AU2630500A - Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase (mmp) inhibitors/tnf-alpha converting enzyme (tace) inhibitors - Google Patents

Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase (mmp) inhibitors/tnf-alpha converting enzyme (tace) inhibitors Download PDF

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AU2630500A
AU2630500A AU26305/00A AU2630500A AU2630500A AU 2630500 A AU2630500 A AU 2630500A AU 26305/00 A AU26305/00 A AU 26305/00A AU 2630500 A AU2630500 A AU 2630500A AU 2630500 A AU2630500 A AU 2630500A
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phenyl
sulfonyl
methyl
ynyloxy
hydroxy
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AU769418B2 (en
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Jannie Lea Baker
James Ming Chen
Mila Ti Du
Jeremy Ian Levin
Vincent Premarana Sandanayaka
Aranapakam Mudumbai Venkatesan
Arie Zask
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Wyeth Holdings LLC
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Wyeth LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyrane Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

WO 00/44723 PCT/USOO/01864 -1 ALKYNYL CONTAINING HYDROXAMIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MATRIX METALLOPROTEINASE (MMP) INHIBITORS / TNF-ALPHA CONVERTING ENZYME (TACE) INHIBITORS FIELD OF INVENTION 5 This invention relates to acetylenic hydroxamic acids which act as inhibitors of TNF-x converting enzyme (TACE). The compounds of the present invention are useful in disease conditions mediated by TNF-a, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss. 10 BACKGROUND OF THE INVENTION Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of 15 enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors. It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid 20 tumors, has also recently been shown to have a gelatinase component to its pathology. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal 25 ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, 30 proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neo- WO 00/44723 PCTIUSOO/01864 -2 vascularization and corneal graft rejection. For recent reviews, see: (1) Recent Advances in Matrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H. Davidson, A. H. Drummond, P. Huxley and M. Whittaker, Research Focus, Vol. 1, 16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16, (3) Curr. Medicinal 5 Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther. Patents (1995) 5(2): 1087-110, (5) Exp. Opin. Ther. Patents (1995) 5(12): 1287-1196: (6) Exp. Opin. Ther. Patents (1998) 8(3): 281-259. TNF-a converting enzyme (TACE) catalyzes the formation of TNF-a from membrane bound TNF-a precursor protein. TNF-a is a pro-inflammatory cytokine 10 that is believed to have a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W. Exp. Opin. Ther. Patents 1998, 8(5), 531; Grossman, J. M.; Brahn, E. J. Women's Health 1997, 6(6), 627; Isomaki, P.; Punnonen, J. Ann. Med. 1997, 29, 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5), 613.] septic shock [Mathison, et. al. J. Clin. Invest. 1988, 81, 1925; Miethke, et. al. J. Exp. Med. 1992, 175, 91.], graft rejection [Piguet, 15 P. F.; Grau, G. E.; et. al. J. Exp. Med. 1987, 166, 1280.], cachexia [Beutler, B.; Cerami, A. Ann. Rev. Biochem. 1988, 57, 505.], anorexia, inflammation [Ksontini, R,; MacKay, S. L. D.; Moldawer, L. L. Arch. Surg. 1998, 133, 558.], congestive heart failure [Packer, M. Circulation, 1995, 92(6), 1379; Ferrari, R.; Bachetti, T.; et. al. Circulation, 1995, 92(6), 1479.], post-ischaemic reperfusion injury, inflammatory 20 disease of the central nervous system, inflammatory bowel disease, insulin resistance [Hotamisligil, G. S.; Shargill, N. S.; Spiegelman, B. M.; et. al. Science, 1993, 259, 87.] and HIV infection [Peterson, P. K.; Gekker, G.; et. al. J. Clin. Invest. 1992, 89, 574; Pallares-Trujillo, J.; Lopez-Soriano, F. J. Argiles, J. M. Med. Res. Reviews, 1995, 15(6), 533.]], in addition to its well-documented antitumor properties [Old, L. 25 Science, 1985, 230, 630.]. For example, research with anti-TNF-a antibodies and transgenic animals has demonstrated that blocking the formation of TNF-cx inhibits the progression of arthritis [Rankin, E.C.; Choy, E.H.; Kassimos, D.; Kingsley, G.H.; Sopwith, A.M.; Isenberg, D.A.; Panayi, G.S. Br. J. Rheumatol. 1995, 34, 334; Pharmaprojects, 1996, Therapeutic Updates 17 (Oct.), aul97-M2Z.]. This 30 observation has recently been extended to humans as well as described in "TNF-a in Human Diseases", Current Pharmaceutical Design, 1996, 2, 662.
WO 00/44723 PCTUSOO/01864 -3 It is expected that small molecule inhibitors of TACE would have the potential for treating a variety of disease states. Although a variety of TACE inhibitors are known, many of these molecules are peptidic and peptide-like which suffer from bioavailability and pharmacokinetic problems. In addition, many of these 5 molecules are non-selective, being potent inhibitors of matrix metalloproteinases and, in particular, MMP-1. Inhibition of MMP-1 (collagenase 1) has been postulated to cause joint pain in clinical trials of MMP inhibitors [Scrip, 1998, 2349, 20] Long acting, selective, orally bioavailable non-peptide inhibitors of TACE would thus be highly desirable for the treatment of the disease states discussed above. 10 Sulfone hydroxamic acid inhibitors of MMPs, of general structure I have been disclosed [Burgess, L.E.; Rizzi, J.P.; Rawson, D.J. Eur Patent Appl. 818442. Groneberg, R.D.; Neuenschwander, K.W.; Djuric, S.W.; McGeehan, G.M.; Bums, C.J.; Condon, S.M.; Morrissette, M.M.; Salvino, J.M.; Scotese, A.C.; Ullrich, J.W. PCT Int. Apple. WO 97/24117. Bender, S.L.; Broka, C.A.; Campbell, J.A.; 15 Castelhano,A.L.; Fisher, L.E.; Hendricks, R.T.; Sarma, K. Eur. Patent Appl. 780386. Venkatesan, A. M.; Grosu, G. T.; Davis, J. M.; Hu, B.; O'Dell, M. J. PCT Int. Apple. WO 98/38163.]. An exemplification of this class of MMP inhibitor is RS 130830, shown below. 0 , HOH R3 HOHW S Y 0 C1 02 RS-1 30830 20 Within the sulfone-hydroxamic acid class of MMP inhibitor, the linker between the sulfone and hydroxamic acid moieties has been extended to three carbons (I, n = 2) without significant loss in potency [Barta, T. E.; Becker, D. P.; Villamil, C. I.; WO 00/44723 PCTIUSOO/01864 -4 Freskos, J. N.; Mischke, B. V.; Mullins, P. B.; Heintz, R. M.; Getman, D. P.; McDonald, J. J. PCT Int. Apple. WO 98/39316. McDonald, J. J.; Barta, T. E.; Becker, D. P.; Bedell, L. J.; Rao, S. N.; Freskos, J. N.; Mischke, B. V. PCT Int. Apple. WO 98/38859.]. 5 Piperidine sulfone hydroxamic acids, II (n = 1) have been reported [Becker, D. P.; Villamil, C. I.; Boehm, T. L.; Getman, D. P.; McDonald, J. J.; DeCrescenzo, G. A. PCT Int. Apple. WO 98/39315.]. Similar piperidine derivatives in which the methylene linking the piperidine ring to the sulfone has been deleted (H, n = 0) have been reported [Venkatesan, A. M.; Grosu, G. T.; Davis, J. M.; Baker, J. L. PCT Int. 10 Apple. WO 98/37877.]. 0 R2 HOH crY' n 0 1 x Ri Sulfone-hydroxamic acids III, in which a hydroxyl group has been placed alpha to the hydroxamic acid, have been disclosed [Freskos, J. N.; Boehm, T. L.; 15 Mischke, B. V.; Heintz, R. M.; McDonald, J. J.; DeCrescenzo, G. A.; Howard, S. C. PCT Int. Apple. WO 98/39326. Robinson, R. P. PCT Int. Apple. WO 98/34915.]. HOH R1 HOR 20 Sulfone-based MMP inhibitors of general structure IV, which utilize a thiol as the zinc chelator, have been reported [Freskos, J.N.; Abbas, Z.S.; DeCrescenzo, G.A.; Getman, D.P.; Heintz, R.M.; Mischke, B.V.; McDonald, J.J. PCT Int. Apple. WO 98/03164]. 02 HS aX.. R2 IV 25 WO 00/44723 PCT/USOO/01864 -5 Inhibitors of stromelysin with general structure V have been disclosed [Shuker, S.B.; Hajduk, P.J.; Meadows, R.P.; Fesik, S.W. Science, 1996, 274, 1531 1534. Hajduk, P.J.; Sheppard, G.; Nettesheim, D.G.; Olejniczak, E.T.; Shuker, S.B.; Meadows, R.P.; Steinman, D.H.; Carrera, Jr., G.M.; Marcotte, P.A.; Severin, J.; 5 Walter, K.; Smith, H.; Gubbins, E.; Simmer, R.; Holzman, T.F.; Morgan, D.W.; Davidsen, S.K.; Summers, J.B.; Fesik, S.W. J. Am. Chem. Soc. 1997, 119, 5818 5827. Olejniczak, E.T.; Hajduk, P.J.; Marcotte, P.A.; Nettesheim, D.G.; Meadows, R.P.; Edalji, R.; Holzman, T.F.; Fesik, S.W. J. Am. Chem. Soc. 1997, 119, 5828 5832. Fesik, S. W.; Summers, J. B.; Davidsen, S. K.; Sheppard, G. S.; Steinman, D. 10 H.; Carrera, G. M.; Florjancic, A.; Holms, J. H. PCT Int. Apple. WO 97/18188.]. X(CH2)nO NHOH R1 R2 V Salah et al., Liebigs Ann. Chem. 195, (1973) discloses some aryl substituted thio and aryl substituted sulfonyl acetohydroxamic acid derivatives of general 15 formula 1. These compounds were prepared to study the Mannich reaction. Subsequently, they were tested for their fungicidal activity. Mannich Reaction R /IS CONHOH R O 0 (O)n (O)n HN N 1 20 Some sulfone carboxylic acids are disclosed in U.S. patent 4,933,367. Those compounds were shown to exhibit hypoglycemic activity.
WO 00/44723 PCT/USOO/01864 -6 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-a converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal 5 wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection. In accordance with this invention there is provided a group of compounds of general formula I: 0 8
R
1 2 R2R Rg R X A (C 10 RI R10 R11 OH wherein: R, is hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or -C4 15 C8-cycloheteroalkyl;
R
2 and R, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, -CN, or -CCH; R, is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, 20 alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, -C(O)-Rj, -SO 2 -R, -C(O)-NHR, -C(O)NR 5
R
6 , -C(O)RINR 5 R , -C(O)-OR,
-C(NH)-NH
2 .
R
5 and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 25 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or -C4-C8 cycloheteroalkyl; WO 00/44723 PCT/USOO/01864 -7 R , R, R , and R are each, independently, hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C4-C8-cycloheteroalkyl, alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms; with the proviso that one of the pairs R8 and R9, R9 and R10 or R10 and R11, together with 5 the carbon atom or atoms to which they are attached, form a cycloalkyl ring of 3-6 carbon atoms, or a -C4-C8-cycloheteroalkyl ring;
R
12 is hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C4-C8-cyclo heteroalkyl, or alkyl of 1-6 carbon atoms; 10 AisO, S, SO, SO 2 , NR, or CH 2 ; X is 0, S, SO, SO2, NR, or CH2; Y is aryl or heteroaryl, with the proviso that A and X are not bonded to adjacent 15 atoms of Y; and n is 0-2; or a pharmaceutically acceptable salt thereof. In some preferred aspects of the invention, Y is phenyl, pyridyl, thienyl, 20 furanyl, imidazolyl, triazolyl or thiadiazolyl, with the proviso that A and X are not bonded to adjacent atoms of Y. In still other preferred embodiments of the invention Y is phenyl, thienyl or furanyl. 25 In accordance with certain preferred embodiments of the invention R 8 and R 9 , together with the carbon atom to which they are attached form a C 4 -C, cyclohetero alkyl ring and K is NR. The most preferred matrix metalloproteinase and TACE inhibiting compounds 30 of this invention are: 1-(4-Bromo-benzyl)-4-(4-but-2-ynyxoy-benzenesulfonyl)-piperdine-4 carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine-4 carboxylic acid hydroxyamide; WO 00/44723 PCT/USOO/01864 -8 4-( 4 -But-2-ynyloxy-benzenesulfonyl)- 1-( 4 -chloro-benzyl)-piperdine-4 carboxylic acid hydroxyamide; 1 -Benzyl- 4
-(
4 -but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxamide; 5 1-( 4 -Bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine-4 carboxylic acid hydroxyamide; 1-( 4 -Bromo-benzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4 carboxylic acid hydroxyamide; 4
-(
4 -But-2-ynyloxy-benzenesulfonyl)- 1-( 4 -fluoro-benzyl)-piperdine-4 10 carboxylic acid hydroxyamide; 4-( 4 -But-2-ynyloxy-benzenesulfonyl)- 1 -( 4 -cyano-benzyl)-piperidine-4 carboxylic acid hydroxamide; 4-( 4 -But-2-ynyloxy-benzenesulfonyl)- 1-(4-methyl-benzyl)-piperidine-4 carboxylic acid hydroxamide; 15 4-( 4 -But-2-ynyloxy-benzenesulfonyl)-1-(3,4- dichloro-benzyl)-piperidine-4 carboxylic acid hydroxamide; 1-(4-Bromo-benzyl)-4-( 4 -prop- 2 -ynyloxy-benzenesulfonyl)-piperdine-4 carboxylic acid hydroxyamide; 1-(4-Bromo-benzyl)-4-[ 4
-(
4 -piperdin-4-yl-but-2-ynyloxy)-benzenesulfonyl] 20 piperdine-4-carboxylic acid hydroxyamide; 1- (4-Bromo-benzyl)-4-
[
4
-(
4 -morpholin-4-yl-but-2-ynyloxy)-benzene sulfonyl]-piperdine-4-carboxylic acid hydroxyamide; 4-( 4 -But- 2 -ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine-1 carboxylic acid tert-butyl ester; 25 4-( 4 -But- 2 -ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxyamide 1-( 4 -Bromo-benzyl)-4-(4-but-2-ynyloxy-phenylsulfanyl)-piperidine-4 carboxylic acid hydroxyamide; 4-( 4 -But- 2 -ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxylic 30 acid hydroxyamide; WO 00/44723 PCT/USOO/01864 -9 4
-(
4 -But- 2 -ynyloxy-benzenesulfonylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide; 4-( 4 -But- 2 -ynyloxy-benzenesulfinylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide; 5 4-{ [4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxytetrahydro-2H-pyran-4 carboxamide; 1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperdine carboxamide; 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-isopropyl-4-piperidine 10 carboxamide; 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-(3-pyridinylmethyl)-4 piperidine carboxamide; 3- { [4-(2-Butynyloxy)phenyl] sulfonyl } -1 -ethyl-N-hydroxy-3 -piperidine carboxamide; 15 3- { [4-(2-butynyloxy)phenyl] sulfonyl } -1 -(4-chlorobenzyl)-N-hydroxy-3 piperidinecarboxamide; 4-{ [4-(2-Butynyloxy)phenyl]sulfonyl}-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl] piperidine-4-carboxylic acid hydroxyamide; 4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-(3-pentanyl)-piperidine-4-carboxylic acid 20 hydroxyamide; 1-(4-Methoxy-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4 carboxylic acid hydroxyamide; 1-(4-Chloro-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide; 25 tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl}methyl)-4-[(hydroxyamino) carbonyl]- 1 -piperidinecarboxylate; 4-({ [ 4 -(But-2-ynyloxy)phenyl]thio}methyl)-N-hydroxypiperidine-4 carboxamide; tert-Butyl-4-({ [4-(2-butynyloxy)phenyl]sulfinyl}methyl)-4-[(hydroxyamino) 30 carbonyl]- 1 -piperidinecarboxylate; WO 00/44723 PCT/USOO/01864 -10 4-[[[4-(2-Butynyloxy)phenyl]sulfinyl]methyl]-N-hydroxy-4-piperidine carboxamide; tert-Butyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino) carbonyl]piperidine- 1 -carboxylate; 5 tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino) carbonyl]- 1 -piperidinecarboxylate; I -Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-N-hydroxy-4 piperidinecarboxamide; 1-(2-Butynyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)methyl)-N-hydroxy-4 10 piperidinecarboxamide hydrochloride; N-i -(tert-Butyl)-4-({ [4-(2-butynyloxy)phenyl] sulfonyl} methyl)-N-4-hydroxy 1,4-[4-(2-butynyloxy)phenyl] sulfonyl} methyl)-N-4-hydroxy- 1,4-1] sulfonyl} methyl)-N-4-hydroxy-1,4-piperidinedicarboxamide; Methyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl4methyl)-4-[(hydroxyamino) 15 carbonyl]- 1-piperidinecarboxylate; Benzyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino) carbonyl]- 1 -pip eridinecarboxylate; 1-Benzyl-4-({[4-(2-butynyloxy)phenyl] sulfonyl) methyl)-N-hydroxy-4 butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide; 20 4-({[4-(2-Butynyloxy)phenyl]sulfonyl)methyl)-N-hydroxy-1-[(2,2,5-trimethyl 1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide; 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[3-hydroxy-2 (hydroxymethyl)-2-methylpropanoyl]-4-piperidinecarboxamide; 1-[Amino(imino)methyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N 25 hydroxy-4-1]-4-({ [4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4 oxy)phenyl]sulfonyl)methyl)-N-hydroxy-4-piperidinecarboxamide; 4-({ [4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy- 1 -(4-hydroxy-2 butynyl)- henyl] sulfonyl) methyl)-N-hydroxy- 1 -(4-hydroxy-2-butynyl)-4 piperidinecarboxamide; WO 00/44723 PCT/USOO/01864 -11 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl} methyl)- 1 -ethyl-N-hydroxypiperidine 4- carboxamide triflouroacetic acid salt; 2-chloro-5-(chloromethyl) thiophene4-({[4-(But-2-ynyloxy)phenyl]-sulfonyl} methyl)-1-[(5-chlorothien-2-yl)methyl]-N- hydroxypiperidine-4-carboxamide 5 triflouroacetic acid salt; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(pyridin-4 ylmethyl)piperidine-4-carboxamide triflouroacetic acid salt; 4-({[4-(But-2-ynyloxy)phenyl] sulfonyl} methyl)-N-hydroxy- 1 -(pyridin-3 ylcarbonyl)piperidine-4-carboxamide triflouroacetic acid salt; 10 1 -Benzoyl-4-({ [4-(but-2-ynyloxy)phenyl] sulfonyl) methyl)-N-hydroxy piperidine-4- carboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(thien-2 ylcarbonyl) piperidine-4-carboxamide; 4-({[4-(But-2-ynyloxy)phenyl] sulfonyl} methyl)-N- 1 -ethyl-N-4-hydroxy 15 piperidine- 1,4-dicarboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-N-1- phenyl piperidine- 1,4-dicarboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N- 1 -,N- I -diethyl-N-4 hydroxypiperidine-1,4-dicarboxamide; 20 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy- 1 -(morpholin-4 ylcarbonyl)piperidine-4-carboxamide; 4-({ [4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-N- 1-methyl-N-I phenylpiperidine-1,4-dicarboxamide; Octyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl)methyl)-4-[(hydroxyamino) 25 carbonyl] piperidine-1-carboxylate; 4-Methoxyphenyl4-({[4-(but-2-ynyloxy)phenyl]sulfonyl)methyl)-4-[(hydroxy amino) carbonyl]piperidine-1-carboxylate; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy- 1 -(phenylsulfonyl) piperidine-4-carboxamide; 30 4-({ [4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy- 1 -[(1-methyl-IH imidazol-4-yl)sulfonyl]piperidine-4-carboxamide; WO 00/44723 PCT/USOO/01864 -12 1-[2-(Benzylamino)acetyl]-4-({[4-(but-2-ynyloxy)phenyl]-sulfonyl}methyl)-N hydroxypiperidine-4-carboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy- 1 -(2-morpholin-4 ylacetyl)piperidine-4-carboxamide; 5 4-({ [4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy- 1-[2-(4-methyl piperazin- I -yl)acetyl]piperidine-4-carboxamide; 1 -Acetyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid hydroxamide; 1 -Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid 10 hydroxamide; 1-(4-Methoxybenzoyl)-4-(4-but-2-ynyloxy benzenesulfonyl)piperidine-4 carboxylic acid hydroxamide; 4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy- 1 -(pyrrolidine- 1 -carbonyl)-4 piperidinecarboxamide; 15 Ethyl 4-(4-but-2-ynyloxybenzenesulfonyl)-4-[(hydroxyamino)carbonyl]-1 piperidinecarboxylate; 4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy- 1 -[(trifluoromethyl)sulfonyl] 4- piperidinecarboxamide; 4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinylcarbonyl)- 4 20 piperidinecarboxamide; 4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy- 1 -(2-thienylcarbonyl)- 4 piperidinecarboxamide; 4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(4-methoxyphenyl) sulfonyl]-4-piperidinecarboxamide; 25 4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,3-dioxan 5-yl)carbonyl]-4-piperidinecarboxamide; Tert-butyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl] 1 -piperidinecarboxalate; 4- {[4-(2-butynyloxy)phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide 30 hydrochloride; WO 00/44723 PCT/USOO/01864 -13 Methyl ({4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl] 1 -piperidinyl}methyl)benzoate hydrochloride; 4-({4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl]-1 piperidinyl)methyl)benzoic acid hydrochloride; 5 1-[4-(Aminocarbonyl)benzyl]-4-{ [4-(2-butynyloxy)phenyl]sulfonyl}-N hydroxy-4-piperidinecarboxamide hydrochloride; Tert-butyl 4-{[4-(but-2-ynyloxy)phenyl]sulfinyl}-4-[(hydroxyamino) carbonyl]piperidine- I -carboxalate; 4-(4-(But-2-ynyloxy-benzenesulfinyl)-piperidine-4-carboxylic acid 10 hydroxamide hydrochloride; and 1-(4-Bromo-benzyl)-4-(4-But-2-ynyloxy-benzenesulfinyl)-piperidine-4 carboxylic acid hydroxamide hydrochloride; and pharmaceutical salts thereof. 15 Heteroaryl, as used throughout, is a 5-10 membered mono- or bicyclic aromatic ring having from 1-3 heteroatoms selected from N, NR7, S and 0. Heteroaryl is preferably N co N N,
R
7 R7 NN K 0N 20 WO 00/44723 PCT/USOO/01864 -14 wherein K is defined as 0, S or -NR,, and R, is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, -C(O)-R, -So 2 -Rj, -C(O)-NHR,, -C(O)NR 5 R , 5 C(O)R, NR 5 R , -C(O)-OR, -C(NH)-NH2 Preferred heteroaryl rings include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, 10 benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole. Heteroaryl groups of the present invention may be mono or disubstituted. -C4-C8-cycloheteroalkyl is defined as 15 ~> K K K K R7 -- -N -K NR7I K K , K K Ior -,NR7 K 'N N' R7. wherein K is 0, S or NR7 and R7 is as defined before. Preferred heterocycloalkyl rings include piperidine, piperazine, morpholine, 20 tetrahydropyran, tetrahydrofuran or pyrrolidine. Heterocycloalkyl groups of the present invention may optionally be mono- or di substituted.
WO 00/44723 PCT/USOO/01864 -15 Aryl, as used herein refers to phenyl or naphthyl aromatic rings which may, optionally be mono- or di- substituted. Alkyl, alkenyl, alkynyl, and perfluoroalkyl include both straight chain as well 5 as branched moieties. Alkyl, alkenyl, alkynyl, and cycloalkyl groups may be unsubstituted (carbons bonded to hydrogen, or other carbons in the chain or ring) or may be mono- or poly-substituted. Aralkyl as used herein refers to a substituted alkyl group, -alkyl-aryl, wherein alkyl is lower alkyl and preferably from 1-3 carbon atoms, and aryl is as previously 10 defined. Heteroaralkyl as used herein refers to a substituted alkyl group, alkyl heteroaryl wherein alkyl is lower alkyl and preferably from 1-3 carbon atoms, and heteroaryl is as previously defined. 15 Halogen means bromine, chlorine, fluorine, and iodine. Suitable substituents of aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, alkenyl, alkynyl and cycloalkyl include, but are not limited to halogen, alkyl of 1-6 carbon atoms; alkenyl of 2-6 carbon atoms; alkynyl of 2-6 carbon atoms, cycloalkyl 20 of 3-6 carbon atoms, -OR 5 , =0, -CN, -COR, perfluoroalkyl of 1-4 carbon atoms, -O-perfluoroalkyl of 1-4 carbon atoms, -CONRR 6 , -S(O)nR,,
-OPO(OR)OR
6 , -PO(OR,)R 6 , -OC(O)OR,, -ORNRR 6 , -OC(O)NRR , -C(O)NR0R , -COOR, -SO 3 H, -NR 5 R , -N[(CH 2
)
2
]
2
NR
5 , -NR 5 COR,,
-NR
5 COOR , -so 2
NR
5 R , -NO 2 , -N(R)SO 2 R,, -NR 5
CONR
5 R , 25 -NR 5
C(=NR
6
)NRR
6 , -NR 5 C(=NR,)N(SO2R)R 6 , -NRC(=NR 6 )N(C=OR,)R , -tetrazol-5-yl, -SO 2 NHCN, -SO2NHCONR 5
R
6 , phenyl, heteroaryl or -C4C8 cycloheteroalkyl; wherein -NRR may form a pyrrolidine, piperidine, morpholine, thiomorpholine, oxazolidine, thiazolidine, pyrazolidine, piperazine, or azetidine ring; 30 WO 00/44723 PCT/USOO/01864 -16
R
5 and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or -C4-C8 cycloheteroalkyl; 5 R 7 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, -C(O)-R,, -S0 2 -R,, -C(O)-NHRJ, -C(O)-OR,, -C(NH)-NH 2 ; and n is 0-2. 10 When a moiety contains more than one substituent with the same designation each of those substituents may be the same or different. Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, 15 malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or 20 potassium, when a compound of this invention contains an acidic moiety. The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry, the present invention includes such optical 25 isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. It is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one 30 racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
WO 00/44723 PCTIUSOO/01864 -17 The compounds of this invention are shown to inhibit the enzymes MMP-1, MMP-9, MMP-13 and TNF-ca converting enzyme (TACE) and are therefore useful in the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, graft rejection, insulin resistance, bone disease and HIV 5 infection. In particular, the compounds of the invention provide enhanced levels of inhibition of the activity of TACE in vitro and in cellular assay and/or enhanced selectivity over MMP-1 and are thus particularly useful in the treatment of diseases mediated by TNF. Also according to the present invention, there are provided processes for 10 producing the compounds of the present invention, which processes comprise one of the following: a) reacting a compound of formula 0 2 X3 AR(C)n OH 1io R11 wherein n, X, Y, A, RpR, R 3 , R 8
R
9 R, and R 1 1 are as defined above or a reactive derivative thereof, with a compound of formula 15 R 12 NHOH wherein R 1 2 is as defined above, to give a compound of formula I; or b) deprotecting a compound of formula: 0 R2 R3 R8 R9 XA (C)n NR 12 0R 30
R
1 R
R
1 o 1 WO 00/44723 PCT/US0O/01864 -18 wherein n, X, Y, A, R, R,, R 3 , R 8 , R 9 , RIO, R,, and R 2 , are defined above, and RO is a suitable protecting group such as t-butyl, benzyl, and trialkylsilyl, to give a corresponding compound of formula I or 5 c) cleaving a resin supported hydroxamate derivative containing the group 0 -0-NH (C)X A X R, R1o R11 wherein n, X, Y, A, RI R 2 , R 3 , R 8 , R,, RIO, and RI, are defined above to give a compound of formula I; 10 or d) resolving a mixture (e.g. racemate) of optically active isomers of a compound of formula I to isolate one enantiomer or diastereomer substantially free of the other enantiomer or diastereomers; or 15 e) acidifying a basic compound of formula I with a pharmaceutically acceptable acid to give a pharmaceutically acceptable salt; or f) converting a compound of formula I having a reactive substituent group or site to a compound of formula I having a different substituent group or site. 20 With regard to process a) the reaction can be carried out by processes known in the art, e.g. by reaction of an acid chloride or mixed anhydride reactive derivative with the compound of formula R, 2
NHOH.
WO 00/44723 PCT/USOO/01864 -19 Removal of protecting groups, as illustrated by process b) can be carried out by processes known in the art to provide the hydroxamic acid, -see for example Scheme 16 below. 5 Process c) may be carried using a strong acid such as TFA to cleave the hydroxamate from the resin. With regard to process d) standard separation techniques may be used to isolate particular enantiomeric or diastereomeric forms. For example a racemic 10 mixture may be converted to a mixture of optically active diastereoisomers by reaction with a single enantiomer of a 'resolving agent' (for example by diastereomeric salt formation or formation of a covalent bond). The resulting mixture of optically active diastereoisomers may be separated by standard techniques (e.g. crystallisation or chromatography) and individual optically active diastereoisomers 15 then treated to remove the 'resolving agent' thereby releasing the single enantiomer of the compound of the invention. Chiral chromatography (using a chiral support, eluent or ion pairing agent) may also be used to separate enantiomeric mixtures directly. 20 The compounds of formula I may be isolated in the form of a salt of a pharmaceutically acceptable acid e.g. an organic or inorganic acid by treatment with an acid such as described above. With regard to process e) compounds of formula I having a reactive 25 substituent group such as hydroxy or amino or site such as -S- can be converted to other compounds of formula I in known manner, e.g. alcohol to ester or ether. Reactive sites such as a sulfur atom can be oxidized to SO or SO2. (e.g. as shown in Scheme 4 below). If necessary reactive substituent groups may be protected during the synthesis of compounds of formula I and removed as a last step -see Schemes 4 30 and 17 below.
WO 00/44723 PCTUSOO/01864 -20 PROCESS OF THE INVENTION. The compounds of the present invention may be conveniently prepared 5 according to one of the general processes outlined below. The compounds of the present invention, where n = 0, X = 0, S or NR , and
R
8 and R' taken with the carbon atom to which they are attached, form a six membered heterocyclic ring containing N-R 7 , S or 0 and A = S, SO or SO 2 may be prepared according to one of the general processes outlined below. 10 As outlined in scheme 1, the appropriately substituted mercaptan derivative was alkylated using c-bromo acetic acid ester derivative in refluxing chloroform using N,N-diisopropylethylamine as base. The sulfide derivative thus obtained was reacted with appropriately substituted propargyl bromide derivative in refluxing acetone using K 2
CO
3 as base. In the case of X=-N-R the N-alkylation can be carried 15 out in DMF/NaH at room temperature. The sulfide derivative thus obtained was oxidized using m-chloroperbenzoic acid in CH 2 Cl 2 or by using Oxone in methanol/ water. The sulfone thus obtained can be converted to the corresponding piperidine derivative by reacting it with bis(2-chloroethyl)N-substituted amine derivative.
WO 00/44723 PCT/USOO/01864 -21 SCHEME 1 SYNTHESIS: x a SH B NOI s X= OH, SH, NHR 7 O A=S d R1 O R N HO Hx x e I PSNHH a. Diisopropylethyamine/ CHCl/ RT/ 3 Hr; b. K 2
CO
3 / Acetone/ Prpargyl bromide 5 derivative; c. Oxone/ MeOH:THF/THF/ RT; d: K 2
CO
3 / 18-Crown-6/ (C 4 H,),dNBr Acetone/Bis-2-chloroethyl N-substituted amine derivative/ Reflux; e: NaOHI/ THF:MeOH/RT and (COCl)/ NH 2 OH.HC1/ Et 3 N/ THF/ DMF. Bis-2-chloroethyl N-substituted amines can be prepared from the substituted 10 diethanolamine and thionyl chloride. (Scheme 2). The cyclic product obtained by the above mentioned operation, can be hydrolyzed to carboxylic acid and subsequently converted to the hydroxamic acid as outlined in scheme 1.
WO 00/44723 PCT/USOO/01864 -22 SCHEME 2 H R7 R7 a b HO OH HO OH CI C a: Diisopropylethylamine/R 7 Br/CHC 3 / Reflux; b: SOCI) CH 2 Clf Reflux 5 The corresponding sulfides and sulfoxides can be prepared starting from the corresponding saturated heterocyclic carboxylic acid derivative. (Scheme-3). N-Boc protected isonipecotic acid can be lithiated using tert-butyllithium and the resulting anion was reacted with appropriately substituted disufides. The sufide derivative can be converted to hydroxamic acids by the procedure outlined above. 10 SCHEME:3 a / b Q COOH S COOH S CONHOH C CONHOH OS CONHOH a: tert-Butyllithium/-78C/ THF/Bis(4-but-2-ynyloxyphenyl)disufide; b: (COCl)/ NHOH.HCI/EtN/DMF/CH2Cl, c: 1.HCl/ Dioxane; c: 2:RBr/ EtN; d: MeOH/30% 15 H 2 0 2 WO 00/44723 PCTIUSOO/01864 -23 These sulfides subsequently can be converted to the sulfoxides using 30% hydrogen peroxide at room temperature. The required disulfides can be prepared from the appropriately substituted thiol and DMSO/HCl oxidation. This procedure can be applied to any saturated, fused or non-fused heterocyclic carboxylic acid 5 derivative. (Scheme 4) SCHEME:4 O O COOH COOH 'N. b R7 O O CONHOH CONHOH X X d R7 R7 N CONHOH CONHOH 0 1 0 0 a: tert-Butyllithium/-78C/ THF/Bis(4-but-2-ynyloxyphenyl)disufide; b: (COCl)/ 10 NH 2 OH.HCl/Et 3 N/DMF/CHClc: CH2C1/ HCl/ MeOH / R 7 Br/ Et 3 N; d: MeOHI30% H2 2 ; e: Oxone/MeOHI/THF/Rt. Alternatively, sulfone derivatives can also be lithiated and carbonylated using either dry ice or CO 2 gas. (Scheme 5). The sulfone derivative can be a mono WO 00/44723 PCTIUSO0/01864 -24 heterocyclic, bicyclic , benzo fused or hetero aryl such as pyridyl, thienyl, furanyl, pyrazinyl, pyrimidyl, thiazolyl fused ring systems. SCHEME:5 S S O.S.NR7 ~1II.aOSNR7 COOH OCONHOH 5 a: n-Butyllithium and quench with CO 2 ; b: (COCl)/DMF/NH2OH.HCI/ Et 3 N The oxygen analogue can be prepared (Scheme 6) from the appropriately substituted alkynyloxy-benzenesulfonyl acetic acid ethyl ester and 2-chloroethyl ether. The corresponding pyran derivative can be hydrolyzed to carboxylic acid, 10 which can be converted to the hydroxamic acid derivative. SCHEME 6 x0
COOC
2
H
5 S COOC 2
H
5 b CONHOH S COOH a: 2-Chloroethyl ether/ K 2 C0/1 8-Crown-6/n-(C 4 H,), Br/Acetone/ Reflux; 15 b: ION. NaOHITHF/MeOH/RT; c: (COCl)/DMF/NH 2 OH.HC1/Et 3
N.
WO 00/44723 PCT/USOO/01864 -25 The thiols used as intermediates for the synthesis of compounds of the invention can be made according to Scheme 7. Thus, sulfonic acid salts 1, where
XR
50 is a hydroxy, thiol or substituted amino moiety may be alkylated with acetylenes 5 2, where J is a suitable leaving group such as halogen mesylate, tosylate, or triflate to give 3. Acetylenes 2 are commercially available or known compounds, or they may be synthesized by known methods by those skilled in the art. The sulfonic acid salts 3 may be converted into the corresponding sulfonyl chloride or other sulfonylating agent 4 by known methods, such as reaction with oxalyl chloride, phosphorus 10 oxychloride or other reagent compatible with substituents R 1 , R 2 and R, and the acetylene. The sulfonyl chloride 4 can then be reduced to the corresponding thiol 5 using triphenylphosphine in a suitable solvent mixture such as dichloromethane/DMF at a temperature of between -20'C and 30'C.
WO 00/44723 PCT/USOO/01864 -26 SCHEME 7 R5oXc+ R1R X SO3Na ' SO 3 Na 1 2 R1 3 R5oX - S-SQ XR 5 o 6 RyS-S-& ,R R2 SO2,- R21X SH
R
3 R R2 cisogi R 3~ SO3 R3 1 " R3 R 1 I I SH 7 8ii 4 Ri RiR R2X S1 2
RCIS
3 H I I SO3H 8 910 2 XH XH R 1112
R
2 R3 13 5 Alternatively, disulfide 6 may be converted into di-acetylene 7 by reaction with compounds 2, followed by reduction of the disulfide bond to provide the desired thiols 5. Bisacetylenes 7 may also be converted into thiols 5 via sulfonyl chlorides 4. Alkylation of the phenol, thiophenol, aniline or protected aniline 8 with 2 to give 9, followed by reaction with chlorosulfonic acid provides sulfonic acids 10 which are 10 readily converted into 4 with oxalyl chloride or similar reagents and subsequently WO 00/44723 PCTUSOO/01864 -27 reduced to thiols 5. Thiophenols 11 are also precursors to 5 via protection of the thiol with a triphenylmethyl or other suitable protecting group, alkylation of XH, where X is 0, N or S, and deprotection of the sulfur. Scheme 8: R3 2 R 2~ R R 3 2AR 1 R 1A 1 R11~R RjR1 K 2 00 3 I AH 5 R" 14 15 0 16 0 mCOOR30 9
R
1 1 1 R 2R R 1C )O RR 2
R
3 R1 R3) R1 R 2 R11 Hil 1 R1 R X .CONHOH R COOR3 ANHOH
R
9 R9 0 18 XR25 R9COOR3oR20 R117 AH
A<COOR
3 o AkCOOR 3 19 20 R 9 21 R 9
XR
25 XH +0K _______ -b 16/17 R11 RoA Oa RIO 2 A COOR3 5 0 22 23 WO 00/44723 PCT/USOO/01864 -28 Compounds of the invention wherein X is N, 0, S, SO or SO 2 , can be synthesized according to Scheme 8 and Scheme 9. Alkylation of the para disubstituted aryl 14, or its protected equivalent, with acetylene 2 in the presence of a base such as potassium carbonate in a polar aprotic solvent such as acetone or DMF at 5 a temperature of between 20'C and 120'C provides the mono-propargylic ether 15. Those skilled in the art will recognize that protecting groups may be required to avoid undesirable side reactions and increase the yield of the reaction. The need and choice of protecting group for a particular reaction is known to those skilled in the art. Reaction of this compound with *-propiolactone, or a substituted propiolactone 10 derivative (wherein the substituents are defined as before), in the presence of a base such as potassium t-butoxide in a polar solvent, or solvent mixture, such as THF or DMF affords the carboxylic acid 16. Conversion of carboxylic acid 16 into the corresponding hydroxamic acid, 17, is accomplished via formation of an activated ester derivative such as an acid chloride or acid anhydride followed by reaction with 15 hydroxylamine. It is understood by those skilled in the art that when A is sulfur, in Scheme 8 and all relevant subsequent Schemes, the sulfur can be oxidized to the corresponding sulfoxide or sulfone at any stage after formation of the thioether, using a suitable oxidant such as oxone, air, m-chloroperbenzoic acid or hydrogen peroxide. Compounds 18 are also accessible from the Michael addition of compound 15 20 to a cyclic acrylate ester, or substituted acrylate ester (substituents are defined as before), to provide 18, in which R, is hydrogen or a suitable carboxylic acid protecting group. Deprotection of the ester moiety then provides carboxylic acid, which can be converted into the analogous hydroxamic acid. Similarly, Michael addition of mono-protected 1,4-disubstituted aryl 19, where XR,, is hydroxy or 25 protected hydroxy, thiol or amine, gives compound 20. Unmasking of the protecting group gives thiol, aniline or phenol 21 which can be alkylated with propargyl derivative 2 to provide 18. Mono protected compound 19 can also be reacted with D-propionolactone to provide 22. Alternatively, 22 can be deprotected followed by alkylation to give 16 and 17. 30 WO 00/44723 PCT/USOO/01864 -29 Synthesis of compounds of the invention wherein X is N, 0, S, SO or SO 2 , and the linker between the proximal heteroatom and the hydroxamic acid is a one or three carbon chain can be synthesized according to Scheme 9. Compound 19, where
XR
25 is hydroxy or protected hydroxy, thiol or amine, can react with ester 24 or 5 lactone 24a, in which R 30 is hydrogen or a suitable carboxylic acid protecting group, with an appropriately substituted leaving group such as halogen, tosylate, mesylate or triflate, to provide 25. Unmasking of the heteroatom X of compound 25 then provides 26, which may next be alkylated with propargylic derivative 2 to give acetylene-ester 27. Ester 27 can be converted into the corresponding hydroxamic acid 28 through 10 conversion of the ester into the carboxylic acid by acid or base hydrolysis, followed by conversion into the hydroxamic acid as described in Scheme 1. Alternatively, compound 15, prepared as shown in Scheme 8, can be alkylated directly with ester 24 or lactone 24a to give 27 and then 28. Substituents on the carbon alpha to the hydroxamic are defined as before. 15 WO 00/44723 PCT/USOO/01864 -30 SCHEME 9 R25 j C ORo RR25 H 24 CDeprotect 24 Base A AH or A i 3 or COOR3o COOR30 1925 n 26n O R2 24a
R
3 ' (for A = S) I R1 R3 R1 R3 R1 R3J 2 Mn CONHOH AW COR30 28 27 R1CpOR Rio COR31 Ri Base 0 24a (for A = S) R3 R 1 AH Compounds of the invention wherein A is a methylene or substituted 5 methylene group, and X is oxygen, can be obtained according to Scheme 10. Esters or carboxylic acids 29, commercially available or known in the literature, can be converted into the corresponding phenols, 30. Alkylation of the phenol with acetylene 2 gives the propargylic ethers, 31, which can be converted into the corresponding carboxylic acids and thence the hydroxamic acids, 33, as described in Scheme 1. 10 Substituents on the carbon alpha to the hydroxamic, are defined as before.
WO 00/44723 PCT/USOO/01864 -31 SCHEME 10 Me C Rio oBBr 3 H
R
3 - RC R 1 o 0 i 1 - - I Rio~ 1 RI i.<i
COOR
3 o N COOR3oj 2 IiCOOR 3 0 29 30 R1 31 Ri RR20 Rio Ru1 R3r I l Rio Ril R CO NHOH 3 COOH Ri 33 32 5 Compounds of the invention wherein A is -SO 2 -, and R. and R, are not hydrogen, are available starting from 4-fluorobenzenethiol 34 as shown in Scheme 11. Deprotonation of the thiol followed by reaction with --propiolactone, or an acrylate ester, or ester deriavtive 24, and subsequent oxidation of the resulting thioether provides sulfone-acid 35. Displacement of the 4-fluoro substituent of 35, or 10 its corresponding ester, with propargyl derivative 36, wherein X is N, 0 or S, then provides sulfone 16. Compound 16 can be converted into the compounds of the invention according to Scheme 1. Fluoroaryl 35 can also react with a masked hydroxyl, thiol or amino group (HXR 4 0 , wherein R 4 0 is a suitable protecting group) in the presence of a base such as sodium hydride in a polar aprotic solvent such as DMF 15 to provide 36. Deprotection of 36 followed by alkylation with acetylenic derivative 2 then gives 16.
WO 00/44723 PCT/USOO/01864 -32 SCHEME 11 FF H _R2 __ R1 1) Base R2- - R1 R3 36 SH p-propiolactone 10 R11 or acrylate 02 <CO2R3o 02 10 R 34 or 24. n n 2) Oxidation 35 16 HXR 40
R
2 Base
R
3 2
XR
4 o H Deprotect R1 X O022~o0 C02R3o n 36 37 5 Compounds of the invention wherein X is NH are also available starting from the appropriate commercially available nitro aryl compound 38 (Scheme 12).Thus, the anion of compound 38 can be used to alkylate p-propiolactone, or a substituted derivative, or a cyclic acrylate ester to provide 40 and 39 respectively. Reduction of 10 the nitro group followed by alkylation of the resulting aniline then gives 16. Compound 38 can also be alkylated with ester derivative 24 to afford nitro-ester 40, followed by reduction to give the corresponding aniline, analogous to compound 26 of Scheme 9.
WO 00/44723 PCTUSOO/01864 -33 SCHEME 12 R3
NO
2 N0 2 1) Reduction / 0 2
R
30 R10 2) AH 9 R1 0 A C2R3
R
2
R
1 A 38 Base R9 CO2H
R
9 39 16 ,) 1?0 NH2 24 COOR 3 o N 2 4 n R 110 Base A C) ORfo A COORso or n 11 40 26
R
1 1& 5 Compounds of the invention wherein R, alpha to the hydroxamic acid, is a hydroxy group can be obtained via epoxides 41, as shown in Scheme 13. These epoxides are available through the oxidation of the corresponding acrylate esters or by the Darzens reaction of an alpha-halo ester with a ketone. Reaction of the epoxide with thiol, phenol or aniline 19 in the presence of base or Lewis acid catalyzed 10 epoxide ring opening, provides alpha-hydroxy ester 42. Deprotection of 42 followed by alkylation with propargyl derivative 2 gives 44. Conversion of the ester of 44 into the analogous hydroxamic acid as described in Scheme 1 then provides 45. Compounds 45, wherein A is sulfur, may be converted into the analogous sulfoxides or sulfones through oxidation with hydrogen peroxide, air, Oxone or other suitable 15 reagent at this point. Similarly, thiol, phenol or aniline 15 can be reacted with 41 to give 44. The hydroxyl group of compound 43 can also be manipulated through its conversion into a suitable leaving group, such as halide or sulfonate ester, followed by displacement with various nucleophiles including amines to provide 44.
WO 00/44723 PCT/USOO/01864 -34 SCHEME 13 X R25 R O 8 R 25 XH 41 R 10
R
9 Deprotect AH A 10 AHC 2R3o Ro C02R30 19 a. R 9 0R 3
R
8
R
9 C23 42 43 42 R3- _ 1 R,~ do H o R3 2O R1R 2 I R RR10 A R 1O C sONHOH aRC2~ 45 44 O R3oO a R10 Re 41 R3 R2 - R AH 15 5 Another route to alpha-hydroxy hydroxamic acids of the invention is shown in Scheme 14. Compound 15 can be alkylated with alcohol 46 to give 47. Oxidation of the alcohol, with or without concomitant oxidation of the thioether (for A = S), gives the aldehyde 48. Reaction of aldehyde 48 with trimethylsilyl cyanide or other suitable reagent then provides the cyanohydrin 49. Hydrolysis of the nitrile 49 into the WO 00/44723 PCTUSOO/01864 -35 corresponding carboxylic acid followed by conversion into the hydroxamic acid as described in Scheme 1 gives 50. SCHEME 14 R2
R
3 --
R
3 R1
R
3 -R1 R 10
R
11 X 1 X x HO 9.J 46 Oxidation 46 0 0
R
11 ~ RIO R 11 AA H 15 47 48 0 TMSCN
R
3 R R 3
-
R>i OR 11 R R 1 X X A CONHOH A CN OH OH 5 50 49 Compounds described in the present invention (from Example 30 to 63) were prepared as per the Schemes 15 and Scheme 16. In scheme 15, the t-Boc-protected 10 ethyl isonipecotate 51 was carefully alkylated using diiodomethane to yield the monoiodo compound 52. This was subsequently converted to different hydroxamic acid derivatives as depicted in Scheme 15. In scheme 16, the N-Boc group was selectively removed using TMSOTf/ 2,6-Lutidine. After the derivatisation of the nitrogen, the O-tBu was removed using TFA in methylene chloride. 15 WO 00/44723 PCTUSOO/01864 -36 Scheme 15 NaOH
SO
3 Na (COCI)2 SPPh3 Brg _CH2CI2 CH2Cl2 O DMF DMF COOEt COOEt COOEt (BOC)20 , LDA N N CH 2 1 2 N H BOC BOC 0 1. NaOH/MeOH/THF S N HOH 2.EDC/HOBT/NH 2 0H N 3. HCI N R = BO R H Oxone 30% H 2 0 2 NHOH l 0 BOC R R = BOC 1. NaOH/MeOH/THF R = H 2.EDC/HOBT/NH 2 OH 3.HCI OT 2.RX, RCOX,RNCO, ROCOX I 0 0 0, N 3. NaOH/MeOH/THF N A 4. EDC/HOBT/NH 2 OH O R, R R = BOC R =H WO 00/44723 PCT/USOO/01864 -37 Scheme 16 O ~1. NaOH/MeOH/THF
CO
2 Et CO 2 H N N BOC BOC I 1..EDC/HOBT/NH 2 OtBu SI O TMSOTf ISO CONHOtBu 2,6-Lutidine CONHOtBu N N H BOC 1.RX, RCOX,RNCO, ROCOX O= O TFA/ CH2Cl2O CONHOtBu CONHOH N N A A 5 Alternatively, compounds (wherein A = SO 2 and n = 0) described in examples 64 to 74 and 80 were prepared as depicted in Scheme 17.
WO 00/44723 PCTUSOO/01864 -38 Scheme 17 COOMe 0 O0O LDA/ -780 C 0 S NaOH/ MeOH/THF
SO
2 F N EDC,HOBT,NH 2 0H BoBo 1. HCI/MeOHH 2.RXEt 3 N HOHN R N Boo 1. HCI/MeOH 2NH2Oo' 2. RX Et 3 N R .NaOH/MeOHITHF 0 2.EDC,HOBT,NH 2 0H HOHN N R 5 WO 00/44723 PCT/USOO/01864 -39 Example 1 1-(4-Bromo-benzyl)-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine 4-carboxylic acid hydroxyamide 5 Step 1: To a stirred solution of 4-mercapto phenol (12.6 g. 100 mmol) and N,N diisopropylethylamine (13.0 g, 100 mmol) in chloroform (200 ml), ethyl bromoacetate (17.0 g, 100 mmol) in chloroform (30 ml) solution was added slowly at room temperature. After the addition was complete, the reaction mixture was 10 refluxed for 1 hr and cooled to room temperature. The reaction mixture was washed well with water, dried over anhydrous MgSO,; filtered and concentrated. The oily product obtained was taken to next step without purification. Step 2: 15 A mixture of K 2 CO, (15 gm, excess), ( 4 -hydroxy-phenylsulfanyl)-acetic acid ethyl ester (5 g, 23.6 mmol) and 1-bromo-2-butyne (9.34 g, 35.4 mmol) was refluxed with stirring for 8 hrs. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous MgSO 4 , filtered and 20 concentrated. The product obtained was taken to next step with out purification. Yield 6.0 g (96%); yellow oil; MS: 264.0 El (M*H). Step 3: To a stirred solution of (4-but-2-ynyloxy-phenyl sulfanyl)-acetic acid ethyl 25 ester (101 g, 380 mmol) in MeOH: THF (3:1) (1000 ml), Oxone (670.0 g, excess) in water (1000 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 8 hrs. The reaction mixture was then diluted with chloroform (600 ml) and filtered. The organic layer was separated and washed once with a saturated solution of NaHSO, (400 ml). The chloroform layer was washed well with 30 water, dried and concentrated. The oily product was dissolved in MeOH (100 ml) WO 00/44723 PCT/USOO/01864 -40 and hexane (600 ml) was added. The separated colorless solid was filtered and washed with hexane. Yield 108 g (96%); mp. 91 - 93'C; MS: 297 (M*H)*. Step 4: 5 A mixture of diethanolamine (22.5 g, 150 mmol), 4-bromobenzyl bromide (25 g, 100 mml) and N,N-diisopropylethylamine (19.0 g, 150 mmol) was refluxed for 24 hrs in chloroform (500 ml) solution. The reaction mixture was then concentrated and the residue was extracted with chloroform. It was washed well with water, dried over anhydrous MgSO 4 , filtered and concentrated. The crude product obtained was taken 10 to next step with out purification. Yield 33.6 g (99%); Yellow oil, MS: 273.8 (M+H)*. Step 5: 2- [(4-Bromobenzyl)- (2-hydroxy-ethyl)-amino] -ethanol (33.28 g, 122 mmol) 15 was dissolved in methanolic hydrogen chloride (100 ml) at 00 C. Methanol was removed in vacuo and the hydrochloride salt was suspended in CH 2 Cl 2 ( 300 ml). To a stirred solution of the above mentioned suspension, thionyl chloride (30 g, excess) was added slowly at room temperature. The reaction mixture was brought to gentle reflux for 3 hrs. The reaction mixture was then concentrated and the (4-bromo 20 benzyl)-bis-(2-chloro-ethyl)-amine was used in the next step with out purification. Yield: 47 g (99%); brown solid; mp 1250 C; MS: 309.8 (M+H)*. Step 6: A stirred mixture of anhydrous K 2 CO2 ( 10 g, excess), 18-crown-6 (1 g), 25 tetrabutylammonium bromide (1.0 g), ( 4 -but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (2.8 g, 9.46 mmol) and ( 4 -bromo-benzyl)-bis-(2-chloro-ethyl)-amine (4.9 g, 14.2 mmol) in anhydrous acetone (200 ml) was refluxed for 24 hrs. The reaction mixture was then cooled and filtered and the filtrate was concentrated. The crude product was extracted with chloroform, washed well with water, dried and 30 concentrated. The brown colored material was purified by column chromatography WO 00/44723 PCT/USOO/01864 -41 on silica gel by eluting with 50% ethylacetate : hexane. Yield 1.36 g (27%); brown oil; MS: 534 (M+H)* Step 7: 5 1-( 4 -Bromo-benzyl)-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4 carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-but-2-ynyloxy benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (1.36 g, 2.54 mmol) dissolved in THF:methanol (100: 50 ml) and 10 N NaOH (15 ml). The reaction mixture was stirred at room temperature for 24 hrs. The reaction mixture was then 10 concentrated and residue was cooled and neutralized with concentrated HCl. The separated solid was extracted with chloroform:methanol (3:1) (300 ml) and washed with water. The chloroform layer was dried and concentrated. The product was crystallized from methanol. Yield 800 mg (62%); off white solid; mp 197 'C; MS: 507.9 (M+H)* 15 Step 8: To a stirred solution of 1-(4-bromo-benzyl)-4-(4-but-2-ynyxoy-benzene sulfonyl)-piperdine-4-carboxylic acid (750 mg, 1.5 mmol) and DMF (1 ml) in CH 2 Cl 2 (100 ml), oxalyl chloride (508 mg, 4.0 mmol) in methylene chloride (2 ml) was 20 added dropwise at 0" C. After the addition, the reaction mixture was warmed to room temperature and stirred for 1 hr. The acid chloride thus formed was concentrated to remove excess oxalyl chloride and redissolved in CH 2 C1 2 (30 ml). In a separate flask, hydroxylamine hydrochloride (690 mg, 10 mmol) was dissolved in DMF (10 ml) and triethylamine (10 g, 10 mmol) was added. The reaction mixture was further diluted 25 with acetonitrile (25 ml) and stirred at 0' C. The acid chloride was slowly added into the hydroxylamine and after the addition was complete, the reaction mixture was brought to room temperature and stirred for 24 hrs. The reaction mixture was concentrated and the residue was extracted with chloroform, washed well with water and dried over anhydrous Na 2
SO
4 . The product was purified by silica gel column 30 chromatography by eluting it with 10% methanol:ethyl acetate. 270 mg of 1-(4 bromo-benzyl)-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid WO 00/44723 PCT/USOO/01864 -42 hydroxyamide was isolated as a hydrochloride salt, a white powder. Yield 52%; mp 153 'C; MS: 522.9 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 6 1.85 (t, J=2.04 Hz, 3H), 2.23 (m, 2H), 2.49 (m, 2H), 2.83 (m, 2H), 3.36 (m, 2H), 4.28 (s, 2H) 4.89 (d, J=2.2 Hz, 2H), 7.18 (d, J= 9 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.68 (m, 4H), 9.37 (s, 5 1H), 10.25 (s, 1H) Example 2 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine 4-carboxylic acid hydroxyamide 10 2- [(2-Hydroxy-ethyl)- (4-methoxy-benzyl)-amino] -ethanol was prepared according to the general method as outlined in Example I (Step 4). Starting from diethanolamine ( 10.5g, 100mmol). and 4-methoxy benzyl chloride ( 15.6g, 100 mmol). Yield 21g, (98%); yellow oil; MS: 226 (M+H)* 15 Bis-(2-chloro-ethyl)-(4-methoxy-benzyl)-amine was prepared according to the general method as outlined in Example 1 (Step 5). Starting from 2-[(2-hydroxy ethyl)-(4-methoxy-benzyl)-amino]-ethanol (11.2 g, 50mmol). Yield 14g, ( 99%); dark brown low melting solid; MS: 263 (M+H)* 20 4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4 carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (2 g, 6.73 mmol) and bis-(2-chloro-ethyl)-(4-methoxy-benzyl)-amine (2.61 g, 8.75 mmol) and following the procedure as outlined in Example 1 (Step 6) 2.5 g of 25 the product was isolated. Yield 2.5 g (77%); yellow oil; MS: 486 (M+H)* 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine-4 carboxylic acid was prepared starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)-1 (4-methoxy-benzyl)-piperdine-4-carboxylic acid ethyl ester (2.5 g, 5.15 mmol) 30 dissolved in THF:methanol (3:1, 200 ml) and 10 N NaOH (15 ml). The resulting WO 00/44723 PCT/USOO/01864 -43 reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 1.26 g (54%); off white solid; mp 223 'C; MS: 458 (M+H)* Starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl) 5 piperdine-4-carboxylic acid (1 g, 2.19 mmol) and following the procedure as outlined in Example 1, (Step 8), 350 mg of 4-(4-but-2-ynyloxy-benzenesulfonyl)-l-(4 methoxy-benzyl)-piperdine-4-carboxylic acid hydroxyamide was isolated as a hydrochloride salt, an off white solid. Yield 31%; mp 162 'C; MS: 473 (M+H)*; 'H NMR (300 MHz, DMSO-d,): 5 1.86 (t, J= 2.13 Hz, 3H), 2.23 (m, 2H), 2.49 (m, 2H), 10 2.73 (m, 2H), 3.39 (m, 2H), 3.77 (s, 3H), 4.21 (d, J= 4.26 Hz, 2H), 4.89 (d, J=2.28 Hz, 2H), 6.99 (d, J= 8.7 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.68 (d, J= 9 Hz, 2H), 9.37 (s, 1H), 10.21 (s, 1H), 11.17 (s, 1H). Example 3 15 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-chloro-benzyl)-piperdine 4-carboxylic acid hydroxyamide 2- [(4-chlorobenzyl)- (2-hydroxy-ethyl)-amino] -ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (14.3 g, 95 mmol). and 4-chlorobenzyl chloride (10.2 g, 63 mmol). 20 Yield 12.1 g, (84%); yellow oil; MS: 230 (M+H)* (4-Chloro-benzyl)-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in Example 1 (Step 5). Starting from 2-[(4 chlorobenzyl)-(2-hydroxy-ethyl)-amino] -ethanol (12 g, 52.4 mmol). Yield 41.27 g, 25 (90%); yellow powder; mp 115 'C; MS: 303 (M+H)* 4-(4-But-2-ynyloxy-benzenesulfonyl)-I-(4-chloro-benzyl)-piperdine-4 carboxylic acid ethyl ester was prepared according to the general method as outlined in Example I (Step 6). Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid 30 ethyl ester (4 g, 13.5 mmol) and (4-chloro-benzyl)-bis-(2-chloro-ethyl)-amine (4.9 g, 16.2 mmol). Yield 3.5 g (53%); white crystals; MP 91.8'C; MS: 490 (M+H)* WO 00/44723 PCTUSOO/01864 -44 4-(4-But-2-ynyloxy-benzenesulfonyl)- 1-(4-chloro-benzyl)-piperdine-4 carboxylic acid was prepared starting from 4
-(
4 -but-2-ynyloxy-benzenesulfonyl)-1 (4-chloro-benzyl)-piperdine-4-carboxylic acid ethyl ester (3.14 g, 6.42 mmol) 5 dissolved in THF:methanol 3:1 (100 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 2.37 g (80%); white solid; mp 205 'C; MS: 461.9 (M+H)* Starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)- 1-(4-chloro-benzyl) 10 piperdine-4-carboxylic acid (2.31 g, 5.01 mmol) and following the procedure as outlined in Example 1 (Step 8), 790 mg of 4 -(4-but-2-ynyloxy-benzenesulfonyl)-1 (4-chloro-benzyl)-piperdine-4-carboxylic acid hydroxyamide was isolated as a hydrochloride salt, a yellow solid. Yield 31%; mp 130 'C; MS: 476.9 (M+H); 'H NMR (300 MHz, DMSO-d,): 6 1.856 (s, 3H), 2.23 (m, 2H), 2.73-2.89 (m, 4H), 3.37 15 (d, 2H), 4.28 (m, 2H), 4.89 (d, 2H), 7.18 (d, J = 8.94 Hz, 2H), 7.54 (s, 4H), (d, J=8.88 Hz, 2H), 9.40 (s, 1H), 10.3 (s, 1H). Example 4 1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine 20 4-carboxylic acid hydroxyamide Bis-(2-Chloro-ethyl)-benzyl amine was prepared according to the general method as outlined in Example 1 (Step 5). Starting from N-benzyldiethanolamine (164.6 g, 844 mmol). Yield 178.5 g (79%); brown solid; MS: 231.9 (M+H)* 25 1-Benzyl-4-( 4 -but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (2 g, 6.73 mmol) and bis-(2-chloro-ethyl)-benzyl amine (2.3 g, 8.8 mmol). Yield 3.33 g (99%); yellow oil; MS: 455.9 (M+H)* 30 WO 00/44723 PCTUSOO/01864 -45 1 -Benzyl-4-( 4 -but- 2 -ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid was prepared starting from 1-benzyl-4-( 4 -but- 2 -ynyloxy-benzenesulfonyl)-piperdine 4-carboxylic acid ethyl ester (3 g, 6.6 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined 5 in Example 1 (Step 7). Yield 1.65 g (59%); off white powder; mp 191 'C; MS: 428 (M+H)* Starting from 1 -benzyl- 4
-(
4 -but-2-ynyloxy-benzenesulfonyl)-piperdine-4 carboxylic acid (1.55 g, 3.63 mmol) and following the procedure as outlined in 10 Example 1 (Step 8), 1.08 g of 1-benzyl- 4 -(4-but-2-ynyloxy-benzenesulfonyl) piperdine-4-carboxylic acid hydroxyamide was isolated as a hydrochloride salt, an off white powder. Yield 62%; mp 175 'C; MS: 443 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 6 1.85 (t, J= 2.16 Hz, 3H), 2.25 (m, 2H), 2.49 (m, 4H), 2.77 (m, 2H), 4.28 (d, J=4.3 Hz, 2H), 4.89 (d, J= 2.28, 2H), 7.18 (m, 2H), 7.46 (m, 5 H), 7.73 (m, 15 2H), 9.36 (s, 1H), 10.27 (s, 1H), 11.08 (s, 1H). Example 5 1-( 4 -Bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine 4-carboxylic acid hydroxyamide 20 ( 4 -Pent-2-ynyloxy-phenylsulfanyl)-acetic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 2). Starting from (4 hydroxy-phenylsulfanyl)-acetic acid ethyl ester (5 g, 30 mmol) and 2-pentynyl chloride (3.7 g, 36.6 mmol) 7.15 g of the product isolated. Yield 7.15 g (86%); brown oil; MS: 278 El (M+H)* 25
(
4 -Pent-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 3). Starting from (4 pent-2-ynyloxy-phenylsulfanyl)-acetic acid ethyl ester (7.04 g, 25.3 mmol) and oxone (25 g) (4-Pent-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester was isolated. Yield 30 8 g (99%); yellow oil; MS: 310.9 (M+H)* WO 00/44723 PCT/USOO/01864 -46 1-(4-Bromo-benzyl)-4-( 4 -pent-2-ynyloxy-benzenesulfonyl)-piperidine-4 carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from ( 4 -pent- 2 -ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (4 g, 12.9 mmol) and (4-bromo-benzyl)-bis-(2-chloro-ethyl)-amine (5.83 5 g, 16.8 mmol, 2.85 g of the product was isolated. Yield 2.85 g (31%); low melting white solid; MS: 549.9 (M+H)* 1-( 4 -Bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine-4 carboxylic acid was prepared starting from 1-( 4 -bromo-benzyl)-4-(4-pent-2-ynyloxy 10 benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (2.64 g 4.8 mmol) dissolved in THF:methanol (100:50 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 1.6 g (65%); off white solid; mp 217 'C; MS: 521.9 (M+H)* 15 Starting from 1-( 4 -bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl) piperdine-4-carboxylic acid (1.55 g, 2.98 mmol) and following the procedure as outlined in Example 1 (Step 8), 200 mg of 1-( 4 -bromo-benzyl)-4-(4-pent-2-ynyloxy benzenesulfonyl)-piperdine-4-carboxylic acid hydroxyamide was isolated as a HCl salt, a yellow solid. Yield 12%; mp 62 'C; MS: 536.9 (M+H)*;'H NMR (300 MHz, 20 DMSO-d,): 6 1.069 (t, J = 7.47 Hz, 3H), 2.26 (m, 2H), 2.49 (m, 2H), 2.73 (m, 2H), 2.89 (s, 2H), 3.40 (d, 2H), 4.26 (d, 2H), 4.9 (m, 2H) 7.18 (m, 2H), 7.48 (d, J= 8.4 Hz, 2H), 7.66 (m, 4H), 10.39 (s, 1H), 11.19 (s, 1H). Example 6 25 1-( 4 -Bromo-benzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine 4-carboxylic acid hydroxyamide
(
4 -Oct-2-ynyloxy-phenylsulfanyl)-acetic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 2). Starting from (4 hydroxy-phenyl-sulfanyl)-acetic acid ethyl ester (5 g, 30 mmol) and 1-bromo-2 30 octyne (6.9 g, 36.6 mmol) 8.9 g of ( 4 --oct- 2 -ynyloxy-phenylsulfanyl)-acetic acid ethyl ester was isolated. Yield 8.9 g (92%); yellow oil; MS: 320 El (M+H)* WO 00/44723 PCT/USOO/01864 -47 (4-Oct-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 3). Starting from (4 oct-2-ynyloxy-phenylsulfanyl)-acetic acid ethyl ester (8.8 g, 27.5 mmol) 8.45 g of (4 5 -oct-2-ynyloxy-phenylsulfonyl)-acetic acid ethyl ester was isolated. Yield 8.45 g (87%); yellow oil; MS: 352 El (M+H)* 1-(4-Bromo-benzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4 carboxylic acid ethyl ester was prepared according to the general method as outlined 10 in Example 1(Step 6). Starting from (4-oct-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (4 g, 11.4 mmol) and (4-bromo-benzyl)-bis-(2-chloro-ethyl)-amine (5.13 g, 14.8 mmol) 1.47 g of 1-(4-bromo-benzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl) piperdine-4-carboxylic acid ethyl ester was isolated .Yield 1.47 g (22%); yellow solid; MS: 591.9 (M+H)* 15 1-(4-Bromobenzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4 carboxylic acid was prepared starting from 1-(4-bromobenzyl)-4-(4-oct-2-ynyloxy benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (1.36 g, 2.3 mmol) dissolved in THF:methanol (50:50 ml) and 10 N NaOH (10 ml). The resulting reaction mixture 20 was worked up as outlined in Example 1 (Step 7). Yield 660 mg (51%); off white solid; mp 199 'C; MS: 562 (M+H)* Starting from 1-(4-bromo-benzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl) piperdine-4-carboxylic acid (570 mg, 1.01 mmol) and following the procedure as 25 outlined in Example 1 (Step 8), 100 mg of 1-(4-bromo-benzyl)-4-(4-oct-2-ynyloxy benzenesulfonyl)-piperdine-4-carboxylic acid hydroxyamide was isolated as a hydrochloride salt, a white powder. Yield 17%; mp 140 'C; MS: 579 (M+H)*; 'H NMR (300 MHz, DMSO-d,): 6 0.828 (t, J=7.14 Hz, 3H), 1.25 (m, 6H), 1.38 (m, 2H), 2.27 (m, 2H), 2.49 (m, 4H), 2.73 (m, 2H), 4.03 (m, 2H), 4.91 (s, 2H), 7.18 (d, 30 J= 9 Hz, 2H), 7.47 (d, J= 8.1 Hz, 2H), 7.68 (m, 4H), 9.43 (s, 1H), 10.25 (s, 1H), 11.19 (s, 1H).
WO 00/44723 PCT/USOO/01864 -48 Example 7 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperidine 4-carboxylic acid hydroxyamide 5 2-[(4-Fluoro-benzyl)-(2-hydroxy-ethyl)-amino] -ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (15.7 g, 150 mmol). and 4-fluoro-benzyl chloride (14.4 g, 100 mmol) 20 g of the product was isolated. Yield 20 g, (93%%); yellow oil; MS: 215 (M+H)* 10 (4-Flouro-benzyl)-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in Example 1 (Step 5). Starting from 2-[(4-fluoro benzyl)-(2-hydroxy-ethyl)-amino]-ethanol (23.6g, 110 mmol) 28 gms of the product was isolated. Yield 28 g, (96%); brown solid; mp 98-99 'C; MS: 251 (M+H)* 15 4 -(4-But-2-ynyloxy-benzenesulfonyl)- 1-(4-fluoro-benzyl)-piperidine-4 carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (5 g, 16.9 mmol) and (4-fluoro-benzyl)-bis-(2-chloro-ethyl)-amine (5.8 g, 20 20.1 mmol) 5.3 g of the product was isolated. Yield 5.3 g (67%); Brown oil; MS: 474 (M+H)* 4-(4-But-2-ynyloxy-benzenesulfonyl)- 1 -(4-fluoro-benzyl)-piperidine-4 carboxylic acid was prepared starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)-1 25 ( 4 -fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester (9.5g, 20 mmol) dissolved in THF:methanol 3:1 (100 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 5.7 g (63%); white solid; mp 106-106 'C; MS: 447 (M+H)* 30 Starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)- 1 -(4-fluoro-benzyl) piperidine-4-carboxylic acid (5.7 g, 13 mmol) and following the procedure as WO 00/44723 PCTUSOO/01864 -49 outlined in Example 1 (Step 8), 4.1 g of 4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4 fluoro-benzyl)-piperdine-4-carboxylic acid hydroxyamide was isolated as a HCl salt, a yellow solid. Yield: 64%; mp 162-4 'C; MS: 461 (M+H)*; 'H NMR (300 MHz, CDCl 3 ): 6 1.92 (s, 3H), 2.02-2.32 (m, 6H), 2.86 (m, 2H), 3.41 (d, 2H), 4.84 (d, 2H), 5 7.01 (d, J = 8.94 Hz, 2H), 7.15 (d, J=8.88 Hz, 2H), 7.25 (d, J=9 Hz, 2H), 7.74 (d, J= 9.0 Hz, 2H), 9.4-9.7 (bs, 1H). Example 8 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine 10 4-carboxylic acid hydroxyamide 4-{ [Bis- (2-hydroxyethyl)-amino] -methyl} benzonitrile was prepared according to the general method as outlined in Example I (Step 4) starting from diethanolamine (10.2 g, 97 mmol) and ox-bromo-p-tolunitrile (15.8g, 81 mmol). Yield, (68%); white solid; mp 163 'C MS: 221.2 (M+H)* 15 4- { [Bis-(2-chloroethyl)-amino]-methyl}benzonitrile was prepared according to the general method as outlined in Example I (Step 5) starting from 4-{[bis-(2 hydroxyethyl)-amino]-methyl}benzonitrile (33.28 g, 122 mmol). Yield g, (%); brown solid; mp 'C; MS: (M+H)* 20 4-(4-But-2-ynyloxy-benzenesulfonyl)- 1-(4-cyano-benzyl)-piperidine-4 carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from 4
-(
4 -but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (5.86g, 19.8 mmol) and 4-cyano-benzyl-bis-(2-chloro-ethyl)-amine 25 (5.4g, 18 mmol) 4.7 g of the product was isolated. Yield (52%); amber oil; MS: 481.0 (M+H)* 4 -(4-But-2-ynyloxy-benzenesulfonyl)- 1-(4-cyano-benzyl)-piperidine-4 carboxylic acid was prepared starting from 4 -(4-But-2-ynyloxy-benzenesulfonyl)-l 30 (4-cyano-benzyl)-piperidine-4-carboxylic acid ethyl ester(4 g, 8.3 mmol) dissolved in THF:Methanol (60: 30 ml) and 10 N NaOH (10 ml). The resulting reaction mixture WO 00/44723 PCT/USOO/01864 -50 was worked up as outlined in Example 1 (Step 7). Yield 1.8g (48%); off white solid; MS: 441.9 (M+H)* Starting from 4-(4-But-2-ynyloxy-benzenesulfonyl)- 1- (4-cyano-benzyl) 5 piperidine-4-carboxylic acid (1.8g, 4 mmol) and following the procedure as outlined in Example 1 (Step 8), 0.20 g of 4
-(
4 -But- 2 -ynyloxy-benzenesulfonyl)-1-(4-cyano benzyl)-piperidine-4-carboxylic acid hydroxamide was isolated as a hydrochloride salt, white solid. Yield 20%; mp 109.6 'C; MS: 468.0 (M+H)*; 'H NMR (300 MHz, DMSO-d,): 6 1.86 (m, 3H), 2.25 (m, 4H), 2.5 (m, 2H), 2.85 (d, 2H), 4.39 (s, 2H), 10 4.88 (s, 2H), 7.15-7.19 (d, J=13.2, 2H), 7.67-7.70 (d, J=13.5, 2H), 7.78 (m, 2H), 7.96-7.99 (d, J=9.6, 2H), 9.42 (s, 1H), 10.14 (s, 1H), 11.20 (s, 1H) Example 9 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidine 15 4-carboxylic acid hydroxamide 2- [(2-Hydroxy-ethyl)-(4-methyl-benzyl)-amino] -ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (4.84g, 46 mmol) and 4-methylbenzyl bromide (8.5g, 46 mmol), 8.2 g of the product was isolated. Yield, (85%); white solid; MS: 210.1 (M+H)* 20 4-Methyl-benzyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 1 (Step 5). Starting from 2-[(2-Hydroxy ethyl)-(4-methyl-benzyl)-amino]-ethanol (6.0 g, 20 mmol) 5.2 g of the product was isolated. Yield: (84%); yellow solid; mp 145-147 'C; MS: 245.9 (M+H)* 25 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidine-4 carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from 4-(4-but - 2 -ynyloxy-benzenesulfonyl)-acetic 30 acid ethyl ester (5.75g, 19.0 mmol) and 4-methyl-benzyl-bis-(2-chloro-ethyl)-amine (6.04, 208 mmol) 6.47 g of the product was isolate. Yield: (72%); amber oil; MS: 470
(M+H)*
WO 00/44723 PCT/USOO/01864 -51 4-( 4 -But-2-ynyloxy-benzenesulfonyl)- 1 -( 4 -methyl-benzyl)-piperidine-4 carboxylic acid was prepared starting from 4
-(
4 -But-2-ynyloxy-benzenesulfonyl)-1
(
4 -methyl-benzyl)-piperidine-4-carboxylic acid ethyl ester ester (6.4 g, 13.6 mmol) 5 dissolved in THF:Methanol (30: 20 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in Example I (Step 7). Yield 2.3g (48%); off white solid; mp 213 'C MS: 441.9 (M+H)* Starting from 4
-(
4 -But-2-ynyloxy-benzenesulfonyl)- 1 -(4-methyl-benzyl) 10 piperidine-4-carboxylic acid (2.0g, 5.0 mmol) and following the procedure as outlined in Example 1 (Step 8), 3.6g of 4
-(
4 -But- 2 -ynyloxy-benzenesulfonyl)-1-(4 methyl-benzyl)-piperidine-4-carboxylic acid hydroxamide was isolated as a HCl salt, off-white solid. Yield 1.2g (28%); mp 188 'C; MS: 457.0 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 6 1.86 (s, 3H), 2.27 (m, 2H), 2.50 (m, 4H), 2.64 (m, 2H), 4.23 15 4.24 (d, J=4.5, 2H), 4.89 (d, J=1.8, 2H), 7.16-7.19 (d, J=9 2H), 7.24-7.26 (d, J=7.5, 2H), 7.37-7.40 (d, J=8.1, 2H), 9.36 (s, 1H), 10.11 (s, IH), 11.20 (s, 1H) Example 10 4
-(
4 -But-2-ynyloxy-benzenesulfonyl)-1-(3,4- dichloro-benzyl)-piperidine-4 20 carboxylic acid hydroxyamide 2- [(2-Hydroxy-ethyl)- (3,4-dichlor-benzyl)-amino] -ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (4.84g, 46 mmol) and 3,4-dichlorobenzyl chloride (8.97g, 46 mmol) , 9.4 g of the product was isolated. Yield, (78%); white solid; MS: 264.3 (M+H)* 25 3
,
4 -Dichloro-benzyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in Example 1 (Step 5). Starting from 2-[(2-Hydroxy ethyl)-(3,4-dichloro-benzyl)-amino]-ethanol (10.7 g, 41 mmol), 10.7 g of the product was isolated. Yield: (84%); yellow solid; mp 218-220 'C; MS: 301.8 (M+H)* 30 4
-(
4 -But-2-ynyloxy-benzenesulfonyl)- 1-(3, 4 -dichloro-benzyl)-piperidine-4 carboxylic acid ethyl ester was prepared according to the general method as outlined WO 00/44723 PCTUSOO/01864 -52 in Example I (Step 6). Starting from 4-(4-but - 2 -ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (6.1g, 23 mmol) and 3
,
4 -dichloro-benzyl-bis-(2-chloro-ethyl)-amine (8.6g, 25 mmol), 4.9 g of the product was isolated. Yield:(41%); amber oil; MS: 523.8 (M+H)* 5 4-( 4 -But-2-ynyloxy-benzenesulfonyl)- 1-(3, 4 -dichloro-benzyl)-piperidine-4 carboxylic acid was prepared starting from 4
-(
4 -But-2-ynyloxy-benzenesulfonyl)-1 (3,4-dichloro-benzyl)-piperidine-4-carboxylic acid ethyl ester ester (8.6 g, 16.4 mmol) dissolved in THF:Methanol (40: 30 ml) and 10 N NaOH (15 ml). The 10 resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 2.lg (38%); off white solid; mp 232 'C MS: 495.9 (M+H)* Starting from 4
-(
4 -But-2-ynyloxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl) piperidine-4-carboxylic acid (2.06g, 4.0 mmol) and following the procedure as 15 outlined in Example 1 (Step 8), 1.2g of 4
-(
4 -But-2-ynyloxy-benzenesulfonyl)-1-(3,4 dichloro-benzyl)-piperidine-4-carboxylic acid hydroxamide was isolated as a HCl salt, off-white solid. Yield 1.2g (56%); mp 213 0 C; MS: 510.9 (M+H)*; 'H NMR (300 MHz, DMSO-d,): 6 1.86 (s, 3H), 2.30 (m, 2H), 2.50 (m, 4H), 2.80 (m, 2H), 4.40 (s, 2H), 4.90 (s, 2H), 7.16-7.19 (d, J=9 2H), 7.51-7.54 (d, J=8.4, 2H), 7.66-7.69 (d, 20 J=9.0, 2H), 7.75-7.86 (d, J=11.7, 2H), 7.88 (s, 1H), 9.38 (s, 1H), 10.44 (s, 1H), 11.19 (s, 1H). Example 11 1-( 4 -Bromo-benzyl)- 4
-(
4 -prop-2-ynyloxy-benzenesulfonyl)-piperdine 25 4-carboxylic acid hydroxyamide Step 1:
(
4 -Prop-2-ynyloxy-phenylsulfanyl)-acetic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 2). Starting from (4 hydroxy-phenylsulfanyl)-acetic acid ethyl ester (example 1, 1" paragraph) ( 2.12g, 30 10 mmol) and propargyl bromide ( 1.8g, 15mol) 2.4 g of the product was isolated. Yield: (96%); amber oil; MS: 251(M+H)* WO 00/44723 PCT/USOO/01864 -53 Step 2: (4-Prop-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 3). Starting from (4 prop-2-ynyloxy-phenyl sulfanyl)-acetic acid ethyl ester ( 2.5g, 10 mmol) 2.8 g of (4 5 Prop-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester was isolated. Yield (99%); brown oil ; MS: 283 (M+H)* Step 3: 1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4 10 carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-prop-2-ynyloxy-benzenesulfonyl)- acetic acid ethyl ester (21.62 g, 76.7 mmol) and (4-bromo-benzyl)-bis-(2-chloro-ethyl) amine (31.9g, 92 mmol), 23 g of the ester derivative was isolated. Yiel: (58%); yellow oil; MS: 521.9 (M+H)*. 15 Step 4: 1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4 carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-prop-2-ynyloxy benzene-sulfonyl)-piperdine-4-carboxylic acid ethyl ester (5 g, 9.59 mmol) dissolved 20 in THF:methanol (150:50 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in Example 1( Step 7). Yield 3.4 g (72%); brown low melting solid; MS: 491.9 (M-H) Step 5: 25 Starting from 1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl) piperdine-4-carboxylic acid (3 g, 6.1 mmol) and following the procedure as outlined in Example I (Step 8), 580 mg of 1-(4-bromo-benzyl)-4-(4-prop-2-ynyloxy benzene-sulfonyl)-piperdine-4-carboxylic acid hydroxyamide was isolated as an HCl salt, off white powder. Yield 18%; mp 155 'C; MS: 508.8 (M+H)*; 1 H NMR (300 30 MHz, DMSO-d,): 5 2.22 (m, 2H), 2.50 (m, 2H), 2.79 (m, 2H), 3.45 (m, 2H), 4.27 (m, 2H), 4.96 (d, J=2.3 Hz, 2H), 7.2 (d, J=9 Hz, 2H), 7.48 (m, 2H), 7.68 (m, 4H), 9.37 (s, 1H), 10.36 (s, 1H), 11.19 (s, 1H).
WO 00/44723 PCT/USOO/01864 -54 Example 12 1-(4-Bromo-benzyl)-4-[4-(4-piperdin-4-yl-but-2-ynyloxy)-benzenesulfonyl] piperdine-4-carboxylic acid hydroxyamide 5 To a stirred solution of piperidine (1.63 g, 19.2 mmol) diluted in dioxane (100 mL) acetic acid (5mL) was added. The reaction fumed and stirred for 5 minutes. 1 (4-bromo-benzyl)-4-( 4 -prop- 2 -ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (5.0 g, 9.6 mmol), paraformaldehyde (0.29 g, 9.6 mmol) and the copper(I)chloride (0.35g) was added to the piperidine solution. The reaction turned 10 green and was heated at reflux for 1 hour turned brown. It was then concentrated and diluted in ice water then brought to pH 8 with NH 4 OH and extracted in CHCl 3 . The organic layer was washed 4 times with water then dried over Na 2
SO
4 then concentrated. The product was purified by silica gel column chromatography by eluting it with 5% methanol: chloroform solution. 15 Yield 5.15 g (87%); brown oil; MS: 309.9 (M+2H) 2 ., 618.8 (M+H)* 1-(4-Bromo-benzyl)-4-[4-(4-piperidin-1-yl-but-2-ynyloxy)-benzenesulfonyl] piperdine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-[4-(4 piperidin-1-yl-but-2-ynyloxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (4.64 g, 7.5 mmol) dissolved in THF:methanol (50:150 ml) and 10 N NaOH (20 20 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 3.35 g (76%); off white solid; mp 180 'C; MS: 295.9 (M+2H) 2 . 590.9 (M+H)* Starting from 1-( 4 -bromo-benzyl)-4-[4-(4-piperidin-1-yl-but-2-ynyloxy) 25 benzene-sulfonyl]-piperidine-4-carboxylic acid (1.9 g, 3.2 mmol) and following the procedure as outlined in Example 1 (Step 8), 810 mg of 1-(4-bromo-benzyl)-4 [4-(4-piperidin-1-yl-but-2-ynyloxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as a hydrochloride salt, a pale yellow solid. Yield 40%; mp 209 'C; MS: 303.4 (M+2H) 2 . 605.9 (M+H)*; 'H NMR (300 MHz, DMSO-d): 6 30 1.70 (m, 2H), 2.29 (m, 2H), 2.76 (m, 4H), 3.40 (m, 10H), 4.14 (s, 2H), 4.26 (2H), WO 00/44723 PCT/USOO/01864 -55 7.24 (d, J= 9 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.67 (m, 4H), 9.39 (s, 1H), 10.45 (s, 1H). Example 13 5 1-(4-Bromo-benzyl)-4-[4-(4-morpholin-4-yl-but-2-ynyloxy)-benzenesulfonyl] piperdine-4-carboxylic acid hydroxyamide To a stirred solution of morpholine (1.68 g, 19.2 mmol) diluted in dioxane (100 mL) acetic acid (5 mL) was added. The reaction fumed and stirred for 5 minutes. 1-(4-bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4 10 carboxylic acid ethyl ester (5.0 g, 9.6 mmol), paraformaldehyde (0.29 g, 9.6 mmol) and the copper(I)chloride (0.35g) was added to the piperidine solution. The reaction turned green and was heated at reflux for 1 hour turned brown. It was then concentrated and diluted in ice water then brought to pH 8 with NH40H and extracted in CHCl 3 . The organic layer was washed 4 times with water then dried over Na 2
SO
4 15 then concentrated. The product, 1-(4-Bromo-benzyl)-4-[4-(4-morpholin-4-yl-but-2 ynyloxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was purified by silica gel column chromatography by eluting it with 5% methanol: chloroform solution. Yield 3.0 g (50%); colorless solid ; mp 110' C; MS: 311 (M+2H) 2 ., 621 (M+H)* 20 1-(4-Bromo-benzyl)-4- [4- (4-morpholin-4-yl-but-2-ynyloxy)-benzene sulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-(4-bromo benzyl)-4-[4-(4-morpholin-4-yl-but-2-ynyloxy)-benzenesulfonyl]-piperidine-4 carboxylic acid ethyl ester (2.87g, 4.6 mmol) dissolved in THF:methanol (3:1, 150 25 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 2.26 g (83%); white powder; mp 198 'C; MS: 593.1 (M+H)* Starting from 1-(4-bromo-benzyl)-4-[4-(4-morpholin-4-yl-but-2-ynyloxy) 30 benzenesulfonyl]-piperidine-4-carboxylic acid (2.1 g, 3.55 mmol) and following the procedure as outlined in example 1, 1.8 g of 1-(4-bromo- benzyl)-4-[4-(4-morpholin- WO 00/44723 PCT/USOO/01864 -56 4-yl-but-2-ynyloxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as a hydrochloride salt, a white solid. Yield 80%; mp 94 'C; MS: 304.4 (M+2H) 2 . 607.9 (M+H)*;'H NMR (300 MHz, DMSO-d,): 6 2.38 (m, 2H), 2.46 (m, 2H), 2.75 (m, 2H), 3.35 (m, 2H), 3.87, (m, 8H), 4.21 (s, 2H), 4.26 (s, 2H), 5.10 (s, 5 2H), 7.24 (d, J = 9 Hz, 2H), 7.51 (d, J= 8.4 Hz, 2H), 7.67 (m, 4H), 9.42 (s, 1H), 10.69 (s, 1H), 11.13 (s, 1H) Examples of compound where A = S or S=0. 10 Example 14 4-(4-But-2-ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine 1-carboxylic acid tert-butyl ester To a solution of triphenylphosphine (24.7g, 94.2 mmol) and dimethyl formamide (0.6 mL) in dichloromethane (25 mL) was added a solution of 4-but-2 15 ynyloxy-phenylsulfonyl chloride (7.69g, 31.4 mmol) in dichloromethane dropwise over 30 min. After an additional 2h, 1N aqueous hydrochloric acid (20 mL) and water was added. The organic layer was separated and concentrated in vacuo. Aqueous sodium hydroxide (1N, 50 mL) was added and the solid removed by filtration. The aqueous phase was washed with diethyl ether (3x), treated with 1N 20 aqueous hydrochloric acid (50 mL) and extracted with ether (3x). the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated to give the thiol as an oil (3.77g). This material was dissolved in dimethylsulfoxide (40 mL) and concentrated hydrochloric acid was added (2 mL). After 18h, diethyl ether was added and the organic phased was washed with water (5x) and dried over 25 anhydrous magnesium sulfate. Concentration in vacuo gave a yellow solid which was filtered through silica gel with hexane:ethyl acetate to give bis (4-but-2-ynyloxy phenyl) disulfide as a yellow solid (3.0g, 80%). 'HNMR (CDCl3: 300MHz): 1.86 (s, -CH3, 3H), 4.63 (s, -CH2, 2H), 6.90 (d, ArH, 2H, J = 9 Hz), 7.40 (d, ArH, 2H, J = 9 Hz). 30 To a solution of N-BOC-isonipecotic acid (0.62g, 2.7 mmol) in tetrahydrofuran (20 mL) at -78 'C was added tert-butyllithium (3.4 mL, 1.7M in WO 00/44723 PCT/USOO/01864 -57 hexane, 5.7 mmol). After 10 min at -78 C the yellow solution was warmed to 0 0 C in an ice bath. After 30 min the colorless solution was cooled to -78 C whereupon bis (4-but-2-ynyloxy phenyl) disulfide(1.0 g, 2.8 mmol) was added as a solution in tetrahydrofuran (6 mL). The reaction mixture was allowed to warm to 25 "C. After 5 1.5h ethyl acetate was added followed by 6 mL of IN aqueous hydrochloric acid in 20 mL of water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Chromatography on silica gel (methanol/methylene chloride) gave the product (0.55g). 'H NMR (DMSO-d6): 1.38 (s, OtBu, 9H), 1.5 - 1.6 (m, CHH, 2H), 1.84 (s, CH3, 3H), 1.89 - 1.99 (m, CHH, 10 2H), 2.95 - 3.05 (m, CHH, 2H), 3.6 - 3.7 (m, CHH, 2H), 4.8 (s, CH2, 2H), 6.95 (d, ArH, 2H, J = 9 Hz), 7.38 (d, ArH, 2H, J = 9 Hz). Dimethylformamide (0.163 mL) was added to a solution of oxalyl chloride (1.06 mL of a 2.OM solution in dichloromethane) in dichloromethane (2 mL) at 0 C. 15 After 15 min a solution of the acid in dimethylformamide (5 mL) was added and the reaction mixture was allowed to warm to room temperature. After lh the reaction mixture was added to a mixture of hydroxylamine hydrochloride (0.737 g), triethylamine (2.22 mL), water (5.7 mL) and tetrahydrofuran (22.8 mL) that had been stirring at 0 C for 15 min. The reaction was held at 0 C for 18h then diluted with 20 dichloromethane and washed with saturated aqueous sodium bicarbonate (3X), then dried over potassium carbonate and concentrated in vacuo to give 480 mg of 4-(4 but-2-ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine- 1 -carboxylic acid tert-butyl ester. 'H NMR (DMSO-d6): 1.37 (s, OtBu, 9H), 1.5 - 1.6 (m, CHH, 2H), 1.84 (s, CH,, 3H), 1.9 - 2.0 (m, CHH, 2H), 3.05 - 3.15 (m, CHH, 2H), 3.5 - 3.6 (m, 25 CHH, 2H), 4.8 (s, CH 2 , 2H), 6.9 (d, ArH, 2H), 7.4 (d, ArH, 2H), 8.8 (s, NHOH, 1H), 10.7 (d, NHOH, IH).
WO 00/44723 PCT/USOO/01864 -58 Example 15 4-(4-But-2-ynyloxy-phenylsulfanyl)-piperidine 4-carboxylic acid hydroxyamide 4-(4-But-2-ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine-1 5 carboxylic acid tert-butyl ester, prepared by the method outlined in Example 14 (Step 3) (0.175g, 0.4 mmol), was treated with 4N hydrochloric acid in dioxane (5 mL) at 25 *C for 1h 15 min. The reaction mixture was concentrated in vacuo, diethyl ether was added and the resulting precipitate isolated by filtration to give 4-(4-but-2-ynyloxy phenylsulfanyl)-piperidine-4-carboxylic acid hydroxyamide as a white solid (0. 12g). 10 Electrospray Mass Spectroscopy: ((M+H)* = 321) Example 16 1-(4-Bromo-benzyl)-4-(4-but-2-ynyloxy-phenylsulfanyl)-piperidine 4-carboxylic acid hydroxyamide 15 4-(4-But-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxy amide (prepared by the procedure outlined in example 15) (0.15g, 0.5 mmol) in methanol (5 mL) and dimethylformamide (2.5 mL) was treated with triethylamine (0.15 mL, 1.1 mmol) followed by 4-bromobenzylbromide (0.13g, 0.53 mmol). After 6h the solution was diluted with ethyl acetate, acidified to pH = 6 with IN aqueous 20 hydrochloric acid, washed sequentially with water, aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate. Concentration in vacuo gave 1-(4 bromo-benzyl)-4-(4-but-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxyamide. 'HNMR (DMSO-d6): 1.5 - 1.6 (m, CHH, 2H), 1.8 (s, CH3, 3H), 1.9 2.2 (m, CHH, 4H), 2.5 - 2.6 (m, CHH, 2H), 3.4 (s, CH2Ar, 2H), 4.75 (s, CH2, 2H), 25 6.9 (d, ArH, 2H), 7.2 (d, ArH, 2H), 7.3 (d, ArH, 2H), 7.5 (d, ArH, 2H), 8.8 (s, NHOH, 1H), 10.6 (d, NHOH, 1H). Electrospray Mass Spectroscopy: ((M+H)* = 489/491) Examples of compounds , where n = 1 and A = S, S=O or SO 2 30 WO 00/44723 PCT/USOO/01864 -59 Example 17 4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran 4-carboxylic acid hydroxyamide 4-But-2-ynyloxy-benzenesulfonic acid sodium salt 5 To a solution of 52.35g (0.225 mol) of 4-hydroxybenzenesulfonate sodium salt in 1L of isopropanol and 225 mL of a 1.ON solution of sodium hydroxide was added 59.96g (0.45 mol) of 1-bromo-2-butyne. The resulting mixture was heated to 700 for 15h and then the isopropanol was removed by evaporation in vacuo. The resulting white precipitate was collected by filtration, washed with isopropanol and 10 ether and dried in vacuo to give 56.Og (100%) of the butynyl ether as a white solid. 4-But-2-ynyloxy-benzenesulfonyl chloride To a 0' solution of 43.8 mL (0.087 mol) of oxalyl chloride in 29 mL of dichloro-methane was dropwise added 6.77 mL (0.087 mol) of DMF followed by 15 7.24g (0.029 mol) of 4-but-2-ynyloxy-benzenesulfonic acid sodium salt . The reaction mixture was stirred for 10 minutes at 0' then let warm to room temperature and stirred for 2 days. The reaction was then poured into ice and extracted with 150 mL of hexanes. The organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 6.23g (88%) of the sulfonyl chloride as 20 a yellow solid; m.p. 63-65'C. El Mass Spec: 243.9 (M'). But-2-ynyloxy-benzene To a solution of 6.14g (23.40 mmol) of triphenylphosphine dissolved in 100 mL of benzene and 50 mL of THF was added 1.75 mL (23.40 mmol) of 2-butyn- 1 -ol. 25 After five minutes 2.00g (21.28 mmol) of the phenol, dissolved in 10 mL of THF, was added to the reaction followed by 3.69 mL (23.40 mmol) of diethyl azodicarboxylate. The resulting reaction mixture was stirred for 18h at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 2.18g (70%) of the 30 desired propargylic ether as a clear liquid. El Mass Spec: 146.0 M' WO 00/44723 PCTIUSOO/01864 -60 4 -But-2-ynyloxy-benzenesulfonyl chloride To a solution of 0.146g (1.0 mmol) of the but-2-ynyloxy-benzene in 0.3 mL of dichloromethane in an acetone/ice bath under N 2 was dropwise added a solution of 0.073 mL (1.1 mmol) of chlorosulfonic acid in 0.3 mL of dichloromethane. After the 5 addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 2h. To the reaction was then dropwise added 0.113 mL (1.3 mmol) of oxalyl chloride, followed by 0.015 mL DMF. The reaction was heated to reflux for 2h and then diluted with hexane and poured into ice water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 10 0.130g (53%) of the desired product as a light brown solid. 4 -But-2-ynyloxy-benzenethiol To a solution of 11.8g (.045 mol) of triphenylphosphine dissolved in 10 mL of dichloromethane and 0.3 mL of DMF was added 3.67g (.015 mol) of the 4-but-2 15 ynyloxy-benzenesulfonyl chlorid , dissolved in 15 mL of dichloromethane and the resulting mixture was stirred for 2h at room temperature. After the addition of 5 mL of 1N HCl solution the reaction was stirred for 0.5h followed by the addition of 15 mL of brine. The organics were separated and concentrated in vacuo and the residue was diluted with ether and 2.5N sodium hydroxide solution. The resulting precipitate 20 was filtered off and the aqueous layer was acidified to pH2 and extracted with ether. The combined organics were washed with brine, dried over Na 2 So 4 , filtered through Magnesol@ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes/ether (4:1) to provide 1.13g (42%) of the thiol as a yellow oil. CI Mass Spec: 179 (M+H). 25 4-( 4 -But- 2 -ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxylic acid To a solution of 0.1 12g (2.81 mmol) of 60% sodium hydride in 2 mL of THF, cooled to 0' C, was added a solution of 0.500g (2.81 mmol) of 4-but-2-ynyloxy benzenethiol, dissolved in 3 mL of THF. The resulting mixture was stirred for 0.5h at 30 room temperature, then cooled to 5' C, followed by the addition of 0.518g (3.65 mmol) of neat 2 ,7-dioxaspiro[3,5]nonane-1-one while keeping the reaction WO 00/44723 PCT/USOO/01864 -61 temperature below 100 C. The reaction was allowed to warm to room temperature and stirred for an additional 0.5h and then quenched with 3 mL of 3N HCI solution and 3 mL of water. The resulting mixture was extracted with dichloromethane and the combined organics were washed with water and brine, dried over Na 2
SO
4 , filtered 5 through a plug of silica gel and concentrated in vacuo. The residue was triturated with hexanes and acetonitrile and filtered to give 0.72g of the carboxylic acid as a semi solid. Electrospray Mass Spec: 319 (M-H) 4
-(
4 -But- 2 -ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxylic acid 10 hydroxyamide To a 0' C solution of 0.74g (2.31 mmol) of the product of 4-(4-but-2 ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxylic acid, dissolved in 7 mL of dichloromethane and 0.175 mL of DMF was added 1.27 mL (2.54 mmol) of a 2M solution of oxalyl chloride. The reaction was warmed to room temperature and 15 stirred for 2h and then recooled to 0' C. A mixture of 0.875 mL (14.2 mmol) of a 50% hydroxylamine solution, 5.0 mL of THF and 2.0 mL of t-butanol were then added to the reaction. The reaction was stirred at room temperature for 1h and then concentrated in vacuo. The residue was extracted with dichloromethane and the combined organics were washed with water and brine, dried over Na 2 SO, filtered and 20 concentrated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol (92:8) to provide 0.212g of the sulfide-hydroxamic acid as a white solid; m.p.135-137 0 C. Electrospray Mass Spec: 336 (M+H)* Example 18 25 4
-(
4 -But- 2 -ynyloxy-benzenesulfonylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide To a 0' C solution of 0.186g (0.56 mmol) of the product of 4-(4-but-2 ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide, dissolved in 1.2 mL of THF and 4.8 mL of methanol was dropwise added a solution 30 of 0.619g (1.008 mmol) of Oxone@ in 3 mL of water, while keeping the temperature below 200 C. After the addition was complete the reaction was stirred at room WO 00/44723 PCT/USOO/01864 -62 temperature for 3h. The reaction mixture was then poured into a cooled solution of 2.5 mL of toluene and 5 mL of ethyl acetate and the precipitate was filtered off. The filtrate was extracted with ethyl acetate/toluene and the combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was 5 triturated with ethyl acetate/toluene (5:2), filtered and dried in vacuo to provide 0. 12g (55%) of the sulfone-hydroxamic acid as a white solid; m.p. 184-185' C. Electrospray Mass Spec: 368 (M+H)* Example 19 10 4-(4-But-2-ynyloxy-benzenesulfinylmethyl)-tetrahydro-pyran 4-carboxylic acid hydroxyamide To a 0 0 C solution of 0.288g (0.80 mmol) of the product of 4-(4-but-2 ynyloxy-benzenesulfanylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide dissolved in 20 mL of methanol was added 7.0 mL of 30% hydrogen peroxide 15 solution. The reaction was allowed to warm to room temperature and stirred for 24h. The reaction mixture was then recooled to 0 0 C, quenched with saturated Na 2 SO, and concentrated in vacuo. The residue was diluted with water and dichloromethane. The organics were washed with water and brine, dried over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 20 dichloromethane/methanol (95:5) to provide 0.050g of the sulfoxide as a white solid. Electrospray Mass Spec: 351.9 (M+H)* Example 20 4-{14-(2-butynyloxy)phenyljsulfonyl}-N-hydroxytetrahydro-2H-pyran-4 25 carboxamide Step 1: Ethyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl} tetrahydro-2H-pyran-4-carboxylate (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (10 g, 33.8 mmol) was added to a stirring solution of potassium carbonate (12 g), 18-crown-6 (0.5 g), 2 30 chloroethyl ether (4.75 ml, 40.5 mmol), and tetrabutyl ammonium bromide (0.5 g) in methyl ethyl ketone (200 ml). The mixture was heated at reflux overnight before the WO 00/44723 PCTIUSO0/01864 -63 salts were filtered off and the filtrate was concentrated. The residue was dissolved in chloroform and washed with water. The organic layer was dried over Na 2
SO
4 , filtered and concentrated. The compound was isolated using silica-gel column chromatography by eluting it with 20% ethyl acetate: hexane solution. Ethyl 4-{[4 5 (2-butynyloxy)phenyl]sulfonyl} tetrahydro-2H-pyran-4-carboxylate was isolated as a yellow oil (10.06 g). Yield 80%; MS: 367.2 (M+H)* 4-{[4-(2-butynyloxy)phenyl]sulfonyl} tetrahydro-2H-pyran-4-carboxylic acid was prepared according to the general method as outlined in example 1 (step7), 10 starting from ethyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl) tetrahydro-2H-pyran-4 carboxylate (10 g, 27.3 mmol); 2.7 g white solid. mp: 197 'C; Yield 30%; MS: 337.2 (M-H)~ Starting from a crude mixture of 4 -{[4-(2-butynyloxy) phenyl] sulfonyl} 15 tetrahydro-2H-pyran-4-carboxylic acid (2.59 g, 7.66 mmol), and following the procedure as outlined in Example 1 (step 8), 1.51 g of 4 -{[4-(2-butynyloxy) phenyl] sulfonyl}-N-hydroxytetrahydro-2H-pyran-4-carboxamide was isolated as off white crystals. Mp: 210 'C; Yield: 58%; MS: 354.2 (M+H)*; 'H NMR (300 MIHz, DMSO d 6 ): 8 1.85 (t, J=2.28 Hz, 3H), 1.92 (in, 2H), 2.20 (d, J=13.1 Hz, 2H), 3.15 (t, 20 J=1 1.52, 2H), 3.86 (d of d, 2H), 4.88 (d, J=2.34 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.66 (d, J=8.91 Hz, 2H), 9.16 (s, 1H), 11 (s, 1H). Example 21 1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperdine 25 carboxamide Ethyl [(3-hydroxyphenyl) sulfanyl] acetate was prepared according to the general method as outlined in example I (step 1), starting from ethyl bromoacetate (7.95 g, 47.6 mmol) and 3-hydroxythiophenol (7.95 g, 47.6 mmol); 4.21 g yellow oil. Yield 41%; MS: 211.2 (M-H)~ 30 WO 00/44723 PCT/USOO/01864 -64 Ethyl { [3 -(2-butynyloxy)phenyl]sulfanyl) acetate was prepared according to the general method as outlined in example 1 (step 2), starting from ethyl [(3-hydroxy phenyl)sulfanyl]acetate (3.87g, 18.3 mmol) and 4-bromo-2-butyne (2.66 g, 20 mmol); 5.16 g yellow oil. Yield 100%; MS(EI): 264.1 (M+H)* 5 Ethyl{ [3-(2-butynyloxy)phenyl]sulfonyl} acetate was prepared according to the general method as outlined in example 1 (step 3), starting from ethyl{ [3-(2-butynyl oxy)phenyl]sulfanyl}acetate (5g, 18.9 mmol) and oxone (23.3 g, 37.9 mmol); 6.19 g yellow oil. Yield 100%; MS(EI): 296.1 (M+H)* 10 Ethyl 1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-4-piperdine carboxylate was prepared according to the general method as outlined in example 1 (step 6), starting from ethyl{[3-(2-butynyloxy)phenyl]sulfonyl} acetate (3 g, 10.1 mmol) and Benzyl-bis- (2-chloro-ethyl) amine hydrochloride (2.88 g, 10.7 mmol); 2.91 g yellow 15 oil. Yield 63%; MS: 456.3 (M+H)* 1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-4-piperdine carboxylic acid was prepared according to the general method as outlined in example 1 (step7), starting from ethyl I -benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-4-piperdine carboxylate (2.9 20 g, 6.37 mmol); 1.10 g off white powder. mp: 171 'C; Yield 40%; MS: 428.4 (M+H)* Starting from 1-benzyl-4-{ [3-(2-butynyloxy)phenyl]sulfonyl}-4-piperdine carboxylic acid (1 g, 2.34 mmol), and following the procedure as outlined in Example 1 (step 8), 460 mg of 1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4 25 piperdine carboxamide was isolated as an off white solid. mp: 91.4'C; Yield: 41%; MS: 443.4 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 6 1.83 (t, 3H), 2.23-2.27 (m, 2H), 2.73-2.89 (m, 2H), 3.29 (m, 2H), 3.68 (q, 2H), 4.31 (m, IH), 4.39 (d, J=5 Hz, 1H), 4.85 (d, J=2.25, 2H), 7.25-7.61 (in, 9H), 9.1 (s, IH), 11.2 (s, 1H).
WO 00/44723 PCT/USOO/01864 -65 Example 22 4-{[4-(2-butynyloxy)phenylsulfonyl}-N-hydroxy-1-isopropyl-4-piperidine carboxamide Ethyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl)-1-isopropyl-4-piperidine 5 carboxylate was prepared according to the general method as outlined in example 1 (step 6), starting from ( 4 -but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (6g, 20.3 mmol) and isopropyl [bis(2-chloroethyl)] amine hydrochloride (4.88 g, 22.3 mmol); 5.28 g brown oil. Yield 64%; MS: 408.2 (M+H)* 10 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-isopropyl-4-piperidine carboxylic acid was prepared according to the general method as outlined in example 1 (step7), starting from ethyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-isopropyl-4-piperidine carboxylate (5.25 g, 13 mmol); 2.06 g yellow solid. mp: 233 *C; Yield 42%; MS: 380.1 (M+H)* 15 Starting from 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-isopropyl-4-piperidine carboxylic acid (1.9 g, 5 mmol), and following the procedure as outlined in Example 1 (step 8), 107 mg of 4
-{[
4
-(
2 -butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-isopropyl-4 piperidine carboxamide was isolated as an brown solid. mp: 105'C; Yield: 5%; MS: 395.2 (M+H)*; 1 H NMR (300 MHz, DMSO-d 6 ): 5 1.2 (m, 6H), 1.85 (t, 3H), 2.27 (m, 20 2H), 2.73 (m, 2H), 3.06 (m, 2H), 3.52 (m, 2H), 3.57 (m, 1H), 4.89 (m, 2H), 7.19 (m, 2H), 7.71 (m, 2H), 9.3 (s, 1H), 11.4 (s, 1H). Example 23 4-{1[4-(2-butynyloxy)phenyljsulfonyl}-N-hydroxy-1-(3-pyridinylmethyl)-4 25 piperidine carboxamide Ethyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(3-pyridinylmethyl)-4-piperidine carboxylate was prepared according to the general method as outlined in example (step 6), starting from ( 4 -but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (4g, 16.9 mmol) and 3-pyridyl methyl [bis(2-chloroethyl)] amine hydrochloride (4.18 g, 30 18.6 mmol); 370 mg brown oil. Yield 5%; MS: 457.4 (M+H)* WO 00/44723 PCTUSOO/01864 -66 4- { [4-(2-butynyloxy)phenyl]sulfonyl }-1 -(3-pyridinylmethyl)-4-piperidine carboxylic acid was prepared according to the general method as outlined in example I (step 6), starting from ethyl 4-{[ 4
-(
2 -butynyloxy)phenyl]sulfonyl}-1-(3-pyridinyl methyl)-4-piperidine carboxylate (320 mg, 0.7 mmol); 150 mg yellow solid. Yield 5 50%; MS: 429.2 (M+H)* Starting from 4-{[4-(2-butynyloxy)phenyl]sulfonyl)-1-(3-pyridinyl methyl)-4 piperidine carboxylic acid (860 mg, 2 mmol), and following the procedure as outlined in Example 1 (step 8), 800 mg of 4
-{[
4
-(
2 -butynyloxy)phenyl]sulfonyl)-N-hydroxy-1 10 ( 3 -pyridinylmethyl)-4-piperidine carboxamide was isolated as a white solid. mp: 115'C; Yield: 84%; MS: 444.1 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 6 1.86 (t, J=1.98 Hz, 3H), 2.32 (m, 2H), 2.46 (s, 2H), 2.84 (m, 2H), 3.46 (d, J=12 Hz, 2H), 4.45 (s, 2H), 4.89 (d, 2.1 Hz, 2H), 7.17 (d, J=8.9 Hz, 2H), 7.68 (d, J=8.85 Hz, 2H), 7.9 (t, J=5.6 Hz, 1H), 8.0 (s, 1H), 8.51 (d, J=7.9 Hz, 1H), 8.87 (d, J= 4.6 Hz, 1H), 15 8.99 (s, 1H), 11.4 (s, 1H). Example 24 3 -{14-(2-Butynyloxy)phenyl]sulfonyl}-1-ethyl-N-hydroxy-3 piperidinecarboxamide 20 Step 1: Piperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl ester To a stirred solution of ethyl nipecotate (5.1 g, 33 mmol) in CH 2 Cl 2 (75 ml) and triethylamine (3.7g, 36 mmol) was added portionwise di-t-butyldicarbonate (7.1g, 33 mmol). The reaction mixture was stirred at room temperature for 18 h, quenched with ice water and extracted with chloroform. The organic layer was dried over sodium 25 sulfate, filtered, concentrated and chromatographed on a silica-gel column with 20:80 ethyl acetate:hexane. Piperidine 1,3dicarboxylic acid 1-tert-butyl ester-3-ethyl ester was isolated as a waxy solid. Yield 6.86 g ( 82%). MS (ES): m/z 258.2 (M+H)*.
WO 00/44723 PCT/USOO/01864 -67 Step 2: 1-(tert-Butyl) 3-ethyl 3-{[4-2-butynyloxy)phenyl]sulfonyl}-1,3 piperidine dicarboxylate To a stirred solution of diisopropylamine (7.2g, 28 mmol) in THF (25 ml) at -78' C was added n-butyllithium (1.6m solution in hexanes, 19.0 ml, 30.8 mmol). The 5 mixture was stirred for 30 min at 0*C. The mixture was then cooled to -78' C and piperidine -1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (5.3g, 28 mmol) in THF (20 ml) was added slowly. The reaction mixture was stirred for 30 min then 4 but-2-ynyloxy-benzenesulfonyl fluoride (6.4g, 28 mmol) in THF (15 ml) was added slowly. The reaction was warmed to room temperature and after 4 hrs quenched with 10 ice water and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, concentrated and chromatographed on a silica-gel column with 20% ethyl acetate:hexane to afford 1-(tert-Butyl) 3-ethyl 3-{[4-2-butynyloxy)phenyl] sulfonyl}-1,3-piperidine dicarboxylate as a white solid. Yield 9.8 g (76%); mp 103.4"C; MS (ES): m/z 466.4 (M+H)+. 'H NMR (300 MHz, DMSO-d 6 ): 6 1.07 (t, 15 3H), 1.34 (s, 9H), 3.31 (s, 3H), 3.84 (in, 2H), 4.00 (in, 4H), 4.53 (d, 2H), 4.91 (in, 4H), 7.22 (d, 2H), 7.71 (d, 2H). Step 3: To a stirred solution of 1-(tert-Butyl) 3-ethyl 3-{[4-2-butynyloxy) phenyl]sulfonyl}-1,3-piperidine dicarboxylate (5.45g, 11.7 mmol) in methylene 20 chloride(25 ml) at 0 C was added a saturated solution of hydrogen chloride in methylene chloride (25 ml). After 5 hours the solution was concentrated to afford ethyl 3- { [4-(2-butynyloxy)phenyl] sulfonyl) -3 -piperidinecarboxylate hydrogen chloride and is stored under nitrogen. White hygroscopic solid; Yield 3.47g (74%); MS (ES): m/z 366.2 (M+H)* 25 Step 4: (Ethyl 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-ethyl-3-piperidine carboxylate) 3- { [4-(2-Butynyloxy)phenyl] sulfonyl} -3 -piperidinecarboxylate hydrogen chloride (2.97g, 8.0 mmol), ethyl iodide (1.28g, 8 mmol) and dry powdered potassium 30 carbonate (3.8g) in dry acetone (60 ml) was heated to reflux for 18 hours. The mixture was allowed to cool and the potassium salts were filtered and concentrated. The WO 00/44723 PCT/USOO/01864 -68 residue was extracted with chloroform and washed with H 2 0, dried over sodium sulfate and concentrated to afford ethyl 3-{ [4-(2-butynyloxy)phenyl]sulfonyl} -1-ethyl 3-piperidinecarboxylate. This product was used without further purification. Amber gum, yield 3.47 g (99%); MS (ES): m/z 394 (M+H)*. 5 Step 5 : 3- { [4-(2-butynyloxy)phenyl] sulfonyl}- I -ethyl-3 -piperidinecarboxylic acid 3- { [4-(2-butynyloxy)phenyl] sulfonyl -1 -ethyl-3 -piperidinecarboxylic acid was prepared starting from ethyl 3- { [4-(2-butynyloxy)phenyl] sulfonyl} -1 -ethyl-3 piperidinecarboxylate (3.2g, 8.0 mmol) dissolved in THF:Methanol (15:25 ml) and 10 NaOH (15 ml). The resulting reaction misture was worked up as outlined in example 1 (step 7). Yield 2.11g (71%), white solid: mp 159.20 C; MS (ES): m/z 366.3 (M+H) + Step 6: 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-ethyl-N-hydroxy-3 piperidinecarboxamide 15 Starting from 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-ethyl-3-piperidinecarboxylic acid (2.0g, 5.5 mmol) and and following the procedure as outlined in example 1 (step 8), 0.193g of 3-{[4-(2-butynyloxy)phenyl]sulfonyl)-1-ethyl-N-hydroxy-3-piperidine carboxamide hydrogen chloride was isolated as a white solid. Yield 10%; mp190.3' C; MS (ES): m/z: 405.3 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 6 1.18 (in, 3H), 1.97 20 (in, 2H), 2.55 (in, 2H), 3.21(m, 5H), 3.52 9S, 3H), 3.82 (d, 1H), 4.91 (m, 2H), 7.19 (d, 2H), 7.51 (s, 5H), 8.67 (s, 1H), 9.48 (s, 1H). Example 25 3-{1[4-(2-butynyloxy)phenyl]sulfonyl)-1-(4-chlorobenzyl)-N-hydroxy-3 25 piperidinecarboxamide Step 1: Ethyl 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-3-piperidine carboxylate Starting from ethyl 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-3-piperidine carboxylate hydrogen chloride (1.lg, 2.7 mmol) and 4-chlorobenzyl chloride (0.485, 30 3.0 mmol) in dry acetone (50 ml) and following the procedure outlined in example 24, (step 4), Ethyl 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-3-piperidine- WO 00/44723 PCT/USOO/01864 -69 carboxylate was isolated as a brown oil. This product was taken to the next step without further purification. Yield 1.66g (99%); MS (ES): m/z: 491.3 (M+H)* Step 2: 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-3-piperidine 5 carboxylic acid 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-l-3-piperidinecarboxylic acid was prepared starting from ethyl 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(4-chloro benzyl)-3-piperidinecarboxylate (1.64g, 3.3 mmol) dissolved in THF:Methanol (15:50 ml) and NaOH (15 ml). The resulting reaction mixture was worked up as outlined in 10 example 1 (step 7); Yield 1.11g (75%), white solid: mp 115.20 C; MS (ES): m/z 462.1 (M+H)* Step 3: 3- { [4-(2-butynyloxy)phenyl] sulfonyl} -1 -(4-chlorobenzyl)-N-hydroxy 3-piperidinecarboxamide 15 Starting from 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-3 piperidinecarboxylic acid (1.lg, 2.4 mmol) and and following the procedure as outlined in example 1, (step 8), 0.48g of 3 -{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(4 chlorobenzyl)-3-N-hydroxy-3-piperidinecarboxamide hydrogen chloride was isolated as a white solid. Yield 43%; mp 124.4 0 C; MS (ES): m/z: 477.1 (M+H)* ; 1 H NMR 20 (300 MHz, DMSO-d 6 ): 5 2.0 (in, 2H), 3.39 (in, 5H), 4.27 (d, 2H), 4.89 (in, 2H), 7.14 (d, 2H), 7.15 (in, 4H), 7.61 (d, 2H), 8.95 (s, 111), 9.46 (s, 1H). Example 26 4 -{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl] 25 piperidine-4-carboxylic acid hydroxyamide. A mixture of diethanolamine (2.1 g, 20 mmol), 4
-(
2 -piperidin-1-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol) and K 2 C0 3 (10 g, excess) was refluxed in acetone (100 ml) for 24 hrs. At the end, reaction mixture was cooled to room temperature and filtered. It was concentrated to dryness and redissolved in touene (200 ml) and thionyl 30 chloride (6.75 g, 50 mmol). It was heated to 800 C for 1 hr and the separated brown solid, bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine was filtered WO 00/44723 PCT/USOO/01864 -70 and dried. The crude product was taken to next step with out purification. Yield: 7.0 g, (89%). 4- { [4-(2-Butynyloxy)phenyl]sulfonyl} -1 -[4-(2-piperidin- 1 -yl-ethoxy)-benzyl] 5 piperidine-4-carboxylic acid ethylester was was prepared according to the general method as outlined in example 1 (step 6), starting from ethyl{[4-(2-butynyloxy) phenyl]sulfonyl}acetate (2.9 g, 10.0 mmol) and bis-(2-chloro-ethyl)-[4-(2-piperidin-l yl-ethoxy)-benzyl]-amine dihydrochloride (4.3 g, 10 mmol), 2.8 g of product (brown oil) was isolated.. Yield 48%; MS: 583 (M+H)* 10 4-{ [4-(2-Butynyloxy)phenyl]sulfonyl}-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl] piperidine-4-carboxylic acid was prepared according to the general method as outlined in example 1 (step7), starting from 4
-{[
4 -(2-Butynyloxy)phenyl]sulfonyl}-1 [4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethylester (3.0 g, 15 5.15 mmol); 2.2 g of white powder. mp: 172 'C; Yield 77%; MS: 555 (M+H)* Starting from 4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-[4-(2-piperidin-1-yl ethoxy)-benzyl]-piperidine-4-carboxylic acid (5.0 g, 9.0 mmol), and following the procedure as outlined in Example 1 (step 8), 1.8 g of 4-{[4-(2-Butynyloxy)phenyl] 20 sulfonyl}-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxy amide was isolated as an yellow spongy solid. The dihydrochloride salt was prepared by dissolving the free amine with methanolic hydrochloric acid. mp: 124'C; Yield: 1.8 g (32%); MS: 570 (M+H)*. 25 Example 27 4-{[4-(2-Butynyloxy)phenylsulfonyl}-l-(3-pentanyl)-piperidine-4-carboxylic acid hydroxyamide. 4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-(3-pentanyl)-piperidine-4-carboxylic acid ethyl ester was was prepared according to the general method as outlined in 30 example 1 (step 6), starting from ethyl{ [ 4 -(2-butynyloxy)phenyl]sulfonyl} acetate (8.8 WO 00/44723 PCTUSOO/01864 -71 g, 30.0 mmol) and bis-(2-chloro-ethyl)-(3-pentanyl)-amine dihydrochloride (7.4 g, 30 mmol), 3.5 g of product (brown oil) was isolated.. Yield 26%; MS: 436 (M+H)* 4-{ [4-(2-Butynyloxy)phenyl]sulfonyl} -1 -(3-pentanyl)-piperidine-4-carboxylic 5 acid was prepared according to the general method as outlined in example 1 (step7), starting from 4- { [4-(2-Butynyloxy)phenyl] sulfonyl } -1 -(3 -pentanyl)-piperidine-4 carboxylic acid ethyl ester (3.0 g, 6.8 mmol); 2.5 g of spongy yellow solid. mp: 98 'C; Yield 90%; MS: 408 (M+H)* 10 Starting from 4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-(3-pentanyl)-piperidine-4 carboxylic acid (2.5 g, 6.1 mmol), and following the procedure as outlined in Example I (step 8), 1.8 g of 4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-(3-pentanyl)-piperidine-4 carboxylic acid hydroxyamide was isolated as an yellow spongy solid. The hydrochloride salt was prepared by dissolving the free amine with methanolic hydrochloric acid. mp: 101 15 103'C; Yield: 1.1 g (42%); MS: 460 (M+H)*. 1 H NMR (300 MHz, DMSO-d 6 ): 6 1.8 (t, 6H), 1.5-1.7 (in, 6H), 1.9 (s, 3H), 2.3- 2.7 (in, 8H), 3.0 (in, 2H), 3.4 (s, 3H), 3.6 (d, 2H), 4.9 (s, 2H), 7.21 (d, 2H), 7.8 (d, 2H), 9.3 (s, 1H), 9.8 (s, 1H), 11.2 (s, 1H). Example 28 20 1-(4-Methoxy-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4 carboxylic acid hydroxyamide. 1-(4-Methoxy-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4 carboxylic acid ethyl ester was prepared according to the general method as outlined in example 1 (step 6), starting from ( 4 -prop- 2 -ynyloxy-benzenesulfonyl)-acetic acid ethyl 25 ester (prepared as described in example 11, step 1 and 2)(10.0 g, 35.0 mmol) and 4 methoxy-benzyl)-bis-(2-chloro-ethyl)-amine hydrochloride (10.5 g, 35 mmol), 6.0 g of product (brown oil) was isolated.. Yield 36%; MS: 472 (M+H)* 1-(4-Methoxy-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4 30 carboxylic acid was prepared according to the general method as outlined in example I (step7), starting from 1-(4-Methoxy-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)- WO 00/44723 PCTIUSOO/01864 -72 piperidine-4-carboxylic acid ethyl ester (6.0 g, 12.73 mmol); 5.0 g of spongy yellow solid. mp: 208 'C; Yield 92%; MS: 444 (M+H)* Starting from 1-( 4 -Methoxy-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine 5 4-carboxylic acid (6.0 g, 13.5 mmol), and following the procedure as outlined in Example 1 (step 8), 2.0 g of 1-( 4 -Methoxy-benzyl)-4-(4-prop-2-ynyloxy-benzene sulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an yellow spongy solid. The hydrochloride salt was prepared by dissolving the free amine with methanolic hydrochloric acid. mp: 150*C; Yield: 2.0 g (29%); MS: 459 (M+H)*. 1H 10 NMR (300 MHz, DMSO-d 6 ): 6 2.3-2.8 (m, 6H), 3.3 (d, 2H), 3.5 (s, 3H), 4.2 (s, 2H), 5.0 (s, 2H), 7.3 (d, 2H), 7.5 (d, 21H), 7.6 (d, 2H), 7.7 (d, 2H),10.9 (s, 1H), 11.2 (s, IH). Example 29 15 1-( 4 -Chloro-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4 carboxylic acid hydroxyamide. 1-( 4 -Chloro-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4 carboxylic acid ethyl ester was prepared according to the general method as outlined in example 1 (step 6), starting from (4-prop-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl 20 ester (prepared as described in example 11, step 1 and 2)(10.0 g, 35.0 mmol) and 4 chloro-benzyl)-bis-(2-chloro-ethyl)-amine hydrochloride (10.5 g, 35 mmol), 8.0 g of product (brown oil) was isolated.. Yield 48%; MS: 475 (M+H)* 1-( 4 -Chloro-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4 25 carboxylic acid was prepared according to the general method as outlined in example 1 (step7), starting from 1-( 4 -chloro-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (6.0 g, 12.63 mmol); 5.0 g of spongy yellow solid. mp: 205 'C; Yield 92%; MS: 448 (M+H)* 30 Starting from 1-( 4 -Chloro-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl) piperidine-4-carboxylic acid (6.0 g, 13.4 mmol), and following the procedure as WO 00/44723 PCT/USOO/01864 -73 outlined in Example 1 (step 8), 2.0 g of 1-(4-chloro-benzyl)-4-(4-prop-2-ynyloxy benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an yellow spongy solid. The hydrochloride salt was prepared by dissolving the free amine with methanolic hydrochloric acid. mp: 146'C; Yield: 4.0 g (59%); MS: 499 (M+H)*. 1 H 5 NMR (300 MHz, DMSO-d 6 ): 6 2.0-2.5 (m, 6H), 3.2 (d, 2H), 4.18 (s, 2H), 4.9 (s, 2H), 7.42 (d, 2H), 7.61 (d, 2H), 7.71 (d, 2H), 7.85 (d, 2H),11.0 (s, 1H), 11.2 (s, 1H). Example 30 tert-butyl-4-({[4-(2-butynyloxy)phenyllsulfanyl}methyl)-4 10 [(hydroxyamino)carbonyl]-1-piperidinecarboxylate Step 1: Piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester To a solution of of ethyl isonipecotate (4.72g, 0.03 mmol) in 30mL of THF was added slowly di-tert-butyl dicarbonate (7.2g, 0.03 mmol) at room temperature. The resulting mixture was stirred for two hours and diluted with EtOAc. The organics 15 were washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:9) to provide 7.52g (97%) of the desired product as a colorless oil. Electrospray Mass Spec : 258.3 (M+H)* 20 Step 2: 1 -(tert-Butyl) 4-ethyl 4-(iodomethyl)piperidine- 1,4-dicarboxylate To a solution of piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester (12.8 g, 49.74 mmol) in 73mL of dry TIF under N 2 atmosphere at -42'C was added 24.87mL (49.74mmol) of 2M Lithium diisopropylamine in heptane/THF/ethylbenzene dropwise to not exceed -40"C. After one hour, 4.OmL (49.74mmol) of diiodomethane was 25 added and the solution was warmed to ambient temperature overnight. The resulting solution was diluted with H20 and extracted with ethyl acetate. The organics were washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo to provide 18.84g(95%) of the desired product as a brown oil. Electrospray Mass Spec : 398.2 (M+H)* 30 WO 00/44723 PCTIUSOO/01864 -74 Step 3: 4 -But-2-ynyloxy-benzenesulfonic acid sodium salt: To a solution of 4-hydroxybenzenesulfonate sodium salt ( 5 2.35g, 0.225) in IL of isopropanol and 225mL of a .0N solution of sodium hydroxide was added 5 9.96g (0.45mol) of 1 bromo-2-butyne. The resulting mixture was heated to 700 for 15h and 5 then the isopropanol was removed by evaporation in vacuo. The resulting white precipitate was collected by filtrtation, washed with isopropanol and ether and dried in vacuo to give 45.08g (81%) of the desired product as a white solid. Step 4: 4 -But-2-ynyloxy-benzenesulfonyl chloride 10 To a stirred solution of oxalyl chloride (47.8 ml, 0.545 mol) at 0 0 C in 240mL of CH 2
CI
2 was added a DMF (43.0 ml) solution of 4 -but- 2 -ynyloxy-benzenesulfonic acid sodium salt in a drop wise manner. The reaction mixture was stirred at 0 C for 30min and then let warm to room temperature and stirred for 18h. The reaction was then poured into ice and extracted with hexanes. The organics were washed with 15 water and brine, dried over MgSO 4 , filtered and concentrated in vacuo to provide 42.Og (95%) of the desired product as yellow solid . Step 5: 4 -But-2-ynyloxy-benzenethiol To a solution of 11.8g (0.045mol) of triphenylphosphine in 1OmL of CH 2
C
2 20 and 0.3mL of DMF was added dropwise a solution of 4 -but-2-ynyloxy-benzene sulfonyl chloride in 15 mL CH 2
CI
2 . Stirred at room temperature for two hours, added 5mL of IN HCl, stirred for 30 min., and then added 15mL of brine. The organics were separated and concentrated in vacuo. The residue was diluted with ether and filtered the insolubles. The filtrate was washed with 2.5N NaOH and the aqueous solution 25 separated, acidified and extracted with ether. The organics were washed with H 2 0, brine, dried over MgSO 4 , filtered and concentrated in vacuo to give 1.54g (58%) of the desired product as a pale yellow oil.
WO 00/44723 PCT/USOO/01864 -75 Step 6: 1-(tert-butyl) 4-ethyl 4-({[4-(2-butynyloxy)phenyl]sulfanyl} methyl)-1,4 piperidinedicarboxylate A mixture of 0.294g (0.74mmol) of 1-(tert-Butyl) 4-ethyl 4-(iodomethyl) piperidine-1,4-dicarboxylate, 0.145 (0.814mmol) of 4-but-2-ynyloxy-benzenethiol and 5 0.204g (1.48mmol) of K 2
CO
3 in 2.0mL of DMF was stirred at room temperature for 18 h. The resulting mixture was diluted with EtOAc, washed with H 2 0, brine, dried over MgSO 4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc:Hexanes (1:19) to provide 0.328g (99%) of the desired product as a colorless oil. Electrospray Mass Spec : 448.3 (M+H)* 10 Step 7: 4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-piperidine-1,4- dicarboxylic acid mono-tert-butyl ester A mixture of 0.288g (0.0643mmol) of 1-(tert-butyl) 4-ethyl 4-({[4-(2 butynyloxy)phenyl]sulfanyl}methyl)-1,4-piperidinedicarboxylate, 3.25mL of 1N NaOH 15 3.25mL of THF and 3.25mL of MeOH was heated to reflux for 3h. The organics were removed and the residue was diluted with H 2 0, acidified and extracted with EtOAC. The organics were washed with H 2 0, brine, dried over mgSO 4 , filtered and concentrated in vacuo to provide 0.241g (89%) of the desired product as an off white gum. Electrospray Mass Spec: 464.3 (M+FA-H)~ 20 Step 8: WAY 173665 tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl}methyl)-4 [(hydroxyamino)carbonyl]- 1 -piperidinecarboxylate To a solution of 0.204g (0.49mmol) of 4 -(4-But-2-ynyloxy-phenylsulfanyl methyl)-piperidine-1,4- dicarboxylic acid mono-tert-butyl ester, 0.079g (0.58mmol) of 1-hydroxybenzotriazole in 2.5mL of DMF was added 0.112g (0.84mmol) of 1-(3 25 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and stirred at room temperature for lh. Then added 0.3mL of 50% aqueous hydroxylamine and stirred for 18h. The resulting mixture was diluted with EtOAc, washed with H 2 0, brine, dried over MgSO 4 , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1.5% MeOH/ CH 2 Cl 2 to provide 0.077g (36%) of the desired 30 product as a white solid. Electrospray Mass Spec: 435.2 (M+H)* WO 00/44723 PCT/USOO/01864 -76 Example 31 4-({[4-(But-2-ynyloxy)phenyl]thio}methyl)-N-hydroxypiperidine-4-carboxamide To a solution of 0. 143g (0.033mmol) of tert-butyl-4-({ [4-(2-butynyloxy) phenyl]sulfanyl}methyl)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate in 5 5mL of CH 2 Cl 2 and 1mL of MeOH was added 5mL of 4M HCl in dioxane and stirred for lh. The reaction was concentrated in vacuo and the residue was triturated with ether and filtered to provide 0.093g (76%) of the desired product as a pale orange solid. Electrospray Mass Spec: 335.3 (M+H)* 10 Example 32 tert-Butyl-4-({[4-(2-butynyloxy)phenylsulfinyl}methyl)-4-[(hydroxyamino) carbonyl]-1-piperidinecarboxylate To a slurry of tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl}methyl)-4 [(hydroxyamino)carbonyl]-l-piperidinecarboxylate (0.24g, 0.55 mmol) at 0"C in 7mL 15 of MeOH was added dropwise 3.5mL of 30% hydrogen peroxide. The reaction was allowed to warm to room temperature and stirred for 18h. The reaction was cooled to 0"C and quenched with 3.5mL of a saturated solution of Na 2
SO
3 . The organaics were removed and the aqueous solution was extracted with CH 2 Cl 2 . The organics were washed with H 2 0, brine, dried over MgSO 4 , filtered and concentrated in vacuo. 20 The residue was triturated with ether to provide 0.166g (67%) of the desired product as an off white solid. Electrospray Mass Spec: 451.3 (M+H)* Example 33 4-[[14-(2-Butynyloxy)phenyl] sulfinyll methyl]-N-hydroxy-4 25 piperidinecarboxamide 4-({[4-(2-Butynyloxy)phenyl]sulfinyl}methyl)-N-hydroxy-4-piperidinecarbox amide was prepared according to the general method as outlined in Example 31. Starting from tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfinyl}methyl)-4-[(hydroxy amino)carbonyl]-l-piperidinecarboxylate (0.082 g, 0.18 mmol), 0.0 6 6g (95%) of the 30 desired product was isolated as a white solid. Electrospray Mass Spec:351.2 (M+H)* WO 00/44723 PCT/USOO/01864 -77 Example 34 tert-Butyl-4-({14-(but-2-ynyloxy)phenylsulfonyl}methyl)-4 [(hydroxyamino)carbonyl]piperidine-1-carboxylate To a solution of tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl}methyl)-4 5 [(hydroxyamino)carbonyl]-1-piperidinecarboxylate (0.422g, 0.97 mmol) in 8mL of MeOH, 4mL of CH 2
C
2 and 2mL of THF was added a solution of 1.79g (2.91mmol) of OXONE in 8mL of H 2 0 and stirred at room temperature for 18h. The solid was filtered and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc, washed with H 2 0, brine, dried over MgSO 4 , filtered, and concentrated to 10 provide 0.351g (77%) of the desired product as a white solid. Electrospray Mass Spec: 467.3 (M+H)* Example 35 tert-butyl-4-({[4-(2-butynyloxy)phenylsulfonyl}methyl)-4 15 [(hydroxyamino)carbonyll-1-piperidinecarboxylate tert-Butyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino) carbonyl]-1-piperidinecarboxylate was prepared according to the general method as outlined in Example 31. Starting from tert-Butyl-4-({[4-(but-2-ynyloxy) phenyl]sulfonyl)methyl)-4-[(hydroxyamino)carbonyl]piperidine-1-carboxylate (0.10g, 20 0.214mmol) 0.074g (86%) of the desired product was isolated as white solid. Electrospray Mass Spec: 367.3 (M+H)* Example 36 1-Acetyl-4-[[[4-(2-butynyloxy)phenyllsulfonyllmethyl]-N-hydroxy-4 25 piperidinecarboxamide Step 1: 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-1,4- piperidine dicarboxylic acid, 1 -tert-butyl 4-ethyl ester To a solution of 1-(tert-butyl) 4-ethyl 4-({[4-(2-butynyloxy)phenyl]sulfanyl)methyl) 1,4- piperidinedicarboxylate (1.66 g, 3.7 mmol) (prepared in example 30, step 6) in 30 20mL of CH 2 C1 2 was added tetrabutylammonium oxone (17.38g, 14.7 mmol) and stirred at room temperature for 18h. The reaction was concentrated in vacuo and the WO 00/44723 PCT/USOO/01864 -78 residue was diluted with EtOAc, washed with H 2 0, 5% KHSO 4 , brine, dried over MgSO 4 , filtered and concentrated to provide 1.69g (95%) of the desired product as a pale yellow gum. Electrospray Mass Spec: 480.3 (M+H)* 5 Step 2 4
-[[[
4
-(
2 -Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid, ethyl ester 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester was prepared according to the general method as outlined in Example 31. Starting from 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-1,4-piperidinedicarboxylic 10 acid 1-tert-butyl 4-ethyl ester (1.62g 3.4mmol), 1.335g (95%) of the desired product was isolated as a tan solid. Electrospray Mass Spec: 380.2 (M+H)* Step 3: 1-Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid, ethyl ester 15 To a solution of 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidine carboxylic acid ethyl ester (0.24g, 0.576mmol), triethylamine (0.32 ml) and catalytic amount of 4-Dimethylaminopyridine in 6.0mL of CH 2 Cl 2 was added a solution of acetyl chloride (0.068 ml, 0.864 mmol) in 1.OmL of CH 2 Cl 2 . The reaction stirred at room temperature for 4h and washed with H 2 0, brine, dried over MgSO 4 , filtered 20 through a pad of silica gel and concentrated to provide 0.242g (100%) of the desired product as a colorless gum. Electrospray Mass Spec: 422.2 (M+H)* Step 4: 1-Acetyl-4-(4-but-2-ynyloxy-benzenesulfonylmethyl)-piperidine-4- carboxylic acid 25 1-Acetyl- 4 -(4-but-2-ynyloxy-benzenesulfonylmethyl)-piperidine-4- carboxylic acid was prepared according to the general method as outlined in Example 30, (step 7). Starting from I-Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-4-piperidine carboxylic acid, ethyl ester (0.22 g, 0.524 mmol), 0.141 g of the desired product was isolated as a pale yellow solid. Electrospray Mass Spec: 438.2 (M+FA-H)~ 30 WO 00/44723 PCT/USOO/01864 -79 Step 5: 1-Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-N-hydroxy-4 piperidinecarboxamide I -Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-N-hydroxy-4 piperidinecarboxamide was prepared according to the general method as outlined in 5 Example 30 (step 8). Starting from I-Acetyl-4-(4-but-2-ynyloxy-benzenesulfonyl methyl)-piperidine-4-carboxylic acid, (0.122 g, 0.31 mmol) 0.048g (38%) of the desired product was isolated as a pale yellow solid. Electrospray Mass Spec: 409.2 (M+H)* 10 Example 37 1-(2-Butynyl)-4-({1[4-(2-butynyloxy)phenylsulfonyl}methyl)-N-hydroxy-4 piperidinecarboxamide hydrochloride Step 1: 1-(2-Butynyl)-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-4 piperidinecarboxylic acid, ethyl ester 15 A mixture of 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidine carboxylic acid ethyl ester (0.208 g,0.5 mmol), 1-bromo-2-butyne (0.044 ml, 0.53 mmol) and K 2
CO
3 (0.138 g, 1.0 mmol)in 5.OmL of DMF was stirred at room temperature for 6h. The reaction was diluted with EtOAc and washed with H 2 0, brine, dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was 20 chromatographed on silica gel eluting with EtOAc:hexanes (1:1) to provide 0.183g (85%) of the desired product as a pale yellow gum. Electrospray Mass Spec: 432.2 (M+H)* Step 2: 1-( 2 -Butynyl)-4-[4-(2-butynyloxy)benzenesulfonylmethyl]-piperidine-4 25 carboxylic acid 1-( 2 -Butynyl)-4-[4-(2-butynyloxy)benzenesulfonylmethyl]-piperidine-4 carboxylic acid was prepared according to the general method as outlined in example 30 (step 7). Starting from 1-( 2 -Butynyl)-4-[[[4-(2-butynyloxy)phenyl]sulfonyl] methyl]-4-piperidinecarboxylic acid, ethyl ester, (0.153 g, 0.354 mmol), 0.12 g (84%) 30 of the desired product was isolated as a white solid. Electrospray Mass Spec: 404.2
(M+H)*
WO 00/44723 PCT/USOO/01864 -80 Step 3: 1-(2-Butynyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4 piperidinecarboxamide hydrochloride 1-(2-Butynyl)-4-({ [4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4 5 piperidinecarboxamide hydrochloride was prepared according to the general method as outlined in Example 30 (step 8). Starting from 1-(2-butynyl)-4-[4-(2-butynyloxy) benzenesulfonylmethyl]-piperidine-4-carboxylic acid, (0. 15g , 0.34mmol) ,0.05g of the desired product, which was dissolved in 1.OmL of CH 2 Cl 2 and treated with 0.225mL of IM HCl in CH 2 Cl2 . The solution was stirred for lh, and concentrated in vacuo. The 10 residue was triturated with ether to provide 0.044g (28%) of the hydrochloride of the desired product as a beige solid. Electrospray Mass Spec: 419.2 (M+H)* Example 38 N-1-(tert-Butyl)-4-({[4-(2-butynyloxy)phenylsulfonyl}methyl)-N-4-hydroxy-1,4 15 14-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-1,4-1]sulfonyl)methyl)-N 4-hydroxy-1,4-piperidinedicarboxamide Step 1: 1-tert-Butylcarbamoyl-4-(4-but-2-ynyloxy-benzenesulfonymethyl)- piperidine 4-carboxylic acid ethyl ester To a solution of tert-butylisocyanate (0.097 ml, 0.85 mmol) in 8.0mL of 20 CH 2 Cl 2 , was added 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidine carboxylic acid ethyl ester (prepared from example 36, step 2) (0.337 g, 0.81 mmol) and triethylamine (0.135 ml, 0.97 mmol) and stirred at room temperature for 2h. The reaction was diluted with CH 2 Cl 2 and washed with H 2 0, brine, dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was triturated with ether:hexanes (1:1) 25 to provide 0.284g (73%) of the desired product as a white solid. Electrospray Mass Spec: 479.2 (M+H)* Step 2: 1-[(tert-Butylamino)carbonyl]-4-({[4-(2-butynyloxy)phenyl] sulfonyl}methyl) 4-onyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxylic acid 30 1-[(tert-Butylamino)carbonyl]-4-({ [4-(2-butynyloxy)phenyl]sulfonyl} methyl)-4-onyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl methyl)-4-piperidine WO 00/44723 PCT/USOO/01864 -81 carboxylic acid was prepared according to the general method as outlined in Example 30 (step 7). Starting from 1-tert-butylcarbamoyl-4-(4-but-2-ynyloxy-benzene sulfonylmethyl)-piperidine-4-carboxylic acid ethyl ester (0.259g, 0.54 mmol), 0.169 g, (69%) of the desired product was isolated as white solid. Electrospray Mass 5 Spec: 451.4 (M+H)* Step 3: N-I-(tert-Butyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl} methyl)-N-4-hydroxy 1,4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-1,4-]sulfonyl}methyl)-N 4-hydroxy- 1,4-piperidinedicarboxamide 10 N- 1-(tert-Butyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4 hydroxy- 1, 4
-[
4
-(
2 -butynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy- 1,4-1] sulfonyl}methyl)-N-4-hydroxy-1,4-piperidinedicarboxamide was prepared according to the general method as outlined in Example 30 (step 8). Starting from 1-[(tert Butylamino)carbonyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-onyl]-4-({ [4 15 (2-butynyloxy) phenyl]sulfonyl}methyl)-4-piperidinecarboxylic acid (0.149g, 0.33 mmol), 0.077 g of the desired product was isolated as pale yellow solid. Electrospray Mass Spec: 466.3 (M+H)* Example 39 20 Methyl 4 -({[4-(2-butynyloxy)phenyl]sulfonyl)methyl)-4 [(hydroxyamino)carbonyl]- 1-piperidinecarboxylate Step 1: 4
-(
4 -But- 2 -ynyloxy-benzenesulfonylmethyl)-piperidine-1,4- dicarboxylic acid ethyl ester methyl ester To a solution of 4 -[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidine 25 carboxylic acid ethyl ester (0.354 g, 0.85 mmol) in 1.LOn of CH 2
CI
2 under N 2 atmosphere was added dropwise a solution of N,O-bis(trimethylsilyl)acetamide (0.462 ml, 1.87 mmol) in 0.5mL of CH 2 Cl 2 and stirred for lh. The reaction was cooled to 0C and added dropwise a solution of 0.079mL (1.02mmol) of methylchloroformate in 0.5mL of CH 2 Cl 2 . The reaction was allowed to stir at room temperature for lh and 30 cooled to 0"C, quenched with pH7 buffer solution and extracted with EtOAc. The organics was washed with H 2 0, brine, dried over MgSO 4 , filtered, and concentrated in WO 00/44723 PCT/USOO/01864 -82 vacuo. The residue was chromatographed on silica gel eluting with EtOAc:hexanes (1:2) to provide 0.315g (85%) of the desired product as a colorless oil. Electrospray Mass Spec: 438.3 (M+H)* 5 Step 2: 4
-(
4 -But- 2 -ynyloxy-benzenesulfonylmethyl)-piperidine-1,4- dicarboxylic acid monomethyl ester 4
-(
4 -But- 2 -ynyloxy-benzenesulfonylmethyl)-piperidine- 1,4-dicarboxylic acid monomethyl ester was prepared according to the general method as outlined in Example 30 (step 7). Starting from 4
-(
4 -But-2-ynyloxy-benzenesulfonylmethyl) 10 piperidine-1,4- dicarboxylic acid ethyl ester methyl ester (0.277 g, 0.633 mmol), 0.175g (67%) of the desired product was isolated as white solid. Electrospray Mass Spec: 410.2 (M+H)* Step 3: Methyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino) 15 carbonyl]- 1-pip eridinecarboxylate Methyl-4-({[ 4 -(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino) carbonyl]-1-piperidinecarboxylate was prepared according to the general method as outlined in Example 30 (step 8). Starting from 4
-(
4 -But-2-ynyloxy-benzenesulfonyl methyl)-piperidine-1,4-dicarboxylic acid monomethyl ester (0.15 g, 0.366 mmol), 20 0.053g (34%) of the desired product was isolated as a white solid. Electrospray Mass Spec: 425.3 (M+H)* Example 40 Benzyl 4-({1[4-(2-butynyloxy)phenyljsulfonyl}methyl)-4 25 [(hydroxyamino)carbonylj- 1-piperidinecarboxylate Step 1: 4
-(
4 -But- 2 -ynyloxy-benzenesulfonylmethyl)-piperidine-1,4-dicarboxylic acid benzyl ester ethyl ester 4
-(
4 -But- 2 -ynyloxy-benzenesulfonylmethyl)-piperidine-1,4- dicarboxylic acid benzyl ester ethyl ester was prepared according to the general method as outlined in 30 Example 39 (step 1). Starting from 4
-[[[
4
-(
2 -Butynyloxy)phenyl]sulfonyl]methyl]-4- WO 00/44723 PCT/USOO/01864 -83 piperidinecarboxylicacid ethyl ester (0.312 g, 0.75), 0.337g (87%) of the desired product was isolated as colorless oil. Electrospray Mass Spec: 514.2 (M+H)* Step 2: 4-(4-But-2-ynyloxy-benzenesulfonylmethyl)-piperidine-1,4- dicarboxylic acid 5 monobenzyl ester 4-(4-But-2-ynyloxy-benzenesulfonylmethyl)-piperidine-1,4- dicarboxylic acid monobenzyl ester was prepared according to the general method as outlined in Example 30 (step 7). Starting from 4-(4-But-2-ynyloxy-benzenesulfonylmethyl) piperidine-1,4- dicarboxylic acid benzyl ester ethyl ester (0.32g, 0.623 mmol) , 0.2 g of 10 the desired product was isolated as white solid.. Electrospray Mass Spec: 484.2 (M-H)~ Step 3: Benzyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino) carbonyl]- I-piperidinecarboxylate 15 Benzyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino) carbonyl]-1-piperidinecarboxylate was prepared according to the general method as outlined in Example 30, (step 8). Starting from 4-(4-But-2-ynyloxy-benzene sulfonylmethyl)-piperidine-1,4-dicarboxylic acid monobenzyl ester (0.18 g, 0.37 mmol), 0.106 g (57%)of the desored product was isolated as off-white solid. 20 Electrospray Mass Spec: 501.3 (M+H)* Example 41 1-Benzyl-4-({14-(2-butynyloxy)phenylI sulfonyl} methyl)-N-hydroxy-4 butynyloxy)phenyljsulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide 25 Step 1: Ethyl- 1 -benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl)methyl)-4-4-(2-butynyl oxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxylate Ethyl-i -benzyl-4-({[4-(2-butynyloxy)phenylsulfonyl}methyl)-4-4-(2-butynyloxy) phenyl]sulfonyl}methyl)-4-piperidinecarboxylate was prepared according to the general method as outlined in Example 37 (step 1). Starting from 4-[[[4-(2-Butynyl 30 oxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylicacid ethyl ester (prepared in WO 00/44723 PCT/USOO/01864 -84 Example 36, step 2) (0.312g,0.75 mmol), 0.265g of the desired product was isolated as white solid.Electrospray Mass Spec: 470.2 (M+H)* Step 2: 1-Benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-piperidine 5 carboxylic-benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-piperidine carboxylic acid 1 -Benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxylic benzyl-4-({[4-(2-butynyloxy)phenyljsulfonyl}methyl)-4-piperidinecarboxylic acid was prepared according to the general method as outlined in Example 30 (step 7). 10 Starting from Ethyl-1-benzyl-4-({ [4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-4-(2 butynyloxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxylate (0.25g, 0.53 mmol), 0.227g (90%) of the desired product was isolated as a white solid. Electrospray Mass Spec: 442.2 (M+H)* 15 Step 3: 1-Benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4 utynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxaniide 1-Benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-butynyl oxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide was prepared according to the general method as outlined in Example 30 (step 8). Starting from 1 20 Benzyl-4-({[4-(2-butynyloxy)phenyllsulfonyl}methyl)-4-piperidinecarboxylic-enzyl 4-({[4-(2 butynyloxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxylic acid (0.211g, 0.44 mmol), 0.108g of the desired product was isolated as white solid.. Electrospray Mass Spec: 457.2 (M+H)* 25 Example 42 4 -({14-(2-Butynyloxy)phenyljsulfonyl}methyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,3 dioxan- 5 -yl)carbonyl]-4-piperidinecarboxamide Step 1: Ethyl 4-({ [ 4 -(2-butynyloxy)phenyl]sulfonyl}methyl)-1-[(2,2,5- trimethyl-1,3 dioxan-5-yl)carbonyl]-4-piperidinecarboxylate 30 Ethyl 4-(([4-(2-butynyloxy)phenyl]sulfonyl}methyl)-1-[(2,2,5- trimethyl-1,3-dioxan 5-yl)carbonyl]-4-piperidinecarboxylate was prepared according to the general method WO 00/44723 PCT/USOO/01864 -85 as outlined in Example 30 (step 8). Starting from 4-[[[4-(2-Butynyloxy) phenyl]sulfonyl]methyl]-4-piperidinecarboxylicacid ethyl ester (0.333g, 0.8 mmol) and 2,2,5-trimethyl-(1,3)dioxane-5-carboxylic acid (0.168g, 0.96 mmol), 0.339g (79%) of the desired product was isolated as a white solid. Electrospray Mass Spec: 5 536.1 (M+H)* Step 2: 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-1-[(2,2,5-trimethyl-1,3-dioxan 5-yl)carbonyl]-4-piperidinecarboxylic acid 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-I-[(2,2,5-trimethyl-1,3-dioxan-5-yl) 10 carbonyl]-4-piperidinecarboxylic acid was prepared according to the general method as outlined in Example 30 (step 7). Starting from ethyl 4-({[4-(2-butynyloxy) phenyl]sulfonyl}methyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidine carboxylate (0.299g, 0.558 mmol), 0.235g (83%) of the desired product was isolated as white solid. Electrospray Mass Spec: 506.2 (M-H)~ 15 Step 3: 4-({[4-(2-Butynyloxy)phenyl]sulfonyl)methyl)-N-hydroxy-1-[(2,2,5 trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide 4-({[4-(2-Butynyloxy)phenyl]sulfonyl)methyl)-N-hydroxy-1-[(2,2,5 trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide was prepared according 20 to the general method as outlined in Example 30 (step 8). Starting from 4-({[4-(2 Butynyloxy)phenyl]sulfonyl}methyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4 piperidinecarboxylic acid (0.22g, 0.433 mmol), 0.16 g of the desired product was isolated as white solid. Electrospray Mass Spec: 523.2 (M+H)* 25 Example 43 4-({[4-(2-Butynyloxy)phenylsulfonyl}methyl)-N-hydroxy-1-13-hydroxy-2 (hydroxymethyl)-2-methylpropanoyll-4-piperidinecarboxamide A mixture of 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1 [(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide (0.106 g, 0.2 30 mmol) and 2mL of 1N HCl in 2mL of THF was stirred at room temperature for 4h. The reaction was diluted with EtOAc, washed with H 2 0, saturated NaHCO 3 , brine, WO 00/44723 PCTIUSOO/01864 -86 dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was triturated with ether to provide 0.67g (71%) of the desired product as an off white solid. Electrospray Mass Spec: 483.2 (M+H)* 5 Example 44 1-[Amino(imino)methyl]-4-({1[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N hydroxy-4-1]-4-({[4-(2-butynyloxy)phenylsulfonyl}methyl)-N-hydroxy-4 oxy)phenyljsulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide Step 1: N,N'-t-Boc-protected thiourea: To a stirred solution of thiourea (0.57g, 7.5 10 mmol) in 150mL of THF under N 2 at 0"C was added 60% NaH (1.35g, 33.8 mmol) in mineral oil. After 5 minutes, the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 10 minutes. The reaction mixture was cooled to 0C and 3.6g (16.5mmol) of di-tert-butyl dicarbonate was added. After 30 minutes, the ice bath was removed and the reaction was stirred for 2h. The reaction was then 15 quenched with saturated NaHCO 3 solution, poured into water and extracted with 3x EtOAc. The organics were washed with H 2 0, brine, dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was triturated with hexane to provide 1.72g (83%) of the desired product as a white solid. 20 Step 2: tert-Butyl4-[(tert-butoxyamino)carbonyl]-4-({[4-(2-yloxy)phenyl] sulfonyl)methyl)-1-piperidinecarboxylate tert-Butyl4-[(tert-butoxyamino)carbonyl]-4-({[4-(2-yloxy)phenyl]sulfonyl) methyl)-1-piperidinecarboxylate was prepared according to the general method as outlined in Example 30 (step 8). Starting from 4-(4-but-2-ynyloxy-benzenesulfony 25 methyl)-piperidine-1,4- dicarboxylic acid mono-tert-butyl ester (2.53 g, 5.6 mmol) and O-tert-butyl-hydroxylamine hydrochloride (1.4 g, 11.2 mmol), 2.31 g (79%) of the desired product was isolated as a white solid. Electrospray Mass Spec: 523.2 (M+H)* WO 00/44723 PCTUSOO/01864 -87 Step 3: N-(tert-Butoxy)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[4-(2 butynyloxy)phenyl]sulfonyl)methyl)-4-piperidinecarboxamide To a solution of tert-Butyl4-[(tert-butoxyamino)carbonyl]-4-({[4-(2-yloxy) phenyl]sulfonyl)methyl)-l-piperidinecarboxylate (3.0 g, 5.5 mmol) in 6mL of CH 2 Cl 2 5 was added of trimethylsilyltrifluoromethylsulfonate (1.1 ml, 6.05 mmol) followed by 0.7mL of 2,6-lutidine. The reaction was stirred for lh and diluted with CH 2
C
2 . The organics were washed with H 2 0, saturated NaHCO 3 , brine, dried over MgSO 4 , filtered, and concentrated in vacuo to provide 2.01g (86%) of the desired product as an off white solid. Electrospray Mass Spec: 423.2 (M+H)* 10 Step 4: [[4-[(tert-Butoxyamino)carbonyl]-4-[[[4-(2-[4-(2-butynyloxy)phenyl] sulfonyl}methyl)-4-piperidinecarboxamide butoxycarbonyl)amino] methylene]carbamic acid, tert-butyl ester To a mixture of N-(tert-Butoxy)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[4 15 (2-butynyloxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxamide (0.127g, 0.3mmol), the di-t-boc-protected thiourea (obtained from step 1) (0.091g, 0.33 mmol)and triethylamine (0.092 ml) in 3mL of DMF was added mercury(II) chloride (0.09g, 0.33 mmol) and stirred for lh at 0*C. The reaction was diluted with EtOAc and filtered through a pad of celite. The organics were washed with H0, brine, dried 20 over MgSO 4 , filtered, and concentrated in vacuo. The residue was triturated with hexanes to provide the desired product as a white solid. . Electrospray Mass Spec: 665.5 (M+H)* Step 5: 1-[Amino(imino)methyl]-4-({[4-(2-butynyloxy)phenyl] sulfonyl} methyl)-N hydroxy-4-1]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4 25 oxy)phenyl]sulfonyl)methyl)-N-hydroxy-4-piperidinecarboxamide A mixture of [[4-[(tert-Butoxyamino)carbonyl]-4-[[[ 4 -(2-[4-(2-butynyloxy) phenyl]sulfonyl}methyl)-4-piperidinecarboxamidebutoxycarbonyl)amino]methylene] carbamic acid, tert-butyl ester (0.135g, 0.2 mmol) and 3mL of trifluoroacetic acid in 2mL of CH 2
CI
2 was heated at 60'C for 24h. The reaction was concentrated in vacuo 30 and was prep HPLC to provide 0.032g (31%) of the desired product as a beige solid. Electrospray Mass Spec: 409.3 (M+H)* WO 00/44723 PCT/USOO/01864 -88 Example 45 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(4-hydroxy-2 butynyl)- henyllsulfonyl}methyl)-N-hydroxy-1-(4-hydroxy-2-butynyl)-4 5 piperidinecarboxamide Step 1: Ethyl-4-({[ 4 -(2-butynyloxy)phenyl]sulfonyl}methyl)-1-(4-{[(3-chloroanilino) carbonyl]oxy)- 2 -butynyl)-4-piperidinecarboxylate Ethyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-1-(4-{[(3-chloroanilino) carbonyl]oxy}- 2 -butynyl)-4-piperidinecarboxylate was prepared according to the 10 general method as outlined in Example 37 (step 1). Starting from 4 -[[[4-(2-Butynyl oxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (0.291 g,0.7 mmol) and 4-chloro-2-butynyl-(3-chlorophenyl)carbamate (0.19g, 0.735), 0.27 g (64%) of the desired product was isolated as pale yellow oil. Electrospray Mass Spec: 601.3 (M+H)* 15 Step 2: Ethyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl)methyl)-1-(4-hydroxy-2-butynyl) 4- nyloxy)phenyl]sulfonyl}methyl)-1-( 4 -hydroxy-2-butynyl)-4-piperidine carboxylate A solution of ethyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-1-(4-{[(3 chloroanilino) carbonyl]oxy}- 2 -butynyl)-4-piperidinecarboxylate (from step 1) 0.22g, 20 0.366 mmol) and lithiumhydroxide hydrate (0.019g, 0.44 mmol) in 4mL MeOH was heated to reflux for 3h. The reaction was concentrated, diluted with H 2 0, acidified to pH3 and extracted with CH 2
CI
2 . The organics were washed with H 2 0, brine, dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 3% MeOH/ CH 2
CI
2 to provide 0. 12g ( 73%) of the desired 25 product as an yellow oil. Electrospray Mass Spec: 448.3 (M+H)* Step 3: 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-1-(4-hydroxy-2-butynyl)-4 nyl]sulfonyl)methyl)-1-( 4 -hydroxy-2-butynyl)-4-piperidinecarboxylic acid 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-1-(4-hydroxy-2-butynyl)-4-ynyl] 30 sulfonyl}methyl)-1-( 4 -hydroxy-2-butynyl)-4-piperidinecarboxylic acid was prepared according to the general method as outlined in Example 30 (step 7). Starting from WO 00/44723 PCTIUSOO/01864 -89 ethyl-4-({ [4-(2-butynyloxy)phenyl]sulfonyl}methyl)- 1-(4-hydroxy-2-butynyl)-4 piperidinecarboxylate (0.115g, 0.257 mmol), 0.08g (74%) of the desired product was isolated as white solid. Electrospray Mass Spec: 420.4 (M+H)* 5 Step 4: 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(4-hydroxy-2 butynyl)- henyl]sulfonyl}methyl)-N-hydroxy-1-( 4 -hydroxy-2-butynyl)-4-piperidine carboxamide 4-({[ 4
-(
2 -Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy- I -(4-hydroxy-2 butynyl)phenyl]sulfonyl}methyl)-N-hydroxy-I-( 4 -hydroxy-2-butynyl)-4-piperidine 10 carboxamide was prepared according to the general method as outlined in Example 30 (step 8). Starting from 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-I-(4-hydroxy 2-butynyl)-4-nyl]sulfonyl}methyl)-1-( 4 -hydroxy-2-butynyl)-4-piperidinecarboxylic acid (0.073g, 0.174 mmol), 0.026g (34%) of the desired product was isolated as white solid. Electrospray Mass Spec: 435.3 (M+H)* 15 Methods for the solution phase synthesis of the compounds of the present invention is as shown in the following scheme. O-fVSO 2 ONHOtBu ONHOtBu N A B O SO 2 CONHOH H N R 20 Example 46 4 -({1 4 -(But-2-ynyloxy)phenyl]sulfonyl}methyl)-1-ethyl-N-hydroxypiperidine-4 carboxamide triflouroacetic acid salt 25 Step A: A solution of N-(tert-butoxy)-4-({[ 4 -2-butynyloxy)phenyl]sulfonyl} methyl)-4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl-4-piperidinecarboxyamide (0.097g, 0.23mmol), ethyl iodide (0.019mL ,0.24mmol)and triethylamine (0.096mL, 0.69mmol) in 2mL of CH2CI2 was shaken at room temperature for 18h and then concentrated in vacuo.
WO 00/44723 PCT/USOO/01864 -90 Step B: A solution of the residue from Step A in 1mL of CH2Cl2 and 1mL of trifluoroacetic acid was heated at 50'C for 2h and then concentrated in vacuo to provide the desired product. 5 The following hydroxamic acids were synthesized according to the procedures of 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-1-ethyl-N-hydroxypiperidine-4 carboxamide triflouroacetic acid salt using the appropriate reagents. Example 47: Reagent - 0.029mL (0.24mmol) of 2-chloro-5-(chloromethyl)thiophene 10 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-1-[(5-chlorothien-2-yl)methyl]-N hydroxypiperidine-4-carboxamide triflouroacetic acid salt Example 48: Reagent - 0.0496g (0.24mmol) of 4-picolyl chloride hydrochloride 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(pyridin-4-ylmethyl) 15 piperidine-4-carboxamide triflouroacetic acid salt Example 49 4-({[4-(But-2-ynyloxy)phenyllsulfonyl}methyl)-N-hydroxy-1-(pyridin-3 ylcarbonyl)piperidine-4-carboxamide triflouroacetic acid salt 20 Step A: A solution of N-(tert-butoxy)-4-({ [4-92-butynyloxy)phenyl] sulfonyl)methyl)-4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl-4-piperidine carboxy amide (0.097g, 0.23mmol), triethylamine (0.064mL, 0.64mmol), nicotinoyl chloride hydrochloride (0.061g ,0.34mmol), and 4-dimethylaminopyridine (0.002 g) in 2mL of CH2C12 was shaken at room temperature for 18h and then concentrated in vacuo. 25 Step B: same as Step B of Example 46. The following hydroxamic acids were synthesized according to the procedures of 4 ({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-I -(pyridin-3-ylcarbonyl) piperidine-4-carboxamide triflouroacetic acid salt using the appropriate reagents. 30 WO 00/44723 PCT/USOO/01864 -91 Example 50 Reagent - 0.04mL (0.276mmol) of benzoyl chloride 1-Benzoyl-4-({[4-(but-2-ynyloxy)phenyllsulfonyl}methyl)-N-hydroxypiperidine 4- carboxamide 5 Example 51 Reagent - 0.037mL (0.276mmol) of 2-thiophenecarbonyl chloride 4-({14-(But-2-ynyloxy)phenylsulfonyl}methyl)-N-hydroxy-1-(thien-2 ylcarbonyl) piperidine-4-carboxamide 10 Example 52 4-({[4-(But-2-ynyloxy)phenyllsulfonyl}methyl)-N-1-ethyl-N-4-hydroxypiperidine 1,4-dicarboxamide Step A: A solution of N-(tert-butoxy)-4-({[ 4 -92-butynyloxy)phenyl]sulfonyl}methyl) 15 4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl-4-piperidinecarboxyamide (0.097g, 0.23mmol), triethylamine (0.064mL, 0.64mmol) and ethyl isocyanate (0.02mL, 0.253mmol) in 2mL of CH2Cl2 was shaken at room temperature for 18h and then concentrated in vacuo. Step B: same as Step B of Example 46. 20 The following hydroxamic acids were synthesized according to the procedures of Example 52.using the appropriate reagents. Example 53 Reagent - 0.275mL (0.253mmol) of phenylisocyanate 25 4-({1[4-(But-2-ynyloxy)phenylsulfonyl}methyl)-N-4-hydroxy-N-1 phenylpiperidine-1,4-dicarboxamide Example 54 Reagent - 0.32mL (0.253mmol) of diethylcarbamyl chloride 30 4-({[4-(But-2-ynyloxy)phenyljsulfonyl}methyl)-N-1-,N-1-diethyl-N-4 hydroxypiperidine-1,4-dicarboxamide WO 00/44723 PCTUSOO/01864 -92 Example 55 Reagent - 0.0295mL (0.253mmol) of morpholine carbonyl chloride 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(morpholin-4 5 ylcarbonyl)piperidine-4-carboxamide Example 56 Reagent - 0.043g (0.253mmol) of methylphenylcarbamoyl chloride 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-N-1-methyl-N-1 10 phenylpiperidine-1,4-dicarboxamide Example 57 Octyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-4 [(hydroxyamino)carbonyl]piperidine-1-carboxylate 15 Step A: A solution of 0.097g (0.23mmol) of N-(tert-butoxy)-4-({[4-92-butynyloxy) phenyl]sulfonyl}methyl)-4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl-4-piperidine carboxyamide (0.097g, 0.23mmol), octyl chloroformate (0.0495 ml, 0.253 mmol) and diisopropylethylamine (0.08 ml, 0.46 mmol) in 2mL of CH2Cl2 was shaken at room temperature for 18h and then concentrated in vacuo. 20 Step B: same as StepB of Example 46. The following hydroxamic acids were synthesized according to the procedures of Example 57 using the appropriate reagents. 25 Example 58 Reagent - 0.038mL (0.253mmol) of 4-methoxyphenyl chloroformate 4-Methoxyphenyl4-({[4-(but-2-ynyloxy)phenyllsulfonyl}methyl)-4 [(hydroxyamino) carbonyllpiperidine-1-carboxylate WO 00/44723 PCT/USOO/01864 -93 Example 59 Reagent - 0.0323mL (0.253mmol) of benzenesulfonyl chloride 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(phenylsulfonyl) piperidine-4-carboxamide 5 Example 60 Reagent - 0.0457g (0.253mmol) of 1-methylimidazole-4-sulfonyl chloride 4-({[4-(But-2-ynyloxy)phenyllsulfonyl)methyl)-N-hydroxy-1-[(1-methyl-IH imidazol-4-yl)sulfonylpiperidine-4-carboxamide 10 Example 61 1-[2-(Benzylamino)acetyl]-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-N hydroxypiperidine-4-carboxamide Step A: A solution of N-(tert-butoxy)-4-({[4-2-butynyloxy)phenyl] sulfonyl)methyl) 15 4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl-4-piperidine carboxyamide (0.097g, 0.23mmol), triethylamine (0.064mL, 0.64mmol), chloroacetyl chloride (0.064 ml, 0.64 mmol), and 4-dimethylaminopyridine (0.002 g) in 2mL of CH2Cl2 was shaken at room temperature for 18h. The solution was then treated with benzyl amine (0.075mL, 0.69mmol) and was shaken for 18h and then concentrated in vacuo. 20 Step B: same as Step B of Example 46. The following hydroxamic acids were synthesized according to the procedures of Example 61 using the appropriate amine reagents. 25 Example 62 Reagent - 0.O6OmL (0.69mmol) of morpholine 4-({1[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(2-morpholin-4 ylacetyl)piperidine-4-carboxamide 30 WO 00/44723 PCT/US0O/01864 -94 Example 63 Reagent - 0.076mL (0.69mmol) of N-methylpiperazine 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-12-(4 methylpiperazin-1-yl)acetyl]piperidine-4-carboxamide 5 Example # HPLC retention time (min.) 1
MS
2 (M+H)* 46 1.85 395 47 2.20 498 48 1.71 458 49 2.11 472 52 2.30 438 53 2.85 486 57 3.80 523 58 2.98 517 54 2.87 466 55 2.33 480 56 2.84 500 59 2.92 507 60 2.40 511 50 2.67 471 51 2.64 477 61 2.14 514 62 1.86 494 63 1.84 507 LC conditions: Hewlett Packard 1100; YMC ODS-A 4.6 mmx50 mm5 u column at 23'C; lOuL injection; Solvent A: 0.05% TFA/water; Solvent B: 0.05% TFA/acetonitrile; Gradient: Time 0: 98% 10 A; 1 min: 98% A;7 min: 10% A, 8 min: 98% A; Post time 1 min. Flow rate 2.5 mL/min; Detection: 220 and 254 nm DAD 2 Mass Spec conditions: API-electrospray 15 Example 64 1-Acetyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid hydroxamide Step 1: 4-But-2-ynyloxybenzenesulfonyl fluoride: To a solution of 4-but-2-ynyloxybenzenesulfonyl chloride (prepared from 20 Example 30, step 4) (2.0 g, 8.18 mmol) in acetonitrle (10 ml) was added KF-CaF 2 (2.85g, 16.3 mmol) and the resulting mixture was stirred for 4 hours at room temperature. The reaction mixture was filtered and the filterate was concentrated. The crude product was dissolved in EtOAc and washed with water. The organic layer WO 00/44723 PCT/USOO/01864 -95 was dried over anhydrous Na 2
SO
4 and the solvent was removed to obtain 1.5 g (80%) of the product as solid. Step 2: 4-(4-But-2-ynyloxybenzenesulfonyl)-piperidine-1,4-dicarboxylic acid tert 5 butyl ester methyl ester To a solution of diisopropylamine(1.58 mL, 11.3 mmol) in THF(25 mL) at 00 C was added 2.5M n-BuLi(4.68 mL, 11.7 mmol) and the resulting mixture was stirred for 15 min at that temperature. The reaction mixture was cooled to -78' C and a solution of 1-(tert-butyl)-4-methyl 1,4-piperidinecarboxylate (prepared from example 10 30, step 1) (2.67g, 11.0 mmol) in THF(40 mL) was added. The resulting mixture was stirred for 1h and a solution of 4-but-2-ynyloxy benzenesulfonyl fluoride (2.5g, 11.0 mmol) in THF(25 mL) was added into it. After stirring for 4h at rt, the reaction was quenched with satd. aqueous NI 4 Cl solution and extracted with EtOAc, dried over anhydrous Na 2
SO
4 . The crude product was purified by silica gel chromatography to 15 obtain 2.6g(53%) of the product as a solid; 1 H NMR(300 MHz, CDCl 3 ) 5 1.44(s, 9H), 1.87(m, 3H), 1.98(m, 2H), 2.32(m, 2H), 2.62(m, 2H), 3.74(s, 3H), 4.17(m, 2H), 4.74(m, 2H), 7.09(d, 2H, J= 7.2 Hz), 7.71(d, 2H, J= 7.2 Hz). Step 3: 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl 20 ester: To a solution of product from step 2 (500 mg, 1.11 mmol) in methylene chloride (10 ml) was added 4M HCl (2 ml) and the resulting mixture was stirred for 2 hours at room temperature. The solid was filtered, washed with ether to obtain 410mg(95%) of the product as a solid. 'H NMR(300 MHz, CDCl):6 1.86(m, 3H), 25 2.52(m, 4H), 2.89(m, 2H), 3.52(m, 2H), 3.74(s, 3H), 4.74(m, 2H), 7.10(d, 2H, J= 8.7 Hz), 7.69(d, 2H, J= 8.7 Hz). Step 4: 1-Acetyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid methyl ester 30 To a solution of product from step 3 (105 mg, 0.23 mmol) in methylene chloride (1 ml) was added triethylamine (93 mg, 0.92 mmol), acetyl chloride(18 mg, WO 00/44723 PCT/USOO/01864 -96 0.23 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 8 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 75 mg (80%) of the product as a solid. 5 Step 5: 1 -Acetyl- 4
-(
4 -but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid: A solution of the ester, from step 4 (240 mg, 0.61 mmol)) and lithium hydroxide (18 mg, 0.75 mmol)) in tetrahydrofuran/methanol/water (3:3:2) mixture was stirred at room temperature for 15 hours. The mixture was concentrated, acidified to 10 pH 3-5 with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent under vacuuo gave the acid. Yield : 200 mg, (87%). 'H NMR(300 MHz, acetone-d 6 ):6 1.84(t, 3H, J= 2.8 Hz), 1.90-2.05(m, 2H), 2.06(s, 3H), 2.25-2.51(m, 3H), 3.06(m, 1H), 4.04(m, 1H), 4.63(m, 1H), 4.86(q, 1H, J= 2.0). 15 Step 6: 1-Acetyl-4-( 4 -but- 2 -ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid hydroxamide: To a solution of 1-acetyl- 4
-(
4 -but-2-ynyloxybenzenesulfonyl)piperidine-4 carboxylic acid (180 mg, 0.48 mmol) in dimethylformamide was added hydroxybenzo 20 triazol (77mg, 0.57 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (127 mg, 0.66) and N-methylmorpholine (0.078 ml, 0.71 mmol). The resulting mixture was stirred for 1 h at room temperature when 50% aqueous hydroxylamine solution (0.145 ml, 2.37 mmol) was added and the mixture was stirred for 15 h at that temperature. The solvent was removed in vacuo and ethyl 25 acetate/water was added to the crude product. The organic layer was separated and washed successively with IN aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to obtain 100 mg (53%) of the product as a solid. 'H NIR(300 MHz, CDCl 3 ):5 1.64(m, 1H), 1.85(m, 3H), 1.99(s, 3H), 30 2.31(m, 4H), 2.83(m, 1H), 3.88(m, 1H), 4.41(m, 1H), 4.88(m, 2H), 7.16(d, 2H, J= 9.0 Hz), 7.66(d, 2H, J= 9.0 Hz), 9.20(m, 1H), 11.00(m, 1H); MS-ES: m/z395.2 (M+H)*.
WO 00/44723 PCTUSOO/01864 -97 Example 65 1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid hydroxamide 5 Step 1: 1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid methyl ester To a solution of 4
-(
4 -but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester, (400 mg, 1.03 mmol) in chloroform (10 ml) was added triethylamine (416 mg, 4.12 mmol), benzoyl chloride(144 pl, 1.24 mmol) followed 10 by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 375 mg (80%) of the product as a solid. MS-ES: m/z 456.1 (M+H)*. 15 Step 2: 1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid 1 -Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid was prepared, starting from 1 -benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid methyl ester (300 mg, 0.66 mmol) and lithium 20 hydroxide (18 mg, 0.75 mmol). The resulting reaction mixture was worked up as outlined in Example 64, (step 5). Yield: 250 mg(86%) of the acid. HR - MS: m/z Calculated for C 23 23
NO
6 S 442.1319; Found 442.1317. Step 3: 1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid 25 hydroxamide The general procedure for step 6 (Example 64) was followed using 1-benzoyl 4
-(
4 -but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid (100 mg, 0.23 mmol) in dimethylformamide (2 ml), 1-hydroxybenzotriazole(36 mg, 0.27 mmol), 1 [3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(62 mg, 0.32 mmol), 30 N-methylmorpholine (0.038 ml, 0.35 mmol), and hydroxylamine (0.083 ml, 1.15 mmol) to obtain 40 mg( 38%) of the product as a solid. MS-ES: m/z 457.2 (M+H)*.
WO 00/44723 PCTIUSOO/01864 -98 Example 66 1-(4-Methoxybenzoyl)-4-(4-but-2-ynyloxy benzenesulfonyl)piperidine-4 carboxylic acid hydroxamide. Step 1: 1-(4-Methoxybenzoyl)-4-(4-but-2-ynyloxybenzenesulfonyl) piperidine-4 5 carboxylic acid methyl ester To a solution of 4
-(
4 -but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (260 mg, 0.77 mmol) in chloroform (7 ml) was added triethylamine (311 mg, 3.08 mmol), 4-methoxybenzoyl chloride(158 mg, 0.92 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 10 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 280 mg (75%) of the product as a solid. HR - MS: m/z Calculated for C 2 sH 7 NOS 486.1581; Found 486.1576. 15 Step 2: 1-( 4 -Methoxybenzoyl)-4-(4-but-2-ynyloxybenzenesulfonyl) piperidine-4 carboxylic acid. 1-( 4 -Methoxybenzoyl)-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4 carboxylic acid. was prepared following the procedure of Example 64 (step 5). Starting from 1-(4-methoxybenzoyl)-4-(4-but-2-ynyloxybenzenesulfonyl) piperidine 20 4-carboxylic acid methyl ester 250 mg, 0.52 mmol) in 4ml of tetrahydrofuran: methanol (1:1) and 1N sodium hydroxide (1.03 ml, 1.03 mmol) 150 mg of (62%) of the acid was isolated. HR - MS: m/z Calculated for C H 2 5NOS 472.1425; Found 472.1426. 25 Step 3: 1-( 4 -Methoxybenzoyl)-4-(4-but-2-ynyloxybenzenesulfonyl) piperidine-4 carboxylic acid hydroxamide: 1-( 4 -Methoxybenzoyl)-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4 carboxylic acid hydroxamide was prepared following the procedure Example 64 (step 6). Starting from 1-( 4 -methoxybenzoyl)-4-(4-but-2-ynyloxybenzenesulfonyl) 30 piperidine-4-carboxylic acid (90 mg, 0.19 mmol) in dimethylformamide (2 ml), 1 hydroxybenzotriazole (31 mg, 0.23 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride(51 mg, 0.27 mmol), N-methylmorpholine (0.031 ml, WO 00/44723 PCTUSOO/01864 -99 0.28 mmol), and hydroxylamine (0.068 ml, 0.95 mmol), 70 mg( 76%) of the product was isolated as solid. HR - MS: m/z Calculated for CH 2
HN
2 0 7 S 487.1534; Found 487.1531. 5 Example 67 4
-(
4 -But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(pyrrolidine-l-carbonyl)-4 piperidinecarboxamide Stepl: 4 -(4-but-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1-carbonyl)-piperidine-4 carboxylic acid methyl ester 10 To a solution of 4
-(
4 -but- 2 -ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (400 mg, 1.03 mmol) in chloroform (10 ml) was added triethylamine (208 mg, 2.06 mmol), pyrrolidinecarbonyl chloride (206 mg, 1.54 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and 15 extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 400 mg (87%) of the product as a solid; MS ES: m/z 449.3 (M+H)*. Step 2: 4
-(
4 -but-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1-carbonyl)-piperidine-4 20 carboxylic acid : 4-( 4 -But-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1-carbonyl)-piperidine-4 carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1-carbonyl) piperidine-4-carboxylic acid methyl ester (250 mg, 0.52 mmol) in 4ml of 25 tetrahydrofuran: methanol (1:1) and IN sodium hydroxide (1.03 ml, 1.03 mmol), 150 mg of (62%) of the acid was isolated. HR - MS: m/z Calculated for C 24
H
2 5 NOS 472.1425; Found 472.1426. Step 3: 4
-(
4 -But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(pyrrolidine-1-carbonyl) 30 4 -piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4
-(
4 -But-2-ynyloxybenzenesulfonyl)-N-hydroxy- 1 -(pyrrolidine- 1 carbonyl)-4-piperidinecarboxalic acid (255 mg, 0.23 mmol) in dimethylformamide (6 WO 00/44723 PCT/USOO/01864 -100 ml), 1-hydroxybenzotriazole(96 mg, 0.71 mmol), 1-[3-(dimethylamino)propyl]-3 ethylcarbodiimide hydrochloride(157 mg, 0.82 mmol), N-methylmorpholine (0.099 ml, 0.84 mmol), and hydroxylamine (0.181 ml, 2.8 mmol), 150 mg( 60%) of the product was isolated as a solid. HR - MS: m/z Calculated for C 21
H,N
3 ,S 450.1693; 5 Found 450.1692. Example 68 Ethyl 4-(4-but-2-ynyloxybenzenesulfonyl)-4-[(hydroxyamino)carbonyl]-1 piperidinecarboxylate 10 Step 1: 1-Ethyl 4-methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1,4-piperidine dicarboxylate To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (400 mg, 1.03 mmol) in chloroform (10 ml) was added sodium bicarbonate (865 mg, 10.3 mmol), ethylchloroformate(0.147 ml, 1.54 mmol). The 15 resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 425 mg (98%) of the product as a solid. MS ES: m/z 424.4 (M+H)*. 20 Step 2: 1-(Ethylcarbonyl)-4-(4-but-2-ynyloxybenzenesulfonyl)-1-piperidine carboxylic acid 1-(Ethylcarbonyl)-4-(4-but-2-ynyloxybenzenesulfonyl)-1-piperidine carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from 1-Ethyl 4-methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1,4-piperidine 25 dicarboxylate (400 mg, 0.95 mmol) in 8ml of tetrahydrofuran: methanol; water (1:1:0.5) and lithium hydroxide (50 mg, 2.04mmol), 340 mg of (88%) of the acid was isolated. HR - MS: m/z Calculated for C 19 23 NOS 408.1122; Found 408.1126. Step 3: Ethyl 4-(4-but-2-ynyloxybenzenesulfonyl)-4-[(hydroxyamino)carbonyl]-1 30 piperidinecarboxylate Ethyl 4-(4-but-2-ynyloxybenzenesulfonyl)-4-[(hydroxyamino)carbonyl]-1 piperidinecarboxylate was prepared following the procedure Example 64 (step 6).
WO 00/44723 PCTUSOO/01864 -101 Starting from 1-(Ethylcarbonyl)-4-( 4 -but-2-ynyloxybenzenesulfonyl)-1-piperidine carboxylic acid (225 mg, 0.55 mmol) in dimethylformamide (6 ml), 1-hydroxy benzotriazole (89 mg, 0.66 mmol), 1-[ 3 -(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(148 mg, 0.77 mmol), N-methylmorpholine (0.091 ml, 0.86 mmol), and 5 hydroxylamine (0.168 ml, 2.75 mmol), 150 mg( 64%) of the product was isolated as a solid. HR - MS: m/z Calculated for C,,HN 2 0 7 S 425.1377; Found 425.1375. Example 69 4
-(
4 -But- 2 -ynyloxybenzenesulfonyl)-N-hydroxy-1-[(trifluoromethyl)sulfonyl]-4 10 piperidinecarboxamide Step 1: Methyl 4
-(
4 -but-2-ynyloxybenzenesulfonyl)-1-[(trifluoromethyl) sulfonyl]-4 piperidinecarboxylate To a solution of 4
-(
4 -but- 2 -ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (350 mg, 0.90 mmol) in chloroform (10 ml) was added triethyl 15 amine (182 mg, 1.81 mmol), trifluoromethanesulfonyl chloride(0.125 ml, 1.17 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 245 mg (56%) of the product as a solid. HR - MS: m/z 20 Calculated for C,,H,FN0,S 2 484.0706; Found 484.0700. Step 2: 4
-(
4 -but-2-ynyloxybenzenesulfonyl)-1-[(trifluoromethyl) sulfonyl]-4 piperidinecarboxylic acid 4
-(
4 -but-2-ynyloxybenzenesulfonyl)-1-[(trifluoromethyl)sulfonyl]-4 25 piperidinecarboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from Methyl 4-( 4 -but-2-ynyloxybenzenesulfonyl)-1-[(trifluoromethyl) sulfonyl]-4-piperidinecarboxylate (225 mg, 0.47 mmol) in 8ml of tetrahydrofuran: methanol; water (1:1:0.5) and lithium hydroxide (24 mg, 0.98mmol), 175 mg of (80%) of the acid was isolated. MS-ES: m/z 468.1 (M-H)-. 30 WO 00/44723 PCT/USOO/01864 -102 Step 3: 4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(trifluoromethyl) sulfonyl]-4-piperidinecarboxamide. 4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(trifluoromethyl) sulfonyl]-4-piperidinecarboxamide was prepared following the procedure Example 64 5 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(trifluoromethyl) sulfonyl]-4-piperidinecarboxylic acid (145 mg, 0.31 mmol) in dimethylformamide (3 ml), 1-hydroxybenzotriazole(50 mg, 0.37 mmol), 1-[3-(dimethylamino)propyl]-3 ethylcarbodiimide hydrochloride(83 mg, 0.47 mmol), N-methylmorpholine (0.051 ml, 0.47 mmol), and hydroxylamine (0.095 ml, 1.55 mmol), 90 mg( 60%) of the 10 product was isolated as a solid. HR - MS: m/z Calculated for CHFN 2 0,S2 485.0659; Found 485.0666. Example 70 4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinylcarbonyl)- 4 15 piperidinecarboxamide Step 1: Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)- 1-(3-pyridinylcarbonyl)- 4 piperidinecarboxylate To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) was added 20 triethylamine (443 mg, 4.39 mmol), nicotinyl chloride (276 ml, 1.55 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 460 mg (78%) of the product as a solid. HR - MS: m/z 25 Calculated for C 23
HN
2 OS 457.1428; Found 457.1428. Step 2 : 4-(4-But-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)- 4-piperidine carboxylic acid 4-(4-But-2-ynyloxybenzenesulfonyl)- 1 -(3-pyridinylcarbonyl)-4-piperidine 30 carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)- WO 00/44723 PCT/USOO/01864 -103 4-piperidinecarboxylate (430 mg, 0.94 mmol) in 8ml of tetrahydrofuran: methanol (1:1), and IN sodium hydroxide (1.89 ml, 1.89 mmol) to obtain 235 mg(57%) of the acid. HR - MS: m/z Calculated for C 22
H
22
N
2 0,S 443.1271; Found 443.1270. 5 Step 3: 4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinylcarbonyl)- 4 piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-But-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4 piperidinecarboxylic acid (195 mg, 0.44 mmol) in dimethylformamide (4 ml), 1 hydroxybenzotriazole (72 mg, 0.53 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl 10 carbodiimide hydrochloride(119 mg, 0.62 mmol), N-methylmorpholine (0.072 ml, 0.66 mmol), and hydroxylamine (0.135 ml, 2.2 mmol), 65 mg( 32%) of the product was isolated as a solid. HR - MS: m/z Calculated for C 22 HN306S 458.1380; Found 458.1373. 15 Example 71 4
-(
4 -but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(2-thienylcarbonyl)- 4 piperidinecarboxamide Step 1: Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)- 4 piperidinecarboxylate 20 To a solution of 4
-(
4 -but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) was added triethylamine (261 mg, 2.58 mmol), thiophenylcarbonyl chloride(227 mg, 1.55 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with 25 methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 480 mg (81%) of the product as a solid. HR - MS: m/z Calculated for C 22
H
23
NO
6
S
2 462.1040; Found 462.1039. Step 2: 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)- 4-piperidine 30 carboxylic acid 4 -(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4-piperidine carboxylic acid was prepared following the procedure of Example 64 (step 5).
WO 00/44723 PCT/USOO/01864 -104 Starting from Methyl 4-( 4 -but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4 piperidinecarboxylate (435 mg, 0.94 mmol) in 8ml of tetrahydrofuran: methanol (1:1), and IN sodium hydroxide (1.89 ml, 1.89 mmol) to obtain 360 mg(86%) of the acid. HR - MS: m/z Calculated for C 21
H
21 NO6s2 448.0883; Found 448.0882. 5 Step 3: 4-( 4 -but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(2-thienylcarbonyl)- 4 piperidinecarboxamide 4-( 4 -but-2-ynyloxybenzenesulfonyl)-N-hydroxy- 1-(2-thienylcarbonyl)-4 piperidinecarboxamide was prepared following the procedure Example 64 (step 6). 10 Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)- 1-(2-thienylcarbonyl)-4 piperidinecarboxylic acid (335 mg, 0.75 mmol) in dimethylformamide (7 ml), I hydroxybenzotriazole (121 mg, 0.90 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride(201 mg, 1.05 mmol), N-methylmorpholine (0.124 ml, 1.13 mmol), and hydroxylamine (0.229 ml, 3.75 mmol), 216 mg( 62%) of the 15 product was isolated as a solid. HR - MS: m/z Calculated for CH 21 H20S2 463.0992; Found 463.0988. Example 72 4
-(
4 -but-2-ynyloxybenzenesulfonyl)-N-hydroxy-l-[(4-methoxyphenyl)sulfonyl] 20 4-piperidinecarboxamide. Step 1 : Methyl 4-( 4 -but-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl) sulfonyl]-4-piperidinecarboxylate To a solution of 4
-(
4 -but- 2 -ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride(10 ml) was added 25 triethylamine (261 mg, 2.58 mmol), 4-methoxyphenylsulfonyl chloride(320 mg, 1.55 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 590 mg (88%) of the product as a solid. 30 HR - MS: m/z Calculated for C2H2 NO,S2 522.1251; Found 522.1252.
WO 00/44723 PCT/USOO/01864 -105 Step 2: 4 -(4-But-2-ynyloxybenzenesulfonyl)-I-[(4-methoxyphenyl) sulfonyl]-4 piperidinecarboxylic acid 4-(4-But-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl)sulfonyl]-4 piperidine carboxylic acid was prepared following the procedure of Example 64 (step 5 5). Starting from methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl) sulfonyl]-4-piperidinecarboxylate (545 mg, 1.04 mmol) in 8ml of tetrahydrofuran: methanol (1:1), and 1N sodium hydroxide (2.09 ml, 2.09 mmol) to obtain 446 mg (85%) of the acid. HR - MS: m/z Calculated for C 23
HNOS
2 508.1094; Found 508.1073. 10 Step 3 : 4
-(
4 -but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(4-methoxyphenyl) sulfonyl]-4-piperidinecarboxamide 4
-(
4 -But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1 -[(4-methoxyphenyl) sulfonyl]-4-piperidinecarboxamide was prepared following the procedure Example 64 15 (step 6). Starting from 4-(4-But-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl) sulfonyl]-4-piperidinecarboxylic acid (402 mg, 0.79 mmol) in dimethylformamide (8 ml), 1-hydroxybenzotriazole (128 mg, 0.95 mmol), 1-[3-(dimethylamino)propyl]-3 ethylcarbodiimide hydrochloride (212 mg, 1.11 mmol), N-methylmorpholine (0.130 ml, 1.19 mmol), and hydroxylamine (0.242 ml, 3.95 mmol), 396 mg (96%) of the 20 product was isolated as a solid. HR - MS: m/z Calculated for C 23
H
26
N
2 0 8
S
2 523.1203; Found 523.1198. Example 73 4
-(
4 -but-2-ynyloxybenzenesulfonyl)-N-hydroxy-l-[(2,2,5-trimethyl-1,3-dioxan-5 25 yl)carbonyl]-4-piperidinecarboxamide Step 1: Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5 yl)carbonyl]-4-piperidinecarboxylate Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5 yl)carbonyl]-4-piperidinecarboxylate was prepared following the procedure Example 30 64 (step 6). Starting from 4
-(
4 -but- 2 -ynyloxy-benzenesulfonyl)-piperidine-4 carboxylic acid methyl ester (500 mg, 1.29 mmol) in dimethylformamide (10 ml),
(
2
,
2 ,5-trimethyl-1,3-dioxan-5-yl)carboxylic acid (224 mg, 1.29 mmol), 1-hydroxy- WO 00/44723 PCT/USOO/01864 -106 benzotriazole (209 mg, 1.56 mmol), 1-[ 3 -(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (346 mg, 1.81 mmol), and N-methylmorpholine (0.212 ml, 1.94 mmol), to obtain 385 mg( 59%) of the product as a solid. HR - MS: m/z Calculated for
C
25
H
33
NO
8 S 508.2000; Found 508.1998. 5 Step 2: 4-( 4 -but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5 yl)carbonyl]-4-piperidinecarboxylic acid 4
-(
4 -But-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl]-4-piperidinecarboxylic acid was prepared following the procedure of 10 Example 40 (step 5). Starting from Methyl 4
-(
4 -but-2-ynyloxybenzenesulfonyl)-1 [(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylate (335 mg, 0.66 mmol) in 4ml of tetrahydrofuran: methanol (1:1), and 1N sodium hydroxide (1.3 ml, 1.3 mmol) to obtain 315 mg(97%) of the acid. HR - MS: m/z Calculated for
CH
31 NOS 494.1843; Found 494.1835. 15 Step 3: 4-( 4 -But- 2 -ynyloxybenzenesulfonyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,3 dioxan-5-yl)carbonyl]-4-piperidinecarboxamide: 4-( 4 -But- 2 -ynyloxybenzenesulfonyl)-N-hydroxy1- [(2,2,5-trimethyl- 1,3-di oxan-5-yl)carbonyl]-4-piperidinecarboxamide was prepared following the procedure 20 Example 64 (step 6). Starting from 4
-(
4 -but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5 trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylic acid (280 mg, 0.57 mmol) in dimethylformamide (6 ml), 1-hydroxybenzotriazole (92 mg, 0.57 mmol), 1-[3 (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (153 mg, 0.80 mmol), N methylmorpholine (0.094 ml, 0.85 mmol), and hydroxylamine (0.174 ml, 2.85 mmol), 25 180 mg (62%) of the product was isolated as a solid. HR - MS: m/z Calculated for
CH
32
N
2 0 8 S 531.1771; Found 531.1768. Example 74 4
-(
4 -But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[3-hydroxy-2 30 (hydroxymethyl)-2-methylpropanoyl]-4-piperidinecarboxamide To a solution of product from Example 73 (150 mg, 0.29 mmol) in tetrahydrofuran (2 ml) was added 1N aqueous hydrochloric acid (2 ml) and the WO 00/44723 PCTUSOO/01864 -107 resulting mixture was stirred for 4 hours. The organic layer was washed with sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Solvent was removed to obtain 40 mg (29%) of the product. HR - MS: m/z Calculated for C 21 H 2
N
2 0 8 S 469.1639; Found 469.1637. 5 Example 75 Tert-butyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl]-1 piperidinecarboxalate Step 1: 1 -(tert-butoxycarbonyl)- 4- { [4-(2-butynyloxy)phenyl] sulfonyl } -4 10 piperidinecarboxylic acid A solution of 4
-(
4 -but-2ynyloxybenzenesulfonyl)-piperidine-1,4-dicarboxylic acid tert-butyl ester methyl ester (from example 64, step 2) (15g, 33.2 mmol) in water (100 mL), methanol (50 mL) and tetrahydrofuran (50 mL) was treated with lithium hydroxide hydrate (2.73g, 66.4 mmol) and heated at reflux for 8h. The reaction 15 mixture was concentrated in vacuo and filtered through celite. To the filtrate was added aqueous IN hydrochloric acid. A thick gum was obtained which was dissolved in dichloromethane and washed with water. Concentration of the organic phase gave a foam (14.9 g). Trituration with diethyl ether gave 1-(tert-butoxycarbonyl)-4-{[4-(2 butynyloxy)phenyl]sulfonyl}-4 -piperidinecarboxylic acid as a white powder. 20 Electrospray MS m/z 482 (M-H) Step 2 : Tert-butyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino) carbonyl]- 1 -piperidinecarboxalate Dimethylformamide (3.53 mL, 46 mmol) was added to a solution of oxalyl chloride (22.9 mL of a 2.OM solution in dichloromethane) in dichloromethane (25 25 mL) at 0"C. After 15 min a solution of 1-(tert-butoxycarbonyl)-4-{[4-(2-butynyloxy) phenyl]sulfonyl)-4-piperidinecarboxylic acid (10g, 22.9 mmol) in dimethylformamide was added and the reaction mixture was allowed to warm to room temperature. After 1 h the reaction mixture was added to a mixture of hydroxylamine hydrochloride (16 g, 229 mmol), triethylamine (48 mL, 344 mmol), water (123 mL) and tetrahydrofuran 30 (500 mL) that had been stirring at 0 0 C for 15 min. The reaction was allowed to warm to room temperature. After 18h it was then diluted with ethyl acetate and washed with WO 00/44723 PCT/USOO/01864 -108 saturated aqueous sodium bicarbonate (3X), then dried over potassium carbonate and concentrated in vacuo. Trituration with diethyl ether gave tert-butyl 4-{[4-(2 butynyloxy)phenyl]sulfonyl)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxalate as a white powder (6.3g). 'H NMR (dmso d6, 300 MHz) 6 1.38 (s, 9H, t-butyl), 1.6 5 1.7 (in, 2H, CHH), 1.85 (t, 3H, CH3, J = 2.2 Hz), 2.2 - 2.3 (m, 2H, CHH), 2.5 - 2.7 (in, 2H, NCHH), 3.9 - 4.0 (in, 2H, NCHH), 4.87 (q, 2H, OCH2, J = 2.2 Hz), 7.1 7.7 (m, 4H, ArH). Electrospray MS m/z 453 (M+H)* Example 76 10 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperidinecarboxamide hydrochloride To tert-butyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino) carbonyl]-1-piperidinecarboxalate (prepared from Example 75) (6.3g, 13.9 mmol) was added 4N hydrochloric acid in dioxane. After 6h the reaction mixture was 15 comcentrated in vacuo. Methanol was added and the resulting mixture concentrated in vacuo. Dichloromethane was added and removed in vacuo (2X). Trituration with diethyl ether gave 4-{[4-(2-butynyloxy)phenyl]sulfonyl)-N-hydroxy-4-piperidine carboxamide hydrochloride as a white powder (5.14g). 1H NMR (dmso d6, 300 MHz) 6 1.86 (t, 3H, CH3, J = 2.2 Hz), 2.0 - 2.7 (in, 8H, CH2), 4.89 (q, 2H, OCH2, 20 J = 2.2 Hz), 7.1 - 7.8 (in, 4H, ArH), 8.8 - 11.0 (in, 4H, N112, NHOH). Electrospray MS m/z 353 (M+H)* Example 77 Methyl ({4-{[4-(2-butynyloxy)phenyllsulfonyl}-4-[(hydroxyamino)carbonyl]1 25 piperidinyl) methyl)benzoate hydrochloride To 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperidinecarboxamide hydrochloride (prepared from Example 76) (2.5 g, 6.43 mmol) and methyl 4 (bromomethyl)benzoate (1.62 g, 7.07 mmol) in methanol (100 mL) at 50 0 C was added triethylamine (2.25 mL, 16.1 mmol). After 30 min additional methanol (50 mL) was 30 added. After 18 h the reaction mixture was concentrated in vacuo and IN aqueous hydrochloric acid (10 mL) and water was added. The resulting solid was isolated and WO 00/44723 PCT/US0O/01864 -109 to it was added methanol (20 mL) and IN hydrochloric acid in diethylether (15 mL). To the resulting solution was added diethyl ether. Trituration of the precipitate gave methyl ({ 4- { [4-(2-butynyloxy)phenyl]sulfonyl} -4-[(hydroxyamino)carbonyl]- 1 piperidinyl}methyl)benzoate hydrochloride as a white powder (2.4 g). 'H NMR (dmso 5 d6, 300 MHz) 5 1.85 (t, 3H, CH3, J = 2.2 Hz), 2.1 - 3.5 (in, 8H, CH2), 3.87 (S, 3H, OCH3), 4.40 (bd s, 2H, NCH2Ar), 4.89 (q, 2H, OCH2, J = 2.2 Hz), 7.1 - 8.1 (m, 8H, ArH), 9.3 - 11.2 (in, 3H, NH, NHOH). Electrospray MS m/z 501.5 (M+H)* Example 78 10 4-({4-{1[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl]-1 piperidinyl}methyl)benzoic acid hydrochloride To methyl ({4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino) carbonyl]-1-piperidinyl}methyl)benzoate hydrochloride (Prepared from example 77) (0.072g, 0.134 mmol) in methanol (1 mL) was added IN aqueous sodium hydroxide 15 (0.5 mL). After 18 h IN aqueous hydrochloric acid (0.5 mL) was added and the reaction mixture concentrated in vacuo. Water was added and the precipitate triturated to give 4-({4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino) carbonyl]-1-piperidinyl}methyl)benzoic acid hydrochloride as an off-white solid (0.040 g). 1 H NMR (dmso d6, 300 MHz) 6 1.85 (t, 3H, CH3, J= 2.2 Hz), 2.1 - 3.5 (in, 8H, 20 CH2), 4.37 (bd s, 2H, NCH2Ar), 4.89 (q, 2H, OCH2, J = 2.2 Hz), 7.0 - 8.1 (in, 8H, ArH), 9.3 - 11.2 (in, 3H, NH, NHOH), 13.1 (bd s, 1H, COOH). Electrospray MS m/z 487.1 (M+H)* Example 79 25 1-14-(Aminocarbonyl)benzyl]-4-{1[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4 piperidinecarboxamide hydrochloride To methyl ({4-{ [4-(2-butynyloxy)phenyl]sulfonyl)-4-[(hydroxyamino) carbonyl]-1-piperidinyl}methyl)benzoate hydrochloride (from example 77) (0.20 g) in methanol (10 mL) was added concentrated aqueous ammonium hydroxide (4 mL). 30 After several weeks the reaction mixture was concentrated in vacuo and chromatographed on silica gel (methanol/dichloromethane) to give a white powder which was dissolved in dichloromethane and methanol. IN Hydrochloric acid in WO 00/44723 PCT/USOO/01864 -110 diethylether was added followed by additional diethylether. Trituration gave 1-[4 (aminocarbonyl)benzyl]-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4 piperidinecarboxamide hydrochloride as a white powder (0.106 g). 'H NMR (Dmso d6, 300 MHz) 5 1.85 (t, 3H, CH3, J = 2.2 Hz), 2.2 - 3.5 (in, 8H, CH2), 4.33 (bd s, 5 2H, NCH2Ar), 4.89 (q, 2H, OCH2, J = 2.2 Hz), 7.1 - 8.0 (in, 8H, ArH), 7.47 (s, 1H, CONH), 8.04 (s, 1H, CONH), 9.35 (bd s, 1H, NHOH), 10.44 (bd s, 1H, NHOH), 11.1 (s, 1H, NH). Electrospray MS m/z 486.3 (M+H)* Example 80 10 Tert-butyl 4-{[4-(but-2-ynyloxy)phenyljsulfinyl}-4 [(hydroxyamino)carbonyl]piperidine- 1-carboxalate To tert-butyl 4-{ [4-(but-2-ynyloxy)phenyl]sulfanyl}- 4 -[(hydroxyamino)carbonyl] piperidine-1-carboxalate (0.30 g) (obtained from example 14) in methanol (10 mL) was added 30% aqueous hydrogen peroxide (3 mL). After 3 days water and 15 dichloromethane were added and the organic phase washed with aqueous Na2SO3. Concentration of the organic phase gave material which was dissolved in methanol (8 mL) and treated with 30% aqueous hydrogen peroxide. After several days workup as above gave tert-butyl 4-{[4-(but-2-ynyloxy)phenyl]sulfinyl}-4-[(hydroxyamino) carbonyl]piperidine-1-carboxalate as a colorless foam (0.26 g). . 'H NMR (dmso d6, 20 300 MHz) 6 1.38 (s, 9H, t-butyl), 1.5 - 1.7 (in, 2H, CHH), 1.85 (t, 3H, CH3, J = 2.2 Hz), 2.1 - 2.2 (in, 2H, CHH), 2.5 - 2.7 (in, 2H, NCHH), 3.8 - 4.0 (in, 2H, NCHH), 4.81 (q, 2H, OCH2, J = 2.2 Hz), 7.1 - 7.4 (in, 4H, ArH), 9.1 (s, 1H, NHOH), 10.8 (s, 1H, NHOH). Electrospray MS m/z 437.2 (M+H)* 25 Example 81 4
-(
4 -(But- 2 -ynyloxy-benzenesulfinyl)-piperidine-4-carboxylic acid hydroxamide hydrochloride To tert-butyl 4-{[4-(but-2-ynyloxy)phenyl]sulfinyl)-4-[(hydroxyamino) carbonyl]piperidine-1-carboxalate (prepared from example 80) (0.26 g) was added 4N 30 hydrochloric acid in dioxane (4 mL). After 1 h the reaction mixture was concentrated in vacuo. Methanol was added and removed in vacuo. Dichloromethane was added and removed in vacuo 3X to give 4
-(
4 -(But-2-ynyloxy-benzenesulfinyl)-piperidine-4- WO 00/44723 PCT/USOO/01864 -111 carboxylic acid hydroxamide hydrochloride as a yellow solid (0.19 g). 1 H NMR (dmso d6, 300 MiHz) 6 1.86 (t, 3H, CH3, J = 2.2 Hz), 1.7 - 2.8 (m, 8H, CH2), 4.82 (q, 2H, OCH2, J = 2.2 Hz), 7.1 - 7.5 (m, 4H, ArH), 8.4 - 11.0 (m, 4H, NH2, NHOH). Electrospray MS m/z 337.2 (M+H)* 5 Example 82 1-( 4 -Bromo-benzyl)-4-(4-But-2-ynyloxy-benzenesulfinyl)-piperidine-4-carboxylic acid hydroxamide hydrochloride To a solution of 4
-(
4 -(But-2-ynyloxy-benzenesulfnyl)-piperidine-4-carboxylic 10 acid hydroxamide hydrochloride (prepared from example 81) (0.162 g, 0.434 mmol) and 4-bromobenzylbromide (0.120 g, 0.478 mmol) in methanol was added triethylamine (0.13 mL, 0.91 mmol). After 4 h the reaction mixture was concentrated in vacuo and chromatographed on silica gel (methanol/dichloromethane) to give an oily solid which was dissolved in dichloromethane. To the solution was added IN 15 hydrochloric acid in ether (1 mL). Concentration in vacuo gave 1-(4-Bromo-benzyl) 4
-(
4 -But- 2 -ynyloxy-benzenesulfinyl)-piperidine-4-carboxylic acid hydroxamide hydrochloride as a tan solid (0.102 g). 1 H NIR (dmso d6, 300 MHz) 5 1.85 (t, 3H, CH3, J = 2.2 Hz), 1.9 - 3.5 (m, 8H, CH2), 3.87 (S, 3H, OCH3), 4.3 (bd s, 2H, NCH2Ar), 4.82 (q, 2H, OCH2, J = 2.2 Hz), 7.0 - 7.8 (m, 8H, ArH), 9.2 - 11.1 (m, 20 3H, NH, NHOH). Electrospray MS m/z 505.1/507.2 (M+H)* Pharmacology Representative compounds of this invention were evaluated as inhibitors of the enzymes MMP-1, MMP-9, MMP-13 and TNF-a converting enzyme (TACE). 25 The standard pharmacological test procedures used, and results obtained which establish this biological profile are shown below. Test Procedures for Measurin2 MMP- 1, MMP-9, and MMP- 13 Inhibition These standard pharmacological test procedures are based on the cleavage of a 30 thiopeptide substrates such as Ac-Pro-Leu-Gly(2-mercapto-4-methyl-pentanoyl)-Leu Gly-OEt by the matrix metalloproteinases MMP-1, MMP-13 (collagenases) or MMP-9 (gelatinase), which results in the release of a substrate product that reacts WO 00/44723 PCTUSOO/01864 -112 colorimetrically with DTNB (5,5'-dithiobis(2-nitro-benzoic acid)). The enzyme activity is measured by the rate of the color increase. The thiopeptide substrate is made up fresh as a 20 mM stock in 100% DMSO and the DTNB is dissolved in 100% DMSO as a 100 mM stock and stored in the dark at room temperature. Both the 5 substrate and DTNB are diluted together to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl2) before use. The stock of enzyme is diluted with buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2, 0.02% Brij) to the desired final concentration. The buffer, enzyme, vehicle or inhibitor, and DTNB/substrate are added in this order to a 96 well plate (total reaction volume of 200 pl) and the 10 increase in color is monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader and the increase in color over time is plotted as a linear line. Alternatively, a fluorescent peptide substrate is used. In this test procedure, the peptide substrate contains a fluorescent group and a quenching group. Upon cleavage of the substrate by an MMP, the fluorescence that is generated is quantitated 15 on the fluorescence plate reader. The assay is run in HCBC assay buffer (50mM HEPES, pH 7.0, 5 mM Ca+ 2 , 0.02% Brij, 0.5% Cysteine), with human recombinant MMP-1, MMP-9, or MMP-13. The substrate is dissolved in methanol and stored frozen in 1 mM aliquots. For the assay, substrate and enzymes are diluted in HCBC buffer to the desired concentrations. Compounds are added to the 96 well plate 20 containing enzyme and the reaction is started by the addition of substrate. The reaction is read (excitation 340 nm, emission 444 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear line. For either the thiopeptide or fluorescent peptide test procedures, the slope of the line is calculated and represents the reaction rate. The linearity of the reaction 25 rate is confirmed (r 2 >0.85). The mean (x±sem) of the control rate is calculated and compared for statistical significance (p<0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generated using multiple doses of drug and IC50 values with 95% CI are estimated using linear regression.
WO 00/44723 PCT/USOO/01864 -113 Test Procedure for Measuring TACE Inhibition Using 96-well black microtiter plates, each well receives a solution composed of 10 kL TACE (final concentration lpg/mL), 70pL Tris buffer, pH 7.4 containing 10% glycerol (final concentration 10 mM), and 10 pL of test compound solution in 5 DMSO (final concentration 1pM, DMSO concentration <1%) and incubated for 10 minutes at room temperature. The reaction is initiated by addition of a fluorescent peptidyl substrate (final concentration 100 pM) to each well and then shaking on a shaker for 5 sec. The reaction is read (excitation 340 nm, emission 420 nm) for 10 min. and the 10 increase in fluorescence over time is plotted as a linear line. The slope of the line is calculated and represents the reaction rate. The linearity of the reaction rate is confirmed (r 2 >0.85). The mean (x±sem) of the control rate is calculated and compared for statistical significance (p<0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response 15 relationships can be generate using multiple doses of drug and IC50 values with 95% CI are estimated using linear regression. Human Monocytic THP- 1 Cell Differentiation Assay For Soluble Proteins (THP- 1 Soluble Protein Assay) 20 Mitogenic stimulation of THP- 1 cells cause differentiation into macrophage like cells with concomitant secretion of tumor necrosis factor (TNF-a) and TNF receptor (TNF-R p75/80 and TNF-R p55/60) and Interleukin-8 (IL-8), among other proteins. In addition, non-stimulated THP-1 cells shed both the p75/80 and the p55/60 receptors over time. The release of membrane bound TNF-a and possibly 25 TNF-R p75/80 and TNF-R p55/60, but not IL-8, is mediated by an enzyme called TNF-a converting enzyme or TACE. This assay can be used to demonstrate either an inhibitory or a stimulatory compound effect on this TACE enzyme and any cytotoxic consequence of such a compound. THP-1 cells (from ATCC) are a human monocytic cell line which were 30 obtained from the peripheral blood of a one year old male with acute monocytic WO 00/44723 PCT/USOO/01864 -114 leukemia. They can be grown in culture and differentiated into macrophage like cells by stimulation with mitogens. For the assay, THP-1 cells are seeded from an ATCC stock which was previously grown and frozen back at 5 x 106/ml/vial. One vial is seeded into a T25 5 flask with 16 mls of RPMI-1640 with glutamax (Gibco) media containing 10 % fetal bovine serum, 100 units/ml penicillin, 100 pg/ml streptomycin, and 5 x 10 5 M 2 mercapto-ethanol (THP- 1 media). Each vial of cells are cultured for about two weeks prior to being used for an assay and then are used for only 4 to 6 weeks to screen compounds. Cells are subcultured on Mondays and Thursdays to a concentration of 1 10 x 105/ml. To perform an assay, the THP-1 cells are co-incubated in a 24 well plate with 50 ml/well of a 24 mg/ml stock of Lipopolysacharide (LPS) (Calbiochem Lot# B13189) at 37iC in 5% CO 2 at a concentration of 1.091 x 106 cells/ml (1.1 ml/well) for a total of 24 hours. At the same time, 50 ml/well of drug, vehicle or THP-1 15 media is plated in appropriate wells to give a final volume of 1.2 ml/well. Standard and test compounds are dissolved in DMSO at a concentration of 36 mM and diluted from here to the appropriate concentrations in THP-1 media and added to the wells at the beginning of the incubation period to give final concentrations of 100 mM, 30 mM, 10 mM, 3 mM, 1 mM, 300 nM, and 100 nM. Cell exposure to DMSO was 20 limited to 0.1 % final concentration. Positive control wells were included in the experiment which had mitogen added but no drug. Vehicle control wells were included as well, which were identical to the positive control wells, except that DMSO was added to give a final concentration of 0.083%. Negative control wells were included in the experiment which had vehicle but no mitogen or drug added to 25 the cells. Compounds can be evaluated for their effect on basal (non-stimulated) shedding of the receptors by replacing the LPS with 50 ml/well of THP-1 media. Plates are placed into an incubator set at 5% C02 and at 37o C. After 4 hours of incubation, 300 ml/well of tissue culture supernatant (TCS) is removed for use in an TNF-a ELISA. Following 24 hours of incubation, 700 ml/well of TCS is removed 30 and used for analysis in TNF-R p75/80, TNF-R p55/60 and IL-8 ELISAs.
WO 00/44723 PCT/USOO/01864 -115 In addition, at the 24 hours timepoint, and the cells for each treatment group are collected by resuspension in 500 pl/well of THP-1 media and transferred into a FACS tube. Two ml/tube of a 0.5 mg/ml stock of propidium iodide (PI) (Boerhinger Mannheim cat. # 1348639) is added. The samples are run on a Becton Dickinson 5 FaxCaliber FLOW cytometry machine and the amount of dye taken up by each cell is measured in the high red wavelength (FL3). Only cells with compromised membranes (dead or dying) can take up PI. The percent of live cells is calculated by the number of cells not stained with PI, divided by the total number of cells in the sample. The viability values calculated for the drug treated groups were compared to 10 the viability value calculated for the vehicle treated mitogen stimulated group ("vehicle positive control") to determine the "percent change from control". This "percent change from control" value is an indicator of drug toxicity. The quantity of soluble TNF-a, TNF-R p75/80 and TNF-R p55/60 and IL-8 in the TCS of the THP- 1 cell cultures are obtained with commercially available ELISAs 15 from R&D Systems, by extrapolation from a standard curve generated with kit standards. The number of cells that either take up or exclude PI are measured by the FLOW cytometry machine and visualized by histograms using commercially available Cytologic software for each treatment group including all controls. Biological variability in the magnitude of the response of THP-1 cell cultures 20 requires that experiments be compared on the basis of percent change from "vehicle positive control" for each drug concentration. Percent change in each soluble protein evaluated from the "vehicle positive control" was calculated for each compound concentration with the following formula: 25 % Change = p/ml (compound) -p/ml (veh pOS control) x 100 pg/ml (veh pos control) - pg/ml (veh neg control) For the soluble protein (TNF-a, p75/80, p55/60, IL-8) studies under stimulated conditions, the mean pg/ml of duplicate wells were determined and the 30 results expressed as percent change from "vehicle positive control". For the soluble protein (p75/80 and p55/60 receptors) studies under non-stimulated conditions, the WO 00/44723 PCT/USOO/01864 -116 mean pg/ml of duplicate wells were determined and the results expressed as percent change from "vehicle positive control" utilizing the following formula: % Change = p2/ml (compound neg control) - p2/ml (veh neg control X 100 5 pg/ml (veh neg control) IC50 values for each compound are calculated by non-linear regression analysis using customized software utilizing the JUMP statistical package. For the cell viability studies, the viabilities (PI exclusion) of pooled duplicate 10 wells were determined and the results expressed as % change from "vehicle positive control". The viability values calculated for the compound treated groups were compared to the viability value calculated for the "vehicle positive control" to determine "percent change from control" as below. This value "percent change from control" is an indicator of drug toxicity. 15 % Change = % live cells (compound) -1 X 100 % live cells (veh pos control) References: 20 Bjornberg, F., Lantz, M., Olsson, I., and Gullberg, U. Mechanisms involved in the processing of the p55 and the p75 tumor necrosis factor (TNF) receptors to soluble receptor forms. Lymphokine Cytokine Res. 13:203-211, 1994. Gatanaga, T., Hwang, C., Gatanaga, M., Cappuccini, F., Yamamoto, R., and Granger, G. The regulation of TNF mRNA synthesis, membrane expression, and release by 25 PMA- and LPS-stimulated human monocytic THP-1 cells in vitro. Cellular Immun. 138:1-10, 1991. Tsuchiya, S., Yamabe, M., Yamagughi, Y., Kobayashi, Y., Konno, T., and Tada, K. Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int. J. Cancer. 26:1711-176, 1980. 30 WO 00/44723 PCT/USOO/01864 -117 Results of the above in vitro matrix metalloproteinase inhibition, TACE inhibition and THP standard pharmacological test procedures are given in Table 1 below. 5 Table 1: Example # TACE IC, a THP @3 M MMP1 IC', c MMP9 IC,,a MMP13 IC',a 1 65 46% 3.3 385 155 2 82 68% 2.57 164 39.6 3 55 34% 9 280 90 4 90 25% 2.6 148 47.3 5 188 30% .3 400 180 6 393 NT 32.9% 58.9% 60% 7 123 21% 2.5 225 59.4 8 195 21% 4.7 218 72 9 166 12% 2.1 96.2 35.2 10 11 98 7% 0.143 5.8 3.1 12 41.8% +58 15 1000 1500 13 882 +69% 10 2000 800 14 67% NT 26% 21% 32% 15 38% NT 24% 25% 24% 16 46% NT 10 2056 1465 17 139 0 10 2296 946 18 11.4 45% 10 1276 98 19 74 4% 10 10000 1321 20 30.1 47% 2643nM 568 121 21 509 6% > 10 3504 858 22 48.4% 5% > 10 1814 1076 23 86.2 62% 3206 nM 160 64.4 24 180 41% 5671 nM 2078 463 25 695 3% > 10 2740 1177 26 136 63% 1994 nM 25.1 22.1 27 168 13% > 10 1542 426 28 150 13% 106 nM 15.4 5.3 29 127 13% 91 nM 16 4.7 30 102 0 >10 5899 2911 31 314 8 >10 >10000 >10000 32 100 0 >10 >10000 2752 33 327 8 >10 -5000 -10000 34 33 68 -10 1393 102 35 57 14 >10 >10000 -10000 36 4.8 58 3.9 2828 380 37 18 NT 8.6 8575 1024 38 19 53 -10 1443 279 11 NT 3.77 4275 809 63 41 0.707 425 36 37 60 2.677 1121 254 WO 00/44723 PCT/USO0/01864 -118 Example # TACE IC.a THP @3 .Mb MMP1 IC 0 MMP9 IC a MMP13 ICa 42 12 78% -10 >10000 1627 43 13 66 -10 >10000 1640 44 56 49 35% 50.6% 2381 45 25 48 3.8 3584 423 46 105 NT NT NT 55.6% 47 227 NT NT NT 275 48 66 NT NT NT 1035 49 32.6 NT NT NT 1727 50 18.3 NT NT NT 352 51 21.5 NT NT NT 403 52 41.8 NT NT NT 3710 53 20.8 NT NT NT 1165 54 32.2 NT NT NT 104 55 70.7 NT NT NT 600 56 31.1 NT NT NT 3.2 57 694 NT NT NT 458 58 21.1 NT NT NT 179 59 53.3 NT NT NT 11.2 60 38.4 NT NT NT 8.0 61 56.4 NT NT NT 575 62 64.6 NT NT NT 64.6 63 66.6 NT NT NT 2229 64 47 30 4.076 560 136 65 73 3 3.532 448 105 66 106 73 2.768 430 81 67 72 18 2.028 853 345 68 77 10 2.249 1333 503 69 115 14 3.999 1246 499 70 87 62 2.963 639 113 71 113 14 3.117 811 183 72 221 56 4.157 1211 369 73 NT NT NT NT NT 74 132 39 4.338 963 287 75 134 -4 2.588 1951 284 76 201 26 4.503 7886 4019 77 114 52 2.187 149 349 78 64.5 64 1.051 364 73.7 79 70 83 2.420 129 50.6 80 90 -7 186 122 40 81 277 25 1.877 1035 593 82 135 16 257 125 62 a = nM or % inhibition b = % inhibition c = .tM or % inhibition, unless otherwise indicated 5 WO 00/44723 PCT/USOO/01864 -119 Based on the results obtained in the standard pharmacological test procedures described above, the compounds of this invention were shown to be inhibitors of the enzymes MMP-1, MMP-9, MMP-13 and TNF-a converting enzyme (TACE) and are therefore useful in the treatment of disorders such as arthritis, tumor metastasis, tissue 5 ulceration, abnormal wound healing, periodontal disease, graft rejection, insulin resistance, bone disease and HIV infection. The compounds of this invention are also useful in treating or inhibiting pathological changes mediated by matrix metalloproteinases such as atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from 10 atherosclerotic plaque rupture, restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, 15 glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/ neovascularization and corneal graft rejection. 20 Compounds of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, 25 compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of 30 the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl WO 00/44723 PCTIUS0O/01864 -120 cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or 5 suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. 10 Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier can 15 also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral 20 administration may be either liquid or solid composition form. The compounds of this invention may be administered rectally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an 25 aerosol. The compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive 30 devices. The creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type. Pastes comprised of absorptive powders WO 00/44723 PCT/USOO/01864 -121 dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix 5 containing the active ingredient. Other occlusive devices are known in the literature. The dosage to be used in the treatment of a specific patient suffering a MMP or TACE dependent condition must be subjectively determined by the attending physician. The variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient. Treatment will generally be initiated 10 with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. Precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated and standard medical principles. 15 Preferably the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a 20 capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

Claims (10)

1. A compound of formula 0 R2 R 8 R9 R12 x A ~(C)n N R110 11 OH 5 wherein: RI is hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or -C4 C8-cycloheteroalkyl; 10 R 2 and R 3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, -CN, or -CCH; R, is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 15 carbon atoms, -C(O)-R, -So0
2 -R, -C(O)-NHR,, -C(O)NR 5 R , -C(O)RINR 5 R , -C(O)-ORJ, -C(NH)-NH 2 R 5 and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of
3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or -C4-C8 cycloheteroalkyl; 20 R , R, , R1 , and R are each, independently, hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C4-C8-cycloheteroalkyl, alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms; with the proviso that one of the pairs R8 and R9, R9 and RIO or R10 and RI1, together with the carbon atom or atoms to which they are attached, form a cycloalkyl ring of 25 3-6 carbon atoms, or a -C4-C8-cycloheteroalkyl ring; R 12 is hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C4-C8-cyclo heteroalkyl, or alkyl of 1-6 carbon atoms; WO 00/44723 PCTIUSOO/01864 -123 A is 0, S, SO, SO 2 , N14, or CH2; X is 0, S, SO, SO 2 , NR 7 , or CH 2 ; 5 Y is aryl or heteroaryl, with the proviso that A and X are not bonded to adjacent atoms of Y; and n is 0-2; 10 or a pharmaceutically acceptable salt thereof. 2. A compound of Claim 1 wherein Y is phenyl, pyridyl, thienyl, furanyl, imidazolyl or triazolyl or thiadiazolyl. 15 3. A compound of Claim 1 selected from the group consisting of: 1-(4-Bromo-benzyl)-4-(4-but-2-ynyxoy-benzenesulfonyl)-piperdine-4 carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)- 1-(4-methoxy-benzyl)-piperdine-4 carboxylic acid hydroxyamide; 20 4-(4-But-2-ynyloxy-benzenesulfonyl)- 1-(4-chloro-benzyl)-piperdine-4 carboxylic acid hydroxyamide; 1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxamide; 1-(4-Bromo-benzyl)-4-( 4 -pent-2-ynyloxy-benzenesulfonyl)-piperdine-4 25 carboxylic acid hydroxyamide; 1-( 4 -Bromo-benzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4 carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-benzenesulfonyl)- 1 -(4-fluoro-benzyl)-piperdine-4 carboxylic acid hydroxyamide; 30 4-(4-But-2-ynyloxy-benzenesulfonyl)- I -(4-cyano-benzyl)-piperidine-4 carboxylic acid hydroxamide; 4-(4-But-2-ynyloxy-benzenesulfonyl)- 1-(4-methyl-benzyl)-piperidine-4 carboxylic acid hydroxamide; WO 00/44723 PCT/USOO/01864 -124 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(3,4- dichloro-benzyl)-piperidine-4 carboxylic acid hydroxamide; 1-( 4 -Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4 carboxylic acid hydroxyamide; 5 1-(4-Bromo-benzyl)-4-[4-( 4 -piperdin- 4 -yl-but-2-ynyloxy)-benzenesulfonyl] piperdine-4-carboxylic acid hydroxyamide; 1-(4-Bromo-benzyl)-4-[ 4 -( 4 -morpholin-4-yl-but-2-ynyloxy)-benzene sulfonyl]-piperdine-4-carboxylic acid hydroxyamide; 4 -( 4 -But- 2 -ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine-1 10 carboxylic acid tert-butyl ester; 4 -( 4 -But- 2 -ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxyamide 1-( 4 -Bromo-benzyl)-4-(4-but-2-ynyloxy-phenylsulfanyl)-piperidine-4 carboxylic acid hydroxyamide; 15 4 -( 4 -But- 2 -ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide; 4 -( 4 -But- 2 -ynyloxy-benzenesulfonylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide; 4 -( 4 -But- 2 -ynyloxy-benzenesulfinylmethyl)-tetrahydro-pyran-4-carboxylic 20 acid hydroxyamide; 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxytetrahydro-2H-pyran-4 carboxamide; 1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperdine carboxamide; 25 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-isopropyl-4-piperidine carboxamide; 4- { [4-(2-butynyloxy)phenyl] sulfonyl } -N-hydroxy- 1 -(3 -pyridinylmethyl)-4 piperidine carboxamide; 3- { [4-(2-Butynyloxy)phenyl] sulfonyl) -1 -ethyl-N-hydroxy-3 -piperidine 30 carboxamide; WO 00/44723 PCT/USOO/01864 -125 3-{[4-(2-butynyloxy)phenyl]sulfonyl)-1 -(4-chlorobenzyl)-N-hydroxy-3 piperidinecarboxamide; 4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1 -[4-(2-piperidin- 1 -yl-ethoxy)-benzyl] piperidine-4-carboxylic acid hydroxyamide; 5 4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-(3-pentanyl)-piperidine-4-carboxylic acid hydroxyamide; 1-(4-Methoxy-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4 carboxylic acid hydroxyamide; 1-(4-Chloro-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4 10 carboxylic acid hydroxyamide; tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl)methyl)-4-[(hydroxyamino) carbonyl]- 1 -piperidinecarboxylate; 4-({[4-(But-2-ynyloxy)phenyl]thio}methyl)-N-hydroxypiperidine-4 carboxamide; 15 tert-Butyl-4-({[4-(2-butynyloxy)phenyl]sulfinyl}methyl)-4-[(hydroxyamino) carbonyl]- 1 -pip eridinecarboxylate; 4-[[[4-(2-Butynyloxy)phenyl]sulfinyl]methyl]-N-hydroxy-4-piperidine carboxamide; tert-Butyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino) 20 carbonyl]piperidine- 1 -carboxylate; tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino) carbonyl]- 1 -piperidinecarboxylate; I -Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-N-hydroxy-4 piperidinecarboxamide; 25 1-(2-Butynyl)-4-({ [4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4 piperidinecarboxamide hydrochloride; WO 00/44723 PCT/USOO/01864 -126 N-1 -(tert-Butyl)-4-({ [4-(2-butynyloxy)phenyl]sulfonyl)methyl)-N-4-hydroxy 1,4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy- 1,4-]sulfonyl} methyl)-N-4-hydroxy- 1,4-piperidinedicarboxamide; Methyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl)methyl)-4-[(hydroxyamino) 5 carbonyl]- 1-piperidinecarboxylate; Benzyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino) carbonyl]- 1-piperidinecarboxylate; 1-Benzyl-4-({[4-(2-butynyloxy)phenyl] sulfonyl} methyl)-N-hydroxy-4 butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide; 10 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[(2,2,5-trimethyl 1, 3 -dioxan-5-yl)carbonyl]-4-piperidinecarboxamide; 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[3-hydroxy-2 (hydroxymethyl)-2-methylpropanoyl]-4-piperidinecarboxamide; I -[Amino(imino)methyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N 15 hydroxy-4-1]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4 oxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide; 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy- 1 -(4-hydroxy-2 butynyl)- henyl]sulfonyl}methyl)-N-hydroxy-1-(4-hydroxy-2-butynyl)-4 piperidinecarboxamide; 20 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-I -ethyl-N-hydroxypiperidine 4- carboxamide triflouroacetic acid salt; 2-chloro-5-(chloromethyl) thiophene4-({[ 4 -(But-2-ynyloxy)phenyl]-sulfonyl} methyl)-1-[(5-chlorothien-2-yl)methyl]-N- hydroxypiperidine-4-carboxamide triflouroacetic acid salt; 25 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(pyridin-4 ylmethyl)piperidine-4-carboxamide triflouroacetic acid salt; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(pyridin-3 ylcarbonyl)piperidine-4-carboxamide triflouroacetic acid salt; 1 -Benzoyl-4-({[ 4 -(but-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy 30 piperidine-4- carboxamide; WO 00/44723 PCTUSOO/01864 -127 4-({ [4-(But-2-ynyloxy)phenyl] sulfonyl) methyl)-N-hydroxy- 1 -(thien-2 ylcarbonyl) piperidine-4-carboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl methyl)-N-1-ethyl-N-4-hydroxy piperidine-1,4-dicarboxamide; 5 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-N-1- phenyl piperidine-1,4-dicarboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-1-,N-1-diethyl-N-4 hydroxypiperidine- 1,4-dicarboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl methyl)-N-hydroxy- 1 -(morpholin-4 10 ylcarbonyl)piperidine-4-carboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-N- 1-methyl-N-I phenylpiperidine- 1,4-dicarboxamide; Octyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl4methyl)-4-[(hydroxyamino) carbonyl] piperidine-1-carboxylate; 15 4-Methoxyphenyl4-({[4-(but-2-ynyloxy)phenyl]sulfonyl4methyl)-4-[(hydroxy amino) carbonyl]piperidine- 1 -carboxylate; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl) methyl)-N-hydroxy- 1 -(phenylsulfonyl) piperidine-4-carboxamide; 4-({ [4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy- 1 -[(1-methyl-1 H 20 imidazol-4-yl)sulfonyl]piperidine-4-carboxamide; 1-[2-(Benzylamino)acetyl]-4-({[4-(but-2-ynyloxy)phenyl]-sulfonyl}methyl)-N hydroxypiperidine-4-carboxamide; 4-({ [4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy- 1 -(2-morpholin-4 ylacetyl)piperidine-4-carboxamide; 25 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy- 1 -[2-(4-methyl piperazin- I -yl)acetyl]piperidine-4-carboxamide; 1 -Acetyl- 4 -( 4 -but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid hydroxamide; I -Benzoyl- 4 -(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid 30 hydroxamide; WO 00/44723 PCT/USOO/01864 -128 1-(4-Methoxybenzoyl)-4-(4-but-2-ynyloxy benzenesulfonyl)piperidine-4 carboxylic acid hydroxamide; 4 -( 4 -But-2-ynyloxybenzenesulfonyl)-N-hydroxy- 1 -(pyrrolidine- 1 -carbonyl)-4 piperidinecarboxamide; 5 Ethyl 4 -( 4 -but-2-ynyloxybenzenesulfonyl)-4-[(hydroxyamino)carbonyl]-1 piperidinecarboxylate; 4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy- 1 -[(trifluoromethyl)sulfonyl] 4- piperidinecarboxamide; 4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinylcarbonyl)- 4 10 piperidinecarboxamide; 4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(2-thienylcarbonyl)- 4 piperidinecarboxamide; 4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy- 1 -[(4-methoxyphenyl) sulfonyl]-4-piperidinecarboxamide; 15 4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,3-dioxan
5-yl)carbonyl]-4-piperidinecarboxamide; Tert-butyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl] 1 -piperidinecarboxalate; 4- { [4-(2-butynyloxy)phenyl]sulfonyl} -N-hydroxy-4-piperidinecarboxamide 20 hydrochloride; Methyl ({4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl] 1 -piperidinyl}methyl)benzoate hydrochloride; 4-({4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl]-1 piperidinyl)methyl)benzoic acid hydrochloride; 25 1-[4-(Aminocarbonyl)benzyl]-4-{[4-(2-butynyloxy)phenyl]sulfonyl)-N hydroxy-4-piperidinecarboxamide hydrochloride; Tert-butyl 4-{[4-(but-2-ynyloxy)phenyl]sulfinyl}-4-[(hydroxyamino) carbonyl]piperidine- 1 -carboxalate; 4 -( 4 -(But-2-ynyloxy-benzenesulfinyl)-piperidine-4-carboxylic acid 30 hydroxamide hydrochloride; and WO 00/44723 PCT/USOO/01864 -129 1-( 4 -Bromo-benzyl)-4-(4-But-2-ynyloxy-benzenesulfinyl)-piperidine-4 carboxylic acid hydroxamide hydrochloride; and pharmaceutical salts thereof. 5 4. A method of inhibiting pathological changes mediated by TNF-a converting enzyme (TACE) in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound having the formula I as defined in claim 1; or a pharmaceutically acceptable salt thereof. 10 5. The method of Claim 4 wherein the condition treated is rheumatoid arthritis, graft rejection, cachexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease or HIV infection. 15
6. A pharmaceutical composition comprising a compound having the formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 20
7. A process for preparing a compound of formula I as claimed in claim 1, which comprises one of the following: a) reacting a compound of formula 0 X AR (C)n OH R1 R 1io R11 wherein n, X, Y, A, R 1 , R 2 , R 3 , R
8 , R,, R,,, and RH are as defined in claim 1 or a 25 reactive derivative thereof, with a compound of formula R 12 NHOH wherein R,2 is as defined in claim 1, to give a compound of formula I; WO 00/44723 PCT/USOO/01864 -130 or b) deprotecting a compound of formula: 0 R2 R 3 R 8 R
9 I X -A (C)n NR 12 0R 30 R 10 wherein n, X, Y, A, R, R2, R, R, R, R 1 , RI, and R12, are defined in claim 1, and R 30 5 is a suitable protecting group such as t-butyl, benzyl, and trialkylsilyl, to give a corresponding compound of formula I or c) cleaving a resin supported hydroxamate derivative containing the group 0 R8 R 9 R 3 R -0-NH (C)n A X R1 R
10 R11 10 wherein n, X, Y, A, R, R 2 , R, R8 R, R, and R, 11 are defined in claim 1 to give a compound of formula I wherein R12 is hydrogen; or d) resolving a mixture (e.g. racemate) of optically active isomers of a compound of formula I to isolate one enantiomer or diastereomer substantially free of the other 15 enantiomer or diastereomers; or e) acidifying a basic compound of formula I with a pharmaceutically acceptable acid to give a pharmaceutically acceptable salt; or 20 f) converting a compound of formula I having a reactive substituent group or site to a compound of formula I having a different substituent group or site.
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