4-metholcyclopropylbenzoyl)piperidine from Part A in DMSO (1 mL) was heated to 110° C. for 18-48 h.
  • the mixture was cooled, dissolved in saturated aqueous NH 4 + Cl ⁇ (5 mL), and extracted with dichloromethane (3 ⁇ 3 mL).
  • the combined organic layer was blown down, and the crude product was purified by crystallization using ethanol and ether.
  • Example R MS (ES) m/z 278 463.1704 279 499.2304 280 281 495.4984 282 479.1416 283 572.2800 284 539.2017 285 489.2049 286 477 287 515 288 483.1992 289 503 290 487 291 487 292 491 293 503 294 473 295 509 296 557 297 557 298 541 299 491 300 541 301 501 302 509 303 501 304 501 305 517 306 521 307 505 308 501 309 559 310 311 499 312 499 313 515 314 529 315 516 316 517 317 318 517 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 437 348 349 350 351
  • the MMP-1 was obtained from MMP-1 expressing transfected HT-1080 cells provided by Dr. Harold Welgus of Washington University in St. Louis, Mo.
  • the MMP-1 was activated using 4-aminophenylmercuric acetate (APMA), and then purified over a hydroxamic acid column.
  • APMA 4-aminophenylmercuric acetate
  • the MMP-2 was obtained from MMP-2 expressing transfected cells provided by Dr. Gregory Goldberg of Washington University.
  • the MMP-9 was obtained from MMP-9 expressing transfected cells provided by Dr. Gregory Goldberd.
  • the MMP-13 was obtained as a proenzyme from a full-length cDNA clone using baculovirus, as described by V. A. Luckow, “Insect Cell Expression Technology,” Protein Engineering: Principles and Practice , pp. 183-218 (edited by J. L. Cleland et al., Wiley-Liss, Inc., 1996).
  • the expressed proenzyme was first purified over a heparin agarose column, and then over a chelating zinc chloride column. The proenzyme was then activated by APMA for use in the assay. Further details on baculovirus expression systems may be found in, for example, Luckow et al., J.
  • the enzyme substrate was a methoxycoumarin-containing polypeptide having the following sequence:
  • MCA methoxycoumarin
  • Dpa 3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine.
  • This substrate is commercially available from Baychem (Redwood City, Calif.) as product M-1895.
  • the subject hydroxamate (or salt thereof) was dissolved at various concentrations using 1% dimethyl sulfoxide (DMSO) in a buffer containing 100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl 2 , and 0.05% polyethyleneglycol (23) lauryl ether at a pH of 7.5. These solutions were then compared to a control (which contained equal amount of DMSO/buffer solution, but no hydroxamate compound) using MicrofluorTM White Plates (Dynatech, Chantilly, Va.). Specifically, The MMPs were activated with APMA or trypsin.
  • DMSO dimethyl sulfoxide
  • the study of angiogenesis depends on a reliable and reproducible model for the stimulation and inhibition of a neovascular response.
  • the corneal micropocket assay provides such a model of angiogenesis in the cornea of a mouse. See, A Model of Angiogenesis in the Mouse Cornea ; Kenyon, B M, et al., Investigative Ophthalmology & Visual Science, July 1996, Vol. 37, No. 8.
  • the corneal pocket is made by anesthetizing a 7 week old C57Bl/6 female mouse, then proptosing the eye with ajeweler's forceps. Using a dissecting microscope, a central, intrastromal linear keratotomy of approximately 0.6 mm in length is performed with a #15 surgical blade, parallel to the insertion of the lateral rectus muscle. Using a modified cataract knife, a lamellar micropocket is dissected toward the temporal limbus. The pocket is extended to within 1.0 mm of the temporal limbus. A single pellet was placed on the corneal surface at the base of the pocket with a jeweler's forceps. The pellet was then advanced to the temporal end of the pocket. Antibiotic ointment was then applied to the eye.
  • mice were dosed on a daily basis for the duration of the assay. Dosing of the animals was based on bioavailability and overall potency of the compound. an exemplary dose was 10 or 50 mg/kg (mpk) bid, po.
  • Neovascularization of the corneal stroma begins at about day three and was permitted to continue under the influence of the assayed compound until day five. At day five, the degree of angiogenic inhibition was scored by viewing the neovascular progression with a slit lamp microscope.
  • mice were anesthetized and the studied eye was once again proptosed.
  • the maximum vessel length of neovascularization, extending from the limbal vascular plexus toward the pellet was measured.
  • the contiguous circumferential zone of neovascularization was measured as clock hours, where 30 degrees of arc equals one clock hour.
  • mice Five to six mice were utilized for each compound in each study. The studied mice were thereafter compared to control mice and the difference in the area of neovascularization was recorded as an averaged value. Each group of mice so studied constitutes an “n” value of one, so that “n” values greater than one represent multiple studies whose averaged result is provided in the table. A contemplated compound typically exhibits about 25 to about 75 percent inhibition, whereas the vehicle control exhibits zero percent inhibition.
  • PC-3 human pancreatic cancer eclls (ATCC CRL 1435) were grown to 90% confluence in F12/MEM (Gibco) containing 7% FBS (Gibco). Cells were mechanically harvested using a rubber scraper, and then washed twice with cold medium. The resulting cells were resuspended in cold medium with 30% matrigel (Collaborative Research) and the cell-containing medium was maintained on ice until used.
  • mice at 7-9 weeks of age were anesthetized with avertin [2,2,2-tribromethanol/t-amyl alcohol (1 g/1 mL) diluted 1:60 into phosphate-buffered sline] and 3-5 ⁇ 10 6 of the above cells in 0.2 mL of medium were injected into the left flank of each mouse. Cells were injected in the morning, whereas dosing with an inhibitor began at 6 PM. The animals were gavaged BID from day zero (cell injection day) to day 25-30, at which time the animals were euthanized and tumors weighed.
  • avertin 2,2,2-tribromethanol/t-amyl alcohol (1 g/1 mL) diluted 1:60 into phosphate-buffered sline
  • the cells used in the assay are the human moncytic line U-937 (ATCC CRL-1593).
  • the cells are grown in RPMI w/10% FCS and PSG supplement (R-10) and are not permitted to overgrow.
  • the assay is carried out as follows:
  • test compound in 65 uL R-10 to the appropriate wells of a 96-well flat bottom tissue culture plate.
  • the initial dilution from a DMSO stock 100 mM compound
  • Each dilution of 65 ul (in triplicate) yields final compound test concentrations of 100 ⁇ M, 33.3 ⁇ M, 11.1 ⁇ M, 3.7 ⁇ M, 1.2 ⁇ M and 0.4 ⁇ M.
  • test system is incubated at 37° C. in 5% CO 2 overnight (18-20 hr) under 100% humidity.
  • a 50 ⁇ L aliquot of working solution containg 5 mL R-10, 5 mL MTS solution [CellTiter 96 AQueous One Solution Cell Proliferation Assay Cat.#G358/0,1 (Promega Biotech)] and 250 ul PMS solution are added to each well containing the remaining supernatant and cells and the cells incubated at 37° C. in 5% CO 2 until the color develops.
  • the system is excited at 570 nm and read at 630 nm.
  • [0412] Plate 100 ⁇ L/well 2 ⁇ g/mL mouse anti-human TNFrII antibody (R&D Systems #MAB226) in 1 ⁇ PBS (pH 7.1, Gibco) on NUNC-Immuno Maxisorb plate. Incubate the plate at 4° C. overnight (about 18-20 hr).
  • Blocking solution is 1 mg/mL gelatin in PBS with 1 ⁇ thimerasol.
  • Wash buffer is 0.5 mL Tween® 20 in 1 liter of PBS.
  • chondrocyte monolayers are washed 2 times in DMEM/1% PSF/G and then allowed to incubate in fresh DMEM/1% FBS overnight. The next morning, chondrocytes are washed once in DMEM/1% PSF/G. The final wash is allowed to sit on the plates in the incubator while making dilutions. Media and dilutions are made as described in the following Table C: TABLE C control media DMEM alone IL-1 media DMEM + IL-1 (5 ng/ml) drug dilutions Make all compound stocks at 10 mM in DMSO. Make a 100 ⁇ M stock of each compound in DMEM in 96-well plate. Store in freezer overnight.
  • Plates are labeled and only the interior 24 wells of the plate are used. On one of the plates, several columns are designated as IL-1 (no drug) and control (no IL-1, no drug). These control columns are periodically counted to monitor 35S-proteoglycan release. Control and IL-1 media are added to wells (450/L) followed by compound (50 ⁇ L) so as to initiate the assay. Plates are incubated at 37° C. with 5% CO 2 atmosphere. At 40-50% release (when CPM from IL-1 media is 4-5 times control media) as assessed by liquid scintillation counting (LSC) of media samples, the assay is terminated (about 9 to about 12 hours).
  • LSC liquid scintillation counting
  • FIG. 1 Another assay for measuring aggrecanase inhibition has been reported in WIPO Int'l Publ. No. WO 00/59874. That assay reportedly uses active aggrecanase accumulated in media from stimulated bovine cartilage (BNC) or related cartilage sources and purified cartilage aggrecan monomer or a fragment thereof as a substrate. Aggrecanase is generated by stimulation of cartilage slices with interleukin-1 (IL-1), tumor necrosis factor alpha (TNF- ⁇ ), or other stimuli.
  • IL-1 interleukin-1
  • TNF- ⁇ tumor necrosis factor alpha
  • cartilage reportedly is first depleted of endogenous aggrecan by stimulation with 500 ng/ml human recombinant IL- ⁇ for 6 days with media changes every 2 days. Cartilage is then stimulated for an additional 8 days without media change to allow accumulation of soluble, active aggrecanase in the culture media.
  • agents which inhibit MMP-1, -2, -3, and -9 biosynthesis are included during stimulation. This BNC conditioned media containing aggrecanase activity is then used as the source of aggrecanase for the assay.
  • Aggrecanase enzymatic activity is detected by monitoring production of aggrecan fragments produced exclusively by cleavage at the Glu373-Ala374 bond within the aggrecan core protein by Western analysis using the monoclonal antibody, BC-3 (Hughes, et al., Biochem J, 306:799-804 (1995)).
  • This antibody reportedly recognizes aggrecan fragments with the N-terminus, 374ARGSVIL, generated upon cleavage by aggrecanase.
  • the BC-3 antibody reportedly recognizes this neoepitope only when it is at the N-terminus and not when it is present internally within aggrecan fragments or within the aggrecan protein core.
  • the assay is run for 4 hr at 37° C., quenched with 20 mM EDTA, and analyzed for aggrecanase-generated products.
  • a sample containing enzyme and substrate without drug is included as a positive control and enzyme incubated in the absence of substrate serves as a measure of background. Removal of the glycosaminoglycan side chains from aggrecan reportedly is necessary for the BC-3 antibody to recognize the ARGSVIL epitope on the core protein.
  • proteoglycans and proteoglycan fragments are enzymatically deglycosylated with chondroitinase ABC (0.1 units/110 g GAG) for 2 hr at 37° C. and then with keratanase (0.1 units/110 g GAG) and keratanase II (0.002 units/10 g GAG) for 2 hr at 37° C. in buffer containing 50 mM sodium acetate, 0.1 M Tris/HCl, pH 6.5.
  • aggrecan in the samples is precipitated with 5 volumes of acetone and resuspended in 30 ⁇ L of Tris glycine SDS sample buffer (Novex) containing 2.5% beta mercaptoethanol.
  • Samples are loaded and then separated by SDS-PAGE under reducing conditions with 4-12% gradient gels, transferred to nitrocellulose and immunolocated with 1:500 dilution of antibody BC3.
  • membranes are incubated with a 1:5000 dilution of goat anti-mouse IgG alkaline phosphatase second antibody and aggrecan catabolites visualized by incubation with appropriate substrate for 10-30 minutes to achieve optimal color development. Blots are quantitated by scanning densitometry and inhibition of aggrecanase determined by comparing the amount of product produced in the presence versus absence of compound.

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Abstract

This invention is directed to aromatic sulfone hydroxamates (also known as aromatic sulfone hydroxamic acids) and salts thereof that, inter alia, tend to inhibit matrix metalloproteinase (also known as matrix metalloprotease or MMP) activity and/or aggrecanase activity. This invention also is directed to a treatment method that comprises administering such a compound or salt in an MMP-inhibiting and/or aggrecanase-inhibiting effective amount to an animal, particularly a mammal having (or disposed to having) a pathological condition associated with MMP activity and/or aggrecanase activity.

Description

    CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
  • This patent claims priority as a continuation-in-part to U.S. patent application Ser. No. 09/570,731 (filed May 12, 2000), which, in turn, claims priority to U.S. patent application Ser. No. 09/311,837 (filed May 14, 1999) and Ser. No. 09/256,948 (filed Feb. 24, 1999), which, in turn, claim priority to U.S. patent application Ser. No. 09/191,129 (filed Nov. 13, 1998), Ser. No. 09/186,410 (filed Nov. 5, 1998), 60/066,007 (filed Nov. 14, 1997), 60/095,347 (filed Aug. 4, 1998), 60/095,501 (filed Aug. 6, 1998), and 60/101,080 (filed Sep. 18, 1998). The entire texts of the above-referenced patent applications are incorporated by reference into this patent.[0001]
    • FIELD OF THE INVENTION
  • This invention is directed generally to proteinase (also known as “protease”) inhibitors, and, more particularly, to aromatic sulfone hydroxamate compounds (also known as “aromatic sulfone hydroxamic acid compounds”) and salts thereof (particularly pharmaceutically acceptable salts) that, inter alia, inhibit matrix metalloproteinase (also known as “matrix metalloprotease” or “MMP”) and/or aggrecanase activity. This invention also is directed to pharmaceutical compositions of such compounds and salts, and methods of using such compounds and salts to prevent or treat conditions associated with MMP and/or aggrecanase activity, particularly pathological conditions. [0002]
    • BACKGROUND OF THE INVENTION
  • Connective tissue is a required component of all mammals. It provides rigidity, differentiation, attachments, and, in some cases, elasticity. Connective tissue components include, for example, collagen, elastin, proteoglycans, fibronectin, and laminin. These biochemicals make up (or are components of) structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea, and vitreous humor. [0003]
  • Under normal conditions, connective tissue turnover and/or repair processes are in equilibrium with connective tissue production. Degradation of connective tissue is carried out by the action of proteinases released from resident tissue cells and/or invading inflammatory or tumor cells. [0004]
  • Matrix metalloproteinases, a family of zinc-dependent proteinases, make up a major class of enzymes involved in degrading connective tissue. Matrix metalloproteinases are divided into classes, with some members having several different names in common use. Examples are: MMP-1 (also known as collagenase 1, fibroblast collagenase, or EC 3.4.24.3); MMP-2 (also known as gelatinase A, 72 kDa gelatinase, basement membrane collagenase, or EC 3.4.24.24), MMP-3 (also known as stromelysin 1 or EC 3.4.24.17), proteoglycanase, MMP-7 (also known as matrilysin), MMP-8 (also known as collagenase II, neutrophil collagenase, or EC 3.4.24.34), MMP-9 (also known as gelatinase B, 92 kDa gelatinase, or EC 3.4.24.35), MMP-10 (also known as stromelysin 2 or EC 3.4.24.22), MMP-1 I (also known as stromelysin 3), MMP-12 (also known as metalloelastase, human macrophage elastase or HME), MMP-13 (also known as collagenase 111), and MMP-14 (also known as MT1-MMP or membrane MMP). See, generally, Woessner, J. F., “The Matrix Metalloprotease Family” in [0005] Matrix Metalloproteinases, pp.1-14 (Edited by Parks, W. C. & Mecham, R. P., Academic Press, San Diego, Calif. 1998).
  • Excessive breakdown of connective tissue by MMPs is a feature of many pathological conditions. Inhibition of MMPs therefore provides a control mechanism for tissue decomposition to prevent and/or treat these pathological conditions. Such pathological conditions generally include, for example, tissue destruction, fibrotic diseases, pathological matrix weakening, defective injury repair, cardiovascular diseases, pulmonary diseases, kidney diseases, liver diseases, and diseases of the central nervous system. Specific examples of such conditions include, for example, rheumatoid arthritis, osteoarthritis, septic arthritis, multiple sclerosis, a decubitis ulcer, corneal ulceration, epidermal ulceration, gastric ulceration, tumor metastasis, tumor invasion, tumor angiogenesis, periodontal disease, liver cirrhosis, fibrotic lung disease, emphysema, otosclerosis, atherosclerosis, proteinuria, coronary thrombosis, dilated cardiomyopathy, congestive heart failure, aortic aneurysm, epidermolysis bullosa, bone disease, Alzheimer's disease, and defective injury repair (e.g., weak repairs, adhesions such as post-surgical adhesions, and scarring). [0006]
  • Matrix metalloproteinases also are involved in the biosynthesis of tumor necrosis factors (TNFs). Tumor necrosis factors are implicated in many pathological conditions. TNF-α, for example, is a cytokine that is presently 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. TNF-α can cause and/or contribute to the effects of inflammation (e.g. rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, fibrotic diseases, cancer, infectious diseases (e.g., malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, cardiovascular diseases (e.g., post-ischemic reperfusion injury and congestive heart failure), pulmonary diseases, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage, and acute phase responses like those seen with infections and sepsis and during shock (e.g., septic shock and hemodynamic shock). Chronic release of active TNF-α can cause cachexia and anorexia. TNF-α also can be lethal. [0007]
  • Inhibiting TNF (and related compounds) production and action is an important clinical disease treatment. Matrix metalloproteinase inhibition is one mechanism that can be used. MMP (e.g., collagenase, stromelysin, and gelatinase) inhibitors, for example, have been reported to inhibit TNF-α release. See, e.g., Gearing et al. [0008] Nature 376, 555-557 (1994). See also, McGeehan et al. See also, Nature 376, 558-561 (1994). MMP inhibitors also have been reported to inhibit TNF-α convertase, a metalloproteinase involved in forming active TNF-α. See, e.g., WIPO Int'l Pub. No. WO 94/24140. See also, WIPO Int'l Pub. No. WO 94/02466. See also, WIPO Int'l Pub. No. WO 97/20824.
  • Matrix metalloproteinases also are involved in other biochemical processes in mammals. These include control of ovulation, postpartum uterine involution, possibly implantation, cleavage of APP (β-amyloid precursor protein) to the ainyloid plaque, and inactivation of (α[0009] 1-protease inhibitor (α1-PI). Inhibiting MMPs therefore may be a mechanism that may be used to control of fertility. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor (e.g., α1-PI) supports the treatment and prevention of pathological conditions such as emphysema, pulmonary diseases, inflammatory diseases, and diseases of aging (e.g., loss of skin or organ stretch and resiliency).
  • Numerous metalloproteinase inhibitors are known. See, generally, Brown, P. D., “Synthetic Inhibitors of Matrix Metalloproteinases,” in [0010] Matrix Metalloproteinases, pp. 243-61 (Edited by Parks, W. C. & Mecham, R. P., Academic Press, San Diego, Calif. 1998).
  • Metalloproteinase inhibitors include, for example, natural biochemicals, such as tissue inhibitor of metalloproteinase (TIMP), α2-macroglobulin, and their analogs and derivatives. These are high-molecular-weight protein molecules that form inactive complexes with metalloproteinases. [0011]
  • A number of smaller peptide-like compounds also have been reported to inhibit metalloproteinases. Mercaptoamide peptidyl derivatives, for example, have been reported to inhibit angiotensin coniierting enzyme (also known as ACE) in vitro and in vivo. ACE aids in the production of angiotensin II, a potent pressor substance in mammals. Inhibiting ACE leads to lowering of blood pressure. [0012]
  • A wide variety of thiol compounds have been reported to inhibit MMPs. See, e.g., WO95/12389. See also, WO96/11209. See also, U.S. Pat. No. 4,595,700. See also, U.S. Pat. No. 6,013,649. [0013]
  • A wide variety of hydroxamate compounds also have been reported to inhibit MMPs. Such compounds reportedly include hydroxamates having a carbon backbone. See, e.g., WIPO Int'l Pub. No. WO 95/29892. See also, WIPO Int'l Pub. No. WO 97/24117. See also, WIPO Int'l Pub. No. WO 97/49679. See also, European Patent No. EP 0 780 386. Such compounds also reportedly include hydroxamates having peptidyl backbones or peptidomimetic backbones. See, e.g, WIPO Int'l Pub. No. WO 90/05719. See also, WIPO Int'l Pub. No. WO 93/20047. See also, WIPO Int'l Pub. No. WO 95/09841. See also, WIPO Int'l Pub. No. WO 96/06074. See also, Schwartz et al., [0014] Progr. Med. Chem., 29:271-334(1992). See also, Rasmussen et al., PharmacoL Ther., 75(1): 69-75 (1997). See also, Denis et al., Invest New Drugs, 15(3): 175-185 (1997). Sulfamato hydroxamates have additionally been reported to inhibit MMPs. See, WIPO Int'l Pub. No. WO 00/46221. And various aromatic sulfone hydroxamates have been reported to inhibit MMPs. See, WIPO Int'l Pub. No. WO 99/25687. See also, WIPO Int'l Pub. No. WO 00/50396. See also, WIPO Int'l Pub. No. WO 00/69821.
  • It is often advantageous for an MMP inhibitor drug to target a certain MMP(s) over another MMP(s). For example, it is typically preferred to inhibit MMP-2, MMP-3, MMP-9, and/or MMP-13 (particularly MMP-13) when treating and/or preventing cancer, inhibiting of metastasis, and inhibiting angiogenesis. It also is typically preferred to inhibit MMP-13 when preventing and/or treating osteoarthritis. See, e.g., Mitchell et al., [0015] J Clin. Invest., 97:761-768 (1996). See also, Reboul et al., J Clin. Invest., 97:2011-2019 (1996). Normally, however, it is preferred to use a drug that has little or no inhibitory effect on MMP-1 and MMP-14. This preference stems from the fact that both MMP-1 and MMP-14 are involved in several homeostatic processes, and inhibition of MMP-1 and/or MMP-14 consequently tends to interfere with such processes.
  • Many known MMP inhibitors exhibit the same or similar inhibitory effects against each of the MMPs. For example, batimastat (a peptidomimetic hydroxamate) has been reported to exhibit IC[0016] 50 values of from about 1 to about 20 nM against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat (another peptidomimetic hydroxamate) has been reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum similar to batimastat, except that Marimastat reportedly exhibited an IC50 value against MMP-3 of 230 nM. See Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
  • Meta analysis of data from Phase I/II studies using Marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, and prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although Marimastat exhibited some measure of efficacy via these markers, toxic side effects reportedly were observed. 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, and then spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction reportedly permits treatment to continue. See Rasmussen et al., [0017] Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.
  • Another enzyme implicated in pathological conditions associated with excessive degradation of connective tissue is aggrecanase, particularly aggrecanase-1 (also known as ADAMTS-4). Specifically, articular cartilage contains large amounts of the proteoglycan aggrecan. Proteoglycan aggrecan provides mechanical properties that help articular cartilage in withstanding compressive deformation during joint articulation. The loss of aggrecan fragments and their release into synovial fluid caused by proteolytic cleavages is a central pathophysiological event in osteoarthritis and rheumatoid arthritis. It has been reported that two major cleavage sites exist in the proteolytically sensitive interglobular domains at the N-terminal region of the aggrecan core protein. One of those sites has been reported to be cleaved by several matrix metalloproteases. The other site, however, has been reported to be cleaved by aggrecanase-1. Thus, inhibiting excessive aggrecanase activity provides a method for preventing or treating inflammatory conditions. See generally, Tang, B. L., “ADAMTS: A Novel Family of Extracellular Matrix Proteases,” [0018] Int'l Journal of Biochemistry & Cell Biology, 33, pp. 33-44 (2001). Such diseases reportedly include, for example, osteoarthritis, rheumatoid arthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, and psoriatic arthritis. See, e.g., European Patent Application Publ. No. EP 1 081 137 A1.
  • In addition to inflammatory conditions, there also is evidence that inhibiting aggrecanase may be used for preventing or treating cancer. For example, excessive levels of aggrecanase-1 reportedly have been observed with a ghoma cell line. It also has been postulated that the enzymatic nature of aggrecanase and its similarities with the MMPs would support tumor invasion, metastasis, and angiogenesis. See Tang, [0019] Int'l Journal of Biochemistry & Cell Biology, 33, pp. 33-44 (2001).
  • Various hydroxamate compounds have been reported to inhibit aggrecanase-1. Such compounds include, for example, those described in European Patent Application Publ. No. EP 1 081 137 A1. Such compounds also include, for example, those described in WIPO PCT Int'l Publ. No. WO 00/09000. Such compounds further include, for example, those described in WIPO PCT Int'l Publ. No. WO 00/59874. [0020]
  • In view of the importance of hydroxamate compounds and salts thereof in the prevention or treatment of several NMP- and/or aggrecanase-related pathological conditions and the lack of enzyme specificity exhibited by at least some of the hydroxamates that have been in clinical trials, there continues to be a need for hydroxamates having greater enzyme inhibition specificity (preferably toward MMP-2, MMP-9, MMP-13, and/or aggrecanase, and particularly toward MMP-13 and/or aggrecanase), while exhibiting little or no inhibition of MMP activity essential to normal bodily function (e.g., tissue turnover and repair). The following disclosure describes hydroxamate compounds and salts thereof that tend to exhibit such desirable activities. [0021]
    • SUMMARY OF THE INVENTION
  • This invention is directed to compounds that inhibit MMP (particularly MMP-2, MMP-9, and/or MMP-13) and/or aggrecanase activity, while generally exhibiting relatively little or no inhibition against MMP activity essential to normal bodily function (particularly MMP-1 and MMP-14 activity). This invention also is directed to a method for inhibiting MMP and/or aggrecanase activity, particularly pathological activity. Such a method is particularly suitable to be used with mammals, such as humans, other primates (e.g., monkeys, chimpanzees. etc.), companion animals (e.g., dogs, cats, horses. etc.), farm animals (e.g., goats, sheep, pigs, cattle, etc.), laboratory animals (e.g., mice, rats, etc.), and wild and zoo animals (e.g., wolves, bears, deer, etc.). [0022]
  • Briefly, therefore, the invention is directed in part to a compound or salt thereof. The compound has a structure corresponding to Formula X: [0023]
    Figure US20040209914A1-20041021-C00001
  • The variables Z, R, E, and Y are described in more detail below. [0024]
  • The present invention also is directed to treatment methods that comprise administering a compound described above (or pharmaceutically-acceptable salt thereof) in an effective amount to a host mammal having a condition associated with pathological metalloprotease and/or aggrecanase activity. A contemplated compound or salt thereof tends to exhibit, for example, inhibitory activity of one or more matrix metalloprotease (MMP) enzymes (e.g., MMP-2, MMP-9 and MMP-13), while exhibiting substantially less inhibition of MMP-1 and/or MMP-14. By “substantially less” it is meant that a contemplated compound exhibits an IC[0025] 50 value ratio against one or more of MMP-2, MMP-9, or MMP-13 as compared to its IC50 value against MMP-1 and/or MMp-14 (e.g., IC50 MMP-13:IC50 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 described in the Example section below.
  • In one embodiment, the process comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to prevent or treat the condition. Such a condition may be, for example, tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, and a central nervous system disease. Specific examples of such conditions include osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermolysis bullosa, aortic aneurysm, weak injury repair, an adhesion, scarring, congestive heart failure, coronary thrombosis, emphysema, proteinuria, and Alzheimer's disease. [0026]
  • In another embodiment, the prevention or treatment method comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to inhibit matrix metalloprotease-2, matrix metalloprotease-9, and/or matrix metalloprotease-13 activity. [0027]
  • In another embodiment, the prevention or treatment method comprises administering an above-described compound or pharmaceutically acceptable salt, thereof to the host animal in an amount effective to prevent or treat a condition associated with TNF-α convertase activity. Examples of such a condition include inflammation, a pulmonary disease, a cardiovascular disease, an autoimmune disease, graft rejection, a fibrotic disease, cancer, an infectious disease, fever, psoriasis, hemorrhage, coagulation, radiation damage, acute-phase responses of shock and sepsis, anorexia, and cachexia. [0028]
  • In another embodiment, the prevention or treatment method comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to prevent or treat a condition associated with aggrecanase activity. Such a condition may be, for example, an inflammatory disease or cancer. [0029]
  • This invention additionally is directed, in part, to pharmaceutical compositions comprising the above-described compounds or pharmaceutically acceptable salts thereof, and the use of those compositions in the above-described prevention or treatment processes. [0030]
  • This invention further is directed, in part, to the use of an above-described compound or pharmaceutically acceptable salt thereof for production of a medicament for use in the treatment of a condition related to MMP activity. As noted above, such a condition may be, for example, tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, and a central nervous system disease. [0031]
  • Further benefits of Applicants' invention will be apparent to one skilled in the art reading this patent.[0032]
    • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • This detailed description of preferred embodiments is intended only to acquaint others skilled in the art with Applicants' invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This detailed description and its specific examples, while indicating the preferred embodiments of this invention, are intended for purposes of illustration only. This invention, therefore, is not limited to the preferred embodiments described in this patent, and may be variously modified. [0033]
    • A. Compounds of this Invention
  • In accordance with this invention, Applicants have found that certain aromatic sulfone hydroxamates tend to be effective toward inhibiting MMPs, particularly those associated with excessive (or otherwise pathological) breakdown of connective tissue. Specifically, Applicants have found that these hydroxamates tend to be effective for inhibiting MMP-2 MMP-9, and/or MMP-13, which can be particularly destructive to tissue if present or generated in abnormally excessive quantities or concentrations. Applicants also have discovered that many of these hydroxamates tend to be effective toward inhibiting pathological aggrecanase activity. Applicants have further discovered that these hydroxamates tend to be selective toward inhibiting aggrecanase and/or MMPs associated with pathological condition conditions, and tend to avoid excessive inhibition of MMPs (particularly MMP-1 and MMP-14) essential to normal bodily function (e.g., tissue turnover and repair). Applicants have found, for example, that these hydroxamates tend to be particularly active toward inhibiting MMP-2, MMP-9, MMP-13, and/or aggrecanase activity in in vitro assays that are generally predictive of in vivo activity, while exhibiting minimal inhibition toward MMP-1 and/or MMP-14 in such assays. Examples of such in vitro assays are discussed in the example section below. Compounds (or salts) that are particularly useful as selective MMP inhibitors exhibit, for example, an in vitro IC[0034] 50 value against one or more of MMP-2, MMP-9, and MMP-13 that is no greater than about 0.1 times the IC50 value against MMP-1 and/or MMP-14, more preferably no greater than about 0.01 times the IC50 value against MMP-1 and/or MMP-14, and even more preferably 0.001 times the IC50 value against MMP-1 and/or MMP-14.
  • Without being bound by theory, the advantages of the selectivity of a contemplated compound can be appreciated by considering the roles of the various MMP and aggrecanase enzymes. For example, inhibition of MMP-1 is believed to be undesirable due to the role of MMP-1 as a housekeeping enzyme (i.e., helping to maintain normal connective tissue turnover and repair). Inhibition of MMP-1 can lead to toxicities or side effects such as such as joint or connective tissue deterioration and pain. On the other hand, MMP-13 is believed to be intimately involved in the destruction of joint components in diseases such as osteoarthritis. Thus, potent and selective inhibition of MMP-13 is typically highly desirable because such inhibition can have a positive effect on disease progression in a patient (in addition to having an anti-inflammatory effect). [0035]
  • Another advantage of the compounds and salts of this invention is their tendency to be selective with respect to tumor necrosis factor release and/or tumor necrosis factor receptor release. This provides the physician with another factor to help select the best drug for a particular patient. Without being bound by theory, it is believed that there are multiple factors to this type of selectivity to be considered. The first is that presence of tumor necrosis factor can be desirable for the control of cancer in the organism, so long as TNF is not present in a toxic excess. Thus, uncontrolled inhibition of release of TNF can be counterproductive and actually can be considered an adverse side effect even in cancer patients. In addition, selectivity with respect to inhibition of the release of the tumor necrosis factor receptor can also be desirable. The presence of that receptor can be desirable for maintaining a controlled tumor necrosis level in the mammal by binding excess TNF. [0036]
  • Briefly, therefore, this invention is directed, in part, to a compound or salt thereof (particularly a pharmaceutically acceptable salt thereof). The compound has a structure corresponding to Formula X: [0037]
    Figure US20040209914A1-20041021-C00002
  • In some preferred embodiments: [0038]
  • Z is —C(O)—, —N(R[0039] 6)—, —O—, —S—, —S(O)—, —S(O)2—, or —N(S(O)2R7)—. In some particularly preferred embodiments, Z is —O—. In other particularly preferred embodiments, Z is —N(R6)—.
  • R[0040] 6 is hydrogen, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, carboxy-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, carboxy, C1-C6-alkylcarbonyl, R8R9-aminocarbonyl, aryl-C1-C6-alkyl, arylcarbonyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, halo-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, perfluoro-C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarylcarbonyl, heterocyclylcarbonyl, aryl, heterocyclyl, heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, C5-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, aminocarbonyl, C1-C6-alkylimino(R10)carbonyl, arylimino(R10)carbonyl, C5-C6-heterocyclylimino(R10)carbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, C5-C6-heteroaryl-C1-C6-alkyl, halo-C1-C6-alkylcarbonyl, hydroxy-C1-C6-alkylcarbonyl, thiol-C1-C6-alkylcarbonyl, C3-C6-alkenyl, C3-C6-alkynyl, aryloxycarbonyl, R8R9-aminoimino(R10)methyl, R8R9-amino-C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfonyl-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl, or R8R9-amino-C1-C6-alkyl.
  • In some particularly preferred embodiments, R[0041] 6 is C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C1-C6-alkylsulfonyl, C3-C6-alkenyl, or C3-C6-alkynyl.
  • R[0042] 7 is aryl-C1-C6-alkyl, aryl, heteroaryl, heterocyclyl, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, carboxy-C1-C6-alkyl, or hydroxy-C1-C6-alkyl.
  • R[0043] 8 and R9 are independently selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkylcarbonyl, arylcarbonyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryl-C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, carboxy-C1-C6-alkyl, carboxyaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl. Here, the amino-C1-C6-alkyl nitrogen optionally is substituted with up to 2 substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkylcarbonyl. Preferably, no greater than one of R8 and R9 is hydroxy.
  • Alternatively, R[0044] 8 and R9, together with the atom to which they are bonded, form a 5- to 8-membered heterocyclic or heteroaryl ring containing up to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • R[0045] 10 is hydrogen, hydroxy, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryl-C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, carboxy-C1-C6-alkyl, carboxyaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl. Here, the amino-C1-C6-alkyl nitrogen optionally is substituted with up to 2 substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkylcarbonyl.
  • E is a bond, —C(O)—, or —S—. [0046]
  • Y is hydrogen, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocyclyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, or aminoalkyl. Here, the aryl, heteroaryl, arylalkyl, or heterocyclyl optionally is substituted with up to 2 substituents independently selected from the group consisting of alkylcarbonyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino. The amino, in turn, optionally is substituted with up to 2 substituents independently selected from the group consisting of alkyl and arylalkyl. In some particularly preferred embodiments, Y comprises a cyclic structure, i.e., Y is optionally substituted aryl, arylalkyl, cycloalkyl, heteroaryl, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, heterocyclyl, or cycloalkyl. In one such embodiment, Y is optionally substituted phenyl. In another such embodiment, Y is optionally substituted phenylmethyl. In still another such embodiment, Y is optionally substituted heteraryl. And in still yet another such embodiment, Y is optionally substituted heteroarylmethyl. [0047]
  • R is hydrogen, cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, arylalkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, arylalkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroarylalkyl, cycloalkyl, heterocylyloxy, heterocylylthio, heterocylylamino, cycloalkyloxy, cycloalkylthio, heteroarylalkoxy, heteroarylalkylthio, arylalkoxy, arylalkylthio, arylalkylamino, heterocylyl, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylcarbonyloxy, arylalkylcarbonyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino, aminocarbonyl, or aminoalkyl. [0048]
  • The nitrogen of an R amino may be unsubstituted. Alternatively, the amino nitrogen may be substituted with up two substituents that are independently selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, arylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, and alkylcarbonyl. Alternatively, the amino nitrogen optionally may be substituted with two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that: (i) contains from zero to two additional heteroatoms that are independently selected from the group consisting of nitrogen, oxygen, and sulfur; and (ii) optionally is substituted with up to two substituents independently selected from the group consisting of aryl, alkyl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, alkylcarbonyl, cycloalkyl, heterocylylalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocylylalkyl, hydroxyalkoxyalkyl, arylalkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocylylalkoxy, benzofused cycloalkylcarbonyl, heterocyclylalkylcarbonyl, and cycloalkylcarbonyl. [0049]
  • The nitrogen of an R aminocarbonyl is may be unsubstituted. Alternatively, the aminocarbonyl nitrogen may be the reacted amine of an amino acid. Alternatively, the aminocarbonyl nitrogen may be substituted with up to two substituents independently selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroarylalkyl, cycloalkyl, arylalkyl, trifluoromethylalkyl, heterocylylalkyl, benzofused heterocylylalkyl, benzofused cycloalkyl, and N,N-dialkylsubstituted alkylamino-alkyl. Alternatively, the aminocarbonyl nitrogen may be substituted with two substituents such that the two substituents, together with the aminocarbonyl nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that optionally is substituted with up to two substituents independently selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocyclylalkyl, hydroxy, hydroxycarbonyl, aryl, arylalkyl, heteroaralkyl, and amino. Here, the amino nitrogen, in turn, optionally is substituted with: (i) two substituents independently selected from the group consisting of alkyl, aryl, and heteroaryl; or (ii) two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring. [0050]
  • The nitrogen of an R aminoalkyl may be unsubstituted. Alternatively, the aminoalkyl nitrogen may be substituted with up to two substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, and alkylcarbonyl. Alternatively, the aminoalkyl nitrogen may be substituted with two substituents such that the two substituents, together with the aminoalkyl nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring. [0051]
  • In one particularly preferred embodiment, R is halogen (preferably chloro or fluoro, and even more preferably chloro). In another particularly preferred embodiment, R is hydrogen so that the compound corresponds in structure to Formula XA: [0052]
    Figure US20040209914A1-20041021-C00003
  • In other embodiments directed to compounds corresponding in structure to Formula X: [0053]
  • Z is —C(O)—, —N(R[0054] 6)—, —O—, —S—, or —S(O)2—. In one particularly preferred embodiment, Z is —N(R6)—. In another particularly preferred embodiment, Z is —O—.
  • R[0055] 6 is hydrogen, arylalkoxycarbonyl, alkylcarbonyl, alkyl, alkoxyalkyl, cycloalkyl, heteroarylcarbonyl, heteroaryl, cycloalkylalkyl, alkylsulfonyl, haloalkylcarbonyl, alkenyl, alkynyl, and R8R9-aminoalkylcarbonyl.
  • In some particularly preferred embodiments, R[0056] 6 is hydrogen, aryl-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkyl (preferably isopropyl), C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroaryl, heteroarylcarbonyl, halo-C1-C6-alkylcarbonyl, or R8R9-amino-C1-C6-alkylcarbonyl.
  • In other particularly preferred embodiments, R[0057] 6 is C1-C6-alkyl (preferably ethyl), C1-C6-alkoxy-C1-C6-alkyl (preferably methoxyethyl), C3-C6-cycloalkyl (preferably cyclopropyl), C3-C8-cycloalkyl-C1-C6-alkyl (preferably cyclopropylmethyl), C3-C6-alkenyl (preferably C3-alkenyl), C3-C6-alkynyl (preferably C3-alkynyl), or C1-C6-alkylsulfonyl (preferably methylsulfonyl).
  • R[0058] 8 and R9 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylcarbonyl, haloalkyl, and aminoalkyl. Here, the aminoalkyl nitrogen optionally is substituted with up to two substituents independently selected from the group consisting of alkyl.
  • Alternatively, R[0059] 8 and R9, together with the atom to which they are bonded, form a 5- to 8-membered heterocyclyl or heteroaryl containing up to 3 (in many instances, no greater than 2) heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Here, any such heterocyclyl or heteroaryl (particularly heterocyclyl) optionally is substituted with one or more substituents independently selected from the group consisting of hydroxy, keto, carboxy, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxyalkyl, alkoxycarbonylalkyl, heterocyclylalkyl, alkoxycarbonyl, and aminoalkyl. The aminoalkyl nitrogen, in turn, optionally is substituted with up to two substituents independently selected from the group consisting of alkyl.
  • E is a bond, —C(O)—, or —S—. [0060]
  • Y is cycloalkyl, 2,3-dihydroindolyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. Here, the cycloalkyl, 2,3-dihydroindolyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, keto, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkoxy, alkylcarbonyl, haloalkoxy, alkylthio, alkoxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkoxy, cycloalkylalkoxyalkyl, aryl, arylalkyl, arylalkoxy, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylcarbonyl, heterocyclylcarbonylalkyl, alkylsulfonyl, amino, aminoalkyl, and aminocarbonyl. These optional substituents, in turn, optionally are substituted with one or more substituents independently selected from the group consisting of halogen, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylcarbonyl. Additionally, the nitrogen of the amino, aminoalkyl, or aminocarbonyl optionally is substituted with up to two substituents independently selected from the group consisting of alkyl and cycloalkylalkyl. [0061]
  • In some preferred embodiments, E is —C(O)—, and Y is heterocyclyl, aryl (particularly phenyl), heteroaryl, or arylmethyl (particularly phenylmethyl). Here, the heterocyclyl, aryl, heteroaryl, or arylmethyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C[0062] 1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, halo-C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-cycloalkyl, aryl, aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, heterocyclyl, heterocyclyl-C1-C6-alkyl, heteroaryl, heteroarylcarbonyl, heterocyclylcarbonyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl. These optional substituents, in turn, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and C1-C6-alkylcarbonyl. Additionally, the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl and C3-C6-cycloalkyl-C1-C6-alkyl.
  • In other preferred embodiments, E is —C(O)—, and Y is aryl (particularly phenyl), heteroaryl, arylmethyl (particularly phenylmethyl), or heteroarylmethyl. The aryl, heteroaryl, arylmethyl, or heteroarylmethyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C[0063] 1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl-C1-C6-alkyl, C3-C6-cycloalkyloxy, C3-C6-cycloalkyl-C1-C6-alkoxy, C3-C6-cycloalkyl-C1-C6-alkoxy-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl. And the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl. In some such preferred embodiments, Y is optionally substituted phenyl. Such compounds include, for example:
    Figure US20040209914A1-20041021-C00004
  • In other such preferred embodiments, Y is optionally substituted heteroaryl. Such compounds include, for example, compounds wherein Y is optionally substituted thienyl: [0064]
    Figure US20040209914A1-20041021-C00005
  • In other preferred embodiments, E is a bond, and Y is aryl (particularly phenyl), 2,3-dihydroindolyl, heterocyclyl, or heteroaryl. The aryl, 2,3-dihydroindolyl, heterocyclyl, or heteroaryl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, keto, hydroxy, C[0065] 1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, aryl, aminocarbonyl, and C1-C6-alkylsulfonyl. These optional substituents, in turn, also are optionally substituted with one or more substituents independently selected from the group consisting of halogen, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy. Additionally, the nitrogen of the aminocarbonyl optionally is substituted with up to 2 substituents independently selected from the group consisting of C1-C6-alkyl.
  • In other preferred embodiments, E is a bond, and Y is heteroaryl, aryl (particularly phenyl), or heterocyclyl. The heteroaryl, aryl, or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C[0066] 1-C6-alkyl, C1-C6-alkoxy, and aryl. The optional aryl substituent(s), in turn, optionally is/are substituted with one or more substituents independently selected from the group consisting of halo-C1-C6-alkyl.
  • In other preferred embodiments, E is —S—, and Y is cycloalkyl, aryl, arylmethyl, or heteroaryl. The cycloalkyl, aryl (particularly phenyl), arylmethyl (particularly phenylmethyl), or heteroaryl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, halo-C[0067] 1-C6-alkyl, and halo-C1-C6-alkoxy.
  • In other preferred embodiments, E is —S—, and Y is heteraryl. [0068]
  • In the above embodiments, R preferably is halogen (preferably chloro or fluoro, and even more preferably chloro). Alternatively, R preferably is hydrogen so that the compound corresponds in structure to Formula XA (shown above). [0069]
    • B. Preparation of Useful Compounds
  • Exemplary chemical transformations that can be useful for preparing compounds and salts of this invention are described in detail in, for example, WIPO Int'l Publ. Nos. WO 00/69821 (published Nov. 23, 2000); WO 00/50396 (published Aug. 31, 2000); and 99/25687 (published May 27, 1999). These references are hereby incorporated by reference into this patent. The reader also is referred to the Example section below, which describes the preparation of numerous compounds and salts of this invention. [0070]
    • C. Salts of the Compounds of this Invention
  • The compounds of this invention can be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound. [0071]
  • Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means with a compound of this invention by reacting, for example, the appropriate acid or base with the compound. [0072]
  • Pharmaceutically-acceptable acid addition salts of the compounds of this invention may be prepared from an inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric, hydrobromic acid, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate. [0073]
  • Pharmaceutically-acceptable base addition salts of the compounds of this invention include, for example, metallic salts and organic salts. Preferred metallic salts include alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts, and other physiological acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred organic salts can be made from tertiary amines and quaternary amine salts, such as tromethamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl (C[0074] 1-C6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • Particularly preferred salts of the compounds of this invention include hydrochloric acid (HCl) salts and trifluoroacetate (CF[0075] 3COOH or TFA) salts.
    • D. Preventing or Treating Conditions Using the Compounds and Salts of this Invention
  • One embodiment of this invention is directed to a process for preventing or treating a pathological condition associated with MMP activity in a mammal (e.g., a human, companion animal, farm animal, laboratory animal, zoo animal, or wild animal) having or disposed to having such a condition. Such a condition may be, for example, tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, and a central nervous system disease. Specific examples of such conditions include osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermolysis bullosa, aortic aneurysm, weak injury repair, an adhesion, scarring, congestive heart failure, coronary thrombosis, emphysema, proteinuria, and Alzheimer's disease. [0076]
  • The condition may alternatively (or additionally) be associated with TNF-α convertase activity. Examples of such a condition include inflammation (e.g., rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, a fibrotic disease, cancer, an infectious disease (e.g., malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, a cardiovascular disease (e.g., post-ischemic reperfusion injury and congestive heart failure), a pulmonary disease, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage, acute phase responses like those seen with infections and sepsis and during shock (e.g., septic shock, hemodynamic shock, etc.), cachexia, and anorexia. [0077]
  • The condition may alternatively (or additionally) be associated with aggrecanase activity. Examples of such a condition include inflammation diseases (e.g., osteoarthritis, rheumatoid arthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, and psoriatic arthritis) and cancer. [0078]
  • In this patent, the phrase “preventing a condition” means reducing the risk of (or delaying) the onset of the condition in a mammal that does not have the condition, but is predisposed to having the condition. In contrast, the phrase “treating a condition” means ameliorating, suppressing, or eradicating an existing condition. The pathological condition may be, for example: (a) the result of pathological MMP and/or aggrecanase activity itself, (b) affected by MMP activity (e.g., diseases associated with TNF-α), and/or (c) affected by aggrecanase activity. [0079]
  • A wide variety of methods may be used alone or in combination to administer the hydroxamates and salt thereof described above. For example, the hydroxamates or salts thereof may be administered orally, parenterally, by inhalation spray, rectally, or topically. Oral administration can be advantageous if, for example, the patient is ambulatory, not hospitalized, and physically able and sufficiently responsible to take drug at the required intervals. This may be true even if the person is being treated with more than one drug for one or more diseases. On the other hand, IV drug administration can be advantageous in, for example, a hospital setting where the dose (and thus the blood levels) can be well controlled. A compound or salt of this invention also can be formulated for IM administration if desired. This route of administration may be desirable for administering prodrugs or regular drug delivery to patients that are either physically weak or have a poor compliance record or require constant drug blood levels. [0080]
  • Typically, a compound (or pharmaceutically acceptable salt thereof) described in this patent is administered in an amount effective to inhibit a target MMP(s). The target MMP is/are typically MMP-2, MMP-9, and/or MMP-13, with MMP-13 often being a particularly preferred target. The preferred total daily dose of the hydroxamate or salt thereof (administered in single or divided doses) is typically from about 0.001 to about 100 mg/kg, more preferably from about 0.001 to about 30 mg/kg, and even more preferably from about 0.01 to about 10 mg/kg (i.e., mg hydroxamate or salt thereof per kg body weight). Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound or salt will be repeated a plurality of times. Multiple doses per day typically may be used to increase the total daily dose, if desired. [0081]
  • Factors affecting the preferred dosage regimen include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; the route of administration; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular hydroxamate or salt thereof employed; whether a drug delivery system is utilized; and whether the hydroxamate or salt thereof is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely, and, therefore, can deviate from the preferred dosage regimen set forth above. [0082]
    • E. Pharmaceutical Compositions Containing the Compounds and Salts of this Invention
  • This invention also is directed to pharmaceutical compositions comprising a hydroxamate or salt thereof described above, and to methods for making pharmacetucal compositions (or medicaments) comprising a hydroxamate or salt thereof described above. [0083]
  • The preferred composition depends on the method of administration, and typically comprises one or more conventional pharmaceutically acceptable carriers, adjuvants, and/or vehicles. Formulation of drugs is generally discussed in, for example, Hoover, John E., [0084] Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.: 1975). See also, Liberman, H. A. See also, Lachman, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N.Y., 1980).
  • Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the hydroxamates or salts thereof are ordinarily combined with one or more adjuvants. If administered per os, the hydroxamates or salts thereof can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation, as can be provided in a dispersion of the hydroxamate or salt thereof in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally can be prepared with enteric coatings. [0085]
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents. [0086]
  • “Parenteral administration” includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents. Acceptable vehicles and solvents include, for example, water, 1,3-butanediol, Ringer's solution, isotonic sodium chloride solution, bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids (e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic and non-ionic detergents), and/or polyethylene glycols. [0087]
  • Formulations for parenteral administration may, for example, be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The hydroxamates or salts thereof can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. [0088]
  • Suppositories for rectal administration can be prepared by, for example, mixing the drug with a suitable nonirritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, such as cocoa butter; synthetic mono-, di-, or triglycerides; fatty acids; and/or polyethylene glycols [0089]
  • “Topical administration” includes the use of transdermal administration, such as transdermal patches or iontophoresis devices. [0090]
  • Other adjuvants and modes of administration known in the pharmaceutical art may also be used. [0091]
    • F. Definitions
  • The term “alkyl” (alone or in combination with another term(s)) means a straight-or branched-chain saturated hydrocarbyl group typically containing from 1 to about 20 carbon atoms, more typically from about 1 to about 8 carbon atoms, and even more typically from about 1 to about 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, and the like. [0092]
  • The term “alkenyl” (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl group containing one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms. Examples of such groups include ethenyl (vinyl); 2-propenyl; 3-propenyl; 1,4-pentadienyl; 1,4-butadienyl; 1-butenyl; 2-butenyl; 3-butenyl; decenyl; and the like. [0093]
  • The term “alkynyl” (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl group containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms. Examples of such groups include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like. [0094]
  • The term “carbocyclyl” (alone or in combination with another term(s)) means a saturated cyclic, partially saturated cyclic, or aryl hydrocarbyl group containing from 3 to 14 carbon ring atoms (“ring atoms” are the atoms bound together to form the ring or rings of a cyclic group). A carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples of such single-ring carbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. A carbocyclyl alternatively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl”), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl”), fluoreneyl, decalinyl, and norpinanyl. [0095]
  • The term “cycloalkyl” (alone or in combination with another term(s)) means a saturated cyclic hydrocarbyl group containing from 3 to 14 carbon ring atoms. A cycloalkyl may be a single carbon ring, which typically contains from 3 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropanyl, cyclobutanyl, cyclopentyl, and cyclohexyl. A cycloalkyl alternatively may be 2 or 3 carbon rings fused together, such as, decalinyl or norpinanyl. [0096]
  • The term “aryl” (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl. [0097]
  • In some instances, the number of carbon atoms in a hydrocarbyl group (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicated by the prefix “C[0098] x-Cy-”, wherein x is the minimum and y is the maximum number of carbon atoms in the group. Thus, for example, “C1-C6-alkyl” refers to an alkyl group containing from 1 to 6 carbon atoms. Illustrating further, C3-C6-cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
  • The term “hydrogen” (alone or in combination with another term(s)) means a hydrogen radical, and may be depicted as —H. [0099]
  • The term “hydroxy” (alone or in combination with another term(s)) means —OH. [0100]
  • The term “nitro” (alone or in combination with another term(s)) means —NO[0101] 2.
  • The term “cyano” (alone or in combination with another term(s)) means —CN, which also may be depicted as or —COOH: [0102]
    Figure US20040209914A1-20041021-C00006
  • The term “keto” (alone or in combination with another term(s)) means an oxo radical, and may be depicted as ═O. [0103]
  • The term “carboxy” (alone or in combination with another term(s)) means —C(O)—OH, which also may be depicted as: [0104]
    Figure US20040209914A1-20041021-C00007
  • The term “amino” (alone or in combination with another term(s)) means —NH[0105] 2. The term “monosubstituted amino” (alone or in combination with another term(s)) means an amino group wherein one of the hydrogen radicals is replaced by a non-hydrogen substituent. The term “disubstituted amino” (alone or in combination with another term(s)) means an amino group wherein both of the hydrogen atoms are replaced by non-hydrogen substituents, which may be identical or different.
  • The term “halogen” (alone or in combination with another term(s)) means a fluorine radical (which may be depicted as —F), chlorine radical (which may be depicted as —Cl), bromine radical (which may be depicted as —Br), or iodine radical (which may be depicted as —I). Typically, a fluorine radical or chlorine radical is preferred. [0106]
  • If a group is described as being “substituted”, at least one hydrogen on the group is replaced with a non-hydrogen substituent. Thus, for example, a substituted alkyl group is an alkyl group wherein at least one hydrogen on the alkyl group is replaced with a non-hydrogen substituent. It should be recognized that if there are more than one substitutions on a group, each non-hydrogen substituent may be identical or different. [0107]
  • If a group is described as being “optionally substituted”, the group may be either substituted or not substituted. [0108]
  • The prefix “halo” indicates that the group to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl means an alkyl group wherein at least one hydrogen radical is replaced with a halogen radical. Examples of haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like. Illustrating further, “haloalkoxy” means an alkoxy group wherein at least one hydrogen radical is replaced by a halogen radical. Examples of haloalkoxy groups include chlormethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as “perfluoromethyoxy”), 1,1,1,-trifluoroethoxy, and the like. It should be recognized that if a group is substituted by more than one halogen radical, those halogen radicals may be identical or different. [0109]
  • The prefix “perhalo” indicates that every hydrogen radical on the group to which the prefix is attached is replaced with independently selected halogen radicals, i.e., each hydrogen radical on the group is replaced with a halogen radical. If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the term “perfluoro” means that every hydrogen radical on the group to which the prefix is attached is substituted with a fluorine radical. To illustrate, the term “prefluoroalkyl” means an alkyl group wherein each hydrogen radical is replaced with a fluorine radical. Examples of perfluoroalkyl groups include trifluoromethyl (—CF[0110] 3), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, perfluorodecyl, and the like. To illustrate further, the term “perfluoroalkoxy” means an alkoxy group wherein each hydrogen radical is replaced with a fluorine radical. Examples of perfluoroalkoxy groups include trifluoromethoxy (—O—CF3), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, perfluorodecoxy, and the like.
  • The term “carbonyl” (alone or in combination with another term(s)) means —C(O)—, which also may be depicted as: [0111]
    Figure US20040209914A1-20041021-C00008
  • This term also is intended to encompass a hydrated carbonyl group, i.e., —C(OH)[0112] 2—.
  • The term “aminocarbonyl” (alone or in combination with another term(s)) means —C(O)—NH[0113] 2, which also may be depicted as:
    Figure US20040209914A1-20041021-C00009
  • The term “oxy” (alone or in combination with another term(s)) means an ether group, and may be depicted as —O—. [0114]
  • The term “alkoxy” (alone or in combination with another term(s)) means an alkylether group, i.e., —O-alkyl. Examples of such a group include methoxy (—O—CH[0115] 3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
  • The term “alkylcarbonyl” (alone or in combination with another term(s)) means —C(O)-alkyl. For example, “ethylcarbonyl” may be depicted as: [0116]
    Figure US20040209914A1-20041021-C00010
  • The term “aminoalkylcarbonyl” (alone or in combination with another term(s)) means —C(O)-alkyl-NH[0117] 2. For example, “aminomethylcarbonyl” may be depicted as:
    Figure US20040209914A1-20041021-C00011
  • The term “alkoxycarbonyl” (alone or in combination with another term(s)) means —C(O)—O-alkyl. For example, “ethoxycarbonyl” may be depicted as: [0118]
    Figure US20040209914A1-20041021-C00012
  • The term “carbocyclylcarbonyl” (alone or in combination with another term(s)) means —C(O)-carbocyclyl. For example, “phenylcarbonyl” may be depicted as: [0119]
    Figure US20040209914A1-20041021-C00013
  • Similarly, the term “heterocyclylcarbonyl” (alone or in combination with another term(s)) means —C(O)-heterocyclyl. [0120]
  • The term “carbocyclylalkylcarbonyl” (alone or in combination with another term(s)) means —C(O)-alkyl-carbocyclyl. For example, “phenylethylcarbonyl” may be depicted as: [0121]
    Figure US20040209914A1-20041021-C00014
  • Similarly, the term “heterocyclylalkylcarbonyl” (alone or in combination with another term(s)) means —C(O)-alkyl-heterocyclyl. [0122]
  • The term “carbocyclyloxycarbonyl” (alone or in combination with another term(s)) means —C(O)—O-carbocyclyl. For example, “phenyloxycarbonyl” may be depicted as: [0123]
    Figure US20040209914A1-20041021-C00015
  • The term “carbocyclylalkoxycarbonyl” (alone or in combination with another term(s)) means —C(O)—O-alkyl-carbocyclyl. For example, “phenylethoxycarbonyl” may be depicted as: [0124]
    Figure US20040209914A1-20041021-C00016
  • The term “thio” or “thia” (alone or in combination with another term(s)) means a thiaether group, i.e., an ether group wherein the ether oxygen atom is replaced by a sulfur atom. Such a group may be depicted as —S—. This, for example, “alkyl-thio-alkyl” means alkyl-S-alkyl. [0125]
  • The term “thiol” or “sulfhydryl” (alone or in combination with another term(s)) means a sulfhydryl group, and may be depicted as —SH. [0126]
  • The term “(thiocarbonyl)” (alone or in combination with another term(s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a group may be depicted as —C(S)—, and also may be depicted as: [0127]
    Figure US20040209914A1-20041021-C00017
  • The term “alkyl(thiocarbonyl)” (alone or in combination with another term(s)) means —C(S)-alkyl. For example, “ethyl(thiocarbonyl)” may be depicted as: [0128]
    Figure US20040209914A1-20041021-C00018
  • The term “alkoxy(thiocarbonyl)” (alone or in combination with another term(s)) means —C(S)—O-alkyl. For example, “ethoxy(thiocarbonyl)” may be depicted as: [0129]
    Figure US20040209914A1-20041021-C00019
  • The term “carbocyclyl(thiocarbonyl)” (alone or in combination with another term(s)) means —C(S)-carbocyclyl. For example, “phenyl(thiocarbonyl)” may be depicted as: [0130]
    Figure US20040209914A1-20041021-C00020
  • Similarly, the term “heterocyclyl(thiocarbonyl)” (alone or in combination with another term(s)) means —C(S)-heterocyclyl. [0131]
  • The term “carbocyclylalkyl(thiocarbonyl)” (alone or in combination with another term(s)) means —C(S)-alkyl-carbocyclyl. For example, “phenylethyl(thiocarbonyl)” may be depicted as: [0132]
    Figure US20040209914A1-20041021-C00021
  • Similarly, the term “heterocyclylalkyl(thiocarbonyl)” (alone or in combination with another term(s)) means —C(S)-alkyl-heterocyclyl. [0133]
  • The term “carbocyclyloxy(thiocarbonyl)” (alone or in combination with another term(s)) means —C(S)—O-carbocyclyl. For example, “phenyloxy(thiocarbonyl)” may be depicted as: [0134]
    Figure US20040209914A1-20041021-C00022
  • The term “carbocyclylalkoxy(thiocarbonyl)” (alone or in combination with another term(s)) means —C(S)—O-alkyl-carbocyclyl. For example, “phenylethoxy(thiocarbonyl)” may be depicted as: [0135]
    Figure US20040209914A1-20041021-C00023
  • The term “sulfonyl” (alone or in combination with another term(s)) means —S(O)[0136] 2—, which also may be depicted as:
    Figure US20040209914A1-20041021-C00024
  • Thus, for example, “alkyl-sulfonyl-alkyl” means alkyl-S(O)[0137] 2-alkyl.
  • The term “aminosulfonyl” (alone or in combination with another term(s)) means —S(O)[0138] 2—NH2, which also may be depicted as:
    Figure US20040209914A1-20041021-C00025
  • The term “sulfoxido” (alone or in combination with another term(s)) means —S(O)—, which also may be depicted as: [0139]
    Figure US20040209914A1-20041021-C00026
  • Thus, for example, “alkyl-sulfoxido-alkyl” means alkyl-S(O)-alkyl. [0140]
  • The term “heterocyclyl” (alone or in combination with another term(s)) means a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. A heterocyclyl alternatively may be 2 or 3 rings fused together. [0141]
  • The term “heteroaryl” (alone or in combination with another term(s)) means an aromatic ring containing from 5 to 14 ring atoms. At least one of the ring atoms is a heteroatom, with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring, which typically contains from 5 to 7 ring atoms, and more typically from 5 to 6 ring atoms. A heteroaryl alternatively may be 2 or 3 rings fused together. [0142]
  • Examples of single-ring heterocyclyls and heteroaryls include furanyl, dihydrofurnayl, tetradydrofurnayl, thiophenyl (also known as “thiofuranyl”), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as “azoximyl”), 1,2,5-oxadiazolyl (also known as “furazanyl”), or 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (including 1,2-pyranyl or 1,4-pyranyl), dihydropyranyl, pyridinyl (also known as “azinyl”), piperidinyl, diazinyl (including pyridazinyl (also known as “1,2-diazinyl”), pyrimidinyl (also known as “1,3-diazinyl”), or pyrazinyl (also known as “1,4-diazinyl”)), piperazinyl, triazinyl (including s-triazinyl (also known as “1,3,5-triazinyl”), as-triazinyl (also known 1,2,4-triazinyl), and v-triazinyl (also known as “1,2,3-triazinyl”)), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as “pentoxazolyl”), 1,2,6-oxazinyl, or 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl or 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl. [0143]
  • Examples of heterocyclyl and heteroaryl rings having 2 or 3 rings fused together include, for example, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples of fused-ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (also known as “isobenzazolyl” or “pseudoisoindolyl”), indoleninyl (also known as “pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl”), benzazinyl (including quinolinyl (also known as “1-benzazinyl”) or isoquinolinyl (also known as “2-benzazinyl”)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as “1,2-benzodiazinyl”) or quinazolinyl (also known as “1,3-benzodiazinyl”)), benzopyranyl (including “chromanyl” or “isochromanyl”), benzothiopyranyl (also known as “thiochromanyl”), benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as “coumaronyl”), isobenzofuranyl, benzothienyl (also known as “benzothiophenyl”, “thionaphthenyl”, or “benzothiofuiranyl”), isobenzothienyl (also known as “isobenzothiophenyl”, “isothionaphthenyl”, or “isobenzothiofuiranyl”), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenyl, and acridinyl. [0144]
  • As may be seen in the preceding paragraphs, the term “heteroaryl” includes 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1,2,3-tiiazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as 1,2-, 1,4-, 2,3- and 2,1-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl. [0145]
  • A carbocyclyl, heterocyclyl, or heteroaryl optionally can be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as “alkanoyl”), aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, and cycloalkylalkoxycarbonyl. More typically, a carbocyclyl or heterocyclyl may optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, —OH, —C(O)—OH, keto, C[0146] 1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkylcarbonyl, aryl, aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkoxy-C1-C6-alkyl, aryl-C1-C6-alkoxycarbonyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, cycloalkyl-C1-C6-alkoxy, cycloalkyl-C1-C6-alkoxy-C1-C6-alkyl, and cycloalkyl-C1-C6-alkoxycarbonyl. The alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl, aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, or arylalkoxycarbonyl substituent(s) may further be substituted with, for example, one or more halogen. The aryls or cycloalkyls are typically single-ring groups containing from 3 to 6 ring atoms, and more typically from 5 to 6 ring atoms.
  • An aryl or heteroaryl optionally can be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, —OH, —CN, —NO[0147] 2, —SH, —C(O)—OH, amino, aminocarbonyl, aminoalkyl, alkyl, alkylthio, carboxyalkylthio, alkylcarbonyl, alkylcarbonyloxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxyalkylthio, alkoxycarbonylalkylthio, carboxyalkoxy, alkoxycarbonylalkoxy, carbocyclyl, carbocyclylalkyl, carbocyclyloxy, carbocyclylthio, carbocyclylalkylthio, carbocyclylamino, carbocyclylalkylamino, carbocyclylcarbonylamino, carbocyclylcarbonyl, carbocyclylalkyl, carbonyl, carbocyclylcarbonyloxy, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, carbocyclyloxyalkoxycarbocyclyl, carbocyclylthioalkylthiocarbocyclyl, carbocyclylthioalkoxycarbocyclyl, carbocyclyloxyalkylthiocarbocyclyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylthio, heterocyclylamino, heterocyclylalkylamino, heterocyclylcarbonylamino, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, heterocyclyloxycarbonyl, heterocyclylcarbonyloxy, heterocyclylalkoxycarbonyl, heterocyclyloxyalkoxyheterocyclyl, heterocyclylthioalkylthioheterocyclyl, heterocyclylthioalkoxyheterocyclyl, and heterocyclyloxyalkylthioheterocyclyl. More typically, an aryl or heteroaryl may, for example, optionally be substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —CN, —NO2, —SH, —C(O)—OH, amino, aminocarbonyl, amino-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkylthio, carboxy-C1-C6-alkylthio, C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyloxy, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkylthio, C1-C6-alkoxycarbonyl-C1-C6-alkylthio, carboxy-C1-C6-alkoxy, C1-C6-alkoxycarbonyl-C1-C6-alkoxy, aryl, aryl-C1-C6-alkyl, aryloxy, arylthio, aryl-C1-C6-alkylthio, arylamino, aryl-C1-C6-alkylamino, arylcarbonylamino, arylcarbonyl, aryl-C1-C6-alkylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, aryl-C1-C6-alkoxycarbonyl, aryloxy-C1-C6-alkoxyaryl, arylthio-C1-C6-alkylthioaryl, arylthio-C1-C6-alkoxyaryl, aryloxy-C1-C6-alkylthioaryl, cycloalkyl, cycloalkyl-C1-C6-alkyl, cycloalkyloxy, cycloalkylthio, cycloalkyl-C1-C6-alkylthio, cycloalkylamino, cycloalkyl-C1-C6-alkylamino, cycloalkylcarbonylamino, cycloalkylcarbonyl, cycloalkyl-C1-C6-alkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyloxycarbonyl, cycloalkyl-C1-C6-alkoxycarbonyl, heteroaryl, heteroaryl-C1-C6-alkyl, heteroaryloxy, heteroarylthio, heteroaryl-C1-C6-alkylthio, heteroarylamino, heteroaryl-C1-C6-alkylamino, heteroarylcarbonylamino, heteroarylcarbonyl, heteroaryl-C1-C6-alkylcarbonyl, heteroaryloxycarbonyl, heteroarylcarbonyloxy, and heteroaryl-C1-C6-alkoxycarbonyl. Here, one or more hydrogens bound to a carbon in any such group may, for example, optionally be replaced with halogen. In addition, the cycloalkyl, aryl, and heteroaryl are typically single-ring groups containing 3 to 6 ring atoms, and more typically 5 or 6 ring atoms.
  • In some embodiments, an aryl or heteroaryl optionally is substituted with one or more substituents independently selected from the group consisting of cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocylyloxy, heterocylylthio, heterocylylamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocylyl, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino, aminocarbonyl, and aminoalkyl. Here, the amino nitrogen optionally is substituted with: [0148]
  • (i) up two substituents that are independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl, and alkanoyl; or [0149]
  • (ii) two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that: [0150]
  • (a) contains from zero to two additional heteroatoms that are independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0151]
  • (b) optionally is substituted with up to two substituents independently selected from the group consisting of aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocylylalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocylylalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocylylalkoxy, benzofused cycloalkylcarbonyl, heterocyclylalkylcarbonyl, and cycloalkylcarbonyl. [0152]
  • The aminocarbonyl nitrogen is: [0153]
  • (i) unsubstituted; [0154]
  • (ii) the reacted amine of an amino acid; [0155]
  • (iii) substituted with one or two substituents independently selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocylylalkyl, benzofused heterocylylalkyl, benzofused cycloalkyl, and N,N-dialkylsubstituted alkylaminoalkyl; or [0156]
  • (iv) substituted with two substituents such that the two substituents, together with the aminocarbonyl nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that optionally is substituted with up to two substituents independently selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocylylalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl, and amino, wherein the amino nitrogen optionally is substituted with: [0157]
  • (a) two substituents independently selected from the group consisting of alkyl, aryl, and heteroaryl; or [0158]
  • (b) two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring. [0159]
  • The aminoalkyl nitrogen optionally is substituted with: [0160]
  • (i) up to two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl; or [0161]
  • (ii) two substituents such that the two substituents, together with the aminoalkyl nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring. [0162]
  • A prefix attached to a multi-component group only applies to the first component. To illustrate, the term “alkylcycloalkyl” contains two components: alkyl and cycloalkyl. Thus, the C[0163] 1-C6- prefix on C1-C6-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the C1-C6-prefix does not describe the cycloalkyl component. To illustrate further, the prefix “halo” on haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl group is substituted with one or more halogen radicals. If halogen substitution may alternatively or additionally occur on the alkyl component, the group would instead be described as “halogen-substituted alkoxyalkyl” rather than “haloalkoxyalkyl.” And finally, if the halogen substitution may only occur on the alkyl component, the group would instead be described as “alkoxyhaloalkyl.”
  • If substituents are described as being “independently selected” from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s). [0164]
  • When words are used to describe a substituent, the rightmost-described component of the substituent is the component that is bound at the location of the replaced hydrogen. To illustrate, benzene substituted with methoxyethyl has the following structure: [0165]
    Figure US20040209914A1-20041021-C00027
  • As can be seen, the ethyl is bound to the benzene, and the methoxy is the component of the substituent that is the component furthest from the benzene. As further illustration, benzene substituted with cyclohexanylthiobutoxy has the following structure: [0166]
    Figure US20040209914A1-20041021-C00028
  • When words are used to describe a linking element between two other elements of a depicted chemical structure, the rightmost-described component of the substituent is the component that is bound to the left element in the depicted structure. To illustrate, if the chemical structure is X-L-Y and L is described as methylcyclohexanylethyl, the chemical would be X-ethyl-cyclohexanyl-methyl-Y. [0167]
  • When a chemical formula is used to describe a substituent, the dash on the left side of the formula indicates the portion of the substituent that is bound at the location of the replaced hydrogen. To illustrate, benzene substituted with —C(O)—OH has the following structure: [0168]
    Figure US20040209914A1-20041021-C00029
  • When a chemical formula is used to describe a linking element between two other elements of a depicted chemical structure, the leftmost dash of the substituent indicates the portion of the substituent that is bound to the left element in the depicted structure. The rightmost dash, on the other hand, indicates the portion of the substituent that is bound to the right element in the depicted structure. To illustrate, if the depicted chemical structure is X-L-Y and L is described as —C(O)—N(H)—, the chemical would be: [0169]
    Figure US20040209914A1-20041021-C00030
  • The term “pharmaceutically acceptable” is used adjectivally in this patent to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product. [0170]
  • With reference to the use of the words “comprise” or “comprises” or “comprising” in this patent (including the claims), Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicants intend each of those words to be so interpreted in construing this patent, including the claims below. [0171]
    • EXAMPLES
  • The following examples are merely illustrative, and not intended to be limiting to the remainder of this disclosure in any way. [0172]
  • Abbreviations are often used for reagents and solvents in the specific examples that follow. Those abbreviations include the following: [0173]
  • BOC=t-butoxycarbonyl [0174]
  • DEAD=diethyl azodicarboxylate [0175]
  • DMF=dimethylfonmamide [0176]
  • DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone [0177]
  • EtOAc=ethyl acetate [0178]
  • EDC=1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride [0179]
  • Et[0180] 2O=diethyl ether
  • HOBT=1-hydroxybenzotriazole [0181]
  • MeOH=methanol [0182]
  • MeCl[0183] 2=methylene chloride
  • MsCl=methanesulfonyl chloride [0184]
  • NMM=N-methyl morpholine [0185]
  • THF=tetrahydrofruan [0186]
  • TsCl=toluenesulfonyl chloride [0187]
  • THP-O-hydroxylamine=O-tetrahydropyran-hydroxylamine and O-tetrahydro-2H-pyran-2-yl-hydroxylamine [0188]
  • The preparation of compounds useful in the synthesis of compounds of the invention are provided herein below in Preparative Examples I through XI. [0189]
    • Preparative Example I Preparation of 1,1-dimethylethyl ester 4-[(hydroxyamino)-carbonyl]-4-[(phenoxyphenyl)-sulfonyl]-1-piperidinecarboxylic acid
  • [0190]
    Figure US20040209914A1-20041021-C00031
  • Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (DMSO; 20 mL) was heated to 65° C. for 5 hr. The solution remained at ambient temperature for 18 hr. The solution was extracted with ethyl acetate and the combined organic layers were washed with H[0191] 2O and saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).
  • Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) drop-wise over 20 min. The solution was stirred overnight (about 18° C.) at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (7:3 ethyl acetate/hexanes) and concentrated in vacuo to give the BOC-piperidine compound (26.2 g, quantitative yield) as a clear, colorless oil. [0192]
  • Part C: To a solution of diisopropylamine (2.8 mL, 20 mmoL) in THF (30 mL), cooled to −78° C., was added n-butyl lithium (12.5 mL, 20 mmol) drop-wise. After 15 min, the BOC-piperidine compound of part B (2.6 g, 10 mmol) in THF (10 mL) was added drop-wise. After 1.5 hr, the solution was cooled to −60° C. and the disulfide of part A (2.0 g, 10 mmol) in THF (7 mL). The solution was stirred at ambient temperature for 2 hr. The solution was diluted with H[0193] 2O and extracted with ethyl acetate. The organic layer was washed with H2O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfide as an oil (1.8 g, 40%).
  • Part D: To a solution of the sulfide of part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to 0° C., was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hr followed by dilution with H[0194] 2O and extraction with dichloromethane. The organic layer was washed with 10 percent Na2SO4, H2O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15 g, 59%).
  • Part E: To a solution of the sulfone of part D (800 mg, 1.63 mmol) in THF (9 mL) and ethanol (9 mL) was added NaOH (654 mg, 16.3 mmol) in H[0195] 2O (3 mL). The solution was heated at 65° C. for 18 hr. The solution was concentrated in vacuo and the residue was dissolved in H2O. Following acidification with 2N HCl to pH 4, the solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the acid as a white foam (790 mg, quantitative yield). Analytical calculated for C23H27NO7S: C, 59.86; H, 5.90; N, 3.04; S, 6.95. Found: C, 59.49; H, 6.37; N, 2.81; S, 6.59.
  • Part F: To a solution of the acid of part G (730 mg, 1.58 mmol) in DMF (9 mL) was added HOBT (256 mg, 1.90 mmol) followed by EDC (424 mg, 2.21 mmol), 4-methylmorpholine (0.521 mL, 4.7 mmol) and 50 percent aqueous hydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for 20 hr and additional N-hydroxybenzotriazole.H[0196] 2O (256 mg), EDC (424 mg) and 50 percent aqueous hydroxylamine (1.04 mL) were added. After an additional 24 hr of stirring, the solution was diluted with H2O and extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. Reverse phase chromatography (on silica, acetonitrile/H2O) provided the title compound as a white solid (460 mg, 61%). HPLC purity: >99%. Analytical calculated for C23H28N2O7S: C, 57.97; H, 5.92; N, 5.88; S, 6.73. Found: C, 57.95; H, 6.02; N, 5.81; S, 6.85.
    • Preparative Example II Preparation of N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide, monohydrochloride
  • [0197]
    Figure US20040209914A1-20041021-C00032
  • Part A: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) drop-wise over 20 min. The solution was stirred overnight (about 18 hr) at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (ethyl acetate/hexanes) and concentrated in vacuo to give the BOC-piperidine compound as a clear, colorless oil (26.2 g, quantitative yield). [0198]
  • Part B: A solution of 4-fluorothiophenol (50.29 g, 390 mmol) in DMSO (500 mL) was heated to 65° C. for 6 hr. The reaction was quenched into wet ice and the resulting solid was collected by vacuum filtration to provide the disulfide as a white solid (34.4 g, 68.9%). [0199]
  • Part C: To a solution of the BOC-piperdine compound of part A (16 g, 62 mmol) in THF (300 mL) cooled to minus 50° C. was added lithium diisopropylamide (41.33 mL, 74 mmol) and the solution was stirred for 1.5 hr at 0° C. To this solution was added the disulfide of part B (15.77 g, 62 mmol), and the resulting solution was stirred at ambient temperature for 20 hr. The reaction was quenched with the addition of H[0200] 2O and the solution was concentrated in vacuo. The aqueous residue was extracted with ethyl acetate and the organic layer was washed with 0.5N KOH, H2O, and saturated NaCl. Chromatography (on silica, hexane/ethyl acetate) provided the sulfide as an oil (18.0 g, 75%).
  • Part D: To a solution of the sulfide of part C (16.5 g, 43 mmol) in dichloromethane (500 mL) cooled to 0° C. was added 3-chloroperbenzoic acid (18.0 g, 86 mmol) and the solution was stirred for 20 hr. The solution was diluted with H[0201] 2O and extracted with dichloromethane. The organic layer was washed with 10 percent Na2SO3, H2O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (10.7 g, 60%).
  • Part E: Into a solution of the sulfone of part D (10 g, 24.0 mmol) in ethyl acetate (250 mL) was bubbled HCl gas for 10 min followed by stirring at ambient temperature for 4 hr. Concentration in vacuo provided the amine hydrochloride salt as a white solid (7.27 g, 86%). [0202]
  • Part F: To a solution of the amine hydrochloride salt of part E (5.98 g, 17.0 mmol) in DMF (120 mL) was added potassium carbonate (4.7 g, 34.0 mmol) followed by propargyl bromide (2.02 g, 17.0 mmol) and the solution was stirred for 4 hr at ambient temperature. The solution was partitioned between ethyl acetate and H[0203] 2O, and the organic layer was washed with H2O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the propargyl amine as a yellow oil (5.2 g, 86%).
  • Part G: To a solution of the propargyl amine of part F in DMF (15 mL) was added thiophenol (0.80 mL, 7.78 mmol) and CsCO[0204] 3 (2.79 g, 8.56 mmol) and the solution was heated to 70° C. for 6 hr. The solution was partitioned between ethyl ether and H2O. The organic layer was washed with H2O and saturated NaCl, and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the S-phenoxyphenyl compound as an oil (1.95 g, 56%).
  • Part H: To a solution of the S-phenoxyphenyl of part G (1.81 g, 4.06 mmol) in ethanol (21 mL) and H[0205] 2O (3.5 mL) was added KOH (1.37 g, 24.5 mmol) and the solution was heated to 105° C. for 4.5 hr. The solution was acidified to a pH value of 1 with concentrated HCl solution and then concentrated to provide the acid as a yellow residue that was used without additional purification (1.82 g).
  • Part I: To a solution of the acid of part H (1.82 g, 4.06 mmol) in acetonitrile (20 mL) was added O-tetrahydro-2H-pyran-2-yl-hydroxylamine (723 mg, 6.17 mmol) and triethylamine (0.67 mL, 4.86 mmol). To this stirring solution was added EDC (1.18 g, 6.17 mmol) and the solution was stirred for 18 hr. The solution was partitioned between H[0206] 2O and ethyl acetate. The organic layer was washed with H2O, saturated NaHCO3 and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as a white solid (1.32 g, 63%).
  • Part J: To a solution of the protected hydroxamate of part 1 (9.65 g, 18.7 mmol) in methanol (148 mL) cooled to 0° C. was added acetyl chloride (4.0 mL, 56.2 mmol), and the solution was stirred for 45 min at ambient temperature. Concentration in vacuo followed by trituration with ethyl ether provided the title compound as a white solid (8.10 g, 94%). MS(CI) MH[0207] + calculated for C21H22N2O4S2: 431, found 431.
    • Preparative Example III Preparation of N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide, monohydrochloride
  • [0208]
    Figure US20040209914A1-20041021-C00033
  • Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (20 mL) was heated to 65° C. for 5 hr. The solution remained at ambient temperature for 18 hr. The solution was extracted with ethyl acetate and the combined organic layers were washed with H[0209] 2O and saturated NaCl, and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).
  • Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) dropwise over 20 min. The solution was stirred overnight at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (ethyl acetate/hexane) and concentrated in vacuo to give the BOC-piperidine compound as a clear, colorless oil (26.2 g, quantitative yield). [0210]
  • Part C: To a solution of diisopropylamine (2.8 mL, 20 mmoL) in THF (30 mL), cooled to −78° C., was added n-butyl lithium (12.5 mL, 20 mmol) dropwise. After 15 min, the BOC-piperidine compound of Part B (2.6 g, 10 mmol) in THF (10 mL) was added dropwise. After 1.5 hr, the solution was cooled to −60° C. and the disulfide of Part A (2.0 g, 10 mmol) in THF (7 mL) was added. The solution was stirred at ambient temperature for 2 hr. The solution was diluted with H[0211] 2O and extracted with ethyl acetate. The organic layer was washed with H2O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfide as an oil (1.8 g, 40%).
  • Part D: To a solution of the sulfide of Part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to 0° C., was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hr followed by dilution with H[0212] 2O and extraction with dichloromethane. The organic layer was washed with 10 percent Na2SO4, H2O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15 g, 59%).
  • Part E: Into a solution of the sulfone of Part D (3.56 g, 7.0 mmol) in ethyl acetate (100 mL) cooled to 0° C. was bubbled HCl gas for 5 min. Concentration in vacuo followed by trituration with ethyl ether provided the amine hydrochloride salt as a white solid (3.5 g, quantitative yield). MS(CI) MH[0213] + calculated for C20H23NO5S: 390, found 390.
  • Part F: To a solution of the amine hydrochloride salt of part E (2.6 g, 6 mmol) and K[0214] 2CO3 (1.66 g, 12 mmol) in DMF (50 mL) was added propargyl bromide (892 mg, 6 mmol) and the solution was stirred at ambient temperature for 4 hr. The solution was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the propargyl amine as a white solid (2.15 g, 82%).
  • Part G: To a solution of the propargyl amine of part F (2.15 g, 5 mmol) in THF (30 mL) and ethanol (30 mL) was added NaOH (2.0 g, 50 mmol) and the solution was heated at 65° C. for 48 hr. The solution was concentrated in vacuo and the aqueous residue was acidified to a pH value of 5. Vacuum filtration of the resulting precipitate provided the acid as a white solid (2.04 g, quantitative yield). [0215]
  • Part H: To a solution of the acid of part G (559 mg, 1.4 mmol) in dichloromethane (5 mL) was added triethylamine (0.585 mL, 4.2 mmol) and 50 percent aqueous hydroxylamine (0.925 mL, 14.0 mmol) followed by bromotris(pyrrolidino)phosphonium hexafluourphosphate (PyBroP®; 718 mg, 1.54 mmol). The solution was stirred at ambient temperature for 4 hr. The solution was diluted with H[0216] 2O and extracted with dichloromethane. The organic layer was washed with saturated NaCl and dried over magnesium sulfate. Reverse phase chromatography (on silica, acetonitrile/H2O) provided the hydroxamate as a white solid (140 mg, 25%). Analytical calculation for C21H22N2O5S: C, 60.85; H, 5.37; N, 6.76; S, 7.74. Found: C, 60.47; H, 5.35; N, 6.61; S, 7.46.
  • Part I: To a solution of the hydroxamate of part H (121 mg, 0.292 mmol) in methanol (2 mL) cooled to 0° C. was added acetyl chloride (0.228 mL, 0.321 mmol) in methanol (1 mL). After stirring at ambient temperature for 30 min, the solution was concentrated under a stream of N[0217] 2. Trituration with ethyl ether provided the title compound as a white solid (107 mg, 81%). Analytical calculation for C21H22N2O5S.HCl.0.3H2O: C, 55.27; H, 5.21; N, 6.14. Found: C, 54.90; H, 5.37; N, 6.07.
    • Preparative Example IV Preparation of 4-[(4-fluorophenyl)sulfonyl]tetrahydro-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide
  • [0218]
    Figure US20040209914A1-20041021-C00034
  • Part A: In dry equipment under nitrogen, sodium metal (8.97 g, 0.39 mol) was added to methanol (1000 mL) at 2° C. The reaction was stirred at ambient temperature for 45 min, at which time the sodium had dissolved. The solution was chilled to 5° C. and p-fluorothiophenol (41.55 mL, 0.39 mmol) was added, followed by methyl 2-chloroacetate (34.2 mL, 0.39 mol). The reaction was stirred at ambient temperature for 4 hr, filtered, and concentrated in vacuo to give the sulfide as a clear colorless oil (75.85 g, 97%). [0219]
  • Part B: To a solution of the sulfide from part A (75.85 g, 0.38 mol) in methanol (1000 mL) were added water (100 mL) and Oxone® (720 g, 1.17 mol) at 20° C. An exotherm to 67° C. was noted. After 2 hr, the reaction was filtered and the cake was washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with brine, dried over MgSO[0220] 4, filtered, and concentrated in vacuo to give the sulfone as a crystalline solid (82.74 g, 94%).
  • Part C: To a solution of the sulfone from part B (28.5 g, 0.123 mol) in N,N-dimethylacetamide (200 mL) were added potassium carbonate (37.3 g, 0.27 mol), bis-(2-bromoethyl)ether (19.3 mL, 0.147 mol), 4-dimethylaminopyridine (0.75 g, 6 mmol), and tetrabutylammonium bromide (1.98 g, 6 mmol). The reaction was stirred overnight (about 18 hr) at ambient temperature. The reaction was slowly poured into 1N HCl (300 mL), the resultant solid filtered and the cake washed well with hexanes. The solid was recrystallized from ethyl acetate/hexanes to give the pyran compound as a beige solid (28.74 g, 77%). MS (ES+) MH+ calculated for C[0221] 13H15O5S1F1: 303, found 303.
  • Part D: In dry equipment under nitrogen, the pyran compound from part C (8.0 g, 26.5 mmol) was dissolved in dry tetrahydrofuran (250 mL) and a solution of potassium trimethylsilonate (10.2 g, 79.5 mmol) in dry tetrahydrofuran (15 mL) was added at ambient temperature. After 90 min, water (100 mL) was added and the solution concentrated in vacuo. The residue was taken up in water and extracted with ethyl acetate to remove unreacted starting material. The aqueous solution was treated with 6N HCl until pH═I. The slurry was extracted with ethyl acetate and the combined extracts washed with water, dried over Na[0222] 2SO4, filtered, and concentrated in vacuo. The residue was heated in diethyl ether, the solid filtered and dried to give the carboxylic acid as a crystalline solid (5.78 g, 76%). HRMS (ES−) M−H calculated for C12H13O5S1F1: 287.04, found 287.04.
  • Part E: In dry equipment under nitrogen, the carboxylic acid from part D (9.1 g, 31.6 mmol) was dissolved in dry N,N-dimethylformamide (70 mL) and the remaining reagents were added to the solution in the following order: N-hydroxybenzotriazole hydrate (5.1 g, 37.9 mmol), N-methylmorpholine (10.4 mL, 94.8 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (11.5 g, 98 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.48 g, 44.2 mmol). After 3 hr at ambient temperature, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO[0223] 4, saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes) provided the title compound as a crystalline solid (9.7 g, 80%). HRMS (ES+) MH+ calculated for C17H22NO6S1F1: 388.12, found 388.12.
    • Preparative Example V Preparation of tetrahydro-N-hydroxy-4-[[4-[4-trifluoromethoxy)-phenoxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide
  • [0224]
    Figure US20040209914A1-20041021-C00035
  • Part A: To a solution of the title compound of Preparative Example TV (3.1 g, 8 mmol) in N,N-dimethylacetamide (20 mL) were added cesium carbonate (8.8 g, 27 mmol) and p-(trifluoromethoxy)phenol (2.1 mL, 16 mmol). The slurry was stirred at 95° C. for 19 hr. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na[0225] 2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes) provided the substituted THP-protected hydroxamate as a white foam (4.2 g, 96%). HRMS (ES+) MH+ calculated for C24H26N1O8S1F3: 546.14, found 546.14.
  • Part B: To a slurry of the THP-protected hydroxamate from part A (4.0 g, 7.3 mmol) in dioxane (20 mL) were added a 4N HCl dioxane solution (20 mL) and methanol (20 mL). After 15 min, at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over Na[0226] 2SO4, filtered, and concentrated in vacuo. The product was recrystallized (acetone/hexanes) to give the title compound as a white solid (2.2 g, 65%). HRMS (ES+) M+NH4 + calculated for C19H18N1O7S1F3: 479.11, found 479.11.
    • Preparative Example VI Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-(2-phenoxy-ethoxy)phenyl]sulfonyl]-4-piperidine carboxamide, monohydrochloride
  • [0227]
    Figure US20040209914A1-20041021-C00036
  • Part A: To a solution of the product of Preparative Example II, part E, (14.36 g, 40 mmol) in methanol (50 mL) was added acetic acid (24.5 g, 400 mmol), a portion (about 2 g) of 4-Angstrom molecular sieves, (1-ethoxycyclopropyl)-oxytrimethyl silane (25.8 mL, 148 mmol) and sodium cyanoborohydride (7.05 g, 112 mmol). The solution was heated at reflux for 8 hr. The precipitated solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with H[0228] 2O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo. The solid was filtered, washed with H2O/diethyl ether to give the desired cyclopropyl amine {ethyl 4-[(4-fluorophenyl-sulfonyl)]-1-cyclopropyl-4-piperidinecarboxylate} as a white solid (11.83 g, 81.5%). MS MH+ calculated for C17H22NO4SF: 356, found: 356.
  • Part B: A solution of the cyclopropyl amine of Part A (2.0 g, 5.6 mmol), ethylene glycol phenyl ether (2.8 mL, 23 mmol), and cesium carbonate (7.3 g, 23 mmol) in DMAC (10 mL) was heat at 125-135° C. for 18 hr under an atmosphere of nitrogen. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried over magnesium sulfate, concentrated in vacuo, dissolved in diethyl ether, precipitated as the hydrochloride salt, and dried at 40° C. in a vacuum oven. The solid was dissolved into a mixture of water, acetonitrile, and ethanol and then the pH was adjusted to 12 with 1N NaOH solution. The mixture was concentrated in vacuo to remove ethanol and acetonitrile. The solid was isolated by filtration, washed with water, and dried at 50° C. in a vacuum oven to afford the ether as a white solid (1.8 g, 68%): MS+ calcd. for C[0229] 25H31NO6S 474, found 474. Anal. calcd. for C25H31NO6S: C, 63.40; H, 6.60; N, 2.96; S, 6.77. Found: C, 63.35; H, 6.59; N, 2.99; S, 6.61.
  • Part C: A mixture of the ether of part B (1.8 g, 3.7 mmol) and a 50% NaOH aqueous solution (3.0 g, 37 mmol) in THF (32 mL), EtOH (32 mL), and H[0230] 2O (16 mL) was heated at 60° C. under a N2 atmosphere for 24 hr. The material was concentrated in vacuo and triturated with diethyl ether to give a solid. The tan solid was dissolved into a mixture of water, ethanol, and THF, precipitated by adjusting the pH to 3 with concentrated hydrochloric acid, concentrated in vacuo, triturated with water, and dried at 50° C. in a vacuum oven to give a crude white solid acid (2.3 g).
  • A mixture of the crude white solid acid (2.3 g), N-hydroxybenzotriazole (1.9 g, 14 mmol), 4-methylmorpholine (1.6 mL, 14 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.1 g, 9.4 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.7 g, 14 mmol) in DMF (90 mL) was stirred at ambient temperature under a nitrogen atmosphere for 2 days. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was washed with 1N NaOH solution, water, and brine, dried over magnesium sulfate, concentrated in vacuo, and purification by flash chromatography (20:80 to 40:60 ethyl acetate/toluene) to afford the protected hydroxamate as a white solid: (0.43 g, 21%): MS MH+ calcd. for C[0231] 28H36N2O7S 545, found 545. Anal. calcd. for C28H36N2O7S: C, 61.74; H, 6.66; N, 5.14; S, 5.89. Found: C, 61.72; H, 6.75; N, 5.06; S, 5.91.
  • Additional compound was isolated by acidifying the aqueous layer to pH of 3, collecting the solid by filtration, and drying to give a white solid (0.80 g). [0232]
  • Part D: To an ambient temperature solution of acetyl chloride (0.31 mL, 4.4 mmol) in methanol (11 mL) under a nitrogen atmosphere was added the protected hydroxamate of part C (0.80 g, 1.5 mmol). After stirring for 2.5 hr, the precipitate was collected by filtration, washed with diethyl ether, and dried at 45° C. in a vacuum oven to afford the title compound as a white solid (0.58 g, 79%): MS MH+ calcd. for C[0233] 23H28N2O6S 461, found 461. Anal. calcd. for C23H28N2O6S.1.5HCl: C, 53.62; H, 5.77; N, 5.44; S, 6.22. Found: C, 53.47; H, 5.79; N, 5.41; S, 6.16.
    • Preparative Example VII Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride
  • [0234]
    Figure US20040209914A1-20041021-C00037
  • Part A: To a solution of the product of Preparative Example II, Part D (30 g, 161 mmol) in dichloromethane (50 mL) cooled to 0° C. was added trifluroacetic acid (25 mL) and the solution was stirred at ambient temperature for 1 hr. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the trifluoroacetate salt and K[0235] 2CO3 (3.6 g, 26 mmol) in N,N-dimethylformamide (50 mL) cooled to 0° C. was added 2-bromoethyl methyl ether (19 mL, 201 mmol), and solution was stirred at ambient temperature for 36 hr. Then, N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over MgSO4. Concentration in vacuo provided the methoxyethyl amine as a light yellow gel (26.03 g, 86.8%).
  • Part B: To a solution of methoxyethyl amine (6.0 g, 16.0 mmol) of Part A and powdered K[0236] 2CO3 (4.44 g, 32 mmol) in N,N-dimethylformamide (30 mL) was added 4-(trifluoromethoxy)phenol (5.72 g, 32 mmol) at ambient temperature and the solution was heated to 90° C. for 25 hr. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H2O and dried over MgSO4. Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (7.81 g, 91.5%).
  • Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone of Part B (7.81 g, 14.7 mmol) in ethanol (14 mL) and tetrahydrofuran (14 mL) was added NaOH (5.88 g, 147 mmol) in H[0237] 2O (28 mL) from an addition funnel at ambient temperature. The solution was then heated to 60° C. for 18 hr. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH=2. Vacuum filtration of white precipitation provided the acid as a white solid (5.64 g, 73.3%).
  • Part D: To a solution of the acid of Part C (5.64 g, 10.8 mmol), N-methyl morpholine (4.8 mL, 43.1 mmol), 1-hydroxybenzotriazole (4.38 g, 32.4 mmol) and O-tetrahydropyranyl hydroxylamine (2.5 g, 21.6 mmol) in N,N-dimethylformamide (50 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.2 g, 32.4 mmol), and the solution was stirred at ambient temperature for 24 hr. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO[0238] 3, H2O and dried over MgSO4. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl-protected hydroxamate as a white foam (6.65 g, quantitative yield).
  • Part E: To a solution of 4N HCl in dioxane (28 mL, 110 mmol) was added a solution of the tetrahydropyranyl-protected hydroxamate of Part D (6.65 g, 11.03 mmol) in methanol (3 mL) and dioxane (9 mL) and was stirred at ambient temperature for 3 hr. Concentration in vacuo and trituration with diethyl ether provided the title compound as a white solid (4.79 g, 78.2%). Analytical calculation for C[0239] 22H25N2O7SF3.HCl.0.5H2O: C, 46.85; H, 4.83; N, 4.97; S, 5.69. Found: C, 46.73; H, 4.57; N, 4.82; S, 5.77.
    • Preparative Example VIII Preparation of N-hydroxy-1-[2-(4-morpholinyl)-ethyl]-4-[[4-[4-(trifluoromethyl)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide, dihydrochloride
  • [0240]
    Figure US20040209914A1-20041021-C00038
  • Part A: To a suspension of 4-bromopiperidine hydrobromide (107.0 g, 0.436 mol) in tetrahydrofuran (1 L) was slowly added triethylamine (122 mL, 0.872 mol) followed by di-tert-butyl dicarbonate (100 g, 0.458 mol), which was added in several portions. The resulting mixture was stirred at ambient temperature for 22 hr then filtered and concentrated in vacuo. The solids were washed with hexanes and then collected by filtration to give the Boc-piperidine compound as an amber oil (124 g, >100%). [0241]
  • Part B: To a solution of 4-fluorophenol (50.0 g, 0.390 mol) in acetone (400 mL), degassed with N[0242] 2, was added Cs2CO3 (159 g, 0.488 mol). After degassing the resulting mixture with N2 for 5 min, the Boc-piperidine compound of Part A (85.9 g, 0.325 mol) was added. The resulting mixture was stirred at ambient temperature for 18 hr and then filtered through a pad of Celite®, washing with acetone. The filtrate was concentrated in vacuo to provide the sulfide as a tan residue (98.5 g, 97%).
  • Part C: To a solution of the sulfide of Part B (8.00 g, 25.7 mmol) in dichloromethane (90 mL) and methanol (15 mL) was added monoperoxyphthalic acid magnesium salt hexahydrate (19.1 g, 38.6 mmol) in two portions. The resulting mixture was stirred at ambient temperature for 1.5 hr and then filtered. The filtrate was washed with saturated NaHCO[0243] 3 and then with saturated NaCl. The combined aqueous layers were extracted with dichloromethane (100 mL). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo. The resulting solids were washed with hexanes then dissolved in dichloromethane and filtered through a pad of Celite®, washing with dichloromethane. The filtrate was concentrated in vacuo and recrystallization from ethyl acetate provided the sulfone as a white crystalline solid (4.45 g, 50%).
  • Part D: To a solution of sulfone of Part C (7.00 g, 20.4 mmol) in N,N-dimethylformamide (40 mL) was added Cs[0244] 2CO3 (19.9 g, 61.2 mmol) and α,α,α-trifluoro-p-cresol (3.97 g, 24.5 mmol). The resulting mixture was heated at 80° C. for 16 hr. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The resulting residue was treated with H2O and the solids were collected by filtration. The solids were then washed with hexanes then methanol to provide the biaryl ether as a tan solid (8.60 g, 87%).
  • Part E: To a solution of the biaryl ether of Part D (8.59 g, 17.7 mmol) in tetrahydrofuran (100 mL), cooled to 0° C., was slowly added lithium bis(trimethylsilyl)amide (22.0 mL, 11.0M in tetrahydrofuran, 22.0 mmol), at such a rate that the temperature of the reaction never exceeded 1° C. The resulting mixture was stirred at 0° C. for 1 hr then a solution of methyl chloroformate (2.05 mL, 26.6 mmol) in tetrahydrofuran (5.0 mL) was slowly added, at such a rate that the temperature of the reaction mixture never exceeded 4° C. After the addition was complete, the mixture was slowly permitted to warm to ambient temperature. Saturated NH[0245] 4Cl (50 mL) was added and the tetrahydrofuran was removed in vacuo. Water (50 mL) was added to the residue which was then extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over Na2SO4. Recrystallization from methanol provided the methyl ester as a pale yellow crystalline solid (7.66 g, 80%).
  • Part F: To a solution of the methyl ester of Part E (7.66 g, 14.1 mmol) in dioxane (30 mL) and methanol (10 mL) was added a solution of 4N HCl in dioxane (10 mL, 40 mmol). After stirring at ambient temperature for 2 hr, additional 4N HCl in dioxane (10 mL, 40 mmol) was added. After stirring at ambient temperature for 2.5 hr, the reaction mixture was concentrated in vacuo to provide the amine as an off-white solid (6.80 g, >100%). [0246]
  • Part G: To a suspension of the amine of Part F (3.00 g, 6.25 mmol) in acetonitrile (20 mL) was added K[0247] 2CO3 (3.46 g, 25.0 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.22 g, 6.56 mmol) and a catalytic amount of NaI. The resulting mixture was heated at reflux for 22 hr. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo to provide the morpholinyl ethyl amine as a tan solid (3.45 g, >100%).
  • Part H: To a solution of the morpholinyl ethyl amine of Part G (3.45 g, 6.25 mmol) in tetrahydrofuran (60 mL) was added potassium trimethylsilanolate (1.60 g, 12.50 mmol). After stirring at ambient temperature for 25 hr, H[0248] 2O was added. The reaction mixture was then neutralized (pH 7) with 1N HCl. The tetrahydrofuran was removed in vacuo and the resulting precipitate was collected by filtration and washed with diethyl ether to provide the amino acid as an off-white solid (2.87 g, 85%).
  • Part I: To a suspension of the amino acid of Part H (2.87 g, 5.29 mmol) in dichloromethane (25 mL) was added N-methylmorpholine (1.74 mL, 15.9 mmol), O-(tetrahydropuranyl)hydroxylamine (0.682 g, 5.82 mmol) and PyBroP® (2.96 g, 6.35 mmol). After stirring at ambient temperature for 19 hr, additional N-methylmorpholine (0.872 mL, 7.94 mmol), O-(tetrahydropuranyl) hydroxylamine (0.310 g, 2.65 mmol) and PyBroP® (1.48 g, 3.17 mmol) were added. The resulting mixture was stirred at ambient temperature for 3 hr and then concentrated in vacuo. The residue was partitioned between ethyl acetate and H[0249] 2O. The organic layers were washed with saturated NaCl and dried over Na2SO4. Chromatography (on silica, methanol/chloroform) provided the protected hydroxamate as an off-white solid (2.62 g, 77%).
  • Part J: To a solution of the protected hydroxamate of Part I (2.62 g, 4.08 mmol) in dioxane (9 mL) and methanol (3 mL) was added a solution of 4N HCl in dioxane (10 mL, 40.0 mmol). The resulting mixture was stirred at ambient temperature for 2 hr and then diethyl ether (20 mL) was added. The resulting solids were collected by filtration to give the title compound as an off-white solid (2.31 g, 90%). MS MH[0250] + calculated for C25H31O6N3SF3: 558, found 558.
    • Preparative Example IX Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride
  • [0251]
    Figure US20040209914A1-20041021-C00039
  • Part A: To a solution of the product of Preparative Example VI, Part A, (6.97 g, 19.6 mmol) in DMF (500 mL) was added K[0252] 2CO3 (3.42 g, 18.0 mmol) and 4-(triflouromethoxy)phenol (3.7 g, 24.8 mmol). The solution was stirred at 90° C. for 40 hr. The solution was diluted with H2O (600 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo to afford the desired diaryl ether as an oil (8.5 g, quantitative). HRMS MH+ calculated for C24H26NSO6F3: 514.1511. Found 514.1524.
  • Part B: To a solution of diaryl ether from Part A (8.4 g, 16.4 mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (6.54 g, 164 mmol) in water (20 mL) and the solution was heated at 60° C. for 18 hr. The solution was concentrated in vacuo to remove most of organic solvents and the aqueous residue was acidified to pH=4.0. The resulting precipitate was filtered to give the desired filtered to give the hydrochloride salt as a white solid (5.01 g, 63%). HRMS MH[0253] + calculated for C22H22NSO6F3: 486.1198, found 486.1200.
  • Part C: To a solution of the hydrochloride salt of Part B (5.0 g, 10.3 mmol) in DMF (80 mL) were added 1-hydroxybenzotriazole (1.65 g, 12.3 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranyl hydroxylamine hydrochloride (1.8 g, 15.4 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.60 g, 12.3 mmol). The solution was stirred at ambient temperature for 42 hr. The solution was diluted with H[0254] 2O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo. Chromatography on silica gel, eluting with 30% ethyl acetate/hexane provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (5.41 g, 89%).
  • Part D: To a solution of tetrahydropyranyl-protected hydroxamate of Part C (5.4 g, 9.2 mmol) in dioxane (80 mL) and methanol (20 mL) was added 4 N HCl/dioxane (50 mL). The reaction was stirred at ambient temperature for 2.5 hr, the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (4.02 g, 81%). HRMS MH[0255] + calculated for C22H23N2SO6F3: 501.1307, found 501.1324.
    • Preparative Example X Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride
  • [0256]
    Figure US20040209914A1-20041021-C00040
  • Part A: To a solution of the product of Preparative Example VI, Part A, (5.96 g, 15.0 mmol) in DMF (100 mL) was added K[0257] 2CO3 (12.34 g, 38.0 mmol) and
    Figure US20040209914A1-20041021-P00900
    Figure US20040209914A1-20041021-P00900
    □-trifluoromethyl phenol (3.65 g, 22.5 mmol). The solution was stirred 90° C. for 28 hr. The solution was diluted with H2O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo to afford desired aryl ether as an oil (7.54 g, quantitative)
  • Part B: To a solution of aryl ether from Part A (7.54 g, 15.0 mmol) in ethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH (6.06 g, 151.0 mmol) in water (20 mL) and the solution was heated at 60° C. for 18 hr. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2.0. The resulting precipitate was filtered to give the desired hydrochloride salt as a white solid (7.98 g, quantitative). MS MH[0258] + calculated for C22H22NSO5F3: 470, found 470.
  • Part C: To a solution of the hydrochloride salt of Part B (7.60 g, 15.0 mmol) in DMF (100 mL) were added 1-hydroxybenzotriazole (2.44 g, 18.0 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranyl hydroxylamine hydrochloride (2.63 g, 22.5 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.02 g, 21.0 mmol). The solution was stirred at ambient temperature for 96 hr. The solution was diluted with H[0259] 2O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo. Chromatography on silica eluting with 30% ethyl acetate/hexane provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (5.93 g, 69%).
  • Part D: To a solution of tetrahydropyranyl-protected hydroxamate of Part C (3.8 g, 6.7 mmol) in dioxane (100 mL) was added 4 N HCl/dioxane (30 mL). The reaction was stirred at ambient temperature for 2 hr, then the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (3.33 g, 96%). MS MH[0260] + calculated for C22H23N2SO5F3: 485, found 485.
    • Preparative Example XI Preparation of Resin II
  • Step 1: Attachment of Compound of Preparative Example IV to Resin I. [0261]
  • A 500 mL round-bottomed flask was charged with of resin I [Floyd et al., [0262] Tetrahedron Lett. 1996, 37, 8045-8048] (8.08 g, 9.7 mmol) and 1-methyl-2-pyrrolidinone (50 mL). A magnetic stirring bar was added, and the resin slurry slowly stirred. A separate solution of the compound of Part D, Preparative Example IV (5.58 g, 19.4 mmol) in 1-methyl-2-pyrrolidinone (35 mL) was added to the slurry followed by addition of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (10.1 g, 19.4 mmol) in one portion. Once the hexafluorophosphate salt had dissolved, 4-methylmorpholine (4.26 mL, 39 mmol) was added dropwise. The reaction slurry was stirred at room temperature for 24 hr, then the resin was collected in a sintered-disc funnel and washed with N,N-dimethylformamide, methanol, methylene chloride and diethyl ether (3×30 mL each solvent). The resin was dried in vacuo to yield 10.99 g polymer-bound hydroxymate as a tan polymeric solid. Theoretical loading on polymer was 0.91 mmol/g. FTIR microscopy showed bands at 1693 and 3326 cm−1 indicative of the hydroxamate carbonyl and nitrogen-hydrogen stretches, respectively.
  • Step 2: Preparation of Resin III: [0263]
  • Reaction of Resin II with Nucleophiles [0264]
  • Resin II (50 mg, 0.046 mmol) was weighed into an 8 mL glass vial, and a 0.5 M solution of a nucleophile in 1-methyl-2-pyrrolidinone (1 mL) was added to the vessel. In the case of phenol and thiophenol nucleophiles, cesium carbonate (148 mg, 0.46 mmol) was added, and in the case of substituted piperazine nucleophiles, potassium carbonate (64 mg, 0.46 mmol) was added. The vial was capped and heated to 70 to 155° C. for 24-48 hr, then cooled to room temperature. The resin was drained and washed with 1-methyl-2-pyrrolidinone, 1-methyl-2-pyrrolidinone/water (1:1), water, 10% acetic acid/water, methanol, and methylene chloride (3×3 mL each solvent). [0265]
  • Large Scale Preparation of Resin IIIa: [0266]
  • Resin II (5 g, 0.91 mmol) was weighed into an oven-dried three-necked round bottom flask fitted with a temperature probe, an overhead stirring paddle, and a nitrogen inlet. Anhydrous 1-methyl-2-pyrrolidinone (35 mL) was added to the flask followed by ethyl isonipecotate (7.0 mL, 45.5 mmol). The resin slurry was stirred slowly with the overhead stirrer, and the mixture was heated to 80° C. with a heating mantle for 65 hr. The flask was thereafter cooled to room temperature. [0267]
  • The resin was collected in a sintered-disk glass funnel and washed with N,N-dimethylformamide, methanol and methylene chloride (3×30 mL each solvent). The resin was dried in vacuo to provide 5.86 g of resin IIIa as off-white resin beads. The theoretical loading of the polymer was 0.81 mmol/g. TFA cleavage performed on 50 mg of resin Ea as described in step 3 yielded 10.4 mg of off-white solid spectroscopically indistinguishable from a known sample. [0268]
  • Step 3: Cleavage of Hydroxamic Acids from the Polymer-Support [0269]
  • Resin III was treated with a trifluoroacetic acid/water mixture (19:1, 1 mL) for 1 hr at room temperature. During that time, the resin became a deep red color. The resin was then drained and washed with trifluoroacetic acid/water (19:1) and methylene chloride (2×1 mL each solvent), collecting the combined filtrates in a tared vial. The volatiles were removed in vacuo, then a toluene/methylene chloride mixture (2 mL each) was added to the residue. The mixture was again concentrated in vacuo. The product was characterized by electrospray mass spectroscopy. [0270]
  • Step 4: Hydrolysis of Polymer-Bound Ester: Preparation of Resin IVa [0271]
  • Resin IIIa (5.8 g, 4.5 mmol) was weighed into a three-necked round bottomed flask fitted with an overhead stirring paddle. 1,4-Dioxane was added to the flask, and the resin slurry was stirred for 15 min. Then, a 4 M solution of KOH (5 mL, 20 mmol) was added, and the mixture was stirred for 44 hr. The resin was thereafter collected in a sintered-disk glass funnel and washed with dioxane/water (9:1), water, 10% acetic acid/water, methanol and methylene chloride (3×30 mL each solvent). The resin was dried in vacuo to yield 5.64 g of resin IVa as off-white polymer beads. FTIR microscopy showed bands at 1732 and 1704 cm[0272] −1 and a broad band from 2500-3500 cm−1. The theoretical loading of the polymer-bound acid was 0.84 mmol/g.
    • Examples 1-45
  • The following compounds were prepared by parallel synthesis (resin based synthesis, automated synthesis) using parallel synthesis from Resin IVa as described previously in Preparative Example XI the following compounds were prepared: [0273]
    Figure US20040209914A1-20041021-C00041
    MS
    Example Amine R (M + H)
    1 3,5-Dimethylpiperidine
    Figure US20040209914A1-20041021-C00042
         		508
    2 1-(1-phenylethyl)-piperazine
    Figure US20040209914A1-20041021-C00043
         		585
    3 1-(2-phenylethyl)-piperazine
    Figure US20040209914A1-20041021-C00044
         		585
    4 1-(2-chlorophenyl)- piperazine
    Figure US20040209914A1-20041021-C00045
         		591
    5 1-(4-methoxyphenyl)-2- methylpiperazine
    Figure US20040209914A1-20041021-C00046
         		585
    6 1-(5-Chloro-2- methylphenyl)piperazine
    Figure US20040209914A1-20041021-C00047
         		605
    7 1-(2-methoxyphenyl)- piperazine
    Figure US20040209914A1-20041021-C00048
         		587
    8 1-Acetylpiperazine
    Figure US20040209914A1-20041021-C00049
         		523
    9 1-(2,4-Dimethylphenyl)- piperazine
    Figure US20040209914A1-20041021-C00050
         		585
    10 N-(2-hydroxyethyl)- piperazine
    Figure US20040209914A1-20041021-C00051
         		525
    11 1-(Ethoxy-carbonylmethyl)- piperazine
    Figure US20040209914A1-20041021-C00052
         		567
    12 1-(2-Fluorophenyl)- piperazine
    Figure US20040209914A1-20041021-C00053
         		575
    13 1-(2-Furoyl)- piperazine
    Figure US20040209914A1-20041021-C00054
         		575
    14 1-(Cyclopentyl)-piperazine
    Figure US20040209914A1-20041021-C00055
         		549
    15 1-(2-Propyl)- piperazine
    Figure US20040209914A1-20041021-C00056
         		523
    16 N-(2-(1-Piperazino)- acetyl)pyrrolidine
    Figure US20040209914A1-20041021-C00057
         		592
    17 1-(3-Dimethyl- aminopropyl)- piperazine
    Figure US20040209914A1-20041021-C00058
         		566
    18 1-(2-Methoxyethyl)- piperazine
    Figure US20040209914A1-20041021-C00059
         		539
    19 1-(2-Dimethyl-aminoethyl)- piperazine
    Figure US20040209914A1-20041021-C00060
         		552
    20 1-(2-Ethoxyphenyl)- piperazine
    Figure US20040209914A1-20041021-C00061
         		601
    21 1-(4-Fluorphenyl)- piperazine
    Figure US20040209914A1-20041021-C00062
         		575
    22 1-(2-Pyridyl)- piperazine
    Figure US20040209914A1-20041021-C00063
         		558
    23 2-(1-piperazinyl)-pyrimidine
    Figure US20040209914A1-20041021-C00064
         		559
    24 4-Piperazino- acetophenone
    Figure US20040209914A1-20041021-C00065
         		599
    25 1-(4-Nitrophenyl)- piperazine
    Figure US20040209914A1-20041021-C00066
         		602
    26 1-(3,5-Dichloropyrid-4- yl)piperazine
    Figure US20040209914A1-20041021-C00067
         		626
    27 4-(2-Methoxyphenyl)- piperidine
    Figure US20040209914A1-20041021-C00068
         		586
    28 N-[2-Nitro-4- (trifluoromethyl)- phenyl]piperazine
    Figure US20040209914A1-20041021-C00069
         		670
    29 1-[3-(Trifluormethyl)-pyrid- 2-yl]- piperazine
    Figure US20040209914A1-20041021-C00070
         		626
    30 cis-3,5-Dimethyl- morpholine
    Figure US20040209914A1-20041021-C00071
         		510
    31 1-(2,4-Difluorphenyl)- piperazine
    Figure US20040209914A1-20041021-C00072
         		593
    32 1-(4-Pyridyl)- piperazine
    Figure US20040209914A1-20041021-C00073
         		558
    33 1-(4-Trifluoromethyl- phenyl)-piperazine
    Figure US20040209914A1-20041021-C00074
         		625
    34 1-Allylpiperazine
    Figure US20040209914A1-20041021-C00075
         		521
    35 1-(2-Pyrazinyl)-piperazine
    Figure US20040209914A1-20041021-C00076
         		559
    36 1-[3-Chloro-5- (trifluoromethyl)pyrid-2- yl)]piperazine
    Figure US20040209914A1-20041021-C00077
         		660
    37 1-(2-(4-Morpholino)- ethyl)piperazine
    Figure US20040209914A1-20041021-C00078
         		594
    38 3-Chlorophenyl-piperazine
    Figure US20040209914A1-20041021-C00079
         		591
    39 4-(Hydroxymethyl)- piperidine
    Figure US20040209914A1-20041021-C00080
         		510
    40 cis-2,6-Dimethyl-piperazine
    Figure US20040209914A1-20041021-C00081
         		509
    41 3-Methylpiperidine
    Figure US20040209914A1-20041021-C00082
         		494
    42 1-[4-(Trifluormethyl)- 2-pyrimidyl]- piperazine
    Figure US20040209914A1-20041021-C00083
         		627
    43 1-[4-(Trifluormethyl)- 2-pyridyl]- piperazine
    Figure US20040209914A1-20041021-C00084
         		626
    44 3,5-Dimethyl- piperidine
    Figure US20040209914A1-20041021-C00085
         		508
    45 3,5-Dimethyl- piperidine
    Figure US20040209914A1-20041021-C00086
         		508
    • Examples 46-47 Step 12: Further Synthesis of Resin III
  • Into a 8 mL glass vial was placed resin II (200 mg, 0.18 mmol) and cesium carbonate (0.98 g mg, 3 mmol) (no cesium carbonate used with piperidine and pyrrolidine nucleophiles). One mL of a 1.8 M solution of the amine nucleophile to be reacted in 1-methyl-2-pyrrolidinone (1.8 mmol) was added and the vial was capped and heated to 100° C. for 30 hr. Then the vessel was cooled to room temperature, and the resin was drained and washed with 1-methyl-2-pyrrolidinone, 1:1 1-methyl-2-pyrrolidinone/water, water, 1:9 acetic acid/water, methanol and methylene chloride (3×3 mL each solvent). [0274]
  • The following hydroxamic acids were synthesized from Resin III with the indicated amines, followed by release from the polymer using the reaction conditions in Step 3. [0275]
    Figure US20040209914A1-20041021-C00087
    Example Amine R MS (M + H)
    46 1-(2-Methoxyphenyl)- piperidine
    Figure US20040209914A1-20041021-C00088
         		475
    47 4-(4-Methoxybenzoyl)- piperidine
    Figure US20040209914A1-20041021-C00089
         		503
    • Example 48 Preparation of N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxamide
  • [0276]
    Figure US20040209914A1-20041021-C00090
  • Step 1: Hydrolysis of methyl 4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxylate. To a solution of methyl 4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxylate (10.0 g, 31 mmol) dissolved in tetrahydrofuran (150 mL) was added potassium trimethylsilanolate (12.1 g) and stirred 2 hr. Water was added to the reaction mixture and extracted with ethyl acetate (2×100 mL). The pH value of the aqueous layer was adjusted to 2 with 2M hydrochloric acid and extracted with ethyl acetate (2×100 mL). The latter organics were washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow solid (8.20 g). [0277]
  • Step 2: Loading on resin. The compound obtained in step 1 (4.0 g, 13.1 mmol) was dissolved in 1-methyl-2-pyrrolidinone (15 mL) and added to a suspension of resin I (6.0 g, 6.6 mmol; Preparative Example XI) in 1-methyl-2-pyrrolidinone (40 mL). To this solution were added pyBOP (6.85 g) and N-methylmorpholine (2.9 mL), and the mixture was stirred with overhead stirring 16 hr. The resin was filtered and washed with dimethylformamide (3×50 mL), methanol (3×50 mL), dichloromethane (3×50 mL) and ether (3×50 mL). The resin was dried in vacuo to provide resin MT-III (6.79 g). [0278]
  • Step 3: Aryl fluoride displacement of resin MT-III. A suspension of resin MT-III (200 mg, 0.17 mmol), 1-methyl-2-pyrrolidinone (2 mL), cesium carbonate (560 mg) and 4-methoxyphenyl (306 mg) were stirred at 105° C. for 16 hr. The reaction mixture was cooled and the resin filtered. The resin was washed with dimethylformamide (3×5 mL), methanol (3×5 mL), 10% aqueous acetic acid (3×5 mL), methanol (3×5 mL) and dichloromethane (3×5 mL). To the resin was added 95% aqueous trifluoroacetic acid and the reaction mixture was agitated for 1 hr. The resin was drained and washed with dichloromethane (2×1 mL). The solvent was evaporated. The residue was purified by RPHPLC to provide N-hydroxy-4-[[4-(4-methoxy-phenoxy)phenyl]sulfonyl]-4-thianecarboxamide (17.9 mg) as a pale yellow oil. [0279]
    • Examples 49-50
  • The following hydroxamic acids were prepared by the method of Example 48 using the appropriate amine. [0280]
    Figure US20040209914A1-20041021-C00091
    MS (ES)
    Example R Amine m/z
    49 4-(4-fluoro-benzoyl) 4-(4-fluorobenzoyl)- 507
    piperidyl piperidine (M + H)+
    50 4-(2-methoxy-phenyl) 4-(2-methoxyphenyl)- 491
    piperidyl piperidine (M + H)+
    • Example 51 Preparation of N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxamide-1,1-dioxide
  • [0281]
    Figure US20040209914A1-20041021-C00092
  • Step 1: Oxidation of Resin MT-III. A suspension of resin MT-III (2.0 g, 1.72 mmol), m-chloroperbenzoic acid (4.37 g) and dichloromethane (25 mL) was stirred at room temperature for 20 hr. The resin was filtered and washed with dichloromethane (3×25 mL), dimethylformamide (3×25 mL), methanol (3×25 mL), 1M aqueous sodium bicarbonate (2×25 mL), methanol (3×25 mL), dichloromethane (3×25 mL) and ether (3×25 mL). The resin was dried in vacuo to afford resin MT-IV (2.16 g). [0282]
  • Step 2: Aryl fluoride displacement of resin MT-IV. N-hydroxy-4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxamide 1,1-dioxide was prepared by the method of Example 48 using resin MT-IV in the place of resin MT-III. ES (MS) m/z 473 (M+NH[0283] 4)+.
    • Example 52
  • The following hydroxamic acid was prepared by the method of Example 51 using 4-(4-fluoro-benzoyl)-piperidine as the amine. MS (ES) m/z 539 (M+H)[0284] +.
    Figure US20040209914A1-20041021-C00093
    • Example 53 Preparation of N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]-piperidyl]phenyl]sulfonyl]-4-thianecarboxamide
  • [0285]
    Figure US20040209914A1-20041021-C00094
  • Step 1: Aryl fluoride displacement of Resin MT-III. To a suspension of resin MT-III (4.06 g, 3.4 mmol) in 1-methyl-2-pyrrolidinone (40 mL) was added ethyl isonipecotate (5.25 mL), and the mixture was heated to 100° C. for 16 hr. The cooled reaction mixture was filtered and the resin was washed with methanol (3×25 mL), dichloromethane (1×10 mL) and ether (3×25 mL). The resin was dried in vacuo to afford resin MT-V (4.21 g). [0286]
  • Step 2: Hydrolysis of resin MT-V. To a suspension of resin MT-V (4.13 g) in tetrahydrofuran (20 mL) was added 4M aqueous potassium hydroxide (10 mL) and stirred at room temperature for 5 days. The resin was filtered and washed with methanol (3×25 mL), dichloromethane (3×25 mL) and ether (3×25 mL). The resin was dried in vacuo to afford resin MT-VI. [0287]
  • Step 3: Conversion to amide. To a suspension of resin MT-VI (268 mg) in 1-methyl-2-pyrrolidinone (2 mL) were added 3,5-dimethyl-piperidine (299 μL), pyBOP (587 mg) and diisopropylethyl amine (393 μL), and mixture was stirred 40 hr. The resin was filtered and washed with dimethylformamide (3×2 mL), methanol (3×2 mL), 10% aqueous acetic acid (3×2 mL), methanol (3×2 mL), dichloromethane (3×2 mL) and glacial acetic acid (1×2 mL). The resin was treated with 95% aqueous trifluoroacetic acid (2 mL) and agitated 1 hr. The resin was washed with dichloromethane (2 mL) and methanol (2 mL). The filtrate was evaporated. The residue was purified by RPHPLC to afford N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]piperidyl]phenyl]sulfonyl]-4-thianecarboxamide (7.5 mg) MS (ES) m/z 524 (M+H)[0288] +.
    • Example 54 Preparation of 1,1-dimethylethyl-3,6-dihydro-4-[2-(trifluoromethyl)phenyl]-1 (2H)-pyridinecarboxylate
  • [0289]
    Figure US20040209914A1-20041021-C00095
  • Part A: An oven-dried 1.0 liter flask fitted with a thermometer and nitrogen inlet was charged with 55 mL of a 2 M solution of lithium diisopropoylamide in tetrahydrofuran and 50 mL of tetrahydrofuran. The flask was immersed in a dry ice/acetone bath. When the temperature of the solution was less than −70° C., a solution of N-t-butoxycarbonylpiperidinone (20.0 g, 0.1 mole) in 100 mL tetrahydrofuran was added dropwise, maintaining the temperature less than −65° C. After complete addition, the flask was stirred with cooling for 20 min. Then a solution of N-trifluoromethanesulfonimide (38.2 g, 0.107 mole) was added drop-wise maintaining the temperature less than −65° C. After complete addition, the dry ice/acetone bath was swapped with an ice/water bath. The reaction was stirred overnight (about 18 hr), slowly warming to room temperature. After 16 hr, the solvent was removed in vacuo, and the residue was purified by column chromatography on neutral alumina, yielding 26.53 g of product as a yellow oil. Electrospray mass spectroscopy showed m/z 332 (M+H). [0290]
  • Part B: A three-necked 15 mL round-bottom flask was charged with the product from Part A (6 g, 18.1 mmol), o-trifluorobenzeneboronic acid (4.94 g, 26 mmol), lithium chloride (2.34 g, 55 mmol), 2 M sodium carbonate (26 mL, 52 mmol) and ethylene glycol dimethyl ether (60 mL). Nitrogen was bubbled through the solution for 10 min, then palladium tetrakistriphenylphosphine (1.06 g, 0.92 mmol) was added. The mixture was heated to reflux for 1.5 hr, then cooled to room temperature. The solvent was removed in vacuo, then the residue was partitioned between 100 mL of methylene chloride and 100 mL of 2 M sodium carbonate with 3 mL concentrated ammonium hydroxide. The aqueous layer was extracted with an additional 100 mL methylene chloride, then the combined organic layers were dried over magnesium sulfate and concentrated to give 8.42 g of crude product as a dark brown oil. Purification via flash column chromatography (10% ethyl acetate3/hexanes) yielded 2.76 g of pure product as a yellow oil. Electrospray mass spectroscopy showed m/z 328 (M+H). [0291]
    • Example 55 Preparation of 1,2,3,6-tetrahydro-4-[2-trifluoromethyl)phenyl]pyridine
  • [0292]
    Figure US20040209914A1-20041021-C00096
  • The title compound of Example 54 (300 mg, 0.92 mmol) was dissolved in methylene chloride (5 mL) in a 15 mL round-bottom flask, and 5 mL of trifluoroacetic acid was added dropwise. After 15 min, the solvent was removed in vacuo, and the residue partitioned between 20 mL of ethyl acetate and 20 mL of 2 M sodium carbonate. The organic layer was washed with additional 2 M sodium carbonate, dried over magnesium carbonate and concentrated in vacuo to yield 195 mg of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 228 (M+H). [0293]
    • Example 56 Preparation of 4-[2-(trifluoromethyl)phenyl]piperidine
  • [0294]
    Figure US20040209914A1-20041021-C00097
  • Part A: A solution of the title compound of Example 54 (2.3 g, 7 mmol) in 20 mL ethanol was added to a hydrogenation flask containing 1 g of 4% palladium on carbon (0.38 mmol). The mixture was placed under 100 PSI hydrogen and heated to 50° C. for 5 hr. Then the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo to give 2.27 g of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 330 (M+H). [0295]
  • Part B: The product from Part A above (2.24 g, 6.8 mmol) was dissolved in 100 mL methylene chloride, and 100 mL of trifluoroacetic acid was added dropwise. After 15 min, the solvent was removed in vacuo, and the residue partitioned between 100 mL of ethyl acetate and 100 mL of 2 M sodium carbonate. The organic layer was washed with additional 2 M sodium carbonate, dried over magnesium carbonate and concentrated in vacuo to yield 1.12 g of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 230 (M+H). [0296]
    • Example 57 General Description for Preparation of Hydroxamic Acids via Aryl Fluoride Displacement with Amines
  • Part A: A 2 dram vial was charged with aryl fluoro compound of Preparative Example IV (170 mg, 0.44 mmol), 1 ml of 2-methylpyrrolidinone, cesium carbonate (360 mg, 1.1 mmol) and 0.66 mmol of an amine. A small magnetic stirring bar was added, then the vial was capped and placed in a Pierce Reacti-therm™ at 115° C. The reaction progress was followed by analytical HPLC. When the reaction was greater than 90% complete, the vial was cooled to room temperature. The reaction mixture was diluted with 5 mL of water, then 1.2 mL of 5% hydrogen chloride/water was added dropwise. Then, the entire mixture was poured onto a column of Celite. The column was washed exhaustively with ethyl acetate (30-40 mL) and the filtrate was collected and concentrated to give the crude products. [0297]
  • Part B: The product from above was dissolved in 2 mL 1,4-dioxane and 2 mL of methanol in a 4 dram vial with a small magnetic stirring bar. A solution of 4 N hydrogen chloride in 1,4-dioxane was carefully added to the reaction, and the mixture was stirred for 2 hr. Then the solvent was removed in vacuo and the residue purified by preparative reversed-phase HPLC. [0298]
    • Examples 58-60
  • The following hydroxamic acids were prepared using the method described above in Example 57 with the indicated amine as the starting material. [0299]
    Figure US20040209914A1-20041021-C00098
    m/z from
    electrospray
    mass
    Example amine R spectroscopy
    58 Product of Example 56
    Figure US20040209914A1-20041021-C00099
         		513.3 (M + H)
    59 Product of Example 55
    Figure US20040209914A1-20041021-C00100
         		511.2 (M + H)
    60 4-(2-keto- benzimid- azolinyl)- piperidine
    Figure US20040209914A1-20041021-C00101
         		501 (M + H)
    • Examples 61-69
  • Using the procedures outlined in Examples 54, 55, and 57 and other methods outlined above, the following analogs are made from the indicated boronic acid: [0300]
    Figure US20040209914A1-20041021-C00102
    Example Boronic acid R
    61
    Figure US20040209914A1-20041021-C00103
    Figure US20040209914A1-20041021-C00104
    62
    Figure US20040209914A1-20041021-C00105
    Figure US20040209914A1-20041021-C00106
    63
    Figure US20040209914A1-20041021-C00107
    Figure US20040209914A1-20041021-C00108
    64
    Figure US20040209914A1-20041021-C00109
    Figure US20040209914A1-20041021-C00110
    65
    Figure US20040209914A1-20041021-C00111
    Figure US20040209914A1-20041021-C00112
    66
    Figure US20040209914A1-20041021-C00113
    Figure US20040209914A1-20041021-C00114
    67
    Figure US20040209914A1-20041021-C00115
    Figure US20040209914A1-20041021-C00116
    68
    Figure US20040209914A1-20041021-C00117
    Figure US20040209914A1-20041021-C00118
    69
    Figure US20040209914A1-20041021-C00119
    Figure US20040209914A1-20041021-C00120
    • Example 70 Preparation of 4-[[4-[4-[(3,5-dimethyl-1-piperidinyl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide, monohydrochloride
  • [0301]
    Figure US20040209914A1-20041021-C00121
  • Part A: To a solution of isonipecotic acid (5.8 g, 44.9 mmol) in water (200 mL) was added sodium carbonate (4.62 g, 44.9 mmol) followed by the drop-wise addition of di-tert-butyl-dicarbonate (10.1 g, 46.3 mmol) in dioxane (40 mL). After 4 hr, the solvent was concentrated in vacuo and the solution was extracted with ethyl ether. The aqueous layer was acidified with 3N hydrochloric acid to pH=2. The solution was extracted with ethyl ether and the organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided N-Boc-isonipecotic acid as a white solid (9.34 g, 90%). [0302]
  • Part B: To a solution of the N-Boc-isonipecotic acid of part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hr. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a clear colorless oil (1.21 g, 89%). [0303]
  • Part C: To a solution of the amide of part B (1.20 g, 3.84 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 1 hr. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (956 mg, 2.56 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.92 g, 8.96 mmol) was added and the solution was heated to 100° C. for 18 hr. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an oil (1.53 g, 68%). MS(CI) MH[0304] + calculated for C30H47N3O6S: 578, found 578.
  • Part D: To a solution of the phenylamine of part C (1.5 g, 2.6 mmol) in ethanol (9 mL) and tetrahydrofuran (9 mL) was added sodium hydroxide (1.02 g, 26 mmol) in water (5 mL) and the solution was heated to 60° C. for 20 hr. The solution was concentrated and the residue was diluted with water and acidified to pH=3 with 3N hydrochloric acid. Vacuum filtration provided the acid as a beige solid (500 mg, 33%). MS(CI) MH[0305] + calculated for C28H43N3O6S: 550, found 550.
  • Part E: To a solution of the acid of part D (492 mg, 0.84 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (136 mg, 1.01 mmol), 4-methylmorpholine (0.46 mL, 4.20 mmol), and O-tetrahydropyranyl hydroxylamine (147 mg, 1.26 mmol). After 1 hr, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (225 mg, 1.18 mmol) was added and the solution was stirred for 72 hr at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the protected hydroxamate as an oil (524 mg, 96%). MS(CI) MH[0306] + calculated for C33H51N4O7S: 649, found 649.
  • Part F: To a solution of the protected hydroxamate of part E (514 mg, 0.79 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hr. The solution was concentrated in vacuo and trituration (ethyl ether) provided the title compound as a white solid (360 mg, 76%). MS(CI) MH[0307] + calculated for C28H44N4O6S: 565, found 565. HRMS calculated for C28H44N4O6S: 565.3060, found 565.3070. Analytical calculation for C28H44N4O6S 2HCl:2H2O: C, 49.92; H, 7.48; N, 8.32; S, 4.76; Cl, 10.52. Found: C, 49.41; H, 7.55; N, 7.85; S, 4.53; Cl, 10.78.
    • Example 71 Preparation of 4-[[4-[4-[(3,5-dimethyl-1-piperidinyl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide
  • [0308]
    Figure US20040209914A1-20041021-C00122
  • A solution of the hydroxamate of Example 70, part F (50 mg, 0.08 mmol) in water (2 mL) was neutralized with saturated sodium bicarbonate. The aqueous solution was extracted with ethyl acetate. Concentration in vacuo provided the hydroxamate free base as an orange solid (35 mg, 75%). [0309]
    • Example 72 Preparation of rel-4-[[4-[4-[[(3R,5R)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide, monohydrochloride
  • [0310]
    Figure US20040209914A1-20041021-C00123
  • Part A: To a solution of the N-Boc-isonipecotic acid of Example 70, Part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hr. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a clear colorless oil (1.4 g, quantitative yield). [0311]
  • Part B: To a solution of the amide of part A (1.4 g, 4.49 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hr. Concentration in vacuo provided a solid that was added directly to a solution of the compound of Preparative Example II, Part D, (1.24 mg, 2.99 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.42 g, 10.5 mmol) was added and the solution was heated to 100° C. for 20 hr. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow solid (1.90 g, quantitative yield). MS(CI) MH[0312] + calculated for C32H49N3O7S: 620, found 620.
  • Part C: To a solution of the phenylamine of part B (1.9 g, 3.0 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.2 g, 30 mmol) in water (5 mL) and the solution was heated to 60° C. for 20 hr. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. The solution was extracted with ethyl acetate and washed with 1M hydrochloric acid and saturated sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided the acid as a yellow oil (1.9 g, quantitative yield). MS(CI) MH[0313] + calculated for C30H45N3O7S: 592, found 592.
  • Part D: To a solution of the acid of part C (1.87 g, 3.00 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (486 mg, 3.6 mmol), 4-methylmorpholine (1.65 mL, 15 mmol), and O-tetrahydropyranyl hydroxylamine (526 mg, 4.5 mmol). After 1 hr, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (805 mg, 4.2 mmol) was added and the solution was stirred for 18 hr at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as an oil (1.63 g, 79%). [0314]
  • Part E: To a solution of the protected hydroxamate of part D (1.61 g, 2.33 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 45 min. The solution was concentrated in vacuo and trituration (ethyl ether) a white solid. Reverse phase chromatography (on silica, acetonitrile/water (hydrochloric acid)) produced fractions A, B, C and D. Concentration in vacuo of fraction A provided the title compound as a white solid (59 mg). MS(CI) MH[0315] + calculated for C25H38N4O5S: 507, found 507.
    • Example 73 Preparation of rel-1,1-dimethylethyl 4-[[4-[4-[[(3R,5R)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate
  • [0316]
    Figure US20040209914A1-20041021-C00124
  • From the reverse phase chromatography of Example 72, Part E, fraction C was concentrated in vacuo to provide the title compound as a white solid (49 mg). MS(CI) MH[0317] + calculated for C30H46N4O7S: 607, found 607.
    • Example 74 Preparation of rel-4-[[4-[4-[[(3R,5S)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide, monohydrochloride
  • [0318]
    Figure US20040209914A1-20041021-C00125
  • From the reverse phase chromatography of Example 72, Part E, fraction B was concentrated in vacuo to provide the title compound as a white solid (198 mg). MS(CI) MH[0319] + calculated for C25H38N4O5S: 507, found 507.
    • Example 75 Preparation of rel-1,1-dimethylethyl 4-[[4-[4-[[(3R,5S)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate
  • [0320]
    Figure US20040209914A1-20041021-C00126
  • From the reverse phase chromatography of Example 72, Part E, fraction D was concentrated in vacuo to provide the title compound as a white solid (242 mg). MS(CI) MH[0321] + calculated for C30H46N4O7S: 607, found 607.
    • Example 76 Preparation of 4-[[4-[4-[(2,3-dihydro-1H-indol-1-yl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide, monohydrate
  • [0322]
    Figure US20040209914A1-20041021-C00127
  • Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B (750 mg, 3.27 mmol) in dichloromethane (3 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (564 mg, 3.21 mmol). The solution was cooled to 0° C. and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After 2 hr, indoline (0.36 mL, 3.21 mmol) was added and the solution was stirred for 22 hr at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (940 mg, 89%). [0323]
  • Part B: To a solution of the amide of part A (935 g, 2.83 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hr. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A, (705 mg, 1.89 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.15 g, 6.61 mmol) was added and the solution was heated to 110° C. for 18 hr. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (893 mg, 81%). MS(CI) MH[0324] + calculated for C31H41N3O6S: 584, found 584.
  • Part C: To a solution of the phenylamine of part B (885 g, 1.52 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (607 mg, 15.2 mmol) in water (5 mL) and the solution was heated to 60° C. for 20 hr. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (475 g, 53%). MS(CI) MH[0325] + calculated for C29H37N3O6S: 556, found 556.
  • Part D: To a solution of the acid of part C (465 g, 0.79 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (128 mg, 0.95 mmol), 4-methylmorpholine (0.43 mL, 3.95 mmol), and O-tetrahydropyranyl hydroxylamine (139 mg, 1.18 mmol). After 1 hr, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (212 mg, 1.10 mmol) was added and the solution was stirred for 18 hr at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (305 mg, 60%). MS(CI) MH[0326] + calculated for C34H46N4O7S: 655, found 655.
  • Part E: To a solution of the protected hydroxamate of part D (300 mg, 0.46 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (5 mL) and the solution was stirred for 2 hr. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (260 mg, 94%). MS(CD) MH[0327] + calculated for C29H34N4O6S: 571, found 571.
  • The following compounds were prepared by parallel synthesis (resin based synthesis, automated synthesis) procedures utilizing reactions such as acylation and nucleophilic displacement: [0328]
    • Example 77
  • [0329]
    Figure US20040209914A1-20041021-C00128
    • Example 78
  • [0330]
    Figure US20040209914A1-20041021-C00129
    • Example 79
  • [0331]
    Figure US20040209914A1-20041021-C00130
    • Examples: 80-118
  • [0332]
    Figure US20040209914A1-20041021-C00131
    Example R1R2NH Amine MS (ES) m/z
    80
    Figure US20040209914A1-20041021-C00132
         		Ethyl amine 592 (M + H)
    81
    Figure US20040209914A1-20041021-C00133
         		3-(Aminomethyl) pyridine 655 (M + H)
    82
    Figure US20040209914A1-20041021-C00134
         		Imidazole 615 (M + H)
    83
    Figure US20040209914A1-20041021-C00135
         		3-Amino-1-propanol 622 (M + H)
    84
    Figure US20040209914A1-20041021-C00136
         		Histamine 658 (M + H)
    85
    Figure US20040209914A1-20041021-C00137
         		2-Thiophene methyl amine 660 (M + H)
    86
    Figure US20040209914A1-20041021-C00138
         		Morpholine 634 (M + H)
    87
    Figure US20040209914A1-20041021-C00139
         		2-(Aminomethyl) pyridine 655 (M + H)
    88
    Figure US20040209914A1-20041021-C00140
         		4-(Aminomethyl) pyridine 655 (M + H)
    89
    Figure US20040209914A1-20041021-C00141
         		Ethanolamine 608 (M + H)
    90
    Figure US20040209914A1-20041021-C00142
         		N,N,N-Trimethyl ethylenediamine 649 (M + H)
    91
    Figure US20040209914A1-20041021-C00143
         		1-Methylpiperazine 647 (M + H)
    92
    Figure US20040209914A1-20041021-C00144
         		N,N-Dimethyl ethylenediamine 635 (M + H)
    93
    Figure US20040209914A1-20041021-C00145
         		Piperazine 633 (M + H)
    94
    Figure US20040209914A1-20041021-C00146
         		Thiomorpholine 650 (M + H)
    95
    Figure US20040209914A1-20041021-C00147
         		N-Propylcyclopropne methylamine 660 (M + H)
    96
    Figure US20040209914A1-20041021-C00148
         		(Aminomethyl) cyclopropane 618 (M + H)
    97
    Figure US20040209914A1-20041021-C00149
         		Dimethylamine 592 (M + H)
    98
    Figure US20040209914A1-20041021-C00150
         		Diethylamine 620 (M + H)
    99
    Figure US20040209914A1-20041021-C00151
         		Piperidine 632 (M + H)
    100
    Figure US20040209914A1-20041021-C00152
         		(R)-(-)-2-Pyrrolidine methanol 648 (M + H)
    101
    Figure US20040209914A1-20041021-C00153
         		Pyrrolidine 618 (M + H)
    102
    Figure US20040209914A1-20041021-C00154
         		1-(2-(2-Hydroxyethoxy) ethyl)piperazine 721 (M + H)
    103
    Figure US20040209914A1-20041021-C00155
         		Isonipecotamide 675 (M + H)
    104
    Figure US20040209914A1-20041021-C00156
         		2-(2-Aminoethoxy) ethanol 652 (M + H)
    105
    Figure US20040209914A1-20041021-C00157
         		3,3′-Iminobis(N,N- dimethylpropylamine) 734 (M + H)
    106
    Figure US20040209914A1-20041021-C00158
         		Bis(2-Methoxy ethyl)amine 680 (M + H)
    107
    Figure US20040209914A1-20041021-C00159
         		4-Hydroxy piperidine 648 (M + H)
    108
    Figure US20040209914A1-20041021-C00160
         		N-(Carboethoxy methylpiperazine 719 (M + H)
    109
    Figure US20040209914A1-20041021-C00161
         		1-(2-Morpholinoethyl) piperazine 746 (M + H)
    110
    Figure US20040209914A1-20041021-C00162
         		1-(2-Methoxyethyl) piperazine 691 (M + H)
    111
    Figure US20040209914A1-20041021-C00163
         		1-(2- Dimethylaminoethyl) piperazine 704 (M + H)
    112
    Figure US20040209914A1-20041021-C00164
         		2-Methoxyethylamine 622 (M + H)
    113
    Figure US20040209914A1-20041021-C00165
         		2,2,2-Trifluoroethyl amine 646 (M + H)
    114
    Figure US20040209914A1-20041021-C00166
         		1,2,4-Triazole 616 (M + H)
    115
    Figure US20040209914A1-20041021-C00167
         		Methoxyamine 594 (M + H)
    116
    Figure US20040209914A1-20041021-C00168
         		Ethyl isonipecotate 704 (M + H)
    117
    Figure US20040209914A1-20041021-C00169
         		2-Pyrrolidinone 632 (M + H)
    118
    Figure US20040209914A1-20041021-C00170
         		Isonipecotic acid 676 (M + H)
    • Example 119 Preparation of
  • [0333]
    Figure US20040209914A1-20041021-C00171
  • Part A. Preparation of aryl fluoride. To a solution of ethyl 4-[(4-fluorophenyl)sulfonyl]-1-(2-methoxyethyl)-4-piperidinecarboxylate (57 mmol) in dioxane (90 mL) and water (45 mL) was added LiOH (4.8 g, 3.5 eq). The mixture was stirred at 60° C. overnight, cooled to room temperature, and concentrated in vacuo. The aqueous layer was treated with concentrated HCl until the pH was approximately 4. The solid was collected and dried. Next, the solid (47.8 mmol) in DMF (100 mL) was added NMM (26.2 mL, 239 mmol) and (benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)uronium tetrafluoroborate (32.3 g, 62.1 mmol). The mixture was stirred at room temperature for 15 min, and O-(tetrahydro-211-pyran-2-yl)hydroxylamine (6.71 g, 57.32 mmol) was then added. After 48 hr at room temperature, the mixture was quenched with sat. NH[0334] 4 +Cl−, and then extracted with CH2Cl2 three times. The combined organic layer was dried and concentrated in vacuo. The residue was purified over SiO2 using hexane/CH2Cl2 and then CH2Cl2/MeOH to give 20 g of protected hydroxyamide as an orange oil.
  • Part B. Aryl fluoride displacement. A solution of the aryl fluoride from Part A (0.45 mmol), Cs[0335] 2CO3 (1.35 mmol, 3 eq), and 4-(4-chlorobenzoyle)piperidine (Maybridge Chemical Co., England, 0.67 mmol, 1.5 eq) in DMSO (1 mL) was heated to 110° C. for 18-48 hr. The mixture was then cooled, dissolved in saturated aq. NH4 +Cl− (5 mL), and extracted with dichloromethane (3×3 mL). The combined organic layer was blown down. The crude product was purified by RPHPLC (eluting with 10% to 90% acetonitrile/water), and the pure fractions were combined and concentrated.
  • Part C. Conversion of the THP hydroxamic acid of Part B to the hydroxamic acid. The residue from Part B was dissolved in 2 mL of 4M HCl and 1 mL of MeOH, stirred at room temperature for 1 h, and then blown down. THEO M+H=564.1935; Observed: HI RES M+H=564.1949. [0336]
    • Example 120 Preparation of
  • [0337]
    Figure US20040209914A1-20041021-C00172
  • Part A. Preparation of 4-(4-n-propylbenzoyl)piperidine. To a solution of magnesium (147 mmol, 5 eq) in 40 mL of THF at 0° C. was added 1-bromo-4-(n-propyl)benzene (88.24 mmol, 3 eq). The solution was allowed to warm to room temperature over approximately 3 hr. The weinreb amide (29.4 mmol, 1 eq) having the following structure: [0338]
    Figure US20040209914A1-20041021-C00173
  • was added, and then the mixture was stirred at room temperature for 18 hr. The mixture was quenched with saturated NH[0339] 4 +Cl−, and then extracted with CH2Cl2 three times. The combined organic layer was washed with saturated NH4 +Cl−, dried over MgSO4, and concentrated in vacuo. The residue was purified over 70 g of SiO2, eluting with ethylacetate:hexanes (1:10) to ethylacetate:hexanes (1:3). The piperidine was dissolved in 20 mL of CH2Cl2 and 20 mL of trifluoroacetate. The resulting mixture was stirred at room temperature for 1 hr, and then concentrated in vacuo. The residue was treated with 5% NaOH until a solid precipitated out. The solid was collected and then dissolved in dichloromethane, dried, and concentrated in vacuo. The residue was recrystallized in MeOH/Ether to give 5.07 g of 4-(4-n-propylbenzoyl)piperidine.
  • Part B. Aryl fluoride displacement. A solution of the aryl fluoride (0.45 mmol., as prepared in Part A of the preceding example), Cs[0340] 2CO3 (1.35 mmol, 3 eq), and the 4-(4-n-propylbenzoyl)piperidine prepared in Part A above (0.65 mmol, 1.5 eq) in DMSO (1 mL) was heated to 110° C. for 18-48 hr. The mixture was cooled, dissolved in saturated aqueous NH4 +Cl− (5 mL), and extracted with dichloromethane (3×3 mL). The combined organic layer was blown down. The crude product was purified by RPHPLC (eluting with 10% to 90% acetonitrile/water), and the pure fractions were combined and concentrated.
  • Part C. Conversion of the THP hydroxamic acid of Part B to the hydroxamic acid. The residue from Part C was dissolved in 2 mL of 4M HCl and 1 mL of MeOH, stirred at room temperature for 1 h, and then blown down. Theo: M+H=572.2794; Observed: Hi Res M+H=572.2755; [0341]
    • Example 121 Preparation of
  • [0342]
    Figure US20040209914A1-20041021-C00174
  • Part A: [0343]
    Figure US20040209914A1-20041021-C00175
  • To a solution of n-butylthiophene (Lancaster, 5.0 g, MW 140.26, 1.1 eq) in tetrahydrofuran (80 ml) at 0° C. was dripped in 1.6 M n-butyllithium in hexanes (Aldrich, 24 ml, 1.2 eq). The mixture stirred at 0° C. for 0.5 hr under N[0344] 2. The reaction vessel was then cooled to −78° C., and a solution of the weinreb amide (shown in the reaction above) in tetrahydrofuran (30 ml) was slowly added. The dry ice bath was removed, and the reaction was allowed to warm to room temperature. After 3 hr, the conversion was complete. The reaction was quenched with water (50 ml), and the organic layer was removed in vacuo. More water (100 ml) was added, and the mixture was extracted with diethylether (3×100 ml). The organic layers were washed with water (2×) and brine (1×), dried over Na2SO4, and concentrated to afford a brown oil that was chromatographed (ethylacetate:hexanes, 1:9) to afford 7.5 g of a pale yellow solid (67% crude yield). 1H NMR showed the desired compound.
  • Part B: [0345]
    Figure US20040209914A1-20041021-C00176
  • To a solution of Compound I (7.4 g, MW 351.50, 1.0 eq) in acetonitrile (10 ml) was added 4 N HCl in dioxane (Pierce, 40 ml). After 1 hr, the solvent was evaporated, and the residue was slurried in diethylether to afford a white solid that was collected and dried for 5.8 g (97% yield). [0346] 1H NMR showed the desired Compound II.
  • Part C: [0347]
    Figure US20040209914A1-20041021-C00177
  • To a solution of Compound II (2.1 g, MW 287.85, 1.5 eq) in dimethylsulfoxide (Aldrich, 15 ml) was added CsCO[0348] 3 (Aldrich, 6.4 g, MW 325.8, 4.0 eq). After stirring for 5 min, Compound III (2.0 g, MW 401.49, 1.0 eq) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was then diluted with water (15 ml), and extracted with ethylacetate (3×100 ml). The organic layer was washed with water (1×), washed with brine (2×), dried over Na2SO4, and concentrated to a crude brown solid which was recrystallized from hot methanol for 1.83 g of an orange crystalline solid (59% yield). 1H NMR showed the desired Compound IV.
  • Part D: [0349]
    Figure US20040209914A1-20041021-C00178
  • To a solution of Compound IV (1.8 g, MW 632.88, 1.0 eq) in methylene chloride (5 ml) was added trifluoroacetic acid (10 ml). The mixture was stirred for 4 hr at room temperature. The mixture was then concentrated to ⅓ volume, and diethylether was added to afford a solid, which was collected and dried for 1.4 g tan solid (88% yield). [0350] 1H NMR and LCMS showed the desired Compound V.
  • Part E: [0351]
    Figure US20040209914A1-20041021-C00179
  • To a solution of Compound V (1.3 g, 2.2 mmol) in N,N-dimethylformamide (8 ml) was added triethylamine (Aldrich, 1.2 ml, 8.8 mmol), followed by N-hydroxybenzotriazole hydrate (Aldrich, 0.6 g, 4.4 mmol), O-tetrahydro-2H-pyran-2-yl)hydroxylamine (0.4 g, 3.3 mmol), and, lastly, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (Sigma, 0.9 g, 4.8 mmol). The mixture was stirred for 2 days at room temperature. The mixture was diluted with water (10 ml), and extracted with ethylacetate (3×75 ml). The organic layers were combined, and washed with a saturated sodium bicarbonate solution (1×1 50 ml) and brine (1×150 ml). The organic layer was then dried over Na[0352] 2SO4, and concentrated to afford an orange foam that was recrystallized from methanol to afford a pale yellow solid (1.2 g, 80% yield). 1H NMR and LCMS showed the desired Compound VI.
  • Part F: [0353]
    Figure US20040209914A1-20041021-C00180
  • The Compound VI (1.2 g, 1.8 mmol) was treated with methanol (0.5 ml) and 4 N HCl in dioxane (5 ml) for 1 hr. The solvents were concentrated to ⅓ the volume via an N[0354] 2 stream. Diethylether was then added to the residue to afford a solid that was collected and dried to a white solid (1.0 g, 91% yield). 1H NMR showed the desired Compound VII. HRMS confirmed this finding (theo M=H 592.2515, observed: 592.2498).
    • Example 122 Preparation of
  • [0355]
    Figure US20040209914A1-20041021-C00181
  • Part A: [0356]
    Figure US20040209914A1-20041021-C00182
  • To an ice-cold suspension of isopropylphosphonium iodide (Aldrich, 40.7, MW 432.29, 3.0 eq) at 0° C. in tetrahydrofuran (240 ml) was slowly added n-butyllithium (Aldrich, 1.6 M, 58.9 ml, 3.0 eq). After 1 hr, a solution of 5-bromo-2-thiophene carboxaldehyde (Aldrich, 6.0 g, MW 191.05, 1.0 eq) in tetrahydrofuran (60 ml) was added in one shot. The ice bath was removed, and the mixture warmed to ambient temperature and stirred 2.5 hours. The reaction was quenched with water (110 ml) followed by 1 N HCl (110 ml). An emulsion developed that was filtered through a coarse frit funnel. The filtrate was separated and the organic was washed with brine (200 ml), dried over Na[0357] 2SO4, and concentrated to afford a black oil. Purification on silica gel (ethyl acetate/hexanes) gave 3.4 g of a yellow oil (50% yield). 1H NMR showed desired Compound I.
  • Part B: [0358]
    Figure US20040209914A1-20041021-C00183
  • To a solution of Compound I (2.89 g, MW 217.13, 1.5 eq) in tetrahydrofuran (25 ml) at −40° C. was dripped 2.0M isopropylmagnesium chloride in tetrahydrofuran (Aldrich, 6.9 ml, 1.55 eq). The mixture was stirred at −40° C. for 1.5 hr under N[0359] 2. A solution of the weinreb amide (shown in the above reaction) in tetrahydrofuran (30 ml) was quickly added. The dry ice bath was removed, and the mixture was allowed to warn to room temperature and stirred overnight. The reaction was quenched with 1 N HCl (25 ml), followed by water (25 ml). The organic layer was removed in vacuo. The aqueous residue was extracted with diethylether (3×100 ml). The organic layers were washed with water (2×) and brine (1×), dried over Na2SO4, and concentrated to afford a brown oil that was slurried with hexanes. A solid formed, which was subsequently filtered to afford 1.9 g of gray solid (61% crude yield). 1H NMR showed the desired Compound II.
  • Part C: [0360]
    Figure US20040209914A1-20041021-C00184
  • To Compound II (1.9 g, MW 349.49, 1.0 eq) was added 4 N HCl in dioxane (Pierce, 10 ml). After 1 hr, the solvent was evaporated, and the residue was slurried in diethylether to afford a gray solid that was collected and dried for 1.4 g (93% yield). [0361] 1H NMR showed the desired Compound III.
  • Part D: [0362]
    Figure US20040209914A1-20041021-C00185
  • To a solution of Compound III (1.4 g, MW 285.83, 1.5 eq) in dimethylsulfoxide (Aldrich, 10 ml) was addded CsCO[0363] 3 (Aldrich, 4.0 g, MW 325.8, 4.0 eq). After 5 min, Compound IV (1.3 g, MW 401.49, 1.0 eq) was added, and the reaction was stirred at 100° C. for 24 hr. The mixture was then diluted with water (15 ml), and extracted with ethylacetate (3×100 ml). The organic layers were washed with water (1×) and brine (2×), dried over Na2SO4, and concentrated for a crude yellow solid, which was recrystallized from hot methanol for 0.98 g of a yellow crystalline solid (50% yield). LCMS (M+H) showed the desired Compound V.
  • Part E: [0364]
    Figure US20040209914A1-20041021-C00186
  • To a solution of Compound V (0.98 g, MW 630.86, 1.0 eq) in methylene chloride (4 ml) was added trifluoroacetic acid (4 ml, TFA). The mixture was stirred for 4 hr at room temperature. The mixture was then concentrated to ⅓ volume, and diethylether was added to afford a solid, which was collected and dried for 1.0 g tan solid (93% yield). [0365] 1H NMR and LCMS showed the desired Compound VI.
  • Part F: [0366]
    Figure US20040209914A1-20041021-C00187
  • To a solution of Compound VI (1.0 g, MW 688.77, 1.0 eq) in N,N-dimethylformamide (5 ml) was added triethylamine (Aldrich, 0.8 ml, MW 101.19, 4.0 eq) followed by N-hydroxybenzotriazole hydrate (Aldrich, 0.38 g, MW 135.13, 2.0 eq),)-(tetrahydro-2H-pyran-2-yl), hydroxylamine (0.25 g, MW 117.16, 1.5 eq), and, lastly, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (Sigma, 0.59 g, MW 191.76, 2.2 eq). The mixture stirred at ambient temperature for 18 hr. To work up the reaction was diluted with water (10 ml) and extracted with ethylacetate (3×75 ml). The organics were combined and washed with a saturated sodium bicarbonate solution (1×150 ml), and brine (1×150 ml). The organic was then dried over Na[0367] 2SO4, and concentrated to afford a 0.9 g of a brown oil (96% yield). 1H NMR and LCMS showed the desired Compound VII.
  • Part G: [0368]
    Figure US20040209914A1-20041021-C00188
  • The Compound VII (0.9 g, MW 673.88, 1.0 eq) was treated with methanol (0.5 ml) and 4 N HCl in dioxane (5 ml) for 1 hr). The solvents were concentrated to ⅓ the volume via an N[0369] 2 stream. Diethylether was then added to the residue to afford a solid that was collected and dried for a brown solid (0.32 g, 40% yield). 1H NMR showed the desired Compound VIII. HRMS confirmed this observation (theo. M+H 590.2359, observed M+H 590.2364).
    • Example 123 Preparation of
  • [0370]
    Figure US20040209914A1-20041021-C00189
  • Part A. Preparation of Aryl Fluoride Ester: [0371]
    Figure US20040209914A1-20041021-C00190
  • To a solution of molecular slieves (7.5 g), ethyl 5-[(4-fluorophenyl(sulfonyl]-4-piperidinecarboxylate, monohydrate (15 g, 42.6 mmol) in methanol (75 mL), and acetic acid (9 mL) was added sodium cyano borohydride (7.23 g, 115 mmol). The mixture was stirred at room temperature for 48 hr. The mixture was then quenched with sat. NH[0372] 4 +Cl−, and extracted with CH2Cl2 three times. The combined organic layer was dried and concentrated in vacuo. The residue was then recrystallized using ethanol and ether to give 12.1 g (32.7 mmol) of the aryl fluoride ester.
  • Part B. Aryl fluoride displacement. A solution of the aryl fluoride from Part A (0.45 mmol), Cs[0373] 2CO3 (1.35 mmol, 3 eq), and 4-(4-chlorobenzoyle)piperidine (Maybridge, England, 0.67 mmol, 1.5 eq) in DMSO (1 mL) was heated to 1110° C. for 18-48 h. The mixture was cooled, dissolved in saturated aqueous NH4 +Cl− (5 mL), and extracted with dichloromethane (3×3 mL). The combined organic layer was blown down, and the crude product was purified by crystallization using ethanol and ether.
  • Part C. Converting the ethyl ester to the hydroxamic acid. A solution of ethyl ester (5 g) in ethanol (8 mL), tetrahydrofuran (4 mL), and 50% aqueous NaOH (2 mL) was heated to 50° C. for approximately 2 hr (additional ethanol and THF can be added if the solid was not completely soluble after 1 hr at 50° C.). The residue was neutralized to a pH of 5-6 with aqueous HCl. The aqueous layer was concentrated in vacuo, and the resulting solid was washed with acetonitrile and water, and dried under high vacuum. A solution of the acid, NMM (3 eq), EDC (1.4 eq), and HOBT (1.5 eq) in DMF (5 mL) was heated at 40° C. for 2 hr. The amine was added, and then stirred at room temperature for 18-48 hr. The reaction mixture was quenched with saturated aqueous NH[0374] 4 +Cl−, and extracted with dichloromethane. The combined organic layer was concentrated. The THP amide was purified over SiO2 using CH2Cl2/methanol/triethylamine (the THP amide may alternatively be purified by reverse-phase chromatography). The resulting solid was then dissolved in 10 mL of 4M HCl and 10 mL of methanol, and stirred at room temperature until completion (30 min to 120 min). The mixture was then blown down, and the resulting solid was re-dissolved in methanol and poured into isopropyl alcohol. The solid was collected and dried. THEO M+H=560.1986; observed HI RES M+H=560.1999.
    • Example 124 Preparation of
  • [0375]
    Figure US20040209914A1-20041021-C00191
  • Part A. Preparation of 4-(4-metholcyclopropylbenzoyl)piperidine. To a solution of 4-bromophenylcyclopropyl ketone (Acros, 20 g, 89 mmol) in THF (75 mL) was added sodium borohydride (2.25 g, 60 mmol) and aluminum trichloride (3.95 g, 30 mmol) in small portions at −5° C. The mixture was allowed to warm to room temperature for 18 hr, and then stirred an additional 3 hr at 40° C. The mixture was then cooled, quenched with saturated NH[0376] 4 +Cl−, and extracted with CH2Cl2 three times. The combined organic layer was dried and concentrated in vacuo. The mixture was chromatographed over 70 g of SiO2 eluting with EtOAc:Hexane (0:100 to 10:90) to give 14.55 g (69 mmol) of 4-methyl cyclopropyl aryl bromide. To a cooled to 0° C. solution of the 4-methyl cyclopropyl aryl bromide (7.75 g, 36.7 mmol) in 20 mL of THF was added magnesium (55 mmol, 3 eq), followed by dibromoethane (10 uL) in small portions, keeping the mixture cold. The solution was stirred for 3 hr. The weinreb amide described in Example 120 (5 g, 18.4 mmol) was added at 0° C., and the mixture was stirred at room temperature for 48 hr. The mixture was then quenched with saturated NH4 +Cl−, and extracted with CH2Cl2 three times. The combined organic layer was dried and concentrated in vacuo. The mixture was chromatographed over 70 g of SiO2 eluting with EtOAc/Hexane (0:100 to 30:70) to give 5.54 g (16 mmol) of the desired BOC-protected piperidine. The BOC-protected piperidine was then dissolved in 20 mL of CH2Cl2 and 20 mL of TFA, and stirred at room temperature for 1 hr. The mixture was concentrated in vacuo, and the residue was treated with 5% NaOH and water, and then extracted with CH2Cl2 three times. The combined organic layer was dried and concentrated in vacuo to give 3.47 g (14.3 mmol) of the 4-(4-metholcyclopropylbenzoyl)piperidine.
  • Part B. Aryl fluoride displacement. A solution of ethyl 4-[(4-fluorophenyl)sulfonyl]-1-(2-methoxyethyl)-4-piperidinecarboxylate (0.45 mmol), Cs[0377] 2CO3 (1.35 mmol, 3 eq), and 4-(4-metholcyclopropylbenzoyl)piperidine from Part A in DMSO (1 mL) was heated to 110° C. for 18-48 h. The mixture was cooled, dissolved in saturated aqueous NH4 +Cl− (5 mL), and extracted with dichloromethane (3×3 mL). The combined organic layer was blown down, and the crude product was purified by crystallization using ethanol and ether.
  • Part C. Converting the ethyl ester to the hydroxamic acid. A solution of ethyl ester (5 g) in ethanol (8 mL), tetrahydrofuran (4 mL), and 50% aqueous NaOH (2 mL) was heated to 50° C. for approximately 2 hr (additional ethanol and THF can be added if the solid is not completely soluble after 1 hr at 50° C.). The residue was neutralized to a pH of 5-6 with aqueous HCl. The aqueous layer was concentrated in vacuo, and the resulting solid was washed with acetonitrile and water, and dried under high vacuum. A solution of the acid, NMM (3 eq), EDC (1.4 eq), and HOBT (1.5 eq) in DMF (5 mL) was heated at 40° C. for 2 hr. The amine was added, and then stirred at room temperature for 18-48 hr. The reaction mixture was quenched with saturated aqueous NH[0378] 4 +Cl−, and extracted with dichloromethane. The combined organic layer was concentrated. The THP amide was purified over SiO2 using CH2Cl2/methanol/triethylamine (the THP amide may alternatively be purified by reverse-phase chromatography). The resulting solid was then dissolved in 10 mL of 4M HCl and 10 mL of methanol, and stirred at room temperature until completion (30 min to 120 min). The mixture was then blown down, and the resulting solid was re-dissolved in methanol and poured into isopropyl alcohol. The solid was collected and dried. THEO M+H=584.2794; observed HI RES M+H=584.2795.
    • Examples 125-387
  • The following compounds were prepared in a manner similar to that used in the preceding examples. In the tables that follow, a generic structure is shown above the table with substituent groups being illustrated in the table along with available mass spectral data. [0379]
    Figure US20040209914A1-20041021-C00192
    Example R K MS (ES) m/z
    125
    Figure US20040209914A1-20041021-C00193
    Figure US20040209914A1-20041021-C00194
    126
    Figure US20040209914A1-20041021-C00195
    Figure US20040209914A1-20041021-C00196
    127
    Figure US20040209914A1-20041021-C00197
    Figure US20040209914A1-20041021-C00198
    128
    Figure US20040209914A1-20041021-C00199
    Figure US20040209914A1-20041021-C00200
    129
    Figure US20040209914A1-20041021-C00201
    Figure US20040209914A1-20041021-C00202
    130
    Figure US20040209914A1-20041021-C00203
    Figure US20040209914A1-20041021-C00204
    131
    Figure US20040209914A1-20041021-C00205
    Figure US20040209914A1-20041021-C00206
    132
    Figure US20040209914A1-20041021-C00207
    Figure US20040209914A1-20041021-C00208
    133
    Figure US20040209914A1-20041021-C00209
    Figure US20040209914A1-20041021-C00210
         		516
    134
    Figure US20040209914A1-20041021-C00211
    Figure US20040209914A1-20041021-C00212
    135
    Figure US20040209914A1-20041021-C00213
    Figure US20040209914A1-20041021-C00214
    136
    Figure US20040209914A1-20041021-C00215
    Figure US20040209914A1-20041021-C00216
         		600
    137
    Figure US20040209914A1-20041021-C00217
    Figure US20040209914A1-20041021-C00218
         		530
    138
    Figure US20040209914A1-20041021-C00219
    Figure US20040209914A1-20041021-C00220
         		636
    139
    Figure US20040209914A1-20041021-C00221
    Figure US20040209914A1-20041021-C00222
         		596
    140
    Figure US20040209914A1-20041021-C00223
         		—H 502
    141
    Figure US20040209914A1-20041021-C00224
    Figure US20040209914A1-20041021-C00225
         		579
    142
    Figure US20040209914A1-20041021-C00226
    Figure US20040209914A1-20041021-C00227
         		542
    143
    Figure US20040209914A1-20041021-C00228
    Figure US20040209914A1-20041021-C00229
         		614
    144
    Figure US20040209914A1-20041021-C00230
    Figure US20040209914A1-20041021-C00231
         		585
    145
    Figure US20040209914A1-20041021-C00232
    Figure US20040209914A1-20041021-C00233
         		549
    146
    Figure US20040209914A1-20041021-C00234
         		—H 574
    147
    Figure US20040209914A1-20041021-C00235
    Figure US20040209914A1-20041021-C00236
         		564
    148
    Figure US20040209914A1-20041021-C00237
    Figure US20040209914A1-20041021-C00238
         		616
    149
    Figure US20040209914A1-20041021-C00239
    Figure US20040209914A1-20041021-C00240
         		598
    151
    Figure US20040209914A1-20041021-C00241
    Figure US20040209914A1-20041021-C00242
         		540.2160
    152
    Figure US20040209914A1-20041021-C00243
    Figure US20040209914A1-20041021-C00244
         		524.225
    153
    Figure US20040209914A1-20041021-C00245
    Figure US20040209914A1-20041021-C00246
         		544.1673
    154
    Figure US20040209914A1-20041021-C00247
    Figure US20040209914A1-20041021-C00248
         		524.2218
    155
    Figure US20040209914A1-20041021-C00249
    Figure US20040209914A1-20041021-C00250
         		540.2155
    156
    Figure US20040209914A1-20041021-C00251
    Figure US20040209914A1-20041021-C00252
         		560.2387
    157
    Figure US20040209914A1-20041021-C00253
    Figure US20040209914A1-20041021-C00254
         		555.2666
    158
    Figure US20040209914A1-20041021-C00255
    Figure US20040209914A1-20041021-C00256
         		540.2548
    159
    Figure US20040209914A1-20041021-C00257
    Figure US20040209914A1-20041021-C00258
         		554.2698
    160
    Figure US20040209914A1-20041021-C00259
    Figure US20040209914A1-20041021-C00260
         		562.2378
    161
    Figure US20040209914A1-20041021-C00261
    Figure US20040209914A1-20041021-C00262
         		541.2488
    162
    Figure US20040209914A1-20041021-C00263
    Figure US20040209914A1-20041021-C00264
    163
    Figure US20040209914A1-20041021-C00265
    Figure US20040209914A1-20041021-C00266
         		593.2131
    164
    Figure US20040209914A1-20041021-C00267
    Figure US20040209914A1-20041021-C00268
         		578.1976
    165
    Figure US20040209914A1-20041021-C00269
    Figure US20040209914A1-20041021-C00270
         		592.2151
    166
    Figure US20040209914A1-20041021-C00271
    Figure US20040209914A1-20041021-C00272
         		600.1865
    167
    Figure US20040209914A1-20041021-C00273
    Figure US20040209914A1-20041021-C00274
         		579.1984
    168
    Figure US20040209914A1-20041021-C00275
    Figure US20040209914A1-20041021-C00276
         		543.2647
    169
    Figure US20040209914A1-20041021-C00277
    Figure US20040209914A1-20041021-C00278
         		528.2550
    170
    Figure US20040209914A1-20041021-C00279
    Figure US20040209914A1-20041021-C00280
         		542.2700
    171
    Figure US20040209914A1-20041021-C00281
    Figure US20040209914A1-20041021-C00282
         		550.2390
    172
    Figure US20040209914A1-20041021-C00283
    Figure US20040209914A1-20041021-C00284
         		529.2505
    173
    Figure US20040209914A1-20041021-C00285
    Figure US20040209914A1-20041021-C00286
         		539.2338
    174
    Figure US20040209914A1-20041021-C00287
    Figure US20040209914A1-20041021-C00288
         		567.2653
    175
    Figure US20040209914A1-20041021-C00289
    Figure US20040209914A1-20041021-C00290
         		560.2249
    176
    Figure US20040209914A1-20041021-C00291
    Figure US20040209914A1-20041021-C00292
         		544.2489
    177
    Figure US20040209914A1-20041021-C00293
    Figure US20040209914A1-20041021-C00294
         		559.2616
    178
    Figure US20040209914A1-20041021-C00295
    Figure US20040209914A1-20041021-C00296
         		587.2933
    179
    Figure US20040209914A1-20041021-C00297
    Figure US20040209914A1-20041021-C00298
         		580.2504
    180
    Figure US20040209914A1-20041021-C00299
    Figure US20040209914A1-20041021-C00300
         		546.1840
    181
    Figure US20040209914A1-20041021-C00301
    Figure US20040209914A1-20041021-C00302
         		569.2797
    182
    Figure US20040209914A1-20041021-C00303
    Figure US20040209914A1-20041021-C00304
         		542.2349
    183
    Figure US20040209914A1-20041021-C00305
    Figure US20040209914A1-20041021-C00306
         		578.1288
    184
    Figure US20040209914A1-20041021-C00307
    Figure US20040209914A1-20041021-C00308
         		607.2381
    185
    Figure US20040209914A1-20041021-C00309
    Figure US20040209914A1-20041021-C00310
         		573.1654
    186
    Figure US20040209914A1-20041021-C00311
    Figure US20040209914A1-20041021-C00312
         		564.1965
    187
    Figure US20040209914A1-20041021-C00313
    Figure US20040209914A1-20041021-C00314
         		576.2552
    188
    Figure US20040209914A1-20041021-C00315
    Figure US20040209914A1-20041021-C00316
         		556.2506
    189
    Figure US20040209914A1-20041021-C00317
    Figure US20040209914A1-20041021-C00318
         		568.2862
    190
    Figure US20040209914A1-20041021-C00319
    Figure US20040209914A1-20041021-C00320
         		590
    191
    Figure US20040209914A1-20041021-C00321
    Figure US20040209914A1-20041021-C00322
         		602.2935
    192
    Figure US20040209914A1-20041021-C00323
    Figure US20040209914A1-20041021-C00324
         		584.1298
    193
    Figure US20040209914A1-20041021-C00325
    Figure US20040209914A1-20041021-C00326
         		534.1860
    194
    Figure US20040209914A1-20041021-C00327
    Figure US20040209914A1-20041021-C00328
         		530.2332
    195
    Figure US20040209914A1-20041021-C00329
    Figure US20040209914A1-20041021-C00330
    196
    Figure US20040209914A1-20041021-C00331
    Figure US20040209914A1-20041021-C00332
         		580.2848
    197
    Figure US20040209914A1-20041021-C00333
    Figure US20040209914A1-20041021-C00334
         		594.3011
    198
    Figure US20040209914A1-20041021-C00335
    Figure US20040209914A1-20041021-C00336
         		608.3148
    199
    Figure US20040209914A1-20041021-C00337
    Figure US20040209914A1-20041021-C00338
         		608.3152
    200
    Figure US20040209914A1-20041021-C00339
    Figure US20040209914A1-20041021-C00340
         		582.2997
    201
    Figure US20040209914A1-20041021-C00341
    Figure US20040209914A1-20041021-C00342
         		598.296
    202
    Figure US20040209914A1-20041021-C00343
    Figure US20040209914A1-20041021-C00344
         		612.3124
    203
    Figure US20040209914A1-20041021-C00345
    Figure US20040209914A1-20041021-C00346
         		626.3276
    204
    Figure US20040209914A1-20041021-C00347
    Figure US20040209914A1-20041021-C00348
         		626.3268
    205
    Figure US20040209914A1-20041021-C00349
    Figure US20040209914A1-20041021-C00350
         		600.3107
    206
    Figure US20040209914A1-20041021-C00351
    Figure US20040209914A1-20041021-C00352
         		580.1822
    207
    Figure US20040209914A1-20041021-C00353
    Figure US20040209914A1-20041021-C00354
         		546.1850
    208
    Figure US20040209914A1-20041021-C00355
    Figure US20040209914A1-20041021-C00356
         		514.2382
    210
    Figure US20040209914A1-20041021-C00357
    Figure US20040209914A1-20041021-C00358
         		540.2539
    211
    Figure US20040209914A1-20041021-C00359
    Figure US20040209914A1-20041021-C00360
         		578.2106
    212
    Figure US20040209914A1-20041021-C00361
    Figure US20040209914A1-20041021-C00362
         		558.2667
    213
    Figure US20040209914A1-20041021-C00363
    Figure US20040209914A1-20041021-C00364
         		546.1847
    214
    Figure US20040209914A1-20041021-C00365
    Figure US20040209914A1-20041021-C00366
         		560.2012
    215
    Figure US20040209914A1-20041021-C00367
    Figure US20040209914A1-20041021-C00368
         		570.2608
    216
    Figure US20040209914A1-20041021-C00369
    Figure US20040209914A1-20041021-C00370
         		584.2755
    217
    Figure US20040209914A1-20041021-C00371
    Figure US20040209914A1-20041021-C00372
         		598.2953
    218
    Figure US20040209914A1-20041021-C00373
    Figure US20040209914A1-20041021-C00374
         		586
    219
    Figure US20040209914A1-20041021-C00375
    Figure US20040209914A1-20041021-C00376
         		598.1441
    220
    Figure US20040209914A1-20041021-C00377
    Figure US20040209914A1-20041021-C00378
         		578.1966
    221
    Figure US20040209914A1-20041021-C00379
    Figure US20040209914A1-20041021-C00380
         		548.1988
    222
    Figure US20040209914A1-20041021-C00381
    Figure US20040209914A1-20041021-C00382
         		528.2543
    223
    Figure US20040209914A1-20041021-C00383
    Figure US20040209914A1-20041021-C00384
         		593.2431
    224
    Figure US20040209914A1-20041021-C00385
    Figure US20040209914A1-20041021-C00386
         		578.2359
    225
    Figure US20040209914A1-20041021-C00387
    Figure US20040209914A1-20041021-C00388
         		564.2202
    226
    Figure US20040209914A1-20041021-C00389
    Figure US20040209914A1-20041021-C00390
         		614.3261
    227
    Figure US20040209914A1-20041021-C00391
    Figure US20040209914A1-20041021-C00392
         		614.2932
    228
    Figure US20040209914A1-20041021-C00393
    Figure US20040209914A1-20041021-C00394
         		656.3399
    229
    Figure US20040209914A1-20041021-C00395
    Figure US20040209914A1-20041021-C00396
    230
    Figure US20040209914A1-20041021-C00397
    Figure US20040209914A1-20041021-C00398
         		614.3273
    231
    Figure US20040209914A1-20041021-C00399
    Figure US20040209914A1-20041021-C00400
         		602.2901
    232
    Figure US20040209914A1-20041021-C00401
    Figure US20040209914A1-20041021-C00402
         		568.2876
    233
    Figure US20040209914A1-20041021-C00403
    Figure US20040209914A1-20041021-C00404
         		570.2970
    234
    Figure US20040209914A1-20041021-C00405
    Figure US20040209914A1-20041021-C00406
         		584.3166
    235
    Figure US20040209914A1-20041021-C00407
    Figure US20040209914A1-20041021-C00408
         		572.2787
    236
    Figure US20040209914A1-20041021-C00409
    Figure US20040209914A1-20041021-C00410
         		584.3161
    237
    Figure US20040209914A1-20041021-C00411
    Figure US20040209914A1-20041021-C00412
         		596.3014
    238
    Figure US20040209914A1-20041021-C00413
    Figure US20040209914A1-20041021-C00414
         		560.2437
    239
    Figure US20040209914A1-20041021-C00415
    Figure US20040209914A1-20041021-C00416
         		614.2883
    240
    Figure US20040209914A1-20041021-C00417
    Figure US20040209914A1-20041021-C00418
         		629.3014
    242
    Figure US20040209914A1-20041021-C00419
    Figure US20040209914A1-20041021-C00420
    243
    Figure US20040209914A1-20041021-C00421
    Figure US20040209914A1-20041021-C00422
         		622.2636
    244
    Figure US20040209914A1-20041021-C00423
    Figure US20040209914A1-20041021-C00424
         		616.3040
    245
    Figure US20040209914A1-20041021-C00425
    Figure US20040209914A1-20041021-C00426
         		602.2876
    246
    Figure US20040209914A1-20041021-C00427
    Figure US20040209914A1-20041021-C00428
         		600.3109
    247
    Figure US20040209914A1-20041021-C00429
    Figure US20040209914A1-20041021-C00430
         		586.2949
    248
    Figure US20040209914A1-20041021-C00431
    Figure US20040209914A1-20041021-C00432
         		572.2778
    249
    Figure US20040209914A1-20041021-C00433
    Figure US20040209914A1-20041021-C00434
         		570.3007
    250
    Figure US20040209914A1-20041021-C00435
    Figure US20040209914A1-20041021-C00436
         		606.2664
    252
    Figure US20040209914A1-20041021-C00437
    Figure US20040209914A1-20041021-C00438
         		580.2147
    253
    Figure US20040209914A1-20041021-C00439
    Figure US20040209914A1-20041021-C00440
         		587.2914
    254
    Figure US20040209914A1-20041021-C00441
    Figure US20040209914A1-20041021-C00442
         		554.5692
    256
    Figure US20040209914A1-20041021-C00443
    Figure US20040209914A1-20041021-C00444
         		541.1650
    257
    Figure US20040209914A1-20041021-C00445
    Figure US20040209914A1-20041021-C00446
         		574.2388
    258
    Figure US20040209914A1-20041021-C00447
    Figure US20040209914A1-20041021-C00448
         		543.2291
    259
    Figure US20040209914A1-20041021-C00449
    Figure US20040209914A1-20041021-C00450
         		500.2019
    260
    Figure US20040209914A1-20041021-C00451
    Figure US20040209914A1-20041021-C00452
         		514.2376
    261
    Figure US20040209914A1-20041021-C00453
    Figure US20040209914A1-20041021-C00454
         		516.1723
    262
    Figure US20040209914A1-20041021-C00455
    Figure US20040209914A1-20041021-C00456
         		518.2130
    263
    Figure US20040209914A1-20041021-C00457
    Figure US20040209914A1-20041021-C00458
         		514.2194
    264
    Figure US20040209914A1-20041021-C00459
    Figure US20040209914A1-20041021-C00460
         		518.2432
    265
    Figure US20040209914A1-20041021-C00461
    Figure US20040209914A1-20041021-C00462
         		514.2375
    266
    Figure US20040209914A1-20041021-C00463
    Figure US20040209914A1-20041021-C00464
         		530.1880
    267
    Figure US20040209914A1-20041021-C00465
    Figure US20040209914A1-20041021-C00466
         		532.2307
    268
    Figure US20040209914A1-20041021-C00467
    Figure US20040209914A1-20041021-C00468
         		528.2557
    269
    Figure US20040209914A1-20041021-C00469
    Figure US20040209914A1-20041021-C00470
         		516.2557
    270
    Figure US20040209914A1-20041021-C00471
    Figure US20040209914A1-20041021-C00472
         		518.1880
    271
    Figure US20040209914A1-20041021-C00473
    Figure US20040209914A1-20041021-C00474
         		536.1979
    272
    Figure US20040209914A1-20041021-C00475
    Figure US20040209914A1-20041021-C00476
         		498.2450
    273
    Figure US20040209914A1-20041021-C00477
    Figure US20040209914A1-20041021-C00478
         		512.2615
    274
    Figure US20040209914A1-20041021-C00479
    Figure US20040209914A1-20041021-C00480
         		532.2061
  • [0380]
    Figure US20040209914A1-20041021-C00481
    Ex-
    am-
    ple R K MS (ES) m/z
    275
    Figure US20040209914A1-20041021-C00482
    Figure US20040209914A1-20041021-C00483
         		578.2068
    276
    Figure US20040209914A1-20041021-C00484
    Figure US20040209914A1-20041021-C00485
         		594.2005
    277
    Figure US20040209914A1-20041021-C00486
    Figure US20040209914A1-20041021-C00487
         		578.2053
  • [0381]
    Figure US20040209914A1-20041021-C00488
    Example R MS (ES) m/z
    278
    Figure US20040209914A1-20041021-C00489
         		463.1704
    279
    Figure US20040209914A1-20041021-C00490
         		499.2304
    280
    Figure US20040209914A1-20041021-C00491
    281
    Figure US20040209914A1-20041021-C00492
         		495.4984
    282
    Figure US20040209914A1-20041021-C00493
         		479.1416
    283
    Figure US20040209914A1-20041021-C00494
         		572.2800
    284
    Figure US20040209914A1-20041021-C00495
         		539.2017
    285
    Figure US20040209914A1-20041021-C00496
         		489.2049
    286
    Figure US20040209914A1-20041021-C00497
         		477
    287
    Figure US20040209914A1-20041021-C00498
         		515
    288
    Figure US20040209914A1-20041021-C00499
         		483.1992
    289
    Figure US20040209914A1-20041021-C00500
         		503
    290
    Figure US20040209914A1-20041021-C00501
         		487
    291
    Figure US20040209914A1-20041021-C00502
         		487
    292
    Figure US20040209914A1-20041021-C00503
         		491
    293
    Figure US20040209914A1-20041021-C00504
         		503
    294
    Figure US20040209914A1-20041021-C00505
         		473
    295
    Figure US20040209914A1-20041021-C00506
         		509
    296
    Figure US20040209914A1-20041021-C00507
         		557
    297
    Figure US20040209914A1-20041021-C00508
         		557
    298
    Figure US20040209914A1-20041021-C00509
         		541
    299
    Figure US20040209914A1-20041021-C00510
         		491
    300
    Figure US20040209914A1-20041021-C00511
         		541
    301
    Figure US20040209914A1-20041021-C00512
         		501
    302
    Figure US20040209914A1-20041021-C00513
         		509
    303
    Figure US20040209914A1-20041021-C00514
         		501
    304
    Figure US20040209914A1-20041021-C00515
         		501
    305
    Figure US20040209914A1-20041021-C00516
         		517
    306
    Figure US20040209914A1-20041021-C00517
         		521
    307
    Figure US20040209914A1-20041021-C00518
         		505
    308
    Figure US20040209914A1-20041021-C00519
         		501
    309
    Figure US20040209914A1-20041021-C00520
         		559
    310
    Figure US20040209914A1-20041021-C00521
    311
    Figure US20040209914A1-20041021-C00522
         		499
    312
    Figure US20040209914A1-20041021-C00523
         		499
    313
    Figure US20040209914A1-20041021-C00524
         		515
    314
    Figure US20040209914A1-20041021-C00525
         		529
    315
    Figure US20040209914A1-20041021-C00526
         		516
    316
    Figure US20040209914A1-20041021-C00527
         		517
    317
    Figure US20040209914A1-20041021-C00528
    318
    Figure US20040209914A1-20041021-C00529
         		517
    319
    Figure US20040209914A1-20041021-C00530
    320
    Figure US20040209914A1-20041021-C00531
    321
    Figure US20040209914A1-20041021-C00532
    322
    Figure US20040209914A1-20041021-C00533
    323
    Figure US20040209914A1-20041021-C00534
    324
    Figure US20040209914A1-20041021-C00535
    325
    Figure US20040209914A1-20041021-C00536
    326
    Figure US20040209914A1-20041021-C00537
    327
    Figure US20040209914A1-20041021-C00538
    328
    Figure US20040209914A1-20041021-C00539
    329
    Figure US20040209914A1-20041021-C00540
    330
    Figure US20040209914A1-20041021-C00541
    331
    Figure US20040209914A1-20041021-C00542
    332
    Figure US20040209914A1-20041021-C00543
    333
    Figure US20040209914A1-20041021-C00544
    334
    Figure US20040209914A1-20041021-C00545
    335
    Figure US20040209914A1-20041021-C00546
    336
    Figure US20040209914A1-20041021-C00547
    337
    Figure US20040209914A1-20041021-C00548
    338
    Figure US20040209914A1-20041021-C00549
    339
    Figure US20040209914A1-20041021-C00550
    340
    Figure US20040209914A1-20041021-C00551
    341
    Figure US20040209914A1-20041021-C00552
    342
    Figure US20040209914A1-20041021-C00553
    343
    Figure US20040209914A1-20041021-C00554
    344
    Figure US20040209914A1-20041021-C00555
    345
    Figure US20040209914A1-20041021-C00556
    346
    Figure US20040209914A1-20041021-C00557
    437
    Figure US20040209914A1-20041021-C00558
    348
    Figure US20040209914A1-20041021-C00559
    349
    Figure US20040209914A1-20041021-C00560
    350
    Figure US20040209914A1-20041021-C00561
    351
    Figure US20040209914A1-20041021-C00562
    352
    Figure US20040209914A1-20041021-C00563
    353
    Figure US20040209914A1-20041021-C00564
    354
    Figure US20040209914A1-20041021-C00565
    355
    Figure US20040209914A1-20041021-C00566
    356
    Figure US20040209914A1-20041021-C00567
    357
    Figure US20040209914A1-20041021-C00568
    358
    Figure US20040209914A1-20041021-C00569
    359
    Figure US20040209914A1-20041021-C00570
    360
    Figure US20040209914A1-20041021-C00571
    361
    Figure US20040209914A1-20041021-C00572
    362
    Figure US20040209914A1-20041021-C00573
    363
    Figure US20040209914A1-20041021-C00574
    364
    Figure US20040209914A1-20041021-C00575
    365
    Figure US20040209914A1-20041021-C00576
    366
    Figure US20040209914A1-20041021-C00577
    367
    Figure US20040209914A1-20041021-C00578
    368
    Figure US20040209914A1-20041021-C00579
    369
    Figure US20040209914A1-20041021-C00580
    370
    Figure US20040209914A1-20041021-C00581
    371
    Figure US20040209914A1-20041021-C00582
    372
    Figure US20040209914A1-20041021-C00583
    373
    Figure US20040209914A1-20041021-C00584
    374
    Figure US20040209914A1-20041021-C00585
    375
    Figure US20040209914A1-20041021-C00586
         		581
    376
    Figure US20040209914A1-20041021-C00587
         		545.2320
    377
    Figure US20040209914A1-20041021-C00588
         		529.2383
    378
    Figure US20040209914A1-20041021-C00589
         		551.0854
    379
    Figure US20040209914A1-20041021-C00590
         		555.252
    380
    Figure US20040209914A1-20041021-C00591
         		569.2687
    381
    Figure US20040209914A1-20041021-C00592
         		569.2676
    382
    Figure US20040209914A1-20041021-C00593
         		543.2524
    383
    Figure US20040209914A1-20041021-C00594
    384
    Figure US20040209914A1-20041021-C00595
         		530.2315
    385
    Figure US20040209914A1-20041021-C00596
         		556.2482
    386
    Figure US20040209914A1-20041021-C00597
    387
    Figure US20040209914A1-20041021-C00598
    • Example 388 In Vitro Metalloprotease Inhibition
  • Several hydroxamates and salts thereof were assayed for MMP activity by an in vitro assay generally following the procedures outlined et al., [0382] FEBS Lett., 296(3), 263 (1992).
  • Recombinant human MMP-1, MMP-2, MMP-9, MMP-13, and were used in this assay. These enzymes were prepared in the Assignee's es following usual laboratory procedures. Specifics for preparing and e enzymes can be found in the scientific literature describing these See, e.g., [0383] Enzyme Nomenclature (Academic Press, San Diego, Calif., d the citations therein). See also, Frije et al., J Biol. Chem., 26(24), (1994).
  • The MMP-1 was obtained from MMP-1 expressing transfected HT-1080 cells provided by Dr. Harold Welgus of Washington University in St. Louis, Mo. The MMP-1 was activated using 4-aminophenylmercuric acetate (APMA), and then purified over a hydroxamic acid column. [0384]
  • The MMP-2 was obtained from MMP-2 expressing transfected cells provided by Dr. Gregory Goldberg of Washington University. [0385]
  • The MMP-9 was obtained from MMP-9 expressing transfected cells provided by Dr. Gregory Goldberd. [0386]
  • The MMP-13 was obtained as a proenzyme from a full-length cDNA clone using baculovirus, as described by V. A. Luckow, “Insect Cell Expression Technology,” [0387] Protein Engineering: Principles and Practice, pp. 183-218 (edited by J. L. Cleland et al., Wiley-Liss, Inc., 1996). The expressed proenzyme was first purified over a heparin agarose column, and then over a chelating zinc chloride column. The proenzyme was then activated by APMA for use in the assay. Further details on baculovirus expression systems may be found in, for example, Luckow et al., J. Virol., 67, 4566-79 (1993). See also, O'Reilly et al, Baculovirus Expression Vectors: A Laboratory Manual (W.H. Freeman and Co., New York, N.Y., 1992). See also, King et al., The Baculovirus Expression System: A Laboratory Guide (Chapman & Hall, London, England, 1992).
  • The enzyme substrate was a methoxycoumarin-containing polypeptide having the following sequence: [0388]
  • MCA-ProLeuGlyLeuDpaAlaArgNH[0389] 2
  • Here, “MCA” is methoxycoumarin and “Dpa” is 3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine. This substrate is commercially available from Baychem (Redwood City, Calif.) as product M-1895. [0390]
  • The subject hydroxamate (or salt thereof) was dissolved at various concentrations using 1% dimethyl sulfoxide (DMSO) in a buffer containing 100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl[0391] 2, and 0.05% polyethyleneglycol (23) lauryl ether at a pH of 7.5. These solutions were then compared to a control (which contained equal amount of DMSO/buffer solution, but no hydroxamate compound) using Microfluor™ White Plates (Dynatech, Chantilly, Va.). Specifically, The MMPs were activated with APMA or trypsin. Then the various hydroxamate/DMSO/buffer solutions were incubated in separate plates at room temperature with the activated MMP and 4 um of the MMP substrate. The control likewise was incubated at room temperature in separate plates with the MMP and 4 uM of the MMP substrate. In the absence of inhibitor activity, a fluorogenic peptide was cleaved at the gly-leu peptide bond of the substrate, separating the highly fluorogenic peptide from a 2,4-dinitrophenyl quencher, resulting in an increase of fluorescent intensity (excitation at 328 nm/emission at 415). Inhibition was measured as a reduction in fluorescent intensity as a function of inhibitor concentration using a Perkin Elmer (Norwalk, Conn.) L550 plate reader. The IC50's were then calculated from these measurements. The results are set forth in the following Table A.
    Inhibition Table A (nM)
    Example MMP-13 MMP-2 MMP-1
    Number IC50(nM) IC50(nM) IC50(nM)
    4 15.6 2,900 >10000
    5 15.6 2,900 >10000
    6 18.1 >10000 >10000
    7 18.0 4,500 >10000
    8 50.0 2,500 >10000
    9 12.2 5,600 >10000
    10 40.0 6,000 >10000
    11 37.0 2,700 >10000
    12 6.70 1,400 >10000
    13 31.6 3,500 >10000
    14 45.0 >10000 >10000
    15 28.0 5,500 >10000
    16 42.5 4,800 >10000
    17 70.0 7,000 >10000
    18 >10000 >10000 >10000
    19 90.0 10,000 >10000
    20 23.5 4,500 >10000
    21 6.00 1,600 >10000
    22 10.7 3,600 >10000
    23 6.40 1,600 >10000
    24 6.70 700 >10000
    25 4.00 445 >10000
    28 10.0 800 >10000
    29 20.0 4,500 >10000
    30 18.1 >10000 >10000
    31 15.8 2,100 >10000
    32 30.0 1,750 >10000
    33 67.4 6,000 67.4
    34 19.3 3,700 >10000
    35 26.8 900 >10000
    36 70.0 5,400 >10000
    37 82.5 >10000 >10000
    38 17.9 5,000 >10000
    39 19.0 1,050 >10000
    40 80.0 5,700 >10000
    41 11.4 6,000 >10000
    42 20.0 6,500 >10000
    44 40.0 5,700 >10000
    45 10.0 >10000 >10000
    46 20.0 2,000 >10000
    47 4.10 562 >10000
    48 0.2 0.3 3,000
    49 2.00 59.0 >10000
    50 50.0 5,000 >10000
    51 2.20 0.45 >10000
    52 32.6 900 >10000
    53 27.8 7,000 >10000
    58 28.8 900 >10000
    59 110 1,000 >10000
    60 11.4 1,200 >10000
    70 43.5 2,050 >10000
    72 80.0 10,000 >10000
    73 9.00 8,300 >10000
    74 76.9 10,000 >10000
    75 4.80 >10000 >10000
    76 32.7 2,700 >10000
    77 160 >10000 >10000
    78 70.0 >10000 >10000
    79 37.3 >10000 >10000
    80 70.0 >10000 >10000
    81 19.3 >10000 >10000
    82 20.0 7,300 >10000
    83 90.0 >10000 >10000
    84 105 >10000 >10000
    85 14.8 9,000 >10000
    86 13.8 >10000 >10000
    87 130 >10000 >10000
    88 19.3 9,000 >10000
    89 60.0 >10000 >10000
    90 150 >10000 >10000
    91 35.0 >10000 >10000
    92 50.0 >10000 >10000
    93 50.0 >10000 >10000
    95 100 >10000 >10000
    96 63.1 >10000 >10000
    97 59.1 >10000 >1,000
    98 50.0 >10000 >10000
    99 50.0 >10000 >10000
    100 34.9 >10000 >10000
    101 40.0 >10000 >10000
    102 30.6 9,000 >10000
    103 37.3 >10000 >10000
    104 90.0 >10000 >10000
    105 175 >10000 >10000
    106 115 >10000 >10000
    107 30.6 7,000 >10000
    108 28.6 >10000 >10000
    109 60.0 >10000 >10000
    110 40.0 >10000 >10000
    111 40.0 10,000 >10000
    112 48.5 >10000 >10000
    113 60.0 10,000 >10000
    114 120 >10000 >10000
    115 200 >10000 >10000
    116 77.0 >10000 >10000
    117 65.0 >10000 >10000
    118 420 >10000 >10000
    119 1.0 200 >10000
    120 0.85 126 >10000
    (an average of 2 (an average of 2
    experiments) experiments)
    121 0.1 58.8 >10000
    122 0.1 106.5
    123 0.1 46.3 >10000
    124 0.4 56.4 >10000
    126 11.1 400
    127 3.0 80.0
    128 5.5 230
    129 11.4 260
    130 3.0 700 >10000
    132 50.0 430
    133 1.7 16.1 >10000
    134 4.5 427 >10000
    135 0.5 8.0
    136 50.4 246 >10000
    137 0.7 4.5 >10000
    138 5.9 1500 >10000
    139 1.8 330 >10000
    140 18.1 800 >10000
    141 1.4 160 >10000
    142 6.0 420 >10000
    143 2.1 100 >10000
    145 210 2100 >10000
    146 4.0 200 >10000
    147 20.0 145 >10000
    148 2.9 80.0 >10000
    149 16.9 210 >10000
    151 1.3 127.6 >10000
    152 0.6 56.3 >10000
    153 0.2 30.6 >10000
    154 2.4 176.5 >10000
    155 1.4 43.8 >10000
    156 0.7 1335.9 >10000
    157 2.7 781.6 >10000
    158 2.4 217.8 >10000
    159 0.5 32.2
    160 0.4 197.5 >10000
    161 0.3 234.7
    162 2.7 494.6 >10000
    163 3.4 3231.9 >10000
    164 5.4 942.3 >10000
    165 85.9 1754
    166 438 >10000
    167 4.7 2949
    168 2.1 2181.2 >10000
    169 2.6 1061.7 >10000
    170 1.3 134.1 >10000
    171 1.9 405.4 >10000
    172 3.1 649.1
    173 0.9 117.3
    174 1.1 1069.1 >10000
    175 0.7 136.6 >10000
    176 0.4 122.3 >10000
    177 1.4 166.8
    178 3.0 1976.5
    179 0.7 161.3 >10000
    180 0.3 52.7 >10000
    181 2.3 935.7 >10000
    182 1.1 115.4 >10000
    183 0.7 37.9 >10000
    184 1.5 360.2 >10000
    185 5.1 87.4 >10000
    186 3.5 94.4 >10000
    187 2.7 242.4 >10000
    188 2.0 249.9 >10000
    189 <0.1 258 >10000
    190 0.2 23.1 >10000
    191 3.0 2286.9 >10000
    192 1.3 103.3 >10000
    193 0.4 98.7 >10000
    194 9.1 1229.7 >10000
    195 0.3 462.8 >10000
    196 1.0 750.1 >10000
    197 1.4 1720.1 >10000
    198 12.0 2565.6
    199 11.7 3390.0 >10000
    200 0.5 1398.8 >10000
    201 0.2 6315.4 >10000
    202 0.4 1017.6 >10000
    203 0.6 816.4 2367
    204 0.2 1045.8 >10000
    205 <0.1 411.5 >10000
    206 1.8 199.4 >10000
    207 1.1 4.4 >10000
    208 0.1 19.6 >10000
    210 1.1 13.1 >10000
    211 1.2 122.3 >10000
    212 0.2 109.7 >10000
    213 0.5 25.8 >10000
    214 1.7 159.8 >10000
    215 0.9 22.7 >10000
    216 1.5 46.4 >10000
    217 1.3 270.0 >10000
    218 0.2 75.7 >10000
    219 4.9 258.2 >10000
    220 1.7 289.8 >10000
    221 3.4 301.1 >10000
    222 1.0 196.6 >10000
    223 2.5 80.4 >10000
    224 0.4 72.9 >10000
    225 0.2 40.8 >10000
    226 <0.1 1024 >10000
    227 1.4 132.1 >10000
    228 19.5 154.6
    229 0.2 8.5 >10000
    230 0.1 745.0 >10000
    231 0.5 39.4 >10000
    232 1.3 624.4 >10000
    233 1.2 1046.1 >10000
    234 7.5 2444.7 >10000
    235 0.8 118.0 >10000
    236 1.5 1848.4 >10000
    237 2.1 1914.8 >10000
    238 1.8 62.1
    239 0.6 75.8
    240 2.8 86.0
    242 1.0 87.5
    243 0.3 56.0 >10000
    244 0.2 15.2
    245 1.1 38.6
    246 1.0 2712.9 >10000
    247 0.3 111.4 >10000
    248 0.6 141.0 >10000
    249 5.8 >10000 >10000
    250 2.1 107.2
    252 0.4 14.3
    253 1.7 38.7 >10000
    254 1.3 132.0 >10000
    256 7.5 35.4
    257
    258 14.1 45.4
    259 0.4 0.6
    260 0.4 1.2 >10000
    261 0.8 1.0
    262 1.0 1.7
    263 1.5 2.6 >10000
    264 0.8 3.1
    265 0.5 3.2
    266 1.7 4.5
    267 0.4 1.7 >10000
    268 1.2 5.0 >10000
    269 1.4 4.5 >10000
    270 1.1 1.9 >10000
    271 0.8 1.7 >10000
    272 1.3 5.9 >10000
    273 2.5 13.4
    274 2.1 5.2 >10000
    275 183.6 6736.9
    276 126.7 2733.4
    277 274.5 >10000
    279 160 3300 >10000
    280 27.1 500 >10000
    281 11.4 500 >10000
    282 0.7 2.0 >10000
    284 33.7 5400 >10000
    285 35.0 3100 >10000
    287 70.0 >10000 >10000
    288 4.4 60.7 >10000
    289 6.0 160 >10000
    290 0.4 82.0 >10000
    291 0.8 160 >10000
    292 3.2 35.0 >10000
    293 37.3 1400 >10000
    294 3.1 120 >10000
    295 28.6 300 >10000
    296 25.1 210 >10000
    297 15.8 250 >10000
    298 34.9 240 >10000
    299 9.4 106 >10000
    300 14.8 240 >10000
    301 37 3000 >10000
    302 1.9 35 >10000
    303 3.1 590 >10000
    304 1.6 270 >10000
    305 6.0 3300 >10000
    306 9.0 800 >10000
    307 0.9 145 >10000
    308 3.0 1280 >10000
    309 22.0 270 >10000
    310 6.0 4500 >10000
    311 3.7 700 >10000
    312 1.2 175 >10000
    313 3.0 445 >10000
    314 12.2 3700 >10000
    315 4.5 700 >10000
    316 2.0 700 >10000
    317 4.0 23.5 >10000
    318 5.7 130 >10000
    319 4.0 175 >10000
    320 2.3 10,000 >10000
    321 200 1400 >10000
    322 140 1400 >10000
    323 7.0 505 >10000
    324 11.3 70.0 >10000
    325 11.0 1750 >10000
    326 3.0 70.0 >10000
    327 5.0 4700 >10000
    328 4.5 186 >10000
    329 20.0 1800 ND
    330 — — ND
    331 1.2 250 ND
    332 1.3 120 ND
    333 3.7 600 >10000
    334 5.5 440 ND
    335 2.7 1500 >10000
    336 2.0 34.9 ND
    337 1.7 40.0 ND
    338 — — ND
    339 — — ND
    340 16.5 10,000 >10000
    341 — — ND
    342 2.0 76.9 ND
    374 5.6 970 >10000
    375 34.4 2663
    376 6.4 2185.4 >10000
    377 0.4 361.4 >10000
    378 0.3 28.4 >10000
    379 0.6 1266.4 >10000
    380 9.7 2287.6 >10000
    381 3.5 639.9 >10000
    382 0.3 1305.4 >10000
    383 36.9 382.4
    384 2.9 52.9
    385 3.2 34.6
    386 15.2 1901.1
    387 4.5 344.4
    • Example 389 In Vivo Angiogenesis Assay
  • The study of angiogenesis depends on a reliable and reproducible model for the stimulation and inhibition of a neovascular response. The corneal micropocket assay provides such a model of angiogenesis in the cornea of a mouse. See, [0392] A Model of Angiogenesis in the Mouse Cornea; Kenyon, B M, et al., Investigative Ophthalmology & Visual Science, July 1996, Vol. 37, No. 8.
  • In this assay, uniformly sized Hydron™ pellets containing bFGF and sucralfate were prepared and surgically implanted into the stroma mouse cornea adjacent to the temporal limbus. The pellets were formed by making a suspension of 20 μL sterile saline containing 10 μg recombinant bFGF, 10 mg of sucralfate and 10 μL of 12 percent Hydron™ in ethanol. The slurry was then deposited on a 10×10 mm piece of sterile nylon mesh. After drying, the nylon fibers of the mesh were separated to release the pellets. [0393]
  • The corneal pocket is made by anesthetizing a 7 week old C57Bl/6 female mouse, then proptosing the eye with ajeweler's forceps. Using a dissecting microscope, a central, intrastromal linear keratotomy of approximately 0.6 mm in length is performed with a #15 surgical blade, parallel to the insertion of the lateral rectus muscle. Using a modified cataract knife, a lamellar micropocket is dissected toward the temporal limbus. The pocket is extended to within 1.0 mm of the temporal limbus. A single pellet was placed on the corneal surface at the base of the pocket with a jeweler's forceps. The pellet was then advanced to the temporal end of the pocket. Antibiotic ointment was then applied to the eye. [0394]
  • Mice were dosed on a daily basis for the duration of the assay. Dosing of the animals was based on bioavailability and overall potency of the compound. an exemplary dose was 10 or 50 mg/kg (mpk) bid, po. Neovascularization of the corneal stroma begins at about day three and was permitted to continue under the influence of the assayed compound until day five. At day five, the degree of angiogenic inhibition was scored by viewing the neovascular progression with a slit lamp microscope. [0395]
  • The mice were anesthetized and the studied eye was once again proptosed. The maximum vessel length of neovascularization, extending from the limbal vascular plexus toward the pellet was measured. In addition, the contiguous circumferential zone of neovascularization was measured as clock hours, where 30 degrees of arc equals one clock hour. The area of angiogenesis was calculated as follows. [0396] area = ( 0.4 × clock   hours × 3.14 × vessel   length   ( in   mm ) ) 2
    Figure US20040209914A1-20041021-M00001
  • Five to six mice were utilized for each compound in each study. The studied mice were thereafter compared to control mice and the difference in the area of neovascularization was recorded as an averaged value. Each group of mice so studied constitutes an “n” value of one, so that “n” values greater than one represent multiple studies whose averaged result is provided in the table. A contemplated compound typically exhibits about 25 to about 75 percent inhibition, whereas the vehicle control exhibits zero percent inhibition. [0397]
    • Example 390 In Vivo PC-3 Tumor Reduction
  • PC-3 human pancreatic cancer eclls (ATCC CRL 1435) were grown to 90% confluence in F12/MEM (Gibco) containing 7% FBS (Gibco). Cells were mechanically harvested using a rubber scraper, and then washed twice with cold medium. The resulting cells were resuspended in cold medium with 30% matrigel (Collaborative Research) and the cell-containing medium was maintained on ice until used. [0398]
  • Balb/c nu/nu mice at 7-9 weeks of age were anesthetized with avertin [2,2,2-tribromethanol/t-amyl alcohol (1 g/1 mL) diluted 1:60 into phosphate-buffered sline] and 3-5×10[0399] 6 of the above cells in 0.2 mL of medium were injected into the left flank of each mouse. Cells were injected in the morning, whereas dosing with an inhibitor began at 6 PM. The animals were gavaged BID from day zero (cell injection day) to day 25-30, at which time the animals were euthanized and tumors weighed.
  • Compounds were dosed at 10 mg/mL in 0.5% methylcellulose/0.1% polysorbate 80 to provide a 50 mg/kg (mpk) dose twice each day, or diluted to provide a 10 mg/kg (mpk) dose twice each day. Tumor measurements began on day 7 and continued every third or fourth day until completion of the study. Groups of ten mice were used in each study and nine to ten survived. Each group of mice so studied constitutes an “n” value of one, so that “n” values greater than one represent multiple studies whose averaged result is provided in the table. [0400]
    • Example 391 Tumor Necrosis Factor Assays
  • Cell Culture. [0401]
  • The cells used in the assay are the human moncytic line U-937 (ATCC CRL-1593). The cells are grown in RPMI w/10% FCS and PSG supplement (R-10) and are not permitted to overgrow. The assay is carried out as follows: [0402]
  • 1. Count, then harvest cells by centrifugation. Resuspend the pellet in R-10 supplement to a concentration of 1.540×10[0403] 6 cells/mL.
  • 2. Add test compound in 65 uL R-10 to the appropriate wells of a 96-well flat bottom tissue culture plate. The initial dilution from a DMSO stock (100 mM compound) provides a 400 uM solution, from which five additional three-fold serial dilutions are made. Each dilution of 65 ul (in triplicate) yields final compound test concentrations of 100 μM, 33.3 μM, 11.1 μM, 3.7 μM, 1.2 μM and 0.4 μM. [0404]
  • 3. The counted, washed and resuspended cells (200,000 cells/well) in 130 μL are added to the wells. [0405]
  • 4. Incubation is for 45 min to 1 hr at 37° C. in 5% CO[0406] 2 in a water saturated container.
  • 5. R-10 (65 uL) containing 160 ng/mL PMA (Sigma) is added to each well. [0407]
  • 6. The test system is incubated at 37° C. in 5% CO[0408] 2 overnight (18-20 hr) under 100% humidity.
  • 7. Supernatant, 150 μL, is carefully removed from each well for use in the ELISA assay. [0409]
  • 8. For toxicity, a 50 μL aliquot of working solution containg 5 mL R-10, 5 mL MTS solution [CellTiter 96 AQueous One Solution Cell Proliferation Assay Cat.#G358/0,1 (Promega Biotech)] and 250 ul PMS solution are added to each well containing the remaining supernatant and cells and the cells incubated at 37° C. in 5% CO[0410] 2 until the color develops. The system is excited at 570 nm and read at 630 nm.
  • TNF Receptor II ELISA Assay [0411]
  • 1. Plate 100 μL/well 2 μg/mL mouse anti-human TNFrII antibody (R&D Systems #MAB226) in 1×PBS (pH 7.1, Gibco) on NUNC-Immuno Maxisorb plate. Incubate the plate at 4° C. overnight (about 18-20 hr). [0412]
  • 2. Wash the plate with PBS-Tween (1×PBS w/0.05% Tween). [0413]
  • 3. Add 200 μL 5% BSA in PBS and block at 37° C. in a water saturated atmosphere for 2 hr. [0414]
  • 4. Wash the plate with PBS-Tween. [0415]
  • 5. Add sample and controls (100 ul of each) to each well. The standards are 0, 50, 100, 200, 300 and 500 pg recombinant human TNFrII (R&D Systems #226-B2) in 100 μL 0.5% BSA in PBS. The assay is linear to between 400-500 pg of standard. [0416]
  • 6. Incubate at 37° C. in a saturated atmosphere for 1.5 hr. [0417]
  • 7. Wash the plate with PBS-Tween. [0418]
  • 8. Add 100 μL goat anti-human TNFrII polyclonal (1.5 μg/mL R&D Systems #AB226-PB in 0.5% BSA in PBS). [0419]
  • Incubate at 37° C. in a saturated atmosphere for 1 hr. [0420]
  • 10. Wash the plate with PBS-Tween. [0421]
  • 11. Add 100 μL anti-goat IgG-peroxidase (1:50,000 in 0.5% BSA in PBS, Sigma #A5420). [0422]
  • 11. Incubate at 37° C. in a saturated atmosphere for 1 hr. [0423]
  • 12. Wash the plate with PBS-Tween. [0424]
  • 13. Add 10 μL KPL TMB developer, develop at room temperature (usually about 10 min); then terminate with phosphoric acid and excite at 450 nm and read at 570 nm. [0425]
  • TNFα ELISA Assay. [0426]
  • Coat Immulon® 2 plates with 0.1 mL/well of lug/mL Genzyme mAb in 0.1 M NaHCO3 pH 8.0 buffer overnight (about 18-20 hr) at 4° C., wrapped tightly in Saran® wrap. [0427]
  • Flick out coating solution and block plates with 0.3 mL/well blocking buffer overnight at 4° C., wrapped in Saran® wrap. [0428]
  • Wash wells thoroughly 4× with wash buffer and completely remove all wash buffer. Add 0.1 mL/well of either samples or rhTNFα standards. Dilute samples if necessary in appropriate diluant (e.g. tissue culture medium). Dilute standard in same diluant. Standards and samples should be in triplicates. [0429]
  • Incubate at 37° C. for 1 hr in humified container. [0430]
  • Wash plates as above. Add 0.1 mL/well of 1:200 dilution of Genzyme rabbit anti-hTNFa. [0431]
  • Repeat incubation. [0432]
  • Repeat wash. Add 0.1 mL/well of 1 μg/mL Jackson goat anti-rabbit IgG (H+L)-peroxidase. [0433]
  • Incubate at 37° C. for 30 min. [0434]
  • Repeat wash. Add 0.1 mL/well of peroxide-ABTS solution. [0435]
  • Incubate at room temperature for 5-20 min. [0436]
  • Read OD at 405 nm. [0437]
  • 12 Reagents are: [0438]
  • Genzyme mouse anti-human TNF? monoclonal (Cat.# 80-3399-01) [0439]
  • Genzyme rabbit anti-human TNF? polyclonal (Cat.#IP-300) [0440]
  • Genzyme recombinant human TNF? (Cat.#TNF-H). [0441]
  • Jackson Immunoresearch peroxide-conjugated goat anti-rabbit IgG (H+L) (Cat.#111-035-144). [0442]
  • Kirkegaard/Perry peroxide ABTS solution (Cat#50-66-01). [0443]
  • Immulon 2 96-well microtiter plates. [0444]
  • Blocking solution is 1 mg/mL gelatin in PBS with 1× thimerasol. [0445]
  • Wash buffer is 0.5 mL Tween® 20 in 1 liter of PBS. [0446]
    • Example 392 In Vitro Aggrecanase Inhibition Assay
  • Assays for measuring the potency (IC[0447] 50) of a compound toward inhibiting aggrecanase are known in the art.
  • One such assay, for example, has been reported in European Patent Application Publ. No. EP 1 081 137 A1. In that assay, primary porcine chondrocytes from articular joint cartilage are isolated by sequential trypsin and collagenase digestion followed by collagenase digestion overnight and are plated at 2×10[0448] 5 cells per well into 48 well plates with 5 μCi/ml35S (1000 Ci/mmol) sulphur in type 1 collagen coated plates. Cells are allowed to incorporate label into their proteoglycan matrix (approximately 1 week) at 37° C. under an atmosphere of 5% CO2. The night before initiating the assay, chondrocyte monolayers are washed 2 times in DMEM/1% PSF/G and then allowed to incubate in fresh DMEM/1% FBS overnight. The next morning, chondrocytes are washed once in DMEM/1% PSF/G. The final wash is allowed to sit on the plates in the incubator while making dilutions. Media and dilutions are made as described in the following Table C:
    TABLE C
    control media DMEM alone
    IL-1 media DMEM + IL-1 (5 ng/ml)
    drug dilutions Make all compound stocks at 10 mM in DMSO.
    Make a 100 μM stock of each compound in DMEM
    in 96-well plate. Store in freezer overnight.
    The next day, perform serial dilutions in DMEM
    with IL-1 to 5 μM, 500 nM, and 50 nM.
    Aspirate final wash from wells and add 50 μM of
    compound from above dilutions to 450 μL of IL-1 media
    in appropriate wells of the 48 well plates.
    Final compound concentrations
    equal 500 nM, 50 nM, and 5 nM.
    All samples completed in triplicate
    with control and IL-1 alone on each plate.
  • Plates are labeled and only the interior 24 wells of the plate are used. On one of the plates, several columns are designated as IL-1 (no drug) and control (no IL-1, no drug). These control columns are periodically counted to monitor 35S-proteoglycan release. Control and IL-1 media are added to wells (450/L) followed by compound (50 μL) so as to initiate the assay. Plates are incubated at 37° C. with 5% CO[0449] 2 atmosphere. At 40-50% release (when CPM from IL-1 media is 4-5 times control media) as assessed by liquid scintillation counting (LSC) of media samples, the assay is terminated (about 9 to about 12 hours). Media is removed from all wells and placed into scintillation tubes. Scintillate is added and radioactive counts are acquired (LSC). To solubilize cell layers, 500 μL of papain digestion buffer (0.2 M Tris, pH 7.0, 5 mM DTT, and 1 mg/ml papain) is added to each well. Plates with digestion solution are incubated at 60° C. overnight. The cell layer is removed from the plates the next day and placed in scintillation tubes. Scintillate is then added, and samples counted (LSC). The percent of released counts from the total present in each well is determined. Averages of the triplicates are made with control background subtracted from each well. The percent of compound inhibition is based on IL-1 samples as 0% inhibition (100% of total counts).
  • Another assay for measuring aggrecanase inhibition has been reported in WIPO Int'l Publ. No. WO 00/59874. That assay reportedly uses active aggrecanase accumulated in media from stimulated bovine cartilage (BNC) or related cartilage sources and purified cartilage aggrecan monomer or a fragment thereof as a substrate. Aggrecanase is generated by stimulation of cartilage slices with interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), or other stimuli. To accumulate BNC aggrecanase in culture media, cartilage reportedly is first depleted of endogenous aggrecan by stimulation with 500 ng/ml human recombinant IL-β for 6 days with media changes every 2 days. Cartilage is then stimulated for an additional 8 days without media change to allow accumulation of soluble, active aggrecanase in the culture media. To decrease the amounts of matrix metalloproteinases released into the media during aggrecanase accumulation, agents which inhibit MMP-1, -2, -3, and -9 biosynthesis are included during stimulation. This BNC conditioned media containing aggrecanase activity is then used as the source of aggrecanase for the assay. Aggrecanase enzymatic activity is detected by monitoring production of aggrecan fragments produced exclusively by cleavage at the Glu373-Ala374 bond within the aggrecan core protein by Western analysis using the monoclonal antibody, BC-3 (Hughes, et al., Biochem J, 306:799-804 (1995)). This antibody reportedly recognizes aggrecan fragments with the N-terminus, 374ARGSVIL, generated upon cleavage by aggrecanase. The BC-3 antibody reportedly recognizes this neoepitope only when it is at the N-terminus and not when it is present internally within aggrecan fragments or within the aggrecan protein core. Only products produced upon cleavage by aggrecanase reportedly are detected. Kinetic studies using this assay reportedly yield a Km of 1.5+/−0.35 μM for aggrecanase. To evaluate inhibition of aggrecanase, compounds are prepared as 10 mM stocks in DMSO, water, or other solvents and diluted to appropriate concentrations in water. Drug (50/L) is added to 50 μL of aggrecanase-containing media and 50 μL of 2 mg/ml aggrecan substrate and brought to a final volume of 200 mL in 0.2 M Tris, pH 7.6, containing 0.4 M NaCl and 40 mM CaCl[0450] 2. The assay is run for 4 hr at 37° C., quenched with 20 mM EDTA, and analyzed for aggrecanase-generated products. A sample containing enzyme and substrate without drug is included as a positive control and enzyme incubated in the absence of substrate serves as a measure of background. Removal of the glycosaminoglycan side chains from aggrecan reportedly is necessary for the BC-3 antibody to recognize the ARGSVIL epitope on the core protein. Therefore, for analysis of aggrecan fragments generated by cleavage at the Glu373-Ala374 site, proteoglycans and proteoglycan fragments are enzymatically deglycosylated with chondroitinase ABC (0.1 units/110 g GAG) for 2 hr at 37° C. and then with keratanase (0.1 units/110 g GAG) and keratanase II (0.002 units/10 g GAG) for 2 hr at 37° C. in buffer containing 50 mM sodium acetate, 0.1 M Tris/HCl, pH 6.5. After digestion, aggrecan in the samples is precipitated with 5 volumes of acetone and resuspended in 30 μL of Tris glycine SDS sample buffer (Novex) containing 2.5% beta mercaptoethanol. Samples are loaded and then separated by SDS-PAGE under reducing conditions with 4-12% gradient gels, transferred to nitrocellulose and immunolocated with 1:500 dilution of antibody BC3. Subsequently, membranes are incubated with a 1:5000 dilution of goat anti-mouse IgG alkaline phosphatase second antibody and aggrecan catabolites visualized by incubation with appropriate substrate for 10-30 minutes to achieve optimal color development. Blots are quantitated by scanning densitometry and inhibition of aggrecanase determined by comparing the amount of product produced in the presence versus absence of compound.
  • The above detailed description of preferred embodiments is intended only to acquaint others skilled in the art with the invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This invention, therefore, is not limited to the above embodiments, and may be variously modified. [0451]

Claims (74)

1. A compound or a salt thereof, wherein:
the compound corresponds in structure to the Formula X:
Figure US20040209914A1-20041021-C00599
E is selected from the group consisting of a bond, —C(O)—, and —S—;
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, heterocyclyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein:
the aryl, heteroaryl, arylalkyl, or heterocyclyl optionally is substituted with up to 2 substituents independently selected from the group consisting of alkylcarbonyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein:
the amino nitrogen optionally is substituted with up to 2 substituents independently selected from the group consisting of alkyl and arylalkyl; and
R is selected from the group consisting of hydrogen, cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, arylalkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, arylalkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroarylalkyl, cycloalkyl, heterocylyloxy, heterocylylthio, heterocylylamino, cycloalkyloxy, cycloalkylthio, heteroarylalkoxy, heteroarylalkylthio, arylalkoxy, arylalkylthio, arylalkylamino, heterocylyl, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylcarbonyloxy, arylalkylcarbonyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino, aminocarbonyl, and aminoalkyl, wherein:
the amino nitrogen optionally is substituted with:
up two substituents that are independently selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, arylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, and alkylcarbonyl, or
two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that:
contains from zero to two additional heteroatoms that are independently selected from the group consisting of nitrogen, oxygen, and sulfur,
optionally is substituted with up to two substituents independently selected from the group consisting of aryl, alkyl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, alkylcarbonyl, cycloalkyl, heterocylylalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocylylalkyl, hydroxyalkoxyalkyl, arylalkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocylylalkoxy, benzofused cycloalkylcarbonyl, heterocyclylalkylcarbonyl, and cycloalkylcarbonyl,
the aminocarbonyl nitrogen is:
unsubstituted,
the reacted amine of an amino acid,
substituted with one or two substituents independently selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroarylalkyl, cycloalkyl, arylalkyl, trifluoromethylalkyl, heterocylylalkyl, benzofused heterocylylalkyl, benzofused cycloalkyl, and N,N-dialkylsubstituted alkylamino-alkyl, or
substituted with two substituents such that the two substituents, together with the aminocarbonyl nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that optionally is substituted with up to two substituents independently selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocylylalkyl, hydroxy, hydroxycarbonyl, aryl, arylalkyl, heteroaralkyl, and amino, wherein the amino nitrogen optionally is substituted with:
two substituents independently selected from the group consisting of alkyl, aryl, and heteroaryl; or
two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring, and
the aminoalkyl nitrogen optionally is substituted with:
up to two substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, and alkylcarbonyl, or
two substituents such that the two substituents, together with the aminoalkyl nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring.
2. A compound or salt according to claim 1, wherein R is halo.
3. A compound or salt according to claim 1, wherein the compound corresponds in structure to Formula XA:
Figure US20040209914A1-20041021-C00600
4. A compound or salt according to claim 3, wherein the salt is a pharmaceutically acceptable salt.
5. A compound or salt according to claim 3, wherein Y is selected from the group consisting of aryl, arylalkyl, cycloalkyl, heteroaryl, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, heterocyclyl, and cycloalkyl, wherein:
the aryl, heteroaryl, arylalkyl, or heterocyclyl optionally is substituted with up to 2 substituents independently selected from the group consisting of alkylcarbonyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein:
the amino nitrogen optionally is substituted with up to 2 substituents independently selected from the group consisting of alkyl and arylalkyl.
6. A compound or salt according to claim 3, wherein E is a bond.
7. A compound or salt according to claim 3, wherein E is —C(O)—.
8. A compound or salt according to claim 3, wherein E is —S—.
9-13 (canceled)
14. A compound or a salt thereof, wherein:
the compound corresponds in structure to Formula X:
Figure US20040209914A1-20041021-C00601
E is selected from the group consisting of a bond, —C(O)—, and —S—; and
Y is selected from the group consisting of cycloalkyl, 2,3-dihydroindolyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein:
any such substituent optionally is substituted with one or more optionally substituted substituents independently selected from the group consisting of halogen, hydroxy, keto, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkoxy, alkylcarbonyl, haloalkoxy, alkylthio, alkoxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkoxy, cycloalkylalkoxyalkyl, aryl, arylalkyl, arylalkoxy, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylcarbonyl, heterocyclylcarbonylalkyl, alkylsulfonyl, amino, aminoalkyl, and aminocarbonyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylcarbonyl, and
the nitrogen of the amino, aminoalkyl, or aminocarbonyl optionally is substituted with up to two substituents independently selected from the group consisting of alkyl and cycloalkylalkyl; and
R is selected from the group consisting of hydrogen and halogen.
15. A compound or salt according to claim 14, wherein the compound corresponds in structure to Formula XA:
Figure US20040209914A1-20041021-C00602
16-25 (canceled).
26. A compound or salt according to claim 15, wherein E is —C(O)—.
27-28 (canceled).
29. A compound or salt according to claim 26, wherein:
Y is selected from the group consisting of heterocyclyl, aryl, heteroaryl, and arylmethyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, halo-C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-cycloalkyl, aryl, aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, heterocyclyl, heterocyclyl-C1-C6-alkyl, heteroaryl, heteroarylcarbonyl, heterocyclylcarbonyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and C1-C6-alkylcarbonyl, and
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl and C3-C6-cycloalkyl-C1-C6-alkyl.
30. A compound or salt according to claim 29, wherein Y is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, halo-C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-cycloalkyl, aryl, aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, heterocyclyl, heterocyclyl-C1-C6-alkyl, heteroaryl, heteroarylcarbonyl, heterocyclylcarbonyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and C1-C6-alkylcarbonyl, and
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl and C3-C6-cycloalkyl-C1-C6-alkyl.
31. A compound or salt according to claim 29, wherein Y is thienyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, halo-C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-cycloalkyl, aryl, aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, heterocyclyl, heterocyclyl-C1-C6-alkyl, heteroaryl, heteroarylcarbonyl, heterocyclylcarbonyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and C1-C6-alkylcarbonyl, and
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl and C3-C6-cycloalkyl-C1-C6-alkyl.
32-33 (canceled).
34. A compound or salt according to claim 26, wherein:
Y is selected from the group consisting of aryl, heteroaryl, arylmethyl, and heteroarylmethyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl-C1-C6-alkyl, C3-C6-cycloalkyloxy, C3-C6-cycloalkyl-C1-C6-alkoxy, C3-C6-cycloalkyl-C1-C6-alkoxy-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl.
35. A compound or salt according to claim 34, wherein Y is phenyl or phenylmethyl, wherein:
the phenyl or phenylmethyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl-C1-C6-alkyl, C3-C6-cycloalkyloxy, C3-C6-cycloalkyl-C1-C6-alkoxy, C3-C6-cycloalkyl-C1-C6-alkoxy-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl.
36-40 (canceled).
41. A compound or salt according to claim 34, wherein Y is thienyl or thienylmethyl, wherein:
the thienyl or thienylmethyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl-C1-C6-alkyl, C3-C6-cycloalkyloxy, C3-C6-cycloalkyl-C1-C6-alkoxy, C3-C6-cycloalkyl-C1-C6-alkoxy-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl.
42-46 (canceled).
47. A compound or salt according to claim 15, wherein E is a bond.
48-49 (canceled).
50. A compound or salt according to claim 47, wherein:
Y is selected from the group consisting of aryl, 2,3-dihydroindolyl, heterocyclyl, and heteroaryl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, keto, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, aryl, aminocarbonyl, and C1-C6-alkylsulfonyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy, and
the nitrogen of the aminocarbonyl optionally is substituted with up to 2 substituents independently selected from the group consisting of C1-C6-alkyl.
51. A compound or salt according to claim 50, wherein Y is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, keto, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, aryl, aminocarbonyl, and C1-C6-alkylsulfonyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy, and
the nitrogen of the aminocarbonyl optionally is substituted with up to 2 substituents independently selected from the group consisting of C1-C6-alkyl.
52. A compound or salt according to claim 47, wherein:
Y is selected from the group consisting of heteroaryl, aryl, and heterocyclyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-alkoxy, and aryl, wherein:
the aryl optionally is substituted with one or more substituents independently selected from the group consisting of halo-C1-C6-alkyl.
53. A compound or salt according to claim 50, wherein Y is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-alkoxy, and aryl, wherein:
the aryl optionally is substituted with one or more substituents independently selected from the group consisting of halo-C1-C6-alkyl.
54. A compound or salt according to claim 15, wherein E is —S—.
55-56 (canceled).
57. A compound or salt according to claim 54, wherein:
Y is selected from the group consisting of cycloalkyl, aryl, arylmethyl, and heteroaryl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy.
58. A compound or salt according to claim 54, wherein:
Y is heteroaryl.
59. A method for treating a pathological condition in an animal, wherein:
the method comprises administering a compound recited in claim 1 (or a pharmaceutically acceptable salt thereof) to the animal in an amount effective to treat the condition;
the condition is treatable by inhibiting matrix metalloprotease activity; and
the condition is selected from the group consisting of tissue destruction, a fibrotic disease, matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, and a central nervous system disease.
60. A method according to claim 59, wherein the compound corresponds in structure to Formula XA:
Figure US20040209914A1-20041021-C00603
61. A method according to claim 59, wherein the condition is selected from the group consisting of osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermolysis bullosa, aortic aneurysm, weak injury repair, an adhesion, scarring, congestive heart failure, coronary thrombosis, emphysema, proteinuria, and Alzheimer's disease.
62. A method according to claim 59, wherein the condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, septic arthritis, corneal ulceration, epidermal ulceration, gastric ulceration, tumor metastasis, tumor invasion, tumor angiogenesis, periodontal disease, proteinuria, Alzheimer's disease, coronary thrombosis, bone disease, and defective injury repair.
63 (canceled).
64. A method for treating a pathological condition in an animal, wherein:
the condition is treatable by inhibiting matrix metalloprotease-2, matrix metalloprotease-9, and/or matrix metalloprotease-13 activity; and
the method comprising administering a compound recited in claim 1 (or a pharmaceutically-acceptable salt thereof) to the animal in an amount effective to inhibit matrix metalloprotease-2, matrix metalloprotease-9, and/or matrix metalloprotease-13.
65. A method according to claim 64, wherein the compound corresponds in structure to Formula XA:
Figure US20040209914A1-20041021-C00604
66. A method according to claim 64, wherein the compound inhibits matrix metalloprotease-13 selectively over both matrix metalloprotease-1 and matrix metalloprotease-14.
67-68 (canceled).
69. A method for treating a pathological condition in an animal, wherein:
the method comprises administering a compound recited in claim 1 (or a pharmaceutically-acceptable salt thereof) to the animal in an amount effective to or treat the condition, and
the condition is treatable by inhibiting with TNF-α convertase activity.
70-71 (canceled).
72. A method for treating a pathological condition in an animal, wherein:
the condition is treatable by inhibiting aggrecanase activity; and
the method comprises administering a compound of claim 1 (or a pharmaceutically-acceptable salt thereof) to the animal in an amount effective to or treat the condition.
73. A method according to claim 72, wherein the compound corresponds in structure to Formula XA:
Figure US20040209914A1-20041021-C00605
74-78 (canceled).
79. A method for treating a pathological condition in an animal, wherein:
the method comprises administering a compound recited in claim 14 (or a pharmaceutically acceptable salt thereof) to the animal in an amount effective to treat the condition;
the condition is treatable by inhibiting matrix metalloprotease activity; and
the condition is selected from the group consisting of tissue destruction, a fibrotic disease, matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, and a central nervous system disease.
80. A method according to claim 79, wherein the compound corresponds in structure to Formula XA:
Figure US20040209914A1-20041021-C00606
81. A method according to claim 79, wherein Y is selected from the group consisting of heterocyclyl, aryl, heteroaryl, and arylmethyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, halo-C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-cycloalkyl, aryl, aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, heterocyclyl, heterocyclyl-C1-C6-alkyl, heteroaryl, heteroarylcarbonyl, heterocyclylcarbonyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and C1-C6-alkylcarbonyl, and
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl and C3-C6-cycloalkyl-C1-C6-alkyl.
82. A method according to claim 79, wherein Y is selected from the group consisting of aryl, heteroaryl, arylmethyl, and heteroarylmethyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl-C1-C6-alkyl, C3-C6-cycloalkyloxy, C3-C6-cycloalkyl-C1-C6-alkoxy, C3-C6-cycloalkyl-C1-C6-alkoxy-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl.
83. A method according to claim 79, wherein the condition is selected from the group consisting of osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermolysis bullosa, aortic aneurysm, weak injury repair, an adhesion, scarring, congestive heart failure, coronary thrombosis, emphysema, proteinuria, and Alzheimer's disease.
84. A method for treating a pathological condition in an animal, wherein:
the condition is treatable by inhibiting matrix metalloprotease-2, matrix metalloprotease-9, and/or matrix metalloprotease-13 activity; and
the method comprising administering a compound recited in claim 14 (or a pharmaceutically-acceptable salt thereof) to the animal in an amount effective to inhibit matrix metalloprotease-2, matrix metalloprotease-9, and/or matrix metalloprotease-13.
85. A method according to claim 84, herein the compound corresponds in structure to Formula XA:
Figure US20040209914A1-20041021-C00607
86. A method according to claim 84, wherein Y is selected from the group consisting of heterocyclyl, aryl, heteroaryl, and arylmethyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, halo-C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-cycloalkyl, aryl, aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, heterocyclyl, heterocyclyl-C1-C6-alkyl, heteroaryl, heteroarylcarbonyl, heterocyclylcarbonyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and C1-C6-alkylcarbonyl, and
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl and C3-C6-cycloalkyl-C1-C6-alkyl.
87. A method according to claim 84, wherein Y is selected from the group consisting of aryl, heteroaryl, arylmethyl, and heteroarylmethyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl-C1-C6-alkyl, C3-C6-Cycloalkyloxy, C3-C6-cycloalkyl-C1-C6-alkoxy, C3-C6-cycloalkyl-C1-C6-alkoxy-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl.
88. A method according to claim 84, wherein the compound inhibits matrix metalloprotease-13 selectively over both matrix metalloprotease-1 and matrix metalloprotease-14.
89-90 (canceled).
91. A method for treating a pathological condition in an animal, wherein:
the method comprises administering a compound recited in claim 14 (or a pharmaceutically-acceptable salt thereof) to the animal in an amount effective to treat the condition, and
the condition is treatable by inhibiting TNF-α convertase activity.
92-95 (canceled).
96. A method for treating a pathological condition in an animal, wherein:
the condition is treatable by inhibiting aggrecanase activity; and
the method comprises administering a compound of claim 14 (or a pharmaceutically-acceptable salt thereof) to the animal in an amount effective to treat the condition.
97. A method according to claim 96, herein the compound corresponds in structure to Formula XA:
Figure US20040209914A1-20041021-C00608
98. A method according to claim 96, wherein Y is selected from the group consisting of heterocyclyl, aryl, heteroaryl, and arylmethyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, halo-C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-cycloalkyl, aryl, aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, heterocyclyl, heterocyclyl-C1-C6-alkyl, heteroaryl, heteroarylcarbonyl, heterocyclylcarbonyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and C1-C6-alkylcarbonyl, and
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl and C3-C6-cycloalkyl-C1-C6-alkyl.
99. A method according to claim 96, wherein Y is selected from the group consisting of aryl, heteroaryl, arylmethyl, and heteroarylmethyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl-C1-C6-alkyl, C3-C6-cycloalkyloxy, C3-C6-cycloalkyl-C1-C6-alkoxy, C3-C6-cycloalkyl-C1-C6-alkoxy-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl.
100-104 (canceled).
105. A pharmaceutical composition comprising a compound recited in claim 1 or a pharmaceutically acceptable salt thereof.
106. A pharmaceutical composition according to claim 105, wherein the compound corresponds in structure to Formula XA:
Figure US20040209914A1-20041021-C00609
107. A pharmaceutical composition comprising a compound recited in claim 14 or a pharmaceutically acceptable salt thereof.
108. A pharmaceutical composition according to claim 107, wherein the compound corresponds in structure to Formula XA:
Figure US20040209914A1-20041021-C00610
109. A pharmaceutical composition according to claim 107, wherein Y is selected from the group consisting of heterocyclyl, aryl, heteroaryl, and arylmethyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, halo-C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-cycloalkyl, aryl, aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, heterocyclyl, heterocyclyl-C1-C6-alkyl, heteroaryl, heteroarylcarbonyl, heterocyclylcarbonyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and C1-C6-alkylcarbonyl, and
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl and C3-C6-cycloalkyl-C1-C6-alkyl.
110. A pharmaceutical composition according to claim 107, wherein Y is selected from the group consisting of aryl, heteroaryl, arylmethyl, and heteroarylmethyl, wherein:
any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl-C1-C6-alkyl, C3-C6-cycloalkyloxy, C3-C6-cycloalkyl-C1-C6-alkoxy, C3-C6-cycloalkyl-C1-C6-alkoxy-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl, wherein:
the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl.
111. A compound or salt according to claim 14, wherein the compound corresponds in structure to the following formula:
Figure US20040209914A1-20041021-C00611
112. A method according to claim 59, wherein the condition is osteoarthritis.
113. A method according to claim 79, wherein the condition is osteoarthritis.
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