CZ20001690A3 - Aromatic sulfonohydroxamic acid, metalloprotease inhibitor - Google Patents

Abstract

Use of an effective amount of aromatic sulfonhydroxamic acid acids of formula I for the manufacture of a medicament for treatment a host mammal having a pathological condition matrix metalloprotease activity, which comprises administration a compound of formula I or a pharmaceutically acceptable salt thereof acceptable salts, in an effective amount to the host mammal having such a condition, wherein said metalloprotease inhibitor matrix inhibits the activity of one or more of MMP-2, MMP9 and MMP-13, while exhibiting substantially less inhibitory activity activity against MMP-1. The enzyme inhibitor administered is responsive with a structure of formula I wherein R 1 and R 2 are both H or R1 and R2 form, together with the atoms to which they are a 5-, 8-membered ring containing one, two or three ring heteroatoms, oxygen, sulfur or nitrogen, R 3 is optionally substituted aryl or optionally substituted heteroaryl radical. Also disclosed are novel compounds selectively inhibiting metalloproteases, production methods such compounds and pharmaceutical compositions comprising the same inhibitor.

Description

Technical field

The invention relates to proteinase inhibitors (proteases) and in particular to the use of aromatic sulfonhydroxamic acid compounds which are useful inter alia as selective inhibitors of matrix metalloproteinases in the process for treating conditions associated with pathological matrix metalloproteinase activity, selective inhibitors alone, proteinase inhibitor compositions, intermediates for synthesis proteinase and methods for preparing proteinase inhibitors.

BACKGROUND OF THE INVENTION

Connecting tissues, extracellular matrix components and basement membranes are essential components of all mammals. These components are biological materials that provide rigidity, differentiation, attachment and, in some cases, elasticity of biological systems, including human beings and other mammals. The connective tissue components include, for example, collagen, elastin, proteoglycans, fibronectin, and laminin. These biochemicals form or are components of structures such as skin, bones, teeth, tendons, cartilage, basement membranes, bloodstream, cornea and enamel.

Under normal conditions, connective tissue replacement and repair processes are controlled and in equilibrium. Loss of this equilibrium for whatever cause leads to a number of disease states. Inhibition of the enzymes responsible for loss of equilibrium provides a control mechanism for this tissue breakdown and thus for the treatment of these diseases.

The connective tissue or connective tissue components are degraded by the action of proteinase enzymes released from resident tissue cells or from invasive inflammatory cells or tumor cells. The major class of enzymes having this function are zinc metalloproteinases (metalloproteases).

Metalloprotease enzymes are divided into classes of several members having more commonly used different names. 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 (MMP13), 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 Β ( 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 matrix metalloprotease with attached numerals forming differences between specific members of the MMP family.

The uncontrolled breakdown of connective tissue by metalloproteases is a feature of a number of pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis, coma, epidermal or gastric ulceration, metastasis, tumor invasion or angiogenesis, osteoarthritis, proteinuria, Alzheimer's disease, coronary thrombosis, and bone disease. Defective injury repair processes can also occur. This can cause incorrect wound healing resulting in poor repair, adhesions and scarring. Such defects may later lead to disfigurement and / or permanent disability as in postoperative adhesions.

Matrix metalloproteases are also involved in tumor necrosis factor (TNF) biosynthesis. Inhibition of the production or activity of TNF and related compounds is an important mechanism for the clinical treatment of disease. For example, TNF-α is a cytokine now believed to be first produced as a 28 kDa cell-associated molecule. It is released as an active 17 kDa form, which can mediate a large number of malignant effects in vitro and in vivo. For example, TNF can cause or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infections, meningitis, fever, psoriasis, cardiovascular / pulmonary effects such as poisphemus trauma, flushing, haemorrhage, coagulation, hypertoxic alveolar injury, radiation damage and acute phase responses as seen in 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.

TNF-α convertase is a metalloprotease involved in the formation of soluble TNF-α. Inhibition of TNF-α convertase inhibits the production of active TNF-α. Compounds that inhibit both TNF activity and TNF-α production have been described 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 also been shown to inhibit TNF release (Gearing et al., Nature 376, 555-557 (1994), McGeehan et al., Nature 376, 558-561 ( 1994)). There remains a need for potent TNF-α convertase inhibitor agents.

MMP is also involved in other biochemical processes in mammals. Ovulation control, uterine post-partum involution, possible implantation, cleavage of APP (precursor protein β • ·

-amyloid) to amyloid plaque and inactivation of the cis-protease inhibitor (oq-PI). Inhibition of these metalloproteases makes it possible to control fertility and to treat or prevent Alzheimer's disease. In addition, increasing and maintaining levels of natural or administered as a protease inhibitor drug, or a biochemical such as cq-PI, promotes the treatment and prevention of diseases such as emphysema, lung diseases, inflammatory diseases and aging diseases such as loss of tension and skin resilience or organs.

Inhibition of selected MMPs may also be desirable in other cases. Treatment of cancer and / or inhibition of metastasis or inhibition of angiogenesis are examples of approaches to the treatment of diseases where selective inhibition of stromelysin, gelatinase A or B or collagenase III appears to be relatively the most important enzyme or enzymes for inhibition, particularly as compared to collagenase I (MMP1). A drug that does not inhibit collagenase I may have a better therapeutic profile. Osteoarthritis, another predominant disease believed that cartilage degradation in inflamed joints is at least partially due to MMP-13 released from cells, such as stimulated chrondrocytes, can best be treated by administering drugs whose one mode of action is MMP-13 inhibition. See, for example, Mitchel et al., J. Clin. Invest., 97, 761-768 (1996) and Reboul et al., J. Clin. Invest., 97, 2011-2019 (1996).

Metalloprotease inhibitors are known. Examples include natural biochemicals such as tissue inhibitor of metalloproteinase (TIMP), a2 ^_ma kroglobulin and their analogues and 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 peptides hunting derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin Converting Enzyme (ACE) assists in the production of angiotensin II, a potent pressure substance in mammals. Inhibition of this enzyme leads to a decrease in blood pressure. Metalloprotease (MMP) inhibitors containing an amide or peptidylamide are known, for example, as shown in WO 95/12389, WO 96/11209 and US 4,595,700. MMP inhibitors containing a hydroxamate group are described in a number of published patent applications, such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386, which disclose compounds with a carbon backbone, and WO 90/05719, WO 93 / 20047, WO 95/09841 and WO 96/06074, which disclose hydroxamates which have peptides in the backbone or peptidomimetic spine, as in an article by Schwartz et al., Progr. Copper. Chem., 29: 271-334 (1992) and in Rasmussen et al., Pharmacol. Ther. , 75 (1): 69-75 (1997) and Denis et al., Invest. New. Drugs, 15 (3): 175-185 (1997).

One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes.

• • • •

For example, a peptidomimetic hydroxamate known as batimastat is reported to exhibit IC 50 values from about 1 to about 20 nanomoles (nmol) against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat, another broad spectrum MMP inhibitor, has been reported to be very similar to batimastat, except that marimastat exhibits IC 50 values against MMP-3 of 230 nmol. Rasmussen et al., Pharmacol. Ther., 75 (1): 69-75 (1997).

Meta analysis of data from phase I / II studies using marimastat in patients with rapidly progressing, difficult to treat solid tumor cancers (colon, pancreas, ovary, prostate) indicated a dose-dependent decrease in cancer-specific antigens as surrogate markers of biological activity. Although marimastat has shown some efficacy with these markers, toxic side effects have been reported. The most common drug-related toxicity of marimastat in these clinical trials was muscle and bone pain and stiffness, often starting in the small joints of the hands, expanding into the arms and shoulders. A short dosing interval of 1-3 weeks followed by dose reduction allows continued treatment, Rasmussen et al., Pharmacol. Ther. 75 (1): 69-75 (1997). He believes that this phenomenon may cause a lack of specificity of the inhibitory effect among MMPs.

International Application WO 98-38163, published September 3, 1998, discloses a broad class of hydroxamate inhibitors of MMP and TACE. The compounds of WO 98-38163 contain one or two substituents on the hydroxamic functionality and a substituent which may be an aromatic sulfonyl group near one or both of these substituents.

International Application WO 98-37877, published September 3, 1998, discloses compounds that contain a 5- to 7-membered heterocyclic ring near the hydroxamic function and may contain an aromatic sulfonyl group near the heterocyclic ring of one or both of these substituents.

Although many of the known MMP inhibitors such as batimastat, marimastat and hydroxamates of WO 98-37877 and WO 98-38163 exhibit a broad spectrum of activity against MMPs, these compounds are not particularly selective in their inhibitory activity. This lack of selectivity may be the cause of the pain and stiffness of the muscles and bones observed during their use. In addition, it may be therapeutically advantageous to use a drug that is selective in its activity over the generally active material so that the treatment may be more closely adapted to the pathological condition occurring in the host mammal. The following describes a method for treating a host mammal having a condition associated with the pathological activity of a matrix metalloprotease that utilizes a compound selectively inhibiting one or more MMPs while exhibiting less activity against at least MMP-1.

9

SUMMARY OF THE INVENTION

The invention is directed to a method of treatment comprising administering an aromatic sulfonhydroxamic acid metalloprotease inhibitor in an effective amount to a host mammal having a condition associated with the pathological activity of the matrix metalloprotease. Among other things, the contemplated molecule exhibits excellent inhibitory activity against one or more matrix metalloproteinase (MMP) enzymes, such as MMP-2, MMP-9 and MMP-13, while generally showing substantially less inhibition of at least MMP-1. Substantially less means that the compound of the invention exhibits an IC 50 value against one or more of MMP-2, MMP-9 and MMP-13 compared to an IC 50 value against MMP-1, for example IC 50 Q MMP-2: IC 50 Q MMP-1, which is less than 1:10, preferably less than 1: 100, and most preferably less than 1: 1000 in the in vitro inhibition assay used below. 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 of at least MMP-1, as well as compositions comprising such an MMP inhibitor as an active ingredient. The invention further encompasses intermediates in the preparation of an aromatic sulfonhydroxamic acid molecule and a process for preparing an aromatic sulfonhydroxamic acid molecule.

Briefly, one embodiment of the invention is directed to a method of treatment comprising administering an aromatic sulfonhydroxamic acid metalloprotease inhibitor that selectively inhibits the activity of the matrix metalloprotease as above in an effective amount to a host mammal having a condition associated with the pathological activity of the matrix metalloprotease. The enzyme inhibitor administered corresponds to the structure of Formula (I) below, or a pharmaceutically acceptable salt thereof:

I kde

R 6 and R 6 are both hydrido, or R 6 and R 6 together with the atoms to which they are attached form a 5 to 8-membered ring containing one, two or three ring heteroatoms, which are oxygen, sulfur or nitrogen; · • 4 44 ·· · * * 44 4 · · · ·

44 4 4 44 4 • 4 44444 4 · ·

4 4 4 4

44 44 ··

Ι <3 in formula I is an optionally substituted aryl or an optionally substituted heteroaryl radical. When R 1 is a substituted aryl or substituted heteroaryl radical, the substituent is selected from the group consisting of aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxy, arylthio, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, arylcarbonylalkyl, aralkoxyalkyl, aralkoxyalkyl, , arylthioalkyl, aralkylthioaryl, sulfoxide or sulfone of any of the thio substituents and a structure containing two or more 5- or 6-membered rings selected from the group consisting of aryl, heteroaryl, carbocycle or heterocycle.

The substituent bonded to the aryl or heteroaryl group of the R 6 group itself may be substituted with one or more substituents, for example the substituent substituent is optionally substituted. When an aryl or heteroaryl group is substituted and the substituent group itself (substituent or radical) is itself substituted, the latter is independently selected from the group consisting of cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, arylkoxycarbonyl, , alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heteroarylamino, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, hydroxyalkoxy, hydroxyalkylthio, aralkyryloxy, aralkyryloxy, aralkylamino, heteroalkyloxy , aralkonoyl, alkanoyloxy, aralkonoyloxy, hydroxyalkyl, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxy alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl arylcarbonyl, aralkonoyl, heteroarylcarbonyl and alkonoyl, or (iii) wherein the amino nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring containing no to two heteroatoms which are nitrogen, oxygen or sulfur and wherein the ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkonoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethylalkoxy, benzoalkyl heterocyclic, , aralkoxycarbonyl, hydroxycarbonyl, aryloxy, carbonyl, benzo-linked heterocycloalkoxy, benzo-linked cycloalkylcarbonyl, heterocycloalkylcarbonyl, and aryloxy; cycloalkylcarbonyl, carbonylamino, wherein the carbonylamino nitrogen is (i) unsubstituted or (ii) is a reacted amino acid amine or (iii) is substituted with one or two substituents independently selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl or (iv) a carboxamine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic, heteroaryl or benzo-linked heterocycloalkyl ring which is itself unsubstituted or substituted once or two groups independently selected selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl, and an amino group wherein the amine nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group formed by alkyl, aryl and heteroaryl; or (iii) wherein the amino nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring, and an aminoalkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkonoyl, or (iii) wherein the amine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring.

Preferably in practice R 1 and R 1 together with the atoms to which they are attached form a 6-membered ring.

The group R ^ preferably has a length greater than about hexyl (chain - (CH 2) 5 CH 3). The group R 1 preferably has a length less than the eicosyl group (chain - (CH 2) 19 CH 3) and more preferably a length less than the stearyl group (chain - (CH 2) 17 CH 3). A preferred group R 1 contains two or more 5- or 6-membered rings. The intended group R1, when rotating about the axis drawn by position 1 associated with SO2 and position 4 of the 6-membered ring or position 1 associated with SO2 and 3,4 by a 5-membered ring radical, defines a three-dimensional volume whose widest dimension is a width transverse to the axis of rotation of about one furanyl ring to about the width of two phenyl rings.

· 99 · 99 99 99

9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 ·· 999 9 999 99 99 9 • ·· 9 9 9 9 9 9 9

999 »» »»

It is also preferred that the group is an aryl or heteroaryl group with a single ring, selected from the group consisting of one other aryl or heteroaryl group with a single ring, which itself is substituted in its own 4-position when it is a 6-membered ring and in its possesses a 3- or 4- position when it is a 5-membered ring, optionally substituted with a substituent selected from the group consisting of another aryl or heteroaryl, C3-C44 alkyl, N-piperidinyl, N-piperazyl, phenoxy, thiophenoxy groups, 4-thiopyridil groups, phenylazo groups and benzamino groups. The substituent of a 5- or 6-membered aryl or heteroaryl group may itself be substituted as discussed previously.

A preferred compound for use in the method of the invention has a structure which corresponds to formula (II) below, or a pharmaceutically acceptable salt thereof:

where

R 14 is hydrido, a pharmaceutically acceptable cation or C (W) R 6, wherein W is O or S and r 15 _is selected from the group consisting of C 1 -C 8 -alkyl, aryl, C 1 -C 8 -alkoxy, heteroaryl-C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl-C 1 -C 8 -alkyl, aryloxy, ar-C 1 -C 8 -alkoxy, ar-C 1 -C 8 -alkyl, heteroaryl, and amino C 1 -C 8 -alkyl, wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, ar-C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkoxycarbonyl and (C) -C8 -alkonoyl, or (iii) wherein the amine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring, m is zero, 1 or 2, n is zero, 1 or 2, p is zero, 1 or 2,

44

9 9 9

4 9 4

9 4 4 8

4 9

44

4 4 *

9 4 4 • · 4

4 4 4

4 4

4994 44

4 9 9

9 4 9

4 4 9 4

4 4 9

44 the sum of m + η + ρ = 1, 2, 3 or 4, (a) one of X, Y and Z is selected from the group consisting of C (O), NR NR, O, S, S (O), S (O 12 and NS (O) 2 R 7 and the remaining two X, Y and Z are CR 1 -R 9 and Ο-ύθίύ 1 or (b) X, Y and Z together form a group selected from NR ⁶ C (O) , NR ⁶ S (O) NR ⁶ S (O) _2, NR6s, NR ⁶ O, NRS ⁶ (O), SS NRŮNR ⁶ and OC (O), one of the remaining X, Y and Z form CR8R9, or n zero and X, Y and Z together form a group selected from the group consisting of

where the wavy lines are bonds to the atoms of the indicated ring, ftft ftftftft ftftftft ftft ftft

W · · ··· «····· ftft * · · ftft« ··· <<

R 6 and R 6 are independently selected from the group consisting of hydrido, C 1 -C 8 -alkonoyl, C 6 -C 8 -alkyl, aroyl, bis-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl- C 1 -C 8 -alkyl, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -perAluoroalkyl, C 1 -C 8 -trifluoromethylalkyl, C 1 -C 8 -fluoroalkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxyalkyl C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, C1-C6-heterocycloalkylcarbonyl, C3-aryl, C1-C6-heterocyclo, C3-C3heteroaryl, C3-C3-cycloalkyl-C1-C6-alkyl C1-C6-aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkylculphonyl, C1-C6-alkyl -C8-heteroarylsulfonyl, carboxy-C8-C8-alkyl, C8-C8-alkoxycarbonyl-C8-C8-alkyl, aminocarbonyl, C8-C8-alkyliminocarbonyl, C8-C8-heterocycloiminocarbonyl, C8-arylthio-C8-C8-C8-C8-C8-C8-alkyl alkyl, C1-C4-alkylthio-C6-C6-alkyl. Cf _? -arykhio-C 3 -C 5 -alkenyl, C 1 -C 4 -alkylthio-C 8 -C 8 alkenyl, C 8 -C 8 -heteroaryl-C 8 -C 8 -alkyl, halo-C 8 -C 8 -alkonoyl, hydroxy-C 8 -C 8 -alkonoyl, thiol -C 1 -C 8 -alkonoyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 5 -alkoxycarbonyl, aryloxycarbonyl, CR 3 R 4 C 1 -C 3 -alkoxy -alkylcarbonyl, hydroxy-C 1 -C 8 -alkyl, aminocarbonyl, wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii) is substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl , C3-C6-cycloalkyl and C1-Cgalkonoyl, hydroxyaminocarbonyl, aminosulfone, wherein the aminosulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C1-C6-alkyl, ar-C1- Cgalkyl, C 3 -C 6 -cycloalkyl and C 1 -C 8 -alkonoyl, amino-C 1 -C 8 -alkylsulfone, wherein the amino-C 1 -C 8 -alkylsulfone nitrogen is (i) unsubstituted or (ii) substituted one or two substituents independently selected from the group consisting of (4-05alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 5 -cycloalkyl and C 1 -C 8 -alkonoyl, and amino-C 1 -C 8 -alkyl, wherein amino-C 1-6 -alkyl -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 8 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 6 -cycloalkyl and C 8 -C 8 -alkyl -alkonoyl group,

R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 6 -carboxyalkyl and hydroxy-C 1 -C 8 -alkyl; · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

R ⁸ and R ⁹ and ΐύθ and RH are independently selected from the group consisting of hydrido, hydroxy, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, hetero-C 1 -C 8 -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 , C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, hydroxyC 1 -C 8 -alkyl, hydroxyalkylcarbonyl-C 8 -alkyl groups -C8-alkyl, hydroxycarbonylar-C1-C6-alkyl, amino carbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1- C 6 -alkyl, arylthio-C 1 -C 6 -alkyl, heteroarylthio-C 1 -C 6 -alkyl, sulfoxide or sulfone of any of the thio substituents, perfluoro-C 1 -C 6 -alkyl, trifluoromethyl-C 1 -C 6 -alkyl, halo-C 1- C 1 -C 6 -alkyl, alkoxycarbonylamino-C 1 -C 8 -alkyl, and amino-C 1 -C 8 -alkyl, wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents which are independently selected from the group consisting of C 1 -C 8 alkyl, ar-C 1 -C 8 -alkyl, cycloalkyl and C 1 -C 8 -alkonoyl, or wherein R 6 and R ⁹ or R ¹⁰ and R 11 and carbon k to which they are attached form a carbonyl group, or wherein R 8 and R ⁹ or R ⁹ and R ^8, or R ⁸ and R ⁹ together with the atoms to which they are attached form a 5- to 8-membered carbocyclic ring or 5- to 8-membered heterocyclic ring containing one or two hetero atoms which are nitrogen, oxygen or sulfur, with the proviso that only one of R and R ⁹ & R ¹⁰ or ^N and R is hydroxy,

R 12 and R 12 'are independently selected from the group consisting of hydrido, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl, heteroaryl, heteroaralkyl, C 1 -C 6 -alkynyl, C 1 -C 6 -alkenyl. thio ΙΕ] -C (-, alkyl, cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, heterocycloalkyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, amino -C 1 -C 8 -alkyl, C 1 -C 8 -alkoxyC 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyalkylcarbonyl-C 1 -C 8 -alkyl, hydroxycarbonylar-C 1 -C 8 -alkyl -alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, sulfoxide or sulfone of any of these thio substituents, perfluoro-C 1 -C 6 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 -C 8 -alkyl, and amino-C 1 -C 8 -alkyl wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or 9 (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, cycloalkyl and C 1 -C 8 -alkonoyl, is selected from the group consisting of hydrido, benzyl, phenyl, C 1 -C 8 -alkyl, C 8 -C 8 alkinyl, C C 1 -C 8 -alkenyl and C 1 -C 8 -hydroxyalkyl, and

G-A-R-E-Y is a substituent preferably having a length greater than a pentyl group, and more preferably a length greater than a hexyl group. The substituent G-A-R-E-Y preferably has a length less than the icosyl group and more preferably a length less than the stearyl group.

In this substituent:

G is an aryl or heteroaryl group,

A is selected from the group consisting of (1) -O-, (2) -S-, (3) -NR ¹⁷ -, (4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO-, wherein R ¹⁷ is hydrogen, C 1 -C 6 -alkyl or phenyl, (S) -CO-O- or -O-CO-, (6) -O-CO-O-, (7) -HN = NH-, (8) -NH-CO-NH-, (9) -C: C-, (10) -NH-CO-O- or O-CO-NH-, (11) -N = N-, (12) -NH- CO-NH- and (13) -CS-N (R 18) - or -N (R 6) -CO-, wherein R 18 is hydrogen, C 1 -C 6 -alkyl or phenyl, or (A) is absent and G is bonded directly to R ,

R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl,

9 • φ φ φ φ φ φ φ hetero hetero φ φ · · · · hetero hetero hetero hetero hetero hetero hetero hetero hetero hetero hetero hetero ary ary ary hetero ary ary ary ary hetero hetero alkyl hetero hetero hetero hetero hetero hetero hetero hetero hetero hetero hetero hetero kde hetero hetero , the cycloalkyl, heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1 -C 6 -alkylene dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino and alkoxycarbonyl and R is other than alkyl or alkoxyalkyl when A is -O- or -S-,

E is selected from the group consisting of (1) -CO-N (R ¹⁹ ) or -N (R ¹⁹ ) -CO-, wherein R ¹⁹ is a heterocycloalkyl or cycloalkyl group, (2) -CONH- or -NHCO-, and ( (3) -CO-, (4) -SO ₂ -NR ¹⁹ or -R ¹⁹ -SO ₂ -, (5) -SO ₂ -, (6) -NH-SO ₂ - or -SO ₂ -NH-, or (7) E is absent and R is bound directly to Y, and

Y is absent or is selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, arylkoxy, aralkoxy, heteroarylkoxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, cyclohexyl, heterocycloalkylethyl, heterocycloalkyl an aminoalkyl group wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents selected from the group consisting of alkanoyl, halo, nitro, aralkyl, aryl, alkoxy and an amino group wherein the amine nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from hydrido, alkyl and aralkyl.

A particularly preferred compound for use in the method of the invention corresponds to the structure of formula (III) below, or a pharmaceutically acceptable salt thereof:

• · · ·

9

9 9 9

999 98 • «9

9 9

wherein iU is an aryl or heteroaryl group with a single ring that is 5- or 6-membered and is itself substituted in its own 4-position when it is a 6-membered ring, and in its 3- or 6-membered ring

4-position when it is a 5-membered ring with a substituent selected from the group consisting of thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4 -fluorothiophenoxy, phenoxy, 4-trifluoromethoxyphenoxy, 4-trifluoromethylphenoxy, 4- (trifluoromethylthio) -phenoxy, 4- (trifluoromethylthio) thiophenoxy, 4-fluoro-3-chlorophenoxy, 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-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-methoxy phenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, N-piperidyl, N-piperazinyl and 4- a benzyloxyphenoxy group.

A particularly preferred compound for use in the method of the invention corresponds to the structure of formula (IV) below, or a pharmaceutically acceptable salt thereof:

wherein R 1 is as defined above for formula I, and more preferably as defined for formula II (wherein the R 1 group is a G-A-R-E-Y substituent), and even more preferably as defined for formula III, and

Z is selected from the group consisting of C (O), NR A, S, S (O), S (O) 2, and NS (O) 2 R A • ft ftftftft ftft ftft · · Ftftftft ftftft ·

Where R 6 is selected from the group consisting of hydrido, C 1 -C 5 -alkyl, Cq-C 5 -alkonoyl, benzyl , benzoyl, C 3 -C 5 -alkynyl, C 3 -C 5 -alkenyl, C 1 -C 3 -alkoxy-C 1 -C 4 -alkyl, C 3 -C 8 -cycloalkyl, heteroaryloxy-C 1 -C 8 -alkyl, C 1 -C 5 -hydroxyalkyl, C 1 -C 5 -hydroxyalkyl, C 5 -C 6 -alkylcarbonyl, C 1 -C 5 -alkoxy C 1 -C 5 -alkylcarbonyl, C 1 -C 9 -C 1 -C 5 -alkylcarbonyl or C 1 -C 5 -alkyl-C 1 -C 5 -alkyl, wherein R 1 and R 2 are independently hydrido, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxycarbonyl or aryl-C 1 -C 5 -alkoxycarbonyl, or CR 1 R 5 together form a heterocyclic ring containing 5- to 8-atoms in the ring, and

R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 6 -alkyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkenyl, C 1 -C 6 -carboxyalkyl and C 1 -C 8 -hydroxyalkyl.

An even more preferred group of compounds for use in the method of the invention corresponds to the structure of formula (V) below, or a pharmaceutically acceptable salt thereof:

where

Z is as defined above for formula (IV),

W and Q are independently oxygen (O), NR ^ or sulfur (S), and R ^ is as defined in formula IV and q is zero or one, so that when q is zero, the trifluoroalkyl group is bonded directly to the phenyl ring shown .

The use of a compound of formulas I-V or a pharmaceutically acceptable salt of one of these compounds is contemplated in the process described above. In addition, the compounds of formulas II, III, IV and V and their pharmaceutically acceptable salts are compounds of the invention.

The present invention also contemplates a precursor or intermediate of compounds of Formulas I-V. Such an intermediate corresponds to the structure of formula VI below

4>

(CH ₂ ) _n -Z 2

R \

₂₀ (CH ₂ ) _n

O /

(CH _{2) p,} R

S (O)

VI where m, η, ρ, X, Z, Y and R ¹⁴ are as defined above for formula (Π), g is zero, 1 or 2, and R ²⁴ is R A as defined in formulas I, III or IV, is a GAREY substituent of Formula II (Formula VIA) or R 1 'is an aryl or heteroaryl group which is substituted with a linking substituent reactive to coupling with another group (Formula VIB), such as a nucleophilically displaceable leaving group D.

VIB

Exemplary nucleophilically displaceable leaving groups D include halo (fluoro, chloro, bromo or iodo), nitro, azido, phenylsulfoxido, aryloxy, C 1 -C 8 -alkoxy, C 1 -C 8 -alkylsulfone or arylsulfone and a trisubstituted amino group, all three substituents independently being independently aryl, ar-C 1 -C 8 -alkyl or C 1 -C 8 -alkyl.

r 20 is -O-R 21, wherein R 41 is selected from the group consisting of hydrido, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl, and a pharmaceutically acceptable cation, or (b) -NH-OR 2A where r 22 is _{e a} selectively removable protecting group such as 2-tetrahydropyranyl, C 1 -C 8 -acyl, aroyl, benzyl, benzyl, p -methoxybenzyloxycarbonyl (MOZ), benzyloxycarbonyl, C (-C 8) alkoxycarbonyl, C 1 -C 8 -alkoxy-C 11 ·? - C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy-CF 3 -, a trisubstituted silyl or nitrophenyl group, a peptide synthesis resin and the like.

► Φ ► ► ► ► ► ► ► ► ► ► ► ► ► ► ► ► ►

The trisubstituted silyl group is substituted with C 1 -C 8 -alkyl, aryl or ar-C 8 -C 6 -alkyl.

A particularly preferred precursor of the intermediate to the intermediate of formula (VI) is the intermediate of formula (VII)

wherein m, n, p, g, X, Z, Y, D and R 6 are as defined above for Formula VI.

Among the many advantages and benefits of this invention is providing compounds and compositions effective as inhibitors of matrix metalloproteinase activity, providing such compounds and compositions that are effective in inhibiting metalloproteinases in diseases and diseases causing uncontrolled disintegration of connective tissue.

More particularly, it is an advantage of the present invention to provide a compound and composition effective for selectively inhibiting certain metalloproteinases such as one or more of MMP-2, MMP-9 and MMP13 associated with pathological conditions such as rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periosteal disease, proteinuria, Alzheimer's disease, coronary thrombosis and bone disease.

It is an advantage of the present invention to provide compounds, compositions and methods effective for treating pathological conditions by selective inhibition of metalloproteinases such as MMP-2, MMP-9 and MMP-13 associated with such conditions with minimal side effects induced by inhibition of other metalloproteinases such as MMP-1 whose activity is necessary or desirable for normal body function. Yet another advantage of the invention is to provide a process for preparing such compounds.

Another advantage of the invention is a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.

Another advantage of the invention is to provide a process for preparing such compositions.

• ·

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Still other advantages and benefits of the present invention will be apparent to those skilled in the art from the following description.

In accordance with the present invention, it has been discovered that certain aromatic sulfonhydroxamic acids (hydroxamates) are effective for inhibiting matrix metalloproteinases (MMPs) believed to be associated with uncontrolled or otherwise pathological breakdown of connective tissue. In particular, it has been found that certain aromatic sulfone hydroxamates are effective for inhibiting one or more enzymes, such as MMP-2, MMP-9 and MMP-13, which may be particularly destructive to tissues when present or produced in abnormal amounts or concentrations, and thus exhibit pathological activity. Among these pathological activities is the promotion of tumors and tumor cells in the basement membrane penetration process and the development of new or improved blood supply such as angiogenesis.

In addition, these aromatic sulfone hydroxamates have been found to be selective in inhibiting one or more of MMP-2, MMP-9 and MMP-13, without unnecessarily inhibiting other collagenases required for normal body function, such as tissue repair and repair. In particular, it has been found that when the aromatic sulfone hydroxamate of the invention or a pharmaceutically acceptable salt thereof is particularly active in inhibiting one or more of MMP-2, MMP-9 and MMP-13 in an in vitro assay, it is predicted that one or more of MMP-2, MMP-9 and MMP-13 act as an aromatic sulfone hydroxamate of the invention or a pharmaceutically acceptable salt thereof, while having a limited or minimal in vitro inhibitory effect on MMP-1.

Thus, there is a substantial difference in the activity of the compound used in the method of the invention against one or more of MMP-2, MMP-9 and MMP-13 and MMP-1. This substantial difference is tested using the in vitro inhibition assay discussed in the Examples. A substantial difference in activity corresponds to a compound exhibiting an IC 50 value against one or more of MMP-2, MMP-9, and

MMP-13, which is about 0.1 values against MMP-1, more preferably 0.01 values against MMP-1, and most preferably 0.001 values against MMP-1 or more. Indeed, some compounds exhibit a selectivity difference as measured by IC50 values that exceed the assay limits of 100,000 times. These selectivities are illustrated below in the inhibition tables.

Unless otherwise stated, the compound may inhibit MMP-2 activity compared to MMP-9 or MMP-13 and MMP-1. Similarly, the compound may inhibit the activity of MMP-13 and MMP-2 while showing less inhibition against MMP-1 and MMP-9. In addition, the compound may inhibit the activity of the MMP enzyme while having less effect on the release of tumor necrosis factor.

The advantages of compound selectivity can be evaluated without wishing to be bound by theory, by considering the therapeutic use of the compounds. For example, inhibition of MMP-1 is considered undesirable η

ι;

• φ «

Vzhledem Ι> · due to its role in the maintenance of the enzyme, which helps maintain normal connective tissue turnover and repair. Inhibition of MMP-1 may lead to toxicities and side effects such as connective tissue breakdown and pain, on the other hand, it has been suggested that MMP-13 is directly involved in the destruction of joint components in diseases such as osteoarthritis. Thus, a strong and selective inhibition of MMP-13 over that of MMP-1 is highly desirable because an MMP-13 inhibitor may have a positive effect on the progression of the disease in addition to having an anti-inflammatory effect.

Inhibition of MMP-2 and MMP-9 may be desirable to inhibit tumor growth, metastasis, invasion, or angiogenesis. The selective inhibition profile of MMP-2 and MMP-9 over MMP-1 may provide a therapeutic advantage.

Yet another advantage of a compound of the invention is selectivity with respect to the release of tumor necrosis factor and / or tumor necrosis factor receptor, which provides the physician with yet another factor to assist in selecting the best drug for a given patient. Without wishing to be bound by theory, we believe that there are several factors of this type of selectivity that must be taken into account.

The first is that the presence of tumor necrosis factor may be desirable for cancer control in the body if TNF is not present in a toxic excess. Thus, uncontrolled inhibition of TNF release may be counterproductive and in fact may be considered an adverse side effect in cancer patients. In addition, selectivity with respect to tumor necrosis factor receptor release may also be desirable. The presence of this receptor may be desirable to maintain a controlled level of tumor necrosis in a mammal by binding excess TNF.

The compound for selective inhibition of MMPs useful in the method of the invention can be administered by a variety of routes and provide adequate therapeutic levels in the blood of an enzymatically active inhibitor. For example, the compound may be administered orally (IG, PO) or intravenously (IV). Oral administration is preferred if the patient is out-patient, not hospitalized, physically capable of responsibly receiving the drug at desired intervals. This is true even if a person is treated with more than one drug for one or more diseases, on the other hand, intravenous administration is advantageous in a hospital setting where dose and hence blood levels can be well controlled. The intended inhibitor may also be formulated for IM administration, if desired. This route of administration may be desirable for drug delivery or regular drug delivery to patients who are either physically weak or have poor discipline records or require constant drug levels in the blood.

Thus, one embodiment of the invention is directed to a method of treatment comprising administering an aromatic sulfonhydroxamic acid metalloprotease inhibitor or a pharmaceutically acceptable salt thereof in an effective amount to a host mammal having a condition associated with the pathological activity of the matrix metalloprotease. Contemplated aromatic inhibitory compound ··· · 44 ··· · · · 4 * 4 4 4 • 4 t 4 44944 44 • 9 4 4 9 9 4

The sulfonhydroxamic acid useful in this process inhibits the activity of one or more of MMP-2, MMP-9, and MMP-13 and exhibits substantially less inhibitory activity of at least MMP-1 in the in vitro inhibition assay discussed above and discussed in detail below.

The aromatic sulfonhydroxamic acid inhibitor compound for use in the method of the invention corresponds to the structure of formula (I) below:

where: I

In one embodiment, R 1 and R 2 are both hydrido. In another embodiment, R 1 and R 2 together with the atoms to which they are attached form a 5- to 8-membered ring containing one, two or three ring heteroatoms, which are oxygen, sulfur or nitrogen.

It is preferred that R 6 and R 6 together with the atoms to which they are attached form a 5- to 8-membered ring containing one or two ring heteroatoms, although R 6 and R 6 together with the atoms to which they are attached form a 5- to 8-membered ring containing one, two or three ring heteroatoms. The heterocyclic ring may itself be substituted with up to six C 1 -C 8 alkyl groups which contain another 5- to 8-membered carbocyclic ring a heterocyclic ring, an amino group or contain one or two oxo (carbonyl) groups.

r 3 in formula I is an optionally substituted aryl or an optionally substituted heteroaryl radical. This R 6 radical is selected from the group consisting of aryl, heteroaryl, aralkyl, heteroaralkyl, araloxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, aralkylalkyl, aralkylaryl, alkylthio, alkylthio, aralkoxyaryl, aralkoxyaryl, arylaxyaryl, arylaloxyaryl or a sulfone of any of the thio substituents and a fused ring structure containing two or more 5- or 6-membered rings selected from the group consisting of aryl, heteroaryl, carbocycle or heterocycle.

The substituent in which R 1 is contained is itself substituted with one or more substituents independently selected from the group consisting of cyano, perfluoroalkyl, trifluoromethyl alkyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio,,, th. Aralkyl, aryl, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, cycloalkylthio, heteroarylamino, cycloalkoxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio alkoxy, aralkyloxy, aralkylamino, heterocyclooxy, aralkylamino, heterocyclooxy, aralkyloxy, heterocyclooxy, heterocyclooxy, heterocyclooxy, , alkonoyl, arylcarbonyl, aralkonoyl, alkanoyloxy, aralkonoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxy alkoxy, hydroxycarbonylalkoxy, hydroxycarbonylalkoxy, hydroxycarbonyloxy, ituated or (ii) substituted with one or two substituents attached thereto, which are independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkonoyl, heteroarylcarbonyl and alkonoyl, or (iii) wherein the amine group; the nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring containing no to two heteroatoms which are nitrogen, oxygen or sulfur and wherein the ring itself is (a) unsubstituted or (b) substituted independently by one or two groups selected from the group consisting of aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkonoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzo linked heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, aralkoxycarbonyl, aralkoxycarbonyl, benzo linked heterocycloalkylcarbonyl, heterocycloalkylcarbonyl, and cycloalkylcarbonyl, carbonylamino, wherein the carbonylamino nitrogen is (i) unsubstituted or (ii) is a reacted amino acid amine or (iii) is substituted with one or two substituents selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzo linked heterocycloalkyl, benzo linked cycloalkyl and N, N-disubstituted aminoalkyl, or (iv) a carboxamine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic, heteroaryl or benzo linked heterocycloalkyl which is itself unsubstituted or substituted by one or two groups independently selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl, and an amino group wherein the amine nitrogen is (i ) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl and heteroaryl, or (iii) wherein the amine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring, and wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, and alkoxycarbonyl; or (iii) wherein the amine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring. The compound of formula I may also be used in the form of a pharmaceutically acceptable salt.

The group R ³ has a length greater than the pentyl group (chain - (CH 2) 4 CH 3) and is more preferably greater than the length of the hexyl group (chain - (CH 2 CH 3)). and more preferably a length less than the stearyl group (- (CH 2) 17 CH 3 chain) when rotating about the axis drawn by position 1 associated with SO 2 and the substituent bound to position 4 of the 6-membered ring or position 1 associated with SO 2 and position 3; In the 5-membered ring, R 1 defines a three-dimensional volume whose widest dimension has a width transverse to the axis of rotation of about one furanyl ring to about the width of two phenyl rings.

When the R 1 group associated with SO 2 is 4-phenoxyphenyl, for the purpose of illustration, the compound can be imagined as a phenoxyphenylsulfone derivative of a 5- to 8-membered N-hydroxycarboxamide ring. Exemplary compounds are thus:

N-hydroxy-1-methyl- (4- (phenoxyphenylsulfonyl)) - 4-piperidinecarboxamide,

N-hydroxy- (4- (phenoxyphenylsulfonyl)) - tetrahydro-2H-pyran-4-carboxamide

N-hydroxy-1-methyl- (2,6-dioxo-4- (phenoxyphenylsulfonyl)) - 4-piperidinecarboxamide,

N-hydroxy-2,2-dimethyl- (5- (phenoxyphenylsulfonyl)) - 1,6-dioxane-5-carboxamide,

N-hydroxy-1,2-dimethyl-6-oxo- (4- (phenoxyphenylsulfonyl)) - 4-piperidinecarboxamide,

N-hydroxy-2,26,6-tetramethyl- (4- (phenoxyphenylsulfonyl)) - 4-piperidinecarboxamide,

N-hydroxy-1-methyl- (4-phenoxyphenylsulfonyl) -4-piperidinecarboxamide,

N-hydroxy-1,3-dimethyl- (5- (phenoxyphenylsulfonyl)) - hexahydro-5-pyrimidinecarboxamide,

2-N-amino-hydroxy- (5- (phenoxyphenylsulfonyl)) - 1,4,5,6-tetrahydro-5-pyrimidinecarboxamide,

N-hydroxy-1,1-dioxo- (4- (phenoxy phenylsulfonyl)) - 1 (lambda6), 2,6-thiadiazine-4-carboxamide, «· · • • • 4 4

9 94

4 4

9 4

99 4 4

9 · · ·

4 4 9

9 4

4 4 4

9 9 4

4 9 9

N-hydroxy-2-oxo- (5- (phenoxyphenylsulfonyl)) - hexahydro-5-pyrimidinecarboxamide, N-hydroxy- (2- (phenoxyphenylsulfonyl)) - 4-piperidinecarboxamide N-hydroxy-1-methyl- (4-phenoxyphenylsulfonyl) -tetrahydro-2-furancarboxamide, N-hydroxy-1-methyl- (2- (phenoxyphenylsulfonyl)) - 2-pyrrolidinecarboxamide, N-hydroxy-2-methyl- (4- (phenoxyphenylsulfonyl)) - 8-azabicyclo ( 3,2,1) octane-3-carboxamide, N-hydroxy-1,1-dioxo- (4- (phenoxyphenylsulfonyl)) - hexahydro-1 (lambda6) -thiopyrancarboxamide,

N-hydroxy- (3-phenoxyphenylsulfonyl)) - tetrahydro-3-furancarboxamide,

N-hydroxy- (3- (phenoxyphenylsulfonyl)) - 3-pyrrolidinecarboxamide, N-hydroxy-4- (4- (phenylthio) phenyl) sulfonyl) -1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride, monomethanesulfonate N-hydroxy-4- (4- (phenylthio) phenyl) sulfonyl) -1- (2-propynyl) -4-piperidinecarboxamide, tetrahydro-N-hydroxy-4 - ((4- (4 - ((trifluoromethyl) phenoxy) (phenyl) sulfonyl) -2-pyran-4-carboxamide

N-hydroxy-1-methyl- (4-phenoxyphenylsulfonyl) -4-piperidinecarboxamide, N-hydroxy-1- (4-pyridinylmethyl) -4 - ((4- (4- (trifluoromethyl) phenoxy) phenyl) sulfonyl) hydrochloride 4-piperidinecarboxamide, N-hydroxy-1- (3-pyridinylmethyl) -4 - ((4- (4- (trifluoromethyl) phenoxy) phenyl) sulfonyl) -4-piperidinecarboxamide dihydrochloride, N-hydroxy-1 - (- 2-pyridinylmethyl) -4 - ((4- (4- (trifluoromethyl) phenoxy) phenyl) sulfonyl) -4-piperidinecarboxamide, hydroxy-1- (3-pyridinylmethyl) -4 - ((4- (4- (trifluoromethyl) trifluoromethyl) dihydrochloride) (phenoxy) phenyl) sulfonyl) -4-piperidinecarboxamide, N-hydroxy-1- (2-methoxyethyl) -4 - ((4- (4- (trifluoromethyl) phenoxy) phenyl) sulfonyl) -4-piperidinecarboxamide monohydrochloride, N monohydrochloride -hydroxy-1- (2-methoxyethyl) -4 - ((4- (4- (trifluoromethyl) thio) phenoxy) phenyl) sulfonyl) -4-piperidinecarboxamide,

4 4 4

4 • 444 44

44

4 4 ·

4 4 4

4 ···

4 4 ·· • 4 4 4

4 · · 4

1-cyclopropyl-N-hydroxy-4 - ((4- (4- (trifluoromethyl) phenoxy) phenyl) sulfonyl) -4-piperidinecarboxamide monohydrochloride and the like.

A number of exemplary Rl and ^R2 groups that together form a heterocyclic ring are shown in the tables that follow hereinafter, and in the descriptions of 5- to 8-membered rings and specific examples of such compounds are aromatic sulfone acid of the invention.

In particularly preferred practice, R and R ² in formula I together with the atoms to which they are attached form a 5- to 8-membered ring containing one, two or three heteroatoms. Most preferably, the ring is a 6-membered ring that contains one heteroatom located at the 4-position relative to the position at which the SO ₂ group is bound. Other preferred compounds for use in the method of the invention correspond to the structure of one or more of formulas II, ΠΙ, IV or V, discussed below.

One embodiment of the preferred compound used in the method of the invention has a structure that corresponds to formula (II) below:

where

R 14 is hydrido, a pharmaceutically acceptable cation or C (W) R 6, wherein W is O or S and r 15 _is selected from the group consisting of C 1 -C 8 -alkyl, aryl, C 1 -C 8 -alkoxy, heteroaryl-C 1 -C 6 alkyl, C 3 -C 8 -alkyl-C 1 -C 6 -alkyl, aryloxy, ar-C 1 -C 8 -alkoxy, heteroaryl and amino C 1 -C 6 alkyl, wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, C 1 -C 8 -cycloalkyl-C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkoxycarbonyl and C 1 -C 8 -alkonoyl groups, or (iii) wherein the amino C 1 -C 4 alkyl nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring, m is zero, 1 or 2;

4

44

4 4 4 4

4 4

4444 44

4 4 · 4 ·

4

44 · 4 4

4 4 ·> · 4 »4 4 4 • · * 4 n is zero, 1 or 2, p is zero, 1 or 2, the sum of m + n + p = 1, 2, 3 or 4, (a) one of X, Y and Z are selected from the group consisting of C (O), NR NR O, S, S (O), S (O) 2 and NS (O) ₂ R ^7, and the remaining two X, Y and Z are CR ⁸ R ⁹ and CRW 1, or (b) X, Y and Z together form a group selected from the group consisting of NR ⁶ C (O), NR ⁶ S (O), NR ⁶ S (O) ₂ , NR ⁶ S, NR ^δ O, NRS ⁶ (O), SS, NR ⁶ NR ⁶ and OC (O), one of the remaining X, Y and Z being CR ⁸ R ⁹ , or (c) n is zero and X, Y and Z together form a group, which is selected from the group consisting of

9 • 9 ·

where the wavy lines are bonds to the atoms of the indicated circle,

9 9 9

9 9 9

9

9 * 99

9909 ·· 9 »• 9 99

9 9 ·

0 9 t

9 9 9

And R 6 are independently selected from the group consisting of hydrido, C 1 -C 8 -alkonoyl, C 8 -C 1 -C 8 -alkyl, aroyl, bisiC 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-C 1 -C 8 -alkyl, C1-C6-alkyl, C1-C8-haloalkyl, C1-C8-perfluoroalkyl, C1-C8-trifluoromethyl-alkyl, C1-C8-perfluoroalkoxy-C1-C8-alkyl, C1-C8-alkoxy-C1-C8- alkyl, C 1 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, C 8 -C 8 -heterocycloalkylcarbonyl, C 8 -C 8 -aryl, C 5 -C 8 -heterocyclo, C 5 -C 8 -heteroaryl, C 8 -C 8 -cycloalkyl-C 8 -C 8 -alkyl, C 8 -C 8 -heterocycloalkyl aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-arylsulfonyl, C1-C6-alkyl; alkylsulfonyl, C 1 -C 8 -heteroarylsulfonyl, carboxy-C 1 -C 8 -alkyl, C 1 -C 4 -alkoxycarbonyl-C 1 -C 8 -alkyl, aminocarbonyl, C 1 -C 8 -alkyliminocarbonyl, C 8 -aryliminocarbonyl, C 3 -C 8 -heterocycloiminocarbonyl, C 8 -arylthio-C 1 -C 8 -alkyl, C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl, C 8-arylthio C 1 -C 8 -alkenyl, C 1 -C 6 alkylthio C 1 -C 8 -alkynyl, C 8 -C 8 -heteroaryl-C 8 -C 8 -alkyl- alkyl, h alo-C 1 -C 8 -alkonoyl, hydroxy-C 1 -C 8 -alkonoyl, thiol C 1 -C 8 -alkonoyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 - C 5 -alkoxycarbonyl, aryloxycarbonyl, C 1 -C 6 -C 1 -C 5 -alkylcarbonyl, hydroxy-C 1 -C 8 -alkyl, aminocarbonyl, wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii) is

- substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 6 -cycloalkyl and C 1 -C 8 -alkonoyl, hydroxy-aminocarbonyl, an aminosulfone group, wherein the aminosulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 6 -cycloalkyl and C 1 -C 6 -alkonoyl, amino-C 1-6- A C8-alkylsulfone group wherein the amino-C8-C8-alkylsulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C1-C8-alkyl, ar-C1-C8-alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, and amino-C 1 -C 6 -alkyl, wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents which are independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl C3-C6-cycloalkyl and C1-C6-alkonoyl, r7 is selected from the group consisting of benzyl, phenyl, C1-C6-alkyl, C3-C6-alkenyl, C3-C8-alkynyl and hydroxy-C1-C8; -alkyl, • 4 4 β · • 4

4

4444 1

R ⁸ and R ⁹ and R ¹⁹ and R ⁿ are independently selected from the group consisting of hydrido, hydroxy, Cj-Cg alkyl, aryl, ar-C-Cg alkyl, heteroaryl, heteroaryl-C | lower alkyl, C2-Cg alkynyl- , C 2 -C 8 -alkenyl, thiol-C 1 -C 8 -alkyl C (-C 8 -C 8 -alkylthio-C 1 -C 8 -alkyl cycloalkyl, cycloalkyl C (-C 8 -alkyl), heterocycloalkyl-C (-C 8 -alkyl), C (-C 8 -C 8 -alkyl) alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxyacylcarbonyl-C1-C6-alkyl -C 8 -alkyl, hydroxycarbonylar-C 1 -C 8 -alkyl, aminocarbonyl-C 1 -C 8 -alkyl, aryloxy-C 1 -C 8 -alkyl, heteroaryloxy-C 1 -C 8 -alkyl, arylthio-C 1 - C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, sulfoxide or sulfone of any of the thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino- C 1 -C 8 -alkyl and amino-C 1 -C 8 -alkyl wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from or from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, cycloalkyl and C 1 -C 8 -alkonoyl, or wherein R ⁸ and R ⁹ or R ⁶ and R ⁶ and the carbon to which they are attached form a carbonyl group or wherein R ⁸ and R ⁹ or R ⁹ and R ⁸ , or R ⁸ and R ⁹ together with the atoms to which they are attached form a 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring containing one or two hetero atoms which are nitrogen, oxygen or sulfur, with the proviso that only one of R ⁸ and R ⁹ or R ⁹ and R is hydroxy, _and R12 _are independently r12'j selected from the group consisting of hydrido, C) -C8-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6- alkyl, heterocycloalkyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C ( -C8-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxyalkylcarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl amino, carbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C] -C 8 -alkyl, heteroarylthio-C 1 -C 8 -alkyl, sulfoxide or sulfone of any of these thio substituents, perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 -C 8 -alkyl and amino-C 1 -C 8 -alkyl wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C] lower alkyl, Ar-C] lower alkyl, cycloalkyl and Cj-Cg-alkonoylem, · • • • ftft ftftft ftft ftft ft • • • · ftft ftft ftft · _e j R13 is selected from the group consisting of hydrido , benzyl, phenyl, C1-C6-alkyl, 63-65 alkynyl, 62-65-alkenyl and 61-65-hydroxyalkyl, and

G-A-R-E-Y is a substituent preferably having a length greater than a pentyl group, and more preferably a length greater than a hexyl group. The substituent G-A-R-E-Y preferably has a length less than the icosyl group and more preferably a length less than the stearyl group.

In this substituent:

G is an aryl or heteroaryl group,

A is selected from the group consisting of (1) -O-, (2) -S-, (3) -NR ¹⁷ -, (4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO-, wherein R ¹⁷ is hydrogen, C 1 -C 6 -alkyl or phenyl, (S) -60-O- or -O-60-, (6) -O-60-O-, (7) -HN = NH-, ( 8) -NH-6O-NH-, (9) -6: 6-, (10) -NH-60-O- or 0-60-NH-, (11) -N = N-, (12) - 00-NH-NH- and (13) 6S-N (R @ ¹⁾ - or -N (R @ ¹⁾ - 6O-, wherein R @ ¹ is hydrogen, 61-65 -alkyl or phenyl, or (a ) is missing and G is bound directly to R,

R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, heterocycloalkoxyalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroaryloxyalkyl, heteroaryloxyalkyl, heteroaryloxyalkyl, heteroaryloxyalkyl, heteroaryloxyalkyl, heteroarylalkyl, heteroarylalkyl, or the heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or

4

4

4 • 44 ·· 4 4

4 4 4

4 4 4

4 4

4445 44 ·· 4 «

4 4 4 4

4 4 4

Two substituents selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethyllalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1 -C ₂ -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, nitro, nitro, nitro, hydroxyalkyl, alkanoylamino and alkoxycarbonyl and R is other than alkyl or alkoxyalkyl when A is -O- or -S-,

E is selected from the group consisting of (1) -CO-N (R 6) or -N (R ¹⁹ ) -CO-, wherein R ¹⁹ is _a heterocycloalkyl or cycloalkyl group, (2) -CONH- or -NHCO-, and (3) -CO-, (4) -SO ₂ -NR ¹⁹ or -R ¹⁹ -SO ₂ -, (5) -SO ₂ -, (6) -NH-SO ₂ - or -SO ₂ -NH- or (7) E is absent and R is bound directly to Y and

Y is absent or selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, arylkoxy, aralkoxy, heteroarylkoxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, alkoxy, heterocycloalkylethyl, heterocycloalkyl wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkanoyl, halo, nitro, aralkyl, aryl, alkoxy and amino, wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from hydrido, alkyl and aralkyl.

The G-A-R-E-Y substituent preferably contains two to four carbocyclic or heterocyclic rings, including the aryl and heteroaryl groups G. More preferably, each of these rings is 6-membered. Other 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 , alkyl, alkoxy, perfluoroalkoxy and perfluoroalkylthio.

A more preferred compound for use in the method of the invention corresponds to the structure of formula (III) below:

4 »*

Wherein is a group consisting of an aryl or heteroaryl group with a single ring that is 5- or 6-membered and is itself substituted in its own 4-position when it is a 6-membered ring, and in its 3- or 4-position when it is a 5-membered ring, a substituent selected from the group consisting of thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoromethoxyphenoxy,

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-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 4-benzyloxyphenoxy.

R 14 is hydrido, a pharmaceutically acceptable cation or C (W) R 6, wherein W is O or S and r 15 _is selected from the group consisting of C 1 -C 8 -alkyl, aryl, C 1 -C 8 -alkoxy, heteroaryl-C 1 -C 8 »Alkyl, C 3 -C 8 -cycloalkyl-C 1 -C 8 -alkyl, aryloxy, ar-C 1 -C 8 -alkoxy, heteroaryl and amino C 1 -C 8 -alkyl, wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, C 1 -C 8 -cycloalkyl-C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkoxycarbonyl and C 1 -C 8 -alkyl; -C 8 -alkonoyl, or (iii) wherein the C 1 -C 8 -alkyl amino nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring, m is zero, 1 or 2, n is zero, 1 or 2 , p is zero, 1 or 2, • 4 ·· 44 • 4 4 4 • · 4

4 · 4 4

4 4 4 4 4

4 «

4 4 4 4

4 4 4

4 4 4

44 the sum of m + n + p = 1, 2, 3 or 4, (a) one of X, Y and Z is selected from the group consisting of C (O), NR ⁶ , O, S, S (O), S And (b) X, Y and Z together form a group selected from the group consisting of NR ⁶ C (O), NR ⁶ S (O) NR ⁶ S (O) _2, NR ⁶ S, NR ⁶ O, NRS ⁶ (O), SS, NR ⁶ NR ⁶ and OC (O), one of the remaining X, Y and Z form CR ^ rA or (c) n is zero and X, Y and Z together form a group selected from the group consisting of δ o

where the wavy lines are bonds to the atoms of the indicated circle,

R ⁶ and R ⁶ are independently selected from the group consisting of hydrido, C 1 -C 8 -alkonoyl, C 8 -aryl-C 1 -C 8 -alkyl, aroyl, bis (C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl) -C 1 -C 8 -alkyl -alkyl- C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 6 -perfluoroalkyl, C 1 -C 8 -trifluoromethylalkyl, C 1 -C 8 -fluoroalkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, C 3 -C 8- cycloalkyl, C3-C3-heterocycloalkyl, C1-C8-heterocycloalkylcarbonyl, C3-aryl, C5-C8-heterocyclo, C5-C8-heteroaryl,

C3-C8-cycloalkyl-C1-C8-alkyl, C1-aryloxy-C1-C8-alkyl, heteroaryloxy-C1-C8-alkyl, heteroaryl-C1-C8-alkoxy-C1-C8-alkyl. heteroarylthio-C 1 -C 8 -alkyl, C 1 -C 8 -arylsulfonyl, C 1 -C 8 -alkylsulfonyl, C 1 -C 8 -heteroarylsulfonyl, carboxy-C 1 -C 8 -alkyl, C 1 -C 6 alkoxycarbonyl-C 1 -C 8 -alkyl, aminocarbonyl, C) -Cg-alkylimino carbony lem, Cgφ <> φ φ · · · · · · · · · · · · · · · · · φ · · · φ · φ · φ · φ · aryliminocarbonyl, C3-C8-heterocycloiminocarbonyl, C1-C8-arylthio-C1-C8-alkyl, C1-C8-alkylthio-C1-C8-alkyl, C1-C8-arylthio-C3-C8-alkenyl. C 1 -C 8 -alkylthio-C 1 -C 8 -alkenyl, C 5 -C 8 -heteroaryl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkonoyl, hydroxy-C 8 -C 8 -alkonoyl, thiol-C 8 -C 8 -alkonoyl, C 3 -C 8 -alkenyl , C 3 -C 8 -alkynyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 8 -alkoxycarbonyl, aryloxycarbonyl, CR ⁸ R ⁹ -C ¹ -C 5 -alkylcarbonyl, hydroxy-C 1 -C 8 -alkyl, aminocarbonyl, wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii) is substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -convoyl, hydroxyaminocarbonyl, amino a sulfone group wherein the aminosulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl an amino-C 1 -C 8 -alkylsulfone group wherein the amino-C 1 -C 8 -alkylsulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, and amino-C 1 -C 8 -alkyl, wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl,

R ⁷ is selected from the group consisting of aryl, aryl, heteroaryl, hetero cyclo, C 1 -C 8 -alkyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl and hydroxy-C 1 -C 8 -alkyl,

R ⁸ and R ⁹ and R ¹⁰ and R ⁿ are independently selected from the group consisting of hydrido, hydroxy, CjCg -alkyl, aryl, ar-CjCg-alkyl, heteroaryl, heteroaryl-CjCg-alkyl, C2-Cgalkinylem, C2-Cg- alkenyl, thio 1 -C 1 -C 8 -alkyl C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, heterocycloalkyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyalkylcarbonyl-C 1 -C 8 -alkyl , hydroxycarbonylar-C 1 -C 8 -alkyl, aminocarbonyl-C 1 -C 8 -alkyl, aryloxy-C 1 -C 8 -alkyl, hetero aryloxy-C 1 -C 8 -alkyl, arylthio-C 1 -C 8 -alkyl, heteroarylthio-C 1 - C 8 -alkyl, sulfoxide or sulfone of any of the thio substituents, perAuoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, et ·· ·· ·· · · · 4 4 4 * 44 4444

444 4444 444 «

444 444445 44 4

4, 4, 44, 444 «

44.44 44 44 44 44 44 alkoxycarbonylamino-C 1 -C 8 -alkyl and amino-C 1 -C 8 -alkyl wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents which are independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, cycloalkyl and C 1 -C 8 -alkonoyl, or wherein and R ⁹ or R ⁹ and R ¹¹ and the carbon to which they are attached form a carbonyl group, or wherein R 6 and R ⁹ or R ⁶ and R 6, or R 6 and R ⁶ together with the atoms to which they are attached form a 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring containing one or two heteroatoms by which are nitrogen, oxygen or sulfur, with the proviso that only one of R and R ⁹ or R ⁹ and R is hydroxy, R 12 _and R1 2 'j _are independently selected from the group consisting of hydrido, C | lower alkyl, aryl, ar-C ₁ -C 8 -alkyl, heteroaryl, heteroaralkyl, C ₂ -C 8 -alkynyl, C ₂ -C 8 -alkenyl, thio-C 8 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, hetero cycloalkyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy -C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyalkylcarbonyl-C 1 -C 8 -alkyl, hydroxycarbonylar-C 1 -C 8 -alkyl, aminocarbonyl-C 1 -C 8 -alkyl, aryloxy-C 1 -C 8 -alkyl -alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, sulfoxide or sulfone of any of these thio substituents, perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 -C 8 -alkyl, and amino-C 1 -C 8 -alkyl, wherein amino-C 1 -C 8 -alkyl -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents which are independently selected from the group consisting of Cj-Cg-alkyl, Ar-C-Cg alkyl, cycloalkyl and Cj-Cg-alkonoylem and 13 j _e selected from the group consisting of hydrido, benzyl, phenyl, C 1 -C 8 -alkyl, C ₂ -C ₈ alkynyl, C ₂ -C ₈ -alkenyl and C 1 -C 8 -hydroxy an alkyl group. Again, the use of a compound of formula III as a pharmaceutically acceptable salt is contemplated.

Preferences for the compound of formula III, which also applies to the compound of formula II, include the following which are independently preferred: (a) the sum of m + η + p = 1 or 2, and more preferably 2, (b) Z is -O-, -S- or NR ⁶ (c) NR ⁶ is selected from the group consisting of C 3 -C 8 -cycloalkyl, C 1 -C 8 -alkyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkyl, amino sulfonyl, heteroaryl-C 1 -C 8 -alkyl, aryloxycarbonyl and C 1 -C 8 -alkoxycarbonyl and (d) m = n = zero, ρ = 1 and Y is NR ⁹ . Another preference for a compound of both «9 · β β 4 4 9

4 4

4 4 4

9 4

944 4 »9 95

44 · - 4 · 4

4 4 9

4 4 4

4 4 «

49 of Formulas II and III is that R ¹⁴ is hydrido or that W of QWJR ¹⁵ prodrug form is O and R ¹⁵ is C 1 -C 8 -alkyl, aryl, C 1 -C 8 -alkoxy, heteroaryl-C 1 -C 8 -alkyl, C 5 -C 8 -cycloalkyl-C 1 -C 4 -alkyl or aryloxy.

An even more preferred compound for use in the method of the invention corresponds to the structure of formula (IV) below:

wherein R ³ is as defined above for formulas I, III, and more preferably, as defined for formula II (wherein this R ³ group is a GAREY substituent), Most preferably, R ³ is as defined for formula III.

Z is selected from the group consisting of O, S, NR ⁶ , SO, SO ₂ and NSO ₂ R a wherein R ⁶ is selected from the group consisting of hydrido, C 1 -C 5 -alkyl, C 1-6 -alkonoyl, benzyl, benzoyl, C 6-6 -alkynyl , C 3 -C 5 -alkenyl, C 1 -C 3 -alkoxy-C 1 -C 4 -alkyl, C 3 -C 8 -cycloalkyl, heteroaryl-C 1 -C 4 -alkyl, C 1 -C 5 -hydroxyalkyl, C 1 -C 5 -carboxyalkyl, C 1 -C 5 - alkoxy Cl-C5-alkylcarbonyl, CR iii R ⁹ -C 5 -alkylcarbonyl or CR ⁹ R ^ -C j-C5-alkyl, wherein R ^ and ^R9 are independently hydrido, Cl-C5-alkyl, C ^ -alkoxycarbonyl arylC 1 -C 5 -alkoxycarbonyl, or CR 3 R ⁹ together form a heterocyclic ring containing 5- to 8-ring atoms and r ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 8 -alkyl, C 3 -C 5 -alkynyl C 3 -C 6 -alkenyl, C 1 -C 8 -carboxyalkyl and C 1 -C 8 -hydroxyalkyl. Most preferably Z is O or NR ⁶ . Also contemplated herein is the use of a compound of Formula IV as a pharmaceutically acceptable salt.

An even more preferred group of compounds for use in the method of the invention corresponds to the structure of formula V below:

where

Z is as defined above for formula IV,

W and Q are independently oxygen (O), NR ^ or sulfur (S), and R ^ is as defined in formula IV and q is zero or one, so that when q is zero, the trifluoroalkyl group is bonded directly to the phenyl ring shown . Also contemplated herein is the use of a compound of Formula V as a pharmaceutically acceptable salt.

Particularly preferred compounds in the group defined by Formula V have the structural formulas shown below:

HIM'

O

CF ₃

 · · * * * * * * * * * * * * * * ® ® ® ® ® ® ® ® ® ® ® ®

Also particularly preferred are the following compounds:

• to · · · * * to ♦ to to to to to to to to to to to to to to to to to to to ·· ·· · ····

A number of particularly preferred compounds whose structures correspond to formulas I to V are illustrated in the Tables and Examples below.

As noted earlier, the compounds of formulas II, III, IV and V and their pharmaceutically acceptable salts are themselves compounds of the invention.

Preferably, in practice, the R 2 group associated with SO 2 is an aryl or heteroaryl group, that is a 5- or 6-membered single ring which is itself substituted by another single or aryl or heteroaryl group having an alkyl or alkoxy group having a chain length of about 3 up to 16 carbon atoms (and more preferably up to 14 carbon atoms in length), phenoxy, thio phenoxy (C6H5-S-), phenylazo (C6H5-N2-), N-piperidyl (C5HJON-), Npiperazyl (NC4H9N) -) or a benzamido group (-NHC (O) C 8 H 5). Here, a single ring aryl or heteroaryl group R 6 is substituted in its own 4-position when it is a 6-membered ring and in its 3- or 4-position when it is a 5-membered ring.

The aryl or heteroaryl group of the R 2 group linked to SO 2 is preferably itself substituted in its own 4-position when it is a 6-membered ring and in its 3- or 4-position when it is a 5-membered ring. A particularly preferred substituent is a single ring aryl or heteroaryl group, phenoxy, thiophenoxy, phenylazo, N-piperidyl, N-piperazyl or benzamido group, which is itself unsubstituted or can be substituted alone. The 4- and 3-ring positions discussed herein are numbered from the substituent linkage positions as compared to the formalized ring position numbering used in the heteroaryl nomenclature, as discussed below. Here, single atoms such as halogens (fluorine, chlorine, bromine or iodine) or substituents containing a chain length of one to five atoms other than hydrogen, groups such as phenyl, C4-C4 alkyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethyl or carbooxyethyl are preferred although the longer substituents may be adapted to the total length of the icosyl group.

Examples of particularly preferred substituted R 2 groups linked to SO 2 include 4 (phenyl) phenyl (biphenyl), 4- (4'-methoxyphenyl) phenyl, 4- (phenoxy) phenyl, 4- (thiophenyl) phenyl (4- (phenyl'thio) 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.

Since the SO2-linked radical of the R1 group itself is preferably substituted by a 6-membered ring, two nomenclature systems are used together to facilitate understanding of the positions of the substituents. The first system uses position numbering for the ring directly linked to the SO2 group, while the second system uses ortho, meta or para to position one or more substituents of the 6-membered ring linked to the aryl or heteroaryl group linked to SO2. Although the ortho, meta and para position nomenclature are not normally used for aliphatic ring systems, they are considered to be readily understood to describe the compounds when used in conjunction with the ring number system associated with the SO2 group. Where R 1 is other than a 6-membered ring, the positions of the substituents are numbered from the bond position of the aromatic or heteroaromatic ring. A formal chemical nomenclature is used to name each compound.

Thus, the 1-position of the above-discussed aryl or heteroaryl linked to SO 2 is at the position at which the SO 2 group binds to the ring. The 4- and 3-positions of the rings are numbered here from the positions of the substituent bound to the SO 2 bond as compared to the formalized numbering of the ring positions used in the heteroaryl nomenclature.

When studied along its longest chain, the substituent R1, including its own substituent, has a total length greater than the saturated chain of five carbon atoms (pentyl group), more preferably a length greater than the saturated chain of six carbon atoms (hexyl group) such as heptyl chain length or longer . The substituent R1 also has a length less than the saturated chain of about 20 carbon atoms (icosyl group, icosyl was formerly called eicosyl, and more preferably about 18 carbon atoms (stearyl group), although it may be present). Many more atoms in the ring structures or substituents, this length requirement is discussed further below.

Looking more generally and disregarding the specific groups from which it is constructed, the substituent R ³ (radical, group or region) has a length that is greater than the pentyl groups. Such substituent R ³ also has a length that is less than the icosyl (didecyl) groups. That is to say that R ³ is a substituent having a minimum length greater than the saturated chain of five carbon atoms and more preferably a length greater than the hexyl group, but shorter than the saturated chain of twenty carbon atoms and more preferably a length shorter than the chain of eighteen carbon atoms. Most preferably, R ³ has a length that is greater than the octyl group and less than the lauryl group.

More specifically, R ³ has a minimum hexyl group length only when the substituent consists of two rings that can be joined or simply covalently linked together by an exocyclic bond. When ^R3 does not contain two linked or tied rings, for example when the group R ³ includes an alkyl or second, third or fourth ring substituent, ^R3 has a length that is greater than a hexyl group. Examples of such two-ring R ³ groups are 2-naphthyl or 2-quinolinyl (each having a chain length of five carbon atoms). Without wishing to be bound by theory, we believe that the presence of multiple rings in ^R3 enhances selectivity of the enzyme activity and inhibitor profile.

The chain length of the group is measured along the longest linear chain of the atoms in the group by the skeletal atoms of the ring, where necessary. Each atom in the chain, such as carbon, oxygen or nitrogen, is considered a carbon atom to facilitate calculation.

Such lengths can be readily determined as needed using published bond angles, bond lengths, and atomic radii to draw and measure a string, usually folded, as appropriate, or by constructing models using commercially available kits whose bond angles, lengths, and atomic radii are within in accordance with accepted published values. The lengths of the groups (substituents) can also be determined somewhat less precisely provided that all atoms have saturated carbon bond lengths, unsaturated and aromatic bonds have the same lengths as saturated bonds, and that the bond angles for the unsaturated bonds are the same as saturated bonds, prefers the aforementioned measurement methods. For example, a phenyl or pyridyl group has a chain length of four carbons, such as a propoxy group, while a biphenyl group has a chain length of about eight carbons using a measurement procedure.

• 4 • 4 • 4 • 4 • 4

In addition, when the R A is rotated about an axis positioned at position 1 associated with SO ₂ and position 4 of the 6-membered ring or position 1 associated with SO ₂ and 3,4 of the 5-membered ring, the substituent defines a three-dimensional volume with the widest dimension a width of about one furanyl ring to about a width of two phenyl rings transverse to the axis of rotation.

When this criterion is applied to the rotational width as well as the criterion previously discussed, the 2-naphthyl substituent or the 8-purinyl substituent is a suitable size group. On the other hand, the 1-naphthyl group or the 7- or 9-purinyl group is too broad in rotation and is excluded from being a RA group.

As a consequence of these length and width requirements, R 1 substituents such as 4- (phenyl) phenyl (biphenyl), 4- (4'-methoxyphenyl) phenyl), 4- (phenoxy) phenyl, 4- (thiophenyl) phenyl, (4- (phenylthio) phenyl), 4- (azophenyl) phenyl, 4- ⁽⁴ -trifluormethylthio) 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 R 1 substituents. These substituents may themselves also be substituted on the second ring of the SO ₂ group in meta or para or both by a single atom or substituent containing the longest chain length of up to five carbon atoms, excluding hydrogen.

Without wishing to be bound by theory, it is believed that the length of the R 1 substituent group bound to the SO ₂ group plays a role in the overall activity of the inhibitory compound generally against MMP enzymes.

The length of the substituent group R1 also appears to play a role in the selective activity of the inhibitor compound against particular MMP enzymes.

In a particularly preferred practice, R 1 is a group R 1 R y where Ph is phenyl. The phenyl ring (Ph) and the group PhR ^{7 '} is substituted in its para position (position 4) by a group R 3', which may be another aryl or heteroaryl group with a single ring, piperidyl group, piperazyl group, thiophenoxy group (CgFy-S-) ), a phenylazo group (C ₈ H ₅ -N ₂ -), or a benzamido group (-NHC (O) C ₆ H ₅ ).

In one embodiment of a particularly preferred aromatic sulfone hydroxamate inhibitor compound, R ⁷ is phenoxy and is itself substituted in its own para position by a group selected from the group consisting of halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, dimethylamine , C 1 -C 4 -alkylene carboxyl, C 1 -C 4 -alkoxy ftft ft ft ft ft ft ft ft ft • ftft carbonyl by C4-C3-alkylene, trifluoromethyl and carboxamido by C3-C3 alkylene. It is understood that any substituent R ² · 4 may be substituted with a group from the list above. Such substitution is preferred in the para position.

The present invention also contemplates an intermediate useful for the preparation of compounds of Formulas I-V. Such an intermediate corresponds to the structure of formula VI below

wherein g is zero, 1 or 2, R 20 is -Ο-R ²¹ , wherein R ²¹ is selected from the group consisting of hydrido, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, and a pharmaceutically acceptable cation or (b) -NH-OR ²² , wherein R ²² is a selectively removable protecting group such as 2-tetrahydropyranyl, C 1 -C 8 -acyl, aroyl, benzyl, benzyl, methoxybenzyl (MOZ) carbonyl C 1 -C 8 alkoxy, trisubstituted silyl or nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C 1 -C 8 -alkyl, aryl or ar-C 1 -C 8 -alkyl.

m is zero, 1 or 2, n is zero, 1 or 2, p is zero, 1 or 2, the sum of m + n + p = 1,2, 3 or 4, (a) one of X, Y and Z is selected from the group consisting of C (O), NR 4, O, S, S (O), S (O) 2, and NS (O) 2 R ^7, and the remaining two X, Y and Z are CR ⁹ R ⁹ and CR ⁹ R ¹¹ ; b) X, Y and Z together form a group selected from the group consisting of NR ⁶ C (O), NR ⁶ S (O), NR ⁶ S (O) ₂ , NR ⁶ S, NR ⁶ O, NRS ⁶ ( O), SS, NR ⁶ NR ⁶ and OC (O), one of the remaining X, Y and Z being CR 8r 9, or this to this to to this to »Toto toto toto toto toto toto toto toto c c c c c c c c c c c c c zero and X, Y and Z together form a group selected from the group consisting of

where the wavy lines are bonds to the atoms of the indicated circle,

R ⁶ and R ⁶ are independently selected from the group consisting of hydrido, C 1 -C 6 -alkonoyl, C 5 aryl-C 1 -C 8 -alkyl, aroyl, bisC 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkyl; lower alkyl, Cj-Cg-haloalkyl, Ci-Cg perfluoroalkyl, CpCg-trifluoromethyl laikylem, C4 C6perfluoralkoxy-CPC-alkyl, Ci-Ce-alkoxy-Ci-Cg-alkyl, _C3-C6 cycloalkyl, _C3-C8 heterocycloalkyl, _C3-C8 -heterocykloalkylkarbonylem C ^ -aryl, C-O-heterocycle, C5Cg-heteroaryl, _C3-C8 cycloalkyl-Cl-C6-alkyl, Cg-aryloxy-C Cg- alkyl, heteroaryl44 φ φ φ φ φ φ • Φ φ Φ • • φ · · · φ φ φ φ φ φ φ φ φ φ φ φ φ oxy oxy oxy oxy oxy oxy oxy j hetero j j C 1 -C 6 -alkoxy-C 1 -C 8 -alkyl, heteroarylthio-C 1 -C 8 -alkyl, C 1 -C 8 -arylsulfonyl, C 1 -C 8 -alkylsulfonyl, C 1 -C 8 -heteroarylsulfonyl, carboxy-C 1 -C 8 -alkyl, C 1 -C 4 -alkoxycarbonyl -C (-C8-alkyl, aminocarbonyl, C8-C8-alkyliminocarbonyl, C8-aryliminocarbonyl, C8-C8-heterocycloiminocarbonyl, C8-arylthio- C 1 -C 8 -alkyl, C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl, C 8 -C 14 arylthio-C 3 -C 8 -alkenyl, C 1 -C 14 alkylthio-C 13 -C 8 -alkynyl, C 5 -C 8 -heteroaryl -C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkonoyl, hydroxy-C 1 -C 8 -alkonoyl, thiol-C 1 -C 8 -alkonoyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 4 -alkoxy-C 1 C 1 -C 4 -alkyl, C 1 -C 8 -alkoxycarbonyl, aryloxycarbonyl, C 1 -C ⁹ -C 1 -C 5 -alkylcarbonyl, hydroxy-C 1 -C 8 -alkyl, aminocarbonyl, wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii) is substituted one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, hydroxyaminocarbonyl, amino sulfone, wherein the aminosulfonic nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, amino-C 1 -C 8 -alkylsulfone, wherein amino-C 1 -C 8 -alkylsulfo the new nitrogen is (i) unsubstituted or (ii) substituted by one or two substituents independently selected from the group consisting of C1-C6 alkyl, ar-C1-C6 alkyl, C1-C6-cycloalkyl and C1-C6- an alkonoyl group and an amino-C 1 -C 8 -alkyl group, wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl,

R ⁷ is selected from the group consisting of benzyl, phenyl, C 1 -C 8 -alkyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl and C 1 -C 8 -hydroxyalkyl, R ⁸ and R ⁹ and R ⁹ and R ⁸ are independently selected from the group consisting of hydrido, hydroxy, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, hetero-C 1 -C 8 -alkyl,

C 2 -C 8 -alkynyl, C 2 -C 8 -alkenyl, thiol-C 1 -C 8 -alkyl C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl 1 cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, heterocycloalkyl-C 1 -C 8 -alkyl, C 1 -C8-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C (-C8-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxyC1-C6-alkyl, hydroxyalkylcarbonyl-C j -Cg-alkyl, hydroxycarbonylar-C 1 -Cg-alkyl, • ftft ft ft ft ft * ft * ft * ft ft * ft ft * ft ft ft ft ft ft ft ft ft ft ft

4 <ft · ftftft «♦ amin 9 amin amin amin 9 9 9 9 9 9 9 9 9 9 9 9 9 9 -C8-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, sulfoxide or sulfone of any of the thio substituents, perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 -C 8 -alkyl and amino-C 1 -C 8 -alkyl, wherein the amino C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 8 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, cycloalkyl and C 1 -C 8 -alkonoyl, or wherein R 6 and R 6 or R ¹ and R ¹¹ and the carbon to which they are attached form a carbonyl group, or wherein R ¹ and R ¹ or R ¹ and R 1, or R 1 and R 10 together with the atoms to which they are attached form 5- to 8-membered carbocyclic ring or a 5-to 8-membered heterocyclic ring containing one or two hetero atoms which are nitrogen, oxygen or sulfur, with the proviso that only one of R ^ and R ^ or R ¹ and R ® ¹¹ hy -hydroxy, R12 _and R12 'j _are independently selected from the group consisting of hydrido, C-C ^ -alkyl, aryl, ar-C-Cg alkyl, heteroaryl, heteroaralkyl, Cy-C ^ -alkynyl, C-Cg-alkenyl. thiol • C 1 -C 8 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, heterocycloalkyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkyl -alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxyalkylcarbonyl-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 -alkyl, heteroarylthio-C 1 -C 6 -alkyl, sulfoxide or sulfone of any of these thio substituents, per-C 1 -C 6 -alkyl, trifluoromethyl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, alkoxycarbonylamino-C 1 -C 6 -alkyl; C1-C6-alkyl and amino-C1-C6-alkyl, 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 C1-C6-alkyl, ar-C-alkyl, cycloalkyl and C ^ -alkonoylem, r 13 j _e is selected from the group consisting of hydrido, benzyl, phenyl, C -C 1-6 -alkyl, C 2 -C 5 -alkynyl, C 2 -C 6 -alkenyl and C 1 -C 6 -hydroxyalkyl, and

R ²⁴ is R ³ as defined in Formulas I, ΠΙ, IV or is a GAREY substituent of Formula II (Formula VIA). Alternatively, R ²⁴ is R ³ 'is an aryl or heteroaryl group, which is substituted with a linking substituent reactive with another group (Formula VIB), such as a nucleophilically displaceable leaving group.

4444 4444 4,444

4 44 44 4 44 44 4

444 4,444 4 4,444 4

44 44 4444

4 4 4 44 44

Exemplary nucleophilically displaceable leaving groups D include halo (fluoro, chloro, bromoiodo), nitro, azido, phenylsulfoxido, aryloxy, C 1 -C 8 -alkoxy, C 1 -C 8 -alkylsulfone or arylsulfone and a trisubstituted amino group in which the three substituents are independently aryl, ar-C 1 -C 8 -alkyl or C 1 -C 8 -alkyl. Other linking substituents. include, without limitation, a hydroxyl group and an amine group, which may be linked to carbonyl-containing groups to form esters, urethanes, carbonates, amides, and ureas. Similarly, carbonate linking substituents may be used to form an ester, thioester or amide. Thus, the linking substituent is useful for converting a linking substituent, such as the G-A-R-E-Y substituent discussed above, by forming a covalent bond.

The compound of formula (VI) may be combined with another group on the linking substituent R-T to form a compound whose newly formed group R 1 corresponds to formulas I, III, IV or is G-A-R-E-Y. Examples of such linkages are nucleophilic displacements to form ethers and thioethers, as well as the formation of ester, amide, urea, urethane and the like.

A particularly preferred precursor of the intermediate to the intermediate of formula VI is

VII

· 4

4 • ·

4

4444 44

4 4

44 44 * 4 • 4 4 4 4

4 4 4 4 4 5

444 44 44 ·

Wherein m, n, p, g, X, Z, Y, D and R ⁷⁹ are as defined above for Formula VI.

R20 preferably -OR _e j N, where R @ ⁷ is a selectively removable protecting group such as 2-tetrahydropyranyl, C -C acyl, aroyl, benzyl, benzyl, methoxybenzyl (MOZ) carbonyl-C alkoxy, o-nitrophenyl, peptide synthesis resin, such as the so-called Merrifield peptide synthesis resin, commercially available from Sigma Chemical CO., and the like, 2-tetrahydropyranyl is particularly preferred. The group -NH-OR ⁷⁷ (R ⁷⁹ ) in formulas VI and VII is thus to be considered as the reaction product of a hydroxyl amine whose oxygen is bound to a selectively removable protecting group and to a carboxyl group.

With respect to the compound of each of Formulas VI and VII, the letter of subscript g is used to show the oxidation state of the sulfur atom. Where g is zero, the sulfur is non-oxidized, and the depicted compound is typically a reaction product of a sulfur sulfide-containing synton, as further shown in the examples. Where g is 1, the sulfur is oxidized to the sulfoxide, while when g is 2, the sulfur is oxidized to the sulfone, as also shown below. Compounds of formulas VI or VII wherein g is zero or 1 are typically intermediates themselves to form a similar compound wherein g is 2 and the intermediate is preferably a sulfone.

Thus, the preferred intermediate corresponds to the structure of Formula VI IA below

VIIA

In the description of molecules and groups, the descriptors of the molecules may be combined to give words or sentences that describe the structural groups, or they may be combined to describe the structural groups. Such descriptors are used herein. General illustrative examples include such terms as aralkyl (or arylalkyl), heteroaralkyl, heterocycloaralkyl, cycloaralkylalkyl, aralkoxycarbonyl and the like. A specific example of a compound encompassed by this 9

9999

9 9

9 9

999

The aralkoxycarbonyl descriptor is C6H5-CH2-CH2-OCH2-O (C = O) -, wherein C8H3- is phenyl. It should also be noted that a structural group may have more than one descriptive word or sentence in the art, for example, heteroaryloxyalkylcarbonyl may also be called heteroaryloxyalkanoyl. Such combinations are used herein to describe the processes, compounds and compositions of the invention and other examples described below. The following list is not intended to be exhaustive or exhaustive, but gives illustrative examples of the words or sentences used herein.

As used herein, the term alkyl, alone or in combination, refers to a straight or branched chain alkyl group containing from 1 to about 12 carbon atoms, preferably from 1 to about 10 carbon atoms, and more preferably from 1 to about 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the like.

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

The term alkynyl, alone or in combination, means a straight chain hydrocarbon group having one or more triple bonds and containing from 2 to about 12 carbon atoms, preferably from 2 to about 10 carbon atoms, and more preferably from 2 to about 6 carbon atoms. Examples of alkynyl groups include ethynyl, 2-propynyl, 3-propynyl, decinyl, 1-butynyl, 2-butynyl, 3-butynyl and the like.

The word carbonyl or oxo, alone or in combination, means a group - (C = O) - wherein the other two bonds (valence) may be independently substituted. The term carbonyl is also intended to include the hydrated carbonyl group -C (OH) 2 -.

The term thiol or sulfhydryl, alone or in combination, means a thiaether group, for example an ether group, wherein the ether oxygen is replaced by a sulfur atom.

The term amino, alone or in combination, means an amine or NH ₂ group, while the term mono-substituted amino, alone or in combination, means a substituted amino -N (H) (substituent) group wherein one hydrogen atom is replaced by a substituent, and disubstituted amino means -N (substituent) 2, wherein both hydrogen atoms of the amino group are replaced with independently selected substituents.

• · ··

4 4

4

4

4 4

4444 ··

4 4 4

4 4 4

443 4 4

4 4 4

44

Amines, amino groups and amides are compounds that can be designated as primary ( ¹⁹ ), secondary ( ¹⁹ ), tertiary (III ⁹ ), or unsubstituted, mono-substituted or disubstituted depending on the degree of substitution of the amino nitrogen. Quaternary amine (IV ⁹ ) means nitrogen with four substituents (-N ⁺ (substituent) 4), which is positively charged and accompanied by a counterion, while the N-oxide means that one substituent is oxygen and the group is represented as (-N ⁺ ( substituent) ^_ 3O), such charges are internally compensated.

The term cyano, alone or in combination, means a -C-triple bond-N (-CN) group. The term azido, alone or in combination, means a -CN-triple bond-N (-NN group). The term hydroxyl, alone or in combination, means an -OH group. The term nitro, alone or in combination, means a -NO ₂ group. The term azo, alone or in combination, means an -N = N- group wherein the bonds at the terminal positions independently can be substituted.

The term hydrazino, alone or in combination, means an -NH-NH- group wherein the two remaining valences shown may be independently substituted. The hydrogen atoms of the hydrazino group can be independently replaced by substituents and the nitrogen atoms can form acid addition salts or be quaternized.

The term sulfonyl, alone or in combination, means a -S (O) ₂ - group wherein the other two bonds (valence) may be independently substituted. The term sulfoxide, alone or in combination, means a -SO- group wherein the other two valences may be independently substituted.

The term sulfone, alone or in combination, means a -SO ₂ group wherein the indicated two valences may be independently substituted. The term sulfoxido, alone or in combination, means a -SO- group wherein the other two bonds (valences) can be independently substituted. The term sulfenamide, alone or in combination, means a -SN = group wherein the remaining three bonds (valences) can be independently substituted.

The term sulfide, alone or in combination, means an -S- group wherein the other two bonds (valences) can be independently substituted.

The term alkoxy, alone or in combination, means an alkyl etheric group wherein the term alkyl has been defined above. Examples of suitable alkyl etheric and etheric groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

• 4

4

44 ♦ 4 · 9

4 4 · 4

4 4 4

4 4 4 4

4 4 4

4444 44

4 4 4 4

4 4 4 4

4 4 4 4 4

4 4 4 4

44

The term cycloalkyl, alone or in combination, means a cyclic alkyl group containing 3 to about 8 carbon atoms. The term cycloalkylalkyl means an alkyl group which is substituted by a cycloalkyl group containing 3 to 8, preferably 3 to about 6 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The heterocyclic (heterocyclo) or heterocyclo portion of a heterocyclocarbonyl, heterocyclooxycarbonyl, heterocycloalkoxycarbonyl heterocycloalkyl group and the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Such a group may be optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo and the like and or on a secondary nitrogen atom (e.g. -NH-) of the ring by an alkyl alkanoyl, aryl or arylalkyl, or a tertiary nitrogen atom (e.g. N-) an oxido group which is attached via a carbon atom. A tertiary nitrogen atom with three substituents can also be attached to form an N-oxide group (= N (O) -).

The term aryl, alone or in combination, means a 5- or 6-membered ring-containing carbocyclic aromatic group or a linked ring system containing two or three rings having all ring carbon atoms, for example an aryl group. Examples of carbocyclic groups include phenyl, indenyl and naphthyl groups.

The term heteroaryl, alone or in combination, means a 5- or 6-membered aromatic group containing a ring or a linked ring system (group) containing two or three rings having carbon atoms as well as one or more heteroatoms in the ring (s), such as sulfur oxygen, or nitrogen. Examples of such heterocyclic or heteroaryl groups are piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl, benzyloxycarbonylimidazol-4-yl and the like), pyrazolyl, pyridyl, pyrizinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, trienyl, trienyl, triazole , oxadiazolyl, thiazolyl, thiadiazolyl, indolyl (2-indolyl and the like), quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl and the like), isoquinolinyl (e.g., 1-isoquinolines 1,3-isoquinolinyl and similarly), tetrahydroquinolinyl (e.g. 1,2,3,4-tetrahydro-2-quinolinyl and the like), tetrahydroisoquinolinyl (e.g. 1,2,3,4-tetrahydro-1-oxo-quinolinyl and the like), quinozalinyl, beta -carbolinyl, 2-benzofurancarbonyl, benzothiophenyl, 1-, 2-, 4- or 5-benzimidazolyl and the like groups.

When an aryl or heteroaryl group is a substituent (group, substituent or radical), it may itself be substituted, the latter being independently selected from this. This group consisting of cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethyllalkyl, aralkoxycarbonyl, arylkoxycarbonyl, hydroxy, halo, alkyl, alkoxy , nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, hetero • cyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, heteroaralkylthio, alkoxyalkoxy, aralkyloxy, aralkyloxy, aralkyloxy, aralkyloxy, aralkyloxy, aralkyloxy, aralkyloxy, aralkyloxy, aralkyloxy, , alkonoyl, arylcarbonyl, aralkonoyl, alkanoyloxy, aralkonoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkyl thio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkyl, alkoxycarbonylalkylthio, amino, wherein the amino substituent is selected from (i) unsubstituted, selected from (i) unsubstituted; alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkonoyl, heteroarylcarbonyl, heteroaralkonoyl and alkonoyl group, or (iii) wherein the amine nitrogen and the two substituents attached thereto form a 5- to 8-membered ring containing a 5- or 8-membered heterocycle none to two other heteroatoms which are nitrogen, oxygen or sulfur, and wherein the ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of alkyl, aryl, aralkyl, heteroaryl, hydroxy, alkoxy, alkonoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzo-linked heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzo-linked heterocycloalkylcarbonyl, cycloalkylcarbonyl, carbocarbonyl, ) unsubstituted or (ii) is an reacted amino acid amine, or (iii) is substituted with one or two substituents independently selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzo-linked heterocycloalkyl, benzo-linked and cycloalkyl An Ν-disubstituted aminoalkyl group, or (iv) a carboxamine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic, heteroaryl or benzo linked heterocycloalkyl ring which is itself a unsubstituted or substituted with one or two groups independently selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl, and an amino group wherein the amine nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents which are independently selected from the group consisting of alkyl, aryl and heteroaryl; or (iii) wherein the amine nitrogen; and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring and an aminoalkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl , alkoxycarbonyl, and an alkonoyl group; or (iii) wherein the amine nitrogen and the two substituents are attached thereto. The ring forms a 5- to 8-membered heterocyclic or heteroaryl ring.

The term aralkyl, alone or in combination, means an alkyl group as defined above, such as benzyl, 2-phenylethyl and the like.

The term aralkoxycarbonyl, alone or in combination, means a group of the formula aralkyl-O (O) -O-, in which the term aralkyl is as defined above. An example of an aralkoxycarbonyl group is benzyloxycarbonyl. The term aryloxy means a group of the formula aryl-Ο-, in which the term aryl has the meaning given above.

The terms heteroaralkyl and heteroaryloxy mean groups structurally similar to aralkyl and aralkoxy which are formed from heteroaryl groups. Examples of groups include 4-picolinyl and 2-pyrimidinoxy.

The terms alkanoyl or alkylcarbonyl, alone or in combination, mean an acyl group derived from an alkanecarboxylic acid. Examples of groups include: formyl, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl and the like.

The terms aralkanoyl or aralkylcarbonyl means an acyl group derived from an aryl substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinamoyl), 4-phenylbutyryl, (2-naphthyl) acetyl, 4-chlorohydrocinamoyl, 4-amino hydrocinamoyl, 4-methoxyhydrocinamamyl .

The terms aroyl or arylcarbonyl mean an acyl group derived from an aromatic carboxylic acid. Examples of such groups include aromatic carboxylic acids, optionally substituted benzoic or naphthoic acid, such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4- (benzyloxycarbonyl) benzoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl, 6- (benzyloxycarbonyl) - 2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3- (benzyloxyformamide) -2-naphthoyl and the like.

The term cycloalkylalkoxycarbonyl means an acyl group of the formula cycloalkylalkyl-OCO-, wherein cycloalkyl is as defined above. The term aryloxyalkanoyl means an acyl group of the formula aryl-O-alkanoyl, wherein aryl and alkanoyl are as defined above. Expression * ·

«* 4 •

4

heterocycloxycarbonyl means an acyl group derived from heterocycle-O-CO-, wherein the heterocycle is as defined above.

The term heterocyclohdroalkanoyl is an acyl group of the formula heterocyclo-substituted alkanecarboxylic acid, wherein heterocyclo is as defined above. The term heterocycloalkoxycarbonyl means an acyl group derived from a heterocyclo substituted hydrocarbyl-O-CO-, wherein heterocyclo is as defined above. The term heteroaryloxycarbonyl means an acyl group derived from heteroaryl-O-CO-, wherein heteroaryl is as defined above.

The term aminocarbonyl, alone or in combination, means a carbonyl (carbamoyl) group derived from an amine substituted carboxylic acid, wherein the amino group (amide nitrogen) may be unsubstituted (-NH 2) or a substituted primary or secondary amino group containing one or two substituents selected from hydrogen alkyl, aryl, aralkyl, cycloalkyl and cycloalkyl groups and the like as mentioned. The hydroxamate is N-hydroxycarboxamide.

The term aminoalkanoyl means an acyl group derived from an amino substituted alkanecarboxylic acid, wherein the amino group may be a primary or secondary amino group containing substituents independently selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl groups and the like.

The term halogen means fluorine, chlorine, bromine or iodine. The term haloalkyl means an alkyl group as defined above wherein one or more hydrogen atoms are replaced by halogen. Examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.

The term perfluoroalkyl means an alkyl group wherein each hydrogen atom has been replaced by a fluorine atom. Examples of such perfluoroalkyl groups, in addition to trifluoromethyl from above, are perfluorobutyl, per fluor isopropyl, perfluordodecyl and perfluordecyl.

The term perfluoroalkoxy, alone or in combination, means a perfluoroalkyl etheric group wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkoxy groups, in addition to trifluoromethoxy (F 3 C-O-), are perfluorobutoxy, perfluoroisopropoxy, perfluordodecoxy and perfluordecoxy.

The term perfluoroalkylthio, alone or in combination, means a thioetheric group wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkyl

groups, in addition to trifluoromethylthio (F 3 C-S-), are perfluorobutylthio, perfluoroisopropylthio, perfluordodecylthio and perfluordecylthio.

The term aromatic ring in combination as a substituted aromatic ring sulfone, or a substituted aromatic ring sulfoxide means aryl or heteroaryl as defined above.

The term pharmaceutically acceptable is used herein as an adjective. This means that the modified word is suitable for use as a pharmaceutical product. Pharmaceutically acceptable cations include, but are not limited to, suitable alkali metal salts (group Ia), alkaline earth salts (group IIa), and other physiologically acceptable metal ions. Examples of 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, in part including trimethylamine, diethylamine, Ν, d-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, meglumine (N-methylglucamine), and procaine. Examples of pharmaceutically acceptable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitronic acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyronic acid, oxalic acid, oxallacetic acid, propionic acid, benzoic acid and the like.

The M used in the reaction schemes that follow represent a leaving group such as a halogen, a phosphate ester or a sulfate ester.

Preparation of useful compounds

Schemes A to C and Schemes 1 to 19 below show chemical procedures that may be useful for preparing compounds useful in the present invention, for example, 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 shown. Compounds of formula VI and formula VII may be used as intermediates for the preparation of compounds of formulas I, II, III, IV and V or of drug precursors or MMP inhibitors.

In Schemes A to C, J independently represents R ²⁹ or other synthetically useful groups such as amides, acid chlorides, mixed anhydrides and the like. In Scheme C, n is 0, 1 or 2, and is preferably 1 or 2. In these schemes, n corresponds to g in formulas VI and VII. The symbol P represents a protecting group which may also be a member of the group R ⁹ . In Scheme A, for simplicity and clarity of illumination, the positional isomers shown with ring bonding are standard.

SS 4 4 4 4 4 4 ··· 4 4 · · · 'S' · '4 ·· ·· · ········ · 4 · 4 4 ·· ··. Other schemes typically show only one positional isomer, but positional isomers are represented by these structures and reactions in a manner consistent with Formulas I, II, III, IV, V, VI, and VII. The symbol B similarly represents O, S, SO, SO 3 and NR 6 The symbols C and C 'are independently electrophilic groups or groups capable of participating in the condensation reaction. It should be noted here that a 6-membered ring is shown for purposes of illustration, but procedures and / or reagents are useful to represent combinations allowing the preparation of 5- to 6-membered rings.

The structures in Schemes 1 through 19 are also shown with compounds that represent other compounds of the invention. The aromatic ring in Scheme C is aryl or heteroaryl. The groups -A-R-EY- are defined as before. The shown reactions requiring spiroheterocyclic nitrogen may not be applicable to such sulfur or nitrogen compounds.

9 • 9 9 «« 9 9 9 9 9 9 9 9 9 9 9 9 9 9

Scherrrer-A

Step 5

Step 8

Step 9, S (O) _n R ^d · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 44 44

Scheme A shows step 1, reducing a heteroaryl compound to a carboxyl derivative. Generally, the first product is an hydrogen-containing amine heterocycle when the starting material is an aromatic or R ^6- containing heterocycle when the starting material is a partially unsaturated heterocycle.

Compound 2 may react in different ways depending on the needs of the chemist. In step 2, nitrogen can be protected by preparing, for example, a carbobenzoxyl (Z) or t-butoxycarbonyl derivative. Such acylations can be carried out by methods well known in the art, particularly in the field of amino acids and peptide synthesis. The acylation process with activated carboxyl or sulfonyl-containing reagents to prepare compounds is performed in the same manner. Examples of such acylation groups are carbonyl azides, anhydrides, mixed anhydrides, carbodiimide derivatives or other less traditional activated ester groups such as the hydroxybenzotriazole derivative. These acylations can take place in the presence of a base, including mild bases such as triethylamine or N-methylmorpholine, if desired. The preparation of some activated ester reagents and their use to prepare other compounds useful in the present invention may be discussed. It should be remembered that the groups forming P and serving as a selectively removable protecting group may also be included as part of the group R ⁶ .

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

Steps 3, 7 and 8 show the preparation of derivatives of sulfur-containing compounds or of intermediates thereof. The starting material for these steps (e.g., compounds 2, 5 and 6) can be reacted with a base to deprotonate the carbon alpha to the carbonyl functionality. The anion may react with a sulfur electrophile to form a sulfone, sulfoxide or sulfide. Such electrophiles may, for example, take the form of R ²⁴ S-SR ²⁴ , R ²⁴ SO ₂ Cl, R ²⁴ SOC1, R ²⁴ SC1, R ²⁴ SC1, R ²⁴ S (O) -SR ²⁴ and the like, wherein R ²⁴ is aryl or heteroaryl a sulfur-containing material and containing a linking substituent R 1 ', which may be used to prepare one of the R ²⁴ containing groups. The preparation of the anion requires a base and a strong base such as metal amides, hydrides or alkyls may be required, as discussed herein. The solvents are aprotic. Dipolar aprotic solvents with an inert atmosphere are preferred. The following schemes usually use the R 1 'for the R ²⁴ group for example illustration.

4 4 4 4 4 4 4 4 4 4 4 4 4 4 9 4 5

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

Schemes A, steps 6, 9, 10, and 12 independently illustrate the interconversion of groups within J. Examples of such conversions are the substitution of a hydroxamic acid ester or hydroxamic acid derivative into an activated hydroxamic acid derivative, conversion of a carboxylic acid into an activated carbonyl acid derivative or a hydroxamic acid derivative. (drug precursor or protected derivative) or deprotection of the hydroxamate derivative. The preparation of activated carbonyl compounds by their reaction with nucleophiles such as hydroxamic acid, protected hydroxamate or drug precursor from hydroxamic acid is discussed below as the conversion of protected hydroxamic acid derivatives to 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 well known in the art, others are discussed in detail herein. Step 6 illustrates the conversion of compound 4 to compound 9 without first converting to compound 7.

• to ·· ········································ · · «·············

Scheme B

Step 5

HONH

Scheme B shows an alternative method of preparing compounds of the invention. The above-indicated reagent in step 1 is a reagent with two active groups to the heteroatoms (B) shown previously. Here again, the reagent shown has been selected to allow a clear illumination of the reaction, but is also intended to represent reagents that allow the preparation of the position of heteroatoms and compounds with 5-, 7- and 8-membered rings. These reagents will be readily selected by those skilled in the art.

The C and C 'in the reagent in this step 1 are independently an electrophile or a group convertible into an electrophile. Such groups include halides, sulfonic acid esters, epoxides, thioepoxides, hydroxyl groups and the like. This reagent reacts with the nucleophilic anion of 9-carbonyl groups. containing an sulfur such as Compound 1. The anion is formed by deprotonation of Compound 1, and examples of bases suitable for such deprotonation are discussed below. The reaction with the electrophilic reagent from above 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, for example, the reaction can be carried out as a single flask or as a two-step process as desired.

Step 3 shows the mutual conversion of the groups J, if desired. Step 4 uses a reagent wherein C is, for example, a nucleophile as discussed above and C 'is an electrophile or a nucleophile, such as hydroxyl, thiol, or R-amino. It is noted that C 'may independently be a nucleophile or an electrophile when m is 2, for example the groups C' may not be the same when m is 2. When m is 2, reaction with the second mole of base provides the skilled chemist an alternative preparation of compound 5. C 1 is hydroxyl, thiol or R 1 -amino and m is 2, one skilled in the art can condense compound 4 with, for example, an aldehyde or ketone under reducing conditions or subsequent reduction to form the compound. As above, a compound wherein m is 2 can be formed in one step (single flask process) or in two steps, allowing the chemist to select the reagent (s) to be the same (one flask) or different (two steps).

Scheme b also illustrates the interconversion of the groups within J, the oxidation state of the sulfur, and the groups on the nitrogen, e.g. These methods and methods are discussed above for the reactions in Scheme A.

Scheme C

(B)

• 4 4 4

4

4444 «444

4 4 4 · «44 4,444

4 4 4

44

Scheme C shows the nucleophilic displacement of Group D as defined herein. This reaction can be performed in a similar manner to the displacement reactions as discussed herein. Selection of the oxidation state of the sulfur is within the skill of the art, but sulfoxide or sulfone groups are preferred, and sulfone is most preferred. Displacement can be performed either before or after methylene of the carbonyl group that reacts to form a spiro heterocyclic group.

Steps 1, 2 and 3 also show that although nucleophilic displacement can be performed with a single nucleophile (Nu), the product of this reaction can be modified by methods well known in the art and shown herein to give the -AREY- group as defined above .

A non-limiting illustration of such a process is given when D is fluoride. The fluoride leaving group may be directly replaced by the anion of 4-trifluoromethylphenol, 4-trifluoromethoxyphenol, 4-trifluoromethylthiophenol and the like to form the compound. This is a one-flask process for compound 4. Other compounds included in -AREY- can be prepared by displacing the fluoride leaving group with ammonia to obtain an amine, which can then be acylated according to the methods discussed herein with, for example, 4-trifluoromethylbenzoyl chloride to form another compound. product.

The functional group R ⁹ may be altered or further modified to the compounds or in the steps of the schemes as desired or desired by one skilled in the art to prepare the compounds. Mention may be made of the interconversion of dual-purpose functional groups such as short-term and long-term protecting groups to other R ⁹ groups. A number of other routine and or useful conversions, including the preparation of synthetic intermediates, are well known in the art. Several non-limiting examples of such conversions or reactions include: reduction, nucleophilic displacement / substitution reaction, exchange or preparation of carboxylic or sulfonic acids, amides, esters, acid halides, acid anhydrides, mixed anhydrides and the like, electrophilic displacement / substitution reactions, oxidation, ring conversion / chain, ring opening reactions, condensation reactions including those requiring sulfone or carbonyl groups and / or carbon-hydrogen bonds affected by one or both of these groups. The selection of preparative methods or conversion methods of compounds and the order of reactions is within the skill of the art. It is expected that if a given sequence or method proves undesirable, an alternative is selected. Included in the selection are methods for preparing or adding groups in a single step using a convergent inhibition strategy or preparing the final group R ⁹ with step-by-step strategy monitoring.

In general, the choice of starting material and reaction conditions may be varied as is well known to those skilled in the art. Usually, no single set of conditions is limiting, as variations may be applied as needed. The conditions may also be selected at will, so that the conditions can be selected to the extent that the conditions are as follows: to to a «to to to to to to to to to to to to to They fit a specific purpose, such as small-scale or large-scale preparations. In both cases, the use of less safe or less environmentally friendly materials is usually minimized. Examples of such materials are diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, chloroform, benzene and the like.

These reactions can be carried out under a dry inert atmosphere, such as nitrogen or argon, if desired. Selected reactions known to those skilled in the art may be carried out under a dry atmosphere, such as dry air, while other synthetic steps, for example aqueous acidic or basic hydrolysis of the ester or amide, may be performed under laboratory air. In addition, some processes of these syntheses can be carried out in pressure equipment at pressures above, equal to and below atmospheric pressure. The use of such a device helps to control gaseous reagents such as hydrogen, ammonia, trimethylamine, methylamine, oxygen and the like, and can also help prevent the ingress of air or moisture into the ongoing reaction. This discussion is not intended to be exhaustive and it is readily appreciated that one skilled in the art can readily identify and apply additional or alternative methods, conditions, reactions and systems.

The reaction shown is usually carried out at a temperature between -25 ° C and a reflux temperature under an inert atmosphere such as nitrogen or argon. The solvent or solvent mixture may vary widely depending on the reagents and other conditions and may include polar or dipolar aprotic solvents, as calculated, or mixtures of these solvents. The reactions can be carried out at lower temperatures, such as dry ice / acetone or liquid nitrogen temperature, if it is desired to carry out such reactions as metalation or anion formation using a strong base.

In some cases, amines such as trimethylamine, pyridine may serve as reagents and or solvents, or as cosolvents. Sometimes protecting groups may be used in these reactions and other reactions of these schemes to maintain or retain groups in other portions of the molecule (s) at positions that are not desirable reaction centers. Examples of such groups that one of ordinary skill in the art can maintain or retain include amines, hydroxyls, thiols, acids and the like. Such protecting groups may include acyl groups, aralkyl groups, carbamoyl groups, alkoxyalkyl ethers, cycloalkoxy ethers, aralkyl groups, silyl groups including trisubstituted silyl groups, ester groups and the like. Examples of such protecting groups include acetyl, trifluoroacetyl, tetrahydropyran (THP), benzyl, tert-butoxycarbonyl (BOC or TBOC), benzyloxycarbonyl (Z or CBZ) tert-butyldimethylsilyl (TBDMS), or methoxyethoxymethylene (MEM). The preparation of such protecting groups as well as their removal are well known in the art. Protecting · · · ♦ 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 4 9

9 4 4 4 9 944 4 4 · · ·

49 44 4 9945

4944 44 49 44 49 ·· groups can also be used as substituents in compounds whose usefulness is as a drug rather than an intermediate.

Many reactions or processes require bases that can act as reactants, reagents, deprotonating agents, acid quenchers, salt forming agents, solvents, cosolvents, and the like. Bases which may be used include, for example, metal hydroxides such as sodium, potassium, lithium or magnesium hydroxides, metal oxides such as sodium, potassium, lithium, calcium or magnesium oxides, metal carbonates such as sodium, potassium, lithium, calcium or magnesium, metal bicarbonates, such as sodium bicarbonate or potassium bicarbonate, primary (Ιθ), secondary (ΙΙθ) or tertiary (ΙΙΙθ) organic amines, such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary hydroxides ammonium. Examples of such amines include, but are not limited to, triethylamine, trimethylamine, diisopropylamine, methyldiisopropylethylamine, diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine, N-methylmorpholine, N, N -dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-t-piperidine, 1,1,5,5-tinamide pyridine, quinoline, tetramethylenediamine and the like.

Non-limiting examples of ammonium hydroxides, usually prepared from amines and water, may include ammonium hydroxide, triethylammonium hydroxide, trimethylammonium hydroxide, methyldiisopropylammonium hydroxide, tribenzylammonium hydroxide, dimethylbenzylammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium methylide, N, N-n-piperidium pime, N, N ° -dimide. hydroxide and the like.

Non-limiting examples of quaternary ammonium hydroxides may include tetraethylammonium hydroxide, tetramethylammonium hydroxide, dimethyldiisopropylethylammonium hydroxide, benzylmethyldiisopropylammonium hydroxide, methyldiazabicyclononylammonium hydroxide, N, N, N -dimethylmorpholine, N, N-dimethylmorphide hexylpiperidinium hydroxide and the like.

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 may 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 methylmagnesium chloride, organocadmium reagents such as dimethylcadmium and the like may also serve as bases acting as salt formation or catalytic reaction. Quaternary hydroxides · 4 · 4 · 4 · 4

,. _t ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ammonium or mixed salts are also useful to assist in phase transfer coupling or to serve as phase transfer reagents.

Pharmaceutically acceptable bases can be reacted with acids to prepare pharmaceutically acceptable salts. It should be remembered that optically active bases can be used to prepare optically active salts that can be used for optical resolution.

The reaction medium may generally consist of a single solvent, mixed solvents of the same or different classes, or the solvent may serve as a reagent in a single or mixed solvent system. The solvents may be protic, aprotic or dipolar aprotic.

Non-limiting examples of protic reaction solvents include water, methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanol and the like. Typical aprotic solvents include acetone, tetrahydrofuran (THF), dioxane, diethyl ether, tert-butyl methyl ether (TBME), aromatic solvents such as xylene, toluene or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloethane, methylene chloride, ethylene dichloride ( EDC), hexane, heptane, isooctane, cyclohexane and the like. Dipolar aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, DMSO, hexamethylphosphoric 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 multiprotic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid , triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines to form esters or amides or thiols for preparing products and the like.

The preparation of the compounds herein may require oxidation of nitrogen or sulfur to N-oxide derivatives or sulfoxides or sulfones. Reagents for this process may include, but are not limited to, peroxoxymonosulfate (OXON (R)), hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, permenic acid, tert-butyl hydroperoxide, tert-butyl hypochlorite, sodium hypochlorite, chromium, meta sodium periodate, periodic acid and the like. Weaker agents are most useful for the preparation of sulfones and sulfoxides. Protic, aprotic, dipolar aprotic solvents may be selected, either pure or mixed, for example methanol / water.

4

4444 4449 4 · · ·

4 4 44 4 4 44 4 ·· 449 944444 44 4 • • 9 49 4 4449

945 4 44 49 44 44 44

The oxidation can be carried out at a temperature of about -78 ° C to about 50 ° C and is normally selected in the range of -10 ° C to about 40 ° C. The sulfoxide is best prepared using one oxidizing agent. In the case of more active oxidizing agents, it may be desirable but not necessary for the reactions to be carried out under an inert gas atmosphere with or without degassed solvents. It should be remembered that the oxidation of the sulfoxide sulfone can be carried out in a single step or in two steps over the sulfoxide as desired by the chemist.

Reduction is a well known process and a useful method is hydrogenation. In such cases (catalytic reduction), the metal catalyst, such as Rh, Pd, Pt, Ni and the like, may be with or without another carrier, such as carbon, barium carbonate and the like. The solvents may be protic or aprotic pure solvents or mixed solvents as desired. The reductions can be carried out at atmospheric pressure up to many times the atmospheric pressure with atmospheric pressure up to a preferred pressure of about 276 kPa or at very high pressures in a special hydrogenation apparatus well known in the art. 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 using, for example, aldehydes and ketones. Hydrogen transfer reagents such as sodium cyanoborohydride, aluminum hydride, lithium aluminum hydride, borane, sodium borohydride, diisobutylaluminum hydride and the like may also be useful as reagents for reductive alkylation. Acyl groups can be reduced in a similar manner to give substituted amines.

An alternative method of alkylating carbon or nitrogen is by direct alkylation. Such alkylation is well known in the art and can be accomplished by reacting activated carbon containing at least one hydrogen with a base to form the corresponding anion, adding an electrophilic reagent and allowing the reaction to proceed SN2. The amine to be alkylated reacts similarly, but may not be necessary deprotonation. Electrophiles include halogen derivatives, sulfonate esters, epoxides, and the like.

The bases and solvents for the alkylation reactions are those discussed above. Preferred are bases that are hindered so that competition with the electrophile is minimized. Other 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 aprotic or dipolar aprotic solvents such as acetone, acetonitrile, DMF and the like are examples of preferred classes.

In many reactions during various syntheses, acids are used. For example, removal of a THP protecting group to form a hydroxamic acid. The acid may be a mono-, di- or tri- protonic organic acid or an inorganic acid. Examples of an example include an acid

4 «* 4 ** • 4 · 4 4 · 4

4 4 * · • 4 4 4

5 · · «

4 · 4 4 4 4

444 4 * · · * • 4 «4 4« 4 44 Hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, hydrobromic acid, hydrofluoric acid, carbonic acid, phosphorous acid, p-toluene acid sulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, difluoroacetic acid, benzoic acid, methanesulfonic acid, benzene sulfonic acid, 2,6-dimethylbenzene sulfonic acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, and trinitrobenzoic acid. They may also be Lewis acids such as aluminum chloride, boron trifluoride, antimony pentafluoride and the like. Acids in protic form can also be used for the hydrolysis of esters, amides, and the like, as well as catalysis of exchange reactions.

Conversion of a carboxylic acid such as an ester or amide to a hydroxamic acid or a hydroxamic acid derivative such as an O-arylalkylether or O-cycloalkoxyalkylether group is useful. When hydroxylamine is used, reaction of the ester or amide with one or more equivalents of hydroxylamine hydroxyl chloride at or above room temperature in a solvent or solvents, usually protic or partially protic, as calculated above, can give the hydroxamic acid directly. This exchange process can be further catalysed by the addition of an additional acid. Alternatively, a base such as an alcohol salt, for example sodium methoxide in methanol, may be used to form hydroxylamine from hydroxylamine hydroxyl chloride in situ, which may be exchanged with an ester or amide. As mentioned above, the exchange can be performed with a protected hydroxylamine such as tetrahydropyranylhydroxylamine (ΤΗΡΟΝΗ ₂ ), benzylhydroxylamine (BnONH ₂ ) and the like. In this case, the products of the compound, as shown in Schemes A, B and C, i.e. tetrahydropyranyl (THP) or benzyl (Bn), are hydroxamic acid derivatives. Deprotection, if desired, for example, after further transformation in another part of the molecule or after storage, is achieved by standard methods well known in the art, such as hydrolysis of the THP group as discussed above, or reductive removal of the benzyl group with hydrogen and metal. a catalyst such as palladium, platinum, palladium on carbon or nickel.

In the case where R ²⁶ is hydroxyl, for example where the intermediate is a carboxylic acid, standard coupling reactions can be used. For example, the acid may be converted to an acid chloride, mixed anhydride or activated estrer such as hydroxybenzotriazole and reacted with hydroxylamine or protected hydroxylamine in the presence of a non-competitive base to a compound acylated on nitrogen. This is the same product as discussed above. Links of this type are well known in the art, and in particular in the field of peptides and amino acid chemistry.

Ftft ftft ftftftft ftftftft ftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftft

The compounds of the invention may have one or more asymmetric carbon atoms and may therefore exist in the form of optical isomers, enantiomers, diastereomers, as well as in the form of racemic or non-racemic mixtures. The compound may also exist in other isomeric forms such as ortho, meta or 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 prevented isomers. rotation. The isomer may exist in equilibrium with other isomers in mammalian or test systems. Such a compound may also exist as an isomeric equilibrium system with a solvent or water, for example a hydrated ketone or an aldehyde, as is well known in the art. All isomers are included as compounds of the invention.

The chemical reactions described above are generally described in terms of their broadest application for the preparation of compounds useful in the present invention. Sometimes these reactions may not be applicable to each compound within the scope of the claims or may be uncertain in the case. The compounds that occur will be readily recognized by those skilled in the art. In all such cases, the reactions can either be carried out successfully by conventional modifications well known in the literature, for example, by appropriate protection of interfering groups, by substitution of alternative conventional reagents, by routine modification of the reaction conditions described herein, or by other reactions described herein or otherwise by conventional reactions will be useful for preparing the corresponding compounds of the invention.

Scheme 1

MeO ^/ ^ ^{x 'CI} MS

MeO

AND

Λ

TFA ^<HS TxO ^to IL / DMF • • · · · • · • · • · • · · · · ·

NH ₂ OH EDC, HoBt

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

MeO n

⁰ OO ch ₂ o / KHCO ₃ ► MeO

O A) 'θ RCORZH *

R

- Me ₀ oo o

Ooo

1) LiOH

2) NH ₂ OH / EDC-HOBt r ° r '

Scheme 2 • to • to • to • ¹ • ¹ • ⁴ n ^K2C ° ^{3 /} Í ^MF MeO O ^ 00 • 2χ ch ₂ o / khco _{3 —-} i MeoXXJ U ^{RC0R / H +} ^

A and -MeO4XgA.

⁴⁰⁰ 4 iΛ

1) LiOH

2) NH ₂ OH / EDC-HOBt -► HOHN.

'Λ 6

Scheme 3

MeO.

Scheme 4

h ₂ feet

EDC / HOBT / DMF

ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft

Scheme 6

H ₃ CO '

NaOCH3,

Cl

HS

O,

OPh

Oxone, THF, water or

Oxone, CH ₃ OH, water

NaH, DMF

⁹ v

H ₃ CO ·

OPh

1) NaOH, EtOH

2) EDO, HOBt, DMF

3) aq, NH ₂ OH

4) HCl, dioxane i

Boc 4

NaH, DMF / HCl

CH ₃

H ₃ CO '

OPh

1) NaOH, EtOH

2) EDO, HOBt, DMF

3) aq, NH ₂ OH

4 • 4

4

Diagram 7 • 4 44 · 4 4

4 4 4 4

Scheme 8 ·· **. 4 4 4 4

4 4 4 ·

4 4 4 4

4444 44 ·· * ·

H ₃ CO '

OPh

Oxone, THF, water or

Oxone, CH ₃ OH, water

• ·

Scheme 10 ·· • 4 4 · • · 4 ♦ * · · · · 444 44 ♦ «·

A ♦ ·

4 · · · ·

4 *

4 4

4

• 4 · 4

Scheme 11 • ·

9 9

9 9

9 9 9 9 9 9 9 9

9 9 9

9 9 9

9 9 9

Boc

12.81 g

-►

HCl / EA

Low: 14 ° C

HOHN

! 10.82 g (98%) 1 H: HCl SC-75474

444

Scheme 12 • · • · ♦ ···

· «

4 4

4 4 ·

4 • 4 # 4

EDC / HOBT η ₂ ηοην

OPh

HCl

ΕΑ

ΕΑ ϊ

BOC

♦ φ φφ φφ φ

φ φ · · · · · · · · · · • · · · · · · · · · · · · · ·

Scheme 13

In a similar manner, the following can be prepared: compounds

OH

OH

OH

N

AND

Boc

O

HOHN

OPh

4 «· 3

Scheme 14 ·

4 4 • 4 4

444

4 • 4 • 4

4 • 4 ·

4 · ··

4 4

4 4 4

4 4 4

4 4

Λ / _ζ ν N-Cbz

OPh ^with v7 ^_oph _ = ·

=. / K ₂ CO ₃

Br

4

9

499 · · 9 9 9 9 9 9 999 999

Scheme 15

9

4

9 ·

9

4 ·

OH

1) CH ₃ SO ₂ Cl.

Et3N

CN

1) H ₂ SO ₄ , 90 ° C

2) NaOH, CH ₃ OH

0 '

2) KCN or NaCN, DMSO '0 or

HCl, HOCalOOC

NaOH, EtOH

HIM

O

1) EDC, HOBt, DMF

2) aq. NH20THP

1) EDC, HOBt, DMF

2) aq. NH ₂ OH

4 • 4

4

4

4

4 • 4

4

4

4444 • 4 * 4

Μ ·· <

4 4 4

4 4 4 · 9 ·

4 4

44 1

Scheme 16

ΣΤ k ₂ co ₃ ,

H ₂ O / AcCN

PPh ₃ ,

CC1 ₄

(i) HS — Ar

K ₂ CO ₃

DMF

2) Oxone, THF / H ₂ O

3) RX, DMF, K ₂ CO ₃

1) LiOH, H ₂ O / AcCN

2) EDC, HOBT, DMF H ₂ NOH

• this to • · · · · · · · ··· ···

Scheme 17 ··

nh ₂ nh ₂ from scheme 3

1) Br-CN, DMF

2) LiOH, H ₂ O / AcCN

1) EDC, HOBT, DMF H ₂ NOH

nh ₂ • 4 4 4 4

4 444

4 4

44

Diagram 18 • 4 «4 • 4 4 4

4 4 4

4 4

4444 44

4 4 4

4 4 4

4 4 4

4 4 4 • 44

Ph p-TsOH (1 eq) of MCPBA p-TsOH (1 eq) of MCPBA

1) HCl

2) H ₂ NOH EDC / HOBT / DMF

1) HCl

2) H ₂ NOH EDC / HOBT / DMF

99

9 9

9

9

9

9999 98 • · 9

Scheme 19

99 99 99

9 9 9 9 9

9 · · · · ·

999 99 99 · • 9 9 · · · · ·

OH

CO ₂ H 'S

1) H ₂ SO ₄ , 90 ° C

2) NaOH, CH 3 OH or

HCl, HOAc 100 ° C

WITH'

CH 3 OH, HCl Robe - * CH ₃ OH, SOCl ₂

2) aq. NH ₂ OH

Tables 1 to 150 below show a series of aromatic sulfonhydroxamic acid inhibitory compounds or structural formulas that illuminate substituent groups. Each group of compounds is illuminated by a general formula or formulas, followed by a series of preferred groups constituting various substituents that can be attached at a position clearly shown in the general formula. The symbols of the substituents, for example R 1, and R 1, and are not typically the same as previously used. One or two bonds (wavy line) are shown with these substituents to indicate the respective attachment positions in the shown compound. This system is well known in the chemical industry.

9 9 9 9 10 11 12 13 14 15 16 17

9 9 9 9 · <* ·· * · · · communications and is widely used in scientific publications and presentations. For example, in Table 2, R ¹ and R ² together with the atoms to which they are attached form a variable group with structural units that can be substituted for and R ² are shown together in this table.

Table 1

with-·

O ₂

N (CH ₂ ) ₄ CH ₃

Table 2

9999 99 «0 • 9 9 • 999 9

9 9 • * 9 0 ··

0 0 9

9 9 ·

0 · ·

9 0 *

09 /

and

Table 3

· · * * * * * * * * * *

··· 44 44 44 ···· 444 * 4 · · ·

4 ·· 4 4 ·· 4 4 4 4 • 4,444 4,444 «4 · 4 · · · 4 4 · 4 4 4

4444 44 44 44 44 44

Table 5

this to this to this to it to it to this to ····································

O ^ x ^ _CH3

O _{x /} - _X / CF ₃

O ^ CF,

Ck -Ph ° Ph

Ph

CH ₃

1

CHa

CHq

COOH

Η ^N \ / CH ₃

• 4 4 · 4 4 · 4

4 4 4

4444 44

44 44 44 • 4 4 4 * 44 4 • 44 4 4 44 «• 4,444 44 44 4 • 4 4 · 4 4 ·

44 44 44

Wch, [

_CH2 Br _{i8jJ QX-CH2F} OI l ₂ 1 ¹¹ JU

X .Nx ^ \ ^ CH ₃ 'CHq

O? /? ₍ ΓCH ^{17 % TCH} 2 ^Cl 2)

H

N ^ CFa 26 ¹² y ^ch 3 19 Ύ Ύ ^{ν 3}

Η

_E N_ CH ₃ FO

H ^{N ph ph}

O

O ^ A ^ Ph

H

H n ^ ch ₃ o

CO _{2 and} Et 27

tPy o

> o

HqC,

ÍTA č

H \ u ^K SN CH ₃

H

4 4 4

4

4

4

4444 44

4 4

Table 7

44 44 44 • · · 4 4 4 4

444445 44 4

4 4 4 4 4 • 4 44 ·· ··

····························· 4 4 · 44

4,444 44 44 4

4 4 444

44 44 44

Table 8

• ·

9 09

9 0 ·

9 9

9 9

9 9

9099 09

99

9 90

φ • · · · · φ φ φ · · · · · · φ φ φ φ φ φ · · · · φ φ φ

/ X ζκΖϊtt

4 44 44 44 44

4444 4 4 4 4 4444

4 4 44 4 4 4 4 · 4 4 4 4 4 444 4 4 4 4 4

44 44 4444

4444 44 44 44 44 44

χι ζχ ζχ ζχ ζχ ζχ ζχ

Η

Ν.

och ₃

CH ₃ ~ ch ₃ 4 4 4 4 4 4 4 4 4 4 4 4 4 · 4 · 4 · 4 · 4 · 4 · 4

Ph

4 «« 4 »4 ·· • 4 4 · 4 4 4 4 4 5 6 7 8 9

4 4 4 4 4

4444 44 44 44

• 4 4 4

4 4 4

4 4 4

4 4 4

44

CH,

Ί

Ν '

₃ ch ₃ ch ₃ ¹⁰

Ύ ^ ΟΟΟΗ ch ₂ i

CH ₂ Br

CH ₂ OH

^l2 YIV ^N Y ^CH '

H ΎΓΐ

H

Νχ / \

CH,

0 *

0 0 0

9 0 0

0 0 «« 0 • 0 *> 0 »

0 «00

0 0

9 9 • 00 0 9 * ·· • 0 0 0 · 0 Λ

0 0>

00

cu • · Φ · • φ · · ·

• • •

Table 16

100 ALIGN!

Ov

Cl

CFa

4

Table 17

101

4 · ·

4

4 4 C • 4 4®

4 · · · · ·

4 · · 4 · 4 · 4 · 4 · 4 · 4 · 4

102

4444

ZX ΖΧ ζχ ζχ ζχ ζχ

Ν.

Ν

 ·· • · ·

»Φ Φ Φ · · · · · · · ·

Φ Φ • • • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

103

Ph

Table 20

104

CH,

CH,

CH,

CH, I

CH ₂ Br ^i? 10 ^CH 2 ^{Cl 2}

X, /

H

COOH χ ^^ / 0Η ₂ ΟΗ

XJ

H

NyCH ₃

O

¹² ? Ar ^? H ^{? 19} ?? ^{F? 26} ?? CH? 1 XX?

H

CH,

H ^N \ xCH ₃

CH,

CO ₂ H 27

H

H .N.

.CH,

O

0χΛ _Ν ' ^{€ Η} 3

H

O _x / x. _o ^ _CH3

H

N. '. CH ₃ oo

NgPh x and r ^ph

H ₃ C ²⁹ Al

N ^ _CH3

H _I6 drawbar ,,.

·

Table 21 • 0

0 0 · 0 0 0

105. * Ϊ ί ··. • · «· · · · · · · · • · 1 • ϊ ί ·« · «* ·· ·» · · · * *. *, 4 ·· ·· »· H ₃ C / _{Z /.}

HIM'

F, C.

to it to it • this * »·

106 to to «to to to to to to« ««

Table 22

Table 23

107

* · • 4 • 4 4

4 4 · 4 · 44 · 4 · 4 4 ·

4 4 4 4 4 4 4 4 4

4 ·· *

4 4 · ·

108

4 * 44

4 · · · · ·

444 * ···

4444 44 44 44 «3 4 ·

• • •

Table 25 • it

109 to · ♦

this to this to this this to this this to this this to this this · «

44

4 ·

4 4 ·· ♦ 4 4 9

9 9

9 9 9 * 44

4

4

4

4 4

4 4

4 4 · 4

110

Ph

Ph

N

O.

(A .Ph

S _xx CH ₃

NT

^ Ph ji ^ N ²⁰

jy

I

Ph n

-WITH

N

N.

j3

N ··

444

4

111

4 «

4 «44

ch ₃

CH, · 4 · 4 ♦ · * *

4 **

4 4 4 4

4 4 4 •

4 4

. 9 4 • 4 4

4 ·

4 4

²³

-ď, c.,

x.CT * ₁₈ µX- ^{CH 2 F}

XX "

H

Yx / NYX / CL1

ÁJ

H ch ₂ oh

H

NyCH ₃

O

H

Nx

-ΥΓ Y ^and r “OT” ·

'ch ₃

CO ₂ H 27

• Nx ^ x \ xCH ₃

O, · ·, α / -γ ^Ν χ / ΟΗ ₃

JU .. ^^ x x _Q XH ₃

O

OxJ- _{n- 3}

H

O ≤ x ≤ _{about 3} -CH

JI J OO

Sx _p .Ph ²⁹ AAn ^X ch ₃

O

O ^ _N ' ^Ph

H

112 this to this this to this this to this this to this · To · to · to ·

'ΐσ • · · * * * * * * * * * * • • • * • • • • • • · · · · · · · · · ·

113

Table 30

114 φφφφ ··

• · · · · ·

Table 31 ·· »0 0’ 10 0 I · 0

115

Table 32

116 μ · *

φ · · φ φ φ φ · · · φ · · · · · · · · · · · · · · · · · · · · ·

φ φ φ φ φ φ φ · · # φ φφ

⁰ ^ cf ₃

^ / O ^ CF ₃

_N

-WITH

CL ^ Ph

σ ° Ph

N

SxxCH ₃

S ^ Ph

117 · 5 ··· · ·

Table 33

this this · e ··

Table 34

118 this this • it this it this it · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

► ·· • · ·

0 0

0

0 * 0

120 · <· <> 00 0

Table 35

Table 36

120 • 4 • 4

4 ·

• ·

Table 37

121 toto toto toto toto toto <<<<to to to to to to to to to to to to to to to to to to to · <·

• · • ·

122 • 9 ι • β • 9 «

9 ··· · 9

9 * 9

9

• · »

9 9

Table 39

123

• · • ·

Ph

, 0 _vx Ph ° ^ Ph

44 ·· ··

124

Table 40

4 «··» · 4 (• · 4 4 ·· »· 4 1

F 4 4 <

ΙΓ ^ Ύ 'Ph

·······························

125 to do it to do

126 9 9 9 9

9999 99 ·· · ♦

9 9

99

HIM'

Table 42

NH ₂

NH

Table 43

127 9 9 9 9 0 0 444

4 4 4 4

44 44

44

4 4 4

4 4 4

4 4 ·

4 4 4

44

• ·

128

Table 44

· To to to to to to toto toto toto toto toto toto toto toto toto toto toto toto toto toto

Table 45

129 ··

ZZ ZZ ZZ ZZ ZZ ZZ • to ·· • to · · · this · ·· ··

Table 46

130

4

4 4 444 44

44444 44 ·

4 4 4 4 4 5

44 44 44

, O _{x /} CH ₃

SX / CH ₃

O ^ Ů

/ Ph

r ^ N

O.AJ

CL / Ph

Ph

N

131

··

132 ·· ·· · * ·· .... «· * * * * * * * * * * * * * *« «« ««

,. · · · · · · · · · · · · · · · · · · ·

Table 48

AJ XT ftft ftft ftftftftft ftft

Table 49

133 ftft ft ft ft ft ft ft ft ft ft 4 ft ft ft

► ftft 4 ft. Ft

φ

Table 50

134 • φ «φ φ φ

φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ ar φ φ

136 «0 0«

0 · 0 ·

0 «9

0 0

0 «9 9 ♦ · · 9 9 • 9 0 0 0 09 9

9 9

0 * “9 ·· 99 · 9 0» ♦ · 9 <0 9

9 0 0

AT"

Table 51

_r

O

O

O

Table 52

136 4 4 4 4

-ΖΆ ZE zfb 'tt ζΐχ ZE tt

Table 53

137 to ······· · to ···· · to · to · to ··· it it

-S _xx CH ₃

XX

CF,

Ph

NI, 0

S ^ Ph

| ^ N pl

XO

XŮ

· ♦ · · · · · · · · ·

138

Table 54

·· ··

Q * xx '/ ffCH, I

CH, ff-ff, 0 ~

•, cr

COOH x ^ X ^ CH ₂ OH

Jj

H

^ N / \ / CH ₃ ^ S ^ N ^ _CH3 19

May ²⁶ J o

H

CH,

CH, "C ±" o

Ox / CH 2 -CH

αd-cn _N - ³ H

H n _x .ch ₃ Λ ooo

c <Y _N .Ph H

2 _7JJ QP ²⁸ AP

CH,

H

N. _Q .Ph oo

H ₃ C.

²⁹ JfX A

CH ₃

H

139

Table 55 · · <<<<<<<<<

I · · 1 1 1 1 1 1 1 1 1 1 1

140

N.

·· ·· • · <

• · <

· * ··

Table 56

O

NH _r

WITH

0 ₂

R ³

·· 00 · · · · · · · ·

0 ··· 0 · 0 · 0 · 0 · 0 ·

0 · ·

0 · 9 ·

9 0 ·

0 ·

Table 57

141 ·· ··· 0 ·· ··

Ο.

Cl

Ο.

cf ₃

ο.

CF, ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft

Table 58

142 ftft ft ft ft ft

O _r

R ³

4

143

Table 59

44

- - - · · ·

4 4 4 4 4 5

4 · · * ···

4444 ·· ·· ·· • · 4

4 4

4 4

4 4

4

• 4

144 «· 44 44 ·· ·· _{Λ a} · · 4 44 4 · · 4 :: • ........

• · · · ··· · · i; 444 44 44 4

O.

S _xx CH ₃

CM, 0.

jy

CF,

N.

St. / Ph

AND

-S>

Ph

N

N

CH,

CH,

CH,

COOH

'CH,

ΦΦ · φ · φ · · · · · φ ·

Φ φ · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

145

CH ₂ I ²³ i

CH ₂ C1

Xf 2 CH ₂ ^Br ₂ f

H ²⁵ XrY ^{H 3 11} · CH 2 ^OH

H

N 1 / CH ₂ / CH ₃ o

(X> 1 _N .CH ₃

H

Y> H ₃ o

Table 62

146 · »146 · · ·« «« «« «« «« «« «« «« «« «146« « · · · Toto · · · · ···

XX ¹⁶ XX

147 ·· ·· · · · · · · · ·

4 4 4 ·

44 4 4 • • 44 • 4 4 · • 4 4 4 <444

4 4

44

44

4 4 4

4 4 4

4 4 4 4

4 4 4

4 «44

148 ftft ftft I ftftft ftft ftft ftft ftft ft ft ft ft ft ft ft ft • · · '• ft ··

CF,

Table 65

149 · <<♦ • 4 9 w · · ·

4 4 · 4 4

9 4 4 4

4 4 4 4

4 * 4 4 · 4 «♦ * · 4 • 4 4 4 4

4 4 9 4

445 99 »4 *

9 9 9 4 • 4

Table 66

150

• • •

Table 67

151

S. .Ph

^{Sx /} Ph

CL .Ph

WITH.

Qr ° ^ ^ph

with.

• 4 • ·

152 · · · · · · · ·

4 · 4 · 44 44 4 «4 · 4

4 4 4 • · · · · · · ·

CH, ^ <\ ΧΉ ₂ Ι ₂ ^ rc ' ₃

XrVCHoCl

COOH 1 X 2 x CH ₂ Br ₂ CH ₂ OH " ¹² XrY" íTA ²⁶ r ^cHj

N _x ^ X / CH ₃ O -AY ⁰

CH,

CO ₂ H 27 N 2 O ₃

Ο ^ / χθ.0Η ₃

O, ° C, _N, CH ₃ H

JM oo o

<xA _K Jh

H .Nx

H, C.

²⁹ Ex

• · 4 4

4 4 ·

4 4 4

4 444

4 ·

44 • 4

Table 69

153

• ·

Table 70

154 ·· · *. · *.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

155 ·· 44

4 · · ·

4 4 4 4 4 • 4 4 4 4

4 4 4 4 • 444 44 44

4 4 4 4

44443 ·· 4 · 4 4 4

4 · 44

·· ··

• ⁴ ·····

Table 72

156 ··

I ♦ · ·

I · 4 ··· ··· ⁴

Table 73

157 ftft ftft ftft ftftftft ftft ftft ftft ftftft ft ftftft ft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft

• In · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

I »·«

158

444 • 4

159 • * 5 ·

4 4

4444 44

4

• · • ·

160 · · · · · e · · · * * * * * * * * * * * * * * * * * * * · · · ··· · ·

• φ

Table 77

161 ·· ·· · · · · · · φ · φ · φ · φ · φ · φ

Φ φ »» φ φ φ φ φ ♦ φ • • · · · ·

HIM

162

to · •>

Table 79

163 this • this • 9 • this • to • to • to • to • to • to • to • to • to • to • to • to • to ^ R ³

O · ft ·· · · · · · · · · · · · · ftft · ftft ftft

164

ZE ZE ZE ZE ZE ZE

H

4

165 »4 4 4 · 4 · 4 4 4 * 44 * 4 4 4 4 4 4 4 44 44 44

CM

Cr 6

CF,

O.

/ Ph

AA

(X / CF

^{7 14} s 10 ^z0 ^ ^ph

Xr

Ph

N

166

WITH

Table 83

167 • 4 · 4 · 4 4 · 4 4 ·

4 ··· 4 45 4

4,444 44 44 4

4 4 4 4 4 5

44 44 44

, ΟΗ

ΦΦ φφ φ φ φ φ φ φ φ

Φφφ φφφ φφφφ φφ • φ

168 φφ φφ φ

φ φ φ φ φ · · · · φ φ φ φ φ · · · φ φ · φ

To · • to to to to to to to to to to to to to to to to to to to

Table 85 ·· • to

169 • to · to · · · · ·····

, 0H

N

H

170

Table 86

O • · · * * * * * * * * * * * * * * * * * * * * * * · · ·· ··

Table 87

171 ft. Ftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftft · · ··· · · · · · · · · ·

• · ·

Table 88

172 * 4 · * • 4 4 • · · «« 44 »· 4 · 4 · · 4 · ·

4 · ·

44 • 4 4 4 • 4 4 • 4 4 • 4 4 4

44

JcP '”

Ph

Ph

SxxCH ₃

173

j φ φ

174

¹⁶ •• This ··

Table 91

175

to to · to · to · to · to · · · · · · · · · · · · · · to ·

H

R ³ _r

R ³

WITH

0 ₂

• · · · · · · · · · · · ·

176 •>> • • • • • • • • • • • • • • • •

»· · · · ·

177

Table 93

·· ··

9 <

• ··· »· 4 ·· ·· ·· ··

• · ·

Table 94

178 φφφ φ φ φφφφ φφ φφ ··

• to • to • to * to • to • to

H ₃

XX / Ph

179

Ph

Sx ^ xxCH ₃

CH,

CH, ₄ COOH ⁵ O ⁷ XX

Φ Φ ΦΦΦ

Φ Φ Φ

ΦΦ ΦΦ

Φ · ΦΦ • Φ Φ Φ

Φ Φ Φ Φ

Φ Φ Φ Φ

Φ Φ Φ Φ

ΦΦ ΦΦ

180

ίο% ^/ \ .ch ₂ i

CH ₂ Br

CH ₂ OH ch ₂ f ^, VA.ch, ci

H

N _XX CH ₃

T

Y 2 CH ₃ o

, .. o ^ _n ch, iH · α · ϊ ^H • Fk.CF, 26

CH,

H ^N X / CH ₃

CO ₂ H 27

H

Nk ^^ CH

H, C, ²⁹ RX AXR

H

XI .N.

s' V o

ΦΦ φ φ · · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

181

• · • ·

Table 98 ί 82 * · 1 • 4

4 1

4 4 4 4 4

HIM'

_r

R ^J

In iY ° '

·· ··

4 4 ·

4 ·

4 ·

4 ·

4444 ··

183 »

4 • · ·

4 • ·

4 ·

4 4 4

4 ··

4 4 4 • · · ·

4 4 · · · ·

4 ··

N.

184

Table 100

-O

HIM

J · · · · · · · · · · · · · · · · · · · · · · · ·

• • • •

Table 101

185 · «· ft · ···· · ···

• t »t * f * · *

H ^N Y

CH, n ~ ch ₃

• 4

186

Table 102

4 4

(λ J’h

Ph

Ph

S \ / \ XI1 ₃

• 4 4 4 4 44 4

4 4 <5 4 44444 44 4 • 44 44 4 444 *

* 44 44 44 44 44 44

187

• ·

I ·· 9 · · · · · <

99

188

Table 104

• «

4 * · ► 4 4 4 4

4 4 «· · ·

4 · ·

4444 44

189

190 • a · · «*

4 4 4 4

4 4 4 ·

4 4 4 4 4

4 4 4 4

4445 44 4 ·

ch ₃

^ v / O.

Cl

₃

Ον

Ον

CF,

tt tt tt tt tt tt

4 4

Table 108

HIM'

Ox. Xx'CF ₃

.Ph θχχ-Χ

Ph

and.

193

Table 109 / -NH

JR ³ to this this to this this to this this to this

16

jy

Ph

194. * · ♦ · ♦ · »<

• · · · · · · · ♦ ♦ ♦

Table III! -NH

195 ftft ftft ftft ftft ftft ftft ftft ft ft ft ft ft ft ft ft ft ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft ·

Table 111

• 4 44

4 4 ·

4 · ·

4 4 4 ·

4 4 4

4 · 44 ·· ··· · · · · · 4 ·

4 4

44 ·· ··

196

4 ·

4 4 4

4 4 · 4 · 44

4 4 4

Table 113

197 9 9

9494 99

44 4 4 4

94

CH ₃

O.

.CF,

O.

CF,

O.

Table 114

198 ····················· · 9

9 9 9 ·

9 · «·

99

9 9 9 9 9 9

99

• 4 4 4

4 4

199

4 4

4444 44

44

4 4 4

4 4 4

4 444

4 4

44 ··

ΖΧ ζχ ζχ ζχ ζχ ζχ ζχ

200 • 4 · · · · · · · · · · · · · ·

444 4,444 * 4,444 ·

4 ······· 4 4 ··· • 444 44 ·· ·· ·· ··

Table 116 ch ₃

AND

Ox / CH 3

Ph

S ^^ _CH3

CK / CF ₃

(k / Ph

Ph

Ph

CHa

oJv

S ^ / _CH3

O.

TO

/ Ph

XA 'ojj

N

NL

X n

201 • 44 44 44 44 44 44 44

01¾

CH, ^{10 11}

Table 117

CH,

H / \ /

HO £ Sat ₂

More specifically, (X) / CFFBr

CH, F

XT ™ '' Xy '' rr ^N T ^ θχΚ / ^ CH, OO ^H \\ / '

'CH,

y0Y'i π ^H

N _Y ²⁶ J0r CF ₃ ^N) C ^Cfi «[Τ 'UV ¹ P ^ o ^ o CH

yA '-CH, J &lt; 5 * 0

O i // 'v

P ^ OxAn-ch,

ΛΝ ^H ^^ OxA.rPh “Xj 'Ν'

H

20 ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ft ft <<ftft ft ft ftft ftft ft ft ftft · Ftft · ftft ftft

C

H

N.

Table 118 ch ₃

N.

_r

WITH

0 ₂

R ³

203 »1 ·· • 3 · ·

4 * · 4

IMf 44

4 4 5 • 4 44

4

44

«. 4 4 4

4 »4

4 4 4

4 4 4

44

• 4 • 4 • 4 • 4 • 4

4 · ·

4 4 4

204

Table 120 _of (c

_r

R ’

· · · · · · · · · · · · · ·

9 0 9 ·· ·· ··. .. · · · · · · · · · · 9 9 9 0 0 · · · · · · · · · ·

205

Table 121

• do it

206 to to totofl to to to to to to

Table 122

Sxx = CH ₃

xS ^ x ^ ^ _CH3

• ·

/ 1

208 ······················ 4 4 4 4

4 · · · ·

· 4

209 4 4

4 4

4 4 • 4

4

Table 125

210 ft · · ftft · · · · · · · · · · · · · · ···

h ₃ co.

f ₃ c

IFC

• *

99 «9 9 9 • 9

9 9

9 ·

9 ··· 9

9 9

211 • 99

Table 127

4

4

212

4 4 •

4 • 444 44

44

4 4 4 4

4 4 4 4

4 ·

HIM

Η .Νχ

Table 128

Ν.

-Γ

R ³

• 4

213

Table 129 • 4

4 4 4

4 4

4 4

4 4

4444 44

44 ·· ·· • 44 4 4 44 4 44 44 4 4 · · · · 444 44 44 ·

4 4 4 4 4 5

44 44 ··

CJ • ft · · ft ·

214

Table 130 ftft ftft ftft ftft ftftft ftftft ft ftft ft ftft ftft ftft ftft ftft ft ftft ft ftft

215

Table 131 ft ft ftft ftft ftft ftftft ftft ftft ftft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft

·· ··

216

Table 132 ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft Ftft ftft ftft ftft ftft

9,999 · ··· · · 9 9

217 • ·

Table 133 99 99 99 9 9 9

9 • ·

9

9 • · ·

218

Table 134 • • • • • • • • • • •

x ⁷

R

• · ·

219

Table 135

• ·

220

Table 136

; ι

-scf ₂ cf ₃

sch> cf ₃

• 4 4 4 4 4 444 444444 44 4

221

Table 137

CF ₂ CF ₃

CF ₃ OCF ₂ CF ₂ CF ₃ SCH> _CF3

ft * · · · · ··· · ·

222

Table 138 · ftft · ft

• ·

223

Table 139

44 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 ·

4 4 4 · 4 4 44

44 • 4 · 4 · 4 · ·

44443 44 4 • 4 4 4 4

4 4 · a a

224

Table 140 to it

225

Table 141 »90 • 0 0 * • 0 · 99

9 9

9999 99

99 • 0 9 · 9 9 9 990

9 0

00

SCF ₂ CF ₃ c ^ cf ₃

och ₂ ch ₃

4 44 44 44 44 44

43 4 4 «4 4 4 · · 4

4 44 44 4 44 44 4

4,444 4,444 44 44 4

44 44 4444

4444 44 44 44 44 44

226

Table 142

λ — o — C n — scf ₂ cf ₃

------- č ύ — O — č n — OCH ₂ CH ₃

. ··. * ·. · To ** ** ** **. ** ** ** **... ** .her;

•. . .., • this · · · ·

.... *. ,, ,,

227

Q o .o \ // 3

S — R ³

Table 143

\ // -'- λ <r \ d

CH ₂ OCF ₃ ch ₂ scf ₃ ch ₂ ch ₂ and ₃

-ch ₂ ch ₂ —scf ₃ \\ Z / ^ - s-Λ / ^ - ch ₂ and ₃ vy ~ ^s A ^ “ ^! ° ^CF5

O- ^with -O- " ^{! Scf} " - "-" - CH ₂ CH ₂ OCH,

ΧΖ / ¹ - ^S -X / -CH2CH2 ^- OCF 2 Z) ^- - () -CH ₂ CH ₂ -SCF ₃ • ft

228 ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft · ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft · Ftft · ftft ftft

CHCH-OG ⁷ 3

Cri-SCI ^ · · · ·· · «·· ·· ············································· ··· ·· ·· ·· ·· ··

229

230 ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ft ft ft ft ftft ftft · ftft ··

Table 146

ClbOOý

Cl-hClbOCl;

CB &lt; _{1 &gt;} -SCF3

CILOGl ;,

CUCHOGF,

ci ^ ch, -ocf ₃ ci ^ ch> -scf ₃

231 \ //

Table 147

cihoal ·,

V //

• 4 4 «• 4 4 • • · 4 • · ·« 4

4 4

4 4 4 »4 • 4 4 4 4

4 4 4

4 4 4 • 44

* in * 4 »4

4 ♦ 4 * 4 4 4

232

Table 148 ♦ 4 4 4

4 4

4 4 • 445 4 «

«1 2 3 4 5 · ·

4 *

4 4

4 4 4

4 4 4

4 4 4

CHOCH, mscis

CIIC11OG1

CcZ

CJCli-SCIs

• ·

Table 149

CILOClf ⁸ cikciboaf

ClbCl2-OCF ₃ ch, ch, -scf ₃

ciw) ai ₃

CEbOCF ₃

CH> SCF3

CIFCIbOCFf

CIbClF-O (F ₃

CBPb-SCT •

234

Table 150

4 · 4

• · • ·

235 «·· · · · _Λ . · · ···· ·· ·· ·· ··

The inhibitory compound is used to treat a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee, or a human having a condition associated with the pathological activity of a matrix metalloprotease.

Also contemplated is the use of a metalloprotease inhibitor compound for treating a disease state that may be affected by metalloprotease activity, such as TNF- + convertase. Examples of such disease states are acute phase responses to shock and sepsis, coagulation responses, bleeding and cardiovascular effects, fever and inflammation, anorexia and cachexia.

In the treatment of a disease state associated with the pathological activity of a matrix metalloproteinase, the inhibitory compound may be used, where appropriate, in the form of an amine salt derived from an inorganic or organic acid. Examples of reindeer acids include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentapropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, glycerophosphate, glycerophosphate , hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoleate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalucate, thionate, thionate, thionate, propionate, thionate, thionate, , mesylate and undecanoate.

The nitrogen-containing basic group can also be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides, dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides, and others, to achieve increased water solubility. Water- or oil-soluble products are thus obtained as desired. Reindeer is formed by combining the basic compounds with the desired acid.

Compounds useful in this invention other than acids may also form salts. Examples include salts with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, or with organic bases or basic quaternary ammonium salts.

In some cases, salts may also be used as an aid in the isolation, purification, or resolution of the compounds of the invention.

The total daily dosage administered to the host mammal in single or divided doses in an effective amount to inhibit the MMP enzyme may be, for example, in an amount of about 0.001 to about

236 • ·

4 • 4 4 4 · 4

mg / kg body weight and more regularly from about 0.01 to 10 mg. Dosage unit compositions may contain such amounts or proportions thereof to provide a daily dose. A suitable dose may be administered daily in several divided doses.

Multiple doses per day may also increase the total daily dose if required by the person prescribing the drug.

The dosage regimen for treating a disease state with the compound and / or composition of the present invention is selected in accordance with a variety of factors including type, age, weight, sex, diet and medical condition of the patient, severity of the disease, route of administration, pharmaceutical considerations such as activity, efficacy, the pharmacokinetic and toxicological profiles of the compound used, whether a drug delivery system is used and whether the compound is administered as part of a combination of drugs. The dosage regimen actually employed may vary widely and thus be different from the preferred dosage regimen outlined above.

The compound useful in the present invention may be formulated as a pharmaceutical composition. Such a composition may then be administered orally, parenterally, by inhalation spray, rectally or topically in unit dosage formulations containing the desired conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles of choice. Topical administration may also require the use of transdermal administration, such as transdermal patches or iontophoresis devices. The term parenterally, as used herein, includes subcutaneous injections, intravenous, intramuscular, intrastemal injections or infusion techniques. Drug formulations are discussed, for example, in Hoover, John. E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975 and in Liberman, H.A. and Lachman, L. Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, Ν. Y. 1980.

Injectable formulations, for example, sterile injectable aqueous and oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may 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 may be employed including synthetic mono- and diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethylacetamide, a surfactant, may be used

237 including ionic and non-ionic detergents as well as polyethylene glycols. Mixtures of solvents and wetting agents as discussed above are also useful.

Suppositories for rectal administration of the drug may be prepared by mixing the drug with a suitable non-irritating excipient such as coconut butter, synthetic mono-, di- and triglycerides, fatty acids and polyethylene glycols that are solid at ordinary temperature but liquid at rectal temperature and thus melt in the rectum and releases the medicine.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of the invention are usually combined with one or more adjuvants suitable for the indicated route of administration. When administered orally, the inhibitory compound, the aromatic sulfone hydroxamate, may be mixed with lactose, sugar, starch powder, alkanoic acid cellulose esters, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium phosphorus salts and sulfur, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidine or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation, as may be provided by dispersing the active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents, such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills may additionally be prepared with enteric coatings.

For therapeutic use, formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in oral administration. The inhibitory compound, the aromatic sulfone hydroxamate, can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride or in various buffers. Other adjuvants and routes of administration are well and widely known in the pharmaceutical art.

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

238

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending on the host mammal being treated and the particular mode of administration.

DETAILED DESCRIPTION OF THE INVENTION

Without further explanation, 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 but not limiting of the remainder of the application in any way.

Example 1

Preparation of N-hydroxy-2 - ((4-phenoxyphenyl) sulfonyl) acetamide

Part A: To a solution of 3-bromopyruvic acid hydrate (1.95 g, 11.7 mmol) cooled to 0 ° C in methanol (50 mL) was added 4- (phenoxy) benzenethiol (2.35 g, 11.7 mmol). ). The solution was stirred for 15 minutes followed by concentration in vacuo. The residue was partitioned between ethyl acetate and HgO. Concentration in vacuo gave the crude sulfide as a yellow solid which was used without additional purification.

Part Β: To a solution of the crude sulfide of Part A (1.2 g, below 2.6 mmol) in methanol / H 2 O cooled to 0 ° C was added Oxone ® (3.5 g, 5.72 mmol). The solution was stirred for 1 hour. Excess Oxone ® was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated ΝβΗΟΟβ and saturated NaCl dried over MgSO 4. After concentration in vacuo, the resulting residue was dissolved in methanol and thionyl chloride (1.9 g, 26 mmol) was added. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfone as a solid (350 mg, 44%). MS (CI) MH ⁺ calcd for C 15 H 14 O 5 S: 307, found 308.

Part C: To a solution of the sulfone (350 mg, 1.1 mmol) in methanol (2 mL) and THF (2 mL) was added 50% aqueous hydroxylamine (1 mL). The solution was stirred overnight. Three with Ethyl Acetate

239

to give the title compound as a white solid (270 mg, 77%). HPLC purity: over 99%. MS (CI) MH ⁺ calcd for C 14 H 13 NO 5 S: 308, found 308.

Example 2

Preparation of N-hydroxy-2-methyl-2 - ((4-phenoxyphenyl) sulfonyl) propanamide

HOHN

Part A: To a solution of 4- (phenoxy) benzenethiol (3.8 g, 18.8 mmol) in methanol (60 mL) cooled to 0 ° C was added t-butyl bromoacetate (2.8 mL, 18.8 mmol) and triethylamine (2.6 mL, 19.0 mmol). The solution was stirred for 30 minutes and then concentrated in vacuo. The residue was partitioned between ethyl acetate and H 2 O and the organic layer was washed with saturated NaCl and dried over MgSO 4.

Concentration in vacuo gave the sulfide as an oil. To a solution of the sulfide in dichloromethane (85 mL) was added p-chloroperbenzoic acid (13.8 g, 43.2 mmol) over 15 minutes. The solution was stirred at ambient temperature for 2 hours. The reaction was quenched by addition of aqueous Na 2 SO 4. After 30 minutes, the solution was filtered through a pad of Celite® and the filtrate was washed with 25% aqueous hydroxylamine, 1M HCl and saturated NaCl and dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfone as a solid (4.0 g, 68%). Part Β: To a solution of the sulfone of Part A (3.2 g, 9.2 mmol) in THF (65 mL) cooled to 0 ° C was added sodium hydride (730 mg. 60% dispersion in mineral oil, 18.4 mmol). ). After 10 minutes, methyl iodide (2.28 mL, 36.8 mmol) was added dropwise and the mixture was stirred at ambient temperature for 18 hours. The reaction was quenched by addition of aqueous H 2 O and concentrated in vacuo. The aqueous residue was diluted with ethyl acetate and the organic layer was washed with H 2 O and dried over Na 2 SO 4. Concentrate in vacuo the dimethyl compound as an off-white solid (3.2 g, 92%). HPLC purity: 95%.

Part C: To a solution of the dimethyl compound of Part B (3.2 g, 8.5 mmol) in anisole (10 mL) was added trifluoroacetic acid (30 mL) and the solution was stirred for 30 minutes. Concentration in vacuo followed by friction (ethyl ether) gave the acid as a white solid (750 mg, 28%). HPLC purity: 99%. MS (CI) MH ⁺ calcd for C 15 H 15 O 5 S: 321, found 321.

240

Part D: To a solution of the acid from Part C (723 mg, 2.26 mmol) in DMF (4.5 mL) was added hydroxybenzotriazole * H2O (HOBT, 366 mg, 2.71 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 476 g, 2.49 mmol). When the solution was stirred at ambient temperature for 1 hour, 50% aqueous hydroxylamine (0.40 mL, 6.8 mmol) was added. After 15 minutes, the solution was partitioned between ethyl acetate and H 2 O. The organic layer was washed with H 2 O and saturated NaCl and dried over Na 2 SO 4. Reverse phase chromatography (acetonitrile / H2O) gave the title compound as a white foam (434 mg, 57%). HPLC purity: 99%. MS (CI) M + Li ⁺ calcd for C 16 H 17 NO 5 ^S : 342, found 342.

Example 3

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

Part A: A solution of 4- (phenoxy) benzenethiol (2.03 g, 10.0 mmol) in DMSO (20 mL) was heated at 65 ° C 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 H 2 O and saturated NaCl and dried over MgSO 4. Concentration in vacuo gave the disulfide as a yellow oil (2.3 g, quantitative yield).

Part Β: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added dropwise a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF over 20 minutes. THF (5 mL). The solution was stirred overnight at ambient temperature and concentrated in vacuo to give a light oil. The oil was filtered through silica gel (7: 3, ethyl acetate / hexanes) and concentrated in vacuo. This afforded the BOC-piperidine compound (26.2 g, quantitative yield) as a clear colorless oil.

Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol) in THF (30 mL) cooled to

-78 ° C n-butyl lithium (12.5 mL, 20 mmol) was added dropwise. After 15, it was added dropwise

The BOC-piperidine Compound from Part B in THF (10 mL). After 1.5 hours, the solution was cooled to 241 ° C and the disulfide from Part A (2.0 g, 10 mmol) in THF (7 mL) was added. The solution was stirred at ambient temperature for 1 hour. The solution was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with H ₂ O and saturated NaCl and dried over MgSO 2. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfide as an oil (1.8 g, 40%).

Part D: To a solution of the sulfide of Part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to 0 ° C was added p-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred at ambient temperature for 1.5 hours. This was followed by dilution of H ₂ O and extraction with dichloromethane. The organic layer was washed with 10% Na ₂ SO 4, H ₂ O and saturated NaCl and dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfone as a solid (1.15 g, 59%).

Part E: To a solution of the sulfone from Part D (800 mg, 1.63 mmol) in THF (65 mL) and ethanol (9 mL) was added NaOH (654 mg, 1.63 mmol) in H ₂ O (3 mL). . The solution was heated at 65 ° C for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in H ₂ O. After acidification with 2M HCl to pH 4, the solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over MgSO 4. Concentration in vacuo gave the acid as a white foam (790 mg, quantitative yield). Calcd for C 23 H 27 NO 7 S: C, 59.86; H, 5.90; N, 3.04; S, 6.95. Found: C, 59.49, H, 6.37, N, 2.81, S, 6.59.

Part F: To a solution of acid E in part (730 mg, 1.58 mmol) in DMF (9 mL) was added HOBT (259 mg, 1.90 mmol) followed by EDC (420 mg, 2.21 mmol), 4. - methylmorpholine (0,521 ml,

4.7 mmol) and 50% aqueous hydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for 20 hours and additional hydroxybenzotriazole * H ₂ O (256 mg) and EDC (424 mg) and 50% aqueous hydroxylamine (1.04 mL) were added. After stirring for an additional 24 hours, the solution was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO 4 Reversed phase chromatography (silica gel, acetonitrile / H ₂ O) gave the title compound as a white solid (460 mg, 61%). HPLC purity: over 99%. Calcd for C ₂₃ H ₂₈ N ₂ O ₇ S: 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.

Example 4

Preparation of N-hydroxy-4 - ((4-phenoxyphenyl) sulfonyl) -4-piperidinecarboxamide hydrochloride

HOHN

242

N HCl

Η

Part A: A solution of 4- (phenoxy) benzenethiol (2.03 g, 10.0 mmol) in DMSO (20 mL) was heated at 65 ° C 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 H 2 O and saturated NaCl and dried over MgSO 2. Concentration in vacuo gave the disulfide as a yellow oil (2.3 g, quantitative yield).

Part Β: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added dropwise a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF over 20 minutes. THF (5 mL). The solution was stirred overnight at ambient temperature and concentrated in vacuo to give a light oil. The oil was filtered through silica gel (7: 3, ethyl acetate / hexane) and concentrated in vacuo. This gave the BOC-piperidine compound as a clear colorless oil (26.2 g, quantitative yield).

Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol) in THF (30 mL) cooled to -78 ° C was added dropwise n-butyl lithium (12.5 mL, 20 mmol). After 15 minutes, the BOC-piperidine compound from Part B in THF (10 mL) was added dropwise. After 1.5 hours, the solution was cooled to -60 ° C and the disulfide from 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 H 2 O and extracted with ethyl acetate. The organic layer was washed with H 2 O and saturated NaCl and dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfide as an oil (1.8 g, 40%).

Part D: To a solution of the sulfide of Part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to 0 ° C was added p-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred at ambient temperature for 1.5 hours. This was followed by dilution of H 2 O and extraction with dichloromethane. The organic layer was washed with 10% Na 2 SO 4, H 2 O and saturated NaCl and dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfone as a solid (1.15 g, 59%).

Part E: To a solution of the sulfone from Part D (800 mg, 1.63 mmol) in THF (65 mL) and ethanol (9 mL) was added NaOH (654 mg, 1.63 mmol) in H 2 O (3 mL). The solution was heated to 65 ° C

243 · • * toto toto toto • • • • • • • • • • • • • · · · · · · · · · · · · · · · · · · · · · · · · · · To ·· hours. The solution was concentrated in vacuo and the residue was dissolved in H 2 O. After acidification with 2M HCl to pH 4, the solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over MgSO 4. Concentration in vacuo gave the acid as a white foam (790 mg, quantitative yield). For C23H27NO7S: C, 59.86; H, 5.90; N, 3.04; S, 6.95. Found: C, 59.49, H, 6.37, N, 2.81, S, 6.59.

Part F: To a solution of acid E in part (730 mg, 1.58 mmol) in DMF (9 mL) was added HOBT (259 mg, 1.90 mmol) followed by EDC (420 mg, 2.21 mmol), 4. - methylmorpholine (0,521 ml,

4.7 mmol) and 50% aqueous hydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for 20 hours and additional hydroxybenzotriazole * H 2 O (256 mg) and EDC (424 mg) and 50% aqueous hydroxylamine (1.04 mL) were added. After stirring for an additional 24 hours, the solution was diluted with H 2 O and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO 4 p HPCL in reverse phase (acetonitrile / H 2 O) to give the title compound as a white solid (460 mg, 61%). HPLC purity: over 99%. 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.

Part G: HCl gas was bubbled into a solution of the hydroxamate of Part F (385 mg, 0.808 mmol) in ethyl acetate (25 mL) cooled to 0 ° C for 5 minutes. After standing for 30 minutes, the solution was concentrated in vacuo. Trituration with ethyl ether gave the title compound as a white solid (330 mg, quantitative yield). MS (CI) MH ⁺ calculated for C 18 H 20 N 2 O 5 S: 377, found 377. Analysis calculated for C 18 H 20 N 2 O 5 S + 1HCl * 0.25H 2 O: C, 51.35, H, 5.17, N, 6.65, S, 7.62, Cl, 9.26. Found: C, 51.58, H, 5.09, N, 6.55, S, 8.02, Cl, 9.09.

Example 5

Preparation of (E) N-hydroxy-2 - ((4-phenoxyphenyl) sulfonyl) -3-phenyl-2-propenamide

Part A: To a solution of 4- (phenoxy) benzenethiol (5.00 g, 24.7 mmol) cooled to 0 ° C in methanol (50 mL) was added tert-butyl bromoacetate (3.99 mL, 24.7 mmol). After I add

244 triethylamine (3.60 mL, 25.8 mmol) was stirred for 40 minutes. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with H 2 O and saturated NaCl and dried over Na 2 SO 4. Concentration in vacuo gave the sulfide as an oil (7.9 g, quantitative yield).

Part Β: To a solution of the crude sulfide of Part A (7.9 g, 24.7 mmol) in methanol (180 mL) and H 2 O (20 mL) was added Oxone ® (38.4 g, 62.5 mmol) and the mixture was stirred for 22 hours. The mixture was acidified with 2.5M HCl to pH 4 and decanted to remove insoluble salts. The decantate was concentrated to half volume and partitioned between ethyl acetate and H 2 O. The organic layer was washed with H 2 O and saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfone as a yellow solid (5.79 g, 67%).

Part C: To a solution of the sulfone of Part B (2.5064 g, 7.20 mmol) and benzaldehyde (0.748 mL, mmol) in benzene (20 mL) was added acetic acid (0.15 mL) and piperidine (0.05 mL). ml). The solution was heated to reflux for 2 hours and the condensate was collected by Dean-Stark well. After an additional 1.5 hours of reflux, the solution returned to ambient temperature and stirred for 18 hours. The solution was diluted with ethyl acetate and washed with H 2 O and saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica gel, ethyl acetate / hexane) followed by friction (ethyl acetate / hexane) gave the unsaturated sulfone as a white solid (1.97 g, 73%). HPLC purity: over 98%.

Part D: HCl gas was bubbled into the unsaturated sulfone solution from Part C (0.5053 g, 1.16 mmol) for 1 hour. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with H 2 O and dried over Na 2 SO 4. Concentration in vacuo gave the acid as an oil (0.41 g, 93%).

Part Ε: To the acid solution from Part D (461 mg, 1.21 mmol) was added thionyl chloride (3.0 mL) and the solution was heated to 100 ° C for 1 hour. Concentration in vacuo gave the acid chloride as an amber oil (380 mg, 79%).

Part F: To a solution of the acid chloride from Part E (380 mg, 0.95 mmol) in THF (20 mL) was added 50% aqueous hydroxylamine (1.7 mL, 9.5 mmol). The solution was stirred for 1 hour at 0 ° C.

The solution was diluted with ethyl acetate, washed with H 2 O and saturated NaCl, and dried over Na 2 SO 4.

Reverse phase chromatography (acetonitrile / H2O) followed by friction (ethyl acetate / hexane) gave the title compound as a white solid (131 mg, 35%). HPLC purity: over 97%.

Example 6

44

Β 4 4 '

4 <

245 • ·

4

Β 4 4 «

44

Preparation of N-hydroxy-4 - ((4-phenoxyphenyl) sulfonyl) -4- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

Part A: A solution of 4- (phenoxy) benzenethiol (2.03 g, 10.0 mmol) in DMSO (20 mL) was heated at 65 ° C 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 H 2 O and saturated NaCl and dried over MgSO 4. Concentration in vacuo gave the disulfide as a yellow oil (2.3 g, quantitative yield).

Part Β: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added dropwise over 20 minutes a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF ( 5 ml). The solution was stirred overnight at ambient temperature and concentrated in vacuo to give a light oil. The oil was filtered through silica gel (ethyl acetate / hexane) and concentrated in vacuo. This gave the BOCpiperidine Compound as a clear colorless oil (26.2 g, quantitative yield).

Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol) in THF (30 mL) cooled to -78 ° C was added dropwise n-butyl lithium (12.5 mL, 20 mmol). After 15 minutes, the BOC-piperidine compound from Part B in THF (10 mL) was added dropwise. After 1.5 hours, the solution was cooled to -60 ° C and the disulfide from 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 H 2 O and extracted with ethyl acetate. The organic layer was washed with H 2 O and saturated NaCl and dried over MgSO 2. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfide as an oil (1.8 g, 40%).

Part D: To a solution of the sulfide of Part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to 0 ° C was added p-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred at ambient temperature for 1.5 hours. This was followed by dilution of H 2 O and extraction with dichloromethane. The organic layer was washed with 10% Na 2 SO 4, H 2 O and saturated NaCl and dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfone as a solid (1.15 g, 59%).

246 • 4 4

4 «99

4 «*

4

999 9 99 • 4 4 · ·· ·

4 · 9 9 9 · 4 4

9999 99 9

9 9 9 9 9

99 · 99

Part E: To a solution of the sulfone from Part D (3.56 g, 7.0 mmol) in ethyl acetate (100 mL) cooled to 0 ° C was added HCl gas for 5 minutes. Concentration in vacuo followed by rubbing with the amine hydrochloride salt as a white solid (3.5 g, quantitative yield). MS (CI) MH ⁺ calcd for C 20 H 23 NO 5 ^S : 390, found 390.

Part F: To a solution of the amine hydrochloride salt of part E (2.6 g, 6 mmol) and K 2 CO 3 (1.66 g, 12 mmol) in DMF (50 mL) was added propargyl bromide (892 mg, 6 mmol) and the solution was was stirred at ambient temperature for 4 hours. The solution was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layers were washed with H ₂ O and dried over MgSO 2. Chromatography (on silica gel, ethyl acetate / hexane) gave propargylamine as a white solid (2.15 g, 82%).

Part G: To a solution of propargylamine from Part F (2.15 g, 5 mmol) in THF (30 mL) and ethanol (30 mL) was added NaOH (2.0 g, 59 mmol) and the solution was heated to 65 ° C. 48 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH 5. Vacuum filtration of the resulting precipitate gave the acid as a white solid (2.04 g, quantitative yield).

Part Η: To a solution of the acid from Part G (730 mg, 1.58 mmol) in dichloromethane (75 mL) was added triethylamine (0.585 mL, 4.2 mmol), 50% aqueous hydroxylamine (0.925 mL, 14.0 mmol). and then bromotriol (pyrrolidino) phosphonium hexafluorophosphate (PyBroP (R), 418 g, 1.54 mmol). The solution was stirred at ambient temperature for 4 hours. The solution was diluted with H ₂ O and extracted with dichloromethane. The organic layer was washed with saturated NaCl and dried over MgSO 2. Reverse phase chromatography (silica gel, acetonitrile / H ₂ O) gave the hydroxamate as a white solid (140 mg, 25%). Calcd for C2iH ₂ 2N ₂ 0gS: C, 60.85; N, 5.37; N, 6.76; S, 7.74. Found: C, 60.47, N, 5.35, N, 6.61, S, 7.46.

Part I: To a solution of the hydroxamate of Part H (121 mg, 0.292 mmol) in methanol (2 mL) cooled to 0 ° C was added acetyl chloride (0.228 mL, 0.321 mmol) in methanol (1 mL). The solution was concentrated in a stream of N _2, and three with ethyl ether gave the title compound as a white solid (107 mg, 81%).

C2lH23N O5S ₂ * HCl * 0.3H ₂ O: C, 55.27, H, 5.21, N, 6.14.

Found: C, 54.90, H, 5.37, N, 6.07.

Example 7

Preparation of N- (4 - ((2-hydroxyamino) -2-oxoethylsulfonyl) phenyl) benzamide

247 •

Part A: To a suspension of 2- (4-aminophenylthio) acetic acid (20.00 g, 0.109 mmol) in methanol (100 mL) was added dropwise thionyl chloride (24.0 mL, 0.327 mmol). Additional methanol (100 mL) was added and the suspension was heated to reflux for 2 hours. The solution was concentrated in vacuo and the residue was dissolved in H 2 O and neutralized with saturated NaHCO 3. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated NaCl and dried over Na 2 SO 4. Concentration in vacuo gave the methyl ester as a dark purple oil. (22.75 g, quantitative yield).

Part Β: To a solution of the methyl ester of Part A (5.00 g, 25.35 mmol) and triethylamine (7.07 mL, 50.70 mmol) in dichloromethane (50 mL) was added benzoyl chloride (3.24 mL, 27 mL). (89 mmol) and the solution was stirred at ambient temperature for 2 hours. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate, THF and H 2 O. The organic layer was washed with H 2 O and saturated NaCl and dried over Na 2 SO 4. Concentration in vacuo provided benzamide as a purple solid (7.06 g, 92%). HPLC purity: 98%. MS (CI) MH ⁺ calcd for C 19 H 15 NO 3 S: 308, found 308.

Part C: To a solution of the benzamide of Part B (4.00 g, 13.27 mmol) in THF (100 mL) and H 2 O (10 mL) cooled to 0 ° C was added Oxone ® (potassium monopersulfate, 24.47 g, 39.81 mmol). The suspension was stirred overnight (about 18 hours) at ambient temperature. The mixture was filtered to remove excess Oxone ®. The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H 2 O and dried over Na 2 SO 4. Concentration in vacuo provided the sulfone as a pink solid (4.11 g, 93%). HPLC purity: 98%. MS (CI) MH ⁺ calcd for C 16 H 15 NO 5 S: 340, found 340.

Part D: To a solution of the sulfone of Part C (400 mg, 1.2 mmol) in THF (9 mL) was added 50% aqueous hydroxylamine (5.0 mL). The solution was stirred for 8 hours and concentrated in vacuo. Trituration with hot ethyl ether gave the title compound as an off-white solid (348 mg, 78%).

HPLC purity: 97%. MS (CI) MH ⁺ calcd for C 17 H 14 N 2 O 5 S: 335, found 335.

248

Example 8

Preparation of N- (4 - ((2-hydroxylamino) -2-oxo-1-piperidin-4-yl) ethyl) sulfonyl) phenyl) benzamide monohydrochloride

Part A: To a solution of diethethanolamine (22.16 g, 0.211 mol) in THF (100 mL) cooled to 0 ° C was added di-tert-butyl dicarbonate (46.0 g, 0.211 mol) and the solution was stirred over night 20 hours at ambient temperature. The solution was concentrated in vacuo and the resulting residue was filtered through a pad of silica gel (5% methanol / 95% dichloromethane) to give the diol as a clear oil (45.06 g, quantitative yield). MS (CI) MH ⁺ calcd for C 9 H 19 O 4 S: 206, found 206.

Part Β: To a suspension of 2- (4-aminophenylthio) acetic acid (20.00 g, 0.109 mmol) in methanol (100 mL) was added dropwise thionyl chloride (24.0 mL, 0.327 mmol). Additional methanol (100 mL) was added and the suspension was heated to reflux for 2 hours. The solution was concentrated in vacuo and the residue was dissolved in H 2 O and neutralized with saturated NaHCO 3. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated NaCl and dried over Na 2 SO 4. Concentration in vacuo gave the methyl ester as a dark purple oil. (22.75 g, quantitative yield). HPLC purity: 99%.

Part Β: To a solution of the methyl ester of Part B (5.00 g, 25.35 mmol) and triethylamine (7.07 mL, 50.70 mmol) in dichloromethane (50 mL) was added benzoyl chloride (3.24 mL, 27, 89 mmol) and the solution was stirred at ambient temperature for 2 hours. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate, THF and H 2 O. The organic layer was washed with H 2 O and saturated NaCl and dried over Na 2 SO 4. Concentration in vacuo gave benzamide as a purple solid (7.06 g, 92%). HPLC purity: 98%.

Part D: To a solution of the benzamide of Part C (4.00 g, 13.27 mmol) in THF (100 mL) and H 2 O (10 mL) cooled to 0 ° C was added Oxone ® (potassium monopersulfate, 24.47 g, 39.81 mmol). The suspension was stirred overnight (about 18 hours) at ambient temperature. The mixture was filtered to *

249 ft · fttt ftft · excess oxone (R) was removed. The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H 2 O and dried over Na 2 SO 4. Concentration in vacuo gave the sulfone as a pink solid (4.11 g, 93%). HPLC purity: 98%.

Part E: To a solution of the diol from Part A (1.03 g, 5.00 mmol) and methyl ester D (2.00 g, 6.00 mmol) in THF (100 mL) was added 1,1- (azodicarbonyl) dipiperidine (5.05 g, 20.00 mmol). To this suspension was added trimethyl phosphine (20.00 mL of a 1.0 M solution in THF, 20.00 mmol). The mixture was stirred at ambient temperature for 1 hour and then heated to 40 ° C for 18 hours. When the suspension returned to ambient temperature, ethyl ether was added and insoluble solids were removed by filtration. The filtrate was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate and washed with H 2 O saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the piperidine compound as a yellow solid (600 mg, 24%). MS (CI) MH ⁺ calcd for C 25 H 31 N 3 O 7 S: 503, found 503.

Part F: To a solution of the piperidine compound of Part E (950 mg, 1.89 mmol) in THF (10 mL) was added potassium silanolate (970 mg, 7.56 mmol). The solution was stirred at ambient temperature for 72 hours, acidified with 1M HCl to pH 2 and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over MgStXp. Concentration in vacuo gave the acid as a yellow solid (600 mg, 24%). MS (CI) MH ⁺ calcd for C 25 H 30 N 2 O 7 S: C, 503, found: 503.

Part G: To a solution of the acid from Part F (772 mg, 1.48 mmol) in DMF (9 mL) was added HOBT (240 mg, 1.77 mmol), 4-methylmorpholine (0.488 mL, 4.44 mmol), O-tetrahydropyranyl hydroxylamine (538 mg, 4.54 mmol) and EDC (397 mg, 2.07 mmol). The solution was stirred at ambient temperature for 2 hours. After concentration in vacuo, the residue was partitioned between ethyl acetate and H 2 O. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the protected hydroxylamine as a white solid (608 mg, 70%). HPLC purity: over 99%.

Part Η: To a solution of the protected hydroxylamine from Part G (596 mg, 1.01 mmol) in dioxane (3 mL) and methanol (1 mL) was added 4M HCl in dioxane (2.50 mL, 10.14 mmol) and a solution. was stirred at ambient temperature for 50 minutes. Trituration with ethyl ether gave the title compound as a white solid (433 mg, 98%). HPLC purity: 98%. MS (CI) MH ⁺ calcd for C 19 H 21 N 3 O 5 S: 404, found 404.

9 · 0 · • 0 0 0

99000 · 8 0

0 0 0 0

0 0 09

9

9 «0

0 0 0

0000 99

250

Example 9

Preparation of N-hydroxy-4 - ((4-phenylthiophenyl) sulfonyl) -1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added dropwise over 20 minutes a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF ( 5 ml). The solution was stirred overnight (about 18 hours) at ambient temperature and concentrated in vacuo to give a light oil. The oil was filtered through silica gel (ethyl acetate / hexanes) and concentrated in vacuo. The aqueous residue was extracted with ethyl acetate and the organic layer was washed with 0.5M KOH, H 2 O saturated NaCl and dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfide as an oil (18 g, 75%).

Part B: A solution of 4-fluorothiophenol (50.29 g, 390 mmol) in DMSO (500 mL) was heated at 65 ° C for 6 hours. The reaction was poured onto wet ice and the resulting solid was collected by vacuum filtration to give the disulfide as a white solid (34.4 g, 68.9%).

Part C: To a solution of the BOC-piperidine Compound from Part A (16 g, 62 mmol) in THF (300 mL) cooled to -50 ° C was added lithium diisopropylamide (41.33 mL, 74 mmol) and the solution was stirred for 1 h. 5 hours at ambient temperature. The reaction was quenched by the addition of H 2 O and the solution was concentrated in vacuo. The aqueous residue was extracted with ethyl acetate and the organic layer was washed with 0.5% KOH, H 2 O and saturated NaCl. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfide as an oil (18.0 g, 75%).

Part D: To a solution of the sulfide of Part C (16.5 g, 43 mmol) in dichloromethane (500 mL) cooled to 0 ° C was added 3-chloroperbenzoic acid (18.0 g, 86 mmol). The solution was stirred at ambient temperature for 20 hours. The solution was diluted with H 2 O and extracted with dichloromethane. The organic layer was washed with 10% Na 2 SO 4, H 2 O and saturated NaCl and dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfone as a solid (10.7 g, 60%).

• 4 ·

• 4

251

44 44 4444

4444 44 44 44

Part E: To a solution of the sulfone from Part D (10 g, 24.0 mmol) in ethyl acetate (250 mL) was bubbled HCl gas for 10 minutes, then stirred at ambient temperature for 4 hours. Concentration in the bag gave the amine hydrochloride as a white solid (78.27 g, 86%).

Part F: To a solution of the amine hydrochloride from Part E (5.98 mg, 17.0 mmol) in DMF (120 mL) was added potassium carbonate (5.98 g, 17.0 mmol) followed by propargyl bromide (2.02 g). (17.0 mmol) and the solution was stirred at ambient temperature for 4 hours. The solution was partitioned between ethyl acetate and H 2 O. The organic layer was washed with H 2 O and saturated NaCl and dried over MgSO 2. Chromatography (on silica gel, ethyl acetate / hexane) gave propargylamine as a yellow oil (5.2 g, 86%).

Part G: To a solution of propargyl amine from 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 ° C 6 hours. The solution was partitioned between ethyl acetate and H 2 O. The organic layer was washed with H 2 O and saturated NaCl and dried over MgSO 2. Chromatography (on silica gel, ethyl acetate / hexane) gave the S-phenoxyphenyl compound as an oil (1.95 g, 56%).

Part Η: To a solution of S-phenoxyphenyl of part G (1.81 g, 4.06 mmol) in ethanol (21 mL) and H 2 O was added KOH and the solution was heated to 105 ° C for 4.5 hours. The solution was acidified with concentrated HCl solution to pH 1 and then concentrated to give the acid as a yellow residue which was used without additional purification.

Part I: To a solution of the acid from Part H (1.82 g, 4.06 mmol) in acetonitrile (20 mL) was added O-tetrahydropyranyl hydroxylamine (723 mg, 6.17 mmol) and triethylamine (0.67 mL, 4 mL). , 86 mmol). To this stirred solution was added EDC (1.18 g, 6.17 mmol) and the solution was stirred for 18 hours. The solution was partitioned between H 2 O and ethyl acetate. The organic layer was washed with H 2 O, saturated NaHCO 3, and saturated NaCl and dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as a white solid (1.32 g, 63%).

Part J: To a solution of the protected hydroxamate of Part I (9.65 g, 18.7 mmol) in methanol (148 mL) cooled to 0 ° C was added acetyl chloride (4.0 mL, 56.2 mmol) and the solution was was stirred at ambient temperature for 45 minutes. Concentration in vacuo followed by trituration with ethyl ether gave the title compound as a white solid (8.10 g, 94%). MS (CI) MH ⁺ calculated for

C21H22N2O4S2: 431, found 431.

• • • •

252 <φ ·· * · φ φ · φ ·

Example 10

Preparation of 4 - ((4- (1,3-benzodioxol-5-yloxy) phenyl) sulfonyl) -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of propargyl amine from Part F of Example 9 (7.0 g, 19.8 mmol) in DMF (30 mL) was added sesamol (5.52 g, 40 mmol) and potassium carbonate (5.52 g, 40 mmol) and the solution was heated at 85 C for 48 ⁹ h. The solution was partitioned between ethyl acetate and H ₂ O. The organic layer was dried over MgSO 2. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfide as an oil (9.38 g, quantitative yield).

Part Β: To a solution of the sulfide of Part A (2.72 g, 5.92 mmol) in ethanol (30 mL) and H ₂ O was added potassium hydroxide and the solution was heated to reflux for 4 hours. The solution was acidified with concentrated HCl to pH = 3. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile (30 mL). To this solution was added O-tetrahydropyranyl hydroxylamine (1.05 g, 9.0 mmol), triethylamine (1 mL) and EDC (1.72 g, 9.0 mmol), and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and diluted with saturated NaHCl and extracted with ethyl acetate. The organic layer was dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as an oil (2.86 g, 93%).

Part C: To a solution of the protected hydroxamate of Part B (2.86 g, 5.27 mmol) in methanol (40 mL) was added acetyl chloride (1.13 mL, 15.8 mmol) and the solution was stirred for 3 hours. The solution was concentrated in vacuo. Reverse phase chromatography (acetonitrile / H ₂ O) provided the title compound as a white solid (2.2 g, 84%). HPLC purity: 99%. MS (CI) MH ⁺ calcd for C ₂ H ₂₂ N ₂ O ₇ S: 459, found 459.

• ftft

Example 11

253 ft · ft · ftft ft ft · ft ft ft ft ft ft ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft

Preparation of tetrahydro-N-hydroxy-4 - ((4-phenyl-1-piperidinyl) phenyl) sulfonyl) -2H-pyran-4-carboxamide monohydrochloride

HOHN

Part A: To a solution of Na (8.97 g, 390 mmol) in methanol (50 mL) at 0 ° C was added 4-fluorothiophenol (50 g, 390 mmol) methyl chloroacetate (34.2 mL, 390 mmol) and the solution was stirred at ambient temperature for 4 hours. The solution was filtered to remove salts and the filtrate was concentrated in vacuo to afford the sulfide as a colorless oil (75.85 g, 97%).

Part Β: To a solution of the sulfide from Part A (75.85 g, 380 mmol) in methanol (1 L) and H 2 O (100 mL) was added Oxone ® (720 g, 1.17 mmol) and the solution was stirred for 2 hours. The reaction mixture was filtered to remove excess salts and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H 2 O, saturated NaHCO 3 and saturated NaCl and then dried over MgSO 4. Concentration in vacuo gave the sulfone as a white solid (82.74 g, 94%).

Part C: To a solution of the sulfone of Part B (28.5 g, 123 mmol) in N, N-dimethylacetamide (200 mL) was added potassium carbonate (37.3 g, 270 mmol), bis- (2-bromoethyl) ether (19.3 mL, 147 mmol), 4-dimethylpyridine (750 mg, 6 mmol) and tetrabutylammonium bromide (1.98 g, 6 mmol) and the solution was stirred at ambient temperature for 72 hours. The solution was poured into 1M HCl (300 mL) and the resulting precipitate was collected by vacuum filtration. Recrystallization (ethyl acetate / hexane) gave the tetrahydropyran compound as a beige solid (28.74 g, 79%).

Part D: To a solution of the tetrahydropyran compound from Part C (1.21 g, 4.0 mmol) in DMSO (10 mL) was added CSCO 3 (3.26 g, 10.0 mmol) and 4-phenylpiperidine (640 mg, 4 (0 mmol) and the solution was heated at 90 ° C for 2 hours. The solution was diluted with H 2 O and extracted with ethyl acetate. The organic layer was washed with 5% aqueous KHSO 4, saturated NaHCO 3, saturated NaCl, and dried over MgSO 4. Concentration in vacuo gave the amine as a white solid (1.2 g, 67%).

• to • to

254

Part E: To a solution of the amine from Part D (815 mg, 1.84 mmol) in methanol (5 mL) and THF (5 mL) was added 50% aqueous NaOH (2 mL), and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue was diluted with H 2 O and acidified to pH 7. The resulting precipitate was collected by vacuum filtration to give the acid as a white solid (760 g, 86%).

Part F: To a solution of the acid from Part E (620 mg, 1.44 mmol) in dichloromethane (10 mL) and DMF (3 mL) was added PyBroP (810 mg, 1.73 mmol), N-methylmorpholine (0.5 mL). mL, 4.3 mmol) and O-tetrahydro-2H-pyranyl-hydroxylamine (190 mg, 1.59 mmol) and the solution was stirred at ambient temperature for 4 hours. The solution was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with H 2 O and saturated NaCl and then dried over Na 2 SO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the protected hydroxamate as a white solid (630 mg, 83%). MS (CI) MH ⁴ calcd for C 28 H 36 N 2 O 6 S: 529, found 529.

Part G: To a solution of the protected hydroxamate of Part F (600 mg, 1.14 mmol) in dioxane (1.5 mL) and methanol (1.5 mL) was added 4N HCl in dioxane (1.5 mL) and the solution was stirred for 2 hours. The solution was poured into ethyl ether and the resulting precipitate was collected by vacuum filtration. This afforded the title compound as a beige solid (500 mg, 91%). MS (CI) MH ⁺ calcd for C 28 H 28 28 2058: 445, found 445.

Example 12

Preparation of 1-acetyl-N-hydroxy-4 - ((4-phenoxyphenyl) sulfonyl) piperidinecarboxamide

HOHN

N

Part A: To a solution of the sulfone of Example 6, Part D (2.75 g, 5.6 mmol) in THF (10 mL) and ethanol (10 mL) was added NaOH (2.25 g, 56 mmol) and the solution was heated at 70 ° C for 18 hours.

The solution was concentrated in vacuo, the residue was dissolved in H 2 O and extracted with ethyl acetate.

The organic layer was dried over MgSO 4. Concentration in vacuo gave the crude acid as a solid. A solution of the acid in dichloromethane (6 mL) and trifluoroacetic acid (6 mL) was stirred at room temperature.

• ft • · ·

255 ft · 9 ft ft 9 ft. · Stirring at ambient temperature for 1 hour. Concentration in vacuo provided the amine hydrochloride salt as a solid (2.3 g, quantitative yield).

Part Β: To a solution of the amine hydrochloride salt of Part A (2.3 g, below 5.6 mmol) in acetone (10 mL) and H 2 O (10 mL) cooled to 0 ° C was added triethylamine (1.17 mL, 8 mL). (4 mmol) and acetyl chloride (0.60 mL, 8.4 mmol) and the solution was stirred at ambient temperature for 18 h. The solution was concentrated in vacuo to remove acetone and the aqueous solution was extracted with ethyl ether. The aqueous layer was acidified to pH 2 and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and concentration in vacuo gave the N-acetyl compound as a white solid (1.5 g, 65.2%). Part C: To a solution of the N-acetyl compound of Part B (0.6 g, 1.49 mmol) in DMF (10 mL) was added EDC (401 mg, 2.1 mmol) followed by 50% aqueous hydroxylamine (0, 9 mL) and 4-methylmorpholine (0.7 mL, 6.4 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with H 2 O and dried over MgSO 4. Reverse phase chromatography (on silica, acetonitrile / H 2 O) gave the title compound as a white solid (101 mg, 16%). MS (CI) MH ⁺ calcd for θ2θΗ22Νθ6 ^: 419, found 419.

Example 13

Preparation of 4 - ((4- (cyclohexylthio) phenyl) sulfonyl) -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the propargyl amine from Part F of Example 9 (6.5 g, 18.4 mmol) in DMF (10 mL) was added sesamol potassium carbonate (3.81 g, 27.6 mmol) and cyclohexylmercaptan (3 mL). 37 mL, 27.6 mmol). The solution was heated at 100 ° C for 6.5 hours. The solution was diluted with H 2 O and extracted with ethyl acetate. The organic layers were dried over MgSO 4. Chromatography (on silica, hexane / ethyl acetate) gave the sulfide as a yellow oil (6.05 g, 73%).

4 4 4

4 4 4 4

4 4 4

44 ·· 4 · 44 • • 44 4 4 4 4 · · * 444

4 4 4 4 4

ZOO φ · «4 4 4

4444 44 4

Part Β: To a solution of sulfide of part A (612 mg, 1.4 mmol) in ethanol (8.4 mL) and H 2 O (1.4 mL) was added potassium hydroxide (470 mg, 8.4 mmol) and the solution was refluxed for 3 hours. The solution was acidified to pH 3 and concentrated in vacuo. The residue was dissolved in acetonitrile (10 mL). To this solution was added O-tetrahydro-2H-pyran-2-yl hydroxylamine (230 mg, 2.0 mmol) and triethylamine (0.5 mL) followed by EDC (380 mg, 2.0 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue was diluted with saturated NaHCO 3 and extracted with ethyl acetate. The organic layer was dried over MgSO 4.

Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as an oil (246 mg, 34%).

Part C: To a solution of the protected hydroxamate of Part B (246 mg, 0.47 mmol) in methanol (4 mL) was added acetyl chloride (0.11 mL, 1.5 mmol) and the solution was stirred at ambient temperature for 3 hours. After concentration in vacuo, reverse phase chromatography (on silica, acetonitrile / H 2 O) gave the title compound as a white solid (223 mg, quantitative yield).

Example 14

Preparation of N-hydroxy-1-methyl- (4-phenoxyphenylsulfonyl) -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the sulfone from Example 6, Part D (2.67 g, 5.5 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred at ambient temperature for 2 hours. The solution was concentrated in vacuo and the residue was triturated with ethyl ether. This gave the trifluoroacetic acid salt of the crude amine. To a solution of the crude amine salt in methanol (10 mL) was added formaldehyde (37% aqueous solution, 2.0 mL, 27.5 mmol) and pyridine borane (2.2 mL, 22 mmol), and the solution was stirred at room temperature for 18 hours. Surroundings. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H 2 O and dried over MgSO 2. Concentration in vacuo gave the N-methyl compound as a yellow oil (2.17 g, 98%).

257

4444

44 · 4 ·>

43 4 4 43 4

4444 4444 44444 44 4

4 4 4 4 4 5

44 44 44

Part Β: To a solution of the N-methyl compound of Part A (2.17 g, 5.4 mmol) in ethanol (10 mL) in THF (10 mL) was added NaOH (2.0 g, 50 mmol) and the reaction mixture. The mixture was stirred at -65 ° C for 18 hours. The solution was concentrated in vacuo. The residue was dissolved in H 2 O and extracted with ethyl ether. The aqueous solution was acidified to pH 2 and the resulting solid was collected by vacuum filtration to give the acid as a white solid (1.8 g, 90%).

Part C: To a solution of the acid from Part B (0.5 g, 1.3 mmol) in DMF (10 mL) was added EDC (1.06 g, 5.5 mmol) followed by O-tetrahydro-2H-pyranyl- hydroxylamine (490 mg, 4.2 mmol) and 4-methylmorpholine (0.76 mL) and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with H 2 O and dried over MgSO 4 Concentration in vacuo gave the crude protected hydroxamate. To a solution of the crude hydroxamate in methanol (10 mL) was added acetyl chloride (0.28 mL, 3.9 mmol) and the solution was stirred at ambient temperature for 3 hours. The solution was concentrated in vacuo. Reverse phase chromatography (on silica, acetonitrile / H 2 O, 0.0125% HCl) gave the title compound as a white solid (261 mg, 46%). MS (CI) MH ⁺ calcd for C 19 H 22 N 2 O 5 ^S : 391, found 391.

Example 15

Preparation of N-hydroxy-4 - ((4- (4- (methoxy) phenyl) sulfonyl) -1-1- (2-propynyl) 4-piperidinecarboxamide monohydrochloride)

CH

Part A: To a solution of the propargylamine from Part F of Example 9 (2.00 g, 5.66 mmol) in DMF (10 mL) was added cesium carbonate (4.7 g, 14.5 mmol) and 4-methoxythiophenol (1. 80 g, 14.5 mmol).

The solution was heated at 95 ° C for 24 hours. The solution was diluted with ethyl acetate and washed with 1M NaOH and saturated NaCl and dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane) gave the phenoxy compound as a solid (2.67 g, quantitative yield).

• ·

258

Part Β: To a solution of the phenoxy compound of Part A (2.40 g, 5.25 mmol) in ethanol (30 mL) and H 2 O (6 mL) was added potassium hydroxide (2.0 g, 31.37 mmol) and a solution of was refluxed for 4 hours.

The solution was acidified to pH 3 and the residue was collected by vacuum filtration to give the crude acid which was used without additional purification.

Part C: To a solution of the acid from Part B (2.25 g, 5.25 mmol) in acetonitrile (30 mL) was added O-tetrahydro-2H-pyran-2-yl hydroxylamine (1.34 g, 9.0 mmol) ). When the solution was stirred for 15 minutes, EDC (1.72 g, 9.0 mmol) was added and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with saturated NaHCO 3, H 2 O and saturated NaCl, and dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the protected hydroxamate as a white solid (0.93 g, 33%).

Part D: To a solution of the protected hydroxamate of Part C (0.93 g, 1.7 mmol) in methanol (15 mL) was added acetyl chloride (0.36 mL, 5.1 mmol) and the solution was stirred for 3 hours. The solution was concentrated in vacuo to give the title compound as a solid (650 mg, 82%). For C22H24N2O6S HCl: C, 54.84; H, 5.24; N, 5.82; S, 6.67; Cl, 6.67. Found: C, 53.10, H, 6.37, N, 5.59, S, 7.04, Cl, 6.32.

Example 16

Preparation of 4 - ((4- (4-butoxy-1-piperidinyl) phenyl) sulfonyl) -tetrahydro-N-hydroxy-2H-pyran-4-carboxamide monohydrochloride

HOHN

CH ₃

Part A: To a solution of the tetrahydropyran compound from Part C of Example 11 (1.95 g, 6.46 mmol) in DMSO (25 mL) were added CSCO 3 (7.4 g, 22.6 mmol) and 4-butoxypiperidine (1 25 g,

6.46 mmol) and the solution was heated at 90 ° C for 1 hour. The solution was diluted with H 2 O and extracted with ethyl acetate. The organic layer was washed with 5% aqueous KHSO 4, saturated with NaHCO 3.

259 saturated NaCl and dried over MgSO 4 Chromatography (on silica, ethyl acetate / dichloromethane) gave the amine as a yellow oil (1.85 g, 65%).

Part Β: To a solution of the amine from Part A (1.65 g, 3.76 mmol) in THF (10 mL) was added potassium trimethylsilanolate (530 mg, 4.13 mmol) and the solution was stirred at ambient temperature for 22 hours. The solution was concentrated in vacuo and the crude residue was used as it was in the next reaction.

Part C: To a solution of the crude acid from Part B (1.74 g, 3.76 mmol) in dichloromethane (10 mL) was added PyBroP (2.10 g, 4.51 mmol), N-methylmorpholine (1.24 mL). , 11.3 mmol) and Otetrahydro-2H-pyranyl-hydroxylamine (484 mg, 4.14 mmol) and the solution was stirred at ambient temperature for 30 minutes. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with H 2 O and saturated NaCl and then dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane / methanol) gave the title compound as a white solid (1.0 g, 88%). MS (CI) MH ⁺ calcd for C 21 H 32 N 2 O 5 S: 441, found 441.

Example 17

Preparation of 1-cyclopropyl-N-hydroxy-4 - ((4-phenoxyphenyl) sulfonyl) -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the amine hydrochloride salt of Example 6, part E (2.13 g, 5.0 mmol) in methanol (25 mL) was added 3A molecular sieve, acetic acid (2.86 mL, 50 mmol) and stirred for 5 minutes. To this solution was added ((1-ethyloxycyclopropyl) oxy) trimethylsilane (6.08, 30 mmol) then sodium cyanoborohydride (1.41 g, 22.0 mmol) and the solution was heated to reflux for 18 hours. Excess salts and sieves were removed by filtration and the filtrate was concentrated. The residue was diluted with ethyl acetate, washed with saturated 1M NaOH, H 2 O, and saturated NaCl and dried over MgSO 2. Chromatography (on silica, ethyl acetate / hexane) gave cyclopropyl amine as a solid (1.90 g, 86%).

• ·

260 · 4 4

4 4 4

4 4

4 4

4 4

4444 44

4 4

4 4

44

4 4 4

4 4 4

4 4 4 4

4 4 4

4 44

Part Β: To a solution of cyclopropyl amine from Part A (1.9 g, 4.2 mmol) in ethanol (12 mL) in THF (12 mL) was added NaOH (1.71 g, 4.3 mmol) in H 2 O ( 10 ml) and the solution was heated at 62 ° C for 20 hours. The solution was concentrated in vacuo. The residue was dissolved in H 2 O and acidified to pH 5 with 1M HCl. The resulting solid was collected by vacuum filtration to give the acid as a white solid (1.49 g, 82%). MS (CI) MH ⁺ calculated for C 21 H 23 NO 5 S: 402, found 402. HRMS calculated for C 21 H 23 NO 5 S: 402.1375, found 402.1350.

Part C: To a solution of the acid from Part B (1.49 g, 3.4 mmol) in dichloromethane (50 mL) was added triethylamine (1.42 mL, 10.21 mmol) then 50% aqueous hydroxylamine (2.25 mL). mL, 34.0 mmol) and PyBroP (3.17 g, 6.8 mmol). The solution was stirred for 72 hours. The mixture was diluted with H 2 O and the organic layer was separated, washed with saturated NaCl and dried over MgSO 4. Concentration in vacuo followed by reverse phase chromatography (on silica, acetonitrile / H 2 O) gave the hydroxamate.

The hydrochloride salt was prepared by dissolving the free base (830 mg, 2.0 mmol) in methanol (20 mL) followed by the addition of acetyl chloride (0.17 mL, 2.0 mmol). The solution was stirred at 0 ° C for 10 minutes. The resulting white solid was collected by vacuum filtration and washed with cold ethyl ether. This afforded the title compound (595 mg, 66%). HRMS calcd for C 21 H 24 N 2 O 5 S: 416.1407 found 416.1398. For C21H24N2O5S: C, 55.68, H, 5.56, N, 6.18, S, 7.08, Cl, 7.83. Found: C, 55.39, H, 5.72, N, 6.15, S, 7.29, Cl, 9.17.

Example 18

Preparation of N-hydroxy-1- (methylsulfonyl) -4- (phenoxyphenyl) sulfonyl) -4-piperidinecarboxamide

Part A: To a solution of the amine hydrochloride salt of Example 6, Part E (1.06 g, 2.5 mmol) in dichloromethane (10 mL) was added triethylamine (0.76 mL, 5.5 mmol) and methanesulfonyl chloride.

• ·

261 (0.23 mL, 3.0 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H 2 O. The organic layer was washed with H 2 O and saturated NaCl and dried over MgSO 2. Chromatography (on silica, hexane / ethyl acetate) gave methanesulfonamide as a solid (2.1 g, 58%).

Part Β: To a solution of methanesulfonamide of Part A (2.0 g, 4.15 mmol) in ethanol (8.4 mL) and H 2 O (1.4 mL) was added potassium hydroxide (470 mg, 8.4 mmol) and the solution was heated for 65 hours. The solution was concentrated in vacuo and the remaining aqueous solution was acidified to pH 4. The solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over MgSO 4. Concentration in vacuo gave the acid as a yellow foam (1.46 g, 80%).

Part C: To a solution of the acid from Part B (1.46 g, 3.38 mmol) in dichloromethane (50 mL) was added trimethylamine (1.41 mL, 10.1 mmol), 50% aqueous hydroxylamine (2.2 mL). , 33.8 mmol) and PyBroP (3.16 g, 6.76 mmol). The solution was stirred at ambient temperature for 72 hours. The solution was diluted with H 2 O and the organic layer was separated, washed with saturated NaCl, and dried over MgSO 4.

Reverse phase chromatography (on silica, acetonitrile / H2O) followed by trituration with ethyl ether gave the title compound as a white solid (160 mg, 11%). For C19H22N2O7S2: C, 50.21, H, 4.88, N, 6.16, S, 14.11. Found: C, 48.72, H, 5.36, N, 5.61, S, 12.81.

Example 19

Preparation of 4 - ((4- (cyclohexylthio) phenyl) sulfonyl) -N-hydroxy-4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the sulfone of Example 9, Part D (10.1 g, 24.0 mmol) in DMF (20 mL) was added potassium carbonate (5.0 g, 36.0 mmol) followed by cyclohexyl mercaptan (4, 20 mL). 4 mL, 36.0 mmol) and the solution was heated at 65 ° C for 6.5 hours. The solution was partitioned between ethyl acetate and H 2 O. Organic • ·

262 φ φ · · φ φ φ φ φ φ φ φ φ φ · · · · vrstva »» »vrstva vrstva vrstva vrstva vrstva vrstva vrstva vrstva vrstva vrstva vrstva vrstva vrstva vrstva se se vrstva se se se se vrstva se se ethyl acetate / hexane) gave the sulfide as an oil (8.2 g, 76%).

Part Β: To a solution of the sulfide in ethanol (10 mL) and THF (10 mL) was added NaOH (1.81 g, 45 mmol) in H ₂ O (10 mL) and the solution was heated at 65 ° C for 18 hours. The solution was concentrated in vacuo and the aqueous residue acidified to pH 2. The solution was extracted with dichloromethane and dried over MgSO 2. Concentrate in vacuo acid as a white solid (830 mg, 38%).

Part C: To a solution of the acid from Part B (2.0 g, 4.0 mmol) in dichloromethane (25 mL) was added N-methylmorpholine (1.32 mL, 12.0 mmol), PyBroP (2.12 g, 2.12 mmol). ) and 50% aqueous hydroxylamine (2.6 mL, 40 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O and the layers were separated. The organic layer was washed with H ₂ O and saturated NaCl and dried over MgSO 4. Chromatography (on silica, ethyl acetate / methanol) gave the hydroxamate as a solid (1.4 g, 70%).

Part D: HCl gas was bubbled into a solution of the hydroxamate of Part C (1.31 g, 2.63 mmol) in ethyl acetate (70 mL) cooled to 0 ° C for 30 minutes. The solution was concentrated in vacuo. Reverse phase chromatography (on silica, acetonitrile / H ₂ O (HCl)) provided the title compound as a white solid (378 mg, 33%). Calcd for C ₈ H _{2 2} g N ₂ O4S: C, 49.70, H, 6.26, N, 6.44; S, 14.74, Cf 8.15. Found: C, 48.99, H, 6.34, N, 6.24, S, 14.66, Cl, 8.56.

Example 20

Preparation of tetrahydro-N-hydroxy-4 - ((4-phenyl-1-piperazinyl) phenyl) sulfonyl) 2H-pyran-4-carboxamide dihydrochloride

HCl

Part A: To a solution of the tetrahydropyran compound of Example 11, Part C (1.96 g, 6.5 mmol) in DMSO (20 mL) was added CSCO3 (4.9 g, 15 mmol) and 4-phenylpiperazine (1.1 ml, 7.15 • · «« • ·

4 ··· ·· ·· ··

263 «« 99 99 99

9 9 9 9 9 9 9

9,999 9 9 9 9 9

9 9 9 9 9

99 99 99 mmol) and the solution was heated at 90 ° C for 45 minutes. The solution was diluted with FfyO and extracted with ethyl acetate. The organic layer was washed with 5% aqueous KHSO 4, saturated NaHCO 3, saturated NaCl, and dried over MgSO 4. Concentration in vacuo provided the amine as a beige solid (1.7 g, 59%).

Part Β: To a solution of the amine from Part A (1.5 mg, 3.38 mmol) in THF (20 mL) was added potassium trimethylsilanolate (480 mg, 3.72 mmol) and the solution was stirred at ambient temperature for 22 hours. Concentration in vacuo gave the crude acid salt, which was used without purification in the next step.

Part C: To a solution of the acid salt of Part B (1.58 g, 3.38 mmol) in dichloromethane (10 mL) and DMF (3 mL) was added PyBroP (1.89 g, 4.06 mmol), N- methyl morpholine (1.1 mL, 10.1 mmol) and O-tetrahydro-2H-pyranyl-hydroxylamine (435 mg, 3.72 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and H 2 O and the organic layer was separated, washed with H 2 O and saturated NaCl, and dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane / methanol) gave the protected hydroxamate as a white foam (1.7 g, 95% over two steps).

Part D: To a solution of the protected hydroxamate of Part C (1.28 g, 2.4 mmol) in dioxane (5 mL) and methanol (5 mL) was added 4M HCl in dioxane (5 mL), and the solution was stirred for 2 hours at ambient temperature. The solution was poured into ethyl ether and the resulting precipitate was collected by vacuum filtration. This gave the title compound as a white solid (900 mg, 73%). MS (CI) MH ⁺ calcd for C 22 H 27 N 3 O 5 S: 446, found 446.

Example 21

Preparation of 4 - ((4- (cyclohexylthio) phenyl) sulfonyl) -1-cyclopropyl-N-hydroxy-4-piperidinecarboxamide monohydrochloride

N HCI o ·

265 • to <* to «

Part A: To a solution of the sulfone from Example 9, Part D (10.1 g, 24.0 mmol) in THF (20 mL) was added potassium carbonate (5.0 g, 36.0 mmol) followed by cyclohexyl mercaptan (4.4). ml, 36.0 mmol) and the solution was heated at 85 ° C for 6.5 hours. The solution was partitioned between ethyl acetate and H 2 O. The organic layer was washed with saturated NaCl and dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane) gave the sulfide as an oil (8.2 g, 76%).

Part B: HCl gas was bubbled into a solution of the sulfide of Part B (8.2 g, 17.0 mmol) in ethyl acetate (100 mL) cooled to 0 ° C for 30 minutes. The solution was concentrated in vacuo to give the amine as a white solid (5.99 g, 79%). MS (CI) MH ⁺ calcd for C 20 H 29 NO 4 S: 412, found 412. Part C: To a solution of the amine from Part B (2.24 g, 5.0 mmol) in methanol (20 mL) was added acetic acid (2.86 mL). , (50 mmol) and then ((1-ethyloxycyclopropyl) oxytrimethylsilane (6.03, 30 mmol) and sodium cyanoborohydride (1.41 g, 22.0 mmol) and the solution was heated to reflux for 18 hours. The solution was concentrated in vacuo. ethyl acetate and washed with 1M NaOH, H 2 O and saturated NaCl and dried over MgSO 4 Chromatography (on silica, ethyl acetate / hexane) gave the cyclopropyl amine as a white solid (1.97 g, 87%).

Part D: To a solution of the cyclopropyl amine of Part C (1.9 g, 4.2 mmol) in ethanol (10 mL) in THF (10 mL) was added NaOH (1.68 g, 42.0 mmol) in H 2 O ( 10 ml) and the solution was heated at 68 ° C for 18 hours. The solution was concentrated in vacuo. The resulting solid was collected and washed with ethyl ether to give the acid as a white solid (1.07 g, 80%).

Part E: To a solution of the acid from Part D (1.61 g, 3.0 mmol) in dichloromethane (30 mL) was added N-methylmorpholine (1.0 g, 9.0 mmol), PyBroP (1.54 g, 3.3 mmol) and 50% aqueous hydroxylamine (2.0 mL, 30 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and H 2 O, the organic layer was washed with H 2 O and saturated NaCl and then dried over MgSO 4. Filtration through a pad of silica (ethyl acetate / methanol) gave the hydroxamate as a white solid (1.07 g, 80%).

Part F: To a solution of the hydroxamate of Part E (1.07 g, 2.4 mmol) in cold methanol (2 mL) was added acetyl chloride (0.27 mL, 3.6 mmol). The solution was stirred for 30 minutes. The solution was concentrated in vacuo. Reverse phase chromatography (acetonitrile / H2O) gave the title compound as a white solid (245 mg, 21%).

• · «« «« «« «

265

Example 22

Preparation of 4 - ((4 - ((4-fluorophenyl) thio) phenyl) sulfonyl) -N-hydroxy-4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the sulfone of Example 9, Part D (6.0 g, 14.4 mmol) in DMF (30 mL) was added potassium carbonate (2.39 g, 17.3 mmol) and 4-fluorothiophenol (3, 4, 10 mmol). 3 mL, 28.1 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was diluted with ethyl acetate and washed with 1M NaCl and saturated NaCl, and dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane) gave the sulfide as a solid (6.6 g, 87%).

Part B: To a solution of the sulfide of Part B (6.6 g, 12.6 mmol) in ethanol (90 mL) and FF 10 (20 mL) was added NaOH (5.04 g, 126 mmol) and the solution was heated to 70 ° C. ° C. The mixture was acidified to pH 4 and the solution was extracted with ethyl acetate, the organic layer was washed with H 2 O and saturated NaCl and then dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / ethanol) gave a solid acid (4.8 g, 79%).

Part C: To a solution of the acid from Part B (4.8 g, 10.0 mmol) in DMF (30 mL) was added 4-methylmorpholine (3.03 g, 30.0 mmol) then O-tetrahydro-2H-pyranyl- hydroxylamine (7.45 g, 50.0 mmol) and PyBroP (5.59 g, 12.0 mmol) and 50% aqueous hydroxylamine (2.0 mL, 30 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with H 2 O and saturated NaCl and then dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as a white solid (4.0 g, 67%).

Part D: HCl gas was bubbled into a solution of the protected hydroxamate of Part D (4.0 g, 6.7 mmol) in ethyl acetate (120 mL) for 5 minutes. It was then stirred at ambient temperature for 1.5 hours. The resulting solid was collected by vacuum filtration to give the title compound as a white solid (1.90 g, 64%). MS (CI) MH ⁺ calcd for C 18 H 19 N 2 O 4 S 2 F: 411, found

411.

• · • ·

··· ft

266 · »ft ··

Example 23

Preparation of N-hydroxy-4 - ((4- (4- (1H-imidazol-1-yl) phenoxy) phenyl) sulfonyl) -1- (2-propynyl-4-piperidinecarboxamide dihydrochloride)

CH

Part A: To a solution of the amine hydrochloride salt of Example 9, Part F (3.00 g, 8.49 mmol) in DMF (13 mL) was added K 2 CO 3 (2.35 g, 17.0 mmol) and 4- (1H). -imidazol-1-yl) phenol (2.72 g,

17.0 mmol) and the solution was heated at 64 ° C for 64 hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H 2 O. The organic layer was washed with H 2 O and saturated NaCl and dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the ethyl ester as a white foam (2.36 g, 56%).

Part Β: To a solution of the ethyl ester of Part A (2.36 g, 5.33 mmol) in ethanol (2.8 mL) and H 2 O (4.6 mL) was added KOH (1.80 g, 32.1 mmol). ) and the solution was heated at 100 ° C for 4.5 hours. The solution was acidified to pH 1 with concentrated HCl solution and then concentrated to give the acid as a brown solid which was used without additional purification (2.87 g).

Part C: To a solution of the acid from Part B (2.87 g, 5.33 mmol) in acetonitrile (24 mL) was added O-tetrahydro-2H-pyran-2-yl-hydroxylamine (870 mg, 7.45 mmol) , EDC (1.43 g, 7.45 mmol) and N-methylmorpholine (1.21 mL, 11.0 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue was diluted with H 2 O and extracted with ethyl acetate. The organic layer was washed with H 2 O and saturated NaCl and dried over MgSO 4. Chromatography (chloroform, methanol) gave the protected hydroxylamine as a white solid (1.62.0 g, 53%).

Part D: To a solution of the protected hydroxylamine from Part C (1.60 g, 2.83 mmol) in methanol (23 mL) was added acetyl chloride (0.61 mL, 8.52 mmol) and the solution was stirred for 1 hour.

The solution was concentrated in vacuo. Reverse Phase Chromatography (on essential oil, acetonitrile / H2O)

267 • β · φ · ala φ ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala ala compound (975 mg, 62%). MS (CI) MH + calcd for C 24 ^H 25 ^{N 4} O 5: 481, found 481. Analysis calculated for C 24 ^H 25 ^{N 4} O 5 S 2 HCl: C, 52.08,

H, 4.73; N, 10.12; S, 5.79; Cl, 12.81. Found: C, 51.59, H, 4.84, N, 10.93, S, 5.51, Cl, 11.98.

Example 24

Preparation of 4 - ((4- (4-fluorophenyl) thiophenyl) sulfonyl)) - N -hydroxy-1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

/

CH

Part A: To a solution of propargyl amine from Part F of Example 9 (4.06 g, 11.49 mmol) in DMF (20 mL) was added potassium carbonate (3.18 g, 22.98 mmol) and 4-fluorothiophenol (2 mL). (95 g, 22.98 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was diluted with ethyl acetate and washed with H 2 O and saturated NaCl and then dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane) gave the sulfide as a solid (4.46 g, 84%).

Part Β: To a solution of sulfide of Part A (4.12 g, 9.7 mmol) in tetrahydropyran (90 mL) and ethanol (30 mL) was added sodium hydroxide (3.86 g, 97.0 mmol) and the solution was was heated at 65 ° C for 2 hours. The solution was concentrated in vacuo. The residue was dissolved in H 2 O and acidified to pH 4 with 2M HCl. The resulting residue was collected by vacuum filtration. This gave the acid as a white solid (4.0 g, 95%).

Part C: To a solution of the acid from Part B (4.0 g, 9.2 mmol) in DMF (50 mL) and 4-methylmorpholine (2.8 g, 27.7 mmol) was added O-tetrahydro-2H-pyranyl-hydroxylamine (6.88 g, 46.1 mmol) and PyBroP (5.16 g, 11.1 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo, the residue was dissolved in ethyl acetate. The solution was washed ······

268

H 2 O and saturated NaCl and dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as a white solid (2.8 g, 56%).

Part G: HCl gas was bubbled into a solution of the protected amine from Part C (2.8 g, 5.1 mmol) in ethyl acetate (100 mL) for 10 minutes. The solution was stirred for 1 hour. The solution was concentrated in vacuo and the solid was recrystallized (ethanol). This afforded the title compound as a white solid (1.12 g, 45%). MS (CI) MH ⁺ calcd for C 21 H 21 N 2 O 4 S 2 F: 449, found 449.

Example 25

Preparation of 4 - ((4- (4-chlorophenyl) thio) phenyl) sulfonyl) -tetrahydro-N-hydroxy-2H-pyranyl-4-carboxamide

Part A: To a solution of the tetrahydropyran compound from Part C of Example 11 (8.0 g, 26.5 mmol) in THF (250 mL) was added potassium trimethylsilanolate (10.2 g, 79.5 mmol) and the solution was stirred for 1 hour. 5 hours. The reaction was quenched with H 2 O, acidified to pH 2.5 and the solution was extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4 - Concentration in vacuo gave the acid salt as a white solid (5.78 g, 76%)

Part Β: To a solution of the acid salt of Part A (5.4 g, 18.7 mmol) in DMF (10 mL) was added HOBT (3.04 g, 22.5 mmol), N-methylmorpholine (6.2 mL). , 56.2 mmol), O-tetrahydro-2H-pyranyl-hydroxylamine (6.8 g, 58.1 mmol) and EDC (5.0 g, 26.2 mmol) and the solution was stirred at ambient temperature for 3 hours. The solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and H 2 O. The organic layer was washed with 5% aqueous KHSO4, H2O, saturated ΝβΗΟΟβ, saturated NaCl, and then dried over Na2SO4. Concentration in vacuo gave the protected hydroxamate as a white solid (6.34 g, 87%).

Part C: To a solution of p-chlorothiophenol (2.71 g, 18.7 mmol) in DMF (10 mL) was added potassium carbonate (2.6 g, 18.7 mmol) followed by the protected hydroxamate from Part B (2, 9 g, 7.5, and the solution was heated to 75 ° C for 5 hours The solution was concentrated in vacuo.

269 9 4 4 4 4 4 4 Ethyl acetate and H2O. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane / methanol) gave the sulfide as a white foam (3.56 g, 93%). MS (CI) MH ⁺ calcd for C 23 H 26 ClNO 5 S 2: 512, found 512.

Part D: To a solution of the sulfide of Part C (3.5 g, 6.8 mmol) in dioxane (10 mL) was added 4N HCl in dioxane (10 mL). After stirring for 10 minutes, methanol (10 mL) was added and stirring was continued for 1 hour. The solution was concentrated in vacuo. Recrystallization (acetone / hexane) gave the title compound as a white solid (2.4 g, 83%). MS (CI) MH ⁺ calcd for C 18 H 18 ClNCl 2 S: 428, found 428.

Example 26

Preparation of tetrahydro-N-hydroxy-4 - ((4- (4- (1H-1,2,4-triazol-1-yl) phenoxy) phenyl) sulfonyl)) - 2H-pyran-4-carboxamide monohydrochloride

Part A: To a solution of the protected hydroxamate of Part B of Example 25 (2.9 g, 7.5 mmol) in DMF (10 mL) was added 4- (1,2,4-triazol-1-yl) phenol (2, 2, 3, 4, 5, 10). 47 g, 15 mmol) followed by CSCO 3 (7.33 g, 22.5 mmol) and the solution was heated at 95 ° C for 5 hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H 2 O. The organic layer was washed with H 2 O and saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica gel, ethyl acetate / hexane / methanol) gave phenol as a white solid (3.16 g, 80%).

Part Β: To a solution of the phenol from Part A (2.8 g, 5.3 mmol) in dioxane (10 mL) was added 4M HCl in dioxane (10 mL). After stirring for 5 minutes, methanol (10 mL) was added and stirring was continued for 1 hour. The solution was poured into ethyl ether and the resulting precipitate was collected by vacuum filtration. This afforded the title compound as a white solid (2.44 g, 96%). MS (CI)

MH ⁺ calculated for C 20 H 20 N 4 O 6 S: 445, found 445.

• 4

270

4

4444 44 • 4 • 4 ·

4 4

444

4 »« 3

Example 27

Preparation of 1-cyclopropyl-N-hydroxy-4 - ((4- (4-fluorophenyl) thio) phenyl) sulfonyl) -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the sulfide of Example 9, Part D (7.06 g, 13.5 mmol) in ethyl acetate (150 mL) was bubbled HCl gas for 7 minutes and stirred at 0 ° C for 15 minutes. The solution was concentrated in vacuo to give the amine as a white solid (6.43 g, quantitative yield).

Part Β: To a solution of the amine from Part A (6.4 g, 13.9 mmol) in methanol (65 mL) was added acetic acid (7.96 mL, 139 mmol) and a 3A molecular sieve measure. To this mixture was added ((1-ethyloxycyclopropyl) oxytrimethylsilane (16.8, 84 mmol) followed by sodium cyanoborohydride (3.9 g, 62 mmol), and the solution was heated at reflux for 6 hours. The residue was dissolved in ethyl acetate, washed with H 2 O 2 M NaOH and saturated NaCl, and dried over MgSO 2. Filtration through a pad of silica gel (hexane / ethyl acetate) gave cyclopropyl amine as a white solid (6.49 g, quantitative yield).

Part C: To a solution of cyclopropyl amine from Part B (6.4 g, 13.8 mmol) in ethanol (30 mL) in THF (30 mL) was added NaOH (5.5 g, 138 mmol) in VH 2 O (23 mL). and the solution was heated at 65 ° C for 12 hours. The solution was concentrated in vacuo and the aqueous layer was acidified to pH 5 with 2N HCl. The resulting white precipitate was collected by filtration to give the acid as a white solid (5.2 g, 87%). MS (CI) MH ⁺ calcd for C 21 H 23 NO 4 S 2 F: 436, found 436.

Part D: To a solution of the acid from Part C (2.27 g, 5.2 mmol) in DMF (60 mL) was added HOBT (845 mg, 6.2 mmol) followed by N-methylmorpholine (1.71 mL, 15 mL). , 6 mmol), EDC (1.40 g,

7.28 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (913 mg, 7.8 mmol) and the solution was stirred at ambient temperature for 72 hours. The solution was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with H 2 O and saturated NaCl and then dried over MgSO 4 4 • 4.

·

271 · · · 4 · · 4 ·

4 · · · · ···

Chromatography (on silica, ethyl acetate / hexane / methanol) gave the protected hydroxamate as a white solid (1.95 g, 70%).

Part E: To a solution of the protected hydroxamate of Part D (3.2 g, 6.0 mmol) in cold methanol (100 mL) was added acetyl chloride (1.3 mL, 18.0 mmol) in methanol (30 mL). The solution was stirred at ambient temperature for 4 hours. The solution was concentrated in vacuo and the residue was triturated with ethyl ether to give the title compound as a white solid (2.86 g, 98%). MS (CI) MH ⁺ calculated for C 21 H 23 N 2 O 4 S 2 F: 451, found 451. Analysis calculated for

For C21H23N2O4S2F: C, 51.32; H, 5.02; N, 5.70; S, 13.05; Cl, 7.21. Found: C, 50.99, H, 4.91, N, 5.65, S, 13.16, Cl, 7.83.

Example 28

Preparation of N-hydroxy-4 - ((4-phenylthio) phenyl) sulfonyl) -1- (2-propenyl-4-piperidinecarboxamide monohydrochloride)

Part A: To a solution of the amine hydrochloride salt of Example 9, Part F (4.78 g, 10.8 mmol) in DMF (25 mL) was added K 2 CO 3 (2.98 g, 21.6 mmol) and allyl bromide (0.935). mL, 10.8 mmol) and the solution was stirred at ambient temperature for 5 hours.

The solution was partitioned between ethyl acetate and H ₂ O. The organic layer was washed with H ₂ O and saturated NaCl and dried over MgSO 4. Filtration through a pad of silica (hexane / ethyl acetate) gave allyl amine as an oil (4.80 g, quantitative yield).

Part Β: To a solution of allyl amine from Part A (4.8 g, 10.8 mmol) in ethanol (25 mL) and THF (25 mL) was added NaOH (4.3 g, 108 mmol) and the solution was heated to 65 ° C 18 hours. The solution was concentrated in vacuo and diluted with H ₂ O. The aqueous solution was acidified to pH 3.

272 ft ftftftft ft ftftftft ftftft ft ftft · ftft ftft The precipitate was collected by vacuum filtration. This gave the acid as a beige solid (4.1 g, 84%). MS (CI) MH ⁺ calcd for C 20 H 23 O 4 46 4 ^: 41845, found 418.

Part C: To a solution of the acid of Part B (4.1 g, 9.0 mmol) in DMF (90 mL) was added HOBT (1.46 g, 11.0 mmol) followed by N-methylmorpholine (2.97 mL, 2.7 mmol), O-tetrahydro-2H-pyranyl-hydroxylamine (1.58 g, 13.5 mmol) and EDC (2.42 g, 13.0 mmol) and the solution was stirred for 72 h. The solution was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with H 2 O and saturated NaCl and then dried over MgSO 4. Chromatography (on silica, ethyl acetate / methanol) gave the protected hydroxamate as a white solid (4.11 g, 88%).

Part D: To a solution of the protected hydroxamate of Part C (4.11 g, 8.0 mmol) in ethyl acetate (100 mL) cooled to 0 ° C was added acetyl chloride (1.71 mL, 24.0 mmol). The solution was stirred at ambient temperature for 4 hours. The solution was concentrated in vacuo and trituration with ethyl ether gave the title compound as a white solid (3.53 g, 95%). Analysis calculated for

C21H24N2O4S2HCl 0.5H2O: C, 52.76; H, 5.48; N, 5.86; S, 13.42; C, 7.42. Found: C, 52.57, H, 5.69, N, 6.29, S, 12.59, Cf 7.80.

Example 29

Preparation of 1- (cyclopropylmethyl) -N-hydroxy-4 - ((4-phenoxyphenyl) sulfonyl)) 4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the amine hydrochloride salt of Example 6, Part E (2.13 g, 5.0 mmol) in DMF (10 mL) was added K 2 CO 3 (1.4 g, 10.0 mmol) and bromomethylcyclopropane (0.30 g, 10 mmol). 48 mL, 5.0 mmol) and the solution was stirred at ambient temperature for 18 hours. The solution was partitioned between ethyl acetate and ethyl acetate

H2O. The organic layer was washed with H 2 O and saturated NaCl and dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane) gave a solid cyclopropylmethylamine (2.09 g,

91%).

• to • to

273> toto toto toto toto toto toto toto ** ** ** ** ** ** ** ** ** ** 99 ** *

Part Β: To a solution of cyclopropylmethylamine from Part A (2.0 g, 4.4 mmol) in ethanol (12 mL) and THF (12 mL) was added NaOH (1.75 g, 44 mmol) and the solution was heated to 65 ° C. ° C. The solution was concentrated in vacuo and the aqueous residue was acidified to pH 5. The resulting precipitate was collected by vacuum filtration. This gave the acid as a white solid (1.58 g, 79%). HRMS calcd for C 22 H 25 NO 5 S: 414.1375, found 414.1334.

Part C: To a solution of the acid of Part B (1.58 g, 3.5 mmol) in dichloromethane (50 mL) was added triethylamine (1.46 mL, 10.5 mmol) followed by 50% aqueous hydroxylamine (2.3 mL). , 35 mmol) and PyBroP (3.26 g, 6.99 mmol) and the solution was stirred at ambient temperature for 72 hours. The solution was washed with H 2 O and saturated NaCl and then dried over MgSO 4. Reverse phase chromatography (acetonitrile / H 2 O) gave the hydroxamate as a white solid (3.2 g, quantitative yield).

Part D: To a solution of the hydroxamate of Part C (1.5 g, 3.5 mmol) in cold methanol (20 mL) was added acetyl chloride (0.25 mL, 3.5 mmol) in methanol (5 mL) and a solution of was stirred at 0 ° C for 15 minutes. When the solution was stirred at ambient temperature for an additional 30 minutes, it was concentrated in vacuo. Trituration with ethyl ether gave the title compound as a white solid (229 mg, 7%).

Example 30

Preparation of N-hydroxy-1- (2-methoxyethyl) -4 - ((4-phenoxyphenyl) sulfonyl) -4 monohydrochloride. piperidinecarboxamide

Part A: To a solution of the amine hydrochloride salt of Part E of Example 6 (2.5 g, 5.87 mmol) and potassium carbonate (1.6 g, 11.57 mmol) in N, N-dimethylformamide (25 mL) was added 2-bromoethyl methyl ether and then stirred at ambient temperature for 18 hours. The Ν, Ν-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4. Concentration in vacuo gave methoxyethyl amine as a bright yellow gel (2.63 g, quantitative yield).

• ·

9 • 9

9 • 9 ·

9

274

9 «999 99

9 9 ♦

9 «« • 099

Part Β: To a solution of methoxyethyl amine from Part A (2.63 g, 5.87 mmol) in tetrahydrofuran (18 mL) and ethanol (18 mL) was added sodium hydroxide (2.1 g, 5.25 mmol) in water (6 mL). The solution was heated to reflux for 12 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether (2 x 100 mL) and acidified to pH = 2. Vacuum filtration of the resulting precipitate gave the acid as a white solid (2.4 g, quantitative yield).

Part C: To a solution of the acid of Part B (2.0 g, 4.33 mmol), also containing Nmethylmorpholine (1.8 mL, 16.4 mmol) in Ν, Ν-dimethylformamide (20 mL) was added 1- (3dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.1 g, 16.2 mmol) and the solution was stirred at ambient temperature for 20 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with H 2 O and dried over MgSO 4. Concentration in vacuo gave the amide as an off-white foam (1.60 g, 71.1%).

Part D: To a solution of the amide of Part C (1.58 g, 3.05 mmol) in methanol (20 mL) cooled to 0 ° C was added acetyl chloride (0.65 mL, 9.15 mmol) and the resulting solution was stirred 3 hours at the same temperature. The solution was concentrated in vacuo and reverse phase chromatography (on C-18 silica, acetonitrile / H 2 O with 0.01% HCl) gave hydroxamate hydrochloride as a white solid (0.65 g, 45.5%). For C21H26N2O6S.HCl.0.75H2O: C, 52.06; H, 5.93; N, 5.78; S, 6.62. Found: C, 51.94, H, 5.67, N, 5.91, S, 6.66.

Example 31

Preparation of N-hydroxy-4 - ((4-phenoxyphenyl) sulfonyl) -1- (1-pyrrolidinylacetyl-4-piperidinecarboxamide monohydrochloride)

275 • 4 ·· 4 «* · ·· 44 • 4 4 4 4 · · 4 44 4 • 4 4 4 44 4 4 44 4 · 4 4 4 444 4 4 4 4 4

44 44 4444

4444 44 444 · 44 44

Part A: To a solution of the sulfone from Part D of Example 6 (2.75 g, 5.6 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added sodium hydroxide (2.25 g, 56 mmol) in water ( 20 ml). The solution was heated at 70 ° C for 20 hours. The solution was concentrated in vacuo and the dry residue was dissolved in H 2 O. The aqueous layer was extracted with ethyl acetate. The combined organic layers were again washed with fbO and dried over MgSO 4. Concentration in vacuo gave the BOC-acid as a white foam (2.3 g, 88.8%).

Part Β: To a solution of BOC-acid from Part A (2.3 g, 4.98 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL, 77.8 mmol) and the resulting solution was stirred at room temperature for 1 hour. Surroundings. Concentration in vacuo gave the amine as a white foam (2.44 g, quantitative yield).

Part C: To a solution of the amine from Part B (2.4 g, 4.3 mmol) and triethylamine (3.5 mL, 24.4 mmol) in acetone (15 mL) and H 2 O (15 mL) was added chloroacetyl chloride ( 1.2 mL, 14.7 mmol) and the solution was stirred at ambient temperature for 20 hours. The acetone was evaporated and the aqueous layer was acidified to pH = 2. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with H 2 O and dried over MgSO 2.

Part D: To a solution of the chloroacetyl amide of Part C (2.78 g, 4.93 mmol) and potassium carbonate (5 g, 36 mmol) in N, N-dimethylformamide (20 mL) was added pyrrolidine (3 mL, 36 mmol). The solution was then stirred at ambient temperature for 18 hours. Ν, Ν-dimethylformamide was evaporated under high vacuum and reverse phase chromatography (acetonitrile / ethyl acetate with 0.01% HCl) gave pyrrolidineacetyl amide (0.25 g, 10.7%).

Part E: To a pyrrolidinacetyl amide solution of Part D (0.25 g, 0.53 mmol) also containing N-methylmorpholine (0.14 mL, 1.27 mmol), 1-hydroxybenzotriazole (0.17 g, 1.2 mmol) and O-tetrahydro-2H-pyranyl-hydroxylamine (0.15 g, 1.26 mmol) in N, N-methylformamide (4 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.23 g, 1.2 mmol) and the solution was then stirred at ambient temperature for 18 hours. The solution was concentrated under high vacuum and the residue dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO 3, H 2 O and dried over MgSO 4. Concentration in vacuo gave the THP amide as a white foam (0.25 g, 83.3%).

Part F: To a solution of the amide of Part E (0.25 g, 0.437 mmol) in methanol (4 mL) cooled to 0 ° C was added acetyl chloride (0.075 mL, 1.05 mmol) and the resulting solution was stirred for 2.5 hours at ambient temperature. The solution was concentrated in vacuo and chromatography

4 ·

276 ·· 4 · * 4 5

4 • 4 4

4444 44

4 ·

4 4

4 4

444

4 4

44

44

4 4 4

4 4 4

4 4 4

4 4 4

44 in reverse phase (on C-18 essential oil, acetonitrile / H 2 O with 0.01% HCl) gave hydroxamate hydrochloride as a white solid (80 mg, 29%). For C24H29N3O5S.HCl.0.9H2O: C, 53.36; H, 5.98; N, 7.78. Found: C, 53.61, H, 5.71, N, 7.71. HSMS calcd for C 24 H 29 N 3 O 6 S: 488.1855, found 488.1835.

Example 32

Preparation of 1-cyclopropyl-N-hydroxy-4 - ((4-phenylthio) phenyl) sulfonyl) -4-piperidinecarboxamide monohydrochloride

dd

Part A: A solution of 4-fluorothiophenol (50.29 g, 0.39 mmol) in dimethylsulfoxide (500 mL) was heated at 65 ° C for 5 hours. The solution was cooled to ambient temperature and poured into vigorously stirred ice water. The precipitate was filtered and washed twice with water. Drying under high vacuum gave the disulfide as a yellow oil (34.39 g, 68.9%) at ambient temperature.

Part B: A solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in tetrahydrofuran (5 mL) was added dropwise over 20 minutes to a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in tetrahydrofuran ( 100 ml). The resulting solution was stirred overnight (about 18 hours) at ambient temperature and concentrated in vacuo to give a light oil. The oil was filtered through silica gel (7: 3, ethyl acetate / hexane) and concentrated in vacuo. This gave the BOC-piperidine compound as a clear colorless oil (26.2 g, quantitative yield).

Part C: To a solution of the BOC-piperidine Compound (15.96 g, 62 mmol) in tetrahydrofuran (300 mL) cooled to -40 ° C was added lithium diisopropylamide (41.33 mL, 74 mmol). The solution was stirred at -40 ° C for 1 hour and a half hour at 0 ° C. Then the solution was cooled again to -40 ° C and part A disulfide (15.77 g, 62 mmol) in tetrahydrofuran (20 mL) was added. The resulting solution was stirred at ambient temperature for 18 hours. The solution was diluted with H 2 O and extracted with ethyl acetate. The organic layer was washed with H 2 O and saturated NaCl and dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the sulfide as an oil (18 g, 75%).

• • • ft

277 ··· ftft ftft ftft ·· ··

Part D: To a solution of Part C sulfide (16.5 g, 43 mmol) in dichloromethane (500 mL) cooled to 0 ° C was added m-chloroperbenzoic acid (18.5 g, 107 mmol). After 2 hours, the solution was diluted with dichloromethane, washed with 1M KOH, H 2 O, and dried over MgSO 4. Concentration in vacuo gave thiophenyl BOC-sulfone as a white solid (44.34 g, 91%).

Part F: To a solution of thiophenyl BOC-sulfone of Part E (8.6 g, 17 mmol) in dichloromethane (30 mL) trifluoroacetic acid (TFA, 30 mL) and the resulting solution was stirred at ambient temperature for 2 hours. Concentration in vacuo gave the amine TFA salt as a yellow gel (8.7 g, quantitative yield).

Part G: Acetic acid (6.8 mL, 119 mmol) was added to a solution of the amine TFA salt of Part F (6 g, 11.9 mmol). After stirring at ambient temperature for 5 minutes, (1-ethoxycyclopropyl) oxytrimethylsilane (14.3, 71.4 mmol) was added followed 5 minutes later by sodium cyanoborohydride hydrate (3.35 g, 53.55 mmol). Then the solution was heated to reflux for 18 hours. Methanol was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 1M NaOH, H 2 O and dried over MgSO 4. Concentration in vacuo gave cyclopropylamine as an off-white powder (4.9 g, 92.6%).

Part Η: To a solution of cyclopropylamine from Part G (4.88 g, 10.95 mmol) in tetrahydrofuran (12.5 mL) and ethanol (12.5 mL) was added NaOH (4.3 g, 100 mmol) in VH 2 O ( 25 ml). The solution was then heated to 50 to 55 ⁹ C for 12 hours and stirred 12 hours at ambient temperature. The solution was acidified to pH = 2 and concentrated in vacuo to give the acid as a white solid along with NaCl in the mixture. To a solution of this mixture in acetonitrile (50 mL) were sequentially added Otetrahydropyronylamine (1.95 g, 16.3 mmol), N-methylmorpholine (2.4 mL, 21.9 mmol) and 1- (3dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.41 g, 16.3 mmol). The solution was then stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with H 2 O and dried over MgSO 4. Concentration in vacuo gave tetrahydropyronyl (THP) amide as a white solid (3.0 g, 53.1%).

Part I: To a solution of THP amide of Part H (3 g, 5.8 mmol) in methanol (45 mL) cooled to 0 ° C was added acetyl chloride (1.5 mL, 21.1 mmol) and the solution was stirred for 2 hours. 5 at ambient temperature. Vacuum filtration of the precipitate gave the hydroxamate hydrochloride as a white solid (1.844 g, 68.3%). Calcd for C21H24N2O4S2.HCl: C, 53.78, H, 5.37, N,

5.97, S, 13.67. Found: C, 53.40, H, 5.26, N, 5.95, S, 13.68.

Example 33 • ·

278

ΦΦ * · * φ φ φ φ · · · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Preparation of N-hydroxy-1-methyl-4 - ((4-phenylthio) phenyl) sulfonyl) -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the TFA amine salts of Example 32, Part F (2.67 g, 5.14 mmol) and 37% formaldehyde in an aqueous solution (2.0 mL, 25.7 mmol) in methanol (20 mL) was added. pyridine (2.6 mL, 25.7 mmol) was added at ambient temperature. The solution was then stirred at ambient temperature for 18 hours. The solution was acidified to destroy excess reagents. Methanol was evaporated and the residue was partitioned between NaHCO 3 and ethyl acetate. The aqueous NaHCO 3 layer was extracted with ethyl acetate. The combined organic layers were washed with H 2 O and dried over MgSO 4. Concentration in vacuo gave methyl amine as an off-white foam (1.6 g, 76).

Part Β: To a solution of methylamine of Part A (1.63 g, 3.88 mmol) in ethanol (20 mL) was added KOH (1.31 g, 23.2 mmol) in water (4 mL) and the resulting solution was heated at 50 ° C for 8 hours, 70 ° C for 4 hours and stirred at ambient temperature for 18 hours. The solution was acidified and concentrated in vacuo. This gave the acid as a white solid along with NaCl in the mixture. To a solution of this mixture in N, N-dimethylformamide (50 mL) was added sequentially O-tetrahydropyronylamine (0.92 g, 7.76 mmol), N-methylmorpholine (1.05 mL, 7.76 mmol) and 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.5 g, 7.76 mmol). The solution was stirred at ambient temperature for 72 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO 3, H 2 O and dried over MgSO 4. Concentration in vacuo and chromatography (silica, dichloromethane / methanol) gave THP amide as a white solid (0.46 g, 24.2%).

Part C: To a solution of THP amide of Part B (0.22 g, 0.45 mmol) in methanol (5 mL) cooled to 0 ° C was added acetyl chloride (0.096 mL, 13.5 mmol) and the resulting solution was stirred for 3 hours at ambient temperature. The solution was concentrated in vacuo and reverse phase chromatography (on C-18 silica, acetonitrile / O 2 with 0.01% HCl) gave hydroxamate hydrochloride as a white solid (0.12 g, 60.6%). HSMS calcd for C 19 H 22 N 2 O 4 S: 407.1099, found 407.1105.

• · • ·

279 ft · ftft · ft · ft · ft · ft · ftft · ftft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft ·

Example 34

Preparation of N-hydroxy-1- (1-methylethyl) -4 - ((4-phenylthio) phenyl) sulfonyl) -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of BOC-sulfone of Part E of Example 32 (11.19 g, 22.12 mmol) in ethyl acetate (150 mL) was bubbled HCl gas for 20 minutes. The solution was stirred at the same temperature for an additional 40 minutes. Concentration in vacuo and titration with ether gave the amine hydrochloride (9.88 g, quantitative yield).

Part Β: To a solution of the amine hydrochloride from Part A (4.7 g, 10.6 mmol), triethylamine (2.0 mL, 27.2 mmol) and acetone (2.0, 27.2 mmol) in dichloromethane (100 mL). mL) was added at ambient temperature triacethoxyborohydride (5.7 g, 26.9 mmol) followed by acetic acid (1.5 mL, 26.9 mmol). The solution was stirred for 18 hours and then partitioned between 1M NaOH and ether. The aqueous layer was extracted with ether and the combined organic layers were washed with 1M NaOH, H 2 O and dried over MgSO 4. Concentration in vacuo gave isopropyl amine as a white foam (4.58 g, 96.2).

Part C: To a solution of isopropyl amine from Part B (4.58 g, 10.2 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added NaOH (2.1 g, 5.25 mmol) in water ( 20 ml). The solution was heated at 60 ° C for 13.5 hours, then stirred at ambient temperature for 18 hours. The solution was acidified and concentrated in vacuo. This gave the acid as a white solid along with NaCl in the mixture. To a solution of this mixture in N, N-dimethylformamide (75 mL) was sequentially added 1-hydroxybenzotriazole (1.94 g, 14.4 mmol), O-tetrahydropyronylamine (1.8 g, 15.1 mmol), Nmethylmorpholine (3.37) mL, 30.7 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.74 g, 14.3 mmol). The solution was stirred at ambient temperature for 48 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated ΝβΗΟΟβ, H 2 O and dried over MgSO 2. Concentration in vacuo and chromatography (silica, dichloromethane / methanol) gave THP amide as a white solid (3.78 g, 71.3%).

280 4 4 4 44

Part D: To a solution of the THP amide of Part C (1.15 g, 2.2 mmol) in methanol (20 mL) was added acetyl chloride (0.096 mL, 13.5 mmol) and the resulting solution was stirred at room temperature for 2.5 h. Surroundings. The solution was concentrated in vacuo and reverse phase chromatography (on C-18 silica, acetonitrile / H 2 O with 0.01% HCl) gave hydroxamate hydrochloride as a white solid (0.69 g, 66.3%). For C21H26N2O4S2.HCl.H2O: C, 51.58, H, 5.98, N, 5.73, S, 13.11. Found: C, 51.76, H, 5.47, N, 5.72, S, 12.68.

Example 35

Preparation of N-hydroxy-1- (1-methoxyethyl) -4 - ((4-phenylthio) phenyl) sulfonyl) -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the amine hydrochloride from Part A of Example 34 (4.3 g, 9.43 mmol) in N, N-dimethylformamide (40 mL) was added 2-bromoethyl methyl ether (1.9, 20.2 mmol). The solution was stirred at ambient temperature for 48 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 gave methoxyethyl amine as a white foam (4.26 g, 95.3%).

Part Β: To a solution of methoxyethyl amine from Part A (4.26 g, 9.2 mmol) in tetrahydrofuran (5 mL) and ethanol (18 mL) was added sodium hydroxide (3.7 g, 92.5 mmol) in water (9 mL). The resulting solution was heated at 60 ° C for 12 hours and stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether (2 x 100 mL) and acidified to pH = 2. Vacuum filtration of the resulting precipitate gave the acid as a white solid (3.5 g, 87.5%).

Part C: Acid solution of Part B (3.4 g, 7.8 mmol), also containing N-methylmorpholine (2.6 mL, 23.4 mmol), 1-hydroxybenzotriazole (3.16 g, 23.4 mmol) O-tetrahydro-2H-pyranyl-hydroxylamine (1.85 g, 15.5 mmol) in N, N-dimethylformamide (20 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.47 g) , 23.4 mmol).

01 01 4 4 4 4

2ο 1 · · · · ··· · · ····· · · · ···

The solution was stirred at ambient temperature for 36 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO 3, H 2 O and dried over MgSO 4. Concentration in vacuo gave the amide as an off-white foam (2.98 g, 71.5%).

Part D: To a solution of Part C amide (2.98 g, 5.6 mmol) in methanol (40 mL) cooled to 0 ° C was added acetyl chloride (1.19 mL, 16.8 mmol) and the resulting solution was stirred 3 hours at ambient temperature. The solution was concentrated and reverse phase chromatography (on C-18 silica, acetonitrile / H 2 O with 0.01% HCl) gave hydroxamate hydrochloride as a white solid (2.29 g, 84.6%). Calcd for C21H26N2O6S. HCl. H, 5.77; N, 5.57; S, 12.74. Found: C, 50.41, H, 5.85, N, 5.73, S, 12.83.

Example 36

Preparation of monohydrochloride-acetyl-N-hydroxy-4 - ((4-phenylthio) phenyl) sulfonyl) -4-piperidinecarboxamide

Part A: To a solution of phenyl thiophenyl BOC-sulfone from Part E of Example 32 (7 g, 1.29 mmol) in tetrahydrofuran (25 mL) and ethanol (25 mL) was added sodium hydroxide (5.1 g, 12.9 mmol). ) in water (50 mL). The solution was heated to reflux for 20 hours. After cooling, the solution was concentrated in vacuo and the dry residue was dissolved in H 2 O. The aqueous layer was extracted with ether and acidified to pH = 2 followed by extraction with ethyl acetate. The combined organic layers were washed again with H 2 O and dried over MgSO 4. Concentration in vacuo gave the BOC-acid as a white foam (3.9

Part Β: To a solution of BOC-acid from Part A (2.3 g, 4.98 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL, 77.8 mmol) and the resulting solution was stirred at room temperature for 1 hour. Surroundings. Concentration in vacuo gave the amine as a white foam (2.44 g, quantitative yield).

Part C: To a solution of the amine from Part B (5.0 g, 12.08 mmol) and triethylamine (8.7 mL, 60.4 mmol) in acetone (20 mL) and H 2 O (20 mL) cooled to 0 ° C acetyl chloride (4.6 ml,

282 • 44 44 44 ·· 44

4 4 4 4 4 4 4 · 4 · 4 • 4 4 4 44

4,444 4 4 4 4 4 4 44 4

44 44 4444

4444 44 44 44 (4 (4 mmol)) and the solution was stirred at ambient temperature for 40 hours. The acetone was evaporated and the aqueous layer was acidified to pH = 2. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with H 2 O and dried over MgSO 4. Concentration in vacuo gave acetyl amide as a slightly yellow foam (5 g, quantitative yield).

Part D: A solution of the acetyl amide of Part C (5 g, 11.9 mmol) also containing N • methylmorpholine (5.3 mL, 35.7 mmol), 1-hydroxybenzotriazole (4.8 g, 35.7 mmol) and Otetrahydro -2H-pyranyl-hydroxylamine (2.8 g, 23.5 mmol) in N, N-dimethylformamide (50 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (6.8 g, 35.7) mmol) and the solution was stirred at ambient temperature for 20 hours. The solution was concentrated under high vacuum and the residue dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO 3, KHSO 4, H 2 O and dried over MgSO 4. Concentration in vacuo provided the THP amide as a white foam (6.07 g, 98.2%).

Part E: To a solution of THP amide of Part D (6.07 g, 11.7 mmol) in methanol (100 mL) cooled to 0 ° C was added acetyl chloride (2.5 mL, 35.1 mmol) and the solution was stirred 3 hours at ambient temperature. The solution was concentrated and chromatography (on silica, methanol / dichloromethane) gave the hydroxamate hydrochloride as a white solid (3.3 g, 65%). Calcd for C ₂ 4H29N3O6S.HC1.0,9H2O: C, 53.36, H, 5.98, N, 7.78. Found: C, 53.61, H, 5.71, N, 7.94. HSMS calcd for C ₂₄ H 29 N ₃ O ₆ S: 488.1855, found 488.1835.

Example 37

Preparation of 1-Acetyl-4 - ((4- (1,3-benzodioxol-5-yloxy) phenyl) sulfonyl) -N-hydroxy-4-piperidinecarboxamide monohydrochloride

HOHN

zX HCl cn ch ₃

Part A: To a solution of the sulfone of Part D of Example 32 (25 g, 67.3 mmol) and powdered potassium carbonate (23.3 g, 16.9 mmol) in Ν, Ν-dimethylformamide was added sesamol (23.24 g) at ambient temperature. (16.8 mmol) and the solution was heated at 90 ° C for 24 hours. The solution is

283 • to · *>

To to • to to to to to to to to to to to to to to to to to to a a a a a a Concentrate under high vacuum and dissolve the residue in ethyl acetate. The organic layer was washed with saturated 1M NaOH, H 2 O and dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave sesamol BOC-sulfone as a white foam (33.6 g, 93.6%).

Part Β: To a solution of sesamol BOC-sulfone from Part A (29.31 g, 54.93 mmol) in ethanol (60 mL) and tetrahydrofuran (60 mL) was added at room temperature an addition funnel NaOH (21.97 g, 544). mmol) over 20 minutes. The solution was then heated at 60 ° C for 9 hours, then at ambient temperature for 12 hours. The solution was concentrated in vacuo and diluted with H 2 O. The aqueous layer was extracted with ether and acidified with hay pH = 2. This was then extracted with ethyl acetate and the combined organic layers were washed with H 2 O and dried over MgSO 4. Concentration in vacuo gave the acid as a white solid (25.3 g, 91%).

Part C: HCl gas was bubbled into a solution of the acid from Part B (20.3 g, 40.15 mmol) in ethyl acetate cooled to 0 ° C. After 1.5 hours vacuum filtration of the white precipitate gave the amine hydrochloride salt as a white solid (16 g, 93.6%).

Part D: To a solution of the amine hydrochloride of part C (8.1 g, 19.01 mmol) and triethylamine (13.2 mL, 95.05 mmol) in acetone (150 mL) and H 2 O (150 mL) cooled to 0 ® C was added acetyl chloride (5.4 mL, 76 mmol). The solution was stirred at ambient temperature for 18 hours. The acetone was evaporated and the aqueous layer was acidified to pH = 2. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with H 2 O and dried over MgStXp. Concentration in vacuo gave acetyl amide as a pale yellow foam (9.24 g, quantitative yield).

Part E: To a solution of acetyl amide from Part D (9.1 g, 20.33 mmol), N-methylmorpholine (6.7 mL, 61 mmol), 1-hydroxybenzotriazole (8.2 g, 60 mmol) and O- tetrahydro-2H-pyranyl-hydroxylamine (4.85 g, 40 mmol) in N, N-dimethylformamide (40 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.65 g, 60 mmol). The resulting solution was stirred at ambient temperature for 20 hours. The solution was then concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO 3, KHSO 4, H 2 O and dried over MgSO 4. Concentration in vacuo and chromatography (on silica gel, ethyl acetate / hexane) gave the THP amide as a white foam (10 g, 89.7%).

Part F: To a solution of 4M HCl in dioxane (20 mL) was added a solution of the amide from Part E (5.0 g, 9.1 mmol) in methanol (5 mL) and dioxane (15 mL). The solution was stirred at ambient temperature for 30 minutes.

Vacuum filtration of the white precipitate gave the hydroxamate hydrochloride salt as a white solid (80 mg, 29%). For C21H22N2O8S.HCl: C, 54.34; H, 5.15; N, 5.49.

S, 6.43. Found: C, 54.54, H, 4.79, N, 6.06, S, 6.93. HSMS calcd for C 21 H 22 N 2 O 8 S: 463.1175, found 463.118.

Example 38

Preparation of 4 - ((4- (3,4-dimethoxyphenoxy) phenyl) sulfonyl) -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

Part A: HCl gas was bubbled into a solution of the sulfone of Part D of Example 32 (10 g, 24 mmol) in ethyl acetate cooled to 0 ° C. After 4 hours vacuum filtration of the white precipitate gave the amine hydrochloride salt as a white solid (16 g, 93.6%).

Part Β: To a solution of the amine hydrochloride from Part A and powdered potassium carbonate (4.7 g, 34 mmol) in N, N-dimethylformamide (120 mL) was added propargyl bromide (2.022 g, 17 mmol) at ambient temperature and then added. stirring for 4 hours. The solution was diluted with ethyl acetate and washed with H 2 O, saturated NaCl, and dried over MgSO 4. Chromatography (on ethyl acetate / hexane) gave propargyl amine as a white solid (5.2 g, 86%).

Part C: To a solution of propargyl amine from Part B (8 g, 22.63 mmol) and powdered potassium carbonate (4.7 g, 34 mmol) in N, N-dimethylformamide (120 mL) was added at ambient temperature.

3,4-dimethoxyphenol (6.98 g, 45 mmol). The mixture was heated at 90 ° C for 36 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated 1M NaOH, H 2 O and dried over MgSO 2. Concentration in vacuo and chromatography (on silica gel, ethyl acetate / hexane) gave the phenoxy propargyl amine as a yellow gel (10 g, 90.9%).

Part D: A solution of NaOH (8.2 g, 200 mmol) in H 2 O (30 mL) was added via a dropping funnel at ambient temperature to a solution of the phenoxy propargyl amine from Part C (10 g, 20.5 mmol) ethanol (15 mL) and tetrahydrofuran (15 mL). The resulting solution was then heated at 60 ° C for 48 hours and left at ambient temperature for 48 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was

285 was extracted with ether and acidified to pH = 2. Vacuum filtration of the white precipitate gave the acid as a white solid (9.4 g, quantitative yield).

Part E: To a solution of the acid from Part D (9.4 g, 20.5 mmol), N-methylmorpholine (6.8 mL, 62 mmol), 1-hydroxybenzotriazole (8.3 g, 60 mmol) and O-tetrahydro- 2H-pyranyl-hydroxylamine (4.8 g, 40 mmol) in Ν, Ν-dimethylformamide (50 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.7 g, 60 mmol). The resulting solution was then stirred at ambient temperature for 20 hours. The solution was concentrated under high vacuum and the residue dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO 3, H 2 O and dried over MgSO 4. Concentration in vacuo and chromatography (silica gel, ethyl acetate / hexane) gave the THP amide as a white foam (10 g, 89.7%).

Part F: To a solution of 4M HCl in dioxane (38 mL, 152 mmol) was added a solution of the amide from Part E (8.5 g, 15.2 mmol) in methanol (8 mL) and dioxane (24 mL). The resulting mixture was stirred at ambient temperature for 80 minutes. Concentration of the vacuum and titration with ether gave the hydroxamate hydrochloride as a white solid (7.7 g, quantitative yield). HSMS calcd for C 23 H 24 N 2 O 7 S: 475.1461, found 475.1539.

Example 39

Preparation of 4 - ((4- (3,5-dimethoxyphenoxy) phenyl) sulfonyl) -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of propargylamine from Part B of Example 38 (2 g, 5.6 mmol) and powdered potassium carbonate (1.9 g, 13.7 mmol) 3,5-dimethoxyphenol (6.98 g, 45 mmol). The resulting mixture was heated at 90 ° C for 36 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1M NaOH, H 2 O and dried over MgSO 4. Chromatography (on silica gel, ethyl acetate / hexane) gave the phenoxy propargyl amine as a pale yellow gel (2.76 g, quantitative yield).

286 »tt» ····· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 4 · *

4 ·

Part Β: To a solution of the phenoxy propargyl amine from Part A (2.75 g, 5.6 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added a solution of NaOH (2.3 g, 56 mmol) in VH 2 O (10 mL). ml) at ambient temperature. The solution was then heated at 60 ° C for 48 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 gave the acid as a white solid (2 g, 77.2).

Part C: Acid solution of Part B (2 g, 4.3 mmol) also containing Nmethylmorpholine (1.9 mL, 17.2 mmol), 1-hydroxybenzotriazole (1.74 g, 13.2 mmol) and O-tetrahydro- 2H-pyranyl-hydroxylamine (1.02 g, 8.6 mmol) in N, N-dimethylformamide (20 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.47 g, 12.9 mmol) ). The resulting solution was then stirred at ambient temperature for 20 hours. The solution was concentrated under high vacuum and the residue dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO 3, H 2 O and dried over MgSO 4. Concentration in vacuo and chromatography (on silica, ethyl acetate / hexane) gave the THP amide as a white foam (2.4 g, quantitative yield).

Part D: To a solution of 4M HCl in dioxane (13 mL, 52 mmol) was added a solution of the amide from Part C (2.43 g, 4.35 mmol) in methanol (2 mL) and dioxane (6 mL), and the mixture was stirred 80 minutes at ambient temperature. Vacuum filtration of the precipitate and washing with ether gave the hydroxamate hydrochloride as a white solid (1.25 g, 56.3). For C23H28N2O7S.1.5HCl: C, 52.20; H, 5.24; N, 5.29. Found: C, 52.00, H, 5.05, N, 5.17.

Example 40

Preparation of 4 - ((4- (1,3-benzodioxol-5-yloxy) phenyl) sulfonyl) -N-hydroxy-4-piperidinecarboxamide monohydrochloride

HOHN

Part A: To a solution of N-BOC-carboxylic acid of Part B of Example 37 (1.25 g, 2.47 mmol), N-methylmorpholine (1.00 g, 9.89 mmol) and 1-hydroxybenzotriazole hydrate (0.40 g) ,

2.96 mmol) in N, N-dimethylformamide (8 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.616 g, 3.21 mmol) at ambient temperature and after 5 minutes a solution of O-tetrahydro- 2H-pyranyl-hydroxylamine (0.39 g, 3.33 mmol) in N, N287

-dimethylformamide (2 mL). After two days, the pale yellow solution was concentrated in vacuo. This gave a residue which was dissolved in ethyl acetate and washed successively with water (3x) and brine, and dried over Na 2 SO 4. Concentration gave the THP amide as a white foam (10 g, 89.7%).

Part Β: To a solution of 4M HCl in dioxane (20 mL) was added an amide solution from Part E (5.0 g,

9.1 mmol) in methanol (5 mL) and dioxane (15 mL) The solution was stirred at ambient temperature for 30 minutes. Vacuum filtration of the white precipitate gave the hydroxamate hydrochloride salt as a white solid (80 mg, 29%). For C21H22N2O8S.HCl: C, 54.34; H, 5.15; N, 5.49; S, 6.43. Found: C, 54.54, H, 4.79, N, 6.06, S, 6.93. HSMS calcd for C 21 H 22 N 2 O 8 S: 463.1175, found 463.118.

Example 41

Preparation of 4 - ((4- (3,4-dimethoxyphenoxy) phenyl) sulfonyl) -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

Part A: HCl gas was bubbled into a solution of the sulfone of Part D of Example 32 (10 g, 24 mmol) in ethyl acetate cooled to 0 ° C. After 4 hours vacuum filtration of the white precipitate gave the amine hydrochloride salt as a white solid (16 g, 93.6%).

Part Β: To a solution of the amine hydrochloride of Part A and powdered potassium carbonate (4.7 g, 34 mmol) in N, N-dimethylformamide (120 mL) was added propargyl bromide (2.022 g, 17 mmol) at ambient temperature and then stirred for 4 hours. clock. The solution was diluted with ethyl acetate and washed with H 2 O, saturated NaCl, and dried over MgSO 4. Chromatography (on ethyl acetate / hexane) gave propargyl amine as a white solid (5.2 g, 86%).

Part C: To a solution of propargylamine from Part B (8 g, 22.63 mmol) and powdered potassium carbonate (4.7 g, 34 mmol) in N, N-dimethylformamide (120 mL) was added at ambient temperature.

3,4-dimethoxyphenol (6.98 g, 45 mmol). The mixture was heated at 90 ° C for 36 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated 1M NaOH, H 2 O and dried over MgSO 4. Concentration in vacuum and »» »» »» »» »» »» »»

288::; ί ··; ·: Ί; Chromatography (on silica gel, ethyl acetate / hexane) gave the phenoxy propargylamine as a yellow gel (10 g, 90.9%).

Part D: A solution of NaOH (8.2 g, 200 mmol) in H 2 O (30 mL) was added via a dropping funnel at ambient temperature to a solution of the phenoxy propargyl amine from Part C (10 g, 20.5 mmol) ethanol (15 mL) and tetrahydrofuran (15 mL). The resulting solution was then heated to 60 ° C for 48 hours and left at ambient temperature for 48 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 gave the acid as a white solid (9.4 g, quantitative yield).

Part E: To a solution of the acid from Part D (9.4 g, 20.5 mmol), N-methylmorpholine (6.8 mL, 62 mmol), 1-hydroxybenzotriazole (8.3 g, 60 mmol) and O-tetrahydro- 2H-pyranyl-hydroxylamine (4.8 g, 40 mmol) in N, N-dimethylformamide (50 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.7 g, 60 mmol). The resulting solution was then stirred at ambient temperature for 20 hours. The solution was concentrated under high vacuum and the residue dissolved in ethyl acetate. The organic layer was washed with saturated ΝβΗΟΟβ, H2O and dried over MgSO4. Concentration in vacuo and chromatography (on silica gel, ethyl acetate / hexane) gave the THP amide as a white foam (10 g, 89.7%).

Part F: To a solution of 4M HCl in dioxane (38 mL, 152 mmol) was added a solution of the amide from Part E (8.5 g, 15.2 mmol) in methanol (8 mL) and dioxane (24 mL). The resulting mixture was stirred at ambient temperature for 80 minutes. Concentration of the vacuum and titration with ether gave the hydroxamate hydrochloride as a white solid (7.7 g, quantitative yield). HSMS calcd for C 23 H 24 N 2 O 7 S: 475.1461, found 475.1539.

Example 42

Preparation of 4 - ((4- (1,3-benzodioxol-5-yloxy) phenyl) sulfonyl) -N-hydroxy-1-4-methylsulfonyl) -4-piperidinecarboxamide

289 • 4 U «4 · 444 · 4 · 4 · 4

4 4 «4 ·· · 4 · 4 · 444 4 4444« 4 «· ·· 44 4 · 4 4 ό

4444 44 44 4 · 4 4 4

Part A: a solution of the sulfone of Part D of Example 32 (25 g, 67.3 mmol) in N, N-dimethylformamide was added powdered potassium carbonate (23.3 g, 0.169 mol) and sesamol (23.2 g, 0.168 mol). The solution was immersed in an oil bath at 90 ° C and stirred for 25 hours. Ethyl acetate was added to the solution and the organic layer was washed with water, 1M NaOH, water, dried over MgSO 4, filtered, and concentrated in vacuo. Silica gel chromatography eluting with ethyl acetate / hexane (15/85) gave the ethyl ester compound as an oil (29.3 g, 82%).

Part Β: To a solution of the ethyl ester of Part A (29.3 g, 54.93 mmol) in ethanol (60 mL) and tetrahydrofuran (60 mL) was added a solution of NaOH (21.9 g, 0.549 mol) in water (120 mL). ml) and the solution was heated at 65 ° C for 10 hours. The solution was concentrated in vacuo and the aqueous residue acidified to pH = 3. The solution was extracted with ethyl acetate. The solution was dried over MgSO 4, filtered, and concentrated in vacuo. This gave the acid as a yellow foam (25.6 g, 92.1%).

Part C: To a solution of the acid of Part B (22.3 g, 40.15 mmol) in ethyl acetate at 0 ° C was bubbled HCl gas for 20 minutes. The solution was stirred at 0 ° C for 1.5 hours. The resulting precipitate was filtered and washed with ether to give the amine hydrochloride as a white solid (16.0 g, 93.5%).

Part D: To a solution of the amine hydrochloride from Part C (7.5 g, 17.0 mmol) in dichloromethane (200 mL) was added methanesulfonyl chloride (2.0 g, 25.0 mmol) and the solution was stirred at room temperature for 18 hours. Surroundings. The solution was washed with H 2 O and saturated NaCl and then dried over MgSO 4 and concentrated in vacuo. This gave the acid as a white solid (6.97 g, 85%).

Part E: To the acid solution of Part D (7.37 g, 15.0 mmol) was added 1-hydroxybenzotriazole (2.43 g, 18.0 mmol), N-methylmorpholine (4.94 mL, 45.0 mmol), Otetrahydro-2H-pyranyl- hydroxylamine (2.65 g, 22.5 mmol) followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.02 g, 21.0 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H 2 O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4.

290

4 · · ·

4 4 <··· 4 44 4 ·· 44 4 4,444 «44 44 44 4 44 444« 444 44 44 44 44

Chromatography (on silica, eluting with 50% ethyl acetate / hexane) gave the protected hydroxamate as a solid (7.54 g, 85%).

Part F: To a solution of the THP-protected hydroxamate of Part E (6.32 g, 10.8 mmol) in dioxane (75 mL) and methanol (25 mL) was added 4N HCl in dioxane (30 mL). After stirring at ambient temperature for 1 hour, the solution was concentrated in vacuo. Trituration with ethyl ether gave the title compound. Chromatography (on silica, 5% methanol / ethyl acetate) gave the hydroxamate as a white solid (4.32 g, 80%). MS calculated for C 22 H 22 N 2 O 9 S 2 + 1: 499.0845, found 499.0848.

Example 43

Preparation of 4 - ((4- (3,4-dimethylphenoxy) phenyl) sulfonyl)) - N -hydroxy-1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

Part A: A mixture of the fluoro compound of Part F of Example 9 (2.0 g, 5.66 mmol), 3,4-dimethylphenol (2.0 g, 16.5 mmol) and potassium carbonate (2.3 g, 8.8 mmol) in N, N-dimethylformamide (15 mL) was heated at 90 ° C overnight (about 18 hours) under a nitrogen atmosphere. The brown mixture was concentrated in vacuo and purified by chromatography (on silica, ethyl acetate / hexane). This gave the 3,4-dimethylphenoxyphenyl compound as a bright yellow oil (2.0 g, 79% yield). For C25H29NO5S: C, 65.91; H, 6.42; N, 3.04; S, 7.04. Found: C, 65.76, H, 6.37, N, 3.03, S, 7.00.

Part B: A solution of the 3,4-dimethylphenoxyphenyl compound of Part A (2.0 g, 4.93 mmol) and potassium hydroxide (1.7 g, 29.7 mmol) in a mixture of ethanol (25 mL) and water (4 mL) was stirred at reflux for 4 hours under a nitrogen atmosphere. The solution was cooled with an ice bath, then acidified with concentrated hydrochloric acid and concentrated to a crude residue. Crude residue, O-tetrahydro-2H-pyranyl-hydroxylamine (0.88 g, 7.50 mmol), triethylamine (0.81 mL, 5.81 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in of acetonitrile (24 mL) was stirred overnight at ambient temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, a saturated bicarbonate solution.

Φ

9 9

291 «v v v v v 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

4 and a saturated salt solution. After drying over MgSO 4, the filtrate, as a THP-protected hydroxamate, was concentrated to a yellow foam.

Part C: The THP-protected hydroxamate (920 mg, 1.75 mmol) of Part B was dissolved in methanol (16 mL). Acetyl chloride (0.37 mL, 5.3 mmol) was added. After three hours of concentration followed by reverse phase HPLC afforded the title compound as a white solid (611 mg, 79%). MS (EI) MH ⁺ calculated for C 23 H 28 N 2 O 5 S: 443, found 443.

Example 44

Preparation of 4 - ((4- (4-chlorophenyl) thiophenyl) sulfonyl)) - 1- (propynyl) -4-piperidinecarboxylic acid monohydrochloride and monohydrochloride

4 - ((4- (4-chlorophenyl) thiophenyl) sulfonyl)) - 1- (propynyl) -N-hydroxy-4-piperidinecarboxylic acid

Part A: A mixture of the fluoro compound of Part F of Example 9 (2.0 g, 5.66 mmol), 4-chlorothiophenol (1.0 g, 6.94 mmol) and potassium carbonate (1.1, g, 8.00 mmol) in N, N-dimethylformamide (12 mL) was stirred overnight (about 18 hours) under a nitrogen atmosphere. The mixture was concentrated in vacuo. The residue was diluted with H 2 O and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over MgSO 4, and concentrated in vacuo to a yellow oil. The oil was purified by chromatography (on silica, ethyl acetate / hexane). This afforded the 4-chlorophenylthiophenol compound as a white solid (2.0 g, 75% yield). For C23H24NO4S2Cl: C, 57.791, H, 5.06, N, 2.93, S, 13.42, Cl, 7.42. Found: C, 57.57, H, 5.11, N, 2.94, S, 13.19, Cl, 7.43.

Part B: The chlorophenylthiophenol compound from Part A (2.04 g, 4.27 mmol) was diluted with ethanol (30 mL) and water (5 mL). Potassium carbonate (1.55 g, 27.7 mmol) was added and the mixture was heated at reflux for 3 hours. After completion of the reaction, the solution was cooled and acidified with concentrated HCl to pH = 1-3. The solvent was removed by rotary evaporation and the residue was azeotroped to dryness by repeated addition of acetonitrile. Furthermore, the acid hydrochloride •

292 ft · ft · ft ft dried on a vacuum line, then transferred as a whole to the coupling reaction. It was assumed that the saponification was complete.

Part C: The carboxylic acid hydrochloride from the previous step (4.27 mmol) was suspended in acetonitrile (20 mL). N-methylmethylmorpholine (about 1.0 mL) was added followed by O-tetrahydro-2H-pyranyl-hydroxylamine (585 mg, 5 mmol). After 5 minutes 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 955 mg, 5 mmol) was added. The mixture was stirred overnight (about 18 hours), then the solvent was removed by rotary evaporation and the residue was diluted half with saturated NaHCO 3 (50 mL) and the product was extracted into ethyl acetate (2 x 100 mL). In this example, an unprocessable emulsion complicated the recovery of the compounds. The combined organic layers were dried over MgSO 4, filtered through silica, concentrated and chromatographed (flash silica, ethyl acetate / hexane). This gave the title THP-protected hydroxamate (162 mg, 7%, from ester) as a foam after concentration. MS (CI) MH ⁺ calcd for C 21 H 22 N 2 O 4 S 2 Cl: 450, found 450. Because mass recovery was poor, the silica filter cake was extracted with 1: 1 methanol: ethyl acetate to give 4 - ((4- (4-chlorophenyl) thiophenyl) monohydrochloride) sulfonyl) -1- (propynyl) -4-piperidinecarboxylic acid (540 mg, 26%).

Part D: The THP-protected hydroxamate of Part C (441 mg, 0.80 mmol) was dissolved in methanol (2 mL). Acetyl chloride (0.2 mL, 3 mmol) was added. After 3 hours, concentration followed by reverse phase HPLC gave the title hydroxamate compound as a pink solid (162 mg, 44%). MS (CI) MH ⁺ calcd for C 21 H 22 N 2 O 4 S 2: 465, found 465.

Example 45

Preparation of 4 - ((4-cyclopentylthio) phenyl) sulfonyl) -N-hydroxy-1- (2'-propynyl) -4-piperidinecarboxamide monohydrochloride

* · · »44 44 44 · 4 4

4 «44

909 44 4 4 · 4,444 4 4 · 4 ·

From «“ J «44« 4 4 4444

444 4. 44 44 44 4 4 44

Part A: The propargylamine from Part F of Example 9 (3.05 g, 8.5 mmol) was mixed with potassium carbonate (1.38 g, 10 mmol), N, N-dimethylformamide (6 mL) and cyclopentyl mercaptan (1.02). ml, 10 mmol). The mixture was heated at 80 ° C for 4 hours and at 95 ° C for 2.5 hours. TLC was monitored. Aqueous work-up was achieved using water (10 mL) and ethyl acetate (2 x 100 mL). The combined organic layers were dried over MgSO 4, concentrated, and chromatographed (flash silica, eluent ethyl acetate / hexane). This gave the cyclopentyl mercaptyl compound as an oil (3.2 g, 86%).

Part B: The cyclopentyl mercaptyl compound of Part A (3.12 g, 7.13 mmol) was diluted with ethanol (50 mL) and water (8 mL). Potassium carbonate (2.59 g, 46.3 mmol) was added and the mixture was heated at reflux for 3.5 hours. After completion of the reaction, the solution was cooled and acidified with concentrated HCl to pH = 1-3. The solvent was removed by rotary evaporation and the residue was azeotroped to dryness by repeated addition of acetonitrile. The carboxylic acid hydrochloride was further dried on a vacuum line, then transferred as a whole to the coupling reaction. It was assumed that the saponification was complete.

Part C: The carboxylic acid hydrochloride of Part B (7.13 mmol) was suspended in acetonitrile (50 mL). N-methylmorpholine (about 2.0 mL) was added followed by O-tetrahydro-2H-pyranyl-hydroxylamine (1.05 g, 9 mmol). After 5 minutes, EDC, (1.72 g, 9 mmol) was added. The mixture was stirred overnight (about 18 hours), then the solvent was removed by rotary evaporation and the residue was diluted in half with saturated NaHCO 3 solution (50 mL) and the product was extracted into ethyl acetate (2 x 100 mL). The combined organic layers were dried over MgSO 4, filtered through silica, concentrated, and chromatographed (flash silica, ethyl acetate / hexane). This gave an O-THP-protected hydroxamate (2.0 g, 51%, from ester) as a foam after concentration.

Part D: The O-THP-protected hydroxamate (2.0 g, 3.95 mmol) was dissolved in methanol (16 mL). Acetyl chloride (0.86 mL, 12 mmol) was added over 2 minutes. The reaction mixture was stirred at ambient temperature for 4 hours, then concentrated with repeated addition of chloroform and acetonitrile. The title compound precipitated as a white solid (1.77 g, 98%). MS (El)

MH ⁺ calculated for θ2θΗ26 ^ 2θ4 ^ 2 ^; 422, found 422.

• to • to • to

294 • to • to

Example 47

Preparation of N-hydroxy-4 - ((4- (phenylthiophenyl) sulfonyl)) -1- (2-propynyl) -4-piperidinecarboxamide,

1-oxide and N-hydroxy-4 - ((4- (phenylthiophenyl) sulfonyl)) -1- (2-propynyl) -4-piperidinecarboxamide,

HIM

HC

Part A: m-chloroperbenzoic acid (57-86%, 120 mg) was added to a solution of Nhydroxy-4 - ((4- (phenylthiophenyl) sulfonyl)) -1- (2-propynyl) -4-piperidinecarboxamide (title compound of the example) 9) (215 mg, 0.5 mmol) at 0θ in methanol (5 mL). It was allowed to warm slowly to ambient temperature and after 16 hours the mixture was passed through a micron filter and concentrated. Reverse phase HPLC (Delta Pak 50 X 300 mm, 15 micrometer C ₈ 100)

Angstrom, a 30 minute gradient method starting with dilute HCl (0.5 mL / L): acetonitrile 80:20, ending with 50:50) separated the 5 major components. The first and second peaks from the column gave, after concentration, 14 (6%) and 16 mg (7%), two compounds which were assigned as N-hydroxy-4 - ((4- (phenylsulfinyl) phenyl) sulfonyl) diastereomers) - 1- (2-propynyl) -4-piperidinecarboxamide based on their NMR spectra. The third peak was not identified. The fourth peak was assigned by NMR as N-hydroxy-4 - ((4- (phenylthiophenyl) sulfonyl)) -1- (2-propynyl) -4-piperidinecarboxamide, 1-oxide (147 mg, 66%). MS (EI) MH ⁺ calculated for C 21 H 22 N 2 O 5 S 2: 447, found 447. The last peak contained 73 mg of the recovered 3-chlorobenzoic acid.

Example 48

Preparation of N-hydroxy-2,2-dimethyl- (4- (phenoxyphenylsulfonyl)) - 1,3-dioxanecarboxamide

HIM.

O

• · ·

295 ftft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft

Part A: A fresh sodium methoxide solution was prepared by slowly adding hexane washed sodium beads (9.4 g, 410 mmol) to methanol (1 L) at 0 ⁹ C. To this cooled solution was added 4-fluorothiophenol (50 g, 390 mmol). followed by 2 • chloroacetate (42.3 g, 390 mmol). After warming to ambient temperature, the solution was stirred overnight (about 18 hours). The methanol was removed in vacuo and the residue was taken up in ethyl acetate (300 mL). The organic layer was washed with H 2 O (2 x 200 mL) and dried over MgSO 4. Concentration gave the methyl ester sulfide product as a clear oil (71.8 g, 92%).

Part Β: To a solution of the methyl ester sulfide product of Part A (71.8 g, 358 mmol) in 70% methanol / FP10 (1 L) was slowly added Oxone ™ (660 g, 1.08 mol). The mixture was stirred overnight (about 18 hours). Excess Oxone ™ was filtered off and methanol was removed from the filtrate in vacuo. The remaining aqueous solution was extracted with ethyl acetate (3 x 300 mL). The organic layers were washed with H 2 O (2 x 300 mL) and dried over MgSO 4. Concentration gave the sulfone product as a brown oil (82 g, 98%).

Part C: To the prepared suspension of KHCO 3 (1.0 g, 9.8 mmol) in 37% formaldehyde solution was added the sulfone product from Part B (28.6 g, 123 mmol). The reaction mixture was stirred for 1 hour and then saturated sodium sulfate solution (20 mL) was added. After 30 minutes, the mixture was extracted with diethyl ether (4 x 100 mL). The organic layers were washed with H 2 O (2 x 300 mL) and dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane) gave the sulfone diol product as a clear oil (15.3 g, 42%).

Part D: The sulfone diol product of Part C (1.3 g, 4.5 mmol) was dissolved in acetone (40 mL) along with 2,2-dimethoxypropane (1.1 mL, 9.0 mmol) and p-toluenesulfone monohydrate acid (0.03 mg, 0.14 mmol) and the resulting mixture was refluxed for 6 hours. After cooling, the mixture was neutralized with solid Na 2 CO 3 (pH about 7), filtered and concentrated. The residue was dissolved in chloroform (50 mL) and washed with water (2 x 30 mL). Drying over MgSO 4 and concentration gave the dimethyl ketal product as an opaque oil (1.4 g, 94%).

Part E: Phenol (0.6 g, 6.3 mmol) and cesium carbonate (2.0 g, 6.3 mmol) were added to a solution of dimethyl ketal product (1.4 g, 4.2 mmol) from Part D in N, N-dimethylformamide (20 mL). The mixture was heated at 90 ° C for 5 hours, diluted with H 2 O (20 mL) and extracted with ethyl acetate (4 x 100 mL). The organic layers were washed with brine (1x100ml) and water (1x100ml). Concentration gave phenol-O-phenol dimethyl ketal as a dark brown oil (1.51 g, 88%).

296 • 0 · 9,990 0 9,999

9 9 9 09 9 9 09 1

9 «090 099009 99

98 9 «9« 009

0909 98 «9 00 00 99

Part F: To a solution of phenol-O-phenol dimethyl ketal of part E (1.5 g, 3.4 mmol) in tetrahydrofuran (10 mL) was added aqueous lithium hydroxide solution (0.34 g, 14.8 mmol, in H 2 O ( 5 ml)). The reaction mixture was stirred for 2 hours and diluted with H 2 O (15 mL) and acidified with 30% HCl _and q to pH = 3. The acidic solution was extracted with diethyl ether (3 x 100 mL). Drying over MgSO 4 and concentration gave the carboxylic acid product as a brown oil (1.5 g, quantitative yield).

Part G: To a solution of the carboxylic acid product of Part F (1.3 g, 3.3 mmol) and hydrate

1-hydroxybenzotriazole (0.54 g, 4.0 mmol) in Ν, Ν-dimethylformamide (15 mL) was added 4-methylmorpholine (1.67 g, 16.5 mmol), O-tetrahydro-2H-pyranyl-hydroxylamine (1 , 2 g, 10.2 mmol) and EDC (0.88 g, 4.6 mmol). After stirring overnight, DMF was removed in vacuo. The residue was taken up in ethyl acetate / water (1: 1, 50 mL). The organic layer was washed with brine (1 x 20ml) and water (1 x 20ml) and dried over Na 2 SO 4 - Chromatography (on silica, ethyl acetate / hexane) gave the THP-protected hydroxamate product as a white solid (0.27 g, 24%) .

Part Η: To a solution of the THP-protected hydroxamate product of Part G (0.36 g, 0.73 mmol) in dioxane (3 mL) and methanol (1 mL) was added 4N HCl in dioxane (2 mL). The reaction mixture was stirred for 5 minutes and then the solvents were removed in vacuo. Reverse phase chromatography (on C-18 silica, acetonitrile / H2O) gave the title compound as a white solid (0.13 g, 44%). MS (FAB) M ⁺ H calculated for C 19 H 21 NO 7 S: 408, found 408.

Example 49

Preparation of tetrahydro-N-hydroxy-4 - ((4- (phenylthio) phenyl) sulfonyl)) - 2H-thiopyran-4-carboxamide

Part A: To a solution of methyl chloroacetate (322 g, 2.96 mol) in Ν, Ν-dimethylacetamide (1

1) Thiophenol (400 g, 3.12 mol) and potassium carbonate (408 g, 2.96 mol) were added. The reaction mixture was stirred overnight (about 18 hours) at ambient temperature. After diluting with a minimum amount of water (800 mL), the mixture was extracted with ethyl acetate (4x 1 L). The organic layers were washed with water (1x

494

4

297

94 • · 4

4444 44

44

94

4 4 • 4 4 • 4 4

9 9

9 4

44

800 mL) and concentrated. This gave the sulfide product as a clear oil (614 g, quantitative yield).

Part Β: To a solution of the sulfide of Part A (75.85 g, 0.38 mol) in methanol (1000 mL) was added water (100 mL) and Oxone ® (720 g, 1.17 mol) at 20 ° C. An exothermic reaction to 67 θθ was recorded. After 2 hours, the reaction mixture was filtered and the cake washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with brine, dried over MgSO 4, filtered, and concentrated in vacuo. This gave the sulfone as a crystalline solid (82.74 g, 94%).

Part C: To a solution of the sulfone of Part B (60.0 g, 258 mmol) in DMA (350 mL) was added dibromethylthioether (76.9 g, 310 mmol) followed by potassium carbonate (78.3 g, 568 mmol). The mixture was stirred for 5 minutes before adding a catalytic amount of 4-dimethylaminopyridine and tetrabutylammonium bromide. The reaction mixture was stirred overnight (about 18 hours) at ambient temperature, then poured into a stirred solution of 10% HCl _and q (2.5 L). The resulting precipitate was filtered and washed with hexane to remove excess thioether. Drying in vacuo (about 18 hours) gave thiopyran-Ph-pF methyl ester as a yellow powder (76.1 g, 93%).

Part D: To a solution of thiopyran-Ph-pF methyl ester of Part C (4.0 g, 12.6 mmol) in N, N-dimethylacetamide (25 mL) was added cesium carbonate (6.1 g, 18.9 mmol) and thiophenol ( 1.1 g, 18.9 mmol). The mixture was stirred at 90 ° C for 2 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were washed with brine (1 x 75 mL) and water (1 x 75 mL) and then dried over MgSO 4. Chromatography (on silica, ethyl acetate / hexane) provided the phenyl-S-phenyl methyl ester as a yellowish solid (3.6 g, 71%).

Part E: To a solution of the phenyl-S-phenylmethyl ester of Part D (3.6 g, 8.8 mmol) in tetrahydrofuran (15 mL) was added potassium trimethylsilonate (1.24 g, 9.7 mmol). The mixture was stirred at ambient temperature for 2-3 hours or until a solid precipitate had formed. After complete hydrolysis, N-methylmorpholine (2.9 mL, 26.4 mmol) was added followed by PyBroP (4.9 g, 10.6 mmol). The solution was stirred for 10 minutes. Aqueous hydroxylamine (0.32 g, 9.7 mmol) was added and the mixture was stirred for an additional 2 hours. After completion, the solvent was removed in vacuo. Chromatography in (reverse phase C-18, acetonitrile / H 2 O) of the residue gave the title compound as an off-white solid (0.82 g, 23%). MS (FAB) M ⁺ H calcd for C 18 H 19 NO 4 S 3: 410, found 410.

Example 50

298 ftft ftft ft ftft ft ftft ftft ftft ftft ftft ft ftft

ft ftft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft

Preparation of 4 - ((4-fluorophenyl) sulfonyl) -tetrahydro-N - ((tetrahydro-2H-pyran-2-yl) oxy) -2H-thiopyran-4-carboxamide

Part A: Thio phenol (400 g, 3.12 mol) and potassium carbonate (408 g, 2.96 mol) were added to a solution of methyl chloroacetate (322 g, 2.96 mol) in Ν, Ν-dimethylacetamide (1 L) ). The reaction mixture was stirred overnight (about 18 hours) at ambient temperature. After diluting with a minimum amount of water (800 mL), the mixture was extracted with ethyl acetate (4x 1 L). The organic layers were washed with water (1 x 800 mL) and concentrated. This gave the sulfide product as a clear oil (614 g, quantitative yield).

Part Β: To a solution of the sulfide of Part A (75.85 g, 0.38 mol) in methanol (1000 mL) was added water (100 mL) and Oxone ® (720 g, 1.17 mol) at 20 ° C. An exothermic reaction was recorded at 67 ° C. After 2 hours, the reaction mixture was filtered and the cake was washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with brine, dried over MgSO 4, filtered, and concentrated in vacuo. This gave the methyl ester sulfone as a crystalline solid (82.74 g, 94%).

Part C: To a solution of methyl ester sulfone of Part B (60.0 g, 258 mmol) in N, N-dimethylacetamide (350 mL) was added 2,2-dibromoethylthioether (76.9 g, 310 mmol) followed by potassium carbonate (78, 3 g, 568 mmol). The mixture was stirred for 5 minutes before adding a catalytic amount of 4-dimethylaminopyridine and tetrabutylammonium bromide. The reaction mixture was stirred overnight (about 18 hours), then poured into a stirred solution of 10% HCl _and q (2.5 L). The resulting precipitate was filtered and washed with hexane to remove excess thioether. Drying in vacuo (about 18 hours) gave thiopyran methyl ester as a yellow powder (76.1 g, 93%).

Part D: To a solution of thiopyran methyl ester from Part C (30.0 g, 94 mmol) in tetrahydrofuran (250 mL) was added potassium trimethylsilonate (28.9 g, 226 mmol). The mixture was stirred at ambient temperature for 2-3 hours or until a solid precipitate had formed. After complete hydrolysis, the solvent was removed in vacuo. Water (200 mL) was added and the mixture was washed with diethyl ether (1 x 200 mL). The aqueous layer was cooled to 0 ° C and 10% HClaq was added slowly until a precipitate formed. The solid was collected and dried under vacuum with oxide

299 · 4 · 4 · 44

44

4 4 4

4 4 4 • 4,444

4 4

44

4 4

4 ·

4 4

44 phosphorous. This gave thiopyran carboxylic acid as a yellow solid (17.8 g,

Part E: To a solution of thiopyran carboxylic acid from part D (17.8 g, 58.5 mmol) in N, N-dimethylformamide (100 mL) was added N-methylmorpholine (19.3 mL, 176 mmol) followed by hydrate 1. -hydroxybenzotriazole (9.5 g, 70.2 mmol), O-tetrahydro-2H-pyranyl-hydroxylamine (10.3 g, 87.8 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (16, 8 g,

87.8 mmol). The mixture was stirred for 3 hours and then diluted with water (100 mL). The mixture was extracted with ethyl acetate (4 x 200 mL). The organic layers were washed with aqueous saturated potassium carbonate solution (1 x 200 mL), 1% HCl _and qa brine (1 x 200 mL). Drying over MgSO 4 and concentration in vacuo gave the title compound as an off-white solid (30.8 g, quantitative yield). MS (FAB) M ⁺ H calcd for C 17 H 22 FNO 5 S 2: 404, found 404. Example 51

Preparation of tetrahydro-N-hydroxy-4 - ((4 - ((4-methoxyphenyl) thio) phenyl) sulfonyl) -2H-thiopyran-4-carboxamide

dimethylacetamide (25 mL) was added 4-methoxyphenol (2.5 g, 17.8 mmol) followed by potassium carbonate (6.2 g, 44.7 mmol). The reaction mixture was heated at 60 ° C for 3 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (4 x 100 mL). The organic layers were washed with water (2 x 50 mL) and dried over MgSO 4. Concentration in vacuo gave the THP-protected phenyl-S-p-phenyl-OMe product as a yellowish solid (9.2 g, quantitative yield).

Part Β: Solution of THP-protected phenyl-S-p-phenyl-OMe product from Part A (9.2 g,

14.9 mol) in dioxane was slowly added 4M HCl in dioxane (10 mL). After stirring overnight (about 18 hours) the solvent was removed. Chromatography of the resulting residue (reverse phase C-18, acetonitrile / H 2 O) gave the title compound as a white solid (1.84 g, 28.3%). MS (FAB)

M ⁺ H calcd for C 19 H 21 NO 5 S 3: 440, found 440.

300 ·· ··· ·· ·· ··

4 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4

4 ·· · · · · · · ·

4 ··· ·· · ♦ ·· ·· ··

Example 52

Preparation of tetrahydro-N-hydroxy-4 - ((4- (phenylthio) phenyl) sulfonyl)) - 2H-thiopyran-4-carboxamide 1,1-dioxide

(100 mL) cooled to 0 ° C was slowly added 50-60% m-chloroperbenzoic acid (17.1 g, 49.5 mmol). The mixture was stirred at 0 ° C for 1 hour and an additional 3 hours as the temperature rose to ambient conditions. Water (200 mL) was added and the mixture was neutralized with 10% ammonium hydroxide (100 mL). The organic layer was washed with water (1 x 200 mL) and dried over MgSO 4. Concentration in vacuo gave an orange oil (3.5 g, 33%). The water / 10% ammonium hydroxide solution was saturated with sodium chloride and extracted with ethyl acetate (2 x 400 mL). The organic layer was dried over MgSO 4 and concentrated. This gave the THP-protected sulfone thiopyran-β-F compound as an orange foam (6.1 g, 57%).

Part Β: To a solution of THP-protected sulfone thiopyran-pF from Part A (9.6 g, 22 mmol) in N, N-dimethylacetamide (120 mL) was added thio phenol (2.9 g, 26.4 mmol) and then potassium carbonate (9.1 g, 66 mmol). The reaction mixture was heated at 60 ° C for 4 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (4 x 100 mL). The organic layers were washed with water (2 x 50 mL) and dried over MgSO 4. Concentration in vacuo provided the THPprotected phenyl-S-phenyl product as an orange oil (5.1 g, 43%).

Part C: To a solution of the THP-protected phenyl-S-phenyl product of Part B (5.1 g, 9.4 mol) in dioxane was slowly added 4N HCl in dioxane (10 mL). After stirring overnight (about 18 hours) the solvent was removed. Chromatography of the resulting residue (reverse phase C-18, acetonitrile / H 2 O) gave the title compound as a pink solid (1.2 g, 29%). MS (FAB)

M ⁺ H calcd for C18H19X0583: 442, found 442.

4 4

4 4

301 4 • 4 • 4 4 4

4 4

4 ·

4 4 4

4 4 4

4 4 • • 44 ··

4 4 4 4

44

Example 53

Preparation of tetrahydro-N-hydroxy-4 - ((4- (4- (1H-1,2,4-triazol-1-yl) phenoxy) phenyl) sulfonyl)) -2H-thiopyran-4-carboxamide monohydrochloride, 1,1-dioxide

(100 mL) cooled to 0 ° C was slowly added 50-60% m-chloroperbenzoic acid (17.1 g, 49.5 mmol). The mixture was stirred at 0 ° C for 1 hour and an additional 3 hours as the temperature rose to ambient conditions. Water (200 mL) was added and the mixture was neutralized with 10% ammonium hydroxide (100 mL). The organic layer was washed with water (1 x 200 mL) and dried over MgSO 4. Concentration in vacuo afforded an orange-yellow oil (3.5 g, 33%). The water / 10% ammonium hydroxide solution was saturated with sodium chloride and extracted with ethyl acetate (2 x 400 mL). The organic layer was dried over MgSO 4 and concentrated. This gave the THP-protected sulfone thiopyranp-F compound as an orange foam (6.1 g, 57%).

Part Β: To a solution of THP-protected sulfonthiopyran-pF from A (6.0 g, 13.8 mmol) in N, N-dimethylformamide (25 mL) was added 4- (1H-1,2,4-triazol-1-yl) phenol (4.4 g, 27.5 mmol) then CSCO 3 (13.4 g, 41.4 mmol). The reaction mixture was heated at 95 ° C for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (4 x 100 mL). The organic layers were washed with water (2 x 50 mL) and dried over MgSO 4. Concentration gave the THP-protected phenyl-Ophenyl triazole product as a brown solid (9.7 g, quantitative yield).

Part C: To a solution of the crude THP-protected phenyl-O-phenyl triazole product of Part B (8.0 g, 13.8 mmol) in acetonitrile (40 mL) was slowly added 10% HCl _and q (100 mL).

Stirring overnight (about 18 hours) removed the acetonitrile. The resulting precipitate was collected. This afforded the title compound as a brown solid (1.3 g, 18%). MS (FAB) M ⁺ H calculated for

C20H21ClN4O7S3: 493, found 493.

4

4

302 · * 4 4

4

44

4 4 ·

4 4 4

4 4 4

4 4 4

44

Example 54

Preparation of 4 - ((4- (4- (2-Aminoethyl)) phenoxy) phenyl) sulfonyl) -tetrahydro-N-hydroxy-2H-thiopyran-4-carboxamide 1,1-dioxide monohydrochloride

O

Part A: To a solution of the title compound of Example 50 (13.0 g, 24.5 mmol) in dichloromethane (100 mL) cooled to 0 ° C was slowly added 50-60% m-chloroperbenzoic acid (17.1 g, 49, 5 mmol). The mixture was stirred at 0 ° C for 1 hour and an additional 3 hours as the temperature rose to ambient conditions. Water (200 mL) was added and the mixture was neutralized with 10% ammonium hydroxide (100 mL). The organic layer was washed with water (1 x 200 mL) and dried over MgSO 4.

Concentration in vacuo afforded an orange-orange oil (3.5 g, 33%). The water / 10% ammonium hydroxide solution was saturated with sodium chloride and extracted with ethyl acetate (2 x 400 mL). The organic layer was dried over MgSO 4 and concentrated. This gave the THP-protected sulfone thiopyranp-F compound as an orange foam (6.1 g, 57%).

Part Β: To a solution of THP-protected sulfone thiopyran-pF from A (6.0 g, 13.8 mmol) in N, N-dimethylacetamide (25 mL) was added tyramine (3.8 g, 28 mmol) followed by CSCO3 (13, 6 g, 42 mmol). The reaction mixture was heated at 95 ° C for 5 hours. Removal of Ν, Ν-dimethylacetamide gave a brown solid (20 g). Chromatography (reverse phase C-18, acetonitrile / H 2 O) gave the THP-protected tyramine product as a brown oil (1.0 g, 13%).

Part C: To the solution of the crude THP-protected tyramine product from Part B (1.0 g,

1.8 mmol) in acetonitrile (40 mL) was slowly added 10% HCl _and q (100 mL). After stirring overnight (about 18 hours) the acetonitrile was removed. The resulting precipitate was collected. This gave the title compound

44 • 9 9 9

· 9 · 9 9

9 9 9

ΦΦ φ φ »· · · · · · · · · ·

303 φ 4 4 4 4 4 · 4 9 as a brown solid (0.9 g, 99%). MS (FAB) M ⁺ H calcd for C 20 H 24 ClN 4 O 7 S 2: 469, found 469.

Example 55

Preparation of 4- (4-fluorophenyl) sulfonyl) -tetrahydro-N - ((tetrahydro-2H-pyran-2-yl) oxy) -2H-pyran-4-carboxamide

Part A: In a dry apparatus under nitrogen, sodium metal (8.97 g, 0.39 mol) was added to methanol (1000 mL) at 2 ° C. The reaction mixture was stirred at ambient temperature for 45 minutes when the sodium was dissolved. The solution was cooled to 5 ° C and 4-fluorothiophenol (41.55 mL, 0.39 mol) was added followed by methyl chloroacetate (34.2 mL, 0.39 mol). The reaction mixture was stirred at ambient temperature for 4 hours, filtered and concentrated in vacuo to afford the sulfide as a clear colorless oil (75.85 g, 97%).

Part Β: To a solution of the sulfide of Part A (75.85 g, 0.38 mol) in methanol (1000 mL) was added H 2 O (100 mL) and Oxone ® 720 g, 1.17 mol) at 20 ° C. An exothermic reaction to 67 ° C was recorded. After 2 hours, the reaction mixture was filtered and the cake washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with brine, dried over MgSO 4, filtered, and concentrated in vacuo. This gave the sulfone as a crystalline solid (82.74 g, 94%).

Part C: To a solution of the sulfone of Part B (28.5 g, 123 mmol) in N, N-dimethylacetamide (200 mL) was added potassium carbonate (37.3 g, 0.27 mol), bis (2-bromoethyl) ether (19 mL). , 3 mL, 0.147 mol), 4-dimethylaminopyridine (0.75 g, 6 mmol) and tetrabutylammonium bromide (1.98 g, 6 mmol). The reaction mixture was stirred overnight (about 18 hours) at ambient temperature. The reaction mixture was poured slowly into 1M HCl (300 mL). The resulting solid was filtered and the cake washed well with hexanes. The solid was recrystallized from ethyl acetate / hexanes. This gave the pyran compound as a beige solid (28.74 g, 77%). MS (ES +) MH ⁺ calculated for C 13 H 15 ^{O 5} S 1 F 1: 303, found 303.

Part D: In a dry nitrogen apparatus, the pyran compound from Part C (8.0 g, 26.5 mmol) was dissolved in dry tetrahydrofuran (250 mL) and trimethylsilonate solution was added to the solution.

304 • a ·· • · «<

Toto toto toto toto toto to to to to to to • • • to>>>>>>>>>>>> potassium (10.2 g, 79.5 mmol) in dry tetrahydrofuran (15 mL) at ambient temperature. After 90 minutes, water (100ml) was added and the solution was 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 6M HCl to pH = 1. The suspension was extracted with ethyl acetate, and the combined extracts were washed with water, dried over Na 2 SO 2, filtered and concentrated in vacuo. The residue was heated with diethyl ether, the solids were filtered and dried. This gave the carboxylic acid as a crystalline solid (5.78 g, 76%). HRMS (ES-) M-H calcd for C12H13O5S1F1: 287.04, found 287.04.

Part Ε: In a dry apparatus under nitrogen, the carboxylic acid of 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- hydrate hydroxybenzotriazole (5.1 g, 37.9 mmol), N-methylmorpholine (10.4 mL, 94.8 mmol) O-tetrahydro-2H-pyranyl-hydroxylamine (11.5 g, 98 mmol) and 1- (3 dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (8.48 g, 44.2 mmol). After 3 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with H 2 O, 5% aqueous KHSO 4, saturated NaHCO 3, brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the title compound as a crystalline solid (5.78 g, 76%). HRMS (ES-) M-H calcd for C 18 H 18 NO 5 SiF 3: 388.12, found 388.12.

Example 56

Preparation of 4 - ((4- (3,4-ifluorophenoxyphenyl) sulfonyl)) tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

-dimethylacetamide (6 mL) was added 3,4-difluorophenol (1.0 g, 7.7 mmol) followed by cesium carbonate (6.6 g, 20.2 mmol). The reaction mixture was heated at 95 ° C for 5 hours. Removal of the N, N-dimethylacetamide in vacuo gave a brown solid (8.3 g, quantitative yield). Chromatography (reverse phase C-18, acetonitrile / H 2 O) gave the THP-protected tyramine product as a brown oil (1.0 g, 13%).

Part C: To a solution of the crude THP-protected tyramine product from Part B (1.0 g, 1.8 mmol) in acetonitrile (40 mL) was slowly added 10% HCl _and q (100 mL). After stirring overnight (about 18 • «

305.:: ⁹ :: ··: ·: ::

(Ftftft ftft ftft (mftft · hr)) acetonitrile was removed. The resulting precipitate was collected. This afforded the title compound as a brown solid (0.9 g, 99%). MS (FAB) M ⁺ H calcd for C 18 H 18 NO 3 S: 414, found 414.

Example 57

Preparation of tetrahydro-N-hydroxy-4 - ((4- (4-iodophenoxy) phenyl) sulfonyl) -2H-pyran-4-carboxamide

-dimethylacetamide (6 mL) was added 4-iodophenol (1.7 g, 7.8 mmol) followed by cesium carbonate (6.6 g,

20.2 mmol). The reaction mixture was heated at 95 ° C for 5 hours. Removal of Ν, Ν-dimethylacetamide in vacuo gave a brown solid (5.7 g, quantitative yield). Chromatography (reverse phase C-18, acetonitrile / H2O) gave the THP-protected iodo product in solution.

Part Β: To a solution of the crude THP-protected iodo product from A in acetonitrile / 40 (40 mL) was slowly added 10% HCl _and q (100 mL). After stirring overnight (about 18 hours) the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (2.6 g, 99%). MS (FAB) M ⁺ H calcd for C 19 H 17 INO 5 S: 504, found 504.

Example 58

Preparation of tetrahydro-N-hydroxy-4 - ((4- (4- (2,4,5-trifluorophenoxy) phenyl) sulfonyl)) - 2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (2.0 g, 5.2 mmol) in N, N-dimethylacetamide (6 mL) was added 2,4,5-trifluorophenol (1.2 g, 7.8 mmol). and then cesium carbonate (10.1 g, 31.0 mmol). The reaction mixture was heated at 95 ° C for 32 hours. Removal of the N, N-dimethylacetamide in vacuo gave a brown solid (5.7 g, quantitative yield).

ft ·

306

Chromatography (reverse phase C-18, acetonitrile / H2O) gave the THP-protected phenol product (1.2 g, 44%).

Part Β: To a solution of the crude THP-protected phenol product from Part A in acetonitrile / f (40 mL) was slowly added 10% HCl _and q (100 mL). After stirring overnight (about 18 hours) the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (0.79 g, 79%). MS (FAB) M ⁺ H calcd for C 18 H 18 F 3 NO 6 S: 430, found 430.

Example 59

Preparation of 4 - ((4- (3,4-dichlorophenoxy) phenyl) sulfonyl)) - tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

-dimethylacetamide (6 mL) was added 3,4-dichlorophenol (1.3 g, 7.8 mmol) then cesium carbonate (6.6 g, 20.2 mmol). The reaction mixture was heated at 95 ° C for 12 hours. Removal of the N, N • dimethylacetamide in vacuo gave a brown solid (5.7 g, quantitative yield). The residue was taken up in acetonitrile / H 2 O (20 mL) and acidified to pH = 6. The resulting white precipitate was collected, giving the THP-protected product as a white cake (1.8 g, 64%).

Part Β: To a solution of the crude THP-protected product from Part A in acetonitrile / H 2 O (20 mL) was slowly added 10% HCl _and q (40 mL). After stirring overnight (about 18 hours) the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (0.71 g, 47%). MS (FAB) M ⁺ H calcd for C 18 H 17 Cl 2 NO 3 S: 447, found 447.

Example 59

Preparation of tetrahydro-N-hydroxy-4 - ((4- (5- (trifluoromethyl) -2-pyridinyl) thio) phenyl) sulfonyl) -2H-pyran-4-carboxamide monohydrochloride

-dimethylacetamide (6 mL) was added 5- (trifluoromethyl) -2-pyridinyl thiophenol (1.4 g, 7.8 mmol) then potassium carbonate (2.2 g, 15.6 mmol). The reaction mixture was heated at 65 ° C for 12 hours.

Removal of Ν, Ν-dimethylacetamide in vacuo gave a brown solid (5.4 g, quantitative yield). Chromatography (reverse phase C-18, acetonitrile / HgO) gave the THP-protected product in solution.

Part Β: To a solution of the crude THP-protected product from Part A in acetonitrile / H 2 O (40 mL) was slowly added 10% HClaq (40 mL). After stirring overnight (about 18 hours) the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (0.20 g, 8%). MS (FAB) M ⁺ H calcd for C 18 H 17 N 2 O 2: C, 463, found 463.

Example 60

Preparation of 4 - ((4- (3,4-dichlorophenyl) thio) phenyl) sulfonyl) -tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

-dimethylacetamide (6 mL) was added 3,4-dichlorothiophenol (1.4 g, 7.8 mmol) followed by potassium carbonate (2.2 g, 15.6 mmol). The reaction mixture was heated at 70 ° C for 6 hours. Removal of the N, N • dimethylacetamide in vacuo gave a brown solid (5.6 g, quantitative yield). Chromatography (reverse phase C-18, acetonitrile / H2O) gave the THP-protected product in solution.

Part Β: To a solution of the crude THP-protected product from Part A in acetonitrile 2 H 2 O (40 mL) was slowly added 10% HCl _and q (40 mL). After stirring overnight (about 18 hours) the acetonitrile was removed. The resulting precipitate was collected, giving the title compound as a white solid (1.5 g, 62%). MS (FAB) M ⁺ H calcd for C 18 H 16 Cl 3 NO 6 S: 463, found 463.

308 «4 4 4 •» e · 4 · 4 4 4 4 4 4 4 4 4 4 4 4 4 444 ¢ 14 · 44 4 4

Example 61

Preparation of 4 - ((4 - ((2-amino-4- (trifluoromethyl) phenyl) thio) phenyl) sulfonyl) monohydrochloride tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

dimethylacetamide (6 mL) was added 2-amino-4- (trifluoromethyl) thiophenol hydrochloride (1.8 g, 7.8 mmol) followed by potassium carbonate (3.6 g, 26 mmol). The reaction mixture was heated at 70 ° C for 8 hours. Removal of the dimethylacetamide in vacuo gave a brown solid (14 g, quantitative yield). Chromatography (reverse phase C-18, acetonitrile / H 2 O) gave the THP-protected product in solution.

Part Β: To a solution of THP-protected product in acetonitrile / H2O (40 mL) was slowly added 10% HCl _and q (40 mL). After stirring overnight (about 18 hours) the acetonitrile was removed. The resulting precipitate was collected to give the title compound as a white solid (1.3 g, 52%). MS (FAB) M ⁺ H calcd for C 18 H 18 Cl 2 NO 3 S: 447, found 447.

Example 62

Preparation of tetrahydro-4 - ((4- (4-phenyl-1-pyridinyl) phenyl) sulfonyl)) - 2H-pyran-4-carboxamide monohydrochloride

O »4 • 4» 4 «1» · · <

4 · 44

444 * ·

4 ·

309 ···· 4

Part A: In a dry apparatus under nitrogen, sodium metal (8.97 g, 0.39 mol) was added to methanol (1000 mL) at 2 ° C. The reaction mixture was stirred at ambient temperature for 45 minutes when the sodium was dissolved. The solution was cooled to 5 ° C and p-fluorothiophenol (41.55 mL, 0.39 mol) was added followed by methyl 2-chloroacetate (34.2 mL, 0.39 mol). The reaction mixture was stirred at ambient temperature for 4 hours, filtered and concentrated in vacuo to afford the sulfide as a clear colorless oil (75.85 g, 97%).

Part Β: To a solution of the sulfide of Part A (75.85 g, 0.38 mol) in methanol (1000 mL) was added H 2 O (100 mL) and Oxone ® 720 g, 1.17 mol) at 20 ° C. An exothermic reaction to 67 ° C was recorded.

After 2 hours, the reaction mixture was filtered and the cake washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with brine, dried over MgSO 4, filtered, and concentrated in vacuo. This gave the sulfone as a crystalline solid (82.74 g, 94%).

Part C: To a solution of the sulfone of Part B (28.5 g, 123 mmol) in N, N-dimethylacetamide (200 mL) was 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 mixture was stirred overnight (about 18 hours) at ambient temperature. The reaction mixture was slowly poured into 1M HCl (300 mL). The resulting solid was filtered and the cake washed well with hexanes. The solid was recrystallized from ethyl acetate / hexanes. This gave the pyran compound as a beige solid (28.74 g, 77%). MS (ES +) MH ⁺ calcd for C 13 H 15 O 5 S 1 F 1: 303, found 303.

Part D: In a dry nitrogen apparatus, to the pyran compound of Part C (1.21 g, 4.0 mmol) in dimethyl sulfoxide (10 mL) was added cesium carbonate (3.26 g, 4.0 mmol) and 4-methylpiperidine (0). , 64 g, 4.0 mmol) in dimethyl sulfoxide (10). The suspension was stirred at 90 ° C for 2 hours. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with 5% aqueous KHSO 4, H 2 O, saturated NaHCO 3, brine, dried over Na 2 SO 4 and concentrated in vacuo. The resulting solid was suspended in diethyl ether, filtered and dried. This gave N-substituted piperidine as a white solid (1.2 g, 67%). MS (FAB +) MH ⁺ calcd for C 24 H 29 N 1 O 5 S 1: 444, found 444.

Part E: To a suspension of N-substituted piperidine of Part D (815 mg, 1.84 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 50% sodium hydroxide (3 mL). After 24 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The suspension was diluted with water (10 mL) and 6M HCl was added until pH = 7. Vacuum filtration of the resulting precipitate gave acid

310 * · · 4 · 4 · ft · 4 · 4 · · · · · · ·

4 · «9 9 9 9 4 9 9

4 4 4 4

4 4 4 • 4 4 «as a white solid (705 mg, 89%). MS (FAB +) MH ⁺ calcd for C 23 H 27 N 1 O 5 S 1: 430, found 430.

Part F: In a dry nitrogen apparatus, the carboxylic acid of Part E (620 mg, 1.44 mmol) was suspended in dichloromethane (10 mL) and N, N-dimethylformamide (3 mL) and the remaining reagents were added to the solution in the following order. : bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (810 mg, 1.73 mmol), N-methylmorpholine (0.5 mL, 4.34 mmol) and O-tetrahydro-2H-pyranyl-hydroxylamine (190 mg, 1.59) mmol). After 4 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with H 2 O, brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the protected hydroxamate as a white solid (630 mg, 83%). MS (FAB +) MH + calcd for C 28 H 22 N 2 O 5 S 1: 529, found 529.

Part G: To a solution of THP-protected hydroxamate of part F (600 mg, 1.14 mmol) in dioxane (1.5 mL) was added a solution of 4N HCl in dioxane (1.5 mL) and methanol (1.5 mL). After 2 hours at ambient temperature, the reaction mixture was poured into diethyl ether (100 mL). Vacuum filtration of the resulting precipitate gave the title compound as a light beige solid (500 mg, 91%). MS (FAB) M + Li calcd for C 23 H 28 N 2 O 5 S 1: 445, found 445.

Example 63

Preparation of 4 - ((4- (4- (1,3-benzodioxol-5-yloxy) -1-pyridinyl) phenyl) sulfonyl)) tetrahydro-N-hydroxy-2H-thiopyran-4-carboxamide monohydrochloride

Part A: In a dry apparatus under nitrogen, 4-hydroxypiperidine was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyl dicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 ° C. After stirring at ambient temperature for 4 hours, the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with H 2 O, 5% aqueous KHSO 4, saturated NaHCO 3, brine, dried and concentrated in vacuo. This gave BOC-piperidine as a white solid (37.7 g, 94%).

Part Β: In a dry apparatus under nitrogen, BOC-piperidine of Part A in dry tetrahydrofuran (100 mL) was cooled to 0 ° C and triphenylphosphine (9.77 g, 37.3 mmol) was added. After stirring at 0 ° C for 15 min, sesamol (5.15 g, 37.3 mmol) was added to the reaction mixture followed by dropwise addition of diethyl azocarboxylate (5.87 mL, 37.7 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes and then at ambient temperature for 20 hours. The reaction mixture was suspended in diethyl ether, the triphenylphosphine oxide was filtered off and the filtrate was concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave substituted BOC-piperidine as a white solid (3.14 g, 39%).

Part C: To a suspension of the substituted BOC-piperidine of Part B (3.14 g, 9.8 mmol) in dioxane was added a 4M solution of HCl in dioxane (15 mL). After 3 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was suspended in diethyl ether and vacuum filtration of the resulting precipitate gave the hydrochloride salt as a white solid (2.3 g, 100%).

Part D: To a suspension of Part C hydrochloride (0.93 g, 3.6 mmol) in N, N • dimethylformamide (10 mL) was added cesium carbonate (2.93 g, 9 mmol) and the title compound of Example 55 (1, 16 g, 3.0 mmol). The suspension was stirred at 90 ° C for 24 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with H 2 O, 5% KHSO 4, saturated NaHCO 3, brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo.

Chromatography (on silica, ethyl acetate / hexanes) gave the substituted THP-protected hydroxamate as a white solid (640 mg, 36%). MS (FAB +) MH + calcd for C 29 H 36 N 2 O 9 S 1: 589, found 589.

Part E: To a suspension of THP-protected hydroxamate of Part D (600 mg, 1.02 mmol) in dioxane was added a 4M solution of HCl in dioxane (3 mL) and methanol (3 mL). After 1 hour at ambient temperature, the reaction mixture was poured into diethyl ether (100 mL). Vacuum filtration of the resulting precipitate gave the title compound as a light beige solid (440 mg, 80%). HRMS (ES +) MH + calcd for C 24 H 28 N 2 O 8 S 1: 505.16, found 505.16.

Example 64

Preparation of tetrahydro-N-hydroxy-4 - ((4- (4-methoxyphenoxyphenyl) sulfonyl)) - 2H-pyran-4-carboxamide

O • 4 ·

312 * 4 • 4 • 4 • 4 4 • 4 «4 · 4 • 4 44 4 * 44 • 4 4 4» «4

4 4 4 4 4 5

44443 44 4

4 4 4 4 4

43 4 «44

Part A: To a solution of the title compound of Example 55 (3.48 g, 9 mmol) in N, N • dimethylformamide (20 mL) was added cesium carbonate (8.8 g, 27 mmol) and 4-methoxyphenol (2.23 g). , mmol). The suspension was stirred at 90 ° C for 24 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the substituted THP-protected hydroxamate as a beige foam (3.82 g, 86%). MS (FAB +) MH + calcd for C 24 H 29 N 1 O 8 S 1: 492, found 492.

Part Β: To a suspension of THP-protected hydroxamate from Part A (3.6 g, 1.02 mmol) in dioxane was added a 4M solution of HCl in dioxane (18 mL) and methanol (18 mL). After 15 minutes at ambient temperature, the reaction mixture was diluted with ethyl acetate, washed with H 2 O, dried over Na 2 SO 4, filtered and concentrated in vacuo. The product was recrystallized (acetone / hexanes). This afforded the title compound as a white solid (2.1 g, 70%). HRMS (ES +) MH + calcd for C19'11N107S1: 408.11, found 408.11.

Example 65

Preparation of tetrahydro-N-hydroxy-4 - ((4- (4-methoxyphenylthio) phenyl) sulfonyl) -2H-pyran-4-carboxamide

-dimethylformamide (20 mL) was added potassium carbonate (1.33 g, 9.6 mmol) and pmethoxybenzenethiol (1.48 mL, 12 mmol). The suspension was stirred at 65 ° C for 24 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the substituted THP-protected hydroxamate as a white foam (4.1 g, 100%). HRMS (ES +) M + NH 4 calcd for C 24 H 29 N 1 O 7 S 2: 525.17 found 525.17.

Part Β: To a suspension of THP-protected hydroxamate from Part A (4.0 g, 7.9 mmol) in dioxane (20 mL) was added a 4M solution of HCl in dioxane (20 mL) and methanol (20 mL). After 15 minutes at ambient temperature, the reaction mixture was diluted with ethyl acetate, washed with H 2 O, dried over Na 2 SO 4, filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexanes). This gave the title compound as a white solid (2.21 g, 67%). HRMS (ES +) MH + calculated for

C19H21NiOgS2: 424.09, found 424.09.

313 • ftft • ft ftft ftft ftft ftftftft ftft ftftft ft • «• ft ftft ft ftft 9 • ftft · ft ft · ftft · ft t ··

Example 66

Preparation of 4 - ((4-fluorophenyl) sulfonyl) -tetrahydro-N-tetrahydro-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (530 mg, 1.38 mmol) in dioxane (5 mL) was added a 4M solution of HCl in dioxane (5 mL) and methanol (5 mL). After 15 minutes at ambient temperature, the reaction mixture was concentrated in vacuo. Reverse phase chromatography (on silica, acetonitrile / H2O) gave the title compound as a beige solid (140 mg, 34%). HRMS (ES +) M + NH 4 calcd for C 12 H 14 F 1 NO 5 S1: 321.09, found 321.06.

Example 67

Preparation of tetrahydro-N-hydroxy-4 - ((4- (4-piperidinyloxy) phenyl) sulfonyl)) 2H-pyran-4-carboxamide monohydrochloride

H

Part A: In a dry apparatus under nitrogen, 4-hydroxy-N-tert-butoxycarbonyl) piperidine (844 mg, 4.2 mmol) was added to 60% sodium hydride (210 mg, 5.25 mol) in dry N, N -dimethylformamide (10 mL) at 0 ° C. The suspension was stirred at ambient temperature for 2 hours. At 5 ° C was added the title compound of Example 55 (1.35 g, 3.5 mmol) and the reaction mixture was heated to 50 C for 3 hr ^9. The reaction mixture was cooled, quenched with water and concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave THP-protected.

4

4 4

4 4

314

44

4 4 4

4 4 4

4 4 4 hydroxamate as a white foam (283 mg, 14%). MS (FAB +) MH + calcd for C 27 H 40 N 2 O 9 S 1:

569, found 569.

Part Β: To a solution of THP-protected hydroxamate of Part A (530 mg, 0.93 mmnl) in dioxane (5 mL) was added a solution of 4M HCl in dioxane (5 mL) and methanol (5 mL). After 15 minutes at ambient temperature, the reaction mixture was concentrated in vacuo. Reverse phase chromatography (on silica, acetonitrile / H2O buffered with 0.01% HCl) gave the title compound as a beige solid (240 mg, 62%). HRMS (ES +) MH + calcd for C 17 H 24 N 2 O 8 Si: 385.14, found 385.14.

Example 68

Preparation of tetrahydro-N-hydroxy-4 - ((4- (4-phenylmethyl) amino) phenyl) sulfonyl) -2H-pyran-4-carboxamide monohydrochloride

Part A: In a solid phase reaction vessel, benzylamine (11 mL, 100 mmol) was added to resin II (as described below, 5.0 g, 4.55 mmol) swollen in dry 1-methyl-2-pyrrolidinone (40 mL). ). The reaction mixture was heated at 100 ° C for 48 hours with good shaking. The resin was transferred to a frit and washed four times with N, N-dimethylformamide (30 ml), four times with methanol (30 ml), four times with dichloromethane (30 ml) and dried. The dried resin was transferred to a flask and a solution of 95% trifluoroacetic acid / 5% water (50 mL) was added. The suspension was stirred for 1 hour, filtered and the cake washed with dichloromethane The combined filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate and saturated NaHCO 3 solution was added until pH = 7. The organic layer was dried over Na 2 SO 4, filtered, and concentrated in vacuo. Reverse phase chromatography (on C-18 essential oil, acetonitrile / H2O buffered with 0.01% HCl) gave the title compound as a reddish solid of 1.01 g, 52%). HRMS (ES +) MH + calcd for C 19 H 22 N 2 O 5 S 1: 408.16, found 408.16.

Example 69

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

315 ··· ♦ · · · • · · · ·

Dimethylacetamide (20 mL) was added cesium carbonate (8.8 g, 27 mmol) and p- (trifluoromethoxy) phenol (2.1 g, 16 mmol). The suspension was stirred at 95 ° C for 19 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the substituted THP-protected hydroxamate as a white foam (4.2 g, 96%). HRMS (ES +) MH + calculated for 24 ^ 26 ^ ^^ 8 ^ ¹ ^ 3- 1 546.14, found 546.14.

Part Β: To a suspension of THP-protected hydroxamate from part A (4.0 g, 7.3 mmol) in dioxane (20 mL) was added a 4M solution of HCl in dioxane (20 mL) and methanol (20 mL). After 15 minutes at ambient temperature, the reaction mixture was diluted with ethyl acetate, washed with H 2 O, dried over Na 2 SO 4, filtered and concentrated in vacuo. The product was recrystallized (acetone / hexanes). This afforded the title compound as a white solid (2.2 g, 65%). HRMS (ES +) M + NH 4 ⁺ calcd for C 19 H 18 N 4 O ₇ S 1 F ₃ : 479.11, found 479.11.

Example 70

Preparation of 4 - ((4- (3,5-difluorophenoxy) phenyl) sulfonyl) tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (3.1 g, 8 mmol) in N, N-dimethylacetamide (20 mL) was added cesium carbonate (8.8 g, 27 mmol) and 3,5-difluorophenol (2, 2 mL). 1 g, mmol). The suspension was stirred at 95 ° C for 48 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na 2 SO 4 (> 4, filtered and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave substituted

THP-protected hydroxamate as a beige foam (3.23 g, 81%). HRMS (ES +) MH + calculated for

C23H25N1O7S1F2: 498.14, found 498.14.

• * ·

316 • to ·· · to · this to •

· To to to to to to to to to to to to to to

Part Β: To a suspension of THP-protected hydroxamate from Part A (3.2 g, 6.3 mmol) in dioxane (20 mL) was added 4N HCl in dioxane (20 mL) and methanol (20 mL). After 15 minutes at ambient temperature, the reaction mixture was diluted with ethyl acetate, washed with H 2 O, dried over Na 2 SO 4, filtered and concentrated in vacuo. The product was recrystallized (acetone / hexanes). This afforded the title compound as a white solid (1.5 g, 57%). HRMS (ES +) M + NH ^{4 4} - calculated for C 18 H 17 N 3 O 5 S 2: 431.11, found 431.11.

Example 71

Preparation of 4 - ((4- (3,5-dichlorophenoxy) phenyl) sulfonyl) tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Dimethylacetamide (20 mL) was added cesium carbonate (8.8 g, 27 mmol) and 3,5-dichlorophenol (2.61 g, 16 mmol). The suspension was stirred at 95 ° C for 48 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the substituted THP-protected hydroxamate as a white foam (4.17 g, 98%). HRMS (ES +) MH + calcd for C 23 H 25 N 10 O 5 S 4: 547.11, found 547.10.

Part Β: To a suspension of THP-protected hydroxamate from part A (3.5 g, 6.6 mmol) in dioxane (20 mL) was added a 4M solution of HCl in dioxane (20 mL) and methanol (20 mL). After 15 minutes at ambient temperature, the reaction mixture was diluted with ethyl acetate, washed with H 2 O, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was suspended in diethyl ether and vacuum filtration of the resulting precipitate afforded the title compound as a white solid (2.98 g, 100%). HRMS (ES +) M + NH 4 ⁺ calcd for C 18 H 17 N 3 O 5 S 2 Cl 2. 463.05, found 463.05.

Example 72 • ·

9

9

• · · · ·

Preparation of tetrahydro-N-hydroxy-4 - ((4- (4- (phenylmethyl) oxy) phenoxy) phenyl) sulfonyl) -2H-pyran-4-carboxamide

317

9 4 9 · · «•

4 9 9

9 99

Part A: To a solution of the title compound of Example 55 (2.7 g, 7 mmol) in N, N-dimethylacetamide (20 mL) was added cesium carbonate (6.84 g, 21 mmol) and 4- (benzyloxy) phenol (2 mL). , 8 g, 14 mmol). The suspension was stirred at 95 ° C for 6 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the substituted THP-protected hydroxamate as a white foam (3.94 g, 99%). HRMS (ES +) M + NH 4 ⁺ calculated for C 30 H 33 N 3 O 8 Si: 585.23, found 585.23.

Part Β: To a suspension of THP-protected hydroxamate from Part A (1.42 g, 2.5 mmol) in dioxane (6.3 mL) was added 4N HCl in dioxane (6.3 mL) and methanol (6.3 mL). ml). After 15 minutes at ambient temperature, the reaction mixture was diluted with ethyl acetate, washed with H 2 O, dried over Na 2 SO 4, filtered and concentrated in vacuo. The product was recrystallized (acetone / hexanes). This afforded the title compound as a white solid (0.56 g, 46%). HRMS (ES +) MH + calcd for ^C 25 ^H 25 ^N 1 7 ^S 1 ^: 484.14, found 484.14.

Example 73

Preparation of tetrahydro-N-hydroxy-4 - ((4- (4-trifluoromethoxy) phenyl) sulfonyl) -2H-pyran-4-carboxamide

-dimethylacetamide (20 mL) was added potassium carbonate (2.21 g, 16 mmol) and p-trifluoromethoxybenzenethiol (2.33 g, 12 mmol). The suspension was stirred at 70 ° C for 2 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo. Chromatography (on essential oil, • • • *

318

00 • 9 0 9

0 0 0 0

9 9

90

00

9 0 · 9 9 0

0 0 9

9 9 9

99 ethyl acetate / hexanes) gave the substituted THP-protected hydroxamate as a white solid (4.4 g, 98%). HRMS (ES +) M + NH 4 ⁺ calcd for C 24 H 26 N 1 O 7 S 2 F 3: 579.14, found 579.14.

Part Β: To a suspension of THP-protected hydroxamate from part A (4.15 g, 7.4 mmol) in dioxane (20 mL) was added a 4M solution of HCl in dioxane (20 mL) and methanol (20 mL). After 15 minutes at ambient temperature, the reaction mixture was diluted with ethyl acetate, washed with H 2 O, dried over Na 2 SO 4, filtered and concentrated in vacuo. The product was recrystallized (acetone / hexanes). This afforded the title compound as a white solid (3.0 g, 85%). HRMS (ES +) M + NH 4 ⁺ calcd for C 19 H 18 N 1 O 6 S 2 F 3: 495.09, found 495.09.

Example 74

Preparation of phenylmethyl 4 - ((2- (hydroxyamino) -2-oxoethyl) sulfonyl) phenyl) carbamate

Part A: To a suspension of 2- (4-aminophenylthio) acetic acid (20.00 g, 0.11 mmol) in methanol (100 mL) cooled to 0 ° C was slowly added thionyl chloride (24.0 mL, 0.33 mmol). ). More methanol (100 mL) was added and the cooling bath was removed. The resulting mixture was heated to reflux for 2 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in VH 2 O and neutralized with saturated NaHCO 3. The aqueous reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4. Concentration in vacuo gave the methyl ester sulfide as a dark purple oil. (22.75 g, quantitative yield).

Part Β: To a solution of methyl ester sulfide from Part A (10.0 g, 50.7 mmol) in dichloromethane (100 mL) was added N-methylmorpholine (11.2 mL, 101.4 mmol) followed by (benzyloxycarbonyloxy) succinimide (12.6 g, 50.7 mmol). The resulting mixture was stirred overnight (about 18 hours) at ambient temperature and then concentrated in vacuo. The residue was dissolved in ethyl acetate and then washed with H 2 O, 5% KHSO 4, saturated NaCl, and dried over Na 2 SO 4. Concentration in vacuo gave benzyloxy carbamate sulfide as a dark oil (16.2 g, 96%).

• ·

• · ·

Part C: To the benzyloxy carbamate sulfide solution of Part B (16.2 g, 48.7 mmol)

319 in tetrahydrofuran (100 mL) and H 2 O (10 mL) were added Oxone ® (90.0 g, 146.4 mmol) and the resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H 2 O, saturated NaCl, and dried over Na 2 SO 4. Concentration in vacuo provided the benzyloxy carbamate sulfone as a brown solid (15.6 g, 88%).

Part D: To a solution of the sulfonbenzyloxycarbamate of Part C (0.25 g, 0.69 mmol) in tetrahydrofuran (3 mL) was added 50% aqueous hydroxylamine (1.5 mL). The resulting mixture was stirred at ambient temperature for 24 hours. The mixture was then diluted with ethyl acetate (30 mL), washed with H 2 O, saturated NaCl, and dried over Na 2 SO 4. Concentration in vacuo followed by washing with hot diethyl ether gave the title compound as a light pink solid (0.20 g, 80%). MS MH ⁺ calculated for C 18 H 18 N 2 O 6 S: 365, found 365.

Example 75

Preparation of N-hydroxy-2 - ((4 - ((phenylamino) carbonyl) amino) phenyl) sulfonyl) acetamide

HIM,

Part A: Hydrogen gas was bubbled into a suspension of the sulfonbenzyloxycarbamate of Part C of Example 74 (13.4 g, 36.8 mmol) and 4% Pd / C in tetrahydrofuran (100 mL). When hydrogen uptake ceased, the mixture was purged with N 2 and then filtered through a pad of Celite ® washing with tetrahydrofuran. The filtrate was concentrated in vacuo. This gave aniline as a brown solid (8.1 g, 96%).

Part Β: To a suspension of aniline from Part A (0.50 g, 2.2 mmol) in dichloromethane (4 mL) was added phenyl isocyanate (0.36 mL, 3.3 mmol). The mixture was stirred overnight (about 18 hours) at ambient temperature and then diluted with dichloromethane (50 mL). The mixture was washed with water and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the urea as a white solid (0.59 g, 78%).

Part C: To a solution of the urea from Part B (0.32 g, 0.92 mmol) in tetrahydrofuran (3 mL) was added 50% hydroxylamine (1.5 mL). The resulting mixture was stirred at ambient temperature for 24 hours. The mixture was then diluted with ethyl acetate (30 mL), washed with water, saturated NaCl, and dried over Na 2 SO 4.

·· ·· • · · · ft ·

Concentration in vacuo followed by washing with hot diethyl ether gave the title compound as a light pink solid (0.24 g, 76%). MS MH + calculated for C 15 H 16 N 2 O 5 S: 350, found 350.

320 • ft ftft ft ft 4 ft ft 4

Example 78

Dihydrochloride Preparation of 5 - ((4- (3,4-dimethylphenoxy) phenyl) sulfonyl) -N &apos; -hydroxy-l, 3-dimethylhexahydro-5-pyrimidinecarboxamide monopotassium salt

Part A: To a solution of Part B of Example 55 (2.00 g, 8.61 mmol) and 1,3,5-trimethylhexahydro-1,3,5-triazine (1.21 mL, 8.61 mmol) in benzene (20 mL) trifluoroacetic acid (0.66 mL, 8.61 mmol) was added slowly. The resulting mixture was heated to reflux for 1 hour, then cooled to ambient temperature. The mixture was extracted with 2M HCl. The aqueous layer was neutralized with saturated NaHCO 3 and then extracted with diethyl ether. The organic layers were washed with saturated NaCl and dried over Na 2 SO 4. Concentration in vacuo gave tetrahydropyrimidine as a clear oil. (2.31 g, 81%).

Part Β: To a solution of tetrahydropyrimidine of Part A (1.26 g, 3.81 mmol) in N, N-dimethylformamide (5.0 mL) was added 3,4-dimethylphenol (0.559 mL, 4.58 mmol) and cesium carbonate (3.72). g, 11.43 mmol). The resulting mixture was heated at 90 ° C for 16 hours. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the biaryl ether as a pale amber oil (1.40 g, 85%).

321 • 4 · 4 · ····

4 4 4 4 4 4 4

4 · «4

4 4 4

9 4

44

Part C: To a solution of the biaryl ether from Part B (0.936 g, 2.16 mmol) in tetrahydrofuran (5.0 mL) was added potassium trimethylsilanolate (0.360 g, 2.81 mmol). The resulting mixture was stirred at ambient temperature for 48 hours and then the solvent was removed. The resulting residue was dissolved in dichloromethane (5.0 mL) and then N-methylmorpholine (0.712 mL, 6.48 mmol), O-tetrahydro-2H-pyranyl-hydroxylamine (0.278 g, 2.38 mmol) was added. After stirring at ambient temperature for 10 minutes, PyBroP® (1.21 g, 2.59 mmol) was added. The resulting mixture was stirred at ambient temperature overnight (about 18 hours), then diluted with water with dichloromethane (50 mL) and washed with water. The organic layer was separated and washed with saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the hydroxamate as a white solid (0.970 g, 87%).

Part F: To a suspension of the hydroxamate of Part E (0.667 g, 1.29 mmol) in dioxane (3.0 mL) and methanol (1.0 mL) was added a 4M solution of HCl in dioxane (3.22 mL, 12.9 mmol). ). After stirring for 30 minutes, the reaction mixture was concentrated in vacuo. Reverse phase chromatography (on silica, acetonitrile / H2O / trifluoroacetic acid) gave the title compound as a white solid (0.379 g, 58%). MS MH ⁺ calculated for C 21 H 28 O 5 N 3 S: 434, found 434.

Example 79

Preparation of 4 - ((4- (4-chloro-3-methylphenoxy) phenyl) sulfonyl) -N-hydroxy-4-piperidinecarboxamide monohydrochloride

cooled to 0 ° C, thionyl chloride (85.0 mL, 1.16 mol) was slowly added dropwise. Once the addition was complete, the cooling bath was removed and the mixture was heated to reflux for 2 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The resulting solids were suspended in ethyl acetate then washed with saturated NaHCO 3. The aqueous layer was concentrated in vacuo and the resulting solids dissolved in hot diethyl ether and decanted from the salts. The organic layers were then concentrated in vacuo. This gave the methyl ester as a white solid (55.4 g, quantitative yield).

Part Β: To a solution of di-tert-butyl dicarbonate (15.3 g, 70.0 mmol) in tetrahydrofuran (100 mL) was added the methyl ester from Part A (10.0 g, 70.0 mmol). The resulting mixture was stirred overnight (about 18

44 • «4 · * 4 4 <· 443 4

5 · · »

4 »

322 ·· • »

4 4

4 · ·

4 4 • 4 <· 44 ·· hours) at ambient temperature and then concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexane) gave BOC-piperidine methyl ester as a pale yellow oil. (10.1 g, 59%).

Part C: To a solution of BOC-piperidine methyl ester of Part B (23.31 g, 0.096 mol) in tetrahydrofuran (500 mL) cooled to -40 ° C was slowly added lithium diisopropylamide (57.5 mL, 2.0 M in THF, 0.115 mol) . The resulting mixture was stirred at -40 ° C for 1 hour and then at 0 ° C for 30 minutes. The mixture was again cooled to -40 ° C and a solution of the disulfide from Part A, Example 6 (24.37 g, 96 mmol) in tetrahydrofuran (60 mL) was added slowly. The resulting mixture was slowly warmed to ambient temperature overnight (about 18 hours) and then H 2 O (200 mL) was added. The mixture was then concentrated in vacuo and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with 0.5M NaOH, H 2 O, saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the sulfide as an amber oil (28.1 g, 79%).

Part D: To a solution of Part C sulfide (28.2 g, 76 mmol) in dichloromethane (250 mL) cooled to 0 ° C was added m-chloroperoxybenzoic acid (48 g, 152 mmol). The resulting mixture was stirred at 0 ° C for 1 hour and then at ambient temperature for 2.5 hours. The mixture was then diluted with H 2 O and 10% NH 4 OH. The organic layer was washed with 10% NH 4 OH, H 2 O and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the sulfone as a white solid (24.7 g, 81%).

Part E: To a solution of the sulfone from Part D (3.00 g, 7.47 mmol) in N, N-dimethylformamide (15 mL) was added 4-chloro-3-methylphenol (1.28 g, 8.96 mmol). and cesium carbonate (7.30 g, 22.42 mmol). The resulting mixture was heated at 80 ° C for 8 hours. The mixture was then concentrated in vacuo and the residue partitioned between H 2 O and ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the biaryl ether as a clear oil (3.26 g, 83%).

Part F: To a solution of the biaryl ether of Part E (3.17 g, 6.05 mmol) in tetrahydrofuran (30 mL) was added potassium trimethylsilanolate (1.01 g, 7.87 mmol). The resulting mixture was stirred at ambient temperature for 20 hours. Additional tetrahydrofuran (40 mL) was added and the mixture was stirred at ambient temperature for 36 hours. Additional potassium trimethylsilanonate (0.233 g, 1.82 mmol) was added and the mixture was stirred at ambient temperature for 36 hours. Tetrahydrofuran was removed and the resulting residue was suspended in dichloromethane (30 mL). To the suspension was added N-methylmorpholine (2.00 mL, 18.15 mmol), Otetrahydro-2H-pyranyl-hydroxylamine (0.780 g, 6.66 mmol) followed by PyBroP® (3.38 g, 7.26 mmol) . The mixture was stirred at ambient temperature for 24 hours, then concentrated in vacuo. The residue was partitioned between H 2 O and ethyl acetate. The organic layer was washed with H 2 O, saturated NaCl, and dried

323 over Na 2 SO 4 - Chromatography (on silica, ethyl acetate / hexane) gave the hydroxamate as an off-white foam (2.98 g, 81%).

Part G: To a solution of Part F hydroxamate (2.98 g, 4.89 mmol) in dioxane (14 mL) and methanol (6 mL) was added a 4M solution of HCl in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 3.5 hours, then diethyl ether was added and the precipitate was collected by filtration. This afforded the title compound as a light pink solid (2.00 g, 88%). MS MH ⁺ calcd for C19H22O5N2CIS: 425, found 425.

Example 80

Preparation of 4 - ((4- (4-chloro-3-methylphenoxy) phenyl) sulfonyl) -4- (hydroxyamino) carbonyl) -1-piperidineacetic acid monohydrochloride

Part A: To a suspension of the title compound of Example 79 (0.250 g, 0.542 mmol) in acetonitrile (4.0 mL) was added tert-butyl bromoacetate (0.088 mL, 0.542 mmol) and potassium carbonate (0.150 g, 1.08 mmol). The resulting mixture was stirred at ambient temperature for 24 hours, then filtered through a pad of Celite® washing with ethyl acetate. The filtrate was then concentrated in vacuo. Reverse phase chromatography (on silica, acetonitrile / H2O / trifluoroacetic acid) gave the tert-butyl ester as a white solid (0.156 g, 53%).

Part B: The tert-butyl ester of Part A (0.156 g, 0.289 mmol) was treated with a solution of 4M HCl in dioxane (1.5 mL) and the resulting mixture was stirred at ambient temperature for 3.5 h at which time additional dioxane (2 mL) was added. After stirring at ambient temperature for 8 hours, the reaction mixture was concentrated in vacuo.

The residue was reacted again with a solution of 4M HCl in dioxane (1.5 mL) at ambient temperature for 4 hours.

Diethyl ether was added to the reaction mixture, and the precipitate was collected by filtration. This gave the title compound β

329 · · · · «

As an off-white solid (0.111 g, 74%). MS MH ⁺ calcd for C21H24O7N2CIS: 483, found 483.

Example 81

Preparation of 4 - ((4- (4-chloro-3-methylphenoxy) phenyl) sulfonyl) -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

HIM

Part A: To a suspension of the title compound of Example 79 (0.500 g, 1.08 mmol) in acetonitrile (8.0 mL) was added propargyl bromide (0.126 mL, 80% solution in toluene, 1.13 mmol) and potassium carbonate (0.300 g). , 2.17 mmol). The resulting mixture was stirred at ambient temperature for 24 hours, then filtered through a pad of Celite® washing with methanol. The filtrate was then concentrated in vacuo. Chromatography (on silica, ethyl acetate) gave N-propargylhydroxamate as a brown solid (0.200 g, 40%).

Part Β: To a solution of N-propargyl hydroxyamate from Part A (0.200 g, 0.432 mmol) in acetonitrile (3.0 mL) and H 2 O (0.5 mL) was added concentrated HCl (0.05 mL). The resulting mixture was stirred at ambient temperature for 5 minutes and concentrated in vacuo. This afforded the title compound as a pink solid (0.200 g, 93%). MS MH ⁺ calcd for C22H24O5N2CIS: 463, found 463.

Example 82

Preparation of 4 - ((4- (4-chloro-3-methylphenoxy) phenyl) sulfonyl) -N-hydroxy-1- (2-propenyl) -4-piperidinecarboxamide monohydrochloride

«To«) • * • this

325 • to • to • to · to · to · to · to · to · to · to · to · to · to · to ·

Part A: To a suspension of the title compound of Example 79 (0.500 g, 1.08 mmol) in acetonitrile (8.0 mL) was added allyl bromide (0.093 mL, 1.08 mmol) and potassium carbonate (0.300 g, 2.17 mmol). ). The resulting mixture was stirred at ambient temperature for 22 hours, then additional allyl bromide (0.054 mL, 1M in acetonitrile, 0.054 mmol) was added and stirring was continued at ambient temperature for 6 hours. The resulting mixture was filtered through a pad of Celite® washing with ethyl acetate. The filtrate was concentrated in vacuo. Chromatography (on silica, methanol / ethyl acetate) gave N-allyl hydroxamate as an off-white solid (0.080 g, 15%).

Part Β: To a solution of N-allyl hydroxamate of Part A (0.080 g, 0.172 mmol) in acetonitrile (3.0 mL) and H 2 O (1.0 mL) was added concentrated HCl (0.05 mL). The resulting mixture was stirred at ambient temperature for 10 minutes and then concentrated in vacuo. This gave the title compound as a white solid (0.100 g, quantitative yield). MS MH ⁺ calcd for C22H26O5N2CIS: 465, found 465.

Example 83

Preparation of 4 - ((4- (4-fluoro-3-methylphenoxy) phenyl) sulfonyl) -N-hydroxy-1- (2-propenyl) -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the sulfone from Part D of Example 79 (5.00 g, 12.45 mmol) in tetrahydrofuran (100 mL) was added potassium trimethylsilanolate (4.79 g, 27.26 mmol). The resulting mixture was stirred at ambient temperature for 1.5 hours, diluted with H 2 O and diethyl ether (100 mL). The aqueous layer was extracted with diethyl ether. The combined organic layers were washed with H 2 O. The aqueous layers were combined and acidified with 2M HCl (pH = 2) and then extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over Na 2 SO 4. This gave the acid as an off-white solid (4.61 g, 96%).

Part Β: To a suspension of the acid from Part A (0.830 g, 2.14 mmol) in dichloromethane (10 mL) was added N-methylmorpholine (0.706 mL, 6.42 mmol) and O-tetrahydro-2H-pyranyl-hydroxylamine (0.276 g, 2.35 mmol). After stirring at ambient temperature for 5 minutes, PyBroP® (1.20 g, 2.57 mmol) was added. The resulting mixture was stirred at ambient temperature for 19 hours. The mixture was concentrated in vacuo and the residue was partitioned between H 2 O and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and dried.

The combined organic layers were washed with saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave p-fluorosulfone as a crystalline solid (0.993 g, 95%).

Part C: To a solution of p-fluorosulfone of Part B (0.485 g, 0.996 mmol) in N, N-dimethylformamide (5 mL) was added 4-fluoro-3-methylphenol (0.133 mL, 1.20 mmol) and cesium carbonate (0.973 g). , 2.99 mmol). The resulting mixture was heated at 60 ° C for 17 hours. Additional 4-fluoro-3-methylphenol (0.055 mL, 0.498 mmol) was added and the temperature of the reaction mixture was raised to 80 ° C for 4 hours and then to 100 ° C for 3 hours. Additional 4-fluoro-3-methylphenol (0.133 mL, 1.20 mmol) was added and the reaction mixture was heated to 100 ° C for 7.5 hours. Additional cesium carbonate was added and heating was continued at 100 ° C for 7 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between H 2 O and ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as an off-white solid (0.490 g, 83%).

Part D: To a solution of the protected hydroxamate of Part C (0.479 g, 0.808 mmol) in dioxane (3 mL) and methanol (1 mL) was added a 4M solution of HCl in dioxane (2.02 mL, 8.08 mmol). The resulting mixture was stirred at ambient temperature for 1.5 hours. Diethyl ether was added and the precipitate was collected by filtration. This afforded the title compound as an off-white solid (0.323 g, 90%). MS MH ⁺ calculated for C 19 H 22 ClN 5 F 2 S: 409, found 409.

Example 84

Preparation of 4 - ((4- (3-chloro-4-fluorophenoxy) phenyl) sulfonyl) -N-hydroxy-4-piperidinecarboxamide monohydrochloride

Part A: To a solution of p-fluorosulfone from Part B of Example 83 (0.485 g, 0.996 mmol) in N, N-dimethylformamide (5 mL) was added 4-fluoro-3-chlorophenol (0.176 g, 1.20 mmol) and cesium carbonate ( 0.973 g, 2.99 mmol). The resulting mixture was heated at 60 ° C for 17 hours. Additional 4-fluoro-3-chlorophenol (0.073 g, 0.498 mmol) was added and the temperature of the reaction mixture was raised to 80 ° C for 24 hours and then raised to 90 ° C. After heating at 90 ° C for 3 hours, additional 4-fluoro-3-chlorophenol (0.176 g, 1.20 mmol) was added and heating at 90 ° C was continued for 7.5 hours. Additional cesium carbonate (0.973

4 4

327

4 • 4

444 »5 ·

445 4 * ·

44 g, 2.99 mmol) and the mixture was heated at 90 ° C for 24 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The residue was partitioned between H 2 O and ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as an off-white solid (0.550 g, 90%).

Part Β: To a solution of the protected hydroxamate of Part A (0.530 g, 0.864 mmol) in dioxane (3 mL) and methanol (1 mL) was added a 4M solution of HCl in dioxane (2.00 mL, 8.00 mmol). The resulting mixture was stirred at ambient temperature for 1.5 hours. Diethyl ether (5 mL) was added and the precipitate was collected by filtration. This afforded the title compound as an off-white solid (0.377 g, 94%). MS MH ⁺ calculated for C19H19O5N2SFCI: 429, found 429.

Example 85

Preparation of 4 - ((4- (4-chlorophenoxy) phenyl) sulfonyl)) - N -hydroxy-1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

-dimethylformamide (20 mL) was added 4-chlorophenol (4.41 g, 13.54 mmol) and cesium carbonate (11.03 g, 33.85 mmol). The resulting mixture was heated at 90 ° C for 5 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The residue was partitioned between H 2 O and ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the biaryl ether as a white solid (4.60 g, 78%).

Part Β: To a solution of the biaryl ether from Part A (4.57 g, 8.96 mmol) in dioxane (10 mL) was added a 4M solution of HCl in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 2.5 hours and then additional dioxane (10 mL) was added. After stirring at ambient temperature for 1.5 hours, the mixture was concentrated in vacuo. The resulting solid was suspended in dioxane (20 mL) and treated again with a 4M solution of HCl in dioxane (10 mL). The mixture was stirred at ambient temperature for 1 hour and then methanol (1 ml) was added and stirring was continued at ambient temperature. After 1 hour, the mixture was concentrated in vacuo. This gave as a white solid (4.14, quantitative yield).

• ·

328 • · · 4 ·· ·· 99

9 9 9 • 9 0

9 9 9

Part C: To a suspension of the amine from Part B (4.00 g, 8.96 mmol) in acetonitrile (20 mL) was added propargyl bromide (1.05 mL, 80% solution in toluene, 9.41 mmol) and potassium carbonate. (2.60 g, 18.82 mmol). The resulting mixture was stirred at ambient temperature for 18 hours, filtered through a pad of Celite® washing with ethyl acetate. This gave propargylamine as a sticky foam (4.14 g, quantitative yield).

Part D: To a solution of N-propargylamine of Part C (4.14 g, 8.96 mmol) in tetrahydrofuran (20 mL) was added potassium trimethylsilanolate (1.26 g, 9.86 mmol). The resulting mixture was stirred at ambient temperature for 17 hours. Additional tetrahydrofuran (5 mL) and potassium trimethylsilanolate (0.350 g, 2.73 mmol) were added. After stirring at ambient temperature for 4 hours, additional tetrahydrofuran (5 mL) was added and stirring was continued at ambient temperature for 24 hours. Additional potassium trimethylsilanolate (0.115 g, 0.896 mmol) was added and the mixture was stirred at ambient temperature for 24 hours. Then, additional potassium trimethylsilanolate was added and the resulting mixture was stirred for an additional 24 hours at ambient temperature. Tetrahydrofuran was removed and the residue was suspended in dichloromethane (30 mL).

To the dichloromethane suspension was added N-methylmorpholine (2.96 mL, 26.9 mmol) and O-tetrahydro-2H-pyranyl-hydroxylamine (1.15 g, 9.86 mmol) followed by PyBroP® (5.01 g, 10.75 mmol). The resulting mixture was stirred at ambient temperature overnight and then concentrated in vacuo. The residue was partitioned between H 2 O and ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as an off-white foam (3.29 g, 69%).

Part E: To a solution of the protected hydroxamate of part D (3.27 g, 6.13 mmol) in dioxane (21 mL) and methanol (7 mL) was added a 4N solution of HCl in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 4 hours, then diethyl ether (75 mL) was added. The solids were collected by filtration, washing with diethyl ether. This afforded the title compound as an off-white solid (2.95 g, 99%). MS MH ⁺ calculated for C21H22O5N2SCI: 449, found 449.

Example 86

Preparation of 4 - ((4- (phenylthio) phenyl) sulfonyl)) - N -hydroxy-4-piperidinecarboxamide monohydrochloride

S ft · · · ftft ·· ftft ftft • ftftft ftftftft ftftftft

590 ftft ftftft ······ ftft ·

Ji / ftft · ·· · ···· • ftft ft ·· ftft ftft ftft ftft

Part A: To the sulfone solution of Part D of Example 79 (0.500 g, 1.25 mmol) in N, N-dimethylformamide (3.0 mL) was added thiophenol (0.154 mL, 1.50 mmol) and potassium carbonate (0.518 g, 3, 75 mmol). The resulting mixture was stirred at ambient temperature for 24 hours, then concentrated in vacuo. The residue was partitioned between H 2 O and ethyl acetate. The organic layers were washed with saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the biaryl thioether as a sticky oil (0.480 g, 78%).

Part Β: To a solution of the biaryl thioether of Part A (2.01 g, 4.09 mmol) in tetrahydrofuran (40 mL) was added potassium trimethylsilanolate (0.682 g, 5.31 mmol). The resulting mixture was stirred at ambient temperature for 23 hours and then concentrated in vacuo. The residue was suspended in dichloromethane (20 mL), then N-methylmorpholine (1.35 mL, 12.27 mmol) and 50% aqueous hydroxylamine (0.265, 4.50 mmol) were added, followed by PyBroP (2.29 g, 4 mL). , 91 mmol). The resulting mixture was stirred at ambient temperature for 16 hours and then concentrated in vacuo. The residue was partitioned between H 2 O and ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4. Part of the sample was subjected to reverse phase chromatography (on silica, acetonitrile / H 2 O / trifluoroacetic acid). This afforded the protected hydroxamate as an off-white solid (0.190 g).

Part C: To a solution of the protected hydroxamate of Part B (0.181 g, 0.367 mmol) in dioxane (5 mL) and methanol (1 mL) was added a 4M solution of HCl in dioxane (3 mL). The resulting mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo. This gave the title compound as an off-white solid (0.170 g, quantitative yield). MS MH ⁺ calculated for C 18 H 21 O 4 N 2 S 2: 393, found 393.

Example 87

Preparation of 4 - ((hydroxyamino) carbonyl) -4 - ((4-phenylthio) phenyl) sulfonyl) -1-piperidineacetic acid monohydrochloride

Part A: To a solution of Example 86 (0.322 g, 0.751 mmol) in acetonitrile (4.0 mL) was added tert-butyl bromoacetate (0.121 mL, 0.751 mmol) and potassium carbonate (0.207 g, 1.50 mmol). The resulting mixture was stirred at ambient temperature for 18 hours, then filtered through a pad of Celite®.

330 · ··φφφ * * * * * * * * s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s. The filtrate was concentrated in vacuo. Reverse phase chromatography (on silica, acetonitrile / H2O / trifluoroacetic acid) provided the tert-butyl ester as an off-white solid (0.150 g, 40%).

Part B: The tert-butyl ester of Part A (0.145 g, 0.286 mmol) was treated with a solution of 4M HCl in dioxane (3.0 mL) and the resulting mixture was stirred at ambient temperature for 7 hours, diethyl ether was added and the precipitate collected by filtration. Reverse phase chromatography (on silica, acetonitrile / H2O / HCl) gave the title compound as an off-white solid (0.060 g, 43%). MS MH ⁺ calculated for 2θΚ23θ6 ^ ^ 2 ^ ^2: 451, found at 451.

Example 88

Preparation of 4 - ((4- (4-chlorophenoxy) phenyl) sulfonyl)) - 4 - ((hydroxyamino) carbonyl) -1-piperidineacetic acid monohydrochloride

Part A: To a suspension of 4-bromopiperidine hydrobromide (40.0 g, 0.16 mmol) in tetrahydrofuran (200 mL) was slowly added triethylamine (45.4 mL, 0.33 mol) followed by di-t-butyl dicarbonate ( 37.4 g, 0.17 mol), which was added in a series of batches. The resulting mixture was stirred at ambient temperature for 7 hours, filtered and concentrated in vacuo. The solids were washed with hexanes and then collected by filtration. This gave the BOC-piperidine compound as an amber oil (45.8 g, over 100%).

Part Β: To a solution of 4-fluorophenol (25.0 g, 0.20 mol) in acetone (150 mL) degassed with N 2 was added cesium carbonate (79.7 g, 0.25 mol). After degassing the resulting mixture for 5 minutes with N 2, the BOC-piperidine compound of Part A (43.1 g, 0.16 mol) was added. The resulting mixture was stirred at ambient temperature for 22 hours, then filtered through a pad of Celite® with acetone washing. The residue was washed with diethyl ether and the solids were collected by filtration. This gave the sulfide as a yellow oil. (47.6 g, 93%).

• 4

331 • 4 • 4 4 4 4 444 44 44 44 44 44

4 4 4 4

4 4 4

Part C: To a solution of the sulfide of Part B (47.3 g, 0.15 mol) in dichloromethane (350 mL) cooled to 0 ° C was added m-chloroperoxybenzoic acid (80 g, 57-86%). Additional dichloromethane (50 mL) was added and the mixture was stirred at 0 ° C for 1 hour and then at ambient temperature for 1.5 hours. The reaction mixture was diluted with H 2 O and aqueous sodium metabisulfite (4.0 g in 50 mL) was added. The mixture was concentrated in vacuo and then extracted with diethyl ether and ethyl acetate. The combined organic layers were washed with 10% NH 4 OH, saturated NaCl, and dried over Na 2 SO 4. Recrystallization from ethyl acetate gave the sulfone as a white solid (18.6 g, 36%).

Part D: To a solution of the sulfone of Part C (8.00 g, 23.3 mmol) in N, N-dimethylformamide (40 mL) was added 4-chlorophenol (22.77 g, 69.90 mmol) and potassium carbonate ( 22.77 g, 69.90 mmol). The resulting mixture was heated at 60 ° C for 4 hours and then increased to 80 ° C for 7 hours. The reaction mixture was cooled to ambient temperature and then concentrated in vacuo. HfyO (100 mL) was added to the residue and the solids were collected by filtration. This afforded the biaryl ether as an off-white solid (10.5 g, 99%).

Part E: To a solution of the biaryl ether from Part D (5.00 g, 11.1 mmol) in tetrahydrofuran (50 mL) cooled to 0 ° C was added lithium bis (trimethylsilyl) amide (13.3 mL, 1M in tetrahydrofuran, 13.3 mmol) at a rate such that the temperature of the reaction mixture never exceeds 2 ° C. After stirring for 30 minutes, dimethyl carbonate (0.048, 0.570 mmol) was added and stirring was continued for 45 minutes. Additional lithium bis (trimethylsilyl) amide (0.500 mL, 1M in tetrahydrofuran, 0.500 mmol) was added slowly, and after 1 hour additional dimethyl carbonate (0.010, 0.119 mmol). After stirring at 0 ° C for 20 minutes, saturated NH 4 Cl was added and the reaction mixture was then concentrated in vacuo. The residue was diluted with MgSO 4 and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over Na 2 SO 4. Recrystallization from methanol gave the methyl ester as a white crystalline solid (3.56 g, 63%).

Part F: To a solution of Part E methyl ester (3.54 g, 6.94 mmol) in dioxane (18 mL) and methanol (6 mL) was added a 4M solution of HCl in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 5 hours and then concentrated in vacuo. This gave the amine as an off-white solid (3.10 g, quantitative yield). Part G: To a solution of the amine from Part F (1.50 g, 3.36 mmol) in acetonitrile (15 mL) was added tert-butyl bromoacetate (0.570 mL, 3.53 mmol) and potassium carbonate (1.16 g, 8 mL). , 40 mmol). The resulting mixture was stirred at ambient temperature for 3 hours, then filtered through a pad of Celite® washing with ethyl acetate. This gave the tert-butyl ester as a pale yellow oil. (1.83 g, over 100%).

Part Η: To a solution of the tert-butyl ester of Part G (1.76 g, 3.36 mmol) in tetrahydrofuran (15 mL) was added potassium trimethylsilanolate (0.475 g, 3.70 mmol). The resulting mixture was stirred overnight (about ♦ 0 • 0)

0 *

0 0

0 0 9 •

332 «

• 000

9 ·

09 · 0 · · · ·

0 9 ·

9 9 9

9 · 0 0 hours) at ambient temperature. Additional tetrahydrofuran (10 mL) was added. After stirring overnight (about 18 hours) at ambient temperature, additional potassium trimethylsilanolate (0.475 g, 3.70 mmol) was added. The resulting mixture was stirred at ambient temperature for 4 hours and then diluted with H 2 O. The reaction mixture was acidified (pH = 7) and then concentrated in vacuo. The solids were washed with diethyl ether and then with H 2 O. This gave the acid as a white foam (0.597 g, 32%).

Part I: To a suspension of Part H acid (0.597 g, 1.17 mmol) in dichloromethane (5 mL) was added N-methylmorpholine (0.386 mL, 3.51 mmol) and O-tetrahydro-2H-pyranyl-hydroxylamine (0.151 g). , 1.29 mmol) and then PyBroP® (0.655 g, 1.40 mmol). The resulting mixture was stirred at ambient temperature overnight (about 18 hours) and then concentrated in vacuo. The residue was partitioned between H 2 O and ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4 ·

Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as a white foam (0.510 g, 72%).

Part J: The protected hydroxamate of Part I (0.510 g, 0.837 mmol) was treated with 4M HCl in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 24 hours, then diethyl ether (20 mL) was added. The solids were collected by filtration. This afforded the title compound as a white solid (0.370 g, 87%). MS MH ⁺ calcd for C2 (H22O7N2SCl: 469, found 469).

Example 89

Preparation of 4 - [[4- (4-chlorophenoxy) phenyl] sulfonyl] -N-hydroxy-1- [2- (4-morpholinyl) ethyl] -4-piperidinecarboxamide dihydrochloride

Part A: To a solution of the amine from Part F, Example 88 (1.00 g, 2.24 mmol) in acetonitrile (10 mL) was added 4- (2-chloroethyl) morpholine (0.438 g, 2.35 mmol) and K 2 CO 3. (1.24 g, 8.96 mmol). The resulting mixture was stirred at ambient temperature for 1.5 hours, then a catalytic amount of NaI was added and stirring continued at ambient temperature for 21 hours. The temperature of the reaction mixture was then raised to 60 ° C for 29 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad

Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo to give the ester as an oily solid (1.15 g, 98%).

Part Β: To a solution of the ester from Part A (1.15 g, 2.20 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.579 g, 4.51 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, then additional tetrahydrofuran (10 ml) was added and stirring was continued at ambient temperature overnight (about 18 hours). The reaction mixture was diluted with H ₂ O (10 mL) and acidified (pH-7) with 1M HCl. The resulting precipitate was collected by filtration to give the acid as a gray solid (0.753 g, 72%).

Part C: To a suspension of the acid from Part B (0.750 g, 1.47 mmol) in dichloromethane (7 mL) was added N-methylImorpholine (0.500 mL, 4.55 mmol) and O-tetrahydro-2H-pyran-2-yl -hydroxylamine (0.198 g, 1.2 mmol) then PyBroP® (0.822 g, 1.76 mmol). The resulting mixture was stirred at ambient temperature for 24 hours, then additional N-methylmorpholine (0.242 mL, 2.21 mmol), Otetrahydro-2H-pyran-2-yl-hydroxylamine, (0.052 g, 0.441 mmol) and PyBroP® ( 0.343 g, 0.735 mmol). The resulting mixture was stirred at ambient temperature for 23 hours and then additional Otetrahydro-2H-pyran-2-yl-hydroxylamine (0.017 g, 0.145 mmol) and PyBroP® (0.073 g, 0.157 mmol) were added. The resulting mixture was stirred at ambient temperature overnight (about 18 hours) and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (on silica, methanol / chloroform) gave the protected hydroxamate as an off-white solid (0.750 g, 84%).

Part D: The protected hydroxamate of Part C (0.730 g, 1.20 mmol) was treated with a solution of 4M HCl in dioxane (10 mL) and methanol (1 mL). The resulting mixture was stirred at ambient temperature for 1 hour, then diethyl ether (20 mL) was added and the solids were collected by filtration to give the title compound as a pale yellow solid (0.625 g, 87%). MS MFT calcd for C ₂₄ H ₁₁ O 6 N ₃ SCl: 525, found 525.

Example 90

Preparation of 4 - [[4- (4-chlorophenoxy) phenyl] sulfonyl] -N ⁴ -hydroxy-N ¹ - (1-methylethyl) -1,4-piperidine dicarboxamide

4 4 4

4 444

4 4

44

HN ^ O

H ₃ C ch ₃

4 4 • • 4

4 4

4 4

44 4 44

44

Part A: To a suspension of the amine from Part F, Example 88 (0.600 g, 1.34 mmol) in dichloromethane (5 mL) was added triethylamine (0.411 mL, 2.95 mmol) and isopropyl isocyanate (0.198 mL, 2.01 mmol). ). The resulting mixture was stirred at ambient temperature for 2 hours, then diluted with dichloromethane (50 mL). The mixture was washed with H ₂ O, saturated NaCl and dried over Na ₂ SO ₄ to give the urea as an off-white solid (0.670 g,> 100%).

Part Β: To a solution of urea from Part A (0.640 g, 1.29 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.199 g, 1.55 mmol). The resulting mixture was stirred at ambient temperature for 17 hours when additional potassium trimethylsilanolate (0.015 g, 0.117 mmol) was added. The resulting mixture was stirred for an additional 24 hours, then tetrahydrofuran was removed by blowing N ₂ over the mixture. To a suspension of the residue in dichloromethane (5 mL) were added N-methylmorpholine (0.426 mL, 3.87 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.181 g, 1.55 mmol) then PyBroP®. (0.902 g, 1.94 mmol). The resulting mixture was stirred at ambient temperature for 7 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as an off-white solid (0.330 g, 44%).

Part C: To a solution of the protected hydroxamate of Part B (0.330 g, 0.569 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of 4M HCl in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 3.5 hours, then diethyl ether was added. The solids were collected by filtration to give the title compound as a white solid (0.259 g, 92%). MS MH + ¹ calculated for C ₂₂ H ₂ 7O6N3SC1: 496, found 496th

Example 91

Preparation of 4 - [(4'-chloro [1,1'-biphenyl] -4-yl) sulfonyl] -N-hydroxy-4 monohydrochloride. piperidinecarboxamide

Part A: To a solution of 4-bromothiophenol (16.98 g, 89.80 mmol) in acetone (200 mL), degassed with N ₂ , was added K ₂ CO 3 (12.41 g, 89.80 mmol). After degassing, the resulting mixture with N ₂ for 5 minutes was added the Boc-piperidine compound from Part A, Example 88 (21.57 g, 81.64 mmol). The resulting mixture was stirred at ambient temperature for 19 hours and then filtered through a pad of Celite®, washing with acetone. The residue was washed with diethyl ether and the solids were collected by filtration to give the sulfide as a green oil (31.7 g,> 100%).

Part Β: To a solution of the sulfide of Part A (31.68 g, 81.64 mmol) in dichloromethane (200 mL) cooled to 0 ° C was added m-chloroperoxybenzoic acid (56.35 g, 50-60%, 163.28 mmol). The resulting mixture became very thick and additional dichloromethane (100 mL) was added. The mixture was stirred at 0 ° C for 1.5 hours and then at ambient temperature for 1.5 hours. The reaction mixture was diluted with H ₂ O (300 mL) and aqueous sodium meta-bisulfite (8.00 g, 42.08 mmol in 50 mL H ₂ O) was added. The dichloromethane was removed in vacuo and the aqueous reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with 10% NH 4 OH, saturated NaCl, and dried over Na ₂ SO 4. Concentration in vacuo gave the sulfone as a yellow oil (33.42 g,> 100%).

Part C: To a solution of the sulfone of Part B (7.80 g, 19.34 mmol) in tetrahydrofuran (100 mL) cooled to 0 degrees Celsius was added lithium bis (trimethylsilyl) amide (23.8 mL, 1M in tetrahydrofuran, 23.8 mmol) at such a rate that the reaction temperature never exceeded 2 degrees Celsius. After stirring at 0 degrees Celsius for 30 minutes, a solution of methyl chloroformate (2.30 mL, 29.8 mmol) in tetrahydrofuran (5 mL) was added at a rate such that the reaction temperature never exceeded 2 degrees Celsius. The resulting mixture was then slowly allowed to warm to ambient temperature. The mixture was diluted with saturated NH 4 Cl and tetrahydrofuran was removed in vacuo. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over Na ₂ SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the ester as a yellow solid (6.33 g, 69%).

Part D: To a solution of the ester from Part C (4.74 g, 10.28 mmol) in dimethoxyethane (50 mL) was added 4-chlorophenylboronic acid (1.77 g, 11.30 mmol), aqueous CS 2 CO 3 (25 mL, 2,0 M,

50.0 mmol) and tetrakis (triphenylphosphine) palladium (0) (1 g). The resulting mixture was stirred at ambient temperature for 3 days. The reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate, and

336

4 · · · · ·

The filtrate was concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexane) provided the biphenyl compound as an off-white solid (4.16 g, 82%).

Part E: To a solution of the biphenyl compound from Part D (1.50 g, 3.04 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.468 g, 3.65 mmol). The resulting mixture was stirred at ambient temperature for 1 hour, additional tetrahydrofuran (5 mL) was added and the reaction mixture was stirred at ambient temperature overnight (about 18 hours). Additional tetrahydrofuran (15 mL) was added and the mixture was stirred for an additional 26 hours at ambient temperature. Additional potassium trimethylsilanolate (0.040 g, 0.304 mmol) was added and the mixture was stirred at ambient temperature overnight (about 18 hours) and then the solvent was purged with N ₂ reaction mixture.

To a suspension of the residue in dichloromethane (20 mL) was added N-methylmorpholine (1.00 mL, 9.12 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.427 g, 3.5 mmol) and then PyBroP® (2.13 g, 4.56 mmol). The resulting mixture was stirred at ambient temperature for 24 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as a white solid (1.25 g, 71%).

Part F: To a solution of the protected hydroxamate of Part E (1.25 g, 2.16 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of 4M HCl in dioxane (10 mL). The resulting mixture was stirred at ambient temperature for 3.5 hours, then diethyl ether (20 mL) was added. The solids were collected by filtration to give the title compound as a white solid (0.900 g, 97%). MS MH ⁺ calculated for C ₁₈ H ₂₀ O ₄ N ₂ SC 1: 395, found 395.

Example 92

Preparation of N-hydroxy-4 - [[4- (methylphenylamino) phenyl] sulfonyl] -4-piperidinecarboxamide monohydrochloride

O

HIM

CH ₃

Part A: To a solution of the ester from Part C, Example 91 (1.00 g, 2.17 mmol) in toluene (4 mL) was added N-methylaniline (0.282 mL, 2.60 mmol), Cs ₂ CO ₃ (0.990) g, 3.04 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.018 g, 0.02 mmol) and (R) - (+) - 2,2'-

- bis (diphenylphosphino) 1,1'-binaphthyl (BINAP; 0.021 g, 0.033 mmol). The resulting mixture was heated to

337 • 9 9 9 9 9 9

100 degrees Celsius for 20 hours. After cooling to ambient temperature, diethyl ether was added, the mixture was filtered through a pad of Celite®, washing with diethyl ether, and the filtrate was concentrated in vacuo.

Chromatography (on silica, ethyl acetate / hexane) gave aniline as a yellow sticky gum (0.930 g,

88%).

Part Β: To a solution of aniline from Part A (0.930 g, 1.90 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.293 g, 2.28 mmol). The resulting mixture was stirred at ambient temperature for 19 hours and then additional potassium trimethylsilanolate (0.024 g, 0.190 mmol) was added. After stirring at ambient temperature overnight (about 18 hours), the solvent was removed by passing N ₂ mixtures.

To a suspension of the residue in dichloromethane (10 mL) was added N-methylmorpholine (0.627 mL,

5.70 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.267 g, 2.28 mmol) then PyBroP® (1.33 g, 2.85 mmol). The resulting mixture was stirred at ambient temperature for 2 days and then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as a white solid (0.860 g, 79%).

Part C: To a solution of the protected hydroxamate of Part B (0.890 g, 1.55 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of 4M HCl in dioxane (5 mL). The resulting mixture was stirred at ambient temperature for 1 hour, then diethyl ether (15 mL) was added. The solids were collected by filtration to give the title compound as a white solid (0.529 g, 80%). MS MH + calculated for C 19 H 24 O 4 N 3 S: 390, found 390.

Example 93

Preparation of 4 - [[4- (4-chlorophenoxy) phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide monohydrochloride

Part A: To a suspension of resin I (4.98 g, 5.87 mmol) in 1-methyl-2-pyrrolidinone (45 mL) in a peptide flask was added the acid from Part A, Example 83 (4.55 g, 11, 74 mmol), benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (6.11 g, 11.74 mmol) and N-methylmorpholine (2.58 mL, 23.48 mmol). The resulting mixture was stirred at ambient temperature for 14 hours

338 ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft The resin was then collected by filtration, the filtrate was removed and set aside, the resin was washed with N-dimethylformamide, H ₂ O, N, N-dimethylformamide, methanol, dichloromethane and finally with diethyl ether. The resin was dried under vacuum at ambient temperature to give the resin bound with p -fluorosulfone as a yellow solid (6.72 g, 95%).

The filtrate was diluted with H ₂ O and extracted with ethyl acetate. The aqueous layer was acidified (pH-2.0) with 2N HCl and then extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na ₂ SO 4. The resulting residue was dissolved in 1-methyl-2-pyrrolidinone (40 mL), the resin added from above, then N-methylmorpholine (1.50 mL, 13.64 mmol) and benzotriazol-1-yl-oxy-tris-pyrrolidino- phosphonium hexafluorophosphate (3.05 g, 5.86 mmol). The resulting mixture was stirred at ambient temperature for 3.5 hours. The resin was then collected by filtration and washed with N, N-dimethylformamide, H ₂ O, V, V-dimethylformamide, methanol, dichloromethane and finally with diethyl ether. The resin was dried under vacuum at ambient temperature to give the resin bound with p -fluorosulfone as a pale orange solid (6.34 g, 89%). The charge (0.78 mmol / g) was determined by cleaving a small portion of the p-fluorosulfone-bound resin with 95% trifluoroacetic acid / H ₂ O.

Part Β: To a suspension of p-fluorosulfone-bound resin (0.700 g, 0.546 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was added p-chlorophenol (0.702 g, 5.46 mmol) and CS 2 CO 3 (1.78 g, 5.46 mmol). The resulting mixture was heated to 110 degrees Celsius for 13 hours. The resin was then collected by filtration and washed sequentially with N, N-dimethylformamide, H ₂ O, N, N-dimethylformamide, 2M HCl, N-dimethylformamide, methanol, and dichloromethane. The resulting resin was again subjected to the reaction conditions from above for 3 hours. The resin was then collected by filtration and washed sequentially with N-dimethylformamide, H ₂ O, N, N-dimethylformamide, 2M HCl, N-dimethylformamide, methanol, and dichloromethane. The solids were dried under vacuum at ambient temperature to give the hydroxamate-bound resin as an orange solid (0.692 g, 91%).

Part C: The hydroxamate-bound resin from Part B (0.692 g, 0.540 mmol) was treated with 95% trifluoroacetic acid / H 2 O (3 mL) for 1 hour at ambient temperature. The resin was filtered and washed with 95% trifluoroacetic acid / H ₂ O (3 mL) and then dichloromethane (2 x 3 mL). The filtrate was then evaporated. Reverse phase chromatography (on silica, acetonitrile / H ₂ O / TFA) provided the hydroxamate. The resulting solid was dissolved in acetonitrile (5 mL) and H ₂ O (0.5 mL) and treated with concentrated HCl. The resulting mixture was stirred at ambient temperature for 5 minutes and concentrated in vacuo to give the title compound as an off-white solid (0.220 g, 91%). MS MFF calcd for C18H20O5N2SCI: 411, found 411.

·· <

• 4 4

4 4

444

339

44 • · · · · ·

4 · ·

4 ·

4444 44

44

Example 94

Preparation of tetrahydro-N-hydroxy-4 - [(4-phenoxyphenyl) sulfonyl] -2H-pyran-4-carboxamide

Part A: To a stirred solution of the methyl ester of Example 55, Part C, (0.96 g, 3.2 mmol) in N, N-dimethylformamide (30 mL) was added phenol (0.3 g, 3.2 mmol). followed by cesium carbonate (3.2 g, 10 mmol). The resulting mixture was heated to 70 degrees Celsius for 5 hours. The solution remained at ambient temperature for 18 hours, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with half saturated NaCl and dried over sodium sulfate. The solvent was removed by rotary evaporation to give the desired phenoxy compound (1.1 g, 92%).

Part B: Sodium hydroxide (1 g, 25 mmol) was added to a solution of the phenoxy compound from Part A (1.1 g, 2.9 mmol) in THF (10 mL) and ethanol (10 mL). The resulting solution was stirred at ambient temperature for 1 hour. The solution was then heated to 80 degrees Celsius for 1 hour. The solvent was removed by rotary evaporation and the resulting sodium salt was acidified with 1 M HCl (50 µl) and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO 4. The solvent was removed by rotary evaporation to give the desired phenoxy carboxylic acid (1.1 g, 99%).

Part C: To a stirred solution of the phenoxycarboxylic acid from Part B (1.1 g, 3 mmol) in DMF (7 mL) was added N-hydroxybenzotriazole-H ₂ O (0.623 g, 4.6 mmol) then 1- [3]. (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.634 g, 3.3 mmol). After 10 minutes, a 50% aqueous hydroxylamine solution (2 mL, 30 mmol) was added and the solution was stirred at ambient temperature for 18 hours. The solution was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with H ₂ O and then half saturated NaCl and then dried over Na ₂ SO ₄ . Reverse phase chromatography (on silica, acetonitrile / H ₂ 0) gave the title compound as a white solid (0.37 g, 33%). HRMS (ES ⁴ ) MH ⁴ after C 18 H 16 NO 6 S 378.1011. Found: 378.0994.

Ft 9 9 9

9 9 4 9 9 ftftft

9989 94 94

340

Example 95

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

94 * · • · ftft · · ftft ftftftft ftft ftftft ftft 4 9 ftftftft «·« · * ·

Part A: To a stirred solution of the methyl ester nitrogen from Example 55, Part C, (1.02 g, 3.4 mmol) in Ν, Ν-dimethylformamide (20 mL) was added thiophenol (0.37 g, 3, 4 mmol) then cesium carbonate (3.3 g, 10.1 mmol) and the solution was heated to 70 degrees Celsius for 17 hours. The solution remained at ambient temperature for 1 hour, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with half saturated NaCl and dried over Na 2 SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the S-phenyl compound (0.6 g, 41%).

Part Β: To a stirred solution of the S-phenyl compound from Part A (0.6 g, 1.4 mmol) in THF (10 mL) and ethanol (10 mL) was added NaOH (0.8 g, 20 mmol). The solution was heated to 80 degrees Celsius for 1 hour. The solution remained at ambient temperature for 18 hours. The solvent was removed by rotary evaporation. The resulting sodium salt was acidified with 1 M HCl (25 mL), extracted with ethyl acetate, and the organic layer was dried over rocked sodium. The solvent was removed by rotary evaporation to give the desired S-phenyl carboxylic acid (0.6 g, quantitative yield).

Part C: To a stirred solution of S-phenyl carboxylic acid from Part B (0.6 g, 1.5 mmol) in DMF (6 mL) was added N-hydroxybenzotriazole-FFO (0.30 g, 2.2 mmol), then 1- [3- (dimethylamino) -propyl] -3-ethylcarbodiimide hydrochloride (0.32 g, 1.6 mmol). After 10 minutes, a 50% aqueous hydroxylamine solution (1.5 mL, 22 mmol) was added and the solution was stirred at ambient temperature for 42 hours. The solution was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with H ₂ O, then half saturated NaCl and dried over sodium sulfate. Reverse phase chromatography (on silica, acetonitrile / H ₂ 0) gave the title compound as a white solid (0.15 g, 26%). HRMS (ES ⁴ ) MH ⁴ for C 18 H 19 NO ⁵ S 2 394.0783. Found: 394.0753.

Φ φ · · φ φ φ φ

Example 96

Preparation of 4 - [[4- (3,4-dimethylphenoxy) phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

341

Part A: To a stirred solution of the methyl ester of Example 55, Part C, (1.04 g, 3.3 mmol) in N, N-dimethylformamide (30 mL) was added 3,4-dimethylphenol (0.4 g, 3 mL). , 3 mmol) then cesium carbonate (3.2 g, 10 mmol). The resulting solution was heated to 88 degrees Celsius for 5 hours. The solution was concentrated by rotary evaporation, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ . The solvent was removed by rotary evaporation to give the desired dimethylphenoxy compound (1.2g, 91%).

Part Β: To a solution of the dimethylphenoxy compound of Part A (1.2 g, 3 mmol) in THF (10 mL) and ethanol (10 mL) was added NaOH (1 g, 25 mmol). The resulting solution was heated to 80 degrees Celsius for 1 hour. The solvent was removed by rotary evaporation. The resulting sodium salt was acidified with 1 M HCl (50 mL) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was removed by rotary evaporation to give the desired dimethylphenoxy carboxylic acid (1.2 g, quantitative yield).

Part C: To a stirred solution of dimethylphenoxycarboxylic acid from Part B (1.2 g, 3 mmol) in DMF (7 mL) was added N-hydroxybenzotriazole-H ₂ O (0.623 g, 4.6 mmol) then 1- [3]. (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.634 g, 3.3 mmol). After 10 minutes, a 50% aqueous hydroxylamine solution (2 mL, 30 mmol) was added and the solution was stirred at ambient temperature for 18 hours. The solution was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with H ₂ O and then half saturated NaCl and dried over Na ₂ SO ₄ . Reverse phase chromatography (on silica, acetonitrile / H ₂ 0) gave the title compound as a white solid (0.52 g, 43%). HRMS (ES +) MH + for C ₂ oH ₂ 3N06S 406.1324. Found: 406.1302.

Example 97

Preparation of tetrahydro-N-hydroxy-4 - [[4 - [(6-methyl-3-pyridinyl) oxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide monohydrochloride

♦ · ·

343 • · ·

Part A: To a stirred solution of the methyl ester of Example 55, Part C (1.02 g, 3.4 mmol) in Ν, Ν-dimethylformamide (20 mL) was added 5-hydroxy-2-methyl-pyridine (0.54 g). , 5 mmol), then cesium carbonate (3.2 g, 10 mmol). The resulting solution was heated to 70 degrees Celsius for 5 hours. The solution remained at ambient temperature for 4 days, then diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with half saturated NaCl and dried over sodium sulfate. The solvent was removed by rotary evaporation to give a heavy oil from which the desired white methyl pyridine compound crystallized at ambient temperature in vacuo (1.2 g, 94%).

Part Β: To a solution of the methyl pyridine compound from Part A (1.2 g, 3.2 mmol) in THF (13 mL) was added potassium trimethylsilanolate (0.5 g, 3.5 mmol). The resulting solution was stirred at ambient temperature for 18 hours. A gel formed during this time. The solvent was removed by rotary evaporation to give the desired methyl pyridine carboxylic acid (1.4 g, quantitative yield).

Part C: To a stirred solution of methylpyridinecarboxylic acid from Part B (1.4 g, 3.2 mmol) in dichloromethane (10 mL) was added bromo-tris-pyrrolidine-phosphonium hexafluorophosphate (1.79 g, 3.8 mmol), then 4-methylmorpholine (0.97 g, 9.6 mmol) then O-tetrahydro-2H-pyran-ylhydroxylamine (0.41 g, 3.5 mmol) and the solution was stirred at ambient temperature for 1.5 hours. The solution was filtered to remove the precipitate and the solvent was removed by rotary evaporation. Chromatography (on silica, ethyl acetate / hexane) gave O-tetrahydropyranmethylpyridine as a white solid (1.48 g, 97%).

Part D: Methanol (3 mL) was added to a stirred solution of methyl pyridine O-tetrahydropyran from Part C (1.48 g, 3.1 mmol) in 4 M HCl in dioxane (5 mL). The solution was stirred at ambient temperature for 3 hours and poured into ethyl ether. The resulting precipitate was collected by vacuum filtration. Reverse phase chromatography (on silica, acetonitrile / H ₂ O / HCl) provided the title compound as a white solid (0.64 g, 53%). HRMS (ES ⁴⁾ MH ⁴ for CigH ₂ on ₂ OOS 393.1120. Found: 393.1110.

Example 98

Preparation of tetrahydro-N-hydroxy-4 - [[4 - [(6-methyl-2-pyridinyl) oxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide

343

44

4 4

4 4

4 9

4 4 4

445 4 · «4

4

Part A: To a stirred solution of the methyl ester of Example 55, Part C (1.0 g, 3.3 mmol) in N, N-dimethylformamide (20 mL) was added 2-hydroxy-6-methyl-pyridine (0.54 g). , 5 mmol), then cesium carbonate (3.2 g, 10 mmol). The resulting solution was heated to 70 degrees Celsius for 5 hours. The solution remained at ambient temperature for 11 hours when additional 2-hydroxy-6-methyl-pyridine (0.3 g, 2.7 mmol) was added to the stirred solution and the resulting solution was heated to 70 degrees Celsius for 3 hours. The solution was concentrated by rotary evaporation, diluted with saturated NaCl in H ₂ O, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was removed by rotary evaporation and chromatography (on silica, ethyl acetate / methanol) gave the desired methylpyridine as a white solid (0.63 g, 49%).

Part Β: To a solution of the methylpyridine compound from Part A (0.63 g, 1.6 mmol) in THF (13 mL) was added potassium trimethylsilanolate (0.5 g, 3.5 mmol). The resulting solution was stirred at ambient temperature for 18 hours. The precipitate that formed was removed by filtration, washed with dichloromethane, and dried in vacuo to give the methyl pyridine carboxylic acid potassium salt (0.4 g, 55%).

Part C: To a stirred solution of methyl pyridine carboxylic acid potassium salt from Part B (0.4 g, 0.9 mmol) in N, N-dimethylformamide (5 mL) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.5 g, 1 mmol) then 4-methylmorpholine (0.27 g, 2.6 mmol) then a 50% aqueous hydroxylamine solution (0.6 mL, 9 mmol). The resulting solution was stirred at ambient temperature for 32 hours. The solution was concentrated by rotary evaporation and reverse phase chromatography (on silica, acetonitrile / H ₂ O) gave the title compound as a white solid (0.162 g, 47%). HRMS (ES ⁺⁾ MH ⁴ for C 8 H ₂ oN ₂ 0 ₆ S 393.1120. Found: 393.1119.

Example 99

Preparation of tetrahydro-N-hydroxy-4 - [[4- [4- (1H-imidazol-1-yl) phenoxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide monohydrochloride

344

Part A: To a solution of the THP pyranfluoro compound of Example 55, Part C (2.0 g, 5.2 mmol) in N, N-dimethylacetamide (6 mL) was added 4- (1,3-imidazole) phenol (12, 12, 14). 9 g, 33.3 mmol) then cesium carbonate (32.5 g, 99.9 mmol). The reaction mixture was heated at 65 degrees Celsius for 12 hours. Removal of the dimethylacetamide in vacuo gave a brown solid. Reverse phase chromatography (on silica, acetonitrile / water) gave the THP-protected product in solution.

Part B: A solution of 10% HCl _aq (100 mL) was slowly added to a solution of the crude THP-protected product from A in acetonitrile / water (100 mL). After stirring overnight (about 18 hours), acetonitrile was removed. The resulting precipitate was collected to give the title compound as a brown solid (6.0 g, 41%). MS (FAB) M ⁺ H calcd for C ₁₈ H 21 N ₃ O ₆ Si: 444, found 444.

Example 100 Preparation of 4 - [[4- (4-chlorophenoxy) -phenyl] sulfonyl] -tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a stirred solution of the THP pyranfluoro compound of Example 55, Part C, (2.9 g,

7.5 mmol) in N, N-dimethylformamide (15 mL) was added p-chlorophenol (1.93 g, 15 mmol) then cesium carbonate (7.3 g, 22.5 mmol). The resulting mixture was heated to 90 degrees Celsius for 1.5 hours. The solution remained at ambient temperature for 18 hours with stirring, and dimethylformamide (20 mL) was added to the stirred solution, then cesium carbonate (2 g, 6.2 mmol). The resulting mixture was heated to 95 degrees Celsius for 3 hours. The solution then remained at ambient temperature for 20 hours, when diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with ethyl acetate

345 to to to to to to to to to to to to · Half this with saturated NaCl and dried over sodium sulfate. The solvent was removed by rotary evaporation. Chromatography (on silica, ethyl acetate / hexane) gave the p-chlorophenoxyphenyl THP-protected hydroxamate compound (2.9 g, 78%).

Part Β: To a solution of p-chlorophenoxyphenyl THP-protected hydroxamate compound from Part A (2.9 g, 5.7 mmol) in dioxane (5 mL) was added 4M HCl in dioxane (5 mL, 20 mmol) then methanol (7.5 mL). The resulting solution was stirred at ambient temperature for 1 hour. The solvent was removed by rotary evaporation. Reverse phase chromatography (on silica, acetonitrile / Ή ₂₀ ) gave the title compound as a white solid (1.35 g, 58%). MS (FAB) MH ^{4 -} after C 18 H 18 NO 6 SCl 412. Found: 412.

Example 101

Preparation of 4 - [[4- (3-chlorophenoxy) phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a stirred solution of the THP pyranfluoro compound of Example 55, Part C, (5.0 g, 13 mmol) in N, N-dimethylformamide (20 mL) was added p-chlorophenol (5 g, 39 mmol) then carbonate cesium (17 g, 52 mmol). The resulting solution was heated to 95 degrees Celsius for 7 hours. The solution was kept at ambient temperature for 7 hours, then diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with half saturated NaCl and dried over sodium sulfate. The solution was concentrated by rotary evaporation. Chromatography (on silica, ethyl acetate / hexane) gave the m-chlorophenoxyphenyl THP-protected hydroxamate compound (5.2 g, 82%).

Part Β: To a solution of the m-chlorophenoxyphenyl THP-protected hydroxamate compound from Part A (5.2 g, 10 mmol) in dioxane (5 mL) was added 4M HCl in dioxane (5 mL, 20 mmol) followed by methanol (10 mL). ). The resulting solution was stirred at ambient temperature for half an hour. The solvent was removed by rotary evaporation to give the title compound as a white solid (3.4 g, 79%). HRMS (ES ⁺ ) M + NH 4 ^{+ after} C ₁₈ H ₁₈ NO ₆ SC 1 429.0887. Found: 429.0880.

Example 102

Preparation of potassium methyl 4- (4 - [(tetrahydro-4 - [(hydroxyamino) carbonyl] -2H-pyran-4-yl) sulfonyl] phenoxy] benzenepropanoate)

346 ft · · · · ft · · ftft · ft · · ft * ·

Part A: To a stirred solution of the THP pyranfluoro compound of Example 55, Part C, (5.0 g, 13 mmol) in N, N-dimethylformamide (45 mL) was added potassium methyl 3- (4-hydroxyphenyl) propanoate (7). g, 39 mmol) then cesium carbonate (17 g, 52 mmol). The resulting mixture was heated to 95 degrees Celsius for 7 hours. The solution then remained at ambient temperature for 7 hours. The solution was then diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with half saturated NaCl and dried over sodium sulfate. The solution was concentrated by rotary evaporation. Chromatography (on silica, ethyl acetate / hexane) gave methyl propanoate phenoxyphenyl THP-protected hydroxamate compound (5.6 g, 79%).

Part Β: To a solution of methyl propanoate phenoxyphenyl THP-protected hydroxamate compound from Part A (5.6 g, 10 mmol) in methanol (5 mL) was added 4M HCl in dioxane (5 mL, 20 mmol). The resulting solution was stirred at ambient temperature for 0.5 hours. The solvent was removed by rotary evaporation. The residue was dissolved in dichloromethane / ethyl acetate and the compound was precipitated with hexane. The precipitate was washed with hexane and dried in vacuo to give the title compound as a white solid (3.8 g, 80%). HRMS (ES *) M ⁺ for C ₂₂ H ₂₅ NO ₅ S 464.138. Found: 464.135.

Example 103

Preparation of 4 - [[4 - [(4-fluorophenyl) thio] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

O • · • 4

347 ··· «··

Part A: To a stirred solution of the THP pyranfluoro nitrogen compound of Example 55, Part C (2.9 g, 7.5 mmol) in N, N-dimethylformamide (25 mL) was added cesium carbonate (4.9 g, 15 mL). mmol) followed by 4-fluoro-thiophenol (1.9 g, 15 mmol). The resulting mixture was heated to 95 degrees Celsius for 7 hours. Cesium carbonate (1.2 g, 3.8 mmol) was added after 1 hour of heating and again after 2 hours. The solution remained at ambient temperature for 9 hours, then concentrated by rotary evaporation, diluted with H ₂ O containing 30% brine and extracted with ethyl acetate. The organic layer was washed with half saturated NaCl and dried over sodium sulfate. The solution was concentrated by rotary evaporation. Chromatography (on silica, ethyl acetate / hexane) followed by reverse phase chromatography (acetonitrile / H ₂ O) gave the fluorophenyl-S-phenyl THP-protected hydroxamate compound (1.9 g, 55%).

Part Β: To a solution of the p-fluorophenyl-S-phenyl THP-protected hydroxamate compound from Part A (1.9 g, 4 mmol) in methanol (5 mL) was added 4M HCl in dioxane (5 mL, 20 mmol). The resulting solution was stirred at ambient temperature for 0.5 hours. The solvent was removed by rotary evaporation. The residue was dissolved in dichloromethane and precipitated with hexane. The precipitate was dried in vacuo to give the title compound as a white solid (1.5 g, 89%). HRMS (ES ⁴ ) M + NH ^{4 4} for C ₁₈ H ₁₈ NO ₅ S ₂ F 429.0954. Found: 429.0948.

Example 104

Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-pyridinylthio) phenyl] sulfonyl] -2H-pyran-4-carboxamide monohydrochloride

Part A: To a stirred solution of the THP pyranfluoro compound of Example 55, Part C (2.9 g,

Potassium carbonate (2.6 g, 19 mmol) was added in N, N-dimethylformamide (20 mL) followed by 4-mercaptopyridine (1.7 g, 15 mmol). The resulting mixture was heated to 75 degrees Celsius for 5 hours. Potassium carbonate (0.26 g, 1.9 mmol) was added. After 1 hour of heating and then after 23 hours. The solution remained at ambient temperature for 14 hours. The solution was concentrated by rotary evaporation, diluted with H ₂ O containing 30% brine and extracted with ethyl acetate.

• ·

348 ftft ftft ftft ftft ftft ftft ftftftft ftftft ftftft ftft ftftftftft ftftftft ftft ftft ftft ft * ftft

The organic layer was washed with half saturated NaCl and dried over Na ₂ SO ₄ . The solution was concentrated by rotary evaporation. Chromatography (on silica, ethyl acetate / hexane) gave the mercaptopyridine THP-protected hydroxamate compound (1.2 g, 33%).

Part Β: To a solution of the mercaptopyridine THP-protected hydroxamate compound from Part A (1.2 g, 2.5 mmol) in acetonitrile (20 mL) was added 12.5 M HCl (0.4 mL, 5 mmol) then methanol (3 mL). The resulting solution was stirred at ambient temperature for 1 hour. The precipitate was filtered, washed with methanol and then ethyl ether and dried under vacuum to give the title compound as a white solid (0.92 g, 86%). HRMS (ES ⁺ ) M + NH 4 ⁺ for C 17 H 18 N 2 O 5 S 2 395.0735. Found: 395.0734.

Example 105

Preparation of 4- [4 - [[tetrahydro-4 - [(hydroxyamino) carbonyl] -2H-pyran-4-yl] sulfonyl] phenoxy] benzenepropanoic acid

O

Part A: To a stirred solution of the title compound of Example 102 (0.1 g, 0.2 mmol) in methanol (0.5 mL) was added aqueous 1M Li (OH) 2 (0.43 mL, 0.43 mmol). . After standing at ambient temperature for 24 hours, the solution was refluxed for 20 hours. The solution was lyophilized to dryness and reverse phase chromatography gave the title compound as a white solid (9 mg, 9%). MS (FAB) M + Li ^{+ for} C ₂₁ H ₂₁ NO ₈ S 456. Found: 456.

349 ·· · «44 4« 4 4 4 4 »· ·

4 4 44 444444 44 4

44 4 «4444

4444 44 44 44 44 44

Example 106

Preparation of tetrahydro-N-hydroxy-4 - [[4 - [[1- (2-propynyl) -4-piperidinyl] oxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide monohydrochloride

Part A: To a heat-dried three-necked flask under a nitrogen atmosphere was added NaH (1.59 g 60%, 40 mmol) suspended in N, N-dimethylformamide (50 mL). The suspension was cooled to 0 degrees Celsius using an ice bath and N-Boc-4-hydroxy piperidine (8 g, 40 mmol) was added, followed by rinsing with N, N-dimethylformamide (10 mL). The ice bath was removed and the stirred solution was allowed to reach ambient temperature within 2 hours. The stirred solution was again cooled to 0 degrees Celsius and the methyl ester compound of Example 55, part C (10 g, 33 mmol) dissolved in N, N-dimethylformamide (40 mL) was added. The ice bath was removed and the solution was stirred at ambient temperature for 48 hours. The solution was concentrated by rotary evaporation. The solution was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After chromatography (on silica, ethyl acetate / hexane / methanol), the crude N-Boc methyl ester was treated with 1 M HCl in methanol. The solvent was removed by rotary evaporation. The residue was then dissolved in acetonitrile (21 mL) to which H ₂ O (21 mL) was added. Reverse phase chromatography (on silica, acetonitrile / H ₂ O) afforded the purified piperidine methyl ester as a HCl salt (4.9 g, 35%).

Part B: To a stirred suspension of the piperidine methyl ester HCl salt of Part A (1.8 g, 4 mmol) in acetonitrile (24 mL) and potassium carbonate (1.8 g, 13 mmol) was added, followed by propargyl bromide (0.58 mL 80%). solution, 5.2 mmol). The mixture was stirred at ambient temperature for 18 hours. The solution was concentrated by rotary evaporation, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ and concentrated by rotary evaporation. Chromatography (on silica, dichloromethane / methanol) gave the propargyl piperidine methyl ester compound (1.1 g, 63%).

Part C: To a solution of the propargylpiperidine methyl ester compound of Part B (1.1 g, 2.7 mmol) in THF (3 mL) was added potassium trimethylsilanolate (0.57 g, 4 mmol). After 5 minutes, THF (12 mL) was added, followed by a second addition of THF (15 mL) after a further 10 minutes. The resulting solution was stirred at ambient temperature for 18 hours during which time a gel formed. The solvent was removed by rotary evaporation and the residue was diluted with H ₂ O and washed with ethyl acetate. Vodná

90 «9 9

9 0 0 0 · 0

0 0 0 0 0> 0 9 9 0 9 9

0 9 ··

0990 99 099 «

350 • •• Φ

9 • · 9

9 «

9 0

9 9 0

The ₁₀₀ layer was acidified and chromatographed (on silica, acetonitrile / H ₂ O) to give the desired propargylpiperidine carboxylic acid after lyophilization (0.64 g, 59%).

Part D: To a stirred solution of propargylpiperidinecarboxylic acid from Part C (0.64 g, 1.6 mmol) in Ν, Ν-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole (0.3 g, 2.3 mmol) then 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.33 g, 1.7 mmol) then O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.57 g, 4.8 mmol). The solution was stirred at ambient temperature for 42 hours, concentrated by rotary evaporation, diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then brine, and dried over Na ₂ SO 4. The solution was concentrated by rotary evaporation and chromatographed on reverse phase (on silica, acetonitrile / H ₂ O) to give the title compound as a white solid after lyophilization (0.2 g, 30%). HRMS (ES ⁺⁾ MH ⁴ to C _{2 ()} H ₂₆ N ₂ O6S 423,159. Found: 423.159.

Example 107

Preparation of 4 - [[4 - [(1-acetyl-4-piperidinyl) oxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: Acetic anhydride (1.7 g, 16 mmol) was added to a stirred suspension of the piperidine methyl ester HCl salt of Example 106, Part A (1.8 g, 4 mmol) in pyridine (2 mL). The mixture was stirred at ambient temperature for 20 minutes. The solution was concentrated by rotary evaporation and chromatographed (on silica, ethyl acetate / methanol) to give the acetyl piperidine methyl ester compound (1.5 g, 83%).

Part Β: To a solution of the acetylpiperidine methyl ester compound from Part A (1.5 g, 3.3 mmol) in THF (5 mL) was added potassium trimethylsilanolate (0.86 g, 6 mmol). After 5 minutes, THF (15 mL) was added, followed by a second addition after an additional 10 minutes of THF (15 mL). The resulting solution was stirred at ambient temperature for 18 hours. The precipitate was collected by filtration to give the desired acetylpiperidine carboxylic acid (1.5 g, 98).

Part C: To a stirred solution of the acetylpiperidine carboxylic acid from Part B (0.9 g, 2 mmol) in dimethylacetamide (5 mL) was added bromo-tris-pyrrolidine-phosphonium hexafluorophosphate (1 g, 2.3 mmol) followed by 4-methylmorpholine (0.6 g, 6 mmol), then aqueous O-tetrahydro-2H-pyran-2

351

44 4 · 4444

444 44 44 44 44 44 yl-hydroxylamine (1.5 mL, 23 mmol) and the solution was stirred at ambient temperature for 48 hours. Reverse phase chromatography (on silica, H ₂ O / acetonitrile) gave the title compound as a white solid (0.1 g, 12%). MS (FAB) MH + for C ₁₉ H ₂₆ N ₂ O ₇ S 427. Found: 427.

Example 108

Preparation of 4 - [[4- (3-chloro-4-fluorophenoxy) phenyl] sulfonyl] -tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a stirred solution of the THP pyranfluoro compound of Example 55, Part C (3.2 g, 7.7 mmol) in N, N-dimethylacetamide (15 mL) was added 3-chloro-4-fluorophenol (1.7 mL) , 12 mmol) then cesium carbonate (5 g, 15.5 mmol). The reaction was heated at 95 degrees Celsius for 2 hours. Cesium carbonate (2.5 g, 8 mmol) was added, and the reaction mixture was heated to 95 degrees Celsius for 6 hours. The solution remained at ambient temperature for 8 hours. The crude reaction mixture was then filtered to remove cesium chloride and product precipitate. The filter cake was suspended in H ₂ O and acidified with HCl to pH 6. After completion of the foam, the precipitate was removed by filtration, washed with H ₂ O, dissolved in H ₂ O / acetonitrile and chromatographed on a reverse phase HPLC column (H ₂ O (acetonitrile) to give 3-chloro-4-fluorophenoxy THP-protected hydroxamate (1.4 g, 35%).

Part Β: To a stirred solution of the 3-chloro-4-fluorophenoxy THP-protected hydroxamate from Part A (1.4 g, 2.7 mmol) in acetonitrile (10 mL) was added 1M aqueous HCl (10 mL). The solution was stirred at ambient temperature for 1 hour. Acetonitrile was evaporated at ambient temperature under a constant stream of nitrogen until a heavy precipitate formed. The precipitate was filtered and the cake was washed with H ₂ O then diethyl ether and dried under vacuum to give the title compound as a white solid (12.5g, 96%). The compound was recrystallized from acetone / hexane to give white crystals (10.9 g, 86%). HRMS (ES) M + NH? for C ₁₈ H ₁₉ NO ₆ SFC1 447.079. Found: 447.080.

Example 109

Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-phenoxy) phenyl] sulfonyl-12H-thiopyran-4-carboxamide

352 ·· »· 4 4 ·

4 · 4 · 4 · 4 · 4 · 44 · 4 · 4 · 4 · 4 444 · 4 * 4

4 4

4 4

4 4

4 44

Part A: To a solution of the thiopyran compound methyl ester of Part C, Example 50 (molecular weight 318, 3 g, 1.0 equivalents) in Ν, Ν-dimethylacetamide (DMA; 40 mL) was added cesium carbonate (12g, 1.5 equivalents). ) and phenol (1.5 g). The mixture was heated to 95 degrees Celsius for 6 hours. Then the reaction mixture was cooled to ambient temperature, the reaction mixture was filtered and N, N-dimethylacetamide was then removed by rotary evaporation. The residue was dissolved in 10% aqueous HCl (100ml) and extracted with ethyl acetate (2x). The ethyl acetate extract was dried over sodium sulfate and removed under reduced pressure to give an oil. The oil was purified on silica gel to give 2 g of the methyl ester. 1 H NMR, MS, and HPLC were consistent with the desired compound.

Part Β: To a solution of the methyl ester compound from Part A (MW 392.2 g) in THF (20 mL) was added potassium trimethylsilanolate (MW 128, 1.6 g, 1.2 equivalents). The mixture was stirred at ambient temperature for 2-3 hours until a solid precipitated. After complete hydrolysis, N-methylmorpholine (2 mL) was added followed by PyBrop (2.3 g, 1.2 equivalents). The solution was stirred for 10 minutes, then aqueous hydroxylamine was added and stirred for an additional 2 hours. After completion of the reaction (2 hours) the solvent was removed by rotary evaporation. The residue was dissolved in water / acetonitrile acidified with TFA (pH = 2), then purified by preparative RPHPLC to give 1 g of the title compound as a white solid. HH NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C 18 H 19 NO 5 S 2: 393, found 393.

Example 110

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

44

4 4 4

4 4 ·

9 4 ··· · ·

44

353

4 ·

4 4 ·

4 4

4 4

4 4

4444 44

4 «3 ·

4 4 9

9

4 4 ·

4 44

Part A: Water (50ml) was added to a solution of the compound of Example 109, Part A (2g) in tetrahydrofuran (50ml). To this vigorously stirred mixture was added Oxone ® (8 g, 3 equivalents). Progress of the reaction was monitored by RPHPLC. After 3 hours, water was added and the product was extracted with ethyl acetate (100 mL, 2x). The ethyl acetate was dried over sodium sulfate. After removal of the solvent under reduced pressure, 1.8 g of the phenoxy methyl ester compound was obtained as a white solid. 1 H NMR, MS, and HPLC were consistent with the desired compound.

Part Β: To a solution of the phenoxymethyl ester compound of Part A (molecular weight 590, 2 g) in tetrahydrofuran (20 mL) was added potassium trimethylsilanolate (molecular weight 128, 1.2 g, 1.2 equivalents). The mixture was stirred for 2-3 hours until a solid precipitated. After complete hydrolysis, N-methylmorpholine (2ml) was added followed by PyBrop (2.3g,

1.2 equivalents). The solution was stirred for 10 minutes, then aqueous hydroxylamine was added with stirring for another 2 hours. After completion of the reaction (2 hours) the solvent was removed by rotary evaporation. The residue was dissolved in water / acetonitrile acidified with trifluoroacetic acid (pH = 2), then purified by preparative RPHPLC to give 500 mg of the title compound as a white solid. ^r H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C 18 H 19 NO 7 S 2: 425, found 425.

Example 111

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

Part A: To a solution of the methyl ester of Example 109, Part A (2 g) in acetic acid / water (25/5 mL) was added hydrogen peroxide (2 mL, 30% solution). The progress of this vigorously stirred reaction was monitored by RPHPLC. After 3 hours, water was added, and the product was extracted with ethyl acetate, and the product was extracted with ethyl acetate.

• ·

354 Φ Φ • φ φ φ φ • φ φ φ φ φ φ φ φφ (100 ml, 2χ). The ethyl acetate was dried over sodium sulfate. Then the solvent was removed under reduced pressure to give 2.1 grams of the sulfoxidopyran phenyl-O-phenyl compound methyl ester as a white solid. 1 H NMR, MS, and HPLC were consistent with the desired compound.

Part Β: To a solution of sulfoxidepyranphenyl-O-phenyl methyl ester of Part A (molecular weight 578, 1.8 g) in tetrahydrofuran (25 mL) was added potassium trimethylsilanolate (molecular weight 128, 1.2 g, 1.2 equivalents) . The mixture was stirred for 2-3 hours until a solid precipitated. After complete hydrolysis, N-methyl morpholine (2 mL) was added followed by PyBrop (2.3 g, 1.2 equivalents). The solution was stirred for 10 minutes, then aqueous hydroxylamine was added with stirring for another 2 hours. After completion of the reaction (12 hours) the solvent was removed by rotary evaporation. The residue was dissolved in trifluoroacetic acid-acidified water / acetonitrile (pH = 2), then purified by preparative RPHPLC to give 500 mg of the title compound as a white solid. 1 H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C 18 H 16 NO 6 OS: 409, found 409.

Example 112

Preparation of tetrahydro-N-hydroxy-4 - [[4- (1-acetyl-4- (4-piperazin-phenoxy) phenyl] sulfonyl 2H-thiopyran-4-carboxamide)

Part A: To a solution of the methyl ester thiopyran compound of Example 50, Part C (molecular weight 318, 5 g, 1.0 equivalent) in Ν, Ν-dimethylacetamide (70ml) was added cesium carbonate (molecular weight 5.5 g, 1.5 equivalents), tetrabutylammonium fluoride (2 mL, 2 M in THF) and 1-acetyl-4- (4-hydroxyphenyl) piperazine (4.9 g). The mixture was stirred and heated to 90 degrees Celsius for 6 hours. The reaction mixture was filtered and Ν, Ν-dimethylacetamide was then removed by rotary evaporation. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (2x). The ethyl acetate was dried over sodium sulfate and removed under reduced pressure to give an oil. The oil was purified on silica gel to give 3 g of the methyl ester. ¹ H NMR, MS, and HPLC were consistent with the desired compound.

Step Β: To a solution of methyl ester of Part A compound (MW 433.3 g) in tetrahydrofuran (50 mL) was added potassium trimethylsilanolate (MW 128, 0.9 g,

355

44 44 44 44 44 44 4 4 4 4 4 · 4

4 * 4 44 4

444 4,444 44 44 4

44 44 4444

4444 44 44 44 44 44

1.2 equivalents). The mixture was stirred for 2-3 hours until a solid precipitated. After complete hydrolysis, N-methyl morpholine (2 mL) was added followed by PyBrop (3.5 g, 1.2 equivalents). The solution was stirred for 10 minutes, then aqueous hydroxylamine was added with stirring for another 2 hours. After completion of the reaction (2 hours) the solvent was removed by rotary evaporation. The residue was dissolved in water / acetonitrile acidified with trifluoroacetic acid (pH = 2) then purified by preparative RPHPLC to give 1.2 g of the title compound as a white solid. 1 H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C 24 H 29 N 3 O 6 S 2: 519, found 519.

Example 113

Preparation of tetrahydro-N-hydroxy-4- (4- (4-thiophenoxy) phenyl) sulfonyl 2H-thiopyran-4-carboxamide

Part A: To a solution of the methyl ester thiopyran compound of Example 50, Part C (5 g) in acetic acid (40 mL) was added water / hydrogen peroxide (8 mL, 4 mL / 4 mL, 30% solution). The progress of this vigorously stirred reaction was monitored by RPHPLC. After 3 hours at ambient temperature, water was added and the product was extracted with ethyl acetate (100 mL, 2x). The ethyl acetate was dried over sodium sulfate. Then the solvent was removed under reduced pressure to give 4.5 g of sulfoxidepyran Ph-p-F methyl ester as a white solid. HH NMR, MS, and HPLC were consistent with the desired compound.

Part Β: To the sulphoxidepyran Ph-p-F methyl ester solution from Part A (molecular weight

318, 5 g, 1.0 equivalent) in DMA (70 mL) were added cesium carbonate (4.5 g,

1.1 equiv) and thiophenol (1.5 g, 1.05 equiv). The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and Ν, Ν-dimethylacetamide was then removed by rotary evaporation. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (2x).

to · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

356 • to »to · to * to to · to · to ·· · · · to ·

The ethyl acetate was dried over sodium sulfate and removed under reduced pressure to give an oil. The oil was purified by preparative RPHPLC to give 2 g of the sulfoxidepyranphenyl-S-Ph methyl ester. 1 H NMR, MS, and HPLC were consistent with the desired compound.

Part C: To a solution of sulfoxidepyranphenyl-S-Ph methyl ester from Part B (molecular weight 590, 5 g) in tetrahydrofuran (100 mL) was added potassium trimethylsilanolate (molecular weight 128, 1.5 g, 2 equivalents). The mixture was stirred at ambient temperature for 2-3 hours until a solid precipitated. After complete hydrolysis, N-methyl morpholine (6 mL) was added followed by PyBrop (4 g, 1.1 equivalents). The solution was stirred for 10 minutes, then aqueous hydroxylamine was added with stirring for another 2 hours. After completion of the reaction (12 hours) the solvent was removed by rotary evaporation. The residue was dissolved in water / acetonitrile acidified with trifluoroacetic acid (pH = 2) then purified by preparative RPHPLC to give 1.9 g of the title compound as a white solid. 1 H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C 18 H 19 NO 5 S 3: 425, found 425.

Example 114

Preparation of tetrahydro-N-hydroxy-4 - [[4- [4- (4-hydroxyphenyl) thiophenoxy) phenyl] sulfonyl 2H-thiopyran-4-carboxamide

Part A: To a solution of the title compound of Example 50 (MW 402.5 g, 1.0 equivalent) in N, N-dimethylacetamide (70 mL) was added 4-hydroxythiophenol (MW 126, 1.6 g, 1). , 3 equivalents) then potassium carbonate (molecular weight 138.5 g, 2.0 equivalents). The reaction mixture was heated at 65 degrees Celsius for 3 hours until HPLC indicated the reaction was complete. The reaction mixture was filtered, Ν, Ν-dimethylacetamide was removed in vacuo. The residue was dissolved in water (100ml) and extracted with ethyl acetate (2x). The ethyl acetate was dried over sodium sulfate and removed under reduced pressure to give the p-OH thiophenoxy compound as a crude oil. 1 H NMR, MS, and HPLC were consistent with the desired compound.

Part B: The crude p-OH thiophenoxy compound of Part A was stirred in HCl / dioxane (50 mL) for 2 hours. The solvent was removed and the residue was dried and dissolved in trifluoroacetic acid-acidified water / acetonitrile (pH = 2), then purified by preparative RPHPLC to give 2.1 µg of the title compound as a yellow solid. 1 H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C 18 H 19 NO 5 S 3: 425, found 425.

357 • ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft

Example 115

Preparation of tetrahydro-N-hydroxy-4 - [[4- [4-aminophenyl) thiophenoxy] phenyl] sulfonyl 2H-thiopyran-4-carboxamide

Part A: To a solution of the title compound of Example 50 (MW 402, 5 g, 1.0 equivalent) in Ν, Ν-dimethylacetamide (70 mL) was added 4-aminothiophenol (MW 126, 1.6 g, 1, 3 equivalents) followed by potassium carbonate (molecular weight 138.5 g, 2.0 equivalents). The reaction mixture was heated at 65 ^° C for 3 hours until HPLC indicated the reaction was complete. The reaction mixture was filtered, and Ν, Ν-dimethylacetamide was removed in vacuo. The residue was dissolved in water (100ml) and extracted with ethyl acetate (2x). The ethyl acetate was dried over sodium sulfate and removed under reduced pressure to give the p-NH ₂ thiophenoxy compound as a crude oil. 1 H NMR, MS, and HPLC were consistent with the desired compound.

Part B: The crude Ρ-ΝΉ2 thiophenoxy compound from Part A was stirred in HCl / dioxane (50 mL) for 2 hours. The solvent was removed and the residue was dried and dissolved in water / acetonitrile acidified with trifluoroacetic acid (pH = 2) then purified by preparative RPHPLC to give

2.1 g of the title compound as a yellow solid. 1 H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C 18 H 20 N 2 O 4 S 3 C 2 HF 3 O 2: 538, found 538.

Example 116

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

s nh ₂ '0' • · · · · · · · · · ·

358

Step A: To a solution of the title compound of Example 50 (MW 402.5 g, 1.0 equivalent) in N, N-dimethylacetamide (50 mL) was added trypamine (3 g, 2 equivalents) followed by cesium carbonate (10 g). , 2.0 equivalents). The reaction was heated at 95 degrees Celsius for 5 hours until HPLC indicated the reaction was complete. The reaction mixture was filtered, N, N-dimethylacetamide was removed in vacuo. The solvent was removed and the residue was dried and dissolved in trifluoroacetic acid-acidified water / acetonitrile (TFA; pH = 2), then purified by preparative RPHPLC to give 2.5 g of the crude methyl ester as a yellow solid. 1 H NMR, MS, and HPLC were consistent with the desired compound.

Step B: The crude methyl ester from reaction step A was stirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed and the residue was dried and dissolved in water / acetonitrile acidified with TFA (pH = 2), then purified by preparative RPHPLC to give 2.2 g of a yellow foamy solid as the trifluoroacetic acid salt of the title compound. 1 H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C20H24N2O5S2 C2HF3O2: 550, found 550.

Example 117

Preparation of tetrahydro-N-hydroxy-4 - [[4- [4-hydroxyphenyl glycine)] phenyl] sulfonyl 2H-thiopyran-4-carhoxamide

HIM.

Step A: To a solution of the title compound of Example 50 (MW 402, 5 g, 1.0 equivalent) in N, N-dimethylacetamide (50 mL) was added hydroxyphenylglycine (3 g, 2 equivalents) followed by cesium carbonate (10 g, 2.0 equivalents). The reaction mixture was heated at 95 degrees Celsius for hours until HPLC indicated the reaction was complete. The reaction mixture was filtered, N, N-dimethylacetamide was removed in vacuo. The solvent was removed, the residue was dried and dissolved in trifluoroacetic acid acidified water / acetonitrile (pH = 2), then purified by preparative RPHPLC to give 2.0 g of the crude methyl ester as a brown solid. HH NMR, MS, and HPLC were consistent with the desired compound.

Step B: The crude methyl ester from reaction step A was stirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed and the residue was dried and dissolved in water / acetonitrile acidified with trifluoroacetic acid (pH = 2), then purified by preparative RPHPLC to afford

2.2 g of brown foam / solid as the trifluoroacetic acid salt of the title compound. 1 H NMR,

MS and HPLC were consistent with the desired compound. MS (CI) M + H calculated for

C20H22N2O7S2 C ₂ HF ₃ O _2nd · 580, found 580th

359

Example 118

Preparation of tetrahydro-N-hydroxy-4 - [[4- [4-hydroxyphenyl glycine)] phenyl] sulfonyl 2H-thiopyran-4-carboxamide

nh ₂

Step A: A solution of the title compound of Example 115 (molecular weight 518, 2.5 g, 1.0 equivalent) in THF (25 mL) and N-Boc N-hydroxysuccinyl glycine (2.1 g, 2 equivalents) containing N- methyl morpholine (2 mL) and 4-dimethylaminopyridine (250 mg) were stirred for 12 hours. When RPHPLC indicated completion of the reaction at this time, the solvent was removed under reduced pressure to give an oil. A 10% aqueous hydrochloric acid solution was added with stirring for an additional 1-2 hours. The solution was then purified by preparative RPHPLC to give 1.2 g of a white foam / solid as the trifluoroacetic acid salt. ¹ H NMR, MS, and HPLC were consistent with the desired compound. The solid was dried under reduced pressure, then suspended in ethyl ether, then 4N HCl / dioxane (20 mL) was added. The HCl salt was filtered and washed with ethyl ether to give the title compound as a brown solid (1.1 g). ¹ H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C 20 H 23 N 3 O 5 S 3 C 2 HF 3 O 2: 595, found 595.

Example 119

Preparation of tetrahydro-N-hydroxy-4 - [[4- (4-pyridinylthio) phenyl] sulfonyl] -2H-thiopyran-4-carboxamide monohydrochloride

360

Step A: To a solution of the title compound of Example 50 (MW 402.5 g, 1.0 equivalent) in N, N-dimethylacetamide (50 mL) was added 4-thiopyridine (3 g, 2 equivalents) followed by cesium carbonate ( 10 g, 2.0 equivalents). The reaction mixture was heated at 75 degrees Celsius for 5 hours until HPLC indicated the reaction was complete. The reaction mixture was filtered, and N, N-dimethylacetamide was removed in vacuo. The residue was dried and dissolved in water / acetonitrile acidified with trifluoroacetic acid (pH = 2), then purified by preparative RPHPLC to give 2.0 g of crude -S-pyridyl THP-protected thiopyran compound as a brown solid. 1 H NMR, MS, and HPLC were consistent with the desired compound.

Step B: The -S-pyridyl THP-protected thiopyran compound from Step A was stirred with aqueous HCl (50 mL) for 1 hour. The solvent was removed and the residue was dried and dissolved in trifluoroacetic acid-acidified water / acetonitrile (pH = 2), then purified by preparative RPHPLC to give 1.8 g of brown foam / glass as the trifluoroacetate salt of the title compound. @ 1 H NMR, MS, and HPLC were consistent with the desired compound. MS (Cl) M + H calcd for C 17 H ₁₈ N ₂ O ₄ S 3 HCl: 447, found 447.

Example 120

Preparation of 4 - [[4 - [(4-aminophenyl) thio] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Step A: To a solution of the title compound of Example 55 (387.5 g, 1.0 equivalent) in N, N-dimethylacetamide (50 mL) was added 4-aminothiophenol (3 g, 2 equivalents) followed by potassium carbonate (10 g). , 2.0 equivalents). The reaction was heated at 60 degrees Celsius for 5 hours until HPLC indicated the reaction was complete. The reaction mixture was filtered, DMA was removed in vacuo. The solvent was removed and the residue was dried and dissolved in water / acetonitrile acidified with trifluoroacetic acid (pH = 2) then purified by preparative RPHPLC to give 2.0 g of crude 4-amino-S-Ph THP-protected thiopyran as a brown solid . HH NMR, MS, and HPLC were consistent with the desired compound.

Step B: The 4-amino-S-Ph THP-protected thiopyran compound from Step A was stirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed and the residue was dried and dissolved in water / acetonitrile acidified with trifluoroacetic acid (pH = 2) then purified by preparative

361

RPHPLC, yielding 1.4 g of brown foam / glass as the trifluoroacetic acid salt of the title compound.

1 H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calculated for

C18H20N2O5S2: 408, found 408.

Example 121

Preparation of tetrahydro-N-hydroxy-4 - [[4 - [(2-methyl-5-benzothiazolyl) oxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide

Step A: To a solution of the title compound of Example 55 (molecular weight 387, 10 g, 1.0 equivalent) in DMA (50 mL) was added hydroxymethyl benzothiazole (8 g, 1.5 equivalents) followed by cesium carbonate (20 g, 2). , 0 equivalents). The reaction mixture was heated at 90 degrees Celsius for 5 hours until HPLC indicated the reaction was complete. The reaction mixture was cooled, then filtered and Ν, Ν-dimethylacetamide was discarded. The filter cake was placed in 10% aqueous HCl stirred for 30 minutes to remove cesium salts. The desired solid was separated from the solution as a gum. This gum was dissolved in ethyl acetate (100 mL) and washed with water and dried over sodium sulfate. The solvent was removed in vacuo to give an oil which was dissolved in water / acetonitrile acidified with trifluoroacetic acid (pH = 2) then purified by preparative RPHPLC to give the 2-methyl-5-benzothiazolyloxy compound. 1 H NMR, MS, and HPLC were consistent with the desired compound.

Step B: The 2-methyl-5-benzothiazolyloxy compound of Step A was stirred in aqueous HCl (20ml) / acetonitrile (20ml) for 1 hour. The solvent was concentrated and the separated solids were filtered to give 6.5 g of the title compound. 1 H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C 20 H 20 N 2 O 6 S 2: 448, found 448.

Example 122

Preparation of 4 - [[4- (4-chloro-3-fluorophenoxy) phenyl] sulfonyl] -tetrahydro-N-hydroxy-2H-pyran-4-carboxamide • c

362 • · ·

O

Cl

F

Step A: To a solution of the title compound of Example 55 (molecular weight 387, 10 g, 1.0 equivalent) in Ν, Ν-dimethylacetamide (50 mL) was added 4-chloro-3-fluorophenol (7 g, 1.4 equivalents) and then cesium carbonate (20g, 2.0 equivalents). The reaction mixture was heated at 90 degrees Celsius for 5 hours until HPLC indicated the reaction was complete. The reaction mixture was cooled, then filtered, DMA was discarded. The filter cake was placed in 10% aqueous HCl stirred for 30 minutes to remove cesium salts. The desired 4-chloro-3-fluorophenoxy compound (11 g) was separated from the solution and filtered. 1 H NMR, MS, and HPLC were consistent with the desired compound.

Step B: The 4-chloro-3-fluorophenoxy compound (3.4 g) from Step A was stirred in aqueous HCl (20 mL) / acetonitrile (20 mL) for 1 hour. The solvent was concentrated and the separated solids were filtered to give 2.0 g of the title compound. 1 H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C 18 H 17 ClFNO 6 S: 429, found 429.

Example 123

Preparation of 4 - [[4- [4- (4-acetyl-1-piperazinyl) phenoxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide trifluoroacetic acid salt

HIM.

O'

Step A: To a solution of the title compound of Example 55 (molecular weight 387, 5 g, 1.0 equivalent) in DMA (50 mL) was added 1-acetyl-4- (4-hydroxy-phenyl) piperazine (3 g, 2). equivalents), then cesium carbonate (10g, 2.0 equivalents). The reaction mixture was heated at 90 degrees Celsius for 5 hours until HPLC indicated the reaction was complete. The reaction mixture was filtered, DMA was removed in vacuo. The residue was dissolved in water / acetonitrile acidified with TFA (pH = 2), then purified by preparative RPHPLC to give 3.1 g of crude 4-acetyl-1-piperazinylphenoxy compound as a brown solid. 1 H NMR, MS, and HPLC were consistent with the desired compound.

A · ·· 44 · 4 44 4 4

44 4 4 · 4 4 · 4 4

363 * · ··· ······ ·· ·

44 44 4) 444

4444 44 4 44 44 · 4

Step B: The 4-acetyl-1-piperazinylphenoxy compound from reaction step A was stirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed and the residue was dried and dissolved in water / acetonitrile acidified with TFA (pH = 2), then purified by preparative RPHPLC to give 2.0 g of brown foam as the trifluoroacetic acid salt of the title compound. 1 H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C24H29N3O7S C2HF3O2: 617, found 617.

Example 124

Preparation of N, N-dimethyl-5- [4 - [[tetrahydro-4 - [(hydroxyamino) carbonyl] -2H-pyran-4-yl] sulfonyl] phenoxy] -1H-indole-2-carboxamide trifluoroacetic acid salt,

Step A: To a solution of the title compound of Example 55 (molecular weight 387, 5g, 1.0 equivalent) in DMA (50 mL) was added 5-hydroxy-2-indole dimethylcarboxylate (3 g, 2 equivalents) then CS 2 CO 3 (10 g). , 2.0 equivalents). The reaction mixture was heated at 90 degrees Celsius for 5 hours until HPLC indicated the reaction was complete. The reaction mixture was filtered, DMA was removed in vacuo. The residue was dissolved in water / acetonitrile acidified with TFA (pH = 2), then purified by preparative RPHPLC to give 2.1 g of crude THP-protected pyran hydroxamate compound as a brown solid. 1 H NMR, MS, and HPLC were consistent with the desired compound.

Step B: The THP-protected pyran hydroxamate compound of Step A was stirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed and the residue was dried and dissolved in water / acetonitrile acidified with TFA (pH = 2), then purified by preparative RPHPLC to give

1.5 g of brown solid as the trifluoroacetic acid salt of the title compound. 1 H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C 23 H 25 N 3 O 7 S: 487, found 487.

♦ ·

Example 125

Preparation of tetrahydro-N-hydroxy-4- [4- [4- (1-methylethyl) phenoxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide

364 • 4 · 4 • 444 44

Step A: To a solution of the title compound of Example 55 (MW 387, 5 g, 1.0 equivalent) in DMA (50 mL) was added 4-isopropylphenol (3 g, 2 equivalents) followed by cesium carbonate (10 g, 2). , 0 equivalents). The reaction mixture was heated at 90 degrees Celsius for 8 hours until HPLC indicated the reaction was complete. The reaction mixture was filtered, the DMA portion was discarded. The filter cake was placed in 10% aqueous HCl stirred for 30 minutes to remove cesium salts. The solids (3.5 g) of the isopropylphenoxyphenyl THP-protected hydroxamate were collected and filtered. ¹ H NMR, MS, and HPLC were consistent with the desired compound.

Step Β: To a stirred solution of aqueous HCl (20 mL) and acetonitrile (20 mL) was added the crude isopropyl-phenoxyphenyl THP-protected hydroxamate from step A, and the resulting mixture was stirred for 1-2 hours. The solvent was concentrated with a stream of nitrogen above the surface of the solution. The solids were filtered and dried to give 2.2 g of the title compound as a brown solid. 1 H NMR, MS, and HPLC were consistent with the desired compound. MS (CI) M + H calcd for C ₂₁ H ₂₅ NO ₆ S: 419, found 419.

Example 126

Preparation of Resin II: Step 1: Attaching Example 55 Part D to Resin I

A 500 ml round bottom flask was filled with 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 suspension was slowly stirred. A separate solution of the compound of Part D of Example 55 (5.58 g, 19.4 mmol) in 1-methyl-2-pyrrolidinone (35 mL) was added to the suspension, then benzotriazol-1-yl-oxy-tris-pyrrolidino was added. -phosphonium hexafluorophosphate (10.1 g, 19.4 mmol) in one portion. Once the hexafluorophosphate salt has dissolved,

4-Methylmorpholine (4.26 mL, 39 mmol) was added dropwise. The reaction suspension was stirred at room temperature for 24 hours, then the resin was collected in a sintered disc funnel and washed with Ν, Ν-dimethylformamide, methanol, dichloromethane and diethyl ether (3 x 30 mL each solvent). The resin was dried under vacuum to give 10.99 g of polymer-bound φ

365 ·· φφ • φ φ φ · · hydroxymate as a brown polymer solid. The theoretical polymer loading was 0.91 mmol / g. FTIR microscopy showed bands at 1693 and 3326 cm ^-1 showing hydroxamate carbonyl and nitrogen-hydrogen stress.

Step 2: Preparation of Resin III: Reaction of Resin II with Nucleophiles

Resin II (50 mg, 0.046 mmol) was weighed into an 8 mL glass tube and a 0.5 M solution of nucleophile in 1-methyl-2-pyrrolidinone (1 mL) was added to the tube. For phenol and thiophenol nucleophiles, cesium carbonate (148 mg, 0.46 mmol) was added, and for substituted piperazine nucleophiles, potassium carbonate (64 mg, 0.46 mmol) was added. The tube was sealed and heated to 70-155 degrees Celsius for 24-48 hours, then cooled to room temperature. The resin was dried and washed with 1-methyl-2-pyrrolidinone, 1-methyl-2-pyrrolidinone / water (1: 1), water, 10% acetic acid / water, methanol, dichloromethane (3 x 3 mL each solvent).

Step 3: Cleavage of hydroxamic acids from the polymeric support

Resin III was treated with trifluoroacetic acid / water (19: 1.1 mL) for 1 hour at room temperature. During this time the resin became dark red. The resin was then dried and washed with trifluoroacetic acid / water (19: 1) and dichloromethane (2 x 1 mL of each solvent), collecting the combined filtrates in weighed tubes. The volatiles were removed in vacuo, then toluene / dichloromethane (2 mL each) was added to the residue. The mixture was again concentrated in vacuo. The product was characterized by electrospray mass spectroscopy.

The following hydroxamic acids were synthesized from resin II using the conditions of step 2 with a nucleophile indicated, then release from the polymer using the reaction conditions of step 3.

MS (ES)

Example number R Nucleophile m / z 126-1 0 4 '-hydroxy-2' -methy lacetophenone 451 (M + NK)

* ·

366 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

4 4

4 4

4 · t · · ·

126-2 s.-CO 5,6,7,8-tetrahydro-2-naphthol 455 (M + NH 4) 126-3 ux 3,4-dichlorophenol 462 (M + NH 4) 126-4 4-hydroxyphenethyl alcohol 439 (M + NH 3) 126-5 gro 4-hydroxy diphenylmethane 485 (M + NH 3) 126-6 4-phenylphenol 471 (M + NH 3) 126-7 4- (methylthio) phenol 441 (M + NH 3) 126-8 3-methoxyphenol 425 (M + NH 3) 126-9 4-chlorophenol 429 (M + NH 3) 126-10 4-bromophenol 590 (M + Cs) 126-11 4- (imidazol-1-yl) -phenol 444 (M + H) 126-12 3-hydroxyphenethyl alcohol 439 (M + NH 3) 126-13 ϊ-, Ο ”” 3- (4-Hydroxy-phenyl) -1-phenol 453 (M + NH 3) 126-14 XČ, 4-Bromo-3-methylpheno1 487 (M + NH 3) 126-15 3-hydroxybenzyl alcohol 425 (M + NH 3)

367 • 44 4 4 · 4 4 · 4

4 »4 4 4 4

44 44 4444

4444 44 44 44

OH

126-16

126-17

126-18

126-19

126-20

126-21

126-22

126-23

126-24

126-25

126-26 ch ₃ ci

4-methoxyphenol

4-chloro-3-methylphenol

O 'ch ₃

2-Naphthol p-cresol (X) -4-hydroxybenzyl alcohol

AND

1-Naphthol

425 (M + NH 4)

558 (M + Cs)

560 (M + Cs)

409 (M + NH 4)

400 (M + H)

445 (M + NH 4)

8-hydroxyjulolidine

-hydroxypyridine

378 (M + H)

472 (M + H)

5-hydroxy-2-methylpyridine

2,3-dihydroxy-pyridine

2,6-quinolinediol

444 (M + H)

392 (M + H)

412 (M + H)

368 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 ·····

9 9 9 9 · ····

9999 99 ·· ·· ftft ··

126-27 4-hydroxyphenyl acetic acid 453 (M + NH 4) 126-28 X * 4-amino-m-creso 1 407 (M + H) 126-29 ς Ά ^ θ ^ΤΡΑ 8-quinolinol 429 (M + H) 126-30 uA 4-cyclopentylphenol 463 (M + NH 4) 126-31 3,4-dimethylthio phenol 439 (M + NK) 126-32 m-thiocresol 425 (M + NK) 126-33 3-methoxythiophenol 441 (M + NK) 126-34 XX », 4-methoxythiophenol 441 (M + NK) 126-35 4-Fluorothiophenol 429 (M + NK) 126-36 3-chlorothio phenol 445 (M + NK) 126-37 GX 4-chlorothiophenol 445 (M + NK) 126-38 Χ " 4-aminothiophenol 426 (M + NK)

369 ft · ···· ftftft ·· ·· ·

126-39

126-40

126-41

126-42

126-43

126-44

126-45

126-46

126-47

126-48

126-49

126-50

2-Naphthalenthiol

461 (M + NR 0

AND

TFA

AND

TFA

piperidine

TFA

OH

Λν ^ υ ^ ν '

A ^ oh - ¹ N TFA σ '

4-Benzyl-4-hydroxypiperidine nipecotamide ^S CH

-hydroxypiperidine

_{N, N '-} 4- (1-pyrrolidinyl) -piperidine

TFA

TFA

O

ethyl nipecotate

3-Piperidinyl-methanol

Λ "

TFA

^tfa <A

TFA1J ch.

4-Benzylpiperidine

4-methylpiperidine

-methylpiperidine

4-hydroxy-4-phenylpiperidine

474 (M + H)

468 (MH +)

385 (M + H)

439 (M + H)

442 (M + H)

512 (M + TFA)

458 (M + H)

382 (M + H)

382 (M + H)

461 (M + H) @ +

Ft · · · ft ♦ · •

370 ftft ftft ft ft ft ft ft ft ft ft ft ft ft

126-51

126-52

126-53

126-54

126-55

126-56

126-57

126-58

126-59

126-60 o

O

NH ₂ ethyl isonipecotate

1,4-dioxa-8-azaspiro (4,5) decane isonipecotamide nipecotamide

TFA

4-piperidino-piperidine

morpholine

442 (M + H)

428 (M + H)

412 (M + H)

412 (M + H)

453 (M + H)

388 (M + NH +)

Λ

N

TFA

4-phenylpiperidine

3,5-dimethyl-piperidine

4- (4-bromophenyl) -4-piperidinol

Br

1-methylpiperazine

444 (M + H)

414 (M + NH +)

538 (M + H)

384 (M + H)

• ··

371

126-61

487 (M + H)

126-62

460 (M + H)

N- (C 3 H 6 -trifluoro-m-tolyl) piperazine

515 (M + H)

126-63 ™

TFA i M

-IN

TFA (2-pyridyl) ^-piperazine

126-64 tfa

TFA

448 (M + H)

126-65 ^1fA ™ J. (4-fluorophenyl) ^ ^{n Erazm} Pip

465 (M + H)

126-66 ™ OAx;

o i-piperonyl- ^piperazine

505 (M + H)

TFA

126-67 _{Ν Ν} ^ ^TFA M

- (4-Methylphenyl) ^-piperazine

492 (M + H)

TFA

NO ₂

126-68 Λη ^ ι

457 (M + H)

TFA

TFA

126-69

TFA

412 (M + H)

-hydroxyethyl-ethoxypiperazine

1-acetylpiperazine

372 • · «44 44 44

4 · 4 ·

44 · 4 44

444445 44 4

4 4 4

44 44 44

126-70

126-71

126-72

1-ethylpiperazine

- (2-fluorophenyl) -piperazine benzyl-1-piperazine carboxylate

397 (M + H)

465 (M + H)

505 (M + H)

126

TFA

O-ethyl-N-piperazine carboxylate

443 (M + H)

127

N- (2-hydroxyethyl) -piperazine

128

TFA

414 (MH +)

TFA

- (2-methoxyphenyl) piperazine

475 (M + H)

Example XX

Preparation of lilac resin on a large scale

Resin II (5 g, 0.91 mmol) was weighed into a drying oven in a three-necked round bottom flask equipped with temperature measurement, overhead stirrer and nitrogen inlet. Anhydrous 1-methyl-2-pyrrolidinone (35 mL) was added to the flask then ethyl isonipecotate (7.0 mL, 45.5 mmol). The resin slurry was stirred slowly with an overhead stirrer and heated to 80 degrees Celsius with a heating mantle for 65 hours. The flask was then cooled to room temperature.

The resin was collected in a sintered glass disc funnel and washed with N, N-dimethylformamide, methanol, and dichloromethane (3X30 mL of each solvent).

The resin was dried under vacuum to give 5.86 g of resin IIIa as off-white resin beads.

The theoretical polymer loading was 0.81 mmol / g. TFA cleavage performed on 50 mg resin IIIa

373 «444 44 ·· ·· ·· · 4 4 44 4 444> 4 ··

444445 44 4

As described in Step 3, 10.4 mg of an off-white solid was spectroscopically indistinguishable using the ethyl isonipecotate of Example 211.

Example YY

Large-scale preparation of Illb resin

Preparation of resin Illb followed the procedure described for the preparation of resin IIIa, except that ethyl nipecotate was replaced with ethyl isonipecotate. The yield after vacuum drying was 5.77 g of Illb resin as pale yellow resin beads. The theoretical polymer loading was 0.81 mmol / g. TFA cleavage performed on 50 mg of Illb resin as described in step 3 gave

14.7 mg of an off-white solid spectroscopically indistinguishable from the reaction product using ethyl nipecotate of Example 212.

Step 4: Hydrolysis from polymer-bound ester:

Preparation of resin IVa

The resin IIIa (5.8 g, 4.5 mmol) was weighed into a three-necked round bottom flask equipped with an overhead stirrer. 1,4-Dioxane was added to the flask and the resin suspension was stirred for 15 minutes. A 4 M KOH solution (5 mL, 20 mmol) was then added and the mixture was stirred for 44 hours. The resin was then collected in a sintered glass disc funnel and washed with dioxane / water (9: 1), water, 10% acetic acid / water, methanol and dichloromethane (3X30 mL each solvent). The resin was dried under vacuum to yield 5.64 g of IVa resin as off-white polymer beads. FTIR microscopy showed bands at 1732 and 1704 cm ^-1 and a wide band at 2500-3500 cm ^-1 . The theoretical charge to the polymer bound acid was 0.84 mmol / g.

Preparation from Ivb resin:

Using the procedure described in Step 4, the Illb resin (5.71 g, 4.5 mmol) was converted to 5.61 g IVb resin. FTIR microscopy showed bands at 1731 and 1705 cm ^-1 and a wide band at 2500-3500 cm ^-1 . The theoretical charge to the polymer bound acid was 0.84 mmol / g.

Step 5: Amide bond formation:

Preparation from resin

Either Iva resin or IVh resin (50 mg, 0.042 mmol) was weighed into a fritted reaction vessel and the vessel was sealed under nitrogen. A 0.5 M solution of hydroxybenzotriazole in 1-methyl-2-pyrrolidinone (0.3 mL, 0.15 mmol) was then added with a 0.5 M solution of diisopropylcarbodiimide in 1-methyl-2-pyrrolidinone (0.3 mL, 0, 15 mmol). The resin is

374 · 0 • 00 • 009 ··

9 0 0

0 · · 0 9 9

The reaction mixture was stirred for 15 minutes using the stirring plate wall, then a 0.7 M solution of the amine in 1-methyl-2-pyrrolidinone (0.3 mL, 0.21 mmol) was added. The reaction mixture was stirred for 6 hours, then the resin was dried and washed with 1-methyl-2-pyrrolidinone (3X 1 mL). The reaction was repeated using the same amounts of reagents described above. The reaction mixture was stirred for 16 hours, then the resin was dried and washed with 1-methyl-2-pyrrolidinone, methanol and dichloromethane (3X 1 mL each solvent).

The following hydroxamic acids were synthesized using the polymer-bound acid shown and the amine shown in step 5 of the reaction conditions, then released from the polymer using step 3 of the reaction conditions.

Example number Resin Amin R Position MS (ES) m / z 129 IVa OH 4 130 IVa methylamine H 4 131 IVa morpholine G 4 482 (M + H) 132 133 IVa IVa ethano lamin 1,3-diaminopropane x _n - ^ ^oh H TFA -Γ'-Ν ' ^Χ ' ^ ^χΖΧ ΝΗ ₂ H 4 4 456 (M + H) 469 (M + H) 134 IVa ethylamine N CH ₃ 4 440 (M + H) 135 IVa glycine t-butyl ester HCl A-V 0 4 470 (M + H)

375 ·· · 44 44 ·· 44 ·· • 444 4 4 * 4 4 44 4 * 4 4 44 4 4 4 * 4

444 · 444 4 44 44 4

4 4 4 4

4444 44 44 3 *

136

IVa

^TFA L-histidine methyl ester

HCl

OH

565 (M + H)

137 138 IVa IVb «n ₂ H OH OH 139 IVb methylamine j < _n x ^CH 3 H 140 IVb morpholine ΑιΛ O 141 IVb ethanolamine X X Y 4 -OH H 142 IVb 1,3-diamino-propane . TFA x ^x n ' ^XXs - ^{/ m} ₂ H 143 IVb ethylamine H 144 IVb glycine t-butyl ester HCl ^{from H} 2 O 145 IVb HCl L-histidine methyl ester / NH TFA AND 0 146 IVb .CL Ax ť γ nh ₂ H OH 147 IVa dimethylamine 1 ch ₃ 148 IVa diethylamine ^ CH ₃

427 (M + H)

427 (M + H)

483 (M + H)

456

M + H)

467 (M + H)

440 (M + H)

470 (M + H)

565 (M + H)

427 (M + H)

440 (M + H)

468 (MH +)

4 ·· · ♦ · · •

376 • «

4 9 • · ·

4

4

4 4 · · ··

4 4

IVa

IVa

IVa

IVa

IVa

IVa

IVb

IVb piperidine

480 (M + H)

-methyl-piperazine

494 (M + H)

N-Boc-piperazine ethyl isonipecotate ethyl nipecotate ethyl pipecolate

IVb

IVb

IVb

IVb

IVb

482 (M + H)

553 (M + H)

553 (M + H)

553 (M + H)

dimethylamine -Ηγθ ³ i ch ₃ 3 440 (M + H)

piperidine

-methyl-piperazine

N-Boc-piperazine ethyl isonipecotate ethyl nipecotate ethyl pipecolate

TFA

TFA

553 (M + H)

553 (M + H)

553 (M + H)

480 (M + H)

494 (M + H)

482 (M + H)

377 ·· · φ · • · • · • · • · φ · · · · · · · · · · · · · · · · · ·

I ··· • Φ φφ φφ φφ

162

IVb hexamethylenimine ^Α ο

495 (M + H)

163 IVb 1,3,3-trimethyl-6- 3 548 azabicyclo [3,2,1] acetane ψκ, H ₃ C H \ (M + H) 164 IVa 1,3,3-trimethyl-6- 4 548 azabicyclo ΑΤν ^Η3 (M + H) [3,2,1] acetane kLX Γ h ₃ c 165 IVa hexamethylenimine R _n ^z λ 4 494 O (M + H) 166 IVb 3-pyrrolidinol rC 3 482 Q- ° h (M + H) 167 IVb (3S) - (-) - 3- (dimethyl JT \ CHR 3 509 amino) -pyrrolidine nA / ³ ch ₃ (M + H) TFA 168 IVb (3S) - (-) - 3- OF 3 481 (t-butoxy- carbonylamino) - nh ₂ (M + H) pyrrolidine TFA 169 IVb cis-2,6-dimethyl- X. _n / '\ |>y' ^CH3 CH 3 510 morpholine (M + H) 170 IVb decahydroquino lin 1 3 534 00 (M + H) 171 IVb 4- (1-pyrrolidinyl) piperidine TFA 3 549 (M + H) 172 IVb pyrrolidine _rC 3 466 O (M + H) 173 IVa 3-pyrrolidinol 4 482

378 · ftft ftft ftft ftft ftft ftft ftft ftft

I · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

^ NX ^{OH OH} (M + H) 174 IVa (3S) - (-) - 3- (dimethyl amino) -pyrrolidine % Y 4 509 (M + H) 175 IVa (3S) - (-) - 3- (t-butoxy- carbonylamino) - pyrrolidine r- TFA or Λ i> - * nh ₂ 4 481 (M + H) 176 IVa cis-2,6-dimethyl- morpholine J- ^ _n x ^> ^CH3Y 4 510 (M + H) 177 IVa decahydroquinoline ch ₃ x / X / »1 4 534

(M + H)

178

IVa

4- (1-pyrrolidinyl) piperidine

549 (MH +)

179 IVa pyrrolidine 4 466 (M + H) 180 IVa 2,2,2-Trifluoroethyl- amine CF ³ H ³ 4 494 (M + H) 181 IVa butylamine HN — y ch ₃ 4 468 (M + H) 182 IVa diallylamine k 2 CH ₂ 4 492 (M + H) 183 IVa 3,3 '-iminobis (N, N-dimethylpropyl-amine) ^/ Ϊ ^CH3 _ ^CH3 \ x ^ _{n -CH3} CH3 TFA 4 582 (M + H) 184 IVa iso-propylamine ch ₃ H ³ 4 454 (M + H) 185 IVa 4-amino- 4 497

44

4 4 ·

4 ·

379

44 44

4 4 4 4

4 4 4 4 • · · 44 44 44 44 ·

4 4 4 4 4

44 44 44 morpholine

HN-N O (_ + M)

186 IVa 3- (Aminomethyl) - pyridine TFA ^H v 4 503 (M + H) 187 IVa cyclohexylamine H 4 494 (M + H) 188 IVa 1-amino indane NH WHAT 4 528 (M + H) 189 IVa 2-thiophene-methylamine 4 508 (M + H) 190 IVa 4-Methyl-piperidine f ~ ^N Q ^ ~ CH3 4 494 (M + H) 191 IVa 4-Benzyl-piperidine “CuO 4 570 (M + H) 192 IVa 4-phenyl-piperidine KX) 4 556 (M + H) 193 IVa 4-Benzyl-4-hydroxy- piperidine ^{J <} cw OH 4 586 (M + H) 194 IVa cycloheptyl-amine H 4 508 (M + H) 195 IVa 4-aminomethyl- pyridine TFA 4 503 (M + H) 196 IVa 2-amino-methyl- pyridine TFA 4 503 (M + H) 197 IVa 4-Fluoro-benzylamine ^A = Xi, 4 520 (M + H) 198 IVa dibenzy lamin 4 592 (M + H) 199 IVa 1,2,3,4-tetrahydro- 4 528

99

9 9 9

9 9 9 · 999

9 9

99

380 isoquinoline ·· 99

9 9 9

9 9

98 • 9 9 9

9 9 9 • 9 9 9 • 9 · 9

99 (M + H)

Large-scale preparation of resin IIIc

Resin II (3.01 g, 2.74 mmol) was weighed into a oven-dried three-necked round-bottom flask equipped with an overhead stirrer, temperature measurement and nitrogen inlet. 1-Methyl-2-pyrrolidinone (25 mL) was then added with piperazine (2.36 g, 27.4 mmol) and cesium carbonate (8.93 g, 27.4 mmol). Additional 1-methyl-2-pyrrolidinone (10 mL) was added and the reaction mixture was heated to 100 degrees Celsius and stirred for 18 hours. The flask was cooled to room temperature and the resin was collected in a sintered glass disc funnel and washed with Ν, im dimethylformamide / water (1: 1), water, 10% acetic acid / water, methanol and dichloromethane (3X 30 mL each solvent). The yield after drying under vacuum was 3.14 g of Illb resin as light yellow resin beads. The theoretical polymer loading was 0.86 mmol / g. TFA cleavage performed on 50 mg of Illb resin as described in Step 3 gave 21 mg of an off-white solid spectroscopically indistinguishable from the compound of Example 209.

Step 6: Amide bond formation with resin IIIc: Preparation of resin VI

Fritted reaction flasks were charged with carboxylic acid (0.215 mmol) and 1-hydroxybenzotriazole (44 mg, 0.326 mmol). The vessel was sealed under nitrogen and 1-methyl-2-pyrrolidinone was then added with diisopropylcarbodiimide (0.034 mL, 0.215 mmol). The solution was stirred on a shaker for 15 minutes, then resin IIIc (50 mg, 0.043 mmol) was added in one portion. The reaction mixture was shaken for 16 hours, then the resin was dried and washed with 1-methyl-2-pyrrolidinone, methanol and dichloromethane (3X 1 mL each solvent). In the case of N-9-fluorenyl-methoxycarbonyl-protected amino acids, the resin was further reacted with piperidine / N, N-dimethylformamide solution (1: 4, 1 mL) for 30 minutes. The resin was dried and washed with Ν, Ν-dimethylformamide, methanol and dichloromethane (3X 1 mL each solvent).

The following hydroxamic acids were synthesized from resin IIIc using step 6 with the carboxylic acid shown and then released from the polymer using step 3 of the reaction conditions.

Ft ft ft ft ft ft

381

• ftftftft • ftftftft ftftft ftft

Example Carboxylic number_acid

MS (ES) m / z

200

Cyclohexanecarboxylic acid

502 (M + Na)

201 1,2,3,4-tetrahydronaphthylene-2-carboxylic acid

545 (M + NKL)

202 cycloheptanecarboxylic acid

511 (M + NH 4)

203 N-9-fluorenylmethoxycarbonyl-Lproline

H, 467 ^N / TFA (M + H)

204

N-9-fluorenylmethoxycarbonyl-Lvaline

467 (M + H)

Step 7: Preparation of Resin VII

Resin IIIc (1.0g, 0.86 mmol) was weighed into an oven-dried 100 ml round bottom flask and a magnetic stir bar and nitrogen needle adapter were added. Dichloromethane (10 mL) was added and the resin suspension was stirred slowly. p-Nitrophenyl chloroformate (0.867 g, 4.3 mmol) was added in one portion followed by dropwise addition of diisopropylethylamine (0.75 mL, 4.3 mmol). A slight heating was noted during the addition. Reaction this «to to ·· · to · to · * · * ·

382 this to this this this this to this it was stirred at room temperature 18 hours, then the resin was collected in a sintered glass disc funnel and washed with dichloromethane, methanol, and dichloromethane (3X 10 mL each solvent).

The polymer-bound product was dried under vacuum to yield 1.25 g of resin VII as brown resin beads. FTIR microscopy showed bands at 1798, 1733, 1696 and 1210 cm ^-1 . The theoretical polymer loading was 0.75 mmol / g.

Step 8: Reaction of Resin VII with Amines. Preparation of resin VIII A vial was charged with resin VII (50 mg, 0.038 mmol) and a small magnetic stir bar and a 0.5 M solution of the amine in 1-methyl-2-pyrrolidinone (1 mL) was added. The vial was sealed and heated to 50 degrees Celsius. The resin suspension was stirred gently for 15 hours, then the vial was cooled to room temperature. The resin was collected in a fritted reaction vessel and washed with 1-methyl-2-pyrrolidinone, methanol and dichloromethane (3X 10 mL each solvent).

The following hydroxamic acids were synthesized from resin VII using step 8 of the reaction conditions with the amine shown and then release from the polymer using step 3 of the reaction conditions.

O

Example Number carboxyl acid R MS (ES) m / z 205 535 (M + H) 206 piperidine ^{Ζ Ό} 481 (M + H) 207 morpholine at 501 (M + Na)

* · ······················

C ftft ft C

383 ···· · · ft · ft

208 dimethylamine rC _K X ^CH 3 N 1 ch ₃ 441 (M + H) 209 piperazine TFA 482 (M + H) 210 1-Methyl-piperazine TFA ch ₃ 496 (M + H) 211 ethyl isonipecotate ΟγΧ 553 (M + H) O 212 ethyl nipecotate 0 552 _x (M + H)

Example xxx

Preparation of 4 - [(4-bromophenyl) sulfonyl] tetrahydro-2H-pyran-4-carboxylic acid

Part A: Preparation

ΟΗ ₃ Ο ₂ Χ

384

An oil dispersion of 60% sodium hydride (4.0 g, 0.1 mol) was weighed into an oven-dried 3-necked 500 ml round bottom flask in a nitrogen glove bag and equipped with nitrogen inlet, temperature measurement, overhead stirrer and rubber septy. Anhydrous tetrahydrofirane (200 mL) was added to the flask, which was then cooled in an ice bath. 4-Bromothiophenol (18.91 g, 0.1 mol) was added dropwise maintaining the temperature below 7 degrees Celsius. Strong gas evolution was noted during the additions. After the addition was complete, the mixture was stirred for 10 minutes with cooling. Then methyl bromoacetate (9.5 mL, 0.1 mol) was added dropwise, keeping the temperature below 7 degrees Celsius. The reaction was stirred for 10 minutes with cooling, then the ice bath was removed and the mixture stirred for an additional 30 minutes. The reaction was quenched by the addition of 5 mL of water, then the solvent was removed on a rotary evaporator. The residual oil was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with 5% hydrogen chloride / water (1 x 200 mL), saturated sodium bicarbonate (1 x 200 mL), and brine (1 x 200 mL). The organic phase was dried over magnesium sulfate and concentrated to give 24.53 g of the product as a yellow oil (94%). 1 H NMR was consistent with the desired structure. Mass spectrum showed m / z 260 (M + H).

Part B: Preparation

The compound from Part A above, (24.5 g, 0.094 mol) was weighed into a 1.0 L round bottom flask equipped with an overhead stirrer and a temperature sensor, then 550 mL of methanol was added followed by 55 mL of water to cause the solution became slightly cloudy. The flask was immersed in an ice bath, and once the temperature dropped below 5 degrees Celsius, Oxone® (144.5 g, 0.235 mol) was added in portions over 5 minutes. A slight increase in temperature to 8 degrees Celsius was noted. The reaction was stirred with cooling for 10 minutes, then the ice bath was removed. After 4 hours, reverse phase liquid chromatography showed a single component at 13.6 minutes. The reaction mixture was filtered and the solids were washed with methanol removal. The combined filtrates were concentrated on a rotary evaporator and the remaining material was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (3 x 200 mL), saturated sodium bicarbonate (1 x 200 mL) and brine (1 x 200 mL), then the organic phase was dried over magnesium sulfate and concentrated to give 25 g of the product as a tan solid. Friction with hexane gave

385

24.3 g of pure sulfone as an off-white solid (88%). @ 1 H NMR was consistent with the desired structure. Mass spectrum showed m / z 293 (M + H).

Part C: Preparation

An oil dispersion of 60% sodium hydride (5.76 g, 0.144 mol) was weighed into a oven-dried 3-necked 1.0 L round bottom flask in a nitrogen glove bag and then equipped with a nitrogen inlet, temperature measurement, overhead stirrer and rubber septa . Anhydrous N, N-dimethylformamide (250 mL) was added to the flask, mechanical stirring was started and the mixture was heated to 50 degrees Celsius. A solution of Part B compound from above (17.59 g, 0.06 mol) and dibromodiethyl ether (14.5 g, 0.06 mol) in 40 mL of Ν, Ν-dimethylformamide were added dropwise to the sodium hydride suspension, maintaining the temperature between 50 and 55 degrees Celsius and the continuous evolution of hydrogen. After the addition was complete, the temperature of the reaction mixture was raised to 65 degrees Celsius and stirred for 2 hours. The flask was then cooled to room temperature and the flask was immersed in an ice bath. When the temperature dropped below 20 degrees Celsius, 0.5 L of ice water was added.

The mixture was transferred to a 4.0 L separatory funnel and an additional 1.0 L of water was added and the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with 5% hydrogen chloride / water (1 x 200 mL), saturated sodium carbonate (1 x 200 mL) and brine (1 x 200 mL), dried over magnesium sulfate and concentrated in vacuo to 18.2 g of crude product as yellow semi-solid substances. Recrystallization from ethyl acetate / hexane gave 6.53 g of pure product as tan crystals (30%). 1 H NMR was consistent with the desired structure. Mass spectrum showed m / z 363 (M + H).

Part D: Preparation of the title compound

A solution of Part C compound from above (4.57 g, 12.6 mmol) in 50 mL dry tetrahydrofuran in an oven-dried 100 mL round bottom flask was stirred at room temperature under nitrogen and 4.84 g of trimethylsilanolate was added in one portion. potassium (37.7 mmol). The mixture was stirred for 2 hours, then 10 mL of water was added dropwise. The volatiles were removed in vacuo and the residue was partitioned between 100 mL of ethyl ether and 100 mL of water. The aqueous layer was acidified to a pH of less than 2 using concentrated hydrogen chloride causing a white precipitate. This mixture was extracted with ethyl acetate (3 x 75 mL) and the combined ethyl acetate layers were dried over magnesium sulfate and concentrated in vacuo to 4.15 g pure product as a white solid (94%). 1 H NMR (CDCl ₃ / CD ₃ OD) 2.10 (m, 4H), 3.28 (m, 2H), 3.90 (m, 2H), 7.60 (m, 4H).

Mass spectrum showed m / z 349 (M + H).

386 «4 4 · • 4 4 4

4 · 4 4 · 4

Step 9: Attach to resin I Preparation from resin IX

According to the procedure shown in step 1 above, 3.13 g of the title compound of the above preparation was reacted with 3.73 g of resin I to 5.19 g of polymer-bound hydroxamate as a tan-brown polymer solid. The theoretical polymer loading was 0.86 mmol / g. FTIR microscopy showed bands at 1693 and 3332 cm ^-1 indicative of hydroxamate carbonyl and nitrogen-hydrogen bonds.

Step 10:

Palladium catalyzed reaction of resin IX with boric acids: Preparation of VH resin

A resin IX (50 mg, 0.043 mmol) was weighed into an 8 mL glass solid phase reaction vessel. The resin was washed with dry dimethoxyethane (2 x 3 mL). A 0.017 M solution of tetrakistriphenyl phosphine palladium (0.6 mL, 0.01 mmol) was added to the flask then 0.6 M boric acid solution in 1: 1 dimethoxyethane / ethanol (0.6 mL, 0.36 mmol) and 2 M solution potassium hydroxide in water (0.4 mL, 0.8 mmol). The vessel was kept under positive argon pressure and heated to 90 degrees Celsius for 16 hours. The vessel was cooled to room temperature, then the resin was dried and washed with 1-methyl-2-pyrrolidinone, 1-methyl-2-pyrrolidinone / water (1: 1), water, acetic acid / water (1: 9), methanol and dichloromethane (3 x 3 mL each solvent).

The following hydroxamic acids were synthesized from resin IX using step 10 of the reaction conditions of the boric acid shown and then grafted from the polymer using step 3 of the reaction conditions.

Example number boric acid

MS (ES) m / z

387 · to · to · · · · · ** ** **

213 phenylboritá acid ^ 0 214 3-nitrophenylboronic acid X 215 thiophene-3-boronic acid 216 4-chlorobenzene boric acid XX 217 4-Methylbenzeneboronic acid ^J ir ^: 218 4- (2-pyrrolidinyl-ethoxy) benzeneboronic acid Xx

362 (M + H)

424 (M + NH3)

367 (M + H)

413 (M + NH3)

414 (M + K)

476 (M + NH3)

219

3- (trifluoromethyl) -benzeneboronic acid Τ T

430 (M + H)

220

4-Fluoro-benzeneboronic acid

221

4- (Trifluoromethyl) benzeneboronic acid

222

4-fluoro-3-methylbenzeneboronic acid

223

3,4-dimethylbenzeneboronic acid

224

1-Naphthyleneboronic acid

417 (M + K)

447 (M + NH3)

411 (M + NH3)

407 (M + NH3)

412 (M + H)

388 ftftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft

225

2-methylbenzeneboronic acid

378 (M + H)

226

4-t-butylbenzeneboronic acid is &lt;

ch ₃

419 (M + H)

227

2-Naphthyleneboronic acid

228

3-formyl-benzeneboronic acid

229 benzo furan-2-boronic acid

230

2-formyl-benzeneboronic acid

231

4-formyl-benzeneboronic acid

232

3-Amino-benzeneboronic acid

CH ₃

CH

CHO

412 (M + H)

390 (M + H)

419 (M + NKQ

390 (M + H)

Example 233

Preparation of monomethanesulfonate salts: N-hydroxy-4 - [[4 (phenylthio) phenyl] sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide monomethanesulfonate

First preparation

Part A: A solution of the compound of Example 9, Part J (2.1 g, 4.5 mmol) in warm H ₂ O (200 mL) was mixed with NaHCO ₃ at ambient temperature. After stirring for 20 minutes, the resulting white solid was collected by filtration, washed with water, and dried at 37 degrees Celsius in a vacuum oven to give the free base of the title compound as a white solid (1.7 g, 86%); Calcd for C ₂ H ₂₂ N ₂ O ₄ S ₂ ^'0, 3% H ₂ O: C, 57.86; H, 5.23; N, 6.43; S, 14.71. Found: C, 57.84; H, 4.96; N, 6.39; S, 14.89.

Part B: Methanesulfonic acid (0.28 mL, 4.1 mmol) was added to a solution of the free base of Part A (1.6 g, 3.7 mmol) in methanol (10 mL) at ambient temperature. After 3 hours, the resulting solids were collected by filtration, washed with methanol, and dried at ambient temperature in a vacuum oven to give the title compound monomethanesulfonate as a white solid (1.6 g, 81%): Analysis calculated for: C ₂₁ H ₂₂ N ₂ O ₄ S ₂ CFCl 3: C, 48.51; H, 5.18; N, 5.14; S, 17.66. Found: C, 48.88; H, 5.15; N, 5.23; S, 17.81.

Second preparation

Methanesulfononic acid (0.91 mL, 14 mmol) was added to a solution of the protected hydroxamate of Example 9, Part I (6.0 g, 12 mmol) in methanol (37 mL) under a nitrogen atmosphere. After 1 hour the precipitate was collected by filtration, washed with methanol and dried at 40 degrees Celsius in a vacuum oven for 1 day to give the title compound monomethanesulfonate as a white solid (5.5 g, 89%) identical to the material of Example 233, first preparation.

The methanesulfonate salts of the other cyclic amine compounds described herein can similarly be prepared using the two preparation methods above.

Examples 234-280

The compounds of Examples 234-280 were prepared as described for the Examples

129 to 199.

390 • 4

4 4 44

Example Prys-Amin resin number

234

235

236

237

238

239

240

241

242

243

244

245

246

IVb

IVb

IVb

IVb

IVb

IVb

IVa

IVa

IVa

IVa

IVa

IVa

IVb

N-methyl homopiperazine

6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline HCl tetrahydropyridine

R-3-hydroxy-piperidine HCl phenylpiperazine benzylpiperazine methyl homopiperazine

6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline HCl tetrahydropyridine R-3-hydroxy-piperidine HCl phenylpiperazine benzylpiperazine hydroxyethylpiperazine

Position

L-n n - „4

MS (ES) m / z

508 (M + H)

587 (M + H)

477 (M + H)

495 (M + H)

558 (M + H)

572 (M + H)

508 (M + H)

587 (M + H)

477 (M + H)

495 (M + H)

558 (M + H)

572 (M + H)

526 (M + H)

391

IVb

IVb

IVb

IVb

IVb

IVb

IVb

IVb

IVb

IVb

IVb

IVb

IVb

IVb

IVb

- (4-Methoxyphenyl) piperazine 2HCl

- (3-chlorophenyl) -piperazine HCl 1- (m-tolyl) -piperazine 2HCl

- (2,5-dimethylenyl) piperazine 1- (p-tolyl) piperazine 2HCl

- (3-methoxyphenyl) piperazine 2HCl 1- (3,4-dichlorophenyl) piperazine 1- (2-methoxy) -piperazine HCl nipecotamide

- (4-Methoxyphenyl) -2-methyl-piperazine 1- (2,3-xylyl) -piperazine HCl

isonipecotamide 1- (2- (2-hydroxy, ethoxyethyl) -piperazine)

1-ethylpiperazine 1- (2-chlorophenyl) piperazine HCl

588 (M + H)

592 (M + H)

572 (M + H)

586 (M + H)

572 (M + H)

588 (M + H)

624 (M + H)

588 (M + H)

522 (M + H)

522 (M + H)

568 (M + H)

508 (M + H)

592 (M + H)

601 (M + H)

392

44 4 4 1 • 4 4 4

I 4 4 4 4 4

4 44

IVb 2-methylpiperidine

IVb 3,5-dimethylpiperidine \ ^'N y

IVb N- (2-piperidylmethyl) - diethylamine AND 4 IVb thiomorpholine HCl G ^with γΜ 4 IVb N-methylpropargylamine 4 IVb N-methyl-U-alanine nitrile 1 4 IVb 1-Methyl-4- (methylamino) piperidine X / - \ N— (N— / \ _ / 4 IVb 2-ethylpiperidine Aj- / ^- 4

<X

IVb 1-piperazinecarboxaldehyde

IVb 2-piperidinethanol

IVb 2- (methylamino) ethanol

IVb N-methylallyl amine

IVb 2- (piperidinomethyl) -piperidine

IVb 1- (1-phenylethyl) -piperazine

IVb 1- (2-Phenylethyl) piperazine

O

• 4 4 4

4 4 4

4 4 4 4

4 4 4

4 44

495 (M + H)

507 (M + H)

566 (M + H)

497 (M + H)

465 (M + H)

478 (M + H)

522 (M + H)

507 (M + H)

508 (M + H)

525 (M + H)

470 (M + H)

465 (M + H)

578 (M + H)

586 (M + H)

586 (M + H)

393 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · · · · · · <

• · · · · · · ·

277 IVb N, N-dimethyl-N ' -ethylenediamine

511 (M + H)

278 IVb N, N-Diethyl-N-methylenethylenediamine / N 'N

526 (M + H)

279 IVb 1-Cyclohexylpiperazine

562 (M + H)

280 IVb 2,6-dimethylpiperidine

507 (M + H)

Examples 281 to 288

The following hydroxamic acids were synthesized from resin IX using step 10 of the boric acid shown and then cleaving from the polymer using step 3, previously discussed for Examples 213-232:

Example number boric acid R MS (ES) m / z 281 4-methoxybenzeneboronium 393 (M + H) acid AA 282 3-methoxybenzeneboronium 393 (M + H) acid X 283 4-methylthiobenzeneboronium 400 (M + H) acid x _s .

4-MeNHSO 2 -benzene

454 (M + H)

284 • 0 • 0 • 9 0 ·

• 0

··

0 «

394

9 9 • 090 • «0 9 boric acid

285

4-Carboxybenzeneboronic acid

406 (M + H)

286

2-Trifluoromethyl-benzeneboronic acid

430 (M + H)

287

3,5-bis- (trifluoromethyl) benzeneboronic acid

288

2,3,4-Trifluorobenzeneboronic acid

497 (M + H)

415 (M + H)

Examples 289-294

Step 11: Preparation of Resin XI.

A fritted reaction vessel was charged with resin IIIc (50 mg, 0.043 mmol). A 0.43M solution of isocyanate in 1-methyl-2-pyrrolidinone (1 mL, 0.43 mmol) was added followed by diisopropylethylamine (75 µL, 0.43 mmol). The vessel was sealed under nitrogen and stirred on a wall shaker and heated to 50 degrees Celsius for 48 hours. Then the vessel was cooled to room temperature and the resin was dried and washed with 1-methyl-2-pyrrolidinone, 1: 1 1-methyl-2-pyrrolidinone / water, water, 1: 9 acetic acid / water, methanol and dichloromethane (3X1). ml of each solvent).

The following hydroxamic acids were synthesized from resin IIIc using step 11 of the shown isocyanate and then release from the polymer using the reaction conditions in step 3.

Example Number Isocyanate R MS (FAB) m / z 289 phenylisocyanate 489.1 (M + H). 290 4-Fluorophenyl isocyanate Ύ, 507.2 (M + H) 291 4-Phenoxyphenyl isocyanate άχο 581.3 (M + H) 292 4-butoxyphenyl isocyanate 561.4 (M + H). 293 4-Phenylphenyl isocyanate 7 <K) 565.2 (M + H). 294 α, α, α-trifluoro m-tolyl isocyanate 557.2 (M + H). υ

Examples 295 to 300

Step 12

Synthesis of resin XII.

In a fritted reaction vessel, resin VII (50 mg, 0.038 mmol) and cesium carbonate (122 mg, 0.38 mmol) were charged. A 0.43 M solution of phenol in 1-methyl 1-2-pyrrolidinone (1 mL, 0.43 mmol) was added, then the vessel was sealed under nitrogen. The reaction mixture was stirred on a shaker and heated to 50 degrees Celsius for 48 hours. Then the vessel was cooled to room temperature and the resin was dried and washed with 1-methyl-2-pyrrolidinone, 1: 1 1-methyl-2-pyrrolidinone / water, water, 1: 9 acetic acid / water, methanol and dichloromethane ( 3X 1 ml of each solvent).

• · ftftft

The following hydroxamic acids were synthesized from resin IIIc using step 11 of the shown isocyanate and then release from the polymer using the reaction conditions in step 3.

ft ·

396 ftft ft ft ft ft ft ft ft ft ft ft ft & ft ft ft

O

Example number Phenol R MS (FAB) m / z 295 phenol 490 (M + H) 296 3-methoxyphenol 520 (M + H) 297 4-chlorophenol 'XX 524.1 (M + H). 298 p-cresol XX 504.3 (M + H) 299 4-phenylphenol 566.3 (M + H) 300 4-Hydroxy-diphenylmethane ^In ° XXO 580.2 (M + H)

Example 301-323:

Large-scale resin preparation Xa

A fritted reaction vessel was charged with resin IX (1 g, 0.86 mmol) and a 0.008 M solution of tetrakis (triphenylphosphine) palladium (0) in ethylene glycol dimethyl ether (5 mL, 0.04)

397 mmol). A 1 M solution of 2-formylbenzeneboronic acid in a 1: 1 mixture of ethanol and ethylene glycol dimethyl ether (6 mL, 6 mmol) was then added with 1M cesium carbonate in water (2 mL, 2 mmol). The vessel was sealed under argon and heated to 90 degrees Celsius for 16 hours. Then, the vessel was cooled to room temperature and the resin was dried and washed with the following order of solvents: dimethylformamide, 1: 1 dimethylformamide / water, dimethylformamide, water, methanol, dichloromethane (3X 5 mL each solvent). The resin was dried under vacuum to yield 1.025 g of the product as a tan solid polymer solid. The theoretical polymer loading was 0.84 mmol / g. TFA graft performed on 35 mg of resin Xa as described in step 3 gave 11.2 mg of a tan solid.

Large-scale resin preparation Xb.

Preparation from resin Xb followed an identical procedure described for the preparation of resin Xa except that 3-formylbenzeneboronic acid was replaced with 2-formylbenzeneboronic acid. The yield after drying under vacuum was 1.052 g of resin Xb as yellow-brown resin beads. The theoretical polymer loading was 0.84 mmol / g. TFA grafting to 20 mg of resin Xb as described in step 3 yielded 6.5 mg of a tan solid.

Large-scale resin preparation Xc.

Preparation from resin Xc followed an identical procedure described for the preparation of resin Xa except that 4-formylbenzeneboronic acid was replaced with 2-formylbenzeneboronic acid. The yield after drying under vacuum was 1.03 g of resin Xc as yellow-brown resin beads. The theoretical polymer loading was 0.84 mmol / g. TFA grafting on 28 mg of resin Xb as described in step 3 gave 9.4 mg of a tan solid.

Step 13: Synthesis of resin XIII.

A fritted reaction vessel was charged with resin Xa, Xb or Xc (50 mg, 0.042 mmol). A 0.2 M solution of amine in trimethyl orthoformate (1 mL, 0.2 mmol) was added and the vessel was sealed under nitrogen. The reaction mixture was stirred on a shaker for 3 hours. A 0.5 M solution of sodium triacetoxyborohydride in 1-methyl-2-pyrrolidinone (0.8 mL, 0.4 mmol) was then added to the flask and stirred for an additional 40 hours. Then, the resin was dried and washed (3X 1 mL of each solvent) with the following order of solvents: 1-methyl-2-pyrrolidinone, methanol, water, methanol and dichloromethane.

• ·

The following hydroxamic acids were synthesized using the shown resin-bound aldehyde and the shown amine according to the procedure shown in step 13 followed by release from the polymer using the procedure of step 3:

• · ··············

398 :: :::

······································

~ \

R

Example MS (ES) m / z number Resin Amin R Position ice and

301

302

303

304

305

306

307

308

309

Xb

Xb

Xb

Xb

Xb

Xb

Xa

Xa

Xa

1,2,3,4tetrahydroisoquinoline

-methylpiperazine piperazine benzylamine propylamine ethyl isonipecotate benzylamine isopropylamine

1,2,3,4-

508 (M + H)

475 (M + H)

460 (M + H)

482 (M + H)

432 (M + H)

531 (MH +)

482 (M + H)

432 (M + H)

508 (M + H)

399 tetrahydroisoquinoline

Xa

Xc

Xc

Xc

Xc

Xc

Xc

Xc

Xc

Xc

Xc

Xc

Xb

-methylpiperazine piperidine morpholine

-methylpiperazine

1-phenylpiperazine

1-Benzylpiperazine 1- (4-fluorophenyl) piperazine

Ν, Ν, Ν-trimethylethylenediamine hexamethylenimine

-methylhomopiperazine diethylamine pyrrolidine • this this

TFA | 3 dimethylamine

475 (M + H)

458 (M + H)

462 (M + H)

475 (M + H)

535 (M + H)

550 (M + H)

555 (M + H)

475 (M + H)

472 (M + H)

487 (M + H)

448 (M + H)

444 (M + H)

418 (M + H)

400 ·· 44 ί · 4>> 4 4 4 ► 4 4 4

I 4 4 4

323

Xc 1- t -butoxycarbonylpiperazine

460 (M + H)

Large-scale resin preparation Xd

Preparation from resin Xd followed an identical procedure described for the preparation of resin Xa except that 4-carboxybenzeneboronic acid was replaced with 2-formylbenzeneboronic acid. The yield after drying under vacuum was 1.07 g of resin Xd as a tan solid polymer solid. The theoretical polymer loading was 0.83 mmol / g. TFA grafting to 23.5 mg of resin Xd as described in step 3 yielded 4.9 mg of a tan solid.

Step 14: Synthesis of Resin XIV

A fritted reaction vessel was charged with resin Xd (50 mg, 0.042 mmol). The resin was washed with 1-methyl-2-pyrrolidinone (2X3 mL), then a 1.0 M solution of benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate in 1-methyl-2-pyrrolidinone (0.2 mL) was added. , 0.2 mmol) followed by a 0.7 M solution of amine in 1-methyl-2-pyrrolidinone (0.3 mL, 0.21 mmol) and 1.0 M solution of diisopropylethylamine in 1-methyl-2-pyrrolidine (0 , 4 mL, 0.4 mmol). The vessel was sealed under nitrogen and the reaction mixture was stirred on a shaker for 24 hours. Then the resin was dried and washed with 1-methyl-2-pyrrolidinone (3X 1 mL). Reaction with the amine was repeated by adding a 1.0 M solution of benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate in 1-methyl-2-pyrrolidinone (0.2 mL, 0.2 mmol) and a 0.7 M solution of amine in 1-methyl-2-pyrrolidinone (0.3 mL, 0.21 mmol) and a 1.0 M solution of diisopropylethylamine in 1-methyl-2-pyrrolidinone (0.4 mL, 0.4 mmol). The vessel was sealed under nitrogen and the reaction mixture was stirred for an additional 8 hours. Then the resin was dried and washed with the following order of solvents: 1-methyl-2-pyrrolidinone, 1: 1 1-methyl-2-pyrrolidinone / water, water, 1: 9 acetic acid / water, methanol, dichloromethane (3X 1 ml each) solvents).

The following hydroxamic acids were synthesized using resin Xd and the shown amine according to the procedure shown in step 14, followed by release from the polymer using the procedure of step 3:

· 4 4 · 4 4 4 4 «4 4 4 4 4 4 4 * *

401: ϊ · ϊ i * ·; Ί * · • • · · * * * *

Example amine R MS (ES) m / z 324 propylamine H 448 (M + H) 325 piperidine γ ^Ν Ο 472 (M + H) 326 morpholine O 474 (M + H) 327 1-methyl- piperazine TFA 487 (M + H) 328 diethylamine AND 462 (M + H) 329 pyrrolidine AND 458 (M + H) 330 ethyl isonipecotate 546 (M + H) 331 1-phenylpiperazine YZMD TFA 550 (M + H) 332 ethyl nipecotate 546 (M + H) II 0 333 1-Benzylpiperazine TFA ΑΌ 565 (M + H)

00 0 0 0

0 0 0

0 0 0 0

0 0 0

0 *

402

0 0 0 0004 · 0

0 00

334 3,5-dimethylpiperidine Λ 501 (M + H) 335 thiomorpholine hydrochloride 492 (M + H)

Example 336

Preparation of 4 - [[4- [4 - [[(9H-fluoren-9-ylmethoxy) carbonyl] amino] -1-piperidinyl] phenyl] sulfonyl] tetrahydro-2H-pyran-4-carboxylic acid

Part A: To a solution of the product of Example 11, Part B (10.0 g, 34.7 mmol) in 1-methyl-2-pyrrolidinone (70 mL) was added 4- (N-butoxycarbonylamino) piperidine (10.43 g, 52 mL). , 1 mmol) followed by diisopropylethylamine (6.0 mL, 34.7 mmol). The resulting mixture was heated at 80 degrees Celsius for 24 hours and then cooled to room temperature. The crude mixture was poured into 700 mL of water and the cloudy aqueous layer was extracted with ethyl acetate (3X 150 mL). The combined organic layers were washed with 5% potassium bisulfate (2X 150 mL) and brine (2X 150 mL), dried over magnesium sulfate and concentrated in vacuo to give the crude ester as a white foamy solid (13.04 g, 78%). ).

Part Β: To a solution of the ester from Part A (5.74 g, 11.9 mmol) in a mixture of ethanol (80 mL) and tetrahydrofuran (40 mL) was added 2 sodium hydroxide (60 mL; 120 mmol). The resulting solution was heated to 60 degrees Celsius for 1 hour and then cooled to room temperature. The solution was concentrated in vacuo and the residue was partitioned between water (300 mL) and ethyl acetate (200 mL). The aqueous layer was separated and acidified with concentrated hydrochloric acid to pH 2. The resulting white precipitate was collected by vacuum filtration and dried under vacuum to give the carboxylic acid as a white solid (4.88 g, 88%).

Part C: To a suspension of the carboxylic acid from Part B (4.88 g, 10.4 mmol) in dichloromethane (35 mL) was added trifluoroacetic acid (35 mL) resulting in the dissolution of the solid. After fifteen minutes at ambient temperature, the solution was concentrated in vacuo. The product was triturated with diethyl ether to give the amino acid as an off-white solid (4.92 g, 98%).

Part D: A suspension of the amino acid from Part C (4.92 g, 10.21 mmol) in 10% sodium carbonate / water (35 mL), water (100 mL) and dioxane (100 mL) was cooled in an ice bath. To the cooled suspension was added dropwise a solution of 9-fluorenylmethylsuccinimidyl carbonate (3.79 g, 11.23 ftftft ftft).

403 ft ft ft ft ft ft ft ft in dioxane (50 mL). After the addition was complete, the ice bath was removed and the mixture warmed to room temperature. After one hour, the solution was concentrated in vacuo and the residue was partitioned between water (300 mL) and ethyl acetate (200 mL). The aqueous layer was separated and acidified with concentrated hydrochloric acid to pH 2. The formed white precipitate, which was collected by vacuum filtration, was washed with hexanes and dried in vacuo to give the title compound as a white solid (5.46 g, 91%).

Step 15: Preparation of Resin XVI.

Part A: Following the procedure shown in Step 1 above, the product of Example 336 (2.4 g, 4.06 mmol) was reacted with resin I (1.7 g, 2.03 mmol) to afford resin XV as a tan solid polymer solid. (2.82 g). The theoretical polymer loading was 0.71 mmol / g.

Part B. Resin XV from Part A above (2.76 g, 1.96 mmol) was suspended in a 1: 4 solution of piperidine / dimethylformamide (20 mL) in a fritted reaction vessel and stirred on a shaker for 5 minutes. The resin was dried and an additional 1: 4 volume of piperidine / dimethylformamide (20 mL) was added to the flask. The suspension was stirred at room temperature for 30 minutes. Then, the resin was dried and washed with dimethylformamide, methanol and dichloromethane (3X 20 mL each solvent). After drying in vacuo, the title resin was obtained as a tan solid (2.30 g).

Step 16: Acylation / sulfonation of resin XVI.

In a fritted reaction vessel, resin XVI (50 mg, 0.043 mmol) was washed with 1-methyl-2-pyrrolidinone (2 x 1 mL). A 0.22 M solution of acylation or sulfonation reagents in 1-methyl-2-pyrrolidinone (1 mL, 0.22 mmol) was then added to the resin followed by diisopropylethylamine (40 µL, 0.22 mmol). The vessel was sealed under nitrogen and stirred on a table shaker at room temperature for 16 hours. Then the resin was dried and washed with 1-methyl-2-pyrrolidinone, water, 1: 9 acetic acid / water, methanol and dichloromethane (3X 1 mL each solvent).

The following hydroxamic acids were synthesized from resin XVI using step 16 shown by an acylating or sulfonating reagent, followed by release from the polymer using the reaction conditions of step 3.

·· · · · · · · · · ·

Example Acylating or sulfonating reagent R MS (ES) m / z 337 benzoyl chloride Ύ 488.2 (M + H). 338 nicotinyl chloride-HCl 0 TFA 489.2 (M + H). 339 benzenesulfonyl chloride ^V O 463 (M + H) 340 1-Methyl-imidazole-4-sulfonyl chloride 0, o XS ' ^ς τ N— 528.2 (M + H). 341 acetyl chloride 0 426.2 (M + H). 342 methanesulfonyl chloride AND 462.1 (M + H) 343 cyclohexyl isocyanate ΑΌ H 508 (M + H) 344 2-methoxyphenyl isocyanate ap / 0 533 (M + H) 345 phenyl isocyanate AX ^with H 502 (M + H) 346 beta-phenylethyl isocyanate H ^ς H 531 (MH +) 347 isopropyl isocyanate 467 (M + H)

o I ^s Η

405 »» ·· ·

348 4-Fluorophenyl isocyanate AO ’ H 522 (M + H) 349 4- (methylthio) phenyl isocyanate Α <Ο H 549 (MH +) 350 4-Phenoxyphenyl isocyanate A-QAi H 596 (M + H) 351 4-Phenylphenyl isocyanate H 578 (M + H) 352 benzyl isocyanate O Xr-Q 518 (M + H) 353 ethyl isocyanate 0 R- 454 (M + H) 354 alpha, alpha, alpha-trifluoro-m-tolyl isocyanate χχχ, H ⁴ 572 (M + H) 355 ethyl- 3-isocyanate propionate 0 0 H 528 (M + H) 356 methyloxalyl chloride R ° 0 470 (M + H) 357 diethylcarbamyl chloride 0 Xn- 482 (M + H) 358 dimethylcarbamyl chloride 0 ** 1 454 (M + H) 359 diisopropylcarbamyl chloride ⁰ 1 511 (M + H) 360 hydrocinnamoyl chloride 515 (M + H)

361 Cinnamoyl chloride

61 isobutyl chloroformate

363 benzylchloroformate

364 trichloroethyl chloroformate

406

44 44 4 4 4 4 4 4 4 4 4 4 · • 4 4 4 44 * 4 4 4 4 4 4 4 4 4 4 4 4 ··· 4 · 44 4 4 4 •• 44 4 · Yq • 44 44 44 4 < 515 (M + H) 0 483 (M + H) Λ-q 518 (M + H); 557 (M + H)

Examples 365 to 371

Step 17: Reductive alkylating resins XVI.

In a fritted reaction vessel, resin XVI (50 mg, 0.043 mmol) was washed with dichloromethane (2X 1 mL). A 1M solution of aldehyde or ketone in dichloromethane (1 mL, 1 mmol) was then added to the resin. The vessel was sealed under nitrogen and stirred on a table shaker at room temperature for 3 hours. The resin was dried and washed with dichloromethane (3X 1 mL). The resin was then reacted with a 1 M solution of aldehyde or ketone in dichloromethane (1 mL, 1 mmol). The resin was dried and washed with dichloromethane (3X 1 mL each solvent). A 1 M solution of sodium triacetoxyborohydride in 1-methyl-2-pyrrolidinone (1 mL, 1 mmol) was then added to the resins and the reaction was stirred overnight. Then the resin was dried and washed with 1-methyl-2-pyrrolidinone, methanol, water, 1: 9 acetic acid / water, methanol and dichloromethane (3X 1 mL each solvent).

The following hydroxamic acids were synthesized from resin XVI using step 17 with the aldehyde or ketone shown, followed by release from the polymer using the condition of step 3.

• to • to • to • to • to

407

Example number Aldehyde or ketone R MS (ES) m / z 365 butyraldehyde X— 440 (M + H) 366 acetone 427 (M + H) 367 N-propyl-4-pyridone 508 (M + H) 368 4-t-butylcyclohexanone 523 (M + H) 369 2-pyridinecarboxaldehyde TFA 474 (M + H) 370 4 '- (trifluoromethoxy) acetophenone X. », 573 (M + H) 371 2 -uraldehyde 465 (M + H)

Example 372

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

O

408 · · · · 408 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 · · «··

Part A: To a solution of the product of Example 55 (3.1 g, 8 mmol) in dimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol) and 4-butoxyphenol (2.66 g, 16 mmol). . The suspension was stirred at 95 degrees Celsius for 19 hours. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the substituted THP hydroxamate as an off-white foam (3.96 g, 93%). HRMS (ES +) M + NHf calcd for Q 7 H 35 N 1 O 8 SiF: 551.24, found 551.24.

Part Β: To a solution of THP hydroxamate from Part A (3.9 g, 7.3 mmol) in 1,4-dioxane (20 mL) was added 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 Na ₂ SO ₄ , filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound as a white solid (2.75 g, 84%). HRMS (ES +) M + H ⁺ calcd for C ₂₂ H ₂₇ N 4 O ₇ Si: 450.16, found 450.16.

Example 373

Preparation of tetrahydro-N-hydroxy-4 - [[4- [3- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide

HIM

Part A: To a solution of the product of Example 55 (3.1 g, 8 mmol) in dimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol) and m- (trifluoromethyl) phenol (1.95 mL, 16 mmol). The suspension was stirred at ninety-five degrees Celsius for nineteen hours. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the substituted THP hydroxamate as a white foam (4.1 g, 97%). HRMS (ES +) M + H calcd for C ₂₄ H ₂₆ NiO 7 S ₁ F 3: 530.15, found 530.14.

Part Β: To a solution of THP hydroxamate from Part A (3.9 g, 7.4 mmol) in 1,4-dioxane (20 mL) was added 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 Na ₂ SO ₄ , filtered, and filtered.

Concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound as a white solid (1.9 g, 58%). HRMS (ES +) M + H ⁺ calcd for C 19 H ₁₈ N, O ₆ S ₁ F ₃ :

446.09, found 446.09.

Example 374

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

409

Part A: To a solution of the product of Example 55 (3.1 g, 8 mmol) in dimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol) and 4- (methylthio) phenol (2.24 g, 16 mmol). The suspension was stirred at ninety-five degrees Celsius for twenty-four hours. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the substituted THP hydroxamate as a white foam (4.1 g, 100%). HRMS (ES +) M + H + calcd for C 24 H 29 N ₁ O 7 S ₂ : 508.15, found 508.15.

Part Β: To a solution of THP hydroxamate from Part A (4.0 g, 7.9 mmol) in 1,4-dioxane (20 mL) was added 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 Na 2 SO ₄ , filtered and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound as a white solid (1.9 g, 57%). HRMS (ES +) M + H ⁺ calcd for C 19 H 21 N 1 ^O 6 S 2: 424.09, found 424.09.

Example 375

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

410

99 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ····················· · ·

HIM

Part A: To a solution of the product of Example 55 (2.7 g, 7 mmol) in dimethylacetamide (15 mL) was added cesium carbonate (6.84 g, 21 mmol) and 4-hydroxydiphenylmethane (2.8 g, 14 mmol). . The suspension was stirred at ninety degrees Celsius for nineteen hours. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the substituted THP hydroxamate as a pale yellow foam (3.7 g, 96%). HRMS (ES +) M + H ⁺ calcd for C 30 H 33 N 1 ^O 7 Sf 552.21, found 552.21.

Part Β: To a solution of ΊΉΡ hydroxamate from Part A (3.5 g, 6.4 mmol) in 1,4-dioxane (16 mL) was added 4N HCl dioxane solution (16 mL) and methanol (16 mL). After fifteen minutes at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over Na 2 SO ₄ , filtered and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound as a white solid (1.95 g, 67%). HRMS (ES &lt; + &gt;) M + H &lt; ⁺ &gt;

Example 376

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

Part A: To a solution of the product of Example 55 (2.7 g, 7 mmol) in dimethylacetamide (20 mL) was added cesium carbonate (6.84 g, 21 mmol) and 4- (benzyloxy) phenol (2.8 g, 14 mmol). The suspension is * and

4 ftftft ftftft ftft ft ft ft

> · E ·

It was stirred at ninety-five degrees Celsius for six hours. The reaction was concentrated in vacuo.

The residue was taken up in ethyl acetate, washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave substituted

THP hydroxamate as a white foam (3.94 g, 99%). HRMS (ES +) M + NH ₄ ⁺ calculated for

C30H33N1O8 Si: 585.23, found 585.23.

Part Β: To a solution of THP hydroxamate from part A (1.5 g, 2.64 mmol) in glacial acetic acid (5 mL) was added concentrated HCl (5 mL) and the reaction was heated to sixty degrees Celsius for twenty minutes. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate. The ethyl acetate extract was washed three times with water, brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound as a white solid (810 mg, 78%). HRMS (ES +) M + NH + calcd for C ₁₈ H 19 N ₁₀ O ₇ Si: 468.15, found 468.15.

Example 377

Preparation of tetrahydro-N-hydroxy-4 - [[4- [4 - [(1-methylethyl) thio] phenoxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide

Part A: To a suspension of 4-hydroxythiophenol (5.0 g, 40 mmol) and potassium carbonate (8.0 g, 58 mmol) in dimethylformamide (70 mL) was added 2-iodopropane (7.0 g, 41 mmol). The suspension was stirred at ambient temperature for one hour. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed twice with water, 10% HCl solution, brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the substituted phenol as a clear colorless oil (5.1 g, 76%).

Part Β: To a solution of the product of Example 55 (3.1 g, 8 mmol) in dimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol) and phenol from Part A (2.7 g, 16 mmol). ). The suspension was stirred at ninety-five degrees Celsius for fifteen hours. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave substituted it

412.

· · · · · · · · · · · · · · · · · · · · _E · · · · · · · · · · · · · · · · · · · · · · · · · · ·

THP hydroxamate as a white foam (4.15 g, 97%). HRMS (ES +) M + H ⁺ calcd for C 20 H 33 N 1 ^O 7 S 2: 536.18, found 538.17.

Part C: To a solution of THP hydroxamate from Part A (3.9 g, 7.3 mmol) in 1,4-dioxane (18 mL) was added 4N HCl dioxane solution (18 mL) and methanol (18 mL). After fifteen minutes at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over Na ₂ SO 4, filtered and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound as an off-white solid (2.32 g, 71%). HRMS (ES +) M + H ⁺ calcd for C ₂₁ H ₂₅ NiO ₆ S ₂ : 452.12, found 452.12.

Example 378

Preparation of tetrahydro-N-hydroxy-4 - [[4- [4- (1-methylethoxy) phenoxy) phenyl] sulfonyl] -2H-pyran-4-carboxamide

Part A: To a solution of benzoic acid 4-hydroxyphenyl ester (8.57 g, 40 mmol) in dimethylacetamide (65 mL) was added potassium carbonate (8.3 g, 60 mmol) and 2-iodopropane (5 mL, 50 mmol). . The suspension was stirred at sixty-five degrees Celsius for one hour. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed three times with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to yield the isopropoxy compound as a light gray solid (9.7g, 95%).

Part Β: To a suspension of the isopropoxy compound of Part A (9.7 g, 38 mmol) in 1,4-dioxane (20 mL) and water (20 mL) was added 2.5M sodium hydroxide solution (26 mL, 65 mmol). . The suspension was stirred at sixty degrees Celsius for four hours. The reaction was cooled and a solution of 6N hydrochloric acid was added until pH = 5. The reaction was extracted with dichloromethane. The organic layer was washed with 5% ammonium hydroxide solution four times, water, brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to yield phenol as an amber oil (5.4 g, 94%).

Part C: To a solution of the product of Example 55 (3.1 g, 8 mmol) in dimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol) and phenol from Part B (2.4 g, 16 mmol). ). The suspension was stirred at ninety-five degrees Celsius for twenty-one hours. The reaction was concentrated in vacuo.

The residue was taken up in ethyl acetate, washed with water three times, brine, dried over Na ₂ SO ₄ .

The 413 was filtered and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the substituted THP hydroxamate as an off-white foam (3.65 g, 88%). HRMS (ES +) M + H ⁺ calcd for C 26 H 33 N 1 ^O 8 Si: 520.20, found 520.20.

Part D: To a solution of THP hydroxamate from part C (3.5 g, 6.7 mmol) in 1,4-dioxane (17 mL) was added 4N HCl dioxane solution (17 mL) and methanol (17 mL). After fifteen minutes at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound as an off-white solid (2.2 g, 80%). HRMS (ES +) M + ΗΓ calcd for C 21 H 25 N 1 O 7 S 1: 436.14, found 436.14.

Example 379

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

Part A: Sodium hydride (60% oil dispersion) (11 g, 0.275 mol) was added to a dry apparatus under nitrogen to a solution of 4- [4- (trifluoromethyl) phenoxy] -phenol (50.0 g, 0.197 mol) in dry dimethylformamide (150 mL) at 0 degrees Celsius. After fifteen minutes a solution of dimethylthiocarbamoyl chloride (32.0 g, 0.259 mol) in dry dimethylformamide (100 mL) was added. The reaction was stirred at ambient temperature for sixteen hours. The reaction was poured into a 10% hydrochloric acid solution (1 L). Vacuum filtration of the resulting precipitate gave the thiono compound as a white solid (67.0 g, 100%).

Part B: The thiono compound from Part A (70 g, 0.2 mol) was heated to 317 degrees Celsius for 30 minutes behind the safety shield. The reaction exothermed to 330 degrees Celsius. The heating was removed and the reaction returned to ambient temperature to give the thiocarbamate as a brown solid (70 g, 100%).

Part C: To a solution of the thiocarbamate of Part B (65.0 g, 0.19 mol) in methanol (510 mL) with a nitrogen stream below the surface was added 2.5M sodium hydroxide solution (160 mL, 0.4 mol).

The suspension was stirred at 74 degrees Celsius for two hours. The reaction was cooled and methanol was removed in vacuo. The residue was diluted with water (100 mL) and extracted four times with diethyl ether.

4 4 4 9 9 9 9 9

4i4 · *! of * of: · *: ·: :::

••••• 4 · · · 9 9 9 9

A stream of nitrogen under the surface was introduced into the aqueous solution and sodium chloroacetate (22.2 g, 0.19 mol) was added. The reaction was stirred at ambient temperature for 30 minutes and the nitrogen stream was removed. After 12 hours the solution was cooled and 6M hydrochloric acid was added until pH = 1. The suspension was extracted four times with ethyl acetate. The combined ethyl acetate extracts were washed with 0.1 M hydrochloric acid, water, brine, dried over Na ₂ SO 4, filtered, and dried in vacuo to give the thioacetic acid as a tan solid (61.0 g, 98%).

Part D: To a solution of the thioacetic acid from Part C (54.45 g, 0.166 mol) in tetrahydrofuran (370 mL) was added water (45 mL) and Oxone® (306 g, 0.498 mol) at 20 degrees Celsius. An exotherm at 42 degrees Celsius was recorded. After 2 hours the reaction was filtered and the cake washed well with tetrahydrofuran and then water (250 mL) was added to the filtrate. The filtrate was concentrated in vacuo. The suspension was extracted with ethyl acetate four times. The combined extracts were washed with water three times, brine, dried over MgSO ₄ , filtered, and concentrated in vacuo to give the sulfone as a beige solid (60.0 g, 100%).

Part E: A solution of the sulfone from Part D (119.52 g, 0.332 mol) in methanol (660 mL) and 4M hydrochloric acid in dioxane solution (20 mL) was stirred at ambient temperature for 12 hours. The reaction was heated to boiling and cooled slowly to ambient temperature. The resulting crystals were filtered, washed well with cold methanol and dried to give the methyl ester as a white solid (89.4 g, 72%).

Part F: To a solution of the methyl ester of Part E (64.5 g, 0.180 mol) in dimethylacetamide (360 mL) was added potassium carbonate (66.8 g, 0.48 mol), bis- (2-bromoethyl) ether ( 40 mL, 0.305 mol), 4-dimethylaminopyridine (1.1 g, 9 mmol) and tetrabutylammonium bromide (2.9 g, 9 mmol). The reaction was stirred overnight at ambient temperature. The reaction was poured slowly into 1M HCl (500 mL). The resulting precipitate was filtered, washed with water, then hexanes. The solids were recrystallized from methanol to give the pyran compound as a white solid (62.8 g, 79%). MS (ES +) M + NF + Calc'd for C 20 H 19 O 56 S 1 F 3: 462.12, found 462.12.

Part G: In a dry apparatus under nitrogen, the pyran compound from Part F (64.0 g, 0.144 mol) was dissolved in dry tetrahydrofuran (250 mL) and a solution of potassium trimethylsilonate (55.9 g, 0.432 mol) in dry tetrahydrofuran ( 40 ml) at ambient temperature. After two hours, water (200 mL) was added and the solution was concentrated in vacuo. The suspension was extracted with ethyl acetate to remove unreacted starting material. The aqueous solution was treated with 6N HCl to pH = 1. The suspension was extracted with ethyl acetate and the combined extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was heated in diethyl ether, the resulting solids were filtered and dried to give the carboxylic acid.

9 9 9

9 9 • 9 9

9 9 9

415 acid as a white solid (56.3 g, 91%). HRMS (ES +) M + NH 4 ⁺ calcd for C 18 H ₁₀ O ₆ StF ₃ : 448.10, found 448.10.

Part Η: In a dry apparatus under nitrogen, the carboxylic acid from part G (49.0 g, 0.114 mol) was dissolved in dry dimethylformamide (280 mL) and the remaining reagents were added to the solution in the following order: N-hydroxybenzotriazole hydrate (18.5 g, 0.137 mol), N-methylmorpholine (37.5 mL, 0.342 mol), O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (41.3 g, 0.353 mol) and 1- (3-dimethylaminopropyl) -3 -ethylcarbodiimide hydrochloride 30.6 g, 0.160 mol). After four hours at ambient temperature, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water 5% KHSO 4, saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give THP hydroxamate as a white foam (62.6 g, 100% ). HRMS (ES +) M + NH ₄ ⁺ calcd for C ₂₄ H ₂₆ NO ₇ SiF ₃ : 547.17, found 547.17.

Part I: To a solution of THP hydroxamate from part H (58.5 g, 0.11 mol) in 1,4-dioxane (280 mL) was added 4M HCl dioxane solution (280 mL) and methanol (280 mL). After fifteen minutes at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was recrystallized (acetone / hexanes) to give the title compound as a white solid (42.79 g, 87%) HRMS (ES +) M + NH ₄ ⁺ calcd for C ₁₉ H ₁₈ NO ₆ SiF ₃ : 463, found 463.

Example 380

Preparation of 4 - [[4 - ([1,1-biphenyl] -4-yloxy] phenyl) sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (2.0 g, 5.2 mmol) in dimethylacetamide (8 mL) was added 4-phenylphenol (Aldrich, 1.3 g, 7.8 mmol) followed by cesium carbonate (6 mL). 8 g, 20.8 mmol). The reaction was heated at ninety-five degrees Celsius for five hours. Precipitation of the dimethylacetamide in vacuo gave a brown solid (5.3 g, quantitative yield). Chromatography (reverse phase, C-18 acetonitrile / water) gave the THP-protected biphenyl product in solution.

• 4 ·

416

Part Β: To the collected THP-protected diphenyl product from A in acetonitrile / water (50 mL) was slowly added 10% HClaq (100 mL). After stirring overnight (about 18 hours), acetonitrile precipitated.

The resulting precipitate was collected to give the title compound as a white solid (2.0 g, 83%).

MS (FAB) M + H calculated for C 24 H 23 NO 6 S: 454, found 454.

Example 381

Preparation of tetrahydro-N-hydroxy-4 - [[4 - [[4- (trifluoromethyl) phenyl] thio] phenyl] sulfonyl] -2H-pyran-4-carboxamide

4 • 4

Part A: To a solution of the product of Example 55 (2.0 g, 5.2 mmol) in dimethylacetamide (6 mL) was added 4-trifluoromethylthiophenol (Maybridge, 2.0 g, 11.2 mmol) followed by potassium carbonate (2 mL). , 9 g, 20.8 mmol). The reaction was heated at sixty-five degrees Celsius for 12 hours. Stripping of the dimethylacetamide in vacuo gave a brown solid (6.5 g, quantitative yield). Chromatography (reverse phase, C-18 acetonitrile / water) gave the THP-protected trifluoromethyl product in solution.

Part Β: To a solution of the crude THP-protected trifluoromethyl product in acetonitrile / water (40 mL) was slowly added 10% HClaq (100 mL). After stirring overnight (about 18 hours) acetonitrile precipitated. The resulting precipitate was collected to give the title compound as a tan solid (0.75 g, 31%). MS (FAB) M ⁺ H calcd for C 19 H 18 F 3 NO 5 S 2: 462, found 462.

• 4

417

Example 382

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

Part A: To a solution of the product of Example 55 (2.0 g, 5.2 mmol) in dimethylacetamide (6 mL) was added 4- (trifluoromethylthio) thiophenol (Aldrich, 1.5 g, 7.8 mmol) then cesium carbonate. (6.8 g,

20.8 mmol). After addition of a catalytic amount of potassium fluoride, the reaction was heated at ninety-five degrees Celsius for 12 hours. Precipitation of the dimethylacetamide in vacuo gave a brown solid (7.2 g, quantitative yield). Chromatography (reverse phase, C-18 acetonitrile / water) gave the THP-protected trifluoromethylthio product in solution.

Part Β: To a solution of the crude THP-protected trifluoromethylthio product from A in acetonitrile / water (40 mL) was slowly added 10% HClaq (100 mL). After stirring overnight (about 18 hours), acetonitrile precipitated. The resulting precipitate was collected to give the title compound as a tan solid (0.60 g, 24%). MS (FAB) - calcd for C19H18F3NO6S2: 476, found 476.

Example 380

Preparation of 4 - [[4- [4-chloro-3- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

O · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · _1O ··· · ···

4io ··· ···················

Part A: To a solution of the product of Example 55 (2.0 g, 5.2 mmol) in dimethylacetamide (6 mL) was added 4-chloro-3-trifluoromethylphenol (Avocado, 1.5 g, 7.8 mmol) then carbonate cesium (6,8 g,

20.8 mmol). The reaction was heated at ninety-five degrees Celsius for twelve hours. Stripping of the dimethylacetamide in vacuo gave a brown solid (7.6 g, quantitative yield). Chromatography (reverse phase, C-18 acetonitrile / water) gave the THP-protected product in solution.

Part Β: To a solution of the crude THP-protected product in acetonitrile / water (40 mL) was slowly added 10% HCl (100 mL). After stirring overnight (about 18 hours), acetonitrile precipitated. The resulting precipitate was collected to give the title compound as a white solid (0.92 g, 37%). MS (FAB) M + H calcd for C ₁₉ H ₁₇ ClF ₃ NO ₆ S: 480, found 480.

Example 384

Preparation of 4 - [[4- [4- (1,1-dimethylethyl) phenoxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4 'carboxamide

Part A: To a solution of the product of Example 55 (5.0 g, 12.9 mmol) in dimethylacetamide (25 mL) was added 4-t-butylphenol (Avocado, 2.9 g, 19.4 mmol) then cesium carbonate ( 20.4 g, 20.862.5 mmol). The reaction was heated at ninety-five degrees Celsius for twelve hours. Stripping of the dimethylacetamide in vacuo gave a brown solid (9.4 g, quantitative yield). Chromatography (reverse phase, C-18 acetonitrile / water) gave the THP-protected product in solution.

Part Β: To a solution of the crude THP-protected product in acetonitrile / water (60 mL) was slowly added 10% HClaq (100 mL). After stirring overnight (about 18 hours), acetonitrile precipitated. The resulting precipitate was collected to give the title compound as a white solid (0.28 g, 5%). MS (FAB) M + H calculated for C 22 H 27 NO 6 S: 434, found 434.

Example 385

Preparation of 4 - [[4- [3,5-bis (trifluoromethyl) phenoxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide • ftftft ··tftft · ftftftt · ftftt ftftftft ftft ft · ft · ftft ft

410 ftft ftftft · ftftft ftft ftft "17" ··················

Part A: To a solution of the product of Example 55 (3.0 g, 7.7 mmol) in dimethylacetamide (15 mL) was added 3,5-ditrifluoromethylphenol (2.9 g, 19.4 mmol) then cesium carbonate (20 mL). 4 g, 20.862.5 mmol). The reaction was heated at ninety-five degrees Celsius for twelve hours. Stripping of the dimethylacetamide in vacuo gave a brown solid (14.7 g, quantitative yield). Chromatography (reverse phase, C-18 acetonitrile / water) gave the THP-protected product in solution.

Part Β: To a solution of the crude THP-protected product in acetonitrile water (60 mL) was slowly added 10% HClaq (100 mL). After stirring overnight (about 18 hours), acetonitrile precipitated. The resulting precipitate was collected to give the title compound as a white solid (1.2 g, 31%). MS (FAB) M ^H H calcd for C ₂₀ Hi7F6NO ₆ S: 514, found 514th

Example 386

Preparation of tetrahydro-N-hydroxy-4 - [[4- [3-methyl-4- (1-methylethyl) phenoxy] phenyl] sulfonyl] -2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (4.0 g, 10.3 mmol) in dimethylacetamide (20 mL) was added 4-isopropyl-3-methylphenol (Aldrich, 2.3 g, 15.5 mmol) then carbonate cesium (16.8 g, 51.5 mmol). The reaction was heated at ninety-five degrees Celsius for twelve hours. Stripping of the dimethylacetamide in vacuo gave a brown solid (18.3 g, quantitative yield). Chromatography (reverse phase, C-18 acetonitrile / water) gave the THP-protected product in solution.

Part Β: To a solution of the crude THP-protected product from A in acetonitrile / water (40 mL) was slowly added 10% HCl _aq (100 mL). After stirring overnight (about 18 hours), acetonitrile precipitated.

····. · · · · · · · · · · · · · · · · · · · · · · · · · · ·

49η ··· ·· · ····

HZU, · «· ·· ·· ·· ·· **

The resulting precipitate was collected to give the title compound as a tan solid (1.8 g,

%). MS (FAB) - calcd for C 22 H 27 F 3 NO 6 S: 432, found 432.

Example 387

Preparation of tetrahydro-N-hydroxy-4 - [[4 - [(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl] oxy] phenyl] sulfonyl] -2H- pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (5.0 g, 12.9 mmol) in dimethylacetamide (25 mL) was added 2,2,3,3-tetrafluoro-6-hydroxybenzodioxane (Oakwood, 4.3 g, 19 g). , 4 mmol) then cesium carbonate (21.0 g, 64.5 mmol). The reaction was heated at ninety-five degrees Celsius for 5 hours. Stripping of the dimethylacetamide in vacuo gave a brown solid (11.3 g, quantitative yield). Chromatography (reverse phase, C-18 acetonitrile / water) gave the THP-protected product in solution.

Part Β: To the collected THP-protected product from A in acetonitrile / water (50 mL) was slowly added 10% HCl _aq (100 mL). After stirring overnight (about 18 hours), acetonitrile precipitated. The resulting precipitate was collected to give the title compound as a white solid (3.5 g, 54%). MS (FAB) - calcd for C 20 H 17 F 4 NO 8 S: 506, found 506.

Example 388

Preparation of N-hydroxy-1- [2- (4-morpholinyl) ethyl] -4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide dihydrochloride

• • • • • • • • • • • • • • 4 4 4 4 4

4 4 4 4 4

421

4444 44 44

44

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) then di-tert-butyl bicarbonate (100 g, 0.458 mol), which was added in multiple doses. 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%).

Part Β: To a solution of 4-fluorophenol (50.0 g, 0.390 mol) in acetone (400 mL), degassed with N ₂ , was added CS ₂ CO 3 (159 g, 0.488 mol). After degassing the resulting mixture with N ₂ for 5 minutes, the Boc-piperidine compound from 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 give the sulfide as a tan residue (98.5 g, 97%).

Part C: To a solution of the sulfide of Part B (8.00 g, 25.7 mmol) in dichloromethane (90 mL) and methanol (15 mL) was added monoperoxyphthalic acid magnesium salt hexahydrate (19.1 g, 38.6 mmol) in two doses. The resulting mixture was stirred at ambient temperature for 1.5 hours and then filtered. The filtrate was washed with saturated NaHCl and then saturated NaCl. The combined aqueous layers were extracted with dichloromethane (100 mL). The combined organic layers were dried over Na ₂ SO ₄ and then concentrated in vacuo. 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 gave the sulfone as a white crystalline solid (4.45 g, 50%).

422 ·· ·· ······················

Part D: To a solution of the sulfone of Part C (7.00 g, 20.4 mmol) in N, N-dimethylformamide (40 mL) was added Cs ₂ CO ₃ (19.9 g, 61.2 mmol) and α, α, α-trifluoro-β-cresol (3.97 g, 24.5 mmol). The resulting mixture was heated to 80 degrees Celsius for 16 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The resulting residue was treated with H ₂ O and the solids were collected by filtration. The solids were then washed with hexanes then methanol to give the biaryl ether as a tan solid (8.60 g, 87%).

Part E: To a solution of the biaryl ether of part D (8.59 g, 17.7 mmol) in tetrahydrofuran (100 mL) cooled to 0 degrees Celsius was slowly added lithium bis (trimethylsilyl) amide (22.0 mL, 1.0 M). in tetrahydrofuran, 22.0 mmol) at a rate such that the reaction temperature never exceeded one degree Celsius. The resulting mixture was stirred at 0 degrees Celsius for 1 hour, then a solution of methyl chloroformate (2.05 mL, 26.6 mmol) in tetrahydrofuran (5.0 mL) was added slowly at a rate such that the reaction temperature never exceeded 4 degrees Celsius. After the addition was complete, the mixture was slowly allowed to warm to ambient temperature. Saturated NH 4 Cl (50 mL) was added and 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 Na ₂ SO ₄ . Recrystallization from methanol gave the methyl ester as a pale yellow crystalline solid (7.66 g, 80%).

Part F: To a solution of the methyl ester of Part E (7.66 g, 14.1 mmol) in dioxane (30 mL) and methanol (10 mL) was added a solution of 4M HCl in dioxane (10 mL, 40 mmol). After stirring at ambient temperature for 2 hours, additional 4M 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 give the amine as an off-white solid (6.80 g,> 100%).

Part G: To a suspension of the amine from Part F (3.00 g, 6.25 mmol) in acetonitrile (20 mL) was added K ₂ CO ₃ (3.46 g, 25.0 mmol), 4- (2-chloroethyl) ) morpholine hydrochloride (1.22 g, 6.56 mmol) and a catalytic amount of NaI. The resulting mixture was heated at reflux for 22 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 give morpholinyl ethyl amine as a tan solid (3.45 g,> 100%).

Part Η: To a solution of morpholinyl ethyl amine from 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, H ₂ O was added. The reaction mixture was then neutralized (pH 7) with 1M.

HCl. Tetrahydrofuran was removed in vacuo and the resulting precipitates were collected by filtration and washed with diethyl ether to give the amino acid as an off-white solid (2.87 g, 85%).

423 ·· ·· 44 t *

4 ··· 4 45 4

4 4 4 4 4 5

444 4,444

4 4 4 4 4

4444 44 44 44

Part I: To a suspension of the amino acid from Part H (2.87 g, 5.29 mmol) in dichloromethane (25 mL) was added N-methylmorpholine (1.74 mL, 15.9 mmol), O- (tetrahydropyranyl) 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- (tetrahydropyranyl) hydroxylamine (0.310 g, 2.65 mmol) and PyBroP® (1.48 g, 3) were added. , 17 mmol). The resulting mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and H 2 O. The organic layers were washed with saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (on silica, methanol / chloroform) gave the protected hydroxamate as an off-white solid (2.62 g, 77%).

Part J: To a solution of the protected hydroxamate of Part I (2.62 g, 4.08 mmol) in dioxane (9 mL) and methanol (3 mL) was added a solution of 4M 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 ^4: 558, found 558. Fig.

Example 389

Preparation of N-hydroxy-1- (4-pyridinylmethyl) -4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide dihydrochloride

CF ₃

Part A: To a suspension of the amine from Part F, Example 388 (1.50 g, 3.13 mmol) in acetonitrile (10 mL) was added K 2 CO 3 (1.73 g, 12.5 mmol) and 4-picolyl chloride hydrochloride ( 0.565 g, 3.44 mmol). After stirring at reflux for 21.5 hours, the reaction mixture was filtered through a pad of Celite® washing with ethyl acetate. The filtrate was concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave picolyl amine as a clear gum (1.44 g, 86%).

Part Β: To a solution of picolyl amine from Part A (1.44 g, 2.69 mmol) in tetrahydrofuran (20 mL) was added potassium trimethylsilanolate (0.690 g, 5.38 mmol). The resulting mixture was stirred at ftft ftft ftft ftft ftftft ftftftft ftftftft ftft · ft · ftftftft

494 · ambient temperature for 20 hours and then tetrahydrofuran was removed by purging N ₂ reaction mixtures. Water (8 mL) was added and the reaction mixture was neutralized (pH 7) with 2M HCl. The resulting precipitate was collected by filtration to give the amino acid as a white solid (1.31 g, 94%).

Part C: To a suspension of the amino acid from Part B (1.31 g, 2.52 mmol) in N, N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.408 g, 3.02 mmol), N-methylmorpholine ( 0.831 mL, 7.56 mmol), O- (tetrahydropyranyl) hydroxylamine (0.443 g, 3.78 mmol) and 1- 3 - [(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.676 g, 3.53 mmol). The resulting mixture was stirred at ambient temperature for 3 days, then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The combined organic layers were washed with saturated NaHCO ₃ , saturated NaCl, and dried over Na ₂ SO ₄ . Chromatography (on silica, ethyl acetate / hexanes) gave the protected hydroxamate as a white foam (1.24 g, 79%).

Part D: To a solution of the protected hydroxamate of Part C (1.24 g, 2.00 mmol) in dioxane (6 mL) and methanol (2 mL) was added a solution of 4M HCl in dioxane (5.00 mL, 20.0 mmol). ). After stirring at ambient temperature for 2.5 hours, the reaction mixture was concentrated in vacuo. The resulting foam was then reacted again with a solution of 4M HCl in dioxane (3 mL) for 15 minutes, then diethyl ether was added and the resulting precipitate was collected by filtration to give the title compound as an off-white solid (1.04 g, 85%). MS MH ⁴ calculated for C ₂₅ H ₂₅ O ₅ N3SF3: 536, found 536th

Example 390

Preparation of N-hydroxy-1- (3-pyridinylmethyl) -4 - [[4- [4-trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide

Part A: To a suspension of the amine from Part F, Example 388 (1.00 g, 2.08 mmol) in acetonitrile (10 mL) was added K ₂ CO 3 (1.15 g, 8.33 mmol) and 3-picolyl chloride hydrochloride (0.375 g, 2.29 mmol).

After stirring at reflux for 12 hours, the reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave the picolyl amine as a pale yellow foam (0.740 g, 67%).

425

Part Β: To a solution of picolyl amine from Part A (0.740 g, 1.38 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.355 g, 2.77 mmol). The resulting mixture was stirred at ambient temperature for 17 hours, then additional potassium trimethylsilanolate (0.044 g, 0.343 mmol) was added and the resulting mixture was stirred at ambient temperature for 2 hours. Tetrahydrofuran was removed by blowing N _{2 through the} reaction mixture. Water (5 mL) was added and the reaction mixture was neutralized (pH 7) with 2N HCl. The resulting precipitate was collected by filtration and dried by concentration in vacuo with acetone to give the amino acid as an off-white solid (0.700 g, 97%).

Part C: To a suspension of the amino acid from Part B (0.700 g, 1.34 mmol) in Ν, im-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.218 g, 1.61 mmol), Nmethylmorpholine (0.442 mL, 4.02) mmol), O- (tetrahydropyranyl) hydroxylamine (0.235 g, 2.01 mmol) and 1-3 - [(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.360 g, 1.88 mmol). The resulting mixture was stirred at ambient temperature for 23 hours, then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The combined organic layers were washed with H ₂ O, saturated NaHCO 3, saturated NaCl, and dried over Na ₂ SO 4. Chromatography (on silica, ethyl acetate / hexanes) gave the protected hydroxamate as an off-white foam (0.500 g, 60%).

Part D: To a solution of the protected hydroxamate of Part C (0.500 g, 0.807 mmol) in dioxane (1.5 mL) and methanol (0.5 mL) was added a solution of 4M HCl in dioxane (3.0 mL, 12.00 mmol). ). After stirring at ambient temperature for 2 hours, diethyl ether was added and the resulting precipitate was collected by filtration to give the title compound as a yellow solid (0.363 g, 74%). MS MH + calculated for C ⁴ ₂ 5H ₂ 5O5N3SF _3: 536, found 536th

Example 391

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

Part A: To a suspension of the amine from Part F, Example 388 (1.26 g, 2.63 mmol) in acetonitrile (10 mL) was added K ₂ CO ₃ (1.45 g, 10.5 mmol) and 2-picolyl chloride hydrochloride (0.475 g, 2.89 mmol).

426 • 4 * 4

9 ·

4444 44 • * 4 · · 4 4 4> 4 ·· 4 44 «4 444« 4 4 4 4

4 4 4 4 4 5

44 44 44

After stirring at reflux for 12 hours, the reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexanes) gave picolyl amine as an amber oil (1.40 g, 99%).

Part Β: To a solution of picolyl amine from Part A (1.40 g, 2.62 mmol) in tetrahydrofuran (20 mL) was added potassium trimethylsilanolate (0.672 g, 5.24 mmol). The resulting mixture was stirred at ambient temperature for 15 hours. Tetrahydrofuran was removed by blowing N 2 through the reaction mixture. H ₂ O (5 mL) was added and the reaction mixture was neutralized (pH 7) with 2N HCl. The resulting precipitate was collected by filtration and dried by concentration in vacuo with acetonitrile to give the amino acid as an off-white solid (1.07 g, 79%).

Part C: To a suspension of the amino acid from Part B (1.07 g, 2.06 mmol) in N, N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.333 g, 2.47 mmol), N-methylmorpholine ( 0.679 mL, 6.18 mmol), O- (tetrahydropyranyl) hydroxylamine (0.362 g, 3.09 mmol) and 1- 3 - [(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.553 g, 2.88 mmol). The resulting mixture was stirred at ambient temperature for 19 hours, then concentrated in vacuo. The residue was partitioned between H 2 O and ethyl acetate. The combined organic layers were washed with H 2 O, saturated NaHCO 3, saturated NaCl, and dried over Na ₂ SO ₄ . Chromatography (on silica, methanol / dichloromethane) gave the protected hydroxamate as a white solid (1.03 g, 81%).

Part D: To a solution of the protected hydroxamate of Part C (1.03 g, 1.66 mmol) in dioxane (3.0 mL) and methanol (1.0 mL) was added a solution of 4N HCl in dioxane (3.0 mL, 12.00 mmol). After stirring at ambient temperature for 1.5 hours, diethyl ether was added and the resulting precipitate was collected by filtration to give the title compound as a light pink solid (0.970 g, 96%). MS MH + calculated for C25H25O5N3SF3 ^4: 536, found 536th

Example 392

Preparation of N-hydroxy-4 - [[4 - [(4-methoxyphenyl) amino] phenyl] sulfonyl] -4-piperidinecarboxamide monohydrochloride

Part A: To the ester from Part C, Example 91 (1.00 g, 2.17 mmol) was added CS 2 CO 3 (0.990 g, 3.04 mmol), BINAP (0.061 g, 0.098 mmol), tris (dibenzylideneacetone) dipalladium ( 0) (0.060 g,

427

0.07 mmol), p-anisidine (0.320 g, 2.60 mmol) and toluene (4 mL). The resulting mixture was heated to

100 degrees Celsius for 22 hours. After cooling to ambient temperature, diethyl ether was added and the mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo.

Chromatography (on silica, ethyl acetate / hexane) gave the aniline as an orange foam (0.810 g, 74%).

Part Β: To a solution of the aniline from Part A (0.780 g, 1.55 mmol) in tetrahydrofuran (4.0 mL) was added potassium trimethylsilanolate (0.238 g, 1.86 mmol). The resulting mixture was stirred at ambient temperature for 17 hours and then additional potassium trimethylsilanolate (0.020 g, 0.1955 mmol) was added. After stirring at ambient temperature for 24 hours, additional potassium trimethylsilanolate (0.040 g, 0.310 mmol) was added. After stirring at ambient temperature for 26 hours, the solvent was removed by blowing N 2 over the mixture. To a suspension of the residue in dichloromethane (10 mL) was added N-methylmorpholine (0.511 mL,

4.65 mmol), O- (tetrahydropyranyl) hydroxylamine (0.218 g, 1.86 mmol) followed by PyBroP® (1.08 g, 2.33 mmol). The resulting mixture was stirred at ambient temperature for 3 days and then concentrated in vacuo. The residue was partitioned between H 2 O and ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over Na ₂ SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as an off-white solid (0.600 g, 66%).

Part C: To a solution of the protected hydroxamate of Part B (0.580 g, 0.984 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of 4M HCl in dioxane (2.5 mL, 10.0 mmol). The resulting mixture was stirred at ambient temperature for 1 hour then diethyl ether (10 mL) was added. The solids were collected by filtration to give the title compound as a white solid (0.437 g, 100%). MS MH + calcd for C19H24O5N3S ^4: 406, 406th

Example 393

Preparation of N-hydroxy-4 - [[4 - [[4- (trifluoromethoxy) phenyl] amino] phenyl] sulfonyl] -4-piperidinecarboxamide monohydrochloride

Part A: To the ester solution from Part C, Example 91 (3.27 g, 7.09 mmol) was added CS 2 CO 3 (3.23 g, 9.92 mmol), BINAP (0.066 g, 0.107 mmol), tris (dibenzylideneacetone) 1-Dipalladium (0) (0.065 g, 0.071 mmol), 4-trifluoromethoxyaniline (1.15 mL, 8.51 mmol) and toluene (14 mL).

• ·

• • · φ · φ

The resulting mixture was heated to 100 degrees Celsius for 22 hours. After cooling to ambient temperature, the 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) gave the aniline as a tan solid (3.59 g, 91%).

Part Β: To a solution of the aniline from Part A (1.03 g, 1.84 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.331 g, 2.58 mmol). The resulting mixture was stirred at ambient temperature for 24 hours and then additional potassium trimethylsilanolate (0.118 g, 0.092 mmol) was added. After stirring at ambient temperature for 24 hours, the solvent was removed by blowing N? over the mixture. H ₂ O was added and the reaction mixture was acidified (pH 3) with 1M HCl. The aqueous reaction mixture was extracted with ethyl acetate, and the combined organic layers were washed with saturated NaCl and dried over Na ₂ SO ₄ . Concentration in vacuo gave the acid as a tan solid (1.01 g, 100%).

Part C: To a suspension of the acid from Part B (1.00 g, 1.84 mmol) in N, N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.298 g, 2.21 mmol), N-methylmorpholine (0.607). mL, 5.52 mmol), O- (tetrahydropyranyl) hydroxylamine (0.323 g, 2.76 mmol) and 1-3 - [(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.494 g, 2.58 mmol). The resulting mixture was stirred at ambient temperature for 17 hours, then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The combined organic layers were washed with H ₂ O, saturated NaHCO 3, saturated NaCl, and dried over Na ₂ SO ₄ . Chromatography (on silica, ethyl acetate / hexanes) gave the protected hydroxamate as a white solid (0.960 g, 81%).

Part D: To a solution of the protected hydroxamate of Part C (0.960 g, 1.49 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of 4N HCl in dioxane (4.0 mL, 16.0 mmol). The resulting mixture was stirred at ambient temperature for 2.5 hours. The solvent was then removed by blowing N _{2 through the} reaction mixture. Diethyl ether (20 mL) was added and the precipitate was collected by filtration to give the title compound as a light pink solid (0.716 g, 100%). MS MH + calculated for C 19 H 21 O 5 N 3 SF 3: 460, found 460.

Example 394

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

Part A: To a solution of the aniline from Part A, Example 392 (2.55 g, 4.57 mmol) in dioxane (9.0 mL) and methanol (3.0 mL) was added a solution of 4M HCl in dioxane (10 mL, 40 mmol). After stirring at ambient temperature for 2 hours, the reaction mixture was concentrated in vacuo to give the amine as a tan solid (2.36 g,> 100%).

Part Β: To a suspension of the amine from Part A (1.50 g, 3.03 mmol) in acetonitrile (12 mL) was added K 2 CO 3 (1.26 g, 9.09 mmol) and 2-bromoethyl methyl ether (0.313 mL, 3.33 mmol). After stirring at reflux for 23 hours, CS 2 CO 3 (2.96 g, 9.09 mmol) was added. After 6 hours at reflux, the reaction mixture was filtered through a pad of Celite®, washing with dichloromethane. The filtrate was concentrated in vacuo. Chromatography (on silica, methanol / dichloromethane) gave methoxy ethyl amine as a tan solid (1.13 g, 72%).

Part C: To a solution of methoxy ethyl amine from Part B (1.13 g, 2.19 mmol) in tetrahydrofuran (20 mL) was added potassium trimethylsilanolate (0.561 g, 4.38 mmol). The resulting mixture was stirred at ambient temperature for 18 hours and then additional potassium trimethylsilanolate (0.140 g, 1.09 mmol) was added. After stirring at ambient temperature for 5 hours, the solvent was removed by blowing N ₂ over the mixture. Water (8 mL) was added and the reaction mixture was neutralized (pH 7) with 1M HCl. The solids were collected by filtration and dried in vacuo with acetonitrile to give the amino acid as an off-white solid (0.900 g, 82%).

Part D: To a suspension of the amino acid from Part C (0.900 g, 1.79 mmol) in N, N-dimethylformamide (8.0 mL) was added 1-hydroxybenzotriazole (0.290 g, 2.15 mmol), N-methylmorpholine ( 0.590 mL, 5.37 mmol), O- (tetrahydropyranyl) hydroxylamine (0.315 g, 2.69 mmol) and 1- 3 - [(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.480 g, 2.51 mmol). The resulting mixture was stirred at ambient temperature for 16 hours, then concentrated in vacuo. The residue was partitioned between H ₂ O and ethyl acetate. The combined organic layers were washed with H ₂ O, saturated NaHCO ₃ , saturated NaCl, and dried over Na ₂ SO ₄ . Chromatography (on silica, methanol / dichloromethane) gave the protected hydroxamate as an off-white solid (0.870 g, 81%).

Part E: To a solution of the protected hydroxamate of Part D (0.870 g, 1.45 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of 4M HCl in dioxane (10 mL, 40.0 mmol). The resulting mixture was stirred at ambient temperature for 2.0 hours. The reaction mixture was concentrated in vacuo and then reacted again with 4M HCl (3 mL) for 30 minutes. The solvent was then removed by blowing N 2 through the reaction mixture. Diethyl ether (30 mL) was added and the precipitate was collected by filtration to give the title compound as a light pink solid (0.771 g, 96%). MS MH + calculated for

C22H27O6N3SF3: 518, found 518.

430

Example 395

Preparation of N-hydroxy-4 - [[4 - [[4- (trifluoromethyl) phenyl] amino] phenyl] sulfonyl] -4-piperidinecarboxamide monohydrochloride

HIM

Part A: To the ester solution from Part C, Example 91 (3.16 g, 6.85 mmol) was added Cs ₂ CO ₃ (3.13 g, 9.59 mmol), BINAP (0.064 g, 0.103 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.063 g, 0.069 mmol), α, α, α-trifluoromethylaniline (1.03 mL, 8.22 mmol) and toluene (14 mL). The resulting mixture was heated to 100 degrees Celsius for 17 hours. After cooling to ambient temperature, the mixture was filtered through a pad of Celite®, washing with dichloromethane, and the filtrate was concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexane) gave the aniline as a light orange foam (3.08 g, 83%).

Part Β: To a solution of the aniline from Part A (1.00 g, 1.84 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.473 g, 3.69 mmol). The resulting mixture was stirred at ambient temperature for 25 hours, then the solvent was removed by blowing N 2 over the mixture. Water was added and the reaction mixture was acidified (pH 3) with 1M HCl. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated NaCl and dried over Na ₂ SO 4. Concentration in vacuo gave the acid as an orange foam (1.00 g,> 100%).

Part C: To a suspension of the acid from Part B (0.972 g, 1.84 mmol) in N, N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.298 g, 2.21 mmol), N-methylmorpholine (0.607 mL,

5.52 mmol), O- (tetrahydropyranyl) hydroxylamine (0.323 g, 2.76 mmol) and 1-3 [(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.494 g, 2.58 mmol). The resulting mixture was stirred at ambient temperature for 18 hours, then concentrated in vacuo. The rest is

• ·

431 ·· 99

9 ♦ · ·

9 · · ·

4 9 · · 999 · 9 ·· divided between H ₂ O and ethyl acetate. The combined organic layers were washed with H ₂ O, saturated NaHCO ₃ , saturated NaCl, and dried over Na ₂ SO ₄ . Chromatography (on silica, ethyl acetate / hexanes) gave the protected hydroxamate as a white solid (0.970 g, 84%).

Part D: To a solution of the protected hydroxamate of Part C (0.950 g, 1.51 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of 4M HCl in dioxane (4.0 mL, 16.0 mmol). The resulting mixture was stirred at ambient temperature for 1.5 hours. Diethyl ether (20 mL) was added and the precipitate was collected by filtration to give the title compound as a white solid (0.630 g, 87%). MS MH ⁺ calculated for C 19 H ₂₁ O ₄ N ₃ SF ₃ : 444, found 444.

Example 396

Preparation of N-hydroxy-1- (2-methoxyethyl) -4 - [[4 - [[4-trifluoromethyl) phenyl] amino] phenyl] sulfonyl] -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the aniline from Part A, Example 395 (2.07 g, 3.82 mmol) in dioxane (9.0 mL) and methanol (3.0 mL) was added a solution of 4M HCl in dioxane (10 mL, 40 mmol). After stirring at ambient temperature for 2 hours, the reaction mixture was concentrated in vacuo to give the amine as a yellow solid (1.89 g,> 100%).

Part Β: To a suspension of the amine from Part A (1.83 g, 3.82 mmol) in acetonitrile (20 mL) was added K ₂ CO ₃ (1.58 g, 11.46 mmol) and 2-bromoethyl methyl ether ( 0.395 mL, 4.20 mmol). After stirring at reflux for 18 hours, the reaction mixture was filtered through a pad of Celite®, washing with dichloromethane, and the filtrate was concentrated in vacuo. Chromatography (on silica, methanol / dichloromethane) gave methoxy ethyl amine as an off-white solid (1.58 g, 83%).

Part C: To a solution of methoxy ethyl amine from Part B (1.58 g, 3.15 mmol) in tetrahydrofuran (30 mL) was added potassium trimethylsilanolate (0.810 g, 6.31 mmol). The resulting mixture was stirred at ambient temperature for 3 days and then the solvent was removed by blowing N ₂ over the mixture. Water (10 mL) was added and the reaction mixture was neutralized (pH 7) with 1M HCl. Fixed * ·

432 ’; The substances were collected by filtration and dried in vacuo with acetonitrile to give the amino acid as a pink solid (1.32 g, 86%).

Part D: To a suspension of the amino acid from Part C (1.32 g, 2.71 mmol) in N, N-dimethylformamide (12 mL) was added 1-hydroxybenzotriazole (0.439 g, 3.25 mmol), N-methylmorpholine ( 0.894 mL, 8.13 mmol), O- (tetrahydropyranyl) hydroxylamine (0.476 g, 4.07 mmol) and 1-3 - [(dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.727 g, 3.79 mmol). The resulting mixture was stirred at ambient temperature for 20 hours, then concentrated in vacuo. The residue was partitioned between H 2 O and ethyl acetate. The combined organic layers were washed with H 2 O, saturated NaHCO 3, saturated NaCl, and dried over Na 2 SO ₄ . Chromatography (on silica, methanol / ethyl acetate) gave the protected hydroxamate as an off-white solid (1.39 g, 88%).

Part E: To a solution of the protected hydroxamate of Part D (1.40 g, 2.39 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of 4M HCl in dioxane (5.98 mL, 23.9 mmol). ). The resulting mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture was concentrated to near dryness by purging the N 2 reaction mixture. Diethyl ether (25 mL) was added and the precipitate was collected by filtration. The resulting solids were dissolved in methanol (1 mL) and treated with 4M HCl in dioxane (1.5 mL). After stirring at ambient temperature for 1.5 hours, the reaction mixture was slowly added to diethyl ether (50 mL). The resulting precipitate was collected by filtration to give the title compound as an off-white solid (1.08 g, 84%). MS MH + calculated for C22H27O5N3SF3 ^4: 502, found 502nd

Example 397

Preparation of ethyl 1- (2-methoxyethyl) -3-phenylpropoxy) phenyl] sulfonyl] -4-piperidinecarboxylate

Part A: A mixture of methoxyethyl amine, ethyl (4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate (1.5 g, 4.0 mmol), 3-phenyl-1- propanol (2.2 mL, 16 mmol) and K 2 CO 3 (2.2 g, 16 mmol) in DMAC (6 mL) was heated at 125 degrees Celsius for 1 day and 135 degrees Celsius.

Celsius for 3 days. Then the mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give a crude oil. The oil was purified by flash chromatography (20:80 hexane / ethyl acetate) to give the ether as a brown oil (1.35 g, 67%).

Part B: A mixture of the ether of Part A (1.3 g, 2.7 mmol) and a 50% aqueous solution of NaOH (2.1 g, 27 mmol) in THF (23 mL), EtOH (23 mL) and H ₂ O (12 mL) was heated at 60 degrees Celsius under a nitrogen atmosphere for 24 hours. The material was concentrated in vacuo and rubbed with diethyl ether to give a solid. The solid was dissolved in water, cooled in an ice bath and acidified with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with cold water and dried at ambient temperature in a vacuum oven for 3 days to give the crude acid.

A mixture of the crude acid from above (1.1g), N-hydroxybenzotriazole (0.36 g, 2.7 mmol), 4-methylmorpholine (0.74 mL, 6.7 mmol), O-tetrahydro-2H-pyran-2- yl-hydroxylamine (0.39 g, 3.3 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.60 g, 3.1 mmol) in DMF (11 mL) was stirred at room temperature under nitrogen atmosphere for 18 hours. The mixture was concentrated in vacuo and dissolved into a solution of saturated NaHCO 3 (90 mL), ethyl acetate (25 mL) and a few drops of 2M NaOH. The aqueous layer was extracted with additional ethyl acetate. The combined ethyl acetate layers were washed with saturated NaHCO 3 solution, water and brine. After drying over magnesium sulfate, the filtrate was concentrated in vacuo to give a dark yellow oil. The oil was purified by flash chromatography (40:60 acetonitrile / toluene) to afford the protected hydroxamate as a yellow oil (0.32 g, 25%): MS MH + calculated for C 29 H 40 N ₂ O ₇ S 561, found 561.

Part C: To a solution of the protected hydroxamate of Part 2B (0.28 g, 0.50 mmol) in methanol (4.0 mL) was added acetyl chloride (0.11 mL, 1.5 mmol) and the solution was stirred at ambient under a nitrogen atmosphere for 2.5 hours. The solution was diluted with diethyl ether and concentrated. The solid was triturated with diethyl ether and dried at 40 degrees Celsius in a vacuum oven to give the title compound as an offwhite solid (0.15 g, 20%): MS MH + calcd for _C2 4H3 ₂ N ₂ 0óS 477, found 477th

Example 398

Preparation of 1-cyclopropyl-N-hydroxy-4 - [[4- (2-phenoxyethoxy) phenyl] sulfonyl] -4-piperidinecarboxamide monohydrochloride

434

· · · · · · · · · · · · · · To · · · · · · · · · · · · · · · · ·

Part A: To a solution of the product of Example 9, 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 sieve (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 solid precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO _4j filtered and concentrated in vacuo. The solids were filtered, washed with H ₂ O / diethyl ether to give the desired cyclopropyl amine {ethyl (4 - [(4-fluorophenylsulfonyl)] - 1-cyclopropyl-4-piperidinecarboxylate)} as a white solid (11, 83 g, 81.5%). MS MfT calculated for C ₁₇ H ₂₂ NO ₄ SF: 356, found: 356.

Part B: A solution of cyclopropylamine from 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 heated at 125135 degrees Celsius for 18 hours under a nitrogen atmosphere. 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 solids were dissolved in a mixture of water, acetonitrile and ethanol, and then the pH was adjusted to 12 with 1M NaOH solution. The mixture was concentrated in vacuo to remove ethanol and acetonitrile. The solids were collected by filtration, washed with water, and dried at 50 degrees Celsius in a vacuum oven to give the ether as a white solid (1.8 g, 68%): MS + calculated for C ₂₅ H ₃ NO ₆ S 474, found 474. Anal. Calcd. for C ₂₅ H ₃₀ NO ₆ S: C, 63.40; H, 6.60; N, 2.96; S, 6.77. Found: C, 63.35; H, 6.59; N, 2.99; S, 6.61.

Part C: A mixture of ether from Part B (1.8 g, 3.7 mmol) and a 50% aqueous solution of NaOH (3.0 g, 37 mmol) in THF (32 mL), EtOH (32 mL) and H ₂ O (16 mL) was heated at 60 degrees Celsius under a nitrogen atmosphere for 24 hours. The material was concentrated in vacuo and rubbed with diethyl ether to give a solid. The tan solid was dissolved in a mixture of water, ethanol and THF, precipitated by adjusting the pH to 3 with concentrated hydrochloric acid, concentrated in vacuo, rubbed with water, and dried at 50 degrees Celsius in a vacuum oven to give a crude white solid (2.3 g).

44

4 4 4

435 ·· ·· · · · · · · · · · · · ·

A mixture of 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) were 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 1 N NaOH solution, water and brine, dried over magnesium sulfate, concentrated in vacuo and purified 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 + calculated for C 28 H 36 N 2 O 7 S 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.

Another compound was isolated by acidifying the aqueous layer to pH 3, collecting the solid by filtration and drying to give a white solid (0.80 g).

Part D: To a solution of acetyl chloride at ambient temperature (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 give the title compound as a white solid (0.58 g, 79%): MS MH + calculated for C23H28N2O6S 461 , found 461. Anal. Calcd for C ₂₃ H 28 N ₂ O ₆ S · 1.5HCl: C, 53.62; H, 5.77; N, 5.44; S, 6.22. Found: C, 53.47; H, 5.79; N, 5.41; S, 6.16.

Example 399

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

Part A: A solution of the amine hydrochloride salt of the product of Example 410 (2.4 g, 4.6 mmol), 3-picolyl chloride (1.5 g, 8.8 mmol) and potassium carbonate (4.3 g, 31 mmol) in DMF (12) was heated at 50 degrees Celsius for 1 day under a nitrogen atmosphere. The mixture was concentrated in vacuo, dissolved in water and extracted with ethyl acetate. The organic layers were washed

·· • ·

water and brine, dried over magnesium sulfate, concentrated in vacuo. The residue was purified by flash chromatography (50:50 ethyl acetate / hexane) to give 3-picolyl amine as an amber oil (1.6 g, 60%): MS MH + calculated for C ₂₇ H 27 N ₂ O ₆ SF ₃ 565, found 565. Anal. .

436 calcd for C 14 H 14 N 2 O 6 SFs: C, 57.44; H, 4.82; N, 4.96; S, 5.68. Found: C, 57.49; H, 5.10;

N, 4.69; S, 5.67

Part B: A mixture of 3-picolyl amine of part 4A (1.5 g, 2.6 mmol) and a 50% aqueous solution of NaOH (2.1 g, 26 mmol) in THF (22 mL), EtOH (22 mL) and H ₂ O (11 mL) was heated at 65 degrees Celsius under a nitrogen atmosphere for 24 hours. The material was concentrated in vacuo and rubbed with diethyl ether to give a solid. The tan solid was dissolved in water and the pH was adjusted to 1 with concentrated hydrochloric acid. The mixture was concentrated in vacuo and dried at 45 degrees Celsius in a vacuum oven to give a crude white solid acid (2.5 g): MS MH + calculated for C ₂₅ H ₂₃ N ₂ O ₆ SF 3 537, found 537.

Part C: A mixture of the crude white acid from Part B (2.5 g), N-hydroxybenzotriazole (1.0 g, 7.7 mmol), 4-methylmorpholine (0.64 mL, 7.7 mmol), O-tetrahydro -2H-pyran-2-yl-hydroxylamine (0.60 g, 5.1 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.5 g, 7.7 mmol) in DMF ( 40 ml) was stirred at ambient temperature under a nitrogen atmosphere for 5 days. The mixture was concentrated in vacuo, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (5:95 methanol / chloroform) to afford the protected hydroxamate as a white foam (1.1 g, 66%): MS MH + calculated for C 30 H 31 N ₃ O ₇ SF3 636, found 636.

Part D: A solution of the protected hydroxamate of Part C (1.0 g, 1.6 mmol) and acetyl chloride (0.34 mL, 4.7 mmol) in methanol (11 mL) under nitrogen atmosphere at ambient temperature was stirred for 2 For 5 hours and then poured into diethyl ether. The solids were collected by filtration and dried at 46 degrees Celsius in a vacuum oven to give the title compound as a white solid (0.85 g, 87%): Anal. Calcd. for C ₂₅ H ₂₄ N ₃ O ₆ SF _{3 •} ² 2HCl: C, 47.53; H, 4.18; N, 6.65; S, 5.08. Found: C, 47.27; H, 4.34; N, 6.60; S, 5.29. MS MH + calculated for C ₂₅ H ₂₄ N ₃ O ₆ SF ₃ 552, found 552.

· ♦ ·· • 4

4 4 4

437 ··

4 4 4 •

4 4 4 4

4 4 4 4

Example 400

Preparation of N-Hydroxy-4- [4- (4-methoxyphenoxy) phenyl] sulfonyl] -1- (2-pyridinylmethyl) -4-piperidinecarboxamide dihydrochloride

Part A: Ethyl 4 - [(4-fluorophenylsulfonyl)] - 4-piperidinecarboxylate hydrochloride (2.02 g, 5.76 mmol) was combined with powdered potassium carbonate (2.48 g, 18 mmol) and N, N-dimethylformamide (12 mL). 2-Picolyl hydrochloride (1.0 g, 6.1 mmol) was added and the mixture was stirred for 24 hours at 40 degrees Celsius. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed (ethyl acetate) to give the desired pyridine ester as an oil (2.30 g, quantitative yield).

Part B: Pyridine ethyl ester from Part A (2.30 g, 5.76 mmol) was combined with powdered potassium carbonate (1.29 g, 9 mmol), 4-methoxyphenol (1.12 g, 9.0 mmol) and N, N-dimethylformamide (3 mL) and the mixture was heated at 75-80 degrees Celsius for twenty-four hours. Additional 4-methoxyphenol (300 mg) and potassium carbonate (350 mg) were added and the mixture was stirred for another three hours at ninety degrees Celsius. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were dried using magnesium sulfate, concentrated and chromatographed to give the desired ester as an oil (2.85 g, quantitative yield).

Part C: The ester from Part B (2.85 g) was combined with ethanol (18 mL), water (6 mL), and potassium hydroxide (2.24 g, 40 mmol). The mixture was brought to reflux and heated for four and a half hours. It was cooled to 0 degrees Celsius and acidified using concentrated aqueous hydrogen chloride. The solvent was removed and the resulting solids were dried azeotropically with acetonitrile. Vacuum was applied until a constant weight was reached.

The crude hydrochloride was stirred with N-methylmorpholine (1 mL), 1-hydroxybenzotriazole (0.945 g, 7 mmol), O-tetrahydropyranyl hydroxylamine (0.82 g, 7 mmol) and N, N-dimethyformamide (21 mL). After 10 minutes, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) was added and the mixture was stirred overnight. The reaction was then diluted with half-saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (200 mL, then 50 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed (9: 1 ethyl acetate: hexane) to give the desired O-tetrahydropyranyl-protected hydroxamate as a yellow oil (2.82 g, 88%).

Part D: The O-tetrahydropyranyl-protected hydroxamate of Part C (2.82 g, 5 mmol) was diluted with methanol (20 mL). Acetyl chloride (2.1 mL, 30 mmol) was added over 2 minutes. The reaction was stirred for 4 hours at ambient temperature, then concentrated to give 2.59 g of the crude dihydrochloride salt, which was recrystallized from ethanol / water to give 525 mg (18%) of the title hydroxamate in the first batch. MS (EI) MH ⁺ calcd for C 25 H 27 N 3 O 6 S: 498, found 498.

Example 401

Preparation of N-Hydroxy-4- [4- (4-cyclohexylthio) phenyl] sulfonyl] -1- (2-methoxyethyl) -4-piperidinecarboxamide hydrochloride

HCl

Part A: Ethyl 4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate (5.5 g, 14 mmol) was combined with powdered potassium carbonate (2.76 g, 20 mmol) , Ν, N-dimethylformamide (7 mL) and cyclohexyl mercaptan (2.4 mL, 20 mmol) and stirred at ambient temperature for 2 days. The temperature was raised to 45-50 degrees Celsius and stirring was continued for another 24 hours. Additional amounts of potassium carbonate (1.0 g) and cyclohexyl mercaptan (1.0 mL) were introduced and the reaction was heated for 16 additional hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL, then 25 mL). The combined organic layers were dried, concentrated and chromatographed (ethyl acetate) to afford the desired sulfide as a yellow oil (3.59 mL, 53%).

Part B: The sulfide of Part A (3.59 g, 7.4 mmol) was converted to the tetrahydropyranyl-protected hydroxamate by saponification then coupling with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride according to the procedure of Example 401, Part C, resulting in gave 2.16 g (54%) of the desired tetrahydropyranyl protected hydroxamate as an oil.

• 4

439

Part C: The tetrahydropyranyl-protected hydroxamate of Part B (2.16 g, 4 mmol) was diluted with methanol (16 mL). Acetyl chloride (1.1 mL, 16 mmol) was added over one minute. The reaction was stirred for four hours, then concentrated and azeotroped with acetonitrile to give 1.11 g of crude product which was recrystallized from absolute ethanol to give 804 mg of the title compound (41%) in a first crop. MS (EI) MH ⁴ calcd for C 21 H 32 N 2 O 5 S 2; 457, found 457.

Example 402

Preparation of N-Hydroxyl-1- (2-methoxyethyl) -4 - [[(phenylmethoxy) phenyl] sulfonyl] -4-piperidinecarboxamide

HIM'

Part A: Ethyl 4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate (1.58 g,

4.5 mmol) was combined with powdered potassium carbonate (2.42 g, 18 mmol), N, N-dimethylacetamide (5 mL) and benzyl alcohol (1.94 mL, 18 mmol) and stirred at 140 degrees Celsius for sixteen hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (125 mL, then 25 mL). The combined organic layers were dried, concentrated, and chromatographed (ethyl acetate) to give the desired ethyl ester as an oil (1.16 mL, 56%).

Part B: The ethyl ester from Part A (1.16 g, 2.5 mmol) was converted to the tetrahydropyranyl protected hydroxamate by saponification then coupling with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride according to the procedure of Example 401, Part C, to give 880 mg (80%) of the tetrahydropyranyl protected hydroxamate as an oil.

Part C: The tetrahydropyranyl protected hydroxamate of Part B (880 mg, 2.0 mmol) was diluted with methanol (8 mL). Acetyl chloride (0.68 mL, 10 mmol) was added over one minute. The reaction was stirred for three hours, then concentrated and azeotroped with acetonitrile to give the crude product, which was converted to the free base by adding fairly saturated aqueous sodium bicarbonate (25 mL) to neutralize the hydrogen chloride, then extracted with ethyl acetate (100 mL, then 50 mL). ml). The organic phase was dried with magnesium sulfate, concentrated and chromatographed (9: 1 dichloromethane: methanol, 1% ammonium hydroxide),

440

to give the title hydroxamate as glass, (327 mg, 36%). MS (EI) MET calculated for

C22H28N2O6S: 447, found 447.

Example 403

Preparation of N-hydroxyl-1- (1-methylethyl) -4 - [[4- (2-phenylethoxy) phenyl] sulfonyl] -4-piperidine carboxamide

N ·

HIM

II 'Z- \

OO ⁰

Part A: Ethyl 4 - [(4-fluorophenylsulfonyl)] - 1- (1-methylethyl) -4-piperidinecarboxylate) (2.75 g, 7.7 mmol) was combined with powdered potassium carbonate (2.62 g) , 19 mmol), Ν, N-dimethylformamide (10 mL) and 2-phenylethanol (2. mL, 19 mmol) and stirred at 85 degrees Celsius for twenty-four hours. Additional potassium carbonate (1.3 g) and 2-phenylethanol were added and the temperature was raised to 110 degrees Celsius for 48 hours, then to 135 degrees Celsius for four hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL, then 25 mL). The combined organic layers were dried, concentrated, and chromatographed (ethyl acetate) to give the desired ethyl ester as an oil (3.19 mL, 90%).

Part B: The ethyl ester from Part A (3.19 g, 6.9 mmol) was converted to the tetrahydropyranyl-protected hydroxamate by saponification then coupling with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride according to the method of Example 401, Part C, resulting in yielded 2.27 g (64%) of the title compound as an oil.

Part C: Tetrahydropyranyl-protected hydroxamate from Part B (2.27 mg, 4.4 mmol) was diluted with methanol (16 mL). Acetyl chloride (0.68 mL, 10 mmol) was added over one minute. The reaction was stirred for three hours, then concentrated and azeotroped with acetonitrile to give the crude product, which was converted to the free base by addition of saturated sodium bicarbonate (25 mL) to neutralize hydrogen chloride, then extracted with ethyl acetate (100, then 50 mL). ). The organic phase was dried with magnesium sulfate, concentrated and chromatographed (9: 1 dichloromethane: methanol, 1% ammonium hydroxide) to give the desired hydroxamate as a glass (819 mg, 42%). MS (EI) MH ⁺ calcd for C 23 H 30 N 2 O 5 S: 449, found 449.

• 0

Example 404

Preparation of N-hydroxy-4 - [(4-phenylthiophenyl) sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide phosphoric acid salt

441

N-Hydroxy-4 - [(4-phenylthiophenyl) sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide (430 mg, 1.0 mmol) was dissolved in methanol (15 mL). Concentrated phosphoric acid (67 µL) was added and the solution was then concentrated in vacuo. The residue was recrystallized from methanol, isolated by filtration, and then recrystallized a second time from methanol / methyl t-butyl ether to give the title phosphate as a solid (215 mg, 41%). Analytical calculation for C 21 H 22 N 2 O 4 .H 3 PO 4: C, 47.72; H, 4.77; N, 5.30. Found: C, 47.63; H, 5.04; N, 4.82.

Example 405

Preparation of p-toluenesulfonic acid salt of N-hydroxy-4 - [(4-phenylthiophenyl) sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide

N-Hydroxy-4 - [(4-phenylthiophenyl) sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide (516 mg,

1.0 mmol) was combined with p-toluenesulfonic acid monohydrate (200 mg, 1.05 mmol) and the mixture was dissolved in methanol (3 mL). After four hours, the resulting white precipitate was collected by filtration to give 488 mg (81%) of the title tosylate salt, which was characterized spectroscopically.

442

·· ··

Example 406

Preparation of 4 - [[4 - [(2,3-dihydro-1H-inden-2-yl) amino] phenyl] sulfonyl] -N'-hydroxy-4-piperidinecarboxamide monohydrochloride,

Part A: A solution of the product of Example 9, Part D (0.979 g, 2.36 mmol), 2-aminoindan hydrochloride (1.00 g, 5.89 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in N, N-dimethylformamide (8 mL) was heated to 95 degrees Celsius for 22 hours. The reaction was then cooled, diluted with ethyl acetate (50 mL) and washed three times with water and once with brine, then dried over sodium sulfate. Concentration gave a residue which was chromatographed on silica gel. Elution with ethyl acetate / hexane (30/70) gave the desired 4-aminosulfone derivative (450 mg, 36%). MS (EI) MH + calculated for C ₂₈ H ₃₆ N ₂ O ₆ S: 529, found 529. HRMS M + calculated for C ₂₈ H ₃₆ N ₂ O ₆ S: 528.2294, found 528.2306.

Part Β: To a solution of the ethyl ester from Part A (450 mg, 0.85 mmol) in ethanol (3 mL), water (2 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (340 mg, 8.5 mmol) and the solution was heated to 60 degrees Celsius for 26 hours. The solution was cooled and then diluted with water (10 mL) then 10% aqueous hydrochloric acid (3 mL) to bring the pH to 2. The resulting solution was extracted with ethyl acetate. The organic extracts were combined and washed with water and brine and dried over sodium sulfate to give the desired carboxylic acid as a light brown foam (376 mg, 88%). Analytical calculation for C ₂₆ H ₃₂ N ₂ O ₆ S: C, 62.38; H, 6.44; N, 5.60; S, 6.40. Found: C, 62.48; H, 6.69; N, 5.42; S, 6.27.

Part C: To a solution of the carboxylic acid of Part B (305 mg, 0.609 mmol) in N, N-dimethylformamide (2 mL) was added 4-methylmorpholine (247 mg, 2.44 mmol), Nhydroxybenzotriazole (99 mg, 0.73 mmol). and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (152 mg, 0.79 mmol) followed by O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (97 mg, 0.82 mmol) . After stirring for 3 days at ambient temperature, the solution was concentrated to an oil. Water was added and the mixture was extracted with ethyl acetate. The organic extracts were washed with water and brine and dried over sodium sulfate. Concentration gave a brown foam which was chromatographed on

443 it to silica gel. Elution with ethyl acetate / hexane (40/60) gave the protected hydroxamate derivative as a colorless glass (0.38 g, 100%). MS Calcd for C31H41N3O7S: 600, found 600.

Part D: To a solution of the protected hydroxamate of Part C (350 mg, 0.584 mmol) in methanol (3 mL) and 1,4-dioxane (1.5 mL) was added 4 HCl / 1,4-dioxane (1.5 mL). (6 mmol) and the solution was stirred at ambient temperature for 3 hours. Concentration gave a residue which was rubbed with diethyl ether to give the title compound as a solid, which was filtered and dried for 40 hours at 51 degrees Celsius (249 mg, 94%). HRMS (ESI) MH ⁴ calcd for C 21 H 25 N 3 O ⁴ S: 416.1644, found 416.1647.

Example 407

Preparation of 4 - [[4- (dimethylamino) phenyl] sulfonyl] -N-hydroxy-4-piperidine • carboxamide monohydrochloride

Part A: A solution of the product of Example 9, Part D (0.979 g, 2.36 mmol), monohydrochloride

Of 2-aminoindan (1.00 g, 5.89 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in N, N-dimethylformamide (8 mL) was heated to 95 degrees Celsius for 22 hours. The reaction was then cooled, diluted with ethyl acetate (50 mL) and washed three times with water and then brine, then dried over sodium sulfate. Concentration gave a residue which was chromatographed on silica gel. Elution with ethyl acetate / hexane (30/70) gave the 4-N, N-dimethylaminosulfone derivative (590 mg, 57%) together with the product of Example 406. MS (EI) MH ⁺ calculated for C 21 H 32 N 2 O 6 S: 441, found 441. HRMS calculated for C21H32N2O6S: 440.1981, found 440.1978.

Part Β: To a solution of the ethyl ester of Part A (580 mg, 1.3 mmol) in ethanol (4 mL), water (3 mL) and tetrahydrofuran (4 mL) was added sodium hydroxide (520 mg, 13 mmol) and a solution of was heated to 62 degrees Celsius for 5 hours. The solution was cooled and then diluted with water (5 mL) then 10% aqueous hydrochloric acid (5 mL) to acidify to pH = 2. The resulting solution was extracted with ethyl acetate. The organic extracts were combined and washed with water and brine and dried over sodium sulfate to give the desired carboxylic acid as a light brown foam (520 mg, 97%). MS MH + calculated for C19H28N2O6S ^4: 413, found 413th

444

Part C: To a solution of the carboxylic acid of Part B (500 mg, 1.21 mmol) in N, N-dimethylformamide (4 mL) was added 4-methylmorpholine (490 mg, 4.8 mmol), N-hydroxybenzotriazole (197 mg). , 1.45 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (302 mg, 1.57 mmol) followed by O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (192 mg , 1.63 mmol). After stirring for 3 days at ambient temperature, the solution was concentrated to an oil. Water (25 mL) was added and the mixture was extracted with ethyl acetate. The organic extracts were washed with water and brine and dried over sodium sulfate. Concentration gave a brown oil that crystallized from ethyl acetate, hexane and dichloromethane (1: 1: 2) to afford the protected hydroxamate derivative as a colorless solid (506 mg, 82%). MS MH ⁺ calculated for C 24 H 37 N 3 O 7 S: 512, found 512.

Part D: To a solution of the protected hydroxamate of Part C (477 mg, 0.932 mmol) in methanol (3 mL) and 1,4-dioxane (3 mL) was added 4 HCl / 1,4-dioxane (2.3 mL, 9 mL). (3 mmol) and the solution was stirred at ambient temperature for 3 hours. Concentration gave a residue which was rubbed with diethyl ether to give the title compound as a solid, which was filtered and dried for 40 hours at 51 degrees Celsius (372 mg, 100%). HRMS (ESI) MH + calcd for C 14 H 21 N 3 O 4 S: 328.1331, found 328.1343.

Example 408

Preparation of 1-cyclopropyl-4 - [[4 - [(2,3-dihydro-1,4-benzodioxin-6-yl) oxy] phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the product of Example 398, Part A (1.36 g, 3.47 mol) in N, N-dimethylformamide (8 mL) was added 6-hydroxybenzo-1,4-dioxane (792 mg, 5, 21 mmol) then cesium carbonate (2.83 g, 8.69 mmol). The solution was heated at 100 degrees Celsius for 20 hours. The solution was partitioned between ethyl acetate and H ₂ O. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with H ₂ O and saturated NaCl and dried over Na ₂ SO 4. Filtration through a pad of silica (ethyl acetate / hexane) gave the phenoxyphenyl compound as an orange oil (1.81 g, quantitative yield). MS (CI) MH ^&lt; + &^gt;: Calcd.

• 4 · k ♦ '4

445 •

Part Β: To a solution of the phenoxyphenol compound from Part A (1.81 g, <3.47 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added sodium hydroxide (1.39 g, 34.7 mmol) in H ₂ O (5 mL). The solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated in vacuo and the aqueous residue acidified to pH = 2 with 10% HCl. The resulting solids were collected by vacuum filtration to give the acid as a yellow solid (1.23 g, 72%). MS (CI) MH ⁺ calculated for C 23 H 25 NO 7 S: 460, found 460. HRMS calculated for C 23 H 25 NO 7 S: 460.1430, found 460.1445.

Part C: To a suspension of the acid from Part B (1.21 g, 2.46 mmol) in N, N-dimethylformamide (20 mL) was added N-hydroxybenzotriazole (399 mg, 2.95 mmol), 4-methylmorpholine (0 , 81 mL, 7.38 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (432 mg, 3.69 mmol). After stirring for one hour, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (660 mg, 3.44 mmol) was added and the solution was stirred for 20 hours at ambient temperature. The solution was partitioned between ethyl acetate and H ₂ O and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na ₂ SO 4. Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as a yellow oil (940 mg, 70%). MS (CI) MH ⁺ calcd for C 28 H 34 N 2 O 2 S: 559, found 559.

Part D: To a solution of the protected hydroxamate of Part C (920 mg, 1.68 mmol) in 1,4-dioxane (15 mL) was added 4M HCl in 1,4-dioxane (10 mL). After stirring at ambient temperature for 2 hours, the resulting precipitate was collected by vacuum filtration and washed with ethyl ether to give the title compound as a white solid (510 mg, 60%). MS (CI) MET calcd for C 23 H 26 N 2 O 7 S: 475, found 475. HRMS calcd for C 23 H 26 NO 7 S: 475.1539, found 475.1553. Analytical calculation for C23H26N2O7S · 1.15Ηα · 0.5Η ₂ Ο: C, 52.57; H, 5.40; N, 5.33; Cl, 7.76. Found: C, 52.62; H, 5.42; N, 5.79; Cl, 7.71.

Example 409

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

Part A: To a solution of the product of Example 9, Part D (1.5 g, 3.61 mmol) in N, N-dimethylformamide (10 mL) was added cesium carbonate (2.94 g, 9.03 mmol) and α. , α, α-trifluoro-β-cresol (877 mg, 5.41 mmol). The solution was heated to ninety degrees Celsius for 20 hours. The solution was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Filtration through a pad of silica (ethyl acetate) gave the diaryl ether as a yellow oil (2.30 g, quantitative yield). MS (CI) MH + calculated for ⁴ C26H30NO7SF3: 558, found 558. Fig.

Part Β: To a solution of the diaryl ether from Part A (2.30 g, <3.61 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added sodium hydroxide (1.44 g, 36.1 mmol) in H ₂ O (5 ml) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated and the aqueous residue was acidified to pH = 2 with 10% HCl and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Concentration in vacuo gave the acid as a solid (2.11 g, quantitative yield). MS (CI) MH ⁴ calcd for C ₂₄ H ₂₆ NO ₇ SF ₃ : 530, found 530.

Part C: To a solution of the acid from Part B (2.11 g, <3.61 mmol) in Ν, Ν-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (586 mg, 4.33 mmol), 4-methylmorpholine ( 1.19 mL, 10.83 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (634 mg, 5.41 mmol). After stirring for one hour, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (969 mg, 5.05 mmol) was added and the solution was stirred for 18 hours. The solution was partitioned between ethyl acetate and H ₂ O. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with H ₂ O and saturated NaCl and dried over MgSO ₄ . Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as a clear colorless oil (1.40 g, 62%). MS (CI) MH + calculated for C29H35N2O8SF3 ^4: 629, found 629th

Part D: To a solution of the protected hydroxamate of Part C (1.40 g, 2.23 mmol) in 1,4-dioxane (10 mL) was added 4M HCl in 1,4-dioxane (15 mL) and the solution was stirred for 2 hours . The solution was diluted with ethyl ether and the resulting precipitate was collected by vacuum filtration to give the title compound as a white solid (747 mg, 70%). HPLC purity: 97.5%. MS (CI) MH + calculated for ^four

C19H19N2O5SF3: 445, found 445. HRMS calculated for C19H19N2O5SF3: 445.1045, found

445.1052. Analytical calculation for C ₉ H ₁₉ N2O5SF3 * 0.5H ₂ O «l 0HCl: C, 46.58; H, 4.32; N,

5.72; S, 6.55; Cl, 7.24. Found: C, 46.58; H, 3.82; N, 5.61; S, 6.96; Cl, 7.37.

Example 410

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

447 φ φ φ · · · · · · • φ φ • • • • φ »» »» »φ φ φ φ φ φ

Part A: To a solution of the product of Example 9, Part D (1.5 g, 3.61 mmol) in N, N-dimethylformamide (10 mL) was added cesium carbonate (2.94 g, 9.03 mmol) and 4 mL. - (trifluoromethoxy) phenol (0.70 mL, 5.41 mmol). The solution was heated at ninety degrees Celsius for 20 hours. The solution was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with saturated NaCl and dried over Na ₂ SO 4. Filtration through a pad of silica (ethyl acetate) gave the phenoxyphenol as a yellow oil (2.11 g, quantitative yield). MS (CI) MNa ⁺ calculated for C 26 H 30 NO 8 SF 3: 596, found 596.

Part Β: To a solution of phenoxyphenol from Part A (2.11 g, <3.61 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added sodium hydroxide (1.44 g, 36.1 mmol) in H ₂ O (5 ml) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated and the aqueous residue was acidified to pH = 2 with 10% HCl and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Concentration in vacuo gave the acid as a solid (2.2 g, quantitative yield). MS (CI) MH + calcd for C ₂₄ H ₂₆ NO ₈ SF 3: 546, found 546.

Part C: To a solution of the acid from Part B (2.2 g) in N, N-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (586 mg, 4.33 mmol), 4-methylmorpholine (1.19 mL, 10 mL). , 83 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (634 mg, 5.41 mmol). After stirring for thirty minutes, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (969 mg, 5.05 mmol) was added and the solution was stirred for 96 hours. The solution was partitioned between ethyl acetate and H ₂ O. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with H ₂ O and saturated NaCl and dried over MgSO ₄ . Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as a clear, colorless oil (1.26 g, 53%).

• ♦

448

Part D: To a solution of the protected hydroxamate of Part C (1.26 g, 1.96 mmol) in 1,4-dioxane (10 mL) was added 4M HCl in 1,4-dioxane (10 mL) and the solution was stirred for 2 hours. The solution was diluted with ethyl ether and the resulting precipitates were collected by vacuum filtration to give the title compound as a white solid (455 mg, 47%). HPLC purity: 98%. MS (CI) MH + calculated for C 19 H 19 N 2 O 6 SF 3: 461, found 461. HRMS calculated for C 19 H 19 N 2 O 6 SF 3: 461.0994, found 461.0997. Analytical calculation for C 19 H 19 N ₂ O ₆ SF ₃ * 1.0HCl: C, 45.93; H, 4.06; N, 5.64; S, 6.45; Cl, 6.45. Found: C, 46.23; H, 4.07; N, 5.66; S, 6.59; Cl, 7.03.

Example 411

Preparation of 1-Cyclopropyl-4 - [[4 - [(2,3-dihydro-1,4-benzodioxin-6-yl) amino] phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the ester from Part C, Example 91 (1.57 g, 3.40 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (10 mL). After stirring for one hour, the resulting precipitates were collected by vacuum filtration to give the amine monohydrochloride as a white solid (1.16 g, 86%).

Part B: To a suspension of the amine monohydrochloride from Part A (1.16 g, 2.91 mmol) in methanol (10 mL) was added acetic acid (1.68 mL, 29.1 mmol), followed by (1-ethyoxycyclopropyl) -oxytrimethylsilane. (3.51 mL, 17.5 mmol) and sodium cyanoborohydride (823 mg, 13.1 mmol). The solution was heated to reflux for six hours. The solution was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with H ₂ O, aqueous sodium hydroxide and saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave the N-cyclopropyl compound as a white solid (1.03 g, 88%).

Part C: To a solution of the N-cyclopropyl compound of Part B (1.0 g, 2.49 mmol) in toluene (6 mL) was added cesium carbonate (1.14 g, 3.49 mmol), tris (dibenzylideneacetone) dipalladium. (0) (69 mg,

R - (+) - 2,2'-Bis (diphenylphosphino) -1,1'-binaphthyl (69 mg, 0.112 mmol) and 1,4-benzodioxan-6-amine (451 mg, 2.99 mmol) and the solution was heated at 100 degrees Celsius for 19 hours. The solution was diluted with ethyl ether and filtered through Super Cel®. The filtrate was concentrated to a

0 »

449 • 4 *

0 «0 l 0 0 ·

0 0 0 0 0 0

000 * 0 00 · 0 0 0 0 0 0

40% chromatography (on silica, ethyl acetate / hexane) gave the aniline compound as an orange oil (561 mg, 48%). MS (CI) MH + calculated for C24H28N2O6S ^4: 473, found 473rd

Part D: To a solution of the aniline compound from Part C (550 mg, 1.16 mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate (297 mg, 3.48 mmol) and the solution was stirred for 18 hours at ambient temperature. The solution was concentrated and the resulting residue was suspended in H ₂ O. The solids were collected by vacuum filtration to give the crude acid (282 mg).

Part Ε: To a solution of the crude acid from Part D (282 mg, 0.62 mmol) in Ν, Ν-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (100 mg, 0.74 mmol), 4-methylmorpholine (0.20 mL, 1 mL). , 86 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (108 mg, 0.93 mmol). After stirring for 30 minutes, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (166 mg, 0.87 mmol) was added and the solution was stirred for 72 hours. The solution was partitioned between ethyl acetate and H 2 O and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with H 2 O and saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (on silica, ethyl acetate / hexane) gave the protected hydroxamate as a white solid (150 mg, 43%). MS (CI) MH + calculated for C28H3SN3O7S ^4: 558, found 558. Fig.

Part F: To a solution of the protected hydroxamate of Part E (133 mg, 0.24 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (10 mL) the solution was stirred for 1.5 hours . The solution was diluted with ethyl ether and the resulting precipitates were collected by vacuum filtration to give the title hydroxamate as a white solid (80 mg, 66%). MS (CI) MH + calculated for C23H27N3O6S ^4: 474, found 474. HRMS calculated for C23H27N3O6S: 474.1699, found 474.1715. Analytical calculation for C ₂₃ H ₂₇ N ₃ O ₆ S · 1.5HCl · 1.5H ₂ O: C, 49.75; H, 5.72; N, 7.57; S, 5.77; Cl, 9.58. Found: C, 49.78; H, 5.52; N, 8.05; S, 9.16; Cl, 5.76.

Example 412

Preparation of 1-Cyclopropyl-4 - [[4- [4 - [[4- (2,3-dimethylphenyl) -1-piperazinyl] carbonyl] -1-piperidinyl] phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide trihydrochloride

o • 4 ·

450

4444 · «44 · ··

4 4 · * 4 4

44443 44 4

4 4 4 4 4 5

4 4 4 43 4 4.

Part A: To a solution of isonipecotic acid (10.5 g, 81.3 mmol) in H ₂ O (325 mL) was added sodium carbonate (8.37 g, 81.3 mmol) and stirred until homogeneous. . To this solution was added dropwise di-tert-butyl bicarbonate (18.22 g, 83.5 mmol) in 1,4-dioxane (77 mL) and the resulting solution was stirred at ambient temperature for 72 hours. The solution was concentrated in vacuo and the resulting aqueous solution was washed with ethyl ether. The aqueous solution was acidified to pH = 2 with concentrated HCl. The solution was extracted with ethyl ether and concentrated in vacuo to give a white solid. Recrystallization (ethyl acetate) gave N-Boc-isonipecotic acid as a white solid (10 g, 54%).

Part Β: To a solution of N-Boc-isonipecotic acid from Part A (2.14 g, 9.33 mmol) in dichloromethane (19 mL) was added 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1). , 82 g, 9.49 mmol), N-hydroxybenzotriazole (1.32 g, 9.77 mmol) and 1- (2,3-xylyl) piperazine monohydrochloride (2.47 g, 10.89 mmol). After 30 minutes, diisopropylethylamine (0.74 mL, 20.7 mmol) was added and the solution was stirred for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 1M HCl, saturated NaHCO 3 and saturated NaCl. The solution was dried over MgSO 4. Recrystallization (ethyl acetate / hexane) gave the amide as an off-white solid (2.65 g, 71%).

Part C: To a solution of the amide from Part B (1.0 g, 3.75 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 15 minutes. The solution was concentrated in vacuo and the resulting oil was dissolved in N, N-dimethylacetamide (10 mL). To this solution was added the product of Example 398, Part A (979 mg, 2.50 mmol) and cesium carbonate (3.67 g, 11.25 mmol), and the solution was heated at 110 degrees Celsius for 17 hours. The solution was partitioned between ethyl acetate and H ₂ O. The organic layer was washed with H ₂ O and saturated NaCl and dried over Na ₂ SO 4. Concentration in vacuo provided the piperidine compound as a white solid (1.89 g, quantitative yield). MS (CI) MH calcd for C 35 H 48 N 4 O 5 S: 637, found 637.

Part D: To a solution of the piperidine compound of Part C (1.89 g) in ethanol (8 mL) and tetrahydrofuran (8 mL) was added sodium hydroxide (1.0 g, 25 mmol) in H ₂ O (5 mL). The solution was heated at 50 degrees Celsius for 8 hours and at 62 degrees Celsius for 8 hours. The solution was concentrated in vacuo and the residue was diluted with H ₂ O and acidified to pH = 3 with 3M HCl. The resulting precipitate was collected by vacuum filtration to give the acid as a white solid (1.16 g, 65%). MS (CI) MH ⁴ calcd for C 33 H 44 N ⁴ O 5 S: 609, found 609.

Part E: To a solution of the acid from Part D (1.16 g, 1.62 mmol) in N, N-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (262 mg, 1.94 mmol), 4-methylmorpholine (0 , 90 mL, 8.2 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (284 mg, 2.4 mmol). After stirring for 45 minutes, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (334 mg, 2.2-4 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . Friction (dichloromethane) gave the protected hydroxamate as a white solid (850 mg, 75%). MS (CI)

MH ⁴ calcd for C38H53N5O6S: 708, found 708. Analytical calculation for C38H53N5O6S451 ♦ 44 44 * ♦ · * ♦ 4 4 4 »4 *

4 4 4 4 4 ·

4 «« 4 «44

4 4 4 4 4

4,444 · 4 * • 0.5H ₂ O: C, 63.66; H, 7.59; N, 9.77; S, 4.47. Found: C, 63.68; H, 7.54; N, 9.66; S, 4.67.

Part F: To a solution of the protected hydroxamate of part E (746 mg, 1.07 mmol) in methanol (10 mL) was added 4M HCl in 1,4-dioxane (10 mL) and the solution was stirred for one hour. The resulting solid was collected by vacuum filtration and washed with ethyl ether to give the title compound as a white solid (650 mg, 83%). MS (CI) MH + calculated for C33H45N5O5S ^4: 624, found 624. HRMS calculated for C33H49N5O5S: 624.3220, found 624.3253. Analytical calculation for C ₃₃ H ₄₅ N ₅ O ₅ S · 3.5HCl ₃ H ₂ O: C, 51.82; H, 6.59; N, 9.16. Found: C, 52.04; H,

6.30; N, 8.96.

Example 413

Preparation 4 - [[4- [4 - [[4- (2,3-Dimethylphenyl) -1-piperazinyl] carbonyl] -1-piperidinyl] phenyl] sulfonyl] -N-hydroxy-1- (2-methoxyethyl) trihydrochloride -4-piperidine-carboxamide

Part A: To a solution of isonipecotic acid (10.5 g, 81.3 mmol) in H ₂ O (325 mL) was added sodium carbonate (8.37 g, 81.3 mmol) and stirred until homogeneous. . To this solution was added dropwise di-tert-butyl bicarbonate (18.22 g, 83.5 mmol) in 1,4-dioxane (77 mL) and the resulting solution was stirred at ambient temperature for 72 hours. The solution was concentrated in vacuo and the resulting aqueous solution was washed with ethyl ether. The aqueous solution was acidified to pH = 2 with concentrated HCl. The solution was extracted with ethyl ether and concentration in vacuo gave a white solid. Recrystallization (ethyl acetate) gave N-Boc-isonipecotic acid as a white solid (10 g, 54%).

Part Β: To a solution of N-Boc-isonipecotic acid from Part A (2.14 g, 9.33 mmol) in dichloromethane (19 mL) was added 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide

452 hydrochloride (1.82 g, 9.49 mmol), N-hydroxybenzotriazole (1.32 g, 9.77 mmol) and 1- (2,3-xylyl) piperazine hydrochloride (2.47 g, 10.89 mmol) ). After 30 minutes, diisopropylethylamine (0.74 mL, 20.7 mmol) was added and the solution was stirred for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 1M HCl, saturated NaHCO ₃ and saturated NaCl. The solution was dried over MgSO ₄ . Recrystallization (ethyl acetate / hexane) gave the amide as an off-white solid (2.65 g, 71%).

Part C: To a solution of the amide of Part B (965 mg, 2.41 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 15 minutes. The solution was concentrated in vacuo and the resulting oil was dissolved in N, N-dimethylacetamide (10 mL). To this solution was added ethyl 4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate (600 mg, 1.61 mmol) and cesium carbonate (2.75 g, 8.43 mmol). ) and the solution was heated at 110 degrees Celsius for 20 hours. The solution was partitioned between ethyl acetate and H 2 O. The organic layer was washed with H 2 O and saturated NaCl and dried over Na 2 SO ₄ . Concentration in vacuo gave the piperidine compound as a white solid (1.26 g, quantitative yield). MS (CI) MH ⁺ calcd for C 35 H 50 N 4 O 6 S: 655, found 655.

Part D: To a solution of the piperidine compound of Part C (1.26 g) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (644 mg, 16 mmol) in H 2 O (5 mL). The solution was heated at sixty degrees Celsius for 8 hours and at sixty-two degrees Celsius for 8 hours. The solution was concentrated in vacuo and the residue was diluted with H 2 O and acidified to pH = 3 with 3M HCl. The resulting precipitate was collected by vacuum filtration to give the acid as a white solid (650 mg, 65%). MS (CI) MH ⁴ calcd for C 33 H 46 N ⁴ O 6 S: 627, found 627.

Part E: To a solution of the acid from Part D (620 g, 0.94 mmol) in N, N-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (152 mg, 1.13 mmol), 4-methylmorpholine (0.52 mL, 4.7 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (165 mg, 1.4 mmol). After stirring for 45 minutes, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (252 mg, 1.32 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and H 2 O and the organic layer was washed with H 2 O and saturated NaCl and dried over Na 2 SO ₄ . Concentration in vacuo provided the protected hydroxamate as a white solid (641 mg, 94%). MS (CI) MH + calculated for C38H55N5O7S ^4: 726, found 726th

Part F: To a solution of the protected hydroxamate of part E (630 mg, 0.87 mmol) in methanol (8 mL) was added 4M HCl in 1,4-dioxane (10 mL) and the solution was stirred for one hour. The resulting solid was collected by vacuum filtration and washed with ethyl ether to give the title compound as a white solid (624 mg, 83%). MS (CI) MH ⁺ calcd for C 33 H 47 N 5 O 6 S: 642, found 642.

Example 414

Preparation of N-hydroxy-4 - [[4- [4- (1-methylethyl) phenoxy] phenyl] sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

453 ·· ·· · 9 9

9 9

9999 99

9

99 • ♦ ·

9 9 9

9 9 9

9 9 9

9 9 9

Part A: To a solution of the product of Example 9, Part E (6.0 g, 15.4 mmol) and powdered K ₂ CO ₃ (8.0 g, 38.5 mmol) in Ν, Ν-dimethylformamide (70 mL) 4-isopropylphenol (5.24 g, 38.5 mmol) was added at ambient temperature and the solution was heated to ninety degrees Celsius for 32 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1M NaOH, H ₂ O and dried over MgSO 4. Chromatography on silica eluting with ethyl acetate / hexane gave the diaryl ether as a pale yellow gel (6.89 g, 87%).

Part Β: To a solution of the diaryl ether from Part A (6.89 g, 14.7 mmol) in ethanol (14 mL) and tetrahydrofuran (14 mL) was added NaOH (5.88 g, 147 mmol) in H ₂ O (28 mL). ml) via addition funnel at ambient temperature. The solution was then heated at sixty degrees Celsius for 17 hours and ambient temperature for 24 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 gave the acid as a white solid (6.56 g, quantitative yield).

Part C: To a solution of the acid from Part B (6.56 g, 14.86 mmol), N-methylmorpholine (6.5 mL, 59.4 mmol), 1-hydroxybenzotriazole (6.0 g, 44.6 mmol) and O-tetrahydropyranyl hydroxyl amine (3.5 g, 29.7 mmol) in N, N-dimethylformamide (50 mL) was added 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (8.5 g, 44 (6 mmol) and the solution was stirred at ambient temperature for 20 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO 3, H ₂ O and dried over MgSO 4. Concentration in vacuo and chromatography on silica eluting with ethyl acetate / hexane gave the tetrahydropyranyl protected hydroxamate as a white foam (8.03 g, quantitative yield).

Part D: To a solution of 4M HCl in dioxane (37 mL, 149 mmol) was added a solution of tetrahydropyranyl protected hydroxamate from Part C (8.03 g, 14.9 mmol) in methanol (5 mL) and dioxane (15 mL), and the solution was stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with diethyl ether gave the title compound as a white solid (5.0 g, 71.1%). Analytical calculation for C ₂₄ H 28 N ₂ O ₅ S.HCl, 0.9H ₂ O · C, 56.61; H, 6.10; N, 5.50; S, 6.30. Found: C,

56.97; H, 6.05; N, 5.41; S, 5.98. HRMS calcd for MH ⁴ C24H28N2O5S: 457.1797, found

457.1816.

Example 415

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

454 · · * * * * * 9 9 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 • ftft * ftft 44 ··

Part A: To a solution of the product of Example 9, Part D (25 g, 67.3 mmol) and powdered K 2 CO 3 (23.3 g, 169 mmol) in Ν, Ν-dimethylformamide (150 mL) was added sesamol (23.2 g). g, 168 mmol) at ambient temperature and the solution was heated at 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 1M NaOH, H ₂ O and dried over MgSO ₄ . Chromatography on silica eluting with ethyl acetate / hexane gave the desired diaryl ether as a pale yellow gel (33.6 g, 93.6%).

Part Β: To a solution of the diaryl ether from Part A (4.0 g, 7.4 mmol) in dichloromethane (7 mL) cooled to 0 degrees Celsius was added trifluoroacetic acid (7 mL) and the solution was stirred at ambient temperature for 2 hours. Concentration in vacuo gave the trifluoroacetate amine salt as a pale yellow gel. To a solution of the trifluoroacetate salt and K 2 CO 3 (3.6 g, 26 mmol) in Ν, Ν-dimethylformamide (50 mL) was added 2-bromoethyl methyl ether (1.8 mL, 18.7 mmol) and the solution was stirred at ambient temperature for 36 hours. The Ν, Ν-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over Mg ₂ SO _fourth Concentration in vacuo gave the methoxyethyl amine as a pale yellow gel (3.7 g, quantitative yield).

Part C: To a solution of methoxyethylamine from Part B (3.7 g, 7.5 mmol) in ethanol (7 mL) and tetrahydrofuran (7 mL) was added NaOH (3.0 g, 75 mmol) in H ₂ O (15 mL). ml) via addition funnel at ambient temperature. The solution was then heated at sixty degrees Celsius for 19 hours and at ambient temperature.

•> ·>

«· ···

455 12 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 gave the acid as a white solid (4.0 g, quantitative yield).

Part D: To a solution of the acid from Part C (4.0 g, 7.5 mmol), N-methylmorpholine (3.3 mL, 30 mmol), 1-hydroxybenzotriazole (3.0 g, 22.5 mmol) and O -tetrahydropyranylhydroxylamine (1.8 g, 15 mmol) in N, N-dimethylformamide (100 mL) was added 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (4.3 g, 22.5 mmol), and the solution was stirred at ambient temperature for 3 days. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO 3, H ₂ O and dried over Mg ₂ SO 4. Concentration in vacuo and chromatography on silica eluting with ethyl acetate / hexane gave the tetrahydropyranyl protected hydroxamate as a white foam (2.40 g, 57.1%).

Part E: To a solution of 4M HCl in dioxane (11 mL, 43 mmol) was added a solution of tetrahydropyranyl-protected hydroxamate from Part D (2.4 g, 4.3 mmol) in methanol (2 mL) and dioxane (6 mL), and the solution was stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with ether gave the hydroxamate hydrochloride as a white solid (1.88 g, 85.8%). Calcd for C22H26N2O8S.HCl.H2O: C, 49.58; H, 5.48; N, 5.26; S, 6.02. Found: C, 49.59; H, 5.53; N, 5.06; S, 5.71. HRMS MH + calcd for C 18 H 18 N 2 O 8 S: 479.1488, found 479.1497.

Example 416

Preparation of N-hydroxy-1- (2-methoxyethyl) -4 - [[4- [4- (trifluoroethoxy) phenoxy] phenyl] sulfonyl} -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the product of Example 9, Part D (30 g, 161 mmol) in dichloromethane (50 mL) cooled to 0 degrees Celsius, was added trituric acetic acid (25 mL), and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo gave the amine trifluoroacetate as a pale yellow gel. To a solution of the trifluoroacetate salt and K 2 CO 3 (3.6 g, 26 mmol) in N, N-dimethylformamide (50 ft

456 ftft ftft ftft ftft ft ftft ftft ftft ftft ftft ftft ftft ft ft ftft ftft ftft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft 2-Bromoethyl methyl ether (19 mL, 201 mmol) was added and the solution was stirred at ambient temperature for 36 hours. Then, Ν, Ν-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over MgSO ₄ . Concentration in vacuo provided the methoxyethyl amine as a pale yellow gel (26.03 g, 86.8%).

Part Β: To a solution of methoxyethyl amine (6.0 g, 16.0 mmol) in part and powdered K 2 CO 3 (4.44 g, 32 mmol) in N, N-dimethylformamide (30 mL) was added 4- (trifluoromethoxy) phenol (5.72 g, 32 mmol) at ambient temperature and the solution was heated at 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 1 N NaOH, H ₂ O and dried over MgSO ₄ . Chromatography on silica eluting with ethyl acetate / hexane gave trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (7.81 g, 91.5%).

Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone from Part B (7.81 g, 14.7 mmol) in ethanol (14 mL) and tetrahydrofuran (14 mL) was added NaOH (5.88 g, 147 mmol) in H ₂ O (28 mL) via addition funnel at ambient temperature. The solution was then heated at 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 gave the acid as a white solid (5.64 g, 73.3%).

Part D: To a solution of the acid from 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 hydroxyl amine (2.5 g, 21.6 mmol) in N, N-dimethylformamide (50 mL) were added 1 N - [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 NaHCO 3, H ₂ O and dried over MgSO ₄ . Concentration in vacuo and chromatography on silica eluting with ethyl acetate / hexane gave the tetrahydropyranyl-protected hydroxamate as a white foam (6.65 g, quantitative yield).

Part E: To a solution of 4M HCl in dioxane (28 mL, 110 mmol) was added a solution of tetrahydropyranyl-protected hydroxamate from Part D (6.65 g, 11.03 mmol) in methanol (3 mL) and dioxane (9 mL), and stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with diethyl ether gave the title compound as a white solid (4.79 g, 78.2%). Analytical calculation for C ₂₂ H ₂₅ N ₂ O ₇ SF ₃ · HCl, 0.5H ₂ O: C, 46.85; H, 4.83; N, 4.97; S, 5.69. Found: C, 46.73; H, 4.57; N, 4.82; S, 5.77.

ft

44

Example 417

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

457

4 4

9994 * 9

4 9

4 *

444

4 ·

44

Part A: To a solution of ethyl 4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate (1.47 g, 3.9 mmol) and powdered K ₂ CO ₃ (1, 6 g, 11.7 mmol) in N, N-dimethylformamide (15 mL) was added 4-isopropylphenol (1.07 g, 7.8 mmol) at ambient temperature and the solution was heated at ninety degrees Celsius for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1M NaOH, H ₂ O and dried over MgSO ₄ . Chromatography on silica eluting with ethyl acetate / hexane gave the diaryl ether as a pale yellow gel (1.77 g, 92.2%).

Part Β: To a solution of the diaryl ether of Part A (1.77 g, 3.6 mmol) in ethanol (3.5 mL) and tetrahydrofuran (3.5 mL) was added NaOH (1.46 g, 36 mmol) in H ₂ O (7 mL) at ambient temperature. The solution was then heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with diethyl ether and acidified to pH = 2. Vacuum filtration of the white precipitate gave the acid as a white solid (1.39 g, 83.7%).

Part C: To a solution of the acid from Part B (1.39 g, 3.0 mmol), N-methylmorpholine (1 mL, 9 mmol), 1-hydroxybenzotriazole (1.22 g, 9 mmol) and O-tetrahydropyranylhydroxylamine (0 , 72 g, 6.0 mmol) in Ν, Ν-dimethylformamide (90 mL) was added 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.72 g, 9.0 mmol) and the solution was was stirred at ambient temperature for 48 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO ₃ , H ₂ O and dried over MgSO ₄ . Concentration in vacuo and chromatography on silica eluting with ethyl acetate / hexane gave the tetrahydropyranyl protected hydroxamate as a white foam (1.65 g, 98.2%).

Part D: To a solution of 4M HCl in dioxane (7.35 mL, 29.4 mmol) was added a solution of tetrahydropyranyl protected hydroxamate from Part C (1.65 g, 2.94 mmol) in methanol (1 mL) and dioxane ( 3 ml) and the solution was stirred at ambient temperature for 3 hours. Concentration in vacuo and three with diethyl ether gave the title compound as a white solid (1.2 g, 79.5%). Analytical

458 · Calculation for C ₂ 4H ₃₂ N ₂ O ₆ S.HCl, 0.5H ₂ O: C, 55 , 22; Η, 6.56; Ν, 5.37; S, 6.14. Found: C 55.21; H, 6.41; N, 5.32; S, 6.18.

Example 418

Preparation of N-hydroxy-1- (2-methoxyethyl) -4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl} -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of ethyl 4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate (6 g, 16.0 mmol) and powdered K ₂ CO ₃ (4.44 g) , 32 mmol) in N, N-dimethylformamide (50 mL) was added 4-trifluoromethylphenol (5.72 g, 32 mmol) at ambient temperature and the solution was heated at ninety degrees Celsius for 48 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N NaOH, H ₂ O and dried over MgSO ₄ . Chromatography on silica eluting with ethyl acetate / hexane gave the desired diaryl ether as a pale yellow gel (2.66 g, 32.1%).

Part Β: To a solution of the diaryl ether of Part A (1.5 g, 2.9 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added NaOH (1.22 g, 29 mmol) in H ₂ O ( 6 ml) at ambient temperature. The solution was then heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with diethyl ether and acidified to pH = 2. Vacuum filtration of the white precipitate gave the desired acid as a white solid (1.0 g, 70.9%).

Part C: To a solution of the acid from Part B (1.0 g, 2.05 mmol), N-methyl morpholine (0.68 mL,

6.1 mmol), 1-hydroxybenzotriazole (0.84 g, 6.15 mmol) and O-tetrahydropyranyl hydroxyl amine (0.5 g, 4.1 mmol) in N, N-dimethylformamide (20 mL) were added 1 - [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.18 g, 6 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 NaHCO ₃ , H ₂ O and dried over MgSO ₄ . Concentration in vacuo and chromatography on silica eluting with ethyl acetate / hexane gave the tetrahydropyranyl protected hydroxamate as a white foam (1.16 g, 96.7%).

• · ·

459 «• 9 9 9 459 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 · · · · · · · · · · ·

Part D: To a solution of 4M HCl in dioxane (5 mL, 20 mmol)) was added a solution of tetrahydropyranyl-protected hydroxamate from part C (1.16 g, 2 mmol) in methanol (1 mL) and dioxane (3 mL) and stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with diethyl ether gave the title compound as a white solid (0.79 g, 74.5%). Analytical calculation for C ₂ H 25 N ₂ O ₆ SF ₃ · HCl: C, 49.03; H, 4.86; N, 5.20; S, 5.95. Found: C, 48.85; H, 4.60; N, 5.22; S, 6.13.

Example 419

Preparation of N-hydroxy- (1- (2-methoxyethyl) -4 - [[4- [4- (trifluoromethyl) thio) phenoxy] phenyl] sulfonyl} -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of ethyl 4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidine carboxylate (5 g, 13.4 mmol) and powdered K ₂ CO ₃ (3, 7 g, 27 mmol) in N, N-dimethylformamide (20 mL) was added 4- (trifluoromethylthio) phenol (3.9 g, 20 mmol) at ambient temperature and the solution was heated at ninety degrees Celsius for 24 hours. The solution was concentrated under high vacuum, and the residue was dissolved in ethyl acetate. The organic layer was washed with 1M NaOH, H ₂ O and dried over MgSO ₄ . Chromatography on silica eluting with ethyl acetate / hexane gave the desired diaryl ether as a pale yellow gel (5.94 g, 81.04%).

Part Β: To a solution of the diaryl ether from Part A (5.94 g, 210 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added dropwise NaOH (4.34 g, 108 mmol) in H ₂ O (20 mL). ml) at ambient temperature. The solution was then heated at sixty degrees Celsius for 24 hours and ambient temperature for an additional 24 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with diethyl ether and acidified to pH = 2. Vacuum filtration of the white precipitate gave the acid as a white solid (5.5 g, quantitative yield).

Part C: To a solution of the acid from Part B (5.5 g, 10.8 mmol), N-methylmorpholine (3.6 mL,

32.4 mmol), 1-hydroxybenzotriazole (4.4 g, 32.4 mmol) and O-tetrahydropyranylhydroxylamine

460 (2.6 g, 21.8 mmol) in N, N-dimethylformamide (200 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 NaHCO ₃ , H ₂ O, and dried over MgSO ₄ . Concentration in vacuo and chromatography on silica eluting with ethyl acetate / hexane gave the tetrahydropyranyl-protected hydroxamate as a white foam (4.66 g, 69.8%).

Part D: To a solution of 4M HCl in dioxane (20 mL, 79 mmol)) was added a solution of tetrahydropyranyl protected hydroxamate from Part C (4.65 g, 7.9 mmol) in methanol (2.5 mL) and dioxane (8 mL). ml) and stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with diethyl ether gave the title compound as a white solid (3.95 g, 92.1%). Analytical calculation for C ₂₂ H ₂₅ N ₂ O ₆ S ₂ F ₃ · HCl: C, 46.27; H, 4.59; N, 4.91; S, 11.23. Found: C, 46.02; H, 4.68; N, 4.57; S, 11.11.

Example 420

Preparation of N-hydroxy-1- (1-methylethyl) -4 - [[4- [4- (1-methylethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the product of Example 9, Part D (30 g, 161 mmol) in dichloromethane (40 mL) cooled to 0 degrees Celsius, was added trifluoroacetic acid (30 mL), and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo gave the trifluoroacetate salt as a pale yellow gel. To a solution of the trifluoroacetate salt and triethylamine (28 mL, 201 mmol) in dichloromethane (250 mL) cooled to 0 degrees Celsius was added acetone (24 mL, 320 mmol) and sodium triacetoxyborohydride (68 g, 201 mmol) in small portions followed by addition. acetic acid (18.5 mL, 320 mmol) and the solution was stirred at ambient temperature for 48 hours. Then the dichloromethane was evaporated under high vacuum and the residue was diluted with diethyl ether. The organic layer was separated

461

44 49 94 ·· • · · 4

1 2 3 4 5 6 7 8 9

444 4,999 44 94 9

9 9 9 4

9444 44 44 44 44 44 washed with 1M NaOH, water and dried over MgSO ₄ . Concentration in vacuo gave isopropyl amine as a pale yellow gel (21.03 g, 72.8%).

Part Β: To a solution of isopropyl amine (4 g, 11.2 mmol) from Part A and powdered K ₂ CO ₃ (3.09 g, 22.4 mmol) in Ν, Ν-dimethylformamide (30 mL) was added 4- isopropylphenol (3.05 g, 22 mmol) at ambient temperature and the solution was heated at 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 1M NaOH, H ₂ O and dried over MgSO ₄ . Chromatography on silica eluting with ethyl acetate / hexane gave the desired diaryl ether as a pale yellow gel (5.10 g, 96.2%).

Part C: To a solution of the diaryl ether from Part B (5.10 g, 10.77 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added NaOH (4.3 g, 108 mmol) in H ₂ O (20 mL). ml) via addition funnel at ambient temperature. The solution was then heated at sixty degrees Celsius for 24 hours and at ambient temperature for an additional 24 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with diethyl ether and acidified to pH = 2. Vacuum filtration of the white precipitate gave the desired acid as a white solid (4.80 g, quantitative yield).

Part D: To a solution of the acid from Part C (4.80 g, 10.8 mmol), N-methylmorpholine (3.6 mL,

32.4 mmol), 1-hydroxybenzotriazole (4.4 g, 32.4 mmol) and O-tetrahydropyranylhydroxylamine (2.6 g, 21.6 mmol) in Ν, Ν-dimethylformamide (100 mL) were added 1- [ 3- (dimethylamino) propyl] 3-ethylcarbodiimide hydrochloride (6.17 g, 32.4 mmol) and the solution was stirred at ambient temperature for 7 days. The solution was filtered to remove unreacted starting material and the filtrate was concentrated under high vacuum. The residue was dissolved in ethyl acetate and the organic layer was washed with saturated aqueous NaHCO ₃ , H ₂ O and dried over MgSO ₄ . Concentration in vacuo and chromatography on silica eluting with ethyl acetate / hexane gave the tetrahydropyranyl protected hydroxamate as a white foam (2.45 g, 41.7%).

Part E: To a solution of 4M HCl in dioxane (11.2 mL, 45 mmol) was added a solution of tetrahydropyranyl-protected hydroxamate from part D (2.45 g, 11.03 mmol) in methanol (4 mL) and dioxane (8 mL). ) and stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with diethyl ether gave the title compound as a white solid (2.01 g, 89.7%). Analytical calculation for C2 ₄ H ₃ 2N ₂ O ₅ S.HCl, 0.5H ₂ O: C, 56.96; H, 6.77; N, 5.54; S, 6.34. Found: C, 56.58; H, 6.71; N, 5.44; S, 6.25.

• 9 9 »

Example 421

Preparation of 4 - [[4- (1,3-benzodioxol-5-yloxy) phenyl] sulfonyl] -1-cyclopropyl-N-hydroxy-4-piperidinecarboxamide monohydrochloride

462 ·· «9 9 9

9 999

9 9

99 9

9 9 9 • · · ···

Part A: To a solution of the product of Example 9, Part D (9.0 g, 22.0 mmol) in DMF (30 mL) was added K ₂ CO ₃ (4.55 g, 33 mmol) and sesamol (4.55). g, 33 mmol). The solution was stirred at ninety degrees Celsius for 24 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo. Silica gel chromatography eluting with 10% ethyl acetate / hexane gave the desired ester as an oil (9.3 g, 79%). HRMS MH + calcd for C ₂₆ H 31 NSO 9 · 534.1798, found 534.1796.

Part Β: To a solution of the ester from Part A (9.3 g, 17 mmol) in ethyl acetate (100 mL) cooled to 0 degrees Celsius, HCl gas was bubbled for 10 minutes. The reaction was stirred at this temperature for 0.5 hours. The solution was concentrated in vacuo to give the hydrochloride salt (7.34 g, 92%). MS MH calculated for C ₂₁ H ₂₃ NSO ₇ : 434.1273, found 434.1285.

Part C: To a solution of the hydrochloride salt of Part B (7.34 g, 15.6 mmol) in methanol (60 mL) was added acetic acid (8.94 mL, 156 mmol), a portion (about 2 g) of 4-Å. molecular sieves, (1-ethoxycyclopropyl) -oxytrimethyl silane (18.82 ml, 93.6 mmol) and sodium cyanoborohydride (4.41 g,

70.2 mmol). The solution was refluxed for 8 hours. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO 4, filtered and concentrated in vacuo. Silica gel chromatography eluting with 100% ethyl acetate gave the desired cyclopropyl amine as a solid (7.9 gm, 100%). MS MH calculated for C ₂₄ H ₂₇ NSO ₇ : 474.1586, found 474.1599.

·· ··>

it to it to it to it to it

·· * ·

463 · to · to »» toto toto toto toto>>

·· «to

Part D: To a solution of the cyclopropyl amine of Part C (7.9 g, 16.7 mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (6.68 g, 166.8 mmol) in water (30 ml) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue acidified to pH = 3. The resulting precipitate was filtered to give the desired carboxylic acid (6.14 g, 76%). MS MET calculated for C 22 H 25 NSO 7: 446.1273. Found: 446.1331.

Part Ε: To a solution of the carboxylic acid from Part D (6.14 g, 12.7 mmol) in DMF (60 mL) was added 1-hydroxybenzotriazole (2.06 g, 15.2 mmol), N-methylmorpholine (4.2 mL, 38.0 mmol) and Otetrahydropyranylhydroxylamine (2.23 g, 19.0 mmol) then 1,3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (3.41 g, 17.8 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H 2 O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo. Silica gel chromatography eluting with 40% ethyl acetate / hexane gave the desired tetrahydropyranyl protected hydroxamate as a solid (6.67 g, 96%).

Part F: To a solution of the tetrahydropyranyl protected hydroxamate of Part E (6.67 g, 12.0 mmol) in dioxane (70 mL) was added 4 HCl / dioxane (6.6 mL). After stirring at ambient temperature for 3 hours, the solution was concentrated in vacuo. Reverse phase C18 column chromatography eluting with acetonitrile / (HCl) water gave a white solid (4.21 gm, 69%). MS MH + calcd for C22H24N2SO7 ^4: 461.1382. Found: 461.1386.

Example 422

Preparation of 1-Cyclopropyl-4 - [[4- (4-ethoxyphenoxy) phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide monohydrochloride

C ₂ H _p

HCl

N

464

Part A: To a solution of the product of Example 9, Part D (8.0 g, 19.2 mmol) in DMF (30 mL) was added K ₂ CO ₃ (4.00 g, 28.8 mmol) and 4-ethoxyphenol. (3.99 g, 28.8 mmol). The solution was stirred at ninety degrees Celsius for 24 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO _4, filtered, and concentrated in vacuo. Silica gel chromatography eluting with 10% ethyl acetate / hexane gave the desired ester as an oil (9.62 g, 94%). MS MH + calculated for C ⁴ H _{27 3 8} 5NSO: 534.2162. Found: 534.2175.

Part Β: To a solution of the ester from Part A (9.62 g, 18 mmol) in ethyl acetate (100 mL) cooled to 0 degrees Celsius, HCl gas was bubbled for 5 minutes. The reaction was stirred at this temperature for 0.5 hours. The solution was then concentrated in vacuo to give the hydrochloride salt (8.1 g, 96%). MS MH + calculated for C ⁴ H _{22 2} 7NSO _6: 434.1637. Found: 434.1637.

Part C: To a solution of the hydrochloride salt of Part B (8.1 g, 17.2 mmol) in methanol (70 mL) was added acetic acid (9.86 mL, 172 mmol) a portion of 4-Å molecular sieves (ca. 2). g), (1'-ethoxycyclopropyl) oxytrimethyl silane (20.7 ml, 103 mmol) and sodium cyanoborohydride (4.86 g,

77.4 mmol). The solution was refluxed for 8 hours. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with 1 NaOH, saturated NaCl and dried over MgSO _4j filtered and concentrated in vacuo. Trituration with diethyl ether gave the desired cyclopropyl amine as a white solid (6.84 g, 84%).

Part D: To a solution of cyclopropyl amine from Part C (6.84 gm, 14.0 mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (5.60 g, 140 mmol) in water (30 mL). ) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue acidified to pH = 3. Filtration gave the desired acid (6.07 g, 88%). ⁴ MS MH calcd for C22H27NSO6: 446. Found 446th

Part E: To a solution of the acid from Part D (6.07g, 12.6 mmol) in DMF (60 mL) was added 1 • hydroxybenzotriazole (2.04 g, 15.1 mmol), N-methylmorpholine (4.15 mL). , 37.8 mmol) and O-tetrahydropyranyl hydroxyl amine (2.21 g, 18.9 mmol) then 1,3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (3.38 g, 17.6 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO 4, filtered, and concentrated in vacuo. Silica gel chromatography eluting with 60% ethyl acetate / hexane provided the desired tetrahydropyranyl protected hydroxamate as a white foam (6.29 g, 92%). MS MH + calcd for C28H36N2SO7 ^4: 545.2321. Found: 545.2316.

Part F: To a solution of tetrahydropyranyl-protected hydroxamate of part E (2.84 g, 5.0 mmol) in dioxane (40 mL) was added 4 HCF dioxane (30 mL). After stirring at ambient temperature for 2.5 hours, the solution was concentrated in vacuo. Trituration of the resulting solid with diethyl ether and filtration gave the desired hydroxamate as a white solid (2.33 g, 90%). MS M + calcd for

C23H28N2SO6: 460.1677. Found 460.1678.

Example 423

Preparation of 4 - [[4- (cyclohexylthio) phenyl] sulfonyl] -N-hydroxy-1- (methylsulfonyl) -4-piperidinecarboxamide

465 ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft

Part A: To a solution of the product of Example 9, Part D (10.0 g, 24.0 mmol) in DMF (20 mL) was added K 2 CO 3 (4.99 g, 36.0 mmol), cyclohexyl mercaptan (4.40 g). , 36.0 mmol). The solution was stirred at ninety degrees Celsius for 48 hours. The solution was diluted with H 2 O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO _4j filtered and concentrated in vacuo. Trituration with ethanol gave the desired sulfide as a white solid (7.16 g, 58%).

Part Β: To a solution of the sulfide from Part B (9.46 g, 18.5 mmol) in ethanol (30 mL) and tetrahydrofuran (30 mL) was added a solution of NaOH (7.39 g, 185 mmol) in water (15 mL) ) and the solution was heated at sixty-five degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue acidified to pH = 3.5. The resulting white solid was collected by filtration, washed with H 2 O and ethyl ether to give the desired carboxylic acid (8.57 g, 95%).

Part C: To a solution of the carboxylic acid of Part B (8.3 g, 17.0 mmol) in ethyl acetate (200 mL) cooled to 0 degrees Celsius, HCl gas was bubbled for 15 minutes. The reaction was then stirred at this temperature for 0.5 hours. The solution was concentrated in vacuo to give a residue which was triturated with diethyl ether to give the desired hydrochloride salt as a white solid (7.03 g, 98%).

MS MH + calcd for C ₁₈ H ₂₅ N ₂ O ₄ : 384.1303. Found 384.1318.

«· ·· · · · · · · ·

466 • · · 9

99

Part D: To a solution of the hydrochloride salt of Part C (1.0 g, 2.4 mmol) was added N-methyl morpholine (654 mL, 5.9 mmol) then mesyl chloride (280 mL, 3.6 mmol) in dichloromethane (20 mL). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (400 mL) and extracted with dichloromethane. The organic layer was washed with water, saturated NaCl and dried over MgSO 4 filtered and concentrated in vacuo to yield the desired methanesulfomanide as a foam (1.0 g, quantitative yield).

Part E: To a solution of methanesulfonamide from Part D (1.3 g, 2.9 mmol) in DMF (30 mL) was added 1-hydroxybenzotriazole (474 mg, 3.5 mmol), N-methylmorpholine (956 mL, 8, 7 mmol), tetrahydropyranyl hydroxyl amine (509 mg, 4.3 mmol) then 1- 3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (778 mg, 4.06 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo. Silica gel chromatography eluting with 30% ethyl acetate / hexane gave the desired tetrahydropyranyl protected hydroxamate as a white foam (1.05 g, 82%).

Part F: To a solution of the tetrahydropyranyl protected hydroxamate of Part E (1.05 g, 1.97 mmol) in dioxane (30 mL) was added 4 HCl / dioxane (10 mL). After stirring at ambient temperature for 2.5 hours, the solution was concentrated in vacuo. Reverse phase C18 column chromatography eluting with acetonitrile / (HCl) water gave a white solid (602 mg, 64%). MS M ⁺ after C 19 H ₂₅ N ₂ S ₃ O 6: 477, found 477.

Example 424

Preparation of N-hydroxy-1- (methylsulfonyl) -4 - [[4- (phenylthio) phenyl] sulfonyl] -4-piperidinecarboxamide

Part A: To a solution of the product of Example 9, Part D (40.0 g, 96.0 mmol) in DMF (200 mL) was added K ₂ CC 3 (20 g, 144 mmol) and thiophenol (22.2 g). , 144 mmol). The solution was stirred at ambient temperature for 24 hours. The solution was then diluted with H ₂ O (1 L) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl, and dried over MgSO _4, filtered and concentrated in vacuo. Chromatography (on silica, eluting with 15% ethyl acetate / hexane) gave the desired sulfide as a white solid (44.4 g, 91%).

Part Β: To a solution of the sulfide from Part A (31.2 g, 6.6 mmol) in ethyl acetate (500 mL) cooled to zero degrees Celsius, HCl gas was bubbled for 30 minutes. The reaction was stirred at this temperature for 1.5 hours. The solution was concentrated in vacuo and the resulting solid was triturated with diethyl ether to give the hydrochloride salt as a white solid (26.95 g, 96%).

Part C: To a solution of the hydrochloride salt of Part B (2.0 g, 4.7 mmol) was added N-methyl morpholine (1.29 mL, 11.7 mmol) followed by mesyl chloride (550 mL, 7.05). mmol) in dichloromethane (35 mL). The solution was stirred at ambient temperature for 48 hours. The solution was diluted with H ₂ O (400 mL) and extracted with dichloromethane. The organic layer was washed with water, saturated NaCl and dried over MgSO _4j filtered and concentrated in vacuo to yield the desired methanesulfonamide as a white solid (2.17 gm, 96%).

Part D: To a solution of the methanesulfonamide of Part C (2.1 g, 4.3 mmol) in ethanol (25 mL) and tetrahydrofuran (25 mL) was added a solution of NaOH (1.72 g, 43 mmol) in water (10 mL). ) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue acidified to pH = 3.5. The resulting precipitate was filtered to give the desired carboxylic acid as a white solid (2.1 g, quantitative yield).

Part E: To a solution of the carboxylic acid from Part D (1.98 g, 4.3 mmol) in DMF (30 mL) was added 1-hydroxybenzotriazole (705 mg, 5.2 mmol), N-methyl morpholine (1.54). ml, 12.9 mmol) and O-tetrahydropyranyl hydroxyl amine hydrochloride (755 mg, 6.5 mmol) followed by 1-3 (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.17 g, 6.1 mmol) . The solution was stirred at ambient temperature for 3 days. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo. Reverse phase C18 column chromatography eluting with acetonitrile / (HCl) water gave the desired tetrahydropyranyl protected hydroxamate as a white solid (1.86 g, 80%). HRMS MH + calculated for C ⁴ H ₂₄ ON _{2 3 3} 0 ₇ S: 555.1293, found 555.1276.

Part F: To a solution of the tetrahydropyranyl protected hydroxamate of part E (1.86 g, 3.5 mmol) in dioxane (30 mL) and methanol (10 mL) was added 4 HCl / dioxane (20 mL). After stirring at ambient temperature for 2.5 hours, the solution was concentrated in vacuo. Reverse phase C18 column chromatography eluting with acetonitrile / (HCl) water gave the title compound as a white solid (1.48 gm, 91%). HRMS MH + calculated for C ⁴ H _{9 22} N ₂ O ₆ S _3: 471.0718 Found 471.0728.

Ftft ftft ftft ftft ftft ft ftft ft ftft ftft

Example 425

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

468 ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft

Part A: To a solution of the product of Example 398, Part A (6.97 g, 19.6 mmol) in DMF (500 mL) was added K ₂ CO ₃ (3.42 g, 18.0 mmol) and 4- ( trifluoromethoxy) phenol (3.7 g, 24.8 mmol). The solution was stirred at ninety degrees Celsius for 40 hours. The solution was diluted with H ₂ O (600 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo to give the desired diaryl ether as an oil (8.5 g, quantitative yield). HRMS MH + calcd for C ₂₄ H ₂₆ NSO ₆ F ₃ · 514.1511. Found 514.1524.

Part Β: To a solution of the 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 the organic solvents and the aqueous residue acidified to pH = 4.0. The resulting precipitate was filtered to give the desired hydrochloride as a white solid (5.01 g, 63%). HRMS MH + calcd for C ₂₂ H ₂₂ NSO ₆ F ₃ : 486.1198, found 486.1200.

Part C: To a solution of the hydrochloride from Part B (5.0 g, 10.3 mmol) in DMF (80 mL) was added -1-hydroxybenzotriazole (1.65 g, 12.3 mmol), N-methylmorpholine (3, 3 mmol, 50 mL). 4 mL, 30.9 mmol) and O4-tetrahydropyranyl hydroxylamine monohydrochloride (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 H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo. Silica gel chromatography eluting with 30% ethyl acetate / hexane provided the desired tetrahydropyranyl protected hydroxamate as a white solid (5.41 g, 89%).

• * φ · ·

Part D: Κ of a solution of tetrahydropyranyl protected hydroxamate from Part C (5.4 g, 9.2 mmol) in dioxane (80 mL) and methanol (20 mL) was added 4 HCl / dioxane (50 mL). The reaction was stirred at ambient temperature for 2.5 hours and the solution was concentrated in vacuo. Trituration with diethyl ether gave the title compound as a white solid (4.02 g, 81%). HRMS MH + calcd for C 22 H 23 N 2 SO 6 F 3: 501.1307, found 501.1324.

469

Example 426

Preparation of 1-cyclopropyl-4 - [(4-ethoxyphenyl) sulfonyl] -N-hydroxy-4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the product of Example 398, Part A (5.87 g, 16.5 mmol) in DMF (50 mL) was added K 2 CO 3 (3.42 g, 24.7 mmol) aa, a, a- ( trifluoromethyl) -β-cresol (4.1g, 24.7 mmol). The solution was stirred at ninety degrees Celsius for 48 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo to give a crude product containing a large percentage of starting material (8.39 g). To this material (8.39 g) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (6.75 g, 169 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 acidified to pH = 3.5. The resulting precipitate was filtered to give the desired hydrochloride salt as a waxy solid (5.04 g, 64%).

Part Β: To a solution of the hydrochloride salt of Part A (5.0 g, 10.3 mmol) in DMF (80 mL) was added 1-hydroxybenzotriazole (1.73 g, 12.8 mmol), N-methylmorpholine (3, 0.75 g, 10.8 mmol). 5 mL, 31.8 mmol) and O4-tetrahydropyranyl hydroxylamine hydrochloride (1.86 g, 15.9 mmol) then 1-3 (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (2.84 g, 14.8 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO ₄ .

470

9 9

9 9 · ·

9 • · • «9

9 9

9 *

Filtered and concentrated in vacuo. Silica gel chromatography eluting with 30% ethyl acetate / hexane gave the desired tetrahydropyranyl-protected hydroxamate as a white solid (1.5 g, 32%).

Part C: To a solution of tetrahydropyranyl-protected hydroxamate of part D (1.5 g, 3.3 mmol) in dioxane (30 mL) and methanol (15 mL) was added 4 HCl / dioxane (50 mL). The reaction was stirred at ambient temperature for 2 hours, then the solution was concentrated in vacuo. Three residues with diethyl ether gave the title compound as a white solid (1.09g, 81%). MS MH ⁺ after C 17 H 24 N 2 SO 5: 369 found 369.

Example 427

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

Part A: To a solution of the product of Example 398, Part A (5.96 g, 15.0 mmol) in DMF (100 mL) was added K ₂ CO ₃ (12.34 g, 38.0 mmol) and α, and α-trifluoromethyl phenol (3.65 g, 22.5 mmol). The solution was stirred at ninety degrees Celsius for 28 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo to give the desired aryl ether as an oil (7.54 g, quantitative yield).

Part Β: To a solution of the 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 acidified to pH = 2.0. The resulting precipitate was filtered to give the desired hydrochloride salt as a white solid (7.98 g, quantitative yield). MS MH ⁺ calculated for C 22 H 22 NSO 5 F 3: 470, found 470.

«· • ·

• «

Part C: To a solution of the hydrochloride of Part B (7.60 g, 15.0 mmol) in DMF (100 mL) was 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) mmol). The solution was stirred at ambient temperature for 96 hours. The solution was diluted with H 2 O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO _4; filtered and concentrated in vacuo. Chromatography on silica eluting with 30% ethyl acetate / hexane provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (5.93g, 69%).

Part D: To a solution of the tetrahydropyranyl protected hydroxamate of Part C (3.8 g, 6.7 mmol) in dioxane (100 mL) was added 4 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 gave the title compound as a white solid (3.33 g, 96%). MS MH + calculated for C22H23N2SO5F3 ^4: 485, found 485 interface.

Example 428

Preparation of N-hydroxy-1- (1-methylethyl) -4 - [[4- (4-trifluoromethyl) phenoxyphenyl] sulfonyl] -4-piperidinecarboxamide monohydrochloride

ch ₃ ch ₃

Part A: To a solution of the product of Example 9, Part D (30.0 g, 80.8 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (30 mL) in dichloromethane (40 mL). The solution was stirred at ambient temperature for 2 hours. The solution was concentrated in vacuo. To the residue dissolved in dichloromethane (150 mL) at 0 degrees Celsius was added triethylamine (28.0 mL, 277 mmol), acetone (24.0 mL, 413 mmol), sodium cyanoborohydride (68 g, 323.1 mmol) and acetic acid. acid (18.5 mL, 308 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solution was diluted with 1M to this to it to it.

472 • «• to * ·

NaOH and extracted with ethyl ether. The organic layer was washed with 1M NaOH, water, saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo to give the desired isopropylamine (21.03 g, 72%).

Part Β: To a solution of isopropylamine from Part A (4.04 g, 11.0 mmol) in DMF (50 mL) was added CsCO ₃ (10.75 g, 33.3 mmol) and α, α, α-trifluoro-β. -cresol (2.67g, 16.5 mmol). The solution was stirred at ninety degrees Celsius for 40 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl, and dried over MgSO ₄ , filtered and concentrated in vacuo. Silica gel chromatography eluting with 30% ethyl acetate / hexane gave the desired diaryl ether as an oil (5.35 g, 97%). HRMS calcd for C ₂₄ H ₂₅ N ₅ O ₅ F 3: 500.1640, Found: 500.1678.

Part C: To a solution of the diaryl ether of Part B (5.3 g, 10.6 mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (4.2 g, 106.0 mmol) in water (25 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue acidified to pH = 3.0. The resulting precipitate was filtered to give the desired hydrochloride salt as a white solid (5.38 g, quantitative yield). MS MH + calculated for C ₂₂ H ₂₄ NSO ₅ F3: 472.1406, found 471.472.1407.

Part D: To a solution of the hydrochloride from Part C (5.4 g, 10.6 mmol) in DMF (90 mL) was added

1-hydroxybenzotriazole (1.72 g, 12.3 mmol), N-methyl morpholine (3.5 mL, 32.0 mmol) and 6-tetrahydropyranyl hydroxyl amine hydrochloride (1.87 g, 15.9 mmol), followed by 1-3 (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (2.8 g, 15.0 mmol). The solution was stirred at ambient temperature for 144 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo. Silica gel chromatography eluting with 2% methanol / ethyl acetate gave the desired tetrahydropyranyl-protected hydroxamate as a white solid (2.74 g, 45%) HRMS MH calcd for C ₂₇ H ₃₃ N ₂ SO ₅ F ₃ : 571.2090, found 571.2103

Part E: To a solution of tetrahydropyranyl protected hydroxamate from Part D (2.7 g, 4.7 mmol) in dioxane (50 mL) was added 4 HCl / dioxane (20 mL). The reaction was stirred at ambient temperature for one hour. Filtration gave the title compound as a white solid (2.08 g, 84%). MS MH calculated for C22H25N2SO5F3: 487, found 487.

· * * · · · «« ««

473 · • 9 9 • • • • • • • • 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 9

Example 429

Preparation of 1-ethyl-N-hydroxy-4 - [[4- [4- (trifluoromethyl) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the product of Example 9, Part D (48 g, 115.0 mmol) in ethyl acetate (750 mL) cooled to zero degrees Celsius, HCl gas was bubbled for 45 minutes and stirred at this temperature for 7 hours. The solution was concentrated in vacuo to give a residue which was triturated with diethyl ether to give the desired hydrochloride salt as a white solid (32.76 g, 81%).

Part Β: To a solution of the hydrochloride from Part A (15.8 g, 45.0 mmol) in DMF (75 mL) was added K 2 CO 3 (12.4 g, 90.0 mmol) and bromoethane (3.4 mL, 45 mL). 0 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (200 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl, and dried over MgSO 4 filtered and concentrated in vacuo to give the desired ethyl amine as an oil (15.4 g, quantitative yield).

Part C: To a solution of ethyl amine from Part B (5.2 g, 15.0 mmol) in DMF (50 mL) was added CsCO ₃ (12.21 g, 37.5 mmol) and α, α, α-trifluoro -p-cresol (3.65 g, 23.0 mmol). The solution was stirred at ninety degrees Celsius for 25 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO _4, filtered, and concentrated in vacuo. Silica gel chromatography eluting with 20% ethyl acetate / hexane gave the desired diaryl ether as an oil (7.3 g, quantitative yield).

Part D: To a solution of the diaryl ether of Part C (7.3 g, 15.0 mmol) in ethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH (6.0 g, 150 mmol) in water (30 mL). ml) and the solution was heated at sixty degrees Celsius for 16 hours. The solution was concentrated in vacuo and the aqueous residue acidified to pH = 4.0. The resulting precipitate was filtered to give the desired hydrochloride salt as a white solid (5.96 g, 80%). HRMS MH calcd for C ₂₁ H ₂₂ NSO ₅ F 3: 458.1249, found 458.1260

Part Ε: To a solution of the hydrochloride salt of Part D (5.96 g, 12.0 mmol) in DMF (80 mL) was added 1-hydroxybenzotriazole (1.96 g, 14.0 mmol), N-methyl morpholine (3 mL). , 9 mL, 36.0 mmol) and tetrahydropyranyl hydroxyl amine hydrochloride (2.11 g, 18.0 mmol) followed by 1-3 * (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (3.24 g, 17.0 mmol) mmol). The solution was stirred at ambient temperature for 168 hours. Insoluble material was removed by filtration and the filtrate was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO _4, filtered and concentrated in vacuo. Silica gel chromatography eluting with 70% ethyl acetate / hexane gave the desired tetrahydropyranyl protected hydroxamate as a white solid (2.80 g, 41%).

Part F: To a solution of the tetrahydropyranyl protected hydroxamate of part E (2.8 g, 5.0 mmol) in dioxane (80 mL) was added 4 HCl / dioxane (20 mL). The reaction was stirred at ambient temperature for 5 hours and the solution was concentrated in vacuo. Trituration with diethyl ether gave the title compound as a white solid (2.08 g, 84%). MS MH ⁺ calculated for C 21 H 23 N 2 SO 5 F 3: 473, found 473.

Example 430

Preparation of 1-ethyl-N-hydroxy-4 - [[4- [4- (1-methylethyl) phenoxy] phenyl] * sulfonyl] -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the product of Example 9, Part D (48 g, 115.0 mmol) in ethyl acetate (750 mL) cooled to zero degrees Celsius, HCl gas was bubbled for 45 minutes. The reaction was stirred at this temperature for 7 hours. The solution was concentrated in vacuo to give a residue which was triturated with diethyl ether to give the desired hydrochloride salt as a white solid (32.8 g, 81%).

Part Β: To a solution of the hydrochloride from Part A (15.8 g, 45.0 mmol) in DMF (75 mL) was added K 2 CO 3 (12.4 g, 90.0 mmol) and bromoethane (3.4 mL, 45.0 mmol). mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with H ₂ O (200 mL) and extracted with ethyl acetate. The organic layer was separated

475 ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft washed with water saturated with NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo to give the desired ethyl amine as an oil (15.4 g, quantitative yield).

Part C: To a solution of the ethyl amine from Part B (5.2 g, 15.0 mmol) in DMF (50 mL) was added CsCO ₃ (12.2 g, 37.5 mmol) and isopropylphenol (3.15). g, 23. 0 mmol). The solution was stirred at ninety degrees Celsius for 5 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl, and dried over MgSO _4, filtered and concentrated in vacuo. Silica gel chromatography eluting with 20% ethyl acetate / hexane gave the desired diaryl ether as an oil (6.2 g, 95%). HRMS MH + calcd for C 25 H 33 N 3 SO 5: 460.2158, Found: 460.2160.

Part D: To a solution of the diaryl ether of Part C (6.2 g, 13.0 mmol) in ethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH (5.2 g, 130 mmol) in water (30 mL). ml) the solution was heated at sixty degrees Celsius for 16 hours. The solution was concentrated in vacuo and the aqueous residue acidified to pH = 4.0. The resulting precipitate was filtered and washed with H ₂ O and diethyl ether to give the desired hydrochloride salt (6.0 g, quantitative yield). HRMS MH + calcd for C 23 H 29 NSO 5: 432.1845, found 432.1859.

Part Ε: To a solution of the hydrogen chloride salt of Part D (6.08 g, 13.0 mmol) in DMF (80 mL) was added 1-hydroxybenzotriazole (2.11 g, 15.6 mmol), N-methyl morpholine (4 mL). , 3 mL, 39.0 mmol) and Otetrahydropyranyl hydroxyl amine hydrochloride (2.28 g, 19.5 mmol) then 1-3 (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (3.49 g, 18.2 mmol) . The solution was stirred at ambient temperature for 168 hours. Insoluble material was removed by filtration and the filtrate was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo. Silica gel chromatography eluting with 50% ethyl acetate / hexane gave the desired tetrahydropyranyl-protected hydroxamate as a white solid (1.7 g, 25%). HRMS MH + calcd for C 28 H 38 N 2 SO 6 · 531.2529, found 531.2537.

Part F: To a solution of tetrahydropyranyl protected hydroxamate of part E (1.7 g, 3.0 mmol) in dioxane (60 mL) was added 4 HCl / dioxane (10 mL). The reaction was stirred at ambient temperature for an hour and the solution was concentrated in vacuo. Reverse phase C18 column chromatography eluting with acetonitrile / (HCl) water gave the title compound as a white solid (860 mg, 59%).

HRMS MH + calcd for C 23 H 30 N 2 SO 5: 447.1954, found 447. 1972

Example 431

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

474 • 4 · 4 4 4

4 4 ··

4 4 4 4 4

4 4 4 4

4444 44 44

44

4 4 4 4 4

4 4 4 4 4

445 44 44 4

4 4 4 4

44 44

Part A: To a solution of the product of Example 398, Part A (4.0 g, 10.2 mmol) in DMF (40 mL) was added K ₂ CO ₃ (12.46 g, 38.0 mmol) and 4-isopropylphenol (4.99 g, 15.3 mmol). The solution was stirred at ninety degrees Celsius for 24 hours. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl, and dried over MgSO ₄₎ filtered and concentrated in vacuo. Chromatography on silica eluting with 30% ethyl acetate / hexane gave the desired diaryl ether as a white solid (3.89g, 76%). HRMS MH + calcd for C ₂₆ H ₃₁ NSO ₅ : 472.2158, Found: 472.2171.

Part Β: To a solution of the diaryl ether from Part A (3.89 g, 8.20 mmol) in ethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH (3.30 g, 82.5 mmol) in water ( 25 ml) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo to remove most of the organic solvents and the aqueous residue acidified to pH = 3.0. The resulting precipitate was filtered and washed with H ₂ O and ethyl ether to give the desired hydrochloride salt (7.98 g, quantitative yield) as a white solid. MS MH + calculated for C ⁴ H _{24 2} 9NSO _5: 444, Found: 444th

Part C: To a solution of the hydrogen chloride salt of Part B (3.6 g, 7.0 mmol) in DMF (70 mL) was added 1-hydroxybenzotriazole (1.22 g, 9.0 mmol), N-methyl morpholine (2 mL). , 3 mL, 21.0 mmol) and Otetrahydropyranyl hydroxylamine hydrochloride (1.23 g, 10.5 mmol) then 1-3 • (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (2.01 g, 10.4 mmol). The solution was stirred at ambient temperature for 15 days. The solution was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo. Silica gel chromatography eluting with 15% ethyl acetate / hexane provided the desired tetrahydropyranyl protected hydroxamate as a white solid (3.51 g, 92%). HRMS MH + calculated for C ₂ 9H _{2 3} 8N SO6: 543.2529, found 543.2539.

• 0 ·

9000

Part D: To a solution of the tetrahydropyranyl protected hydroxamate of Part C (3.51 g, 6.0 mmol) in methanol (10 mL) and dioxane (200 mL) was added 4 HCl / dioxane (30 mL). After stirring at ambient temperature for 2.5 hours, the solution was concentrated in vacuo. Trituration with diethyl ether gave the title compound as a white solid (2.56 g, 86%). MS MH ⁴ calcd for C 24 H ³⁰ N 2 SO 5:

459.1875, found 459.1978.

477

0 9 · 0 9 ·

0 0 0 0 0 0

009 99 90 ·

9 0 0 9 8

00 0 · · ♦

Example 432

Preparation of N-hydroxy-4 - [[4- [4- (1-methylethoxy) phenoxy] phenyl] sulfonyl] -1- (1-methylethyl) -4-piperidinecarboxamide monohydrochloride

ch ₃

Part A: To a solution of ethyl 4 - [(4-fluorophenylsulfonyl)] - 1- (1-methylethyl) -4-piperidinecarboxylate (2.0 g, 5.4 mmol) in Ν, Ν-dimethylformamide (10 mL) 4-isopropyloxyphenol, which can be prepared according to the procedure of J. Indian Chem. Soc., 73, 1996, 507511, (1.63 g, 10.7 mmol) and cesium carbonate (7 g, 21.5 mmol) and the resulting suspension was heated at 60 degrees Celsius for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1M sodium hydroxide, water, and brine and dried over magnesium sulfate. Concentration of the organic phase gave a residue which was purified by silica gel chromatography eluting with ethyl acetate / hexane to give the desired aryl ether (1.06 g, 39%).

Part Β: To a solution of the aryl ether (1.06 g, 2.1 mmol) in ethanol (20 mL) and water (20 mL) was added sodium hydroxide (0.84 g, 21 mmol) and the mixture was heated at 65 degrees Celsius. for 16 hours. The solvents were then removed in vacuo. Water (50 mL) was added and the mixture was concentrated again in vacuo and the resulting mixture was acidified with 2 HCl to pH = 4-5. The solid precipitate was collected by filtration and rinsed with diethyl ether to give the desired carboxylic acid (3.13 g, 100%).

Part C: A solution of the carboxylic acid from Part B (1.0 g, 2.0 mmol) in thionyl chloride (5 mL) was refluxed for 2 hours. The solvent was removed in vacuo. The resulting residue in

478

44 4 ♦♦

4 4 4

4 4 4

4 4

4 4

4 »44 * 4

4 4 ·

4 4 ·

4 4 4

4 4 4

DMF (10 mL) was added N-methyl morpholine (0.66 mL, 6.0 mmol)) and O-tetrahydropyranyl hydroxyl amine hydrochloride (351 mg, 3.0 mmol). The solution was stirred at ambient temperature for 18 hours. The suspension was filtered and the filtrate was diluted with H ₂ O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO ₄ , filtered and concentrated in vacuo. Silica gel chromatography eluting with 90% ethyl acetate / hexane gave the desired tetrahydropyran-protected hydroxamate as a white solid (280 mg, 23%). HRMS calcd for MH ⁴ ₂ C 9 H ₄ oN ₂ S0 _2: 561.2634, found 561.2653.

Part D: To a solution of the tetrahydropyranyl protected hydroxamate of Part C (275 mg, 0.48 mmol) in dioxane (15 mL) was added 4 HCl / dioxane (5 mL). After stirring at ambient temperature for 2 hours, the solution was concentrated in vacuo. Trituration with diethyl ether and filtration of the resulting solid gave the title compound as a white solid (193 mg, 76%). MS MH + calculated for C ⁴ ₂₄ H ₃₂ N ₂ SO _6: 477, found 477th

Example 433

Preparation of 4 - [[4 - [(2-fluorophenyl) -thio] phenyl] sulfonyl] -N-hydroxy-4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the product of Example 9, Part D (6.0 g, 14.4 mmol) in N, N-dimethylformamide (30 mL) was added 2-fluorothiophenol (2.22 g, 17.3 mmol) and potassium carbonate (2.40 g, 17.3 mmol) and the resulting suspension was stirred at ambient temperature for 48 hours. The reaction mixture was then diluted with ethyl acetate (200 mL) and washed with 1M sodium hydroxide (200 mL) and brine (3X). Concentration of the organic phase gave a residue which was purified by silica gel chromatography eluting with ethyl acetate / hexane (1: 4) to give the desired aryl sulfide (8.0 g, 100%) as a white solid.

Part Β: To a solution of the ethyl ester from Part A (8.0 g, 15 mmol) in ethanol (90 mL) and water (20 mL) was added sodium hydroxide (6.1 g, 152 mmol) and the mixture was heated at 65 degrees Celsius for 16 hours. The volatile organics were removed in vacuo and the resulting aqueous mixture was acidified with 2 HCl to pH = 3-4. Solid sodium chloride was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over magnesium sulphate. Removal of the solvent gave the desired carboxylic acid (4.92 g, 68%).

Part C: To a solution of the carboxylic acid of Part B (4.92 g, 9.93 mmol) in N, N'-dimethylformamide (100 mL) was added 4-methylmorpholine (1.52 g, 15.0 mmol), Nhydroxybenzotriazole ( 1.62 g, 12.0 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (2.70 g, 14.1 mmol) followed by O- (tetrahydro-2H-pyran-2- yl) hydroxylamine (2.24 g, 15.0 mmol). After stirring for 16 hours at ambient temperature, the reaction mixture was concentrated to a residue which was dissolved in ethyl acetate (200 mL) and washed with water and brine. Concentration and purification by silica gel chromatography gave the protected hydroxamate derivative (4.9 mg, 83%).

Part D: Hydrogen chloride gas was bubbled into an ice bath cooled solution of the protected hydroxamate of part C (4.9 g, 8.24 mmol) in ethyl acetate (30 mL) for 10 minutes. The mixture was then allowed to stand at ambient temperature for 2 hours, after which time the solvent was removed in vacuo. Fresh ethyl acetate (30 mL) was added and then removed in vacuo and this procedure repeated. Ethyl acetate (50 mL) was then added and the solids collected by filtration to give a solid which was purified by reverse phase chromatography eluting with acetonitrile / water (gradient 20/80 to 100% acetonitrile) to give the title compound (1). , 9 g, 43%). Analytical calculation for C ₁₈ H 19 FN ₂ O ₄ S ₂ · HCl: C, 48.37; H, 4.51; N, 6.27; Cl, 7.93. Found: C, 48.14; H, 4.33; N, 6.21; Cl, 8.64. HRMS (ESI) MH + calcd for C 18 H 18 FN ⁵ O 6 S: 411.0849, found 411.0844.

Example 434

Preparation of 4 - [[4 - [(2-fluorophenyl) -thio] phenyl] sulfonyl] -N-hydroxy-1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the product of Example 9, Part F (4.46 g, 12.6 mmol) in Ν, im-dimethylformamide (30 mL) was added 2-fluorothiophenol (1.94 g, 15.1 mmol) and potassium carbonate (2.09 g, 15.1 mmol) and the resulting suspension was stirred at ambient temperature for 48 hours. Reaction mixture

480 was then diluted with ethyl acetate (200 mL) and washed with 1M sodium hydroxide (200 mL) and brine (3X). Concentration of the organic phase gave the desired aryl sulfide (5.2 g, 90%).

Part Β: To a solution of the ethyl ester from Part A (5.1 g, 11.4 mmol) in ethanol (90 mL) and water (30 mL) was added sodium hydroxide (5.0 g, 125 mmol) and the mixture was heated at 65 degrees Celsius for 16 hours. The organics were removed in vacuo and the resulting aqueous mixture was acidified with 2 HCl to pH = 3-4. Solid sodium chloride was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried with magnesium sulfate. Removal of the solvent gave the desired carboxylic acid (4.5 g, 94%).

Part C: To a solution of the carboxylic acid of Part B (4.5 g, 11.0 mmol) in N, N-dimethylformamide (50 mL) was added 4-methylmorpholine (1.62 g, 16.0 mmol), N- hydroxybenzotriazole (1.73 g, 12.8 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiirnide hydrochloride (2.87 g, 14.9 mmol) then O- (tetrahydro-2H-pyran-2) -yl) hydroxylamine (2.39 g, 16.0 mmol). After stirring for 16 hours at ambient temperature, the reaction mixture was concentrated to a residue which was dissolved in ethyl acetate (200 mL) and washed with water and brine. Concentration and purification by silica gel chromatography gave the protected hydroxamate derivative which was used directly in the next step.

Part D: Hydrogen chloride gas was bubbled into the ice-cooled solution of the protected hydroxamate of Part C in ethyl acetate (30 mL) for 10 minutes. The mixture was then allowed to stand at ambient temperature for 2 hours. After this time, the solvent was removed in vacuo. Fresh ethyl acetate (30 mL) was added and then removed in vacuo and this procedure repeated. Ethyl acetate (50 mL) was then added and the solids collected by filtration to give a solid which was purified by reverse phase chromatography eluting with acetonitrile / water (gradient 20/80 to 100% acetonitrile) to give the title compound (1). , 85 g, 35% for parts C and D). HRMS (ESI) MH + calculated for C 21 H 21 FN 2 O 4 S 2: 449.1005, found 449.1023.

Example 435

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

t «· ·

481 9 9 9 9 9 9 9 9 9 9

9

Part A: To a solution of the product of Example 9, Part F (8.00 g, 22.6 mmol) in N, N-dimethylformamide (50 mL) was added 4-ethoxyphenol (9.38 g, 70 mmol) and cesium carbonate (22 mL). (8 g, 70 mmol) and the resulting suspension was heated at 75 degrees Celsius for 20 hours. The reaction mixture was then diluted with ethyl acetate (1000 mL) and washed with 1M sodium hydroxide, water, and brine. Concentration of the organic phase gave a residue which was purified by silica gel chromatography eluting with ethyl acetate / hexane (1: 2) to give the desired diaryl ether (10.5 g, 99%).

Part Β: To a solution of the ethyl ester of Part A (10.5 g, 22.3 mmol) in ethanol (70 mL) and water (60 mL) was added sodium hydroxide (8.9 g, 222 mmol) and the mixture was heated at 65 degrees Celsius for 16 hours. The volatile organics were removed in vacuo and the resulting aqueous mixture was acidified with 2 HCl to pH = 3-4. Solid sodium chloride was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried with magnesium sulfate. Removal of the solvents gave the desired carboxylic acid (10 g, 100%).

Part C: To a solution of the carboxylic acid of Part B (10 g, 22.5 mmol) in N, N • dimethylformamide (50 mL) was added 4-methylmorpholine (3.42 g, 33.8 mmol), N-hydroxybenzotriazole ( 3.66 g, 27.1 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (6.05 g, 31.6 mmol) then 0- (tetrahydro-2H-pyran-2- yl) hydroxylamine (5.05 g, 33.8 mmol). After stirring for 16 hours at ambient temperature, the reaction mixture was concentrated to a residue that was dissolved in ethyl acetate (200 mL) and washed with water and brine. Concentration and purification by silica gel chromatography eluting with ethyl acetate / hexane (1: 1) gave the protected hydroxamate derivative (6.5 g, 53%), which was used directly in the next step.

Part D: To a solution of the protected hydroxamate of Part C in methanol / 1,4-dioxane (1: 3, 70 mL) was added 4 HCl / 1,4-dioxane (30 mL) and the solution was stirred at ambient temperature for 4 hours . The solvents were then removed in vacuo. Methanol (40 mL) was added and then removed in vacuo. Diethyl ether (100 mL) was added and the resulting solids were collected by filtration to give the title compound (4.3 g, 72%). Analytical calculation for C23H26N2O6S.HCl.H2O: C, 53.85; H, 5.70; N, 5.46; Cl, 6.91; S, 6.25. Found: C, 53.65; H, 5.62; N, 5.41; Cl, 6.86; S, 6.48. MS (ESI) MH calcd for C 23 H 26 N 2 O 6 S: 459, found 459.

φ

Example 436

Preparation of N-hydroxy-4 - [[4- [4- (methylsulfonyl) phenoxy] phenyl] sulfonyl] -1- (2-propynyl) -4-piperidinecarboxamide monohydrochloride

482 * # φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ • «• φ · · ·

Part A: To a solution of the product of Example 9, Part F (2.5 g, 6.4 mmol) in N, N-dimethylformamide (15 mL) was added 4-methylsulfonylphenol (3.5 g, 20.3 mmol) and cesium carbonate (8.7 g, 27 mmol) and the resulting suspension was heated at 90 degrees Celsius for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL) and washed with 1M sodium hydroxide, water, and brine. Concentration of the organic phase gave a residue which was purified by silica gel chromatography eluting with ethyl acetate / hexane (1: 1) to give the desired aryl ether (2.5 g, 77%).

Part Β: To a solution of the ethyl ester from Part A (2.5 g, 4.9 mmol) in ethanol (50 mL) and water (30 mL) was added sodium hydroxide (2.0 g, 49 mmol) and the mixture was heated at 65 degrees Celsius for 8 hours. The solvents were removed in vacuo. Water (50 mL) was added and the mixture was concentrated again in vacuo and the resulting mixture was acidified with 2 HCl to pH = 4-5. The solid precipitate was collected by filtration to give the desired carboxylic acid (1.57 g, 67%).

Part C: To a solution of the carboxylic acid of Part B (1.57 g, 3.3 mmol) in N, N-dimethylformamide (15 mL) was added 4-methylmorpholine (0.5 g, 4.9 mmol), N- hydroxybenzotriazole (0.53 g, 3.9 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.88 g, 4.6 mmol) then O- (tetrahydro-2H-pyran- 2-yl) hydroxylamine (0.74, 4.9 mmol). After stirring for 16 hours at ambient temperature, the reaction mixture was concentrated to a residue that was dissolved in ethyl acetate (200 mL) and washed with water and brine. Concentration and purification by silica gel chromatography eluting with ethyl acetate / hexane gave the protected hydroxamate derivative (1.5 g, 79%), which was used directly in the next step.

Part D: To a solution of the protected hydroxamate of Part C (1.5 g, 2.60 mmol) in methanol 1 / 1,4-dioxane (1: 3, 40 mL) was added 4M HCl / 1,4-dioxane (10 mL). ml) and the solution was stirred at ambient temperature for 3 hours. The solvents were then removed in vacuo. Methanol (30 mL) was added and then added

I ·· · ft · ft · · · · · · · · ·

removed in vacuo. Diethyl ether (100 mL) was added and the resulting solid was collected by filtration to give the title compound (1.35 g, 98%). Calcd for C22H24N2O7S2.HCl: C, 49.95; H,

483

4.76; N, 5.30; Cl, 6.70; S, 12.12. Found: C, 49.78; H, 4.56; N, 5.25; Cl, 6.98; S, 11.98. HRMS (ESI) MH + calcd for C 22 H 24 N 2 O 7 S 2: 493.1103, found 493.1116.

Example 437

Preparation of N-hydroxy-4 - [[4 - ((phenylmethyl) amino] phenyl] sulfonyl] -1- (2-propynyl-4-piperidinecarboxamide monohydrochloride)

Part A: To a solution of the product of Example 9, Part F (2.5 g, 6.4 mmol) in N, N • dimethylformamide (30 mL) was added benzylamine (3.44 g, 32.1 mmol) and cesium carbonate. (10.5 g,

32.3 mmol) and the resulting suspension was heated at 100 degrees Celsius for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL) and washed with water and brine, and dried over magnesium sulfate. Concentration of the organic phase gave a residue which was purified by silica gel chromatography eluting with ethyl acetate / hexane (1: 1) to give the desired benzyl aniline derivative (2.5 g, 88%).

Part Β: To a solution of the ethyl ester from Part A (2.5 g, 5.67 mmol) in ethanol (50 mL) and water (30 mL) was added sodium hydroxide (2.27 g, 56.7 mmol) and the mixture was heated at 65 degrees Celsius for 8 hours. The solvents were removed in vacuo. Water (50 mL) was added and the mixture was concentrated again in vacuo and the resulting mixture was acidified with 2M HCl to pH = 4-5. The solid precipitate was collected by filtration and washed with diethyl ether to give the desired carboxylic acid (2.3 g, 98%).

Part C: To a solution of the carboxylic acid of Part B (2.3 g, 5.57 mmol) in N, N-dimethylformamide (15 mL) was added 4-methylmorpholine (0.85 g, 8.36 mmol), N • hydroxybenzotriazole ( 0.9 g, 6.69 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.5 g, 7.8 mmol) then O- (tetrahydro-2H-pyran-2- yl) hydroxylamine (1.25, 8.36 mmol). After stirring for 16 hours at ambient temperature, the reaction mixture was concentrated to a residue that was dissolved in ethyl acetate and washed with water and brine. Concentration and cleaning • to • to • to • to

·· to ·

484 chromatography on silica gel eluting with ethyl acetate / hexane gave the protected hydroxamate derivative which was used directly in the next step.

Part D: Hydrogen chloride gas was bubbled into the ice-cooled solution of the protected hydroxamate of Part C in ethyl acetate (50 mL) for 10 minutes. The solvent was then removed in vacuo. Ethyl acetate (100 mL) was added and then removed in vacuo. Ethyl acetate (100 mL) was then added and the resulting solids were collected by filtration to give the title compound (1.6 g, 62% after steps C and D). HRMS (ESI) MH + calcd for C 22 H 25 N 3 O ⁴ S: 428.1644, found 428.1652.

Example 438

Preparation of 1-ethyl-N-hydroxy-4 - [[4 - [[4- [trifluoromethyl) phenyl] methoxy] phenyl] sulfonyl] -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the product of Example 429, Part B (1.0 g, 2.9 mmol) in N, N 'dimethylacetamide (30 mL) was added 4- (trifluoromethyl) benzyl alcohol (1.53 g, 74 mmol) and cesium carbonate (2.85 g, 8.74 mmol) and the resulting suspension was heated at 95-100 degrees Celsius for 8 hours. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1M sodium hydroxide, water and brine. Concentration of the organic phase gave a residue which was purified by silica gel chromatography eluting with ethyl acetate / hexane to give the desired aryl ether (0.8 g, 54%).

Part Β: To a solution of the ethyl ester of Part A (0.8 g, 1.5 mmol) in ethanol (50 mL) and water (50 mL) was added sodium hydroxide (1.0 g, 25 mmol) and the mixture was heated at 60 degrees Celsius for 16 hours. The solvents were removed in vacuo. Water (50 mL) was added and the mixture was acidified with 2 HCl to pH = 4. The solid precipitate was collected by filtration to give the desired carboxylic acid (0.75 g, 99%).

Part C: To a solution of the carboxylic acid of Part B (0.75 g, 1.54 mmol) in N, N-dimethylformamide (10 mL) was added 4-methylmorpholine (0.47 g, 4.6 mmol), N- hydroxy benzo triazole (0.25 g, 1.85 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide; · · »

485. hydrochloride (0.41 g, 2.16 mmol) then O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.35, 2.3 mmol). After stirring for 16 hours at ambient temperature, the reaction mixture was concentrated to a residue which was dissolved in ethyl acetate (200 mL) and washed with water and brine. Concentration and purification by silica gel chromatography eluting with ethyl acetate / hexane gave the protected hydroxamate derivative (250 mg, 57%).

Part D: To a solution of the protected hydroxamate of Part C (250 mg, 0.43 mmol) in methanol / 1,4-dioxane (1: 3, 20 mL) was added 4M HCl / 1,4-dioxane (5 mL) and the solution was stirred at ambient temperature for 3 hours. The solvents were then removed in vacuo. Another portion of ethyl acetate was added and then removed in vacuo. Diethyl ether (100 mL) was added and the resulting solids were collected by filtration to give the title compound (190 mg, 82%). MS (CI) MH ⁺ calcd for C 22 H 25 ^{F 3} N 2 ^{O 5 S} : 487, found 487.

Example 439

Preparation of 1-Cyclopropyl-N-hydroxy-4 - [[4- [4- (1-methylethoxy) phenoxy] phenyl] sulfonyl] -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the product of Example 398, Part A (2.49 g, 7.0 mmol) in N, N-dimethylacetamide (30 mL) was added 4-isopropoxyphenol, which can be prepared according to the procedure of J. Indian Chem. Soc. 73.1996, 507-511, (1.28 g, 8.4 mmol) and cesium carbonate (5.48 g, 16.8 mmol) and the resulting suspension was heated at 60 degrees Celsius for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1M sodium hydroxide, water and brine. Concentration of the organic phase gave a residue which was purified by silica gel chromatography eluting with ethyl acetate / hexane to give the desired aryl ether (2.8 g, 82%).

Part Β: To a solution of the ethyl ester from Part A (2.8 g, 5.7 mmol) in ethanol (50 mL) and water (50 mL) was added sodium hydroxide (2.3 g, 57 mmol) and the mixture was heated at 60 degrees Celsius for 16 hours. The solvents were removed in vacuo. Water (50 ml) was added and the mixture was acidified with 4 4.

486 · 4 4444 4 4444

4444 44 ·· ·· «· ··

HCl to ρ = 4. The solid precipitate was collected by filtration to give the desired carboxylic acid (1.4 g, 53%).

Part C: To a solution of the carboxylic acid of Part B (1.4 g, 3.1 mmol) in N, N-dimethylformamide (15 mL) was added 4-methylmorpholine (0.92 g, 9.1 mmol), N- hydroxybenzotriazole (0.49 g, 3.66 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.82 g, 4.26 mmol) then O- (tetrahydro-2H-pyran- 2-yl) hydroxylamine (0.68 g,

4.5 mmol). After stirring for 16 hours at ambient temperature, the reaction mixture was concentrated to a residue which was dissolved in ethyl acetate and washed with water and brine. Concentration and purification by silica gel chromatography eluting with ethyl acetate / hexane gave the protected hydroxamate derivative which was used directly in the next step.

Part D: To a solution of the protected hydroxamate of Part C in methanol / 1,4-dioxane (1: 3.20 mL) was added 4 HCl / 1,4-dioxane (10 mL) and the solution was stirred at ambient temperature for 3 hours . The solvents were then removed in vacuo. Another portion of ethyl acetate was added and then removed in vacuo. Diethyl ether was added and the resulting solids were collected by filtration to give the title compound (0.3 g, 19% for parts C and D together). Analytical calculation for C ₂₄ H ₃₀ N ₂ O ₆ S.HCl: C, 56.41; H, 6.11; N, 5.48. Found: C, 56.04; H, 5.82; N, 5.44. MS (CI) MH + calcd for C ₂₄ H ₃₀ N ₂ O ₆ S: 475, found 475.

Example 440

Preparation of 4 - [[4 - [[2- (4-chlorophenyl) ethyl] amino] phenyl] sulfonyl] -1-ethyl-N-hydroxy-4-piperidinecarboxamide monohydrochloride

Part A: To a solution of the product of Example 429, Part B (1.0 g, 2.91 mmol) in N, N-dimethylacetamide (20 mL) was added 4-chlorophenethylamine (0.91 g, 5.8 mmol) and cesium carbonate (3.80 g, 11.6 mmol) and the resulting suspension was heated at 90 degrees Celsius for 24 hours.

The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1M sodium hydroxide, water and brine. Concentration of the organic phase gave a residue which was purified.

487 ·· ř · · ««

4 4 <

4 4 4

4 · 4 silica gel chromatography eluting with ethyl acetate / hexane to give the desired aryl ether (0.8 g,

58%).

Part Β: To a solution of the ethyl ester of Part A (0.8 g, 1.7 mmol) in ethanol (50 mL) and water (50 mL) was added sodium hydroxide (1.0 g, 25 mmol) and the mixture was heated at 60 degrees Celsius for 16 hours. The solvents were removed in vacuo. Water (50 mL) was added and the mixture was acidified with 2 HCl to pH = 4. The solid precipitate was collected by filtration to give the desired carboxylic acid (0.75 g, 92%).

Part C: To a solution of the carboxylic acid of Part B (0.75 g, 1.7 mmol) in N, N • dimethylformamide (20 mL) was added 4-methylmorpholine (0.51 g, 5.1 mmol), N- hydroxybenzotriazole (0.27 g, 2.0 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.45 g, 2.3 mmol) then O- (tetrahydro-2H-pyran-2) -yl) hydroxylamine (0.37 g, 2.5 mmol). After stirring for 16 hours at ambient temperature, the reaction mixture was concentrated to a residue that was dissolved in ethyl acetate and washed with water and brine. Concentration and purification by silica gel chromatography eluting with ethyl acetate / hexane gave the protected hydroxamate derivative which was used directly in the next step.

Part D: To a solution of the protected hydroxamate of Part C in methanol / 1,4-dioxane was added 4 HCl / 1,4-dioxane (10 mL) and the solution was stirred at ambient temperature for 3 hours. The solvents were then removed in vacuo. Another portion of ethyl acetate was added and then removed in vacuo. Diethyl ether was added and the resulting solids were collected by filtration to give the title compound (30 mg, 4% for parts C and D together).

Example 441

Preparation of N-hydroxy-1- (2-methoxyethyl) -4 - [[4 - [[[4- (trifluoromethoxy) phenyl] methyl] amino] phenyl] sulfonyl] -4-piperidinecarboxamide monohydrochloride

Part A: To a solution of ethyl (4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate (1.38g, 3.7 mmol) in Ν, Ν-dimethylformamide (20 mL) 44 trifluoromethyloxy) benzylamine (1.0 g, 5.2 mmol) and cesium carbonate (1.7 g, 5.2 mmol) were added and the resulting ftftftft ft · ftftftft · · · · · ft ·

The 488 ftft ftft suspension was heated at 90 degrees Celsius for 24 hours. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1M sodium hydroxide, water and brine. Concentration of the organic phase gave a residue which was purified by silica gel chromatography eluting with ethyl acetate / hexane to give the desired trifluoromethoxy compound (0.6 g, 30%).

Part Β: To a solution of the ethyl ester from Part A (0.6 g, 1.1 mmol) in ethanol (30 mL), water (30 mL) and tetrahydrofuran (15 mL) was added sodium hydroxide (0.44 g, 11 mL). mmol) and the mixture was heated at 60 degrees Celsius for 16 hours. The solvents were removed in vacuo. Water (50 mL) was added and the mixture was acidified with 2 HCl to pH = 4. The solid precipitate was collected by filtration to give the desired carboxylic acid (0.5 g, 88%).

Part C: To a solution of the carboxylic acid of Part B (0.50 g, 0.98 mmol) in N, N-dimethylformamide (10 mL) was added 4-methylmorpholine (0.15 g, 1.5 mmol), N-hydroxybenzotriazole. (0.16 g, 1.2 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.27 g, 1.4 mmol) then O- (tetrahydro-2H-pyran-2). -yl) hydroxylamine (0.22 g, 1.5 mmol). After stirring for 16 hours at ambient temperature, the reaction mixture was concentrated to a residue that was dissolved in ethyl acetate and washed with water and brine. Concentration and purification by silica gel chromatography eluting with ethyl acetate / hexane gave the protected hydroxamate derivative (110 mg, 18%).

Part D: To a solution of the protected hydroxamate of Part C (110 mg, 0.18 mmol) in methanol / 1,4-dioxane (1: 4, 20 mL) was added 4 HCl / 1,4-dioxane (7 mL) and the solution was stirred at ambient temperature for 3 hours. The solvents were then removed in vacuo. An additional portion of methanol (20 mL) was added and then removed in vacuo. Diethyl ether was added and the resulting solids were collected by filtration to give the title compound (30 mg, 31%). MS (ESI) MH + calcd for C 23 H 28 F 3 N 3 O 6 S: 532, found 532.

Example 442

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

489 ·· ··· · · · · · · · · · · · 9 ····

9 9 9 9 999991 99 9

9 9 9 9 9

9999 99 99 99 99 99

Part A: To a solution of ethyl (4 - [(4-fluorophenylsulfonyl)] - 1- (2-methoxyethyl) -4-piperidinecarboxylate) (2.0 g, 5.4 mmol) in N, N-dimethylformamide (20 mL) 4-isopropoxyphenol, which can be prepared according to the procedure of J. Indian Chem. Soc. 73, 1996, 507-511, (1.63 g, 10.7 mmol) and cesium carbonate (7 g, 21.5 mmol) and the resulting suspension was heated at 60 degrees Celsius for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1M sodium hydroxide, water, and brine and dried over magnesium sulfate. Concentration of the organic phase gave a residue which was purified by silica gel chromatography eluting with ethyl acetate / hexane to give the desired aryl ether (1.37 g, 50%).

Part Β: To a solution of the ethyl ester from Part A (1.37 g, 2.7 mmol) in ethanol (30 mL) and water (30 mL) was added sodium hydroxide (1.08 g, 27 mmol) and the mixture was heated at 65 degrees Celsius for 16 hours. The solvents were then removed in vacuo. Water (50 mL) was added and the mixture was concentrated again in vacuo and the resulting mixture was acidified with 2M HCl to pH = 4-5. The solid precipitate was collected by filtration and rinsed with diethyl ether to give the desired carboxylic acid (1.25 g, 100%).

Part C: To a suspension of the carboxylic acid of Part B (1.25 g, 2.7 mmol) in N, N-dimethylformamide (15 mL) was added 4-methylmorpholine (0.82 g, 8.1 mmol), O- (tetrahydro) -2H-pyran-2-yl) hydroxylamine (0.61, 4.1 mmol) then bromo-tris-pyrrolidine-phosphonium hexafluorophosphate (PyBroP, 1.51 g, 3.3 mmol). After stirring for 16 hours at ambient temperature, the reaction mixture was concentrated to a residue that was dissolved in ethyl acetate and washed with water and brine. Concentration and purification by silica gel chromatography eluting with ethyl acetate / hexane gave the protected hydroxamate derivative (1.0 g, 63%).

Part D: Hydrogen chloride gas was bubbled into the ice-cooled solution of the protected hydroxamate of part C (1.0 g, 1.7 mmol) in ethyl acetate (20 mL) for 5 minutes. After stirring at ambient temperature for 5 hours, the solvent was removed in vacuo. Ethyl acetate (30 mL) was added and then removed in vacuo. Ethyl acetate (30 mL) was added again and the resulting solids were collected by filtration to give the title compound (0.5 g, 56%). Analytical calculation for C ₂ HC1 4H32N2O ₇ ^'1 5H2O: C, 51.84; H, 6.53; N, 5.04; Cl, 6.38; S, 5.77. Found: C, 51.87; H, 6.12; N, 4.92; Cl, 6.38; S, 5.84. MS MEČ calcd for C 24 H 32 N 2 O 7 S: 493, found 493.

0 09 90 09

100 0 0 90 0

0 0 0 0 0 0

009 9 * 10

9 0 0 9 ·

0990 90 90 9 ·

Example 443

Preparation of N-Hydroxy-1- (2-pyridinylmethyl) -4- [4- (4-trifluoromethoxyphenoxy) phenyl] sulfonyl] -4-piperidinecarboxamide dihydrochloride

490

00

0 0 ·

9 9 ·

9 9 0

Part A: The aryl fluoride of Example 9, Part D (6.22 g, 15 mmol) was combined with powdered potassium carbonate (3.04 g, 22 mmol), 4- (trifluoromethoxy) phenol (3.92 g, 322 mmol). ) and N, N-dimethylformamide (7 mL) and the mixture was stirred at ninety degrees Celsius for sixteen hours. Additional 4- (trifluoromethoxy) -phenol (1 g) and potassium carbonate (800 mg) were added and the reaction continued at 115 degrees Celsius for twenty additional hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL, then 2 X 25 mL). The combined organic layers were dried using magnesium sulfate, concentrated, and chromatographed to give the desired aryl ether as an oil (9.6 g, about quantitative yield).

Part B: The aryl ether from Part A (9.6 g, about 15 mmol) was dissolved in ethyl acetate (45 mL). A solution of HCl in dioxane (4M, 12 mL) was added and the mixture was stirred at ambient temperature for three hours. Thin-layer chromatography showed incomplete deprotection. Concentrated aqueous HCl (4 mL) was added and the reaction was heated to reflux several times with a thermometer. The solution was concentrated and then azeotroped with acetonitrile to give the desired piperidine hydrochloride salt as a foam (9.6 g). Nuclear Magnetic Resonance Spectroscopy showed some contamination with 4 (trifluoromethoxy) phenol, which had to be transferred from Part A.

The piperidine hydrochloride salt (6.0 g) was dissolved in ethyl acetate (125 ml) and washed with aqueous sodium hydroxide (2 g NaOH in 50 ml water). The organic layer was dried with magnesium sulfate and filtered through a pad of silica gel. The phenolic contaminant eluted. The desired piperidine was then released from the filter cake eluting with methanol containing 1% aqueous ammonium hydroxide (about 100 mL). The filtrate was concentrated and azeotroped with acetonitrile to yield 3.3 g (7.3 mmol).

• ft ftft · ftft ·· · · · · · · · · · ·

J <\ 1 ··· ···· ····

491 · · · · t t t t t <<<<<<<<<

Part C: Piperidine from Part B (1.24 g, 2.7 mmol) was combined with powdered potassium carbonate (828 mg, 6.0 mmol), 2-picolyl hydrochloride (492 mg, 3.0 mmol) and N, N-dimethylformamide (3 mL) and the mixture was stirred at ambient temperature for 2 hours, then heated at 50 degrees Celsius for an additional 2 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (150 mL, then 50 mL). The combined organic layers were dried using magnesium sulfate, concentrated and chromatographed to give the desired ester as an oil (1.13 g, 74%).

Part D: The ester from Part C (1.1 g, 2.0 mmol) was combined with ethanol (6 mL), water (2 mL), and potassium hydroxide (0.90 g, 16 mmol). The mixture was brought to reflux and heated for 4.5 hours. The solution was then cooled to zero degrees Celsius and acidified using concentrated aqueous hydrogen chloride. The solvents were removed and the resulting solids were dried azeotropically with acetonitrile. Vacuum was applied until a constant weight was reached.

The crude acid hydrochloride was mixed with N-methylmorpholine (about 0.5 mL), 1-hydroxybenzotriazole (0.405 g, 3 mmol), O-tetrahydropyranyl hydroxylamine (0.35 g, 3.0 mmol) and N, N-dimethyformamide ( 9 ml). After 10 minutes, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.57 g, 3.0 mmol) was added and the mixture was stirred overnight. The reaction was then diluted with half saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (100 mL, then 25 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed (9-1 ethyl acetate: methanol) to give the desired tetrahydropyranyl-protected hydroxamate as a yellow oil (1.20 g, 95%).

Part E: Tetrahydropyranyl-protected hydroxamate (1.20 g, 1.90 mmol) was diluted with methanol (9 mL). Acetyl chloride (0.78 mL, 11 mmol) was added over 2 minutes. The reaction was stirred at ambient temperature for 2 hours, then concentrated to give the desired disodium hydrogen chloride (1.20 g, quantitative yield) as a white crystalline solid. Analytical calculation for C ₂₅ H ₂₄ F ₃ N ₃ O ₆ S, 2HCl, 1/3 H ₂ O: C, 47.58; H, 4.07; N, 6.66. Found: C, 47.31; H, 4.14; N, 6.80.

Example 444

In vitro inhibition of metalloprotease

Compounds prepared as described in the Examples above were tested for activity in an in vitro experiment. According to the procedure of Knight et al., Febs. Lett. 296 (3): 263 (1992). Briefly, MMP activated with 4-aminophenylacetate mercuric (ΑΡΜΑ) or trypsin was incubated with various inhibitor concentrations for 5 minutes at room temperature and purified first through a heparin column.

492 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Agarose and then through a column of chelating zinc chloride. The proenzyme was activated for use in the ΑΡΜΑ assay. MMP-1 expressed in transfected HT-1080 cells was provided by dr. Howard Welgus of Washington University, St. St. Louis, MO. The enzyme was also activated using ΑΡΜΑ and 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. Mons. Gregory Goldberg also from Washington University. Studies that were conducted using MMP-2 in the presence of 0.02% 2-mercaptoethanol are shown in the table below the asterisk. Additional specifications for the preparation and use of these enzymes can be found in the scientific literature describing enzymes. See, for example, Enzyme Nomenclature. Academic Press, San Diego, CA (1992) and citations there and Frije et al., J. Biol. Chem., 26 (24): 16766-16773 (1994). The substrate of the enzyme is methoxycoumarin containing a polypeptide with the following chain: MCA-ProLeuGlyLeuDpaAlaArgNH 2> wherein MCA is methoxycoumarin and Dpa is 3- (2,4-dinitrophenyl) -L-2,3-diaminopropionyl alanine. This substrate is commercially available from Baychem as product M-1895.

The assay used in the assays contained 100 mmol Tris-HCl, 10 mmol NaCl, 10 mmol CaCl 2, and 0.05% polyethylene glycol (23) lauryl ether at pH 7.5. Assays were performed at room temperature and dimethylsulfoxide (DMSO) was used to dissolve the inhibitory compound at a final concentration of 1 percent.

The test compound in DMSO / buffer solution was compared to the same volume of DMSO / buffer without inhibitor as the control using Microfluor (TM) white plates (Dynatech). The inhibitor or control solution was kept on the plate for 10 minutes and then the substrate was added to a final concentration of 4 μΜ.

In the absence of inhibitory activity, the fluorogenic peptide cleaved at the Gly-Leu peptide bond and separated the highly fluorogenic peptide from the 2,4-dinitrophenyl quencher, resulting in increased fluorescence intensity (excitation at 328 nm / emission at 415 nm). Inhibition was measured by decreasing fluorescence intensity as a function of inhibitor concentration using a Perkin Elmer L550 plate reader. IC 50 values were calculated from these values. The results are shown in Tables A and B below, showing _IC50 values _at the _appropriate sites, where appropriate

Inhibition Table A (nmol)

MMP-13 MMP-2 MMP-1 MMP-9 IC ₅₀ o (nM) IC 50 (nM) IC ₅₀ (nM) IC ₅₀ (nM) 5.1 2.6 6600 31.6 0.25 0.1 220 1.4 0.3 0.2 1140 0.35 0.23 1090 5 4800 1800 > 10000 0.25 0.15 327 37.2 1,8 > 10000 235 24.1 4 > 10000 290 0.5 0.2 9000 1.5 0.4 0.2 1600 0.3 6 4.4 > 10000 <0.1 <0.1 464 0.6 0.4 > 10000 8 0.1 <0.1 464 0.4 0.2 3600 0.2 2.4 100 ALIGN! > 10000 2500 0.3 0.2 400 0.3 0.5 0.3 800 9 13.9 > 10000 1.7 23.5 10000 0.6 1.3 > 10000 1,2 0.9 > 10000 0.2 <0.1 2275 0.4 1 > 10000 3.7 3 2.6 > 10000 0.5 0.2 7700 7 0.45 0.4 > 10000 4 <0.1 <0.1 770 0.3 0.15 > 10,000

Inhibition Table B (nmol)

MMP-1 MMP-2 MMP-9 MMP-13 IC ₅₀ (nM) IC ₅₀ o (nM) IC ₅₀ (nM) IC ₅₀ (nM) 350 0.1 0.3 0.1 370 <0.1 0.2 > 10000 0.1 2.5 0.2 > 10000 0.5 9.4 0.8 > 10000 1.1 1,2 > 10000 0.3 3 0.5 7300 0.4 8 0.6 1000 0.2 0.3 > 10000 20 May 135 22nd > 10000 230 24.5 4400 0.4 2.4 1.9 1200 0.15 0.2

494

2200 7000 > 10000 > 10000 0.2 0.4 <0.1 8000 1.3 0.4 0.8 0.2 > 10000 8800 2.5 1.7 710000 710000 > 10000 7 ~ 14.6 > 10000 3000 3100 210 0.2 0.25 > 10000 76.9 90.0 5500 0.7 1.3 > 10000 2.7 5.9 > 10000 0.3 92 1.5 > 10000 60 120 1200 0.1 0.3 1500 <0.1 0.15 1200 <0.1 0.2 > 10000 83 30 > 10000 130 180 > 10000 64 147 > 10000 1500 2000 > 10000 > 10000 > 10000 > 10000 18.1 530 1.5 1470 <0.1 0.15 8000 0.6 4.4 0.7 > 10000 4590 36000 1600 239 268 > 10000 5.3 130 6 1140 <0.1 0.2 <0.1 1500 0.2 7.3 0.8 3600 0.35 5 0.8 2100 <0.1 0.3 1140 <0.1 0.2 <0.1 > 10000 130 480 > 10000 60 900 > 10000 6 50 10 > 10000 1 1.7 3000 0.1 1,8 0.2 3300 0.1 0.3 4000 0.1 0.3 8000 1,2 5 1.5 8000 1,8 2.5 500 <0.1 0.4 <0.1 > 10000 2.5 3.5 7200 0.8 13.9 0.35 1100 0.2 0.5 0.2 1200 0.15 0.4 0.25 1200 0.1 0.1 1800 1.5 40 2.1 > 10000 1800 2430 8000 0.4 3.5 0.7

268 <0.1 0.4 <0.1 > 10000 1 3.6 0.5 5000 0.2 1.3 0.3 4000 8.2 16.7 > 10000 37 23.4 > 10000 0.4 1 435 <0.1 0.3 0.15 1800 0.3 2.9 0.45 2000 <0.1 0.2 > 10000 0.8 10 0.7 > 10000 1.5 42.8 0.65 > 10000 3500 114 0.85 > 10000 27.1 12.1 > 10000 12.1 6 2000 0.4 0.4 500 0.1 0.7 0.3 2700 0.4 10 0.5 3700 0.5 1.3 1000 7 3.2 > 10000 0.9 4 3000 0.65 31.6 0.4 4500 0.3 31.6 0.6 2350 2 15.3 5.5 3700 0.6 45.4 4.8 2850 0.3 50 0.8 > 10000 1.5 30 1.7 4000 0.4 0.4 1200 <0.1 0.2 600 ο, ι 0.15 3600 1,8 27.8 1,8 1000 0.5 1.1 > 10000 0.4 7 0.5 8000 11.3 10 > 10000 37 40 > 10000 23.8 20 May > 10000 > 100 1000 > 10000 57.7 45.9 > 10000 650 10 > 10000 420 > 10000 90 27 Mar: 9000 29 4 > 10000 500 65 > 10000 445 40 > 10000 300 34.7 > 10000 > 100 > 100 > 10000 1000 25.4 > 10000 1000 60 > 10000 > 100 > 100 > 10000 600 70 > 10000 900 23.9 > 10000 800 30.7

Φ φ • · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

496

> 10000 > 100 > 100 > 10000 650 32.6 > 10000 2700 31 > 10000 2400 31 > 10000 1600 15.5 > 10000 1300 14.5 > 10000 1500 35 > 10000 2400 16.5 > 10000 2700 13.5 > 10000 1600 27 Mar: > 10000 > 1000 > 100 > 10000 3300 27.8 > 10000 6000 90 > 10000 5000 80 > 10000 2500 15.6 > 10000 4700 33.7 > 10000 > 1000 > 100 > 10000 > 1000 > 100 > 10000 4000 77.4 > 10000 1750 20 May > 10000 330 13.6 > 10000 > 1000 > 100 > 10000 > 1000 > 100 > 10000 > 1000 > 100 10000 > 1000 > 100 10000 > 1000 > 100 > 10000 > 1000 > 100 > 10000 > 1000 > 100 > 10000 > 1000 > 100 8000 900 > 100 10000 > 1000 > 100 > 10000 400 25 > 10000 400 21 > 10000 540 > 100 > 10000 440 100 ALIGN! 5000 128 4 10000 121 6.1 > 10000 240 4 > 10000 288 40 > 10000 94 Ί > 10000 210 17.5 > 10000 120 10 > 10000 290 12.1 > 10000 350 9.4 3700 94 8 > 10000 220 10.6 > 10000 350 4 > 10000 330 10 > 10000 390 6 10000 165 8 10000 100 ALIGN! 14.5

ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ftftft ftft ftft ftft ftft ftft> 10000

7000> 10000> 10000> 10000> 10000> 10000

8500> 10000

7300> 10000> 10000> 10000> 10000> 10000> 10000> 10000

310

1100

250

1000

600> 10000> 10000

145

1600

100 ALIGN!

1100> 10000> 10000> 10000> 10000

600> 10000> 10000

650 <100

497

240 25 145 8 270 14.5 155 1.4 24 17.5 22.4 13.6 54 9.15 31 30 25 27.1 12.7 2 > 10.0 20 May 30.6 28 27 Mar: 27 Mar: 19 Dec 20 May 27 Mar: 20 May 33 24 33 20 May <1.0 <1.0 <1.0 <1.0 <1.0 <1.0 <1 <1.0 <1.0 <1.0 <1.0 <1.0 <1.0 <1.0 <1.0 <1.0 <1.0 <1.0 <1.0 <1.0 <1.0 <1.0 18.1 16.7 54 70 18.6 6 <1 <1 <1.0 <1.0 <1 <1 > 100 > 100 <1.0 <1.0 <1.0 <1.0

4 4 • 4 4 • 4

498

Example 445

In vivo angiogenesis assay

The study of angiogenesis is dependent on a reliable and reproducible model for stimulating and inhibiting the neovascular response. The comic microcapsule assay provides such a model as a model of angiogenesis in mouse comie. See: A Model of Angiogenesis in Flea Cornea,

Kenyon, Β. M. et al., Investigative Ophthalmology and Visual Science, July 1996, vol. 37, No. 8.

In this test, uniformly sized Hydron ™ pellets containing bFGF and sucralfate were prepared and surgically implanted in mouse comune trees adjacent to stemporal limbus. Pellets were formed by preparing a suspension of 20 μΐ sterile saline containing 10 μg recombinant bFGF and 10 mg sucralfate and 10 μΐ 12% Hydron ™ in ethanol. The suspension was then deposited on a 10 x 10 mm piece of sterile nylon fabric. After drying, the nylon fibers were separated from the fabric to release the pellets.

A dome pocket was made by anesthetizing a 7 week old female C57B1 / 6 mouse, then pulling out the eye with jewelry tweezers. Using a separating microscope, a central intrastromal linear keratomy of approximately 0.6 mm was performed using surgical scalpel # 15, parallel to the lateral rectus muscle output. A lamellar microcapsule to the temporal limbus was excised with a modified cataract knife. The pocket expanded up to 1.0 mm to the temporal limb. A single pellet at the base of the pocket was placed on the surface of the comey with the tweezers. The pellet was then moved to the temporal end of the pocket. Then an antibiotic ointment was applied to the eye.

Mice were dosed daily for the duration of the test. Animal dosing was based on the bioavailability and overall potency of the compound. An exemplary dose was 10 or 50 mg / kg bid, po. Neovascularization by the comeal trees begins about day 3 and was allowed to proceed under the influence of the test compound until day 5. On day 5, the degree of angiogenic inhibition was evaluated by examining the neovascular procedure with a slit lamp microscope.

The mice were anesthetized and the study eye was pulled out again. The maximum vascular length of the neovascularization extending from the limb vascular plexus to the pellet was measured. In addition, the continuous perimeter zone of neovascularization was measured as a clock where 30 degrees of circumference equals one hour. The area of angiogenesis was calculated as follows:

(0.4 x hours x 3.14 vessel length (mm)

Area = --------------------------------------- 2

499

0 »· · · · · · 0 0 9 9 9 9

909 9009 0 0 0 9 • 0 999 9 0000 09.09

00 0 0000 0000 90 · · 99 ·

Five to six mice were used for each compound in each study. The study mice were then compared to control mice and the difference in neovascularization area was recorded as an average value. Each group of mice thus studied constitutes an n 'value of one, so n values greater than one represent a series of studies, the average result of which is given in the table. A compound of the invention typically exhibits about 25 to about 75 percent inhibition, while vehicle control exhibits zero percent inhibition.

Data for the four compounds of the examples are given at doses of 10 and 50 mpk.

Inhibition of angiogenesis

Dose

Example 10 mok 50mnk Marimastat - 48 (n = 5) 4 18 (n = 2) 41 (n = 5) 9 50 (n = 3) 46 (n = 2) 10 47 (n = 1) 54 (n = 3) 24 53 (n = 1) 78 (n = 1)

Example 446

In vivo reduction of PC-3 tumor

PC-3 human pancreatic cancer cells (ATCC CRL 1435) were grown to 90% confluency in F12 / MEM (Gibco) containing 7% FBS (Gibco). Cells were harvested mechanically using a rubber squeegee and then washed twice with cold medium. The resulting cells were resuspended in cold medium with 30% matrigel (Collaborative Research) and the cells containing the medium were kept on ice until use.

Balb / c nu / nu mice 7-9 weeks old were anesthetized with avertine [2,2,2-tribromethanol / t-amyl alcohol (1 g / 1 mL) diluted 1:60 into phosphate-buffered mucus] and 3-5x10θ cells from above in 0.2 ml medium were injected into the left flank of each mouse. Cells were injected in the morning while inhibitor dosing began at 18 hours. The animals were kept BID from day zero (day of cell injection) until day 25-30, when the animals were euthanized and tumors weighed.

Compounds were dosed at 10 mg / ml in 0.5% methylcellulose / 0.1% polysorbate 80 giving a 50 mg / kg (mpk) dose twice daily or diluted to give a 10 mg / kg (mpk) dose twice daily. Tumor measurements began on day 7 and continued every third or fourth day until study termination. Groups of ten mice were used in each study and nine to ten survived.

Thus, each group of mice forms an n value of one, so n values greater than one represent a series of studies whose average result is given in the table. The results of this study for a number of previously discussed compounds are shown as the average reduction in tumor weight.

500

Average percentage of tumor weight reduction

Dose

Example 10mDk 50mpk Marimastat <5 39 (n = 3) 4 33 (n = 3) 43 (n = 3) 9 40 (n = 1) 60 (n = 1) 10 nt 59 (n = 1)

Example 447

Tumor necrosis factor tests

Cell culture.

The cells used in the assay are human monocytic line U-937 (ATCC CRL-1593). Cells are grown in RPMI h / 10% FCS and PSG supplement (R-10) and are not allowed to grow. The tests were performed as follows:

1. Count, then harvest cells by centrifuges Resuspend the pellets in the R-10 supplement, to a concentration of 1.540 χ 10 ⁹ cells / ml.

2. Add test compound in 65 µl R-10 to the appropriate wells of a flat bottom 96-well tissue culture plate. An initial dilution from a DMSO stock solution (100 mmol compound) gives a 400 µmol solution from which five additional triple serial dilutions are made. Each dilution of 65 µl (in triplicate) yields final compound concentrations in the assay of 100 µΜ, 33.3 µΜ, 11.1 µΜ, 3.7 µΜ, 1.2 µΜ and 0.4 µΜ.

3. Counted washed and resuspended cells (200,000 cells / well) at 130 µL were added to the wells.

4. Incubate for 45 minutes to one hour at 37 ° C in a 5% saturated water flask.

CO ₂ .

5. R-10 (65 µl) containing 160 ng / ml PMA (Sigma) was added to each well.

501 ·· ·· ·· ·· ·· · 9 · ·

999 999999 99 9

9 9 9 9 9

9999 99 99 99 99 99

6. The assay system was incubated at 37 ° C in 5% CO 2 overnight (18-20 hours) in 100% humidity.

7. Supernatant, 150 µl, was carefully removed from each well for use in the ELIS A assay.

8. For toxicity, a 50 µL aliquot of the working solution containing 5 ml of R-10, 5 ml of MTS solution [CellTiter 96 AQueous One Cell Proliferation Assay Cat. # G358 / 0.1 (Promega Biotech)] and 250 µl of PMS solution were added to each. wells containing the remaining supernatant and the cells and cells were incubated at 37 ° C in 5% CO 2 until color developed. The system is excited at 570 nm and read at 630 nm.

TNF receptor IIELISA

1. 100 µL / well plate of 2 µg / ml murine anti-human TNFrII antiparticles (R&D Systems # MAB226) in 1 x PBS (pH 7.1, Gibco) on a NUNC-Immuno Maxisorb plate. Incubate the plate at 4 ° C overnight (about 18-20 hours).

2. Wash plate with PBS-Tween (1 x PBS h / 0.05% Tween).

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

4. Wash plate with PBS-Tween.

5. Add sample and controls (100 µl each) to each well. Standards are 0, 50, 100, 200, 300 and 500 µg of recombinant human TNFrII (R&D Systems # 222-B2) in 100 µL of 0.5% BSA in PBS. The test is linear with between 400-500 pg standard.

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

7. Wash plate with PBS-Tween.

8. Add 100 µL of goat anti-human TNFrII polyclonal (1.5 µg / ml R&D Systems # AB226PB in 0.5% BSA in PBS).

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

10. Wash plate with PBS-Tween.

11. Add 100 µL anti-goat IgG-peroxidase (1: 50,000 in 0.5% BSA in PBS, Sigma No. A5420).

11. Incubate at 37 ° C in a saturated atmosphere for 1 hour.

12. Wash plate with PBS-Tween.

13. Add 10 µL KPL TMB developer, develop at room temperature (usually about 10 minutes), then quench with phosphoric acid and excite at 450 nm and read at 570 nm.

• 9 • ·

502 ·· · ♦

9 ··· · · 9 9 9 9 9 9 · · 9 9 · 9 999 * 9 9 9 9 9 999 9 9 9 9 9

99 99 9 9999

9999 99 99 99 99 99

TNFα ELISA

Cover Immulon® 2 plates with 0.1 ml / well lug / ml Genzyme mAb in 0.1 M NaHCO3 pH 8.0 buffer overnight (about 18-20 hours) at 4 ° C, packed tightly in a Saran® package.

Discard the covering solution and block the plate with 0.3 ml / well of blocking buffer overnight at 4 ° C, packaged in a Saran® package.

Wash wells 4X thoroughly with washing buffer and completely remove all washing buffer. Add 0.1 ml / well of either samples or rhTNFα standards. Dilute the sample, if necessary, in a suitable diluent (for example, tissue culture medium). Dilute the standard in the same diluent. Standards and samples should be three times.

Incubate at 37 ° C for 1 hour in a humidified container.

Wash plates as above. Add 0.1 ml / well 1: 200 dilution of Genzyme rabbit antihTNFα.

Repeat incubation.

Repeat wash. Add 0.1 ml / well of 1 µg / ml Jackson goat anti-rabbit IgG (H + L) peroxidase.

Incubate at 37 ° C for 30 minutes.

Repeat wash. Add 0.1 ml / well peroxide-ABTS solution.

Incubate at room temperature for 5 to 20 minutes.

Read OD at 405 nm.

Reagents are:

Genzyme mouse anti-human TNF? monoclonal (Cat.No. 80-3399-01)

Genzyme rabbit anti-human TNF? polyclonal (Cat.No. IP-300)

Genzyme of recombinant human TNF? (Cat. No. TNF-H).

Jackson Immunoresearch peroxide-conjugated goat anti-rabbit IgG (H + L) (Cat. No. 111-035144).

Kirkegaard / Perry peroxide ABTS solution (Cat.50-66-01).

Immulon 2 96-well microtiter plates.

The blocking solution is 1 mg / ml gelatin in PBS with 1Xthimerasol.

The wash buffer is 0.5 ml Tween ® 20 in 1 liter PBS.

503 ft

Results:

Example number MTS Toxicity TD _{5 in} micro-moles ŤNFRII Release IC50 in micro-moles TNFα IC ₅ release in micromoles DMSO > 100 > 100 > 100 4 > 100 > 100 > 50 6 > 100 > 100 > 50 9 > 100 > 100 > 50 10 > 100 > 100 > 50 13 > 100 > 100 > 50 27 Mar: 100 ALIGN! > 100 > 80 35 > 100 > 100 > 80 69 100 ALIGN! > 100 > 80 95 > 100 > 100 > 50 379 80 > 100 80

Example 448

Pharmacokinetic (PK) evaluation of MMP inhibitors in rats

Under methophane anesthesia, the femoral artery (all 8 rats) and the femoral vein (only 4 out of 8 rats) were isolated and cannulated with PE50 tubes and secured with 3.0 silk thread. The following assays require two catheters with a venous line used to infuse the compound (in a group of rats receiving the compound by the intravenous (IV) route) and an arterial line used to collect blood samples. The rats are then housed in restraining cages that allow minimal movement and are allowed to recover from anesthesia for about 30 minutes. At time 0 (before dosing), blood samples (400 µL) are taken from the arterial cannula.

One group of rats (4 rats per group) receives the compound via the oral route at a dosing volume of 2 ml / kg (10mg / ml, dissolved in 0.5% methylcellulose, 0.1% Tween® 20), while another group of rats receives the compound via by intravenous cannula at a dosing volume of 2 ml / kg (10 mg / ml, dissolved in 10% EtOH, 50% PEG 400, 40% brine). Blood samples are taken from the arterial cannula at 15, 30, 60, 120, 240 and 360 minutes in the oral group with an additional 3 minute sample taken in the IV group. After each sample, the tubes are rinsed with PBS containing 10 units / ml heparins. The animals were euthanasia ftft. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Anesthetics or carbon monoxide suffocation when the study was terminated at 6 o'clock. A blood sample from each time point was tested for MMP-13 enzyme inhibitory activity and the circulating concentrations of the compound plus the active metabolites were estimated according to a standard curve. Pharmacokinetic (PK) parameters are calculated using the VAX computer program CSTRIP. Parameters are defined in textbooks such as Goodman and Gilman's The Pharmacological Basis Therapeutics, Eighth Edition, McGraw-Hill, Inc., New York (1993) and references therein.

505 ·· ·· · 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9 9 9

9999 99 99 99 99 99

Example number Rat intravenously 20 mpk Rat orally 20 mpk tl / 2 AUC (0-oo) Blood level @ 3 min Crnax AUC (0-6 hrs) BA Blood level @ 6 hr throw. hr * pg / ml pg / ml pg / ml hr * pg / ml % pg / ml

4 1.77 24.80 37.60 1.84 4.14 16.7 0.254 6 1.19 46.39 84.72 22.88 16.45 35.5 0.345 9 1.10 33.67 42.17 13.63 9.43 28.0 0.281 10 0.84 43.01 73.00 18.47 12.93 30.1 0.134 12 0.86 22.11 73.54 1.00 2.45 11.1 0.121 13 1.03 43.08 91.07 21.98 18.08 42.0 0.228 14 1,25 12.92 12.10 4.13 7.66 59.3 0,102 15 Dec 1.01 49.29 120.83 27.16 18.19 36.9 0.192 17 0.74 37.10 63.44 15.72 13.32 35.9 0.135 22nd 1.47 14.05 18.06 0.82 1.82 13.0 0.174 23 0.85 25.01 59,92 7.31 5.93 23.7 0,087 24 2.49 37.35 62.52 9.79 15.88 42.5 0.545 25 - - - 1.48 0.173 26 0.58 17.51 64.01 0.29 0.83 4.7 0.051 27 Mar: 1.10 43.32 43.69 10.87 21.24 49.0 0.427 28 - - - 10,02 24.28 0.537 32 1.03 38.94 51.48 7.65 13.48 34.6 0.529 33 1.91 29.96 24.13 3.33 8.25 27.5 0.543 34 - - - 2.13 0.495 35 - - - 12.59 26.97 1,237 36 0.65 5.74 19.66 0.16 0.73 12.7 0,072 40 - - - 1.55 0,128 42 - - - 0.71 0,036 43 0.82 18.79 61.76 4.17 3.24 17.2 0.040 53 0.97 10.78 31.68 0.37 0.48 4.4 BLD 65 - - - 0.99 0,080 68 - - - 3.41 0,038 69 1.87 63.78 44,00 8.58 22.89 35.9 1,172 70 - - - 3.08 0.131 71 - - - 4.00 0.452 72 - - - 1.42 2.03 0,062 73 - - - 1.89 6.87 0.372 79 1.82 6.11 13.99 0.02 0.07 1.1 0.010 80 - - 40.83 0.03 0.003 81 0.76 38.21 89.01 5.06 6.40 16.7 0,074 89 - - - 1.68 0.196 90 - - - 0.08 0,041 91 - - - 0.17 0.138 93 1.81 13.48 20.88 0.35 1.55 11.5 0,126 94 1.71 25.13 43.37 0.87 1.34 5.3 0.050 95 1.06 19.74 34.71 1.74 4.86 24.6 0.148 96 0.43 0,076

Ft

506 ftft ft ft ftft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft

99 0.68 35.68 99.49 14.25 8.05 22.6 0.071 100 ALIGN! 1.50 24.60 26.06 3.12 11.30 45.9 0.506 103 1.10 19.66 31.11 2.55 0.09 19.9 0.092 104 0.66 9.86 29.82 9.89 4.88 49.4 0.008 108 - - - 2.96 0,108 109 1.12 7.13 13.91 0.93 0.85 11.9 0,027 110 2.67 0.02 0.015 111 0.65 8.49 33.56 0.45 1.11 13.1 0,054 115 1.36 7.81 12.95 1.17 2.00 25.6 0,058 117 0.78 8.69 40.50 0.18 0.28 3.3 0.016 118 1.85 10.97 17.18 0.75 3.32 30.3 0.268 121 - - - 0.31 0,055 123 - - - 1.43 0.017 125 0.73 15.73 25.36 1.11 2.50 15.9 0,119 233 0.85 23.12 31.90 3.33 6.22 26.9 0.584 379 1.74 51.41 37.54 4.30 16.80 32.7 1,154 382 1.71 73.68 48.81 7.27 36.12 49.0 3,113 387 - - - 0.65 0.558 388 0.94 26.10 34.62 0.15 0.68 2.6 0,073 390 1.50 127.63 120.60 23.21 44.20 34.6 1,780 391 1.45 120.92 82.87 24.02 73.24 60.6 2,680 400 104.34 8.55 0.160 408 3.30 25.18 57.40 9.46 4.17 16.6 0.015 410 1.78 29.83 40.08 0.63 2.08 6.7 0.223 414 0.73 26.15 61.89 5.31 6.22 23.8 0,021 416 2.94 230.70 111.17 29.63 156.71 67.9 20.52 418 2.42 209.92 78.55 20.65 77.52 36.9 7,347 421 - - - 13.08 19.21 0,206 427 2.85 36.72 50.74 4.16 8.44 23.0 0.440 437 - - - 4.21 4.43 0,128 438 2.14 9.05 7.46 0.39 1.86 20.6 0.316

·· ··

507 ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · · · ·· ··

Example number Rat 20 mp intravenously C Rat orally 20 mpk tl / 2 AUC (0-oo) Blood level @ 3 min Cmax AUC (0-6hod) BA Blood level @ 6 hr hodi n hr * pg / ml pg / ml pg / ml hr * pg / ml % pg / ml 4 1.77 24.80 37.60 1.84 4.14 16.7 0.254 6 1.19 46.39 84.72 22.88 16.45 35.5 0.345 9 1.10 33.67 42.17 13.63 9.43 28.0 0.281 10 0.84 43.01 73.00 18.47 12.93 30.1 0.134 12 0.86 22.11 73.54 1.00 2.45 11.1 0.121 13 1.03 43.08 91.07 21.98 18.08 42.0 0.228 14 1,25 12.92 12.10 4.13 7.66 59.3 0,102 15 Dec 1.01 49.29 120.83 27.16 18.19 36.9 0.192 17 0.74 37.10 63.44 15.72 13.32 35.9 0.135 22nd 1.47 14.05 18.06 0.82 1.82 13.0 0.174 23 0.85 25.01 59,92 7.31 5.93 23.7 0,087 24 2.49 37.35 62.52 9.79 15.88 42.5 0.545 25 - - - 1.48 0.173 26 0.58 17.51 64.01 0.29 0.83 4.7 0.051 27 Mar: 1.10 43.32 43.69 10.87 21.24 49.0 0.427 28 - - - 10,02 24.28 0.537 32 1.03 38.94 51.48 7.65 13.48 34.6 0.529 33 1.91 29.96 24.13 3.33 8.25 27.5 0.543 34 - - - 2.13 0.495 35 - - - 12.59 26.97 1,237 36 0.65 5.74 19.66 0.16 0.73 12.7 0,072 40 - - - 1.55 0,128 42 - - - 0.71 0,036 43 0.82 18.79 61.76 4.17 3.24 17.2 0.040 53 0.97 10.78 31.68 0.37 0.48 4.4 BLD 65 - - - 0.99 0,080 68 - - - 3.41 0,038 69 1.87 63.78 44,00 8.58 22.89 35.9 1,172 70 - - - 3.08 0.131 71 - - - 4.00 0.452 72 - - - 1.42 2.03 0,062 73 - - - 1.89 6.87 0.372 79 1.82 6.11 13.99 0.02 0.07 1.1 0.010 80 - - 40.83 0.03 0.003 81 0.76 38.21 89.01 5.06 6.40 16.7 0,074 89 - - - 1.68 0.196 90 - - - 0.08 0,041 91 - - - 0.17 0.138 93 1.81 13.48 20.88 0.35 1.55 11.5 0,126 94 1.71 25.13 43.37 0.87 1.34 5.3 0.050 95 1.06 19.74 34.71 1.74 4.86 24.6 0.148 96 0.43 0,076

• • •

508 ·· ··· 4 ·

99 0.68 35.68 99.49 14.25 8.05 22.6 0.071 100 ALIGN! 1.50 24.60 26.06 3.12 11.30 45.9 0.506 103 1.10 19.66 31.11 2.55 0.09 19.9 0.092 104 0.66 9.86 29.82 9.89 4.88 49.4 0.008 108 - - - 2.96 0,108 109 1.12 7.13 13.91 0.93 0.85 11.9 0,027 110 2.67 0.02 0.015 111 0.65 8.49 33.56 0.45 1.11 13.1 0,054 115 1.36 7.81 12.95 1.17 2.00 25.6 0,058 117 0.78 8.69 40.50 0.18 0.28 3.3 0.016 118 1.85 10.97 17.18 0.75 3.32 30.3 0.268 121 - - - 0.31 0,055 123 - - - 1.43 0.017 125 0.73 15.73 25.36 1.11 2.50 15.9 0,119 233 0.85 23.12 31.90 3.33 6.22 26.9 0.584 379 1.74 51.41 37.54 4.30 16.80 32.7 1,154 382 1.71 73.68 48.81 7.27 36.12 49.0 3,113 387 - - - 0.65 0.558 388 0.94 26.10 34.62 0.15 0.68 2.6 0,073 390 1.50 127.63 120.60 23.21 44.20 34.6 1,780 391 1.45 120.92 82.87 24.02 73.24 60.6 2,680 400 104.34 8.55 0.160 408 3.30 25.18 57.40 9.46 4.17 16.6 0.015 410 1.78 29.83 40.08 0.63 2.08 6.7 0.223 414 0.73 26.15 61.89 5.31 6.22 23.8 0,021 416 2.94 230.70 111.17 29.63 156.71 67.9 20.52 418 2.42 209.92 78.55 20.65 77.52 36.9 7,347 421 - - - 13.08 19.21 0,206 427 2.85 36.72 50.74 4.16 8.44 23.0 0.440 437 - - - 4.21 4.43 0,128 438 2.14 9.05 7.46 0.39 1.86 20.6 0.316

It will be apparent from the foregoing that numerous modifications and variations can be made without departing from the scope and scope of the invention. It is to be understood that the invention is not limited to the specific, illustrated examples.

The description is intended to cover all similar modifications in the appended claims.

Claims (141)

PATENT CLAIMS Use of a compound of formula I R 1 and R ² are both hydrido, or R 1 and R ² together with the atoms to which they are attached form a 5- to 8-membered ring containing one, two or three ring heteroatoms which are oxygen, sulfur or nitrogen, R ³ is an optionally substituted aryl or optionally substituted heteroaryl radical and when the aryl or heteroaryl radical is substituted, the substituent is (a) selected from the group consisting of optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy, aralkoxyalkyloxy , aryloxyalkyl, aralkanoylalkyl, araloxyalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylene or a compound of any of the two thioaryl thioaryl groups selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocycloalkyl, and (b) is itself optionally substituted with one or more substituents independently selected from the group consisting of cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethyl hio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, arylkoxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroaralkyl, heteroaralkyl, heteroaralkyl; heteroaryl, arylazo, hydrokarbonylalkoxy, alkoxycarbonyl-alkoxy, alkonoylem, arylcarbonyl, aralkonoylem, alkanoyloxy, aralkonoyloxy, hydroxyalkyl, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyarylem, arylthioalkyl • · thioaryl, aryloxyalkylthioarylem, arylthioalkoxyarylem, hydroxykarbonylalkoxy, hydroxykarbonylalkylthio, alkoxycarbonylalkyl, alkoxy karbonylalkylthio, amino, wherein the amine nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl or (iii) wherein the amine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring containing no to two other heteroatoms, which are nitrogen, oxygen or sulfur, and wherein the ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkonoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzo-linked heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxy-carbonyl, aryloxycarbonyl, benzo-linked heterocycloalkoxy, benzo-linked cycloalkylcarbonyl, heterocycloalkylcarbonyl, and cycloalkylcarbonyl, carbonylamino, wherein the carbonylamino nitrogen is (or) is (or) is (or) with substituted with one or two substituents selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzo-linked heterocycloalkyl, benzo-linked cycloalkyl and a Ν, dis-disubstituted or aminoalkylamino group, and a two-alkyl amino group) attached to form a 5- to 8-membered heterocyclic, heteroaryl or benzo linked heterocycloalkyl ring which is itself unsubstituted or substituted by one or two groups independently selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl, and an amino group wherein the amine nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl and heteroaryl, or (iii) wherein the amine nitrogen and two substituents thereto it is attached to form a 5- to 8-membered heterocyclic or heteroaryl ring, and an aminoalkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and • ··· Or (iii) wherein the amine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring; for the manufacture of a medicament for treating a host mammal having a condition associated with the pathological activity of a matrix metalloprotease comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof in an effective amount to a host mammal having such condition, wherein the matrix metalloprotease inhibitor inhibits the activity of one or more of MMPs -2, MMP-9 and MMP-13, while showing significantly less inhibitory activity against MMP-1. Use according to claim 1, wherein R 1 and R ² together with the atoms to which they are attached form a 5- to 8-membered ring containing one, two or three ring heteroatoms which are oxygen, sulfur or nitrogen. Use according to claim 2, wherein the single-ringed aryl or heteroaryl group, which itself is substituted in the 4-position when it is a 6-membered ring, and in the 3- or 4-position when it is a 5-membered ring, is a substituent selected from the group consisting of one other aryl or heteroaryl group with a single ring, a C3-C44 alkyl group, an N-piperidyl group, an N-piperazinyl group, a phenoxy group, a thiophenoxy group, 4-thiopyridil, phenylazo and benzamino. Use according to claim 3, wherein R 1 contains two or more 5- or 6-membered rings. Use according to claim 3, wherein the group R 1, when rotating about an axis drawn by position 1 associated with SO 2 and position 4 of the 6-membered ring or position 1 associated with SO 2 and 3,4 by a 5-membered ring, defines a three-dimensional a volume whose widest dimension has a width transverse to the axis of rotation of about one furanyl ring to about the width of two phenyl rings. Use according to claim 3, wherein R 1 has a length greater than the pentyl group and a length less than the icosyl group. 4 4 512 4 4 44 4 Use of a compound of formula II wherein R ¹⁴ is hydrido, a pharmaceutically acceptable cation or C (R 1) R a wherein W is O or S and R ¹⁵ is selected from the group consisting of C 1 -C 8 -alkyl, aryl, C 1 -C 8 -alkoxy, heteroaryl-C 1 -C 6 alkyl , C 3 -C 8 -cycloalkyl-C 1 -C 8 -alkyl, aryloxy, ar-C 1 -C 8 -alkoxy, ar-C 1 -C 8 -alkyl, heteroaryl and amino C 1 -C 8 -alkyl, wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, C 1 -C 8 -cycloalkyl-C 1 -C 8 alkyl, ar-C 1 -C 8 -alkoxycarb -nyl, C 1 -C 8 -alkoxycarbonyl and C 1 -C 8 -alkonoyl, or (iii) wherein the amino nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring, m is zero, 1, or 2, n is zero, 1 or 2, p is zero, 1 or 2, the sum of m + η + p = 1,2, 3 or 4, (a) one of X, Y and Z is selected from the group consisting of C (O) , NR ⁶ , O, S, S (O), S (O) 2 and NS (O) ² R ⁷ and the remaining two X, Y and Z are CR ⁸ R ⁹ and CR ⁶ R (1) or (b) X, Y and Z together form a group selected from the group consisting of NR ⁶ C (O), NR ⁶ S (O), NR ⁶ S (O) ₂ , NR ⁶ S, NR ⁶ O, NRS ⁶ (O), SS, NR ⁶ NR ⁶ and OC (O), one of the remaining X, Y and Z being CR ⁸ R ⁹ , or (c) n is zero and X, Y and Z together form a group that is selected from the group consisting of ···· 513 ft where the wavy lines are bonds to the atoms of the indicated ring, R 6 and R 6 are independently selected from the group consisting of hydrido, C 1 -C 8 -alkonoyl, C 8 -C 1 -C 1 -C 8 -alkyl, aroyl, bis (C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl) -C 3 - C 1 -C 6 alkyl, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 perfluoroalkyl, C 1 -C 8 trifluoromethyl-alkyl, C 1 -C 8 perfluoroalkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -fluoromethyl-alkyl; -C8-alkoxy-C1-C8-alkyl, C3-C8-cycloalkyl, C3-C8heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, C8-aryl, C3-C8-heterocyclo, C5-C8-heteroaryl, C8-C8- cycloalkyl-C1-C6-alkyl, C3-aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C8-alkyl; alkyl, C8-arylsulfonyl, C1-C8-alkylsulfonyl, C5-C8-heteroarylsulfonyl, 514 ······ Carboxy-C 1 -C 8 -alkyl, C 1 -C 4 -alkoxycarbonyl-C 1 -C 8 -alkyl, aminocarbonyl, C 1 -C 8 -alkyliminocarbonyl, C 8 -aryliminocarbonyl, C 3 -C 8 -heterocycloiminocarbonyl, C 8 -C 8 -heterocycloiminocarbonyl, C 8 -C 8 -arylthio-C 8 -C 8 - alkyl, C1-C6-alkylthio-C1-C6-alkyl, C1-arylthio-C1-C6-alkenyl, C1-C6-alkylthio-C1-C6-alkenyl, C1-C6-heteroaryl-C1-C6 C 1-4 alkyl, halo-C 1 -C galkonoyl, hydroxy-C 1 -C 8 -alkonoyl, thiol-C 1 -C 8 -alkonoyl, C 3 -C 6 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1-6 -alkyl C 5 -alkoxycarbonyl, aryloxycarbonyl, NR 1 R 1 -C 1 -C 5 -alkylcarbonyl, hydroxy-C 1 -C 8 -alkyl, aminocarbonyl, wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii) is substituted with one or two substituents independently selected from the group C 1 -C 8 -alkyl, ar C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, hydroxyaminocarbonyl, an aminosulfone group, wherein the aminosulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents which j are independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 6 -cycloalkyl and C 1 -C 8 -alkonoyl, amino-C 1 -C 8 -alkylsulfone, wherein the amino-C 1 -C 8 -alkyl the alkylsulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 -alkyl, ar-C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl and C 1 -C 6 -alkonoyl and an amino-C 1 -C 5 -alkyl group wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 -alkyl; alkyl, ar-C 1 -C 8 -alkyl, C 8 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, R? is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 8 -alkyl, C 3 -C 6 -alkenyl, C 8 -C 8 -alkynyl, C 1 -C 6 -carboxyalkyl and C 1 -C 8 -hydroxyalkyl, R 8 and R 10 and R 10 and R 11 are independently selected from the group consisting of hydrido, hydroxy, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, heteroar-C 1 -C 8 -alkyl, C 8 -C 8- alkynyl, C 1 -C 6 -alkenyl, thiol-C 1 -C 6 -alkyl C 1 -C 6 -alkylthio-C 1 -C 6 -alkyl cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, heterocycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkyl -alkoxy-C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyalkylcarbonyl- C 1 -C 8 -alkyl, hydroxycarbonylar-C 1 -C 5 ·· ··· «► · · · · ♦ 515 ···· ♦ · -alkyl, aminocarbonyl-C 1 -C 8 -alkyl, aryloxy-C 1 -C 8 -alkyl, heteroaryloxy-C 1 -C 8 -alkyl, arylthio-C 1 -C 8 -alkyl, heteroarylthio-C 1 -C 8 -alkyl, sulfoxide or sulfone of any of the thio substituents , perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 -C 8 -alkyl, and amino-C 1 -C 8 -alkyl, wherein the amino alkyl nitrogen is (i ) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, cycloalkyl and C 1 -C 8 -alkonoyl, or wherein R ⁸ and R ^9; or R ¹⁰ and R ⁸ and the carbon to which they are attached form a carbonyl group, or wherein R ⁸ and R ⁹ or R ⁹ and r Y or R ⁸ and R ⁹ together with the atoms to which they are attached form a 5- to 8-membered a carbocyclic ring or a 5- to 8-membered heterocyclic ring containing one or two heteroatoms which are nitrogen, oxygen or sulfur, provided that only one of R ⁸ and R ⁹ or R ⁹ and R ¹¹ is hydroxy, R ¹² and R ¹² 'are independently selected from the group consisting of hydrido, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, heteroaralkyl, C 8 -C 8 -alkynyl, C 8 -C 8 -alkenyl, thiol-C 8- C 1 -C 6 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, heterocycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aralkoxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl , C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxyalkylcarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6 -alkyl, aminocarbonyl-C 1 -C 8 -alkyl, aryloxy-C 1 -C 8 -alkyl, heteroaryloxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl, arylthio-C 1 -C 8 -alkyl, heteroarylthio -C 1 -C 8 -alkyl, sulfoxide or sulfone of any of these thio substituents, perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 -C 8 -alkyl , and an amino-C 1 -C 6 alkyl group wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents which are n modifications can be freely selected from the group consisting of Cj-Cg-alkyl hem, ar-C-j-Cg alkyl, cycloalkyl and Cj-Cg-alkonoylem, R 13 j _E is selected from the group consisting of hydrido, benzyl, phenyl, Cj-Cg-alkyl, Cg- C8-alkynyl, C8-C8-alkenyl and C8-C8-hydroxyalkyl, and G-A-R-E-Y is a substituent preferably having a length greater than a pentyl group and a length less than an icosyl group, wherein 516. · · · .. ·: ··· «» ····· ·· G is an aryl or heteroaryl group, A is selected from the group consisting of (1) A (2) -S-, (3) -NR ¹⁷ -, (4) -CO-N (R ⁷ ) or -N (R ⁷ ) -CO-, wherein R 6 ⁷ is hydrogen, C 1 -C 8 -alkyl or phenyl, (S) -CO-O- or -O-CO-, (6) -O-CO-O-, (7) -HN = NH-, (8) -NH-CO-NH-, (9) -C 1 -C-, (10) -NH-CO-O- or O-CO-NH-, (11) -NN-, (12) -NH-CO- NH- and (13) -CS-N (R18) ^_ or -N (R) - C0-, wherein R ^ is hydrogen, C] -Cg-alkyl or phenyl, or (14) a is absent and G is bonded directly na R, R is a group selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, heterocycloalkoxyalkyl, heteroalkylalkyl, heteroaryloxyalkyl, heteroaryloxyalkyl, hetero-aryloxyalkyl, heteroaryloxyalkyl, heteroaryloxy, , the cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1 -C 2 -alkylene- dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino and alkoxycarbonyl and R is other than alkyl or alkoxyalkyl when A is -O- or -S-, 4 4 4 4 · 4 517 «4 · 444 4 · 4 * • 44444 E is selected from the group consisting of (1) -CO-N (R ¹⁹ ) or -N (R ¹⁹ ) -CO-, wherein R ¹⁹ is a heterocycloalkyl or cycloalkyl group, (2) -CONH- or -NHCO-, and (3) ) -CO-, (4) -SO ₂ -NR 19 _{or -R} 19 _-S o _{2 -} (5) -SO ₂ -, (6) -NH-SO ₂ - or -SO ₂ -NH-, or (7) E is absent and R is bound directly to Y, and Y is absent or is selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, arylkoxy, aralkoxy, heteroarylkoxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethyl-alkyl, alkenyl, heterocycloalkyl alkoxycarbonyl and aminoalkyl, wherein the aryl, heteroaryl, or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents selected from the group consisting of alkanoyl, halo, nitro, aralkyl, aryl, alkoxy and amino, wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from hydrido, alkyl and aralkyl; for the manufacture of a medicament for treating a host mammal having a condition associated with the pathological activity of a matrix metalloprotease comprising administering a compound of formula H or a pharmaceutically acceptable salt thereof in an effective amount to a host mammal having such condition, wherein the matrix metalloprotease inhibitor inhibits the activity of one or more of MMPs -2, MMP-9 and MMP-13, while showing significantly less inhibitory activity against MMP-1. Use according to claim 7, wherein the G-A-R-E-Y substituent contains two to four carbocyclic or heterocyclic rings. The use of claim 8, wherein each of the two to four rings is 6-membered. • ft ♦ • ♦ · · · · ·. · ·· · 518 Use according to claim Ί, wherein the G-A-R-E-Y substituent has a length greater than a hexyl group and a length less than a stear group. The use of claim 7, wherein A is -O- or -S-. Use according to claim 7, wherein R is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group. Use according to claim 7, wherein E is absent. Use according to claim 7, wherein Y is selected from the group consisting of hydrido, alkyl, alkoxy, perfluoroalkoxy and perfluoroalkylthio. Use of a compound of the general formula ΠΙ (III) wherein wherein R 1 is an aryl or heteroaryl group with a single ring which is 5- or 6-membered and is itself substituted in its own 4-position when it is a 6-membered ring , and in its 3 or 4 position, when it is a 5-membered ring, a substituent selected from the group consisting of thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoromethoxyphenoxy, 4-trifluoromethylphenoxy, 4- (trifluoromethylthio) phenoxy, 4- (trifluoromethylthio) thiophenoxy, 4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazole-5519 tt); and &quot; &quot; Φ · ··· -yl) oxy, 4- (1H-imidazol-1-yl) phenoxy, 4-chloro-3-methylphenoxy, 3-methylphenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 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-methoxy phenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, and 4-benzyloxyphenoxy, RJ ⁴ is hydrido, a pharmaceutically acceptable cation or C (W) ^R15 where W is O or S and R 15 _{is in} & ybrán from the group consisting of C j lower alkyl, aryl, C j -Cg-alkoxy, heteroaryl-C C1-C6-alkyl, C1-C6-alkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino-C1-C6-alkyl, wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, C 1 -C 8 -cycloalkyl-C 8 -C 8 -alkyl , ar-C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkoxycarbonyl and C 1 -C 8 -alkonoyl, or (iii) wherein the amino C 1 -C 8 -alkyl nitrogen and the two substituents attached thereto form 5- to 8 -membered heterocyclic or heteroaryl ring, m is zero, 1 or 2, n is zero, 1 or 2, p is zero, 1 or 2, the sum of + n + p = 1,2,3 or 4, (a) one of X , Y and Z are selected from the group consisting of C (O), NR 4, O, S, S (O), S (O) 2, and NS (O) ₂ R ^7, and the remaining two X, Y and Z are CR ⁸ R ⁹ and CR ¹⁰ R ^n, or (b) X and Z, Y and Z together form a group that is selected from the group consisting of NR ^ C (O) NR ⁶ S (O) NR ⁶ S (O ) _2, NR ⁶ S, NR ⁶ O, NRS ⁶ (O), SS, NR ⁶ NR ⁶ and OC (O), one of the remaining X, Y and Z form a CR ⁸ R ^9, or (c) n is zero and X, Y and Z together form a group selected from the group consisting of wherein the wavy lines are bonds to the atoms of the indicated ring, R 6 and R 6 are independently selected from the group consisting of hydrido, C 1 -C 8 -alkonoyl, C 8 -C 8 -aryl-C 1 -C 8 -alkyl, aroyl, bis (C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl) - C 1 -C 8 -alkyl, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -fluoroalkyl, C 1 -C 8 -trifluoromethyl-alkyl, C 1 -C 8 -fluoroalkoxy-C 1 -C 8 -alkyl, C 1 -C 8- alkoxy-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, C 8 -C 8 -heterocycloalkylcarbonyl, C 8 -C 8 -aryl, C 8 -C 8 -heterocyclo, C 5 -C 8 -heteroaryl, C 3 -C 8 -cycloalkyl -C 1 -C 8 -alkyl, C 8 -C aryloxy-C 1 -C 8 -alkyl, heteroaryl-oxy-C 1 -C 8 -alkyl, heteroaryl-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, heteroarylthio-C 1 -C 8 -alkyl -alkyl, C8-arylsulfonyl, C1-C8-alkylsulfonyl, C8-C8; 521 «· 1 1 1 521 1 1 1 1 1 1 1 1 1 -heteroarylsulfonyl, carboxy-C 1 -C 8 -alkyl, C 1 -C 2 -alkoxycarbonyl-C 1 -C 8 -alkyl, aminocarbonyl, C 1 -C 8 -alkyliminocarbonyl, C 8 -aryliminocarbonyl, C 8 -C 8 -heterocycloiminocarbonyl, C 8 -arythio-C 8 -C8-alkyl, C1-C6-alkylthio-C1-C6-alkyl, C8-arylthio-C3-C6-alkenyl, C1-C6-alkylthio-C3-C6-alkynyl, C5-C6-heteroaryl-C C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkonoyl, hydroxy-C 1 -C 8 -alkonoyl, thiol-C 1 -C 8 -alkonoyl, CYC 8 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 8 -alkoxy-C 8 -C 8 -alkyl, C 1 -C 8 -alkoxycarbonyl, aryloxycarbonyl, C 1 -C 8 -C 1 -C 8 -alkylcarbonyl, hydroxy-C 1 -C 8 -alkyl, aminocarbonyl, wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii) is substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, hydroxyaminocarbonyl, amino sulfone, wherein the aminosulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two subs substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 8 -C 8 -cycloalkyl, and C 1 -C 8 -alkonoyl, amino-C 1 -C 8 -alkylsulfone, wherein the amino C 1 -C 8 -alkylsulfone; The C8-alkylsulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, C1-C6-cycloalkyl and C1-C6 -alkonoyl, and amino-C 1 -C 8 -alkyl, wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 - alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, R 6 is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 8 -alkyl, C 3 -C 8 -alkynyl, C 3 -C 8 -alkenyl, C 1 -C 8 -carboxyalkyl and hydroxy-C 1 -C 8 -alkyl, R 1 and R 1 and R 1 and R 1 are independently selected from the group consisting of hydrido, hydroxy, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, hetero-C 1 -C 8 -alkyl, C 2 -C 8 -alkyl; C8-alkynyl, C2-C8-alkenyl, thiol-C8-C8-alkylC1-C8-alkylthio-C8-C8-alkylcycloalkyl, cycloalkyl-C8-C8-alkyl, heterocycloalkyl-C8-C8-alkyl, C8-C8- alkoxy-C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxy-alkylcarbonyl -C4-C8-alkyl, hydroxycarbonyl522, 44444, 444, 444-4, ar-C1-C6-alkyl, aminocarbones, C1-C6-alkyl, aryloxy-C C 1 -C 8 -alkyl, heteroaryloxy-C 1 -C 8 -alkyl, arylthio-C 1 -C 8 -alkyl, heteroarylthio-C 1 -C 8 -alkyl, sulfoxide or sulfone of any of these thio substituents, perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 -C 8 -alkyl and amino-C 1 -C 8 -alkyl, wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted; or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, cycloalkyl and C 1 -C 8 -alkonoyl, or wherein a R ⁹ or I ⁹ and iA and carbon to which they are attached form a carbonyl group, or wherein a R ⁹ or R ⁹ , and R ⁸ or R ⁹ together with the atoms to which they are attached form A 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring containing one or two heteroatoms which are nitrogen, oxygen or sulfur, provided that only one of R 8 and R ⁹ or R ⁹ and R ^{3 is} is hydroxy, R ¹² and R ¹² 'are independently selected from the group consisting of hydrido, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, heteroaralkyl, C 2 -C 8 -alkynyl, C ₂ -C 8 -alkenyl, thiol- C 1 -C 8 -alkyl, cycloalkyl, cycloalkyl 1-C 1 -C 8 -alkyl, heterocycloalkyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl -alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl; -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyalkylcarbonyl-C 1 -C 8 -alkyl, hydroxycarbonylar-C 1 -C 8 -alkyl, aminocarbones C 1 -C 8 -alkyl, aryloxy-C 1 -C 8 -alkyl , heteroaryl-oxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, sulfoxide or sulfone of any of these thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein amino-C The i-C8-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of a C1-C8-alkyl, ar-C1-C8-alkyl, cycloalkyl and C1-C8- alkonoylem _r 13 j _e is selected from the group consisting of hydrido, benzyl, phenyl, Cj-Cg-alkyl, C ₂ -Cg alkynyl, C ₂ -Cg alkenyl, and C-j -Cg-hydroxyalkyl group; for the manufacture of a medicament for the treatment of a host mammal having a condition associated with the pathological activity of a matrix metalloprotease, which comprises administering a compound of the formula Ι ft ft ft ft ft ft ft ft ft 523 or a pharmaceutically acceptable salt thereof, in an effective amount to a host mammal having such a condition, wherein the matrix metalloprotease inhibitor inhibits the activity of one or more of MMP-2, MMP-9 and MMP-13 while exhibiting substantially less inhibitory activity against MMP-1. Use according to claim 15, wherein the sum of m + η + ρ = 1 or 2. Use according to claim 15, wherein Z is O, S or NR ⁶ Use according to claim 15, wherein it is selected from the group consisting of C 3 -C 5 cycloalkyl, (4-C 8 -alkyl, C 3 -C 8 -alkenyl, C 1 -C 8 -alkynyl, C 1 -C 8 -alkoxy-C 1 -C 8 alkyl, amino-C 8 -alkyl). -C 8 -alkyl, aminosulfonyl, heteroaryl-C 1 -C 8 -alkyl, aryloxycarbonyl and C 1 -C 8 -alkoxycarbonyl. Use according to claim 15, wherein m = n - zero, ρ = 1 and Y is NRC Use of a compound of formula IV R 6 is an optionally substituted aryl or optionally substituted heteroaryl group, and when the aryl or heteroaryl group is substituted, the contemplated substituent is (a) selected from the group consisting of optionally substituted cycloalkyl, heterocycloalkyl, aryl, 524 heteroaryl, aralkyl, heteroaralkyl, aryloxy, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl , aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, arylthio-aralkyl, aralkylthioalkyl, aralkylthioaryl, sulfoxide or sulfone of any of the thio substituents and the structure of the linked rings containing two or more 5- or 6-membered rings , heteroaryl, cycloalkyl and heterocycloalkyl, and (b) is itself optionally substituted with one or more substituents independently selected from the group consisting of cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, arylkoxycarbonyl, hydroxy, halo, , alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, aryl thio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heteroarylamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, alkoxy, aralkyloxy, aralkylamino, heterocyclo, aralkylamino, heterocycloalkyl, aralkyloxy, heterocyclooxy, arylcarbonyl, aralkonoyl, alkanoyloxy, aralkonoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, hydroxycarbonylalkoxy, hydroxycarbonylalkoxy, hydroxycarbonylalkoxy, ii) substituted with one or two substituents attached thereto, which are independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkonoyl, heteroaryl-carb or (iii) wherein the amine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring containing no to two heteroatoms, which are nitrogen, oxygen or sulfur, and wherein the ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkonoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzo linked heterocycloalkyl, , aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzo-linked heterocycloalkoxy, benzo-linked cycloalkylcarbonyl, heterocycloalkylcarbonyl, and cycloalkylcarbonyl, carbonylamino, rt · »· · ··· 525 o wherein the carbonylamino nitrogen is (i) unsubstituted or (ii) is a reacted amino acid amine or (iii) is substituted with one or two substituents independently selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzo-linked heterocycloalkyl, benzo-linked cycloalkyl and a Ν, dis-disubstituted aminoalkyl substituent, or (iv) a carboxyl group; form a 5- to 8-membered heterocyclic, heteroaryl or benzo linked heterocycloalkyl ring which is itself unsubstituted or substituted by one or two groups independently selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl, and an amino group wherein the amine nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl and heteroaryl, or (iii) wherein the amino nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring, and an aminoalkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkonoyl, or (iii) wherein the amine nitrogen and the two substituents attached thereto form 5- a to 8-membered heterocyclic or heteroaryl ring; and Z is selected from the group consisting of O, S, NR ⁶ , SO, SO 2 and NSO 2 R a wherein R ⁶ is selected from the group consisting of hydrido, C 1 -C 5 -alkyl, C 1 -C 5 -alkonoyl, benzyl, benzoyl, C 3 -C 5 - alkynyl, C 3 -C 5 -alkenyl, C 1 -C 3 -alkoxy-C 1 -C 4 -alkyl, C 3 -C 8 -cycloalkyl, heteroaryl-C 1 -C 8 -alkyl, C 1 -C 5 -hydroxyalkyl, C 1 -C 5- carboxyalkyl, C1-C5-alkoxy, Cj-Cg-alkylcarbonyl, CR ⁸ R ^9, -C] -C5 -alkylcarbonyl or CR ⁸ R ⁹ -C j-Cg-alkyl where ^R8 and ^R9 are independently hydrido, C-C5- alkyl, C 1 -C 5 -alkoxycarbonyl, or aryl-C 1 -C 8 -alkoxycarbonyl, or CR ⁸ R ⁹ together form a heterocyclic ring containing 5- to 8-ring atoms and · · · · · ··· · ··· · ft 526 R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, (4-C 8 -alkyl, C 8 -C 8 -alkynyl, C 3 -C 8 -alkenyl, C 1 -C 8 -carboxyalkyl and C 1 -C 8 -hydroxyalkyl; for the manufacture of a medicament for treating a host mammal having a condition associated with the pathological activity of a matrix metalloprotease comprising administering a compound of formula IV or a pharmaceutically acceptable salt thereof in an effective amount to a host mammal having such condition, wherein the matrix metalloprotease inhibitor inhibits the activity of one or more of MMPs -2, MMP-9 and MMP-13, while showing significantly less inhibitory activity against MMP-1. The use of claim 20, wherein R 6 is a single or single-ring aryl or heteroaryl group that is 5- or 6-membered and which is itself substituted in its own 4-position when it is a 6-membered ring, and in its 3- or 4- position, when it is a 5-membered ring, a substituent selected from the group consisting of one other aryl or heteroaryl group with a single ring, a C3-C14 alkyl group, an N-piperidyl group, an N-piperazine group, a phenoxy group, thiophenoxy 4-thiopyridil, phenylazo and benzamino. The use of claim 20, wherein the length is greater than the pentyl group and the length is less than the icosyl group. The use of claim 20, wherein Z is O, S or NR 6 The use according to claim 23, wherein R 1 is selected from the group consisting of C 3 -C 8 -cycloalkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkyl, C 3 -C 8 -alkenyl, C 3 -C 8- alkynyl, amino-C 1 -C 8 -alkyl, amino sulfonyl, heteroaryl-C 1 -C 8 -alkyl, aryloxycarbonyl and C 1 -C 8 -alkoxycarbonyl. The use of claim 20, wherein R 1 is G-A-R-E-Y, wherein G is an aryl or heteroaryl group, A is selected from the group consisting of (1) -o-, (2) -S-, 527 (3) -NR ¹⁷ -, (4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO-, wherein R ¹⁷ is hydrogen, C 1 -C 6 -alkyl or phenyl, (5) -CO-O- or -O-CO-, (6) -O-CO-O-, (7) -HN = NH-, (8) -NH-CO-NH-, (9) -GC-, (10) -NH-CO-O- or O-CO-NH-, (11) -N = N-, (12) -NH-CO-NH- and (13) -CS-N (R ¹⁸⁾ - or -N (R ¹⁸ ) -CO-, wherein R ¹⁸ is hydrogen, C 1 -C 4 alkyl or phenyl, or (14) A is absent and G is directly attached to R ¹⁸ , R is a group selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, heterocycloalthioalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroaryl, the aryl, heteroaryl, cycloalkyl or hetero-cycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1-6 -C8-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino and alkoxycarbonyl and R is other than alkyl or alkoxyalkyl when A is -O- or -S-, E is selected from the group consisting of (1) -CO-N (R 6) or -N (R 6) -CO-, wherein R 6 is a heterocycloalkyl or cycloalkyl group, (2) -CONH- or -NHCO-, and ( (3) -CO-, (4) -SO ₂ -NR ¹⁹ or -R ¹⁹ -SO ₂ -, (5) -SO ₂ -, (6) -NH-SO ₂ - or -SO ₂ -NH-, or (7) E is absent and R is directly attached to Y, and Y is absent or is selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, arylkoxy, aralkoxy, heteroarylkoxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, cyclohexyl, heterocycloalkylethyl, heterocycloalkyl an aminoalkyl group wherein the aryl, heteroaryl, or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents selected from the group consisting of alkanoyl, halo, nitro, aralkyl, aryl, alkoxy and an amino group wherein the amine nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from hydrido, alkyl and aralkyl. The use of claim 25, wherein the G-A-R-E-Y substituent comprises two to four carbocyclic or heterocyclic rings. The use of claim 26, wherein each of the two to four rings is 6-membered. Use according to claim 25, wherein the substituent G-A-R-E-Y has a length greater than a hexyl group and a length less than a stearyl group. The use of claim 25, wherein A is -O- or -S-. The use of claim 25, wherein R is aryl, heteroaryl, cycloalkyl or heterocycloalkyl. Use according to claim 25, wherein E is absent. The use of claim 25, wherein Y is selected from the group consisting of hydrido, alkyl, alkoxy, perfluoroalkoxy and perfluoroalkylthio. The use of claim 20, wherein R 6 is a group consisting of an aryl or heteroaryl group with a single ring that is 5- or 6-membered and is itself substituted in its own 4-position when it is 6- a 3-membered ring, and in its 3- or 4-position, when it is a 5-membered ring, a substituent selected from the group consisting of thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3, 4-dimethylphenoxy, 4-fluorophenoxy, 4-trifluoromethylphenoxy, 4 (trifluoromethylthio) phenoxy, 4- (trifluoromethylthio) thiophenoxy, 4-chloro-3- fluorophenoxy, 4isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5-yl) oxy, 4- (1H-imidazol-yl) phenoxy, 4-chloro-3-methylphenoxy, 3-methylphenoxy, 4- ethoxyphenoxy, 3,4-difluorophenoxy, 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, 4fe nylphenoxy, 4-benzylphenoxy, 6-quinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, N-piperidyl, N-piperazinyl and 4-benzyloxyphenoxy . Use according to claim 20, wherein the inhibitor corresponds to the structure of the formula Z is O, or NR ⁶ , W and Q are independently oxygen (O), NR ⁶ or sulfur (S), R ⁶ is selected from the group consisting of C 3 -C 8 -cycloalkyl, C 1 -C 8 -alkyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino-C 1 -C 8 - alkyl, aminosulfonyl, heteroaryl-C 1 -C 8 -alkyl, aryloxycarbonyl, and C 1 -C 8 -alkoxycarbonyl, and 530 • · · ftft · Ft q is zero or one, so when q is zero, Q is absent and the trifluoroalkyl group is attached directly to the phenyl ring shown; for the manufacture of a medicament for treating a host mammal having a condition associated with the pathological activity of a matrix metalloprotease comprising administering a compound of Formula V or a pharmaceutically acceptable salt thereof in an effective amount to a host mammal having such condition, wherein the matrix metalloprotease inhibitor inhibits the activity of one or more MMPs -2, MMP-9 and MMP-13, while showing significantly less inhibitory activity against MMP-1. The use of claim 35, wherein q is zero. The use of claim 35, wherein W is O. The use of claim 37, wherein q is zero. The use of claim 37, wherein q is one and Q is O. The use of claim 37, wherein q is one and Q is S. Use according to claim 35, wherein the inhibitor corresponds to the structure of the formula The use of claim 35, wherein the inhibitor corresponds to the structure of the formula 531 ······ · «· ··· 9 999 9 9 • 9 9 9 9999999 9 Use according to claim 35, wherein the inhibitor corresponds to the structure of the formula Use according to claim 35, wherein the inhibitor corresponds to the structure of the formula Use according to claim 35, wherein the inhibitor corresponds to the structure of the formula The use according to claim 35, wherein the inhibitor corresponds to the structure of the formula: - ftftft - ftftft 532 • ft The use of claim 35, wherein the inhibitor corresponds to the structure of the formula The use of claim 35, wherein the inhibitor corresponds to the structure of the formula The use of claim 35, wherein the inhibitor corresponds to the structure of the formula The use of claim 35, wherein the inhibitor corresponds to the structure of the formula HOHN SCF ₃ O '· · · · ···· · 533 ··· ······························ Use according to claim 35, wherein the inhibitor corresponds to the structure of the formula 52. A compound corresponding in structure to formula II, _{(CH2) n} -Z ^ / V ₁₄ (CH _{2) r} R ¹⁴ O — HN. X \ / (CH ₂ ) _p , G — AREY SCX (II) where R ¹⁴ is hydrido, a pharmaceutically acceptable cation or C (W) R 6, wherein W is O or S and R ¹⁵ is selected from the group consisting of C 1 -C 8 -alkyl, aryl, C 1 -C 8 -alkoxy, heteroaryl-C 1 -C 8 - alkyl, C 1 -C 8 -cycloalkyl-C 1 -C 8 -alkyl, aryloxy, ar-C 1 -C 8 -alkoxy, heteroaryl and amino C 1 -C 8 -alkyl, wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, C 1 -C 8 -cycloalkyl-C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkoxycarbonyl and CpC 8 -alkonoyl groups, or (iii) wherein the amino C 1 -C 8 -alkyl nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring, m is zero, 1 or 2, n is zero, 1 or 2, p is zero, 1 or 2, the sum of m + n + p = 1, 2, 3 or 4, 534 ·· 99 ··· 99 · · · 9 9 99 99 9 99 (a) one of X, Y, and Z is selected from the group consisting of C (O), NR ⁹ , O, S, S (O), S (O) ₂ and NS (O) ₂ R ⁷ and the remaining two X, Y and Z are CR ⁸ R ⁹ and CR 4 R ^1!, or (b) X, Y and Z together form a group that is selected from the group consisting of NR ⁹ C (O) NR ⁹ S (O) NR ⁹ S (O) ₂ NR ⁹ S, NR ⁹ O, NRS ⁹ (O), SS, NR ⁶ NR ⁹ and OC (O), one of the remaining X, Y and Z being CR ⁸ R ⁹ , or (c) n is zero and X, Y and Z together form a group, which is selected from the group consisting of wherein the wavy lines are bonds to atoms of the indicated ring, 535 · · · ♦ R R R R R R R R a R a R R R R a a a a a R 4 are independently selected from the group consisting of hydrido, C 1 -C 8 -alkonoyl, C 8 -C aryl -C 1 -C 8 -alkyl, aroyl, bis (C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl) -C 1 -C 8 -alkyl, C 1 -C 6 alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -perfluoroalkyl, C 1 -C 8 -trifluoromethylalkyl, C 1 -C 8 -perfluoroalkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, C 3 -C 8- cycloalkyl, (4-64heterocycloalkyl, C 3 -C 8 -heterocycloalkylcarbonyl, C 8 -C 8 -alkyl, C 8 -C 8 -heterocyclo, C 5 -C 8 -heteroaryl, C 8 -C 8 -cycloalkyl-C 8 -C 8 -alkyl, C 8 -aryloxy-C 8 -C 8 -alkyl, heteroaryloxy-C 1 -C 8 -alkyl, heteroaryl-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, heteroarylthio-C 1 -C 8 -alkyl, C 8 -arylsulfonyl, C 1 -C 8 -alkyl 1 sulfonyl, C 1 -C 8 -heteroarylsulfonyl, carboxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxycarbonyl-C 1 -C 8 -alkyl, aminocarbonyl, C 1 -C 8 -alkyliminocarbonyl, C 8 -aryliminocarbonyl, C 8 -C 8 -heterocycloiminocarbonyl, C 8 -C 13 arylthio C8-alkyl, C] -C 8 -alkylthio-C 1 -C 8 -alkyl, C 8-arylthio-C 3 -C 8 -alkenyl, C 1 -C 4 -alkylthio-C 3 -C 8 -alkynyl, C 5 -C 8 -heteroaryl-C 1 -C 8 -alkyl, halo- C 1 -C 8 -alkonoyl, hydroxy-C 1 -C 8 -alkonoyl, thiol-C 1 -C 8 -alkonoyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 - C 5 -alkoxycarbonyl, aryloxycarbonyl, CR ⁸ R ⁹ -C 1 -C 5 -alkylcarbonyl, hydroxy-C 1 -C 8 -alkyl, aminocarbonyl, wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii) is substituted with one or two substituents independently selected from the group C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, hydroxy-aminocarbonyl, aminosulfone, wherein the aminosulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, amino-C 1 -C 8 -alkyl sulfone, wherein the amino- C 1 -C 8 alkylsulfones nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, and amino-C 1 -C 8 -alkyl, wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, ar-C C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl; 536 ·· ···· * φ φ • • •>>>> φ φ R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 8 -alkyl, C 3 -C 8 -alkynyl, C 3 -C 8 -alkenyl, C 1 -C 8 -carboxyalkyl and C 1 -C 8 -hydroxyalkyl, R ⁸ and R ⁹ and R ¹⁰ and R 11 are independently selected from the group consisting of hydrido, hydroxy, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, hetero-C 1 -C 8 -alkyl, C 2 -C 8 alkynyl, C 2 -C 8 -alkenyl, thiol-C 1 -C 8 -alkyl, C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, heterocycloalkyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkyl -alkoxy C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyalkylcarbonyl- C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio -C 1 -C 8 -alkyl, sulfoxide or sulfone of any of these thio substituents, perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 6 alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 -C 8 -alkyl and amino -C 1 -C 6 alkyl, wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents which are independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, cycloalkyl and C 1 -C 8 -alkonoyl, or wherein R ⁸ and R ⁹ or R ⁹ and R ⁹ and R ⁶ and the carbon to which they are attached form a carbonyl or wherein R ⁸ and R ⁹ or ΐθθ and R ⁸ or R ⁸ and R ⁹ together with the atoms to which they are attached form a 5 to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring containing one or two heteroatoms which are nitrogen, oxygen or sulfur, provided that only one of R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ is hydroxy, R 12 and R ¹² 'are independently selected from the group consisting of hydrido, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, heteroaralkyl, C 2 -C 8 -alkynyl, C 2 -C 8 -alkenyl, thiol-C] -C 8 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, heterocycloalkyl-C 1 -C 6 alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, amino-C 1 - C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyalkylcarbonylC 1 -C 8 -alkyl, hydroxycarbonylar-C 1 -C 8 -alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C 1 -C 8 -alkyl, sulfoxide or sulfone * · 537 ·· ···· this · to · to to · · ··· · · · ·> * To any of these thio substituents, perfluoro-C 1 -C 6 -alkyl, trifluoromethyl-C 1 -C 6 -alkyl, halo -C 1 -C 8 -alkyl, alkoxycarbones of lamino-C 1 -C 8 -alkyl and amino-C 1 -C 6 -alkyl, wherein the amino C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of Cj-Cg-alkyl, Ar-C-j-Cg alkyl, cycloalkyl and Cj-Cg-alkonoylem r! _e j 3 selected from the group consisting of hydrido, benzyl, phenyl, C jC ^ -alkyl, C2Cg- alkynyl, C 1 -C 4 -alkenyl and C 1 -C 8 -hydroxyalkyl, and G-A-R-E-Y is a substituent having a length greater than a pentyl group and a length less than an icosyl group, and wherein G is an aryl or heteroaryl group, A is selected from the group consisting of (DO-, (2) -S-, (3) -NR ¹⁷ -, (4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO-, wherein R ¹⁷ is hydrogen, C 8 -C 8 -alkyl or phenyl, (S) -CO-O- or -O-CO-, (6) -O-CO-O-, (7) -HN = NH-, (8) - NH-CO-NH-, (9) -C = C-, (10) -NH-CO-O- or O-CO-NH-, (11) -N = N-, (12) -NH-CO. -NH- and (13) -CS-N (R ¹⁸ ) - or -N (R ¹⁸ ) -CS-, wherein R ¹⁸ is hydrogen, C 1 -C 6 -alkyl or phenyl, or (14) A is absent and G is bound directly to R, R is a group selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, 538 • ··· ·· ·; Heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyoxyalkyl, arylthioalkyl, heteroarylthioalkylalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl, cycloalkylthioalkyl; , the heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1 -C 2 -alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino and alkoxycarbonyl and R is other than alkyl or alkoxyalkyl when A is -O- or -S-, E is selected from the group consisting of (1) -CO-N (R ^{9 9} ) or -N (R ^{9 9} ) -CO-, wherein the IC ⁹ is a heterocycloalkyl or cycloalkyl group, (2) -CONH- or -NHCO-, and (3) -CO-, (4) -SO ₂ -NR ¹⁹ or -R ¹⁹ -SO ₂ -, (5) -SO ₂ -, (6) -NH-SO ₂ - or -SO ₂ -NH- or (7) E is absent and R is bound directly to Y and Y is absent or selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, arylkoxy, aralkoxy, heteroarylkoxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, alkoxy, heterocycloalkylethyl, heterocycloalkyl wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkanoyl, halo, nitro, aralkyl, aryl, alkoxy and an amino group wherein the amine nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from hydrido, alkyl and aralkyl. · ♦ _{M M M M M M M M M M} .. _{M M M M} The compound of claim 52, wherein the G-A-R-E-Y substituent contains two to four carbocyclic or heterocyclic rings. 539 The compound of claim 52, wherein each of the two to four rings is 6-membered. The compound of claim 52, wherein the G-A-R-E-Y substituent has a length greater than a hexyl group and a length less than a stearyl group. The compound of claim 52, wherein A is -O- or -S-. 57. A compound according to claim 52 wherein R is aryl, heteroaryl, cycloalkyl or heterocycloalkyl. The compound of claim 52, wherein E is absent. The compound of claim 52, wherein Y is selected from the group consisting of hydrido, alkyl, alkoxy, perfluoroalkoxy and perfluoroalkylthio. The compound of claim 52, wherein R 1 is hydrido. The compound of claim 52, wherein W of C (W) R 6 is O and R 6 is alkyl, aryl, C 1 -C 8 -alkoxy, heteroaryl-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl-C 1 -C 8 alkyl 1 or aryloxy. 62. A compound corresponding to the structure of the general formula ΠΙ ^ below} or a pharmaceutically acceptable salt thereof 540 (ΠΙ) wherein where R 6 is an aryl or heteroaryl group with a single ring which is 5- or 6-membered and is itself substituted in its own 4-position when it is a 6-membered ring, and in its 3 or 4-position, when it is a 5-membered ring, a substituent selected from the group consisting of thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophenoxy, phenoxy, 4 -trifluoromethoxyphenoxy, 4-trifluoromethylphenoxy, 4- (trifluoromethylthio) -phenoxy, 4- (trifluoromethylthio) -thiophenoxy, 4chlor-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5yljoxy, 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, 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 4-benzyloxyphenoxy, RL4 is hydrido, a pharmaceutically acceptable cation or C (W) Rl5, wherein W is O or S and R 15 j _E is selected from the group consisting of Cj-Cg alkyl, aryl, Cj-Cg-alkoxy, heteroaryl-C] -alkyl, C3 -C 8 -alkyl-C 1 -C 8 -alkyl, aryloxy, ar-C 1 -C 8 -alkoxy, ar-C 1 -C 8 -alkyl, heteroaryl and amino-C 1 -C 8 -alkyl, wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, C 1 -C 8 -cycloalkyl-C 1 -C 6 alkyl, ar-C 1 -C 8 -alkoxycarb -nyl, C 1 -C 8 -alkoxycarbonyl and C 1 -C 8 -alkonoyl, or (iii) wherein the amino C 1 -C 8 -alkyl nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring, m is zero, 1 or 2, · »· · 541 n is zero, 1 or 2, p is zero, 1 or 2, the sum of + n + p = 1,2, 3 or 4, (a) one of X, Y and Z is selected from the group consisting of C (O), NR ⁹ , O, S, S (O), S (O) ₂ and NS (O) ₂ R ⁷ and the remaining two X, Y and Z are CR ⁸ R ⁹ and CR ⁹ R 8, or (b) X, Y and Z together form a group selected from the group consisting of NR ⁹ C (O), NR ⁶ S (O), NR ⁶ S (O) ₂ , NR ⁶ S, NR ⁶ O, NRS ⁶ (O) , SS, NR ⁹ NR ⁹ and OC (O), one of the remaining X, Y and Z being CR ⁸ R ⁹ , or (c) n is zero and X, Y and Z together form a group selected from the group consisting of · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 542 o I ^R kX NO Xy 1 N <X N '12 R ¹² ' x '12 R ¹² '. Yippee R ¹² R ¹² ' K ¹³ K ¹³ v '13 R ¹³ \ / N X ' ^and x' lY N where the wavy lines are bonds to the atoms of the indicated circle, R ⁶ and R ⁶ 'are independently selected from the group consisting of hydrido, C 1 -C 8 -alkonoyl, C 8 -C 1 -C 8 -alkyl, aroyl, bis (C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl) -C 8 -C8-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethyl, C1-C6perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1- C8-alkyl, (C8-C8-cycloalkyl, C8-C8-heterocycloalkyl, C8-C8-heterocycloalkylcarbonyl, C8-aryl, C8-C8-heterocyclo, C8-C8-heteroalkyl, C3-C8-cycloalkyl-C1-C8 -alkyl, C1-C6-aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-arylsulfonyl , C 1 -C 8 -alkylsulfonyl, C 1 -C 8 -heteroarylsulfonyl, carboxy-C 1 -C 8 -alkyl, C 1 -C 4 -alkoxycarbonyl-C 1 -C 8 -alkyl, aminocarbonyl, C 1 -C 8 -alkyliminocarbonyl, C 8 -aryliminocarbonyl, C8-C8-heterocycloiminocarbonyl, C8-arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, C8-arylthio-C8-C6-alkenyl, C1-C4-alkylthio-C3-C8- alkynyl, C8-C8-heteroa alkyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -convinyl, hydroxy-C 1 -C 8 -alkonoyl, thiol-C 1 -C 8 -alkonoyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C ⁸ -alkoxycarbonyl, aryloxycarbonyl, CR ⁸ R ⁹ -C 1 -C 8 -alkylcarbonyl, hydroxy-C 1 -C 8 -alkyl, aminocarbonyl, wherein the aminocarbonyl nitrogen is (i) unsubstituted or ( ii) is substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, hydroxyaminocarbonyl, 9 9 345 an aminosulfone group wherein the aminosulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 - alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, amino-C 1 -C 8 -alkylsulfone, wherein the amino-C 1 -C 8 -alkylsulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 cycloalkyl and C 1 -C 8 -alkonoyl, and amino-C 1 -C 8 - an alkyl group wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8- cycloalkyl and C 1 -C 8 -alkonoyl group, R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 8 -alkyl, C 3 -C 8 -alkynyl, C 3 -C 8 -alkenyl, C 1 -C 8 -carboxyalkyl and hydroxy-C 1 -C 8 -alkyl, R ⁸ and R ⁹ and R ⁸ and R ⁸ are independently selected from the group consisting of hydrido, hydroxy, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, hetero-C 1 -C 8 -alkyl, C ₂ -C 8 -alkyl -alkynyl, C ₂ -C 8 -alkenyl, thiol-C 1 -C 8 -alkyl C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl 1 cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, heterocycloalkyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkyl, C8-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxy -alkylcarbonyl-C 1 -C 8 -alkyl, hydroxycarbonylar-C 1 -C 8 -alkyl, aminocarbonyl-C 1 -C 8 -alkyl, aryloxy-C 1 -C 8 -alkyl, heteroaryloxy-C 1 -C 8 -alkyl, arylthio-C 1 -C 8 -alkyl -alkyl, heteroarylthio-C 1 -C 8 -alkyl, sulfoxide or sulfone of any of these thio substituents, perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 -C 8 - alkyl and amino-C 1 -C 8 -alkyl, wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents which are independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, cycloalkyl and C 1 -C 8 -alkonoyl, or wherein R ⁸ and R ⁹ or A and IR and the carbon to which they are attached form a carbonyl group or wherein R ⁸ and R ⁹ or R ¹⁰ and R ¹ U or ^R8 and ^R10 together with the atoms to which they are attached form a 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring containing one Or two heteroatoms which are nitrogen, oxygen or sulfur, with the proviso that only one of R 8 and R 9 or R 11 and R 11 is hydroxy, R ¹² and R ¹² 'are independently selected from the group consisting of hydrido, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, heteroaralkyl, C 8 -C 8 -alkynyl, C 8 -C 8 -alkenyl, thiol- C 1 -C 8 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, heterocycloalkyl C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, amino -C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxycarbonyl-C 1 -C 8 -alkyl, hydroxycarbonylar-C C 1 -C 8 -alkyl, aminocarbonyl-C 1 -C 8 -alkyl, aryloxy-C 1 -C 8 -alkyl, heteroaryloxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl, arylthio-C 1 - C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, sulfoxide or sulfone of any of these thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino- C 1 -C 8 -alkyl and amino-C 1 -C 8 -alkyl wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents which are independently selected from the group consisting of Cj-Cg-alkyl, Ar-C] lower alkyl, cycloalkyl and Cj-Cg-aikonoylem, R 13 j _E is selected from the group consisting of hydrido, benzyl, phenyl, C j lower alkyl, C2Cg- alkynyl, C 2 -C 8 -alkenyl and C 1 -C 8 -hydroxyalkyl. The compound of claim 62, wherein the sum of m + η + ρ = 1 or 2. 64. The compound of claim 62 wherein Z is O, S, or NRC A compound according to claim 62, wherein R ⁶ is selected from the group consisting of C 3 -C 5 -cycloalkyl, C 1 -C 8 -alkyl, C 1 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 8 -alkoxy-C 1 -C 8 - alkyl, amino-C1-C6-alkyl, aminosulfonyl, heteroaryl-C1-C6-alkyl, aryloxycarbonyl and C1-C6-alkoxy carbonyl. • · · · 545 • ftft · ftft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · The compound of claim 62, wherein m = n = zero, p = 1, and Y is NBA The compound of claim 62, wherein R ⁴ is hydrido. The compound of claim 62, wherein W of C (W) R ¹⁵ is O and R ¹⁵ is alkyl, aryl, C 1 -C 6 alkoxy, heteroaryl-C 1 -C 8 -alkyl, C 8 -C 8 -cycloalkyl-C 1 -C 8 - alkyl or aryloxy. A compound corresponding to the structure of Formula IV or a pharmaceutically acceptable salt thereof (IV) wherein wherein R ³ is an aryl or heteroaryl group with a single ring that is 5- or 6-membered and is itself substituted in its own 4-position when it is A 6-membered ring, and in its 3 or 4-position, when it is a 5-membered ring, a substituent selected from the group consisting of another single-ring aryl or heteroaryl group, a C3-C14 alkyl group, Npiperidyl group, N-piperazinyl group, phenoxy thiophenoxy, 4-thiopyridil, phenylazo, and benzamino, Z is selected from the group consisting of O, S, NR 1, SO, SO 2, and NSO 2 R 7, wherein R 1 is selected from the group consisting of hydrido, C 1 -C 8 -alkyl, C 1 -C 8 -alkonoyl, benzyl, benzoyl, C 3 -C 8 - alkynyl, C 3 -C 8 -alkenyl, C 1 -C 8 -alkoxy-C 1 -C 4 alkyl, C 8 -C 8 -cycloalkyl, heteroaryl-C 1 -C 8 -alkyl, C 1 -C 8 -hydroxyalkyl, C 1 -C 8 -carboxyalkyl, C 1 -C 8 -alkoxy C 1 -C 8 -alkylcarbonyl, CR 6 R 8 -C 8 -C 8 -alkyl or CR ⁸ R ⁶ -C 1 -C 5 -alkyl, wherein R ⁸ and R 6 are independently hydrido, C 1 -C 5 -alkyl, C 4 -C 5 alkoxycarbonyl or aryl-C 1 -C 5 -alkoxycarbonyl or CR ⁸ R ⁸ together form a heterocyclic ring containing 5- to 8- ring atoms and R ⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 8 -alkyl, C 3 -C 6 -alkynyl, C 1 -C 8 -alkenyl, C 1 -C 8 -carboxyalkyl and C 1 -C 8 -hydroxyalkyl. The compound of claim 69, wherein R ³ has a length greater than the pentyl group and a length less than the icosyl group. A compound according to claim 69, wherein Z is O, S or NR ⁶ . A compound according to claim 69, wherein R ⁶ is selected from the group consisting of C 1 -C 6 cycloalkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 3 -C 6 alkynyl, amino-C 1 -C 8 -alkyl, aminosulfonyl, heteroaryl-C 1 -C 6 -alkyl, aryloxycarbonyl and C 1 -C 8 -alkoxycarbonyl. A compound according to claim 69, wherein R ³ is GAREY, wherein G is an aryl or heteroaryl group, A is selected from the group consisting of (1) -O-, (2) -S-, (3) -NR ¹⁷ -, (4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO-, where R ¹⁷ is hydrogen, C 4 -C 4 -alkyl or phenyl, (S) -CO-O- or -O-CO-, (6) -O-CO-O-, • 99 9 9 9 •·· • 999 9 9 9 9 · · _ε Λη 9 9 9 9 · 99999 * 548 9 »9 ♦ · · ♦ 9 * 99999 99 9 99 9 (7) -ΗΝ = ΝΗ-, (8) -NH-CO-NH-, (9) -CsC-, (10) -NH-CO-O- or O-CO-NH - (11) -Ν = Ν- (12) -NH-CO-NH- and (13) -CS-N (R 1 ⁸⁾ - or -N (R ⁸⁾ -CO-, wherein R ^ ⁸ is hydrogen, C 1 -C 2 -alkyl or phenyl, or (14) A is absent and G is directly attached to R 2, R is a group selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, heterocycloalthioalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroaryl, an aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, C 2 alkoxy, C 1-6 -alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino and alkoxycarbonyl and R is other than alkyl or alkoxyalkyl when A is -O- or -S-, E is selected from the group consisting of (1) -CO-N (R ¹⁹ ) or -N (R ¹⁹ ) -CO-, wherein R ¹⁹ is heterocycloalkyl or cycloalkyl, (2) -CONH- or -NHCO-, and (3) -CO-, (4) -SO ₂ -NR ¹⁹ or -R ¹⁹ -SO ₂ -, (5) -SO ₂ -, (6) -NH-SO ₂ - or -SO ₂ -NH-, or ( 7) E is absent and R is bound directly to Y, and • · 548 Y is absent or is selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, arylkoxy, aralkoxy, heteroarylkoxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, cyclohexyl, heterocycloalkylethyl, heterocycloalkyl an aminoalkyl group wherein the aryl, heteroaryl, or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents selected from the group consisting of alkanoyl, halo, nitro, aralkyl, aryl, alkoxy and an amino group wherein the amine nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from hydrido, alkyl and aralkyl. 74. The compound of claim 69 wherein the G-A-R-E-Y substituent comprises two to four carbocyclic or heterocyclic rings. A compound according to claim 69, wherein each of the two to four rings is 6-membered. The compound of claim 69, wherein the G-A-R-E-Y substituent has a length greater than a hexyl group and a length less than a stearyl group. A compound according to claim 69, wherein A is -O- or -S-. A compound according to claim 69 wherein R is aryl, heteroaryl, cycloalkyl or heterocycloalkyl. The compound of claim 69, wherein E is absent. 80. A compound according to claim 69 wherein Y is selected from the group consisting of hydrido, alkyl, alkoxy, perfluoroalkoxy and perfluoroalkylthio. A compound according to claim 69, wherein R ³ is a group consisting of an aryl or heteroaryl group with a single ring that is 5- or 6-membered and is itself substituted in 549 its own 4-position when it is a 6-membered ring, and in its 3- or 4-position when it is a 5-membered ring, a substituent selected from the group consisting of thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4- methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoromethoxyphenoxy, 4-trifluoromethylphenoxy, 4 (trifluoromethylthio) phenoxy, 4- (trifluoromethylthio) thiophenoxy, 4-chloro ~ 3-fluorophenoxy, 4isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5-yl) oxy, 4- (1H-imidazoll-yl) phenoxy, 4-chloro-3-methylphenoxy, 3-methylphenoxy 4-ethoxyphenoxy, 3,4-difluorophenoxy, 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 4-benzyloxyphenoxy group. The compound of claim 69, wherein R 1 is Ph ² R ² , wherein Ph is a phenyl ring which is substituted at its 4-position by R ² A which is a substituent selected from the group consisting of another aryl or heteroaryl group with a single ring, piperidinyl, piperazinyl, thiophenoxy, phenylazo and benzamido. 83. A compound according to claim 82 wherein R @ ² is itself substituted with a substituent selected from the group consisting of halogen, Cj-C ^ alkoxy, CpC ^ alkyl group, a dimethylamino group, a carboxyl C-C alkylene group, C -C alkoxy carbonyl of a C 1 -C 6 -alkylene group, a trifluoromethyl group and a carboxamido (4 -C 3 alkylene group), or is substituted at the meta and para positions by a methylenedioxy group. 84. A compound according to claim 83 wherein R @ ² is substituted in the para position. A compound according to claim 84, wherein R ²³ is phenoxy. »· · · · · · · 550 The compound of claim 69, wherein the inhibitor corresponds to the structure of the formula 87. A compound corresponding to the structure of Formula V, or a pharmaceutically acceptable salt thereof Z is O, S or NR ⁶ , W and Q are independently oxygen (O), NR ⁶ or sulfur (S), R ⁶ is selected from the group consisting of C 3 -C 8 -cycloalkyl, C 1 -C 8 -alkyl, C 3 -C 8 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkynyl -C 8 -alkoxyC 1 -C 8 -alkyl, amino-C 1 -C 8 -alkyl, aminosulfonyl, heteroaryl-C 1 -C 8 -alkyl, aryloxycarbonyl and C 1 -C 8 -alkoxycarbonyl and q is zero or one, so that when q is zero, trifluoroalkyl the group is bonded directly to the depicted phenyl ring. The compound of claim 87, wherein q is zero. 89. A compound according to claim 87 wherein W is O. 551 • 4,444 «4 4 ·· • 44,444 · 4 4 4444 4,444 4 4 4,444 4444444 4 The compound of claim 89, wherein q is zero. The compound of claim 89, wherein q is one and Q is O. The compound of claim 89, wherein q is one and Q is S. 93. A compound according to claim 87 wherein the inhibitor corresponds to the structure of the formula H HIM The compound of claim 87, wherein the inhibitor corresponds to the structure of the formula HIM H .N 95. A compound according to claim 87 wherein the inhibitor corresponds to the structure of the formula A compound according to claim 87, wherein the inhibitor corresponds to the structure of the formula 4 4 4 444 4 4 4 4 4 4,444 4444444 4 The compound of claim 87, wherein the inhibitor corresponds to the structure of the formula A compound according to claim 87, wherein the inhibitor corresponds to the structure of the formula 99. A compound according to claim 87, wherein the inhibitor corresponds to the structure of the formula: &lt; tb &gt; 100. A compound according to claim 87 wherein the inhibitor corresponds to the structure of the formula HIM 101. A compound according to claim 87 wherein the inhibitor corresponds to the structure of the formula The compound of claim 87, wherein the inhibitor corresponds to the structure of the formula The compound of claim 87, wherein the inhibitor corresponds to the structure of the formula 4 4 4 4 φ 4 4 4 4 * 44 4 4 4 4 4 4 4 4 44 44 4444 4 4 4 44 4 554 104. An intermediate corresponding to the structure of formula (VI): (VI) wherein g is zero, 1 or 2, R ³ is an optionally substituted aryl or optionally substituted heteroaryl radical and when the aryl or heteroaryl radical is substituted, the substituent is (a) selected from the group consisting of optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxyalkyloxyalkyloxyalkyloxyalkyl , aralkanoylalkyl, araloxyalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, aralkylthioaryl, aralkylthioaryl, sulfoxide or sulfone of any of the thienyl groups selected from one or more of thio heteroaryl, cycloalkyl and heterocycloalkyl, and (b) is itself optionally substituted with one or more substituents independently selected from the group consisting of cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio , haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, arylkoxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, 9 «9999 • 9 99 9 9 555 99 9 99 9 9 9 9 9 9 9 9 9 9 99 9999999 9 9 99 9 99 9 heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, heterocyclo, heteroayl, arylazo, hydrocarbonylalkoxy, alkoxycarbonylalkoxy, alkonoyl, arylcarbonyl, aralkonoyl, alkanoyloxy, aralkonoyloxy, hydroxyalkyloxy, hydroxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkyl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkyl, alkoxycarbonyl-alkylthio, amino wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, aralkyl, aralkyl , alkoxycarbonyl, arylcarbonyl, aralkonoyl, heteroarylcarbonyl, heteroaralkonoyl and alkonoyl, or (iii) wherein the amine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring containing 2 to 8 carbon atoms. one to two additional heteroatoms which are nitrogen, oxygen or sulfur and wherein the ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkonoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzo-linked heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzo-linked heterocycloalkoxy, carboalkyl, cycloalkylcarbonyl, benzo-linked cycloalkyl, carbocarbonyl, (ii) is a reacted amino acid amine; or (iii) is substituted with one or two substituents selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzo linked heterocycloalkyl, benzo or (iv) a carboxamine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic, heteroaryl or benzo-linked heterocycloalkyl ring which is itself unsubstituted or substituted by one or two groups independently selected from alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl, and amino groups wherein the amine nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from alkyl , aryl and heteroaryl, or (iii) wherein the amine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring, and 44 444 4 4 4 • • 4 4 * • 4 4 4 4 4 4 4 4 * 4 44 4 556 * 4 aminoalkyl wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkonoyl, or (iii) wherein the amine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring which is substituted with a nucleophilically displaceable leaving group, m is zero, 1 or 2, n is zero, 1 or 2, p is zero, 1 or 2, the sum m + n + p = 1,2,3 or 4, (a) one of X, Y and Z is selected from the group consisting of C (O), NR ⁶ , O, S, S (O), S (O) ₂ and NS (O) ₂ R ² and the remaining two X, Y and Z are CR 4 R ⁹ and CR ³⁹ R 11 or (b) X and Z, Z and Y together form a group selected from NR ⁶ C (O), NR ⁶ S (O), NR ⁶ S (O) ₂ , NR ⁶ S, NR ⁶ O, NR ⁶ (O), SS, NR ⁶ NR ⁶ and OC (O), one remaining X, Y and Z is CR ⁸ R ⁹ , or (c) n is zero and X, Y a Z together form a group that is selected from the group consisting of ·· ···· · · 9 · 9 9 9 9 9 9 9 557 where the wavy lines are bonds to the atoms of the indicated ring, • 9 9 99999 9 9 R ⁶ and R ⁶ 'are independently selected from the group consisting of hydrido, C 1 -C 8 -alkonoyl, C 8 -C 8 -C 1 -C 8 -alkyl, aroyl, bis (C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl) -C 1 -C 8 - alkyl, C 1 -C 8 alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -fluoroalkyl, C 1 -C 8 -trifluoromethyl, C 1 -C 8 -perfluoroalkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 - C8-alkyl, C3-C8-cycloalkyl, C8-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, C8-aryl, C8-C8-heterocyclo, C8-C8-heteroalkyl, C3-C8-cycloalkyl-C1-C8-alkyl, C8-aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-arylsulfonyl, C1-C6-alkyl -C 8 -alkylsulfonyl, C 1 -C 8 -heteroarylsulfonyl, carboxy-C 1 -C 8 -alkyl, C 1 -C 4 -alkoxycarbonyl-C 1 -C 8 -alkyl, aminocarbonyl, C 1 -C 8 -alkyliminocarbonyl, C 8 -aryliminocarbonyl, C 3 -C 8 -heterocycloiminocarbonyl C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl, C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl, C 1 -C 4 -arylthio-C 3 -C 8 -alkenyl, C 1 -C 4 -alkylthio-C 3 -C 8 -alkynyl, C 5 - C8-heteroaryl-C1-C8-a alkyl, halo-C 1 -C 8 -convinyl, hydroxy-C 1 -C 8 -alkonoyl, thiol-C 1 -C 8 -alkonoyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1-6 -alkyl; -C5 -alkoxycarbonyl, aryloxycarbonyl, CR5R5-C1-C5-alkylcarbonyl, hydroxy-C1-C6-alkyl, aminocarbonyl, wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii) is substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl; To hydroxy-aminocarbonyl, an aminosulfonic group, wherein the aminosulfonic nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, amino-C 1 -C 8 -alkylsulfone, wherein the amino-C 1 -C 8 -alkylsulfone nitrogen is (i) ) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 -alkyl, ar-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl and amino-C 1 -C 8 -alkyl; an alkyl group wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 4 -C 5 alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -alkyl -cycloalkyl and C 1 -C 8 -alkonoyl, R ⁷ is selected from arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 6 alkyl, C 1 -C 6 -alkenyl, C 1 -C 8 -alkynyl, C 1 -C 8 -carboxyalkyl and C 1 -C 8 -hydroxyalkyl, R ⁸ and R ⁶ and R ¹⁶ and R 16 are independently selected from the group consisting of hydrido, hydroxy, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl, heteroaryl, hetero-C 1 -C 6 -alkyl, C 8 -C 1-6 alkynyl, C 2 -C 6 -alkenyl, thiol-C 1 -C 8 -alkyl, C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, heterocycloalkyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkyl; C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxyalkylcarbonyl-C1-C6-alkyl -C8-alkyl, hydroxycarbonylar-C1-C6 alkyl, amino-carbonyl-C1-C6 alkyl, aryloxy-C1-C6 alkyl, heteroaryloxy-C1-C6 alkyl, arylthio-C1-C6 alkyl, heteroarylthio-C1-C6 - alkyl, sulfoxide or sulfone of any of the thio substituents, perfluoro-C 1 -C 6 -alkyl, trifluoromethyl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, alkoxycarbonylamino-C 1 -C 6 -alkyl and amino-C 1 -C 6 -alkyl; an alkyl group wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, ar-C 1 -C 6 -alkyl, cycloalkyl and C 1 -C 8 -alkonoyl, or wherein R ⁸ and R ⁶ or R ⁶ and R ¹¹ and the carbon to which they are attached form a carbonyl group, or R ⁸ and R ⁶ or R ¹⁰ and IV ', or R ⁸ and R ⁶ together with the atoms to which they are attached form a 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring containing one or two · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 3 «····» »· Hetero · * · ⁵⁵⁹ .: Λ .. »* heteroatoms which are nitrogen, oxygen or sulfur, provided that only one of R ⁸ and R ⁹ or R ⁹ and R 1 is hydroxy, R ¹² and R ¹² 'are independently selected from the group consisting of hydrido, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, heteroaralkyl, C 2 -C 8 -alkynyl, C 2 -C 8 -alkenyl, thiol-C 1 -C 8 -alkyl -alkyl, cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, heterocycloalkyl-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, amino-C 1 - C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxylcarbonyl-C 1 -C 8 -alkyl, hydroxycarbones and C 1 -C 8 - alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroaryl hio-C 1 -C 8 -alkyl, sulfoxide or sulfone of any of these thio substituents, perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 - C1-C6-alkyl and amino-C1-C6-alkyl, wherein the amino-C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted by one or two substituents ns are independently selected from the group consisting of C] lower alkyl, Ar-C] lower alkyl, cycloalkyl and Cj-Cg-alkonoylem, R 13 j _E is selected from the group consisting of hydrido, benzyl, phenyl, Cj-Cg-alkyl, C 2 -C 8 -alkynyl, C 2 -C 8 -alkenyl and C 1 -C 8 -hydroxyalkyl, and R ²⁹ is -OR ²¹ wherein R ²¹ is selected from the group consisting of hydrido, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl, and a pharmaceutically acceptable cation or (b) -NHO-R ²² wherein R ²² is a selectively removable protecting group. 105. The intermediate of claim 104 wherein R1 is a substituent G-A-R-E-Y, wherein G is an aryl or heteroaryl group, A is selected from the group consisting of (1) -O-, (2) -S-, (3) -NR ^17- , ft ···· · · · · ftft · «ft · ·· ft 560 · ft · ft · ft · ft · (4) -CO-N (R ¹⁷ ) or -N (R ¹⁷ ) -CO-, wherein R ¹⁷ is hydrogen, C 1 -C 8 -alkyl or phenyl, (S) -CO-O- or -O-CO-, (6) -O-CO-O-, (7) -HN = NH-, ( 8) -NH-CO-NH-, (9) -, -, (10) -NH-CO-O- or O-CO-NH-, (11) -N = N-, (12) -NH- CO-NH- and (13) -CS-N (R 18) - or -N (R 6) -CO-, wherein R 6 is hydrogen, C 1 -C 6 alkyl or phenyl, or (14) A is absent and G is bound directly to R, R is a group selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, heterocycloalkoxyalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroaryloxyalkyl, heteroaryloxyalkyl, heteroaryloxyalkyl, heteroaryloxyalkyl, a heteroaryl, cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C 1 -C ₂ alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino and alkoxycarbonyl and R is other than alkyl or alkoxyalkyl when A is -O- or -S-, E is selected from the group consisting of (1) -CO-N (R * ⁹ ) or -N (R ^ ⁹ ) -CO-, wherein R ' ⁹ is a heterocycloalkyl or cycloalkyl group, (2) -CONH- or -NHCO- , and (3) -CO-, (4) -SO ₂ -NR ¹⁹ or -R ¹⁹ -SO ₂ -, · · · · · t · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 561 (5) -SO ₂ -, (6) -NH-SO ₂ - or -SO ₂ -NH-, or (7) E is absent and R is bound directly to Y, and Y is absent or is selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, arylkoxy, aralkoxy, heteroarylkoxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, cyclohexyl, heterocycloalkylethyl, heterocycloalkyl an aminoalkyl group wherein the aryl, heteroaryl, or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two substituents selected from the group consisting of alkanoyl, halo, nitro, aralkyl, aryl, alkoxy and an amino group wherein the amine nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from hydrido, alkyl and aralkyl. 106. The intermediate of claim 104 wherein the G-A-R-E-Y substituent contains two to four carbocyclic or heterocyclic rings. 107. The intermediate of claim 104, wherein each of the two to four rings is 6-membered. 108. The intermediate of claim 104 wherein the G-A-R-E-Y substituent has a length greater than a hexyl group and a length less than a stearyl group. 109. The intermediate of claim 104 wherein A is -O- or -S-. 110. The intermediate of claim 104 wherein R is aryl, heteroaryl, cycloalkyl or heterocycloalkyl. 111. The intermediate of claim 104, wherein E is absent. 112. The intermediate of claim 104 wherein Y is selected from the group consisting of hydrido, alkyl, alkoxy, perfluoroalkoxy and perfluoroalkylthio. • · 562 113. The intermediate of claim 104 wherein is hydrido. 114. The compound of Claim 104 wherein W of the C (W) R is O and R ^ j _alkyl, aryl, C JCG-alkoxy, heteroaryl-C-Cg alkyl, C3-Cg cycloalkyl-C JCG -alkyl or aryloxy. 115. The intermediate of claim 103, wherein R &lt; 6 &gt; is a single ring aryl or heteroaryl group that is 5- or 6-membered and is itself substituted in its own 4-position when it is a 6-membered ring, and in its 3- or 4- position, when it is a 5-membered ring, with a substituent selected from the group consisting of thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoromethoxyphenoxy, 4-trifluoromethylphenoxy, 4- (trifluoromethylthio) phenoxy, 4 (trifluoromethylthio) thiophenoxy, 4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4isopropylphenoxy, (2-methyl-1,3), benzothiazol-5-yl) oxy, 4- (1H-imidazol-1-yl) phenoxy, 4-chloro-3-methylphenoxy, 3-methylphenoxy, 4-ethoxy phenoxy, 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-c hinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxy phenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy and 4-benzyloxyphenoxy 116. The intermediate of claim 103 wherein the selectively displaceable protecting group is selected from the group consisting of 2-tetrahydropyranyl, C1-C8-acyl, aroyl, benzyl, pmethoxybenzyloxycarbonyl, benzyloxycarbonyl, C1-C8-alkoxycarbonyl, C1-C8-alkoxy- C 1 -C 8 -alkoxy-CH 2 - and o-nitrophenyl. 117. The intermediate of claim 103, wherein the nucleophilically displaceable leaving group is selected from the group consisting of halo, nitro, azido, phenylsulfoxido, aryloxy, C1-C6-alkoxy, C 1 -C 8 -alkyl sulfonate or arylsulfonate and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C 1 -C 8 -alkyl or C 1 -C 8 -alkyl. 118. The intermediate of claim 103, wherein g is zero. 119. The intermediate of claim 103, corresponding to the structure of Formula VII (VII) wherein g is zero, 1 or 2, D is a nucleophilically displaceable leaving group, m is zero, 1 or 2, n is zero, 1 or 2, p is zero, 1 or 2, the sum of m + n + p = 1,2, 3 or 4, (a) one of X, Y and Z is selected from the group consisting of C (O), NR 4, O, S, S (O), S (O) 2, and NS (O) 2 R 7, and the remaining two X, Y and Z are CR ⁸ R ⁹ and CR 6 R 6 or (b) X and Z or Z and Y together form a group selected from the group consisting of NR ⁶ C (O), NR ⁶ S (O), NR ⁶ S (O) ₂ , NR ⁶ S, NR ⁶⁰ , NRS ⁶ (O), SS, NR ⁶ NR ⁶ and OC (O), one of the remaining X, Y and Z being CR ⁸ R ⁹ , or (c) n is zero and X, Y and Z together form a group which is selected from the group consisting of ··· · ··· where the wavy lines are bonds to the atoms of the indicated ring, R ⁶ and R ⁶ 'are independently selected from the group consisting of hydrido, C 1 -C 8 -alkonoyl, C 6 -C 8 -aryl-C 1 -C 8 -alkyl, aroyl, bis (C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl) -C 1 -C 8 -alkyl C 1 -C 8 alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -fluoroalkyl, C 1 -C 8 -trifluoromethylalkyl, C 1 -C 8 -perfluoroalkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl , C3-C8 heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, C8-aryl, C5-C8-heterocyclo, C8-C8-heteroaryl, C8-C8-cycloalkyl-C8-C8-alkyl, C8-aryloxy-C8-C8 -alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-arylsulfonyl, C1-C8-alkylsulfonyl, C1-C8- heteroarylsulfonyl, 565 carboxy-C 1 -C 8 -alkyl, C 1 -C 4 -alkoxycarbonyl-C 1 -C 8 -alkyl, aminocarbonyl, C 1 -C 8 -alkyliminocarbonyl, C 8 -aryliminocarbonyl, C 1 -C 8 -heterocycloiminocarbonyl, C 8 -C 8 -heterocycloiminocarbonyl, C 8 -C 8 -heterocycloiminocarbonyl, C 8 -C 8 -heterocycloiminocarbonyl -C8-alkylthio-C1-C6-alkyl, C8-arylthio-C3-C8-alkenyl, C 1 -C 4 -alkylthio-C 3 -C 8 -alkynyl, C 8 -C 8 -heteroaryl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkonoyl, hydroxy-C 1 -C 8 -alkonoyl, thiol-C 1 -C 8 -alkonoyl, C3Cg -alkenyl, -alkynyl C3Cg hem, C j-C4-alkoxy-C1-C4-alkyl, C j - (^ - alkoxycarbonyl, aryloxycarbonyl, CR ⁸ R ⁹ -C j C5-alkylcarbonyl, hydroxy-C C 1 -C 8 -alkyl, aminocarbonyl, wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii) is substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1-6 alkyl; -C 8 -alkonoyl, hydroxyaminocarbonyl, an aminosulfone group, wherein the aminosulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, A C 3 -C 8 -cycloalkyl and a C 1 -C 8 -alkonoyl group, an amino-C 1 -C 8 -alkylsulfone group wherein the amino-C 1 -C 8 -alkylsulfone nitrogen is (i) unsubstituted or (ii) substituted with one n or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl and amino-C 1 -C 8 -alkyl, wherein the amino -C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkyl; A C 8 -alkonoyl group, R ⁷ is selected from arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 6 alkyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 8 -carboxyalkyl and C 1 -C 8 -hydroxyalkyl, R ⁸ and R ⁹ and R ¹⁰ and R ¹¹ are independently selected from the group consisting of hydrido, hydroxy, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, hetero-C 1 -C 8 -alkyl, C 2 -C 8 -alkyl; C 6 alkynyl, C 2 -C 8 -alkenyl, thiol-C 1 -C 8 -alkyl, C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl 1 cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, heterocycloalkyl C 1 -C 8 -alkyl, C 8 -C 8 -alkoxyC 1 -C 8 -alkyl, aralkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyalkylcarbonyl -C 1 -C 8 -alkyl, hydroxycarbonylar-C 1 -C 8 - 566 alkyl, amino-carbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, sulfoxide or sulfone any of the thio substituents, perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 -C 8 -alkyl, and amino-C 1 -C 8 -alkyl, wherein amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 alkyl, ar-C 1 -C 8 -alkyl, cycloalkyl and C 1 -C 8 -alkyl -alkonoyl, or wherein a or R 10 and R 11 and the carbon to which they are attached form a carbonyl group, or wherein R 6 and R 6 or R 19 and R 8, or R 6 and R 10 together with the atoms to which they are attached form 5- a 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring containing one or two heteroatoms which are nitrogen, oxygen or sulfur, provided that only one of R 6 and R 6; or R 10 and R 11 is hydroxy, R ¹² and R ¹² 'are independently selected from the group consisting of hydrido, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₈ -alkynyl, C ₂ -C ₈ -alkenyl, thiol-C 1-6 -alkyl; -C8-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, amino -C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyalkylcarbonyl-C 1 -C 8 -alkyl, hydroxycarbonylar-C 1 - 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 -alkyl, heteroarylthio-C 1 -C 8 -alkyl, sulfoxide or sulfone of any of these thio substituents, perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C] -C 8 -alkyl and amino-C 1 -C 8 -alkyl, wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents, which are independently selected from the group consisting of Cj-Cg-alkyl, Ar-C-Cg alkyl, cycloalkyl and Cj-Cg-alkonoylem, R 13 j _E is selected from the group consisting of hydrido, benzyl, phenyl, C] lower alkyl, C _2-Cg alkynyl, C2-Cg alkenyl and Cj-Cg-hydroxyalkyl, and R20 is (a) -OR ^21, wherein R ² 'j _e is selected from the group consisting of hydrido, C | -Cg hem -alkyl, aryl, an ar-C 1 -C 8 -alkyl group, and a pharmaceutically acceptable cation, or (b) -NHO-R ²² , wherein R ²² is a selectively removable protecting group. 567 120. The intermediate of claim 119 wherein the selectively displaceable protecting group is selected from the group consisting of 2-tetrahydropyranyl, C1-C8-acyl, aroyl, benzyl, pmethoxybenzyloxycarbonyl, benzyloxycarbonyl, C1-C8-alkoxycarbonyl, C1-C8-alkoxyCH2. , C 1 -C 8 -alkoxy-CH 2 - and o-nitrophenyl. 121. The intermediate of claim 119, wherein the nucleophilically displaceable leaving group D is selected from the group consisting of halo, nitro, azido, phenylsulfoxido, aryloxy, C1-C6 alkoxy, C1-C6-alkylsulfonate or arylsulfonate and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C1-C6-alkyl or C1-C6-alkyl. 122. The intermediate of claim 119 wherein the halo group is fluoro. 123. The intermediate of claim 119, wherein g is zero. 124. A pharmaceutical composition comprising a compound of claim 52 dissolved or dispersed in a pharmaceutically acceptable carrier. 125. A pharmaceutical composition comprising a compound of claim 62, dissolved or dispersed in a pharmaceutically acceptable carrier. 126. A pharmaceutical composition comprising a compound of claim 69 dissolved or dispersed in a pharmaceutically acceptable carrier. 127. A pharmaceutical composition comprising a compound of claim 87, dissolved or dispersed in a pharmaceutically acceptable carrier. Zjow, SoU 128. {The preparation of the product, a metalloprotease inhibitor compound, which comprises the step of coupling the intermediate to another group, wherein the intermediate corresponds to the structure of formula VIB and the product corresponds to the structure of formula VIA 568 Φ · · · φ · φ φ · φ R R 3 'g is zero, 1 or 2, R ³ 'is an aryl or heteroaryl group which is substituted with a linking substituent reactive to the linking with another group, R ³ is an optionally substituted aryl or optionally substituted heteroaryl radical and when the aryl or heteroaryl radical is substituted, the substituent is (a) selected from the group consisting of optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxyalkyloxyalkyloxyalkyloxyalkyl , aralkanoylalkyl, araloxyalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, aralkylthioaryl, aralkylthioaryl, sulfoxide or sulfone of any of the thienyl groups selected from one or more of thio heteroaryl, cycloalkyl and heterocycloalkyl, and (b) is itself optionally substituted with one or more substituents independently selected from the group consisting of cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio , haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, arylkoxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroarylalkyl, heteroarylalkyl, heteroaralkyl, heteroaralkyl; , arylazo, hydrocarbonylalkoxy, alkoxycarbonylalkoxy, • 569 alkonoyl, arylcarbonyl, aralkonoyl, alkanoyloxy, aralkonoyloxy, hydroxyalkyl, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxy-alkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, ) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkonoyl, heteroarylcarbonyl, heteroaralkanoyl and alkonoyl, or (iii) wherein the amino nitrogen atom and attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring containing no to two other heteroatoms which are nitrogen, oxygen or sulfur and wherein the ring itself is (a) unsubstituted or (b) substituted with one or two groups n independently selected from the group consisting of aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkonoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzo-linked heterocycloalkyl, hydroxyalkoxycarbonyl, aralkoxyloxy, cycloalkylcarbonyl, heterocycloalkylcarbonyl, and cycloalkylcarbonyl, carbonylamino, wherein the carbonylamino nitrogen is (i) unsubstituted or (ii) is a reacted amino acid amine or (iii) is substituted with one or two substituents selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroalkyl, cycloalkyl, cycloalkyl aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzo linked heterocycloalkyl, benzo linked cycloalkyl and Ν, Ν-disubstituted aminoalkyl, or (iv) carboxamine nitrogen and the two substituents attached thereto form a 5- to 8-membered member a heterocyclic, heteroaryl or benzo linked heterocycloalkyl ring which is itself unsubstituted or substituted by one or two groups independently selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl, and an amino group wherein the amine nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl and heteroaryl, or (iii) wherein the amine nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring , and aminoalkyl 570 ·· ··· · I · ti ·· · · · · · · · 9 · 9999 9 9 9 Wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkonoyl, or (iii) wherein the amine nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring which is substituted with a nucleophilically displaceable leaving group, m is zero, 1 or 2, n is zero, 1 or 2, p is zero, 1 or 2, the sum of + n + p = 1,2,3 or 4, (a) one of X, Y and Z is selected from the group consisting of C (O), NR ⁶ , O, S, S (O), S (O) 2, and NS (O) R ² and the remaining two X, Y and Z are CR ⁸ R ⁹ and CR ⁹ R * I or (b) X and Z or Z and Y together form a group selected from the group consisting of NR ⁶ C (O), NR ⁶ S (O) NR ⁶ S (O) _2, NR ⁶ S, NR ⁶ 0, DCI ⁶ (O), SS, NR ⁶ NR ⁶ and OC (O), one of the remaining X, Y and Z form CR ⁸ R ^9, or (c) n is zero and X, Y and Z together form a group, which is selected from the group consisting of wherein the wavy lines are bonds to the atoms of the indicated ring, R ⁶ and R ⁶ 'are independently selected from the group consisting of hydrido, C 1 -C 8 -alkonoyl, C 8 -C 1 -C 8 -alkyl, aroyl, bis (C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl) -C 8 -C8-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethyl, C1-C6perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6 -alkyl, C 8 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, C 8 -C 8 -heterocycloalkylcarbonyl, C 8 -C 8 aryl, C 8 -C 8 -heterocyclo, C 8 -C 8 -heteroalkyl, C 3 -C 8 -cycloalkyl-C 8 -C 8 -alkyl C1-C6-aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-arylsulfonyl, C1-C6-alkyl -C 8 -alkylsulfonyl, C 1 -C 8 -heteroaryl sulfonyl, carboxy-C 1 -C 8 -alkyl, C 8 -C 8 -alkoxycarbonyl-C 8 -C 8 -alkyl, aminocarbonyl, C 8 -C 8 -alkyliminocarbonyl, C 8 -aryliminocarbonyl, C 8 -C 8 - heterocycloiminocarbonyl, Cgarylthio-C 1 -C 8 -alkyl, C 1 -C 8 -alkylthio-C 1 -C 8 -alkyl, C 8-arylthio-C 3 -C 8 -alkenyl, C 1 -C 8 -alkylthio-C 8 -C 8 -alkynyl, C 8 -C 8 -alkyl- heteroaryl-C i -C 8 -alkyl, halo-C 1 -Cgalkonoyl, hydroxy-C 1 -C 8 -alkonoyl, thiol-C 1 -C 8 -alkonoyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 8 -C 8 -alkoxy-C 1 -C 8 - alkyl, C 1 -C ⁸ -alkoxycarbonyl, aryloxycarbonyl, CR ⁸ R ⁹ -C 1 -C 8 -alkylcarbonyl, hydroxy-C 1 -C 8 -alkyl, aminocarbonyl, wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii) is substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 8 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 8 -C 8 -alkonoyl, 572 · hydroxyaminocarbonyl, an aminosulfone group, where the aminosulfone nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl, amino-C 1 -C 8- an alkyl sulfone group wherein the amino-C 1 -C 8 alkylsulfone nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl and amino-C 1 -C 8 -alkyl, wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected C 1 -C 8 alkyl, ar-C 1 -C 8 -alkyl, (C 1 -C 8 -cycloalkyl and C 1 -C 8 -alkonoyl), R ⁷ is selected from arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 6 alkyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 1 -C 8 -carboxyalkyl and C 1 -C 8 -hydroxyalkyl, R ⁸ and R ⁹ and R ¹⁰ and R 11 are independently selected from the group consisting of hydrido, hydroxy, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, hetero-C 1 -C 8 -alkyl, C 2 -C 8 -alkynyl, C 2 -C 8 -alkenyl, thiol-C 1 -C 8 -alkyl, C 1 -C 8 -alkylthio-C 1 -C 8 alkyl cycloalkyl, cycloalkyl-C 1 -C 8 -alkyl, heterocycloalkyl-C 1 -C 8 - alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl , hydroxyalkylcarbonyl-C 1 -C 8 -alkyl, hydroxycarbonylar C 1 -C 8 -alkyl, aminocarbonyl-C 1 -C 8 -alkyl, aryloxy-C 1 -C 8 -alkyl, heteroaryloxy-C 1 -C 8 -alkyl, arylthio-C 1 -C 8 -alkyl , heteroarylthio-C 1 -C 8 -alkyl, sulfoxide or sulfone of any of the thio substituents, perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 6 alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 -C 8 -alkyl and amino-C 1 -C 6 alkyl, wherein the amino-C 1 -C 8 -alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of C 1 -C 8 -alkyl, ar-C 1 -C 6 -alkyl; ] lower alkyl, cycloalkyl and Cj-Cg-alkonoylem, or wherein R ⁸ and R ⁹ or R ¹⁰ and R ¹¹ and the carbon to which they are attached form a carbonyl group, or wherein R ⁸ and R ⁹ or R ⁹ and R @ ¹ or R @ ⁸ and R @ ⁹ together with the atoms to which they are attached form a 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring containing one • dva φ · · · «or two heteroatoms, which are nitrogen, oxygen or sulfur, provided that only one of R ⁸ and R ⁹ or R ⁸ and R ⁶ is hydroxy, R ¹² and R ¹² 'are independently selected from the group consisting of hydrido, C 1 -C 8 -alkyl, aryl, ar-C 1 -C 8 -alkyl, heteroaryl, heteroaralkyl, C ₂ -C ₈ -alkynyl, C ₂ -C ₈ -alkenyl, thiol-C 1-6- C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, amino-C1-C6-alkyl -C8-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6 alkyl, hydroxyalkylcarbonyl-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, -C 8 -alkyl, sulfoxide or sulfone of any of these thio substituents, perfluoro-C 1 -C 8 -alkyl, trifluoromethyl-C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, alkoxycarbonylamino-C 1 -C 8 -alkyl and amino-C 1 -C 8 -alkyl; A C8-alkyl group wherein the amino-C8-C8-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents ns are independently selected from the group consisting of C lower alkyl, ar-C-Cg alkyl, cycloalkyl and Cj-Cg-alkonoylem, R 13 j _E is selected from the group consisting of hydrido, benzyl, phenyl, Cj-Cg-alkyl, _C2 Cg alkynyl, C ₂ -Cg alkenyl and Cj-Cg-hydroxyalkyl, and R ²⁹ is -OR ²⁰ wherein R ²¹ is selected from the group consisting of hydrido, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl, and a pharmaceutically acceptable cation, or (b) -NHO-R ²² , wherein: R ²² is a selectively removable protecting group. 129. The method of claim 128, comprising the additional step of recovering the product. 130. Řoužitíf of Claim 128 wherein R ²⁹ is -NH-OR ²² wherein R ²² is a selectively removable protecting group. 131. according to claim 130, wherein the selectively removable protecting group is selected from the group consisting of 2-tetrahydropyranyl, C1-C6-acyl, aroyl, benzyl, p-methoxybenzyloxycarbonyl, benzyloxycarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkoxy- C 1 -C 8 -alkoxyCH 2 -, o-nitrophenyl and resins for peptide synthesis. 132. according to claim 128, wherein the linking substituent is a nucleophilically displaceable leaving group. 574 · ♦ ♦ ·...... » 133. The method of claim 12, wherein the nucleophilically displaceable leaving group is selected from the group consisting of halo, nitro, azido, phenylsulfoxido, aryloxy, C1-C6-alkoxy, C1-C6-alkylsulfonate or arylsulfonate and trisubstituted ammonium. a group in which the three substituents are independently aryl, ar-C 1 -C 8 -alkyl or C 1 -C 8 -alkyl. 134. The use of claim 128, wherein g is 2. 135. peužrti | according to claim 128, wherein R 6 is an aryl or heteroaryl group is an aryl group. the 136. according to claim 128, wherein the intermediate corresponding to the structure of formula VI corresponds to the structure of formula VIIA below: (VIIA) wherein D is a nucleophilically displaceable leaving group and is selected from the group consisting of halo, nitro, azido, phenylsulfoxido, aryloxy, C 1 -C 8 -alkoxy, C 1 -C 8 -alkylsulfonate or arylsulfonate and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C 1 -C 8 -alkyl or C 1 -C 8 -alkyl. ··· ··················· 575 137. ^ oožb | according to claim 128 comprising the further step of obtaining the product, the method 138. (Use) according to claim 128, including the further step of selectively removing the R ²² protecting group 139. The method of claim 138, wherein the R ²² protecting group _is removed after the next step of product recovery. 140. jpoužitj according to claim 139, wherein the protecting group R ²² is a tetrahydropyranyl group. 141 of claim 129, wherein R ²¹ in the product after its acquisition is hydrido, and including the further step of reacting the product with hydroxylamine or hydroxylamine, which nitrogen is reacted with a selectively removable protecting group which is selected from the group consisting of 2-tetrahydropyranyl, CpCg-acyl, aroyl, benzyl, p-methoxybenzyloxycarbonyl, benzyloxycarbonyl, C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkoxy-C 1b-, o-nitrophenyl and peptide synthesis resins to form hydroxamic an acid or protected hydroxamate product. 142.φ ©ζζ & ίί according to claim 141 comprising the further step of recovering the formed product.