Aromatic sulfone hydroxamic acid metalloprotease inhibitor

TECHNICAL FIELD

[0002] This invention is directed to proteinase (protease) inhibitors, and more particularly to the use of aromatic sulfone hydroxamic acid compounds that, inter alia, are selective inhibitors of matrix metalloproteinases in a process for treating conditions associated with pathological matrix metalloproteinase activity, the selective inhibitors themselves, compositions of proteinase inhibitors, intermediates for the syntheses of proteinase inhibitors, and processes for the preparation of proteinase inhibitors.

BACKGROUND OF THE INVENTION

[0003] Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. Th se biochemicals makeup, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.

[0004] Under normal conditions, connective tissue turnover and/or repair processes are controlled and in equilibrium. The loss of this balance for whatever reason leads to a number of disease states. Inhibition of the enzymes responsible loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for these diseases.

[0005] Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells. A major class of enzymes involved in this function are the zinc metalloproteinases (metalloproteases).

[0006] The metalloprotease enzymes are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane MMP (MMP-14). MMP is an abbreviation or acronym representing the term Matrix Metalloprotease with the attached numerals providing differentiation between specific members of the MMP group.

[0007] The uncontrolled breakdown of connective tissue by metalloproteases is a feature of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; Alzheimers Disease; coronary thrombosis and bone disease. Defective injury repair processes also occur. This can produce improper wound healing leading to weak repairs, adhesions and scarring. These latter defects can lead to disfigurement and/or permanent disabilities as with post-surgical adhesions.

[0008] Metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF), and inhibition of the production or action of TNF and related compounds is an important clinical disease treatment mechanism. TNF-α, for example, is a cytokine that at present is thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. For example, TNF can cause and/or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects such as post-ischemic reperfusion injury, congestive heart failure, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage and acute phase responses like those seen with infections and sepsis and during shock such as septic shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal, and TNF can help control the growth of tumor cells.

[0009] TNF-α convertase is a metalloprotease involved in the formation of soluble TNF-α. Inhibition of TNF-α convertase (TACE) inhibits production of active TNF-α. Compounds that inhibit both MMPs activity and TNF-α production have been disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466 and WO 97/20824. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan et al., Nature 376, 558-561 (1994)). There remains a need for effective MMP inhibitors. There also remains a need for effective TNF-α convertase inhibiting agents.

[0010] MMPs are involved in other biochemical processes in mammals as well. Included is the control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (β-Amyloid Precursor Protein) to the amyloid plaque and inactivation of α1-protease inhibitor (α1-PI). Inhibition of these metalloproteases permits the control of fertility and the treatment or prevention of Alzheimers Disease. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor drug or biochemical such as α1-PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.

[0011] Inhibition of selected MMPs can also be desirable in other instances. Treatment of cancer and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of approaches to the treatment of diseases wherein the selective inhibition of stromelysin, gelatinase A or B, or collagenase III appear to be the relatively most important enzyme or enzymes to inhibit especially when compared with collagenase I (MMP-1). A drug that does not inhibit collagenase I can have a superior therapeutic profile. Osteoarthritis, another prevalent disease wherein it is believed that cartilage degradation of inflamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by administration of drugs one of whose modes of action is inhibition of MMP-13. See, for example, Mitchell et al., J. Clin. Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest., 97:2011-2019 (1996).

[0012] Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitors of metalloproteinases (TIMPs), α2-macroglobulin and their analogs or derivatives. These endogenous inhibitors are high molecular weight protein molecules that form inactive complexes with metalloproteases. A number of smaller peptide-like compounds that inhibit metalloproteases have been described. Mercaptoamide peptidyl derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) aids in the production of angiotensin II, a potent pressor substance in mammals and inhibition of this enzyme leads to the lowering of blood pressure.

[0013] Thiol group-containing amide or peptidyl amide-based metalloprotease (MMP) inhibitors are known as is shown in, for example, WO95/12389, WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMP inhibitors are disclosed in a number of published patent applications such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 that disclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO 95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidyl back-bones or peptidomimetic back-bones, as does the article by Schwartz et al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. New Drugs, 15(3): 175-185 (1997).

[0014] One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes. For example, the peptidomimetic hydroxamate known as batimastat is reported to exhibit IC50 values of about 1 to about 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat, another peptidomimetic hydroxamate was reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum very similar to batimastat, except that marimastat exhibited an IC50 value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).

[0015] Meta analysis of data from Phase I/II studies using marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although marimastat exhibited some measure of efficacy via these markers, toxic side effects were noted. The most common drug-related toxicity of marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction permits treatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.

[0016] International application WO 98/38163, published on Sep. 3, 1998 disclose a large group of hydroxamate inhibitors of MMPs and TACE. The compounds of WO 98/38163 contain one or two substituents adjacent to the hydroxamate functionality and a substituent that can be an aromatic sulfonyl group adjacent to those one or two substituents.

[0017] International application WO 98/37877, published on Sep. 3, 1998 discloses compounds that contain a 5- to 7-membered heterocyclic ring adjacent to the hydroxamate functionality and can contain an aromatic sulfonyl group adjacent to the heterocyclic ring.

[0018] Although many of the known MMP inhibitors such as batimastat, marimastat and the hydroxamates of WO 98/37877 and WO 98/38163 exhibit a broad spectrum of activity against MMPS, those compounds are not particularly selective in their inhibitory activity. This lack of selectivity may be the cause of the musculoskeletal pain and stiffness observed with their use. In addition, it can be therapeutically advantageous to utilize a medicament that is selective in its activity as compared to a generally active material so that treatment can be more closely tailored to the pathological condition presented by the host mammal. The disclosure that follows describes a process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity that utilizes a compound that selectively inhibits one or more MMPs, while exhibiting less activity against at least MMP-1.

SUMMARY OF THE INVENTION

[0019] The present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity. A contemplated molecule, inter alia, exhibits excellent inhibitory activity of one or more matrix metalloprotease (MMP) enzymes, such as MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1. By “substantially less” it is meant that a contemplated compound exhibits an IC50 value ratio against one or more of MMP-2, MMP-9 or MMP-13 as compared to its IC50 value against MMP-1, e.g., IC50 MMP-2: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 utilized hereinafter. The invention also contemplates particular compounds that selectively inhibit the activity of one or more of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1, as well as a composition containing such a MMP inhibitor as active ingredient. Similarly contemplated are particular compounds such as those of Examples 16, 498, 667, 672 and 684 that selectively inhibit the activity of one or more of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-7, as well as a composition containing such a MMP inhibitor as active ingredient. The invention further contemplates intermediates in the preparation of a contemplated aromatic sulfone hydroxamic acid molecule and a process for preparing an aromatic sulfone hydroxamic acid molecule.

[0020] Briefly, one embodiment of the present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor that selectively inhibits matrix metalloprotease activity as above in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity. The administered enzyme inhibitor corresponds in structure to formula I, below, or a pharmaceutically acceptable salt thereof:

[0021] wherein

[0022] R1 and R2 are both hydrido or R1 and R2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms in the ring that are oxygen, sulfur or nitrogen.

[0023] R3 in formula I is an optionally substituted aryl or optionally substituted heteroaryl radical. When R3 is a substituted aryl or heteroaryl radical, a contemplated substituent is selected from the group consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxy, arylthio, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, an aralkylthioaryl radical, the sulfoxide or sulfone of any of the thio substituents, and a fused ring structure comprising two or more 5- or 6-membered rings selected from the group consisting of aryl, heteroaryl, carbocyclic and heterocyclic.

[0024] The substituent bonded to the aryl or heteroaryl radical of which the R3 radical is comprised itself can be substituted with one or more substituents; i.e., the substituting substituent is optionally substituted. When that aryl or heteroaryl radical is substituted, and the substituting moiety (group, substituent, or radical) is itself substituted, the last-named substituent is independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,

[0025] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo-alkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino

[0026] wherein the carbonylamino nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group,

[0027] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl group

[0028] wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.

[0029] Preferably, the R3 substituent is Ph-Q-A-R-E-Y wherein Ph is phenyl substituted at the 4-position relative to the depicted SO2 group, and -Q-A-R-E-Y is a substituent in which Q is a 5- to 7-membered heterocyclic ring containing one or two nitrogen atoms, one of which is bonded the depicted phenyl group, and whose remaining members are defined hereinafter for the substituent G-A-R-E-Y.

[0030] A compound of formula I is a compound of more general formula A, wherein R3, R1 and R2 are as defined before and R20 is defined below.

[0031] The substituent R20 is (a) —O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b) —NH—O—R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl., benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl or a mixture thereof, (c) —NH—O—R14, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R25 where W is O (oxo) or S (thioxo) and R25 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, ar-C1-C6-alkyl group, or R26 and R27 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur. When used in a contemplated process or method, R20 is —NH—O—R22, as defined above.

[0032] In preferred practice, R1 and R2 together with the atoms to which they are bonded form a 6-membered ring.

[0033] An R3 radical preferably has a length that is greater than that of a pentyl group [a —(CH2)4CH3 chain], more preferably greater than about that of a hexyl group [a —(CH2)5CH3 chain], and most preferably greater than an octyl group [a —(CH2)7CH3 chain]. An R3 radical preferably has a length that is less than that of an icosyl group [a —(CH2)19CH3 chain], and more preferably a length that is less than that of a stearyl group [a —(CH2)17CH3 chain). A preferred R3 group contains two or more 5- or 6-membered rings. A contemplated R3 group, when rotated about an axis drawn through the SO2-bonded 1-position and the substituent-bonded 4-position of a 6-membered ring or the SO2-bonded 1-position and substituent-bonded 3- or 4-position of a 5-membered ring, defines a three-dimensional volume whose widest dimension has the width in a direction transverse to that axis to rotation of about one furanyl ring to about two phenyl rings.

[0034] It is also preferred that a R3 radical be a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring or at its own 3- or 4-position when a 5-membered ring with an optionally substituted substituent selected from the group consisting of one other single-ringed aryl or heteroaryl group, a C3-C14 alkyl group, a N-piperidyl group, a N-piperazyl group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group and a benzamido group. The substituent of the 5- or 6-membered aryl or heteroaryl group can itself be substituted as discussed before.

[0035] A preferred compound for use in a contemplated process has a structure that corresponds to formula II, below, or a pharmaceutically acceptable salt thereof:

[0036] wherein

[0037] R14 is hydrido, a pharmaceutically acceptable cation or C(W)R15 where W is O or S and R15 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;

[0038] m is zero, 1 or 2;

[0039] n is zero, 1 or 2;

[0040] p is zero, 1 or 2;

[0041] the sum of m+n+p=1, 2, 3 or 4;

[0042] (a) one of X, Y and Z is selected from the group consisting of C(O), NR6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining two of X, Y and Z are CR8R9, and CR10R11, or

[0043] (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y and Z being CR8R9, or

[0044] (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of

[0045] wherein wavy lines are bonds to the atoms of the depicted ring;

[0046] R6 and R6′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-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, Cs-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, 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-alkanoyl, hydroxy-C1-C6-alkanoyl, thiol-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl and an R8R9-amino-C1-C6-alkyl group;

[0047] R7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group;

[0048] R8 and R9 and R10 and R11 are independently selected from the group consisting of a hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thio]-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R8 and R9 or R10 and R11 is hydroxy;

[0049] R12 and R12′ are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl;

[0050] R13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group; and

[0051] G-A-R-E-Y is a substituent that preferably has a length greater than that of a pentyl group, and more preferably has a length greater than that of a hexyl group. The substituent G-A-R-E-Y preferably has a length that is less than that of an icosyl group, and is more preferably less than that of a stearyl group. In this substituent:

[0052] G is an aryl or heteroaryl group;

[0053] A is selected from the group consisting of

[0054] (1) —O—;

[0055] (2) —S—;

[0056] (3) —NR17—;

[0057] (4) —CO—N(R17) or —N(R17)—CO—, wherein R17 is hydrogen, C1-C4-alkyl, or phenyl;

[0058] (5) —CO—O— or —O—CO—;

[0059] (6) —O—CO—O—;

[0060] (7) —HC═CH—;

[0061] (8) —NH—CO—NH—;

[0062] (9) —C≡C—;

[0063] (10) —NH—CO—O— or —O—CO—NH—;

[0064] (11) —N═N—;

[0065] (12) —NH—NH—; and

[0066] (13) —CS—N(R18)— or —N(R18)—CS—, wherein

[0067] R18 is hydrogen C1-C4-alkyl, or phenyl; or

[0068] (14) A is absent and G is bonded directly to R;

[0069] R is a moiety selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group, and R is other than alkyl or alkoxyalkyl when A is —O— or —S—;

[0070] E is selected from the group consisting of

[0071] (1) —CO(R19)— or —(R19)CO—, wherein R19 is a heterocycloalkyl, or a cycloalkyl group;

[0072] (2) —CONH— or —HNCO—; and

[0073] (3) —CO—;

[0074] (4) —SO2—R19— or —R19—SO2—;

[0075] (5) —SO2—;

[0076] (6) —NH—SO2— or —SO2—NH—;

[0077] (7) —S—;

[0078] (8) —NH—CO—O— or —O—CO—NH—; or

[0079] (9) E is absent and R is bonded directly to Y; and

[0080] the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.

[0081] A particularly preferred compound for use in a contemplated process corresponds in structure to formula III, below, or a pharmaceutically acceptable salt thereof:

[0082] wherein

[0083] m, n, p, X, Z. Y and R14 are as defined above for formula II, and the R3 radical that is defined below is a sub-set of the previously discussed G-A-R-E-Y substituents.

[0084] Thus, R3 is a radical that is comprised of a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of a thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoromethoxy-phenoxy, 4-trifluoromethylphenoxy, 4-(trifluoromethylthio)-phenoxy, 4-(trifluoromethylthio)-thiophenoxy, 4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl)phenoxy, 4-chloro-3-methylphenoxy, 3-methylphenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4-fluoro-3-chlorophenoxy, 4-(1H-1,2,4-triazol-1-yl)phenoxy, 3,5-difluorophenoxy, 3,4-dichlorophenoxy, 4-cyclopentylphenoxy, 4-bromo-3-methylphenoxy, 4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, N-piperidyl, N-piperazinyl and a 4-benzyloxyphenoxy group.

[0085] A more particularly preferred compound for use in a contemplated process has a structure that corresponds to formula IV, below, or a pharmaceutically acceptable salt thereof:

[0086] wherein R3 is as defined above for formula I, more preferably as defined for formula II (wherein this R3 group is the G-A-R-E-Y substituent), and more preferably still as defined for formula III, and

[0087] Z is selected group the group consisting of O, S, NR6, SO, SO2, and NSO2R7,

[0088] wherein R6 is selected from the group consisting of hydrido, C1-C5-alkyl, C1-C5-alkanoyl, benzyl, benzoyl, C3-C5-alkynyl, C3-C5-alkenyl, C1-C3-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, heteroaryl-C1-C6-alkyl, C1-C5-hydroxyalkyl, C1-C5-carboxyalkyl, C1-C5-alkoxy C1-C5-alkylcarbonyl, and NR8R9—C1-C5-alkylcarbonyl or NR8R9—C1-C5-alkyl wherein R8 and R9 are independently hydrido, C1-C5-alkyl, C1-C5-alkoxycarbonyl or aryl-C1-C5-alkoxycarbonyl, or NR8R9 together form a heterocyclic ring containing 5- to 8-atoms in the ring; and

[0089] R7 is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group.

[0090] A still more preferred group of compounds for use in a contemplated process correspond in structure to formula V, below, or a pharmaceutically acceptable salt thereof:

[0091] wherein

[0092] Z is as previously defined in formula IV;

[0093] W and Q are independently oxygen (O), NR6 or sulfur (S), and R6 is as defined in formula IV; and

[0094] q is zero or one such that when q is zero, the trifluoromethyl group is bonded directly to the depicted phenyl ring.

[0095] Further compounds of formula A are also particularly preferred. One group of these compounds corresponds in structure to formula B (including formulas B, B-A, B-1, B-1A, B-2, B-2A, B-3 and B-3A), formula VIC, and more still particularly to formula VIC-1 and formula VIC-2, and formula VIII, below. In those formulas, ring structure Q is a substituent of the depicted phenyl ring and can itself be substituted. Substituent Q including the depicted nitrogen atom is a heterocylic ring that contains 5- or 7-members, preferably 6-members, and can contain zero or one additional nitrogen atom. The substituents of Q such as A-R-E-Y, R-E-Y and E-Y are as defined before, and such a substituent is bonded at the 4-position relative to that depicted nitrogen atom when Q is a 6- or 7-membered ring and at the 3- or 4-position relative to that depicted nitrogen when Q is a 5-membered ring. The remaining members of such a Q-beraing substituent (e.g., A-R-E-Y) are defined herein for the substituent G-A-R-E-Y. In addition, R20, X, Y, Z, m, n, and p of the ring system and g are as before described, with Z preferably being O or NR6.

[0096] The compounds of formulas IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, below, are more particularly preferred among the compounds of formula VIC, formula VIC-1, formula VIC-2, and formula VIII. In those latter formulas, Z is as before described, with Z preferably being O or NR6, and substituent Q is a 6-membered ring, as is shown. The A moiety of the Q ring substituent -A-R-E-Y (e.g. of formula B or B-1) is preferably absent in some embodiments, as in the compounds of formulas XI through XII, whereas both moieties A and R of that substituent group are absent in compounds of formulas 1× through X. The moieties A, R, E and Y of the substituent group -A-R-E-Y are as defined for the substituent group -G-A-R-E-Y.

[0097] When used in a contemplated in a before-described process, a compound of formulas A, B, and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, a R20 group is preferably —NH—O—R22 as defined above, and such a compound can also be present as a pharmaceutically acceptable salt. In addition, when so used, g is 2 in formulas B, VIC, VIC-1, VIC-2 and VII. The compounds of formulas A, B, and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII and their pharmaceutically acceptable salts are contemplated compounds of this invention.

[0098] The present invention also contemplates a precursor or intermediate compound that is useful in preparing a compound of formulas I-X. Such an intermediate compound corresponds in structure to formula VI, below:

[0099] wherein m, n, p, X, Z and Y are as defined above for formula II, g is zero, 1 or 2 and R24 is R3 as defined in formulas I, III or IV, is the substituent G-A-R-E-Y of formula II (formula VIA) or is R3′, an aryl or heteroaryl group that is substituted with a coupling substituent reactive for coupling with another moiety (formula VIB), such as a nucleophilically displaceable leaving group, D.

[0100] Exemplary nucleophilically displaceable leaving groups, D, include a halo (fluoro, chloro, bromo, or iodo) nitro, azido, phenylsulfoxido, aryloxy, C1-C6-alkoxy, a C1-C6-alkylsulfonate or arylsulfonate group and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C1-C6-alkyl or C1-C6-alkyl.

[0101] R20 is (a)—O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl or a mixture thereof, (c)—NH—O—R14, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R25 where W is O (oxo) or S (thioxo) and R25 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, ar-C1-C6-alkyl group, or R26 and R27 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur.

[0102] A particularly preferred precursor intermediate to an intermediate compound of formula VI is an intermediate compound of formula VII

[0103] wherein m, n, p, g, X, Z, Y, D and R20 are as defined above for formula VI.

[0104] Among the several benefits and advantages of the present invention are the provision of compounds and compositions effective as inhibitors of matrix metalloproteinase activity, the provision of such compounds and compositions that are effective for the inhibition of metalloproteinases implicated in diseases and disorders involving uncontrolled breakdown of connective tissue.

[0105] More particularly, a benefit of this invention is the provision of a compound and composition effective for selectively inhibiting certain metalloproteinases, such as one or more of MMP-2, MMP-9 and MMP-13, associated with pathological conditions such as, for example, rheumatoid arthritis osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's Disease, coronary thrombosis and bone disease.

[0106] An advantage of the invention is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase such as MMP-2, MMP-9 or MMP-13 associated with such conditions with minimal side effects resulting from inhibition of other metalloproteinases, such as MMP-1, whose activity is necessary or desirable for normal body function.

[0107] Yet another advantage of the invention is the provision of a process for preparing such compounds.

[0108] Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.

[0109] A further advantage of the invention is the provision of a process for preparing such compositions.

[0110] Still further benefits and advantages of the invention will be apparent to the skilled worker from the disclosure that follows.

DETAILED DESCRIPTION OF THE INVENTION

[0111] In accordance with the present invention, it has been discovered that certain aromatic sulfone hydroxamic acids (hydroxamates) are effective for inhibition of matrix metalloproteinases (“MMPs”) believed to be associated with uncontrolled or otherwise pathological breakdown of connective tissue. In particular, it has been found that these certain aromatic sulfone hydroxamates are effective for inhibition of one or more enzymes such as MMP-2, MMP-9 and MMP-13, which can be particularly destructive to tissue if present or generated in abnormal quantities or concentrations, and thus exhibit a pathological activity. Included in that pathological activity is the assistance of tumors and tumor cells in the process of penetrating basement membrane, and developing a new or improved blood supply; i.e., angiogenesis.

[0112] Moreover, it has been discovered that these aromatic sulfone hydroxamates are selective in the inhibition of one or more of MMP-2, MMP-9 and MMP-13 without excessive inhibition of other collagenases essential to normal bodily function such as tissue turnover and repair. More particularly, it has been found that a contemplated aromatic sulfone hydroxamate of the invention, or a pharmaceutically acceptable salt thereof, is particularly active in inhibiting of one or more of MMP-2, MMP-9 and MMP-13 in an in vitro assay that is predictive of in vivo activity. In addition, while being selective for one or more of MMP-2, MMP-9 and MMP-13, a contemplated aromatic sulfone hydroxamate, or its salt, has a limited or minimal in vitro inhibitory effect on MMP-1.

[0113] There is thus a substantial difference in the activity of a compound used in a contemplated process toward one or more of MMP-2, MMP-9 and MMP-13 and MMP-1. This substantial difference is assayed using the in vitro inhibition assay discussed in the examples. A substantial difference in activity corresponds to a compound exhibiting an IC50 value against one or more of MMP-2, MMP-9 and MMP-13 that is about 0.1 times that of the compound against MMP-1, and more preferably 0.01 times that against MMP-1 and most preferably 0.001 times that against MMP-1, or more. Indeed, some compounds exhibit selectivity differences measured by IC50 values that exceed the bounds of the assay at the number 100,000-fold. These selectivities are illustrated in the Inhibition Tables hereinafter.

[0114] Put differently, a contemplated compound can inhibit the activity of MMP-2 compared to MMP-9 or MMP-13 and MMP-1. Similarly, a contemplated compound can inhibit the activity of MMP-13 and MMP-2, while exhibiting less inhibition against MMP-1 and MMP-9. In addition, a contemplated compound can inhibit the activity of a MMP enzyme, while having less of an effect on tumor necrosis factor release.

[0115] The advantages of the selectivity of a contemplated compound can be appreciated, without wishing to be bound by theory, by considering the therapeutic uses the compounds. For example, inhibition of MMP-1 is suggested to be undesirable due to its role as a housekeeping enzyme, 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 has been suggested to be intimately involved in the destruction of joint components in diseases such as osteoarthritis. Thus, potent and selective inhibition of MMP-13 compared with inhibition MMP-1 is highly desirable because a MMP-13 inhibitor can have a positive effect on disease progression in a patient in addition to having an anti-inflammatory effect.

[0116] Inhibition of MMP-2 and MMP-9 can be desirable for inhibition of tumor growth, metastasis, invasion and/or angiogenesis. A profile of selective inhibition of MMP-2 and MMP-9 relative to MMP-1 can provide a therapeutic advantage.

[0117] Yet another advantage of a contemplated compound is the selectivity with respect to tumor necrosis factor release and/or tumor necrosis factor receptor release that provides the physician with another factor to help select the best drug for a particular patient. While not wishing to be bound by theory, it is believed that there are several factors to this type of selectivity to be considered.

[0118] 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 cad 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.

[0119] A contemplated selective MMP inhibitor compound useful in a contemplated process can be administered to by various routes and provide adequate therapeutic blood levels of enzymatically active inhibitor. A compound can be administered, for example, by the oral (IG, PO) or intravenous (IV) routes. Oral administration is advantageous if the patient is ambulatory, not hospitalized, physically able and sufficiently-responsible to take drug at the required intervals. This is 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 is an advantage in a hospital setting wherein the dose and thus the blood levels can well controlled. A contemplated inhibitor can also be formulated for IM administration if desired. This route of administration can be desirable for the administration of prodrugs or regular drug delivery to patients that are either physically weak or have a poor compliance record or require constant drug blood levels.

[0120] Thus, in one embodiment, the present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor, or a pharmaceutically acceptable salt thereof, in an effective amount to a host mammal having a condition associated with pathological matrix metalloprotease activity. A contemplated aromatic sulfone hydroxamate inhibitor compound useful in such a process inhibits the activity of one or more of MMP-2, MMP-9 and MMP-13, and exhibits substantially less inhibitory activity against at least MMP-1 in the in vitro assay noted above and discussed in detail hereinbelow. An aromatic sulfone hydroxamate inhibitor compound for use in a contemplated process corresponds in structure to formula I, below:

[0121] wherein

[0122] In one embodiment, R1 and R2 are both hydrido. In another embodiment, R1 and R2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms in the ring that are oxygen, sulfur or nitrogen.

[0123] It is preferred that R1 and R2 together with the atoms to which they are bonded form a five-to eight-membered ring that contains one or two heteroatoms in the ring, although R1 and R2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms. The heterocyclic ring can itself also be substituted with up to six C1-C6-alkyl groups or groups that comprise a another 5- to 8-membered carbocyclic or heterocyclic ring, an amino group, or contain one or two oxo (carbonyl) groups.

[0124] R3 in formula I is an optionally substituted aryl or optionally substituted heteroaryl radical. That R3 radical is selected from the group consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, an aralkylthioaryl radical, the sulfoxide or sulfone of any of the thio substituents, and a fused ring structure comprising two or more 5- or 6-membered rings selected from the group consisting of aryl, heteroaryl, carbocyclic and heterocyclic.

[0125] The substituent of which R3 is comprised itself is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,

[0126] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo-alkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino

[0127] wherein the carboxamido nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group,

[0128] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl-group

[0129] wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring. A compound of formula I can also be used in the form of a pharmaceutically acceptable salt.

[0130] The R3 radical has a length that is greater than that of a pentyl group [a —(CH2)4CH3 chain], is more preferably greater than about the length of a hexyl group [a —(CH2)5CH3 chain), and most preferably is greater than about the length of an octyl group [a —(CH2)7CH3 chain]. A R3 group has a length that is less than that of an icosyl group [eicosyl; a —(CH2)19CH3 chain), and more preferably, a length that is less than that of a stearyl group [a —(CH2)17CH3 chain). When rotated about an axis drawn through the SO2-bonded 1-position and the substituent-bonded 4-position of a 6-membered ring or the SO2-bonded 1-position and substituent-bonded 3- or 4-position of a 5-membered ring, a contemplated R3 radical defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about two phenyl rings in a direction transverse to that axis to rotation.

[0131] A compound of formula I is a compound of more general formula A, wherein R3, R1 and R2 are as defined before and R20 is defined below.

[0132] The substituent R20 is (a)—O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl or a mixture thereof, (c) —NH—O—R14, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R25 where W is 0 (oxo) or S (thioxo) and R25 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d)—NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, ar-C1-C6-alkyl group, or R26 and R27 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur.

[0133] Several exemplary R1 and R2 groups that together form a contemplated heterocyclic ring are shown in the Tables that follow hereinafter, as well as in the descriptions of those 5- to 8-membered rings and the specific Examples, as are several contemplated aromatic sulfone hydroxamic acid compounds.

[0134] In more preferred practice, R1 and R2 of formula I or formula A together with the atom to which they are bonded form a 5- to 8-membered ring that contains one, two or three heteroatoms. Most preferably, that ring is a 6-membered ring that contains one heteroatom located at the 4-position relative to the position at which the SO2 group is bonded. Other preferred compounds for use in a contemplated process correspond in structure to one or more of formulas II, III, IV or V, which are discussed hereinafter.

[0135] In one embodiment, a preferred compound used in a contemplated process has a structure that corresponds to formula II, below:

[0136] wherein

[0137] R14 is hydrido, a pharmaceutically acceptable cation or C(W)R15 where W is O or S and R15 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;

[0138] m is zero, 1 or 2;

[0139] n is zero, 1 or 2;

[0140] p is zero, 1 or 2;

[0141] the sum of m+n+p=1, 2, 3 or 4;

[0142] (a) one of X, Y and Z is selected from the group consisting of C(O), NR6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining two of X, Y and Z are CR8R9, and CR10R11, or

[0143] (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y and Z being CR8R9, or

[0144] (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of

[0145] wherein wavy lines are bonds to the atoms of the depicted ring;

[0146] R6 and R6′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-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, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, 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-alkanoyl, hydroxy-C1-C6-alkanoyl, thio]-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl; NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl and an R8R9-amino-C1-C6-alkyl group;

[0147] R7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group;

[0148] R8 and R9 and R10 and R11 are independently selected from the group consisting of a hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R8 and R9 or R10 and R11 is hydroxy;

[0149] R12 and R12′ are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl;

[0150] R13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group; and

[0151] G-A-R-E-Y is a substituent that preferably as a length greater than that of a pentyl group, and ore preferably has a length greater than that of a hexyl group. The substituent G-A-R-E-Y preferably has a length that is less than that of an icosyl group, and is more preferably less than that of a stearyl group. In this substituent:

[0152] G is an aryl or heteroaryl group;

[0153] A is selected from the group consisting of

[0154] (1) —O—;

[0155] (2) —S—;

[0156] (3) —NR17—;

[0157] (4) —CO—N(R17) or —N(R17)—CO—, wherein R17 is hydrogen, C1-C4-alkyl, or phenyl;

[0158] (5) —CO—O— or —O—CO—;

[0159] (6) —O—CO—O—;

[0160] (7) —HC═CH—;

[0161] (8) —NH—CO—NH—;

[0162] (9) —C≡C—;

[0163] (10) —NH—CO—O— or —O—CO—NH—;

[0164] (11) —N═N—;

[0165] (12) —NH—NH—; and

[0166] (13) —CS—N(R18)— or —N(R18)—CS—, wherein

[0167] R18 is hydrogen C1-C4-alkyl, or phenyl; or

[0168] (14) A is absent and G is bonded directly to R;

[0169] R is a moiety selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group, and R is other than alkyl or alkoxyalkyl when A is —O— or —S—;

[0170] E is selected from the group consisting of

[0171] (1) —CO(R19)— or —(R19)CO—, wherein R19 is a heterocycloalkyl, or a cycloalkyl group;

[0172] (2) —CONH— or —HNCO—; and

[0173] (3) —CO—;

[0174] (4) —SO2—R19— or —R19—SO2—;

[0175] (5) —SO2—;

[0176] (6) —NH—SO2— or —SO2—NH—;

[0177] (7) —S—;

[0178] (8) —NH—CO—O— or —O—CO—NH—; or

[0179] (9) E is absent and R is bonded directly to Y; and

[0180] the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.

[0181] The substituent -G-A-R-E-Y preferably contains two to four carbocyclic or heterocyclic rings, including the aryl or heteroaryl group, G. More preferably, each of those rings is 6-membered. Additional separate preferences for a compound of formula II include: (a) that A is —O— or —S—, (b) R is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, (c) E is absent, and (d) Y is selected from the group consisting of hydrido, an alkyl, alkoxy, perfluoroalkoxy and a perfluoroalkylthio group.

[0182] A more preferred compound for use in a contemplated process has a structure that corresponds to formula III, below:

[0183] wherein R3 is a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of a thiophenoxy, 4-chloro-phenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluoro-phenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoro-methoxyphenoxy, 4-trifluoromethylphenoxy, 4-(trifluoromethylthio)phenoxy, 4-(trifluoromethyl-thio)thiophenoxy, 4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl)phenoxy, 4-chloro-3-methylphenoxy, 3-methyl-phenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4-fluoro-3-chlorophenoxy, 4-(1H-1,2,4-triazol-1-yl)phenoxy, 3,5-difluorophenoxy, 3,4-dichlorophenoxy, 4-cyclopentylphenoxy, 4-bromo-3-methylphenoxy, 4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, and a 4-benzyloxyphenoxy group;

[0184] R14 is hydrido, a pharmaceutically acceptable cation or C(W)R15 where W is O or S and R15 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and a C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;

[0185] m is zero, 1 or 2;

[0186] n is zero, 1 or 2;

[0187] p is zero, 1 or 2;

[0188] the sum of m+n+p 1, 2, 3 or 4;

[0189] (a) one of X, Y and Z is selected from the group consisting of C(O), NR6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining two of X, Y and Z are CR8R9, and CR10R11, or

[0190] (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y and Z being CR8R9, or

[0191] (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of

[0192] wherein wavy lines are bonds to the atoms of the depicted ring;

[0193] R6 and R6′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6 alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-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, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, 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-alkanoyl, hydroxy-C1-C6-alkanoyl, thiol-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl and an R8R9-amino-C1-C6-alkyl group;

[0194] R7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group;

[0195] R8 and R9 and R10 and R11 are independently selected from the group consisting of a hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R8 and R9 or R10 and R11 is hydroxy;

[0196] R12 and R12′ are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thio]-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl; and

[0197] R13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group. Again, the use of a compound of formula III as a pharmaceutically acceptable salt is also contemplated.

[0198] Preferences related to a compound of formula III that also apply to a compound of formula II include the following, which are independently preferred: (a) the sum of m+n+p=1 or 2, and more preferably 2; (b) Z is O, S or NR6; (c) R6 is selected from the group consisting of C3-C6-cycloalkyl, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C6-alkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, aminosulfonyl, heteroaryl-C1-C6-alkyl, aryloxycarbonyl, and C1-C6-alkoxycarbonyl; and (d) m=n=zero, p=1, and Y is NR6. Another preference for a compound of both of formulas II and III is that R14 be hydrido, or that W of the C(W)R15 pro-drug form be 0 and R15 be a C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, or aryloxy group.

[0199] A still more preferred compound for use in a contemplated process corresponds in structure to formula IV, below:

[0200] Here, R3 is as defined above as to formulas I, III and more preferably as defined as to formula II (wherein the R3 radical is the substituent G-A-R-E-Y). Most preferably, R3 is as defined in formula III.

[0201] Z is selected group the group consisting of O, S, NR6, SO, SO2, and NSO2R7,

[0202] wherein R6 is selected from the group consisting of hydrido, C1-C5-alkyl, C1-C5-alkanoyl, benzyl, benzoyl, C3-C5-alkynyl, C3-C5-alkenyl, C1-C3-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, heteroaryl-C1-C6-alkyl, C1-C5-hydroxyalkyl, C1-C5-carboxyalkyl, C1-C5-alkoxy C1-C5-alkylcarbonyl, and NR8R9—C1-C5-alkylcarbonyl or NR8R9—C1-C5-alkyl wherein R8 and R9 are independently hydrido, C1-C5-alkyl, C1-C5-alkoxycarbonyl or aryl-C1-C5-alkoxycarbonyl, or NR8R9 together form a heterocyclic ring containing 5- to 8-atoms in the ring; and

[0203] R7 is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group. Most preferably, Z is O or NR6. Here too, the use of a compound of formula IV as a pharmaceutically acceptable salt is contemplated.

[0204] A still more preferred group of contemplated compounds for use in a contemplated process correspond in structure to formula V, below;

[0205] wherein

[0206] Z is as previously defined for formula IV;

[0207] W and Q are independently oxygen (O), NR6 or sulfur (S), and R6 is as defined in formula IV; and

[0208] q is zero or one such that when q is zero, Q is absent and the trifluoromethyl group is bonded directly to the depicted phenyl ring. Here again, the use of a compound of formula IV as a pharmaceutically acceptable salt is contemplated.

[0209] Further compounds of formula A are also particularly preferred. One group of these compounds corresponds in structure to formula B, formula VIC, and more still particularly to formula VIC-1 and formula VIC-2, and formula VIII, below. In those formulas, ring structure Q including the depicted nitrogen atom is a heterocylic ring that contains 5- or 7-members, preferably 6-members, and can contain zero or one nitrogen atom in addition to that depicted. The members of substituent -A-R-E-Y (or —R-E-Y or -E-Y) are as defined elsewhere in the definition of the members of the substituent -G-A-R-E-Y. Furthermore, substituent -A-R-E-Y (or substituent —R-E-Y or -E-Y) is bonded at the 4-position relative to that depicted nitrogen atom when Q is a 6- or 7-membered ring and at the 3- or 4-position relative to that depicted nitrogen when Q is a 5-membered ring. Still fruther, R20, X, Y, Z, m, n, and p of the ring system and g are as before described.

[0210] More particularly preferred among the compounds of formula VIC, formula VIC-1, formula VIC-2, and formula VIII, are the compounds of formulas IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, below, wherein Z is as before described and the members of substituent group -E-Y and —R-E-Y are as defined for the substituent group -G-A-R-E-Y.

[0211] The use of a compound of formulas A and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2 and X, or a pharmaceutically acceptable salt of one of those compounds is contemplated in a before-described process. In addition, the compounds of those formulas and their pharmaceutically acceptable salts are contemplated compounds of this invention.

[0212] Particularly preferred compounds within the group defined by formula B have the structural formulas shown below:

[0213] Several particularly preferred compounds whose structures correspond to formulas I through XII are illustrated in the Tables and examples provided hereinafter.

[0214] As was noted before, the compounds of formulas I-XII, and their pharmaceutically acceptable salts are themselves contemplated compounds of the invention.

[0215] In preferred practice, an SO2-linked R3 radical is an aryl or heteroaryl group that is a 5- or 6-membered single-ring that is itself substituted with one other single-ringed aryl or heteroaryl group or, with an alkyl or alkoxy group having a chain length of 3 to about 16 carbon atoms (and more preferably a length of up to about 14 carbon atoms), a phenoxy group, a thiophenoxy (C6H5—S—] group, a phenylazo [C6H5—N2—] group, a N-piperidyl [C5H10N—] group, a N-piperazyl [NC4H9N—] group or a benzamido [—NHC(O)C6H5] group. The SO2-linked single-ringed aryl or heteroaryl R3 group here is substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring.

[0216] The SO2-linked aryl or heteroaryl group of a R3 radical is preferably itself substituted at the 4-position when a 6-membered ring or the 3- or 4-position when a 5-membered ring. A particularly preferred substituent is a single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo, N-piperidyl, N-piperazyl or benzamido group that is unsubstituted or can itself be substituted.

[0217] The 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding as compared to formalized ring numbering positions used in heteroaryl nomenclature, as is discussed further hereinbelow. Here, single atoms such as halogen moieties (fluoro, chloro, bromo, or iodo) or substituents that contain one to a chain length of about five atoms other than hydrogen such as phenyl, C1-C4 alkyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethyl or carboxyethyl groups are preferred, although longer substituents can be accommodated up to a total length of an icosyl group.

[0218] Exemplary particularly preferred substituted SO2-linked R3 radicals include 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)-phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(azophenyl)phenyl, 4-[(4′-trifluoromethylthio)phenoxy]phenyl, 4-[(4′-trifluoromethylthio)thiophenyl]phenyl, 4-[(4′-trifluoromethyl)phenoxy]phenyl, 4-[(4′-trifluoromethyl)thiophenyl]phenyl, 4-[(4′-trifluoromethoxy)phenoxy]phenyl, 4-[(4′-trifluoromethoxy)thiophenyl]phenyl, 4-[(4′-phenyl)N-piperidyl]phenyl, 4-[(4′-acetyl)N-piperazyl]phenyl and 4-(benzamido)phenyl.

[0219] Inasmuch as a contemplated SO2-linked aryl or heteroaryl radical of an R3 group is itself preferably substituted with a 6-membered ring, two nomenclature systems are used together herein for ease in understanding substituent positions. The first system uses position numbers for the ring directly bonded to the SO2-group, whereas the second system uses ortho, meta or para for the position of one or more substituents of a 6-membered ring bonded to a SO2-linked aryl or heteroaryl radical. Although ortho, meta and para positional nomenclature is normally not used with aliphatic ring systems, it is believed more readily understood for describing the present compounds when used in conjunction with the numerical system for the first ring bonded to the SO2-group. When a R3 radical is other than a 6-membered ring, substituent positions are numbered from the position of linkage to the aromatic or heteroaromatic ring. Formal chemical nomenclature is used in naming particular compounds.

[0220] Thus, the 1-position of an above-discussed SO2-linked aryl or heteroaryl group is the position at which the SO2-group is bonded to the ring. The 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding from the SO2-linkage as compared to formalized ring numbering positions used in heteroaryl nomenclature.

[0221] When examined along its longest chain of atoms, an R3 radical including its own substituent has a total length that is greater than a saturated chain of five carbon atoms (a pentyl group), and preferably has a length greater than that of a saturated chain of six carbon atoms (a hexyl group); i.e., a length of about a heptyl chain or longer. An R3 radical also has a length that is less than that of a saturated chain of about 20 carbon atoms [an icosyl group (icosyl was formerly spelled eicosyl)] and more preferably about 18 carbon atoms (a stearyl group). Most preferably, the length of R3 is about that of an 8 to about 12 carbon atom chain, even though many more atoms may be present in ring structures or substituents. This length requirement is discussed further below.

[0222] Looked at more generally, and aside from specific moieties from which it is constructed, an R3 radical (group or moiety) has a length that is greater than that of a pentyl group. Such an R3 radical also has a length that is less than that of an icosyl (didecyl) group. That is to say that R3 is a radical having a minimal length longer that a saturated five carbon chain, and preferably greater than a hexyl group, but is shorter than the length of a saturated twenty carbon atom chain, and preferably shorter than an eighteen carbon chain. Most preferably, R3 has a length greater than that of an octyl group and less than that of a lauryl group.

[0223] More specifically, an R3 group has a minimal length of a hexyl group only when that substituent is comprised of two rings that can be fused or simply covalently linked together by exocyclic bonding. When R3 does not contain two linked or fused rings, e.g., where a R3 radical includes an alkyl or second, third or fourth ring substituent, R3 has a length that is greater than that of a hexyl group. Exemplary of such two ring R3 groups are a 2-naphthyl group or a 2-quinolinyl group (each with a six carbon chain length) and 8-purinyl (with a five carbon atom chain length). Without wishing to be bound by theory, it is believed that the presence of multiple rings in R3 enhances selectivity of the enzyme activity inhibitor profile.

[0224] The radical chain lengths are measured along the longest linear atom chain in the radical, following the skeletal atoms around a ring where necessary. Each atom in the chain, e.g. carbon, oxygen, sulfur or nitrogen, is presumed to be carbon for ease in calculation.

[0225] Such lengths can be readily determined by using published bond angles, bond lengths and atomic radii, as needed, to draw and measure a desired, usually staggered, chain, or by building models using commercially available kits whose bond angles, lengths and atomic radii are in accord with accepted, published values. Radical (substituent) lengths can also be determined somewhat less exactly by assuming that all atoms have bond lengths saturated carbon, that unsaturated bonds have the same lengths as saturated bonds and that bond angles for unsaturated bonds are the same as those for saturated bonds, although the above-mentioned modes of measurement are preferred. For example, a phenyl or pyridyl group has a length of a four carbon chain, as does a propoxy group, whereas a biphenyl group has a length of about an eight carbon chain using such a measurement mode.

[0226] In addition, a R3 group when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring or the SO2-bonded position and substituent-bonded 3- or 4-position of a 5-membered ring defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about two phenyl rings in a direction transverse to that axis to rotation.

[0227] Thus, a 2-naphthyl substituent or an 8-purinyl substituent is an appropriately sized R3 group when examined using the above rotational width criterion as well as the before-discussed criterion. On the other hand, a 1-naphthyl group or a 7- or 9-purinyl group is too wide upon rotation and is excluded from being an R3 group.

[0228] As a consequence of these length and width requirements, R3 radicals such as 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)-phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(azophenyl)phenyl, 4-[(4′-trifluoromethylthio)phenoxy]phenyl, 4-[(4′-trifluoromethylthio)thiophenyl]phenyl, 4-[(4′-trifluoromethyl)phenoxy]phenyl, 4-[(4′-trifluoromethyl)thiophenyl]phenyl, 4-[(4′-trifluoromethoxy)phenoxy]phenyl, 4-[(4′-trifluoromethoxy)thiophenyl]phenyl, 4-[(4′-phenyl)N-piperidyl]phenyl, 4-[(4′-acetyl)N-piperazyl]phenyl and 4-(benzamido)phenyl are particularly preferred R3 radicals. Those substituents can themselves also be substituted in the second ring from the SO2 group at the meta- or para-position or both with a single atom or a substituent containing a longest chain length that is preferably of up to five atoms, excluding hydrogen.

[0229] Without wishing to be bound by theory, the length of a R3 radical substituent bonded to the SO2 group is believed to play a role in the overall activity of a contemplated inhibitor compound against MMP enzymes generally. The length of the R3 radical group also appears to play a role in the selective activity of an inhibitor compound against particular MMP enzymes.

[0230] In particularly preferred practice, R3 is a PhR23 group, wherein Ph is phenyl. The phenyl ring (Ph) of a PhR23 group is substituted at its para-position (4-position) by an R23 group that can be another single-ringed aryl or heteroaryl group, a piperidyl group, a piperazinyl group, a phenoxy group, a thiophenoxy [C6H5—S—) group, a phenylazo [C6H5—N2—] group or a benzamido [—NHC(O)C6H5] group.

[0231] In one embodiment of a particularly preferred aromatic sulfone hydroxamate inhibitor compound, an R23 substituent is phenoxy and is itself substituted at its own para-position with a moiety that is selected from the group consisting of a halogen, a C1-C4 alkoxy group, a C1-C4 alkyl group, a dimethylamino group, a carboxyl C1-C3 alkylene group, a C1-C4 alkoxy carbonyl C1-C3 alkylene group, a trifluoromethylthio group, a trifluoromethoxy group, a trifluoromethyl group and a carboxamido C1-C3 alkylene group, or is substituted at the meta- and para-positions by a methylenedioxy group. It is to be understood that any R23 substituent can be substituted with a moiety from the above list. Such substitution at the para-position is preferred.

[0232] The present invention also contemplates a compound that corresponds in structure to formula VI, below, that is useful in preparing a compound of formulas I-V, as well as as an active MMP-inhibiting compound and as a pro-drug form of an inhibitor.

[0233] wherein g is zero, 1 or 2;

[0234] R20 is (a)—O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl or a mixture thereof, (c)—NH—O—R14, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R25 where W is O (oxo) or S (thioxo) and R25 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, ar-C1-C6-alkyl group, or R26 and R27 together with the depicted nitrogen atom form a 5- to 7-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur;

[0235] m is zero, 1 or 2;

[0236] n is zero, 1 or 2;

[0237] p is zero, 1 or 2;

[0238] the sum of m+n+p=1, 2, 3 or 4;

[0239] (a) one of X, Y and Z is selected from the group consisting of C(O), NR6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining two of X, Y and Z are CR8R9, and CR10R11, or

[0240] (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y and Z being CR8R9, or

[0241] (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of

[0242] wherein wavy lines are bonds to the atoms of the depicted ring;

[0243] R6 and R6 are independently selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-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, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, 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-alkanoyl, hydroxy-C1-C6-alkanoyl, thio]-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl and an R8R9-amino-C1-C6-alkyl group;

[0244] R7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group;

[0245] R8 and R9 and R10 and R11 are independently selected from the group consisting of a hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R8 and R9 or R10 and R11 is hydroxy;

[0246] R12 and R12′ are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl;

[0247] R13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group; and

[0248] R24 is R3 as defined in formulas I, III, IV or is the substituent G-A-R-E-Y of formula II (formula VIA). Alternatively, R24 is R3′, an aryl or heteroaryl group that is substituted with a coupling substituent reactive for coupling with another moiety (formula VIB), such as a nucleophilically displaceable leaving group, D.

[0249] Exemplary nucleophilically displaceable leaving groups, D, include a halo (fluoro, chloro, bromo, or iodo) nitro, azido, phenylsulfoxido, aryloxy, C1-C6-alkoxy, a C1-C6-alkylsulfonate or arylsulfonate group and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C1-C6-alkyl or C1-C6-alkyl. Additional coupling substituents include, without limitation, a hydroxyl group and an amino group that can be coupled with carbonyl-containing moieties to form esters, urethanes, carbonates, amides and ureas. Similarly, a carboxyl coupling substituent can be used to form an ester, thioester or amide. Thus, a coupling substituent is useful in converting a coupling substituent-containing aryl or heteroaryl group into a substituent such as a G-A-R-E-Y substituent discussed hereinabove by the formation of a covalent bond.

[0250] A compound of formula VI can be coupled with another moiety at the R3′ coupling substituent to form a compound whose newly formed R3 group is that of formulas I, III, IV or -G-A-R-E-Y. Exemplary of such couplings are the nucleophilic displacement to form ethers and thioethers, as well as the formation of ester, amide, urea, carbonate, urethane and the like linkages.

[0251] More particularly, where a R20 group is —O—R21, with R21 being selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, a precursor carboxylic acid or ester compound is defined that can be readily transformed into a hydroxamic acid, as is illustrated in several examples hereinafter.

[0252] Where a R20 group is —NH—O—R22, wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group, an o-nitrophenyl group, or a peptide synthesis resin and the like, a synthetic intermediate is typically defined. In these compounds, a trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, ar-C1-C6-alkyl or a mixture thereof, such as a trimethylsilyl, dimethylisopropylsilyl, triethylsilyl, triphenylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl, a tribenzylsilyl group, and the like. Exemplary trisubstituted silyl protecting groups and their uses are discussed at several places in Greene et al., Protective Groups In Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York (1991).

[0253] A contemplated peptide synthesis resin is solid phase support also known as a so-called Merrifield's Peptide Resin that is adapted for synthesis and selective release of hydroxamic acid derivatives as is commercially available from Sigma Chemical Co., St. Louis, MO. An exemplary peptide synthesis resin so adapted and its use in the synthesis of hydroxamic acid derivatives is discussed in Floyd et al., Tetrahedron Let., 37(44):8048-8048(1996).

[0254] A 2-tetrahydropyranyl (THP) protecting group is a particularly preferred selectively removable protecting group. A contemplated THP-protected hydroxamate compound of formula VII can be prepared by reacting the carboxylic acid precursor compound of formula VII [where R20 is —O—R21 and R21 is a hydrido group] in water with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine in the presence of N-methylmorpholine, N-hydroxybenzotriazole hydrate and a water-soluble carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The THP protecting group is readily removable in an aqueous acid solution such as an aqueous mixture of p-toluenesulfonic acid or HCl and acetonitrile or methanol. An illustrative THP-protected compound corresponds in structure to formula VIIB, below, wherein m, n, p, g, X, Z. Y, and D are as defined previously.

[0255] Where R20 is —NR26R27, and R26 and R27 are as defined before, an amide compound is defined that can be used as a precursor intermediate and surprisingly as a MMP inhibitor compound. R26 and R27 are both preferably hydrido.

[0256] Where a R group is —NH—O—R14, and R14 is hydrido, or a pharmaceutically acceptable cation, an active hydroxamic acid or hydroxamate is defined. Where a R20 group is —NH—O—R14, and R14 is a C(W)R25 group as defined before, a pro-drug form of the hydroxamic acid is defined that can form a hydroxamic acid or hydroxamate form of the inhibitor in situ.

[0257] A particularly preferred precursor intermediate to an intermediate compound of formula VI is an intermediate compound of formula VII, below

[0258] wherein m, n, p, g, X, Z, Y, D and R20 are as defined above for formula VI.

[0259] In regard to a compound of each of formulas VI and VII, the subscript letter “g” is used to show the oxidation state of the sulfur atom. Where g is zero, the sulfur is unoxidized, and the compound depicted is typically the sulfide reaction product of a sulfur-containing synthon as is illustrated in the examples hereinafter. Where g is 1, the sulfur is oxidized to a sulfoxide, whereas when g is 2, the sulfur is oxidized to a sulfone as is also illustrated hereinafter. A compound of formulas VI or VII wherein g is zero or 1 as itself typically an intermediate in the formation of a similar compound wherein g is 2 and the intermediate is a preferred sulfone.

[0260] A preferred intermediate corresponds in structure to formula VIIA, below, wherein R20, X, Y, Z, m, n, p and D are as defined previously.

[0261] In the written descriptions of molecules and groups, molecular descriptors can be combined to produce words or phrases that describe structural groups or are combined to describe structural groups. Such descriptors are used in this document. Common illustrative examples include such terms as aralkyl (or arylalkyl), heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, aralkoxyalkoxycarbonyl and the like. A specific example of a compound encompassed with the latter descriptor aralkoxyalkoxycarbonyl is C6H5—CH2—CH2—O—CH2—O—(C═O)— wherein C6H5— is phenyl. It is also to be noted that a structural group can have more than one descriptive word or phrase in the art, for example, heteroaryloxyalkylcarbonyl can also be termed heteroaryloxyalkanoyl. Such combinations are used herein in the description of the processes, compounds and compositions of this invention and further examples are described below. The following list is not intended to be exhaustive or drawn out but provide illustrative examples of words or phrases (terms) that are used herein.

[0262] As utilized herein, the term “alkyl”, alone or in combination, means a straight-chain or branched-chain alkyl radical containing 1 to about 12 carbon atoms, preferably 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.

[0263] The term “alkenyl”, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing 2 to about 12 carbon atoms preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms. Examples of suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like.

[0264] The term “alkynyl”, alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and containing 2 to about 12 carbon atoms, preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.

[0265] The term “carbonyl” or “oxo”, alone or in combination, means a —C(═O)— group wherein the remaining two bonds (valences) can be independently substituted. The term carbonyl is also intended to encompass a hydrated carbonyl group —C(OH)2—.

[0266] The term “thiol” or “sulfhydryl”, alone or in combination, means a —SH group. The term “thio” or “thia”, alone or in combination, means a thiaether group; i.e., an ether group wherein the ether oxygen is replaced by a sulfur atom.

[0267] The term “amino”, alone or in combination, means an amine or —NH2 group whereas the term mono-substituted amino, alone or in combination, means a substituted amine —N(H)(substituent) group wherein one hydrogen atom is replaced with a substituent, and disubstituted amine means a —N(substituent)2 wherein two hydrogen atoms of the amino group are replaced with independently selected substituent groups.

[0268] Amines, amino groups and amides are compounds that can be designated as primary (I°), secondary (II°) or tertiary (III°) or unsubstituted, mono-substituted or N,N-disubstituted depending on the degree of substitution of the amino nitrogen. Quaternary amine (ammonium)(IV°) means a nitrogen with four substituents [—N+(substituent)4] that is positively charged and accompanied by a counter ion, whereas N-oxide means one substituent is oxygen and the group is represented as [—N+(substituent)3—O−]; i.e., the charges are internally compensated.

[0269] The term “cyano”, alone or in combination, means a —C-triple bond-N (—C≡N) group. The term “azido”, alone or in combination, means a —N-triple bond-N (—N≡N) group. The term “hydroxyl”, alone or in combination, means a —OH group. The term “nitro”, alone or in combination, means a —NO2 group. The term “azo”, alone or in combination, means a —N═N-group wherein the bonds at the terminal positions can be independently substituted.

[0270] The term “hydrazino”, alone or in combination, means a —NH—NH— group wherein the depicted remaining two bonds (valences) can be independently substituted. The hydrogen atoms of the hydrazino group can be replaced, independently, with substituents and the nitrogen atoms can form acid addition salts or be quaternized.

[0271] The term “sulfonyl”, alone or in combination, means a —SO2— group wherein the depicted remaining two bonds (valences) can be independently substituted. The term “sulfoxido”, alone or in combination, means a —SO— group wherein the remaining two bonds (valences) can be independently substituted.

[0272] The term “sulfone”, alone or in combination, means a —SO2— group wherein the depicted remaining two bonds (valences) can be independently substituted. The term “sulfenamide”, alone or in combination, means a —SON═ group wherein the remaining three depicted bonds (valences) can be independently substituted. The term “sulfide”, alone or in combination, means a —S— group wherein the remaining two bonds (valences) can be independently substituted.

[0273] The term “alkoxy”, alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

[0274] The term “cycloalkyl”, alone or in combination, means a cyclic alkyl radical that contains 3 to about 8 carbon atoms. The term “cycloalkylalkyl” means an alkyl radical as defined above that is substituted by a cycloalkyl radical containing 3 to about 8, preferably 3 to about 6, carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0275] A heterocyclic (heterocyclo) or heterocyclo portion of a heterocyclocarbonyl, heterocyclooxy-carbonyl, heterocycloalkoxycarbonyl, or heterocycloalkyl group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle that contains one or more hetero atoms selected from nitrogen, oxygen and sulphur. Heterocyclo compounds include benzofused heterocyclic compounds such as benzo-1,4-dioxane. Such a moiety can be optionally substituted on one or more ring carbon atoms by halogen, hydroxy, hydroxycarbonyl, alkyl, alkoxy, oxo, and the like, and/or on a secondary nitrogen atom (i.e., —NH—) of the ring by alkyl, aralkoxycarbonyl, alkanoyl, aryl or arylalkyl or on a tertiary nitrogen atom (i.e., ═N—) by oxido and that is attached via a carbon atom. The tertiary nitrogen atom with three substituents can also attached to form a N-oxide [═N(O)-] group.

[0276] The term “aryl”, alone or in combination, means a 5- or 6-membered carbocyclic aromatic ring-containing moiety or a fused ring system containing two or three rings that have all carbon atoms in the ring; i.e., a carbocyclic aryl radical. Exemplary carbocyclic aryl radicals include phenyl, indenyl and naphthyl radicals.

[0277] The term “heteroaryl”, alone or in combination means a 5- or 6-membered aromatic ring-containing moiety or a fused ring system (radical) containing two or three rings that have carbon atoms and also one or more heteroatoms in the ring(s) such as sulfur, oxygen and nitrogen. Examples of such heterocyclic or heteroaryl groups are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl, and the like), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, triazolyl, tetrazolyl, oxazolyl, oxadiazoyl, thiazolyl, thiadiazoyl, indolyl (e.g., 2-indolyl, and the like), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, and the like), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, and the like), tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydro-2-quinolyl, and the like), 1,2,3,4-tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, and the like), quinoxalinyl, β-carbolinyl, 2-benzofurancarbonyl, benzothiophenyl, 1-, 2-, 4- or 5-benzimidazolyl, and the like radicals.

[0278] When an aryl or heteroaryl radical is a substituting moiety (group, substituent, or radical), it can itself substituted, the last-named substituent is independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoro-methoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,

[0279] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo-alkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino

[0280] wherein the carbonylamino nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group,

[0281] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl group

[0282] wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.

[0283] The term “aralkyl”, alone or in combination, means an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and the like.

[0284] The term “aralkoxycarbonyl”, alone or in combination, means a radical of the formula aralkyl-O—C(O)— in which the term “aralkyl” has the significance given above. An example of an aralkoxycarbonyl radical is benzyloxycarbonyl.

[0285] The term “aryloxy” means a radical of the formula aryl-O— in which the term aryl has the significance given above. The phenoxy radical is an exemplary aryloxy radical.

[0286] The terms “heteroaralkyl” and “heteroaryloxy” mean radicals structurally similar to aralkyl and aryloxy that are formed from heteroaryl radicals. Exemplary radicals include 4-picolinyl and 2-pyrimidinoxy, respectively.

[0287] The terms “alkanoyl” or “alkylcarbonyl”, alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include formyl, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.

[0288] The term “cycloalkylcarbonyl” means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid that is optionally substituted by, for example, alkanoylamino, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.

[0289] The terms “aralkanoyl” or “aralkylcarbonyl” mean an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl and the like.

[0290] The terms “aroyl” or “arylcarbonyl” means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.

[0291] The term “cycloalkylalkoxycarbonyl” means an acyl group of the formula cycloalkylalkyl-O—CO— wherein cycloalkylalkyl has the significance given above. The term “aryloxyalkanoyl” means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above. The term “heterocyclooxycarbonyl” means an acyl group having the formula heterocyclo-O—CO— wherein heterocyclo is as defined above.

[0292] The term “heterocycloalkanoyl” is an acyl radical of the formula heterocyclo-substituted alkane carboxylic acid wherein heterocyclo has the significance given above. The term “heterocycloalkoxycarbonyl” means an acyl radical of the formula heterocyclo-substituted alkane-O—CO— wherein heterocyclo has the significance given above. The term “heteroaryloxycarbonyl” means an acyl radical represented by the formula heteroaryl-O—CO— wherein heteroaryl has the significance given above.

[0293] The term “aminocarbonyl” (carboxamide) alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amine reacted with a carboxylic acid wherein the amino (amido nitrogen) group is unsubstituted (—NH2) or a substituted primary or secondary amino group containing one or two substituents selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like, as recited. A hydroxamate is a N-hydroxycarboxamide.

[0294] The term “aminoalkanoyl” means an acyl group derived from an amino-substituted alkanecarboxylic acid wherein the amino group can be a primary or secondary amino group containing substituents independently selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.

[0295] The term “halogen” means fluoride, chloride, bromide or iodide. The term “haloalkyl” means an alkyl radical having the significance as defined above wherein one or more hydrogens are replaced with a halogen. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.

[0296] The term “perfluoroalkyl” means an alkyl group wherein each hydrogen has been replaced by a fluorine atom. Examples of such perfluoroalkyl groups, in addition to trifluoromethyl above, are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.

[0297] The term “perfluoroalkoxy” alone or in combination, means a perfluoroalkyl ether radical wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkoxy groups, in addition to trifluoromethoxy (F3C—O—), are perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy and perfluorodecoxy.

[0298] The term “perfluoroalkylthio” alone or in combination, means a perfluoroalkyl thioether radical wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkylthio groups, in addition to trifluoromethylthio (F3C—S—), are perfluorobutylthio, perfluoroisopropylthio, perfluorododecylthio and perfluorodecylthio.

[0299] The term “aromatic ring” in combinations such as substituted-aromatic ring sulfone or substituted-aromatic ring sulfoxide means aryl or heteroaryl as defined before.

[0300] The term “pharmaceutically acceptable” is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product. Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to appropriate alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts and other physiological acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.

[0301] “M” utilized in the reaction schemes that follow represents a leaving group such as halogen, phosphate ester or sulfate ester.

[0302] Preparation of Useful Compounds

[0303] Schemes A through C and Schemes 1 through 19 hereinbelow illustrate chemical processes and transformations that can be useful for the preparation of compounds useful in this invention; i.e., compounds of formulas I, II, III, IV and V and similar cyclic inhibitors. In addition, the preparation of compounds of formula VI and formula VII is illustrated. Compounds of formula VI and formula VII can be used as intermediates in the preparation of the compounds of formulas I, II, III, IV and V or pro-drugs or MMP inhibitors.

[0304] In Schemes A through C, the symbol J independently represents R20 or other synthetically useful groups such as amides, acid chlorides, mixed anhydrides and the like. The n is 0, 1 or 2 and is preferred to be 1 or 2 in Scheme C. The n of these schemes corresponds to g in formulas VI and VII., and is zero, 1 or 2. The symbol m is 1 or 2. The symbol r is independently 1, 2 or 3. The symbol P represents a protecting group that can also be a member of the group R6. In Scheme A, for simplicity and clarity of illustration positional isomers are illustrated with a bond through the ring in standard fashion. Later Schemes typically only show one positional isomer but positional isomers are represented by these structures and reactions in a manner consistent with Formula I, II, III, IV, V, VI, VII above. Similarly, the symbol B represents O, S, SO, SO2 and NR6. The symbols C and C′ independently are electrophilic groups or groups capable of participating in a condensation reaction. Here to it should be noted that the six-membered ring is shown for illustrative purposes but the procedures and/or reagents are applicable to and represent combinations the permit the preparation of 5- to 8-membered rings.

[0305] The structures in Schemes 1 through 19 are also shown with compounds that represent the other compounds of this invention. The aromatic ring in Scheme C is aryl and heteroaryl. The moieties of -A-R-E-Y are as defined before. Reactions illustrated involving a spiroheterocyclic nitrogen atom may not be applicable to those compounds with sulfur or oxygen.

[0306] Scheme A shows in step 1 the reduction of a heteraryl compound to a carboxyl derivative. Generally, the first product is a hydrogen-containing amine heterocycle when the starting material is aromatic or an R6-containing heterocycle when a partially unsaturated heterocycle is the starting material.

[0307] Compound 2 can be treated in several ways depending on the needs of the chemist. In Step 2, the nitrogen can be protected by preparing, for example, a carbobenzoxy (Z) or tert-butoxycarbonyl derivative. Such acylations can be carried out by methods well known in the art, especially the art of amino acid and peptide synthesis. The process of acylation with activated carboxyl group- or activated sulfonyl group-containing reagents to prepare contemplated compounds is carried out in the same manner. Examples of such acylating groups are carbonyl azides, halides, anhydrides, mixed anhydrides, carbodiimide derivatives or other less traditional activated ester groups such as the hydroxybenzotriazole derivative. These acylations can be run in the presence of base including mild bases such as triethylamine or N-ethylmorpholine if desired. The preparation of some activated ester reagents and their use to prepare other compounds useful in this invention is discussed below. It should be recalled that the groups constituting P and serving as a selectively removable protecting group can also be included as part of the group R6.

[0308] Step 4 of Scheme A shows the alkylation or acylation of Compound 2 to produce compound 5. The process of acylation and alkylation are as discussed herein. In Step 5, the group J can be changed if desired. An example of such a change is exchange of an ester for a THP-protected hydroxamate conversion of a THP-protected hydroxamate inot a hydroxamate or conversion of an acid into a protected hydroxamate or the like.

[0309] Steps 3, 7 and 8 show the preparation of sulfur-containing derivatives of the contemplated compounds or intermediates to those compounds. The starting material for the above steps (e.g., compounds 2, 5 and 6) can be treated with a base to deprotonate the carbon alpha to the carbonyl function. This anion can be reacted with a sulfur electrophile to produce a sulfone, sulfoxide or sulfide. Such electrophiles can be of the form of, for example, R24S—SR24, R24SO2C1, R24SC1, R24SOC1, R24S(O)—SR24 and the like where R24 is as defined before or is an aryl or heteroaryl sulfur-containing material containing a coupling substituent, R3′, that can be used to prepare one of the R24-containing groups. Preparation of the anion requires a base and a strong base may be required such as one of the metal amides, hydrides or alkyls discussed herein. The solvents are nonprotic, and dipolar aprotic solvents are preferred along with an inert atmosphere. Subsequent schemes usually utilize R3 for the R24 group for ease of illustration.

[0310] It should be noted that these processes produce sulfides (thio ethers), sulfoxides or sulfones depending on starting material. In addition, the sulfides can be oxidized to sulfoxides or sulfones, and the sulfoxides can be oxidized to their corresponding sulfone derivatives. The choice of position in the synthetic sequence to change the oxidation state of sulfur as well as the decision to change oxidation state is under the control of the chemist skilled in the art. Methods of oxidizing sulfur are discussed hereinbelow.

[0311] Scheme A, Steps 6, 9, 10 and 12 independently illustrate the interconversion of groups within J. Examples of such interconversions include exchange of an ester for hydroxamic acid or hydroxamic acid derivative, conversion of a carboxylic acid into an activated carbonyl derivative or into a hydroxamic acid or hydroxamic acid derivative (pro-drug or protected derivative), or removal of a protecting group from a hydroxamate derivative. The preparation of activated carbonyl compounds their reaction with nucleophiles such as hydroxamic acid, protected hydroxamates or hydroxamic acid pro-drugs is discussed below as is the conversion of protected hydroxamic acid derivatives into hydroxamic acids. The preparation of, for example, hydroxybenzotriazole/carbodiimide, derived products is discussed herein. The preparation or hydrolysis of esters, amides, amide derivatives, acid chlorides, acid anhydrides, mixed anhydrides and the like are synthetic methods very well known in the art, and are not discussed in detail herein. Step 6 illustrates the conversion of compound 4 into compound 9, without first being converted into compound 7.

[0312] Scheme B illustrates an alternate method of preparing contemplated compounds. The reagent shown above the arrow in Step 1 is a reagent with two active groups in addition to the heteroatoms (B) noted before. Here again, the particular reagent illustrated was selected to permit a clear illustration of the reaction, but it is also intended to represent reagents that permit the preparation of the heteroatom position, and 5-, 7- and 8-membered ring size compounds. These reagents are readily selected by those skilled in the art.

[0313] C and C′ in this Step 1 reagent are independently an electophile or a group convertible into an electrophile. Such groups include halides, sulfonic acid esters, epoxides, thioepoxides, hydroxyl groups, and the like. This reagent is reacted with a nucleophilic anion of a sulfur containing carbonyl compound such as compound 1. The anion is formed by deprotonation of compound 1 and examples of bases suitable for such a deprotonation are discussed below. Treatment with the above electrophilic reagent is carried out under alkylating conditions well known in the art and discussed herein. The product of this reaction can be either Compound 2 or Compound 3; i.e., the reaction can be carried out as a pot or two step process as required.

[0314] Step 3 illustrates the interconversion of J groups if desired as discussed above for Scheme A. Step 4 uses reagent where C, for example, represents a nucleophile as discussed above and C′ represents an electrophile or a nucleophile such as hydroxyl, thiol or R6-amino. It is noted that Cl can be, independently, a nucleophile or an electrophile when m is 2; i.e., the C′ groups are not required to be the same when m is 2. When m is 2, treatment with a second mole of base provides the skilled chemist an alternative preparation of Compound 5. When C′ is hydroxyl, thiol, or R6-amino and m is 2, the person skilled in the art can condense Compound 4 with, for example, an aldehyde or ketone, under reductive conditions or with subsequent reduction to form a contemplated compound. As above, the compound where m is 2 can be made in one step (one pot process) or two steps, thus permitting the chemist the choice of having the reagent(s) be the same (one pot) or different (two step).

[0315] Scheme B also illustrates the interconversions of the groups within J, the oxidation state of the sulfur and groups on nitrogen; i.e., R6 groups, to provide the contemplated compounds. These methods and processes are discussed above for the reactions of Scheme A.

[0316] Scheme C illustrates the nucleophilic displacement of a group D as defined herein. This reaction is carried out in a similar manner to the displacement reactions discussed herein. The choice of oxidation state of the sulfur is made by the person skilled in the art, but sulfoxide or sulfone groups are preferred, and the sulfone is most preferred. The displacement can be carried out either before or after the methylene next to the carbonyl group is reacted to form a Spiro heterocyclic group.

[0317] Steps 1, 2 and 3 also illustrate that although the nucleophilic displacement can be carried out with one nucleophile (Nu), the product of this reaction can be modified by methods well known in the art and as shown herein to provide the group -A-R-E-Y as defined hereinbefore.

[0318] A non-limiting illustration of such a process is provided when D is fluoride. The fluoride leaving group can be directly displaced with the anion of 4-trifluoromethylphenol, 4-trifluoromethoxyphenol, 4-trifluoromethylthiophenol and the like to provide a contemplated compound. This is a one pot process from Compound 4. Other compounds included in -A-R-E-Y can be prepared by displacing the fluoride leaving group with ammonia to provide an amine, which can then be acylated by methods discussed wherein with, for example, 4-trifluoromethylbenzoyl chloride, to form another contemplated product compound.

[0319] The R6 function can be changed and/or further modified in compounds or at steps in the Schemes as desired or required by the person skilled in the art to prepare the contemplated compounds. Interconversion of dual purpose functional groups such as short or long term protecting groups into other R6 groups has been mentioned. Many other routine and/or useful conversions, including the preparation of synthetic intermediates, are very well known in the art. A few non-limiting examples of such conversions or reactions include: reductions; nucleophilic displacement/substitution reactions; exchange or preparation of carboxylic or sulfonic acids, amides, esters, acid halides, mixed anhydrides and the like; electrophilic displacement/substitution reactions; oxidations; ring/chain conversions, ring opening reactions, condensation reactions including those involving sulfonyl or carbonyl groups and/or carbon-hydrogen bonds influenced by either or both of those groups. The selection of preparative methods or conversion methods of the contemplated compounds and the order of the reaction(s) is made by the skilled person. It is expected that should a particular sequence or method prove to be undesirable that an alternative will be selected and used. Included is the choice of preparing/adding the groups in a single step using a convergent inhibitor strategy or preparing the final R6 group following a stepwise strategy.

[0320] Thus, in general, the choices of starting material and reaction conditions can vary as is well known to those skilled in the art. Usually, no single set of conditions is limiting because variations can be applied as required. Conditions are also selected as desired to suit a specific purpose such as small scale preparations or large scale preparations. In either case, the use of less safe or less environmentally sound materials or reagents is usually be minimized. Examples of such materials are diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, chloroform, benzene and the like.

[0321] These reactions can be carried out under a dry inert atmosphere such a nitrogen or argon if desired. Selected reactions known to those skilled in the art, can be carried out under a dry atmosphere such as dry air whereas other synthetic steps, for example, aqueous acid or base ester or amide hydrolysis, can be carried out under laboratory air. In addition, some processes of these syntheses can be carried out in a pressure apparatus at pressures above, equal to or below atmospheric pressure. The use of such an apparatus aids in the control of gaseous reagents such as hydrogen, ammonia, trimethylamine, methylamine, oxygen and the like, and can also help prevent the leakage of air or humidity into a reaction in progress. This discussion is not intended to be exhaustive as it is readily noted that additional or alternative methods, conditions, reactions or systems can be identified and used by a chemist of ordinary skill.

[0322] The illustrated reactions are usually carried out at a temperature of between −25° C. to solvent reflux under an inert atmosphere such as nitrogen or argon. The solvent or solvent mixture can vary widely depending upon reagents and other conditions and can include polar or dipolar aprotic solvents as listed or mixtures of these solvents. Reactions can be carried out at lower temperatures such as dry ice/acetone or liquid nitrogen temperature if desired to carry out such reactions as metalations or anion formations using strong bases.

[0323] In some cases, amines such as triethylamine, pyridine or other non-reactive bases can serve as reagents and/or solvents and/or co-solvents. In some instances, in these reactions and other reactions in these Schemes, protecting groups can be used to maintain or retain groups in other parts of a molecule(s) at locations that is(are) not desired reactive centers. Examples of such groups that the skilled person can maintain or retain include, amines, other hydroxyls, thiols, acids and the like. Such protecting groups can include acyl groups, arylalkyl groups, carbamoyl groups, ethers, alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl groups, silyl groups including trisubstituted silyl groups, ester groups and the like. Examples of such protecting groups include acetyl, trifluoroacetyl, tetrahydropyran (THP), benzyl, tert-butoxy carbonyl (BOC or TBOC), benzyloxycarbonyl (Z or CBZ), tert-butyldimethylsilyl (TBDMS) or methoxyethoxymethylene (MEM) groups. The preparation of such protected compounds as well as their removal is well known in the art. The protecting groups can also be used as substituents in the contemplated compounds whose utility is as a drug rather than as a synthetic intermediate.

[0324] Many reactions or processes involve bases that can act as reactants, reagents, deprotonating agents, acid scavengers, salt forming reagents, solvents, co-solvents and the like. Bases that can be used include, for example, metal hydroxides such as sodium, potassium, lithium, cesium or magnesium hydroxide, oxides such as those of sodium, potassium, lithium, calcium or magnesium, metal carbonates such as those of sodium, potassium, lithium, cesium, calcium or magnesium, metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, primary (I°), secondary (II°) or tertiary (III°) organic amines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary ammonium hydroxides. As non-limiting examples, such amines can include triethylamine, trimethylamine, diisopropylamine, methyldiisopropylamine, diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine, N-methylmorpholine, N,N′-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine, and the like. Non-limiting examples of ammonium hydroxides, usually made from amines and water, can include ammonium hydroxide, triethylammonium hydroxide, trimethylammonium hydroxide, methyldiiospropylammonium hydroxide, tribenzylammonium hydroxide, dimethylbenzylammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium hydroxide, N,N′-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limiting examples, quaternary ammonium hydroxides can include tetraethylammonium hydroxide, tetramethylammonium hydroxide, dimethyldiiospropyl-ammonium hydroxide, benzylmethyldiisopropylammonium hydroxide, methyldiazabicyclononylammonium hydroxide, methyltribenzylammonium hydroxide, N,N-dimethyl-morpholiniumhydroxide, N,N,N′,N′-tetramethylpiperazinium hydroxide, and N-ethyl-N′-hexylpiperidinium hydroxide and the like.

[0325] Metal hydrides, amides or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, aluminum hydride, diisobutylaluminum hydride (DIBAL) sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like can also be suitable reagents. Organometallic deprotonating agents such as alkyl or aryl lithium reagents such as methyl lithium, phenyl lithium, tert-butyl lithium, lithium acetylide or butyl lithium, Grignard reagents such as methylmagnesium bromide or methymagnesium chloride, organocadmium reagents such as dimethylcadmium and the like can also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents. Pharmaceutically acceptable bases can be reacted with acids to form contemplated pharmaceutically acceptable salts. It should also be noted that optically active bases can be used to make optically active salts which can be used for optical resolutions.

[0326] Generally, reaction media can comprise a single solvent, mixed solvents of the same or different classes or serve as a reagent in a single or mixed solvent system. The solvents can be protic, non-protic or dipolar aprotic. Non-limiting examples of protic solvents include water, methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanol and the like. Typical non-protic solvents include acetone, tetrahydrofuran (THF), dioxane, diethyl ether, tert-butylmethyl ether (TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane and the like. Dipolar aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, DMSO, hexamethylphosphorus triamide (HMPA), nitromethane, tetramethylurea, N-methylpyrrolidone and the like. Non-limiting examples of reagents that can be used as solvents or as part of a mixed solvent system include organic or inorganic mono- or multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines for making esters or amides or thiols for making contemplated products and the like.

[0327] The preparation of compounds contemplated herein can require the oxidation of nitrogen or sulfur to N-oxide derivatives or sulfoxides or sulfones. Reagents for this process can include, in a non-limiting example, peroxymonosulfate (OXONE®), hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlactic acid, tert-butyl peroxide, tert-butyl hypochlorite, sodium hydpochlorite, hypochlorous acid, sodium meta-periodate, periodic acid and the like with the weaker agents being most useful for the preparation of sulfones and sulfoxides. Protic, non-protic, dipolar aprotic solvents, either pure or mixed, can be chosen, for example, methanol/water.

[0328] The oxidation can be carried out at temperature of about −780 to about 50° degrees Centigrade, and normally selected from a range −10° C. to about 40° C. Sulfoxides are best prepared using one equivalent of oxidizing agent. It can be desirable in the case of more active oxidizing agents, but not required, that the reactions be carried out under an inert gas atmosphere with or without degassed solvents. It should be noted that the oxidation of sulfides to sulfones can be carried out in one step or two steps via the sulfoxide as desired by the chemist.

[0329] Reduction is a well known process in the art with a useful method being hydrogenation. In such cases (catalytic reduction), there can be a metal catalyst such as Rh, Pd, Pt, Ni or the like with or without an additional support such as carbon, barium carbonate and the like. Solvents can be protic or non-protic pure solvents or mixed solvents as required. The reductions can be carried out at atmospheric pressure to a pressure of multiple atmospheres with atmospheric pressure to about 40 pounds per square inch (psi) preferred or very high pressures in special hydrogenation equipment well known in the art.

[0330] Reductive alkylation of amines or active methylene compounds is also a useful method of preparing compounds. Such alkylations can be carried out under reductive hydrogenation conditions as presented above using, for example, aldehydes or ketones. Hydride transfer reagents such as sodium cyanoborohydride, aluminum hydride, lithium aluminumhydride, borane, sodium borohydride, di-isobutylaluminum hydride and the like are also useful as reagents for reductive alkylation. Acyl groups can be reduced in a similar manner to produce substituted amines.

[0331] Alternative methods of alkylating carbon or nitrogen are direct alkylation. Such an alkylation, as is well known in the art, can be carried by treatment of an activated carbon containing at least one hydrogen with base to form the corresponding anion, adding an electrophilic reagent and permitting the SN2 reaction to proceed. An amine to be alkylated is treated similarly except that deprotonation may not be required. Electrophiles include halogen derivatives, sulfonate esters, epoxides and the like.

[0332] Bases and solvents for alkylation reactions are those discussed above. Preferred are bases that are hindered such that competition with the electrophile is minimized. Additional preferred bases are metal hydrides, amide anions or organometallic bases such as n-butyl lithium. The solvents, solvent mixtures or solvent/reagent mixtures discussed are satisfactory but non-protic or dipolar aprotic solvents such as acetone, acetonitrile, DMF and the like are examples of preferred classes.

[0333] Acids are used in many reactions during various syntheses. For example, removal of the THP protecting group to produce the hydroxamic acid. The acid can be a mono-, di- or tri-protic organic or inorganic acid. Examples of acids include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, hydrobromic acid, hydrofluoric acid, carbonic acid, phosphorus acid, p-toluene sulfonic acid, trifluoromethane sulfonic acid, trifluoroacetic acid, difluoroacetic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid, 2,6-dimethylbenzene sulfonic acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid, and the like. They can also be Lewis acids such as aluminum chloride, borontrifluoride, antimony pentafluoride and the like. Acids in a protic can also be used to hydrolyze esters, amides and the like as well as catalyze exchange reactions.

[0334] Conversion of a carboxylic acid protected as an ester or amide into a hydroxamic acid or hydroxamic acid derivative such as an O-arylalkylether or O-cycloalkoxyalkylether group is useful. In the case where hydroxylamine is used, treatment of an ester or amide with one or more equivalents of hydroxylamine hydrochloride at room temperature or above in a solvent or solvents, usually protic or partially protic, such as those listed above can provide a hydroxamic acid directly. This exchange process can be further catalyzed by the addition of additional acid. Alternatively, a base such as a salt of an alcohol used as a solvent, for example, sodium methoxide in methanol, can be used to form hydroxylamine from hydroxylamine hydrochloride in situ which can exchange with an ester or amide. As mentioned above, exchange can be carried out with a protected hydroxylamine such as tetrahydropyranylhydroxyamine (THPONH2), benzylhydroxylamine (BnONH2), and the like in which case compounds such as shown in Schemes A, B and C that are tetrahydropyranyl (THP) or benzyl (Bn) hydroxamic acid derivatives are the products. Removal of the protecting groups when desired, for example, following further transformations in another part of the molecule or following storage, is accomplished by standard methods well known in the art such as acid hydrolysis of the THP group as discussed above or reductive removal of the benzyl group with hydrogen and a metal catalyst such as palladium, platinum, palladium on carbon or nickel.

[0335] In the case where R20 is hydroxyl; i.e., where the intermediate is a carboxylic acid, standard coupling reactions can be used. For example, the acid can be converted into an acid chloride, mixed anhydride or activated ester such as hydroxybenzotriazole and treated with hydroxylamine or a protected hydroxylamine in the presence of a non-competitive base to the nitrogen acylated compound. This is the same product as discussed above. Couplings of this nature are well known in the art and especially the art related to peptide and amino acid chemistry.

[0336] An amide of this invention, whether used as a drug or as a protecting group, is prepared by treatment of an acid halide, anhydride, mixed anhydride or active ester with a primary amine, secondary amine or ammonia, or their equivalent. These standard coupling reactions are well known in the art and are discussed elsewhere herein. An alternative method of preparation of amides is by the exchange of, for example, an alkoxycarbonyl (ester) or aminecarbonyl (amide) group for an amine or different amine as required. Ester exchange processes are especially useful when less hindered amines, including ammonia, are used to make the corresponding amides of this invention.

[0337] Further, amides can be prepared from hydroxamic acids or protected hydroxamic acid compounds by catalytic reductions or in vivo or in vitro enzymatic processes. For example, catalytic reduction of O-benzylhydroxamic acid compounds is known to produce varying ratios of amide and hydroxamic acid depending upon the catalyst used as well as other reaction conditions such as solvent, temperature, hydrogen gas pressure and the like.

[0338] Compounds contemplated herein can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers, enantiomers, diastereoisomers, as well as in the form of racemic or nonracemic mixtures. A compound can also exist in other isomeric forms such as ortho, meta and para isomers, cis and trans isomers, syn and anti isomers, E and Z isomers, tautomeric isomers, alpha and beta isomers, axial and equatorial isomers and isomers due to hindered rotation. An isomer can exist in equilibrium with another isomer in a mammal or a test system. Such a compound can also exist as an isomeric equilibrium system with a solvent or water, for example, as a hydrated ketone or aldehyde, as is well known in the art. All isomers are included as compounds of this invention.

[0339] The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, are applicable to the preparation of the corresponding compounds that are contemplated.

[0340] Table 1 through Table 165, below, show several contemplated aromatic sulfone hydroxamic acid inhibitor compounds or structural formulas that illustrate substituent groups. Each group of compounds is illustrated by a generic formula, or formulae, followed by a series of preferred moieties or groups that constitute various substituents that can be attached at the position clearly shown in the generic structure. The substituent symbols, e.g., R1 and R2 and R3, are as shown in each Table, and are typically not those used before. One or two bonds (wavy lines) are shown with those substituents to indicate the respective positions of attachment in the illustrated compound. This system is well known in the chemical communication arts and is widely used in scientific papers and presentations. For example in Table 2, R1 and R2 together with the atoms to which they are bonded is the variable group with the structural entities that can substitute for R1 and R2 together shown in the balance of that table.

1TABLE 1

[0341]

2

TABLE 2

II

[0342]

3

TABLE 3

100

[0343]

4

TABLE 4

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

[0344]

5

TABLE 5

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

[0345]

6

TABLE 6

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

[0346]

7

TABLE 7

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

[0347]

8

TABLE 8

199

200

201

202

203

204

205

206

207

208

209

210

[0348]

9

TABLE 9

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

[0349]

10

TABLE 10

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

[0350]

11

TABLE 11

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

[0351]

12

TABLE 12

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

[0352]

13

TABLE 13

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

[0353]

14

TABLE 14

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

[0354]

15

TABLE 15

354

355

356

357

358

359

360

361

362

363

364

365

366

[0355]

16

TABLE 16

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

[0356]

17

TABLE 17

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

[0357]

18

TABLE 18

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

[0358]

19

TABLE 19

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

[0359]

20

TABLE 20

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

[0360]

21

TABLE 21

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

[0361]

22

TABLE 22

511

512

513

514

515

516

517

518

519

520

521

522

[0362]

23

TABLE 23

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

[0363]

24

TABLE 24

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

[0364]

25

TABLE 25

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

[0365]

26

TABLE 26

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

[0366]

27

TABLE 27

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

[0367]

28

TABLE 28

640

641

642

643

644

645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

[0368]

29

TABLE 29

662

663

664

665

666

667

668

669

670

671

672

673

[0369]

30

TABLE 30

674

675

676

677

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

[0370]

31

TABLE 31

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

[0371]

32

TABLE 32

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

[0372]

33

TABLE 33

738

739

740

741

742

743

744

745

746

747

748

749

750

751

752

753

754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

[0373]

34

TABLE 34

769

770

771

772

773

774

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

790

[0374]

35

TABLE 35

791

792

793

794

795

796

797

798

799

800

801

802

[0375]

36

TABLE 36

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

[0376]

37

TABLE 37

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

[0377]

38

TABLE 38

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

[0378]

39

TABLE 39

866

867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

[0379]

40

TABLE 40

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

[0380]

41

TABLE 41

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936

937

938

939

940

941

[0381]

42

TABLE 42

942

943

944

945

946

947

948

949

950

951

952

953

[0382]

43

TABLE 43

954

955

956

957

958

959

960

961

962

963

964

965

966

967

968

969

970

971

972

973

974

975

[0383]

44

TABLE 44

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990

991

992

993

994

[0384]

45

TABLE 45

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

[0385]

46

TABLE 46

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

[0386]

47

TABLE 47

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070

[0387]

48

TABLE 48

1071

1072

1073

1074

1075

1076

1077

1078

1079

1080

1081

1082

1083

1084

1085

1086

1087

1088

1089

1090

1091

1092

[0388]

49

TABLE 49

1093

1094

1095

1096

1097

1098

1099

1100

1101

1102

1103

1104

[0389]

50

TABLE 50

1105

1106

1107

1108

1109

1110

1111

1112

1113

1114

1115

1116

1117

1118

1119

1120

1121

1122

1123

1124

1125

1126

[0390]

51

TABLE 51

1127

1128

1129

1130

1131

1132

1133

1134

1135

1136

1137

1138

1139

1140

1141

1142

1143

1144

1145

[0391]

52

TABLE 52

1146

1147

1148

1149

1150

1151

1152

1153

1154

1155

1156

1157

1158

1159

1160

1161

1162

1163

1164

1165

1166

1167

[0392]

53

TABLE 53

1168

1169

1170

1171

1172

1173

1174

1175

1176

1177

1178

1179

1180

1181

1182

1183

1184

1185

1186

1187

1188

1189

1190

[0393]

54

TABLE 54

1191

1192

1193

1194

1195

1196

1197

1198

1199

1200

1201

1202

1203

1204

1205

1206

1207

1208

1209

1210

1211

1212

1213

1214

1215

1216

1217

1218

1219

1220

1221

[0394]

55

TABLE 55

1222

1223

1224

1225

1226

1227

1228

1229

1230

1231

1232

1233

1234

1235

1236

1237

1238

1239

1240

1241

1242

1243

[0395]

56

TABLE 56

1244

1245

1246

1247

1248

1249

1250

1251

1252

1253

1254

1255

[0396]

57

TABLE 57

1256

1257

1258

1259

1260

1261

1262

1263

1264

1265

1266

1267

1268

1269

1270

1271

1272

1273

1274

1275

1276

1277

[0397]

58

TABLE 58

1278

1279

1280

1281

1282

1283

1284

1285

1286

1287

1288

1289

1290

1291

1292

1293

1294

1295

1296

[0398]

59

TABLE 59

1297

1298

1299

1300

1301

1302

1303

1304

1305

1306

1307

1308

1309

1310

1311

1312

1313

1314

1315

1316

1317

1318

[0399]

60

TABLE 60

1319

1320

1321

1322

1323

1324

1325

1326

1327

1328

1329

1330

1331

1332

1333

1334

1335

1336

1337

1338

1339

1340

1341

[0400]

61

TABLE 61

1342

1343

1344

1345

1346

1347

1348

1349

1350

1351

1352

1353

1354

1355

1356

1357

1358

1359

1360

1361

1362

1363

1364

1365

1366

1367

1368

1369

1370

1371

1372

1373

[0401]

62

TABLE 62

1374

1375

1376

1377

1378

1379

1380

1381

1382

1383

1384

1385

1386

1387

1388

1389

1390

1391

1392

1393

1394

1395

1396

[0402]

63

TABLE 63

1397

1398

1399

1400

1401

1402

1403

1404

1405

1406

1407

1408

1409

[0403]

64

TABLE 64

1410

1411

1412

1413

1414

1415

1416

1417

1418

1419

1420

1421

1422

1423

1424

1425

1426

1427

1428

1429

1430

1431

1432

[0404]

65

TABLE 65

1433

1434

1435

1436

1437

1438

1439

1440

1441

1442

1443

1444

1445

1446

1447

1448

1449

1450

1451

1452

[0405]

66

TABLE 66

1453

1454

1455

1456

1457

1458

1459

1460

1461

1462

1463

1464

1465

1466

1467

1468

1469

1470

1471

1472

1473

1474

1475

[0406]

67

TABLE 67

1476

1477

1478

1479

1480

1481

1482

1483

1484

1485

1486

1487

1488

1489

1490

1491

1492

1493

1494

1495

1496

1497

1498

1499

[0407]

68

TABLE 68

1500

1501

1502

1503

1504

1505

1506

1507

1508

1509

1510

1511

1512

1513

1514

1515

1516

1517

1518

1519

1520

1521

1522

1523

1524

1525

1526

1527

1528

1529

1530

1531

[0408]

69

TABLE 69

1532

1533

1534

1535

1536

1537

1538

1539

1540

1541

1542

1543

1544

1545

1546

1547

1548

1549

1550

1551

1552

1553

1554

[0409]

70

TABLE 70

1555

1556

1557

1558

1559

1560

1561

1562

1563

1564

1565

1566

1567

[0410]

71

TABLE 71

1568

1569

1570

1571

1572

1573

1574

1575

1576

1577

1578

1579

1580

1581

1582

1583

1584

1585

1586

1587

1588

1589

[0411]

72

TABLE 72

1590

1591

1592

1593

1594

1595

1596

1597

1598

1599

1600

1601

1602

1603

1604

1605

1606

1607

1608

[0412]

73

TABLE 73

1609

1610

1611

1612

1613

1614

1615

1616

1617

1618

1619

1620

1621

1622

1623

1624

1625

1626

1627

1628

1629

1630

[0413]

74

TABLE 74

1631

1632

1633

1634

1635

1636

1637

1638

1639

1640

1641

1642

1643

1644

1645

1646

1647

1648

1649

1650

1651

1652

1653

[0414]

75

TABLE 75

1654

1655

1656

1657

1658

1659

1660

1661

1662

1663

1664

1665

1666

1667

1668

1669

1670

1671

1672

1673

1674

1675

1676

1677

1678

1679

1680

1681

1682

1683

1684

[0415]

76

TABLE 76

1685

1686

1687

1688

1689

1690

1691

1692

1693

1694

1695

1696

1697

1698

1699

1700

1701

1702

1703

1704

1705

1706

[0416]

77

TABLE 77

1707

1708

1709

1710

1711

1712

1713

1714

1715

1716

1717

1718

[0417]

78

TABLE 78

1719

1720

1721

1722

1723

1724

1725

1726

1727

1728

1729

1730

1731

1732

1733

1734

1735

1736

1737

1738

1739

1740

[0418]

79

TABLE 79

1741

1742

1743

1744

1745

1746

1747

1748

1749

1750

1751

1752

1753

1754

1755

1756

1757

1758

1759

[0419]

80

TABLE 80

1760

1761

1762

1763

1764

1765

1766

1767

1768

1769

1770

1771

1772

1773

1774

1775

1776

1777

1778

1779

1780

1781

[0420]

81

TABLE 81

1782

1783

1784

1785

1786

1787

1788

1789

1790

1791

1792

1793

1794

1795

1796

1797

1798

1799

1800

1801

1802

1803

1804

[0421]

82

TABLE 82

1805

1806

1807

1808

1809

1810

1811

1812

1813

1814

1815

1816

1817

1818

1819

1820

1821

1822

1823

1824

1825

1826

1827

1828

1829

1830

1831

1832

1833

1834

1835

[0422]

83

TABLE 83

1836

1837

1838

1839

1840

1841

1842

1843

1844

1845

1846

1847

1848

1849

1850

1851

1852

1853

1854

1855

1856

1857

[0423]

84

TABLE 84

1858

1859

1860

1861

1862

1863

1864

1865

1866

1867

1868

1869

[0424]

85

TABLE 85

1870

1871

1872

1873

1874

1875

1876

1877

1878

1879

1880

1881

1882

1883

1884

1885

1886

1887

1888

1889

1890

1891

[0425]

86

TABLE 86

1892

1893

1894

1895

1896

1897

1898

1899

1900

1901

1902

1903

1904

1905

1906

1907

1908

1909

1910

[0426]

87

TABLE 87

1911

1912

1913

1914

1915

1916

1917

1918

1919

1920

1921

1922

1923

1924

1925

1926

1927

1928

1929

1930

1931

1932

[0427]

88

TABLE 88

1933

1934

1935

1936

1937

1938

1939

1940

1941

1942

1943

1944

1945

1946

1947

1948

1949

1950

1951

1952

1953

1954

1955

[0428]

89

TABLE 89

1956

1957

1958

1959

1960

1961

1962

1963

1964

1965

1966

1967

1968

1969

1970

1971

1972

1973

1974

1975

1976

1977

1978

1979

1980

1981

1982

1983

1984

1985

1986

[0429]

90

TABLE 90

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

[0430]

91

TABLE 91

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

2020

[0431]

92

TABLE 92

2021

2022

2023

2024

2025

2026

2027

2028

2029

2030

2031

2032

2033

2034

2035

2036

2037

2038

2039

2040

2041

2042

[0432]

93

TABLE 93

2043

2044

2045

2046

2047

2048

2049

2050

2051

2052

2053

2054

2055

2056

2057

2058

2059

2060

2061

[0433]

94

TABLE 94

2062

2063

2064

2065

2066

2067

2068

2069

2070

2071

2072

2073

2074

2075

2076

2077

2078

2079

2080

2081

2082

2083

[0434]

95

TABLE 95

2084

2085

2086

2087

2088

2089

2090

2091

2092

2093

2094

2095

2096

2097

2098

2099

2100

2101

2102

2103

2104

2105

2106

[0435]

96

TABLE 96

2107

2108

2109

2110

2111

2112

2113

2114

2115

2116

2117

2118

2119

2120

2121

2122

2123

2124

2125

2126

2127

2128

2129

2130

2131

2132

2133

2134

2135

2136

2137

[0436]

97

TABLE 97

2138

2139

2140

2141

2142

2143

2144

2145

2146

2147

2148

2149

2150

2151

2152

2153

2154

2155

2156

2157

2158

2159

[0437]

98

TABLE 98

2160

2161

2162

2163

2164

2165

2166

2167

2168

2169

2170

2171

[0438]

99

TABLE 99

2172

2173

2174

2175

2176

2177

2178

2179

2180

2181

2182

2183

2184

2185

2186

2187

2188

2189

2190

2191

2192

2193

[0439]

100

TABLE 100

2194

2195

2196

2197

2198

2199

2200

2201

2202

2203

2204

2205

2206

2207

2208

2209

2210

2211

2212

[0440]

101

TABLE 101

2213

2214

2215

2216

2217

2218

2219

2220

2221

2222

2223

2224

2225

2226

2227

2228

2229

2230

2231

2232

2233

2234

2235

[0441]

102

TABLE 102

2236

2237

2238

2239

2240

2241

2242

2243

2244

2245

2246

2247

2248

2249

2250

2251

2252

2253

2254

2255

2256

2257

2258

2259

[0442]

103

TABLE 103

2260

2261

2262

2263

2264

2265

2266

2267

2268

2269

2270

2271

2272

2273

2274

2275

2276

2277

2278

2279

2280

2281

2282

2283

2284

2285

2286

2287

2288

2289

2290

2291

[0443]

104

TABLE 104

2292

2293

2294

2295

2296

2297

2298

2299

2300

2301

2302

2303

2304

2305

2306

2307

2308

2309

2310

2311

2312

2313

2314

[0444]

105

TABLE 105

2315

2316

2317

2318

2319

2320

2321

2322

2323

2324

2325

2326

2327

[0445]

106

TABLE 106

2328

2329

2330

2331

2332

2333

2334

2335

2336

2337

2338

2339

2340

2341

2342

2343

2344

2345

2346

2347

2348

2349

2350

[0446]

107

TABLE 107

2351

2352

2353

2354

2355

2356

2357

2358

2359

2360

2361

2362

2363

2364

2365

2366

2367

2368

2369

2370

[0447]

108

TABLE 108

2371

2372

2373

2374

2375

2376

2377

2378

2379

2380

2381

2382

2383

2384

2385

2386

2387

2388

2389

2390

2391

2392

2393

[0448]

109

TABLE 109

2394

2395

2396

2397

2398

2399

2400

2401

2402

2403

2404

2405

2406

2407

2408

2409

2410

2411

2412

2413

2414

2415

2416

2417

[0449]

110

TABLE 110

2418

2419

2420

2421

2422

2423

2424

2425

2426

2427

2428

2429

2430

2431

2432

2433

2434

2435

2436

2437

2438

2439

2440

2441

2442

2443

2444

2445

2446

2447

2448

2449

[0450]

111

TABLE 111

2450

2451

2452

2453

2454

2455

2456

2457

2458

2459

2460

2461

2462

2463

2464

2465

2466

2467

2468

2469

2470

2471

[0451]

112

TABLE 112

2472

2473

2474

2475

2476

2477

2478

2479

2480

2481

2482

2483

[0452]

113

TABLE 113

2484

2485

2486

2487

2488

2489

2490

2491

2492

2493

2494

2495

2496

2497

2498

2499

2500

2501

2502

2503

2504

2505

[0453]

114

TABLE 114

2506

2507

2508

2509

2510

2511

2512

2513

2514

2515

2516

2517

2518

2519

2520

2521

2522

2523

2524

[0454]

115

TABLE 115

2525

2526

2527

2528

2529

2530

2531

2532

2533

2534

2535

2536

2537

2538

2539

2540

2541

2542

2543

2544

2545

2546

[0455]

116

TABLE 116

2547

2548

2549

2550

2551

2552

2553

2554

2555

2556

2557

2558

2559

2560

2561

2562

2563

2564

2565

2566

2567

2568

2569

[0456]

117

TABLE 117

2570

2571

2572

2573

2574

2575

2576

2577

2578

2579

2580

2581

2582

2583

2584

2585

2586

2587

2588

2589

2590

2591

2592

2593

2594

2595

2596

2597

2598

2599

2600

[0457]

118

TABLE 118

2601

2602

2603

2604

2605

2606

2607

2608

2609

2610

2611

2612

[0458]

119

TABLE 119

2613

2614

2615

2616

2617

2618

2619

2620

2621

2622

2623

2624

2625

2626

2627

2628

2629

2630

2631

2632

2633

2634

[0459]

120

TABLE 120

2635

2636

2637

2638

2639

2640

2641

2642

2643

2644

2645

2646

2647

2648

2649

2650

2651

2652

2653

[0460]

121

TABLE 121

2654

2655

2656

2657

2658

2659

2660

2661

2662

2663

2664

2665

2666

2667

2668

2669

2670

2671

2672

2673

2674

2675

[0461]

122

TABLE 122

2676

2677

2678

2679

2680

2681

2682

2683

2684

2685

2686

2687

2688

2689

2690

2691

2692

2693

2694

2695

2696

2697

2698

[0462]

123

TABLE 123

2699

2700

2701

2702

2703

2704

2705

2706

2707

2708

2709

2710

2711

2712

2713

2714

2715

2716

2717

2718

2719

2720

2721

2722

2723

2724

2725

2726

2727

2728

2729

[0463]

124

TABLE 124

2730

2731

2732

2733

2734

2735

2736

2737

2738

2739

2740

2741

2742

2743

2744

2745

2746

2747

2748

2749

2750

2751

[0464]

125

TABLE 125

2752

2753

2754

2755

2756

2757

2758

2759

2760

2761

2762

2763

[0465]

126

TABLE 126

2764

2765

2766

2767

2768

2769

2770

2771

2772

2773

2774

2775

2776

2777

2778

2779

2780

2781

2782

2783

2784

2785

[0466]

127

TABLE 127

2786

2787

2788

2789

2790

2791

2792

2793

2794

2795

2796

2797

2798

2799

2800

2801

2802

2803

2804

2805

2806

2807

[0467]

128

TABLE 128

2808

2809

2810

2811

2812

2813

2814

2815

2816

2817

2818

2819

2820

2821

2822

2823

2824

2825

2826

2827

2828

2829

[0468]

129

TABLE 129

2830

2831

2832

2833

2834

2835

2836

2837

2838

2839

2840

2841

2842

2843

2844

2845

2846

2847

2848

2849

2850

2851

2852

2853

2854

2855

2856

[0469]

130

TABLE 130

2857

2858

2859

2860

2861

2862

2863

2864

2865

2866

2867

2868

2869

2870

2871

2872

2873

2874

2875

2876

2877

2878

2879

2880

2881

2882

2883

[0470]

131

TABLE 131

2884

2885

2886

2887

2888

2889

2890

2891

2892

2893

2894

2895

2896

2897

2898

2899

2900

2901

2902

2903

2904

2905

2906

2907

2908

2909

2910

2911

[0471]

132

TABLE 132

2912

2913

2914

2915

2916

2917

2918

2919

2920

2921

2922

2923

2924

2925

2926

2927

2928

2929

2930

2931

2932

2933

2934

2935

2936

2937

2938

2939

[0472]

133

TABLE 133

2940

2941

2942

2943

2944

2945

2946

2947

2948

2949

2950

2951

2952

2953

2954

2955

2956

2957

2958

2959

2960

2961

2962

2963

2964

2965

2966

2967

[0473]

134

TABLE 134

2968

2969

2970

2971

2972

2973

2974

2975

2976

2977

2978

2979

2980

2981

2982

2983

2984

2985

2986

2987

2988

2989

2990

2991

2992

2993

2994

2995

[0474]

135

TABLE 135

2996

2997

2998

2999

3000

3001

3002

3003

3004

3005

3006

3007

3008

3009

3010

3011

3012

3013

[0475]

136

TABLE 136

3014

3015

3016

3017

3018

3019

3020

3021

3022

3023

3024

3025

3026

3027

3028

3029

3030

3031

[0476]

137

TABLE 137

3032

3033

3034

3035

3036

3037

3038

3039

3040

3041

3042

3043

3044

3045

3046

3047

3048

3049

[0477]

138

TABLE 138

3050

3051

3052

3053

3054

3055

3056

3057

3058

3059

3060

3061

3062

3063

3064

3065

3066

3067

[0478]

139

TABLE 139

3068

3069

3070

3071

3072

3073

3074

3075

3076

3077

3078

3079

3080

3081

3082

3083

3084

3085

[0479]

140

TABLE 140

3086

3087

3088

3089

3090

3091

3092

3093

3094

3095

3096

3097

3098

3099

3100

3101

3102

3103

[0480]

141

TABLE 141

3104

3105

3106

3107

3108

3109

3110

3111

3112

3113

3114

3115

3116

3117

3118

3119

3120

3121

[0481]

142

TABLE 142

3122

3123

3124

3125

3126

3127

3128

3129

3130

3131

3132

3133

3134

3135

3136

3137

3138

3139

[0482]

143

TABLE 143

3140

3141

3142

3143

3144

3145

3146

3147

3148

3149

3150

3151

3152

3153

[0483]

144

TABLE 144

3154

3155

3156

3157

3158

3159

3160

3161

3162

3163

3164

3165

3166

3167

[0484]

145

TABLE 145

3168

3169

3170

3171

3172

3173

3174

3175

3176

3177

3178

3179

3180

3181

[0485]

146

TABLE 146

3182

3183

3184

3185

3186

3187

3188

3189

3190

3191

3192

3193

3194

3195

[0486]

147

TABLE 147

3196

3197

3198

3199

3200

3201

3202

3203

3204

3205

3206

3207

3208

3209

[0487]

148

TABLE 148

3210

3211

3212

3213

3214

3215

3216

3217

3218

3219

3220

3221

3222

3223

[0488]

149

TABLE 149

3224

3225

3226

3227

3228

3229

3230

3231

3232

3233

3234

3235

3236

3237

[0489]

150

TABLE 150

3238

3239

3240

3241

3242

3243

3244

3245

3246

3247

3248

3249

3250

3251

[0490]

151

TABLE 151

3252

3253

3254

3255

3256

3257

3258

3259

3260

3261

3262

3263

3264

3265

3266

3267

3268

3269

3270

3271

3272

3273

3274

3275

3276

3277

3278

3279

3280

3281

3282

3283

3284

3285

3286

3287

3288

3289

3290

3291

3292

3293

3294

[0491]

152

TABLE 152

3295

3296

3297

3298

3299

3300

3301

3302

3303

3304

3305

3306

3307

3308

3309

3310

3311

3312

3313

3314

3315

3316

3317

3318

3319

3320

3321

3322

3323

3324

3325

3326

3327

3328

3329

3330

3331

3332

3333

3334

3335

3336

3337

3338

3339

3340

3341

3342

3343

3344

3345

3346

3347

3348

[0492]

153

TABLE 153

3349

3350

112

3351

3352

113

3353

3354

114

3355

100

3356

115

3357

101

3358

116

3359

102

3360

117

3361

103

3362

118

3363

104

3364

119

3365

105

3366

120

3367

106

3368

121

3369

107

3370

122

3371

108

3372

123

3373

109

3374

124

3375

110

3376

125

3377

111

3378

126

3379

[0493]

154

TABLE 154

3380

127

3381

142

3382

128

3383

143

3384

129

3385

144

3386

130

3387

145

3388

131

3389

146

3390

132

3391

147

3392

133

3393

148

3394

134

3395

149

3396

135

3397

150

3398

136

3399

151

3400

137

3401

152

3402

138

3403

153

3404

139

3405

154

3406

140

3407

155

3408

141

3409

156

3410

[0494]

155

TABLE 155

3411

157

3412

165

3413

158

3414

166

3415

159

3416

167

3417

160

3418

168

3419

161

3420

169

3421

162

3422

170

3423

163

3424

171

3425

164

3426

172

3427

[0495]

156

TABLE 156

3428

3429

3430

3431

3432

3433

3434

3435

3436

3437

3438

3439

3440

3441

3442

3443

3444

3445

3446

3447

3448

3449

3450

3451

3452

3453

3454

3455

3456

3457

3458

3459

3460

3461

3462

3463

3464

3465

3466

3467

3468

3469

3470

[0496]

157

TABLE 157

3471

3472

3473

3474

3475

3476

3477

3478

3479

3480

3481

3482

3483

3484

3485

3486

3487

3488

3489

3490

3491

3492

3493

3494

3495

3496

3497

3498

3499

3500

3501

3502

3503

3504

3505

3506

3507

3508

3509

3510

3511

3512

3513

3514

3515

3516

3517

3518

3519

3520

3521

3522

3523

3524

[0497]

158

TABLE 158

3525

3526

112

3527

3528

113

3529

3530

114

3531

100

3532

115

3533

101

3534

116

3535

102

3536

117

3537

103

3538

118

3539

104

3540

119

3541

105

3542

120

3543

106

3544

121

3545

107

3546

122

3547

108

3548

123

3549

109

3550

124

3551

110

3552

125

3553

111

3554

126

3555

[0498]

159

TABLE 159

3556

127

3557

142

3558

128

3559

143

3560

129

3561

144

3562

130

3563

145

3564

131

3565

146

3566

132

3567

147

3568

133

3569

148

3570

134

3571

149

3572

135

3573

150

3574

136

3575

151

3576

137

3577

152

3578

138

3579

153

3580

139

3581

154

3582

140

3583

155

3584

141

3585

156

3586

[0499]

160

TABLE 160

3587

157

3588

165

3589

158

3590

166

3591

159

3592

167

3593

160

3594

168

3595

161

3596

169

3597

162

3598

170

3599

163

3600

171

3601

164

3602

172

3603

[0500]

161

TABLE 161

3604

3605

3606

3607

3608

3609

3610

3611

3612

3613

3614

3615

3616

3617

3618

3619

3620

3621

3622

3623

3624

3625

3626

3627

3628

3629

3630

3631

3632

3633

3634

3635

3636

3637

3638

3639

3640

3641

3642

3643

3644

3645

3646

[0501]

162

TABLE 162

3647

3648

3649

3650

3651

3652

3653

3654

3655

3656

3657

3658

3659

3660

3661

3662

3663

3664

3665

3666

3667

3668

3669

3670

3671

3672

3673

3674

3675

3676

3677

3678

3679

3680

3681

3682

3683

3684

3685

3686

3687

3688

3689

3690

3691

3692

3693

3694

3695

3696

3697

3698

3699

3700

[0502]

163

TABLE 163

3701

3702

3703

3704

100

3705

101

3706

102

3707

103

3708

104

3709

105

3710

106

3711

107

3712

108

3713

109

3714

110

3715

111

3716

112

3717

113

3718

114

3719

115

3720

116

3721

117

3722

118

3723

119

3724

120

3725

121

3726

122

3727

123

3728

124

3729

125

3730

126

3731

[0503]

164

TABLE 164

3732

127

3733

128

3734

129

3735

130

3736

131

3737

132

3738

133

3739

134

3740

135

3741

136

3742

137

3743

138

3744

139

3745

140

3746

141

3747

142

3748

143

3749

144

3750

145

3751

146

3752

147

3753

148

3754

149

3755

150

3756

151

3757

152

3758

153

3759

154

3760

155

3761

156

3762

[0504]

165

TABLE 165

3763

157

3764

158

3765

159

3766

160

3767

161

3768

162

3769

163

3770

164

3771

165

3772

166

3773

167

3774

168

3775

169

3776

170

3777

171

3778

172

3779

[0505] Treatment Method

[0506] A contemplated inhibitor compound is used for treating a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee or human that has a condition associated with pathological matrix metalloprotease activity.

[0507] Also contemplated is use of a contemplated metalloprotease inhibitor compound in the treatment of a disease state that can be affected by the activity of metalloproteases TNF-α convertase. Exemplary of such disease states are the acute phase responses of shock and sepsis, coagulation responses, hemorrhage and cardiovascular effects, fever and inflammation, anorexia and cachexia.

[0508] In treating a disease condition associated with pathological matrix metalloproteinase activity, a contemplated MMP inhibitor compound can be used in the form of an amine salt derived from an inorganic or organic acid. Exemplary salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.

[0509] Also, a basic nitrogen-containing group can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others to provide enhanced water-solubility. Water or oil-soluble or dispersible products are thereby obtained as desired. The salts are formed by combining the basic compounds with the desired acid.

[0510] Other compounds useful in this invention that are acids can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts.

[0511] In some cases, the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.

[0512] Total daily dose administered to a host mammal in single or divided doses can be in amounts, for example, for 0.001 to 30 mg/kg body weight daily and more usually 0.01 to 10 mg. Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. A suitable dose can be administered, in multiple sub-doses per day. Multiple doses per day can also increase the total daily dose, should this be desired by the person prescribing the drug.

[0513] The dosage regimen for treating a disease condition with a compound and/or composition of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the preferred dosage regimen set forth above.

[0514] A compound of the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.; 1975 and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.

[0515] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.

[0516] Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

[0517] Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, a contemplated aromatic sulfone hydroximate inhibitor compound can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.

[0518] For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from soerile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. A contemplated aromatic sulfone hydroximate inhibitor compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

[0519] Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

[0520] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.

BEST MODE FOR CARRYING OUT THE INVENTION

[0521] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limiting of the remainder of the disclosure in any way whatsoever.

[0522] Abbreviations are often used for reagents and solvents in the specific examples that follow. Those abbreviations and their meanings are as follows:

[0523] BOC=t-butoxycarbonyl

[0524] DEAD=diethyl azodicarboxylate

[0525] DMF=dimethylformamide

[0526] DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone

[0527] EtOAc=ethyl acetate

[0528] EDC=1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride

[0529] Et2O=diethyl ether

[0530] HOBT=1-hydroxybenzotriazole

[0531] MeOH=methanol

[0532] MeCl2=methylene chloride

[0533] MsCl=methanesulfonyl chloride

[0534] NMM=N-methyl morpholine

[0535] THF=tetrahydrofruan

[0536] TsCl=toluenesulfonyl chloride

[0537] THP—O-hydroxylamine=O-tetrahydropyran-hydroxylamine and O-tetrahydro-2H-pyran-2-yl-hydroxylamine

[0538] The preparation of compounds useful in the synthesis of compounds of the invention are provided herein below in Preparative Examples I through XI.

PREPARATIVE EXAMPLE I

Preparation of 1,1-dimethylethyl ester 4-[(hydroxyamino)-carbonyl]-4-[(phenoxyphenyl)-sulfonyl]-1-piperidinecarboxylic acid

[0539]

166

3780

[0540] Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (DMSO; 20 mL) was heated to sixty-five degrees Celsius for 5 hours. The solution remained at ambient temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H2O and saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).

[0541] 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 minutes. The solution was stirred overnight (about eighteen hours) 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.

[0542] Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol in THF (30 mL), cooled to minus seventy-eight degrees Celsius, was added n-butyl lithium (12.5 mL, 20 mmol) drop-wise. After 15 minutes, the BOC-piperidine compound of part B (2.6 g, 10 mmol) in THF (10 mL) was added drop-wise. After 1.5 hours the solution was cooled to minus sixty degrees Celsius and the disulfide of part A (2.0 g, 10 mmol) in THF (7 mL). The solution was stirred at ambient temperature for 2 hours. The solution was diluted with H2O 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%).

[0543] Part D: To a solution of the sulfide of part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to zero degrees Celsius, was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hours followed by dilution with H2O 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%).

[0544] 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 H2O (3 mL). The solution was heated at sixty-five degrees Celsius for 18 hours. 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.

[0545] 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 hours and additional N-hydroxybenzotriazole.H2O (256 mg), EDC (424 mg) and 50 percent aqueous hydroxylamine (1.04 mL) were added. After an additional 24 hours 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

[0546]

3781

[0547] 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 minutes. The solution was stirred overnight (about eighteen hours) 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).

[0548] Part B: A solution of 4-fluorothiophenol (50.29 g, 390 mmol) in DMSO (500 mL) was heated to 65 degrees Celsius for 6 hours. 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%).

[0549] 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 degrees Celsius was added lithium diisopropylamide (41.33 mL, 74 mmol) and the solution was stirred for 1.5 hours at zero degrees Celsius. 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 hours. The reaction was quenched with the addition of H2O 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%).

[0550] Part D: To a solution of the sulfide of part C (16.5 g, 43 mmol) in dichloromethane (500 mL) cooled to zero degrees Celsius was added 3-chloroperbenzoic acid (18.0 g, 86 mmol) and the solution was stirred for 20 hours. The solution was diluted with H2O 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%).

[0551] 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 minutes followed by stirring at ambient temperature for 4 hours. Concentration in vacuo provided the amine hydrochloride salt as a white solid (7.27 g, 86%).

[0552] 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 hours at ambient temperature. The solution was partitioned between ethyl acetate and H2O, 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%).

[0553] 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 CsCO3 (2.79 g, 8.56 mmol) and the solution was heated to 70 degrees Celsius for 6 hours. 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%).

[0554] Part H: To a solution of the S-phenoxyphenyl of part G (1.81 g, 4.06 mmol) in ethanol (21 mL) and H2O (3.5 mL) was added KOH (1.37 g, 24.5 mmol) and the solution was heated to 105 degrees Celsius for 4.5 hours. 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).

[0555] 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 hours. The solution was partitioned between H2O 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%).

[0556] Part J: To a solution of the protected hydroxamate of part I (9.65 g, 18.7 mmol) in methanol (148 mL) cooled to zero degrees Celsius was added acetyl chloride (4.0 mL, 56.2 mmol), and the solution was stirred for 45 minutes 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 C21H22N2O4S2: 431, found 431.

PREPARATIVE EXAMPLE III

Preparation of N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide, monohydrochloride

[0557]

3782

[0558] Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (20 mL) was heated to 65 degrees Celsius for 5 hours. The solution remained at ambient temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H2O and saturated NaCl, and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).

[0559] 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 minutes. 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).

[0560] Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol) in THF (30 mL), cooled to minus seventy-eight degrees Celsius, was added n-butyl lithium (12.5 mL, 20 mmol) dropwise. After 15 minutes, the BOC-piperidine compound of Part B (2.6 g, 10 mmol) in THF (10 mL) was added dropwise. After 1.5 hours, the solution was cooled to minus sixty degrees Celsius 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 hours. The solution was diluted with H2O 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%).

[0561] Part D: To a solution of the sulfide of

[0562] Part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to zero degrees Celsius, was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hours followed by dilution with H2O 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%).

[0563] Part E: Into a solution of the sulfone of

[0564] Part D (3.56 g, 7.0 mmol) in ethyl acetate (100 mL) cooled to zero degrees Celsius was bubbled HCl gas for 5 minutes. 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 C20H23NO5S: 390, found 390.

[0565] Part F: To a solution of the amine hydrochloride salt of part E (2.6 g, 6 mmol) and K2CO3 (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 hours. 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%).

[0566] 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 degrees Celsius for 48 hours. 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).

[0567] 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 hours. The solution was diluted with H2O 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.

[0568] Part I: To a solution of the hydroxamate of part H (121 mg, 0.292 mmol) in methanol (2 mL) cooled to zero degrees Celsius was added acetyl chloride (0.228 mL, 0.321 mmol) in methanol (1 mL). After stirring at ambient temperature for 30 minutes the solution was concentrated under a stream of N2. 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

[0569]

3783

[0570] Part A: In dry equipment under nitrogen, sodium metal (8.97 g, 0.39 mol) was added to methanol (1000 mL) at two degrees Celsius. The reaction was stirred at ambient temperature for forty five minutes at which time the sodium had dissolved. The solution was chilled to five degrees Celsius 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 four hours, filtered, and concentrated in vacuo to give the sulfide as a clear colorless oil (75.85 g, 97%).

[0571] 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 degrees Celsius. An exotherm to 67 degrees Celsius was noted. After two hours, 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 MgSO4, filtered, and concentrated in vacuo to give the sulfone as a crystalline solid (82.74 g, 94%).

[0572] 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 hours) 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 C13H15O5S1F1: 303, found 303.

[0573] 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 ninety minutes, 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=1. The slurry was extracted with ethyl acetate and the combined extracts washed with water, dried over Na2SO4, 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 C12H13O5 S1F1: 287.04, found 287.04.

[0574] 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 three hours at ambient temperature, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, 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 C17H22NO6 S1F1: 388.12, found 388.12.

PREPARATIVE EXAMPLE V

Preparation of tetrahydro-N-hydroxy-4-[[4-[4-trifluoromethoxy)-phenoxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide

[0575]

3784

[0576] Part A: To a solution of the title compound of Preparative Example IV (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 degrees Celsius for nineteen hours. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na2SO4, 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.

[0577] 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 fifteen minutes at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over Na2SO4, 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

[0578]

3785

[0579] 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 hours. The precipitated solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with H2O (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 MH30 calculated for C17H22NO4SF: 356, found: 356.

[0580] 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 degrees Celsius for 18 hours 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 degrees Celsius 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 degrees Celsius in a vacuum oven to afford the ether as a white solid (1.8 g, 68%): MS+ calcd. for C25H31NO6S 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.

[0581] 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 H2O (16 mL) was heated at 60 degrees Celsius under a nitrogen atmosphere for 24 hours. 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 degrees Celsius in a vacuum oven to give a crude white solid acid (2.3 g).

[0582] 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 C28H36N2O7S 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.

[0583] 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).

[0584] 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 hours, the precipitate was collected by filtration, washed with diethyl ether, and dried at 45 degrees Celsius in a vacuum oven to afford the title compound as a white solid (0.58 g, 79%): MS MH+ calcd. for C23H28N2O6S 461, found 461. Anal. calcd. for C23H28N2O6S.1.5 HCl: 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

[0585]

3786

[0586] Part A: To a solution of the product of Preparative Example II, Part D (30 g, 161 mmol) in dichloromethane (50 mL) cooled to zero degrees Celsius was added trifluroacetic acid (25 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the trifluoroacetate salt and K2CO3 (3.6 g, 26 mmol) in N,N-dimethylformamide (50 mL) cooled to zero degrees Celsius was added 2-bromoethyl methyl ether (19 mL, 201 mmol), and solution was stirred at ambient temperature for 36 hours. 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%).

[0587] Part B: To a solution of methoxyethyl amine (6.0 g, 16.0 mmol) of Part A and powdered K2CO3 (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 ninety degrees Celsius for 25 hours. 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%).

[0588] 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 H2O (28 mL) from an addition funnel at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. 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%).

[0589] 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 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3, 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).

[0590] 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 hours. Concentration in vacuo and trituration with diethyl ether provided the title compound as a white solid (4.79 g, 78.2%). Analytical calculation for C22H25N2O7SF3.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

[0591]

3787

[0592] 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 hours 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%).

[0593] Part B: To a solution of 4-fluorophenol (50.0 g, 0.390 mol) in acetone (400 mL), degassed with N2, was added Cs2CO3 (159 g, 0.488 mol). After degassing the resulting mixture with N2 for 5 minutes, 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 hours 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%).

[0594] 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 hours and then filtered. The filtrate was washed with saturated NaHCO3 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%).

[0595] Part D: To a solution of sulfone of Part C (7.00 g, 20.4 mmol) in N,N-dimethylformamide (40 mL) was added Cs2CO3 (19.9 g, 61.2 mmol) and α,α,α-trifluoro-α-cresol (3.97 g, 24.5 mmol). The resulting mixture was heated at eighty degrees Celsius for 16 hours. 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%).

[0596] Part E: To a solution of the biaryl ether of Part D (8.59 g, 17.7 mmol) in tetrahydrofuran (100 mL), cooled to zero degrees Celsius, was slowly added lithium bis(trimethylsilyl)amide (22.0 mL, 1.0M in tetrahydrofuran, 22.0 mmol), at such a rate that the temperature of the reaction never exceeded one degree Celsius. The resulting mixture was stirred at zero degrees Celsius for 1 hour 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 four degrees Celsius. After the addition was complete, the mixture was slowly permitted to warm to ambient temperature. Saturated NH4Cl (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%).

[0597] 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 hours additional 4N HCl in dioxane (10 mL, 40 mmol) was added. After stirring at ambient temperature for 2.5 hours, the reaction mixture was concentrated in vacuo to provide the amine as an off-white solid (6.80 g, >100%).

[0598] Part G: To a suspension of the amine of Part F (3.00 g, 6.25 mmol) in acetonitrile (20 mL) was added K2CO3 (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 hours. 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%).

[0599] 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 hours, H2O 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%).

[0600] Part I: To a suspension of the amino acid of

[0601] Part H (2.87 g, 5.29 mmol) in dichloromethane (25 mL) was added N-methylmorpholine (1.74 mL, 15.9 mmol), 0-(tetrahydropuranyl) hydroxylamine (0.682 g, 5.82 mmol) and PyBroP® (2.96 g, 6.35 mmol). After stirring at ambient temperature for 19 hours 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 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and H2O. 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%).

[0602] 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 hours 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 C25H31O6N3SF3: 558, found 558.

PREPARATIVE EXAMPLE IX

Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride

[0603]

3788

[0604] 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 K2CO3 (3.42 g, 18.0 mmol) and 4-(triflouromethoxy)phenol (3.7 g, 24.8 mmol). The solution was stirred at ninety degrees Celsius for 40 hours. 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.

[0605] 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 sixty degrees Celsius for 18 hours. 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+ calculated for C22H22NSO6F3: 486.1198, found 486.1200.

[0606] 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 hours. The solution was diluted with H2O (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%).

[0607] 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 hours, the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (4.02 g, 81%). HRMS MH+ 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

[0608]

3789

[0609] 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 K2CO3 (12.34 g, 38.0 mmol) and α,α,α-trifluoromethyl phenol (3.65 g, 22.5 mmol). The solution was stirred ninety degrees Celsius for 28 hours. 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)

[0610] 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 sixty degrees Celsius for 18 hours. 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+ calculated for C22H22NSO5F3: 470, found 470.

[0611] 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 hours. The solution was diluted with H2O (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%).

[0612] 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 hours, 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 C22H23N2SO5F3: 485, found 485.

PREPARATIVE EXAMPLE XI

Preparation of Resin II

[0613] Step 1: Attachment of Compound of

PREPARATIVE EXAMPLE IV TO RESIN I

[0614] A 500 mL round-bottomed flask was charged with of resin I [Floyd et al., 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 hours, 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.

[0615] Step 2: Preparation of Resin III:

[0616] Reaction of Resin II With Nucleophiles

[0617] 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 degrees Celsius for 24-48 hours, 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).

[0618] Large Scale Preparation of Resin IIIa:

[0619] 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 degrees Celsius with a heating mantle for 65 hours. The flask was thereafter cooled to room temperature.

[0620] 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 IIIa as described in step 3 yielded 10.4 mg of off-white solid spectroscopically indistinguishable from a known sample.

[0621] Step 3: Cleavage of Hydroxamic Acids From The Polymer-Support

[0622] Resin III was treated with a trifluoroacetic acid/water mixture (19:1, 1 mL) for 1 hour 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.

[0623] Step 4: Hydrolysis of Polymer-Bound Ester: Preparation of Resin IVa

[0624] 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 minutes. Then, a 4 M solution of KOH (5 mL, 20 mmol) was added, and the mixture was stirred for 44 hours. 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.

EXAMPLE 1

Preparation of 1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethoxy) phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide

[0625]

3790

[0626] Part A: To a solution of the product of Preparative Example II, part D, (30 g, 161 mmol) in dichloromethane (50 mL) cooled to zero degrees Celsius was added trifluroacetic acid (25 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the trifluoroacetate salt and K2CO3 (3.6 g, 26 mmol) in N,N-dimethylformamide (50 mL) cooled to zero degrees Celsius was added 2-bromoethyl methyl ether (19 mL, 201 mmol) and solution was stirred at ambient temperature for 36 hours. 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%).

[0627] Part B: To a solution of the methoxyethyl amine (6.0 g, 16.0 mmol) of part A and powdered K2CO3 (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 ninety degrees Celsius for 25 hours. 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%).

[0628] 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 H2O (28 mL) from an addition funnel at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. 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 the white precipitation provided the carboxylic acid as a white solid (5.64 g, 73.3%).

[0629] Part D: To a suspension of the carboxylic acid of part C (200 mg, 0.397 mmol) in methylene chloride (4 mL) was added oxalyl chloride (101 mg, 0.80 mmol). After 15 minutes at ambient temperature the volatiles were removed under vacuum. The solid residue was resuspended in methylene chloride (4 mL) and gaseous ammonia was bubbled through the suspension. Triethylamine (81 mg, 0.80 mmol) was added and the stream of ammonia gas through the reaction was continued for 1 minute. Concentration afforded a solid which was chromatographed (reverse phase C18 silica eluting with a gradient of 30% acetonitrile/water to 100% acetonitrile) to afford the desired primary amide as a colorless powder (6 mg, 3 mg). MS MH+ calculated for C22H25N2 F3O6S: 503, found 503. HRMS M+ calculated for C22H25N2 F3O6S: 503.1464, found 503.1472.

EXAMPLE 2

Preparation of 4-[(4-phenylthiophenyl) sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide

[0630]

3791

[0631] A mixture of the acid from Preparative Example II, part H, (1.29 g, 2.85 mMol), N-hydroxybenzotriazole (1.15 g, 8.54 mMol), 4-methylmorpholine (0.94 mL, 14 mMol), concentrated NH4OH (3 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.64 g, 8.54 mMol) in DMF (25 mL) was stirred at ambient temperature for 20 hours. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, water, and brine, dried over magnesium sulfate, and concentrated in vacuo. Chromatography (on silica, MeOH/CHCl3) afford the title amide as a white solid (0.143 g, 12%). Analytical calculation for C21H22N2O3S2: C, 60.84; H, 5.35; N, 6.76; S, 15.47. Found: C, 60.74; H, 5.31; N, 6.74; S, 15.43.

EXAMPLES 3-58

[0632] 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:

167

3792

MSExampleAmineR(M + H)33,5-Dimethylpiperidine

3793

5084N-Methylpropargylamine

3794

4645N-Methylallylamine

3795

46661-(1-phenylethyl)- piperazine

3796

58571-(2-phenylethyl)- piperazine

3797

58581-(2-chlorophenyl)- piperazine

3798

59191-(4-methoxyphenyl)-2- methylpiperazine

3799

585101-(5-Chloro-2- methylphenyl)piperazine

3800

605111-(2-methoxyphenyl)- piperazine

3801

587121-Acetylpiperazine

3802

523131-(2,4-Dimethylphenyl)- piperazine

3803

58514N-(2-hydroxyethyl)- piperazine

3804

525151-(Ethoxy- carbonylmethyl)- piperazine

3805

567161-(2-Fluorophenyl)- piperazine

3806

575171-(2-Furoyl)-piperazine

3807

575181-(Cyclopentyl)- piperazine

3808

549191-(2-Propyl)-piperazine

3809

52320N-(2-(1-Piperazino)- acetyl)pyrrolidine

3810

592211-(3-Dimethyl- aminopropyl)- piperazine

3811

566221-(2-Methoxyethyl)- piperazine

3812

539231-(2-Dimethyl- aminoethyl)- piperazine

3813

552241-(2-Ethoxyphenyl)- piperazine

3814

601251-(4-Fluorphenyl)- piperazine

3815

575261-(2-Pyridyl)-piperazine

3816

558272-(1-piperazinyl)- pyrimidine

3817

559284-Piperazino- acetophenone

3818

599291-(4-Nitrophenyl)- piperazine

3819

602301-(3,5-Dichloropyrid-4- yl)piperazine

3820

626314-(2-Methoxyphenyl)- piperidine

3821

58632N-[2-Nitro-4- (trifluoromethyl)- phenyl]piperazine

3822

670331-[3-(Trifluormethyl)- pyrid-2-yl]- piperazine

3823

62634cis-3,5-Dimethyl- morpholine

3824

51035N-Propylcyclopropane- methylamine

3825

508361-(2,4-Difluorphenyl)- piperazine

3826

593371-(4-Pyridyl)- piperazine

3827

558381-(4-Trifluoromethyl- phenyl)-piperazine

3828

625391-Allylpiperazine

3829

521401-(2-Pyrazinyl)- piperazine

3830

559411-[3-Chloro-5- (trifluoromethyl)pyrid- 2-yl)]piperazine

3831

660421-(2-(4-Morpholino)- ethyl)piperazine

3832

594433-Chlorophenyl- piperazine

3833

591444-(Hydroxymethyl)- piperidine

3834

51045Diisobutylamine

3835

52446cis-2,6-Dimethyl- piperazine

3836

509473-Methylpiperidine

3837

49448N,N-Diallylamine

3838

492491-[4-(Trifluormethyl)- 2-pyrimidyl]- piperazine

3839

627501-[4-(Trifluormethyl)- 2-pyridyl]- piperazine

3840

62651N,N,N′-Trimethyl- ethylenediamine

3841

49752(4-Ethylaminomethyl)- pyridine

3842

53153Methyl-cyclopropylamine

3843

466543,5-Dimethyl-piperidine

3844

508553,5-Dimethyl-piperidine

3845

50856Isobutylamine

3846

46857Propylamine

3847

45458N-Methyl- isobutylamine

3848

482

EXAMPLES 59-78

[0633] Step 5: Preparation of Resin V

[0634] Into a fritted reaction vessel was weighed resin IVa (100 mg, 0.083 mmol), and the vessel was capped under nitrogen and cooled to zero degrees Celsius. A 1.0 M solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine in methylene chloride (0.4 mL, 0.4 mmol) was added followed by a 1.0 M solution of N-methylmorpholine in methylene chloride (0.6 mL, 0.6 mmol.) The solutions were stirred for 4 hours at zero degrees Celsius and warmed to ambient temperature. A 0.7 M solution of the appropriate amine to be reacted in methylene chloride (0.4 mL, 0.28 mmol) was added and the reaction mixture stirred for 24 hours. The reaction mixture was stirred for 24 hours, then the resin was drained and washed with 1-methyl-2-pyrrolidinone and methylene chloride (4×3 mL each solvent). The reaction was repeated using the same amounts of reagents described above. The reaction was stirred for 4 hours at zero degrees Celsius after the activating step and ambient temperature for 24 hours following amine solution addition. After 24 hours, 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).

[0635] The following hydroxamic acids were synthesized using the indicated polymer-bound acid and the indicated amine in Step 5 followed by release from the polymer using Step 3, before:

168

3849

ExampleAmineRMS (M + H)59Aniline

3850

48860N-Methylaniline

3851

502614-(Trifluoromethyl)- aniline

3852

556624-Aminopyridine

3853

489632-(Trifluoromethoxy)- aniline

3854

572642-Chloroaniline

3855

522652-Fluoroaniline

3856

50666o-Anisole

3857

518672-(Methylamino)- pyridine

3858

503683-(Trifluoromethoxy)- aniline

3859

572693-(Trifluoromethyl)- aniline

3860

556703-Chloroaniline

3861

522713-Fluoroaniline

3862

50672m-Anisole

3863

518734-(Trifluoromethoxy)- aniline

3864

572744-Aminopyrmidine

3865

490754-Fluoroaniline

3866

50676p-Anisole

3867

51877N,N-Dimethyl-1,3- phenylenediamine

3868

53178N,N-Dimethyl-p- phenylenediamine

3869

531

EXAMPLES 79-88

[0636] Step 12: Further Synthesis of Resin III.

[0637] 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 degrees Celsius for 30 hours. 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).

[0638] The following hydroxamic acids were synthesized from Resin III using Step 11 with the indicated amines, followed by release from the polymer using the reaction conditions in Step 3.

169

3870

ExampleAmineRMS (M + H)791-(2-Methoxyphenyl)- piperidine

3871

475804-(4-Methoxybenzoyl)- piperidine

3872

50381Pyrrolidine

3873

355821-(4-Methoxyphenyl)-2- piperazine

3874

490831-(2-Fluorophenyl)- piperazine

3875

464841-(2,4- Diemthylphenyl)- piperiazine

3876

474851-(2-Methoxyphenyl- piperazine

3877

476861-(4-Trifluoromethyl- phenyl)piperazine

3878

514871-(2,4- Difluorophenyl)- piperazine

3879

482881-(2-Chlorphenyl)- piperazine

3880

480

EXAMPLE 89

Preparation of N-hydroxy-4 [[4-(4-trifluoromethoxyphenoxy)phenyl] sulfonyl]-1-(9-fluorenylmethoxy-carbonyl)-4-piperidinecarboxamide

[0639]

3881

[0640] To a solution of 4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-[(1,1diemthylethoxy)-carbonyl]piperidinecarboxylic acid (6.25 g, 11.5 mmol) prepared using techniques discussed elsewhere herein was added 50% trifluoroacetic acid solution in dichloromethane (100 mL) and stirred 1 hour at room temperature. The solvent was evaporated to afford 9.91 g of an oil. The oil was dissolved in acetonitrile (50 mL) and water (50 mL). To the solution was added sodium carbonate to a pH-9-10 followed by a solution of N-(9-fluorenylmethoxy-carbonyloxy)succinimide (3.88 g, 11.5 mmol) in acetone (25 mL). The pH value of the solution was adjusted to 9-10 with sodium carbonate. The reaction mixture was stirred 16 hours. To the reaction mixture was added 2M aqueous hydrochloric acid to a pH value of about 3. The solution was extracted with dichloromethane (3×100 mL). The combined organics were dried over magnesium sulfate, filtered and the solvent evaporated to afford N-hydroxy-4 [[4-(4-trifluoromethoxyphenoxy)phenyl] sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide (8.15 g) as a yellow oil. MS (ES) m/z 668 (M+H)+.

EXAMPLE 90

Preparation of N-hydroxy-4 [[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide

[0641]

3882

[0642] Using the method of Example 89, N-hydroxy-4-[[4-(4-trifluoromethyl-phenoxy)phenyl] sulfonyl]-1-(9-fluorenyl-methoxycarbonyl)-4-piperidinecarboxamide was prepared from 4-[[4-(4-trifluoromethylphenoxy)-phenyl]-sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]-piperidinecarboxylic acid, which itself was prepared using techniques discussed elsewhere herein. MS (ES) m/z 652 (M+H)+.

EXAMPLE 91

Preparation of N-hydroxy-4-[[4-(4-trifluoromethoxyphenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide

[0643]

3883

[0644] Step 1: Preparation of Resin MT-I. To a solution of N-hydroxy-4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxy-carbonyl)-4-piperidinecarboxamide of Example 89 (11.5 mmol) in dimethylformamide (75 mL) were added resin I (Floyd et al., Tetrahedron Lett. 1996, 37, 8045-8048) (7.0 g, 7.67 mmol), pyBOP (8.0 g) and N-methylmorpholine (5.05 mL), and the mixture was stirred with an overhead stirrer 4 days. 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-I.

[0645] Step 2: Fmoc deprotection of Resin MT-I. Resin MT-I was swelled with dimethylformamide (2×100 mL) and drained. To swollen resin MT-1, was added a 20% solution of piperidine in dimethylformamide (100 mL). After 1 hour, the resin was drained and retreated with 20% piperidine in dimethylformamide (100 mL). After 15 minutes the resin was filtered and washed with dimethylformamide (3×100 mL), methanol (3×100 mL), dichloromethane (3×100 mL) and ether (3×100 mL). The resin was dried in vacuo to afford resin MT-II (7.23 g).

[0646] Step 3: Preparation of N-hydroxy-4-[[4-(4-trifluoromethoxyphenoxy)phenyl]sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide from Resin MT-II. To a suspension of resin MT-II (250 mg) in dichloromethane (2 mL) was added diisopropyl-ethylamine (165 μL) and benzoyl chloride (110 μL) and agitated 3 hours. The resin was filtered and washed with dichloromethane (2×10 mL) and methanol (2×10 mL). To the resin was added a solution of 95% trifluoroacetic acid in water and agitated for 1 hour. The resin was drained and washed with methanol (1×2 mL) and dichloromethane (1×2 mL). The filtrate was evaporated. The residue was purified by RPHPLC to afford N-hydroxy-4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide (9.8 mg) as a solid. MS (ES) m/z 565 (M+H)+.

EXAMPLE 92

Preparation of N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide

[0647]

3884

[0648] N-hydroxy-4-[[4-(4-trifluoromethyl-phenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide was prepared by the method of Example 91 from N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide (the product of Example 90). MS (ES) m/z 549 (M+H)+.

EXAMPLE 93

Preparation of N-(2-tetrahydropyranoxy) -4-[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-4-piperidinecarboxamide

[0649]

3885

[0650] Step 1: Boc deprotection of ethyl 4-[[4-(4-trifluoromethoxyphenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]piperidinecarboxylate. To a solution of ethyl 4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)-carbonyl]piperidinecarboxylate (12.58 g, 19.1 mmol; see Example 89) in dichloromethane (50 mL) was added trifluoroacetic acid (50 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to afford a pale yellow oil.

[0651] Step 2: Cbz protection of step 1. The material from step 1 was dissolved in dichloromethane (200 mL). To this solution was added diisopropyl-ethylamine (33.3 mL) and benzyl chloroformate (5.5 mL) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2M aqueous hydrochloric acid to a pH value of about 1 and extracted with dichloromethane (2×100 mL). The combined organics were washed with 2M aqueous HCl (1×100 mL) and brine (1×100 mL), dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow oil.

[0652] Step 3: Hydrolysis of the product of step 2. The material prepared in step 2 was dissolved in tetrahydrofuran (100 mL) and ethanol (50 mL). To this solution was added 1M aqueous sodium hydroxide (50 mL) and 50% aqueous sodium hydroxide (10 mL) and stirred 16 hours. To the solution was added 50% aqueous sodium hydroxide (2 mL) and stirred and additional 24 hours. The tetrahydrofuran and ethanol were evaporated. The pH value of the solution was adjusted to pH about 1 with concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×100 mL), washed with brine (1×100 mL), dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow oil.

[0653] Step 4: Cbz deprotection of step 3. The material prepared in step 3 was dissolved in ethanol (100 mL). This solution was added to 10% palladium on carbon (1.0 g). The solution was placed under 45 psi hydrogen. Additional catalyst was added at 6 hours (1.75 g) and 20 hours (1.0 g 4% Pd/C). After 48 hours the reaction mixture was filtered through a plug of Celite. The filtrate was evaporated and triturated with ether to afford N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide (4.47 g) as a white solid. MS (ES) m/z 545 (M+H)+.

EXAMPLE 94

Preparation of N-(2-tetrahydro-pyranoxy)-4[[4-(4-trifluoromethyl-phenoxy)phenyl]sulfonyl]-4-piperidine-carboxamide

[0654]

3886

[0655] N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide was prepared by the method of Example 93 starting from ethyl 4-[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]piperidinecarboxylate (see Example 90). MS (ES) m/z 529 (M+H)+.

EXAMPLE 95

Preparation of N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(2-fluorophenyl-carbonyl)-4-piperidinecarboxamide

[0656]

3887

[0657] To a solution of N-(2-tetrahydropyranoxy)-4 [[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94, (50 mg) dissolved in dichloromethane (2.5 mL) was added PS-NMM (135 mg, Argonaut) and 2-fluorobenzoyl chloride (12.1 μL) and stirred for 2 hours. To the reaction mixture was added PS-trisamine (50 mg, Argonaut) and the mixture was stirred 1 hour. The reaction mixture was filtered and washed with dichloromethane (2×2 mL) and methanol (1×2 mL). The combined organics were evaporated to afford N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]-sulfonyl]-1-(2-fluorophenylcarbonyl)-4-piperidinecarboxamide (53.5 mg) as a white solid. MS (ES) m/z 583 (M+H)+.

EXAMPLES 96-124

[0658] The following hydroxamic acids were prepared by the method of Example 95 using the appropriate acylating agent.

170

3888

MS (ES)ExampleRAcylating Agentm/z963-fluorophenyl3-fluorobenzoyl583 (M + H)+chloride974-fluorophenyl4-fluorobenzoyl583 (M + H)+chloride982-trifluoro-2-trifluoromethyl-633 (M + H)+methylphenylbenzoyl chloride993-trifluoro-3-trifluoro-633 (M + H)+methylphenylmethylbenzoylchloride100phenylmethylphenylacetyl chloride579 (M + H)+1012-tolyl2-toluoyl chloride579 (M + H)+1024-tolyl4-toluoyl chloride579 (M + H)+1034-methoxy-methyl 4-623 (M + H)+carbonylphenylchlorocarbonylbenzoate1044-methoxyphenyl4-anisoyl chloride595 (M + H)+1052-thienyl2-thiophenecarbonyl571 (M + H)+chloride1062-furyl2-furoyl chloride555 (M + H)+1073-pyridylnicotinoyl chloride566 (M + H)+1084-pyridylisonicotinoyl566 (M + H)+chloride109c-propylcyclopropanecarbonyl529 (M + H)+chloride110trichloromethyltrichloroacetic622 (M + H)+anhydride111trifluoromethyltrifluoroacetic574 (M + H)+anhydride112pentafluorophenylpentafluorobenzoyl655 (M + H)+chloride1134-nitrophenyl4-nitrobenzoyl610 (M + H)+chloride1144-trifluoro-4-trifluoromethyl-633 (M + H)+methylphenylbenzoyl chloride1154-trifluoro-4-trifluoromethoxy-649 (M + H)+methoxyphenylbenzoyl chloride1164-methoxy-4-methoxyphenyl-609 (M + H)+phenylmethylacetyl chloride1173-methoxyphenyl3-anisoyl chloride595 (M + H)+1182-methoxyphenyl2-anisoyl chloride595 (M + H)+1193,5-3,5-dimethoxybenzoyl625 (M + H)+dimethoxyphenylchloride1203,4-3,4-dimethoxybenzoyl625 (M + H)+dimethoxyphenylchloride1212,5-2,5-difluorobenzoyl601 (M + H)+difluorophenylchloride122methoxy-methyl malonyl561 (M + H)+carbonylmethylchloride1234-dimethyl-4-dimethylamino-608 (M + H)+aminophenylbenzoyl chloride1241,1-dimethylethylpivaloyl chloride545 (M + H)+

EXAMPLES 125-138

[0659] The following hydroxamic acids were prepared by the method of Example of 95 using the appropriate isocyanate as the acylating agent.

171

3889

Ex-MS (ES)ampleRNCOIsocyanatem/z125

3890

Phenyl isocyanate580 (M + H)126

3891

4-Fluorophenyl isocyanate598 (M + H)127

3892

4-Methoxybenzyl isocyanate624 (M + H)128

3893

Ethyl isocyanate532 (M + H)129

3894

3-Trifluoromethyl phenyl isocyanate648 (M + H)130

3895

3-Isocyanate propionic acid576 (M + H)131

3896

3-Pyridyl isocyanate581 (M + H)132

3897

4-Chlorophenyl isocyanate614 (M + H)133

3898

3-Fluorophenyl isocyanate598 (M + H)134

3899

4-Acetylphenyl isocyanate622 (M + H)135

3900

2-Fluorophenyl isocyanate598 (M + H)136

3901

4-(Methylthio) phenyl isocyanate626 (M + H)137

3902

Benzyl isocyanate594 (M + H)138

3903

3-Cyanophenyl isocyanate605 (M + H)

EXAMPLES 140-143

[0660] The following hydroxamic acids were prepared by the method of Example 95 using the appropriate acylating agent (electophile) and starting from N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94.

172

3904

Ex-am-MSpleRElectrophile(ES) m/z140

3905

4-trifluoro- methoxybenzoyl chloride633 (M + H)+141

3906

4-trifluoromethyl- phenyl isocyantate632 (M + H)+142

3907

4-trifluoro- methylphenyl thioisocyanate648 (M + H)+143

3908

4-trifluoromethyl- benzenesulfonyl chloride653 (M + H)+

EXAMPLE 144

Preparation of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(4-aminophenylcarbonyl)-4-piperidinecarboxamide

[0661]

3909

[0662] A solution of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(4-nitrophenylcarbonyl)-4-piperidinecarboxamide, the product of Example 113, (56.0 mg) dissolved in acetic acid (2.5 mL) was added to 4% palladium on carbon (20 mg) and placed under 43 psi hydrogen gas for 2.5 h. The reaction mixture was filtered through a pad of celite. The solvent was evaporated to afford N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(4-aminophenylcarbonyl)-4-piperidinecarboxamide (50.2 mg) as a pale yellow solid. MS (ES) m/z 580 (M+H)+.

EXAMPLE 145

Preparation of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]-sulfonyl]-1-(4-carboxyphenylcarbonyl)-4-piperidinecarboxamide

[0663]

3910

[0664] To a solution of the product of Example 103 (57 mg) dissolved in tetrahydrofuran (1 mL) and ethanol (1 mL) was added 1M aqueous sodium hydroxide solution (1 mL) plus 50% aqueous sodium hydroxide (50 μL) and the reaction mixture was stirred 2 hours. The pH value of the reaction mixture was adjusted to 1 with 6M hydrochloric acid. The solution was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified by RPHPLC to afford the acid N-hydroxy-4[[4-(4-trifluoromethyl-phenoxy)phenyl]sulfonyl]-1-(4-carboxyphenylcarbonyl)-4-piperidinecarboxamide (12.8 mg). MS (ES) m/z 631 (M+NH4)+.

EXAMPLE 146

Preparation of N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxamide

[0665]

3911

[0666] 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 hours. 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).

[0667] 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 hours. 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).

[0668] 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 hours. 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 hour. 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.

EXAMPLES 147-151

[0669] The following hydroxamic acids were prepared by the method of Example 146 using the appropriate alcohol.

173

3912

ExampleRAlcoholMS (ES) m/z1474-trifluoro-4-trifluoro-495 (M + NH4)+methoxyphenylmethoxyphenol1484-isopropyl-4-isopropylphenol453 (M + NH4)+phenyl1493-pyridyl3-hydroxypyridine395 (M + H)+1503,4-dimethoxy-3,4-dimethoxyphenol471 (M + NH4)+phenyl1514-pyridyl4-hydroxypyridine395 (M + H)+

EXAMPLES 152-155

[0670] The following hydroxamic acids were prepared by the method of Example 146 using the appropriate amine.

174

3913

ExampleRAmineMS (ES) m/z1524-(4-fluoro-4-(4-fluorobenzoyl)-507 (M + H)+benzoyl)piperidylpiperidine1534-(2-methoxy-4-(2-methoxyphenyl)-491 (M + H)+phenyl)piperidylpiperidine154

3914

N-cyclopropyl-meth- yl-N-methyl-4-pipe- ridine carboxamide496 (M + H)+155pyrrolidinylpyrrolidine371 (M + H)+

Example 156

Preparation of N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxamide-1,1-dioxide

[0671]

3915

[0672] Step 1: Oxidation of Resin MT-III. A suspension of resin MT-III (2.0 g, 1.72 mmol), m-perbenzoic chloroperbenzoic acid (4.37 g) and dichloromethane 25 mL) was stirred at room temperature for 20 hours. 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).

[0673] 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 146 using resin MT-IV in the place of resin MT-III. ES (MS) m/z 473 (M+NH4)+.

EXAMPLES 156-160

[0674] The following hydroxamic acids were prepared by the method of Example 156 using the appropriate alcohol.

175

3916

ExampleRAlcoholMS (ES) m/z1574-trifluoro-4-trifluoro-527 (M + NH4)+methoxyphenylmethoxyphenol1584-isopropylphenyl4-isopropylphenol485 (M + NH4)+1593-pyridyl3-hydroxypyridine427 (M + H)+1604-pyridyl4-hydroxypyridine427 (M + H)+

EXAMPLE 161

[0675] The following hydroxamic acids were prepared by the method of Example 156 using the appropriate amine.

176

3917

ExampleRAmineMS (ES) m/z1614-(4-fluorobenzoyl)4-(4-fluoro-539 (M + H)+piperidylbenzoyl)-piperidine

Example 162

Preparation of N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]-piperidyl]phenyl]sulfonyl]-4-thianecarboxamide

[0676]

3918

[0677] 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 hours. 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).

[0678] 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.

[0679] 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 hours. 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 hour. 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)+.

EXAMPLE 163

Preparation of N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]-piperidyl]phenyl]sulfonyl]-4-thianecarboxamide

[0680] N-hydroxy-4-[[4-[4-[(3,5-dimethyl-piperidyl)carbonyl]piperidyl]phenyl]sulfonyl]-4-thianecarboxamide was prepared by the method of using cis-2,6-dimethylmorpholine as the amine. MS (ES) m/z 526 (M+H)+.

EXAMPLE 164

N-hydroxy-4[[[4-[4-(4-fluorophenyl)-methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide

[0681]

3919

[0682] Step 1: Preparation of amine 4-(4-fluorophenyl)methoxy piperidine. Ninety-five percent dry sodium hydride is weighted in a 25 mL vial. Boc-(4-hydroxy)-piperidine (1 g, 4.97 mmol) in 10 mL of dimethyl formamide is added and the reaction mixture is stirred at room temperature for 15 minutes 4-fluoro benzyl bromide (1.4 g, 7.5 mmol) is added and the reaction mixture is stirred at room temperature for 16 hours, then quenched with water and diluted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10. The Boc-protected amine is dissolved in 3 mL of dichloromethane and 3 mL of trifluoroacetic acid and the reaction mixture is stirred at room temperature for 16 hours and the solvent is evaporated to give 1.8 g of 4-(4-fluorophenyl)-methoxy piperidine. MS: M+H=210.1319.

[0683] Step 2: Preparation of N-hydroxy-4 [[[4-[4-(4-fluorophenyl)methoxy] piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide. To a solution of N-tetrahydropyranoxy-4-fluorophenyl-sulfonyl-1-tetrahydropyrancarboxamide (100 mg, 0.26 mmol) in 1.5 mL of DMA are added the amine from step 1 (0.52 mmol, 2 eq.) and cesium carbonate (420 mg, 1.29 mmol). The reaction mixture is stirred at 100° C. for 48 hours. The reaction is treated with water and filtered through Celite eluting with dichloromethane. The solvent was evaporated and the residue is dissolved in 2 mL of 4M HCl in dioxane. The mixture is stirred at room temperature for 1 hour and 1 mL of methanol is added. After stirring 15 minutes at room temperature, the solvent is evaporated and the residue was purified by RPHPLC eluting with 10% to 90% acetonitrile/water to give N-hydroxy-4-[[[4-[4-(4-fluorophenyl)methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide. MS: M+H=493.1792.

EXAMPLES 165-181

[0684] The following hydroxamic acids were synthesized by the procedure of Example 164:

177

3920

HIEx-Halide startingRES MSamplematerialRM + H165benzyl bromide

3921

475.1913166ethyl iodide

3922

413.17641674-fluoro benzyl bromide

3923

493.1792168iodopropane

3924

427.19181693,5-dimethyl benzyl bromide

3925

144.13911704-chloro benzyl bromide

3926

509.15151713-methyl benzyl bromide

3927

489.20591724-methyl benzyl bromide

3928

489.20741733-trifluoro- methoxy benzyl bromide

3929

559.17381742-trifluoro- methyl benzyl bromide

3930

543.17801754-trifluoro- methoxy benzyl bromide

3931

559.17301763,4-dichloro- benzyl bromide

3932

543.11551773-trifluoro- methyl benzyl bromide

3933

543.17791783,5-dimethoxy- benzyl bromide

3934

535.21201793,4-difluoro- benzyl bromide

3935

511.17051804-cyano- benzyl bromide

3936

500.18351812-phenyl benzyl bromide

3937

551.2196

Example 182

N-hydroxy-4-[[[4-[3-(4-fluorophenyl)-methoxy]piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide

[0685]

3938

[0686] N-hydroxy-4[[[4-[3-(4-fluorophenyl)-methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydro-pyrancarboxamide is prepared by the method of Example 164 starting from Boc-(3-hydroxy)-piperidine in step 1.

Examples 183-184

[0687] The following hydroxamic acids were synthesized using a procedure similar to that of Example 182:

178

3939

HalidestartingExamplematerialRHI RES MS1834-fluroro benzyl bromide

3940

M + H =475.1913184benzyl bromide

3941

M + H =551.2196

Example 185

N-hydroxy-4[[[4-(4-phenoxy)-piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide

[0688]

3942

[0689] N-hydroxy-4 [[[4-(4-phenoxy)piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide is prepared by the method of Example 164 starting from 4-phenoxypiperidine in step 2.

Examples 186-187

[0690] The following hydroxamic acids were synthesized using a procedure similar to that of Example 185:

179

3943

Ex-ampleAmine starting materialRHI RES MS186 187

3944

H 3,5-di- methylM + H = 461.1749 M + H = 489.2065

Example 188

Preparation of N-hydroxy-4[[[4-[(3-trifluoromethyl)phenylcarbamoxy]-piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide

[0691]

3945

[0692] Step 1: A solution of N-tetrahydro-pyranoxy-4-fluorophenylsulfonyl-1-tetrahydro-pyrancarboxamide (1 g, 2.58 mmol), 4-hydroxy-piperidine (392 mg, 3.87 mmol) and cesium carbonate (2.52 g, 7.74 mmol) in 20 mL of NMP is stirred at 100° C. for 48 hours. The reaction mixture is treated with water and neutralized to pH 4 with 5% aqueous HCl. The aqueous layer is extracted twice with ethyl acetate and the combined organic layer is dried using magnesium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10 to give N-tetrahydropyranoxy-4-[[(4-hydroxypiperidyl) phenyl] sulfonyl]-1-tetrahydropyrancarboxamide. MS: M+Na=491.2.

[0693] Step 2: To a solution of alcohol N-tetrahydro-pyranoxy-4[[(4-hydroxypiperidyl)-phenyl]sulfonyl]-1-tetrahydropyrancarboxamide (50 mg, 0.107 mmol) in 2 mL of dichloromethane is added alpha, alpha, alpha-trifluoro-M-tolyl isocyanate (21 mg, 0.112 mmol). The reaction mixture is stirred for 16 hours at room temperature and 21 mg of alpha,alpha,alpha-trifluoro-m-tolyl isocyanate is added. The mixture is stirred 48 hours at room temperature and treated with water. The solvent is evaporated and the residue is dissolved in 2 mL of 4M HCl in dioxane. The mixture is stirred at room temperature for 1 hour and 1 mL of methanol is added. After stirring 15 minutes at room temperature the solvent is evaporated and the residue was purified by RPHPLC eluting with 10% to 90% acetonitrile/water to give N-hydroxy-4-[[[4-[(3-trifluoromethyl)phenyl-carbamoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide. MS: M+Na=594.1.

EXAMPLES 189-191

[0694] The following hydroxamic acids were synthesized using a procedure similar to that of Example 188:

180

3946

ExampleIsocyanate starting materialRMS189alpha,alpha,alpha-tri- fluoro-M-tolyl isocyanate

3947

M + Na = 594.11904-ethoxyphenyl isocyanate

3948

M + Na = 570.21914-fluorophenyl isocyanate

3949

M + H = 522.1742

Example 192

Preparation of N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]-sulfonyl]-1-[[(2-trifluoromethoxy)-phenyl]-sulfonyl-4-piperidinecarboxamide

[0695]

3950

[0696] N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-1-[[(2-trifluoromethoxy)phenyl]-sulfonyl-4-piperidinecarboxamide can be prepared using the method of Example 93 starting from 2-trifluoromethoxybenzene sulfonyl chloride.

EXAMPLES 193-197

[0697] The following hydroxamic acids were synthesized using a procedure similar to that of Example 192:

181

3951

Sulfonyl chlorideExamplestarting materialRMS1932-trifluoro- methoxybenzene sulfonyl chloride

3952

M + NH4 =702.1003194benzene sulfonyl chloride

3953

M + NH4 =618.1216195alpha- toluenesulfonyl chloride

3954

M + NH4 =632.13371963-trifluoro- methylbenzene sulfonyl chloride

3955

M + NH4 =686.10271973-trifluoro- methane sulfonyl chloride

3956

M − H =591.1

EXAMPLE: 198

[0698]

3957

[0699] N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-1-(N-methylthiourea)-4-piperidinecarboxamide was prepared by the method of Example 192 starting with methyl isothiocyanate. M+H=77.

EXAMPLES 199-202

[0700] The following hydroxamic acids were synthesized using the procedure of Example 198:

182

3958

Sulfonyl chlorideMSExamplestarting materialRM + H1992-morpholinoethyl isothiocyanate

3959

633.16432002-piperidinoethyl isothiocyanate

3960

653.1694201pyridine-3- isothiocyanate

3961

597.10942024-dimethylaminophenyl isothiocyanate

3962

639.1526

EXAMPLE 203

Preparation of 1,1-dimethylethyl-3,6-dihydro-4-[2-(trifluoromethyl)phenyl]-[(2H)-pyridinecarboxylate

[0701]

3963

[0702] 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 degrees, 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 degrees. After complete addition, the flask was stirred with cooling for 20 minutes. Then a solution of N-trifluoromethanesulfonimide (38.2 g, 0.107 mole) was added drop-wise maintaining the temperature less than −65 degrees. After complete addition, the dry ice/acetone bath was swapped with an ice/water bath. The reaction was stirred overnight (about eighteen hours), slowly warming to room temperature. After 16 hours, 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).

[0703] 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 minutes, then palladium tetrakistriphenylphosphine (1.06 g, 0.92 mmol) was added. The mixture was heated to reflux for 1.5 hours, 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).

EXAMPLE 204

Preparation of 1,2,3,6-tetrahydro-4-[2-trifluoromethyl)phenyl]pyridine

[0704]

3964

[0705] The title compound of Example 203 (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 minutes, 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).

EXAMPLE 205

Preparation of 4-[2-(trifluoromethyl) phenyl]piperidine

[0706]

3965

[0707] Part A: A solution of the title compound of Example 203 (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 degrees Celsius for 5 hours. 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).

[0708] 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 minutes, 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).

EXAMPLE 206

General Description for Preparation of Hydroxamic Acids via Aryl Fluoride Displacement with Amines.

[0709] 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 degrees Celsius. 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.

[0710] 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 hours. Then the solvent was removed in vacuo and the residue purified by preparative reversed-phase HPLC.

EXAMPLES 207-214

[0711] The following hydroxamic acids were prepared using the method described above in Example 106 with the indicated amine as the starting material.

183

3966

m/z fromelectrospraymassExampleamineRspectroscopy207Product of Example 205

3967

513.3 (M + H)208Product of Example 204

3968

511.2 (M + H)209piperidine

3969

369.2 (M + H)210tetrahydro- piperidine

3970

367.2 (M + H)2114-(2-keto- benzimid- azolinyl)- piperidine

3971

501 (M + H)212hexamethyl- eneimine

3972

383.2 (M + H)2131-methylhomo- piperazine

3973

398.2 (M + H)2141,3,3-trimethyl- 6-azabicyclo- [3.2.1]octane

3974

437.3 (M + H)

EXAMPLES 215-223

[0712] Using the procedures outlined in Examples 203, 204, 206 and other methods outlined above, the following analogs are made from the indicated boronic acid:

184

3975

ExampleBoronic acidR215

3976

3977

216

3978

3979

217

3980

3981

218

3982

3983

219

3984

3985

220

3986

3987

221

3988

3989

222

3990

3991

223

3992

3993

EXAMPLE 224

Preparation of Tetrahydro-N-hydroxy-4-[[4-(pentaflourooxy)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide

[0713]

3994

[0714] Part A: To a solution of the product of Preparative Example IV (2.5 g, 6 mmol) in dimethylformamide (50 mL) was added 4-pentafluroethyloxy phenol (2.0 g, 6 mmol) followed by cesium carbonate (5 g, 12 mmol). The reaction was heated at eighty degrees Celsius for twelve hours. Stripping the dimethylformamide in vacuo afforded a brown solid (5.5 g). The product was dissolvent in ethylacetate (150 ml) and extracted with water, brine and dried over sodium sulfate. The 1H NMR, MS, and HPLC was consistent with desired compound.

[0715] Part B: To the product of part A, crude THP-protected hydroxamate was disolved in acetonitrile/water (40 ml) was slowly added 10% aq HCl (10 ml). After stirring two hours, the acetonitrile was stripped. The resultant precipitate was collected, giving the title compound as a white solid (2.1 g). The 1H NMR, MS, and HPLC was consistent with desired compound. This solid was recrystallized from ethylacetate and hexanes (1.8 g). The 1H NMR, MS, and HPLC was consistent with desired compound. MS (CI) M+H calculated for C23H27BrNO6S: 511, found 511.

EXAMPLE 225

Preparation of Tetrahydro-4-[[4-(pentaflourooxy)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide

[0716]

3995

[0717] Part A. The product of Preparative Example V (2.5 g) was dissolved in methanol (60 mL). To this solution ammonium formate (3 g) was added, followed by Pd on charcoal 20% catalyst. The mixture was heated to reflux for 24 hour. After complete reaction the mixture was cooled filtered through a plug of Celite and the solvent removed under reduced pressure to give pure amide (1.7 g). The 1H NMR, MS, and HPLC was consistent with desired compound. MS (CI) M+H calculated for C23H27BrNO6S: 445, found 445.

EXAMPLE 226

Preparation of 4-(4-pyridyloxy) thiophenol hydrochloride

[0718]

3996

[0719] Part A: Phenol (1500 g, 15.9 mol) and 4-chloropyridine hydrochloride (800 g, 7.1 mol) were combined in a melt at 150° C. under a nitrogen atmosphere. After fifteen hours, the reaction was dissolve in 3N sodium hydroxide solution (5400 mL) and extracted with methylene chloride (4×). The organic extracts were combined, washed with 1N sodium hydroxide solution, water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The isolated oil was dissolved in hexanes (1000 mL) and cooled to −60° C. The precipitate was collected and dried in vacuo to yield 452 g (38%) of the 4-phenoxypyridine as a white solid.

[0720] Part B: A solution of the 4-phenylpyridine from part A (400 g, 2.3 mol) in 1,2-dichloroethane (1250 mL) was cooled in an ice bath under a nitrogen atmosphere and treated with chlorosulfonic acid (400 mL, 6.0 mol). The reaction temperature was held below 12° C. during the addition. The reaction was then heated to 45° C. for 15 hours. The standard work-up procedure afforded 270 grams (40%) of the desired 4-[(pyrid-4-yl)oxy]benzenesulfonic acid.

[0721] Part C: A slurry of the sulfonic acid part B (420 g, 1.5 mol) in acetonitrile (2500 mL) and DMF (40 mL) was warmed to 75° C. under a nitrogen atmosphere and treated with thionyl chloride (243 mL, 3.3 mol) added dropwise over 3 hours. After stirring for one-half hour, the standard work-up procedure afforded 483 grams (100%) of the desired 4-[(pyrid-4-yl)oxy]benzenesulfonyl chloride hydrochloride.

[0722] Part D: A solution of triphenylphosphine (65.6 g, 250.28 mmol) in dry methylene chloride (240 mL) was cooled to zero degrees C. in an ice-water bath, then treated with dimethylformamide (3.4 mL, 3.2 g, 43.40 mmol). The reaction mixture was then treated with the sulfonyl chloride from part C (25.5 g, 83.43 mmol), added as a solid over one-half hour. After two hours in the ice bath, the reaction was treated with 1 N aqueous hydrochloric acid solution (150 mL) and stirred vigorously for one hour. The layers were separated and the aqueous layer was extracted with methylene chloride (1×). The aqueous layer was concentrated in vacuo to yield 17.9 grams (90%) of the 4-(4-pyridyloxy)thiophenol hydrochloride as a tan solid, m/z=204 (M+H).

EXAMPLE 227

Preparation of

[0723]

3997

[0724] Part A: A solution of 4-(4-pyridyloxy)-thiophenol (2.0 g, 8.34 mmol) and tert-butylbromoacetate (1.2 mL, 1.6 g, 8.34 mmol) in dry methanol (30 mL) was cooled to zero degrees C. and treated with triethylamine (2.4 mL, 1.8 g, 17.52 mmol). The addition was done at a rate which held the reaction temperature below 10° C. The ice bath was removed and after two hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield 2.3 grams of the tert-butyl ester of the sulfide acid suitable for the next step.

[0725] Part B: To a solution of the tert-butyl ester of the sulfide acid from part A (2.3 g, 7.25 mmol) in dry anisole (85 mL, 8.1 g, 74.67 mmol) was added trifluoroacetic acid (25.5 mL, 37.7 g, 330.6 mmol). After one-half hour at ambient temperature, the reaction was concentrated in vacuo to 3.7 g of the TFA salt of the sulfide acid suitable for the next step.

[0726] Part C: To a solution of the TFA salt of the acid obtained from part B (2.7 g, 7.19 mmol) in dimethylformamide (10 mL) was added N-hydroxybenzotriazole hydrate (1.5 g, 10.79 mmol), N-methylmorpholine (4.7 mL, 4.4 g, 43.16 mmol), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (2.5 g, 21.58 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.8 g, 9.35 mmol). After sixteen hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, methanol-ethyl acetate/hexanes) afforded 2.1 g (81%) of the THP sulfide hydroxamate as a dry, white foam, m/z=361 (M+H).

[0727] Part D: To a solution of the THP sulfide hydroxamate from part C (2.1 g, 5.83 mmol) in methanol/water (13 mL/2 mL) was added tetrabutylammonium Oxone (5.8 g, 61.29 mmol). After 2 days at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (6×). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, methanol-ethyl acetate/hexanes) afforded 0.9 g (40%) of the THP sulfone hydroxamate as a dry, white foam, m/z=393 (M+H).

[0728] Part E: To a slurry of the THP sulfone hydroxamate from part D (0.9 g, 2.29 mmol) in methanol (0.6 mL) was added 4N HCl dioxane solution (6 mL). After one hour at ambient temperature, the reaction mixture was slowly poured into diethyl ether (200 mL). Filtration afforded 0.6 grams (78%) of the title compound as a white solid, m/z=309 (M+H).

EXAMPLE 228

Preparation of

[0729]

3998

[0730] Part A: A solution of 4-(4-pyridyloxy)-thiophenol (18.0 g, 75.08 mmol) and tert-butylbromoacetate (10.5 mL, 13.9 g, 71.33 mmol) in dry methanol (250 mL) was cooled to 0° C. and treated with triethylamine (22.0 mL, 16.0 g, 157.68 mmol). The addition was done at a rate which held the reaction temperature below 1° C. The ice bath was removed and after one-half hour at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield 21.7 grams of the tert-butyl ester of the sulfide acid suitable for the next step.

[0731] Part B: To a solution of the tert-butyl ester of the sulfide acid from part A (221.7 g, 68.37 mmol) in dry anisole (76.5 mL, 76.1 g, 704.12 mmol) was added trifluoroacetic acid (240 mL, 355 g, 3,117 mmol). After one hour at ambient temperature, the reaction was concentrated in vacuo to yield 34.7 g of the TFA salt of the sulfide acid suitable for the next step.

[0732] Part C: To a solution of the TFA salt of the sulfide acid from part B (34.7 g, 68.37 mmol) in dry methanol (100 mL) was added thionyl chloride (7.5 mL, 12.2 g, 102.5 mmol). After twelve hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield 18.7 grams of the methyl ester of the sulfide acid suitable for the next step.

[0733] Part D: To a solution of the methyl ester of the sulfide acid obtained from part C (18.7 g, 67.92 mmol) in methylene chloride (325 mL) was added tetrabutylammonium Oxone (193 g, 543.4 mmol). After 2 days at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (9×). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, methanol-ethyl acetate/hexanes) afforded 7.3 g (35%) of the methyl ester of the sulfone acid as a dry, white foam, m/z=308 (M+H).

[0734] Part E: To a solution of the methyl ester of the sulfone acid obtained from part D (2.7 g, 8.79 mmol) in dry dimethylformamide (20 mL) was added 18-crown-6 ether (0.5 g, 1.90 mmol) and potassium carbonate (4.9 g, 35.14 mmol). The reaction slurry was treated with bis-(2-bromoethyl)ether (1.1 mL, 2.0 g, 8.79 mmol) and then heated to 60° C. After fifteen hours at 60° C., the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The organic extracts were combined, washed with brine (3×), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, NH3-methanol-ethyl acetate/hexanes) afforded 1.6 g (48%) of the THP sulfone methyl ester as a tan solid, m/z=378 (M+H).

[0735] Part F: To a solution of the THP sulfone methyl ester from part E (1.6 g, 4.24 mmol) in dry tetrahydrofuran (20 mL) was added potassium trimethylsilanoate (1.6 g, 12.72 mmol). After five hours at ambient temperature, the reaction was concentrated in vacuo to yield the potassium salt of the THP sulfone acid as a tan solid suitable for use in the next step.

[0736] Part G: To a slurry of the potassium salt of the THP sulfone acid obtained from part F (1.7 g, 4.24 mmol) in dimethylformamide (20 mL) was added N-hydroxybenzotriazole hydrate (1.1 g, 8.48 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.6 g, 8.48 mmol). After heating the reaction mixture at 40° C. for one-half hour, N-methylmorpholine (1.4 mL, 1.3 g, 12.72 mmol) and 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.0 g, 8.48 mmol) were added. After heating at 45° C. for 15 hours, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and 10% potassium carbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (13×). The organic extracts were combined, washed with water and brine (3×), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, (2M ammonia in methanol-ethyl acetate)/hexanes) afforded 0.7 g (35%) of the THP-protected THP sulfone hydroxamate as a dry, white foam, m/z=463 (M+H).

[0737] Part H: To a slurry of the THP-protected THP sulfone hydroxamate from part G (0.7 g, 1.43 mmol) in methanol (0.4 mL) was added 4N HCl dioxane solution (4 mL). After thirty minutes at ambient temperature, the reaction mixture was slowly poured into diethyl ether (200 mL) and stirred for fifteen minutes. Filtration afforded 0.5 grams (83%) of the title compound as the HCl salt, m/z=379 (M+H).

EXAMPLE 229

Preparation of N-hydroxy-1-(4-methyl-phenyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monohydrochloride

[0738]

3999

[0739] Part A: To a suspension of ethyl 4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate, hydrochloride Preparative Example II (2.56 g, 7.28 mmol) in H2O (50 mL) was added 1.25N NaOH (pH=9.0). The aqueous layer was extracted with diethyl ether (2×75 mL). The combined organic layers were washed with saturated NaCl and dried over Na2SO4. Concentration in vacuo provided the free amine as an off-white solid (1.72 g). To a solution of the free amine (1.70 g, 5.39 mmol) in toluene (25 mL) was added Cs2CO3 (2.34 g, 7.19 mmol) and a solution of 4-bromotoluene (0.877 g, 5.13 mmol) in toluene (5 mL). This was followed by the addition of tris(dibenzyldeneacetone)dipallidium (O) (0.047 g, 0.0513 mmol) and BINAP (0.096 g, 0.154 mmol). The resulting mixture was then heated to one hundred degress Celsius for 17 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate and the filtrate was concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexane) provided the aniline as a yellow oil (1.59 g, 76%).

[0740] Part B: To a solution of the aniline of part A (1.56 g, 3.85 mmol) in N,N-dimethylformamide (8.0 mL) was added K2CO3 (1.06 g, 7.70 mmol) and 4-(trifluoromethoxy)phenol (0.823 g, 4.62 mmol). The resulting mixture was heated to ninety degrees Celsius for 19 hours. The reaction was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between H2O and diethyl ether. The organic layer was washed with saturated NaCl and dried over Na2SO4. Concentration in vacuo provided the biaryl ether as a brown oil (2.42 g, >100%).

[0741] Part C: To a solution of the biaryl ether of part B (2.42 g, 3.85 mmol) in tetrahydrofuran (10 mL) and H2O (10 mL) was added NaOH (1.54 g, 38.50 mmol) in H2O (5.0 mL). The mixture was heated to sixty degrees Celsius for 6 hours then cooled to ambient temperature. The mixture was then acidified (pH=7) with 1N HCl. The solids were collected by vacuum filtration, then suspended in acetonitrile and concentrated in vacuo to give the acid as a tan solid (1.95 g, 95%).

[0742] Part D: To a suspension of the acid of part C (1.95 g, 3.64 mmol) in N,N-dimethylformamide (15 mL) was added 1-hydroxybenzotriazole (0.596 g, 4.37 mmol), N-methylmorpholine (1.19 mL, 10.92 mmol), 0-(tetrahydropuranyl) hydroxylamine (1.28 g, 10.92 mmol) and 1-3-[(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.977 g, 5.10 mmol). The resulting mixture was stirred at ambient temperature for 16 hours then concentrated in vacuo. The residue was partitioned between H2O and ethyl acetate. The combined organic layers were washed with H2O, saturated NaHCO3, saturated NaCl and dried over Na2SO4. Chromatography (on silica, methanol/ethyl acetate) provided the protected hydroxamate as a pale-yellow foam (1.90 g, 83%).

[0743] Part E: To the protected hydroxamate of part D (1.89 g, 3.00 mmol) was added 4N HCl in dioxane (7.50 mL, 30.0 mmol) and methanol (1.22 mL, 30.0 mmol). The resulting mixture was stirred at ambient temperature for 2 hours, then diethyl ether (5 mL) was added and the precipitate was collected by filtration to provide the title compound as a fine white solid (1.56 g, 89%). MS MH+ calculated for C26H25O6N2S1F3: 551, found 551.

EXAMPLE 230

Preparation of N-hydroxy-1-(2-hydroxyethyl)-4-[4-(4-trifluoro-methoxyphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, hydrochloride

[0744]

4000

[0745] Part A: Ethyl 4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate, hydrochloride (3.95 g, 11.3 mmol) Preparative Example II, powdered potassium carbonate (3.45 g, 25 mmol), and N,N-dimethylformamide (11.3 mL) were combined. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (1.85 mL, 12 mmol) was added and the mixture was stirred for 48 hours at ambient temperature. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (100 mL, then 50 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed to afford the desired tetrahydropyranyl ether as an oil (4.44 g, 88%)

[0746] Part B: The tetrahydropyranyl ether from Part A was stirred at 110 degrees Celsius for 20 hours in the presence of powdered potassium carbonate (2.07 g, 15 mmol), 4-(trifluoromethoxy)phenol (2.67 mL, 15 mmol), and N,N-dimethyformamide (5 mL). The mixture was diluted with saturated sodium bicarbonate (50 mL) and was extracted with ethyl acetate (150, then 50 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed to afford the desired aryl ether as an oil (5.72 g, quantitative).

[0747] Part C: The aryl ether from Part C (1.28 g, 2.1 mmol) was refluxed in the presence of potassium hydroxide (954 mg, 16.8 mmol), ethanol (9 mL), and water (3 mL). After 2 hours, the reaction vessel was cooled to zero degrees Celsius. Concentrated hydrochloric acid was added drop-wise to adjust the pH to 4.0. The acidified reaction was concentrated, azeotroped with acetonitrile, and dried in vacuo, affording the crude carboxylic acid, which was used directly in Part D.

[0748] Part D: The carboxylic acid from Part C was converted to O-tetrahydropyranyl hydroxamate using O-tetrahydropyranyl hydroxylamine (351 mg, 3 mmol), N-methylmorpholine (0.5 mL), N-hydroxybenzotriazole (405 mg, 3 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (573 mg, 3 mmol) in N,N-dimethylformamide (9 mL). The tetrahydropyranyl hydroxamate (855 mg, 60%) was obtained as an oil.

[0749] Part E: The tetrahydropyranyl hydroxamate (855 mg, 1.26 mmol) was dissolved in absolute methanol (10 mL). Acetyl chloride (0.78 mL, 11 mmol) was added over 2-3 minutes. After 4 hours both tetrahydropyranyl groups had been cleaved. The reaction was concentrated, azeotroped with chloroform/acetonitrile, and dried in vacuo affording the title compound as a white foam (676 mg, 98%). MS (EI) MH+ calculated for C21H23F3N2O7S: 505, found 505.

EXAMPLE 231

Preparation of N-hydroxy-4-[[4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide, monohydrochloride

[0750]

4001

[0751] Part A: To a solution of the compound of example N-tert-butoxycarbonyl-ethyl 4-(4-fluorophenylsulfonyl)-4-piperidinecarboxylate, hydrochloride of Preparative Example II (1.50 g, 3.61 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.94 g, 9.03 mmol) and (4-trifluoromethylthio) phenol (1.05 g, 5.41 mmol) and the solution was heated to 100 degrees Celsius for 24 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and dried over sodium sulfate. Filtration through silica gel (ethyl acetate) provided the phenoxyphenol compound as an oil (2.35 g, quantitative yield). MS(CI) MH+ calculated for C26H30NO7S2F3: 590, found 590.

[0752] Part B: To a solution of phenoxyphenol compound of part A (2.35 g, <3.61 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added sodium hydroxide (1.44 g, 36.1 mmol) in water (5 mL). The solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated under a stream of nitrogen to remove the solvents and the residue was dissolved in water and acidified to pH=1 with 10% hydrochloric acid. The solution was extracted with ethyl acetate and washed with saturated sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided the carboxylic acid as an oil (2.0 g, quantitative yield).

[0753] Part C: To a solution of the carboxylic acid of part B (2.0 g, <3.61 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (586 mg, 4.33 mmol), 4-methylmorpholine (1.19 mL, 10.8 mmol) and O-tetrahydropyranyl hydroxylamine (634 mg, 5.41 mmol) and the solution was stirred for 30 minutes. The 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (969 mg, 5.05 mmol) was added and the solution was stirred for seven days. 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. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as a clear, colorless oil (1.07 g, 45% yield). MS(CI) MNa+ calculated for C29H35N2O8S2F3: 683, found 683.

[0754] Part D: To a solution of the protected hydroxamate of part C (1.05 g, 1.60 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was diluted with ethyl ether and the resulting white precipitate was collected by vacuum filtration to provide the title compound as a white solid (330 mg, 40% yield). MS(CI) MH+calculated for C19H19N2O5S2F3: 477, found 477. HRMS calculated for C19H19N2O5S2F3: 477.0766, found 477.0766. Analytical calculation for C19H19N2O5S2 HCl: C, 44.49; H, 3.93; N, 5.46; Cl, 6.91. Found: C, 44.51; H, 3.90; N, 5.38; Cl, 6.95.

EXAMPLE 232

Preparation of 1-[4-[[1-cyclopropyl-4-[(hydroxyamino)carbonyl]-4-piperidinyl] sulfonyl]phenyl]-N-methyl-N-(phenylmethyl)-4-piperidinecarboxamide, monohydrochloride

[0755]

4002

[0756] Part A: To a solution of ethyl N-cyclopropyl-4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate (Preparative Example VI, Part A) (2.0 g, 5.11 mmol) in dimethylacetamide (10 mL) was added methyl isonipectotate (1.03 mL, 7.66 mmol) and cesium carbonate (4.16 g, 12.78 mmol) and was heated to one hundred ten degrees Celsius for 18 hours. The solution was cooled to ambient temperature and 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 phenylamine as an oil (1.81 g, 74%). MS(CI) MH+ calculated for C24H34N2O6S: 479, found 479.

[0757] Part B: To a solution of the phenylamine of part A (1.79 g, 3.74 mmol) in tetrahydrofuran (20 mL) was added potassium trimethylsilanoate (960 mg, 7.49 mmol) and the resulting solution was stirred for 18 hours at ambient temperature. The solution was concentrated in vacuo and the residue was dissolved into water. The solution was acidified with 3N hydrochloric acid to pH=3. The resulting precipitate was collected and washed with ethyl ether to provide the acid as a light yellow solid (1.09 g, 63%). MS(CI) MH+ calculated for C23H32N2O6S: 465, found 465.

[0758] Part C: To a solution of the acid of part B (500 mg, 1.08 mmol) in dichloromethane (10 mL) was added 1-hydroxybenzotriazole hydrate (160 mg, 1.19 mmol), triethylamine (0.15 mL, 1.19 mmol) and N-benzylmethylamine (0.33 mL, 2.38 mmol). After thirty minutes the 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added and the solution was stirred for 20 hours at ambient temperature. The solution was diluted with ethyl acetate and washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate) provided the amide as a white solid (480 mg, 78%). MS(CI) MH+ calculated for C31H41N3O5S: 568, found 568.

[0759] Part D: To a solution of the amide of part C (400 mg, 0.71 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (282 mg, 7.1 mmol) in water (3 mL). The solution was heated to sixty degrees Celsius for 24 hours. The solution was concentrated under a stream of nitrogen and the residue was diluted with water and acidified with 3N hydrochloric acid to pH=2. The solution was concentrated to provide the acid as a crude white solid which is used in the next step without further purification. MS(CI) MH+ calculated for C29H37N5O5S: 540, found 540.

[0760] Part E: To a solution of the crude acid of part D (<0.71 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (115 mg, 0.85 mmol), 4-methylmorpholine (0.39 mL) and O-tetrahydropyranyl hydroxylamine (124 mg, 1.06 mmol). After thirty minutes 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (190 mg, 0.99 mmol) was added and the solution was stirred for 18 hours. 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. Chromatography (on silica, ethyl acetate) provided the protected hydroxamate as an oil (184 mg, 41%). MS(CI) MH+ calculated for C34H46N4O6S: 0.639, found 639.

[0761] Part F: To a solution of the protected hydroxamate of part E (180 mg, 0.28 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for one hour. Trituration (ethyl ether) and vacuum filtration provided the title compound as a white solid (96.5 mg, 58%). MS(CI) MH+ calculated for C29H38N4O5S: 555, found 555. HRMS calc. 555.2641, found 555.2644.

EXAMPLE 233

Preparation of 4-[[4-[4-[(3,5-dimethyl-1-piperidinyl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide, monohydrochloride

[0762]

4003

[0763] 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 four hours 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%).

[0764] 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 hours. 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%).

[0765] 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 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII,

[0766] 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 one hundred degrees Celsius for 18 hours. 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+ calculated for C30H47N3O6S: 578, found 578.

[0767] 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 sixty degrees Celsius for 20 hours. 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+calculated for C28H43N3O6S: 550, found 550.

[0768] 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 one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (225 mg, 1.18 mmol) was added and the solution was stirred for 72 hours 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+ calculated for C33H51N4O7S: 649, found 649.

[0769] 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 hours. 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 C28H44N4O6S: 565, found 565. HRMS calculated for C28H44N4O6S: 565.3060, found 565.3070. Analytical calculation for C28H44N4O6S 2 HCl: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 234

Preparation of 4-[[4-[4-[(3,5-dimethyl-1-piperidinyl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide

[0770]

4004

[0771] Part A: A solution of the hydroxamate of Example 233, 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%).

EXAMPLE 235

Preparation of 1-[4-[[4[(hydroxyamino)-carbonyl]-1-(2-methoxyethyl)-4-piperidinyl]sulfonyl]phenyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-4-piperidine-carboxamide, dihydrochloride

[0772]

4005

[0773] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, 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-hydroxy-benzotriazole hydrate (620 mg, 4.59 mmol), 2-(2-methylaminoethyl)pyridine (0.69 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. 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 (1.03 g, 68%). MS(CI) MH+ calculated for C19H29N3O3: 348, found 348.

[0774] Part B: To a solution of the amide of part A (1.0 g, 2.88 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (716 mg, 1.92 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.20 g, 6.72 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. 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 oil (1.20 g, quantitative yield). MS(CI) MH+ calculated for C31H44N4O6S: 601, found 601.

[0775] Part C: To a solution of the phenylamine of part B (1.20 g, 2.00 mmol) in ethanol (8 mL) and tetrahydrofuran (8 mL) was added sodium hydroxide (800 mg, 20 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. Concentration in vacuo provided the crude acid as an oil. MS(CI) MH+ calculated for C29H40N4O6S: 573, found 573.

[0776] Part D: To a solution of the acid of part C (<2.0 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (324 mg, 2.04 mmol), 4-methylmorpholine (1.1 mL, 10.0 mmol), and O-tetrahydropyranyl hydroxylamine (351 mg, 3.00 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (536 mg, 2.80 mmol) was added and the solution was stirred for 18 hours 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. Reverse phase chromatography (on silica, acetonitrile/water) provided the protected hydroxamate as an oil (170 mg, 13% yield over two steps). MS(CI) MH+ calculated for C34H49N5O7S: 672, found 672.

[0777] Part E: To a solution of the protected hydroxamate of part D (160 mg, 0.24 mmol) in dioxane (7 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 30 minutes. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (90 mg, 57%). MS(CI) MH+calculated for C29H37N5O6S: 588, found 588. HRMS calculated for C29H37N5O6S: 558.2856, found 588.2857.

EXAMPLE 236

Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[(phenylamino)-carbonyl]-1-piperidinyl]phenyl]-sulfonyl]-4-piperidinecarboxamide monohydrochloride)

[0778]

4006

[0779] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (4 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (752 mg, 4.28 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.47 mL, 4.28 mmol) was added. After two hours aniline (0.39 mL, 4.28 mmol) was added and the solution was stirred for 20 hours 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 (1.48 g, quantitative yield).

[0780] Part B: To a solution of the amide of part A (1.48 g, 4.28 mmol) in dichloromethane (5 mL) was added trifluoroacetic (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (1.06 mg, 2.85 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.25 g, 9.97 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. 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 oil (1.74 g, quantitative yield). MS(CI) MH+ calculated for C29H39N3O6S: 558, found 558.

[0781] Part C: To a solution of the phenylamine of part B (1.74 g, 2.85 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.14 g, 28.5 mmol) in water (7 mL) and the solution was heated to sixty degrees Celsius for 20 hours. 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 (1.62 g, quantitative yield). MS(CI) MH+ calculated for C27H35N3O6S: 530, found 530.

[0782] Part D: To a solution of the acid of part C (1.60 g, 2.83 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (458 mg, 3.40 mmol), 4-methylmorpholine (1.56 mL, 14.2 mmol), and O-tetrahydropyranyl hydroxylamine (497 mg, 4.24 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (759 mg, 3.96 mmol) was added and the solution was stirred for 18 hours 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 (790 mg, 44%). MS(CI) MH+ calculated for C32H44N4O7S: 629, found 629.

[0783] Part E: To a solution of the protected hydroxamate of part D (780 mg, 1.24 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (580 mg, 80%). MS(CI) MH+calculated for C27H36N4O6S: 545, found 545. HRMS calculated for C27H36N4O6S: 545.2434, found 545.2429.

EXAMPLE 237

Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[[(3-phenyl-propyl)amino]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride

[0784]

4007

[0785] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, 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-phenyl-1-propylamine (0.72 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 18 hours. 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 yellow oil (1.4 g, 93%).

[0786] Part B: To a solution of the amide of part A (1.4 g, 4.05 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. The resulting solid was collected by vacuum filtration and washed with ethyl ether. The solid was added to a solution of the compound of Preparative Example VII, Part A (1.01 mg, 2.70 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.07 g, 9.45 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. 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 (1.71 g, quantitative yield). MS(CI) MH+ calculated for C32H45N3O6S: 600, found 600.

[0787] Part C: To a solution of the phenylamine of part B (1.70 g, 2.70 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.08 g, 27.0 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. 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 white solid (1.15 g, 75%). MS(CI) MH+ calculated for C30H41N3O6S: 572, found 572.

[0788] Part D: To a solution of the acid of part C (1.02 g, 1.68 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (272 mg, 2.02 mmol), 4-methylmorpholine (0.92 mL, 8.4 mmol), and O-tetrahydropyranyl hydroxylamine (295 mg, 2.52 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (451 mg, 2.35 mmol) was added and the solution was stirred for 18 hours 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 an oil (490 mg, 41%). MS(CI) MH+ calculated for C35H50N4O7S: 671, found 671.

[0789] Part E: To a solution of the protected hydroxamate of part D (480 mg, 0.72 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for one hour. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (400 mg, 90%). MS(CI) MH+ calculated for C30H42N4O6S: 587, found 587. Analytical calculation for C30H42N4O6S 2HCl :2H2O: C, 51.79; H, 6.95; N, 8.05; S, 4.61; Cl, 10.19. Found: C,51.34; H, 6.72; N, 7.82; S, 4.59; Cl, 10.92.

EXAMPLE 238

Preparation of rel-4-[[4-[4-[[(3R,5R)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide, monohydrochloride

[0790]

4008

[0791] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, 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 hours. 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).

[0792] 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 hour. 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 one hundred degrees Celsius for 20 hours. 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+ calculated for C32H49N3O7S: 620, found 620.

[0793] 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 sixty degrees Celsius for 20 hours. 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+ calculated for C30H45N3O7S: 592, found 592.

[0794] 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 one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (805 mg, 4.2 mmol) was added and the solution was stirred for 18 hours 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%).

[0795] 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 minutes. 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 C25H38N4O5S: 507, found 507.

EXAMPLE 239

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

[0796]

4009

[0797] Part A: From the reverse phase chromatography of Example 238, Part E, fraction C was concentrated in vacuo to provide the title compound as a white solid (49 mg). MS(CI) MH+ calculated for C30H46N4O7S: 607, found 607.

EXAMPLE 240

Preparation of rel-4-[[4-[4-[[(3R,5S)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide, monohydrochloride

[0798]

4010

[0799] Part A: From the reverse phase chromatography of Example 238, Part E, fraction B was concentrated in vacuo to provide the title compound as a white solid (198 mg). MS(CI) MH+ calculated for C25H38N4O5S: 507, found 507.

EXAMPLE 241

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

[0800]

4011

[0801] Part A: From the reverse phase chromatography of Example 238, Part E, fraction D was concentrated in vacuo to provide the title compound as a white solid (242 mg). MS(CI) MH+calculated for C30H46N4O7S: 607, found 607.

EXAMPLE 242

Preparation of 4-[[4-[4-[[(2,3-dihydro-1H-inden-2-yl)amino]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidine-carboxamide, monohydrochloride

[0802]

4012

[0803] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, 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) 2-aminoindane hydrochloride (853 mg, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. 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 white solid (1.35 g, 90%).

[0804] Part B: To a solution of the amide of part A (1.35 g, 3.92 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided a solid which was added directly to a solution of the title compound of Preparative Example VII, Part A, (976 mg, 2.61 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.97 g, 9.14 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. 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 (1.65 g, quantitative yield). MS(CI) MH+ calculated for C32H43N3O6S: 598, found 598.

[0805] Part C: To a solution of the phenylamine of part B (1.60 g, 2.61 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.04 g, 26 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 18 hours. 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 (1.06 g, 71%). MS(CI) MH+ calculated for C30H39N3O6S: 570, found 570.

[0806] Part D: To a solution of the acid of part E (1.0 g, 1.65 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (267 mg, 1.98 mmol), 4-methylmorpholine (0.91 mL, 8.25 mmol), and O-tetrahydropyranyl hydroxylamine (289 mg, 2.48 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (443 mg, 2.31 mmol) was added and the solution was stirred for 18 hours 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 an oil (575 mg, 52%). MS(CI) MH+ calculated for C35H48N4O7S: 669, found 669.

[0807] Part E: To a solution of the protected hydroxamate of part D (565 mg, 0.85 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was concentrated in vacuo and trituration (ethyl ether) provided the title compound as a white solid (450 mg, 86%). MS(CI) MH+ calculated for C30H40N4O6S: 585, found 585. HRMS calculated for C30H40N4O6S: 585.2747, found 585.2776. Analytical calculation for C30H40N4O6S 2HCl :2H2O: C, 51.94; H, 6.68; N, 8.08; S, 4.62; Cl, 10.22. Found: C, 51.66; H, 6.25; N, 7.80; S, 4.73; Cl, 10.33.

EXAMPLE 243

Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-[(phenylamino)carbonyl]-1-piperidinyl]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride

[0808]

4013

[0809] Part A: To a solution of the product of Example 232, Part B (562 mg, 1.12 mmol) in dichloromethane (3 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (164 mg, 0.93 mmol) and 4-methylmorpholine (0.21 mL, 1.87 mmol). The solution was stirred for 45 minutes and aniline (0.085 mL, 0.93 mmol) was added. The solution was stirred for 72 hours. 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 amide as an oil (434 mg, 86%). MS(CI) MH+calculated for C29H37N3O5S: 540, found 540.

[0810] Part B: To a solution of the amide of part A (425 mg, 0.79 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (315 mg, 7.89 mmol) in water (2 mL) and the solution was heated to sixty degrees Celsius for 18 hours. 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 (261 mg, 60%). MS(CI) MH+ calculated for C27H33N3O5S: 512, found 512.

[0811] Part C: To a solution of the acid of part B (245 mg, 0.45 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (73 mg, 0.54 mmol), 4-methylmorpholine (0.25 mL, 2.25 mmol), and O-tetrahydropyranyl hydroxylamine (79 mg, 0.68 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (121 mg, 0.63 mmol) was added and the solution was stirred for 18 hours 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) provided the protected hydroxamate as a yellow oil (242 mg, 88%). MS(CI) MH+ calculated for C32H42N4O6S: 611, found 611.

[0812] Part D: To a solution of the protected hydroxamate of part C (235 mg, 0.38 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (114 mg, 53%). MS(CI) MH+ calculated for C27H34N4O5S: 527, found 527. HRMS calculated for C27H34N4O5S: 527.2328, found 527.2339.

EXAMPLE 244

Preparation of 1-[4-[[4-[(hydroxyamino)-carbonyl]-1-(2-methoxyethyl)-4-piperidinyl]-sulfonyl]phenyl]-N-methyl-N-phenyl-4-piperidinecarboxamide, monohydrate

[0813]

4014

[0814] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, Part A (500 mg, 2.18 mmol) in dichloromethane (2 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (319 mg, 1.82 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.20 mL, 1.82 mmol) was added. After two hours, N-methylaniline (0.20 mL, 1.82 mmol) was added and the solution was stirred for 20 hours 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 (445 mg, 77%).

[0815] Part B: To a solution of the amide of part A (440 g, 1.38 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (344 mg, 0.92 mmol) in dimethylacetamide (10 mL). Cesium carbonate (1.05 g, 3.22 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. 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 oil (440 mg, 84%).

[0816] Part C: To a solution of the phenylamine of part B (440 mg, 0.77 mmol) in ethanol (7 mL) and tetrahydrofuran (7 mL) was added sodium hydroxide (308 mg, 7.7 mmol) in water (3 mL) and the solution was heated to sixty degrees Celsius for 20 hours. 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 yellow solid and carried on to the next step without additional purification.

[0817] Part D: To a solution of the acid of part C (<0.77 mmol) in N,N-dimethylformamide (10 mL) was added-1-hydroxybenzotriazole hydrate (125 mg, 0.92 mmol), 4-methylmorpholine (0.43 mL, 3.85 mmol), and O-tetrahydropyranyl hydroxylamine (135 mg, 1.16 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (207 mg, 1.08 mmol) was added and the solution was stirred for 24 hours 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 (150 mg, 30%). MS(CI) MH+ calculated for C33H46N4O7S: 643, found 643.

[0818] Part E: To a solution of the protected hydroxamate of part D (150 mg, 0.23 mmol) in dioxane (2 mL) was added 4M hydrochloric acid in dioxane (3 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a yellow solid (75 mg, 55%). MS(CI) MH+ calculated for C28H38N4O6S: 559, found 559. HRMS calculated for C28H38N4O6S: 559.2590, found 559.2613.

EXAMPLE 245

Preparation of 1-acetyl-N-hydroxy-4-[[4-[4-[(phenylamino)carbonyl]-1-piperidinyl]phenyl]sulfonyl]-4-piperidinecarboxamide

[0819]

4015

[0820] Part A: To a solution of the N-Boc-amide of Preparative Example III, Part B, (6.9 g, 11.4 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example II, Part D (3.15 g, 7.6 mmol) in dimethylacetamide (30 mL). Cesium carbonate (8.65 g, 26.6 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. 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 phenylamine as a tan solid (3.92 g, 86%).

[0821] Part B: To a solution of the phenylamine of part A (3.90 g, 6.51 mmol) in methanol (20 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 3 hours. Concentration in vacuo followed by trituration (ethyl ether) provided the amine hydrochloride salt as a yellow solid (3.25 g, 93%).

[0822] Part C: To a solution of the amine hydrochloride salt of part B (500 mg, 0.93 mmol) in dichloromethane (5 mL) was added triethylamine (0.40 mL, 2.79 mmol) followed by acetyl chloride (0.07 mL, 1.02 mmol). The solution was stirred for 3 hours. The solution 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 acylated compound as an oil (390 mg, 77%). MS(CI) MH+ calculated for C28H35N3O6S: 542, found 542.

[0823] Part D: To a solution of the acylated compound of part C (390 mg, 0.72 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (58 mg, 1.44 mmol) in water (1 mL) and the solution was heated to sixty degrees Celsius for 3 hours. 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 water and saturated sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided the acid as a white solid (137 mg, 37%). MS(CI) MH+ calculated for C26H31N3O6S: 514, found 514.

[0824] Part E: To a solution of the acid of part D (137 mg, 0.27 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added 1-hydroxybenzotriazole hydrate (44 mg, 0.32 mmol), 4-methylmorpholine (0.10 mL, 1.08 mmol), and O-tetrahydropyranyl hydroxylamine (47 mg, 0.41 mmol). After one hour 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol) was added and the solution was stirred for 24 hours 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 white solid (140 mg, 85%). MS(CI) MH+ calculated for C31H40N4O7S: 613, found 613.

[0825] Part F: To a solution of the protected hydroxamate of part E (130 mg, 0.21 mmol) in dioxane (2 mL) was added 4M hydrochloric acid in dioxane (3 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a yellow solid (51 mg, 48%). MS(CI) MH+ calculated for C26H32N4O6S: 528, found 528.

EXAMPLE 246

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

[0826]

4016

[0827] 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 zero degrees Celsius and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After two hours, indoline (0.36 mL, 3.21 mmol) was added and the solution was stirred for 22 hours 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%).

[0828] 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 hour. 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 one hundred ten degrees Celsius for 18 hours. 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+ calculated for C31H41N3O6S: 584, found 584.

[0829] 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 sixty degrees Celsius for 20 hours. 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+ calculated for C29H37N3O6S: 556, found 556.

[0830] 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 one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (212 mg, 1.10 mmol) was added and the solution was stirred for 18 hours 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+ calculated for C34H46N4O7S: 655, found 655.

[0831] 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 two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (260 mg, 94%). MS(CI) MH+calculated for C29H34N4O6S: 571, found 571.

EXAMPLE 247

Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[[(phenylmethyl) amino]carbonyl]-1-piperidinyl]phenyl]-sulfonyl]-4-piperidinecarboxamide, monohydrochloride

[0832]

4017

[0833] Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B, (750 mg, 3.27 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (640 mg, 3.34 mmol), 1-hydroxybenzotriazole hydrate (463 mg, 3.43 mmol) and diisopropylethylamine (1.25 mL, 7.19 mmol). After thirty minutes, benzylamine (0.41 mL, 3.76 mmol) was added and the solution was stirred for 22 hours 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 an oil (320 mg, 31%).

[0834] Part B: To a solution of the amide of part A (320 g, 1.0 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example II, Part D, (288 mg, 0.77 mmol) in dimethylacetamide (10 mL). Cesium carbonate (878 g, 2.7 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. 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 (367 mg, 83%). MS(CI) MH+ calculated for C30H41N3O6S: 572, found 572.

[0835] Part C: To a solution of the phenylamine of part B (367 g, 0.64 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (257 mg, 6.4 mmol) in water (2 mL) and the solution was heated to sixty degrees Celsius for 20 hours. 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 (415 g, quantitative yield). MS(CI) MH+calculated for C28H37N3O6S: 544, found 544.

[0836] Part D: To a solution of the acid of part C (415 g, <0.64 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (104 mg, 0.77 mmol), 4-methylmorpholine (0.35 mL, 3.20 mmol), and O-tetrahydropyranyl hydroxylamine (112 mg, 0.96 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (172 mg, 0.90 mmol) was added and the solution was stirred for 18 hours 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 (9 mg, 2%). MS(CI) MH+ calculated for C33H46N4O7S: 643, found 643.

[0837] Part E: To a solution of the protected hydroxamate of part D (9 mg, 0.014 mmol) in dioxane (1 mL) was added 4M hydrochloric acid in dioxane (1 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (2.5 mg, 30%). MS(CI) MH+ calculated for C28H34N4O6S: 559, found 559.

EXAMPLE 248

Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-[[[4-(trifluoromethoxy)-phenyl]amino]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride

[0838]

4018

[0839] 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 zero degrees Celsius and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After two hours, 4-(trifluoromethoxy)aniline (0.43 mL, 3.21 mmol) was added and the solution was stirred for 22 hours 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 (1.16 g, 93%).

[0840] Part B: To a solution of the amide of part A (1.16 g, 2.99 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example VII,

[0841] Part A (743 mg, 1.99 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.26 g, 6.90 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. 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 (1.38 g, quantitative yield). MS(CI) MH+ calculated for C30H38N3O7SF3: 642, found 642.

[0842] Part C: To a solution of the phenylamine of part B (1.38 g, 2.00 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (800 mg, 20 mmol) in water (5 mL), and the solution was heated to sixty degrees Celsius for 20 hours. 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 (536 g, 41%). MS(CI) MH+ calculated for C28H34N3O7SF3: 614, found 614.

[0843] Part D: To a solution of the acid of part C (536 g, 0.83 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (134 mg, 0.99 mmol), 4-methylmorpholine (0.46 mL, 4.15 mmol), and O-tetrahydropyranyl hydroxylamine (145 mg, 1.24 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (223 mg, 1.16 mmol) was added and the solution was stirred for 18 hours 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 (287 mg, 48%). MS(CI) MH+ calculated for C33H43N4O8SF3: 713, found 713.

[0844] Part E: To a solution of the protected hydroxamate of part D (280 mg, 0.39 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (228 mg, 88%). MS(CI) MH+ calculated for C28H35N4O7SF3: 629, found 629.

EXAMPLE 249

Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[[[3-(trifluoro-methoxy)phenyl]amino]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride

[0845]

4019

[0846] 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 zero degrees Celsius and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After two hours 3-(trifluoromethoxy)-aniline (0.43 mL, 3.21 mmol) was added and the solution was stirred for 22 hours 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 (1.20 g, 97%).

[0847] Part B: To a solution of the amide of part A (1.20 g, 3.10 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example VII, Part A, (770 mg, 2.06 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.34 g, 7.21 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. 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 (1.72 g, quantitative yield). MS(CI) MH+ calculated for C30H38N3O7SF3: 642, found 642.

[0848] Part C: To a solution of the phenylamine of part B (1.72 g, <2.06 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (824 mg, 20.6 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 18 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. Concentration in vacuo provided the acid as a crude brown oil which was used in the next step without additional purification.

[0849] Part D: To a solution of the acid of part C (<2.06 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (334 mg, 2.47 mmol), 4-methylmorpholine (1.13 mL, 10.3 mmol), and O-tetrahydropyranyl hydroxylamine (361 mg, 3.09 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (553 mg, 2.88 mmol) was added and the solution was stirred for 18 hours 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 (64 mg, 4% for 2 steps). MS(CI) MH+ calculated for C33H43N4O8SF3: 713, found 713.

[0850] Part E: To a solution of the protected hydroxamate of part-D (63 mg, 0.089 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (5 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (48 mg, 81%). MS(CI) MH+ calculated for C28H35N4O7SF3: 629, found 629.

EXAMPLE 250

Preparation of 1-(2-ethoxyethyl)-N-hydroxy-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monohydrochloride

[0851]

4020

[0852] Part A: To a solution of the product of Preparative Example II, Part D, (1.0 g, 2.4 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the amine trifluoroacetate salt and potassium carbonate (0.99 g, 7.2 mmol) in N,N-dimethylformamide (5 mL) was added 2-bromoethyl ethyl ether (0.33 mL, 2.87 mmol) and the solution was stirred at ambient temperature for 36 hours. 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 magnesium sulfate. Concentration in vacuo provided the ethoxyl ethyl amine as a light yellow gel (0.68 g, 65.4%).

[0853] Part B: To a solution of ethoxyl ethyl amine (0.68 g, 1.56 mmol) of part A and powdered potassium carbonate (0.43 g, 3.1 mmol) in N,N-dimethylformamide (5 mL) was added 4-(trifluoromethoxy)phenol (0.4 mL, 3.08 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and dried over magnesium sulfate. Chromatography on silica eluting with ethyl acetate/hexane provided the desired trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (1.0 g, quantitative).

[0854] Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone of Part B (1.0 g, 1.72 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was added sodium hydroxide (0.688 g, 17.2 mmol) in water (4 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. 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 the white precipitate provided the acid as a white solid (0.94 g, quantitative yield).

[0855] Part D: To a solution of the acid of part C (0.94 g, 1.86 mmol), N-methyl morpholine (0.61 mL, 5.55 mmol), 1-hydroxybenzotriazole (0.76 g, 5.59 mmol) and O-tetrahydropyranyl hydroxylamine (0.33 g, 2.7 mmol) in N,N-dimethylformamide (40 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.06 g, 5.59 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.74 g, 66.1%).

[0856] Part E: To a solution of 4N hydrochloric acid (3 mL, 12 mmol)) in dioxane was added a solution of the tetrahydropyranyl amide of part D (0.74 g, 1.2 mmol) in methanol (0.4 ml) and dioxane (1.2 mL) and was stirred at ambient temperature for 3 hours. Filtration of precipitation gave the title compound as white solid (0.217 g, 32.9%). Analytical calculation for C22H25N2O7SF3.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.

EXAMPLE 251

Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide monomethane-sulfonate (salt)

[0857]

4021

[0858] Part A: To the ethanol solution of the product of Preparative Example VII, Part D, (0.3 g, 0.5 mmol) was added methane sulfonic acid (0.042 mL, 0.65 mmol). After two hours stirring at room temperature the solution was cooled to zero degree Celsius. Filtration of the precipitate gave the title compound as a white crystalline solid (0.105 g, 35%). Analytical calculation for C22H25N2O7SF3. CH4O3S. H2O: C, 43.67; H, 4.94; N, 4.43. Found: C, 43.96; H, 4.62; N, 4.47.

EXAMPLE 252

Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide

[0859]

4022

[0860] Part A: The title compound of Preparative Example VII (15 g, 27 mmol) was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, water, brine and dried over magnesium sulfate. Concentration in vacuo and recrystallization from hot toluene gave the title compound as white crystals (13.14 g, 93.9%). Analytical calculation for C22H25N2O7SF3: C, 50.96; H, 4.86; N, 5.40; S, 6.18. Found: C, 51.33; H, 5.11; N, 5.29; S, 6.50.

EXAMPLE 253

Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide mono(4-methyl-benzenesulfonate) (salt)

[0861]

4023

[0862] Part A: To the ethanol solution of Preparative Example VII (8 g, 13.32 mmol) was added p-toluenesulfonic acid (2.9 g, 15.24 mmol) and the solution was stirred at ambient temperature for 6 hours. Evaporation of the solvent and recrystallization from hot ethanol gave the title compound as white crystals (6.58 g, 71.8%). Analytical calculation for C22H25N2O7SF3.C7H8SO3: C, 50.43; H, 4.82; N, 4.06; S, 9.28. Found: C, 50.36; H, 4.95; N, 4.00; S, 9.47.

EXAMPLE 254

Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide sulfate (2:1) (salt)

[0863]

4024

[0864] Part A: To a solution of Preparative Example VII (0.35 g, 0.58 mmol) in ethanol (1.5 mL) was added sulfuric acid (17 ?L, 0.32 mmol) and the solution was stirred at ambient temperature for 6 hours. Evaporation of solvent and recrystallization from hot acetonitrile gave the title compound as a white powder (180 mg, 54.6%). Analytical calculation for C22H25N2O7SF3.0.7H2SO4: C, 45.00; H, 4.53; N, 4.77; S, 9.28. Found: C, 44.77; H, 4.97; N, 4.41; S, 9.19.

EXAMPLE 255

Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide phosphate (1:1) (salt)

[0865]

4025

[0866] Part A: To the ethyl acetate solution (4 mL) of Example 252 (0.5 g, 0.9 mmol) was added concentrated phosphoric acid (85%, 0.1248 g, 1.08 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol gave the title compound as a white powder (0.4917 g, 82.7%). Analytical calculation for C22H25N2O7SF3.H3PO4.H2O: C, 41.64; H, 4.77; N, 4.42. Found: C, 41.14; H, 4.64; N, 4.25.

EXAMPLE 256

Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monoacetate (salt)

[0867]

4026

[0868] Part A: To a solution of Example 252 (0.5 g, 0.9 mmol) in ethyl acetate (5 mL) was added concentrated acetic acid (63.7 mg, 1.08 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethyl acetate gave the title compound as a white crystalline solid (0.4635 g, 83.0%). Analytical calculation for C22H25N2O7SF3.0.7C2H4O2: C, 50.14; H, 5.00; N, 5.00; S, 5.72. Found: C, 50.47; H, 5.09; N, 5.00; S, 6.13.

EXAMPLE 257

Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide 2-hydroxy-1,2,3-propanetri-carboxylate (3:1) (salt)

[0869]

4027

[0870] Part A: To a solution of Example 252 (0.3 g, 0.578 mmol) in ethyl acetate (5 mL) was added citric acid (41 mg, 0.21 mmol) and the solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol gave the title compound as a white crystalline solid (0.181 g, 53.7%). Analytical calculation for C22H25N2O7SF3.(⅓)C6H9O7. 0.9H2O: C, 48.34; H, 4.99; N, 4.70; S, 5.38. Found: C, 48.42; H, 4.99; N, 4.70; S, 5.38.

EXAMPLE 258

Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monobenzenesulfonate (salt)

[0871]

4028

[0872] Part A: To a solution of Preparative Example VII, Part D (0.4 g, 0.66 mmol) in ethanol (2.5 mL) was added benzene sulfonic acid (0.11 g, 0.69 mmol) and the solution was stirred at ambient temperature for 3 hours. Evaporation of the solvent and recrystallization from hot ethanol at minus 20 degrees Celsius gave the title compound as white crystals (0.28 g, 64.3%). Analytical calculation for C22H25N207SF3.C6H6SO3.0.2H2O: C, 49.44; H, 4.65; N, 4.12; S, 9.43. Found: C, 49.18; H, 4.67; N, 4.08; S, 9.75.

EXAMPLE 259

Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide (2R,3R)-2,3-dihydroxy-butanedioate (2:1) (salt)

[0873]

4029

[0874] Part A: To a solution of Example 252 (0.3 g, 0.578 mmol) in ethyl acetate (5 mL) was added tartaric acid (48 mg, 0.3 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol at zero degrees Celsius gave the title compound as a white solid (0.2 g, 58.3%). Analytical calculation for C22H25N2O7SF3.0.5C4H6O6. 1.25H2O: C, 46.79; H, 4.99; N, 4.55; S, 5.20. Found: C, 47.17; H, 5.20; N, 4.07; S, 5.03

Example 260

Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide phosphate (3:1) (salt)

[0875]

4030

[0876] Part A: To a solution of Example 252 (0.5 g, 0.9 mmol) in ethyl acetate (5 mL) was added phosphoric acid (37 mg, 0.32 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol at zero degrees Celsius gave the title compound as a white solid (0.312 g, 59%). Analytical calculation for C22H25N207SF3.0.33H3PO4. 0.5H2O: C, 47.18; H, 4.86; N, 5.00. Found: C, 47.15; H, 4.73; N, 4.90.

EXAMPLE 261

Preparation of N-hydroxy-1-[2-(1H-imidazol-1-yl)ethyl]-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl] sulfonyl]-4-piperidinecarboxamide, dihydrochloride

[0877]

4031

[0878] Part A: The aryl ether from Example 230, Part B (3.12 g, 5.2 mmol) was dissolved in absolute methanol (50 mL). Acetyl chloride (2.1 mL, 30 mmol) was added over 1 minute. The reaction was stirred for 4 hours, concentrated, azeotroped with chloroform/acetonitrile, and dried in vacuo, affording the desired hydroxyethyl compound as a white solid (2.75 g, 96%). The desired hydroxyethyl product was characterized by NMR spectroscopy.

[0879] Part B: To the dichloromethane solution of the hydroxyethyl compound of Part A (1 g, 1.9 mmol) was added thionyl chloride (3.8 mmol) and reaction solution was stirred at ambient temperature for 12 hours. Concentration in vacuo provided the chloride as a light yellow gel. To the solution of the chloride and potassium carbonate (0.54 g, 3.8 mmol) in N,N-dimethylformamide (5 mL) was added imidazole (0.4 g, 5.7 mmol) and solution was stirred at ambient temperature for 12 hours. 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 magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the imidazole ethyl ester as a light yellow gel (0.82 g, 75.2%).

[0880] Part C: To a solution of imidazole ethyl ester of part A (0.82 g, 1.44 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (0.57 g, 14.4 mmol) in water (6 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile. Concentrated hydrochloric acid was used to acidify the residue to pH=1 and concentration in vacuo gave the carboxylic acid as the product. To a solution of the carboxylic-acid, N-methyl morpholine (0.62 mL, 5.7 mmol), 1-hydroxybenzotriazole (0.59 g, 4.3 mmol) and O-tetrahydropyranyl hydroxylamine (0.34 g, 2.9 mmol) in N,N-dimethylformamide (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.83 g, 5.7 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.27 g, 29.7%).

[0881] Part D: To a solution of 4N hydrochloric acid in dioxane (2 mL, 8 mmol)) was added a solution of the tetrahydropyranyl amide of part B (0.27 g, 0.45 mmol) in methanol (1 ml) and 1,4-dioxane (3 mL) and was stirred at ambient temperature for 3 hours. Evaporation of solvent and trituration with ethyl ether gave the title compound as a white solid (0.179 g, 67%). Analytical calculation for C24H25N4O6SF3.2HCl.1.25H2O: C, 44.35; H, 4.57; N, 8.62. Found: C, 44.57; H, 4.36; N, 7.95.

EXAMPLE 262

Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(1H-1,2,4-triazol-1-yl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide trihydrochloride

[0882]

4032

[0883] Part A: To a solution of the product of Preparative Example II, Part D, (1.5 g, 3.6 mmol) and powdered potassium carbonate (0.99 g, 7.2 mmol) in N,N-dimethylformamide (10 mL) was added 4-(1,2,4-triazole-1-yl)phenol (0.87 g, 5.4 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 32 hours. Solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and dried over magnesium sulfate. Chromatography on silica eluting with ethyl acetate/hexane provided the N-Boc diaryl ether as a light yellow gel (0.907 g, 44.5%).

[0884] Part B: To a solution of N-Boc diaryl ether of part A (0.907 g, 1.6 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the amine trifluoroacetate salt and potassium carbonate (0.44 g, 3.2 mmol) in N,N-dimethylformamide (5 mL) was added 2-bromoethyl methyl ether (0.36 mL, 3.8 mmol) and solution was stirred at ambient temperature for 36 hours. The 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 magnesium sulfate. Concentration in vacuo provided the methoxyl ethyl amine as a light yellow gel (0.82 g, 91%).

[0885] Part C: To a solution of the methoxyl ethyl amine of part B (0.80 g, 1.4 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (0.56 g, 14 mmol) in water (6 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile. Concentrated hydrochloric acid was used to acidify the residue until the pH=1 and concentration in vacuo gave the carboxylic acid as product. To a solution of the carboxylic acid, N-methyl morpholine (0.92 mL, 8.4 mmol), 1-hydroxybenzotriazole (0.57 g, 4.3 mmol) and O-tetrahydropyranyl hydroxylamine (0.34 g, 2.9 mmol) in N,N-dimethylformamide (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.80 g, 4.2 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.39 g, 47.6%).

[0886] Part D: To a solution of 4N hydrochloric acid in dioxane (1.6 mL, 6.4 mmol)) was added a solution of the tetrahydropyranyl amide of part C (0.39 g, 0.66 mmol) in methanol (2 ml) and dioxane (6 mL) and was stirred at ambient temperature for 3 hours. Evaporation of the solvent and trituration with ethyl ether gave the title compound as a white solid (0.34 g, 83%). ESI MS calculated for C23H27N5O6S: 501, found 501.

EXAMPLE 263

Preparation of 1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide monohydrochloride

[0887]

4033

[0888] Part A: To a methanol solution of the product of Example 253 (1.0 g, 1.4 mmol) and 20% palladium on carbon (1.5 g) was added ammonium formate (2.4 g, 38 mmol) and reaction solution was heated to reflux for 72 hours. The reaction solution was filtered through Celite and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on a C-18 reverse phase column eluting with acetonitrile/water with hydrochloric acid provided the title compound as a white powder (181 mg, 23.2%). Analytical calculation for C22H25N2O6SF3.HCl: C, 49.03; H, 4.86; N, 5.20. Found: C, 48.80; H, 4.93; N, 5.29.

EXAMPLE 264

Preparation of N-hydroxy-1-[3-(4-morpholinyl)propyl]-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl] sulfonyl]-4-piperidinecarboxamide dihydrochloride

[0889]

4034

[0890] Part A: To a solution of the product of Preparative Example II, Part D, (15 g, 36 mmol) and powdered potassium carbonate (10 g, 72 mmol) in N,N-dimethylformamide (200 mL) was added 4-(trifluoromethoxy)phenol (19.3 mL, 72 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and residue was dissolved in ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and dried over magnesium sulfate. Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (20 g, quantitative).

[0891] Part B: To a solution of trifluoromethoxyl phenoxyphenyl sulfone (1.0 g, 1.75 mmol) of part A in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the amine trifluoroacetate salt and potassium carbonate (0.48 g, 3.5 mmol) in N,N-dimethylformamide (10 mL) was added morpholino propyl chloride (0.68 g, 3.5 mmol) and solution was stirred at 40 degree Celsius for 36 hours. The 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 magnesium sulfate. Concentration in vacuo provided the morpholino propyl amine as a light yellow gel (1 g, quantitative yield).

[0892] Part C: To a solution of morpholino propyl amine of part B (1 g, 1.6 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (0.67 g, 16 mmol) in water (6 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile. Concentrated hydrochloric acid was used to acidify the residue to pH=1 and concentration in vacuo gave the carboxylic acid as the product. To a solution of the carboxylic acid, N-methyl morpholine (0.18 mL, 4.8 mmol), 1-hydroxybenzotriazole (0.45 g, 3.2 mmol) and O-tetrahydropyranyl hydroxylamine (0.3 g, 2.5 mmol) in N,N-dimethylformamide (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.64 g, 3.2 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.56 g, 50%).

[0893] Part D: To a solution of 4N hydrogen chloride in dioxane (2 mL, 8 mmol)) was added a solution of the tetrahydropyranyl amide of part C (0.56 g, 0.83 mmol) in methanol (3 ml) and dioxane (8 mL) and was stirred at ambient temperature for 3 hours. Evaporation of solvent and tritration with ethyl ether gave the title compound as a white solid (0.476 g, 86.5%). Analytical calculation for C26H32N3O7SF3.2HCl: C, 47.28; H, 5.19; N, 6.36; S, 4.85. Found: C, 46.86; H, 5.35; N, 6.29; S, 5.09.

EXAMPLE 265

Preparation of N-hydroxy-1-(1H-imidazol-2-ylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy] phenyl]-sulfonyl]-4-piperidinecarboxamide dihydrochloride

[0894]

4035

[0895] Part A: To a suspension of the hydrochloride salt from Preparative Example VIII, Part F, (0.988 g, 21.6 mmol) and 2-imidazolecarboxaldehyde (315 mg, 3.28 mmol) in methanol (5 mL) at room temperature was added borane-pyridine complex (0.41 mL, 3.28 mmol). After 18 hours the reaction was concentrated under a stream of nitrogen. Saturated aqueous sodium bicarbonate was then added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine and dried over sodium sulfate. Concentration gave a residue which was purified on silica gel eluting with ammonia-saturated methanol/methylene chloride (3/97) to afford the desired 4(5)-imidazole derivative (1.04 g, 89.7%) as a yellow solid. MS MH+ calculated for C25H26N3O5SF3: 538, found 538.

[0896] Part B: A solution of sodium hydroxide (766 mg, 19.2 mmol) in water (5 mL) was added to a solution of the 4(5)-imidazole derivative of Part A (1.03 g, 1.92 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) and the resulting solution was stirred at ambient temperature for 66 hours. The solution was concentrated in vacuo to afford a residue which was treated with 2 N aqueous hydrochloric acid (14.4 mL, 28.8 mmol). Concentration afforded the desired carboxylic acid as a yellow foam which was used directly without purification.

[0897] Part C: To a solution of the carboxylic acid of

[0898] Part B in dimethylformamide (15 mL) was added sequentially N-methylmorpholine (1.16 g, 11.5 mmol), N-hydroxybenzotriazole (311 mg, 2.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (478 mg, 2.50 mmol), and O-tetrahydropyranyl hydroxylamine (303 mg, 2.6 mmol). After 16 hours at ambient temperature the reaction was warmed to 51 degrees Celsius for 2 hours and then concentrated in vacuo. Water was added and the mixture was extracted sequentially with ethyl acetate and with methylene chloride. The combined organic extracts were washed with brine and dried over sodium sulfate. Concentration gave a residue which was chromatographed on silica gel eluting with ammonia-saturated methanol/methylene chloride (7/93) to afford the desired tetrahydropyranyl-protected hydroxamate (0.50 g, 43%) as an off-white foam. MS MH+calculated for C28H31F3N4O6S: 609, found 609.

[0899] Part D: To a solution of tetrahydropyranyl-protected hydroxamate of part C (500 mg, 0.82 mmol) in methanol (1 mL) and 1,4-dioxane (5 mL) was added 4 N hydrogen chloride/dioxane (2.5 mL). After stirring at ambient temperature for 1 hours, the solution was concentrated in vacuo. Trituration with diethyl ether provided the title compound as a white solid (490 mg, quantitative yield). HRMS MH+ calculated for C23H23N4SO5F3: 525. Found: 525. MS MH+ calculated for C23H23F3N4O5S: 525, found 525.

EXAMPLE 266

Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide

[0900]

4036

[0901] To a solution of the product of Preparative Example IX (2.08 g, 4.0 mmol) in warm water (200 mL) was added sodium bicarbonate to pH=8 and the solution was stirred for 1 hour. The resulting white solid was isolated by filtration, washed with water and dried at 40° C. for 48 hours to afford the title compound as a white solid (1.82 g, 94%). Analytical calculation for C22H23N2SF3O5:H2O, 52.50; H, 5.01; N, 5.57; S, 6.38. Found: C, 52.24; H, 4.65; N, 5.46; S, 6.75.

EXAMPLE 267

Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide mono(4-methylbenzenesulfonate) (salt)

[0902]

4037

[0903] To a solution of the product of Example 266 (550 mg, 1.10 mmol) in ethanol (5 mL) was added p-toluenesulfonic acid (240 mg, 1.26 mmol) and the reaction was then stirred for 3.5 hour. The resulting white solid was isolated by filtration, washed with ethanol and dried at 40° C. for 48 hours to afford the title compound as a white solid (633 mg, 86%). Recrystallized from methanol/water afforded the title compound as analytically pure material. Analytical Calculation for C29H31N2S2F3O9: 51.78; H, 4.64; N, 4.16. Found: C, 51.44; H, 4.32; N, 4.18.

EXAMPLE 268

Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarbox-amide monomethanesulfonate (salt)

[0904]

4038

[0905] To a solution of the product of Example 266 (550 mg, 1.13 mmol) in ethanol (5 mL) was added methane sulfonic acid (82 μL) and the reaction was then stirred for 3.5 hours. Concentration in vacuo afforded the title compound as a solid (640 mg, 97%). Recrystallization from methanol afforded analytically pure title compound. Analytical Calculation for C23H27N2S2F3O9: 46.30; H, 4.56; N, 4.70, S, 10.75. Found: C, 46.10; H, 4.71; N, 4.65; S, 10.99.

EXAMPLE 269

Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethylphenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide

[0906]

4039

[0907] To a solution of the product of Preparative Example X (2.15 g, 4.0 mmol) in warm water (200 mL) was added sodium bicarbonate to pH=8. The solution was stirred for 1 hour. The resulting white solid was isolated by filtration, washed with water and dried at 40 degrees Celsius for 48 hours to afford the titled compound as a white solid (1.96 g, 98%). Analytical Calculation for C22H23N2SF3O5:2H2O: C, 51.26; H, 5.24; N, 5.44; S, 6.21. Found: C, 50.58; H, 4.72; N, 5.33; S, 6.04.

EXAMPLE 270

Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethylphenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide mono(4-methylbenzenesulfonate)(salt)

[0908]

4040

[0909] To a solution of the product of Example 269 (550 mg, 1.13 mmol) in ethanol (5 mL) was added p-toluenesulfonic acid (248 mg, 1.26 mmol) and the solution was stirred for 3.5 hours. The resulting white solid was isolated by filtration, washed with ethanol and dried at 40° C. for 48 hours to afford the title compound as a white solid (705 mg, 95%). Recrystallized from methanol afforded analytically pure material. Analytical Calculation for C29H31N2S2F308: C, 53.04; H, 4.76; N, 4.27; S, 9.77 Found: C, 52.94; H, 4.46; N, 4.30; S, 9.99.

EXAMPLE 271

Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethylphenoxy]-phenyl]sulfonyl]-4-piperidinecarbox-amide monomethanesulfonate (salt)

[0910]

4041

[0911] To a solution of the product of Example 269 (550 mg, 1.13 mmol) in ethanol (5 mL) was added methane sulfonic acid (79 μL) and the reaction was stirred for 3.5 hours. Concentration in vacuo gave the title compound as a solid (569 mg, 87%). Analytical Calculation for C23H27N2S2F308: C, 47.58; H, 4.69; N, 4.82. Found: C, 47.15; H, 4.18; N, 4.74.

EXAMPLE 272

Preparation of 1-acetyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide

[0912]

4042

[0913] Part A: To a solution of the product of Preparative Example II, Part D (33.2 g, 80.0 mmol) in dimethylformamide (150 mL) was added cesium carbonate (65.2-g, 200 mmol) and 4-(trifluromethoxy)phenol (21.4 g, 120 mmol). The solution was mechanically stirred at sixty degrees Celsius for 24 hours. The solution was then diluted with water (1 L) and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on silica gel eluting with 20% ethyl acetate/hexane provided the desired diaryl sulfide as a white solid (45.0 g, quantitative yield).

[0914] Part B: To a solution of the diaryl sulfide from part A (24 g, 42.8 mmol) in ethanol (80 mL) and tetrahydrofuran (80 mL) was added a solution of NaOH (14.8 g, 370 mmol) in water (100 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH 5.0 and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired carboxylic acid as a white foam (23.0 g, quantitative yield)

[0915] Part C: To a solution of carboxylic acid of part B (22.8 g, 43.0 mmol) in ethyl acetate (400 mL) cooled to zero degrees Celsius was bubbled gaseous Hydrogen chloride for 20 minutes. The reaction was stirred at this temperature for 2.5 hours. The solution was then concentrated in vacuo to afford the desired hydrochloride salt as a white foam (21.0 g, quantitative yield).

[0916] Part D: To a solution of the hydrochloride salt of part C (17.0 g, 35.0 mmol) in acetone (125 mL) and water (125 mL) was added triethyl amine (24 mL, 175 mmol). The reaction was cooled to zero degrees Celsius and acetyl chloride (3.73 mL, 53.0 mmol) was added. The solution was then stirred at ambient temperature for 18 hours. Concentration in vacuo gave a residue which was acidified with aqueous hydrochloric acid to pH 1.0 and then extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired methanesulfonamide as a white solid (17.0 g, quantitative yield).

[0917] Part E: To a solution of the methanesulfonamide of part D (14.4 g, 29.6 mmol) in dimethylformamide (250 mL) was added 1-hydroxybenzotriazole (4.8 g, 35.5 mmol), N-methyl morpholine (12.3 mL, 88.8 mmol) and O-tetrahydropyranyl hydroxylamine (5.2 g, 44.4 mmol) followed by 1-3-(dimethylamino) propyl]-3-ethyl carbodiimide hydrochloride (7.99 g, 41.4 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with water (500 mL) and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on a C18 reverse phase column eluting with acetonitrile/water provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (12.0 g, 71%).

[0918] Part F: To a solution of tetrahydropyranyl-protected hydroxamate of part E (12.0 g, 20.5 mmol) in dioxane (250 mL) and methanol (50 mL) was added 4 N hydrogen chloride/dioxane (51 mL). After stirring at ambient temperature for 3.5 hours the solution was concentrated in vacuo. Trituration with diethyl ether and filtration provided the title compound as a white solid (8.84 g, 85%). HRMS MH+ calculated for C21H21N2SO7F3: 503502.1021. Found 502.0979.

EXAMPLE 273

Preparation of N-hydroxy-1-(methyl sulfonyl)-4-[[4-[4-sulfonyl]-(trifluoromethoxy) phenoxy] phenyl]-4-piperidinecarboxamide

[0919]

4043

[0920] Part A: To a solution of the product of Preparative Example II, Part D, (33.2 g, 80.0 mmol) in dimethylformamide (150 mL) was added cesium carbonate (65.2 gm, 200.0 mmol) and 4-(trifluromethoxy)phenol (21.4 g, 120 mmol). The solution was mechanically stirred at sixty degrees Celsius for 24 hours. The solution was then diluted with water (1 L) and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on silica gel eluting with 20% ethyl acetate/hexane provided the desired diaryl sulfide as a white solid (45.0 gm, quantitative yield).

[0921] Part B: To a solution of the diaryl sulfide from part A (21 g, 37.0 mmol) in ethanol (80 mL) and tetrahydrofuran (80 mL) was added a solution of NaOH (14.8 g, 370 mmol) in water (75 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=5.0, and then extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired carboxylic acid as a white foam (19.3 g, 97%)

[0922] Part C: To a solution of carboxylic acid of part B (19.3 g, 37.0 mmol) in ethyl acetate (400 mL) cooled to zero degrees Celsius was bubbled gaseous hydrogen chloride for 30 minutes. The reaction was stirred at this temperature for 2.5 hours. The solution was then concentrated in vacuo to afford the desired hydrochloride salt as a white foam (15.8 g, 93%).

[0923] Part D: To a solution of the hydrochloride salt of part C (15.8 g, 33.0 mmol) in acetone (100 mL) and water (100 mL) was added triethyl amine (23 mL, 164 mmol). The reaction was cooled to zero degrees Celsius and methanesulfonyl chloride (5.1 mL, 66.0 mmol) was added. The solution was stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo and acidified with aqueous hydrochloric acid to pH 1.0. The aqueous residue was extracted ethyl acetate. The organic extract was washed with water, saturated sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired carboxylic acid methanesulfonamide as a white solid (17.6 gm, quantitative yield).

[0924] Part E: To a solution of the methanesulfonamide of part D (18 g, 35.0 mmol) in dimethylformamide (150 mL) was added 1-hydroxybenzotriazole (5.66 gm, 42.0 mmol), N-methyl morpholine (14.0 mL, 105.0 mmol) and O-tetrahydropyranyl hydroxylamine (6.1 g, 52 mmol) followed by 1-3-(dimethylamino) propyl]-3-ethyl carbodiimide hydrochloride (9.4 gm, 49.0 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with water (500 mL) and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on a C18 reverse phase column eluting with acetonitrile/water provided desired tetrahydropyranyl-protected hydroxamate as a white solid (8.17 g, 41%).

[0925] Part F: To a solution of tetrahydropyranyl-protected hydroxamate of part E (8.17 g, 13.0 mmol) in dioxane (100 mL) and methanol (100 mL) was added 4 N hydrogen chloride/dioxane (50 mL). After stirring at ambient temperature for 3.5 hours the solution was concentrated in vacuo. Trituration with diethyl ether provided the title compound as a white solid (6.83 g, 92%). MS MH+ calculated for C20H21NS2O8F: 539. Found 539.

[0926] The following compounds were prepared by parallel synthesis (resin based synthesis, automated synthesis) procedures utilizing reactions such as acylation and nucleophilic displacement:

EXAMPLE 274

[0927]

4044

EXAMPLE 275

[0928]

4045

EXAMPLE 276

[0929]

4046

EXAMPLES: 277-315

[0930]

185

4047

MS (ES)

Example
R1R2NH
Amine
m/z

277

4048

Ethyl amine
592 (M + H)

278

4049

3-(Aminomethyl) pyridine
655 (M + H)

279

4050

Imidazole
615 (M + H)

280

4051

3-Amino-1-propanol
622 (M + H)

281

4052

Histamine
658 (M + H)

282

4053

2-Thiophene methyl amine
660 (M + H)

283

4054

Morpholine
634 (M + H)

284

4055

2-(Aminomethyl) pyridine
655 (M + H)

285

4056

4-(Aminomethyl) pyridine
655 (M + H)

286

4057

Ethanolamine
608 (M + H)

287

4058

N,N,N-Trimethyl ethylenediamine
649 (M + H)

288

4059

1-Methylpiperazine
647 (M + H)

289

4060

N,N-Dimethyl ethylenediamine
635 (M + H)

290

4061

Piperazine
633 (M + H)

291

4062

Thiomorpholine
650 (M + H)

292

4063

N-Propylcyclopropne methylamine
660 (M + H)

293

4064

(Aminomethyl) cyclopropane
618 (M + H)

294

4065

Dimethylamine
592 (M + H)

295

4066

Diethylamine
620 (M + H)

296

4067

Piperidine
632 (M + H)

297

4068

(R)-(−)-2- Pyrrolidine methanol
648 (M + H)

298

4069

Pyrrolidine
618 (M + H)

299

4070

1-(2-(2- Hydroxyethoxy) ethyl)piperazine
721 (M + H)

300

4071

Isonipecotamide
675 (M + H)

301

4072

2-(2-Aminoethoxy) ethanol
652 (M + H)

302

4073

3,3′-Iminobis(N,N- dimethylpropylamine)
734 (M + H)

303

4074

Bis(2-Methoxy ethyl)amine
680 (M + H)

304

4075

4-Hydroxy piperidine
648 (M + H)

305

4076

N-(Carboethoxy methylpiperazine
719 (M + H)

306

4077

1-(2-Morpholinoethyl) piperazine
746 (M + H)

307

4078

1-(2-Methoxyethyl) piperazine
691 (M + H)

308

4079

1-(2- Dimethylaminoethyl) piperazine
704 (M + H)

309

4080

2-Methoxyethylamine
622 (M + H)

310

4081

2,2,2-Trifluoroethyl amine
646 (M + H)

311

4082

1,2,4-Triazole
616 (M + H)

312

4083

Methoxyamine
594 (M + H)

313

4084

Ethyl isonipecotate
704 (M + H)

314

4085

2-Pyrrolidinone
632 (M + H)

315

4086

Isonipecotic acid
676 (M + H)

EXAMPLES: 316-332

[0931]

186

Example
R1R2NH
Amine
MS (ES) m/z

316

4087

3-(Aminomethyl) pyridine
593 (M + H)

317

4088

Imidazole
553 (M + H)

318

4089

Piperidine
570 (M + H)

319

4090

Morpholine
572 (M + H)

320

4091

2-(Aminomethyl) pyridine
593 (M + H)

321

4092

Ethanolamine
546 (M + H)

322

4093

2,2,2-Trifluoro ethylamine
584 (M + H)

323

4094

N,N,N-Trimethyl ethylenediamine
587 (M + H)

324

4095

1-Methylpiperazine
585 (M + H)

325

4096

4-(Aminomethyl) pyridine
593 (M + H)

326

4097

Pyrrolidine
556 (M + H)

327

4098

Bis(2-Methoxy ethyl)amine
618 (M + H)

328

4099

Piperazine
571 (M + H)

329

4100

4-(Ethylamino methyl)pyridine
621 (M + H)

330

4101

1-(2-Methoxy ethyl)pyridine
629 (M + H)

331

4102

N- Propylcyclopropane methylamine
598 (M + H)

332

4103

2-Methoxyethylamine
560 (M + H)

EXAMPLES: 333-347

[0932]

187

Example
R1R2NH
Amine
MS (ES) m/z

333

4104

3-(Aminomethyl) pyridine
635 (M + H)

334

4105

Piperidine
612 (M + H)

335

4106

Morpholine
614 (M + H)

336

4107

2-(Aminomethyl) pyridine
635 (M + H)

337

4108

Ethanolamine
588 (M + H)

338

4109

N,N,N-Trimethyl ethylenediamine
629 (M + H)

339

4110

1-Methylpiperazine
627 (M + H)

340

4111

4-(Aminomethyl) pyridine
636 (M + H)

341

4112

Pyrrolidine
598 (M + H)

342

4113

Bis(2-Methoxy ethyl)amine
660 (M + H)

343

4114

Piperazine
613 (M + H)

344

4115

4-(Ethylamino methyl)pyridine
663 (M + H)

345

4116

1-(2-Methoxy ethyl)pyridine
671 (M + H)

346

4117

N-Propylcyclopropane methylamine
640 (M + H)

347

4118

2-Methoxyethylamine
602 (M + H)

EXAMPLES 348-942

[0933] 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.

188

4119

ExampleRKMS (ES) m/z348

4120

4121

349

4122

4123

499.1131350

4124

4125

583351

4126

4127

580.1366352

4128

4129

538.1282353

4130

4131

610354

4132

4133

355

4134

4135

648356

4136

4137

357

4138

4139

610358

4140

4141

359

4142

4143

648360

4144

4145

361

4146

4147

616362

4148

4149

614363

4150

4151

616364

4152

4153

648365

4154

4155

614366

4156

4157

648367

4158

4159

368

4160

4161

369

4162

4163

370

4164

4165

371

4166

4167

372

4168

4169

539.1201373

4170

4171

374

4172

4173

567.1120375

4174

4175

590.1174376

4176

4177

378

4178

4179

474.1567379

4180

4181

555380

4182

4183

537.1412381

4184

4185

523382

4186

4187

383

4188

4189

384

4190

4191

547.1279385

4192

4193

386

4194

4195

555.1516387

4196

4197

607.1061388

4198

4199

389

4200

4201

516390

4202

4203

539391

4204

4205

538.1272392

4206

4207

538.1252393

4208

4209

394

4210

4211

395

4212

4213

522.1351396

4214

4215

582.2245397

4216

4217

532.2280398

4218

4219

399

4220

4221

528400

4222

4223

401

4224

4225

515.3344402

4226

4227

582.2266403

4228

4229

404

4230

4231

550405

4232

4233

550406

4234

4235

555407

4236

4237

408

4238

4239

600.2162409

4240

4241

548410

4242

4243

411

4244

4245

412

4246

4247

502413

4248

4249

529414

4250

4251

600.2141415

4252

4253

600416

4254

4255

489417

4256

4257

530418

4258

4259

598.2200419

4260

4261

548.2013420

4262

4263

569.2259421

4264

4265

570.2186422

4266

4267

635.2185423

4268

4269

636.2104424

4270

4271

586.2059425

4272

4273

562.1957426

4274

4275

585.1968427

4276

4277

586.1936428

4278

4279

637.2137429

4280

4281

638.2072430

4282

4283

637.2146431

4284

4285

638.2075432

4286

4287

602.1731433

4288

4289

654.1921434

4290

4291

654.1932435

4292

4293

636436

4294

4295

596437

4296

—H502438

4297

4298

579439

4299

4300

411.1211440

4301

4302

480441

4303

4304

542442

4305

4306

540443

4307

—H440444

4308

4309

518445

4310

4311

566446

4312

4313

618447

4314

4315

616448

4316

4317

550.2387449

4318

4319

616450

4320

4321

451

4322

4323

580.1370452

4324

4325

453

4326

4327

454

4328

4329

614455

4330

4331

456456

4332

4333

585457

4334

4335

463458

4336

4337

549459

4338

4339

532460

4340

—H574461

4341

4342

564462

4343

4344

616463

4345

4346

598464

4347

4348

514

[0934]

189

4349

Example
R
MS (ES) m/z

465

4350

505.1746

466

4351

551 (+Na)

467

4352

468

4353

463.1704

469

4354

486

470

4355

503

471

4356

537

472

4357

533.2348

473

4358

499.2304

474

4359

504

475

4360

476

4361

532.2522

477

4362

478

4363

479

4364

539.0842

480

4365

545.1595

481

4366

574.1483

482

4367

503.2238

483

4368

515.2234

484

4369

417

485

4370

475.1910

486

4371

383

487

4372

460

488

4373

438

489

4374

452

490

4375

474

491

4376

476

492

4377

383

493

4378

472

494

4379

472

495

4380

383

496

4381

383

497

4382

517

498

4383

499

4384

503

500

4385

521

501

4386

571

502

4387

571

503

4388

571

504

4389

489.2059

505

4390

507.1987

506

4391

557

507

4392

557

508

4393

557

509

4394

503.2226

510

4395

521.2122

511

4396

571.2056

512

4397

571.2054

513

4398

571.1464

514

4399

379.0964

515

4400

504.1831

516

4401

532.2105

517

4402

470.1935

518

4403

576.2355

519

4404

596.2033

520

4405

518.1945

521

4406

538.1372

522

4407

519

523

4408

560

524

4409

399

525

4410

413

526

4411

493

527

4412

581

528

4413

343.1742

529

4414

399.1597

530

4415

483

531

4416

501

532

4417

551

533

4418

407

534

4419

515

535

4420

460

536

4421

460

537

4422

464

538

4423

460

539

4424

412

540

4425

495.4984

541

4426

479.1416

542

4427

572.2800

543

4428

539.2017

544

4429

489.2049

545

4430

497

546

4431

506

547

4432

479

548

4433

524

549

4434

542

550

4435

520

551

4436

520

552

4437

506

553

4438

476

554

4439

547.2525

555

4440

561.2692

556

4441

561.2679

557

4442

576.2184

558

4443

511.1755

559

4444

500.1830

560

4445

500.1888

561

4446

577.1650

562

4447

413.1750

563

4448

427.1903

564

4449

385.1457

565

4450

637.2067

566

4451

532.2448

567

4452

529.1631

568

4453

529.1603

569

4454

574.1478

570

4455

597.0849

571

4456

574.1473

572

4457

513.1228

573

4458

509.1536

574

4459

509.1529

575

4460

493.1803

576

4461

493.1838

577

4462

476.1847

578

4463

476.1865

579

4464

553.1057

580

4465

476.1879

581

4466

489.2076

582

4467

507.2016

583

4468

584

4469

585

4470

415.1559

586

4471

401.1399

587

4472

443

588

4473

477

589

4474

515

590

4475

538

591

4476

452

592

4477

466

593

4478

472

594

4479

502

595

4480

556

596

4481

457

597

4482

598

4483

415.1911

599

4484

471

600

4485

575.2777

601

4486

575

602

4487

589.2947

603

4488

589.2914

604

4489

601.2936

605

4490

587.2808

606

4491

551.2225

607

4492

587.2048

608

4493

619.2098

609

4494

687.1978

610

4495

857.2070

611

4496

719.2024

612

4497

401.1746

613

4498

581.2323

614

4499

511.1900

615

4500

495.1368

616

4501

521.1980

617

4502

529.0962

618

4503

505.2031

619

4504

475.1898

620

4505

529.1604

621

4506

456.1761

622

4507

398.1751

623

4508

414.1690

624

4509

434.1651

629

4510

510

634

4511

483.1992

635

4512

425

636

4513

507.1910

637

4514

489.2064

638

4515

511.1910

639

4516

521.1962

640

4517

505.2006

641

4518

513.1277

642

4519

517.2410

643

4520

519.2190

644

4521

505

645

4522

428.1821

646

4523

428

647

4524

503

648

4525

506.1830

649

4526

524

650

4527

524.1531

651

4528

490.1912

652

4529

487

653

4530

487

654

4531

491

655

4532

503

656

4533

473

658

4534

659

4535

665

4536

510.1353

666

4537

541.1815

667

4538

475

668

4539

510.1366

669

4540

510.1358

670

4541

671

4542

524

672

4543

535

673

4544

594

674

4545

524

675

4546

578

676

4547

578

677

4548

578

678

4549

540

679

4550

594

680

4551

555

681

4552

528

682

4553

528

683

4554

570

684

4555

514

685

4556

516

686

4557

384.1593

688

4558

527.1658 (M + NH4)

690

4559

535

691

4560

568

692

4561

423.1946

693

4562

441.2080

694

4563

506.1857

695

4564

530.1565

696

4565

540

697

4566

592.1401

698

4567

554.1659

699

4568

608.1355

706

4569

490.1929

707

4570

491

708

4571

714

4572

560.1568

720

4573

459.1987

721

4574

508.2019

722

4575

480.1700

723

4576

441.2053

724

4577

509

725

4578

557

726

4579

557

727

4580

541

728

4581

491

729

4582

541

730

4583

501

731

4584

509

732

4585

501

733

4586

501

734

4587

517

735

4588

521

736

4589

505

737

4590

501

738

4591

559

740

4592

741

4593

752

4594

572

755

4595

467

756

4596

453

757

4597

453

758

4598

451

759

4599

451

760

4600

488

761

4601

451

781

4602

444

782

4603

444

784

4604

786

4605

499

787

4606

499

788

4607

515

789

4608

529

790

4609

516

791

4610

517

793

4611

794

4612

796

4613

517

797

4614

798

4615

799

4616

802

4617

807

4618

811

4619

815

4620

816

4621

822

4622

823

4623

825

4624

826

4625

827

4626

828

4627

829

4628

830

4629

831

4630

832

4631

833

4632

834

4633

835

4634

836

4635

838

4636

841

4637

842

4638

844

4639

845

4640

846

4641

847

4642

848

4643

850

4644

851

4645

852

4646

853

4647

854

4648

856

4649

857

4650

858

4651

859

4652

860

4653

861

4654

862

4655

863

4656

864

4657

867

4658

868

4659

869

4660

872

4661

873

4662

877

4663

878

4664

881

4665

882

4666

883

4667

884

4668

885

4669

886

4670

887

4671

888

4672

889

4673

890

4674

891

4675

892

4676

893

4677

894

4678

895

4679

899

4680

901

4681

902

4682

905

4683

906

4684

909

4685

910

4686

911

4687

912

4688

913

4689

914

4690

915

4691

916

4692

920

4693

921

4694

922

4695

924

4696

926

4697

931

4698

932

4699

939

4700

[0935]

190

4701

Example
R
K
MS

940

4702

4703

941

4704

4705

942

4706

4707

Example 943

In Vitro Metalloprotease Inhibition

[0936] The compounds prepared in the manner described in the Examples above were assayed for activity by an in vitro assay. Following the procedures of Knight et al., FEBS Lett. 296(3):263 (1992). Briefly, 4-aminophenylmercuric acetate (APMA) or trypsin-activated MMPs were incubated with various concentrations of the inhibitor compound at room temperature for 5 minutes.

[0937] More specifically, recombinant human

[0938] MMP-13, MMP-1, MMP-2 and MMP-9 enzymes were prepared in laboratories of the assignee following usual laboratory procedures. MMP-13 from a full length cDNA clone was expressed as a proenzyme using a baculovirus as discussed in V. A. Luckow, Insect Cell Expression Technology, pages 183-218, in Protein Engineering: Principles and Practice, J. L. Cleland et al eds., Wiley-Liss, Inc., (1996). See, also, Luckow et al., J. Virol., 67:4566-4579 (1993); .O'Reilly et al., Baculovirus Expression Vectors: A Laboratory Manual, W. H. Freeman and Company, New York, (1992); and King et al., The Baculovirus Expression System: A Laboratory Guide, Chapman & Hall, London (1992) for further details on use of baculovirus expression systems. The expressed enzyme was purified first over a heparin agarose column and then over a chelating zinc chloride column. The proenzyme was activated by APMA for use in the assay.

[0939] MMP-1 expressed in transfected HT-1080 cells was provided by Dr. Harold Welgus of Washington University, St. Louis, Mo. The enzyme was also activated using APMA and was then purified over a hydroxamic acid column. Dr. Welgus also provided transfected HT-1080 cells that expressed MMP-9. Transfected cells that expressed MMP-2 were provided by Dr. Gregory Goldberg, also of Washington University. Studies carried out using MMP-2 in the presence of 0.02% 2-mercaptoethanol are shown in the table below with an asterisk. Studies with MMP-7 were carried out at pH 7.5 in the presence of 0.02% 2-mercaptoethanol using conditions otherwise similar to those used for the other enzymes. The enzyme was obtaind from a hMMP-7-expressing E. coli clone that was a gift of Dr. Steven Shapiro of Washington University, St. Louis, Mo. Further specifics for preparation and use of these enzymes can be found in the scientific literature describing these enzymes. See, for example, Enzyme Nomenclature, Academic Press, San Diego, Calif. (1992) and the citations therein, and Frije et al., J. Biol. Chem., 26(24): 16766-16773 (1994). The enzyme substrate is a methoxycoumarin-containing polypeptide having the following sequence:

[0940] MCA-ProLeuGlyLeuDpaAlaArgNH2, wherein MCA is methoxycoumarin and Dpa is 3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine. This substrate is commercially available from Baychem as product M-1895.

[0941] The buffer used for assays contained 100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl2 and 0.05 percent polyethyleneglycol (23) lauryl ether at a pH value of 7.5. Assays were carried out at room temperature, and dimethyl sulfoxide (DMSO) at a final concentration of 1 percent was used to dissolve inhibitor compound.

[0942] The assayed inhibitor compound in

[0943] DMSO/buffer solution was compared to an equal amount of DMSO/buffer with no inhibitor as control using Microfluor White Plates (Dynatech). The inhibitor or control solution was maintained in the plate for 10 minutes and the substrate was added to provide a final concentration of 4 μM.

[0944] In the absence of inhibitor activity, a fluorogenic peptide was cleaved at the gly-leu peptide bond, separating the highly fluorogenic peptide from a 2,4-dinitrophenyl quencher, resulting in an increase of fluorescence intensity (excitation at 328 nm/emission at 415 nm). Inhibition was measured as a reduction in fluorescent intensity as a function of inhibitor concentration, using a Perkin Elmer L550 plate reader. The IC50 values were calculated from those values. The results are set forth in the Inhibition Table A, below, reported in terms of IC50 to three significant figures, where appropriate.

191Inhibition Table A (nM)ExampleMMP-13MMP-2MMP-1NumberIC50(nM)IC50(nM)IC50(nM)122.78.5>10,00025,5006,000>10,000815.62,900>10,000915.62,900>10,0001018.1>10,000>10,0001118.04,500>10,0001250.02,500>10,0001312.25,600>10,0001440.06,000>10,0001537.02,700>10,000166.701,400>10,0001731.63,500>10,0001845.0>10,000>10,0001928.05,500>10,0002042.54,800>10,0002170.07,000>10,00022>10,000>10,000>10,0002390.010,000>10,0002423.54,500>10,000256.001,600>10,0002610.73,600>10,000276.401,600>10,000286.70700>10,000294.00445>10,0003210.0800>10,0003320.04,500>10,0003418.1>10,000>10,0003530.09,000>10,0003615.82,100>10,0003730.01,750>10,0003867.46,00067.43919.33,700>10,0004026.8900>10,0004170.05,400>10,0004282.5>10,000>10,0004317.95,000>10,0004419.01,050>10,000453605,000>10,0004680.05,700>10,0004711.46,000>10,0004827.03,200>10,0004920.06,500>10,000513707,000>10,0005290.01,900>10,0005328.91,400>10,0005440.05,700>10,0005510.0>10,000>10,0005655.03,500>10,0005780.02,700>10,0005822.04,000>10,000594.00530>10,0006013.93,700>10,000617.001,500>10,0006214.0690>10,0006320.02,900>10,0006419.3770>10,000655.00195>10,000668.00240>10,0006813.01,800>10,0006918.13,500>10,0007010.6700>10,000717.70270>10,0007213.0800>10,0007315.42,000>10,000749.0080.0>10,0007511.5500>10,000769.00250>10,0007775.03,400>10,0007811.7730>10,0007920.02,000>10,000804.10562>10,0008160.0158>10,000826.70490>10,000832.7021.13,1008428.61,400>10,00085130370>10,000860.612.1>10,000874.0015.5>10,000889.0040.0>10,000910.3<0.1>10,000920.80.1>10,000950.3<0.13,600960.40.17,300970.6<0.1>10,000981.700.2>10,000991.00<0.1>10,0001000.5<0.16,0001011.100.8>10,0001020.60.2>10,0001031.800.3>10,0001040.250.210,0001051.100.310,0001060.20.15>10,0001060.1<0.18,2001080.2<0.15,0001090.3<0.1>10,0001100.60.2>10,0001110.80.15>10,0001120.5<0.1>10,0001130.3<0.1>10,0001140.4<0.1>10,0001150.1<0.1>10,0001160.3<0.1>10,0001170.20.1>10,0001180.2<0.1>10,0001190.30.3>10,0001200.40.1>10,0001210.20.15,0001220.2<0.13,0001230.7<0.1>10,000124<0.1<0.1>10,0001250.4<0.1>10,0001260.7<0.1>10,0001272.900.2>10,0001280.1<0.13,40012937.23.00>10,0001300.50.31,6001310.2<0.18,0001320.5<0.1>10,0001331.400.3>10,0001341.800.3>10,0001350.60.310,0001360.9<0.1>10,0001370.80.110,0001383.900.25>10,00014011.40.8>10,00014120.09.00>10,00014212.610.0>10,00014322.014.5>10,0001440.40.210,0001450.40.23,7001460.20.33,0001470.40.27,7001482.503.70>10,00014915.813.8480150175175>10,000151270290>10,0001522.0059.0>10,00015350.05,000>10,00015418.03,700>10,000155130240>10,0001562.200.45>10,0001570.50.2>10,00016030090.0>10,00016132.6900>10,00016227.87,000>10,00016344.52,500>10,0001643.50440>10,0001653.0048.5>10,00016632.7240>10,00016850.0285>10,00016920.0175>10,0001702.40200>10,0001715.40186>10,0001723.80160>10,0001736.703303,40017423.5800>10,0001752.50290>10,0001764.00250>10,0001778.8052010,00017818.1325>10,00017920.6170>10,0001801.1041.8>10,0001811902,300>10,0001833001,500>10,0001844801,500>10,0001852.2032.6>10,00018710.0600>10,0001887.0235>10,0001897.00235>10,0001904.70136>10,0001913.5025.1>10,0001933.500.15>10,0001940.3<0.1>7,3001951.000.2>10,0001961.60<0.1>10,0001972.70<0.1>10,0001980.3750.257,3001990.2<0.13,0002000.2<0.13,0002010.30.2>10,0002020.40.2>10,00020728.8900>10,0002081101,000>10,00020950.0130>10,0002105.404.504,00021111.41,200>10,000212160240>10,0002131,4002,700>10,0002144,9003,500>10,000224<0.1<0.14,50022518041.8>10,00022728.821.7>10,0002282,4482,000>10,0002290.180.1>10,0002310.20.1>10,00023343.52,050>10,0002352355,300>10,0002369.00400>10,00023713.01,900>10,00023880.010,000>10,0002399.008,300>10,00024076.910,000>10,0002414.80>10,000>10,00024242.51,500>10,00024311.3420>10,00024467.44,400>10,00024520.0800>10,00024632.72,700>10,00024734.51,600>10,0002482.29270>10,00024913.0235>10,000251<0.1<0.15,840252<0.1<0.13,933.33253<0.1,3,400<0.10.152560.20.13,2002570.20.14,1002580.20.1>10,0002600.1<0.15,300261<0.1<0.13,7002621.500.9>10,0002640.2<0.14,5002650.21.30,>10,000<0.12660.1<0.15,5002670.20.1510,000268<0.1,4,000<0.10.22690.2<0.1>10,0002701.001.00>10,0002710.30.17>10,0002720.20.13,6002730.30.1>10,000274160>10,000>10,00027570.0>10,000>10,00027637.3>10,000>10,00027770.0>10,000>10,00027819.3>10,000>10,00027920.07,300>10,00028090.0>10,000>10,000281105>10,000>10,00028214.89,000>10,00028313.8>10,000>10,000284130>10,000>10,00028519.39,000>10,00028660.0>10,000>10,000287150>10,000>10,00028835.0>10,000>10,00028950.0>10,000>10,00029050.0>10,000>10,000292100>10,000>10,00029363.1>10,000>10,00029459.1>10,000>1,00029550.0>10,000>10,00029650.0>10,000>10,00029734.9>10,000>10,00029840.0>10,000>10,00029930.69,000>10,00030037.3>10,000>10,00030190.0>10,000>10,000302175>10,000>10,000303115>10,000>10,00030430.67,000>10,00030528.6>10,000>10,00030660.0>10,000>10,00030740.0>10,000>10,00030840.010,000>10,00030948.5>10,000>10,00031060.010,000>10,000311120>10,000>10,000312200>10,000>10,00031377.0>10,000>10,00031465.0>10,000>10,000315420>10,000>10,0003160.40.2>10,0003171.400.4>10,0003180.30.1>10,0003190.50.2>10,00032012.14.00>10,0003210.50.3>10,0003220.30.3>10,0003231.300.4>10,0003240.70.4>10,0003250.90.2>10,0003260.60.45>10,0003270.90.3>10,0003280.350.4>10,0003290.90.4>10,0003300.50.7>10,0003310.70.2>10,0003322.100.4>10,0003330.80.2>10,0003340.70.3>10,0003350.90.15>10,0003361.00<0.1>10,0003372.700.2>10,0003381.900.2>10,0003391.000.3>10,0003400.3<0.1>10,0003410.60.2>10,0003424.000.3>10,0003431.700.8>10,0003442.900.65>10,0003461.200.2>10,0003473.000.7>10,00034816.50.8>10,0003490.2<0.126003500.1<0.16000351———3521.40.3>10,0003530.3<0.1>10,0003541.615.43550.4<0.170003562.432.63570.30.1>10,000358———35934.912.2>10,00036010.05.63610.5<0.150003622.7<0.1>10,0003630.40.288003641.00.2>10,0003650.30.1>10,00036613.02.5>10,000367———3680.57.03693.35.437037111.1400372———3733.080.03743.34.0>10,00037516.915.6>10,0003765.52303781.70.32003790.30.1>10,000380———381———38211.42603833.0700>10,000384———385———3860.40.22100387———38850.04303891.716.1>10,000390———3910.1<0.154003920.20.1>10,0003934.5427>10,0003940.58.03950.90.5>10,0003964.8330>10,0003974.470.0>10,0003987.070.0>10,0003991.20.3>10,00040023.552040116.9195>10,00040215.8340>10,00040355.34.0>10,0004040.50.25>10,0004054064071.20.1>10,00040825.1800>10,00040922.4275>10,0004100.60.25>10,0004110.2<0.1>10,0004120.40.264004131.10.3800041450.51500>10,00041550.4246>10,0004160.40.230004170.74.5>10,0004187.01400>10,0004194.2400>10,000420———421———422———423———4245.580.0>10,00042520.01000>10,000426———427———428———429———430———431———43213.9100>10,0004334503500>10,0004341903700>10,0004355.91500>10,0004361.8330>10,00043718.1800>10,0004381.4160>10,00043910701600>10,00044026.8240>10,0004416.0420>10,00044210.0211>10,00044390.02200>10,000444———44590.01200>10,0004462707000>10,00044723.9155>10,0004482.4540>10,000449———450———4510.30.13700452<0.1<0.14530.435.0>10,0004542.1100>10,0004556.326.8>10,000456———45718002700>10,0004582102100>10,0004591363100>10,0004604.0200>10,00046120.0145>10,0004622.980.0>10,00046316.9210>10,000464120400>10,00046580370>10,0004669.460>10,00046727.0140>10,000468———4690.812.0>10,0004701402000>10,0004712400>10,000>10,0004724.0200>10,0004731603300>10,00047412.1300>10,00047527.1500>10,00047625.4140>10,00047711.3160>10,00047816.4306>10,0004795.060.0>10,00048018.6155>10,00048150.01400>10,0004826.04.0>10,00048332.610.6>10,000484240100>10,0004858.04.2>10,00048654004000>10,000487140800>10,000488140370>10,0004897701900>10,00049061.03000>10,000491>10,000>10,000>10,0004926100>10,000>10,000493>10,000>10,000>10,0004946503300>10,00049514.521.1>10,00049630.7200>10,00049750.08000>10,0004990.919.3>10,0005003.022.0>10,0005012.5180>10,00050214.063>10,00050310.050.0>10,0005046.3220>10,00050514.072.0>10,0005065.0400>10,00050715.8210>10,00050819.3210>10,000509520>10,000>10,0005107700>10,000>10,00051190006000>10,0005127700>10,000>10,0005137700>10,000>10,0005141.00.65,0005158.027.0>10,00051614.8300>10,00051714.01100>10,00051811.4350>10,00051945.41300>10,00052022.5250>10,0005213.550.0>10,0005222.494.0>10,0005232.4190>10,00052427006400>10,000525290700>10,000526>10,000>10,000>10,00052767009000>10,0005287700>10,000>10,0005298800>10,000>10,00053020.060.7>10,00053113.010.0>10,00053210.0150>10,00053360.0150>10,00053430.0480>10,0005351.935.0>10,0005367.788.0>10,00053770.055.0520053880.0370>10,000539270350>10,00054011.4500>10,0005410.72.0>10,000542———54333.75400>10,00054435.03100>10,0005457.7120>10,0005462.718.6>10,0005475.064.7>10,00054840.0800>10,00054955.32900>10,00055020.02000>10,0005519.0140>10,00055212.8140>10,00055312.850.0>10,0005543.7140>10,0005553.7220>10,0005564.5170>10,00055716.9200>10,0005584.566.4>10,0005597.280.0>10,0005604.5306>10,0005616.0500>10,00056212006300>10,00056370.0235>10,000564150550>10,0005655.5700>10,00056615.857.1>10,0005675.087.7>10,0005681204600>10,00056916.987.7>10,000570290>10,000>10,00057128.6140>10,00057237.23000>10,00057311.4235>10,00057410.6220>10,00057510.7110>10,0005768.878.0>10,0005771072200>10,0005781602000>10,0005792.7100>10,00058037.2700>10,00058127.0480>10,00058230.01800>10,00058370.04700>10,00058427003500>10,00058514003500>10,000586>10,000>10,000>10,0005871.81.0>10,000588———58970.0>10,000>10,00059012180.0>10,00059170.0730>10,00059257.0690>10,000593420650>10,000594570650>10,000595270425>10,0005961.110.6>10,000597670700>10,00059825.4145>10,0006009.0600>10,0006019.01300>10,00060270.03000>10,00060315.82300>10,00060420.02500>10,00060510.62000>10,0006063.077.0>10,0006072.9220>10,0006083.0250>10,00060930.62800>10,0006104251300>10,0006111391800>10,0006122902200>10,0006138.030.7>10,00061422.025.4>10,0006153.111.0>10,0006164.03.7>10,0006177.05.7>10,000618———6194.35.7>10,00062027.8225>10,0006211201500>10,0006225001600>10,0006233501400>10,000624120940>10,0006344.460.7>10,00063513.9260>10,0006363.08.0>10,0006373.822>10,000638———6391.51.594006404.215.8>10,0006414.013.7>10,0006422.21.1>10,0006431.81.260006441.63.388006453701200>10,000646—7800>10,0006476.0160>10,00064825.8110>10,0006491301400>10,00065014.71200>10,00065113.760>10,0006520.482.0>10,0006530.8160>10,0006543.235.0>10,00065537.31400>10,0006563.1120>10,00065812.21000>10,0006591.03.7>10,0006652.329.2>10,00066648.4330>10,00066730135>10,0006682.025.8>10,0006694.322.7>10,0006706716.0130>10,0006726.760>10,00067314.8455>10,0006748.0110>10,00067513.08860006767.790>10,0006777.034.7>10,0006785.050>10,00067968068168268311.3290>10,000684601450>10,0006853/034.7>10,00068642003700>10,00068817.6110>10,0006907.341.8>10,00069110.0130>10,00069210.022.7>10,0006932101900>10,0006943.123.2>10,0006952.022.7>10,00069610.0140>10,00069718.11500>10,00069816.9700>10,00069950.0455>10,00070544.51100>10,0007064.340>10,0007072.39.0>10,0007081143000>10,00071428.8420>10,0007204.536.9>10,00072428.6300>10,00072525.1210>10,00072615.8250>10,00072734.9240>10,0007289.4106>10,00072914.8240>10,000730373000>10,0007311.935>10,0007323.1590>10,0007331.6270>10,0007346.03300>10,0007359.0800>10,0007360.9145>10,0007373.01280>10,00073822.0270>10,00074061175>10,00074150125>10,00075214.8271>10,0007552.220>10,0007567.028.8>10,0007573.328.8>10,0007585.034.7>10,0007593.060.8>10,0007606.025.4>10,0007615.041.8>10,0007695.00.7>10,000770270485>10,00077150010,000>10,0007723504200>10,0007736.02.7>10,000774———775120270>10,0007763.010.0>10,0007772.56.5>10,0007783.312>10,00077940210>10,00078017.580>10,0007818005100>10,00078221.1100>10,0007846.04500>10,0007863.7700>10,0007871.2175>10,0007883.0445>10,00078912.23700>10,0007904.5700>10,0007912.0700>10,0007934.023.5>10,00079415002900>10,0007965.7130>10,0007974.0175>10,00079820.0210>10,00079910.643.5>10,0008022.310,000>10,0008072001400>10,00081114.8110>10,0008151401400>10,0008161200>10,000>10,00082029.01400>10,0008214.010.0>10,00082210.0210>10,0008237.0505>10,00082511.370.0>10,00082640.0650ND82710.0540>10,0008281.512.8ND8296.022.0ND83017.92100>10,0008312.3170>10,00083218.12000>10,00083311.01750>10,000834150780ND8356.020.0>10,0008361354200ND8383.070.0>10,0008412851900ND8425.545.4>10,0008445.04700>10,00084528.62000ND8464.5186>10,00084720.01800ND848——ND8504.5150>10,0008513.742.5ND85225.03000ND85315.8120ND85440.03300ND8561.2250ND8571.3120ND8583.7600>10,0008595.5440ND8602.71500>10,0008612.034.9ND8621.740.0ND863——ND864——ND86716.510,000>10,000868——ND8692.076.9ND8703056000ND

Example 944

In Vivo Angiogenesis Assay

[0945] 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, BM, et al., Investigative Ophthalmology & Visual Science, July 1996, Vol. 37, No. 8.

[0946] 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.

[0947] The corneal pocket is made by anesthetizing a 7 week old C57B1/6 female mouse, then proptosing the eye with a jeweler's forceps. Using a dissecting microscope, a central, intrastromal linear keratotomy of approximately 0.6 mm in length is performed with a #15 surgical blade, parallel to the insertion of the lateral rectus muscle. Using a modified cataract knife, a lamellar micropocket is dissected toward the temporal limbus. The pocket is extended to within 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.

[0948] 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.

[0949] 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.

area = \frac{(0.4 \times clock hours \times 3.14 \times vessel length (in mm))}{2}

[0950] 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.

EXAMPLE 350

In Vivo PC-3 Tumor Reduction

[0951] 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.

[0952] Balb/c nu/nu mice at 7-9 weeks of age were anesthetized with avertin [2,2,2-tribromethanol/t-amyl alcohol (1 g/l mL) diluted 1:60 into phosphate-buffered sline] and 3-5×106 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.

[0953] 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.

EXAMPLE 945

Tumor Necrosis Factor Assays

[0954] Cell Culture.

[0955] 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:

[0956] 1. Count, then harvest cells by centrifugation. Resuspend the pellet in R-10 supplement to a concentration of 1.540×106 cells/mL.

[0957] 2. Add test compound in 65 μL R-10 to the appropriate wells of a 96-well flat bottom tissue culture plate. The initial dilution from a DMSO stock (0.100 mM compound) provides a 400 μM solution, from which five additional three-fold serial dilutions are made. Each dilution of 65 μl (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.

[0958] 3. The counted, washed and resuspended cells (200,000 cells/well) in 130 μL are added to the wells.

[0959] 4. Incubation is for 45 minutes to one hour at 37° C. in 5% CO2 in a water saturated container.

[0960] 5. R-10 (65 uL)containing 160 ng/mL PMA (Sigma) is added to each well.

[0961] 6. The test system is incubated at 37° C. in 5% CO2 overnight (18-20 hours) under 100% humidity.

[0962] 7. Supernatant, 150 μL, is carefully removed from each well for use in the ELISA assay.

[0963] 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% CO2 until the color develops. The system is excited at 570 nm and read at 630 nm.

[0964] TNF Receptor II ELISA Assay

[0965] 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 hours).

[0966] 2. Wash the plate with PBS-Tween (1×PBS w/0.05% Tween).

[0967] 3. Add 200 μL 5% BSA in PBS and block at 37° C. in a water saturated atmosphere for 2 hours.

[0968] 4. Wash the plate with PBS-Tween.

[0969] 5. Add sample and controls (100 μl of each) to each well. The standards are 0, 50, 100, 200, 300 and 500 μg 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.

[0970] 6. Incubate at 37° C. in a saturated atmosphere for 1.5 hours.

[0971] 7. Wash the plate with PBS-Tween.

[0972] 8. Add 100 μL goat anti-human TNFrII polyclonal (1.5 μg/mL R&D Systems #AB226-PB in 0.5% BSA in PBS).

[0973] 9. Incubate at 37° C. in a saturated atmosphere for 1 hour.

[0974] 10. Wash the plate with PBS-Tween.

[0975] 11. Add 100 μL anti-goat IgG-peroxidase (1:50,000 in 0.5% BSA in PBS, Sigma #A5420).

Number	Date	Country
60095347	Aug 1998	US
60095501	Aug 1998	US
60101080	Sep 1998	US
60095347	Aug 1998	US
60095501	Aug 1998	US
60101080	Sep 1998	US
60066007	Nov 1997	US
60095347	Aug 1998	US
60095501	Aug 1998	US
60101080	Sep 1998	US
60066007	Nov 1997	US
60095347	Aug 1998	US
60095501	Aug 1998	US
60101080	Sep 1998	US

	Number	Date	Country
Parent	09570731	May 2000	US
Child	10747796	Dec 2003	US

	Number	Date	Country
Parent	09311837	May 1999	US
Child	09570731	May 2000	US
Parent	09256948	Feb 1999	US
Child	09311837	May 1999	US
Parent	09191129	Nov 1998	US
Child	09311837	May 1999	US
Parent	09186410	Nov 1998	US
Child	09311837	May 1999	US
Parent	09191129	Nov 1998	US
Child	09256948		US
Parent	09186410	Nov 1998	US
Child	09256948		US
Parent	09186410	Nov 1998	US
Child	09191129		US

Aromatic sulfone hydroxamic acid metalloprotease inhibitor

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

CROSS-REFERENCE TO RELATED APPLICATION

Provisional Applications (14)

Divisions (1)

Continuation in Parts (7)